StemCell Therapy

Immunotherapy is a form of cancer treatment that is now being used to treat many different types of cancer. However, stimulating the immune system through activated t-cells may result in T-cells acting upon other body systems or organs, unable to distinguish the cancer, causing inflammation and other adverse events (AEs).

Beth Eaby-Sandy, nurse practitioner at the Abramson Cancer Center, spoke at theCUREpatient-focused sessions held in tandem with theAnnual New York Lung Cancers Symposiumabout immunotherapy AE management. Your body is in a constant state of self-tolerance, she said. These drugs that we use do 1 of 2 things. We are either trying to stimulate the immune system to kill cancer [or] were trying to stop cancer from alluding the immune system.

Any body system or organ can become inflamed or damaged by the overactivity of T-cells. Some types of immunotherapy may result in severe inflammation-related reactions. If patients are experiencing any AEs from immunotherapy, they should be seen and treated immediately.

Hypothyroidism is one of the most common AEs caused byimmunotherapy. Once immunotherapy disables the thyroid gland, it is permanent, and the patient will not regain thyroid function and must then be on levothyroxine for life. Patients may also experience hyperthyroidism, though less common, causing a patient to over-secrete thyroxine and can lead to hypothyroidism if prolonged.

Fatigue is commonly reported in patients who receive immunotherapy, though it is unclear as to what causes it. Another common AE of immunotherapy can be arthritis, induced by T-cells attacking the joints. Low-dose steroids or other drugs traditionally used to manage arthritis are recommended for patients. Nausea and diarrhea (without colitis) have been reported, though not necessarily known why.

More AEs include:

Lowering of blood counts is not commonly seen in immunotherapy as it is in chemotherapy. Hair loss should also not occur, though hair thinning may.

Dont be afraid of immunotherapy! The majority of these patients do very, very well for often long periods of time, so its not something to be afraid of. We can usually manage these side effects very easily, Eaby-Sandy said.

Reference:

Eaby-Sandy. Immunotherapy Adverse Effect Management. Presented at:CUREpatient-focused sessions held in tandem with theAnnual New York Lung Cancers Symposium; November 9, 2019; New York, New York.

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Adverse Events To Be Aware of With Immunotherapy Treatment in Lung Cancer - Cancer Network

MENLO PARK, Calif.--(BUSINESS WIRE)--Personalis, Inc. (Nasdaq: PSNL), a leader in advanced genomics for cancer, today announced that the company will participate in the AACR Tumor Immunology and Immunotherapy conference at the Boston Marriott Copley Place in Boston, MA, November 17-20, including poster presentations on November 18th and 19th.

The company will showcase ImmunoID NeXT, the first platform to enable comprehensive analysis of both a tumor and its immune microenvironment from a single sample. ImmunoID NeXT can be used to investigate the key tumor- and immune-related areas of cancer biology, consolidating multiple oncology biomarker assays into one and maximizing the biological information that can be generated from a precious tumor specimen.

Following is a list of abstracts that will be presented at the meeting.

Scientific Poster Presentations

Poster Number

Title & Presenter

Day & Time

Location

A19

HLA allele-specific loss of heterozygosity detectionusing augmented exome capture approach

Presenter: Rachel Marty Pyke, Ph.D.

November 18:12:30 PM 3:00 PM

Back Bay

B18

Exome scale liquid biopsy monitoring of putativeneoantigens and genomic biomarkers in patientson anti-PD-1 therapy in squamous cell carcinoma ofthe head and neck

Presenter: Charles Abbott, Ph.D.

November 19:4:30 PM 7:00 PM

Back Bay

Personalis will also be exhibiting during the conference (Exhibit # 10). Representatives will be available to answer questions about the companys cancer immunogenomics services.

About Personalis, Inc.

Personalis, Inc. is a growing cancer genomics company transforming the development of next-generation therapies by providing more comprehensive molecular data about each patients cancer and immune response. The companys NeXT Platform is designed to adapt to the complex and evolving understanding of cancer, providing its biopharmaceutical customers with information on all of the approximately 20,000 human genes, together with the immune system, from a single tissue sample. Personalis also provides genomic information to the VA Million Veterans Program as part of their goal to sequence over a million veteran genomes. The Personalis Clinical Laboratory is GxP aligned as well as CLIA88-certified and CAP-accredited. For more information, please visit http://www.personalis.com and follow Personalis on Twitter (@PersonalisInc).

Link:
Personalis, Inc. to Present New Data at the AACR Tumor Immunology and Immunotherapy Conference - Business Wire

According to results of a study presented at the Society of Immunotherapy for Cancer (SITC) Annual Meeting 2019 in National Harbor, Maryland, a next-generation sequencing (NGS)-based approach was capable of simultaneously characterizing all 7 T- and B-cell receptor chains, and also provided potential predictors of treatment benefit in patients with renal cell carcinoma (RCC).

An extensive repertoire of T-celland B-cell populations that expresses a wide range of antigen-specificreceptors are at the heart of the adaptive immune system. More specifically, T-and B-cell receptor diversity is created through random recombination ofvariable (V), diversity (D), and joining (J) gene segments, or V and J genesegments alone. Hence, at any given point in time, the T-cell and B-cellrepertoire in a single individual is represented by a huge number of differentT- and B-cell clones or clonotypes.

Recently, high-throughput NGS hasbeen used to profile the diversity of the T-cell and B-cell repertoire inindividuals. One approach to this process involves RNA-based multiplexpolymerase chain reaction (PCR) amplification of V-D-J or V-J gene segments,followed by high-throughput sequencing of the PCR amplicons, and subsequentbioinformatic interpretation of the reads obtained through NGS.

In thisstudy, a novel quantitative PCR-based NGS technique was reported to allow forthe simultaneous characterization of RNA associated with the loci of all 7 T-and B-cell receptors (ie, the alpha, beta, gamma, and delta chains of theT-cell receptor; and immunoglobulin (Ig)-K and Ig-L of the B-cell receptor)collected from both peripheral blood mononuclear cells (PBMCs) andformalin-fixed paraffin-embedded (FFPE) specimens from patients undergoingtreatment for RCC.

Furthermore,this process was carried out as single reaction that circumvented the problemof PCR dimer artifacts.

Results of this study suggestedthat pretreatment diversity in T-cell receptor alpha and beta chains, as wellas the B-cell to T-cell expression ratio, may be useful predictors of treatmentresponse in patients with RCC.

Reference

Depinet M, Pan W, Wu S, et al. All-in-One, quantitative immune repertoire profiling of PBMC and FFPE for renal cancer treatment evaluation. Presented at the Society for Immunology of Cancer (SITC) Annual Meeting 2019. November 6-10, 2019. National Harbor, MD. Abstract P87.

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High-Throughput Multichain Immune Repertoire Sequencing for Prediction of Treatment Response in Renal Cell Carcinoma - Cancer Therapy Advisor

For most patients,sudden cardiac death iscompletely unexpected, according toDr. Amit Khera, a cardiologist at Massachusetts General Hospital.

Its always particularly devastating because many dont have prior symptoms. Their first symptom is actually dropping dead, Khera said. The question is can we find these people before something really bad happens?

Many scientists, including Khera, theorizedthat one way to find people who might suffer these sudden cardiac deaths fatal events related to an abrupt cardiovascular failure could betheir genetics.

We always had a hunch that maybe there was something in their DNA that predisposed them to this tragedy, he said.

Now, he and his colleagues believe theyve found 14 different gene variants, spread across seven genes that may put their carriers at greater risk for sudden heart death.

The researchers made this discovery by sequencingthe genes of 600 people who died from sudden cardiac death and600 people of the same age whowere healthy. Khera said they focused on 49 genesalreadyknown to be important for cardiovascular disease.

These genes contribute to any of the four major causes [for sudden cardiac death], he said. Sometimes its a weak heart and the pumping function is not quite right. The second is a heart attack. The third is a problem with the hearts rhythm. The last is a tear in a major blood vessel.

After a geneticist on the team analyzed the genetic data, Khera said 14 different versions of 7 genes stood out.

These 14 variants were found in 15 people. Whats really striking is that all 15 people were sudden cardiac death cases and zero were [healthy], he explained.

The team reported their findings Saturday in the Journal of the American College of Cardiology.

After identifying the specific gene variants, theresearchers looked ata larger database of 4,000 individuals. They found that about 1% of the population without a history of heart disease carries them.

Its a really small percent of people, but an important percent," said Khera. "These people are predisposed to sudden cardiac death, and if we can find them then we have tools to prevent disease onset.

Carrying one of these gene variants doesn't mean a person is certain to suffer from sudden cardiac death. But over a period of 15 years, Kherasaid, peoplewho carry at least one of the 14 gene variantsare three times more likely to succumb tosudden cardiac death.

In most cases, doctors saysudden cardiac death arises from preventable causes.

Most of the gene variations underlying [sudden cardiac death] are related to the electrical rhythm of the heart going chaotic or haywire," said Dr. Eric Topol, vice president of Scripps Research and a cardiologist who did not work on the study.

"There are many ways you can prevent this occurrence if you know a person has a high risk mutation, Topol said. Medications or a device like a defibrillator or pacemaker can fix the underlying problem.

There are likely many more mutations that increase the risk for sudden cardiac death.

The more we find of these, the more confident we are that they are the real deal, the better we will, in the future, be at preventing these catastrophes, Topol said. So, I think this is really important work.

And not every sudden cardiac death strikes healthy individuals with no previous history of heart disease, Khera added.

Of course, important lifestyle factors play a role, like smoking over the course of a lifetime or not well controlled blood pressure, he said.

But often, families and friends of those who die from sudden cardiac death dont get a reason for why it happened.

The DNA can provide an explanation as to why this happened, Khera said. And even more importantly, this persons family members may also have the gene variant, and if they know about it then they can take preventative measures.

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Knowing If You Have One Of These 14 Genetic Mutations May Help Prevent Sudden Cardiac Death - WBUR

Mining the rich uncharted territory of the genome, or genetic material of a cancer cell, has yielded gold for Princess Margaret Cancer Centre scientists: new protein targets for drug development against prostate cancer.

Using state-of-the-art, whole-genome sequencing technologies on prostate tumour samples, researchers at the Princess Margaret focused on the often overlooked noncoding regions of the genome: vast stretches of DNA that are free of genes (i.e. that do not code for proteins), but nonetheless harbour important regulatory elements that determine if genes are turned on or off.

Previously dismissed as "junk" DNA, noncoding regions were once thought to have little to offer for a cure against cancer.

But this never dissuaded Dr. Mathieu Lupien, Senior Scientist, Princess Margaret Cancer Centre, to commit his research program to the study of the noncoding genome.

"We are exploring uncharted territory," says Dr. Lupien, who is also an Associate Professor in the Department of Medical Biophysics, University of Toronto, whose lab's tagline is "Decoding cancer through epigenetics."

"Our goal is to conquer cancer in our lifetime. We have to look everywhere including the 'darkest' parts of the genome of cancer cells for that hidden 'gold,'" he says.

In his latest paper, entitled "Cistrome-partitioning reveals convergence of somatic mutations and risk-variants on master transcription regulators in primary prostate tumors," published inCancer Cellon Thursday, Dr. Lupien and a 21-member team of national and international clinicians, scientists, pathologists and computational scientists assessed the role of more than 270,000 mutations found in primary prostate tumours.

They found that these accumulate in specific noncoding regions bound by a specific set of proteins that control the on/off state of genes. Inhibiting these proteins, which Dr. Lupien refers to as "the maestro of the cell," blocks growth of prostate cancer cells, showing their value for drug development.

This represents a new approach that exploits the rich information from all mutations found in tumours, from both coding and noncoding sources. It allows us to prioritize targets for therapy, he explains.

"Just imagine the possibilities the noncoding genome opens up," he adds.

Understanding the non-coding or dark genome is an area of increasing focus for scientists.

In 2003, the Human Genome Project mapped and sequenced the human genome, consisting of all the genes necessary to grow a human being.

It found that about 21,000 protein-coding genes make up about only two per cent of our entire genome the blueprint of life or the human genetic instruction booklet.

And the other 98 per cent of the genome the non-coding (for proteins) portion what role does it play?

Scientists have come to realize that hidden amongst this noncoding DNA are crucial elements that not only control the activity of thousands of genes, but also play a major role in many diseases. Mining this area could provide important sequencing clues for potential cures.

The human genome is incredibly complicated, says Dr. Lupien. He explains that the dark, or as yet undiscovered, portion of the genome contains millions of gene switches, affecting all the cells in our bodies, at various points throughout our lives.

"Now we can start connecting these genetic switches to cancer development to get a more precise understanding of how disease begins and how we can treat it," he says.

Precision medicine currently relies on a few hundred biomarker-drug combination, and we need to expand our list of biomarkers and drugs if we want to deliver on the promise of precision medicine, adds Dr. Lupien. "The inclusion of the noncoding genome in our analysis is a leap in the right direction to achieve our goal," he says.

Reference:Mazrooei, et al. (2019) Cistrome Partitioning Reveals Convergence of Somatic Mutations and Risk Variants on Master Transcription Regulators in Primary Prostate Tumors. Cancer Cell DOI:https://doi.org/10.1016/j.ccell.2019.10.005

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Mining the Genome: Exploring Uncharted Territory To Discover New Drug Targets - Technology Networks

By Stephanie Miceli | Nov. 13, 2019

When Sara Altschule took a 23andMe ancestry test, the results confirmed what she already suspected: She is 77 percent Ashkenazi Jewish. However, months later, after opting into add-on health tests, she received life-changing news: She had a BRCA2 gene mutation, which is particularly prevalent among Ashkenazi Jewish women. Altschules BRCA2 mutation meant her lifetime risk of developing breast cancer is about 69 percent; for ovarian cancer, it is about 17 percent.

As at-home genetic tests grow in popularity, some individuals have expressed concern about the complexities of the results. Speaking about her experience with at-home genetic testing at a recent workshop of the Roundtable on Genomics and Precision Health of the National Academies of Sciences, Engineering, and Medicine, Altschule told attendees, The results not only probably saved my life, but may have also saved the lives of people in my family who now know they are also BRCA2 positive. While empowering for her, she also wishes she had received the results from a genetic counselor not via email.

Traditionally, there have been two main types of genetic testing: traditional tests initiated by a doctor, and direct-to-consumer (at-home) tests. Most people do a combination of both, said keynote speaker Robert Nussbaum, chief medical officer of Invitae. About one-third of people who take an at-home test share the results with a provider, who can make appropriate referrals based on the results, he said.

Knowledge Is Power

After seeing a genetic counselor and getting a more comprehensive blood test, Altschule decided to undergo a preventive double mastectomy at the age of 31. I felt powerless during this process, and I wanted to take my power back. This was the easiest and toughest decision of my life, said Altschule.

Panelist Dorothy Pomerantz, who also received news of her BRCA status via 23andMe, said online test results are not a replacement for a one-to-one conversation with a trusted provider. Pomerantz considers herself lucky to have received actionable information, though she still has complicated feelings about how that information was delivered.

This information is complicated and nuanced. We need someone to walk us through the dark, said Pomerantz. When my genetic counselor confirmed my results, she asked me what I needed in that moment. Did I need to vent? Did I want information? Did I need to be alone or cry?

Affordability Is Part of Accessibility

Aside from having access to genetic testing in the first place, Altschule and Pomerantz acknowledged they had the resources to get immediate follow-up testing and surgery.

What about those who cant get their doctors on the phone? What about those who dont have doctors at all? asked Pomerantz.

Without insurance, someone with a risk of cancer may not have those options, said Sadie Hutson, director of the Cancer Genetics Program at Pikeville Medical Center in Kentucky. In the Appalachian communities where she works, coal mining, the dominant industry, has been linked to high incidences of lung cancer. However, many people have to live with the knowledge of that risk and the inability to act on it.

Affordability of genetic testing is a very real problem, said Hutson.

There is also a dire shortage of genetic counselors in the region, she added. Hutson has partnered with mobile clinics and faith-based organizations that provide genetic testing and counseling free of charge, particularly to the regions Medicaid population. Hutson also noted the importance of offering free follow-up testing to family members.

Panelists discussed the accessibility of direct-to-consumer genetic tests for underserved and rural populations and ways to increase engagement, literacy, and reduce disparities.

Steps Toward Including All of Us

We have a skewed evidence base in human genomics research, said Malia Fullerton, professor of bioethics and humanities at the University of Washington School of Medicine. Because certain populations are underrepresented in research, when they do receive genetic testing, there is a lack of data that they can act on. Joyce Tung, 23andMes vice president of research, acknowledged most of the companys customers are white people of European descent and it wants to change that.

We cant provide information that we dont have, she said. A lack of data can halt progress and new discoveries in diseases that primarily affect diverse communities such as sickle cell disease, which is prevalent in people of African descent. Tung highlighted several initiatives at 23andMe that aim to improve diversity, including the African American Sequencing Project, Global Genetics Project, and the Latino Sequencing Project.

In addition, underrepresented populations are more likely to receive uncertain test results, often because their genetic variants have not been well-studied. As a result, they may experience unnecessary testing or lifestyle changes, or false reassurance, and the psychological burden that comes with it, Fullerton said.

To address the lack of diversity in genetic databases, last year, the National Institutes of Health launched its All of Us research initiative. It aims to collect data from 1 million Americans from various population groups.

The vast majority of 23andMe consumers 80 percent agree to share their data in the hopes of contributing to science and new insights about health and disease. However, the current lack of diversity in genetic databases risks hindering the science.

There is a critical opportunity for multiple sectors to come together to ensure proper inclusion of all individuals in genetic and genomic testing, said Hutson.

Integrating Consumer Genomics into Health Care

Speakers throughout the day acknowledged the challenges around integrating consumer genomics data into clinical care. Consumers often want information fast, but health systems may not be able to quickly provide the confirmation genetic testing following a positive DTC result.

This continuum of care has a lot of access points and a lot of people trying to find pathways, but really it is reflective of the overall health system, said Siobhan Dolan, a professor and vice chair for research at Albert Einstein College of Medicine. Maybe genetics has given people an opportunity to find alternative routes and maybe we could continue to learn from that try to put something together that is continuous.

Visit http://nationalacademies.org/hmd/Activities/Research/GenomicBasedResearch/2019-OCT-29.aspx to view speaker presentations and other information about the Workshop on Exploring the Current Landscape of Consumer Genomics.

Originally posted here:
At-Home DNA Tests Still Need the 'Human Touch,' Say Panelists at Genomics Roundtable Workshop - National Academies of Sciences, Engineering, and...

News

Researcher Tom Cappola tells us about the latest clinical trials and medical breakthroughs to be announced during Scientific Sessions.

Chief of the cardiovascular medicine division in the Perelman School of Medicine at the University of Pennsylvania, Tom Cappola.

For the first time in its near 100-year history, the American Heart Association (AHA)will host its annual meeting in Philadelphia. AHAs Scientific Sessions is the largest cardiovascular meeting in the United States. On November 16-18, the meeting will attract nearly 18,000 attendees from more than 100 countries to the Pennsylvania Convention Center, and an additional two million medical professionals who will participate virtually in lectures and discussions about basic, translational, clinical and population science innovations aimed at reducing disability and deaths caused by cardiovascular disease and stroke.

The American Heart Association is excited to be in Philadelphia, said Michelle Kirkwood, director of National Science Media Relations for AHA. It has been on our wish list for some time, especially since the renovations at the Pennsylvania Convention Center and the citys landmark, robust nonsmoking laws that align directly with the American Heart Associations health and wellness goals. We are excited for our thousands of attendees to visit Philadelphia.

More than 610,000 people die of heart disease in the United States every year, according to the CDC. While heart disease is a leading cause of death for both men and women, it claims the lives of over 400,000 American women each year, or one death every 80 seconds. During the three-day meeting, more than 12,000 leading physicians, scientists, cardiologists and healthcare professionals in the global cardiovascular health community will host 850 educational sessions and more than 4,100 original research presentations to unveil the late-breaking science, clinical trials, and novel therapeutics and pathways that are shaping the future of cardiovascular care.

Its very fitting for Scientific Sessions to be here, chief of the cardiovascular medicine division in the Perelman School of Medicine at the University of Pennsylvania Tom Cappola said. We have the first medical school in the country and the first teaching hospital in the country. It makes sense that these new innovations would be presented in a place where theres already been so much innovation.

Cappola will be one of several Penn researchers leading the Cardiovascular Expert Theater, Innovations in Cardiovascular Therapies session during the meeting. Here are just a few big trends in heart care that Cappola says we can expect to learn more about during this weekends meeting:

Using artificial intelligence to monitor heart health

Artificial intelligence (AI) is having a big impact on cardiovascular care. Results from two preliminary studies to be presented this weekend will show AI can be used to accurately examine electrocardiogram (ECG) test results to possibly predict irregular heartbeat and risk of death. There will also be a presentation on the Apple Heart Study, which found that the Apple Watch and other wearable remote monitoring devices may be capable of detecting atrial fibrillation (aFib), an irregular and often rapid heartbeat that can lead to blood clots, stroke, heart failure and other complications.

Identifying new risk factors for aFib and stroke

George Mason University researchers will present results from two studies that found young people who smoke marijuana regularly have an increased risk of stroke. According to the study findings, young adults between the ages 18 and 44 who reported frequent use of marijuana, cigarettes and e-cigarettes were three times more likely to suffer stroke than young adults who did not smoke marijuana at all. The study also found that African-American males between the ages of 15 and 24 faced the highest risk of being hospitalized for arrhythmia.

In one Penn study to be presented this weekend, researchers found women who are diagnosed with peripartum cardiomyopathy (PPCM) during late pregnancy or within a month following delivery are more likely to experience restored cardiac function and improved outcomes compared to those who are diagnosed later in the postpartum period. The findings underscore the need for increased awareness and monitoring of heart failure symptoms, particularly among black women, who, on average, are diagnosed significantly later than white patients, according to study results.

Making advances in genetics and genomics

Another big trend at this years meeting will be the continued advancement in genetics and genomics, and how thats impacting cardiovascular care.

I think that genomic medicine has arrived and its arriving in waves, but it will ultimately affect all aspects of cardiovascular care, Cappola said. We have lots of people getting their 23andMe for sort of recreational purposes and they dont know what to do with it. But were starting to figure out what to do with that genetic information to improve care.

Another Penn Medicine study to be presented during the meeting will show why taller people may have an increased risk of developing atrial aFib. The research found a strong link between the genetic variants associated with height and ones risk for AFib, for the first time demonstrating that height may be a causal not correlated risk factor for the condition. Researchers hope insight from human genetics in large studies like this one will help them better understand causal risk factors for common disease.

It takes expertise to find links like this. Thats why researchers go to the American Heart Association meetings. You get all the experts together, they share their knowledge and this helps us to actually figure out what to do with this genetic information, Cappola said. Thats true across the board, but its particularly important for genomic medicine as it continues to advance.

Excerpt from:
The American Heart Association's Annual Conference Comes to Philly This Weekend - Philadelphia magazine

A new study led by researchers at Baylor College of Medicine revealed how in utero Zika virus infection can lead to microcephaly in newborns. The team discovered that the Zika virus protein NS4A disrupts brain growth by hijacking a pathway that regulates the generation of new neurons. The findings point at the possibility of developing therapeutic strategies to prevent microcephaly linked to Zika virus infection. The study appeared Thursday in the journal Developmental Cell.

Patients with rare genetic mutations shed light on how Zika virus causes microcephaly

The current study was initiated when a patient presented with a small brain size at birth and severe abnormalities in brain structures at the Baylor Hopkins Center for Mendelian Genomics (CMG), a center directed by Dr. Jim Lupski, professor of pediatrics, molecular and human genetics at Baylor College of Medicine and attending physician at Texas Childrens Hospital, said Dr. Hugo J. Bellen, professor at Baylor, investigator at the Howard Hughes Medical Institute and Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital.

This patient and others in a cohort at CMG had not been infected by Zika virus in utero. They had a genetic defect that caused microcephaly. CMG scientists determined that the ANKLE2 gene was associated with the condition. Interestingly, a few years back the Bellen lab had discovered in the fruit fly model that ANKLE2 gene was associated with neurodevelopmental disorders. Knowing that Zika virus infection in utero can cause microcephaly in newborns, the team explored the possibility that Zika virus was mediating its effects in the brain via ANKLE2.

In a subsequent fruit fly study, the researchers demonstrated that overexpression of Zika protein NS4A causes microcephaly in the flies by inhibiting the function of ANKLE2, a cell cycle regulator that acts by suppressing the activity of VRK1 protein.

Since very little is known about the role of ANKLE2 or VRK1 in brain development, Bellen and his colleagues applied a multidisciplinary approach to tease apart the exact mechanism underlying ANKLE2-associated microcephaly.

The fruit fly helps clarify the mystery

The team found that fruit fly larvae with mutations in ANKLE2 gene had small brains with dramatically fewer neuroblasts brain cell precursors and could not survive into adulthood. Experimental expression of the normal human version of ANKLE2 gene in mutant larvae restored all the defects, establishing the loss of Ankle2 function as the underlying cause.

To understand why ANKLE2 mutants have fewer neuroblasts and significantly smaller brains, we probed deeper into asymmetric cell divisions, a fundamental process that produces and maintains neuroblasts, also called neural stem cells, in the developing brains of flies and humans, said first author Dr. Nichole Link, postdoctoral associate in the Bellen lab.

Asymmetric cell division is an exquisitely regulated process by which neuroblasts produce two different cell types. One is a copy of the neuroblast and the other is a cell programmed to become a different type of cell, such as a neuron or glia.

Proper asymmetric distribution and division of these cells is crucial to normal brain development, as they need to generate a correct number of neurons, produce diverse neuronal lineages and replenish the pool of neuroblasts for further rounds of division.

When flies had reduced levels of Ankle2, key proteins, such as Par complex proteins and Miranda, were misplaced in the neuroblasts of Ankle2 larvae. Moreover, live imaging analysis of these neuroblasts showed many obvious signs of defective or incomplete cell divisions. These observations indicated that Ankle2 is a critical regulator of asymmetric cell divisions, said Link.

Further analyses revealed more details about how Ankle2 regulates asymmetric neuroblast division. They found that Ankle2 protein interacts with VRK1 kinases, and that Ankle2 mutants alter this interaction in ways that disrupt asymmetric cell division.

The Zika connection

Linking our findings to Zika virus-associated microcephaly, we found that expressing Zika virus protein NS4A in flies caused microcephaly by hijacking the Ankle2/VRK1 regulation of asymmetric neuroblast divisions. This offers an explanation to why the severe microcephaly observed in patients with defects in the ANKLE2 and VRK1 genes is strikingly similar to that of infants with in utero Zika virus infection, Link said.

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For decades, researchers have been unsuccessful in finding experimental evidence between defects in asymmetric cell divisions and microcephaly in vertebrate models. The current work makes a giant leap in that direction and provides strong evidence that links a single evolutionarily conserved Ankle2/VRK1 pathway as a regulator of asymmetric division of neuroblasts and microcephaly, Bellen said.

Moreover, it shows that irrespective of the nature of the initial triggering event, whether it is a Zika virus infection or congenital mutations, the microcephaly converges on the disruption of Ankle2 and VRK1, making them promising drug targets.

Another important takeaway from this work is that studying a rare disorder (which refers to those resulting from rare disease-causing variations in ANKLE2 or VRK1 genes) originally observed in a single patient can lead to valuable mechanistic insights and open up exciting therapeutic possibilities to solve common human genetic disorders and viral infections.

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How in utero Zika virus infection can lead to microcephaly in newborns: Baylor research - Outbreak News Today

Scholars are divided on how to regulate heritable genome editing.

Heritable genome editing refers to changing human reproductive cells so that the resulting fetus has genetic changes that its future offspring may inherit.

Proponents of heritable gene-editing champion the possibility of editing out incurable heritable diseases, but others caution that gene editing may have unintended effects. For example, an edit to prevent a child from inheriting a disease might also reduce that childs immunity to other diseases, a concern that is amplified by the fact that any changes to immunity would be heritable.

The debate is no longer theoretical. Shortly after reports of the first live births of gene-edited babies surfaced in 2018, a number of prominent scientists called for a ban on any further experimentation that would result in live births, at least until regulatory schemes were put in place.

This weeks Saturday Seminar explores scholarly works on current and proposed regulatory approaches to heritable gene-editing, as well as the unique challenges to effective regulation given factors like the medical tourism industry.

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The Next Generation's Genes - The Regulatory Review

The taller you are, the higher your risk of developing developing atrial fibrillation, a new study by Penn Medicine says.

The study found a strong association between the genetic variants of height and an increased risk of atrial fibrillation (AFib) a heart condition that causes an irregular and rapid heartbeat. The link appears to be causal, meaning it's more than a correlation.

The studywill be presented on Saturday at the American Heart Association's 2019 Scientific Sessions in Philadelphia.

Researchers analyzed the association by examining data from Genetic Investigation of Anthropometric Trials, a consortium that studied genetic height variants, and Atrial Fibrillation Genetics, a consortium that studied associations between genetic variants and AFib.

They found that the risk of developing AFib increased by 3% for every one-inch increase in height when compared to those who are considered average in height 5 feet, 7 inches.

This association remained strong even after the data was adjusted for additional risk factors, including heart disease and diabetes.

Researchers thenanalyzed more than 7,000 patients enrolled in the Penn Medicine Biobank to study the association on an individual level. They again found again that height and its genetic variants are strongly linked to an increased risk of developing AFib.

Atrial fibrillationcan lead to severe complications such as stroke, blood clots, and heart failure, according to the Mayo Clinic. Patients with AFib do not always exhibit symptoms, but when symptoms do occur they can includepalpitations, shortness of breath and fatigue.

AFib affects more than 33 million people across the world.

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Tall people have a higher likelihood of developing atrial fibrillation, Penn researchers say - PhillyVoice.com

While the rate of death from cancer has been declining since the 1990s, an estimated 9.6 million people died from cancer in 2018, making it the second-leading cause of death worldwide [1]. According to the NCI Cancer Trends Progress Report, in the United States, the incidence and death rates of some cancer types have also been increasing. Together, these facts indicate that despite tremendous recent progress, the research community unfortunately still has a long list of tasks to complete to end global suffering from cancer.

The clinical management of cancer has long been rooted in morphological and histopathological analyses for diagnosis, and the triad of surgery, chemotherapy, and radiation for treatment. However, we are quickly moving towards a pervasive reliance on high resolution, high throughput, molecular marker-based diagnostic as well as precision-targeted therapeutic modalities. The progressive development of the paradigm that defined molecular drivers of cancer has exposed therapeutic vulnerabilities; for example, the BCR-ABL1 gene fusion in chronic myeloid leukemia, KIT mutations in gastrointestinal stromal tumors, ERBB2 amplification in a subset of breast cancers, or EGFR mutations and ALK/ ROS/ RET gene fusions in lung cancers to name a few. Fueled by advances in high-throughput sequencing, it is increasingly practical (and arguably affordable) to systematically pursue Targeted Anticancer Therapies and Precision Medicine in Cancer.

PLOS ONE, together with PLOS Computational Biology, launched a Call for Papers earlier this year to increase understanding of this clinically important area. The scope of this call encompassed four areas: identification and classification of driver genes and somatic alterations; target and drug discovery; mechanisms of drug resistance; and early detection and screening.

Today, we are very happy to announce the launch of the resulting Collection. Featuring an initial set of nearly two dozen papers, with more to be added as they are published, these articles represent diverse facets of ongoing efforts in this area, where general knowledge of cancers serves to inform individual patients care, and at the same time particulars from individual cancer cases contribute to improved resolution of our general knowledge pool.

Somatic aberrations that are critical to the development, growth and progression of cancer are defined as drivers that are typically accompanied by large numbers of incidental aberrations referred to as passengers, acquired in the tumors due to the general chromosomal instability characteristic of advanced cancers. Distinguishing driver aberrations from passengers in individual tumors represents an active area of research that involves development of smarter analytical algorithms, as well as definitive functional characterization of candidate aberrations.

Emilie A. Chapeau et al. developed a conditional inducible transgenic JAK2V617F mouse model that recapitulates aspects of human myeloproliferative neoplasms, including splenomegaly, erythroid expansion and hyperproliferation of bone marrow, with some intriguing differences seen between male and female mice. Importantly, the disease phenotype was reversible when transgene expression was switched off. This work underscores the key role for JAK2V617F in the initiation and maintenance of myeloproliferative neoplasms, and suggests that inhibitors specific to this JAK2 mutation might be efficacious in this disease [2].

Using targeted exon sequencing and array comparative genomic hybridization (CGH), Gayle Pageau Pouliot et al. identified monoallelic mutations in Fanconi-BRCA pathway genes in samples collected from children with T cell acute lymphoblastic leukemia (T-ALL). These mutations appeared to arise in early stages of tumorigenesis, suggesting a potential role for Fanconi-BRCA pathway insufficiency in the initiation of T-ALL. Although PARP inhibitors did not affect viability of isolated T-ALL cells with monoallelic Fanconi-BRCA mutations, these cells were hypersensitive to UV irradiation in vitro or ATR inhibition in vivo, suggesting that ATR inhibitors might have therapeutic value in T-ALL [3].

Three papers in this Collection examine links between genetic alterations and prognosis. Sumadi Lukman Anwar et al. report that LINE-1 hypomethylation in human hepatocellular carcinoma samples correlates with malignant transformation, decreased overall survival and increased tumor size [4]. Investigating HER2-positive breast cancer specimens, Arsalan Amirfallah et al. found that high levels of vacuole membrane protein 1 (VMP1) could potentially contribute to cancer progression and might be a marker of poor prognosis [5]. Finally, in their systematic review and meta-analysis, Chia Ching Lee et al. identified low discordance rates in EGFR mutations between primary lung tumors and distant metastases, although they note some differences depending on metastatic site. Notably, discordance rates appear to be higher in bone metastases compared to central nervous system or lung metastases [6]. These studies provide much-needed leads for the potential development of new diagnostic tests or targeted therapies.

Precision therapy of cancers is premised on the identification of tumor-specific driver aberrations that are necessary for tumor growth and survival. These aberrations represent potential therapeutic targets. While matching therapeutics have been developed for some of the tumor-specific targets, particularly many oncogenic kinases, a large number of defined driver aberrations remain in search of effective therapies. Drug discovery efforts to match defined targets represent a vigorous area of ongoing research with implications for survival and quality of lives of cancer patients worldwide. The development of drugs to treat cancers driven by transcription factors, chromatin modifiers, and epigenetic modulators has proved particularly challenging. On the other hand, recent development of novel immunotherapeutic approaches has spurred research to identify potential targets and matching drug discovery efforts.

This Collection highlights several interesting new strategies to identify potential lead compounds for cancer treatment. Thomas W. Miller et al. describe the development of a biochemical quantitative high-throughput screen for small molecules that disrupt the interaction between CD47 and SIRP. Preclinical studies have shown that disrupting this interaction may provide a new approach for cancer immunotherapy. Small molecular inhibitors that specifically target the interaction between CD47 and SIRP are potentially advantageous over biologics that target CD47, because they might have less on target toxicologic issues and greater tissue penetrance [7].

Work from Gabrielle Choonoo, Aurora S. Blucher et al. examines the feasibility of repurposing existing cancer drugs for new indications. The authors compiled information about somatic mutations and copy-number alterations in over 500 cases of head and neck squamous cell carcinoma (HNSCC) and mapped these data to potential drugs listed in the Cancer Targetome [8]. This approach uncovered pathways that are routinely dysregulated in HNSCC and for which potential anti-cancer therapies are already available, as well as those for which no therapies exist. The work opens new therapeutic avenues in the treatment of this disease and also illuminates which pathways could be prioritized for the development of therapies [9].

Another important approach in extending the clinical utility of existing anti-cancer drugs is to determine whether they are effective in other settings. Indeed, Kirti Kandhwal Chahal et al. have demonstrated that the multi-tyrosine kinase inhibitor nilotinib, which is approved for use in chronic myeloid leukemia, binds the Smoothened receptor and inhibits Hedgehog pathway signaling. Nilotinib decreased viability of hedgehog-dependent medulloblastoma cell lines in vitro and in patient-derived xenografts in vivo, suggesting that nilotinib might be an effective therapy in Hedgehog-dependent cancer [10]. (Check out the authors preprint of this article on bioRxiv.) Darcy Welch, Elliot Kahen et al. took a different approach to identify new tricks for old drugs. By testing two-drug combinations of five established (doxorubicin, cyclophosphamide, vincristine, etoposide, irinotecan) and two experimental chemotherapeutics (the lysine-specific demethylase 1 (LSD1) inhibitor SP2509 and the HDAC inhibitor romidepsin), they found that combining SP2509 with topoisomerase inhibitors or romidepsin synergistically decreased the viability of Ewing sarcoma cell lines in vitro [11].

Two papers in this collection describe potential new therapeutic approaches in cancer. Vagisha Ravi et al. developed a liposome-based delivery mechanism for a small interfering RNA targeting ferritin heavy chain 1 (FTH1) and showed that this increased radiosensitivity and decreased viability in a subpopulation of glioma initiating cells (GICs) [12]. Yongli Li et al. identified 2-pyridinealdehyde hydrazone dithiocarbamate S-propionate podophyllotoxin ester, a podophyllotoxin derivative that inhibits matrix metalloproteinases and Topoisomerase II. Treatment with this compound decreased the migration and invasion of human liver cancer cell lines in vitro, as well as growth of HepG2-derived tumors in mouse xenografts [13].

The success of precision cancer therapy targeting defined somatic aberrations is hampered by an almost inevitable, eventual treatment failure due to the emergence of drug resistance. Resistance often involves new mutations in the therapeutic target itself, or it may result due to activation of alternative pathways. Identification and therapeutic targeting of drug resistant clones represents an ongoing research problem with important practical implications for the clinical management of cancer.

Afatinib is a pan-human epidermal growth factor receptor (HER) inhibitor under investigation as a potential therapeutic option for people with gastric cancer; however, preclinical studies have found that some gastric cancer cell lines are resistant to afatinib treatment. Karolin Ebert et al. identify a potential mechanism behind this lack of response, demonstrating that siRNA-mediated knockdown of the receptor tyrosine kinase MET increases afatinib sensitivity of a gastric cancer cell line containing a MET amplification. As upregulation of MET has been linked to resistance to anti-HER therapies in other cancers, these findings support a role for MET in afatinib resistance in gastric cancer and suggest that combined afatinib and anti-MET therapy might be clinically beneficial for gastric cancer patients [14].

Identifying mechanisms to circumvent drug resistance is critically important to improve response and extend survival, but it is equally important to identify individuals who could be at risk of not responding to anti-cancer therapeutics. Lucas Maahs, Bertha E. Sanchez et al. report progress towards this end, showing that high expression of class III -tubulin in metastatic castration-resistant prostate cancer (CRPC) correlated with decreased overall survival and worse response rate (as measured by changes in prostate-specific antigen (PSA) levels) in CRPC patients who received docetaxel therapy. The development of a biomarker indicating potential treatment resistance to docetaxel could help develop treatment plans with the best chance of success [15].

The converse approach identifying biomarkers that correlate with drug sensitivity could help distinguish subsets of patients who would benefit most from a certain anti-cancer therapy. Kevin Shee et al. mined publicly available datasets to identify genes whose expression correlate with sensitivity and response to chemotherapeutics and found that expression of Schlafen Family Member 11 (SLFN11) correlates with better response to a variety of DNA-damaging chemotherapeutics in several types of solid tumors [16]. Separately, Jason C. Poole et al. validated the use of the Target Selector ctDNA assay, a technology developed by their group that allows the specific amplification of very low frequency mutant alleles in circulating tumor DNA (ctDNA). Testing for EGFR, BRAF and KRAS mutations yielded a very high, >99% analytical sensitivity and specificity with the capability of single mutant copy detection, indicating that accurate molecular disease management over time is possible with this minimally invasive method [17].

Work from Georgios Kaissis, Sebastian Ziegelmayer, Fabian Lohfe et al. uses a machine learning algorithm to differentiate subtypes of pancreatic ductal adenocarcinoma based on 1,606 different radiomic features. Intriguingly, the subtypes identified in their analysis correlated with response to chemotherapeutic regimens and overall survival [18]. An imaging approach taken by Seo Young Kang et al. demonstrates the potential power of fluorodeoxyglucose (FDG) PET/CT scans in determining the response of people with metastatic differentiated thyroid cancer to radioactive iodine treatment [19].

Since cancer growth and development accrues progressive accumulation of somatic aberrations, early detection holds the promise of more effective interventions. Similarly, screening of at risk demographics has been found effective in preventing or better managing cancer care, as exemplified by the significant reduction in cases of cervical cancer after the introduction of the Pap smear as well as human papillomavirus (HPV) testing.

Biomarker development is also critically important for the early detection of cancer and metastatic disease; moreover, biomarkers are being identified that can provide insight into patient prognosis. Several papers in this Collection report interesting findings in the area of biomarker development. A report from Lingyun Xu et al. describes a magneto-nanosensor-based multiplex assay that measures circulating levels of PSA and four proteins associated with prostate cancer. This approach segregates people with prostate cancer from those with benign prostate hyperplasia with high sensitivity and specificity [20].

Two articles provide new insight into markers of disease progression and survival. Vidya Balagopal et al. report the development of a 22-gene hybrid-capture next generation sequencing panel to identify measurable residual disease in patients with acute myeloid leukemia (AML). In their retrospective study, the panel was effective at detecting evidence for residual disease. Importantly, it correctly identified patients who had never relapsed in that no evidence of residual disease was detected in any of these respective samples. Once validated, this approach could potentially be useful in monitoring patients with AML to ensure that recurrence or relapse is identified as soon as possible [21]. Separately, Yoon-Sim Yap et al. use a label-free microfluidic platform to capture circulating tumor cells (CTCs) from people with breast cancer and show that absolute numbers of CTCs predict progression-free survival with higher levels of CTCs correlating with a worse prognosis [22].

Finally, Lucia Suzuki et al. report findings into a potential role for the intestinal stem cell marker olfactomedin 4 (OLFM4) as a biomarker for metastasis in esophageal adenocarcinoma. The authors found that OLFM4 expression was not significantly associated with disease-free or overall survival; however, low OLFM4 expression was detected in poorly differentiated early and advanced-stage esophageal adenocarcinoma and was an independent prognostic variable for lymph node metastasis [23].

This collection of studies encompassing the range of research topics under the banner of targeted anticancer therapies highlights the diversity, complexity and inter-disciplinary nature of research efforts actively contributing to our collective knowledge base with the hope to positively impact the lives of all cancer patients.

We would like to thank all Academic Editors and reviewers for their expert evaluation of the articles in this Collection as well as the authors for their contributions to this field. Special thanks to Senior Editor, Team Manager Emily Chenette for her invaluable help and guidance in publishing this Collection.

Andrew Cherniack

Andrew Cherniack is a group leader in the Cancer Program at the Broad Institute of MIT and Harvard and in the Department of Medical Oncology at the Dana Farber Cancer Institute. He led the Broad Institutes effort to analyze somatic DNA copy number alterations for The Cancer Genome Atlas (TCGA) and is now co-principal investigator of the Broad Institutes copy number Genome Data Analysis Center for the National Cancer Institutes Genomic Data Analysis Network (GDAN). He also leads the oncoming effort to identify new cancer therapeutic targets for the partnership with Bayer. Prior to joining the Broad Institute in 2010, Dr. Cherniack worked in both academia and industry, with a 9-year tenure at the Abbott Bioresearch Center following a similar time period in the Program in Molecular Medicine at UMass Medical School, where he was a postdoctoral researcher and a research assistant professor. Dr. Cherniack holds a Ph.D. in molecular genetics from Ohio State University and a B.A. in biology from the University of Pennsylvania.

Anette Duensing

Anette Duensing is an Assistant Professor of Pathology at the University of Pittsburgh School of Medicine and a Member of the Cancer Therapeutics Program at the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center. Dr. Duensings research focuses on bone and soft tissue sarcomas with the goal of identifying novel therapeutic approaches that target the underlying molecular biology of these malignancies. Her special interest and expertise are in gastrointestinal stromal tumors (GISTs), a sarcoma characterized by mutations in the KIT or PDGFRA receptor tyrosine kinases and the first solid tumor entity that was successfully treated with small molecule kinase inhibitors. Dr. Duensing holds an M.D. degree from the University of Hannover School of Medicine, Germany, and was a research scholar of the Dr. Mildred Scheel Stiftung fr Krebsforschung (German Cancer Aid/Deutsche Krebshilfe) at Brigham and Womens Hospital, Harvard Medical School. She is the recipient of an AACR Scholar-in-Training Award (AACR-AstraZeneca), a Young Investigator Award from The Liddy Shriver Sarcoma Initiative, a UPCI Junior Scholar Award, a Jeroen Pit Science Award, a Research Award from the GIST Group Switzerland and was named Hillman Fellow for Innovative Cancer Research. Dr. Duensing is co-founder and leader of the Pittsburgh Sarcoma Research Collaborative (PSaRC), a highly translational, interdisciplinary sarcoma research program. She is also affiliated with the Department of Urology at the University of Heidelberg, Germany. Dr. Duensing is an Academic Editor for PLOS ONE and author of nearly 70 original articles, reviews and book chapters.

Steven G. Gray

Steven Gray graduated from Trinity College Dublin in 1992. He joined the laboratory of Tomas J. Ekstrm at the Karolinska Institute (Sweden) in 1996 and received his PhD in 2000. He moved to the Van Andel Research Institute in Michigan, USA where he continued his studies on the therapeutic potential of histone deacetylase inhibitors in the treatment of cancer. He also spent time as a visiting fellow at Harvard Medical School, Boston working on epigenetic therapies for neurodegenerative disease. Returning to Europe, Dr. Gray spent some time at the German Cancer Research Centre (DKFZ Heidelberg), and subsequently moved to Copenhagen to work for Novo Nordisk as part of the research team of Prof Pierre De Meyts at the Hagedorn Research Institute working on epigenetic mechanisms underpinning diabetes pathogenesis. Dr. Gray is currently a senior clinical scientist at St Jamess Hospital at the Thoracic Oncology Research Group at St. Jamess Hospital. He holds adjunct positions at both Trinity College Dublin (senior clinical lecturer with the Dept. of Clinical Medicine), and at Technical University Dublin (adjunct senior lecturer, School of Biology DIT). Dr. Gray has published over 100 peer-reviewed articles, 15 book chapters and has edited 1 book. Research in Dr Grays laboratory focuses on Receptor Tyrosine Kinases as potential therapeutic targets for the treatment of mesothelioma; epigenetic mechanisms underpinning drug resistance in lung cancer; targeting epigenetic readers, writers and erasers for the treatment of mesothelioma and thoracic malignancy; circulating tumour cells; and non-coding RNA repertoires in mesothelioma and thoracic malignancy.

Sunil Krishnan

Sunil Krishnan is the Director of the Center for Radiation Oncology Research and the John E. and Dorothy J. Harris Professor of Gastrointestinal Cancer in the department of Radiation Oncology at MD Anderson Cancer Center. He received his medical degree from Christian Medical College, Vellore, India and completed a radiation oncology residency at Mayo Clinic, Rochester, Minnesota. In the clinic, he treats patients with hepatobiliary, pancreatic and rectal tumors with radiation therapy. His laboratory has developed new strategies and tools to define the roles and mechanisms of radiation sensitization with gold nanoparticles, chemotherapeutics, biologics and botanicals. Dr. Krishnan serves as the co-chair of the gastrointestinal scientific program committee of ASTRO, co-chair of the gastrointestinal translational research program of RTOG, consultant to the IAEA for rectal and liver cancers, chair of the NCI pancreatic cancer radiotherapy working group, and Fellow of the American College of Physicians. He has co-authored over 200 peer-reviewed scientific publications, co-authored 17 book chapters, and co-edited 3 books.

Chandan Kumar-Sinha

Chandan Kumar-Sinha is a Research Associate Scientist in the Department of Pathology at the University of Michigan. He obtained Masters in Biotechnology from Madurai Kamraj University, and PhD in Plant Molecular Biology from Indian Institute of Science. He completed a Postdoctoral Fellowship at the Department of Pathology, University of Michigan, where he worked on genomic profiling of cancers. Thereafter, he joined the Advanced Center for Treatment, Research and Education in Cancer in India as a faculty member. After establishing a cancer genomics group there, he moved back to the University of Michigan to pursue translational cancer research. Dr. Kumar-Sinhas current research involves integrative clinical sequencing using high-throughput genome and transcriptome analyses to inform precision oncology. He has authored over 50 peer-reviewed publications, two book chapters, and is named co-inventor on a patent on prostate cancer biomarkers.

Gayle E. Woloschak

Gayle Woloschak is Professor of Radiation Oncology, Radiology, and Cell and Molecular Biology in the Feinberg School of Medicine, Northwestern University. Dr. Woloschak received her Ph.D. in Medical Sciences from the University of Toledo (Medical College of Ohio). She did her postdoctoral training at the Mayo Clinic, and then moved to Argonne National Laboratory until 2001. Her scientific interests are predominantly in the areas of molecular biology, radiation biology, and nanotechnology studies, and she has authored over 200 papers. She is a member of the National Council on Radiation Protection, the International Commission on Radiation Protection and numerous other committees and also serves on the US delegation to the United National Scientific Committee on the Effects of Atomic Radiation.

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Introducing the Targeted Anticancer Therapies and Precision Medicine in Cancer Collection - PLoS Blogs

Innovation in the health care industry is seen by many as a way to address rising health care costs by improving technology, managing Big Data to develop best clinical practices, reducing pain and suffering or maybe even curing diseases.

Recent innovative developments in Michigan include a statewide telestroke program at the University of Michigan, a precision medicine program at Barbara Ann Karmanos Cancer Institute and a device that can identify pathogens developed by Seraph Biosciences Inc., a Detroit-based spinoff company of Wayne State University.

At Crain's 12th annual Health Care Leadership Summit, moderator David Ellis, a futurist and also head of the Detroit International Research and Education Foundation, led a three-member panel on a discussion about how innovation has changed medicine and patient care.

"I like to think that my colleagues here (on the panel) are representative of the people who are moving towards the speed of light, if not at the speed of light" to develop innovative clinical solutions, Ellis said. "Innovation is not just happening, but it is happening faster and faster."

Ellis asked the panel Mollie McDermott, M.D., a neurologist and stroke specialist with Michigan Medicine; Elisabeth Heath, M.D., a medical oncologist at Karmanos; and Greg Auner, a medical engineer at Wayne State University School of Medicine to describe the biggest innovation to happen in their field in the past five years and to project the next five years.

McDermott, who is the director of the telestroke program at Michigan Medicine, said the biggest innovation in her field is the widespread use of a special type of imaging called "perfusion imaging in acute stroke." This advancement can identify tissue that could be saved through the use of thrombolytic therapy, or "clot buster" drugs, in clogged arteries.

"When I started medical school, there were interventions available for stroke out to three hours from last known normal. And now that time has expanded to 24 hours with the idea that we're selecting patients who may benefit based on this specialized imaging. Stroke call has gotten very complicated," McDermott said. "It used to be, three hours and then you're done. Now we're getting called out to 24 hours. Decision-making is very complicated and there is a lack of vascular neurology expertise in our country."

McDermott said Michigan Medicine uses its telestroke program to pass along this vascular neurology expertise to small and rural hospitals where they don't have specialists trained in perfusion imaging.

Heath, who is Karmanos' associate center director of translational sciences, said the field of genomics and precision medicine more specifically precision oncology has grown tremendously over the past five years.

"Explosion would be a small word to characterize (the pace of change) because there's no meeting that you go to now in the world of oncology where that concept (using an individual's DNA to customize cancer treatment) is not discussed," she said.

Heath said Karmanos' partnership with McLaren Healthcare Corp., a 14-hospital system based in Grand Blanc, has been especially helpful in spreading knowledge of precision oncology throughout Michigan.

McDermott said the next five years for telemedicine will bring even more specialists closer to patients in helping to diagnose complex problems. "Patients (are) at home and trying to figure out, do I need to go to the emergency room? Do I need to go to urgent care? Do I need to set up an appointment with my primary care physician? Do I need to call 911? These kinds of decisions (influenced by telemedicine or virtual care) ... seems to be the next place we're headed."

Auner, one of the co-founders of Seraph, said individualized genetic analysis will transform cancer treatment. But the massive amount of data available will challenge researchers and clinicians going forward.

"Something that is quite interesting is deep learning (or) artificial intelligence that can gather through data from different sources, images, diagnostic signals ... and put that together and provide that as a tool," Auner said. "I see that probably is the biggest future breakthrough."

Heath said the next five years will challenge medical researchers because of all the clinical data on patients. "There's a fine line between a hoarder and a collector (of clinical data)," she said. "I would really like to be a collector, not a hoarder. And at this moment we're all hoarders of data and it's wonderful ... but really understanding what it means, especially if on a patient level, that's (another) discussion."

Ellis said one of the problems hospitals, doctors and health insurers have is trusting each other to share claims data and other medical records on patients to deliver appropriate care.

"One of the reasons for that of course, is purely technical. Not every system (electronic health record) is as good as the next and data breaches do occur," Ellis said. "That's got pretty severe implications."

But he said innovations occurring now to share "Big Data" using artificial intelligence and other systems could overcome trust and technical issues.

"I always see a solution. That's why I'm the perpetual optimist," Heath said. "As an oncologist, there's always a solution. I'm not saying it's right, but I think you have to have a plan" to share and use data.

McDermott said changing provider and hospital behavior is difficult. "We're taught basically from day one of medical school not to trust anybody. You have to verify for yourself, don't trust other people's exams," she said. "I don't trust research unless I have read the methods' section. So overcoming that is a cultural, not just a pragmatic phenomenon."

Auner said there is a "scary" aspect as clinical research becomes more individualized to patients "from the standpoint of what is known about a particular patient (and) knowing everything about you genetically."

For example, what if your genetic data and predisposition to disease or illness finds its way to your health insurance company? "(They) may then predict what's going to happen to you and how that may" affect your health and premium dollars charged to you or your employer.

"The knowledge of that can be unnerving," Auner said.

Heath said the big unanswered question out there is who owns the data. She wondered if patients own their data or does the health system, the university, the researcher?

"When you say it's in my medical record, that has a lot of implications when you're talking about genomic data," she said. "Is it just knowing that its the breast cancer gene itself? Is it knowing down to the nucleotide? Are you looking at things that exist only in the webspace because we can't house it in the computer? What is that sort of ownership from a patient level?"

Ellis said the reality is right now there are companies out there like Mark Zuckerberg's Facebook that contends if there is data out there "it's mine, I'll grab it. ... It's a free for all. It's the first come, first served."

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Health care innovation moving at 'speed of light' - Crain's Detroit Business

Clinical genetics experts see value in testing more women for BRCA mutations.

Two widely tested cancer-predisposition genes areBRCA1andBRCA2. Certain inherited mutations in these genes are known to greatly increase the risk of developing several types of cancer, includingbreast,ovarian,prostate, andpancreaticcancers. Genetic testing for BRCA mutations can identify people who may benefit from risk-reduction surgery, like a mastectomy; preventive medications; or targeted therapies.

But there is a huge catch: Commercial testing kits, like the one from 23andMe authorized by the US Food and Drug Administration, test for only the three most common BRCA mutations known to run in families of Ashkenazi Jewish ancestry. Someone could test negative for these specific mutations and still be at risk for cancer from other BRCA mutations that arent included in the test. This false sense of security might dissuade someone from finding out the full extent of their cancer risk.

This is just one of the many reasons why doctors typically recommend that genetic testing be done under the guidance of a clinical genetics expert who can test for more than the most common BRCA mutations and help explain the results. Even then, questions remain about who should have testing.

What the Experts SayCurrently, doctors refer someone for genetic testing if they meet various clinical criteria, like having a family history of cancer or being diagnosed with certain cancers at a young age. But there is evidence that by limiting testing to just these individuals, some people with a BRCA mutation will be missed.

We know from our data at Memorial Sloan Kettering that if you only test people with strong family histories, you miss half the cases, saysLarry Norton, Senior Vice President in the Office of the President and Medical Director of the Evelyn H. Lauder Breast Center at MSK.

Between those with a family history and the entire US population is a large unmapped territory. Just 0.3% of the population (one in 300 individuals) has a dangerous BRCA mutation. Its not clear how to step up testing in a logical and efficient manner to capture those who are at risk.

But testing guidelines are indeed becoming moreinclusive. In August, the US Preventive Services Task Force, an independent panel of health experts, issued updated BRCA testing recommendations. In addition to women with a known family history of breast or ovarian cancer, the updated recommendations include two additional groups: women who previously had breast or ovarian cancer and are now considered cancer free and women of an ancestry known to be at a higher risk, such as Ashkenazi Jewish women.One in 40 individuals of Ashkenazi Jewish ancestry (2.5%) have a harmful BRCA mutation. The updated recommendations were published August 20 in theJournal of the American Medical Association.

In anaccompanying editorial,Mark Robson, Chief of the Breast Medicine Service at MSK, and Susan Domcheck from the University of Pennsylvania, call the addition of women with prior breast and ovarian cancer an important step forward and applaud the decision to include ancestry as a reason for testing.

Identification of individuals at risk of carrying aBRCA1/2mutation can be lifesaving and should be a part of routine medical care, they write.

Low Uptake, Risks of OvertestingEven as testing guidelines are becoming broader, there is evidence that people who are good candidates for testing are not currently availing themselves of it. For example, approximately 15% of women with epithelial ovarian cancer have aBRCA1/2mutation. Given this high frequency, experts recommend testing for all people with ovarian cancer. But that doesnt happen: Less than 30% of such women are actually tested. The numbers are even lower for underrepresented minorities and those from a low socioeconomic background.

On the flip side, Dr. Robson and his co-author caution that there are dangers to overtesting, especially when the tests in question are large multigene panels that can include up to 80 genes.

While there may be value in expanding BRCAtesting, particularly in the Ashkenazi Jewish population, this does not automatically mean that this expansion should be conducted using multigene panel tests, they write.

MSK scientists, including a team led byKenneth Offit, Chief of the Clinical Genetics Service, are actively exploring the best and most strategically effective ways of testing. They are committed to making sure that the most beneficial testing is offered to the people who need it.

Information provided by MSK (Information) is not intended as a substitute for medical professional help or advice but is to be used only as an educational aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition. Use of the Information is further subject toMSKs Website Terms and Conditions.

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Who Should Be Tested for a BRCA Mutation? The Science Is Evolving - Curetoday.com

(MENAFN - The Peninsula) The legal and ethical implications of using stem cells and artificial intelligence (AI) in medicine were discussed at the latest instalment of Weill Cornell Medicine-Qatar's (WCM-Q) Intersection of Law & Medicine series.Expert speakers at the event discussed the impact of recent advances in stem cell science and AI on the practice of medicine in Qatar and explored how new legal frameworks could be developed to protect the rights and safety of patients in the MENA region. The day-long event was organized by WCM-Q in collaboration with Hamad Bin Khalifa University and the University of Malaya of Kuala Lumpur, Malaysia.Stem cells are an exciting area for medical researchers because they have the potential to repair damaged or diseased tissues in people with conditions such as Parkinson's disease, type 1 diabetes, stroke, cancer, and Alzheimer's disease, among many others. Stem cells can also be used by researchers to test new drugs for safety and effectiveness.WCM-Q's Dr. Amal Robay, WCM-Q assistant professor in genetic medicine and director of research compliance, said: 'Stem cells have the capacity for unlimited or prolonged self-renewal, and they can differentiate themselves into many different cell types to become tissue- or organ-specific cells with special functions. The central ethical dilemma of stem cell science arises from the fact that embryonic stem cells are derived from human embryos or by cloning, she explained.Visiting bioethics expert Dr. Jeremy Sugarman of Johns Hopkins University in Baltimore, US said that the public image of stem cell research had been damaged by a small number of high-profile cases in which scientists had behaved unethically. The field had also been hampered by different countries applying different laws to stem cell research, making international collaboration problematic, he said.Meanwhile, the use of AI in healthcare has the potential to leverage analysis of large amounts of data to improve patient outcomes, but poses ethical concerns regarding privacy, the diversity of data sources, biases and relying on non-human entities for potentially life-changing decisions.Dr. Barry Solaiman, assistant professor of law in the College of Law and Public Policy at HBKU said: 'It's very important that we bridge that gap between the professions of law and medicine, and that we understand the fundamental importance of ethicists to the advance of science. We need to consider how lawyers can help to develop laws to ensure that science advances and that it does so in ways that protect everyone involved.The event, which was co-directed by Dr. Solaiman and Dr. Thurayya Arayssi, professor of clinical medicine and senior associate dean for medical education and continuing professional development at WCM-Q, also featured other expert speakers.The event was accredited locally by the Qatar Council for Healthcare Practitioners-Accreditation Department (QCHP-AD) and internationally by the Accreditation Council for Continuing Medical Education (ACCME).

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Researchers from the University of California, Irvine developed a breakthrough cell therapy to improve memory and prevent seizures in mice following traumatic brain injury. The study, titled Transplanted interneurons improve memory precision after traumatic brain injury, was published today inNature Communications.

Traumatic brain injuries affect 2 million Americans each year and cause cell death and inflammation in the brain. People who experience a head injury often suffer from lifelong memory loss and can develop epilepsy.

In the study, the UCI team transplanted embryonic progenitor cells capable of generating inhibitory interneurons, a specific type of nerve cell that controls the activity of brain circuits, into the brains of mice with traumatic brain injury. They targeted the hippocampus, a brain region responsible for learning and memory.

The researchers discovered that the transplanted neurons migrated into the injury where they formed new connections with the injured brain cells and thrived long term. Within a month after treatment, the mice showed signs of memory improvement, such as being able to tell the difference between a box where they had an unpleasant experience from one where they did not. They were able to do this just as well as mice that never had a brain injury. The cell transplants also prevented the mice from developing epilepsy, which affected more than half of the mice who were not treated with new interneurons.

Inhibitory neurons are critically involved in many aspects of memory, and they are extremely vulnerable to dying after a brain injury, saidRobert Hunt, PhD, assistant professor of anatomy and neurobiology at UCI School of Medicine who led the study. While we cannot stop interneurons from dying, it was exciting to find that we can replace them and rebuild their circuits.

This is not the first time Hunt and his team has used interneuron transplantation therapy to restore memory in mice. In 2018, the UCI team used asimilar approach, delivered the same way but to newborn mice, to improve memory of mice with a genetic disorder.

Still, this was an exciting advance for the researchers. The idea to regrow neurons that die off after a brain injury is something that neuroscientists have been trying to do for a long time, Hunt said. But often, the transplanted cells dont survive, or they arent able to migrate or develop into functional neurons.

To further test their observations, Hunt and his team silenced the transplanted neurons with a drug, which caused the memory problems to return.

"It was exciting to see the animals memory problems come back after we silenced the transplanted cells, because it showed that the new neurons really were the reason for the memory improvement, said Bingyao Zhu, a junior specialist and first author of the study.

Currently, there are no treatments for people who experience a head injury. If the results in mice can be replicated in humans, it could have a tremendous impact for patients. The next step is to create interneurons from human stem cells.

So far, nobody has been able to convincingly create the same types of interneurons from human pluripotent stem cells, Hunt said. But I think were close to being able to do this.

Jisu Eom, an undergraduate researcher, also contributed to this study. Funding was provided by the National Institutes of Health.

Reference: Zhu, et al. (2019) Transplanted interneurons improve memory precision after traumatic brain injury. Nature Communications. DOI:https://doi.org/10.1038/s41467-019-13170-w

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Cell Therapy Aims To Improve Memory and Prevent Seizures Following Traumatic Brain Injury - Technology Networks

On this we can all agree: The lifespan of a dog is far too short. The Dog Aging Project hopes to change that.Researchers are hoping to study a group of 10,000 dogs over the course of 10 years to see whether they can improve the life expectancy of canines and their overall quality of life.Dogs' lives are six to 12 times shorter than that of humans, according to a study by the Frontiers in Veterinary Science.The researchers, which include teams from the University of Washington School of Medicine and the Texas A&M University College of Veterinary Medicine & Biomedical Sciences, are being funded by the National Institute of Aging, a division the National Institutes of Health.The researchers' expertise comes from a wide range of fields and institutions. All together, it will be the largest-ever study on aging in dogs. But their scope expands far beyond: The researchers hope that the information they learn could eventually be applied to humans as well."Dogs truly are science's best friends," the research team told CNN in a joint statement. "Though they age more rapidly than humans, they get the same diseases of aging, have a rich genetic makeup, and share our environment.""By studying aging in dogs," they said, "we can more quickly expand our knowledge of aging not just in dogs but also in humans." They added that the group is hopeful that their discoveries could lead to better "prediction, diagnosis, prognosis, treatment and prevention of disease."Now accepting applicantsApplications to the project are officially open.Owners can visit the Dog Aging Project's website to nominate their pooch. The submission process takes less than 10 minutes, and generally consists of questions about your canine to help the researchers learn whether he or she is the right fit.Have more questions? Here's a helpful FAQ.Dogs from all 50 states, and of all ages, sizes and breeds may apply. The researchers will even consider dogs with chronic illnesses, hoping to include as much genetic diversity as possible.That will help them identify biological and environmental factors critical to improving overall health and lifespan.And humans -- your participation is welcome too."Dogs and their owners are the heart of the Dog Aging Project," the researchers said. "People who nominate a dog will have the opportunity to partner with our research team as a citizen scientist."Owners will be asked to fill out surveys about their dog's health and life experience, and sample the dog's saliva, too.

On this we can all agree: The lifespan of a dog is far too short. The Dog Aging Project hopes to change that.

Researchers are hoping to study a group of 10,000 dogs over the course of 10 years to see whether they can improve the life expectancy of canines and their overall quality of life.

Dogs' lives are six to 12 times shorter than that of humans, according to a study by the Frontiers in Veterinary Science.

The researchers, which include teams from the University of Washington School of Medicine and the Texas A&M University College of Veterinary Medicine & Biomedical Sciences, are being funded by the National Institute of Aging, a division the National Institutes of Health.

The researchers' expertise comes from a wide range of fields and institutions. All together, it will be the largest-ever study on aging in dogs. But their scope expands far beyond: The researchers hope that the information they learn could eventually be applied to humans as well.

"Dogs truly are science's best friends," the research team told CNN in a joint statement. "Though they age more rapidly than humans, they get the same diseases of aging, have a rich genetic makeup, and share our environment."

"By studying aging in dogs," they said, "we can more quickly expand our knowledge of aging not just in dogs but also in humans." They added that the group is hopeful that their discoveries could lead to better "prediction, diagnosis, prognosis, treatment and prevention of disease."

Applications to the project are officially open.

Owners can visit the Dog Aging Project's website to nominate their pooch. The submission process takes less than 10 minutes, and generally consists of questions about your canine to help the researchers learn whether he or she is the right fit.

Have more questions? Here's a helpful FAQ.

Dogs from all 50 states, and of all ages, sizes and breeds may apply. The researchers will even consider dogs with chronic illnesses, hoping to include as much genetic diversity as possible.

That will help them identify biological and environmental factors critical to improving overall health and lifespan.

And humans -- your participation is welcome too.

"Dogs and their owners are the heart of the Dog Aging Project," the researchers said. "People who nominate a dog will have the opportunity to partner with our research team as a citizen scientist."

Owners will be asked to fill out surveys about their dog's health and life experience, and sample the dog's saliva, too.

Visit link:
Wanted: 10,000 dogs for the largest-ever study on aging in canines - WBAL Baltimore

Columnist Ben Maldonado traces the eugenicist history of Ray Lyman Wilbur. (Courtesy of Wikimedia Commons)

On Jan. 22, 1916, Ray Lyman Wilbur became the third president of Stanford University. In his inaugural speech, Wilbur promised that Stanford would aim for control of those unnecessary diseases that devour the very marrow of the [human] race and would lead in the fight against oppression, evil, ignorance, filth. These words would have perhaps been less ominous if Wilbur was not a eugenicist.

Between 1916 and 1929 and between 1933 and 1943, Ray Lyman Wilbur served as Stanfords president, leading the same university where he received his bachelors and masters degrees. A physician by training, Wilbur was influential in the development of Stanfords School of Medicine, first as dean then as university president. Wilburs key academic focus was public health: studying the health of America and methods of bettering it. This interest showed clearly in both his work at Stanford and in the Hoover Administration, where he served as Secretary of the Interior.

Wilburs interest in public health, however, also inspired his support of eugenics, the science of human improvement through selective breeding. As historian Martin S. Pernick has argued, public health and eugenics often historically went hand-in-hand what better way could there be of creating an ideal population than controlling who could reproduce and who could be born? Besides being a member of many health associations, Wilbur was also a prominent figure in eugenic organizations, such as the American Eugenics Society and the Eugenics Research Association, and often combined these two pursuits. As he put it in his 1937 article on the health of Black people, a pair of healthy grandfathers and of healthy grandmothers is the greatest personal asset a human being can have. In the name of public health, eugenic policies were therefore a necessity to Wilbur: We would not dream of treating a strain of race horses, he argued before Stanford alumni in 1935, the way we treat ourselves.

This emphasis on eugenics as a form of public health advocacy manifested in Wilburs work in the Hoover Administration as well. As historian Wendy Klein recounts, Wilbur served as conference chair at the 1930 White House Conference on Child Health and Protection, a massive convention attended by thousands of experts on child health, development and education. In his opening speech, Wilbur used eugenic language to emphasize the importance of fit future citizenry, encouraging the United States to become a fitter country in which to bring up children. Wilbur was not just supporting the health of children; he was supporting the goal of breeding eugenically fit children. As he put it in a 1913 speech, Wilbur believed that the products of the marriage of the weak and the unfit, of the criminal, of the syphilis and of the alcohol that fill many of our most splendid governmental buildings must largely disappear.

One of Wilburs greatest contributions to Stanford University as president was the development of the Stanford University School of Medicine, turning it into an organization at the forefront of medical education as well as eugenic education. Wilbur believed that all medical students should be taught the science of eugenics. He encouraged medical universities to study both the health and economic impact of the physically and mentally handicapped, promoting extensive research on eugenics. He presented before the Medical Society of the State of California in 1922, and argued that physicians must be educated to understand the importance of eugenically fit genetic material, for if it deteriorates a family or a race soon dies out. This genetic material must therefore be protected through eugenic means such as the sterilization or segregation of the unfit. With his development of the medical school, Wilbur aimed to emphasize the necessity of racial health in the name of eugenics.

Wilbur was also deeply concerned with race relations and the role of the United States in international affairs. In a 1926 speech, he expressed fear that white women were degenerating and becoming incapable of producing breast milk due to a reliance on dairy milk when nursing. For Wilbur, this was exceptionally frightening as the Chinese, who were immigrating to the American West (to the displeasure of many eugenicists) continued to use breast milk with their babies. Wilbur saw this as a eugenic threat to white dominance. If dairy production were to be halted, Chinese populations would overtake white populations a eugenicists nightmare.

Wilburs concerns with Chinese immigration led him to chair a 1923 survey looking into the potential dangers of Asian immigration into the American West. This Survey of Race Relations, as it was called, was led by many Stanford affiliates, and its findings were presented at a conference on Stanfords campus. Looking at both Chinese and Japanese immigration, this study chaired by Wilbur sought to objectively determine the value of allowing Asian immigrants to travel, stay, and reproduce in the United States. In the end, the survey concluded that Asian immigration was, for the time being, acceptable due to the cheap labor immigrants provided, but interracial marriages and reproduction were deeply discouraged. These attempts to objectively determine the value of immigrants to society was emblematic of a larger eugenic trend to quantify the value of human existence.

Wilburs belief in public health and the objective research of racial health inspired his promotion of eugenic thought. His legacy shows clearly the interconnections of medicine, public health and eugenic thought, and how many projects in the name of human health with noble intent were shaped by racist and ableist assumptions. Though he was less explicitly racist than some of his peers at Stanford, Wilbur still promoted the sterilization of unwanted people and still studied the potential dangers of non-white immigration. Today, Wilbur Hall bears his name, honoring his presidency and contributions to the University. I cannot help but wonder how many residents of that hall would be deemed unwelcome by its namesake.

Contact Ben Maldonado at bmaldona at stanford.edu.

We're a student-run organization committed to providing hands-on experience in journalism, digital media and business for the next generation of reporters.Your support makes a difference in helping give staff members from all backgrounds the opportunity to develop important professional skills and conduct meaningful reporting. All contributions are tax-deductible.

Link:
Eugenics on the Farm: Ray Lyman Wilbur - The Stanford Daily

Osteoarthritis is a degenerative joint disease that is the most common type of arthritis. Usually, it occurs among people of advanced age. But it can begin in middle age or even sooner, especially if theres been an injury to the joint.

While there are treatments available exercise, braces or canes, loss of excess weight, various pain relievers and anti-inflammatory medicines these are no cures, and none of the treatments are predictably effective. In fact, often they dont work at all, or help only a little. Injected steroids or synthetic lubricants can be tried as well. When all else fails, joint replacement surgery can be highly effective. In fact, about a million joint replacements (mostly knees and hips) are performed each year in the US.

So, its no surprise that people with osteoarthritis will try just about anything that seems reasonably safe if it might provide relief. My patients often ask about diet, including anti-inflammatory foods, antioxidants, low-gluten diets, and many others. Theres little evidence that most of these dietary approaches work. When there is evidence, it usually demonstrates no consistent or clear benefit.

Thats why a new study is noteworthy: it suggests that curcumin, a naturally occurring substance found in a common spice, might work for osteoarthritis.

In the study, researchers enrolled 139 people with symptoms of knee osteoarthritis. Their symptoms were at least moderately severe and required treatment with a nonsteroidal anti-inflammatory drug (NSAID). For one month, they were given the NSAID diclofenac (50 mg, twice daily) or curcumin (500 mg, three times daily).

Why curcumin? Its a naturally occurring substance, found in the spice turmeric, that has anti-inflammatory effects. Its use has been advocated for cardiovascular health, arthritis, and a host of other conditions. However, well-designed studies of its health benefits are limited.

Heres what this study found:

Not so fast. Its rare that a single study can change practice overnight, and this one is no exception. A number of factors give me pause:

Studies of this sort are vitally important in trying to understand whether dietary changes can be helpful for arthritis. While this new study provides support for curcumin as a treatment for osteoarthritis of the knee, Id like to see more and longer-term studies in osteoarthritis and other types of joint disease, as well as more extensive testing of its safety, before recommending it to my patients.

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Curcumin for arthritis: Does it really work? - Harvard Health Blog - Harvard Health

Despite recent advances in the treatment of rheumatoid arthritis(RA) attributed to biologic medications, only a minority of patients achieve andmaintain disease remission without the need for continuous immunosuppressive therapy.1Complicating the treatment of RA further is the development of tolerance over timeor failure of patients to respond to currently available therapies.1Thus, the development of new treatment strategies for RA remains a priority.

Nanotherapies for RA have received increasing attention in the past decade because they offer several potential advantages compared with conventional systemic therapies.2 Nanocarriers are submicron transport particles designed to deliver the drug at the site of inflammation the synovium thereby maximizing its therapeutic effect and avoiding unwanted systemic adverse effects.1 This targeted drug delivery approach also has the potential to minimize the amount of drug required to control joint inflammation3 and increase local bioavailability by protecting it from degradation in the circulation.1

In essence, nanotechnology enables the redesign of alreadyeffective rheumatologic medications into nanoformulations that may confer greaterspecificity, longer therapeutic effect, and more amenable safety profile.4Nanoencapsulated nonsteroidal anti-inflammatory drugs (NSAIDs),5 liposomaland polymeric preparations of glucocorticoids,6 and nanosystems thatdirectly inhibit angiogenesis are just several examples of nanotherapies that havebeen tested in experimental models of inflammatory arthritis.7

Despite the promising findings observed in studies to date, further development and subsequent integration of nanotherapies in the management of RA remains hampered by the lack of efficacy and toxicity studies in humans. In an interview with Rheumatology Advisor, Christine Pham, MD, chief of the Division of Rheumatology at the Washington University School of Medicine in St Louis, discussed the advantages and challenges of applying nanotherapies in RA.

RheumatologyAdvisor: How can nanotechnology be applied in the treatment of RA?

ChristinePham, MD: Nanotechnology is a multidisciplinary approach aimed at the deliveryof therapeutic agents using submicron nanocarriers. In RA, the vessels at the siteof inflammation are leaky, allowing passage of these nanocarriers from the circulationto specific target sites in the joint environment.

RheumatologyAdvisor: Which RA drugs are suitable forthis approach?

DrPham: Many conventionalantirheumatic drugs such as methotrexate, glucocorticoids, and NSAIDs have beensuccessfully delivered by nanocarriers to mitigate inflammatory arthritis in experimentalmodels.

RheumatologyAdvisor: Whatare the main advantages of using nanotherapy/nanocarriers, as opposed to systemictherapy, in the treatment of RA?

DrPham: The mainadvantages are selective drug delivery to desired sites of action through passiveor active targeting, which can lead to increased local bioavailability and potentiallycan reduce unwanted off-target side effects. In addition, nanocarriers may increasethe solubility of certain drugs and protect therapeutics against degradation inthe circulation.

RheumatologyAdvisor: Howfar has the medical community gotten in developing (and testing) nanotherapies forRA? Which nanotherapies have shown the most promise?

DrPham: A numberof nanotherapeutics have been developed and tested in animal models of RA. Mosthave shown disease mitigation, however, none has so far made it to the clinic.

RheumatologyAdvisor: Whatneeds to happen before nanotherapies can get fully integrated into clinical practiceand treatment of patients with RA?

DrPham: Insufficientdata regarding long-term toxicity and optimal therapeutic efficacy have hamperedtheir integration into clinical practice. Anticytokine biologics have been verysuccessful, so nanotherapeutics need to show clearly that they have higher efficacyand lower toxicity for pharmaceutical companies to invest in their development forthe clinic.

Rheumatology Advisor: Are any other promising treatment strategies for RA currently under investigation?

DrPham: RNA interference(RNAi) has recently emerged as a specific way to silence gene expression. The invivo delivery of small interfering RNA (siRNA), however, remains a significant hurdle,given the short half-life of the molecule in the circulation. We have used a self-assemblingpeptide-based nanosystem that protects the siRNA from degradation when injectedintravenously and which has shown to mitigate experimental RA.8,9 siRNAworks by knocking down NFkappaB p65, asubunit of NF-kappa-B transcription complex which plays acentral role in inflammation in general and in RA in particular. This platform promisesto have real translational potential.

References

1. Pham CTN. Nanotherapeutic approaches for the treatment of rheumatoid arthritis. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2011;3(6):607-619.

2. Dolati S, Sadreddini S, Rostamzadek D, Ahmadi M, Jadidi-Niaragh F, Yousefi M. Utilization of nanoparticle technology in rheumatoid arthritis treatment. Biomed Pharmacother. 2016;80:30-41.

3. Rubinstein I, Weinberg GL. Nanomedicine for chronic non-infectious arthritis: the clinicians perspective. Nanomedicine. 2012;8(Suppl 1):S77-S82.

4. Henderson CS, Madison AC, Shah A. Size matters nanotechnology and therapeutics in rheumatology and immunology. Curr Rheumatol Rev. 2014;10(1):11-21.

5. Srinath P, Chary MG, Vyas SP, Diwan PV. Long-circulating liposomes of indomethacin in arthritic ratsa biodisposition study. Pharm Acta Helv. 2000;74:399-404.

6. Metselaar JM, Wauben MH, Wagenaar-Hilbers JP, Boerman OC, Storm G. Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes. Arthritis Rheum. 2003;48:2059-2066.

7. Koo OM, Rubinstein I, nyuksel H. Actively targeted low-dose camptothecin as a safe, long-acting, disease-modifying nanomedicine for rheumatoid arthritis. Pharm Res. 2011;28:776-787.

8. Zhou H-F, Yan H, Pan H, et al. Peptide-siRNA nanocomplexes targeting the NF-kB subunit p65 suppress nascent experimental arthritis. J Clin Invest. 2014;124:4363-4374.

9. Rai MF, Pan H, Yan H, Sandell L, Pham C, Wickline SA. Applications of RNA interference in the treatment of arthritis. Transl Res. 2019;214:1-16.

Link:
Nanotherapies for Rheumatoid Arthritis: Advantages, Challenges, and Future Direction - Rheumatology Advisor

Psoriasis in ankylosing spondylitis (AS) is not related to axial psoriatic arthritis (PsA), a type of psoriasis that causes lower back inflammation and pain similar to AS, according to a study published in Rheumatology.

The study included approximately 1303 patients with PsA and 766 patients with AS from 2 Canadian clinics. Of the patients with PsA, 477 had axial PsA and 826 had peripheral PsA. In the AS group, 91 participants had psoriasis and 675 did not.

Patients at both clinics were followed and assessed using a variety of diagnostic tools, with visits every 6 to 12 months for an average of 12.6 years for patients with axial PsA and 6.7 years for the patients with peripheral PsA. The average follow-up for AS with psoriasis was 5.4 years and 3.5 years for those without psoriasis.

The analysis showed that overall, patients with AS were younger at diagnosis, with an average age of 21.3 years in patients with psoriasis and 22.9 years in those without psoriasis compared with axial patients with PsA who had an average age at diagnosis of 34.4 years. There were also more males in both AS groups compared with the axial PsA group.

Spondyloarthritis is a family of inflammatory diseases causing arthritis and involves areas where ligaments and tendons attach to bones. AS is the most common form of spondyloarthritis and mainly affects the joints at the base of the spine where it meets the pelvis.

More patients in both AS groups tested positive for HLA-B27, a genetic marker for inflammatory arthritis of the spine and joints. Of the AS patients with psoriasis, 82% tested positive, while 75% of those without psoriasis tested positive. In the axial PsA group, only 19% tested positive.

Approximately 90% of patients with AS with psoriasis and 92% without psoriasis reported back pain compared with only 21% of patients with axial PsA. Furthermore, compared with patients with axial PsA, patients with AS and with and without psoriasis had a higher grade of sacroiliitis, or inflammation of the joints connecting the lower spine to the pelvis.

When the data were analyzed over time, there was also an increase in joint swelling in both patients with axial PsA and patients with peripheral PsA, whereas patients with AS with or without psoriasis were more likely to have back pain and a higher BASMI, or Bath Ankylosing Spondylitis Metrology Index, a measure of AS disease severity.

The study reveals that axial PsA and AS with psoriasis are 2 different diseases with different genetics, demographics, and disease expression, according to the study authors.

Reference

Excerpt from:
Ankylosing Spondylitis Not Linked to Axial Psoriatic Arthritis - Pharmacy Times