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Archive for the ‘Stem Cell Negative’ Category

Change is coming, and at an ever-accelerating pace – Al Jazeera English

Tuesday, January 12th, 2021

One of the great science and technology stories of 2020 is the development of COVID-19 vaccines, from start, through testing, to delivery, at a rate never seen before. Not just one vaccine. Three. (With more on the way and not counting the vaccines already in use in China and Russia.) All able to pass rigorous tests and examinations.

Two of them came from Big Pharma.

They threw lots of money and lots of researchers at the problem. We have been taught to expect that that is what they do for us. One of the reasons we think that maybe the primary one is that Big Pharma has thrown lots of money and employed lots of experts to tell us how very useful they are.

The throwing the money part seems to be true of Pfizer. But not for the others.

The US government put between $10bn and $18bn into Operation Warp Speed. Several of the programmes main recipients Johnson & Johnson, Novavax, Sanofi with GlaxoSmithKline have yet to deliver a successful vaccine. Moderna, which has, got about $2.5bn.

A headline from Scientific American stated cogently and concisely: For Billion-Dollar COVID Vaccines, Basic Government-Funded Science Laid the Groundwork. The subhead pointed out: Much of the pioneering work on mRNA vaccines was done with government money, though drugmakers could walk away with big profits.

The third vaccine came from Oxford University (In association with AstraZeneca which is Big Pharma and which received substantial sums from Operation Warp Speed). It appears to be much easier to use. It is going to market at about $6-8 for two doses. Compared with $40 for Pfizer and $50-74 for Moderna, per pair. (A fun fact is that these prices are about 25 percent higher in the US than in the European Union). This should remind us that much of the most important work in medicine has come out of universities and that contributing to health and making money are two separate things.

A far more obscure science and technology story appeared on the front page of the business section of the New York Times on December 29, 2019. It is about a guy named Mike Strizki.

Strizkis story is a throwback to the days of individual tinkerer-inventors. People like that telegraph operator, Thomas Edison, those bicycle mechanics, the Wright Brothers, and a daughter of American aristocracy, Mary Phelps Jacob who was later scandalously famous for her wild parties, drug use, open marriage, her whippet named Clytoris, and being the co-founder of the Black Sun Press, making her the literary godmother to the Lost Generation of expatriate writers in Paris who invented the modern brassiere when she was nineteen.

Strizki is the only guy on the East Coast who drives a hydrogen car.

There are more on the West Coast, nearly 9,000, plus 48 buses. They have 42 stations where they can refuel. There are none on the East Coast. Therefore, Mike makes his own hydrogen fuel in his back yard using solar power. The only byproduct from the process is one atom of oxygen for every two atoms of hydrogen. When the hydrogen is put through fuel cells creating the electricity that drives the car, it recombines with oxygen and the only byproduct is water.Such cars routinely go about 484 kilometres (300 miles) on a full tank. Hyperion claims they have a car that gets a bit over 1,609km (1,000 miles) on a single tank. Refilling them is quicker than refilling the gas tank on the old fashioned internal combustion vehicles most of us drive. They do not have to drag about 453 kilogrammes (1,000 pounds) of batteries like full electric vehicles. Yet, Elon Musk of Tesla, who is hugely invested in battery power cars, calls hydrogen fuel cell cars staggeringly dumb.

Mike has also made the first house in the United States to be powered entirely by hydrogen produced on-site using solar power. Keep in mind that Steve Jobs of Apple, Bill Gates of Microsoft and Mark Zuckerberg of Facebook all could be in that category of tinkerer-inventor, at least at their start.

Right now, Elon Musk and his Teslas seem way out ahead of Strizki and his single hydrogen vehicle. But that contest is far from over. Watch for the HTWO, Hyundais new brand dedicated to hydrogen fuel cell power. Daimler Truck, Iveco, OMV, Shell and the Volvo Group are in an alliance named H2Accelerate to promote hydrogen powered trucks.

The point of both of these stories the one about Big Pharma, Big Money, Big University and the other one about the home tinkerer is that science and technology are moving faster and faster.

We are moving closer to actual fusion power. The best research for it seems to be coming out of South Korea. Water cell batteries may soon replace lithium-ion batteries. Check your phone, youve got a computer in your pocket. Quantum computing is on the way. The exponential increase in the amount of material travelling over the internet means we need much greater communication capacity. It is happening. We have gone from megahertz, one million cycles per second, to gigahertz, a billion, and we are on the way to terahertz frequencies, a trillion cycles per second. 3D metal printing is here. Babel earbuds which translate as you go are ready though I must say if its translations are like the ones I get online, it may be like an illiterate babbling in your ear. An Alzheimers blood test may soon be on the market. We can now make artificial structures that mimic early embryos using only stem cells no egg or sperm necessary.

Human history, for the most part, has been a long, flat line of subsistence economies. There were brilliant moments with small brilliant elites but they always rested on the agricultural labour of peons, serfs, slaves, or peasants and fell back again. It was such from the beginning of time until about 1800 with the First Industrial Revolution. Since then, the curve of productivity has been on an upward climb. The 19th and early 20th century is often called the Second Industrial Revolution. We are now in the third, or fourth, or even the fifth industrial revolution or maybe it is the Post-Industrial Revolution or the Digital Age depending on whose book you are reading. Whatever name you prefer to give to this current period, its defining feature remains the same: The changes are coming faster and faster. They are reaching more and more people. They are coming from more and more people.

Yes, of course, we know from the machine guns of WWI, the bombers and then the nuclear weapons of WWII, that technology can be used for destruction. The speed and almost zero cost of internet communication have freed us from the grip of media barons and governments, but then opened the way for exploitation and the spread of disinformation, the existence of alternative facts and tribal truths. Even the changes that would be rated as positive for the general good, are often negative for specific individuals.

We may have anti-science governments. Like the Trump administration has so obviously and obnoxiously been. Yet while they muddled the airwaves with disinformation about the pandemic, they were also the ones who threw billions to science to come up with a vaccine. Big Oil ran campaigns denying climate change, modelled on Big Tobaccos past campaigns claiming cigarettes do not cause cancer,. Yet most of the major oil companies are investing in alternative energy technology.

Big Money invested in established business resists change. Speculative Money and theres lots of it wants to bet on the next big thing which usually has to be, by definition, based on new science and new technology.

This election cycle weve seen that the Internet and social media can do black magic, spreading disinformation, misinformation, and lots of outright lies. They also mean that real information from grammar school to graduate school and beyond is getting to be within reach of the whole world. Its a two-way street. Information, ideas, and research can zip in an instant from a mountain village, a yurt in the desert, public housing, to Harvard, Tohoku, and Oxford.

It would be wonderful if politicians, public intellectuals (if they still exist), sociologists, and economists (should they wish to deal with realities rather than models), turned their thinking and their efforts into figuring out how we as societies and as individuals can best deal with all this change.

Whether they do or they do not, the changes will come, are coming, are here, at that ever-accelerating rate.

The views expressed in this article are the authors own and do not necessarily reflect Al Jazeeras editorial stance.

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MCL Landscape Adapts to Changes After CAR T-Cell Therapy Approval – OncLive

Saturday, January 9th, 2021

Despite the introduction of CAR T-cell therapy to the mantle cell lymphoma (MCL) armamentarium, induction therapy followed by stem cell transplant has maintained a role, said James Gerson, MD, who added that he continues to recommend transplant for patients, since they are still eligible for CAR T-cell therapy upon relapse on transplant.

I tell patients that we have very long-term data that a consolidative transplant for those who are eligible leads to a prolonged remission, Gerson explained. If a patient can be in remission for 10 years, maybe 10 years from now we will have something that is even better and more tolerable than CAR T-cell therapy.

In July 2020, the FDA approved brexucabtagene autoleucel (Tecartus) for the treatment of adult patients with relapsed/refractory MCL. The indication was based on findings from the phase 2 ZUMA-2 trial where brexucabtagene autoleucel, given as a single infusion, induced an 87% objective response rate and a 62% complete response rate in this patient population.

Unlike in diffuse large B-cell lymphoma where more restrictions [with CAR T-cell therapy] exist, any patient with MCL who had 1 prior therapy and relapsed can go straight to CAR T-cell therapy, Gerson said. We can use BTK inhibitors to bridge them, but we dont have to. There are a lot of possibilities.

Though not yet planned, further studies evaluating CAR T-cell therapy in the frontline setting for patients with high-risk MCL may be worth exploring, said Gerson.

In an interview with OncLive during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Gerson, an assistant professor of clinical medicine at Penn Medicine, discussed navigating treatment selection amid the approval of CAR T-cell therapy in MCL and the role of transplant after induction therapy.

OncLive:What induction regimens do you consider for your patients with MCL and how do you select between possible options?

Gerson: For young, fit patients, there is really no right answer for induction therapy because [treatment selection] is based on phase 2, nonrandomized data. Typically, induction therapy involves high-dose chemotherapy. Im actually very intrigued by a recent publication from the French group that looked at obinutuzumab [Gazyva] with DHAP [dexamethasone, cytarabine, and cisplatin; O-DHAP] as frontline therapy for young patients prior to consolidative transplant.

Ive used a lot of R-DHAP [rituximab (Rituxan) plus DHAP], but I havent used this O-DHAP. I think there is rationale to be excited about that option. Even though it is a phase 2 trial, it should [yield] reasonable data to take to insurance and get approval for. Again, it is not something Ive given, but Im very compelled by it and it is something I will try in the coming months.

Then, [we] usually follow [induction therapy] with a stem cell transplant for patients who are eligible.

In the relapsed setting, second-line BTK inhibition is pretty much the standard of care now. There is no right answer between [ibrutinib (Imbruvica) and acalabrutinib (Calquence)]. Anecdotally and by some limited published data, ibrutinib seems to have a higher occurrence of adverse effects [AEs]. Acalabrutinib is a little bit different but seems to be more tolerable in the long run. I tend to tell patients that and then they tend to want the medication that probably has fewer AEs. A lot of us end up choosing acalabrutinib, but from an efficacy standpoint, we have no comparative data. The curves are pretty similar when we look between the 2 trials.

In the era of cellular therapy, what is the role of transplant in MCL?

The challenge, of course, is that with the FDA approval of brexucabtagene autoleucel and CAR T-cell therapy coming into MCL, it is hard to know if we should still be transplanting patients. No one knows the answer because it is obviously not something that has been explored. The only thing that is known is that patients who have been transplanted can still go forward with [CAR T-cell] therapy and respond quite well. Therefore, it is not that getting a transplant means a patient cannot get CAR T-cell therapy in the future.

[With that], I usually tell my patients not to skip transplant because of the approval of brexucabtagene autoleucel in the relapsed/refractory setting. That said, it is an individualized choice. Certainly, some patients might make that choice not to undergo a transplant now that CAR T-cell therapy is available to them should they relapse. Still, in my practice, I will still offer transplant to a patient who is young and fit as a consolidative measure after induction therapy.

Do you see CAR T-cell therapy gaining a more significant role in MCL? Will it eventually moveinto the frontline setting?

Right now, the label given to brexucabtagene autoleucel was very open, [encompassing] any relapsed/refractory patient [with MCL]. That is great not only for patients but for practicing physicians.

[Bringing CAR T-cell therapy to] the frontline setting will likely be investigated in the future, especially for high-risk patients with high MIPI [Mantle Cell Lymphoma International Prognostic Index] scores,TP53mutations, blastoid variant MCL, or pleomorphic variant MCL. [These features] tend to [confer] worse outcomes. There are areas where using [CAR T-cell therapy] in the frontline setting is worth looking into.

It is completely up to the company whether they want to pursue it. Otherwise, it is going to be left to investigator-initiated trials, which are going to be difficult because of the cost associated with CAR T-cell therapy. Some centers may pursue using homegrown CAR T-cell therapy where the cost is much lower for some of these high-risk patients, but I hope the company will pursue such trials in the frontline setting.

What other regimens are potentially on the horizon in MCL and how could they best fit into the paradigm?

There are a lot of similarities between chronic lymphocytic leukemia [CLL] and MCL. A similar triplet strategy to ibrutinib, obinutuzumab, and venetoclax [(Venclexta) in CLL] is being looked at in frontline and relapsed/refractory MCL. That is incredibly exciting and could very well supplant typical [cytarabine]-based induction and transplant. We will need long-term follow-up, so we probably wont know for many years.

Thankfully, with minimal residual disease [MRD], we will possibly be able to know much sooner, because if we can get a large percentage of patients into an MRD-negative state, that is a proxy for outcome. Again, we wont know for probably about 10 years before we get that long-term follow-up, but we will have a good enough idea if we [should] use MRD as a surrogate end point.

Reference

Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Eng J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347

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5 questions facing gene therapy in 2021 – BioPharma Dive

Saturday, January 9th, 2021

Three years ago, the Food and Drug Administration granted a landmark approval to the first gene therapy for an inherited disease, clearing a blindness treatment called Luxturna.

Since then, the regulator has approved one more gene therapy,the spinal muscular atrophy treatment Zolgensma, and given a green light for dozens of biotech and pharmaceutical companies to start clinical testing on others. Genetic medicines for a range of diseases, including hemophilia, sickle cell and several muscular dystrophies, appear in reach, and new science is galvanizing research.

But, entering 2021, the gene therapy field faces major questions after a series of regulatory and clinical setbacks have shaded optimism. "The ups and downs of adolescence are on full display" analysts at Piper Sandler wrote in September, summing up the state of gene therapy research.

Here are five questions facing scientists, drugmakers and investors this year. How they're answered will matter greatly to the patients and families holding out hope for one-time disease treatments.

The FDA was widely expected last year to approve a closely watched gene therapy for hemophilia A, the more common type of the blood disease. Instead, the agency in August surprisingly rejected the treatment, called Roctavian, and asked its developer, BioMarin Pharmaceutical, to gather more data.

The next day, Audentes Therapeutics reported news came a third clinical trial participant had died after receiving the biotech's experimental gene therapy for a rare neuromuscular disease. The tragedy brought flashbacks to past safety scares in gene therapy, although the current wave of treatments being tested have generally appeared safe.

A little less than five months later, the gene therapy field is grappling with two more setbacks. UniQure is exploring whether a study volunteer's liver cancer was caused by its gene therapy for hemophilia B. And Sarepta, one of the sector's top developers, faces significant doubts about its top treatment for Duchenne muscular dystrophy after disclosing a key study missed one of its main goals.

In each case, the drugmakers involved offered explanations and reasons for optimism. BioMarin still expects to obtain an approval; Audentes' trial is now cleared by the FDA to resume testing; UniQure thinks it's unlikely the cancer case is linked to treatment; and Sarepta argued its negative data were the product of unlucky study design.

But taken together, the developments are powerful reminders of both the stakes and uncertainty still facing gene therapy.

All four events also highlighted lingering worries about one-time genetic treatment. In rejecting Roctavian, for example, the FDA seemed to be concerned the impressive benefit hemophilia patients initially experienced may wane over time. The deaths in Audentes' study, meanwhile,renewed warnings about extremely high doses of gene therapy. Researchers have long watched for evidence that replacing or altering genes may cause cancer to develop in rare instances, particularly after four infants developed leukemia in a gene therapy study in the early 2000s.And Sarepta's negative findings were surprising because early signs of dramatic biological benefit that didn't seem to translate into clear-cut functional gains for all patients.

Experts are still confident gene therapy can deliver on its promise. Bu recent events suggest getting there may take a bit longer than some expected.

"The process is the product," is an often-used cliche about gene therapy, which are complex treatments with exacting manufacturing standards.

Most of the roughly 60,000 pages in Spark Therapeutics' application for approval of Luxturna, for instance, involved what's known in the industry as "chemistry, manufacturing and controls."

The therapeutic basis for gene therapy, by contrast, is much clearer for many of the rare, monogenic diseases that developers are targeting. If mutations in a single gene lead to disease, replacing or otherwise fixing that gene should have a large benefit.

"Genetic medicine is not industrialized serendipity," said Gbola Amusa, an analyst at Chardan, contrasting gene therapy with chemical-based drugs."It often is an engineering question."

In 2020, the FDA gave ample notice that it's watching gene (and cell) therapy manufacturing closely.Sarepta,Voyager Therapeutics,Iovance Biotherapeuticsand Bluebird biowere all forced to revise their development timelines after the agency asked for new details about production processes.

"The FDA is saying to companies that you've got to up your standards," Amusa added.

For their part, FDA officials have indicated the spate of data requests are a product of the sharply higher numbers of companies advancing through clinical testing.

While setbacks have piled up for therapies that seek to replace genes, 2020 was a "transformative year" for therapies designed to edit them, according to Geulah Livshits, an analyst at Chardan.

CRISPR gene editing, already widely recognized as a scientific breakthrough, gained further prestige with the awarding of the Nobel Prize in Chemistry to two early pioneers, Jennifer Doudna and Emmanuelle Charpentier.

But the year also brought important progress from early biotech adopters.Editas Medicine and Intellia Therapeutics, for example, notched CRISPR firsts with use of the editing technology inside the human body.

And CRISPR Therapeutics and partner Vertex showed their experimental therapy, which uses CRISPR to edit stem cells, worked exceptionally well in the first 10 patients with either sickle cell disease or beta thalassemia treated in two early studies.

The data are the most concrete sign yet that CRISPR's clinical use can live up to its laboratory promise. While all three companies' therapies are still in early stages, their advances have ginned up substantial investor enthusiasm.

Together, the market value of CRISPR Therapeutics, Editas and Intellia totals nearly $25 billion. Beam Therapeutics, a startup that uses a more precise form of gene editing, is worth nearly $6 billion.

"Gene therapy will have a big role to play," said John Evans, Beam's CEO. "But I do think in the last year or so there's a growing realization that, when possible, you'd probably rather edit than add an extra gene."

Clinical tests will prove that out but, until then, the large upswing in share price for gene editing companies may not be sustainable as valuations creep higher and higher. Some of the recent run-up, for instance,appears driven by money flowing from generalist investors through exchange-trade funds, rather than from investors experienced in handicapping preclinical- or early clinical-stage companies.

"They're overdue for some type of rationalization," predicted Brad Loncar, CEO of Loncar Investments, adding that many companies are targeting similar diseases, most commonly sickle cell and beta thalassemia.

Tasked with replacing faulty genes with functional ones, scientists for the most part have turned to two types of viruses to safely shuttle genetic instructions into cells. Adeno-associated viruses, or AAVs,are typically used for infused treatments, while researchers working on cells extracted from patients generally opt for lentiviruses.

Each virus class has advantages, but also notable drawbacks. AAVs, for instance, can trigger pre-existing immune defenses in some people, making those individuals ineligible or poor candidates for gene therapy. Lentiviruses, by contrast, are known to integrate their DNA directly into the genomes of cells they infect a useful attribute in some regards but limiting in others.

Over decades of gene therapy research, scientists have found ways to tweak and modify these viral vectors to better suit their needs, but the basic tools are the same. Jim Wilson, a gene therapy pioneer who ran the study that led to the death of teenager Jesse Gelsinger in 1999, told attendees at a STAT conference last fall that he's "somewhat disappointed" by slow progress in viral vector research.

And as more and more gene therapies enter clinical testing, the limitations of current viral vectors have become more apparent.

The pace of research might be picking up, however. Recently, a number of companies aiming to build better delivery tools have launched, including Harvard University spinout Dyno Therapeutics and 4D Molecular Therapeutics, which recently raised $222 million in an initial public offering.

Larger companies are interested, too. Roche, Sarepta and Novartis have all partnered with Dyno, for example.

In gene editing, meanwhile, researchers are developing new ways to cut DNA, while Beam and others are advancing different editing approaches altogether.

Billions of dollars have flowed from pharmaceutical companies into gene therapy over the past few years, leaving few large multinational drugmakers without a research presence.

2020 was no different, with sizable acquisitions inked by Bayer and Eli Lilly, as well as an array of smaller investments from Pfizer, Novartis, Johnson & Johnson, Biogen,and UCB. And CSL Behring, best known for its blood plasma products, spent nearly half a billion dollars to buy UniQure's most advanced gene therapy, a treatment for hemophilia B.

Over the past three years, there's been at least $30 billion spent on biotechs involved in gene or cell therapy. (Four deals account for the majority of that value.)

All of that dealmaking, while following promising and compelling science, is ultimately a bet that one-time genetic treatments can be scaled up and commercialized into a lucrative business.

Many of the acquired companies are working on therapies for very rare disorders affecting hundreds or thousands of people. A handful, however, are taking aim at more prevalent conditions, starting with still relatively uncommon diseases like hemophilia to ones affecting millions of people like Parkinson's.

"For gene therapy to meet our lofty expectations not just for investors, but for society it has to make the leap from these ultra-rare diseases," said Loncar.

Commercially, the track record for the few therapies on the market in the U.S. is mixed.Luxturna, now owned by Roche, is a niche product.Zolgensma has broader use and earned Novartis about $1 billion in the year and a half it's been commercially available.

Two cell therapies from Novartis and Gilead, meanwhile, have struggled to gain traction.

Gene therapy's biggest commercial test yet was supposed to come this year, with the expected approval of BioMarin's Roctavian in hemophilia A. The FDA's surprise rejection could mean a yearslong delay in the U.S., but the challenges of pricing, reimbursement and patient access in gene therapy remain dauntingly large.

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RNA molecules are masters of their own destiny – MIT News

Saturday, January 9th, 2021

At any given moment in the human body, in about 30 trillion cells, DNA is being read into molecules of messenger RNA, the intermediary step between DNA and proteins, in a process called transcription.

Scientists have a pretty good idea of how transcription gets started: Proteins called RNA polymerases are recruited to specific regions of the DNA molecules and begin skimming their way down the strand, synthesizing mRNA molecules as they go. But part of this process is less-well understood: How does the cell know when to stop transcribing?

Now, new work from the labs of Richard Young, Whitehead Institute for Biomedical Research member and MIT professor of biology, and Arup K. Chakraborty, professor of chemical engineering, physics, and chemistry at MIT, suggests that RNA molecules themselves are responsible for regulating their formation through a feedback loop. Too few RNA molecules, and the cell initiates transcription to create more. Then, at a certain threshold, too many RNA molecules cause transcription to draw to a halt.

The research, published in Cell on Dec. 16, 2020, represents a collaboration between biologists and physicists, and provides some insight into the potential roles of the thousands of RNAs that are not translated into any proteins, called noncoding RNAs, which are common in mammals and have mystified scientists for decades.

A question of condensates

Previous work in Youngs lab has focused on transcriptional condensates, small cellular droplets that bring together the molecules needed to transcribe DNA to RNA. Scientists in the lab discovered the transcriptional droplets in 2018, noticing that they typically formed when transcription began and dissolved a few seconds or minutes later, when the process was finished.

The researchers wondered if the force that governed the dissolution of the transcriptional condensates could be related to the chemical properties of the RNA they produced specifically, its highly negative charge. If this were the case, it would be the latest example of cellular processes being regulated via a feedback mechanism an elegant, efficient system used in the cell to control biological functions such as red blood cell production and DNA repair.

As an initial test, the researchers used an in vitro experiment to test whether the amount of RNA had an effect on condensate formation. They found that within the range of physiological levels observed in cells, low levels of RNA encouraged droplet formation and high levels of RNA discouraged it.

Thinking outside the biology box

With these results in mind, Young lab postdocs and co-first authors Ozgur Oksuz and Jon Henninger teamed up with physicist and co-first author Krishna Shrinivas, a graduate student in Arup Chakrabortys lab, to investigate what physical forces were at play.

Shrinivas proposed that the team build a computational model to study the physical and chemical interactions between actively transcribed RNA and condensates formed by transcriptional proteins. The goal of the model was not to simply reproduce existing results, but to create a platform with which to test a variety of situations.

The way most people study these kinds of problems is to take mixtures of molecules in a test tube, shake it and see what happens, Shrinivas says. That is as far away from what happens in a cell as one can imagine. Our thought was, Can we try to study this problem in its biological context, which is this out-of-equilibrium, complex process?

Studying the problem from a physics perspective allowed the researchers to take a step back from traditional biology methods. As a biologist, it's difficult to come up with new hypotheses, new approaches to understanding how things work from available data, Henninger says. You can do screens, you can identify new players, new proteins, new RNAs that may be involved in a process, but you're still limited by our classical understanding of how all these things interact. Whereas when talking with a physicist, you're in this theoretical space extending beyond what the data can currently give you. Physicists love to think about how something would behave, given certain parameters.

Once the model was complete, the researchers could ask it questions about situations that may arise in cells for instance, what happens to condensates when RNAs of different lengths are produced at different rates as time ensues? and then follow it up with an experiment at the lab bench. We ended up with a very nice convergence of model and experiment, Henninger says. To me, it's like the model helps distill the simplest features of this type of system, and then you can do more predictive experiments in cells to see if it fits that model.

The charge is in charge

Through a series of modeling and experiments at the lab bench, the researchers were able to confirm their hypothesis that the effect of RNA on transcription is due to RNAs molecules highly negative charge. Furthermore, it was predicted that initial low levels of RNA enhance and subsequent higher levels dissolve condensates formed by transcriptional proteins. Because the charge is carried by the RNAs phosphate backbone, the effective charge of a given RNA molecule is directly proportional to its length.

In order to test this finding in a living cell, the researchers engineered mouse embryonic stem cells to have glowing condensates, then treated them with a chemical to disrupt the elongation phase of transcription. Consistent with the models predictions, the resulting dearth of condensate-dissolving RNA molecules increased the size and lifetime of condensates in the cell. Conversely, when the researchers engineered cells to induce the production of extra RNAs, transcriptional condensates at these sites dissolved. These results highlight the importance of understanding how non-equilibrium feedback mechanisms regulate the functions of the biomolecular condensates present in cells, says Chakraborty.

Confirmation of this feedback mechanism might help answer a longstanding mystery of the mammalian genome: the purpose of non-coding RNAs, which make up a large portion of genetic material. While we know a lot about how proteins work, there are tens of thousands of noncoding RNA species, and we dont know the functions of most of these molecules, says Young. The finding that RNA molecules can regulate transcriptional condensates makes us wonder if many of the noncoding species just function locally to tune gene expression throughout the genome. Then this giant mystery of what all these RNAs do has a potential solution.

The researchers are optimistic that understanding this new role for RNA in the cell could inform therapies for a wide range of diseases. Some diseases are actually caused by increased or decreased expression of a single gene, says Oksuz, a co-first author. We now know that if you modulate the levels of RNA, you have a predictable effect on condensates. So you could hypothetically tune up or down the expression of a disease gene to restore the expression and possibly restore the phenotype that you want, in order to treat a disease.

Young adds that a deeper understanding of RNA behavior could inform therapeutics more generally. In the past 10 years, a variety of drugs have been developed that directly target RNA successfully. RNA is an important target, Young says. Understanding mechanistically how RNA molecules regulate gene expression bridges the gap between gene dysregulation in disease and new therapeutic approaches that target RNA.

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Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market: Industry Analysis and Forecast (2019-2026): By indication type, treatment type,…

Saturday, January 9th, 2021

The Platelet Rich Plasma and Stem Cell Alopecia Treatment market is expected to grow from US$ XXBn in 2018 to USD XX Bn by 2026, at a CAGR of 6.1% during the forecast period.

Platelet Rich Plasma and Stem Cell Alopecia Treatment marketThe report study has analyzed revenue impact of COVID -19 pandemic on the sales revenue of market leaders, market followers and market disrupters in the report and same is reflected in our analysis.Platelet-rich plasma (PRP) a new biotechnology, is the product of a heightened interest in cell-based therapy and tissue engineering. This therapy is defined as an autologous preparation of plasma with concentrated platelets.

Global Atomic Force Microscopes Market Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Drivers and RestrainsFactors contributing to the growth of this market include rise in disease awareness, treatment rate, and growing adoption of novel treatment therapies providing positive patient outcome. Moreover, lower incidences of negative side effects of this therapy are anticipated to fuel demand for platelet rich plasma (PRP) and stem cell therapy.

Treatment options for androgenic alopecia are limited and include topical minoxidil and oral finasteride (FDA approved) alone or in combination. Several reported side effects such as headache and increase in body hair are there for minoxidil whereas loss of libido has been reported with oral finasteride are considered to be major restraint to the global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market.

Hair loss is one of the significant factors that will foster the global hair transplant market growth over the projection period. Increasing patient pool in developing countries significant success rate and hair transplant procedures coupled with innovative technologies also help hair transplant market to grow seamlessly in the near future.

Advance treatments for alopecia are enhanced by dermatologists and patients over regular medications, for example, corticosteroids. More prominent inclination for these treatments emerges from proficient and quicker hair regrowth when contrasted with other corticosteroid medications. Furthermore, simplicity of organization of these novel treatments is anticipated to boost the global market.

Request For View Sample Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Report Pagehttps://www.maximizemarketresearch.com/request-sample/36142/

Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market by key segments

The stem cell therapy segment has been further classified into bone marrow treatment and adipose treatment. The dermatology clinics segment accounted for 88% of the total market revenue in 2018, owing to its lower therapy cost as compared to hospitals.

About 45% men and 35% women develop androgenic alopecia by 60, which is the highest among all the types of alopecia in the year 2018. A study published in the International Journal of Womens Dermatology in 2019 revealed that the use of PRP to treat androgenic alopecia is promising due to its autologous nature, minimal invasiveness, lack of major side effects, and low cost compared to hair restoration surgery.

Global Systemic Inflammatory Response Syndrome Treatment Market Regional AnalysisNorth America is anticipated to held leading position for global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market . In 2018, XX% of women suffer from androgenetic alopecia in North America. This has led the country to dominate the platelet rich plasma & stem cell alopecia treatment market in North America. The market in Asia Pacific is projected to expand at a significantly high CAGR during the forecast period, owing to the emergence of strong local manufacturers offering various technological advancements for platelet rich plasma & stem cell alopecia treatment at lower prices and increase in awareness among people about these treatment methods. Additionally, highest application of PRP for the treatment of alopecia has been observed in the past few years. This is likely to fuel the market in the region. Furthermore, technological advances and huge numbers of investments in Platelet Rich Plasma Therapies by key players are likely to fuel the global market in the emerging regions such as in china and India.

The objective of the report is to present comprehensive analysis of Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market including all the stakeholders of the industry. The past and current status of the industry with forecasted market size and trends are presented in the report with the analysis of complicated data in simple language. The report covers the all the aspects of industry with dedicated study of key players that includes market leaders, followers and new entrants by region. PORTER, SVOR, PESTEL analysis with the potential impact of micro-economic factors by region on the market have been presented in the report. External as well as internal factors that are supposed to affect the business positively or negatively have been analyzed, which will give clear futuristic view of the industry to the decision makers.

Do Inquiry Before Purchasing Market Platelet Rich Plasma and Stem Cell Alopecia Treatment Report Here:@https://www.maximizemarketresearch.com/inquiry-before-buying/36142/

The report also helps in understanding Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market dynamics, structure by analyzing the market segments, and project the Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market size. Clear representation of competitive analysis of key players by Type, price, financial position, product portfolio, growth strategies, and regional presence in the Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market make the report investors guide.Global Platelet Rich Plasma & Stem Cell Alopecia Treatment Market, by Treatment

Platelet Rich Plasma Therapies Stem Cell TherapyGlobal Platelet Rich Plasma & Stem Cell Alopecia Treatment Market, by Indication

Androgenic Alopecia Congenital Alopecia Cicatricial or Scarring AlopeciaGlobal Platelet Rich Plasma & Stem Cell Alopecia Treatment Market, by Type

Men womenKey players operating on Global Platelet Rich Plasma & Stem Cell Alopecia Treatment Market

Kerastem Eclipse Regen Lab SA Restore Hair Replicel LifeScience Histogen Inc. Glofinn Oy Orange County Hair Restoration Center, Hair Sciences Center of Colorado, Anderson Center for Hair, Evolution Hair Loss Institute, Savola Aesthetic Dermatology Center, Virginia Surgical Center, Hair Transplant Institute of Miami, Colorado Surgical Center & Hair Institute.

Major Table Platelet Rich Plasma and Stem Cell Alopecia Treatment Market of Contents Report

Chapter One: Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Overview

Chapter Two: Manufacturers Profiles

Chapter Three: Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Competition, by Players

Chapter Four: Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Size by Regions

Chapter Five: North America Platelet Rich Plasma and Stem Cell Alopecia Treatment Revenue by Countries

Chapter Six: Europe Platelet Rich Plasma and Stem Cell Alopecia Treatment Revenue by Countries

Chapter Seven: Asia-Pacific Platelet Rich Plasma and Stem Cell Alopecia Treatment Revenue by Countries

Chapter Eight: South America Platelet Rich Plasma and Stem Cell Alopecia Treatment Revenue by Countries

Chapter Nine: Middle East and Africa Revenue Platelet Rich Plasma and Stem Cell Alopecia Treatment by Countries

Chapter Ten: Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Segment by Type

Chapter Eleven: Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Segment by Application

Browse Full Report with Facts and Figures of Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Report at:https://www.maximizemarketresearch.com/market-report/global-platelet-rich-plasma-and-stem-cell-alopecia-treatment-market/36142/

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Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market: Industry Analysis and Forecast (2019-2026): By indication type, treatment type,...

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Harpoon Therapeutics : Clin Cancer Res 2021; OnlineFirst version Jan 6, 2021 – Marketscreener.com

Saturday, January 9th, 2021

Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392

CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY

Preclinical Characterization of HPN536, a Trispecic, T-Cell-Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors A C

Mary Ellen Molloy1, Richard J. Austin1, Bryan D. Lemon1, Wade H. Aaron1, Vaishnavi Ganti1, Adrie Jones1,

Susan D. Jones1, Kathryn L. Strobel1, Purbasa Patnaik1, Kenneth Sexton1, Laurie Tatalick1, Timothy Z. Yu1, Patrick A. Baeuerle1,2,3, Che-Leung Law1, and Holger Wesche1

ABSTRACT

Purpose: Mesothelin (MSLN) is a glycophosphatidylinositol- linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast can- cer. Early signs of clinical efcacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic inter- vention, but therapies with improved efcacy are still needed to address the signicant unmet medical need posed by MSLN- expressing cancers.

Experimental Design: We designed HPN536, a 53-kDa, tri- specic, T-cell-activatingprotein-based construct, which binds to MSLN-expressing tumor cells, CD3e on T cells, and to serum albumin. Experiments were conducted to assess the potency, activ-

Introduction

Redirection of cytotoxic T cells with bispecic antibody constructs for cancer therapy has been validated in the clinic (1-6). Blinatumo- mab is the rst and thus far the only bispecic T-cell engager (BiTE) approved by the FDA (7). T-cell-engaging biologics function by forming an immunologic cytolytic synapse between cancer target cells and T cells, which leads to target cell lysis independent of T-cell receptor (TCR) specicity, peptide antigen presentation by HLA, and T-cell costimulation. Despite the clinical success of blinatumomab for treating relapsed and refractory acute lymphoblastic leukemia, other molecules, including BiTE antibodies, showed only limited activity in the treatment of solid tumors (8, 9). Their short plasma half-life required continuous intravenous infusion limiting their utility for most solid tumor indications. Novel designs for T-cell-engaging antibodies aim at overcoming limitations of the rst generation and are already being tested in clinical trials (10).

The Trispecic T-cell-Activating Construct (TriTAC) design has been specically developed to treat solid tumors (11). TriTACs consist of a single polypeptide chain aligning three humanized, antibody- derived binding domains: a single-domain antibody (sdAb) specic for

1Harpoon Therapeutics, South San Francisco, California. 2MPM Capital, Cam- bridge, Massachusetts. 3Institute for Immunology, Ludwig-Maximilians University Munich, Planegg- Martinsried, Munich, Germany.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

Corresponding Author: Mary Ellen Molloy, Harpoon Therapeutics, 131 Oyster

Point Boulevard, 300, South San Francisco, CA 94080. Phone: 773-318-0796;

E-mail: mmolloy@harpoontx.com

Clin Cancer Res 2020;XX:XX-XX

doi: 10.1158/1078-0432.CCR-20-3392

2020 American Association for Cancer Research.

ity, and half-life of HPN536 in in vitro assays, rodent models, and in nonhuman primates (NHP).

Results: HPN536 binds to MSLN-expressing tumor cells and to CD3e on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN- dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans.

Conclusions: HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).

a tumor antigen, a sdAb specic for serum albumin for half-life extension, and a single-chain fragment variable (scFv) specic for the CD3e subunit of the TCR complex (11). Their molecular size of 53 kDa is about one-third of that of an IgG. Binding of TriTACs to tumor antigen and CD3e is monovalent, which minimizes off-target CD3e clustering that can potentially lead to nonspecic T-cell activation. The absence of an Fc-gamma domain for half-life extension is functionally compensated by an albumin-binding domain. HPN424 (11) and HPN536, the rst two TriTACs are in phase I clinical testing in hormone refractory prostate cancer and mesothelin (MSLN)-over- expressing solid tumors, respectively.

Human MSLN is produced as a 71-kDa precursor of 628 amino acids, which is expressed as a glycophosphatidylinositol-linked cell surface glycoprotein. Its 31-kDaN-terminal domain is released as a soluble protein, termed as the megakaryocyte potentiating factor (MPF), while the 40-kDaC-terminal domain remains attached to the plasma membrane as mature MSLN (12-14). MSLN expression on normal tissue is conned to the single-cell mesothelial layer covering the surface of tissues and organs of the pleural, pericardial, and peritoneal cavities (13, 15). MUC16/CA125 is a binding partner for MSLN, implicating a role for MSLN in cell adhesion (16, 17). However, the precise physiologic functions of MSLN have not been dened, and MSLN-knockout mice exhibit no detectable phenotype or developmental abnormality (18).

MSLN is overexpressed in many malignancies, including ovarian cancer (13, 15, 19), pancreatic cancer (20, 21), non-small cell lung cancer (22-26),triple-negative breast cancer (26, 27), and mesothe- lioma (28, 29). In triple-negative breast cancer (25) and in lung and pancreatic adenocarcinomas (22, 23, 30), overexpression of MSLN correlates with poor prognosis. Differential expression of MSLN in cancer versus normal tissue has made it an attractive target for MSLN- directed imaging agents and therapeutics (10, 31-33). A challenge in developing MSLN-directed therapeutics is the expression of MSLN on normal mesothelial cells, potentially leading to dose-limiting toxicities.

Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392

Molloy et al.

Translational Relevance

Patients with mesothelin (MSLN)-overexpressing tumors, including ovarian, pancreatic, lung, and triple-negative breast cancer, have a high unmet clinical need. A number of MSLN- targeted therapeutics have been developed that show limited efcacy and safety in clinical trials. HPN536 is a novel, MSLN- targeted, trispecic, T-cell-activating protein construct that can potently redirect T cells to lyse tumor cells and was remarkably well tolerated in nonhuman primates at single doses up to 10 mg/kg, which is far above the expected therapeutic dose level. Our ndings suggest that HPN536 has the potential for high clinical activity and a wide therapeutic window. Its long serum half-life supports once-weekly dosing in humans. Currently, HPN536 is the only MSLN-targeting,T-cell-engaging biologic in clinical testing.

HPN536 specically redirects T cells for potent redirected lysis of MSLN-expressing cancer cells with concomitant T-cell activation. In three different mouse xenograft models, HPN536 induced durable antitumor activity at very low doses. In cynomolgus monkeys, HPN536 was well tolerated, showed a long serum half-life, and elicited signs of target engagement on mesothelial structures.

Materials and Methods

Protein production

Sequences of TriTACs, sdAbs, and extracellular domains of target proteins fused to an Fc domain or a hexahistidine tag were cloned into mammalian expression vector, pcDNA 3.4 (Invitrogen), preceded by a leader sequence. Expi293 Cells (Life Technologies) were maintained in suspension in Optimum Growth Flasks (Thomson) between 0.2 and

8 106 cells/mL in Expi293 media. Puried plasmid DNA was transfected into Expi293 cells in accordance with Expi293 Expression System Kit (Life Technologies) protocols and cultured for 4-6 days after transfection. Alternatively, HPN536 was produced in CHO- DG44 DHFR-decient cells (34). The amount of expressed proteins in conditioned media was quantitated using an Octet RED96 instru- ment with Protein A Tips (ForteBio/Pall) using appropriate puried control proteins for a standard curve. Conditioned media from either host cell were ltered and puried by protein A afnity and desalted or subjected to preparative size exclusion chromatography (SEC) using an AKTA Pure Chromatography System (GE Healthcare). Protein A puried TriTAC proteins were further puried by ion exchange and

formulated in a buffered solution containing excipients. Final purity was assessed by SDS-PAGE by resolving 2.5 mg/lane on TRIS-Glycine

gels and visualized with Simply Blue Stain (Life Technologies). Native purity was also assessed by analytic SEC using a Yarra SEC150 3 mm

4.6 150 mm Column (Phenomenex) resolved in an aqueous/organic mobile phase buffered at neutral pH on a 1290 LC system and peaks were integrated with OpenLab ChemStation Software (Agilent Technologies).

In vitro afnity measurements

Afnities of HPN536 analyte for albumin, CD3e, and MSLN ligands were measured by biolayer interferometry using an Octet RED96 instrument with Streptavidin Tips (ForteBio/Pall). Experiments were performed at 27 C in PBS plus casein in the absence or presence of 15 mg/mL has, as described in Results section and gure legends. Binding sensograms generated from empirically determined ligand

loads, appropriate serial dilutions of known analyte concentrations, and association and dissociation times were then t globally to a one- to-one binding model using Octet DataAnalysis 9.0 software.

In vitro T-cell-dependent cell cytotoxicity and T-cell activation assays

T cells from healthy donors were puried from leukopaks (leuka- pheresis samples, StemCell Technologies) using EasySep Human T Cell Isolation Kits (StemCell Technologies, 17951) following the manufacturer's instructions. All cancer cell lines were obtained from the ATCC, with the exception of OVCAR8 cells, which were obtained from the NCI (Bethesda, MD). Cell lines were passaged a maximum of 36 times after being received from the ATCC. Cell line authentication and Mycoplasma testing were not performed. T-cell-dependent cell cytotoxicity (TDCC) assays were performed as described previously (35). Briey, luciferase-expressing target cells and puried human T cells were seeded per well of a 384-well plate at a 10:1 T cell-to-target cell ratio. Target cell killing was assessed following incubation for 48 hours at 37oC and 5% CO2. Target cell viability was assessed by incubation with the SteadyGlo Reagent (Promega). Luminescence was measured using a PerkinElmer EnVision Detection System. Activated T cells were identied by CD69 and CD25 surface expression (BD Biosciences). Samples were analyzed on a FACSCelesta Flow Cyt- ometer (BD Biosciences). Flow cytometry data were processed using FlowJo v10 Software (FlowJo, LLC).

Binding of HPN536 on MSLN-expressing OVCAR and T cells Cultured cells were incubated with 1 mg/mL HPN536 or anti-GFP

TriTAC (control) for 1 hour. Binding was detected using Alexa647- anti-TriTAC antibody using a FACSCelesta Flow Cytometer (BD Biosciences). The QIFIKIT (Dako) was used according to the man- ufacturer's instructions to estimate the number of MSLN molecules expressed per cell.

Cytokines in the presence of T cells

To measure the cytokines, AlphaLISA Kits were used (PerkinElmer) per the manufacturer's instructions, except that the assays were performed in 384-well plates instead 96-well plates. Plates containing conditioned media from TDCC assays were used for analysis. Plates were read on a PerkinElmer EnVision Plate Reader equipped with an AlphaLISA module.

In vivo mouse efcacy studies

All mouse studies were performed in accordance with the policies of the Institutional Animal Care and Use Committee (IACUC) at

Harpoon Therapeutics and Charles River Laboratories. For TOV21G and HPAFII experiments, NCG (NOD-Prkdcem26Cd52Il2rgem26Cd22/

NjuCrl) mice received subcutaneous coimplants of human cancer cells (5 106) and human T cells (5 106) in 50% Matrigel (BD Biosciences) on day 0. Human T cells were expanded before implantation using Human T Cell Activation/Expansion Kit (Miltenyi Biotec) according to the manufacturer's instructions. Mice were dosed on days 1-15 (HPAFII, Fig. 4A and TOV21G, Fig. 4C) or days 7-16 (HPAFII, Fig. 4B) via intraperitoneal injection. For NCI-H292 experi- ments, NCG mice received subcutaneous coimplants of human cancer cells (1 107) and human peripheral blood mononuclear cells (PBMC;

1 107). Mice were administered HPN536 daily for 10 days starting on

day 6 via intravenous injection. Tumor size was measured twice weekly and calculated using the following formula: tumor volume (mm3)

(w2 l)/2. Percent tumor growth inhibition (%TGI) was dened as the difference between the mean tumor volume (MTV) of the control

OF2 Clin Cancer Res; 2021

CLINICAL CANCER RESEARCH

Rela

HPN536

An

group and the MTV of the treated group, expressed as a percentage of the MTV of the control group.

Exploratory cynomolgus monkey dose range-ndingstudy The pharmacology, pharmacokinetics, and toxicity of HPN536

were evaluated after a single intravenous bolus dose of 0.1, 1.0, or 10 mg/kg HPN536 in one male and one female cynomolgus monkey per group followed by either a 1- or 3-weekpostdose recovery period. The study followed the protocol and standard operating procedures of the testing facility (Charles River Labo- ratories) and was approved by their IACUC. Pharmacologic activ- ity was evaluated by clinical observations, cytokine assessments, ow cytometry, and evidence of target engagement by histology. Two research electrochemiluminescence assays, a functional assay and an anti-idiotypeassay, were used for measuring HPN536 levels in serum. For the functional assay, HPN536 was captured with biotinylated CD3e and was detected with a sulfo-taggedMSLN. For the anti-idiotypeassay, HPN536 was captured with an anti- idiotype antibody recognizing the anti-albumindomain and was detected with a sulfo-taggedCD3e. Toxicokinetic parameters were estimated using Phoenix WinNonlin pharmacokinetic software. A noncompartmental approach, consistent with the intravenous bolus route of administration, was used for parameter estimation.

Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392

HPN536 an Anti-MSLN/Anti-CD3T-Cell Engager for Solid Tumors

Toxicity endpoints included daily morbidity and mortality, daily clinical observations, weekly body weights, daily food consump- tion, clinical pathology (hematology, clinical chemistry, and coag- ulation), and anatomic pathology (gross necropsy, organ weights, and histopathology).

Results

Production, structure, and biochemical characteristics of

HPN536

Recombinant HPN536 has a molecular weight of approximately

53 kDa. A humanized llama sdAb specic for human MSLN is placed at its N-terminus (Fig. 1A). A humanized llama sdAb specic for human serum albumin (HSA) is placed in the middle of the molecule. The C-terminal end contains a humanized scFv specic for the human CD3e subunit of the TCR complex. GGGGSGGGS linkers connect the three binding domains.

HPN536 is produced by eukaryotic cell culture and secreted as a single, nonglycosylated polypeptide. Stability studies subjecting HPN536 to various stress conditions, including multiple freeze thaw cycles and storage at 4 C and 40 C for 2 weeks, suggest the protein is stable and stress resistant (Supplementary Fig. S1). The high stability of HPN536 ensures limited aggregation, which would otherwise lead to

huMSLN

huCD3e

huALB

A

B

MSLN

ALB

MSLN

CD3

ALB

CD3

In vitro anity

Human KD (nmol/L)

0.21

6.6

6.3

measurements

CynoK D (nmol/L)

1.1

6.2

5.6

Mouse (nmol/L)

210

NB

170

HPN536 binding to MSLN-

HPN536 binding to

expressing OVCAR8 cells

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Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity – Science Advances

Tuesday, January 5th, 2021

Abstract

Various characteristics of cancers exhibit tissue specificity, including lifetime cancer risk, onset age, and cancer driver genes. Previously, the large variation in cancer risk across human tissues was found to strongly correlate with the number of stem cell divisions and abnormal DNA methylation levels. Here, we study the role of synthetic lethality in cancer risk. Analyzing normal tissue transcriptomics data in the Genotype-Tissue Expression project, we quantify the extent of co-inactivation of cancer synthetic lethal (cSL) gene pairs and find that normal tissues with more down-regulated cSL gene pairs have lower and delayed cancer risk. Consistently, more cSL gene pairs become up-regulated in cells treated by carcinogens and throughout premalignant stages in vivo. We also show that the tissue specificity of numerous tumor suppressor genes is associated with the expression of their cSL partner genes across normal tissues. Overall, our findings support the possible role of synthetic lethality in tumorigenesis.

Cancers of different human tissues have markedly different molecular, phenotypic, and epidemiological characteristics, known as the tissue specificity in cancer. Various aspects of this intriguing phenomenon include a considerable variation in lifetime cancer risk, cancer onset age, and the genes driving the cancer across tissue types. The variation in lifetime cancer risk is known to span several orders of magnitude (1, 2). Such variation cannot be fully explained by the difference in exposure to carcinogens or hereditary factors and has been shown to strongly correlate with differences in the number of lifetime stem cell divisions (NSCD) estimated across tissues (2, 3). As claimed by Tomasetti and Vogelstein (2), these findings are consistent with the notion that tissue stem cell divisions can propagate mutations caused either by environmental carcinogens or random replication error (4). In addition, the importance of epigenetic factors in carcinogenesis has long been recognized (5), and Klutstein et al. (6) have recently reported that the levels of abnormal CpG island DNA methylation (LADM) across tissues are highly correlated with their cancer risk. Although both global (e.g., smoking and obesity) and various cancer typespecific (e.g., HCV infection for liver cancer) risk factors are well known (7), no factors other than NSCD and LADM have been reported to date to explain the across-tissue variance in lifetime cancer risk.

Besides lifetime cancer risk, cancer onset age, as measured by the median age at diagnosis, also varies among adult cancers (1). Although most cancers typically manifest later in life [more than 40 years old (1, 8)], some such as testicular cancer often have earlier onset (1). Many tumor suppressor genes (TSGs) and oncogenes are also tissue specific (911). For example, mutations in the TSG BRCA1 are predominantly known to drive the development of breast and ovarian cancer but rarely other cancer types (12). In general, factors explaining the overall tissue specificity in cancer could be tissue intrinsic (10, 13), and their elucidation can further advance our understanding of the forces driving carcinogenesis.

Synthetic lethality/sickness (SL) is a well-known type of genetic interaction, conceptualized as cell death or reduced cell viability that occurs under the combined inactivation of two genes but not under the inactivation of either gene alone. The phenomenon of SL interactions was first recorded in Drosophila (14) and then in Saccharomyces cerevisiae (15). In recent years, much effort has been made to identify SL interactions specifically in cancer, since targeting these cancer SLs (cSLs) has been recognized as a highly valuable approach for cancer treatment (1619). The effect of cSL on cancer cell viability has led us to investigate whether it plays an additional role even before tumors manifest, i.e., during carcinogenesis. In this study, we quantify the level of cSL gene pair co-inactivation in normal (noncancerous) human tissue as a measure of resistance to cancer development (termed cSL load, explained in detail below). We show that cSL load can explain a considerable level of the variation in cancer risk and cancer onset age across human tissues, as well as the tissue specificity of some TSGs. Together, these correlative findings support the effect of SL in impeding tumorigenesis across human tissues.

To study the potential effects of cSL in normal, noncancerous tissues, we define a measure called cSL load, which quantifies the level of cSL gene pair co-inactivation based on gene expression of normal human tissues from the Genotype-Tissue Expression (GTEx) dataset (20). Specifically, we used a recently published reference set of genome-wide cSLs that are common to many cancer types, identified from both in vitro and The Cancer Genome Atlas (TCGA) cancer patient data (21) via the identification of clinically relevant synthetic lethality (ISLE) (table S1A) (22, 23). For each GTEx normal tissue sample, we computed the cSL load as the fraction of cSL gene pairs (among all the genome-wide cSLs) that have both genes lowly expressed in that sample (Methods; illustrated in Fig. 1). We further defined tissue cSL load (TCL) as the median cSL load value across all samples of each tissue type in GTEx (Methods and table S2A). We then proceed to test our hypothesis that TCL can be a measure of the level of resistance to cancer development intrinsic to each human tissue (outlined in Fig. 1).

This diagram illustrates the computation of cSL load for each sample and each tissue type (i.e., TCL) and depicts the outline of this study, where we attempted to explain the tissue-specific lifetime cancer risk, cancer onset age, and TSGs using TCL. See main text and Methods for details.

SL is widely known to be context specific across species, tissue types, and cellular conditions (24). In theory, a cancer-specific cSL gene pair can be co-inactivated in the normal tissue without reducing normal cell fitness, while conferring resistance to the emergence of malignantly transformed cells due to the lethal effect specifically on the cancer cells. Different normal tissues can have varied TCLs (representing the levels of cSL gene pair co-inactivation) as a result of their specific gene expression profiles, and we hypothesized that normal tissues with higher TCLs should have lower cancer risk, as transforming cancerous cells in these tissues will face higher cSL-mediated vulnerability and lethality. To test this hypothesis, we obtained data on the tissue-specific lifetime cancer risk in humans (Methods) and correlated that with the TCL values computed for the different tissue types. We find a strong negative correlation between the TCL (computed from older-aged GTEx samples, age 50 years) and lifetime cancer risk across normal tissues (Spearmans = 0.664, P = 1.59 104; Fig. 2A and table S2A). This correlation is robust, as comparable results are obtained when this analysis is carried out in various ways (e.g., different cutoffs for low expression of genes, different cSL network sizes, and different cancer typenormal tissue mappings; fig. S1 and note S3). We also showed that this correlation is not confounded by the number of poised genes associated with bivalent chromatin, variation in cancer driver gene expression, and immune cell or fibroblast abundance (notes S11 to S13 and figs. S12 to S14). Notably, the cSL load varies with age due to age-related gene expression changes, and the correlation with lifetime cancer risk is not found when the TCL is computed on samples from the young population (20 age < 50 years, Spearmans = 0.0251, P = 0.901; fig. S2A); this is consistent with the observation that lifetime cancer risk is mostly contributed by cancers occurring in older populations (1). We still see a marked negative correlation between TCL and lifetime cancer risk when analyzing samples from all age groups together (Spearmans = 0.49, P = 0.01; fig. S2B). Repeating these analyses using different control gene pairs including (i) random gene pairs, (ii) shuffled cSL gene pairs, and (iii) degree-preserving randomized cSL network (same size as the actual cSL network; note S4) results in significantly weaker correlations (empirical P < 0.001; fig. S3, A to C, and note S4), confirming that the associations found with cancer risk results from a cSL-specific effect.

(A) Scatterplot showing Spearmans correlations between lifetime cancer risk and TCL computed for the older population (age 50 years) (ranked values are used as lifetime cancer risk spans several orders of magnitude.) (B) Lifetime cancer risks across tissues were predicted using linear models (under cross-validation) containing different sets of explanatory variables: (i) TCL only, (ii) the number of stem cell divisions (NCSD) only, and (iii) TCL and NSCD (27 data points). The prediction accuracy is measured by Spearmans , shown by the bar plots. The result of a likelihood ratio test between models (ii) and (iii) is also displayed. (C) A similar bar plot as in (B) comparing the predictive models for cancer risk involving the following variables: (i) TCL only, (ii) the LADM only, and (iii) TCL and LADM combined (21 data points only due to the smaller set of LADM data). A model containing all the three variables does not increase the prediction power (Spearmans = 0.77 under cross-validation) and is not shown. (D) Bar plot showing the correlations between lifetime cancer risk with TCLs computed (age 50 years) using subsets of cSLs: hcSLs, lcSLs, and all cSLs. Spearmans and P values are shown. The hcSLs and lcSLs are identified using data of matched TCGA cancer types and GTEx normal tissues (Methods), which correspond to only a subset of tissue types. To facilitate comparison, here, the correlation for all cSLs was also computed for the same subset of tissues, and therefore, the resulting correlation coefficient is different from that in (A).

While the randomized cSL networks used in the control tests described above provide significantly weaker correlations with cancer risk than those observed with cSLs, many of these correlations are still significant by themselves (fig. S3, B and C). This suggests that there may be a possible association between the expression of single genes in the cSL network (cSL genes) and cancer risk. To investigate this, we computed the tissue cSL single-gene load (SGL; the fraction of lowly expressed cSL genes) for each tissue (Methods). We do find a significant negative correlation between tissue SGL levels and cancer risk (Spearmans = 0.49, P = 0.01; fig. S3D and note S5). This correlation vanishes when we use random sets of single genes (fig. S3F). However, after controlling for the single-gene effect, the partial correlation between TCL and cancer risk is still highly significant (Spearmans = 0.69, P = 6.10 105; fig. S3G), pointing to the dominant role of the SL genetic interaction effect (note S5).

We next compared the predictive power of TCL to those obtained with the previously reported measures of NSCD (2, 3) and LADM (6), using the set of GTEx tissue types investigated here (Methods). We first confirmed the strong correlations of NSCD and LADM with tissue lifetime cancer risk in our specific dataset (Spearmans = 0.72 and 0.74, P = 2.6 105 and 1.3 104, respectively; fig. S4). These correlations are stronger than the one we reported above between TCL and cancer risk. However, adding TCL to either NSCD or LADM in linear regression models leads to enhanced predictive models of cancer risk compared to those obtained with NSCD or LADM alone [log-likelihood ratio (LLR) = 2.18 and 2.39, P = 0.037 and 0.029, respectively]. Furthermore, adding TCL to each of these factors increases their prediction accuracy under cross-validation (Spearmans s from 0.67 and 0.69 with NSCD and LADM alone to 0.71 and 0.77, respectively; Fig. 2, B and C). LADM and NSCD are significantly correlated (Spearmans = 0.66, P = 0.02), while the TCL correlates only in a borderline significant manner with either NSCD (Spearmans = 0.57, P = 0.06) or LADM (Spearmans = 0.52, P = 0.08). Together, these observations support the hypothesis that TCL is associated with tissue cancer risk, with a partially independent role from either NSCD or LADM.

We have shown results that support the role of TCL in impeding cancer development, and we reason that such an effect is dependent on the notion that many of the cSLs are specific to cancer while having weaker or no lethal effects in normal tissues. We tested and found that the co-inactivation of cSL gene pairs is under much weaker negative selection in GTEx normal tissues versus matched TCGA cancers [Wilcoxon rank sum test P = 2.93 106 (fig. S5A), also shown using cross-validation (note S7)]. Moreover, we hypothesize that those cSLs with the highest specificity to cancer (i.e., with the strongest SL effect in cancer and no or the weakest effect on normal cells) should have the strongest effect on cancer development. To test this, we identified the subset of such cSLs (termed highly specific cSLs or hcSLs) and those with the lowest specificity to cancer (termed lowly specific cSLs or lcSLs; Methods) and recomputed the TCLs of all normal GTEx tissues using these two cSL subsets, respectively. The TCLs computed from the hcSLs correlate much stronger with cancer lifetime risk than those computed from the lcSLs (Spearmans = 0.593 versus 0.319; Fig. 2D), testifying that these cSLs with high functional specificity to cancer are more relevant to carcinogenesis. These hcSLs are enriched for cell cycle, DNA damage response, and immune-related genes [false discovery rate (FDR) < 0.05; table S5 and Methods], which are known to play key roles in tumorigenesis.

We have thus established that TCL in the older population is inversely correlated with lifetime cancer risk across tissues. We next hypothesized that higher cSL load in a given normal tissue in the young population may delay cancer onset, which typically occurs later (age >40 years) (1). To test this, we use the median age at cancer diagnosis (1) of a certain tissue as its cancer onset age (table S3 and Methods). We find that the TCL values (for age 40 years) are markedly correlated with cancer onset age (Spearmans = 0.502, P = 0.011; Fig. 3A). This result is again robust to variations in our methods to compute TCL and cancer onset age (fig. S6, table S3, and note S3). We note that the cancer onset age is not significantly correlated with lifetime cancer risk (Spearmans = 0.279, P = 0.28).

(A) Scatterplot showing Spearmans correlations between cancer onset age and TCL (age 40 years). (B) Bar plot showing the correlations between cancer onset age with TCLs computed (age 40 years) using subsets of cSLs: hcSLs, lcSL, and all cSLs. Spearmans and P values are shown. As in Fig. 2D, this analysis was done for a subset of GTEx normal tissues for which we had matched TCGA cancer types to identify the hcSLs and lcSLs (Methods); therefore, the correlation result for all cSLs is also different from that in (A).

Similar to our earlier analysis, we see that the TCLs computed from the hcSLs correlate much stronger with onset age than those from the lcSLs or all cSLs (Spearmans = 0.603 versus 0.157; Fig. 3B and fig. S7A) and also stronger than those obtained from control tests performed as before (empirical P < 0.001; fig. S7, B to D). As with the case of cancer risk, the observed correlation is dominated by the SL genetic interaction effects rather than the single-gene effects (fig. S7, E to G, and note S5).

To further corroborate the relevance of cSL load to carcinogenesis, we next investigated whether carcinogen treatment in normal (noncancer) cell lines and primary cells in vitro can lead to cSL load decrease. First, we analyzed gene expression data from a recent study where human primary hepatocytes, renal tube epithelial cells, and cardiomyocytes were treated with the carcinogen and hepatotoxin thioacetamide-S-oxide (25). We computed the cSL load in each cell type after treatment versus control and found a significant decrease of cSL load only in the hepatocytes (Wilcoxon rank sum test P = 0.014; Fig. 4A), which is consistent with thioacetamide-S-oxides role as a hepatotoxin and a carcinogen primarily in the liver. Second, we collected the gene expression signatures of chemotherapy drug treatments in a total of four primary cells and normal cell lines from the Connectivity Map (CMAP) (26). We quantified the drug-induced cSL load changes indirectly from the gene signatures (Methods), comparing the strongly mutagenic DNA-targeting drugs (n = 6) including alkylating agents and DNA topoisomerase inhibitors to the weak/nonmutagenic taxanes and vinca alkaloids (n = 5), which act on the cytoskeleton and not directly on DNA (27). We find that the strong mutagenic chemotherapy drugs lead to a significantly larger decrease in cSL load (Fig. 4B, P = 0.03 from a linear model controlling for cell type; Methods). The strong mutagenicity of alkylating agents and DNA topoisomerase inhibitors is consistent with their mechanisms of actions; they are also World Health Organization class I carcinogens (28), supported by incidence of secondary cancers in patients treated by these drugs for their primary cancers (29). In contrast, taxanes and vinca alkaloids have shown negative or weak/inconclusive results in mutagenic tests (27, 30). These results are not likely affected by cell death, as the cSL decreased specifically only for the two classes among all tested chemotherapy drugs. Although the CMAP dataset used for this analysis does not include cell viability information, the gene expression of the cells does not show an apoptotic signature after the drug treatment.

(A) Box plots showing the cSL loads in control versus thioacetamide-S-oxidetreated samples in human primary hepatocytes (liver), renal tube epithelial cells (kidney), and cardiomyocytes (heart), using the data from (25). One-sided Wilcoxon rank-sum test P values are shown. (B) Box plots showing the cSL load changes after treatment by different classes of chemotherapy drugs in four cell types, using the CMAP data (26). Asterisk indicates that the cSL load change is estimated indirectly from the CMAP drug treatment gene expression signatures (Methods). Strongly mutagenic drugs (n = 6), including alkylating agents (green points) and DNA topoisomerase inhibitors (purple points), lead to a significantly larger cSL load decrease compared to weak or nonmutagenic drugs (n = 5), including taxanes (red points) and vinca alkaloids (blue points); P = 0.03 from a linear model controlling for cell type. HA1E is an immortalized kidney cell line; PHH, primary human hepatocyte; ASC, adipose-derived stem cell; SKB, human skeletal myoblast. (C) Box plots showing the cSL load in samples of different stages of premalignant lesions in the lung (including normal tissue and lung squamous cell carcinoma) (28). The cSL load shows an overall decreasing trend from normal to different pre-cancer stages to cancer (one-sided Wilcoxon rank sum test of normal versus cancer P = 4.47 105; ordinal logistic regression has negative coefficient 28.7, P = 5.89 107).

Further beyond these in vitro findings, analyzing a recently published lung cancer dataset (31), we find that cSL load decreases progressively as cancers develop from normal tissues throughout the multiple stages of premalignant lesions in vivo (normal versus cancer Wilcoxon rank sum test P = 4.47 105, ordinal logistic regression P = 5.89 107 with negative coefficient 28.7; Fig. 4C). These results provide further evidence supporting cSL as a factor that may be involved in cancer development.

Given the role of cSLs in cancer development, we turned to ask whether cSL may also contribute to the tissue/cancer-type specificity of TSGs (10, 32). Specifically, we reasoned that the loss of function of a gene is unlikely to have cancer-driving effects in tissues where its cSL partner genes are lowly expressed, due to the synthetic lethal effect of such co-inactivation on the emerging cancer cells. In other words, this gene is unlikely to be a TSG in such tissues. To study this hypothesis, we obtained a list of TSGs together with the tissues in which their loss is annotated to have a tumor-driving function from the COSMIC database (table S6A) (11). We further identified the cSL partner genes of each such TSG using ISLE (Methods and table S6B) (22). In total, there are 23 TSGs for which we were able to identify more than one cSL partner gene. Consistent with our hypothesis, we find that in most of the cases, the cSL partner genes of TSGs have higher expression levels in the tissues where the TSGs are known drivers compared to the tissues where they are not established drivers (binomial test for the direction of the effect P = 0.023; Fig. 5A). We identified 10 TSGs whose individual effects are significant (FDR < 0.05) and cSL specific (as shown by the random control test), and all these 10 cases exhibit the expected direction of effect (labeled in Fig. 5A and table S6C; two example TSGs, FAS and BRCA1, are shown in Fig. 5B, details are in fig. S8 and Methods). Reassuringly, these findings disappear under randomized control tests involving random partner genes of the TSGs and shuffled TSGtissue type mappings (note S9), further consolidating the role of cancer-specific cSLs of normal tissues in cancer risk and development.

(A) For each tissue-specific TSG gene Gi, the expression levels of its cSL partner genes in the tissue type(s) where gene Gi is a TSG were compared to those where gene Gi is not an established TSG, using GTEx normal tissue expression data. The volcano plot summarizes the result of comparison with linear models. Positive linear model coefficients (x axis) mean that the expression levels of the cSL partner genes are, on average, higher in the tissue(s) where gene Gi is a TSG. Many cases have near-zero P values and are represented by points (half-dots) on the top border line of the plot. Overall, there is a dominant effect of the cSL partner genes of TSGs having higher expression levels in the tissues where the TSGs are known drivers (binomial test P = 0.023). All TSGs with FDR < 0.05 that also passed the random control tests are labeled. (B) Examples of two well-known TSGs, FAS and BRCA1, are given. The heatmaps display the normalized expression levels of their cSL partner genes (rows) in tissues of where these two genes are known to be TSGs [according to the annotation from the COSMIC database (11)] and in tissues where they are not established TSGs (columns), respectively. High and low expressions are represented by red and blue, respectively. For clarity, one typical tissue type where the TSG is a known driver (e.g., testis for FAS) and three other tissue types where the TSG is not an established driver (and the least frequently mutated) are shown.

In this work, we show that the cSL load in normal tissues is a strong predictor of tissue-specific lifetime cancer risk and is much stronger than the pertaining predictive power observed on the individual gene level. Consistently, we find that higher cSL load in the normal tissues from young people is associated with later onset of the cancers of that tissue. As far as we know, no other factor has been previously reported to be predictive of cancer onset age across tissues. Furthermore, cSL load decreases upon carcinogen treatment in vitro and during cancer development through stages of precancerous lesions in vivo. Last, we show that the activity status of cSL partners of TSGs can explain their tissue-specific inactivation.

We have shown that the correlation between cSL and cancer risk in normal tissues may be explained by the fact that many of the cSLs are specific to cancer and have weak or no functional lethal effect in the normal tissues (Figs. 2D and 3B and fig. S5); therefore, normal tissues can bear relatively high cSL loads without being detrimentally affectedquite to the contrary, they become more resistant to cancer due to the latent effect of these cSLs on potentially emerging cancer cells. We emphasize that while we quantified the cSL loads using the normal tissue data from GTEx, the set of cSLs we used was derived exclusively in cancer from completely independent cancer datasets (and without using any information regarding lifetime cancer risk, onset, or tumor suppressor tissue specificity), so there is no circularity involved. The cSL load in normal tissues was computed to reflect the summed effects of individual cSL gene pairs. The underlying assumption is that the low expression of each cSL gene pair is synthetic sick (i.e., reducing cell fitness to some extent) and that the effects from different cSL gene pairs are additive, consistent with the ISLE method of cSL identification (22). Many experimental screenings of SL interactions also rely on techniques such as RNA interference that inhibits gene expression rather than completely knocks out a gene (33), and it is evident that most of the resulting SL gene pairs have milder than lethal effects. While these cSLs likely act via a diverse range of biological pathways and thus do not provide pathway-specific mechanisms, the additive cancer-specific lethal effect of such cSL gene pairs, however, could form a negative force impeding cancer development from normal tissues.

Obviously, as we are studying the across-tissue association between cSL load and cancer risk, it is essential to focus on cSLs that are common to many cancer types (i.e., pan-cancer). Therefore, we focused on cSLs identified computationally by ISLE via the analysis of the pan-cancer TCGA patient data (22). In contrast, most experimentally identified cSLs are obtained in specific cancer cell lines and are thus less likely to be pan-cancer [and possibly, less clinically relevant (22)]. However, for completeness, we also compiled a set of experimentally identified cSLs from published studies (22, 34) (note S1 and table S1B). The corresponding TCL values computed using this set of cSLs correlate significantly with lifetime cancer risk but not with cancer onset age; the correlation with cancer risk is also markedly weaker than that obtained from ISLE-derived cSLs [Spearmans = 0.433, P = 0.024 (fig. S9A), control tests and detailed analysis are explained in note S4]. These experimentally identified cSLs can explain some cases of tissue-specific TSGs including BRCA1 and BRCA2 (fig. S9E) but do not result in overall significant accountability for a large proportion of TSGs present in the analysis (like in Fig. 5A). This corroborates the importance of pan-cancer cSLs and their relevance to cancer risk.

TCL is not likely to be a corollary of NSCD and LADM [while LADM was thought to be closely related to NSCD (6)], as the cSL load is computed by analyzing expression data of bulk tissues, where stem cells occupy only a minor proportion. We have shown that TCL significantly adds to either NSCD or LADM in predicting lifetime cancer risk (Fig. 2, B and C), which also suggests that cSL load is an independent factor correlated with cancer risk with unique underlying mechanisms. Furthermore, NSCD is measured as the product of the rate of tissue stem cell division and the number of stem cells residing in a tissue (2), and we confirmed that TCL is correlated with lifetime cancer risk independent of both of these components (partial Spearmans = 0.510 and 0.567, P = 0.007 and 0.002, respectively; fig. S10, A and B). We additionally tested and verified that proliferation indices computed for the bulk normal tissues do not correlate with lifetime cancer risk across tissues (Spearmans = 0.062, P = 0.77; fig. S10C and note S10). Furthermore, we verified that our observed correlations are not confounded by the number of samples from each cancer or tissue type (fig. S11).

Since cSL load can vary with age, one may wonder whether cSL load could be extended to correlate with age-specific cancer risk within a tissue (as opposed to across tissues). However, variations in cancer risk across tissues and across ages can be driven by different factors. We did not find a consistent correlation between cSL load computed by age range and age-specific cancer risk in all tissue types (note S14 and fig. S15). Another extension to our current research question is studying the effect of higher-order genetic interactions on cancer risk, which is plausible but challenging to study due to the limited knowledge available on such complex interactions.

While revealing cSL as a previously unknown factor associated with cancer development, our study has several limitations. First, because of the importance of using pan-cancer cSLs as discussed above, we mainly relied on the cSLs computationally inferred by ISLE (22) as one of the most comprehensive pan-cancer cSL datasets. However, current cSL prediction algorithms are far from perfect and should not be regarded as the gold standard for general cSL identification. Only a minor fraction of the large number of predicted cSLs have been experimentally validated only in specific cell types. The cSLs inferred by ISLE should be best viewed as a set of candidate cSL pairs that emerge from genetic screen data in vitro but with further support from patient and phylogenetic data. Future studies that provide experimentally validated pan-cancer cSLs are needed to consolidate our current findings. Second, we have relied on analyzing the gene expression data of bulk tissues from GTEx and not the expression data of the specific cells of origin of the corresponding cancers. More refined future analysis is desirable using single-cell data across normal human tissues as such data becomes more widely available. Last, our study does not establish a causal relationship between the cSL load and the risk of cancer, as it is challenging to experimentally perturb a large number of cSLs simultaneously. The results shown are descriptive and association based, and the causal role of SLs in carcinogenesis remains to be studied mechanistically.

Together, our findings demonstrate strong associations between SL and cancer risk, onset time, and context specificity of tumor suppressors across human tissues. This suggests that beyond the effect on cancer after it has developed, cSL could also play an important role during the entire course of carcinogenesis, although further studies are needed to establish causality. While SL has been attracting tremendous attention as a way to identify cancer vulnerabilities and target them, this is the first time that its potential role in mediating cancer development is uncovered.

The cSL gene pairs computationally identified by the ISLE (identification of clinically relevant SL) pipeline were obtained from (22). We used the cSL network identified with FDR < 0.2 for the main text results, containing 21,534 cSL gene pairs, which is a reasonable size representing only about one cSL partner per gene on average. This also allows us to capture the effects of many weak genetic interactions. Nevertheless, we also used the cSL network with FDR < 0.1 (only 2326 cSLs) to demonstrate the robustness of the results to this parameter (notes S1 and S3). Each gene pair is assigned a significance score [the SL-pair score defined in (22)], that a higher score indicates that there is stronger evidence that the gene pair is SL in cancer. Out of these, we used 20,171 cSL gene pairs whose genes are present in the GTEx data (table S1A). The experimentally identified cSL gene pairs were collected from 18 studies [obtained from the supplementary data 1 of Lee et al. (22) except for those from Horlbeck et al. (34)]. Horlbeck et al. (34) provided a gene interaction (GI) score for each gene pair in two leukemia cell lines. Gene pairs with GI scores of <1 in either cell line were selected as cSLs. A total of 27,975 experimentally identified cSLs were obtained, out of which 27,538 have both their genes present in the GTEx data (table S1B).

The V6 release of GTEx (20) RNA sequencing (RNA-seq) data [gene-level reads per kilobase of transcript, per million mapped reads (RPKM) values] was obtained from the GTEx Portal (https://gtexportal.org/home/). The associated sample phenotypic data were downloaded from dbGaP (35) (accession number phs000424.vN.pN). For comparing the level of negative selection to co-inactivation of cSL gene pairs between normal and cancer tissues, the RNA-seq data of TCGA and GTEx as RNA-seq by expectation-maximization (RSEM) values that have been processed together with a consistent pipeline that helps to remove batch effects were downloaded from UCSC Xena (36). The expression data for each tissue type (normal or cancer) was normalized separately (inverse normal transformation across samples and genes) before being used for the downstream analyses. We mapped the GTEx tissue types to the corresponding TCGA cancer types (table S2B), resulting in one-on-many mappings, e.g., the normal lung tissue was mapped to both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).

Lifetime cancer risk denotes the chance a person has of being diagnosed with cancer during his or her lifetime. Lifetime cancer risk data (table S2A) are from Tomasetti and Vogelstein (2), which are based on the U.S. statistics from the SEER (Surveillance, Epidemiology, and End Results) database (1). We derived the cancer onset age based on the age-specific cancer incidence data from the SEER database with the standard formula (37). Specifically, for each cancer type, SEER provides the incidence rates for 5-year age intervals from birth to 85+ years old. The cumulative incidence (CI) for a specific age range S is computed from the corresponding age-specific incidence rates (IRi, i S) as CI = 5i S IRi, and the corresponding risk is computed as risk = 1 exp(CI). The onset age for each cancer type (table S3) was computed as the age when the CI from birth is 50% of the lifetime CI (i.e., birth to 85+ years old). Usually, the onset age defined as such is between two ages where the actual CI data are available, so the exact onset age was obtained by linear interpolation. Alternative parameters were used to define onset age (note S3) to show the robustness of the correlation between TCL and cancer onset age based on different definitions.

For each sample, we computed the number of cancer-derived SL gene pairs that have both genes lowly expressed and divided it by the total number of cSLs available to get the cSL load per sample. In the ISLE method described in (22), low expression was defined as having expression levels below the 33 percentile in each tissue or cell type. Thus, the ISLE-derived cSL gene pairs were shown to exhibit synthetic sickness effects when both genes in the gene pair are expressed at levels below the 33 percentile in each tissue, even though this appears to be a very tolerant cutoff (22). We therefore adopted the same criterion for low expression for the main results, although we also explored other low expression cutoffs to demonstrate the robustness of the results (note S3).

TCL of each tissue type is the median value of the cSL loads of all the samples (or a subpopulation of samples) in that tissue, with the cSL load of a sample computed as above. For example, TCL for the older population (age 50 years) is the median cSL load for the samples of age 50 years in each tissue type. For analyzing the correlation between the TCLs computed from GTEx normal tissues and cancer risk, we mapped the GTEx tissue types to the corresponding cancer types for which lifetime risk data are available from Tomasetti and Vogelstein (2), resulting in 16 GTEx types mapped to 27 cancer types (table S2A). Gallbladder nonpapillary adenocarcinoma and osteosarcoma of arms, head, legs, and pelvis are not mapped to GTEx tissues and excluded from our analysis. Similarly for the correlation between TCLs and cancer onset age, we mapped GTEx tissue types to the tissue sites from the SEER database (as given in the data slot site recode ICD-O-3/WHO 2008) by their names (table S3).

To investigate the effect on the single-gene level, we computed the cSL SGL in a paralleling way to the computation of the cSL load. Among all the unique genes constituting the cSL network (i.e., cSL genes), we computed the fraction of lowly expressed cSL genes for each sample as the cSL SGL, where low expression was defined in the same way as the computation of cSL load as elaborated above. Similarly, tissue cSL SGL is the median value of the cSL SGLs of all the samples in a tissue.

The lifetime cancer risks across tissue types were predicted with linear models containing three different sets of explanatory variables: (i) the number of total stem cell divisions (NSCD) alone, (ii) TCL alone, and (iii) NSCD together with TCL. LLR test was used to determine whether model (iii) (the full model) is significantly better than model (i) (the null model) in predicting lifetime cancer risks. The three models were also used to predict the lifetime cancer risks with a leave-one-out cross-validation procedure, and the prediction performances were measured by Spearman correlation coefficient. A similar analysis was performed to predict lifetime cancer risks across tissue types with three linear models involving the level of abnormal DNA methylation levels of the tissues (6): (i) the number of LADM alone, (ii) TCL alone, and (iii) LADM together with TCL.

For each pair of GTEx normalTCGA cancer of the same tissue type (table S2B), we computed the fraction of samples where a cSL gene pair i has both genes lowly expressed (defined above) among the normal samples (fni) and cancer samples (fci) and computed a specific score as rsi = fni fci. We selected the hcSLs as those whose specific scores are greater than the 75% percentile of all scores and lcSLs as those with a score below the 25% percentile (table S4, A and B). We compared SL significance scores between the hcSLs and lcSLs in each tissue using a Wilcoxon rank sum test. For each type of the GTEx normal tissues used in this analysis (i.e., those that can be mapped to TCGA cancer types), we also computed the TCL as above but using the hcSLs, lcSLs, or all cSLs, respectively, and analyzed their correlation with lifetime cancer risk or cancer onset age across the tissues.

We designed an empirical enrichment test as below to account for the fact that each cSL consists of two genes. For the hcSLs in each tissue type and each given pathway from the Reactome database (38), we computed the odds ratio (OR) for the overlap between the genes in hcSLs and the genes within the pathway based on the Fishers exact test procedure, with the background being all the genes in the ISLE-inferred cSLs. A greater than 1 OR indicates that the hcSLs are positively enriched for the genes of the pathway. To determine the significance of the enrichment, we repeatedly and randomly sampled the same number of cSLs as that of the hcSLs, computed the ORs similarly, and computed the empirical P value as the fraction of cases where the OR from the random cSLs is greater than that from the hcSLs. We corrected for multiple testing across pathways with the Benjamini-Hochberg method.

The phase I CMAP (26) data were downloaded from the Gene Expression Omnibus database (GSE92742). Level 5 data that represent the consensus perturbation-induced differential expression signature were used. We focused on CMAP data that involve treatment by specific classes of chemotherapy drugs (mutagenic: alkylating agents and DNA topoisomerase inhibitors; nonmutagenic: taxanes and vinca alkaloids) in normal cell lines or primary cells. We identified a total of 11 drugs tested in four cell types. Given the signature (z score) of a drug treatment in a cell, we estimated the drug-induced cSL load change as follows1|S|((i,j)SI(zi<0.5zj<0.5)(i,j)SI(zi>0.5zj<0.5))where S is the set of cSLs, and |S| is the total number of cSL gene pairs. A gene pair is denoted by (i, j), and zi and zj are the z scores of gene i and gene j, respectively. I() is the indicator function. Intuitively, the above formula quantifies the number of cSL gene pairs where both genes are down-regulated with a z score cutoff of 0.5 (i.e., contributing to cSL load increase), minus the number of cSL gene pairs where either gene is up-regulated with a z score cutoff of 0.5 (i.e., contributing to cSL load decrease), normalized by the total number of cSL gene pairs. We then tested whether the mutagenic drugs lead to a larger decrease in cSL load compared to nonmutagenic drugs with a linear model that controls for both cell type and drug.

We obtained the list of TSGs and their associated tissue types from the COSMIC database (11) (https://cancer.sanger.ac.uk/cosmic/download, the Cancer Gene Census data; table S6A). For each TSG, their cSL partner genes were identified using the ISLE pipeline (22) with an FDR cutoff of 0.1 (table S6B). Here, the FDR cutoff is more stringent than that used for the pan-cancer genome-wide cSL network (FDR < 0.2 for the main results) since, here, FDR correction was performed for each TSG, corresponding to a much lower number of multiple hypotheses. As a result, the FDR correction has more power, and a relatively more stringent cutoff can give rise to a more reasonable number of cSL partner genes per TSG. We focused our analysis on 23 TSGs for which more than one cSL partner genes were identified (no cSL partner was identified for most of the other TSGs). The expression levels of the cSL partner genes were then compared between tissue type(s) where the TSG is a known driver and the rest of the tissues where the TSG is not an established driver with linear models. Specifically, the expression levels of the cSL partners were modeled with two explanatory variables: (i) driver status of the TSG in the tissue (binary) and (ii) cSL partner gene (categorical, indicating each of the cSL partner genes of a TSG). The coefficient and P value associated with variable (i) were used to analyze the general trend of differential expression among the cSL partner genes. Positive coefficients of variable (i) means that the expression levels of the cSL partner genes are, on average, higher in the tissue(s) where the TSG is a known driver compared to those in the tissues where the TSG is not an established cancer driver.

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Versiti Blood Centers and Noodles & Company Serve Up Thanks to Blood Donors – PRNewswire

Tuesday, January 5th, 2021

MILWAUKEE, Dec. 30, 2020 /PRNewswire/ -- Versiti Blood Centers and premier partner Noodles & Company are dishing out discounts for life-saving donations during National Blood Donor Month this January.

Since 2016, Noodles & Company has supported Versiti's mission by aligning as a community partner and donating over $1.3 million in discounts and coupons to blood donors. Throughout January 2020, all attempting blood donors will receive a coupon redeemable for $4 off their order when they donate at a Versiti donor center or select community blood drive.

January is National Blood Donor Month, which highlights the critical need for blood during winter when donations often decline. Donors of all blood types are needed, but especially O negative blood donors who carry the universal blood type given to people in emergency situations.

To schedule an appointment, visit versiti.org.

About Versiti Blood Centers Versiti is a not-for-profit organization headquartered in Milwaukee that specializes in blood services, esoteric diagnostic testing, organ, tissue and stem cell donation, medical services and leading-edge research. Founded in 1947, Versiti is the primary provider of blood products and services for more than 250 hospitals in five midwestern states: Illinois, Indiana, Michigan, Ohio and Wisconsin. Versiti collects more than 602,000 units of blood each year at 35 permanent donation sites and more than 12,000 community blood drives. For more, visit versiti.org.

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Versiti Blood Centers and Noodles & Company Serve Up Thanks to Blood Donors - PRNewswire

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January 2021: 2020 Papers of the Year – Environmental Factor Newsletter

Tuesday, January 5th, 2021

Research funded by grantsPFAS linked with liver injury in children

Exposure to per- and polyfluoroalkyl substances (PFAS) in the womb may increase liver injury risk in children, according to NIEHS-funded researchers. This study is the first to examine the impact of early life exposures to a PFAS mixture on child liver injury. PFAS, a large group of synthetic chemicals found in a variety of consumer products, have been linked to immune dysfunction, altered metabolism, brain development, and certain cancers.

The study used data from 1,105 mothers and their children enrolled in the Human Early-Life Exposome, or HELIX, study in Europe. Using computational modeling, the scientists found that higher exposures to PFAS during pregnancy were associated with higher levels of liver enzymes in children. High liver enzyme levels may point to nonalcoholic fatty liver disease (NAFLD). The researchers also identified a profile for children at high risk for liver injury, characterized by high prenatal PFAS exposures.

Citation: Stratakis N, Conti DV, Jin R, Margetaki K, Valvi D, Siskos AP, Maitre L, Garcia E, Varo N, Zhao Y, Roumeliotaki T, Vafeiadi M, Urquiza J, Fernandez-Barres S, Heude B, Basagana X, Casas M, Fossati S, Grazuleviciene R, Andrusaityte S, Uppal K, McEachan RRC, Papadopoulou E, Robinson O, Haug LS, Wright J, Vos MB, Keun HC, Vrijheid M, Berhane KT, McConnell R, Chatzi L. 2020. Prenatal exposure to perfluoroalkyl substances associated with increased susceptibility to liver injury in children. Hepatology 72(5):17581770. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dert/index.htm#a1))

In an NIEHS-funded study, researchers uncovered a previously unknown way that genes code for proteins. Rather than directions going one way from DNA through messenger RNA (mRNA) to proteins, the study showed that RNA can modify how DNA is transcribed into mRNA and translated to produce proteins.

Using mouse stem cells, the scientists found that mRNA modifies how DNA is transcribed using a reversible chemical reaction called methylation, which can change the activity of a DNA segment without changing the sequence. The researchers identified and characterized several proteins that recognized the methylated mRNA. They also discovered a group of RNAs called chromosome-associated regulatory RNAs (carRNAs) that used the same methylation process and controlled how DNA was stored and transcribed. The team found that a specific methylation modification, N6-methyladenosine, served as a switch to control carRNA levels, which regulated DNA transcription.

Citation: Liu J, Dou X, Chen C, Chen C, Liu C, Xu MM, Zhao S, Shen B, Gao Y, Han D, He C. 2020. N 6-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription. Science 367(6477):580586. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dert/index.htm#a1))

Loss of the enzyme topoisomerase 1 (TOP1) leads to DNA damage in neurons and neurodegeneration, according to an NIEHS-funded study. TOP1 plays an important role in facilitating the expression of long genes that are important for neuronal function. The data suggest that TOP1 maintains proper gene function in the central nervous system.

The researchers deleted TOP1 in mouse neurons and examined behavior, development, and underlying indicators of neurodegeneration, such as inflammation. Mice lacking TOP1 showed signs of early neurodegeneration, with brains 3.5-times smaller at postnatal day 15 compared with controls. Although neurons developed normally, mice without TOP1 showed motor deficits, exhibited lower levels of nicotinamide adenine dinucleotide (NAD-plus) a compound critical in energy metabolism and died prematurely. However, when these mice received supplemental NAD-plus, they lived 30% longer, had less inflammation, and showed improved neuronal survival.

Citation: Fragola G, Mabb AM, Taylor-Blake B, Niehaus JK, Chronister WD, Mao H, Simon JM, Yuan H, Li Z, McConnell MJ, Zylka MJ. 2020. Deletion of topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration. Nat Commun 11(1):1962. (Synopsis(https://factor.niehs.nih.gov/2020/6/papers/dert/index.htm#a4))

NIEHS grantees found that a protein known as XPA bends DNA and pauses in response to DNA damage, revealing the location of damaged DNA and potentially promoting the recruitment of DNA repair proteins. Using single molecule experiments and imaging techniques, the researchers observed the biochemistry of a living cell.

The researchers used a new method to calculate the molecular weight of small proteins bound to DNA and tracked proteins involved in DNA repair in 3D using real-time single molecule imaging. XPA cycled through three distinct states on DNA: rapidly hopping over long distances of the DNA strand; slowly sliding over short ranges of DNA while bending local DNA regions; and pausing and forming complexes with bent DNA. XPA paused more frequently in the presence of more DNA damage. The work provided insight into a new damage sensor role for XPA.

Citation: Beckwitt EC, Jang S, Detweiler IC, Kuper J, Sauer F, Simon N, Bretzler J, Watkins SC, Carell T, Kisker C, Van Houten B. 2020. Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search. Nat Commun 11(1):1356. (Synopsis(https://factor.niehs.nih.gov/2020/5/papers/dert/index.htm#a2))

NIEHS grantees found that individual cells in a population respond differently to estrogen stimulation at both the level of single cells and alleles, which are other possible forms of a gene. These differences were not explained by estrogen receptor levels in the cells or receptor activation status.

The researchers treated human breast cancer cells with estrogen and examined two genes, GREB1 and MYC, whose activities are regulated by estrogen. Unexpectedly, individual cells exhibited large differences in the level of gene activation, even between alleles within the same cell. The scientists used automated high-throughput technologies to test small molecule inhibitors of the estrogen receptor regulators. One inhibitor, called MS049, markedly increased the response of individual alleles to estrogen. The researchers altered estrogenic response by inhibiting estrogen receptor regulators, establishing a previously unrecognized regulation path for estrogen to activate genes at the single cell level.

Citation: Stossi F, Dandekar RD, Mancini MG, Gu G, Fuqua SAW, Nardone A, De Angelis C, Fu X, Schiff R, Bedford MT, Xu W, Johansson HE, Stephan CC, Mancini MA. 2020. Estrogen-induced transcription at individual alleles is independent of receptor level and active conformation but can be modulated by coactivators activity. Nucleic Acids Res 48(4):18001810. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dert/index.htm#a3))

NIEHS grantees showed that mice exposed to e-cigarette smoke (ECS) were more likely to develop lung adenocarcinomas, a type of lung cancer. They also found that exposed mice had higher levels of bladder urothelial hyperplasia, an abnormal increase in epithelial cells that can precede development of bladder tumors.

The researchers exposed one group of mice to ECS aerosols generated from e-juice containing nicotine and compared them to a second group of mice exposed to a control aerosol without ECS. A third group of mice was exposed only to filtered air. Of the ECS mice, 22.5% developed lung adenocarcinomas and 57.5% developed urothelial hyperplasia. Mice with ECS-induced lung adenocarcinomas were not more prone to developing urothelial hyperplasia, which suggested that the two outcomes were divergent events and might involve different mechanisms.

Citation: Tang MS, Wu XR, Lee HW, Xia Y, Deng FM, Moreira AL, Chen LC, Huang WC, Lepor H. 2019. 2019. Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice. Proc Natl Acad Sci U S A 116(43):2172721731. (Synopsis(https://factor.niehs.nih.gov/2020/1/papers/dert/index.htm#a1))

NIEHS grantees identified a novel pathway that controls the metabolic response of astrocytes, which are brain and spinal cord cells essential to maintaining central nervous system (CNS) health. Although astrocytes perform various functions, such as providing nerve cells with nutrients, they have been linked to CNS inflammation and multiple sclerosis (MS).

Using a mouse model of MS, researchers found that during the progressive phase of the disease, brain astrocytes switched on metabolic pathways that activated a protein called the mitochondrial antiviral signaling (MAVS) protein. It led to activation of several proinflammatory genes, triggering inflammation in the brain and spinal cord. If the scientists gave the mice the drug miglustat before the onset of MS, they were able to suppress MAVS activation and subsequent inflammation. The findings suggest a new role for MAVS in CNS inflammation and a potential therapeutic target for MS.

Citation: Chao CC, Gutierrez-Vazquez C, Rothhammer V, Mayo L, Wheeler MA, Tjon EC, Zandee SEJ, Blain M, de Lima KA, Takenaka MC, Avila-Pacheco J, Hewson P, Liu L, Sanmarco LM, Borucki DM, Lipof GZ, Trauger SA, Clish CB, Antel JP, Prat A, Quintana FJ. 2019. Metabolic control of astrocyte pathogenic activity via cPLA2-MAVS. Cell 179(7):14831498.e22. (Synopsis(https://factor.niehs.nih.gov/2020/2/papers/dert/index.htm#a3))

NIEHS-funded researchers found that a mutation in the ultraviolet irradiation resistanceassociated gene (UVRAG), which is involved in cell regulation, can disrupt autophagy in mice. Autophagy is the process of removing damaged cells so the body can regenerate newer cells. The scientists say the UVRAG mutation causes increased inflammatory response and tumor development. The study provides the first genetic evidence connecting UVRAG suppression to autophagy regulation, inflammation, and cancer predisposition.

The researchers generated mice that expressed UVRAG with a frameshift mutation, which is a deletion or insertion in DNA that shifts the way the sequence is read. After inducing sepsis or intestinal colitis, they found that mice with the UVRAG mutation displayed increased inflammatory responses in both conditions and increased spontaneous tumor development compared with wild-type mice. The results indicate UVRAG could be one reason people are more susceptible to cancers as they age.

Citation: Quach C, Song Y, Guo H, Li S, Maazi H, Fung M, Sands N, O'Connell D, Restrepo-Vassalli S, Chai B, Nemecio D, Punj V, Akbari O, Idos GE, Mumenthaler SM, Wu N, Martin SE, Hagiya A, Hicks J, Cui H, Liang C. 2019. A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice. Nat Commun 10(1):5681. (Synopsis(https://factor.niehs.nih.gov/2020/2/papers/dert/index.htm#a4))

Exposure to polybrominated biphenyl (PBB) 153, a type of brominated flame retardant, alters DNA methylation in sperm, according to NIEHS grantees. DNA methylation refers to heritable changes in gene expression that occur with no alteration in the DNA sequence. Because PBB153 is toxic to living organisms following direct exposure, the study suggests it may also harm future generations.

The results of a Michigan PBB study showed that PBB153 was associated with gene methylation events in mens sperm. Based on this information, the research team conducted sperm studies and determined that exposure to PBB153 decreased methylation at regions of DNA that control imprinted genes, which are essential for fetal growth and play an important role in other aspects of development. These effects could explain some of the endocrine-related health effects that have been observed among children of PBB-exposed parents.

Citation: Greeson KW, Fowler KL, Estave PM, Thompson SK, Wagner C, Edenfield RC, Symosko KM, Steves AN, Marder EM, Terrell ML, Barton H, Koval M, Marcus M, Easley CA 4th. 2020. Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations. Sci Rep 10(1):8567. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dert/index.htm#a4))

NIEHS grantees determined that in mice, air pollution may play a role in the development of cardiometabolic diseases, such as diabetes, with effects comparable to eating a high-fat diet (HFD). They also established that effects were reversed when exposure to air pollution stopped.

The scientists divided male mice into three categories: those that received clean filtered air; those exposed to concentrated particulate matter 2.5 air pollution; and those that received clean filtered air and were fed an HFD. After 14 weeks, team members measured insulin resistance and glucose levels and assessed epigenetic changes, or chemical tags, that attach to DNA and affect gene expression.

Air pollution exposure was comparable to eating an HFD. Mice in the air pollution and HFD groups had impaired insulin resistance, high glucose, and reduced metabolism. After removing air pollution from the environment, health and epigenetic changes reversed within eight weeks.

Citation: Rajagopalan S, Park B, Palanivel R, Vinayachandran V, Deiuliis JA, Gangwar RS, Das LM, Yin J, Choi Y, Al-Kindi S, Jain MK, Hansen KD, Biswal S. 2020. Metabolic effects of air pollution exposure and reversibility. J Clin Invest 130(11):60346040. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dert/index.htm#a3))

NIEHS researchers learned that mineralocorticoid receptors (MRs) control the gene profiles of neurons within the CA2 brain region, which is associated with learning and memory. MRs are a type of steroid receptor activated by corticosteroid hormones. The findings revealed the essential roles of MRs in the development and maintenance of CA2 neurons, as well as CA2-related behaviors.

In response to environmental stress, the body secretes corticosteroids that bind to MRs or glucocorticoid receptors and that induce gene expression changes in the brain. The CA2 region of the mouse and human hippocampus is enriched with MRs. Neuronal deletion of MRs at embryonic, early postnatal development, or adulthood stages in mice led to significantly reduced expression of CA2 molecular markers. Mice with CA2-targeted deletion of MRs showed disrupted social behavior and altered responses to novel objects. Therefore, MRs control both the identity and function of CA2 neurons.

Citation: McCann KE, Lustberg DJ, Shaughnessy EK, Carstens KE, Farris S, Alexander GM, Radzicki D, Zhao M, Dudek SM. 2019. Novel role for mineralocorticoid receptors in control of a neuronal phenotype. Mol Psychiatry; doi: 10.1038/s41380-019-0598-7 [Online 19 November 2019]. (Synopsis(https://factor.niehs.nih.gov/2020/1/papers/dir/index.htm#a2))

NIEHS researchers discovered a novel symbiotic interaction between mammalian cells and bacteria that boosts nicotinamide adenine dinucleotide biosynthesis in host cells. NAD is a cofactor that exists in all cell types and is necessary for life. Decreased levels of NAD are associated with aging, and elevated levels of its biosynthesis are important to sustain the higher metabolic needs of tumors.

The researchers showed that cancer cell lines infected with Mycoplasma hyorhinis were protected against toxicity by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, which halt NAD biosynthesis. This same effect was observed in vivo, when infected versus noninfected cancer cells were injected in mice. Using a variety of screens and techniques, they showed that this resistance was the result of bacteria providing alternative NAD precursors to mammalian cells through the bacterial nicotinamidase PncA, bypassing the NAMPT-dependent pathway.

Citation: Shats I, Williams JG, Liu J, Makarov MV, Wu X, Lih FB, Deterding LJ, Lim C, Xu X, Randall TA, Lee E, Li W, Fan W, Li J-L, Sokolsky M, Kabanov AV, Li L, Migaud ME, Locasale JW, Li X. 2020. Bacteria boost mammalian host NAD metabolism by engaging the deamidated biosynthesis pathway. Cell Metab 31(3):564579.e7. (Synopsis(https://factor.niehs.nih.gov/2020/5/papers/dir/index.htm#a3)) (Story)

New insights into how the liver adapts to an HFD may lead to novel treatments for obesity-related diseases such as NAFLD, according to a study by NIEHS researchers. They found that long-term consumption of a diet high in saturated fat led to dramatic reprogramming of gene regulation in the mouse liver.

NAFLD involves the buildup of excessive fat in the liver of an individual who is not a heavy user of alcohol, increasing the risk of liver damage. When the scientists fed mice an HFD, the mice became obese and showed other changes similar to metabolic syndrome in humans. Moreover, their livers became fatty and showed wide-ranging abnormalities at both molecular and cellular levels. The livers adaptation to the fat-rich diet was mediated by a protein called hepatocyte nuclear factor 4 alpha.

Citation: Qin Y, Grimm SA, Roberts JD, Chrysovergis K, Wade PA. 2020. Alterations in promoter interaction landscape and transcriptional network underlying metabolic adaptation to diet. Nat Commun 11(1):962. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dir/index.htm#a3)) (Story)

An NIEHS study reported a concerning rise in the prevalence of antinuclear antibodies (ANAs), which are commonly used biomarkers for autoimmunity. ANAs, which are produced by a persons own immune system, bind to and sometimes attack healthy cells. This study is the first to evaluate ANA changes over time in a representative sampling of the U.S. population. The findings may indicate an increase in autoimmune diseases.

Team members used the National Health and Nutrition Examination Survey to analyze serum ANAs in 14,211 participants aged 12 years and older from three time periods. ANA prevalence increased as follows.

The researchers found the largest ANA increases in adolescents, males, non-Hispanic whites, and adults older than 50 years compared with other subgroups.

Citation: Dinse GE, Parks CG, Weinberg CR, Co CA, Wilkerson J, Zeldin DC, Chan EKL, Miller FW. 2020. Increasing prevalence of antinuclear antibodies in the United States. Arthritis Rheumatol 72(6):10261035. (Synopsis(https://factor.niehs.nih.gov/2020/6/papers/dir/index.htm#a4)) (Story)

Ubiquitin (Ub) stimulates the removal of topoisomerase 2 DNA-protein crosslinks (TOP2-DPCs) by tyrosyl-DNA phosphodiesterase 2 (TDP2) according to NIEHS researchers and their collaborators in Spain. The team also reported that TDP2 single nucleotide polymorphisms can disrupt the TDP2-Ub interface. Because TDP2 works with a protein called ZATT to remove dangerous DNA-protein crosslinks, the work is important for understanding how cells handle this type of DNA damage.

Using X-ray crystallography and small angle X-ray scattering analysis, the scientists examined how Ub-dependent links and TDP2 function as they relate to DNA repair and other cellular pathways. Previous studies hypothesized that TDP2 interacts with K48-Ub chains to promote recruitment to TOP2-DPCs that are repaired using a proteasome-mediated TOP2 degradation pathway. However, the authors showed that TDP2 preferentially binds to K63-linked Ub3 and associates with K27 and K63 poly-Ub chains.

Citation: Schellenberg MJ, Appel CD, Riccio AA, Butler LR, Krahn JM, Liebermann JA, Cortes-Ledesma F, Williams RS. 2020. Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2. Nucleic Acids Res 48(11):63106325. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/index.htm#a4))

NIEHS researchers and their collaborators concluded that a protein called tankyrase serves a critical role in mammalian embryonic genome activation (EGA). Using an in vitro culture system, the researchers identified and characterized tankyrase, a factor that allows EGA to occur. The characterization of tankyrase during the oocyte-to-embryo transition fills a gap in knowledge about how factors are activated in mammalian oocytes and early embryos and may lead to improved strategies for treating infertility.

Using a mouse model, the scientists depleted tankyrase from the embryos and observed that they could not perform EGA and stopped developing. They also found that tankyrase is necessary for gene transcription, protein translation, DNA damage repair, and modulation of beta-catenin in the early embryo. This study found a new role for tankyrase during normal development, revealing an essential function of this protein during the oocyte-to-embryo transition.

Citation: Gambini A, Stein P, Savy V, Grow EJ, Papas BN, Zhang Y, Kenan AC, Padilla-Banks E, Cairns BR, Williams CJ. 2020. Developmentally programmed tankyrase activity upregulates beta-catenin and licenses progression of embryonic genome activation. Dev Cell 53(5):545560.e7. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/index.htm#a3)) (Story)

NIEHS researchers showed that an enzyme called CLP1 plays an important role in transfer RNA (tRNA) processing by regulating the ligation of tRNAs. They also demonstrated that mature, functional tRNAs are generated from pre-tRNAs through a process called TSEN, or (tRNA splicing endonuclease)mediated splicing of introns. Mutations in CLP1 and the TSEN complex often lead to severe neurological disorders.

Using a technique that allowed Escherichia coli to produce several proteins at once, the scientists expressed and reconstituted the TSEN protein complex, which cleaved tRNA. TSEN complex alone was sufficient for removing tRNA introns, but CLP1, a binding partner for TSEN, was needed to correctly regulate the ligation step that generates mature tRNAs and tRNA intronic circular RNAs (tricRNAs). Genetic knockdown of CLP1 led to increases in mature tRNAs and tricRNAs, which suggested that CLP1 acts as a negative modulator of tRNA processing.

Citation: Hayne CK, Schmidt CA, Haque MI, Matera AG, Stanley RE. 2020. Reconstitution of the human tRNA splicing endonuclease complex: insight into the regulation of pre-tRNA cleavage. Nucleic Acids Res 48(14):76097622. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/index.htm#a2))

Researchers at NIEHS and the National Toxicology Program developed the Tox21BodyMap to predict which organs in the human body may be affected by a chemical. The tool will help scientists generate novel hypotheses to test, prioritize chemicals for toxicity testing, and identify knowledge gaps.

To identify organs that could potentially be affected by a chemical, Tox21BodyMap used data from 971 high-throughput screening assays that evaluated approximately 10,000 unique chemicals. Specifically, it combined information about which gene an assay targets, how highly expressed that gene is in a human organ, and at what tested concentrations a chemical generated a positive assay result. The result was an overall picture of chemical bioactivity. The Tox21BodyMap provided multiple visualizations of the data, highlighting target organs on a map of the body, as well as showing a web of network connections and providing downloadable data.

Citation: Borrel A, Auerbach SS, Houck KA, Kleinstreuer NC. 2020. Tox21BodyMap: a webtool to map chemical effects on the human body. Nucleic Acids Res 48(W1):W472W476. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/index.htm#a4))

In pregnant women, polyunsaturated fatty acids and their metabolic derivatives called eicosanoids are associated with infant size at delivery, according to NIEHS scientists and their collaborators. This work also provides novel longitudinal characterization of eicosanoids in blood plasma during different gestational ages of pregnancy. The results link inflammatory eicosanoids with adverse fetal growth outcomes.

The blood plasma concentration of polyunsaturated fatty acids, including omega-3 and omega-6, in study participants was found to be higher in cases of low birth weight and lower in cases of higher birth weight. Lower and higher birth weights were defined as equal to or less than the 10th percentile and equal to or greater than the 90th percentile for gestational age, respectively. In addition, certain eicosanoids, which are known to derive from inflammatory processes from these fatty acids, were found to be exclusively higher in pregnancy cases, which resulted in low birth weight.

Citation: Welch BM, Keil AP, van't Erve TJ, Deterding LJ, Williams JG, Lih FB, Cantonwine DE, McElrath TF, Ferguson KK. 2020. Longitudinal profiles of plasma eicosanoids during pregnancy and size for gestational age at delivery: a nested case-control study. PLoS Med 17(8):e1003271. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/index.htm#a2))

Researchers at NIEHS and collaborators at the National Institute of Diabetes and Digestive and Kidney Diseases uncovered the neural basis behind the drive to select calorie-rich foods over nutritionally balanced diets. The findings partly explain the difficulty of dieting.

One group of mice received a standard diet (SD) consisting of regular chow, and another group ate an HFD. When the HFD mice were switched to a SD, they refused to eat. Even after fasting to stimulate their appetites, HFD mice preferred fatty food, rather than regular chow.

However, whenHFD mice were switched to a SD, regular chow no longer fully alleviated the response. The authors also saw that dopamine signaling, which is responsible for the pleasurable feelings from eating, were significantly diminished in the SD mice following HFD exposure.

Citation: Mazzone CM, Liang-Guallpa J, Li C, Wolcott NS, Boone MH, Southern M, Kobzar NP, Salgado IA, Reddy DM, Sun F, Zhang Y, Li Y, Cui G, Krashes MJ. 2020. High-fat food biases hypothalamic and mesolimbic expression of consummatory drives. Nat Neurosci 23(10):12531266. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/index.htm#a4))

To uncover novel deletion patterns in mitochondrial DNA (mtDNA), NIEHS researchers and their collaborators developed LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. The team used the technique to reveal links between mitochondrial DNA replication, aging, and mitochondrial disease.

A mutation in POLG, a nuclear gene responsible for maintaining the mitochondrial genome, is known to be the most common cause of mitochondrial disease, a condition in which the mitochondria fail to produce enough energy for the body to function properly.

The scientists analyzed mtDNA from skeletal muscle biopsies of 41 patients with mitochondrial disease with wild-type and mutated POLG. They used LostArc to detect loss of mtDNA segments by mapping split-reads in the samples to a normal mtDNA reference. Thirty-five million deletion segments were detected in the biopsies. They spanned more than 470,000 unique segments, 99% of which were novel.

Citation: Lujan SA, Longley MJ, Humble MH, Lavender CA, Burkholder A, Blakely EL, Alston CL, Gorman GS, Turnbull DM, McFarland R, Taylor RW, Kunkel TA, Copeland WC. 2020. Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging. Genome Biol 21(1):248. (Synopsis(https://factor.niehs.nih.gov/2020/11/papers/dir/index.htm#a3))

Individual heterogeneity, or genetic variability among samples, can substantially affect reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), according to NIEHS scientists and their collaborators. iPSCs are stem cells that are derived from differentiated cells, such as fibroblasts, and they can both self-renew and are pluripotent, meaning they can be differentiated into other cell types. In a previous publication, the research team obtained fibroblasts from healthy diverse donors and observed that each persons fibroblasts had consistent differences in the ability to be reprogrammed to iPSCs. Ancestry was identified as a large contributing factor.

Using 72 dermal fibroblast-iPSCs from self-identified African Americans and White Americans, the researchers found ancestry-dependent and ancestry-independent genes associated with reprogramming efficiency. They also added 36 new genomic profiles of African American fibroblast-iPSCs pairs to publicly available databases, which will help address the underrepresentation of genomic data from non-European groups.

Citation: Bisogno LS, Yang J, Bennett BD, Ward JM, Mackey LC, Annab LA, Bushel PR, Singhal S, Schurman SH, Byun JS, Napoles AM, Perez-Stable EJ, Fargo DC, Gardner K, Archer TK. 2020. Ancestry-dependent gene expression correlates with reprogramming to pluripotency and multiple dynamic biological processes. Sci Adv 6(47):eabc3851. (Synopsis(https://factor.niehs.nih.gov/2021/1/papers/dir/index.htm#a2))

Researchers in the Division of the National Toxicology Program (DNTP) at NIEHS successfully compiled a rich resource to explore data on polycyclic aromatic compound (PACs) toxicity. This data-driven approach to contextualizing PAC hazard characterization allows researchers to predict eight different toxicity profiles of various PACs and other classes of compounds.

PACs are a structurally diverse class of human-made toxicants found widely in the environment. Unfortunately, information about human exposure and health effects of PACs is limited. To facilitate greater understanding of PAC toxicity in a cost-effective manner, DNTP researchers created an automated approach to identify PAC structures using computer workflows, algorithms, and clusters. Using existing data on similar compounds, the scientists categorized PACs based on structure and hazard characterization. The analysis results are available and searchable through an interactive web application.

Citation: Hsieh JH, Sedykh A, Mutlu E, Germolec DR, Auerbach SS, Rider CV. 2020. Harnessing in silico, in vitro, and in vivo data to understand the toxicity landscape of polycyclic aromatic compounds (PACs). Chem Res Toxicol; doi:10.1021/acs.chemrestox.0c00213 [Online 16 October 2020]. (Synopsis(https://factor.niehs.nih.gov/2020/12/papers/dir/index.htm#a1))

DNTP scientists and their collaborators used computational modeling to probe databases and to identify existing drugs that could be repurposed to fight SARS-CoV-2, the virus that causes COVID-19.

Proteases are enzymes that break down proteins. An essential step in the formation of infectious viral particles is the breakdown of precursor viral proteins by viral proteases. A class of antiviral drugs called protease inhibitors block the activity of viral proteases. The main protease (Mpro) of SARS-CoV-2 is a proposed target for COVID-19 drugs. The structure and activity of Mpro is highly conserved across the coronavirus family. In this study, previous data on drug interactions with SARS-CoV Mpro were used to develop quantitative structure-activity relationship models, which the team used to virtually screen all drugs in the DrugBank database. They identified 42 drugs that could be repurposed against SARS-CoV-2 Mpro.

Citation: Alves VM, Bobrowski T, Melo-Filho CC, Korn D, Auerbach S, Schmitt C, Muratov EN, Tropsha A. 2020. QSAR modeling of SARS-CoV Mpro inhibitors identifies sufugolix, cenicriviroc, proglumetacin, and other drugs as candidates for repurposing against SARS-CoV-2. Mol Inform; doi:10.1002/minf.202000113 [Online 28 July 2020]. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/index.htm#a1))

DNTP scientists evaluated a high-throughput transcriptomics approach using liver and kidney tissue from 5-day assays in male rats to estimate the toxicological potency of chemicals.

Toxicity and carcinogenicity are typically assessed by the resource intensive two-year cancer bioassay. In the 5-day assays, the authors determined toxicological potency based on the most sensitive sets of genes active in the liver and kidney. For most chemicals, the results approximated the toxicological potency derived from the most sensitive histopathological effects independent of target tissue or organ observed in male rats in long-term assays. Notably, these approximations were similar in female rats, as well as in male and female mice. The findings suggest that estimates of transcriptomics-based potency from short-term in vivo assays can, in the absence of other data, provide a rapid and effective estimate of toxicological potency.

Citation: Gwinn WM, Auerbach SS, Parham F, Stout MD, Waidyanatha S, Mutlu E, Collins B, Paules RS, Merrick BA, Ferguson S, Ramaiahgari S, Bucher JR, Sparrow B, Toy H, Gorospe J, Machesky N, Shah RR, Balik-Meisner MR, Mav D, Phadke DP, Roberts G, DeVito MJ. 2020. Evaluation of 5-day in vivo rat liver and kidney with high-throughput transcriptomics for estimating benchmark doses of apical outcomes. Toxicol Sci 176(2):343354. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/index.htm#a1))

Researchers from DNTP studied the effects of gestational and postnatal boron exposure on developing rat pups. The team was the first to show that pups exposed to boric acid, an oxidized form of boron commonly found in the environment, gained significantly less weight during postnatal development.

Pregnant rats were exposed to varying concentrations of boric acid once daily by oral gavage dosing, a technique that administered it directly to the stomach. Food intake, body weight, boron blood plasma levels, and any signs of morbidity were evaluated during gestation. After birth, the pups received boric acid at the same concentration as their mothers, and the scientists monitored the same parameters in the pups for the next 28 days. The team observed that the pups that received the highest dose of boric acid had a 23% reduction in weight gain.

Citation: Watson ATD, Sutherland VL, Cunny H, Miller-Pinsler L, Furr J, Hebert C, Collins B, Waidyanatha S, Smith L, Vinke T, Aillon K, Xie G, Shockley KR, McIntyre BS. 2020. Postnatal effects of gestational and lactational gavage exposure to boric acid in the developing Sprague Dawley rat. Toxicol Sci 176(1):6573. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/index.htm#a1))

When scientists from DNTP analyzed the entire genetic code of tumors in rodent cancer studies, they determined that most rodent tumors whether arising spontaneously or induced by chemicals had DNA mutation signatures resembling those seen in human cancers.

Tumors can form as a result of DNA damage or they can arise spontaneously when physiological processes do not function properly. To understand the mechanism of cancer formation, members of the research team sequenced lung and liver tumor DNA from mice exposed to 20 carcinogens. They compared the sequences to those from tumors that formed spontaneously and from normal tissue. DNA signatures from exposure to 17 of the chemicals were similar to those from spontaneous tumors in mice. The finding suggests chemicals promote tumor formation through mechanisms that build on existing cancer processes.

Citation: Riva L, Pandiri AR, Li YR, Droop A, Hewinson J, Quail MA, Iyer V, Shepherd R, Herbert RA, Campbell PJ, Sills RC, Alexandrov LB, Balmain A, Adams DJ. 2020.The mutational signature profile of known and suspected human carcinogens in mice. Nat Genet 52(11):11891197. (Story)

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January 2021: 2020 Papers of the Year - Environmental Factor Newsletter

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Ozone in the air is bad for birds – Massive Science

Tuesday, January 5th, 2021

In 2007, scientists developed a method to determine the sexes of Atlantic walruses using only their jaws' size and shape. Researchers have now put that sexing (identification of an organism's sex) method to the test with Pacific walruses.

There was some doubt about whether this technique would work for one, Pacific walruses are significantly larger than their Atlantic counterparts. This size difference shows even in individual body parts, including the mandibles.

Yet, the team, led by Nathan Taylor at the University of Alaska, Fairbanks, persisted in applying the sex identification strategy since, if successful, it would significantly reduce the time and financial commitment needed for researching preserved, unidentified walrus specimens. To distinguish between male and female Pacific walruses, they measured the length and height of the jawbone, the minimum jawbone depth (from about the middle point of the jaw to the back), and jaw thickness.

A female Pacific walrus and a calf

USFWS via Wikimedia

The scientists had to be mindful of whether the jawbones were "not fully fused" (not fully developed, unique to juvenile walruses) or "fused" (fully developed, the sign of a mature walrus). Walruses with partially fused mandibles were likely to yield misleading results.

For example, jaws from male walruses that had not yet fully fused were similar in dimensions to mature females' jaws. To ensure the results were accurate, they could only include fully matured, fused specimens.

After measuring 67 modern specimens (33 of which were male, 24 belonging to females, and ten unknown) and 11 archaeological samples, the researchers concluded that jaw size is indeed a reliable body part to distinguish between male and female walruses. The most significant differences were jaw length and thickness, with females notably smaller in both categories.

A male Pacific walrus

Joel Garlich-Miller, USFWS, via Wikimedia

With the original sexing method now confirmed to work for Pacific walruses, scientists will be better prepared to perform several types of analyses, including measuring stable isotopes, trace elements, and hormones in study animals, with greater confidence and less risk of misidentification.

This is a crucial finding, given the insufficient data on Pacific walrus populations, and will hopefully push conservation efforts for this species forward.

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Ozone in the air is bad for birds - Massive Science

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How good are the COVID-19 vaccines? – Massive Science

Tuesday, January 5th, 2021

In 2007, scientists developed a method to determine the sexes of Atlantic walruses using only their jaws' size and shape. Researchers have now put that sexing (identification of an organism's sex) method to the test with Pacific walruses.

There was some doubt about whether this technique would work for one, Pacific walruses are significantly larger than their Atlantic counterparts. This size difference shows even in individual body parts, including the mandibles.

Yet, the team, led by Nathan Taylor at the University of Alaska, Fairbanks, persisted in applying the sex identification strategy since, if successful, it would significantly reduce the time and financial commitment needed for researching preserved, unidentified walrus specimens. To distinguish between male and female Pacific walruses, they measured the length and height of the jawbone, the minimum jawbone depth (from about the middle point of the jaw to the back), and jaw thickness.

A female Pacific walrus and a calf

USFWS via Wikimedia

The scientists had to be mindful of whether the jawbones were "not fully fused" (not fully developed, unique to juvenile walruses) or "fused" (fully developed, the sign of a mature walrus). Walruses with partially fused mandibles were likely to yield misleading results.

For example, jaws from male walruses that had not yet fully fused were similar in dimensions to mature females' jaws. To ensure the results were accurate, they could only include fully matured, fused specimens.

After measuring 67 modern specimens (33 of which were male, 24 belonging to females, and ten unknown) and 11 archaeological samples, the researchers concluded that jaw size is indeed a reliable body part to distinguish between male and female walruses. The most significant differences were jaw length and thickness, with females notably smaller in both categories.

A male Pacific walrus

Joel Garlich-Miller, USFWS, via Wikimedia

With the original sexing method now confirmed to work for Pacific walruses, scientists will be better prepared to perform several types of analyses, including measuring stable isotopes, trace elements, and hormones in study animals, with greater confidence and less risk of misidentification.

This is a crucial finding, given the insufficient data on Pacific walrus populations, and will hopefully push conservation efforts for this species forward.

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How good are the COVID-19 vaccines? - Massive Science

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Stem cells from cord blood can now be used across many conditions: Mayur Abhaya, MD & CEO, LifeCell Internat.. – ETHealthworld.com

Monday, December 28th, 2020

Shahid Akhter, editor, ETHealthworld, spoke to Mayur Abhaya, MD & CEO, LifeCell International, to know more about the latest advancements in Stem cell industry and how it has recovered from the Covid challenges.Impact and challenges of Covid-19 on the Stem cell industry ?One of the biggest issues faced by the stem cell industry during the pandemic was the transport of the cells after collection at birth. It needs to reach the lab within 72 hours and in the case of bone marrow stem cell from donation all the way until it reaches the patient that also has to be completed within 72 hours. The bone marrow cells cannot be handed over in courier. It has to be manually hand carried and that created a huge logistics hurdle were transplants significantly reduced in numbers because of the availability of donors and the transport issues around it.

What are the current global trends in the Stem Cell Industry at large?The recent clinical progress that has been made in the medical space of stem cell transplantation is that now cord blood is considered as a better source than bone marrow cells. This was found in a research study based in US, published in 2020. They have also shown that stem cells from the cord blood can now be used across many conditions with the same treatment protocol. Besides that, the preparation of the patient is different in different conditions but now they have simplified that and reduced the risk of death to a very, very low number. So the cord blood is preferred, as the outcomes are improving.How has Life Cell managed the scenario during the pandemic? Do let us know your challenges and the way forward plan?One of the biggest issues during the pandemic was transport, especially the flight operations because we heavily depend on them for moving the samples across the country. We had to revert to an alternate plan where we had to transport these samples through a relay network from one city to another, through a road network. Luckily LifeCell has operations across the country covering more than 250 cities. So still we had the ability to ensure that our commitment of getting the samples to the lab within those 72 hours was very much possible.

Another major milestone during this pandemic that we were able to help was to support a transplant were a child having Aplastic Anaemia needed not one but two cord blood units for the transplant and within the family they couldnt find a match. Luckily because of the LifeCell network and the inventory size of 50,000 units we were able to meet the requirements of the transplant and happy to share the outcome was very successful. So LifeCell ensures that we have appropriate training for its paramedical staff and they are also provided with the appropriate personal protective gears. There are restrictions on the entry of the team inside during the collection we work with the medical staff in the collection rooms, in the operation theatres to ensure a smooth and a well organised collection and even at the lab we have protocols that ensures hygiene and safety within the team and, the operating rooms we have for processing are also well managed.

Your future plans to ensure the smooth collection of Cord Blood?To ensure business continuity we have our teams located very close to our lab itself, you know, so about 100+ member team are placed within a Kilometer of the operating facility. We have adequate stocks, lots of the testing and the processing, consumables that we use are imported. We, at least, maintain 3 month inventory. We also have onsite power back up systems which include a month of diesel supply, month of liquid nitrogen supply and the teams also have a plan that we have a back site also with arrangements done. If for any reason we have cut off of the Chennai centre we have arrangements with an alternate lab to ensure the continuity of the operations

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Stem cells from cord blood can now be used across many conditions: Mayur Abhaya, MD & CEO, LifeCell Internat.. - ETHealthworld.com

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Allogeneic SCT Benefits Children and Adolescents With Relapsed Anaplastic Large Cell Lymphoma – OncLive

Monday, December 28th, 2020

Findings from the International, Prospective ALCL-Relapse trial [NCT00317408] showed that allogeneic SCT after reinduction chemotherapy can lead to survival improvements in children and adolescents with high-risk relapsed or refractory anaplastic large cell lymphoma (ALCL), provide more insight into how to treat this population.

For patients with early-relapsed ALCL, data showed that autologous SCT wasnt effective.

Current standard chemotherapy reaches an event-free survival (EFS) of 70% at 5 years in children with ALCL, the study authors wrote. Retrospective data on the outcome of pediatric relapsed ALCL show a survival after relapse of more than 50%. In addition, there is no consensus on the optimal treatment approach in relapse, they explained.

Designed by the European Inter-Group for Childhood Non-Hodgkin Lymphoma, the prospective, stratified, multinational clinical trial was opened for patients at sites in 5 countriesthe United Kingdom, Germany, Austria, Switzerland, and the Czech Republic.

Patients were stratified according to the time of relapse, CD3 expression, and prior vinblastine therapy to 3 different consolidation approaches: allogeneic hematopoietic stem cell transplantation (SCT), autologous SCT, or vinblastine monotherapy.

Those whose disease progressed during frontline therapy (very high risk) or with a CD3-positive relapse (high risk) received allogeneic SCT after reinduction chemotherapy. Patients with a CD3-negative relapse within 1 year after initial diagnosis or prior exposure to vinblastine (intermediate risk) received autologous SCT after carmustine, etoposide, cytarabine, and melphalan (BEAM). However, this arm was terminated prematurely, and patients received vinblastine monotherapy instead. Patients with a CD3-negative relapse more than 1 year after initial diagnosis (low risk) received by weekly vinblastine monotherapy (6 mg/m2; maximum, 10 mg) for 24 months.

Investigators analyzed 105 patients; most were male and had ALK-positive tumors. The median age was 12.4 years and median time from initial diagnosis to relapsed/refractory disease was 8.5 months. Patients were recruited from April 2004 to February 2014 and the median follow-up time was 8.1 years.

At 5 years, overall survival (OS) in patients with central nervous systemnegative disease was 78% 4% and EFS, the primary endpoint, was 53% 5%.

Before termination of autologous SCT, EFS rates of patients in the very-high- (n = 17), high- (n = 26), intermediate- (n = 32), and low- (n = 21) risk groups were 41% 12%, 62% 10%, 44% 9%, and 81% 9%. The respective OS rates were 59% 12%, 73% 9%, 78% 7%, and 90% 6%.

Analyzing only the patients in the intermediate-risk group consolidated per protocol by autologous SCT, EFS and OS of 23 patients were 30% 10% and 78% 9%, respectively. The 5 patients with intermediate risk receiving vinblastine monotherapy experienced relapse again.

Compared with data from retrospective analyses, the survival of patients with refractory or relapsed ALCL reached 75% in our prospective trial, demonstrating that relapsed ALCL remains a curable disease, the study authors wrote.

The main limitation to the study was the implementation of the trial as treatment recommendation only in some countries, noted the authors. While recommendations were followed in approximately 90% of patients in the very high risk and high-risk groups, only 70% of patients in the intermediate risk group received autologous SCT, they explained.

Overall, investigators determined that patients with high-risk relapsed disease can benefit from allogeneic SCT and offer a chance for cure.

A long-term remission rate of 81% by outpatient vinblastine monotherapy, with low risk for late effects in patients with a late relapse was also observed by investigators. However, the monotherapy wasnt effective for early relapses.

Patients with early relapsed ALCL dont benefit from consolidation by autologous SCT or vinblastine monotherapy, the authors wrote. However, they may benefit from clinical trials testing a consolidation approach including new targeted therapies. Targeted agents should be tested as reinduction for all but late relapses. Given the efficacy of vinblastine in relapse, this shift-of-paradigm approach should be tested for low-risk patients front line.

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Allogeneic SCT Benefits Children and Adolescents With Relapsed Anaplastic Large Cell Lymphoma - OncLive

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CalvinAyre.com’s most read life stories of 2020 – CalvinAyre.com

Monday, December 28th, 2020

Its time to look back at some of the stories that interested Calvinayre.com readers. Here are the top five stories from the life section that captured the imagination of readers in 2020.

Turn on the Red Light if you want better eyesight

Red lights arent initially associated with healthy eyesight; most people associate red lights with negative situations stop lights, warning lights and even the red-light district. An article that appeared in The Journals of Gerontology puts a positive spin on red lights. The study found that exposure to red lights for a few minutes each day keeps eyesight in better shape as we age.

Next Jeopardy! host odds: Ken Jennings favored over TV hosts

The passing of famed television host Alex Trebek meant that Jeopardy would need a new host. Ken Jennings was chosen to step into the large shoes of Trebek, at least part time, but will he be the permanent host?

Stem Cell Therapy already helping Madonna and Mike Tyson stay young

Mike Tyson and Madonna both swear by stem celling therapy. The Material Girl made the headlines for undergoing stem cell therapy to fix a busted knee. Former heavyweight champ Tyson used the therapy to help him stay youthful. In Tysons case, it seems to have done the trick with a trilogy fight against Evander Holyfield on the cards for 2021.

Ten years in the digital trenches: life as a CalvinAyre.com writer

An industry favourite, Steve Stradbrooke took a quick walk down memory lane to celebrate a decade as a senior writer at Calvinayre.com. Stradbrooke was one of the first on the team in the early days of Calvinayre.com. Buy him a pint to hear some of his stories from the wild west days of Costa Rica to Black Friday.

NASA to give the moon Internet access, SpaceX to give it to Earth

Well end this on a positive note for 2020. Its good to know when we do our first trip to the moon, well have decent internet access. NASA partnered with Nokia to create a cellular network for the moon, while Elon Mush and SpaceX have been creating an internet network from satellites.

Check out the rest of our 2020 year in review.

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CalvinAyre.com's most read life stories of 2020 - CalvinAyre.com

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Coronavirus | Over 6,000 travellers from U.K. traced across States – The Hindu

Monday, December 28th, 2020

Passengers testing positive moved to separate quarantine units.

In line with a Health Ministry directive, several States have stepped up efforts to trace and test persons who have flown in or transited from the United Kingdom between November 25 and December 23, for a more infective version of the COVID-19 virus. Flights between India and the U.K. remain suspended till December 31.

Eleven persons, on board four flights, tested positive for COVID-19 in Delhi and are now admitted to the government-run LNJP Hospital. The Delhi government has also asked the hospital to create a separate isolation unit for passengers from the U.K. who test positive.

Coronavirus | New virus strain increases transmissibility, not severity: V.K. Paul

Around 950 passengers from London were tested at the airport and 11 of them were found positive, according to Genestrings Lab, which conducted the testing. A further 50 people were put under quarantine. Positive samples have been sent to the National Centre for Disease Control for genome sequencing.

In Tamil Nadu, the Health Department tracked 2,724 arrivals from or through the U.K. on different routes to the State from November 25 to December 23.

We found that 179 were double entries. The reconciled figure of those from the U.K. to the State is 2,724. Of this, till Wednesday, we have tracked 996 persons. We have lifted samples from 516 persons. So far, 203 samples have returned negative for COVID-19, Health Secretary J. Radhakrishnan said.

Coronavirus | U.K. strain unlikely to affect efficacy of vaccines, say scientists

The Health Department is also monitoring 111 persons who had moved to a different district after returning. As of Thursday, only one person a 25-year-old man who had returned from the UK by air via Delhi had tested positive and is undergoing treatment in Chennai.

In Kerala, eight persons have tested positive for COVID-19, from amongst the 1,609 travellers from the UK, who reached Kerala between December 9 -23.

As part of the intensified surveillance that has been initiated in the State, health officials have traced a total of 2,116 passengers from UK who arrived in the State till December 23.

Explained | The new coronavirus variant in Britain

All 1,609 passengers were tested using RT-PCR and they will be followed up for the next 14 days. Even those who tested negative will be re-tested using RT-PCR after the quarantine. Apart from the eight passengers who tested positive, their household contacts will also be tested using PCR.

The nasopharyngeal samples from the eight persons who have tested positive for COVID-19 will be sent to the National Institute of Virology, Pune for genome sequencing so that we may identify the virus strain. We have also identified DBT-inStem (Institute for Stem Cell Science and Regenerative Medicine), in Bangalore as another location where we can do genome sequencing, the official said.

A total of 1,016 of the 2,127 U.K. returnees who arrived in Karnataka from December 1 till December 22 have been tested. Out of them six have tested positive and their samples have been sent for genome sequencing.

No home isolation is allowed for passengers from the U.K. who test positive, irrespective of symptoms, till their genome sequencing is completed. Three persons have so far have tested positive and their genome sequencing results are awaited. The sequencing of the positive samples (done to ascertain if they are infected with the new strain of the virus) is likely to take at least four days.

Coronavirus | All international passengers arriving in Karnataka without COVID-19 negative report to be tested

Till then, those who test positive will be isolated in a separate unit in an institutional isolation facility, Jawaid Akhtar, Additional Chief Secretary (Health and Family Welfare) told The Hindu.

Seven persons, of a total 1,200, who had flown in to Hyderabad either directly or via U.K. since December 9, have tested positive for the coronavirus. The samples of these seven positive cases are being sent to the Centre for Cellular and Molecular Biology (CCMB) Hyderabad to check whether the affected persons had the mutated U.K. strain.

Coronavirus | New, more contagious strain in U.K. does not appear to be deadlier: Vivek Murthy

A press release later said officials were trying to trace the primary contacts of positive cases. The health status of those who tested negative was also being monitored. Out of 1,200 UK returnees, as many as 846 persons were traced and tested. Barring the seven, all others tested negative.

A woman who returned from the UK to Rajahmundry has been kept in isolation after testing positive. Overall, information is being gathered on 68 persons who have returned to Andhra Pradesh from the U.K. The Health Department sounded an alert on the likelihood of the spread of the new viral strain on Tuesday and stressed the need for enhanced epidemiological surveillance.

The Chittoor district administration received a list of 38 passengers who came from London via New Delhi and Bengaluru on Thursday. Efforts are on to know more details about them, according to District Medical and Health Officer (DMHO) M. Penchalaiah, who said surveillance teams had been formed to trace them.

(With Bureau inputs)

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Coronavirus | Over 6,000 travellers from U.K. traced across States - The Hindu

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Celtics adjust to two-game series designed to reduce team travel – The Boston Globe

Monday, December 28th, 2020

These are pretty quiet times, Stevens said. I havent left the hotel since Ive been here. And obviously no one from our side can travel unless theyre part of our tested group every single day. All of that are parts of the new unique experiences of being on the road.

Teague said he was able to spend the day after Christmas with his family after all of them tested for negative for COVID-19.

This whole season has been weird, he said. Its had its challenges and curveballs. I leave (the hotel) and then I go home, so its a different experience for me. Its different for me because Im from here. I enjoy being here this long.

Stevens said the two-game series should be something the league considers beyond the pandemic. In January, the Celtics host the Orlando Magic for two straight games and travel to Philadelphia for two. In February, they host Atlanta for a pair.

It makes sense from a travel perspective, a health perspective, Stevens said. Its not just about the COVID health part; its also about the sleep and the opportunity to not overdo it. Theyre playing all the time and if we could lessen the miles of all these teams are traveling, I think thats really important. So I like the idea of a series.

No free throws for Tatum

Jayson Tatum has yet to attempt a free throw this season despite playing 69 minutes and attempting 50 shots through the first two games. Meanwhile reserve forward Semi Ojeleye has attempted seven, including six in the Christmas Day loss to the Brooklyn Nets.

The Celtics are hoping to find a way for Tatum to score easier points, and drawing shooting fouls would help boost what has been an inconsistent offense at times.

No. 1 is, youre always looking to take what the defense gives you, Stevens said. They are very dialed into him. Hes done a good job attacking the rim I thought against Brooklyn. He could finish better at the rim. Hes gonna be such a focal point I think weve talked about trying to get a few easier baskets. Any time you can get to the line its a good thing for us because he makes them. But his lack of getting to the line has a lot more to do with our spacing and our execution that it has with his game.

Free throw attempts arent only a Tatum problem. The Celtics entered Sundays game ranked 29th in the league in free throw attempts (15). Atlanta leads the NBA with 33.5 attempts per game.

Thompson update

Tristan Thompson was again in the starting lineup on a minutes restriction because of a strained left hamstring. He has been limited to 20-plus minutes in the first two games and the Celtics have not revealed when the restriction would be lifted.

Of course Id like to be on the floor with my teammates more but Ive got to trust the training staff, he said. As games go on, hopefully theyll take that restriction [off] , so I can go out and be myself.

Thompson is a plus defender but assigning him to Kevin Durant on Friday could be perceived as an impossible task. Thompson said he relished the matchup. Durant finished with 29 points.

Ive guarded LeBron (James), KD (Durant), Steph (Curry), Kawhi (Leonard), he said. Ill take that challenge every night, I trust myself. Its totally up to the training staff. Id love to play 30 minutes right now and go full speed and go full blast.

Walker on the floor

Kemba Walker traveled with the Celtics and went through a pre-game workout that consisted of shooting 3-pointers and free throws. According to Stevens, Walker has not done anything beyond individual work but Walker did look comfortable and nimble on his left knee, which received a stem cell injection in October. The Celtics initially said Walker would return in January but the club is expected to be cautious with his recovery and it could be several weeks before he returns to action.

Gary Washburn can be reached at gary.washburn@globe.com. Follow him on Twitter @GwashburnGlobe.

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Celtics adjust to two-game series designed to reduce team travel - The Boston Globe

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Exosomes act as messengers and decoys to save healthy cells from viral infection – Massive Science

Monday, December 28th, 2020

In 2007, scientists developed a method to determine the sexes of Atlantic walruses using only their jaws' size and shape. Researchers have now put that sexing (identification of an organism's sex) method to the test with Pacific walruses.

There was some doubt about whether this technique would work for one, Pacific walruses are significantly larger than their Atlantic counterparts. This size difference shows even in individual body parts, including the mandibles.

Yet, the team, led by Nathan Taylor at the University of Alaska, Fairbanks, persisted in applying the sex identification strategy since, if successful, it would significantly reduce the time and financial commitment needed for researching preserved, unidentified walrus specimens. To distinguish between male and female Pacific walruses, they measured the length and height of the jawbone, the minimum jawbone depth (from about the middle point of the jaw to the back), and jaw thickness.

A female Pacific walrus and a calf

USFWS via Wikimedia

The scientists had to be mindful of whether the jawbones were "not fully fused" (not fully developed, unique to juvenile walruses) or "fused" (fully developed, the sign of a mature walrus). Walruses with partially fused mandibles were likely to yield misleading results.

For example, jaws from male walruses that had not yet fully fused were similar in dimensions to mature females' jaws. To ensure the results were accurate, they could only include fully matured, fused specimens.

After measuring 67 modern specimens (33 of which were male, 24 belonging to females, and ten unknown) and 11 archaeological samples, the researchers concluded that jaw size is indeed a reliable body part to distinguish between male and female walruses. The most significant differences were jaw length and thickness, with females notably smaller in both categories.

A male Pacific walrus

Joel Garlich-Miller, USFWS, via Wikimedia

With the original sexing method now confirmed to work for Pacific walruses, scientists will be better prepared to perform several types of analyses, including measuring stable isotopes, trace elements, and hormones in study animals, with greater confidence and less risk of misidentification.

This is a crucial finding, given the insufficient data on Pacific walrus populations, and will hopefully push conservation efforts for this species forward.

Link:
Exosomes act as messengers and decoys to save healthy cells from viral infection - Massive Science

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Experts Reflect on Most Impactful FDA Moves of 2020 in Solid Tumors, Hematologic Malignancies – Targeted Oncology

Monday, December 28th, 2020

Despite the rapid spread of the coronavirus disease 2019 (COVID-19) that plagued not only the oncology field but the healthcare system as a whole, the treatment options for patients with countless different solid tumors and hematologic malignancies were expanded with a number of new FDA approvals indicated throughout 2020. These approvals cover updates in lung, breast, gastrointestinal (GI), and genitourinary (GU) cancers, as well as a variety of hematologic malignancies and other solid tumors.

On Twitter, Targeted Oncology asks in a poll, In what field do you think had the most impactful additions to its armamentarium? The options include lung cancer, breast cancer, hematologic malignancies, and gastrointestinal cancers.

As the year comes to a close, the FDA continues to advance the field with more approvals coming through. On Friday, December 18, 2020, alone, the FDA granted 5 indications approval. These include ponatinib (Iclusig) for treatment of adult patients withs chronic-phase chronic myeloid leukemia who have become resistant or intolerant to therapy following at least 2 prior tyrosine kinase inhibitors (TKIs), osimertinib (Tagrisso) as adjuvant treatment of patients with nonsmall cell lung cancer (NSCLC) whose tumors harbor an EGFR exon 19 deletion or exon 21 L858R mutation for use following tumor resection, the triplet regimen selinexor (Xpovio) plus bortezomib (Velcade) and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least 1 prior therapy, oral relugolix (Relumina) for the treatment of advanced prostate cancer, and a biosimilar to rituximab (Rituxan) was approved for the treatment of adult patients with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), granulomatosis with polyangiitis, and microscopic polyangiitis.

These approvals follow many others that have provided hope throughout the year to physicians and healthcare providers across the United States, but 1 striking area of advancements worth noting this year is the recently approved Emergency Use Authorizations for 2 separate vaccinations for the prevention of coronavirus disease 2019 (COVID-19), which plagued the world, particularly impacting oncology practices treating immunocompromised, sick patients. These approvals, including the BNT162b2 vaccination and the mRNA-1273 Moderna COVID-19 Vaccine on December 18, 2020, demonstrate a crucial step in overcoming the pandemic.

We've learned this year what we can do quickly without being overly hasty, and I think COVID-19 was the ultimate impetus for unity, Mark Lewis, MD, director, GI Oncology, Intermountain Healthcare, told Targeted Oncology. At my center, which is not primarily a research institution, we've run almost 40 trials around COVID-19, largely in-patient, but also largely driven by the clinical need and queries of our intensivists, among others. It's shown us that given the right prompt, you can actually move pretty fast, and learn things very quickly.

Despite the challenges brought on by the pandemic, the healthcare system remained dedicated to keeping patients with cancer safe. Telehealth played a major role in this, as well as other adjustments physicians and cancer centers have made in light of this pandemic. These changes are not only keeping patients safe during these unprecedented times, but they lay the groundwork for the future of treating these patients better in the community setting.

I think we've learned what has to be done at a major research institution and what can be done either at a [community] center or even in the patient's home, said Lewis. Oncology, for a long time, unfortunately, has not been very patient-centric. The idea has been, you're sick, but you need to come to us. Obviously, there are still patients that absolutely have to make that effort to come see us, but on the flipside, we've learned what we can you do remotely and what we can do to bring treatment and research to the patient rather than the other way around.

One important update in the field of oncology in light of the COVID-19 pandemic was the FDAs approval of a new dosage for pembrolizumab (Keytruda) in April 2020, reducing the frequency of clinic visits for patients with cancer. The prior dosage for this immune checkpoint inhibitor was 200 mg every 3 weeks, which remains an approved dosing option, but the newly approved dose of 400 mg is administered every 6 weeks, which is approved across all indications whether the PD-1 inhibitor is given as a monotherapy or in a combination regimen. Pembrolizumab is approved across many disease types and has also gained tumor agnostic approvals over the last few years as well.

We have these really sweeping histology agnostic approvals, and I think the biggest 1 that comes to mind for me is the FDA setting eligibility for immune therapy at a tumor mutational burden [TMB] of greater than 10 mutations/megabase. I think that was pretty amazing, said Lewis. Just in the last couple years, we've seen this shift towards histology agnosticism, whether it's about NTRK fusion proteins, which have become a unicorn in oncology that every oncologist looks for, or we're talking about microsatellite instability [MSI]-high status and eligibility for pembrolizumab.

The immune checkpoint inhibitor pembrolizumab received approval in June 2020, for use in adult and pediatric patients with unresectable or metastatic solid tumors with tissue TMBhigh who have progressed on prior therapy and have no satisfactory alternative treatment options. This marks the second tumor-agnostic approval for the agent, following a prior approval from 2017, for the treatment of patients with MSIhigh or mismatch repair deficient solid tumors.

While we have these very broad indications, now we're also seeing every cancer become a rare cancer. One thing I've seen [more of] this year is selecting out molecular subsets of disease, and a great example is the approval of pralsetinib [formerly BLU-667; Gavreto] for RET-positive tumors, whether of the lung or the thyroid, Lewis said. I think we're seeing that across the categories, which is just site of origin largely, and you can see these mutations that might occur in both lung and thyroid, for the example of RET, and presumably be targetable with the same agent.

Pralsetinib (Gavreto)gained approval in September 2020 for the treatment ofRETfusion-positive NSCLC based on findings from the phase 1/2 ARROW study (NCT03037385), and a few short months later, the RET inhibitor also received approval for use in patients with advanced or metastaticRET-mutant medullary thyroid cancer, as well as those with RET fusion-positive thyroid cancer, also supported by the ARROW data.

Similarly, selpercatinib (formerly LOXO-292; Retevmo) capsules, was approved the treatment of patients with either lung or thyroid cancer who harborRETalterations. This therapy received approval in May 2020, marking it the first approved treatment to target RET. Specifically, the indications for selpercatinib include adult patients with metastatic RET fusionpositive NSCLC, adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, or patients with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine (RAI)refractory, if RAI was appropriate.

Several new therapies gained approval in lung cancer in 2020 across a variety of subsets. In particular, capmatinib (Tabrecta) was approved in May 2020, for the treatment of patients with metastatic NSCLC whose tumors have aMETexon 14 skipping mutation based on the findings from the phase 2 GEOMETRY mono-I study (NCT02414139). This approval fills a gap in the landscape for patients with NSCLC since no other approved therapies target the MET exon 14 mutation in advanced disease.

In March 2020, the FDA approved durvalumab (Imfinzi) as a frontline treatment for adult patients with extensive-stage small cell lung cancer (ES-SCLC) in combination with standard-of-care chemotherapy, etoposide and carboplatin, or cisplatin, offering a new therapeutic approach to a population of patients who have had limited treatment options up until recently. The approval was based on findings from the phase 3 CASPIAN study (NCT03043872), which showed overall survival (OS) analyses favored the durvalumab arm across patient subgroups compared with chemotherapy alone.

The field of breast cancer saw a number of new advances during the year of 2020, many of which impacting patients with metastatic and advanced disease. The FDA granted approval across a number of subsets of patients, including those with HER2-positive disease, triple-negative breast cancer (TNBC), and hormone receptor (HR)-positive disease.

In each of these areas, in the very recent past, there's been a marked expansion of therapeutic options, William J. Gradishar, MD, chief of hematology and oncology, department of medicine, Betsy Bramsen Professorship of Breast Oncology, professor of medicine (hematology and oncology), Northwestern University's Feinberg School of Medicine, told Targeted Oncology. We still have a lot of work to do, patients are still dying of metastatic breast cancer, but we've made significant progress in not only preventing recurrences from developing in patients with early-stage disease, but we've also extended the survival of patients who have metastatic disease.

The FDA granted approval in February 2020 to neratinib (Nerlynx) in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who received at least 2 prior anti-HER2-based regimens in the metastatic setting. This approval was based on supportive findings from the phase 3 NALA trial (NCT01808573). This study showed a 24% reduction in the risk of disease progression or death compared with lapatinib (Tykerb) and capecitabine. Prior to this, neratinib was approved for use as extended adjuvant treatment in adult patients with early-stage HER2-positive disease following adjuvant trastuzumab-based therapy.

In combination with trastuzumab (Herceptin) and capecitabine, tucatinib (Tukysa) received FDA approval for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer in April 2020, including patients with brain metastases who have received at least 1 prior line of HER2-based therapy in the metastatic setting. This approval sparked a lot of excitement in the field, receiving its indication from the FDA 4 months ahead of the Prescription Drug User Fee Act (PDUFA) target action date. The oral, small molecule TKI of HER2 received its approval based on the phase 2 HER2CLIMB study (NCT02614794), which showed a 46% reduction in the risk of disease progression or death among heavily pretreated patients with unresectable, locally advanced, or metastatic HER2-positive disease.

An abundance of new drugs in the HER2 space is a great thing because we can go from 1 therapy to the next. For patients with advanced disease, tucatinib and neratinib are examples of that; these all expand the number of options we have for patients, and tucatinib in particular shows clear evidence of activity in the brain, which is critically important, Gradishar said. In the triple-negative space, sacituzumab govitecan [Trodelvy] is an example of an antibody-drug conjugate [ADC] that has activity, and then, of course, the approval of pembrolizumab has expanded the number of treatment options we have for patients with triple-negative disease.

In April 2020, sacituzumab govitecan received accelerated approval for the treatment of adult patients with metastatic TNBC who have received at least 2 prior lines of therapy for metastatic disease, based on the findings from the phase 3 ASCENT study (NCT02574455). The study demonstrated that sacituzumab govitecan, the first ADC approved specifically in mTNBC, had induced an objective response rate (ORR) of 33.3% (95% CI, 24.6%-43.1%), and the clinical benefit rate was 45.4%, which included stable disease for at least 6 months.

The immune checkpoint inhibitor pembrolizumab plus chemotherapy was approved for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1, and this news was joined by approval of the PD-L1 Immunohistochemistry (IHC) 22C3 pharmDx as a companion diagnostic for identifying patients likely to derive benefit from this therapy. The FDA granted this approval based on the findings from the phase 3 KEYNOTE-355 clinical trial (NCT02819518), which showed statistically significant and clinically meaningful improvement in the median progression-free survival (PFS) of 9.7 months with pembrolizumab and chemotherapy compared with 5.6 months in the chemotherapy-alone arm (HR, 0.65; 95% CI, 0.49-0.86; one-sided P =.0012).

Among other updates in breast cancer, the combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) by subcutaneous injection was approved by the FDA in June 2020 for the treatment of patients with HER2-positive breast cancer that has spread to other parts of the body, as well as for the treatment of adult patients with early HER2-positive breast cancer.This approval, which came 4 months ahead of the PDUFA date, is the first regimen approved for subcutaneous administration that contains 2 monoclonal antibodies. In the FeDeriCa study (NCT03493854), Phesgo was found to have comparable efficacy and safety to the intravenous regimen of pertuzumab and trastuzumab, meeting the studys primary end point of non-inferiority.

There have been a lot of fantastic FDA approvals in the hematologic malignancy space, and obviously, we have to think about multiple myeloma, said Naveen Pemmaraju, MD, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in an interview with Targeted Oncology. When I started out as a faculty 10 years ago, there were just not that many drugs approved, and so in the multiple myeloma space now as a consequence of 5 to 10 years of clinical trials, many of which were negative, we are seeing the appearance of some of these drugs.

Multiple myeloma saw approval of a number of new indications throughout 2020, including the May 2020 approval ofdaratumumab in combination with hyaluronidase-fihj (Darzalex Faspro) as treatment of adult patients with newly diagnosed or relapsed/refractory multiple myeloma, allowing a subcutaneous dosing of daratumumab. The regimen is approved under several indications for patients with multiple myeloma based on findings from the phase 3 COLUMBIA (NCT03277105) and the PLEIADES (NCT03412565) clinical trials. This approval offers patients a more convenient therapeutic option as the fixed-dose injection is administered in approximately 3 to 5 minutes, considerably reducing the treatment burden for these patients.

The immunoconjugate targeting B-cell maturation antigen (BCMA) belantamab mafodotin-blmf (GSK2857916; Blenrep) gained approval in August 2020, for the treatment of patients with relapsed/refractory multiple myeloma who previously received at least 4 prior lines of therapy, which should include an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.This is the first anti-BCMA therapy available for these patients anywhere in the world, which was supported by a unanimous vote from the FDAs Oncologic Drugs Advisory Committee. Based on findings from the phase 2 DREAMM 2 clinical trial (NCT03525678) exploring 2.5-mg/kg and 3.4-mg/kg doses, the lower dose received the FDAs recommendation as an intravenous infusion given over approximately 30 minutes once every 3 weeks.

Selinexor, the only nuclear export inhibitor approved by the FDA for use in 2 hematologic malignancies, generated excitement in the field. This includes the triplet regimen of selinexor with bortezomib/dexamethasone in multiple myeloma that gained approval in December 2020, as well as the accelerated approval for single-agent treatment with selinexor in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, who have had at least 2 prior systemic therapies, including patients with DLBCL arising from follicular lymphoma. This marks the only single-agent oral therapy approved for patients with relapsed/refractory DLBCL.

We saw a lot of movement in the DLBCL space. Up until before CAR T was approved, frankly, we had almost nothing besides chemotherapy. Now in the span of a year, we not only have CAR T-cell therapy, but we have a couple of other agents including tafasitamab which is in combination with lenalidomide and is an active antibody against CD19, Andrew M. Evens, DO, MSc, of the Rutgers Cancer Institute of New Jersey, told Targeted Oncology. Selinexor is the other FDA-approved agent that is an option for patients, so its promising to me in a very difficult disease, especially when relapsed/refractory, just to have now a multitude of agents approved.

The combination of tafasitamab-cxix (Monjuvi) with lenalidomide (Revlimid) was approved for the treatment of adultpatients with relapsed/refractory DLBCL not otherwise specified, including disease arising from low-grade lymphoma and patients who are not eligible for autologous stem cell transplant. The accelerated approval was granted on the basis of findings from the phase 2 L-MIND study (NCT02399085) on the safety and efficacy, as well as the observational retrospective cohort RE-MIND study (NCT04150328) on the real-world use of tafasitamab, the CD19-directed monoclonal antibody.

The approval of tafasitamab and lenalidomide came up this year, and that was certainly a very exciting approval. It is a very innovative chemotherapy-free approach to treatment of patients with relapsed/refractory DLBCL, Alexey V. Danilov, MD, PhD, associate professor of medicine at the Oregon Health & Science University, said to Targeted Oncology. CAR T-cell therapy in mantle cell lymphoma [MCL] has been approved this year as well, and that is also life changing for patients with MCL, where we've had very limited options in those who progressed on ibrutinib or ibrutinib and venetoclax. That's a life-changing option.

The autologous CD19-directed CAR T-cell therapy brexucabtagene autoleucel (formerly KTE-X19; Tecartus) received FDA approval for the treatment of adult patients with relapsed or refractory MCL in July 2020, based on findings from the phase 2 ZUMA-2 clinical trial (NCT02601313). According to Evens, the ORR among the first 60 patients treated and followed for at least 7 months was 93% (95% CI, 84%-98%), and the overall ORR was 85%. The 1-year PFS rate was 61%, and the estimated 1-year OS rate was 83%. Findings demonstrated cytokine release syndrome was observed in 91% of patients with 15% being grade 3 or higher in severity and none being fatal. Neurologic events, another notable side effect associated with CAR T-cell therapy, were observed in 63% with 31% being grade 3 and none being fatal.

Not every patient needs next-generation sequencing, but there are some cancer types where you can make a strong argument that is becoming almost mandatory, said Lewis. A great example from this also would be biliary tract cancers. With cholangiocarcinoma and gallbladder cancer, we know that they are underneath the umbrella groups of highly targetable mutations, whether it's IDH1 or FGFR2. Now, thankfully, it's not just an academic exercise to find the mutation because now we have a drug to pair with it, so another FDA approval I would call attention to was pemigatinib [Pemazyre] for FGFR2-driven cholangiocarcinoma because when I started, there was literally 1 drug for biliary tract cancer, gemcitabine, and now slightly over a decade later, there are a host of possibilities.

Pemigatinib received approval in April 2020, for the treatment of adult patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma who harbor an FGFR2 fusion or rearrangement, representing the first approved treatment for this indication. Findings from cohort A of the phase 3 FIGHT-202 study (NCT02924376) supported this approval, demonstrating an ORR of 36% and a median duration of response of 9.1 months in the multicenter, open-label single-arm study.

The combination of atezolizumab (Tecentriq) plus bevacizumab (Avastin) was approved as treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not had a prior systemic therapy, based on findings from the phase 3 IMbrave150 study (NCT03434379). This study demonstrated a reduced risk of death by 42% with the combination compared with sorafenib (Nexavar) alone (HR, 0.58; 95% CI, 0.42-0.79; P =.0006). Compared with standard of care sorafenib, this regimen is the first to markedly improve survival in the frontline setting for patients with HCC in several years.

In addition, the treatment landscape for patients withHCC was enriched with an approval in March 2020 of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) in patients who have been previously treated with sorafenib. This approval allows for a new second-line option for patients with advanced HCC that has demonstrated promising improvements in OS, according to findings from the phase 1/2 CheckMate-040 study (NCT01658878). This study showed the longest duration of OS in the second-line setting for advanced HCC tested in clinical trials.

Patients with colorectal cancer (CRC) also saw a couple of new additions to the armamentarium, with 1 notable approval being the combination of encorafenib (Braftovi) and cetuximab (Erbitux) as treatment for patients with metastatic CRC with aBRAFV600E mutation, as detected by an FDA-approved test, after prior therapy. The combination received its approval from the FDA based on findings from the phase 3 BEACON CRC study (NCT02928224), which showed significant improvements in OS and a higher response rate compared with standard treatment. Shortly after this news, the FDA granted approval to the therascreen BRAF V600E Kit (therascreen BRAF V600E RGQ PCR Kit) as a companion diagnostic for this regimen.

In the field of GU cancers, the FDA granted several approvals in 2020, providing more treatment options and hope for physicians treating patients with various diseases. In particular, several approvals in prostate cancer stood out, as well as the first and only approval of an immunotherapy that has demonstrated significant overall survival (OS) benefit in the frontline setting in a phase 3 study of bladder cancer; the FDA granted approval to frontline maintenance avelumab (Bavencio) as treatment of patients with locally advanced or metastatic urothelial carcinoma who have not progressed with frontline platinum-based chemotherapy. Avelumab maintenance extended the OS by 50% compared with best supportive care in the phase 3 JAVELIN Bladder 100 study (NCT02603432).

Overall, in my opinion, this is practice-changing because right now instead of finishing chemotherapy frontline and waiting until progression happens, we can utilize avalumab based on this study as a switch maintenance frontline approach, Petros Grivas, MD, PhD, 1 of the principal investigators in the JAVELIN Bladder 100 trial, told Targeted Oncology.

The study demonstrated a 7.1-month improvement in the median OS with frontline avelumab maintenance and best supportive care versus best supportive care alone. The median OS was 21.4 months with avelumab (95% CI, 19.9-26.1) versus 14.3 months in the control arm (95% CI, 12.9-17.9), which was a statistically significant improvement with a 31% reduction in the risk of death in the overall population (HR, 0.69; 95% CI, 0.56-0.86; 2-sidedP= .001).

In prostate cancer, the approval of 2 PARP inhibitors excited the field. In May 2020, the FDA approved olaparib (Lynparza) for the treatment of patients with metastatic castration-resistant prostate cancer(mCRPC) who have deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene mutations and have progressed following prior therapy with a new hormonal agent. The approval of this PARP inhibitor was based on findings from the phase 3 PROfound clinical trial, which demonstrated a 66% reduction in the risk of disease progression or death with olaparib versus enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in patients with BRCA1/2 or ATM mutations.

A few days prior to this approval, rucaparib (Rubraca) received FDA approval for adult patients with mCRPC who have a deleterious BRCA mutation (germline and/or somatic)-associated disease and have received prior androgen receptor-directed therapy and a taxane-based chemotherapy. The TRITON trials provided supportive data for this approval, exploring the use of rucaparib in patients with mCRPC and alterations in HRR-related genes.

Olaparib was approved in prostate cancer, and rucaparib also, so around summertime, there were 2 approvals issued by the FDA. The companion diagnostic was also approved for testing for the patients, said Maha Hussain, MD, who is the Genevieve E. Teuton Professor of Medicine in the Division of Hematology and Oncology, Department of Medicine, and deputy director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine, in an interview with Targeted Oncology. What I'm looking forward to is more approvals from the FDA in prostate cancer. I have to say in my career time, the last 10 years have been really tremendous in terms of the approvals from the FDA in the castration-resistant space. It's exciting times. We've been set back by COVID-19, but I do think that we are on a move forward and an upward ladder, so to speak, in terms of better research, and looking forward to much better times and 2021 and onwards.

The FoundationOneLiquid CDx approval was expanded as a companion diagnostic for olaparib in November 2020. The test was initially granted approval in August 2020 for the indication of patients with any solid tumor. This olaparib indication followed news from October 2020, indicating FoundationOne CDx as a companion diagnostic to identify patients who may receive benefit from rucaparib, alectinib (Alecensa), or alpelisib (Piqray), which are approved in different solid tumors. In the prostate cancer space, the companion diagnostic is used to identify BRCA1/2 and ATM genes in patients with mCRPC who are eligible for treatment with olaparib.

There is a lot of excitement about PARP inhibitors, and there are many PARP inhibitors right now that are undergoing evaluation in prostate cancer, which is exciting, said Hussain. The research in prostate cancer has really blossomed in an incredible way at multiple fronts, and so I do think we're seeing acceleration in terms of the research and its outcomes.

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Experts Reflect on Most Impactful FDA Moves of 2020 in Solid Tumors, Hematologic Malignancies - Targeted Oncology

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FDA Resumes eIND Approval for Severe-to-Critical COVID-19 Patients Use of Vyrologix (leronlimab) Following Full Enrollment in CytoDyn’s Phase 3 Trial…

Monday, December 28th, 2020

FDAs decision will enable CytoDyn to respond to ongoing requests for leronlimab until Phase 3 trial data is unblinded

VANCOUVER, Washington, Dec. 22, 2020 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTC.QB: CYDY), (CytoDyn or the Company"), a late-stage biotechnology company developing Vyrologix (leronlimab-PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced today a treating physician has received authorization from the U.S. Food and Drug Administration (FDA) to administer leronlimab for a COVID-19 patient under emergency IND (eIND).

Nader Pourhassan, Ph.D., President and Chief Executive Officer of CytoDyn, commented, We are very thankful the FDA is allowing severe-to-critical COVID-19 patients access to Vyrologix (leronlimab) again under eIND while we await the unblinding of data from our recently completed Phase 3 registrational trial. We are receiving daily requests from families seeking our drug for a loved one with COVID-19. In recent months, leronlimab received more than 60 eIND authorizations from the FDA, and during the pendency of our COVID-19 trials, we deferred seeking authorizations for eINDs in order to accelerate the pace of enrollment. Now that enrollment has been completed, we are pleased to be able to assist once again and remain hopeful the upcoming results of our Phase 3 trial will enable leronlimab to be more readily available for severe-to-critical COVID-19 patients.

CytoDyns Phase 2b/3 trial to evaluate the efficacy and safety ofleronlimabfor patients with severe-to-critical COVID-19 indications is a two-arm, randomized, double blind, placebo controlled, adaptive design multicenter study. Patients are randomized to receive weekly doses of 700 mg leronlimab, or placebo. Leronlimab and placebo are administered via subcutaneous injection. The study has three phases: Screening Period, Treatment Period, and Follow-Up Period. The primary outcome measured in this study is: all-cause mortality at Day 28. Secondary outcomes measured are: (1) all-cause mortality at Day 14, (2) change in clinical status of subject at Day 14, (3) change in clinical status of subject at Day 28, and (4) change from baseline in Sequential Organ Failure Assessment (SOFA) score at Day 14.

About Coronavirus Disease 2019 CytoDyn completed its Phase 2 clinical trial (CD10) for COVID-19, a double-blinded, randomized clinical trial for mild-to-moderate patients in the U.S. which produced statistically significant results for NEWS2. CytoDyn completed enrollment of 390 patients in its Phase 2b/3 randomized clinical trial for the severe-to-critically ill COVID-19 population and expects to release results in mid-January 2021.

About Leronlimab (PRO 140) The FDA has granted a Fast Track designation to CytoDyn for two potential indications of leronlimab for critical illnesses. The first indication is a combination therapy with HAART for HIV-infected patients and the second is for metastatic triple-negative breast cancer. Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that is important in HIV infection, tumor metastases, and other diseases, including NASH.Leronlimab has completed nine clinical trials in over 800 people and met its primary endpoints in a pivotal Phase 3 trial (leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients).

In the setting of HIV/AIDS, leronlimab is a viral-entry inhibitor; it masks CCR5, thus protecting healthy T cells from viral infection by blocking the predominant HIV (R5) subtype from entering those cells. Leronlimab has been the subject of nine clinical trials, each of which demonstrated that leronlimab could significantly reduce or control HIV viral load in humans. The leronlimab antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements compared with daily drug therapies currently in use.

In the setting of cancer, research has shown that CCR5 may play a role in tumor invasion, metastases, and tumor microenvironment control. Increased CCR5 expression is an indicator of disease status in several cancers. Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer. Leronlimab reduced human breast cancer metastasis by more than 98% in a murine xenograft model. CytoDyn is, therefore, conducting a Phase 1b/2 human clinical trial in metastatic triple-negative breast cancer and was granted Fast Track designation in May 2019.

The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation. It may be crucial in the development of acute graft-versus-host disease (GvHD) and other inflammatory conditions. Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells.CytoDyn is currently conducting a Phase 2 clinical study with leronlimab to support further the concept that the CCR5 receptor on engrafted cells is critical for the development of acute GvHD, blocking the CCR5 receptor from recognizing specific immune signaling molecules is a viable approach to mitigating acute GvHD. The FDA has granted orphan drug designation to leronlimab for the prevention of GvHD. Due to the lack of patients during the COVID-19 pandemic, the Company is closing down its Phase 2 trial for acute GvHD.

About CytoDyn CytoDyn is a late-stage biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. CCR5 appears to play a critical role in the ability of HIV to enter and infect healthy T-cells. The CCR5 receptor also appears to be implicated in tumor metastasis and immune-mediated illnesses, such as GvHD and NASH.

CytoDyn has successfully completed a Phase 3 pivotal trial with leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. The FDA met telephonically with Company key personnel and its clinical research organization and provided written responses to the Companys questions concerning its recent Biologics License Application (BLA) for this HIV combination therapy in order to expedite the resubmission of its BLA filing for this indication.

CytoDyn has completed a Phase 3 investigative trial with leronlimab as a once-weekly monotherapy for HIV-infected patients. CytoDyn plans to initiate a registration-directed study of leronlimab monotherapy indication. If successful, it could support a label extension. Clinical results to date from multiple trials have shown that leronlimab can significantly reduce viral burden in people infected with HIV. No drug-related serious site injection reactions reported in about 800 patients treated with leronlimab and no drug-related SAEs reported in patients treated with 700 mg dose of leronlimab. Moreover, a Phase 2b clinical trial demonstrated that leronlimab monotherapy can prevent viral escape in HIV-infected patients; some patients on leronlimab monotherapy have remained virally suppressed for more than six years.

CytoDyn is also conducting a Phase 1b/2 clinical trial with leronlimab in metastatic triple-negative breast cancer. More information is at http://www.cytodyn.com.

Forward-Looking StatementsThis press release contains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as "believes," "hopes," "intends," "estimates," "expects," "projects," "plans," "anticipates" and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. Forward-looking statements specifically include statements about leronlimab, its ability to have positive health outcomes, the possible results of clinical trials, studies or other programs or ability to continue those programs, the ability to obtain regulatory approval for commercial sales, and the market for actual commercial sales. The Company's forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties including: (i) the sufficiency of the Company's cash position, (ii) the Company's ability to raise additional capital to fund its operations, (iii) the Company's ability to meet its debt obligations, if any, (iv) the Company's ability to enter into partnership or licensing arrangements with third parties, (v) the Company's ability to identify patients to enroll in its clinical trials in a timely fashion, (vi) the Company's ability to achieve approval of a marketable product, (vii) the design, implementation and conduct of the Company's clinical trials, (viii) the results of the Company's clinical trials, including the possibility of unfavorable clinical trial results, (ix) the market for, and marketability of, any product that is approved, (x) the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Company's products, (xi) regulatory initiatives, compliance with governmental regulations and the regulatory approval process, (xii) general economic and business conditions, (xiii) changes in foreign, political, and social conditions, and (xiv) various other matters, many of which are beyond the Company's control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form 10-K, and any risk factors or cautionary statements included in any subsequent Form 10-Q or Form 8-K, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release.

CONTACTSInvestors: Michael MulhollandOffice: 360.980.8524, ext. 102mmulholland@cytodyn.com

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FDA Resumes eIND Approval for Severe-to-Critical COVID-19 Patients Use of Vyrologix (leronlimab) Following Full Enrollment in CytoDyn's Phase 3 Trial...

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Magenta Therapeutics Announces Commencement of First Phase 2 Clinical Trial of MGTA-145 for Stem Cell Mobilization, Oral Presentation of MGTA-145…

Saturday, December 12th, 2020

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Magenta Therapeutics (NASDAQ: MGTA), a clinical-stage biotechnology company developing novel medicines to bring the curative power of stem cell transplant to more patients, today announced final clinical results from its earlier completed Phase 1 clinical trial as well as development updates for its MGTA-145 stem cell mobilization therapy, including commencement of enrollment in a Phase 2 clinical trial in multiple myeloma, and its plans for a Phase 2 clinical trial in allogeneic stem cell transplant for patients with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and myelodysplastic syndrome (MDS). The company also previously announced a clinical collaboration with bluebird bio to evaluate MGTA-145 for mobilizing and collecting stem cells in adults and adolescents with sickle cell disease (SCD). Additional preclinical results were also presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, taking place virtually from December 5-8, 2020, on the Magenta conditioning platform, including MGTA-117 program, which is a targeted antibody-drug conjugate (ADC) to prepare patients for stem cell transplant.

MGTA-145 Advancement to Phase 2 Development in Blood Cancers

The company announced that enrollment has started and is ongoing in a Phase 2 clinical trial of MGTA-145, used in combination with plerixafor, to mobilize and collect stem cells for autologous stem cell transplantation of multiple myeloma patients at Stanford University. Magenta expects that this trial will provide patient-level data on stem cell mobilization and collection, characteristics of the mobilized graft and engraftment in patients with multiple myeloma.

Additionally, through a collaboration with the National Marrow Donor Program/Be The Match, a global leader in facilitating allogeneic hematopoietic stem cell transplantation, Magenta plans to initiate a Phase 2 clinical trial in early 2021 using MGTA-145 to mobilize and collect stem cells from allogeneic donors for transplant in patients with AML, ALL and MDS. Allogeneic stem cell transplant provides a potentially curative therapeutic option for patients with these diseases. This clinical trial will evaluate stem cell mobilization, collection, cell quality, engraftment and the potential for reduced Graft-versus-Host Disease (GvHD), which is of particular importance in the allogeneic transplant setting.

MGTA-145 in Sickle Cell Disease

Magenta Therapeutics recently announced an exclusive clinical collaboration with bluebird bio to evaluate the utility of MGTA-145, in combination with plerixafor, for the mobilization and collection of stem cells in adults and adolescents with SCD.

The data from this clinical trial could provide proof-of-concept for MGTA-145, in combination with plerixafor, as the preferred mobilization regimen for patients with SCD. bluebird bios experience with plerixafor as a mobilization agent in SCD aligns with Magentas combination therapy approach, utilizing MGTA-145 plus plerixafor with potential for safe, rapid and reliable mobilization of sufficient quantities of high-quality stem cells to improve outcomes associated with stem cell transplantation.

MGTA-145 Presentations at ASH

Magenta presented final clinical data from its MGTA-145 stem cell mobilization Phase 1 clinical trial in healthy volunteers at the ASH Annual Meeting. All primary and secondary endpoints were met in the study completed earlier this year.

The results demonstrate that a single dose of MGTA-145, in combination with plerixafor, rapidly and reliably mobilized high numbers of stem cells in a single day without the need for G-CSF for potential use in diseases that can benefit from autologous and/or allogeneic stem cell transplantation. The additional data also offer further confirmation that MGTA-145, in combination with plerixafor, was well tolerated and provides a rapid and reliable method to obtain large numbers of hematopoietic stem cells. Transplant of these cells in preclinical models resulted in enhanced, durable engraftment, in addition to highly immunosuppressive properties, leading to reduced GvHD.

Results from this study provide a robust dataset and proof of concept that MGTA-145, in combination with plerixafor, provides rapid and robust mobilization of stem cells and that these cells have better engraftment potential, are able to be gene modified and engraft and reduce GvHD in preclinical models compared to cells mobilized with other available agents. The data reinforce the availability of compelling opportunities for development in both the autologous and allogeneic transplant settings, said John Davis Jr., M.D., M.P.H., M.S., Head of Research & Development and Chief Medical Officer, Magenta Therapeutics.

The data were presented by Steven M. Devine, MD, Chief Medical Officer of the National Marrow Donor Program/Be The Match and Associate Scientific Director of the CIBMTR (Center for International Blood and Marrow Transplant Research).

Conditioning Program (MGTA-117 and CD45-ADC) Presentations at ASH

Magenta also provided updates on its conditioning platform at the ASH Annual Meeting, including MGTA-117 and CD45-ADC programs. Preclinical data from a study of MGTA-117 demonstrate that it is an effective, potent conditioning agent for transplant with anti-leukemic activity, significantly decreasing tumor burdens, leading to delayed tumor growth and increased median survival rates in animal models of AML. Ongoing GLP toxicology and GMP manufacturing progress continue to be supportive of advancing MGTA-117 towards an IND filing in AML and MDS.

Additionally, preclinical data from a study of Magentas CD45-ADC, a CD45-targeted conditioning agent designed to remove the cells that cause autoimmune diseases to enable curative immune reset, demonstrated the ability to achieve successful outcomes as a single agent in the most challenging disease model through fully mismatched allogeneic hematopoietic stem cell transplant, where only radiation or combinations of toxic chemotherapies are available, potentially providing patients the option of a reduced toxicity conditioning regimen. The company continues to evaluate this program preclinically.

About MGTA-145

MGTA-145 is being developed in combination with plerixafor to harness complementary chemokine mechanisms to mobilize hematopoietic stem cells for collection and transplantation. This new combination has the potential to be the preferred mobilization regimen for rapid and reliable mobilization and collection of hematopoietic stem cells to improve outcomes in autologous and allogeneic stem cell transplantation, which can rebuild a healthy immune system for patients with blood cancers, genetic diseases and autoimmune disorders.

MGTA-145 has the potential to replace the current standard of care for patients and allogeneic donors who currently rely on the use of granulocyte-colony stimulating factor (G-CSF) alone or in combination with plerixafor, which can take up to five days or longer to mobilize sufficient numbers of stem cells, often resulting in significant bone pain and other side effects.

About Magenta Therapeutics

Magenta Therapeutics is a clinical-stage biotechnology company developing medicines to bring the curative power of immune system reset through stem cell transplant to more patients with blood cancer, genetic diseases and autoimmune diseases. Magenta is combining leadership in stem cell biology and biotherapeutics development with clinical and regulatory expertise, a unique business model and broad networks in the stem cell transplant world to revolutionize immune reset for more patients.

Magenta is based in Cambridge, Mass. For more information, please visit http://www.magentatx.com.

Follow Magenta on Twitter: @magentatx.

Forward-Looking Statement

This press release may contain forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as may, will, could, should, expects, intends, plans, anticipates, believes, estimates, predicts, projects, seeks, endeavor, potential, continue or the negative of such words or other similar expressions can be used to identify forward-looking statements. The express or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation risks set forth under the caption Risk Factors in Magentas Annual Report on Form 10-K filed on March 3, 2020, as updated by Magentas most recent Quarterly Report on Form 10-Q and its other filings with the Securities and Exchange Commission. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although Magenta believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. Moreover, except as required by law, neither Magenta nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements included in this press release. Any forward-looking statement included in this press release speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

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Magenta Therapeutics Announces Commencement of First Phase 2 Clinical Trial of MGTA-145 for Stem Cell Mobilization, Oral Presentation of MGTA-145...

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