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Archive for the ‘Stem Cell Negative’ Category

Adipose derived mesenchymal stem cell secretome formulation as a biotherapeutic to inhibit growth of drug resistant triple negative breast cancer |…

Wednesday, December 8th, 2021

One of the major hurdles in cancer therapy is the lack of appropriate treatments that would annihilate the cancer cells to increase the survival of patients. Thus, combinations of various chemicals were used based on the overall molecular phenotype of the type of cancer cells. Therefore, any new strategy that would help in the treatment of any aggressive form of cancer will be welcoming. One such aggressive form of cancer is TNBCs. Current treatment option for treating TNBCs cantered around paclitaxel6,7 and neo-adjuvant therapy8,9. Over a decade, it is becoming clear that stem cell conditioned medium containing secretome may be a good therapeutic in treating cancer35,36,37,38,39,40,41,42,43,44,45. Thus, we here show the functional and biochemical characterization of MSC secretome and its effectiveness in inducing apoptosis in TNBC cells.

Though previous studies had characterised and identified proteins52,53,54 in the secretome, we have prepared the stem cell secretome in a GMP compliant55 FDA approved stem cell media and quantified all the major biomolecules in the freeze dried powder (Fig.1). On the same note, lipid spectral characteristics seen in Fig.1h is indicative of anti-cancerous nature as suggested by Brossa et al.56. Mineral components profiled in Fig.1 could be the crystalline particles seen in control (Fig.1a) and flakes could be formed from protein (growth factor supplements in the chemically defined medium of stem cells) FESEM image (Fig.1a) and (carbohydrate) glucose quantified in Fig.1f. Ca, P and Fe are essential elements constituted as inorganic nutrient supplements in such media. Fe is a key element in cancer cell metabolism and Ca and P are thought to play a beneficial role in cancer. These minerals present in secretome and not present in the form of crystals on flakes in Fig.1b could be due to the presence of metallo-proteins in secretome. Protein and RNA are major components in freeze dried secretome and could be forming the needle like structures in Fig.1b. Exosomes57 present in the secretome could not be definitively identified in control, Fig.1a.

Although stem cell secretome was prepared by many by conditioning stem cells in a growth medium for a specific time35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,52,53,54, the process if not controlled52 and balanced with respect to incubation conditions could lead to nutrient deprivation resulting in cell death or growth arrest35,36,37,38,39,40,41,42,43,44,45. As a result, contradicting results have been reported46,47,48,49,50 and could be attributed to the variability in preparation and processing methods. Thus, to address this issue, we designed our first experiment to address the issue of whether the anti-cancer effects reported35,36,37,38,39,40,41,42,43,44,45 was the outcome of using stem cell conditioned media that is deprived of nutrients or due to the secretome. Towards this, freeze dried secretome were supplemented with nutrients in chemically defined media of TNBCs (CDM). The media alone significantly increased population of cancer stem cells (CD44+/CD24 phenotype) in TNBCs (Fig 2a) likely due to the presence of insulin, hydrocortisone and epidermal growth factor that are known to contribute to colony formation characteristic feature of cancer stem cells51. However, the same markers were substantially decreased when the same media contained secretome (Fig. 2g). For the first time, we show a dose dependent cytotoxic effect of SF which is similar to the anti-cancer effect of secretome reported previously35,36,37,38,39,40,41,42,43,44,45. At 20 mg/ml, the effect on cancer cell death was 50% (Fig. 2b). However, at higher concentrations of SF significant cancer cell death could be observed (Fig. 2c) up to 80%.

It is clear from Fig.2e with different amounts of lyophilized powder of the chemically defined media of MSCs added to the chemical defined media of TNBCs without exposure to MSC cells (secretome free) that the cell viability shown in Fig.2e was not affected compared to control. This suggested there was no effect of changes in the salt concentrations in the chemically defined medium affecting cellular homeostasis. Further, SF dose dependent decrease in cell viability (Fig.2c) corresponded with in Fig.2f showing cellular apoptosis, which suggested that decreased cell viability observed, is indeed due to the result of apoptosis. Since the cell line we used belonged to mesenchymal stem like and mesenchymal like category (MDA-MB-231) among the six different TNBCs due to heterogeneity, we checked for stemness markers CD44+/CD24 and MDR1+4,5 (multi drug resistance protein 1), and also PDL1+6,58 (Programmed Death Ligand 1) as these population of cells can be potentially harmful with respect to invasion and aggressiveness. To our surprise, the percentage of total CD44+/CD24, MDR1+ and PD-L1+ TNBCs following treatment with SF was brought down dramatically (Fig.2g) suggesting the significance of secretome medium in the removal of these aggressive phenotypes from the TNBC population. To further verify our findings we checked the effect of SF on xenograft models of TNBCs.

Tumor microenvironment is known to play a critical role in the response to therapy59 and hence to confirm the anti-cancer potential, tumor spheroids were treated with SF. Results in Fig.3a and supplementary Fig.S2B showed that IC50 value of SF in 3D culture was 32.57mg/ml three times of the IC50 value in 2D culture shown in Fig.2c and Supplementary Fig.S2A, the latter being only 10.54mg/ml SF. Thus there was found evidence indicating greater resistance of spheroids to secretome formulation treatment. It was interesting to note that 50mg/ml SF in 3D culture (Fig.3a) that had similar effect to 20mg/ml SF in 2D (Fig.2c) signifying a difference in response associated with more stem like characteristics59 and metabolic deregulation60.

SF was administered into the tumor for 21 consecutive days in the light of treatment duration previously reported by others10,11,12,41. Thus, the calculated equivalent dose corresponding to once a day intra-tumor administration of 10X secretome is found to be 200mg/ml41. Thus, we treated tumor with 50 and 100mg/ml SF led to undetectable TNBCs from 1mm3 tumor stroma (Fig.3b). As shown in Fig.3b, c, significant suppression of overall tumor growth and CD44+/CD24, MDR1+3,4,5 and PD-L1+6,58 cell types that are involved in stemness and invasion was observed indicating the significance of SF in effectively controlling TNBC growth. Indeed, eradication of these populations has immense value in developing therapies for cancer as cancer stem cells very much drive tumorigenesis, metastasis and therapeutic resistance3,4,5,6,7. The histopathology data of Fig.3d clearly showed necrotic tumor patches with murine cells in the vicinity that developed after SF in vivo treatment.

Figure4a shows that there was no significant difference between 1nM and 100M compared to the reported 100% effective concentration of 10nM61. This is evidence of paclitaxel resistance. Interestingly, the extent of reduction of CD44+/CD24 breast cancer stem cells, multi drug resistance protein 1 (MDR1), programmed death ligand-1(PD-L1) expressing cells were far less than that due to SF seen in Fig.2g. It is to be noted that many reports indicate the use of taxane based therapies for TNBC type9 to overcome the drug resistance mechanisms associated with these cell types3,9. Thus, we compared the effect of paclitaxel with SF by treating TNBCs with SF and paclitaxel near to its IC50 value and beyond singly or in combination (Fig.4). Although, at the IC50 value of paclitaxel we observed significant cell death, a significant population of TNBCs were resistant to paclitaxel and that SF medium alone at 70mg induced significantly more death of TNBCs than paclitaxel (Fig.4ac).

It has been reported that tumor micro environment plays significant role in determining the therapeutic efficacy of paclitaxel3,59. Thus, we verified the effect of SF and paclitaxel in a 3D environment to find its influence on the observed cell death. Using the developed 3D cultures of TNBC (Fig.5), we found similar pattern of cell death as observed in our 2D and in vivo studies confirming the effect and significance of SF medium in inducing cell death. Nonetheless, Figs. 4c and 5 confirms prospective use of SF 70mg/ml in combination with lower doses of paclitaxel. This clearly demonstrate that a combination of MSC secretome with lower doses of paclitaxel can be used to minimise toxic side effects of using higher doses of paclitaxel as previously reported62 in the treatment of highly chemo resistant TNBCs in clinics.

All the results discussed in Figs.1, 2, 3, 4 and 5 suggest the prospective therapeutic potential of SF for clinical management of highly chemo resistant cancer types. Perhaps SF formulation could also favour efficacy of paclitaxel at lower dose which is otherwise highly neuro-toxic when administered at higher doses62. It would be interesting to fractionate or separate each of the biomolecule in Fig.1 to further study the contribution of them towards the anti-cancer effects discussed. In conclusion our study clearly illustrates that SF is effective in suppressing tumor growth and inducing TNBC cell apoptosis in a manner efficient than paclitaxel. Importantly, cells with PDL1+, CD44+/CD24, MDR1+ phenotypes that are potentially harmful with respect to invasion and aggressiveness could significantly be eliminated from TNBC population. Moreover, combination of SF with paclitaxel could be used to reduce the toxic effect of paclitaxel and add value to the finding. In addition, targeting the genes associated with cancer progression and survival following SF treatment could improve the treatment outcome. Further in-depth gene expression studies are required to apprehend the detailed molecular path ways associated with apoptotic mechanisms that are responsible for the anti-cancer potential of stem cell secretome. Protein and RNA characterisation of the secretome would also help to identify molecules responsible for nucleic acid degradation seen in spheroids and mechanisms involved in immune cell infiltration into tumor stroma. Based on our results, we envisage the potential of SF in combination therapies for the treatment of aggressive forms of TNBC.

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Adipose derived mesenchymal stem cell secretome formulation as a biotherapeutic to inhibit growth of drug resistant triple negative breast cancer |...


All at-risk TN-bound travellers test Covid negative – The New Indian Express

Wednesday, December 8th, 2021

Express News Service

CHENNAI:Tamil Nadu on Wednesday tested 88 samples and 50 random samples for Covid-19 from international air travellers who arrived from at-risk countries. All the samples collected tested negative, said a senior Health Department official. The procedures were put in place following the Union Health Ministry issuing guidelines on international arrivals, in the wake of the Omicron variant alert from WHO.

In case if any sample is tested positive, the State will send it for genome sequencing at the State Public Health Laboratory (SPHL) in the DMS campus or the Institute for Stem Cell Science and Regenerative Medicine (InStem) in Bengaluru to confirm the virus variant.

After the emergence of the Omicron variant, the State has also designated 12 government RT-PCR labs to use Thermo Taqpath RT-PCR kits for detecting three target genes in the virus, including the S gene, which would inturn help detect whether its the Omicron variant. It is reported that one of the S gene target is not detected in the Omicron variant due to its mutations.

Speaking to TNIE, Deepak Jacob, MD of Tamil Nadu Medical Services Corporation said the State has over 3.25 lakh Thermo Taqpath kits, and that there is no dearth in its supply. Director of Public Health Dr TS Selvavinayagam, in a video message on Wednesday, said the State has activated a surveillance mechanism after the WHOs alert. He said nodal officers have been appointed at all international airports, and that passengers from 12 countries including China, Hong Kong, United Kingdom and Singapore will be screened and tested.

The State is also sending samples taken from Covid clusters such as those reported in schools for genome sequencing so that the virulence and transmissibility of any new variant in circulation is known, Selvavinayagam added. Reinfection cases; post-vaccination infections; vaccine breakthrough infections; community cluster; unusual transmission events; family clusters; children positive for Covid-19; young adults with severe lung involvement, unexpected disease presentation, and Covid-19 patients with no comorbidities are also put under scanner for genome sequencing. A Health Department official said it will take a maximum of seven days for genome sequencing the samples, and each test would cost nearly Rs 4,000.

Variant of concern

A look at how the State is preparing to identify cases with the Omicron variant of Covid

Any sample with S gene dropout or S gene target failure from government or private RT-PCR labs should be referred to State Public Health Laboratory (SPHL) for sequencing confirmation of Omicron variant

A sudden increasein S gene target failures may be indicative of circulation of Omicron variant. However, confirmation by sequencing is recommended

Thermo Taqpath kits recommended in government labs for detecting three target genes

Institutes with approval for using Thermo Taqpath kitsState Public Health Laboratory, King Institute of Preventive Medicine, Madras Medical College, Kilpauk Medical College, Stanley Medical College,Coimbatore Medical College, ESI Medical College, Trichy Medical College, Salem Medical College, Madurai Medical College, Tuticorin Medical College and Kanyakumari Medical College

Source: Directorate of Public Health

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All at-risk TN-bound travellers test Covid negative - The New Indian Express


Good Stocks To Invest In Right Now? 4 Health Care Stocks To Check Out – FW Business

Wednesday, December 8th, 2021

4 Top Health Care Stocks Worth Watching Now

Health care stocks have and continue to make headway in the stock market now amidst the current pandemic. From firms directly dealing with the global coronavirus outbreak to day-to-day health care providers, investors have plenty of options. For starters, investors appear to be reacting positively to the latest findings on the Omicron variant. While this may just be preliminary data, the variant appears to be more tamed in terms of severity than initially expected. Even so, some of the biggest names in the health care industry are already looking for solutions.

In fact, GlaxoSmithKline (NYSE: GSK) and Vir Biotechnology (NASDAQ: VIR) provided a crucial update on this front earlier today. Namely, data suggests that their coronavirus vaccine, sotrovimab, retains effectiveness against the Omicron variant. On top of that, the duo also notes that the drug is also effective against all other variants of concern defined to date by the WHO. At the same time, there seems to be no shortage of newcomers in the industry as well. As of today, Alvotech, an Iceland-based biopharma firm, is now looking to go public via a $2.25 billion SPAC deal. With all that said, could one of these health care stocks be worth watching in the stock market today?

Best Health Care Stocks For Your December 2021 Watchlist

Acadia Pharmaceuticals Inc.

First up, we have Acadia Pharmaceuticals, a biotech company with more than 25 years of experience in the industry. It has been at the forefront of health care, bringing vital solutions to people who need them most. Also, the company has developed and commercialized the first and only approved therapy for hallucinations and delusions associated with Parkinsons disease psychosis. Specifically, its late-stage development efforts are focused on dementia-related psychosis, negative symptoms of schizophrenia, and Rett syndrome. ACAD stock currently trades at $21.42 as of 2:26 p.m. ET and is up by over 10% on todays opening bell so far.

Investors are likely responding to news that the company posted yesterday. Diving in, Acadia announced positive top-line results from its pivotal Phase 3 Lavender study. The study evaluated the efficacy and safety of trofinetide in 187 girls and young women aged 5-20 years with Rett syndrome. The 12-week placebo-controlled study demonstrated a statistically significant improvement over placebo for both co-primary endpoints. Given this piece of information, will you consider watching ACAD stock right now?

Novavax Inc.

Novavax is a health care company that develops vaccines to counter serious infectious diseases. Through the discovery and commercialization of innovative vaccines, the company has developed experimental vaccines to combat Covid, seasonal influenza, RSV, Ebola, MERS, and SARS. Its NanoFlu vaccine, for instance, is a quadrivalent influenza nanoparticle vaccine that has met all primary objectives in its Phase 3 clinical trial in older results. NVAX stock currently trades at $179.82 as of 2:26 p.m. ET and is up by over 26% on todays opening bell.

On Tuesday, the head of the European Medicines Agency (EMA) says that it could soon approve the Covid vaccine developed by Novavax. Earlier in the month, the company also announced a statement for its Omicron variant response. It is conducting ongoing studies to evaluate multiple variants and is encouraged by its current and ongoing data. The company will also begin testing whether antibodies from previously vaccinated individuals can neutralize the Omicron variant, with lab-based data expected in the coming weeks. With the excitement surrounding Novavax, is NVAX stock worth adding to your portfolio right now?

Cellectis SA

Following that, we have Cellectis, a biopharmaceutical company that develops genome-edited chimeric antigen receptor T-cell technologies as a form of cancer immunotherapy. In essence, it is pioneering the concept of off-the-shelf and ready-to-use gene-edited CAR T-cells to treat cancer patients. It also has a platform to achieve therapeutic gene editing in hemopoietic stem cells for various genetic disorders. CLLS stock currently trades $9.43 as of 2:27 p.m. ET.

Last month, it expanded a collaboration with Cytovia Therapeutics of TALEN gene-edited iPSC-derived (induced pluripotent stem cells) Natural Killer and Chimeric Antigen Receptor Natural Killer cells to include new CAR target and development in China. We are pleased to expand the collaboration with Cellectis to enable Cytovia to develop iNK products that will leverage the high-precision of TALEN to perform gene-editing to minimize the risk of off-target effects and unlock the full potential of NK cells as a first line of defense against cancer, says Cytovia CEO Dr. Daniel Teper. All things considered, is CLLS stock worth buying today?

Intellia Therapeutics Inc.

Another name to consider in the health care world now would be Intellia Therapeutics. For the most part, Intellia is a leading clinical-stage genome editing company. Through its groundbreaking work with CRISPR/Cas9 tech, the company aims to develop gene-editing therapies. The likes of which Intellia conducts tests on via two key approaches. Firstly, its in vivo program employs CRISPR treatments that are injected directly into patient bloodstreams. Secondly, Intellias ex vivo efforts involve the use of CRISPR to treat cancer and autoimmune diseases via engineered cells. Technical details aside, investors appear to be keen on NTLA stock now.

Evidently, the companys shares currently trade at $119.74 as of 2:27 p.m. ET. This would be after gaining by over 110% year-to-date. Regardless, Intellia does not seem to have plans to slow down anytime soon. As of late November, the company revealed plans to expand its ongoing Phase 1 study NTLA-2001. Through this expansion, Intellia will be opening up enrollment into the trials for NTLA-2001 to adults with Transthyretin Amyloidosis with Cardiomyopathy (ATTR-CM). CEO Dr. John Leonard notes that ATTR is a chronic, fatal disease that impacts vital organ function. Could all this make NTLA stock worth keeping an eye on for you?

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Good Stocks To Invest In Right Now? 4 Health Care Stocks To Check Out - FW Business


Pandemic lockdown declined emotional well-being for adults with hearing, vision loss: Study –

Wednesday, December 8th, 2021

Seattle (Representational image), December 7 (ANI): A recent study has found that the lockdown during the pandemic caused mental and emotional issues amongst adults who had sensory impairment.

Peggy Nelson, of the University of Minnesota, outlined the impacts in her presentation at the '181st Meeting of the Acoustical Society of America'.

Nelson and her team surveyed three groups of older adults from the Twin Cities community: people with vision loss, people with hearing loss, and people without either condition. They asked the participants about their worries, well-being, and social isolation at six-week intervals from April 2020 to July 2021. The period corresponded to strict lockdowns in Minnesota, with some restrictions easing toward the end of the study.

"People with low vision were really hit hard," said Nelson.

"Their whole mobility systems are built around public transportation and being around other people," Nelson added.

Masks made conversations especially difficult for adults with hearing loss, leading them to prefer virtual options for health care visits, among other scenarios. However, the overall quieter environment during stay-at-home orders may have compensated for some of the negative effects.

While Moore said that the changes brought by the pandemic often led to a loss of independence for impaired adults, some solutions may be within reach.

"We'll hopefully find a new hybrid world," she said.

"People with low vision can be close to other people as needed, and people with hearing loss can have remote access to clear communication when masks would prevent that," she concluded. (ANI)

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Pandemic lockdown declined emotional well-being for adults with hearing, vision loss: Study -


Impact of microbial contamination of haematopoietic stem cells on post-transplant outcomes: A retrospective study from tertiary care centre in India -…

Tuesday, August 17th, 2021

This article was originally published here

Transfus Med. 2021 Aug 15. doi: 10.1111/tme.12805. Online ahead of print.


BACKGROUND: Haematopoietic stem cells (HSC) may act as a source of infection for the recipient due to manipulation at multiple levels from collection to infusion. Due to the high risk of contamination cultures are usually taken during multiple steps. The clinical significance of microbial contamination of HSC on the post-transplant course and the role of prophylactic antibiotics is relatively unknown.

AIMS AND METHODS: The aim of our study is to investigate the incidence of microbial contamination of haematopoietic stem cell and to assess its impact on the post-transplant febrile neutropenia, engraftment kinetics, hospitalisation and day 100 mortality. Details of all patients admitted in the bone marrow transplantation unit of a tertiary care centre in India between January 2014 and December 2018 were collected from case records.

RESULTS: Of the 1306 stem cell harvests from 503 patients sent for culture, 17 harvests (1.3%) were found to have a culture positive report. Sixteen patients had undergone autologous transplant. Multiple myeloma was most common indication of HSC transplant followed by Non-Hodgkin Lymphoma (NHL). Twelve of 17 HSC cultures were positive at the time of infusion and five were positive at the time of harvest. The five HSC that were culture positive at the time of harvest were culture negative at the time of infusion. Gram-positive organisms were isolated in six cultures and gram-negative in rest. All patients developed febrile neutropenia post-transplantation between day 1 and day 7. The median time of onset of fever was day +5 (1-7), the median duration of fever was 4 days (2-7), the median duration of antibiotic use was 11 days (9-16). Median day for neutrophil engraftment was 11 days (9-16), the median day for platelet engraftment was 14 days (10-25) and median duration of hospitalisation was 15 days (12-78). All patients were alive at day 100 of transplant.

CONCLUSION: This study shows that there appears to be minimal impact of culture positive HSC on transplant related outcomes in terms of engraftment kinetics, duration of hospitalisation and day 100 mortality. Discarding of contaminated HSC may not be required, though on development of febrile neutropenia appropriate antibiotics should be administered based on sensitivity pattern of HSC culture. Larger prospective studies are needed to determine the clinical relevance of such contaminations. Emphasis should be laid on better infection control practices to minimise contamination rates.

PMID:34396610 | DOI:10.1111/tme.12805

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Impact of microbial contamination of haematopoietic stem cells on post-transplant outcomes: A retrospective study from tertiary care centre in India -...


Longeveron: Time to Buy the Di –

Tuesday, August 17th, 2021

Longeveron Inc. (LGVN, Financial) is an emerging clinical-stage biotechnology player that utilizes stem cell research. It is working towards developing regenerative medication via allogeneic mesenchymal stem cells. It is in the progress of building a number of cellular therapies at its facility, utilizing healthy bone marrow of adult donors to develop treatments for aging and aging-related diseases like Alzheimers Disease.

The companys lead candidate is a therapy known as Lomecel-B, an allogeneic product containing medicinal signaling cells from the adult donor bone marrow (from an 18 to 45 age group) and culture expanded in the companys cell processing facility. They identify and use cells with regenerative properties to build a therapy that could carry out various functions, including tissue repair and organ maintenance.

Longeveron has been in the news recently as it released the data of the Phase 2b aging frailty trials for Lomecel-B. The results did not live up to expectations, causing the stock to plunge. However, the long-term prospects of the company have not changed, in my opinion, which could mean now is a great opportunity to buy the dip.

The Phase 2b trial data

Longeveron carried out a multi-center study to assess the effect of its lead candidate Lomecel-B therapy on 148 random subjects. Its trial was partially funded by an SBIR (Small Business Innovation Research) grant from the National Institute of Aging. The company carried out a single peripheral intravenous infusion of the lead candidate in various quantities ranging from 25 million to 200 million cells. It kept the subjects under observation for 52 weeks to evaluate the efficacy and safety of the therapy. The management performed a six-minute walk test on the subjects to assess their exercise tolerance and endurance in order to evaluate the impact of the treatment. This test also analyzed gait speed, short physical performance battery, grip strength, performance-oriented mobility assessment, sexual function, cognition, depression and other factors associated with the subjects in their daily lives.

Longeveron did not see statistically significant results compared to the placebo after 180 days, which is what has disappointed investors and led to the recent selloff. However, the management saw a significant difference from placebo after 270 days of the treatment. Moreover, Lomecel-B continues to demonstrate a high level of safety as no patients showed signs of any severe adverse conditions.

The information is sufficient for Longeveron to continue pursuing their research aggressively, not just in the U.S. but in other countries as well. The management aims to initiate the Phase 2 Japanese Aging Frailty trial this year while waiting for the results of Phase 1/2 HERA trial data. The 'HERA' trial data is expected to evaluate the effects of Lomecel-B on the immune response to influenza vaccination in Aging Frailty subjects.

The importance of aging and frailty research

Aging Frailty-oriented research is gaining a very high amount of importance because of its substantial addressable market. Most patients who suffer from it show symptoms like muscle loss and decreased strength, low-level activity, slow walking, poor energy level and endurance, weight loss, nutritional deficiencies and fatigue. It has a negative impact on muscle and bone tissue health. Apart from muscles and bones, aging and frailty also negatively affects the cardiovascular system, immune system and cognition.

Stem cell treatments for aging-associated diseases are a crucial area of research given the ageing population. However, there are no FDA approved stem cell treatments in the U.S. within this domain. The potential addressable market for aging and frailty is rising sharply due to the gradual increase in average life expectancy as well as declining birth rates. Longeveron is one of the key movers in this domain and has shown significant results through their Lomecel-B therapy trials.

While the trials may not have shown a statistically significant result in a 180-day period, the 270-day data is extremely encouraging for the companys future. Furthermore, if the Lomecel-B trials continue to show success in the upcoming quarters, Longeveron could become a top candidate for a large pharma acquisition.

Is the crash justified?

Longeverons stock crashed after the companys Phase 2b press release came out, but is this crash justified? The trial results may not have been positive for a 180-day time horizon as hoped, but the 270-day results have been encouraging. Moreover, given the fact that the safety of Lomecel-B has been unquestionable, this implies that the company can go ahead with other trials (including the Phase 2 trial for aging and frailty in the Japanese market) with great confidence.

There is also a huge upside potential with respect to the future prospects of Lomecel-Bs application in Alzheimers Disease and other ageing-related diseases. Last but not the least, the company has sufficient cash to go through with multiple trials across different geographies. Thus, I believe that the recent crash in Longeverons stock price is no reason for investors to panic. Moreover, biotech microcap investors with a high risk appetite could see this drop as an investment opportunity.

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Longeveron: Time to Buy the Di -


The latest on the Covid-19 pandemic in the US: Live updates – CNN

Tuesday, August 17th, 2021

The Department of Education is sending letters to the governors of Texas and Florida, as well as Florida school district superintendents, amid an escalating battle between the White House and state officials over school mask guidance as the Delta variant surges.

In a new letter Friday, Education Secretary Miguel Cardona wrote to Republican Gov. Ron DeSantis of Florida that he is deeply concerned by the states executive order restricting the implementation of school mask mandates. Cardona also took aim at the recent threat from the governors office that the state board of education could move towithhold the salariesof superintendents and school board members who disregard his executive order.

Cardona sent a similar warning to Texas Republican Gov. Greg Abbott and the states education commissioner Mike Morath, underscoring how Texass recent actions to block school districts from voluntarily adopting science-based strategies for preventing the spread of COVID-19 that are aligned with the guidance from the Centers for Disease Control and Prevention (CDC) puts these goals at risk and may infringe upon a school districts authority to adopt policies to protect students and educators as they develop their safe return to in-person instruction plans required by Federal law.

This follows statements from White House press secretary Jen Psaki earlier this week, whotold reportersthat the White House and federal government are continuing to look for ways to support local school districts and educators in Florida, as they try to follow the science do the right thing and save lives.

Psaki said later that paying for salaries could be a part of that, and the Department of Education is looking at options. Withholding funds is not the intention, she said.

Previously, Biden and members of his administration havespecificallytargetedthe governors of Florida and Texas for standing in the way of mask and vaccine requirements, pointing to the extraordinary amount of Covid-19 cases and hospitalizations in their states.

In Fridays letter to DeSantis and Corcoran, Cardona pointed to how Florida school districts can use funds from federal Covid relief for educators salaries, noting that any threat by Florida to withhold salaries from superintendents and school board members who are working to protect students and educators (or to levy other financial penalties) can be addressed using ESSER funds at the sole and complete discretion of Florida school districts.

In the letter to Florida school district superintendents, Cardona further emphasized the administrations support, saying, I want you to know that the U.S. Department of Education stands with you. Your decisions are vital to safely reopen schools and maintain safe in-person instruction, and they are undoubtedly in the best interest of your students.

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The latest on the Covid-19 pandemic in the US: Live updates - CNN


How this Holocaust refugee beat Covid-19 against all odds J. – The Jewish News of Northern California

Tuesday, August 17th, 2021

Vitali Voskoboiniks bright blue eyes sparkled behind his glasses as he sat in his sunny Pacifica apartment. At 79, the Holocaust refugee looked full of life; he laughed and smiled, introducing himself first in Russian, then in Hebrew, and then in English.

One would never guess that just a few months ago he was bedridden, unable to breathe independently or speak, and on the brink of death from a severe case of Covid-19.

To me, this is a miracle, said Lena Asadov, who helped care for Voskoboinik as administrator of South San Franciscos Angel Palliative Care and Hospice, Inc.

Asadov said when she had last seen him, Voskoboinik could barely sit on the edge of his bed without collapsing, his body and lungs extremely weakened from months of illness. On July 26, he stood to greet her, and he later walked down to the garden of his home at Terrace Senior Housing two accomplishments that no one was sure he would be able to achieve.

While Voskoboinik is not yet able to resume his two-mile walks to the Pacifica pier, he has made a remarkable recovery a feat Asadov credits to Voskoboiniks fighting spirit and his daughters perseverance.

Voskoboinik was born in 1941, on a train headed to Uzbekistan as his mother was escaping Nazi-occupied Ukraine. He never met his soldier father and only knew him through a series of letters his parents exchanged before his father was killed in the war. Voskoboinik grew up in the Soviet Union, where he met his wife, and together they moved to Israel. They lived there for 20 years before coming to America in 2014.

Voskoboinik passed down his fighting spirit to his only daughter, Yulia Nedzvetski, who advocated day and night for her father after he got sick in January.

Voskoboiniks symptoms began with a cough and difficulty breathing. His condition worsened rapidly, and after six days on antibiotics Voskoboinik was rushed to the ICU at Sutter Healths Mills-Peninsula Medical Center.

Once they had stabilized him, doctors estimated he had only months to live, Nedzvetski said. She refused to accept that prognosis. She had over 30 years of nursing experience in Ukraine, Russia, Israel and the U.S., as well as education in health care management and administration from Ariel University. But she also had something even more powerful: determination to get her father well again.

I knew he would get better, said Nedzvetski, who admitted to being so focused on his recovery she refused to accept that he was in critical condition.

Strict Covid safety precautions prevented her from seeing her father, except for a few times when she came to meet with doctors after she was vaccinated, but this did not stop her from dedicating her time and energy to his care. She left her job as a case manager at the VA and, with her two sons who live in Israel, set to work researching possible treatment options once doctors told her they had done everything they could, she said.

One treatment Nedzvetski suggested was proning, a process of carefully turning a patient in respiratory distress from their back to their stomach to help improve oxygen flow. Another was to use an ECMO machine, which pumps and oxygenates a patients blood outside the body, allowing the heart and lungs to rest. But Nedzvetski said she was told it was only for patients under 65.

I came with three, four, five different treatment options and everything was a no, said Nedzvetski. Its not something we do in the U.S., its not something we do for older people.

Eventually she became so frustrated and desperate she began demonstrating outside the hospital, at one point holding a sign that read Sutter, let the Holocaust survivor get the FDA approved medicine. Although she was able to meet with the ICU director and speak with a roundtable of doctors and nurses, she said they would not approve the treatments she suggested.

Nedzvetski believes that families must advocate even more than usual for their loved ones, with hospitals overwhelmed with Covid patients and visitation restricted. She said such limited access has had a negative impact on patient care.

J. asked Sutter Health about Voskoboiniks case but the hospital declined to comment.

Nedzvetski decided it was time to move her father back home and care for him there with help. But his condition was so dire he was under sedation, on a ventilator and under constant medical watch that as far as the hospital was concerned, he could not be discharged home safely.

Hospitals are and were dealing with a lot during this time, and Yulia did her best finding every possible solution, said Traci Dobronravova, director of Seniors At Home, one of the senior care services through Jewish Family and Childrens Services.

Nedzvetski utilized the help of Brigit Jacoby, Russian bilingual senior care manager at JFCS, who connected her with chaplain Bruce D. Feldstein of Jewish Chaplaincy Services at Stanford Medicine. He helped communicate with the hospital and contacted dozens of agencies about caring for Voskoboinik at home, but almost all saw his medical condition as a costly liability.

When you get into the world of experimental treatments there are a lot of protocols you have to follow, and his case fell outside of that, Feldstein. It really looked like he would not have made it, [and] it is heart-wrenching when theres a situation where you believe they should be able to help but they cant.

Then Nedzvetski found a compassionate ear at Angel Palliative Care and Hospice. I really felt for them, Asadov said. As a Jewish person who was also born in Ukraine, I just knew I needed to do everything I could to help.

Asadov said the transition from the ICU to home was extremely difficult, and that moving a patient on a ventilator to home hospice is not common. Nedzvetski said Sutter agreed to discharge her father home under the condition that she get instruction at the hospital on how to use all of the necessary medical equipment.

Asadov and the Angel Palliative Care and Hospice team helped Nedzvetski turn her home into a makeshift ICU room, complete with a hospital bed, ventilator, feeding tube and other medical supports. Nedzvetski said the agency was there whenever she needed assistance, and that one nurse, Lora Lemenov, even left her own birthday celebration to come help.

Once home, Voskoboinik was given stem cell treatment by a private physician and three days later, according to Nedzvetski, her father began to recover.

Within the month, Voskoboinik was breathing independently. As his condition improved, Angel Palliative Care and Hospice recognized that his care goals had changed and he was in need of rehabilitation services. They were able to safely graduate him from home hospice to a rehabilitation plan with Pacifica Nursing and Rehab Center. He was discharged back home in mid-July.

Asadov hopes that Voskoboiniks story will help change the stigma around hospice care, and make people aware that the goal is to provide comfort and improve patients quality of life, even if it turns out to be their final moments.

Everyone is scared of the word hospice. They hear that and think thats it, this is the end. said Asadov. But for him, hospice wasnt the end of his life. It was a new beginning.

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How this Holocaust refugee beat Covid-19 against all odds J. - The Jewish News of Northern California


Trade-offs among transport, support, and storage in xylem from shrubs in a semiarid chaparral environment tested with structural equation modeling -…

Tuesday, August 17th, 2021


Plant vascular systems play a central role in global water and carbon cycles and drought resistance. These vascular systems perform multiple functions that affect the fitness of plants, and trade-offs are present among these functions. Some trade-offs are well established, but studies have not examined the full suite of functions of these complex systems. Here, we used a powerful multivariate method, structural equation modeling, to test hypotheses about the trade-offs that govern this vital and globally important tissue. We show that xylem traits are broadly governed by trade-offs related to transport, mechanical support, and storage, which are rooted in cellular structure, and that the level of dehydration experienced by plants in the field exerts a strong influence over these relationships.

The xylem in plants is specialized to transport water, mechanically support the plant body, and store water and carbohydrates. Balancing these functions leads to trade-offs that are linked to xylem structure. We proposed a multivariate hypothesis regarding the main xylem functions and tested it using structural equation modeling. We sampled 29 native shrub species from field sites in semiarid Southern California. We quantified xylem water transport (embolism resistance and transport efficiency), mechanical strength, storage of water (capacitance) and starch, minimum hydrostatic pressures (Pmin), and proportions of fibers, vessels, and parenchyma, which were treated as a latent variable representing cellular trade-offs. We found that xylem functions (transport, mechanical support, water storage, and starch storage) were independent, a result driven by Pmin. Pmin was strongly and directly or indirectly associated with all xylem functions as a hub trait. More negative Pmin was associated with increased embolism resistance and tissue strength and reduced capacitance and starch storage. We found strong support for a trade-off between embolism resistance and transport efficiency. Tissue strength was not directly associated with embolism resistance or transport efficiency, and any associations were indirect involving Pmin. With Pmin removed from the model, cellular trade-offs were central and related to all other traits. We conclude that xylem traits are broadly governed by functional trade-offs and that the Pmin experienced by plants in the field exerts a strong influence over these relationships. Angiosperm xylem contains different cell types that contribute to different functions and that underpin trade-offs.

From cells to ecosystems, biological systems are complex and span multiple scales. To fully understand such systems, multivariate analytical methods are a powerful tool (1), yet it is most common to analyze variables separately or descriptively ordinate them. One powerful multivariate analytical framework is structural equation modeling (SEM) (2, 3). Plant vascular systems represent a complex multivariate system, where many traits determine functions in direct and indirect ways and interact with one another. There is much interest in understanding xylem in a systems context (46); however, using SEM to test hypotheses of the full range of xylem function in a single model has yet to be done. A positive development is that several recent studies that have applied SEM to understanding some xylem functions and traits (79).

Xylem functions include transport of water, mechanical support, and storage of water and carbohydrates (reviewed in ref. 6). These functions are interrelated, and associations among traits arise due to mechanistic links between structure and function. This can lead to trade-offs where prowess in one trait necessarily diminishes that of another (10). Traits may also be associated for at least two other reasons: shared ancestry, or when ecological conditions select for a suite of adaptive traits in different lineages in a process called concerted convergence (11).

We present relationships among xylem traits as a multivariate hypothesis in a path diagram (Fig. 1). The path model depicts the multiple variables, and the arrows (paths) represent connections between variables that can be direct (a direct arrow from one to another) or indirect (a direct arrow to a trait that has a direct path to a second trait), where indirect effects can be as important as direct ones. There are two central elements to our hypothesized model. First, that there are different cell types that are specialized to perform xylem functions: vessels conduct water; fibers provide support; and parenchyma stores carbohydrates (see also ref. 12). The division of cellular labor mitigates some direct functional trade-offs found in species with tracheid-based vascular systems (13); nevertheless, trade-offs may arise based on the amount of tissue volume allocated to different cells (4, 14). We examined this trade-off as a latent variable in our SEM model where cellular trade-off is represented by the proportions of different cell types in cross section (Fig. 1). The second centerpiece in our hypothesis is that the hydrostatic pressure potential experienced by plants during droughts or dry periods (Pmin) exerts a mechanical strain giving rise to direct and indirect effects on all other traits (11, 15, 16). This trait is affected by the environment (amount and timing of rainfall, temperature, and soil water content and conductance), and plant traits such as water use and hydraulic conductance, with additional links to many other traits (11).

Hypothesized relationships among the various xylem functions. The arrows represent pathways between two variables. Traits may have direct effects on another trait represented by an arrow directly connecting two traits, and traits may also exert indirect effects when they are connected through an intermediate trait. Latent variables are connected to their measured traits by gray arrows. Cellular trade-off is a latent variable represented by measured fiber, parenchyma, and vessel area in cross section. Tissue strength is represented by xylem density. Omitted are any double-headed arrows for variables with correlated errors (SI Appendix).

We hypothesized that Pmin is directly associated with embolism resistance and indirectly affects hydraulic transport efficiency (Fig. 1). Emboli are gas bubbles that form in conduits that block transport during drought or following freezethaw events (4). Species have evolved broad differences in embolism resistance (xylem safety) that is under strong selection by drought when negative pressures in the xylem exceed safety thresholds, leading to dieback and mortality (1719); moreover, xylem safety is strongly associated with Pmin (20, 21).

Increased embolism resistance is directly linked to reduced hydraulic transport efficiency in a well-studied trade-off (9, 22). Efficiency of xylem refers to the mass flow rate of water for a given pressure gradient and area of tissue (xylem-specific conductivity, Ks). No species has xylem that is simultaneously highly resistant to embolism (very safe) and highly efficient (23). One reason for this is because of the pits and pit membranes that connect conduits. These cellulosic membranes have nanoscopic pores, and the smaller these pores, the more resistant they are to embolism spread; however, smaller pores and thicker membranes reduce transport efficiency (22, 24). The arrangement and connections of the network of vessels in a vascular system is also an important factor (25). Globally and across angiosperm and gymnosperm lineages, a safetyefficiency trade-off has not been supported (16); however, within a specific lineage, community, or growth form, this trade-off can occur, and understanding this context is a research priority (9, 10). Pmin and efficiency are additionally predicted to be directly related because of an effect of Pmin on vessel diameters. Larger-diameter vessels are associated with greater efficiency (26), and such vessels can take longer to develop (27). If water is limited when vessels are developing, then the diminished turgor will limit vessel size (28).

Cellular trade-offs and tissue strength may be directly affected by Pmin because extreme pressures can strain conduits to the point of buckling damage or collapse (29). This threat is minimized by thicker cell walls between conduits, smaller conduit diameters, and an extensive and supportive fiber matrix (13, 30, 31), all of which create a series of direct and indirect paths (Fig. 1). First, these factors should lead to direct associations between Pmin and tissue strength (4, 29, 32) and with cellular trade-offs. A cellular trade-off affects tissue strength because more fibers promote strength at the expense of parenchyma and vessels (6). The association between tissue strength and Pmin creates four indirect paths from tissue strength (Fig. 1). These pathways lead to associations with embolism resistance and efficiency and that are hypothesized to arise because the more negative Pmin a plant experiences, the greater the need for vessels to resist embolism (30). Additionally, efficiency is reduced because smaller-diameter vessels better resist implosion (29), and stronger vessel walls are thicker and create deeper and longer pit chambers (24). Another indirect association is between tissue strength and water storage capacity. For nonsucculent woody species, most water is stored in the lumens of fibers and stronger tissues with thick-walled fibers, and narrow lumens have lower water storage (33). A final indirect association is predicted between tissue strength and Pmin through its effect on water storage, which leads to a feedback loop among these three traits.

Storage of carbohydrates in xylem allows plants to cope with variable and uncertain environments (34). Their diverse functional roles are an area of active research (34), and they are important to understand in the context of trade-offs (6, 8). Stored carbohydrates are found in parenchyma, thus increased storage capacity requires an increase in these cells [living fibers can also be important (35, 36)], which links cellular trade-offs to carbohydrate storage. Parenchyma may be structurally diverse, but they are generally thin-walled living cells that provide the least support to vessels in resisting implosion and mechanical strains contributing to the link between cellular trade-off and tissue strength and embolism resistance (30, 37). Pmin is hypothesized to be directly linked to starch storage because species that experience more negative Pmin osmoregulate by hydrolyzing starch to simple sugars (34, 38), which should create a negative association between Pmin and starch storage.

Two other direct trade-offs are predicted between cellular trade-offs and transport efficiency and embolism resistance. Previous work has found an association between the proportion of vessels in xylem (vessel area) and transport efficiency (32) or the proportion of vessel lumen area (39). We also predicted a direct relationship between cellular trade-offs and embolism resistance. This association could arise due to direct associations between proportions of cellular traits and their importance in resisting the strain of negative pressures, or this may simply be indirect through a direct effect on tissue strength. These associations also create the potential for indirect associations of Pmin with transport efficiency and embolism resistance through association with cellular trade-offs.

We used an SEM approach to test our model and hypotheses (represented in Fig. 1). Both cellular trade-offs and Pmin were predicted to affect all other traits directly or indirectly. Evaluating both simultaneously is informative, but to understand how they affected one another, we created an additional model with Pmin removed. Our hypotheses determined the paths in the diagram and the direction of their effects; however, other formulations are possible and are discussed. We measured variables representing different xylem functions and Pmin in 29 species of chaparral shrubs from Southern California. All species were growing at field sites with a semiarid Mediterranean-type climate. This system has a protracted dry season that places considerable strain on vascular transport traits (40); moreover, the values for xylem traits found among chaparral shrubs, even co-occurring ones, span a wide range, providing abundant trait variation (21, 36). All species were sampled in the same laboratory and using the same methods, thus minimizing errors due to methods differences.

Shrub species (n = 29) were measured at four field sites in Southern California (SI Appendix, Table S1). At all sites, n = 6 different individuals were tagged for sampling for each species at that site. Our goal was to study many independent species, thus sites were selected that contained diverse species (mixed chaparral). We also selected those of a similar community type and that contained abundant individuals of the indicator species chamise (Adenostoma fasciculatum). In chaparral classification, these sites would be mixed/chamise-type chaparral (40). Sites had not experienced a burn in at least 30 y, so they contained mature shrubs. All sites have a Mediterranean-type climate with hot dry summers and cool moist winters. Precipitation is almost entirely rainfall that occurs between November and May each year, with a protracted rainless season occurring in the Summer and Fall months. For more details on the sites, see ref. 36. Most of the samples and data were collected in 2009 and 2010. The phylogeny of the sampled species was reconstructed using the phylomatic database, and it was fine-tuned using a molecular phylogeny (see ref. 36 for additional details).

We measured a suite of traits to represent xylem functions with an aim to include them in a structural equation model. In many cases, there are multiple traits that could represent a function. Because our goal was to present a simple model, we did not include all the measured traits in our model because it was overly complicated and impractical. In the following sections, we highlight the care that we took to compare methods and measures to ensure the traits we chose represented a particular xylem function. The target sample size for all measurements was n = 6 different individuals per species, and the same individuals were used throughout the study to minimize intraspecific error variation. The mean of these six samples was the unit of analysis for species. For all measured traits, we sampled healthy branches that were similarly sized (about 6 mm in diameter) and located in the sunny south side of the outer canopy to minimize branch-to-branch variation. We measured multiple variables on the same stems when possible, which included hydraulic measurements, xylem density, and anatomy. Methods are fully described for most traits. Starch storage and measures of xylem cellular proportions have been previously published (36), and methods for these traits are only briefly described with the relevant publications referenced.

Resistance to embolism of distal branches was measured using a centrifuge method. Samples were brought back to the laboratory and flushed prior to sampling (see next paragraph). This method exposes stems to increasingly negative xylem pressures and measures hydraulic conductivity (Kh) declines in response. The resistance to embolism is expressed as the negative pressure for a given percentage loss of Kh. It is common to use the pressure potential at a loss of 50% of maximum Kh (P50). Here, we used the pressure potential at a 75% loss in Kh (P75). The P50 and P75 were strongly correlated (r = 0.91, P << 0.001), so this choice did not alter the analyses. The sampling protocol followed methods that have been previously published and extensively compared to reference methods (e.g., ref. 41).

Hydraulic efficiency was measured on the same stems as used for P75. Stems were 14 cm long and were flushed for 60 min at 100 kPa with an ultrafiltered (0.01-m pore) and degassed 20 mM KCl solution. The flushing treatment removed emboli from the stem xylem. The stems were then connected to a tubing system with a pressure head of 2 to 3 kPa, and flow through the stem was collected on a four-point balance. The flow rate (kg/ s) was divided by the pressure gradient (MPa/ m) to compute the Kh of the stems. This was divided by the sapwood area to compute the xylem-specific Kh (Ks), which is a trait commonly used to represent transport efficiency. Another trait that can represent efficiency is vessel diameter. We compared our Ks data to vessel diameter to validate them. The Ks was strongly and positively correlated to vessel diameter (r = 0.78, P << 0.001).

The minimum seasonal water potential was measured on distal branchlets at the end of the Fall dry season in 2009 using a pressure chamber (Model 2000, PMS Instrument Co.). Not all sites could be sampled before rains fell in 2009, so additional sampling was completed in Fall 2010. Samples were taken at predawn and midday. In theory, the predawn values equilibrate with soil water potential, and all the organs of the plant are in equilibrium including the stem xylem pressure potential (P). The predawn and midday values were strongly correlated (r = 0.95, P << 0.001), and we report midday values as Pmin. The Pmin values can be challenging to assess in long-lived species. In chaparral systems, because of the predictable and protracted Summer/Fall dry season, it is not that difficult. The Pmin that a species experiences during a typical dry season has been found to be strongly correlated to the Pmin during high-intensity drought (r = 0.87 in ref. 21).

Xylem strength was measured in two ways. One simple estimate of tissue strength is xylem density. This was measured on the same stems used for P75 measures using Archimedes principle. Stems were debarked and depithed and saturated with water. The xylem was submerged in water on a four-point balance. The mass of water displaced, the temperature of the water, and the density of water were used to convert the displaced water mass to a volume. The xylem was then oven dried at 70 C for >3 d, and the dry mass was measured. Xylem density was expressed as tissue dry mass per volume. Modulus of rupture (MOR) of stems was measured using a mechanical properties tester (Model 3342, Instron) following the methods of ref. 30. Xylem density and MOR were strongly correlated (SI Appendix, Fig. S1), thus we chose to use xylem density for simplicity.

Water storage of xylem (capacitance) was measured by generating pressurevolume curves on debarked and depithed samples that were about 1 cm long and 6 mm diameter. This size was necessary so samples would fit into psychrometers (Model C30, Wescor Corp.). Samples were saturated with water and weighed on a four-point balance. They were then placed into psychrometers for >2 h to allow them to equilibrate. The water potential of the psychrometers was measured with a datalogger (Model CR7, Campbell Scientific). Following equilibration, the samples were removed from the chamber, and the masses of the samples were weighed and recorded. The mean mass was taken pre- and postmeasurement and the average used to represent the mass at a water potential. Samples were then air dehydrated for 1 to 5 min and resealed in the psychrometers. This process was repeated between 8 and 16 times until the water potentials were about 6 MPa (the lower limit of these psychrometers). We used an array of 18 psychrometers and, to improve accuracy, psychrometers were calibrated with four to five salt solutions each time a species was sampled. Calibrations were done at three different cooling times, which we found was valuable to measure the most negative water potentials (the longest cooling time) and to get precise readings for more hydrated samples (shorter cooling times). To determine capacitance, curves were generated plotting relative water content (RWC; fresh weight dry weight/saturated weight dry weight) on the y-axis and in response to water potential (SI Appendix, Fig. S2). Capacitance was calculated as the slope (RWC/MPa) of the linear portion of the curve between about 0.3 and 1.5 MPa.

Starch content of xylem was measured using an enzymatic method for samples collected in Fall 2009. Fall was selected because this is the seasonal point when starch storage should be close to its seasonal maximum. Stems were debarked and depithed, and the remaining xylem was ground using a ball mill, consequently, only xylem starch content was measured, which was appropriate for our focus on xylem trade-offs. The starch data we used can be found in another study where our methods are fully described (36).

The proportions of difference cell types, fibers, parenchyma, and vessels were measured in cross sections of the same stems sampled for the same stems in which hydraulic traits were measured (n = 3 to 6 stems/species). Thin sections were made using a microtome and mounted in glycerol. Samples were examined at 200 magnification with a microscope (36).

We used an SEM approach to test our multivariate hypothesis (Fig. 1). We had two latent variables in our model: cellular trade-off and tissue strength. Cellular trade-off was represented by the area of fibers, vessels, and parenchyma measured in cross section, and tissue strength was represented by xylem density. Strength of xylem can be measured in many ways and at different scales (cell to tissue), thus it made conceptual sense to treat is as a latent variable (8); however, we did not statistically analyze it as a latent variable (SI Appendix, Fig. S3). Representing cellular trade-off in this way consistently led to an impossible negative error for fiber area in our models. The negative value was always very small (0.001 to 0.006). Thus, we set fiber error to zero, which has little effect on parameter estimates when the error is very close to zero (42).

The modeling approach consisted of two parts. The first was to develop a path diagram that represented the hypothesized multivariate relationships among xylem traits (Fig. 1). In the second step, we examined if the model provided an adequate fit of the data. Prior to analysis, the data were examined in the context of parametric statistical assumptions. The data were transformed using natural log for all traits except for xylem density and water storage because the transformed relationships were less linear. The absolute value of Pmin and P75 were used (SI Appendix, Table S2). The unstandardized coefficients that we report are transformed and scaled (SI Appendix, Fig. S3). All SEM tests were run using R (R version 4.0.5) package lavaan 0.6 to 8 (43).

Statisticians recommend a larger sample size than we used for SEM models that are relatively complex; however, there are reasons why we did not collect more samples. Our data set consisted of 29 species and six replicates for most variables, so we collected 174 data points for each of the nice measured factors, all of which are time consuming to measure. Another option would be to combine available data to form a larger data set, but this is not presently possible due to lack of data for the full suite of variables that we measured.

Because of our small sample size, we adjusted our model selection criteria in some ways. The goodness of fit of the SEM model was determined by a 2 test that compared the fit of the model to a model with all predictor variables. The null hypothesis was that the tested model would not differ from the fully parameterized model, thus indication of a good model fit is P > 0.05. We report model tests from standard and BollenStine bootstrapped values that are recommended for small sample sizes (3). We also report the comparative fit index and the TuckerLewis index (TLI), where values of >0.95 suggest good model fit. After testing our hypothesized model, we found that it fit the data reasonably well, but there were some paths in the model that were not significantly supported. We ran additional models with these paths removed. We compared these models to our initial hypothesized full model using information theoretic tests (Akaike information criterion [AIC] and Bayesian information criterion [BIC]), with an emphasis on the corrected AIC (AICc), which is adjusted for small sample size. These statistics evaluate the goodness of fit of a model and parsimony. The best-fit models have lower values of AIC and BIC, and values of >|2| are better fitting models.

In additional to analyzing raw trait values, we also ran analyses on phylogenetic independent contrasts (PICs). These were calculated for all traits using branch lengths set to 1 (Mesquite version 3.61). The same processes were followed and models run using PICs.

Additional analyses included assessing the variation across our sites for the nine traits we measured. This was done using boxplots and violin plots (R package ggplot2) and by partitioning the variance of the measured traits among species nested within each site, across the different sites, and within each species (intraspecific; R package lme4 for mixed-effect models). We also analyzed the bivariate relationships among all traits using simple Pearson correlations. We conducted a network analysis that shows correlations among traits in a correlogram. We included a strength analysis that assesses the importance of a trait in a network in the context of how strongly it is correlated with the other variables. The last analysis we conducted was a principal components analysis to describe the multivariate relationships among traits (princomp function in base R and plotted with package ggbiplot). We used a scree plot to determine that two components adequately explained the variation among our traits.

We observed large differences in trait values among the 29 shrub species we analyzed. These values spanned a large proportion of the observed variation across the globe for woody species (9, 38). Sampling many different species across different field sites leads to different sources of variation (SI Appendix, Table S1). We analyzed variation within sites, across sites, and intraspecifically. The general finding was that variation among traits was wide for species sampled within each site, indicating that sites were unlikely to be exerting unique effects on the measured traits (SI Appendix, Fig. S4). This is also supported by the large proportion of overall variance contributed by species nested within site (SI Appendix, Fig. S5). One exception was for Pmin and P75, which at one site (Phantom site) did not have species with values as extremely negative as found at the other sites (SI Appendix, Fig. S4); however, this likely occurred because we did not randomly sample species within a site and instead chose unique species. The Phantom site was established last, and the site contained species that experience highly negative Pmin values, but we elected to not sample them because they were already in our data set from other sites. Moreover, this site receives the second-lowest average rainfall among the four sampled, and it also experiences hot temperatures, suggesting it is not a mesic site in our study (see ref. 36).

Significant and strong bivariate correlations were observed among many of the measured traits (Fig. 2). The extremes were Pmin, which was significantly correlated with all variables except parenchyma area, and parenchyma area, which was only correlated with one other trait (Fig. 2). Not only was Pmin correlated to most variables, it also had many strong associations (SI Appendix, Fig. S6). Fiber area was another trait with many significant and strong associations with other traits (Fig. 2 and SI Appendix, Fig. S6). Making these same comparisons with PICs generally showed the same patterns (SI Appendix, Fig. S7).

Bivariate correlations among all the traits with associated r-values and significance (*** < 0.001; ** < 0.01, * < 0.05, . < 0.10) for raw trait values, and those for PICs are in the supplemental figures (SI Appendix, Fig. S7). Cap. refers to capacitance or water storage, and Par. is short for parenchyma. P75 represents the water potential at 75% loss of hydraulic conductivity and estimates embolism resistance, and Ks is xylem specific conductivity and represents transport efficiency. Details about other traits are described in Materials and Methods.

Summarizing the multivariate relationships among these traits using principal component (PC) analysis showed clear patterns where PC1 captured the inverse relationships between safety and efficiency, tissue strength and starch storage, and vessels and fibers (SI Appendix, Fig. S8). PC2 described the inverse relationship between water storage and xylem density and parenchyma and fibers. The same patterns were apparent when analyzed using PICs (SI Appendix, Fig. S8).

The analyzed SEM model produces different types of variables and coefficients. The coefficients shown along the paths (predictors) represent the relationship between variables (Fig. 3). They are standardized and represent the change expected (positive or negative) if a predictor variable is varied by one SD. In cases where there are multiple predictors for a single trait (embolism resistance, transport efficiency, tissue strength, and starch storage), the coefficients represent partial regression coefficients. We include both standardized coefficients (Fig. 3) and unstandardized coefficients in the transformed units of the measured traits (SI Appendix, Fig. S3 and Table S2).

Results from our analyzed SEM model for raw trait values (A) and PICs (B). The weights of the solid arrows correspond to P values where the thickest is <0.001, intermediate <0.01, and thinnest is <0.05. The dotted arrows correspond to P > 0.05. The values shown along paths are standardized coefficients and SEs in parentheses (SI Appendix, Fig. S3 shows unstandardized coefficients). The variance explained (R2) is shown for each trait. Latent variables are connected to their measured traits by gray arrows. Values are not shown for xylem density because this trait is included within the tissue strength variable, and the values there apply to xylem density.

The overall hypothesized model (Fig. 1) was a good fit of the data [i.e., the fit was not significantly different from a saturated model where all the possible paths were included (Fig. 3A and SI Appendix, Fig. S3 and Table 1)]. The same was true for the model using PICs (Fig. 3B and SI Appendix, Fig. S3 and Table 1). Although the model provided adequate support for covariation among the traits, there were six paths in the model that had high P values (Fig. 3 and Table 1); moreover, the TLI was <0.95. To investigate, we created models with these paths removed and compared the effect on model fit (Table 1). For the six paths with large P values, we proceeded by removing variables with the largest P values, rerunning the model, and evaluating the effect on the P values and model fit. In all cases, removing the paths had little effect on the large P values and model fit, so we removed them all (Table 1). We found that the best-fit model was the full model minus six paths with high P values (Fig. 4 and Table 1). The path between water storage and Pmin was also not significant (P = 0.198); however, removing this path led to a poorer-fitting model (Table 1).

Model fit statistics comparing the fit of different models to our hypothesized model (full model, Fig. 2)

The best-fitting SEM models for raw trait values (A) and PICs (B). The weights of the solid arrows correspond to P values where the thickest is <0.001, intermediate <0.01, and thinnest is <0.05. The dotted arrows correspond to P = 0.198 (A) and 0.220 (B). The values shown along paths are standardized coefficients and SEs in parentheses (SI Appendix, Fig. S3 shows unstandardized coefficients). The variance explained (R2) is shown for each trait. Latent variables are connected to their measured traits by gray arrows. Values are not shown for xylem density because this trait is included within the tissue strength variable, and the values there apply to xylem density.

Among the relationships that were predicted based on our hypotheses, many were not supported by the model. The model showed that transport, tissue strength, and starch storage functions were independent of one another. An important result is that a cellular trade-off was associated with Pmin and was independent of tissue strength. This trade-off was directly linked to starch storage, but it was not associated with any other traits. A network analysis shows Pmin to be a hub trait due to the number and strength of the associations (SI Appendix, Fig. S6). Another direct predicted relationship supported was the inverse relationship (trade-off) between safety from embolism and efficiency.

The results for the raw traits and PICs were virtually identical, thus we focus on raw trait values for simplicity. The direct relationships that were not supported were those between Pmin and efficiency, tissue strength and efficiency and embolism resistance, cellular trade-off and embolism resistance, efficiency, and tissue strength. Pmin and efficiency were associated through a shared relationship with embolism resistance. Tissue strength was not directly related to either embolism resistance or efficiency, thus any relationship it has with these traits is through Pmin and possibly water storage. These indirect relationships highlight Pmin as a central parameter underlying xylem trait relationships.

To explore the influence of Pmin on trait relationships further, we created models with Pmin removed (SI Appendix, Figs. S9S11). The best-fit model was produced from three candidate models (SI Appendix, Table S3). An important result is that cellular trade-offs take on a central role, directly or indirectly affecting all other traits when Pmin is removed (SI Appendix, Figs. S9S11). A good example of how Pmin is exerting influence is between cellular trade-off and tissue strength, both of which have direct paths from Pmin (Fig. 4). In the full model with Pmin this path is insignificant, and the partial standardized regression coefficient is 0.16 (Fig. 3A), thus for every SD increase in cellular trade-off, there is a 0.16 decline in tissue strength (a result of the inverse relationship between vessel area and xylem density). In the model without Pmin, the coefficient goes to 0.47 and it is significant, a result almost entirely due to the absence of Pmin. This analysis did not support a direct association between tissue strength and embolism resistance (SI Appendix, Table S3 and Figs. S9S11).

We proposed a multivariate hypothesis regarding trade-offs in xylem function that predicted how key functional traits were interrelated. These trade-offs have been mostly evaluated individually (5, 6, 8, 37); however, none have done so as part of a multivariate testable model. Such models allow for the identification of direct and indirect relationships, as well as the dependence of traits on one another. Results using PICs were the same as those with raw trait values, suggesting that shared ancestry cannot explain the associations among our sampled traits.

We found that the xylem functions (transport, strength, water storage, and carbohydrate storage) were independent of one another, and the only trait linked to all of them was Pmin. Bivariate relationships indicated significant associations between tissue strength and embolism resistance and cellular trade-offs, but these were not supported by our final SEM model. A key reason for this result is the presence of Pmin in the model and its strong associations with nearly all traits. To explore this, we created a model with Pmin removed. In this model, a cellular trade-off was found to directly affect embolism resistance, tissue strength, and starch storage and indirectly affect efficiency and water storage (all traits in the model). This supports one of our main hypotheses that the balance between the different cell types is a central structural factor affecting xylem function; moreover, it suggests that the cellular functional divisions and the range of different cellular sizes, shapes, and wall thicknesses cannot fully overcome trade-offs (6, 31).

Taken as a whole, the effect of cellular trade-offs and tissue strength is not independent of Pmin. The relationships between embolism resistance and tissue strength and cellular trade-offs are hypothesized to occur because of the need to reinforce vessels against implosion (29, 30), which is more of a threat in species that experience more negative hydrostatic pressures and that are highly resistant to embolism. Thus, the hypothesis that predicts these relationships also predicts a lack of independence among these traits, as we found. One aspect of cellular strength not included here is direct estimate of implosion resistance of individual vessels or vessel pairs (29), which if independent of bulk tissue strength, could affect model results.

Our results highlight the central importance of Pmin as an explanatory variable (11). In the context of a trait network, Pmin is a hub trait (1). Pmin represents the level of dehydration a plant experiences, and within a similar environment and measured at midday, it integrates many plant traits such as rooting patterns (44), stomatal responses (11, 45), leaf turgor and hydraulic conductance (11), and hydraulic conductance of the plant and soil system. The hub effect of Pmin in our model of xylem traits likely occurs because it captures variability in many fundamental aspects of plant function that are associated with xylem function in an example of concerted convergence. A strong relationship between Pmin and embolism resistance is well established (20), but our study shows that tissue strength and embolism resistance and cellular trade-offs are not related independent of Pmin and that Pmin is linked to cellular trade-offs.

The association between Pmin and cellular trade-offs may arise for structural and storage reasons. A shift to containing less fibers and more parenchyma may destabilize the xylem, creating a risk of vessel implosion (30). If so, then more negative Pmin would be associated with more fiber area and reduced parenchyma and vessel area, which was supported as seen among bivariate correlations [note, parenchyma is not significant; ref. 46]. These ideas suggest a link between cellular trade-offs and tissue strength, a relationship not independent of Pmin. Shifting from less fibers to more parenchyma is also associated with greater starch storage (6, 8, 35), and starch storage is strongly associated with Pmin (36). Expressing cellular trade-offs as a latent variable described by all cell types helped to identify important relationships; however, parenchyma performs important functions beyond storage such as defense, radial transport, and refilling of tracheary elements, and these additional functions warrant further study (12, 31, 47). Different types of parenchyma cells and arrangements (axial, ray, paratracheal, contact, isolation, etc.) may associate differently with different functions and predictors (12, 31), which is likely due to functional differences among these parenchyma types (8).

Storage of xylem starch and carbohydrates is an important trait related to drought tolerance and growth (48) and plays a role in xylem refilling (49). We hypothesized that Pmin drives starch storage because starch is hydrolyzed to osmoregulate in dehydration tolerant species that experience highly negative Pmin (38, 50), and this was consistent with our data. The connection between starch storage and Pmin may drive the association between starch storage and embolism resistance (36). Understanding the dynamics of carbohydrates, including its transport, is an important area of active research (34, 50).

Water storage is the only trait in our model that affects Pmin, which gives it the potential to play a critical role in overall xylem function (50). Water storage indirectly links tissue strength to the transport functions through Pmin. Xylem density (tissue strength) correlates with many different xylem traits and ecological and life history traits (51), and its effects on water storage and Pmin are likely important in this context. One caveat is that the association between water storage and Pmin was in the best-fitting model, but it was not strongly supported (P > 0.05 for the path connecting water storage to Pmin). This is mainly due to the hypothesized complex relationship between Pmin, tissue strength, and water storage. This relationship is modeled as nonrecursive (a loop) where water storage indirectly affects itself through its effect on Pmin, which in turn affects tissue strength, then back to water storage. Feedback loops are likely important in the context of selection for and relationships among traits affecting Pmin and are an important area for further study.

Other well-supported relationships in our model are the link between Pmin and embolism resistance and the trade-off between safety from embolism and efficiency. Species widely differ in the Pmin they experience, and Pmin is correlated to drought resistance and embolism resistance (18, 52). This is consistent with the hypothesis that embolism resistance is an important trait associated with plant dehydration avoidance/tolerance strategy. Our results are also consistent with the well-studied trade-off between safety from embolism and efficiency (9). At the global scale, this relationship is weak (23), and it has been argued that the multiple traits affecting this trade-off over diverse selective environments has uncoupled these traits (16). Our study is in a semiarid ecosystem, where strong water limitation likely constrains the range of responses.

Hydraulic efficiency was only strongly and significantly associated with embolism resistance. Bivariate relationships showed some significant relationships, including an association with Pmin and cellular trade-offs (fiber area), yet none of our models suggested direct associations with hydraulic efficiency. Efficiency is indirectly associated with Pmin through a direct path between Pmin and embolism resistance, and in models without Pmin, it is similarly indirectly associated with cellular trade-offs. Pmin could directly affect efficiency if expansion of large vessels was limited by turgor pressure, especially if wider vessels take longer to develop (27); however, chaparral shrubs do not have very large vessels globally speaking (53), thus during a typical hydrological year, interspecific differences may be unlikely. Nevertheless, during a drought, there will certainly be a reduction in xylem growth increment and vessel diameter, which may be driven by Pmin.

We also did not find a direct connection between tissue strength and transport efficiency. This path was predicted to arise because of the need for denser tissues in response to Pmin. The denser tissues were hypothesized to compromise efficiency between vessels with narrower diameters and thicker walls because thicker walls increase the path length through the pits where sap flows in between vessels, and this would decrease hydraulic efficiency (24). Tissue strength is driven by fiber traits (fiber abundance and wall thickness), so angiosperms can adjust their tissue strength independent of transport. However, these relationships may manifest in lineages where the developmental connection between fiber and vessel walls is strong (24).

The ecological context for our study is likely important to understand relationships with transport efficiency. Efficient transport of xylem is broadly associated with fast acquisition and use of resources, competitive ability, and has been linked to greater photosynthetic capacity and may lead to lower construction costs of stems (23). Our study focused on shrubs in a semiarid ecosystem where xylem efficiency may be unlikely to be the primary trait affecting fitness. By contrast, limited water is a likely a primary selective force for traits associated with drought survival. As such, embolism resistance may be under stronger selection than xylem efficiency (18, 52). In ecosystems with greater resources and dominated by trees, the arrows between efficiency to other traits may reverse, whereby it becomes a predictor instead of a response variable. We tried this in the present study, and when we reversed the path between efficiency and embolism resistance in the best-fit model (Table 1), the resulting model fit was poor (2 = 37.77, df = 25, P = 0.049). Direct manipulative tests to examine questions about adaptive significance of xylem traits is an area where more research is needed.

Hypotheses underpinning trait relationships with starch storage may change when carbon gain is limited over a long period by an unfavorable environment. It is well documented that when plants are carbohydrate limited, they produce less-dense tissues (54). Thus, when carbon gain is marginal relative to carbon expenses and phloem transport is impaired (55), starch availability to cambia may be limited and drive reduced tissue density and strength (56, 57). Under such conditions, a direct link between tissue strength and embolism resistance may be important as mechanically weak vessels become vulnerable to collapse (54, 56).

We conclude that xylem traits are broadly governed by trade-offs among cellular traits related to transport, mechanical support, and storage and that the Pmin experienced by plants in the field exerts a strong influence over these relationships. While angiosperms have evolved different cell types that have different functions within the xylem, and there are important functional trade-offs associated with the relative proportions of these different cell types. The important effects of Pmin on xylem traits likely arises because it places a direct mechanical strain on tissues that requires reinforcement to avoid cellular implosion; nevertheless, Pmin can affect xylem function by other pathways and traits not considered in our model because it integrates many functional attributes of plants.

All study data are included in the article and/or SI Appendix. Previously published data were used for this work [some data were previously published in a very different format in Pratt et al. (36)].

We thank Paul Smith, Michael Clem, Christine Hayes, Evan D. MacKinnon, and Hayden Toschi, who helped collect data. This study was supported by the NSF under Grant No. IOS-0845125 to R.B.P. and NSF HRD-1547784 to R.B.P. and A.L.J. Thanks to M. Witter, K. VinZant, and M. Lardner for help with permitting field sites. Two reviewers are thanked for their helpful comments.

Author contributions: R.B.P., A.L.J., and M.F.T. designed research; R.B.P., A.L.J., M.I.P., M.E.D.G., C.A.T., and M.F.T. performed research; R.B.P., A.L.J., and M.F.T. analyzed data; and R.B.P., A.L.J., M.I.P., M.E.D.G., C.A.T., and M.F.T. wrote the paper.

The authors declare no competing interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at

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Oklahoma 10-year-old in remission after being diagnosed with rare form of leukemia 2 years ago – KFOR Oklahoma City

Wednesday, July 21st, 2021

EDMOND, Okla. (KFOR) Edmond 10-year-old, Miller Hines enjoys soccer, his scooter, constructing Legos, and playing with his younger brother.

Miller is a lover of life, I like to say that hes a world shaker and game changer, says his mother, Miranda.

Two years ago, Miranda remembers the cascade of bad news that started with swollen lymph nodes.

He was swollen in his neck area which was concerning but Id also seen that with him when hed had strep throat, she recalls.

But when Miller went to the doctor, the strep test came back negative. Thats when they ran blood tests which revealed alarming results.

Miranda remembers, I did somethingyoure not supposed to do, which is google what this means.

Miller had AML leukemia with an added genetic mutation which made it even more dangerous.

He had a very aggressive form of leukemia. I knew Miller was really, really sick, Miranda recalls. Preparing for his bone marrow transplant and then having the transplant was really brutal.

In the middle of the pandemic, mother and son leaned on each other for dear life.

Miller is such a sweet boy. He made me a mom, and were buddies, and he would often encourage me by saying Mom, Im OK,' Miranda shakes her head as she remembers his efforts to ease her fears.

Holding them both up with medical support and emotional encouragement was their medical team at OU Childrens Hospital, and Jimmy Everest Cancer Center.

Miranda doesnt hold back the tears as she expresses her gratitude, We absolutely adore them. Theres no doubt that they saved Miller.

His treatments included a stem cell transplant, chemotherapy, and gene therapy.

Working in tandem, his treatment plan proved to be successful.

His blood work shows hes free of cancer 17 months after his transplant.

Despite the pain, and even boredom that comes from months of treatment, Miller has happy memories of playing with therapy dogs at the clinic and joking around with the nurses.

Miranda says, We miss them, but we are happiest to run into them outside of the clinic!

Miller wants to get on with the hobbies he had to put on the sidelines.

Hes getting to be a 10-year-old. Hes playing soccer again.And the best thing thats ever happened in my whole life is Miller, so for him to be here and be healthy is incredible, says Miranda.

Its been almost a three-year roller coaster ride the Hines are happy to step off, grateful for a new chapter of childhood ahead.

If youd like to help children like Miller fight cancer, consider donating to

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Oklahoma 10-year-old in remission after being diagnosed with rare form of leukemia 2 years ago - KFOR Oklahoma City


Covid: There’s a serious problem with how we are testing people for the virus Neale Hanvey MP – The Scotsman

Wednesday, July 21st, 2021

This gives Scotland an opportunity, and a pressing need, to chart a different course. This is not political hyperbole. It is based on an NHS career in cancer care where infection prevention and control are a daily struggle for patients with suppressed immune systems.

Having led bone marrow and stem cell transplantation services at both University College Hospital and the Royal Marsden, I have a strong grasp of the systematic approach needed for effective infection protection, control, and treatment.

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While most people are not as vulnerable as transplant patients, with a novel virus like Covid we simply cannot predict how and when the virus will mutate or how this could impact the general population.

There are three interdependent strands to consider: controls such as mask wearing, social distancing and hand hygiene; surveillance testing and genomic studies that chart the progress and development of the virus; and treatment the use of dexamethasone and vaccination programmes.

Get one element wrong and the whole approach could fail.

Until now weve diligently been following guidance across a range of control measures, and the vaccination programme delivered by the ever-valiant NHS workforce has been a great success but weve still seen a sharp rise in Delta-variant cases. This brings me to surveillance.

The problem is the UK and devolved governments have relied on Innova lateral-flow devices (LFDs) as the method of rapid-test surveillance.

This means taxpayers money is being spent to prop up Chinese imports that are being used in a potentially dangerous way, while our domestic diagnostics industrys superior tests have been cast adrift.

As a result, we are now at a perilous crossroads. Failure to use effective controls or robust surveillance risks the Delta variant spreading ever more rapidly, presenting a significant risk of further mutation.

I am already seeing this in my constituency where people have received repeated negative results with Innova LFD tests, only to insist on a PCR test and discover they are Covid positive and at the centre of a new cluster of infections.

To be blunt, the Prime Ministers desire to appease some Tory backbenchers with cries of Freedom Day has endangered all the advances made to date.

Thats why the Scottish government must chart an independent course. Maintain all the sensible controls, continue the vaccination roll-out, but abandon the inappropriate use of these Chinese tests in favour of superior tests made here in Scotland.

There is no good reason to follow Boris over the cliff on his Covid surrender strategy.

Neale Hanvey is the Alba Party MP for Kirkcaldy and Cowdenbeath

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Covid: There's a serious problem with how we are testing people for the virus Neale Hanvey MP - The Scotsman


Profilin 1 Protein and Its Implications for Cancers – Cancer Network

Wednesday, July 21st, 2021


Profilin 1 (PFN1) is a ubiquitous small-molecule protein that exists in all eukaryotes.1 PFN1 was first identified as a G-actin sequestering molecule,2 and subsequently, its true functions in actin polymerization and F-actin dynamics were revealed.3 In the following decades, the structure of PFN1 was recognized to have 3 domains: an actin-binding domain,4 a poly-L-proline (PLP)-binding domain,5 and a phosphoinositide-binding domain.6

PFN1 plays a vital role in many cell functions, including membrane trafficking, endocytosis, cell cycle, motility, proliferation, cell survival, transcription, stemness, and autophagy (Figure 1). Abnormal expression or deletion of PFN1 can affect the normal physiological activity of cells and lead to disease development. PFN1 has been deeply studied in a variety of diseases, some genetic (eg, amyotrophic lateral sclerosis)7 and some chronic (eg, hypertension).8

In the past 10 years, PFN1s role in cancer has received increasing attention. In this review, we summarize the studies of PFN1 in cancer that have been completed in recent years, discuss the roles of PFN1 in cancer, and discuss the implications for tumor diagnosis and therapy in the future.

Early diagnosis of cancers is still a major challenge worldwide, and early detection can notably reduce their associated morbidity and mortality.9 PFN1, a critical actin-binding protein, is found to be dysregulated in many cancers, which makes it possible to use it as a biomarker for diagnosis and prognosis. PFN1 mainly plays a role in the cytoplasm, but it can also be found in the nucleus and can even be secreted into the extracellular space. The rich knowledge in the proteomics field makes the detection of proteins for new diagnostic markers and targets for therapy possible.10

In some tumor types (such as renal cell carcinoma [RCC], gastric cancer, and others), high expression of PFN1 indicates later stage and worse prognosis. Via differential proteomics, PFN1 has been identified in metastatic and primary RCC, and further analysis indicated that high PFN1 expression was associated with poor outcome and that PFN1 could be used as a potential prognostic marker in RCC.11 In clear-cell RCC (ccRCC), the expression of PFN1 was decreased in early-stage tumors compared with normal tissues. However, its expression in stage IV ccRCC was significantly increased. PFN1 was selected as a candidate marker of late-stage ccRCC.12 Results of a recent study determined that the vast majority of ccRCC tumors tend to be selectively PFN1-positive in stromal cells only; dramatic transcriptional upregulation of PFN1 was found in tumor-associated vascular endothelial cells in clinical specimens of ccRCC.13 Tissue microarray results also showed that PFN1 was increased in metastatic ccRCC compared with primary tumors. Univariate analysis suggested that higher PFN1 expression was associated with shorter disease-free survival (HR, 7.36; P = .047) and lower overall survival.14

In gastric cancer, Tanaka et al found that PFN1 was highly expressed in fetal rat stomach. Additionally, PFN1 was overexpressed in some human and rat gastric cancers.15 The results of later studies indicated that PFN1 expression was higher in gastric cancer tissues than in adjacent normal tissues. High PFN1 expression was correlated with tumor infiltration, lymph node metastasis, and tumor-node-metastases (TNM) stage. Functional assays confirmed that silencing PFN1 could inhibit the invasion and migration of gastric cancer cell lines.16

In addition, PFN1 expression was higher in nonsmall cell lung cancer (NSCLC). Lower expression of PFN1 was associated with better prognosis and a higher survival rate in NSCLC.17 Proteomic analysis revealed that PFN1 was differentially expressed in laryngeal carcinoma tissues compared with adjacent normal tissues. Further study results revealed that PFN1 was increased in laryngeal carcinoma tissues compared with adjacent normal tissues, indicating that PFN1 was a novel potential biomarker for the diagnosis of laryngeal carcinoma.18

However, in some other tumors (such as colorectal cancer [CRC], oral carcinoma, and others), the opposite is true. PFN1 was downregulated in pancreatic cancer.19-20 Lower expression of PFN1 was significantly associated with a shorter survival period.20 In late-stage oral squamous cell carcinoma, PFN1 expression was lower than that in normal oral epithelium, and loss of PFN1 expression was related to invasion into and metastasis of lymph nodes.21 PFN1 was also decreased in late advanced hepatocellular carcinoma (HCC) and was associated with a poor survival rate of patients.22-23 In addition, PFN1 was found to be downregulated in nasopharyngeal carcinoma24 and breast cancer.25 Combined with another 4 actin-binding proteins, PFN1 could be used to construct a model for predicting poor prognosis of esophageal squamous cell carcinoma.26

Under normal physiological conditions, PFN1 is involved in multiple cellular functions, such as cell motility, migration, adhesion, and transduction signaling pathways.27 PFN1 is differentially expressed in various types of tissues and cells, which may explain its variable tumorigenic mechanisms in different tumors, even in different stages of the same cancer (Figure 2). Because PFN1 plays important roles in tumorigenesis and progression, targeting PFN1 dysregulation could to some extent influence the prognosis of patients with cancer. Determining the expression of PFN1 could thus be used to distinguish high-risk disease from lower-risk disease. Combination with other indices could further improve the diagnostic and prognostic value of PFN1.

In addition to dysregulation in tumor tissues, PFN1 was also found to bedifferentially expressed in the serum, urine, and extracellular vesicles of patients with cancer, which makes it possible to utilize PFN1 in liquid biopsy analysis of tumors. Compared with tumor tissue biopsy, liquid biopsy is a more practical method for real-time monitoring of patients with cancer.28 In addition, PFN1 was detected in the supernatants of cultured cells.

It has been shown that PFN1 gene expression is increased in peripheral blood cells of patients with HCC compared with healthy controls.29 A 9-gene expression system (including PFN1) was used to discriminate patients with HCC from healthy people.30 Proteomic analysis of serum proteins showed that PFN1 was increased in patients with gallbladder cancer. The expression difference between these patients and healthy controls was more than 2-fold.31 PFN1 was differentially expressed in the urine of patients with invasive and noninvasive bladder cancer. Further studies confirmed that PFN1 was notably decreased in the epithelium of invasive bladder tumors compared with noninvasive tumors, which was associated with the clinical outcomes of bladder cancer.32 In in vitro pancreatic cancer cell lines, PFN1 was downregulated in secretomes compared with nonneoplastic pancreatic ductal cells.33 In invitro cultured RCC cell lines, PFN1 was differentially regulated in the supernatant. Further studies revealed that PFN1 was upregulated in RCC tissues.34 Apart from its dysregulation in serum and urine, PFN1 was found to be downregulated in the circulating leukocytes of patients with breast cancer compared with healthy controls, which provides a new paradigm for highly sensitive and less invasive approaches for the diagnosis of breast cancer.35 Studies have already revealed that PFN1 can be secreted via exosomes or other secretory pathways.36-38

Extracellular PFN1 in the tumor microenvironment can be taken up by recipient cells and execute its function in recipient cells, which in turn may influence the biological behavior of cells in the microenvironment, ultimately affecting tumorigenesis and progression of cancers. As mentioned above, PFN1 is expressed differentially in the serum and urine of patients with cancer, which enables its application as a biomarker for diagnosis and prognosis in liquid biopsy (Table 1).

Cell motility involves membrane protrusion, cell matrix adhesion, cell body translocation, and rear detachment. Many of these processes require the actin cytoskeleton and its regulators. By facilitating the exchange of ATP for ADP on G-actin, PFN1 plays a major role in actin polymerization, thus influencing motility in numerous cells.39 PFN1 also participates in cell motility by regulating actin polymerization and interactions with other regulators of actin cytoskeletons, such as ARP3, VASP, and proteins of cell signaling pathways. Cell-cell adhesion and cell-matrix adhesion are critical contributors to maintaining tissue architecture. Dysregulation of cell-cell adhesion is an important sign in tumor initiation and progression of malignancy. PFN1 can modulate cell adhesion and epithelial-to-mesenchymal transition (EMT) in cancer cells. However, the mechanisms by which PFN1 regulates cell adhesion are still not very clear. Undoubtedly, learning more about the roles of PFN1 in cell adhesion and motility will help us better understand its roles in modulating tumor invasion and migration.

Since PFN1 plays a critical role in actin polymerization, it is an indispensable regulator of cell motility. PFN1 participates in the invasion and metastasis of multiple cancers. However, the roles of PFN1 in regulating cell motility are context specific.27 Exogenous PFN1 with intact actin-binding abilities can ameliorate the adherence and spreading capabilities of cancer cells and exert tumor-suppressive effects in breast cancer.40 Consistent with the results of the study by Wittenmayer et al, Zou et al found that PFN1 overexpression could revert MDA MB-231 cells to an epithelioid phenotype, with restored adherence junctions.41 In addition, PFN1 overexpression could promote AMPK activation and p27 phosphorylation, which in turn induces epithelial morphological reversion of mesenchymal breast cancer through restoration of adherens junctions.42 These studies highlighted the involvement of PFN1 in epithelial adhesion and differentiation, which helped us better understand its roles in cancer cell motility.

Invadopodia are actin-driven membrane protrusions that can deliver matrix metalloproteinases to degrade the matrix and support invasion and dissemination of tumor cells. Any dysregulation of the actin cytoskeleton can impair the formation and maturation of invadopodia.43-46 PFN1 can regulate PI(3,4)P2, which in turn negatively regulates lamellipodin at the leading edge of breast cancer cells and thus inhibits those cells motility.47 The depletion of PFN1 leads to an increase in the level of PI(3,4)P2 in invadopodia and its interacting adaptor Tks5. The interaction of PI(3,4)P2-Tks5 has been shown to promote the anchorage, maturation, and turnover of invadopodia, which in turn enhances the invasiveness and motility of breast cancer.48 Breast cancer is an invasive adenocarcinoma, and numerous studies have found that PFN1 is downregulated in breast cancer tissues.49-54 Overexpression of PFN1 reduces the invasion and migration of breast cancer cells, while loss of PFN1 significantly enhances breast cancer cell motility and invasion. Mechanisms involved in PFN1s negative roles in breast cancer metastasis include Enabled (Ena)/vasodilator stimulated phosphoprotein (VASP)-dependent lamellipodial protrusion,51 miRNA-182 regulation,52 and regulation of PFN1 degradation.53 Mouneimne et al found that PFN1 knockdown (KD) could increase F-actin bundles and enhance stress fiber formation. In that study, the numbers of protrusions in PFN1-KD cells were markedly decreased, and PFN1-KD could inhibit the motility of breast cancer.55 Moreover, Liu et al indicated that the interaction of LMO2-PFN1 and LMO2-ARP3 could promote the formation of lamellipodia/filopodia in basal-type breast cancer cells.56 Ena/VASP is a critical regulator of the actin cytoskeleton at the leading edge of cells, which controls membrane protrusions and cell motility. Cell-substrate adhesion and downregulation of Protein Kinase A (PKA) promote interactions of PFN1 with VASP, which is another mechanism by which PFN1 regulates cell motility.57-58 Knockdown of PFN-1 has been shown to abrogate the inhibitory effect of tyrphostin A9, suggesting that modulating PFN1 expression could have therapeutic potential in the treatment of metastatic breast cancer.59

As in breast cancer, PFN1 was found to be a suppressor of migration in HCC.22,23,60 All-trans retinoic acid60 and guttiferone K22 could inhibit hepatocellular cell migration and proliferation by upregulating the expression of PFN1. In prostate cancer, cathepsin X can inactivate PFN1, thus promoting adhesion, invasion, and migration of cancer cells.61 In CRC, elevated expression of PFN1 obviously inhibited invasion and migration. PFN1 was suppressed by the HLA-F-AS1/miRNA-330-3p/PFN1 or HCP5/miRNA-299-3p/PFN1/AKT axis.62-63

Interestingly, Ding et al showed that in the early stages of metastasis, breast cancer cells exhibit a hyperinvasive phenotype characterized by upregulation of MMP-9 and by faster invasion when PFN1 expression is downregulated. However, in the late stages of metastasis, loss of PFN1 markedly inhibits the growth of metastatic colonies of breast cancer cells.54 Rizwani et al reported that PFN1 expression was elevated in breast cancer tissues and that overexpression of PFN1 could inhibit the migration of breast cancer cells. The phosphorylation of S137 mutants abrogated PFN1s promotion of migration. These studies provided a different vision of PFN1s role in breast cancer metastasis.64

In gastric cancer, silencing PFN1 inhibited the invasion and migration of cells, and the PFN1 expression level in cancer tissue was positively correlated with tumor infiltration and lymph node metastasis.16 However, different conclusions were drawn from the study of Ma et al. The authors found that PFN1 expression was inversely correlated with lymph node metastasis.65 In the lung cancer cell line A549, downregulation of PFN1 inhibited migration.17 In addition, in vitro studies support the importance of PFN1 in the proliferation and migration of RCC cells, and treatment with a novel computationally designed PFN1-actin interaction inhibitor reduced the proliferation and migration of RCC cells in vitro and RCC tumor growth in vivo.13 Additional studies have demonstrated that downregulation of PFN1 can also suppress the migration of laryngeal cancer18 and bladder cancer.66

Although more studies on PFN1 have been completed recently, its roles in cancer metastasis are still unclear. The concentrations of actin and PFN1 are time- and space-specific, and so is the regulation of the actin cytoskeleton (Table 2). Additional thorough studies are needed to comprehend the mechanisms and laws regulating the actin cytoskeleton. More importantly, in addition to actin dependence, PFN1 affects cell migration in an actin-independent manner by interacting with proteins with PIP2 or PLP domains. Furthermore, lncRNAs and microRNAs also modulate the functions of PFN1. All of these proteins and RNAs interact with PFN1 and indirectly influence the functions of cancer cells, which makes understanding the roles of PFN1 in cancer metastasis and other functions more complicated (Table 3).

In yeast, the gene encoding PFN1 is essential for cytokinesis.67 Early studies revealed that PFN1/ embryos died as early as the 2-cell stage, while PFN1/+ embryos displayed reduced survival during embryogenesis compared with wild-type embryos; this indicates that PFN1 is essential for cell division and survival during embryogenesis.68 PFN1 silencing in endothelial cells inhibits proliferation.69 In addition, homozygous deletion of PFN1 in chondrocytes failed to complete abscission at late-stage cytokinesis.70 The results of all these studies imply that PFN1 plays a role in cell proliferation. In breast cancer, PFN1 overexpression (PFN1-OE) has been shown to inhibit cell growth and exert an inhibitory effect on tumorigenesis,25,40,52,71-75 and PFN1-OE suppresses the activation of AKT, which in turn inhibits the growth of tumor cells.71 PFN1-OE cells arrested at the G1 phase, which was partly attributed to the upregulation of P27kip1.72 miRNA-182 could downregulate PFN1 expression and promote triple-negative breast cancer cell proliferation.52 However, Yap et al put forward opposite views. The authors research results revealed that silencing PFN1 resulted in a multinucleation phenotype of breast cancer cells, thus inhibiting proliferation.76 Recent studies from Chakraborty et al also reported that PFN1 knockdown could upregulate SMAD3 and inhibit the proliferation of breast cancer.77 Results of single-cell studies on the extracellular matrix revealed that stiff extracellular matrix led to upregulation of PFN1, possibly promoting the proliferation of breast cancer.78 Apart from breast cancer, PFN1 was also found to suppress proliferation in pancreatic adenocarcinoma,20 endometrial cancer,79 and HCC.23,60 In gastric cancer, silencing PFN1 caused cell cycle arrest at G0/G1 phase, thus restraining cell proliferation.16 Knockdown of PFN1 could also inhibit the proliferation of laryngeal cancer.18 Our previous studies found that overexpression of PFN1 could promote the proliferation of multiple myeloma cells by accelerating the cell cycle from G1 to S phase.80 PFN1 is indispensable for cytokinesis. Nevertheless, PFN1 is involved in regulating cell proliferation not only by impacting cytokinesis but also by modulating cell cyclerelated proteins. Otherwise, PFN1 could also interact with cell signaling pathways and indirectly influence cell proliferation.

Tumor growth is not only about uncontrolled proliferation but also resistance to apoptosis.81 Actin dynamics have notable impacts on multiple stages of apoptosis.82 PFN1, as a critical actin-binding protein, is an indispensable regulator of actin dynamics, through which PFN1 participates in regulating apoptosis. PFN1 overexpression could upregulate the most common tumor-associated hotspot mutation of p53p53R273Hthus sensitizing cancer cells to apoptosis via the intrinsic apoptotic pathway.83 PFN1 has been shown to facilitate apoptosis of breast cancer cells, thus exerting a suppressive effect on tumorigenesis.73,75,83,84 By inducing apoptosis and reducing autophagy, PFN1 has also been shown to sensitize pancreatic cancer cells to irradiation. Additionally, overexpression of PFN1 can significantly elevate apoptotic markers such as cleaved caspase-3 and cleaved PARP after irradiation, suggesting that PFN1 can modulate radiosensitivity partly by regulating apoptosis.85

Given that PFN1 is involved in cell proliferation and apoptosis, it is not difficult to understand its roles in the drug resistance of tumor cells. PFN1 was found to be downregulated in butyrate-treated CRC cells,86 and proteomics studies revealed that PFN1 was differentially expressed in erinacine Atreated CRC cells,87 which suggested the roles of PFN1 in drug-mediated cell death and inhibition of proliferation. In addition, proteomics showed that PFN1 was differentially expressed in mitotane-treated adrenocortical carcinoma,88 and PFN1 was found to be increased in tocotrienol-treated MDA-MB-231 cells,89 indicating its roles in predicting the response to anticancer therapies. Compared with temozolomide (TMZ)-treated glioblastoma cells, PFN1 was downregulated in OKN-007 combined with TMZ-treated glioblastoma cells. Further study results revealed that PFN1 is involved in TMZ resistance.90 Results of our previous studies showed that PFN1 could interact with the Beclin 1 complex and participate in bortezomib resistance in multiple myeloma.80 Since PFN1 is involved in multiple cell processes, including proliferation, apoptosis, and proteomics, it was recognized as a biomarker for therapy sensitivity, and it is worth further exploring its roles in drug resistance. In addition, PFN1 was found to participate in angiogenesis,91-92 initiation of tumors,93 and autophagy.80 Loss of PFN1 in A549 cell lines resulted in fewer early apoptotic cells after treatment with piperlongumine, and PFN1 sensitized A549 cells to anticancer agents.17 PFN1 serves as a bridge for actin-cytoskeleton and cell signaling pathways and is involved in multiple biological and physiological processes. Dysregulation of PFN1 in cancer cells has a notable impact on sensitivity to chemotherapy or radiotherapy and may be a new target for the treatment of drug-resistant or radioresistant patients.

Studies have already confirmed that PFN1 is essential for cell survival in early embryos, as PFN1-KN could induce Drosophila embryos to die at the 2-cell stage.94 For further investigation of PFN1s roles in tissue-specific stem cells, Zheng et al established PFN1flox/flox mice that inducibly delete PFN1 in HSCs. Results showed that PFN1 was essential for the retention and metabolism of mouse hematopoietic stem cells in bone marrow partially through the axis of PFN1/G13/EGR1.95 These study results implied important roles of PFN1 in stem cell function, which were still unclear and deserved further research. Later study results have found that both overexpression and depletion of PFN1 could reduce the stem-like phenotype of MDA-MB-231 (MDA-231) triple-negative breast cancer cells, suggesting that a balanced expression of PFN1 was required for maintenance of optimal stemness and tumor-initiating ability of breast cancer cells.93 Considering that tumor heterogeneity is still an ongoing challenge for cancer treatment and that cancer stem cells (CSC) are considered to be a determining factor of tumor heterogeneity,96 intensive studies on PFN1s roles in CSC may provide us new insight into tumor initiation.

As mentioned above, PFN1 has been shown to be a critical participator of actin dynamics and to play important roles in cell migration. For cytotoxic T lymphocytes (CTLs), migration abilities are essential for patrolling tissues and locating targeted cells.97-98 Schoppmeyer et al thus studied PFN1s roles in CTL functions. The authors found that PFN1 negatively regulated CTL-mediated elimination of target cells and that PFN1 downregulation promoted CTL invasion into a 3D matrix in vitro. In patients with pancreatic cancer, PFN1 expression was substantially decreased in peripheral CD8+ T cells.99 However, considering the complexity of immune responses in vivo, the exact roles of PFN1 in tumor immunity remain unclear and need to be further explored.

Based on previous studies, we found that PFN1participates in multiple biological processes of tumor development and progression. Meanwhile, it is noteworthy that PFN1 plays opposite roles in different tumors and at different periods of tumor, potentially leading to the conclusion that PFN1s function in tumor has spatial and temporal specificity. Future studies on PFN1 should take this into account. PFN1 was shown to be of great significance for diagnosis and prognosis prediction and for monitoring the therapeutic effect of anticancer drugs, and PFN1s roles in tumor stemness and immunity may provide a new avenue for cancer therapy. Although much research has been done on PFN1 and cancer, puzzles still need to be solved. With deepening research, the function of PFN1 in cancer would be further clarified and its clinical value would be more prominent.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Conflicts of Interest: Authors declare no conflicts of interest for this article.

Acknowledgment: The authors are thankful for financial support from the Doctoral Fund Project of Hunan Provincial Peoples Hospital (program number BSJJ201812).


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Profilin 1 Protein and Its Implications for Cancers - Cancer Network


Homing Technology Delivers Therapy to Cancerous Bone – The Scientist

Wednesday, July 21st, 2021

Han Xiao, a protein chemist at Rice University, and Shawn Zhang, a cancer biologist at Baylor College of Medicine, received an email with a big question: When will your drug go to clinical trials? The question came from a patient eager to try out a drug for breast cancer that had metastasized to the bone. When cancer spreads beyond the tissue where it developed, especially to bone, patients outcomes become less optimistic. More than hope hung on the patients email.

Xiao and Zhang developed an innovative therapeutic technology that sends medicine right to cancerous bone tissue by combining two drugs the U.S. Food and Drug Administration (FDA) has already approved. By delivering therapy to tissues such as bone that are notoriously difficult for medicines to access, the new technology, dubbed BonTarg, could be a game changer for patients with metastasized breast cancers and other cancers and bone diseases.

Its quite exciting, particularly because bone metastasis is such a huge problem in breast cancer, said Alana Welm, a breast cancer biologist at the University of Utahs Huntsman Cancer Institute, who was not involved with the new research.

A new technology targets an FDA-approved antibody therapy to cancer in the bone.

Baylor College of Medicine and Rice University

Metastasis to Metastasis

Bone is often the first site of metastasis. Once cancer spreads to bone it will almost inevitably spread to other organs such as the lung, liver, and brain. Metastasis makes cancer difficult or impossible to cure. Metastatic breast cancer, for example, is incurable.

Most metastases originate from other metastases, not the primary tissue. Zhangs group recently showed that bone can act as a launchpad for further metastases.1 They seeded invasive and less aggressive human breast and prostate cancer cell lines in the hind limbs of mice. Within four to eight weeks, they saw metastases in the rodents lungs, livers, kidneys, brains, and additional bones.

Follow-up experiments revealed that once cancer cells are growing in the bone microenvironment, they become more plastic and take on stem cell-like properties. These features allow cancer cells to better adapt to new environments. They leave the bone and spread to other organs, which further advances the disease. Zhang and his team also found that primary metastases in bone can remain small, indicating that further metastases could spread to other organs before the first ones are detectable.

Anything we can do to keep the disease either not going to bones, or to really treat it well once its in the bones, could actually have outcomes for overall survival, Welm said. Treating bone metastases could also alleviate bone pain, spinal compression, and fractures that can make patients lives quite awful, Welm said. To intervene when cancer has only spread to bone represents a huge therapeutic opportunity.

Bone Barriers

To get ahead of the metastatic launchpad in the bone, Zhang and Xiao planned to specifically target breast cancer-derived bone metastases. They started with a proven drug called trastuzumab. Commonly referred to by its brand name Herceptin, trastuzumab is an antibody therapy that targets human epidermal growth factor 2 (HER2), a protein that cells make too much of in about a quarter of breast cancers. The antibody prevents HER2-expressing cancer cells from initiating a cascade of events that leads to proliferation, and may also induce cytotoxicity by attracting the immune systems natural killer cells.

Trastuzumab is a proven therapy that, when given in combination with chemotherapy, has extended overall survival in metastatic breast cancer patients to nearly five years.2 But the drug is not a cure. For many patients, their cancer continues to progress while they are under treatment, and for most, remission rarely lasts.

Bone metastases do not kill patients as often as metastases to internal organs such as the lung or liver, so they do not receive a lot of attention in research. But according to Zhang, Targeting bone metastasis not just kills cancer cells in the bone, it has the potential to prevent cancer cells from going other places in the body.

One difficulty lies in getting drugs to the bone. Despite making billions of blood cells every day, bone tissue holds few blood vessels. Where it does have vasculature, a bone marrow-blood barrier makes it hard for therapies delivered through the circulatory system to arrive at their destination. In addition, antibodies are big molecules. The mineralized matrix structure of bone prevents big molecules from gaining access to the tissue, limiting how effective a drug can be.

In the past, patients were given high doses of antibody therapies to overcome hurdles of getting them to bone. But then the drug ended up in tissues besides the bone, leading to unwanted and sometimes systemic side effects.

People think of antibody drugs as magic bullets that only target cancer cells while missing healthy cells, Xiao said. But research in the clinic has shown that not to be true.

That discrepancy drove Xiao to increase the specificity of the bullet so that it goes to the cancer, but not the healthy tissues. In the new research, he equipped the antibody therapy with a homing device.

Targeting Tumors

Alendronate is a bisphosphonate drug with high affinity for the highly mineralized bone matrix. It has been used to selectively deliver imaging probes, nuclear medicines, and nanoparticles to the bone, and the FDA has approved it to treat bone maladies such as osteoporosis. Xiao joined alendronate to the monoclonal antibody trastuzumab to target the therapy to bone.

Next, Zhang and his team injected the modified drug into the intra-iliac artery, a branch of a major artery in the lower abdomen, of mice with tumors in the hind limb bone derived from a breast cancer cell line.

Within 24 hours, the drug accumulated in the bone and remained there for a week. In contrast, injection with unmodified antibody did not remain in bone past the first day of treatment. The bone-targeted drug also accumulated much more substantially in cancerous bone compared with healthy bone, thanks in part to alendronates affinity for the highly acidic environment of bone metastatic sites.

The conjugated antibody therapy also prevented the development of secondary metastases in most other organs. Zhang and his team let the bone tumors grow for about eight to 12 weeks. Mice treated with trastuzumab harbored metastases in the heart, liver, spleen, lungs, kidney, and brain. Mice treated with alendronate conjugated trastuzumab, however, were mostly devoid of secondary tumors, Zhang and Xiao reported in Science Advances.3

Scans of rodents treated with alendronate-conjugated trastuzumab, individual components, or a salt solution.

Baylor College of Medicine and Rice University

Translatable Technology

The work that theyve done here is quite translatable [to the clinic], Welm said. She added that a trial will likely be straightforward as long as Xiao and Zhang can create a clinical grade version of the compound. The next step is to see whether the therapy works in models with cells derived from patients rather than established cell lines.

She is curious whether the technology could be used with other breast cancer therapies. The FDA recently approved another antibody therapy called Sacituzumab govitecan to treat triple-negative breast cancer. Theoretically, the chemistry Xiao and his team developed to attach alendronate to trastuzumab should work with Sacituzumab govitecan.

For these antibody drugs, even though [trastuzumab] is an older drug, people can modify the antibody, like what we are doingand get more potential from this drug, he said.

The technology allows scientists like Xiao and Zhang to come one step closer to the magic bullet that will take out cancer cells while leaving healthy cells alone. This conjugated antibody is one of the most perfect, best solutions in my mind, to help us gather the bullets to where they need to be, Zhang said.

The team hopes to be ready in time to help the patient who emailed them. This drug can be the next wave of drugs for this patient, Xiao said. We can get a better outcome for her. We want to push this drug to clinical trials as soon as possible, and hopefully this patient can benefit from it.


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Homing Technology Delivers Therapy to Cancerous Bone - The Scientist


Developmental Interest in Allogeneic PlacentaDerived Cell Therapies Expands – OncLive

Wednesday, July 21st, 2021

After closing a merger with GX Acquisition Corp., Celularity Inc., a clinical-stage cellular medicine company, is taking the next step in its evolution to enable further development of novel, off-the-shelf allogeneic placentaderived cellular therapies.1

Celularity aims to transform the way we approach the treatment of cancer and other diseases by harnessing the versatility, unique immune biology, and innate stemness of placental-derived cells, Robert J. Hariri, MD, PhD, found, chairperson, and chief executive officer of Celularity, stated in a press release. We are immensely proud of our clinical development results so far as well as the state-of-the-art manufacturing capabilities we built to support rapid scaling and a competitive cost structure for our placental-derived cell therapeutics. We believe off-the-shelf, allogeneic cell therapies will drive a paradigm shift in how clinicians approach the treatment of cancer and other serious diseases.

CYNK-001, the companys lead product candidate, is the only cryopreserved, allogeneic, off-the-shelf natural killer (NK) cell therapy to be developed from placental hematopoietic stem cells. The agent expresses perforin and granzyme B, has showcased cytotoxic activity against hematological tumors and solid tumor cell lines, and can secrete immunomodulatory cytokines in the presence of tumor cells.

The novel therapy is under investigation as a potential option in multiple myeloma, acute myeloid leukemia (AML), and glioblastoma multiforme; it is also being evaluated in infectious diseases like COVID-19 (NCT04365101).

An ongoing, open-label, multi-dose, phase 1 trial (NCT04310592) is examining the maximum-tolerated dose (MTD) or maximum planned dose of CYNK-001 in an estimated 22 patients with acute myeloid leukemia (AML).2 To participate, patients need to have primary or secondary AML and be in first or second morphological clinical response (CR), morphological CR with incomplete hematologic recovery, or a morphologic leukemia-free state per European LeukemiaNet recommendations for AML Response Criteria.

Patients also need to have MRD positivity, be aged between 18 and 80 years old, have an ECOG performance status of 0 to 2, and be able to be off immunosuppressive therapy for at least 3 days before infusion with the therapy. Patients who previously had central nervous system involvement are allowed to enroll if they had been treated and their cerebral spinal fluid is clear for at least 2 weeks before undergoing lymphodepletion.

Exclusion criteria include significant medical conditions, laboratory abnormalities, bi-phenotypic acute leukemia, acute promyelocytic leukemia, unacceptable organ function, autoimmune disease, uncontrolled graft-vs-host disease (GVHD), and GVHD that requires corticosteroids.

Participants are first given cyclophosphamide plus fludarabine. Then, they are administered CYNK-001 at 3 varying dose levels1.8 billion, 3.6 billion, and 5.4 billion CYNK-001 cellson days 0, 7, and 14. The primary objectives of the research include dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and frequency and severity of adverse effects. Important secondary objectives include the number of patients who convert from MRD-positive to -negative status; time to, and duration of, MRD response; progression-free survival; time to progression; duration of morphologic complete remission; and overall survival.

In June 2021, the study was expanded to include patients with relapsed/refractory AML following a case of conversion to MRD negativity, when the therapy was delivered at its highest dose level.3

The decision to expand the trial followed observations of a patient with NPM-1positive, FLT3-negative AML and good-risk cytogenetics who had been administered 5.4 billion CYNK-001 cells. The patient converted from MRD-positive to -negative status, without experiencing any DLTs.

For this patient, primary induction treatment with 7+3 chemotherapy had failed, and so they had gone on to receive second induction therapy followed by high-dose cytarabine consolidation. At this time point, the patient achieved a complete CR, but MRD was found to be persistent; it did not clear following 4 months of treatment with azacitidine. MRD positivity was confirmed on a marrow biopsy.

The patient went on to enter the phase 1 trial, where they received lymphodepletion, and then received 1.8 billion CYNK-001 cells on days 0, 7, and 14 in the outpatient setting, which totaled to 5.4 billion CYNK-001 cells. On day 28, the patient had converted from MRD positivity to negativity. CYNK-001 cells were present in both the peripheral blood and bone marrow.

Notably, no DLTs have been observed with the therapy at any of the dose levels examined thus far.

The company also shared plans to continue dose escalation with the therapy in the MRD indication up to 9.0 billion CYNK-001 cells. To strengthen the persistence of the treatment, the expansion arms of MRD and relapsed/refractory AML will include an augmented lymphodepletion protocol comprised of cyclophosphamide at 3600 mg and fludarabine at 120 mg over 4 days vs cyclophosphamide at 900 mg plus fludarabine at 75 mg over 3 days.

In April 2021, the FDA granted an orphan drug designation to CYNK-001 as a potential therapeutic option for patients with malignant gliomas.4 As such, the therapy is also under investigation in patients with glioblastoma multiforme as part of another phase 1 trial (NCT04489420).5

To be eligible for enrollment, patients need to have historically confirmed disease at first or second relapse, measurable disease, a Karnofsky performance status of 60 or higher, and acceptable organ function, among other criteria.

Patients who previously received radiation within 12 weeks of their screening MRI; those who were on growth factors with less than 4 weeks of a washout period; those treated with radiotherapy, chemotherapy, or other investigational drugs within 4 weeks; those who received prior cellular or gene therapy; and those with active autoimmune disease, were excluded.

Cohort 1A of the trial will enroll up to 6 patients with recurrent glioblastoma multiforme who will receive intravenous CYNK-001 at a dose of 1.2 x 109 cells on days 0, 7, and 14. From the initial infusion of therapy, patients will be followed for a 42-day DLT period. No other interventions are planned between the last day of treatment.

If DLTs are experienced, cohort 1C, the de-escalation cohort, will include up to 6 patients with recurrent glioblastoma multiforme who will receive the therapy at a dose of 600 x 106 cells on days 0, 7, and 14. These patients will also be followed for DLTs for 42 days post infusion. Cohort 1B, the surgical cohort, will also enroll up to 6 patients, who will be given CYNK-001 at a maximum safe dose of either 1.2 x 109 cells or 600 x 106 cells at days 0, 7, and 14. Patients in this cohort will undergo resection following the last dose of the therapy in the DLT period.

Treatment of cohorts 2A or 2C will only begin after the safety data from cohorts 1A or 1C are determined to be acceptable. Here, patients will first have the Ommaya catheter placement in accordance with institutional policy within 1 week before CYNK-001 infusion on day 0. Cohort 2A will enroll up to 6 patients with recurrent glioblastoma multiforme who will be given the therapy at a dose of 200 x 106 cells +/- 50 x 106 cells intratumorally on day 0, 7, and 14.

Cohort 2C will also include up to 6 patients with recurrent disease who will receive the product at a dose of 200 x 106 cells +/- 50 x 106 cells intratumorally on day 0 and day 7. Lastly, cohort 2B, the surgical intratumoral cohort, will include 6 patients with glioblastoma multiforme who will receive the cellular therapy at a maximum safe dose of either 200 x 106 cells +/- 50 x 106 cells on day 0 and 7.

The primary objectives of the trial are to examine the number of patients who report DLTs with the therapy and toxicities. Important secondary objectives are to evaluate the overall response rate, duration of response, progression-free survival, time to progression, and overall survival.

The safety and efficacy of the cell therapy is also being explored in newly diagnosed patients with multiple myeloma after autologous stem cell transplant, as part of another phase 1 trial (NCT04309084).6 The objective of the program is to achieve durable responses with the therapy in these patients with multiple myeloma who are eligible for transplant in the first-line setting.

Another novel agent in the pipeline is CYNK-101, which is manufactured from NK cells extracted from postpartum placentas. The cells are then genetically engineered to boost cell-killing activity when given with a monoclonal antibody.7 Preclinical data with the product in combination with an antibody showed that the regimen resulted in cell-killing activity when administered to lymphoma cells in vitro.

Additionally, CYNK-CAR products are being developed as allogeneic, off-the-shelf strategies by modifying genes of the human placental hematopoietic stem cellderived NK cells. Several CAR constructs that are designed to target hematologic and solid tumor indications are currently under investigation.

More here:
Developmental Interest in Allogeneic PlacentaDerived Cell Therapies Expands - OncLive


Triple negative breast cancer and non-small cell lung cancer: Clinical challenges and nano-formulation approaches – DocWire News

Wednesday, July 21st, 2021

This article was originally published here

J Control Release. 2021 Jul 14:S0168-3659(21)00357-6. doi: 10.1016/j.jconrel.2021.07.014. Online ahead of print.


Triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) are amongst the most aggressive forms of solid tumors. TNBC is highlighted by absence of genetic components of progesterone receptor, HER2/neu and estrogen receptor in breast cancer. NSCLC is characterized by integration of malignant carcinoma into respiratory system. Both cancers are associated with poor median and overall survival rates with low progression free survival with high incidences of relapse. These cancers are characterized by tumor heterogeneity, genetic mutations, generation of cancer-stem cells, immune-resistance and chemoresistance. Further, these neoplasms have been reported for tumor cross-talk into second primary cancers for each other. Current chemotherapeutic regimens include usage of multiple agents in tandem to affect tumor cells through multiple mechanisms with various such combinations being clinically tested. However, lack of controlled delivery and effective temporospatial presence of chemotherapeutics has resulted in suboptimal therapeutic response. Consequently, passive targeted albumin bound paclitaxel and PEGylated liposomal doxorubicin have been clinically used and tested with newer drugs for improved therapeutic efficacy in these cancers. Active targeting of nanocarriers against surface overexpressed proteins in both neoplasms have been explored. However, use of single agent nanoparticulate formulations against both cancers have failed to elicit desired outcomes. This review aims to identify clinical unmet need in these cancers while establishing a correlation with tested nano-formulation approaches and issues with preclinical to clinical translation. Lipid and polymer-based drug-drug and drug-gene combinatorial nanocarriers delivering multiple chemotherapeutics simultaneously to desired site of action have been detailed. Finally, emerging opportunities such as pharmacological targets (immune check point and epigentic modulators) as well as gene-based modulation (siRNA/CRISPR/Cas9) and the nano-formulation challenges for effective treatment of both cancers have been explored.

PMID:34273417 | DOI:10.1016/j.jconrel.2021.07.014

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Triple negative breast cancer and non-small cell lung cancer: Clinical challenges and nano-formulation approaches - DocWire News


The World’s First Lab-Grown Foie Gras Could Solve This Major Concern – Mashed

Wednesday, July 21st, 2021

Gourmey uses stem cells taken from a fertilized duck egg which are isolated and then fed on a diet of proteins, amino acids, and fats. "The cells multiply as if they are in the egg, then you adjust the nutrients to trigger the cell type that you want," company CEO and cofounder Nicolas Morin-Forest tellsSifted."So if you want liver cells, or muscle cells, you adjust the inputs and the cells react to that. We then harvest muscle cells, fat cells, or liver cells and craft our products."The company says its end product is so successful that an unnamed Michelin-star chef has not been able to tell the lab grown foie gras from its natural counterpart, and that he would cook with the synthesized meat product.

Morin-Forest says their company began with foie gras because it is complex, hard to find due to bans, and it carries premium pricing. But the company wants to do more with what they've created. "Foie gras is just the first application of our current know-how," says Morin-Forest. "With the same starting cells, we can create any type of poultry meat product."

Gourmey's product has been so convincing it's been able to pull together $10 million in additional funding. Fortune notes that with this money, this specialty lab-meat maker expects to begin selling its foie gras before the end of 2022 at the earliest, and by 2023 at the latest.

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The World's First Lab-Grown Foie Gras Could Solve This Major Concern - Mashed


KEYTRUDA (pembrolizumab) Plus Chemotherapy Before Surgery and Continued as a Single Agent After Surgery Showed Statistically Significant Event-Free…

Wednesday, July 21st, 2021

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced positive event-free survival (EFS) data from the pivotal neoadjuvant/adjuvant Phase 3 study KEYNOTE-522. The trial investigated neoadjuvant KEYTRUDA, Mercks anti-PD-1 therapy, plus chemotherapy followed by adjuvant KEYTRUDA as monotherapy (the KEYTRUDA regimen) compared with neoadjuvant chemotherapy followed by adjuvant placebo (the chemotherapy-placebo regimen) in patients with high-risk early-stage triple-negative breast cancer (TNBC). This is the first time an anti-PD-1/L1 therapy has demonstrated a statistically significant EFS result as combined neoadjuvant and adjuvant therapy for these patients. These results are being presented today during a European Society for Medical Oncology (ESMO) Virtual Plenary.

After a median follow-up of 39 months, the KEYTRUDA regimen reduced the risk of EFS events by 37% (HR=0.63 [95% CI, 0.48-0.82]; p=0.00031) versus the chemotherapy-placebo regimen a statistically significant and clinically meaningful EFS result. EFS was defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause. As previously announced, KEYNOTE-522 met the dual primary endpoint of pathological complete response (pCR) at the first interim analysis. The trial is continuing to allow for additional follow-up of overall survival (OS), a key secondary endpoint. At this fourth interim analysis, although these data have not crossed the boundary for statistical significance, there was a 28% reduction in the risk of death with the KEYTRUDA regimen versus the chemotherapy-placebo regimen (HR=0.72 [95% CI, 0.51-1.02]; p=0.03214). The safety profile of the KEYTRUDA regimen was consistent with the known profiles of each regimen, and no new safety concerns were identified.

Given the high rates of recurrence within the first five years of diagnosis, patients with high-risk early-stage TNBC need new treatment options, said Dr. Peter Schmid, lead, Centre for Experimental Cancer Medicine, Barts Cancer Institute in London, England. KEYNOTE-522 was designed to study whether the combined neoadjuvant and adjuvant regimen with KEYTRUDA could help treat the cancer earlier. Now, with more than three years of follow-up, we see the potential of this approach. These event-free survival data are very encouraging for patients and show that this combination of KEYTRUDA plus chemotherapy as neoadjuvant therapy, followed by single-agent KEYTRUDA as adjuvant therapy, may offer women with high-risk early-stage TNBC a new treatment option for this aggressive disease.

These highly anticipated event-free survival results in this TNBC population build upon earlier findings from the KEYNOTE-522 trial and further support the potential use of KEYTRUDA in these patients, said Dr. Vicki Goodman, vice president, clinical research, Merck Research Laboratories. KEYNOTE-522 is the first large randomized Phase 3 study to report a statistically significant and clinically meaningful EFS result among patients with stage II and stage III TNBC. We have submitted these data to the FDA and are working closely with the agency on its review of our application.

KEYTRUDA is currently approved under accelerated approval in the U.S. in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score [CPS] 10) as determined by an FDA-approved test.

Merck is rapidly advancing a broad portfolio in womens cancers with an extensive clinical development program for KEYTRUDA and several other investigational and approved medicines across multiple gynecologic and breast cancers. The KEYTRUDA clinical development program for TNBC encompasses several internal studies and external collaborative trials, including the ongoing studies KEYNOTE-242 and KEYNOTE-355.

Study Design and Additional Data From KEYNOTE-522

KEYNOTE-522 is a Phase 3, randomized, double-blind trial (, NCT03036488). The dual primary endpoints are pCR, defined as pathological stage ypT0/Tis ypN0 at the time of definitive surgery, and EFS, defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause in all patients randomized. Secondary endpoints include pCR rate using alternative definitions, OS in all patients randomized, pCR rate according to all definitions, EFS and OS in patients whose tumors express PD-L1 (CPS 1), safety and health-related quality of life assessments. The study enrolled 1,174 patients who were randomized 2:1 to receive either:

As previously announced, KEYNOTE-522 met the success criterion for the dual primary endpoint of pCR at the first interim analysis; pCR was observed in 64.8% of patients treated with KEYTRUDA plus chemotherapy (n=401), an increase of 13.6% (p=0.00055) from 51.2% in patients treated with placebo plus chemotherapy (n=201). At the fourth interim analysis, KEYNOTE-522 met the success criterion for the dual primary endpoint of EFS. The study is continuing to allow for additional follow-up of OS.

At three years, 84.5% of patients treated with the KEYTRUDA regimen were alive and did not experience an EFS event compared to 76.8% of patients treated with the chemotherapy-placebo regimen.

In pre-specified exploratory subgroup analyses of EFS, the EFS benefit seen with the KEYTRUDA regimen was independent of PD-L1 expression. In the PD-L1-positive subgroup (n=973), defined as CPS 1, treatment with the KEYTRUDA regimen reduced the risk of EFS events by 33% (HR=0.67 [95% CI, 0.49-0.92]) versus the chemotherapy-placebo regimen. In the PD-L1-negative subgroup (n=197), defined as CPS <1, treatment with the KEYTRUDA regimen reduced the risk of EFS events by 52% (HR=0.48 [95% CI, 0.28-0.85]) versus the chemotherapy-placebo regimen.

In a pre-specified but non-randomized exploratory analysis of EFS by pCR outcome, the reduction in EFS events with the KEYTRUDA regimen was observed independent of pCR outcome at definitive surgery.

Treatment-related adverse events (TRAEs) were examined in the neoadjuvant phase, the adjuvant phase and the combined phases. TRAEs in the neoadjuvant phase have been previously reported. At the time of this data cutoff, no patients were still receiving protocol treatment. For the combined neoadjuvant and adjuvant phases, TRAEs occurred in 98.9% of patients receiving the KEYTRUDA regimen (n=783) and 99.7% of patients receiving the chemotherapy-placebo regimen (n=389); Grade 3-5 TRAEs occurred in 77.1% versus 73.3%, respectively. TRAEs led to death in 0.5% of patients receiving the KEYTRUDA regimen (n=4) and 0.3% of patients receiving the chemotherapy-placebo regimen (n=1). No new safety concerns were identified. In the adjuvant phase, TRAEs occurred in 53.7% of patients receiving adjuvant KEYTRUDA (n=588) and 48.6% of patients receiving adjuvant placebo (n=331), including 6.3% and 2.7%, respectively, who had at least one Grade 3 event.

Immune-mediated adverse events (AEs) and infusion reactions of any grade in the combined neoadjuvant and adjuvant phases occurred in 43.6% of patients receiving the KEYTRUDA regimen and 21.9% of patients receiving the chemotherapy-placebo regimen. The most common of these events (occurring in 10% of patients) were infusion reactions (18.0%) and hypothyroidism (15.1%) in patients receiving the KEYTRUDA regimen and infusion reactions (11.6%) in patients receiving the chemotherapy-placebo regimen. Immune-mediated AEs led to death in 0.3% of patients receiving the KEYTRUDA regimen (n=2) and no patients receiving the chemotherapy-placebo regimen. In the adjuvant phase, immune-mediated AEs and infusion reactions occurred in 10.2% of patients receiving adjuvant KEYTRUDA and 6.0% of patients receiving adjuvant placebo, including 2.9% and 0.3%, respectively, who had at least one Grade 3 event.

About Triple-Negative Breast Cancer (TNBC)

Triple-negative breast cancer is an aggressive type of breast cancer that characteristically has a high recurrence rate within the first five years after diagnosis. While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three. Approximately 10-15% of patients with breast cancer are diagnosed with TNBC. TNBC tends to be more common in people who are younger than 40 years of age, who are African American or who have a BRCA1 mutation.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,500 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.


KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or mUC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDASevere and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.


KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

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KEYTRUDA (pembrolizumab) Plus Chemotherapy Before Surgery and Continued as a Single Agent After Surgery Showed Statistically Significant Event-Free...


Human Mesenchymal Stem Cells (hMSC) Market Size 2021 | Global Trends, Business Overview, Challenges, Opportunities and Forecast to 2027 The Bisouv…

Wednesday, March 3rd, 2021

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New Jersey, United States,-The Human Mesenchymal Stem Cells (hMSC) Market report provides in-depth knowledge and insights into the Human Mesenchymal Stem Cells (hMSC) market in terms of market size, market share, factors influencing growth, opportunities, and current and emerging trends. The report has the updated and latest information on the Human Mesenchymal Stem Cells (hMSC) market that has been further validated and verified by industry experts and professionals. The Human Mesenchymal Stem Cells (hMSC) market report provides historical, current, and forecast estimates of sales generation and profit for each segment and sub-segment of the Human Mesenchymal Stem Cells (hMSC) market in every key region around the world. The report also highlights the emerging growth opportunities in the business that are designed to support market growth.

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PromoCell ThermoFisher KURABO Lifeline Cell Technology Merck

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The report provides an in-depth analysis of various market segments based on the product line, applications, major regions, and key companies in the industry. In addition, the report has a single section that provides a detailed analysis of the manufacturing process and includes information gathered from primary and secondary data collection sources. The main source for data collection is interviews with industry experts who provide accurate information about the future market scenario.

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Umbilical Cord Matrix hMSC Bone Marrow hMSC Adipose Tissue hMSC Other

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Medical Application Research Other Applications

Human Mesenchymal Stem Cells (hMSC) Market Report Scope

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[Full text] An Update on the Molecular Pathology of Metaplastic Breast Cancer | BCTT – Dove Medical Press

Wednesday, March 3rd, 2021


Metaplastic breast cancer (MpBC) is a unique histologic subtype of breast cancer, defined by characteristic intra-tumoural heterogeneity. Although rare, MpBC accounts for significant morbidity and mortality, and has a poor prognosis. MpBC tend not to respond well to systemic chemotherapies, and together with emerging data on the genomic landscape of MpBC, there is scope for applying precision oncology in the management strategies of MpBC. We focus herein on the molecular pathology of MpBC and the current status and potential of targeted therapies to manage MpBC.

The clinical features of MpBC are similar to other high-grade cancers of no special type (NST), however, they often present at amore advanced stage. They tend to be large in size, with dimensions ranging from 1.2 to >10 cm and often present as a palpable breast mass, with ill-defined borders on mammography, ultrasonography, and magnetic resonance imaging. MpBC represents 0.21% of all breast cancers the rates vary due to the differing definitions and classification systems used over time.

MpBC do not have any distinctive macroscopic features, with the tumor varying from well-circumscribed to having an irregular border. Microscopically, they comprise a heterogenous group with differing outcomes. In the absence of sufficient molecular and outcome data, the current WHO Classification of Tumours of the Breast1,2 has maintained a descriptive morphological classification system, based on the type of the metaplastic elements present. MpBC are classified monophasic (when there is only one metaplastic component) or biphasic (with two or more metaplastic components such as squamous and spindle, or mixed metaplastic and non-metaplastic components such as spindle and invasive carcinoma NST). Further, MpBC can also be classified into epithelial-only carcinomas (with low-grade adenosquamous carcinoma or pure squamous cell carcinoma), pure (monophasic) sarcomatoid (spindle cell or matrix-producing) carcinomas, and biphasic epithelial and sarcomatoid carcinomas.

The current WHO classification includes (i) adenosquamous carcinoma mostly low grade but can be high grade rarely and (ii) pure squamous cell carcinomas (iii) pure spindle cell carcinoma (iv) fibromatosis-like metaplastic carcinoma, (iv) metaplastic carcinoma with mesenchymal differentiation that includes chondroid (myxoid/cartilaginous), osseous (bone), rhabdomyoid (muscle) and neuroglial, and (v) mixed metaplastic carcinoma where the mix may be multiple metaplastic elements or a mixture of epithelial and mesenchymal elements. Examples of the heterologous elements are shown in Figure 1. The detailed morphology of the subtypes is beyond the scope of this review and the reader is directed to the WHO Tumour Classification of the Breast 5th Ed (2019).2

Figure 1 Examples of Metaplastic breast cancer morphologies. (A) High-grade, pleomorphic de-differentiated carcinoma (IBC-NST). (B) High-grade carcinoma with focal squamous differentiation. (C) Osteoid differentiation. (D) Chondroid differentiation. (E) Spindle differentiation. Scale bar is 100 m.

MpBC are typically, though not invariably triple-negative (TN), lacking expression of estrogen and progesterone receptors (ER/PR), and HER2. Analysis of the SEER data showed that HER2 positive MpBC had an improved overall survival compared to TN, and other MpBC including ER+/PR+/HER2-cases, which accounted for 20% of the cohort.3 Conversely, HER2-positive metaplastic squamous cell carcinomas were recently demonstrated to have a poorer prognosis than the TN metaplastic squamous variants.4 MpBC fit into the claudin-low and/or basal breast cancer intrinsic subtypes,5,6 although whether or not claudin low represents an intrinsic subtype or phenotype has recently come into question.7 A recent large meta-analysis reported that approximately three quarters of all MpBC stain positively for pan-cytokeratin biomarkers (AE1/3, MNF116) and basal cytokeratin biomarkers (34E12, CK5/6, CK14 and CK17). GATA3, a common diagnostic marker used to identify tumours of breast origin, is expressed by only 21% of MpBC, while a novel breast marker, TRPS1, was shown to be highly expressed in 86% of MpBC, as well as non-metaplastic TNBC and BC more broadly.8 Frequent expression of p63 was also noted, as was an absence of staining for CD34.9 Those cases lacking cytokeratin expression were studied in more detail, and determined to be carcinomatous rather than true primary sarcomas in most cases, further evidencing the inter-tumor heterogeneity of breast cancer broadly, and MpBC specifically.10 Indeed, a pure sarcoma of the breast is rare and is a diagnosis of exclusion, requiring extensive sampling; negative stains for p63 and a range of cytokeratins; and, a morphological examination for any evidence of epithelial differentiation.

For the adenosquamous and fibromatosis-like variants of MpBC, the grade is implicitly low, and prognostic outcome is better than for the majority of MpBC which are typically classified as high grade (grade 3) tumors. Although high histologic grading is a relatively consistent finding, its prognostic value is still uncertain.11 A subset of MpBC tumors with extreme, bizarre cytologic pleomorphisms has been reported,11 with a noted enrichment in the spindle phenotype.

With respect to the TNM classification system of cancer stage, MpBC present with a larger tumor size (TNM), with reports indicating that ~60% of MpBC have tumors between 2 and 5 cm (T2;12). As for triple-negative breast cancers more broadly, lymph node (LN; the N of TNM) positivity is not a prominent feature, with LN metastasis documented in about 24% of patients. Distant metastasis (TNM) occurs with or without LN spread in MpBC, and spread to the lungs and brain has been reported.13

The innate plasticity of MpBC has led to suggestions that it is a stem-cell like breast cancer, and a wealth of data show that MpBC express classic stem cell markers. It is presently considered that there exist three categories of breast cancer stem cell (CSC): an ALDH+ epithelial-like CSC; CD44+/CD24 mesenchymal-like CSCs; and, a hybrid epithelial/mesenchymal-like ALDH+/CD44+/CD24 (reviewed in detail in14). The work of Zhang et al15 demonstrated the increased expression of classic stem cell markers ALDH1 and CD44/CD24 ratios in a series of MpBC, much like the above-noted hybrid CSC state, and also expression of characteristic epithelial to mesenchymal transition (EMT) markers (increased ZEB1 and loss of E-cadherin). This expression of stem-like markers was also supported by Gerhard et al,16 with most of their series showing positivity for CD44 and loss of CD24, as well as an enrichment for vimentin and loss of the claudins and E-cadherin. Given that cancer stem cells have well-documented chemoresistance,17 it is unsurprising that MpBC, with their enrichment of both stem-like markers and the hallmarks of EMT,5,18 also respond poorly to chemotherapeutics. Notably, MpBC have a high frequency of PIK3CA mutations (see below) and these mutations correlate with poor response to neoadjuvant chemotherapy in breast cancer subtypes broadly,19 and this holds true in the metastatic setting.20 Drugs targeting the PI3K/AKT axis are emerging in the clinic, may be appropriate for MpBC, and are discussed further below.

As shown in Table 1, the research community has yet to robustly elucidate a molecular landscape for MpBC, most likely due to the extensive sample heterogeneity. There is limited concordance between studies on the mutations present, however this is likely influenced by the sequencing platform (exome vs panel), and also the subtype composition of the cohorts.

Table 1 Genetic Alterations Identified Across MpBC Cohorts and Morphologies

PI-3 Kinase and Ras signaling pathway mutations have been shown to be early events in MpBC pathogenesis.21 Mutation frequencies reported for MpBC range from 26%-75% for TP53, and 23%-70% for PIK3CA (Table 1) and this is supported by a recent meta-analysis of 14 studies encompassing 539 cases.22 Other than TP53 and PIK3CA, the most frequently identified mutations across multiple cohorts occur in PTEN, NF1, HRAS, PIK3R1. Emerging data support that the various morphologic elements feature subtly different mutation profiles, with for example, a lack of PIK3CA mutations found in those MpBC with chondroid differentiation.23 Chondroid tumors were also shown to lack mutations in TERT promoters.21 TERT promoter mutations were enriched in the spindle and squamous type tumors, while TP53 mutations were less likely to be in spindled tumors than other MpBC types.21 An increase in mutations in Wnt pathway genes has been reported for MpBCs,23 with WISP3/CCN6 mutations more frequently seen in the epithelial components, and 3/7 CTNNB1 mutations present only in the spindle compartment of the tumor.24

In spite of the private mutations in the different morphological components as noted above, evidence supports that the different histologies have a shared origin, and following a detailed exome sequencing study, Avigdor et al postulated that methylation and/or non-coding changes may also regulate the phenotypic differentiation.25 To clarify the outstanding elements of the genomic landscape of MpBC, a concerted effort must be made to standardize sequencing approaches on an adequately powered cohort of well-annotated MpBC.

Uterine carcinosarcoma (UCS) are considered the metaplastic cancers of the gynaecological tract, and a recent study performed a comparative analysis of 57 UCS with 35 MpBC.26 Genetic differences unique to the UCS were reported, with a significant enrichment for mutations in FBXW7 and PPP2R1A, and HER2 amplifications, while shared genomic features included alterations in TP53, PIK3CA, PTEN and EMT-related Wnt and Notch signalling components. Interestingly, unlike the UCS, almost half of the profiled MpBC had a dominant homologous recombination deficiency (HRD; signature 3) signature, and these same cases showed other features of a HRD including large scale transitions, and allelic imbalance extending to the telomeres.

In the absence of indications for hormone and anti-HER2 therapies, and given their typically large size at presentation, MpBC are managed with chemotherapeutics in addition to surgery (with/without radiation). However, early studies showed that systemic therapy was less effective in MpBC12 and this data has held true over time and is supported by the overall poor outcomes of MpBC patients.27 In fact, while 90% of diagnoses of MpBC are for localized disease, half of these patients will progress to advanced BC over time.28,29 Treatment in the neoadjuvant setting appears to afford little advantage, with a 1017% pathological complete response rate reported3033 for American studies, while studies in Japan and Turkey reported no complete responders.34,35 It is clear that efficacious treatments for MpBC are an unmet clinical need, and while some clinical trials specifically for MpBC are being initiated, the potential for novel therapeutic interventions must be capitalized upon.

MpBC are characteristically triple-negative BC, thus eliminating these patients from current tailored therapeutic options of hormone therapy and anti-HER2 therapy. This triple-negativity, does however make them eligible for a multitude of trials currently recruiting, including those assessing benefit of immune checkpoint inhibitors; a non-exhaustive list of open trials is presented in Table 2.

Table 2 Active Trials Open to Metaplastic Breast Cancer Patients

MpBC show frequent alterations in the PI3K/AKT/mTOR pathway making them candidates for targeted therapies such as everolimus, temsirolimus, and alpelisib. In a Phase I intervention, a 42% rate of partial/complete remission was reported for a combination of temsirolimus and bevacizumab (HIF inhibitor).36 A 25% response rate (complete/partial response) was achieved in MpBC treated with temsirolimus/everolimus in combination with standard chemotherapy and a 21% objective response rate was also reported for the regimen of doxorubicin, bevacizumab and temsirolimus/everolimus,37 however genetic analysis showed that while PI3K pathway alterations were associated with a significant improvement in objective response rate (31% vs 0%) they were not associated with an improved clinical benefit rate (44% vs 45%). Detailed analysis of this trial data showed an improvement in overall survival for the MpBC patients, and suggests that MpBC histology is an indicator for doxorubicin with bevacizumab and everolimus/temsirolimus.38 A lone MpBC participant in the BELLE-4 Phase II/III trial responded well to a combined therapy of paclitaxel and the PI3K inhibitor buparlisib39 although toxicity was noted, and indeed buparlisib was subsequently discontinued from development, with a significantly higher burden of adverse effects noted for buparlisib than alpelisb in the B-YOND (hormone receptor positive, phase Ib) trial.40 Pre-clinical data in MpBC patient derived xenograft models suggest that a combination of PI3K and MAPK inhibitors may be a potential avenue for therapy in PIK3CA mutated MpBC patients.41

CDK4/6 inhibitors (eg, ribociclib, palbociclib, abemaciclib) are now approved as standard of care for advanced, hormone receptor positive breast cancers, however this proliferation check-point may also be a useful target in TNBC, and trials are underway to determine the efficacy of this approach (reviewed in42), including in combination with immune checkpoint inhibitors (PAveMenT: NCT04360941). A recent case report demonstrated a dramatic but short-term benefit from combined dabrafenib and trametinib in an advanced MpBC patient.43 Dabrafenib and trametinib target BRAF and MEK signalling, respectively, and their application in MpBC has not previously been reported.

Although a pre-clinical study did not support the efficacy of PARP inhibitor olaparib in an MpBC-like mouse model,44 given the recent evidence of a dominant HRD signature in almost 50% of the MpBC profiled,26 the suggestion by Tray et al45 that PARP inhibition for MpBC needs further study is certainly warranted. These studies together support further investigations into a range of targeted therapies and highlight their potential value in MpBC.

The potential benefit of therapeutic modulation of the immune system in breast cancer is becoming increasingly clear for TNBC, as well as MpBC. A case report of a remarkable, durable response to pembrolizumab (anti-PD-1) in combination with nab-Paclitaxel in advanced, pre-treated spindled MpBC was reported in 2017.46 A similar combination of durvalumab (anti-PD-L1) and paclitaxel was also shown to provide a sustained, complete response in a second case report of advanced MpBC, this time with squamous features.47 In this case, 20% of tumor cells stained with medium intensity (clone SP142), and there was an absence of staining in the TILS; while in the former case, 100% of tumor cells stained positively for PD-L1 using the 22C3 clone. Indeed, there is no standardized definition criteria for PD-L1 staining at this stage, and the characterization of expression of this and other immune checkpoint markers across TNBC and MpBC has only recently emerged. As shown in Table 3, heterogeneity in percentage positivity of PD-L1 in tumor cells is reported across TNBC, with a higher rate of positivity consistently reported for MpBC. MpBC tumor cells show a range of PD-L1 expression from 17% to 80%, recording both cytoplasmic and membranous staining, and in the immune cells from 48% to 69%. Combinations of immune-checkpoint inhibitors are also being evaluated, with the DART (Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors, Table 2) trial facilitating an MpBC specific assessment.48 Primary endpoint data confirmed clinical activity of ipilimumab combined with nivolumab and resulted in 3 cases of 17 showing a durable response, which supports further investigation. It is hoped that trials such as the Morpheus-TNBC Phase 1/1b umbrella trial (Table 2, NCT03424005), will provide insights to further our understanding of the biomarkers and patient indicators for a range of immunotherapeutic interventions.

Table 3 PD-L1 Expression in Metaplastic Breast Cancer

The morphologically diverse metaplastic breast cancers account for significant global morbidity and mortality, in spite of their relatively rare frequency, due to their aggressive clinical course. As more molecular pathology data emerges on the genomic underpinnings of this intriguing tumor type, we are increasingly better placed to consider MpBC for targeted therapies and immunotherapies.

We apologize to those authors whose work we could not include due to space restrictions.

The authors report no conflicts of interest in this work.

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Read more:
[Full text] An Update on the Molecular Pathology of Metaplastic Breast Cancer | BCTT - Dove Medical Press


4D Pharma Appointments Paul Maier to the Board as Non-Executive Director – Business Wire

Wednesday, March 3rd, 2021

LEEDS, England--(BUSINESS WIRE)--4D pharma plc (AIM: DDDD), a pharmaceutical company leading the development of Live Biotherapeutic products (LBPs) - a novel class of drug derived from the microbiome, today announces the appointment of Paul Maier as Non-Executive Director of the Board. Mr Maier will also be a member of 4D's Audit and Risk Committee and will serve as the Companys audit committee financial expert under SEC and Nasdaq rules.

With over 25 years of extensive senior operational, international and financial management experience in the pharmaceutical and biotechnology industry, Paul will be able to provide 4D pharma with invaluable insights as we continue to execute across our business both clinically and operationally, said Duncan Peyton, Chief Executive Officer of 4D pharma. Pauls strong track record will support our Board with additional perspective and expertise.

I am excited to join 4D pharmas Board and support its goals to establish a larger global presence while working to bring its differentiated approach and pipeline of Live Biotherapeutics to patients in need, said Paul Maier, Non-Executive Director of 4D pharma. I look forward to working with 4D and offering my experiences in transactional and operational strategy as the company continues to grow, catalyzed by 4Ds upcoming NASDAQ listing.

Mr. Maier has over 25 years of investor and public relations, operational, regulatory, and finance expertise in the healthcare industry. Mr. Maier was previously the Chief Financial Officer of Sequenom Inc., where he was responsible for raising over $360 million in equity and debt financings, expanding institutional sell side research analyst coverage, as well as overseeing and establishing internal financial infrastructure. Previously, he was Senior Vice President and Chief Financial Officer of Ligand Pharmaceuticals (NASDAQ: LGND) where he helped build Ligand from a venture stage company to a commercial, integrated biopharmaceutical organization, raising over $1 billion in equity and debt financings including a successful IPO, and helped negotiate multiple R&D and commercial partnerships and transactions. He has also acted as an independent financial consultant to life sciences companies. Mr. Maier is currently a Board member of Eton Pharmaceuticals, Inc, Biological Dynamics and International Stem Cell Corporation (OTCQB: ISCO). He holds an MBA from Harvard University and a BS in Business Logistics from the Pennsylvania State University.

Additional Disclosures Required under the AIM Rules for Companies

In accordance with Schedule 2(g) of the AIM Rules, Paul Victor Maier (aged 73) currently holds the following directorships:Eton Pharmaceuticals, IncBiological Dynamics, IncInternational Stem Cell Corp.

Previous directorships held in the past five years:Ritter Pharmaceuticals, Inc (Mar 2015 May 2020)Apricus Biosciences, Inc (May 2012 Jan 2019)Mabvax, Inc (June 2014 July 2018)

Paul Maier does not currently hold any ordinary shares in the Company.

Save as set out above there are no further disclosures pursuant to Rule 17 or Schedule Two paragraph (g) of the AIM Rules for Companies in respect of the appointment of Paul Maier.

About 4D pharma

Founded in February 2014, 4D pharma is a world leader in the development of Live Biotherapeutics, a novel and emerging class of drugs, defined by the FDA as biological products that contain a live organism, such as a bacterium, that is applicable to the prevention, treatment or cure of a disease. 4D has developed a proprietary platform, MicroRx, that rationally identifies Live Biotherapeutics based on a deep understanding of function and mechanism.

4D pharma's Live Biotherapeutic products (LBPs) are orally delivered single strains of bacteria that are naturally found in the healthy human gut. The Company has six clinical programs, namely a Phase I/II study of MRx0518 in combination with KEYTRUDA (pembrolizumab) in solid tumors, a Phase I study of MRx0518 in a neoadjuvant setting for patients with solid tumors, a Phase I study of MRx0518 in patients with pancreatic cancer, a Phase I/II study of MRx-4DP0004 in asthma (NCT03851250), a Phase II study of MRx-4DP0004 in patients hospitalized with COVID-19 (NCT04363372), and Blautix in Irritable Bowel Syndrome (IBS) (NCT03721107) which has completed a successful Phase II trial. Preclinical-stage programs include candidates for CNS disease such as Parkinson's disease and other neurodegenerative conditions. The Company has a research collaboration with MSD, a tradename of Merck & Co., Inc., Kenilworth, NJ, USA, to discover and develop Live Biotherapeutics for vaccines.

For more information, refer to

Forward-Looking Statements

This press release contains "forward-looking statements." All statements other than statements of historical fact contained in this announcement, including without limitation statements regarding timing of the clinical trial are forward-looking statements within the meaning of Section 27A of the United States Securities Act of 1933, as amended (the "Securities Act"), and Section 21E of the United States Securities Exchange Act of 1934, as amended (the "Exchange Act"). Forward-looking statements are often identified by the words "believe," "expect," "anticipate," "plan," "intend," "foresee," "should," "would," "could," "may," "estimate," "outlook" and similar expressions, including the negative thereof. The absence of these words, however, does not mean that the statements are not forward-looking. These forward-looking statements are based on the Company's current expectations, beliefs and assumptions concerning future developments and business conditions and their potential effect on the Company. While management believes that these forward-looking statements are reasonable as and when made, there can be no assurance that future developments affecting the Company will be those that it anticipates.

All of the Company's forward-looking statements involve known and unknown risks and uncertainties, some of which are significant or beyond its control, and assumptions that could cause actual results to differ materially from the Company's historical experience and its present expectations or projections. The foregoing factors and the other risks and uncertainties that affect the Company's business, including the risks of delays in the commencement of the clinical trial and those additional risks and uncertainties described the documents filed by the Company with the US Securities and Exchange Commission (SEC), should be carefully considered. The Company wishes to caution you not to place undue reliance on any forward-looking statements, which speak only as of the date hereof. The Company undertakes no obligation to publicly update or revise any of its forward-looking statements after the date they are made, whether as a result of new information, future events or otherwise, except to the extent required by law.

Additional Information about the Transaction and Where to Find it

This press release is being made in respect of a proposed business combination involving 4D and Longevity. Following the announcement of the proposed business combination, 4D filed a registration statement on Form F-4 (the Registration Statement) with the SEC which was declared effective on February 25, 2021. This press release does not constitute an offer to sell or the solicitation of an offer to buy or subscribe for any securities or a solicitation of any vote or approval nor shall there be any sale, issuance or transfer of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. The Registration Statement includes a prospectus with respect to 4Ds ordinary shares and ADSs to be issued in the proposed transaction and a proxy statement of Longevity in connection with the merger. The proxy statement/prospectus has been mailed to the Longevity shareholders on or about February 26, 2021. 4D and Longevity also plan to file other documents with the SEC regarding the proposed transaction.

This press release is not a substitute for any prospectus, proxy statement or any other document that 4D or Longevity may file with the SEC in connection with the proposed transaction. Investors and security holders are urged to read the Registration Statement and, when they become available, any other relevant documents that will be filed with the SEC carefully and in their entirety because they will contain important information about the proposed transaction.

You may obtain copies of all documents filed with the SEC regarding this transaction, free of charge, at the SECs website ( In addition, investors and security holders will be able to obtain free copies of the Registration Statement and other documents filed with the SEC without charge, at the SECs website ( or by calling +1-800-SEC-0330.

Participants in the Solicitation

Longevity and its directors and executive officers and other persons may be deemed to be participants in the solicitation of proxies from Longevitys shareholders with respect to the proposed transaction. Information regarding Longevitys directors and executive officers is available in its annual report on Form 10-K for the fiscal year ended February 29, 2020, filed with the SEC on April 30, 2020. Additional information regarding the participants in the proxy solicitation relating to the proposed transaction and a description of their direct and indirect interests is contained in the Registration Statement.

4D and its directors and executive officers may also be deemed to be participants in the solicitation of proxies from the shareholders of Longevity in connection with the proposed transaction. A list of the names of such directors and executive officers and information regarding their interests in the proposed transaction is included in the Registration Statement.

Originally posted here:
4D Pharma Appointments Paul Maier to the Board as Non-Executive Director - Business Wire


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