Hyperthyroidism is associated with breast cancer risk and mammographic and genetic risk predictors

1. Hyperthyroidism was associated with a higher rate of breast cancer among women.

2. Risk was particularly elevated for those with toxic nodular goiter.

Evidence Rating Level: 2 (Good)

Breast cancer is the most common cancer among women across the world as well as the leading cause of death among women. While much is known about the roles of thyroid hormones in cell proliferation within breast tissue, less is known about the relationship between hyperthyroidism and mammographic features of breast tissue. This national cohort study of women over the age of 20 years in Sweden (n = 3,793,492) included individuals assessed between 2002 and 2011 and sought to investigate the odds ratios of hyperthyroidism based on mammographic and genetic risk predictors. Participants had a main diagnosis of hyperthyroidism and follow-ups ended at breast cancer diagnosis, death, emigration, or final follow-up. Another 68,598 participants joined the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA, 2002-2017) for genotyping, with blood samples being obtained from a subset of 11,991 women who did not have breast cancer when they joined. Findings suggested an increase in breast cancer among patients with hyperthyroidism (incidence rate ratio [IRR] = 1.23, 95% CI 1.12 to 1.36), which was higher for toxic nodular goiter (IRR = 1.38, 95% CI 1.16 to 1.63). Hyperthyroidism was also associated with lower breastfeeding duration, higher body mass index, and early age at first birth. Higher mammographic density was found in women with toxic nodular goiter compared to those without hyperthyroidism. Among those in the KARMA group, hyperthyroidism was associated with a higher polygenic risk score overall (OR = 1.98, 95% CI 1.04 to 3.43) and estrogen receptor-positive specific PRS (OR = 1.90, 95% CI 1.04 to 3.43). Overall, this study found that hyperthyroidism was associated with an increased risk of breast cancer, with particular risk being among those with toxic nodular goiter. Further studies may explore mammographic density and genetic variants of these conditions.

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Foodborne pathogens are very common and usually benign, but certain virulent strains of pathogens can result in severe disease and even death. Distinguishing specific strains of pathogens can help scientists better understand them and develop biomarkers to help detect them in patients, expediting diagnosis and treatment.

UB researchers have now completed the genomic analysis of a specific strain of Shiga-toxin E. coli (STEC) that can cause severe disease outbreaks and is increasingly common. The research could play a role in expanding the understanding of STEC infections and, potentially, in developing vaccines against them.

According to the Centers for Disease Control and Prevention, STEC are estimated to cause more than 265,000 infections per yearin the U.S., and are associated with more than 3,600 hospitalizations and approximately 30 deaths.

Published in BMC Genomics last month, the paper describes the genomic analysis completed on a unique STEC strain isolated from an otherwise healthy 2 -year-old child living in Davidson County, Tennessee. The pathogen caused severe illness, including hemolytic uremic syndrome, a condition that destroys red blood cells, lowers platelets and blocks blood vessels in kidneys, resulting in anemia and kidney damage.

The child survived but was hospitalized for a month and sustained severe complications affecting multiple organ systems, including her lungs, heart, kidney, brain, circulatory system and gastrointestinal tract.

The Shiga-toxin producing E. coli she was infected with is a non-0157 STEC. While the pathogens classified as 0157 STEC infections generally are more common and result in more severe disease, the number of emerging, non-0157 STEC pathogens has been on the increase. Some lead to severe disease, creating a growing public health concern, according to the UB researchers.

The paper states that there are more than 400 of these non-0157 STEC strains, and more than a quarter are reported to cause gastrointestinal disease, often presenting first as bloody diarrhea with hemolytic uremic syndrome and if untreated, in rare cases, death.

The specific pathogen the child was infected with was a STEC 0145:H25. Since genomic studies on emerging non-0157 STEC are limited, our studies are significant because they reveal the genetic makeup of emergent STEC 0145:H25 in comparison with other STEC strains, says Oscar G. Gmez-Duarte, corresponding author on the paper, associate professor and chief of the Division of Pediatric Infectious Diseases in the Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences at UB, and a pediatrician with UBMD Pediatrics.

The findings reveal how this emerging STEC causes severe disease and that it may be as virulent, or even more virulent, than more common STEC strains, leading to severe and even deadly disease in susceptible hosts, he says. It also provides information on how this potentially preventable infection continues to affect vulnerable individuals.

A key finding of the study, he says, was that this 0145:H25 serotype leads to particularly severe infection. Moreover, in addition to carrying virulence genes present in 0157 STEC, it has additional genes and new potential virulence genes as compared to other non-0157 strains that have been studied. These findings deserve further analysis to understand the pathogenesis of these emergent STEC infections, Gmez-Duarte says.

The analysis was conducted through a collaboration between the Department of Pediatrics researchers and colleagues at UBs New York State Center of Excellence in Bioinformatics and LifeSciences, whose expertise in bioinformatics and whole genome sequencing analysis allowed the team to uncover the genetic information critical to understanding where these strains are derived from and how they may be traced to unique reservoirs, such as contaminated food products or infected livestock.

Gmez-Duarte is an expert in infectious gastrointestinal diseases and diarrhea in children. He established a global health research program, the International Enteric Vaccines Research Program (IEVRP), dedicated to studying the epidemiology, pathogenesis and vaccine development of childhood gastrointestinal infections within the U.S. and abroad. He has also conducted vaccine development research for pediatric infectious diseases.

UB co-authors are Julio Guerra of the Department of Pediatrics and Jonathan E. Bard and Donald Yergeau of the Genomics and Bioinformatics Core of UBs NYS Center of Excellence in Bioinformatics and Life Sciences. Chengxian Zhang and Natasha Halasa of Vanderbilt University are also co-authors.

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Genomic analysis reveals insights on virulent, emerging foodborne pathogen - UB Now: News and views for UB faculty and staff - University at Buffalo...

Could gene therapy provide a solution to HIV? A new research project aims to find out.

The National Institutes of Health(NIH) has backed researchers at the University of Southern California and the Fred Hutchison Cancer Center with a five-year, $14.6 million grant to develop a gene therapy that could potentially control HIV without the need for daily medications. Most HIV patients take a well-regimented cocktail of medications each day to control the virus. This therapy could change that. According to an announcement from the Keck School of Medicine at USC, the goal will be to develop a therapy that prepares patients for a stem cell transplantation using their own cells with little to no toxicity, engineers their own stem cells to fight HIV and stimulates those cells to quickly produce new and engineered immune cells once they're reintroduced into the patient. The hematopoietic stem cell transplants, also known as bone marrow transplants, have been used to treat some blood cancers. The idea is to infuse an HIV patient withhealthy donor blood stem cells that can grow into any type of blood or immune cell.

The gene therapy strategy has been inspired by three cases where leukemia patients who also had HIV received blood stem cell transplants from donors who also carried a mutation that confers immunity to HIV. The mutation was in the CCR5 gene, which encodes a receptor that HIV uses to infect immune cells and is present in about 1 percent of the population, USC said.

The program will engineer blood cells to remove CCR5 from a patient's own stem cells.That will be combined with other genetic changes so that the progeny of engineered stem cells will release antibodies and antibody-like molecules that block HIV.

In addition to the potential gene therapy treatment, researchers are also assessing whether or not CAR-T treatments will benefit HIV patients. Researchers from Harvard University developed a Dual CAR T-cell immunotherapy that can potentially help fight HIV infection. First reported by Drug Target Review, the HIV-specific CAR-T cell is being developed to not only target and eliminated HIV-infected cells, but also reproduce in vivo to enable the patients to fight off the infection. HIVs primary target it T cells, which are part of the bodys natural immune response.

Todd Allen, a professor of Medicine at Harvard Medical School, said the Dual CAR-T cell immunotherapy has so far provided a strong, long-lasting response against HIV-infection while being resistant to the virus itself.

According to the report, theDual CAR T cell was developed through the engineering of two CARs into a single T cell. Each of the CARs contained a CD4 protein that allowed it to target HIV-infected cells and a costimulatory domain, which signaled the CAR T cell to increase its immune functions. As DTR reported, the first CAR contained the 4-1BB co-stimulatory domain, which stimulates cell proliferation and persistence, while the second has the CD28 co-stimulatory domain, which increases its ability to kill infected cells.

To protect the CAR-T cells from HIV, the team added the protein C34-CXCR4, which prevents HIV from attaching to and infecting cells. When that was added, the researchers found in animal models that the treatment was long-lived, replicated in response to HIV infection, killed infected cells effectively and was partially resistant to HIV infection.

Still, other researchers are looking to those rare individuals who are infected with HIV but somehow on their own are able to suppress the virus without the need for any treatment. Researchers have sought to replicate what this small percentage of patients can naturally do in other patients who require those daily regimens of medications. Through the sequencing of the genetic material of those rare individuals, researchers made an interesting discovery.

The team discovered large numbers of intact viral sequences in the elite controllers chromosomes. But in this group, the genetic material was restricted to inactive regions, where DNA is not transcribed into RNA to make proteins, MedNewsToday reported.

Now the race is on to determine how this can be replicated and used to treat the nearly 38 million people across the globe who have been diagnosed with HIV.

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New HIV Gene Therapy, CAR-T Treatments Could be on the Horizon for Patients - BioSpace

A new platform that can help identify individuals who are at high risk of hereditary diseases has launched.

Developed by FamHis Inc, FamGenix is a free patient mobile app that is being released worldwide, following a soft launch last November for patients, and the release of the provider portal for clinicians last month. Servers have so far been launched in the US and Europe, and are planned for Canada and Australia in October.

The platform facilitates a telemedicine-based approach to gathering family health histories, aiming to save time and improving accuracy. The concept behind FamGenix is that patients are in control of their own data. They are able to communicate with family members through a feature called FamShare, allowing a secure exchange of data to provide an accurate family history.

Each family member can control their own health record and privacy settings. Important health information, like genetic test results, can be easily shared with other family members via the app, facilitating the process of family tracing for genetic conditions.

With 25 years in the industry, Ive seen firsthand the benefits of an accurate family health history and the effect it has on decision making for healthcare providers and their patients, said Michael Brammer, Founder and CEO of FamHis, Inc.

But the idea that its something to address only when patients are facing a health crisis, is short-sighted. FamGenix is much more than a simple screening tool and is the first of its kind to empower patients to own and maintain their own family health history, indefinitely. Preventative healthcare is the future of medicine and it begins with family history.

Healthcare providers can review the patient data, and the system screens patients to identify those who are high-risk - in other words, who meet criteria for further genetic counseling or testing.

Standard or custom questionnaires help to identify any condition (not just cancer) or other data needed for clinical or research purposes. There is also a white-label option for healthcare providers who want to brand the app as their own in the app stores. FamHis has signed their first white-label license with a prestigious cancer center and has pilots planned in several countries.

The app is available for download from the App Store and Google Play, while healthcare professionals can access a free trial.

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Health history platform launches to trace genetic conditions | Digital Healthcare - Healthcare Global - Healthcare News, Magazine and Website

Johns Hopkins Medicine researchers have added to evidence that a gene responsible for turning off a cells natural suicide signals may also be the culprit in making breast cancer and melanoma cells resistant to therapies that use the immune system to fight cancer. A summary of the research, conducted with mice and human cells, appeared in Cell Reports.When the gene, called BIRC2, is sent into overdrive, it makes too much, or an overexpression, of protein levels. This occurs in about 40% of breast cancers, particularly the more lethal type called triple negative, and it is not known how often the gene is overexpressed in melanomas.

If further studies affirm and refine the new findings, the researchers say, BIRC2 overexpression could be a key marker for immunotherapy resistance, further advancing precision medicine efforts in this area of cancer treatment. A marker of this kind could alert clinicians to the potential need for using drugs that block the genes activity in combination with immunotherapy drugs to form a potent cocktail to kill cancer in some treatment-resistant patients. Cancer cells use many pathways to evade the immune system, so our goal is to find additional drugs in our toolbox to complement the immunotherapy drugs currently in use, says Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Genetic Medicine, Pediatrics, Oncology, Medicine, Radiation Oncology and Biological Chemistry at the Johns Hopkins University School of Medicine, and director of the Vascular Program at the Johns Hopkins Institute for Cell Engineering.

Semenza shared the 2019 Nobel Prize in Physiology or Medicine for the discovery of the gene that guides how cells adapt to low oxygen levels, a condition called hypoxia.

In 2018, Semenzas team showed that hypoxia essentially molds cancer cells into survival machines. Hypoxia prompts cancer cells to turn on three genes to help them evade the immune system by inactivating either the identification system or the eat me signal on immune cells. A cell surface protein called CD47 is the only dont eat me signal that blocks killing of cancer cells by immune cells called macrophages. Other cell surface proteins, PDL1 and CD73, block killing of cancer cells by immune cells called T lymphocytes.

These super-survivor cancer cells could explain, in part, Semenza says, why only 20% to 30% of cancer patients respond to drugs that boost the immune systems ability to target cancer cells.

For the current study, building on his basic science discoveries, Semenza and his team sorted through 325 human genes identified by researchers at the Dana Farber Cancer Institute in Boston whose protein products were overexpressed in melanoma cells and linked to processes that help cancer cells evade the immune system.

Semenzas team found that 38 of the genes are influenced by the transcription factor HIF-1, which regulates how cells adapt to hypoxia; among the 38 was BIRC2 (baculoviral IAP repeat-containing 2), already known to prevent cell suicide, or apoptosis, in essence a form of programmed cell death that is a brake on the kind of unchecked cell growth characteristic of cancer.

BIRC2 also blocks cells from secreting proteins that attract immune cells, such as T-cells and natural killer cells.

First, by studying the BIRC2 genome in human breast cancer cells, Semenzas team found that hypoxia proteins HIF1 and HIF2 bind directly to a portion of the BIRC2 gene under low oxygen conditions, identifying a direct mechanism for boosting the BIRC2 genes protein production.

Then, the research team examined how tumors developed in mice when they were injected with human breast cancer or melanoma cells genetically engineered to contain little or no BIRC2 gene expression. In mice injected with cancer cells lacking BIRC2 expression, tumors took longer to form, about three to four weeks, compared with the typical two weeks it takes to form tumors in mice.

The tumors formed by BIRC2-free cancer cells also had up to five times the level of a protein called CXCL9, the substance that attracts immune system T-cells and natural killer cells to the tumor location. The longer the tumor took to form, the more T-cells and natural killer cells were found inside the tumor.

Semenza notes that finding a plentiful number of immune cells within a tumor is a key indicator of immunotherapy success.

Next, to determine whether the immune system was critical to the stalled tumor growth they saw, Semenzas team injected the BIRC2-free melanoma and breast cancer cells into mice bred to have no functioning immune system. They found that tumors grew at the same rate, in about two weeks, as typical tumors. This suggests that the decreased tumor growth rate associated with loss of BIRC2 is dependent on recruiting T-cells and natural killer cells into the tumor, says Semenza.

Finally, Semenza and his team analyzed mice implanted with human breast cancer or melanoma tumors that either produced BIRC2 or were engineered to lack BIRC2. They gave the mice with melanoma tumors two types of immunotherapy FDA-approved for human use, and treated mice with breast tumors with one of the immunotherapy drugs. In both tumor types, the immunotherapy drugs were effective only against the tumors that lacked BIRC2.

Experimental drugs called SMAC mimetics that inactivate BIRC2 and other anti-cell suicide proteins are currently in clinical trials for certain types of cancers, but Semenza says that the drugs have not been very effective when used on their own.

These drugs might be very useful to improve the response to immunotherapy drugs in people with tumors that have high BIRC2 levels, says Semenza.Reference: Samanta D, Huang TYT, Shah R, Yang Y, Pan F, Semenza GL. BIRC2 Expression Impairs Anti-Cancer Immunity and Immunotherapy Efficacy. Cell Rep. 2020;32(8). doi:10.1016/j.celrep.2020.108073

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

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Cell Suicide Gene Further Linked to Immunotherapy Response - Technology Networks

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Gene in fruit flies, worms, zebrafish, mice and people may help explain some fertility issues

Researchers at Washington University School of Medicine in St. Louis have identified a gene that plays an important role in fertility across multiple species. Pictured is a normal fruit fly ovary (left) and a fruit fly ovary with this gene dialed down (right). Male and female animals missing this gene had substantially defective reproductive organs. The study could have implications for understanding human infertility and early menopause.

A new study from Washington University School of Medicine in St. Louis identifies a specific genes previously unknown role in fertility. When the gene is missing in fruit flies, roundworms, zebrafish and mice, the animals are infertile or lose their fertility unusually early but appear otherwise healthy. Analyzing genetic data in people, the researchers found an association between mutations in this gene and early menopause.

The study appears Aug. 28 in the journal Science Advances.

The human gene called nuclear envelope membrane protein 1 (NEMP1) is not widely studied. In animals, mutations in the equivalent gene had been linked to impaired eye development in frogs.

The researchers who made the new discovery were not trying to study fertility at all. Rather, they were using genetic techniques to find genes involved with eye development in the early embryos of fruit flies.

We blocked some gene expression in fruit flies but found that their eyes were fine, said senior author Helen McNeill, PhD, the Larry J. Shapiro and Carol-Ann Uetake-Shapiro Professor and a BJC Investigator at the School of Medicine. So, we started trying to figure out what other problems these animals might have. They appeared healthy, but to our surprise, it turned out they were completely sterile. We found they had substantially defective reproductive organs.

Though it varied a bit by species, males and females both had fertility problems when missing this gene. And in females, the researchers found that the envelope that contains the eggs nucleus the vital compartment that holds half of an organisms chromosomes looked like a floppy balloon.

This gene is expressed throughout the body, but we didnt see this floppy balloon structure in the nuclei of any other cells, said McNeill, also a professor of developmental biology. That was a hint wed stumbled across a gene that has a specific role in fertility. We saw the impact first in flies, but we knew the proteins are shared across species. With a group of wonderful collaborators, we also knocked this gene out in worms, zebrafish and mice. Its so exciting to see that this protein that is present in many cells throughout the body has such a specific role in fertility. Its not a huge leap to suspect it has a role in people as well.

To study this floppy balloon-like nuclear envelope, the researchers used a technique called atomic force microscopy to poke a needle into the cells, first penetrating the outer membrane and then the nucleuss membrane. The amount of force required to penetrate the membranes gives scientists a measure of their stiffness. While the outer membrane was of normal stiffness, the nucleuss membrane was much softer.

Its interesting to ask whether stiffness of the nuclear envelope of the egg is also important for fertility in people, McNeill said. We know there are variants in this gene associated with early menopause. And when we studied this defect in mice, we see that their ovaries have lost the pool of egg cells that theyre born with, which determines fertility over the lifespan. So, this finding provides a potential explanation for why women with mutations in this gene might have early menopause. When you lose your stock of eggs, you go into menopause.

On the left is a normal fruit fly ovary with hundreds of developing eggs. On the right is a fruit fly ovary that is totally missing the NEMP gene. It is poorly developed and no eggs are visible.

McNeill and her colleagues suspect that the nuclear envelope has to find a balance between being pliant enough to allow the chromosomes to align as they should for reproductive purposes but stiff enough to protect them from the ovarys stressful environment. With age, ovaries develop strands of collagen with potential to create mechanical stress not present in embryonic ovaries.

If you have a softer nucleus, maybe it cant handle that environment, McNeill said. This could be the cue that triggers the death of eggs. We dont know yet, but were planning studies to address this question.

Over the course of these studies, McNeill said they found only one other problem with the mice missing this specific gene: They were anemic, meaning they lacked red blood cells.

Normal adult red blood cells lack a nucleus, McNeill said. Theres a stage when the nuclear envelope has to condense and get expelled from the young red blood cell as it develops in the bone marrow. The red blood cells in these mice arent doing this properly and die at this stage. With a floppy nuclear envelope, we think young red blood cells are not surviving in another mechanically stressful situation.

The researchers would like to investigate whether women with fertility problems have mutations in NEMP1. To help establish whether such a link is causal, they have developed human embryonic stem cells that, using CRISPR gene-editing technology, were given specific mutations in NEMP1 listed in genetic databases as associated with infertility.

We can direct these stem cells to become eggs and see what effect these mutations have on the nuclear envelope, McNeill said. Its possible there are perfectly healthy women walking around who lack the NEMP protein. If this proves to cause infertility, at the very least this knowledge could offer an explanation. If it turns out that women who lack NEMP are infertile, more research must be done before we could start asking if there are ways to fix these mutations restore NEMP, for example, or find some other way to support nuclear envelope stiffness.

This work was supported by the Canadian Institutes of Health, research grant numbers 143319, MOP-42462, PJT-148658, 153128, 156081, MOP-102546, MOP-130437, 143301, and 167279. This work also was supported, in part, by the Krembil Foundation; the Canada Research Chair program; the National Institutes of Health (NIH), grant number R01 GM100756; and NSERC Discovery grant; and the Medical Research Council, unit programme MC_UU_12015/2. Financial support also was provided by the Wellcome Senior Research Fellowship, number 095209; Core funding 092076 to the Wellcome Centre for Cell Biology; a Wellcome studentship; the Ontario Research FundsResearch Excellence Program. Proteomics work was performed at the Network Biology Collaborative Centre at the Lunenfeld-Tanenbaum Research Institute, a facility supported by Canada Foundation for Innovation funding, by the Ontarian Government, and by the Genome Canada and Ontario Genomics, grant numbers OGI-097 and OGI-139.

Tsatskis Y, et al. The NEMP family supports metazoan fertility and nuclear envelope stiffness. Science Advances. Aug. 28, 2020.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Genetic mutations may be linked to infertility, early menopause - Washington University School of Medicine in St. Louis

What should a precision medicine approach be in a pandemic? The gene-centric vision of precision medicine encourages people to expect individualised gene-targeted fixes

Tom Hanks and his wife, Rita Wilson, were among the earliest celebrities to catch the novel coronavirus. In an interview at the beginning of July, Hanks described how differently COVID-19 had affected each of them in March.

My wife lost her sense of taste and smell, she had severe nausea, she had a much higher fever than I did. I just had crippling body aches, he said. I was very fatigued all the time and I couldnt concentrate on anything for more than about 12 minutes.

Why does COVID-19 present such different symptoms or none at all in different people?

Preexisting conditions can only be part of the story. Hanks is over 60 and is a Type 2 diabetic, putting him in a high-risk group. Nevertheless, he survived his brush with the virus with no pneumonia and apparently without any long-lasting effects. Knowing what causes variation in different patients could help physicians tailor their treatments to individual patients an approach known as precision medicine.

In recent years, a gene-centric approach to precision medicine has been promoted as the future of medicine. It underlies the massive effort funded by the US National Institutes of Health to collect over a million DNA samples under the All of Us initiative that began in 2015.

But the imagined future did not include COVID-19. In the rush to find a COVID-19 vaccine and effective therapies, precision medicine has been insignificant. Why is this? And what are its potential contributions?

We are a physician geneticist and a philosopher of science who began a discussion about the promise and potential pitfalls of precision medicine before the arrival of COVID-19. If precision medicine is the future of medicine, then its application to pandemics generally, and COVID-19 in particular, may yet prove to be highly significant. But its role so far has been limited. Precision medicine must consider more than just genetics. It requires an integrative omic approach that must collect information from multiple sources beyond just genes and at scales ranging from molecules to society.

From genetics to microbes

Inherited diseases such as sickle cell anemia and Tay-Sachs disease follow a predictable pattern. But such direct genetic causes are perhaps the exception rather than the rule when it comes to health outcomes. Some heritable conditions for instance, psoriasis or the many forms of cancer depend on complex combinations of genes, environmental and social factors whose individual contributions to the disease are difficult to isolate. At best, the presence of certain genes constitutes a risk factor in a population but does not fully determine the outcome for an individual person carrying those genes.

The situation becomes yet more complicated for infectious diseases.

Viruses and bacteria have their own genomes that interact in complex ways with the cells in the people they infect. The genome of SARS-CoV-2 underlying COVID-19 has been extensively sequenced. Its mutations are identified and traced worldwide, helping epidemiologists understand the spread of the virus. However, the interactions between SARS-CoV-2 RNA and human DNA, and the effect on people of the viruss mutations, remain unknown.

The importance of multi-scale data

Tom Hanks and his wife caught the virus and recovered in a matter of weeks. Presumably each was infected over the course of a few minutes of exposure to another infected person, involving cellular mechanisms that operate on a timescale of milliseconds.

But the drama of their illness, and that of the many victims with far worse outcomes, is taking place in the context of a global pandemic that has already lasted months and may continue for years. People will need to adopt changes in their behavior for weeks or months at a time.

What should a precision medicine approach be in a pandemic? The gene-centric vision of precision medicine encourages people to expect individualised gene-targeted fixes. But, genes, behavior and social groups interact over multiple timescales.

To capture all the data needed for such an approach is beyond possibility in the current crisis. A nuanced approach to the COVID-19 pandemic will depend heavily on imprecise population level public health interventions: mask-wearing, social distancing and working from home. Nevertheless, there is an opportunity to begin gathering the kinds of data that would allow for a more comprehensive precision medicine approach one that is fully aware of the complex interactions between genomes and social behavior.

How to use precision medicine to understand COVID-19

With unlimited resources, a precision medicine approach would begin by analyzing the genomes of a large group of people already known to be exposed to SARS-CoV-2 yet asymptomatic, along with a similar-sized group with identified risk factors who are dying from the disease or are severely ill.

An early study of this kind by Precisionlife Ltd data mined genetic samples of 976 known COVID-19 cases. Of these, 68 high-risk genes were identified as risk factors for poor COVID-19 outcomes, with 17 of them deemed likely to be good targets for drug developments. But, as with all such statistical approaches, the full spectrum of causes underlying their association with the disease is not something the analysis provides. Other studies of this kind are appearing with increasing frequency, but there is no certainty in such fast-moving areas of science. Disentangling all the relevant factors is a process that will take months to years.

To date, precision medicine has proven better suited to inherited diseases and to diseases such as cancer, involving mutations acquired during a persons lifetime, than to infectious diseases. There are examples where susceptibility to infection can be caused by malfunction of unique genes such as the family of inherited immune disorders known as agammaglobulinemia, but these are few and far between.

Many physicians assume that most diseases involve multiple genes and are thus not amenable to a precision approach. In the absence of the kind of information needed for a multi-omic approach, there is a clear challenge and opportunity for precision medicine here: If it is to be the future of medicine, in order to complement and expand our existing knowledge and approaches, it needs to shift from its gene-centric origins toward a broader view that includes variables like proteins and metabolites. It must consider the relationships between genes and their physical manifestations on scales that range from days to decades, and from molecules to the global society.

Colin Allen, Distinguished Professor of History & Philosophy of Science, University of Pittsburgh and David Finegold, Professor, Department of Human Genetics, Pitt Public Health, University of Pittsburgh

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Normal blood cells (left) and the blood cells in sickle cell disease, which do not flow through the circulatory system smoothly. (Credit: Darryl Leja, NHGRI, CC BY 2.0)

First published by GroundUp.

A study performed in Cameroon by a University of Cape Town (UCT) professor may offer hope of treatment for people with sickle cell anaemia (SCA), a disease which affects hundreds of thousands in Africa.

Professor Ambroise Wonkam, principal investigator and director of Genetic Medicine of African Populations in the Division of Human Genetics at UCT, says though the condition was identified more than 100 years ago, a definitive treatment is still not widely available.

Sickle cell anaemia is the most serious in a group of disorders known as sickle cell disease. It is an inherited red blood cell disorder in which there arent enough healthy red blood cells to carry oxygen throughout the body. It is caused by a mutation in a single gene, responsible for production of the protein, haemoglobin. Making up 70% of the content of red blood cells, haemoglobin is essential for transporting oxygen throughout the body.

Normally, the flexible, round red blood cells move easily through blood vessels. In sickle cell anaemia, the red blood cells are shaped like sickles or crescent moons. These rigid, sticky cells can become stuck in small blood vessels, which can slow or block blood flow and oxygen to other parts of the body. (Read this for more information.)

Among the 300,000 babies that are born with the condition every year, 80% are in sub-Saharan Africa, says Wonkam. It is, in essence, an African disease.

Despite the prevalence of SCA in Africa, medical care has been less than optimal. According to Wonkam, it has been shown that, due to the lack of medical interventions, in most African settings, at least 50% of African children with SCA will die before they turn five years old.

However, the same regions of sub-Saharan Africa are also home to SCA patients who are 50 or 60 years old.

Why is it that some people who live in an environment that is not favourable in terms of healthcare access, and stressors including high temperatures, malaria and other infections manage to survive while others die at a much younger age? Wonkam asks. Our hypothesis is that these long survivors living with SCA may be protected by some genetic factors.

To test this, Wonkam and his team recruited SCA patients of 40 years or older, who had received minimal medical intervention, as well as a control group who had suffered strokes, which is one of the severe effects of SCA, and an intermediate group who were under 40 and never had a stroke. The research took place in Cameroon.

In the study, published in the journal Clinical and Translational Medicine, Wonkam and his team found genetic modifiers of long-term survival in individuals with SCA.

People who had survived longer had recurrent changes in specific genes. And patients who had strokes had a mutation in the blood coagulation pathway.

Another finding in the long-term survivor group was that they metabolised the micronutrient selenium efficiently. They also have genes that assist in keeping blood pressure low. Wonkam says that selenium supplementation is worth investigating.

Also, the study found, some patients were protected from some of the vascular complications of the disease by their ability to produce an amino acid called glutamine. Glutamine helps to protect the body against stress due to low oxygen which is one of the side effects of SCA. This ability to produce glutamine can also now be studied further as a possible treatment in other people with the disorder. Glutamine supplements could be one of the options.

It is possible that genes with recurrent mutations that we found in numerous patients provide some protection, and have become prevalent in people with SCA by natural selection. This information can be used in future in gene-modifying therapy.

Modifier genes, which change the actions of other genes, can be beneficial to the health of the patients by countering some of the negative effects of the disorder.

By identifying novel modifier genes, our research is providing additional mechanisms to explain the long-term survival, or complications such as stroke in some patients, says Wonkam.

I believe this is probably one of the landmark findings that have been performed in Africa where most of these patients live, he says. DM

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UCT professors research offers hope of treatment for sickle cell anaemia - Daily Maverick

1. Environmental liability for schizophrenia moderated the association of stressful life events with mental and physical health.

Evidence Rating Level: 2 (Good)

Schizophrenia research has elucidated the roles of environmental and genetic liability as well as stressful life events (SLEs) in schizophrenia pathogenesis. However, few studies have illustrated the interactions of these risk factors and how they impact mental and physical health. This population-based prospective cohort study investigated the prevalence, incidence, course, and consequences of psychiatric disorders in the Netherlands. A total of 6,646 (M [SD] age = 44.26 [12.54] years, 55.25% female) participants were enrolled between November 5, 2007 and July 31, 2009, being followed up with by three assessments across nine years. Follow-ups included recent SLEs and aggregate scores of environmental and genetic liabilities (polygenic risk score for schizophrenia [PRS-SCZ]; exposome score for schizophrenia [ES-SCZ]). SLEs were significantly associated with reduced mental (B = -3.68, 95% CI -4.05 to -3.32) and physical health (B = -3.22, 95% CI -3.66 to -2.79). Genetic and environmental liabilities were associated with poorer mental health (PRS-SCZ: B = -0.93, 95% CI -1.31 to -0.54; ES-SCZ: B = -3.07, 95% CI -3.35 to -2.79), with environmental liability also being associated with reduced physical health (B = -3.19, 95% CI -3.56 to -2.82). The interaction model suggested that ES-SCZ moderated the association of SLEs with physical (B = -0.64, 95% CI -1.11 to -0.17) and mental health (B = -1.08, 95% CI -1.47 to -0.69). PRS-SCZ, however, did not moderate this relationship. Overall, both genetic and environmental liabilities for schizophrenia resulted in mental health outcomes across the population. Exposure to SLEs, specifically in the context of these liabilities, were further associated with poorer health outcomes. Thus, it is important to consider the environmental factors impacting schizophrenia, such that modifiable risk factors should be targets of prevention and ongoing treatment.

Click to read the study in JAMA Psychiatry

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Association of recent stressful life events with mental and physical health in the context of genomic and exposomic liability for schizophrenia - 2...

Scientists observed that different cancers undergo the same genetic mutations at similar stages of evolution, the findings could become part of an evolutionary rule book which would theoretically enable the prediction and prevention of cancers next evolutionary move.

Researchers have identified that there is an element of order to the seemingly chaotic changes to chromosomes that give tumours their heterogeneity. In their paper, the team report that mutations in the chromosomes of cancer cells happen frequently and throughout the development of a tumour; however, some are more likely to occur in the early stages of cancer development and others in the later stages, once a tumour has metastasised.

One of the difficulties in treating cancers is that the genetic make-up of tumours evolves over time. Scientists believe these changes result from errors made in DNA replication, which are more frequent in cancers due to the upregulation of various cell survival pathways and the speed with which cancer cells divide. Unfortunately, the more heterogeneous a tumour is (in other words, the greater the genetic variability of cells within a single tumour), the less likely a patient is to respond successfully to treatment, which ultimately makes recovery less likely and survival shorter.

In their paper published in Nature, researchers at the Francis Crick Institute (the Crick) and the University College London (UCL) Cancer Institute, both UK, sought to identify why these mutations occur and if there is a pattern or order to them.

In collaboration with Germanys Max Delbrck Center for Molecular Medicine, the team developed a technique that analyses multiple samples from a single tumour and used it to identify chromosomal changes in 1421 tumour samples taken from 394 patients with 22 different types of tumours.

They observed that often similar chromosomal changes had taken place in different subclones within a tumour from the same patient. Subclones are different groups of cells within a single tumour. The team found evidence of subclones evolving in parallel in samples taken from 37 percent of patients (146 patients).

The scientists also identified certain chromosomal changes that occurred in multiple tumour types at particular stages of cancer evolution, including changes that could aid in immune evasion or promote tumour growth despite a lack of oxygen.

Thomas Watkins, lead author and PhD student in the Cancer Evolution and Genome Instability Laboratory at the Crick, said: In a tumour there are lots of genetic changes taking place. The fact we saw similar chromosomal changes take hold independently within a tumour in separate subclones suggests these changes are important for the tumour and might lead to subclones with them out-competing other subclones without them.

Professor Charles Swanton, senior group leader at the Crick and UCL, Cancer Research UKs chief clinician and consultant oncologist at UCL Hospital, added: The presence of common changes supports the theory that there are a number of genetic pathways through which tumours must evolve. Identifying these would move us a step closer to writing cancers evolutionary rule book.

The studys authors also revealed that some changes were common in the early stages of a cancers development, while others were more frequent later on, after it metastasised. They added that there were certain events that acted as a catalyst for mutations; for example, whole genome doubling where every chromosome is duplicated appears to open up new evolutionary solutions for the tumour, leading to a wave of late-stage mutations.

Nicholas McGranahan, group leader of the Cancer Genome Evolution Group at the UCL Cancer Institute, commented: There was a sense of order in the mutations we identified, with different mutations likely to appear at different points. So, these changes, which may seem like chromosomal chaos, could actually be something we could predict. Of course, if you could predict them, this opens the door to scientists and doctors developing new treatments which could block these evolutionary pathways.

The team are continuing to leverage their analysis technique on samples taken from patients with lung cancer, as part of Cancer Research UKs TRACERx project. They said that they hope this will lead to new insights about the genetic changes that drive the spread of lung cancer as well as understanding what changes help these tumours to evade the immune system.

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Finding order in the chaos of cancer mutations - Drug Target Review

GAITHERSBURG, Md., Sept. 02, 2020 (GLOBE NEWSWIRE) -- Novavax, Inc. (Nasdaq: NVAX), a late stage biotechnology company developing next-generation vaccines for serious infectious diseases, today announced the publication in The New England Journal of Medicine of Phase 1 data from its Phase 1/2 clinical trial of NVXCoV2373, its COVID19 vaccine candidate adjuvanted with MatrixM, in healthy adults 18-59 years of age. The publication offers further detail on the previously announced results, in which NVXCoV2373 demonstrated a reassuring safety and reactogenicity profile and induced robust antibody responses numerically superior to that seen in human convalescent sera. The manuscript is available at https://www.nejm.org/doi/full/10.1056/NEJMoa2026920?query=featured_coronavirus.

The rapid publication of Phase 1 results from our trial in a prestigious peer-reviewed journal reflects both the importance of the data and the urgent need for an effective vaccine to slow the COVID-19 pandemic, said Gregory M. Glenn, M.D., President of Research and Development at Novavax. Based on the positive Phase 1 results, we have begun multiple Phase 2 clinical trials, from which we expect to collect preliminary efficacy. Novavax is committed to generating the safety, immunogenicity and efficacy data that will support confident usage of the vaccine, both in the US and globally, and the data published today further bolsters our conviction that this is possible.

The Phase 1 portion of the Phase 1/2 clinical trial was randomized, observer-blinded, and placebo-controlled.

NVX-CoV2373 is currently in multiple Phase 2 clinical trials. The Phase 2 portion of the Phase 1/2 clinical trial to evaluate the safety and immunogenicity of NVX-CoV2373 began in August inthe United StatesandAustralia, and expands on the age range of the Phase 1 portion by including older adults 60-84 years of age as approximately 50 percent of the trial population. Secondary objectives include preliminary evaluation of efficacy. In addition, a Phase 2b clinical trial to assess efficacy began inSouth Africain August.

The trial was supported by funding from the Coalition for Epidemic Preparedness Innovations (CEPI) and was conducted at two sites in Australia.

Phase 1 Results Summary

Further details may be found in Novavax August 4 announcement of Phase 1 results and may be accessed here.

About NVX-CoV2373

NVXCoV2373 is a vaccine candidate engineered from the genetic sequence of SARSCoV2, the virus that causes COVID-19 disease. NVXCoV2373 was created using Novavax recombinant nanoparticle technology to generate antigen derived from the coronavirus spike (S) protein and contains Novavax patented saponin-based Matrix-M adjuvant to enhance the immune response and stimulate high levels of neutralizing antibodies. In preclinical trials, NVXCoV2373 demonstrated indication of antibodies that block binding of spike protein to receptors targeted by the virus, a critical aspect for effective vaccine protection. In its Phase 1 portion of the Phase 1/2 clinical trial, NVXCoV2373 was generally well-tolerated and elicited robust antibody responses numerically superior to that seen in human convalescent sera. Phase 2 clinical trials began in August 2020. Novavax has secured $2 billion in funding for its global coronavirus vaccine program, including up to $388 million in funding from the Coalition for Epidemic Preparedness Innovations (CEPI).

About Matrix-M

Novavax patented saponin-based Matrix-M adjuvant has demonstrated a potent and well-tolerated effect by stimulating the entry of antigen-presenting cells into the injection site and enhancing antigen presentation in local lymph nodes, boosting immune response.

About Novavax

Novavax, Inc. (Nasdaq:NVAX) is a late-stage biotechnology company that promotes improved health globally through the discovery, development, and commercialization of innovative vaccines to prevent serious infectious diseases. Novavax is undergoing clinical trials for NVX-CoV2373, its vaccine candidate against SARS-CoV-2, the virus that causes COVID-19. NanoFlu, its quadrivalent influenza nanoparticle vaccine, met all primary objectives in its pivotal Phase 3 clinical trial in older adults. Both vaccine candidates incorporate Novavax proprietary saponin-based Matrix-M adjuvant in order to enhance the immune response and stimulate high levels of neutralizing antibodies. Novavax is a leading innovator of recombinant vaccines; its proprietary recombinant technology platform combines the power and speed of genetic engineering to efficiently produce highly immunogenic nanoparticles in order to address urgent global health needs.

For more information, visit http://www.novavax.com and connect with us on Twitter and LinkedIn.

Novavax Forward-Looking Statements

Statements herein relating to the future of Novavax and the ongoing development of its vaccine and adjuvant products are forward-looking statements. Novavax cautions that these forward-looking statements are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those expressed or implied by such statements. These risks and uncertainties include those identified under the heading Risk Factors in the Novavax Annual Report on Form 10-K for the year ended December 31, 2019, and Quarterly Report on Form 8-K for the period ended June 30, 2020, as filed with the Securities and Exchange Commission (SEC). We caution investors not to place considerable reliance on forward-looking statements contained in this press release. You are encouraged to read our filings with the SEC, available at sec.gov, for a discussion of these and other risks and uncertainties. The forward-looking statements in this press release speak only as of the date of this document, and we undertake no obligation to update or revise any of the statements. Our business is subject to substantial risks and uncertainties, including those referenced above. Investors, potential investors, and others should give careful consideration to these risks and uncertainties.

Contacts:

Novavax

InvestorsSilvia Taylor and Erika Trahanir@novavax.com240-268-2022

MediaBrandzone/KOGS CommunicationEdna Kaplankaplan@kogspr.com617-974-8659

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Novavax Announces Publication of Phase 1 Data for COVID-19 Vaccine Candidate in The New England Journal of Medicine - GlobeNewswire

WORCESTER, Mass., Sept. 02, 2020 (GLOBE NEWSWIRE) -- Mustang Bio, Inc. (Mustang) (NASDAQ: MBIO), a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to MB-107, Mustangs lentiviral gene therapy for the treatment of X-linked severe combined immunodeficiency (XSCID), also known as bubble boy disease, in newly diagnosed infants under the age of two. The FDA previously granted Rare Pediatric Disease Designation in August 2020 and Regenerative Medicine Advanced Therapy designation in August 2019 to MB-107 for the treatment of XSCID in newly diagnosed patients. Additionally, the European Medicines Agency granted Advanced Therapy Medicinal Product classification to MB-107 in April 2020.

The FDA grants Orphan Drug Designation to drugs and biologics that are intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. Orphan Drug Designation provides certain incentives, such as tax credits toward the cost of clinical trials and prescription drug user fee waivers. If a product holding Orphan Drug Designation receives the first FDA approval for the disease in which it has such designation, the product is entitled to seven years of market exclusivity, which is independent from intellectual property protection.

Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, Mustang has had a productive quarter on the regulatory front. We are very pleased to achieve another significant milestone and receive Orphan Drug Designation for MB-107 for the treatment of XSCID in newly diagnosed patients. This designation for MB-107, in addition to its Rare Pediatric Disease Designation, Regenerative Medicine Advanced Therapy designation and Advanced Therapy Medicinal Product classification, continues to enhance our regulatory pathway for a much-needed treatment option to address this devastating rare disease that affects children. We look forward to initiating our pivotal clinical programs for MB-107 in newly diagnosed infants with XSCID and MB-207 in previously transplanted patients with XSCID very soon.

MB-107 is currently being assessed in a Phase 1/2 clinical trial for XSCID in newly diagnosed infants under the age of two at St. Jude Childrens Research Hospital (St. Jude), UCSF Benioff Childrens Hospital in San Francisco and Seattle Childrens Hospital. In May 2020, Mustang submitted an investigational new drug application (IND) to the FDA to initiate a multi-center Phase 2 clinical trial of MB-107 in newly diagnosed infants with XSCID who are between two months to two years of age. The trial is expected to enroll 10 patients who, together with 15 patients enrolled in the current multi-center trial led by St. Jude, will be compared with 25 matched historical control patients who have undergone hematopoietic stem cell transplantation (HSCT). The primary efficacy endpoint will be event-free survival. The initiation of this trial is expected early in the fourth quarter of 2020. Mustang is targeting topline data from this trial in the second half of 2022.

Another Phase 1/2 clinical trial for XSCID in patients over the age of two years, who have received prior HSCT, is underway at the National Institutes of Health, and Mustang expects to file an IND to the FDA to initiate a multi-center Phase 2 clinical trial in this population in the fourth quarter of 2020. This product candidate for XSCID in patients over the age of two years, who have received prior HSCT, is designated MB-207. The FDA granted a Rare Pediatric Disease Designation to MB-207 in August 2020.

About X-linked Severe Combined Immunodeficiency (XSCID)X-linked severe combined immunodeficiency is a rare genetic disorder that occurs in approximately 1 per 225,000 births. It is characterized by the absence or lack of function of key immune cells, resulting in a severely compromised immune system and death by one year of age if untreated. Patients with XSCID have no T-cells or natural killer cells. Although their B-cells are normal in number, they are not functional. As a result, XSCID patients are usually affected by severe bacterial, viral or fungal infections early in life and often present with interstitial lung disease, chronic diarrhea and failure to thrive.

The specific genetic disorder that causes XSCID is a mutation in the gene coding for the common gamma chain (c), a protein that is shared by the receptors for at least six interleukins. These interleukins and their receptors are critical for the development and differentiation of immune cells. The gene coding for c is known as IL-2 receptor gamma, or IL2RG. Because IL2RG is located on the X-chromosome, XSCID is inherited in an X-linked recessive pattern, resulting in almost all patients being male.

About Mustang BioMustang Bio, Inc. is a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases. Mustang aims to acquire rights to these technologies by licensing or otherwise acquiring an ownership interest, to fund research and development, and to outlicense or bring the technologies to market. Mustang has partnered with top medical institutions to advance the development of CAR T therapies across multiple cancers, as well as a lentiviral gene therapy for XSCID. Mustang is registered under the Securities Exchange Act of 1934, as amended, and files periodic reports with the U.S. Securities and Exchange Commission (SEC). Mustang was founded by Fortress Biotech, Inc. (NASDAQ: FBIO). For more information, visit http://www.mustangbio.com.

ForwardLooking StatementsThis press release may contain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, each as amended. Such statements include, but are not limited to, any statements relating to our growth strategy and product development programs and any other statements that are not historical facts. Forward-looking statements are based on managements current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock value. Factors that could cause actual results to differ materially from those currently anticipated include: risks relating to our growth strategy; our ability to obtain, perform under, and maintain financing and strategic agreements and relationships; risks relating to the results of research and development activities; risks relating to the timing of starting and completing clinical trials; uncertainties relating to preclinical and clinical testing; our dependence on third-party suppliers; our ability to attract, integrate and retain key personnel; the early stage of products under development; our need for substantial additional funds; government regulation; patent and intellectual property matters; competition; as well as other risks described in our SEC filings. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law.

Company Contacts:Jaclyn Jaffe and William BegienMustang Bio, Inc.(781) 652-4500ir@mustangbio.com

Investor Relations Contact:Daniel FerryLifeSci Advisors, LLC(617) 430-7576daniel@lifesciadvisors.com

Media Relations Contact:Tony Plohoros6 Degrees(908) 591-2839tplohoros@6degreespr.com

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Mustang Bio Announces Orphan Drug Designation for MB-107 for the Treatment of X-linked Severe Combined Immunodeficiency in Newly Diagnosed Infants -...

The McKusick-Nathans Institute of Genetic Medicine | Department of Genetic Medicineseeks to further the understanding of human heredity and genetic medicine and use that knowledge to treat and prevent disease.

The Department of Genetic Medicineis working to consolidate all relevant teaching, patient care and research in human and medical genetics at Johns Hopkins to provide national and international leadership in genetic medicine. The Department of Genetic Medicineserves as a focal point for interactions between diverse investigators to promote the application of genetic discoveries to human disease and genetics education to the public. It builds upon past strengths and further develops expertise in the areas of genomics, developmental genetics and complex disease genetics. The Department of Genetic Medicineworks to catalyze the spread of human genetic perspectives to other related disciplines by collaboration with other departments within Johns Hopkins.

There are more than 300 dedicated employees in the Department of Genetic Medicine, fulfilling the Johns Hopkins tripartite mission of research, teaching and patient care. They include 45 full-time faculty, 15 residents, more than 70 graduate students and 200 staff.

All too often, when we see injustices, both great and small, we think, that's terrible, but we do nothing. We say nothing. We let other people fight their own battles. We remain silent because silence is easier. Qui tacet consentire videtur is Latin for 'Silence gives consent.' When we say nothing, when we do nothing, we are consenting to these trespasses against us.Roxane Gay

The indifferent and arrogant murder of George Floyd is but one of many searing examples of racism, oppression and sheer wickedness imposed on members of the African-American community over the last 400 years. Repeatedly, over these many years, periods of apparent progress have been undercut by horrific acts of racially-based evil that expose an underlying hard core of racial bias and systematic racism. The sadness, anger and frustration we all feel are compounded by the failure of our society to respond to these events with real and sustained justice. We cannot, however, let these events undermine our quest for meaningful and sustained progress towards correcting the systemic problems and beliefs leading to these events. To quote Martin Luther King Jr., Change does not roll in on the wheels of inevitability, but comes through continuous struggle.

How can we break out of this cycle of modest progress punctuated by horrific failures? The answers to this question are neither simple nor obvious. Success will require a sustained and multi-faceted effort from all of us. Some reactions seem obvious and personally attainable; we must treat all members of our society equally and fairly. In these difficult times, we much reach out to those directly affected with understanding, respect, and support. All of us must commit to and participate in these positive interactions. Beyond these responses of the moment, we must search for ways that we can change the social, economic and personal environment to minimize the likelihood of recurrence and maximize progress towards real equality for all. As geneticists, we treasure diversity and understand many of the biological factors underlying it. Perhaps, one special responsibility for us is to help others in society understand and value diversity and individuality.

As members of the Human Genetics program and Department of Genetic Medicine community, we recognize there are some among us who are more vulnerable to the biases illuminated by the death of George Floyd and many, many others; whose fear of an encounter with the police is amplified by personal and community experience; and whose experience of pain and suffering far exceeds what most of us can fully understand. To those most vulnerable in our Department of Genetic Medicinefamily, we stand with you and raise our voices to support you. We are ready to listen and act in pursuit of a learning environment of which you can be proud and a world into which you will move and feel free to change.

Finally, as we search for appropriate responses, we are grateful to have your voices, your guidance to help illuminate a path forward. We recognize and are encouraged by the outpouring of activism, passion, rage and love from our students, our department, our community and even our own families. We also recognize that this journey, which began centuries ago, will be long, sometimes uncomfortable and inelegant and studded with setbacks. We are, however, committed to do everything in our power to speed its progress.

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Department of Genetic Medicine | Johns Hopkins Medicine

As use of genomic technologies continue to increase in research and clinical settings, the Division of Genetic Medicine serves a key role in bringing together basic, clinical, and translational expertise in genomic medicine, with multidisciplinary faculty comprised of MDs, PhD scientists, and genetic counselors. Demand for expertise in genetics continues to increase, and the Division of Genetic Medicine is committed to advancing scientific discovery and clinical care of patients.

In addition to our Medical Genetics Clinic, genetics services are available through several other Michigan Medicine clinics and programs, including the Breast and Ovarian Cancer Risk Evaluation Program, Cancer GeneticsClinic,Inherited Cardiomyopathies and Arrhythmias Program,Neurogenetics Clinic, Pediatric Genetics Clinic, and Prenatal Evaluation Clinic.

Our faculty are focused on various research areas including cancer genetics, inherited hematologic disorders, neural stem cells,the mechanisms and regulation of DNA repair processes in mammalian cells, predictive genetic testing,understanding the mechanisms controlled by Hox genes, birth defects, bleeding and thrombotic disorders, and human limb malformations.

Division of Genetic Medicinefaculty are actively engaged in the education, teaching, and mentorship of clinicians, and clinical and basic scientists, including undergraduate and graduate students, medical students, residents, and fellows from various subspecialties.

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Genetic Medicine | Internal Medicine | Michigan Medicine ...

Advances in molecular biology and human genetics, coupled with the completion of the Human Genome Project and the increasing power of quantitative genetics to identify disease susceptibility genes, are contributing to a revolution in the practice of medicine. In the 21st century, practicing physicians will focus more on defining genetically determined disease susceptibility in individual patients. This strategy will be used to prevent, modify, and treat a wide array of common disorders that have unique heritable risk factors such as hypertension, obesity, diabetes, arthrosclerosis, and cancer.

The Division of Genetic Medicine provides an academic environment enabling researchers to explore new relationships between disease susceptibility and human genetics. The Division of Genetic Medicine was established to host both research and clinical research programs focused on the genetic basis of health and disease. Equipped with state-of-the-art research tools and facilities, our faculty members are advancing knowledge of the common genetic determinants of cancer, congenital neuropathies, and heart disease. The Division faculty work jointly with the Vanderbilt-Ingram Cancer Center to support the Hereditary Cancer Clinic for treating patients and families who have an inherited predisposition to various malignancies.

Genetic differences in humans at the molecular level not only contribute to the disease process but also significantly impact an individuals ability to respond optimally to drug therapy. Vanderbilt is a pioneer in precisely identifying genetic differences between patients and making rational treatment decisions at the bedside.

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Genetic Medicine | Department of Medicine

It has often been estimated that it takes, on average, 17years to translate a novel research finding into routine clinical practice. This time lag is due to a combination of factors, including the need to validate research findings, the fact that clinical trials are complex and take time to conduct and then analyze, and because disseminating information and educating healthcare workers about a new advance is not an overnight process.

Once sufficient evidence has been generated to demonstrate a benefit to patients, or "clinical utility," professional societies and clinical standards groups will use that evidence to determine whether to incorporate the new test into clinical practice guidelines. This determination will also factor in any potential ethical and legal issues, as well economic factors such as cost-benefit ratios.

The NHGRIGenomic Medicine Working Group(GMWG) has been gathering expert stakeholders in a series of genomic medicine meetingsto discuss issues surrounding the adoption of genomic medicine. Particularly, the GMWG draws expertise from researchers at the cutting edge of this new medical toolset, with the aim of better informing future translational research at NHGRI. Additionally the working group provides guidance to theNational Advisory Council on Human Genome Research (NACHGR)and NHGRI in other areas of genomic medicine implementation, such as outlining infrastructural needs for adoption of genomic medicine, identifying related efforts for future collaborations, and reviewing progress overall in genomic medicine implementation.

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Genomics and Medicine - Genome.gov

Injections of a natural energy molecule prompted regrowth of almost half of the cartilage lost with aging in knees, a new study in rodents shows.

The study results revolve around the long-established idea that machines within animal and human cells turn the sugars, fats, and proteins we eat into energy used by the bodys millions of cells. The molecule most used to store that energy is called adenosine triphosphate, or ATP. Along with this central role in metabolism, adenosine also helps signal other cells and serves as a building block of genetic material, and so is central to the growth of human tissue.

Previous research had shown that maintaining supplies of adenosine, known to nourish the chondrocyte cells that make cartilage, also prevented osteoarthritis in similar animal models of the disease.

In the new NYU Grossman School of Medicineled study, researchers injected adenosine into the joints of rodents whose limbs had been damaged by inflammation resulting from either traumatic injury, such as a torn ligament, or from massive weight gain placing pressure on joints. The biological damage in these cases is similar, researchers say, to that sustained in human osteoarthritis.

Published online in the journal Scientific Reports on August 10, the study rodents received 8 weekly injections of adenosine, which prompted regrowth rates of cartilage tissue between 50 percent and 35 percent as measured by standard laboratory scores.

Our latest study shows that replenishing adenosine stores by injection works well as a treatment for osteoarthritis in animal models of the disease, and with no apparent side effects, says lead study author Carmen Corciulo, PhD, a postdoctoral fellow at NYU Langone.

Dr. Corciulo says it is too soon to use this experimental model as a therapy in people. Clinical trials must await a test drug that can be safely stored for days if not weeks, and experiments in larger mammals.

Study senior investigator Bruce N. Cronstein, MD, the Dr. Paul R. Esserman Professor of Medicine at NYU Langone Health, says the teams research is important because the few existing drug therapies for osteoarthritis such as acetaminophen and COX-2 inhibitor drugs, including naproxen and ibuprofen, only numb joint pain, or like hyaluronic acid just lubricate its tissues. None stall disease progression or reverse the damage. Painkillers, such as opioids, are often prescribed, but are also highly addictive, he cautions.

People with osteoarthritis desperately need more treatment options with fewer side effects, and our research advances that effort, says Dr. Cronstein, who also serves as the director of NYU Langones Clinical and Translational Science Institute. He notes that other experimental medications are being developed elsewhere, including parathyroid hormone to stimulate bone growth, WNT inhibitor drugs to block the bone and cartilage degradation, and growth factor chemicals to promote cartilage growth.

Dr. Cronstein, Dr. Corciulo, and NYU Grossman School of Medicine have a patent application pending for the use of adenosine and other agents that help with its binding to chondrocytes, called A2A receptor agonists, for the treatment of osteoarthritis.

Among the studys other key findings was that a cell-signaling pathway, known as transforming growth factor beta (TGF-beta) and involved in many forms of tissue growth, death, and differentiation, was highly active in cartilage tissue damaged by osteoarthritis, as well as in cartilage tissue undergoing repair after being treated with adenosine. Additional testing in lab-grown chondrocytes from people with osteoarthritis showed different chemical profiles of TGF-beta signaling during breakdown than during growth, providing the first evidence that the pathway switched function in the presence of adenosine (from assisting in cartilage breakdown to encouraging its repair.)

Developing treatments to halt or slow the disease is important, Dr. Cronstein says, because well over 100 million people worldwide are estimated to have osteoarthritis, which is tied to aging, especially in women. This figure, he says, is only expected to grow as more people live longer and obesity rates climb.

Right now, the only way to stop osteoarthritis is to have affected joints surgically replaced, which not only comes with pain and risk of infection, but is also quite costly, says Dr. Cronstein. If new therapies can delay or prevent disease onset and progression, then fewer joint replacements will save people from a lot of pain and expense.

The study was funded by National Institutes of Health grants R01 AR056672 and R01 AR068593, NYU-HHC Clinical and Translational Science Institute grant UL1 TR000038, and the Arthritis Foundation.

Dr. Corciulo and Dr. Cronstein have a patent for the methods and compositions for treating osteoarthritis and promoting cartilage formation (U.S. Patent 10,441,541), which has been assigned to NYU Grossman School of Medicine. They are cofounders of Regenosine Inc., a company that is developing new treatments for osteoarthritis, and in which they hold a financial interest. Dr. Cronstein has consulted for Eli Lilly, Horizon Pharmaceuticals, Bristol Myers Squibb, and Astrazeneca. He also has grants from Arcus Biopharma. All relationships are being managed in accordance with the policies and practices of NYU Langone.

Besides Dr. Cronstein and Dr. Corciulo, other NYU Langone investigators involved in this study are Cristina Castro, MD; Thomas Coughlin, PhD; Samson Jacob, MS; David Fenyo, PhD; Daniel B. Rifkin, PhD; and Oran Kennedy, PhD.

David MarchPhone: 212-404-3528david.march@nyulangone.org

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BEDFORD, Mass.--(BUSINESS WIRE)--Stoke Therapeutics, Inc. (Nasdaq: STOK), a biotechnology company pioneering a new way to treat the underlying cause of genetic diseases by precisely upregulating protein expression, today reported financial results for the second quarter of 2020 and provided business updates.

Today we are announcing that the first patient has been dosed with STK-001, which we believe has the potential to be the first-disease modifying medicine for Dravet syndrome, a severe and progressive genetic epilepsy that is characterized by developmental delays and cognitive impairment, in addition to seizure activity, said Edward M. Kaye, M.D., Chief Executive Officer of Stoke Therapeutics. The start of MONARCH also marks Stokes official transition to a clinical-stage biotech company. We enter this new stage in a strong financial position to execute on our plans for STK-001 in Dravet syndrome and continue to advance the potential of our TANGO platform for additional genetic diseases.

Second Quarter 2020 Business Highlights and Recent Developments

Upcoming Anticipated Milestones

Second Quarter and Year-to-Date Results

About STK-001

STK-001 is an investigational new medicine for the treatment of Dravet syndrome. Stoke believes that STK-001, a proprietary antisense oligonucleotide (ASO), has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome. STK-001 is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. Stoke has generated preclinical data demonstrating proof-of-mechanism and proof-of-concept for STK-001. STK-001 has been granted orphan drug designation by the FDA as a potential new treatment for Dravet syndrome.

About Phase 1/2a Clinical Study (MONARCH)

The MONARCH study is a Phase 1/2a open-label study of children and adolescents ages 2 to 18 who have an established diagnosis of Dravet syndrome and have evidence of a pathogenic genetic mutation in the SCN1A gene. The primary objectives for the study will be to assess the safety and tolerability of STK-001, as well as to characterize human pharmacokinetics. A secondary objective will be to assess the efficacy as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in convulsive seizure frequency over a 12-week treatment period. Stoke also intends to measure non-seizure aspects of the disease, such as quality of life as secondary endpoints. Stoke plans to enroll approximately 40 patients across 20 sites in the United States.

About Dravet Syndrome

Dravet syndrome is a severe and progressive genetic epilepsy characterized by frequent, prolonged and refractory seizures, beginning within the first year of life. Dravet syndrome is difficult to treat and has a poor long-term prognosis. Complications of the disease often contribute to a poor quality of life for patients and their caregivers. The effects of the disease go beyond seizures and often include severe intellectual disabilities, severe developmental disabilities, motor impairment, speech impairment, autism, behavioral difficulties and sleep abnormalities. Compared with the general epilepsy population, people living with Dravet syndrome have a higher risk of sudden unexpected death in epilepsy, or SUDEP. Dravet syndrome affects approximately 35,000 people in the United States, Canada, Japan, Germany, France and the United Kingdom, and it is not concentrated in a particular geographic area or ethnic group.

About Stoke Therapeutics

Stoke Therapeutics (Nasdaq: STOK) is a biotechnology company pioneering a new way to treat the underlying causes of severe genetic diseases by precisely upregulating protein expression to restore target proteins to near normal levels. Stoke aims to develop the first precision medicine platform to target the underlying cause of a broad spectrum of genetic diseases in which the patient has one healthy copy of a gene and one mutated copy that fails to produce a protein essential to health. These diseases, in which loss of approximately 50% of normal protein expression causes disease, are called autosomal dominant haploinsufficiencies. Stoke is headquartered in Bedford, Massachusetts with offices in Cambridge, Massachusetts. For more information, visit https://www.stoketherapeutics.com/ or follow the company on Twitter at @StokeTx.

Cautionary Note Regarding Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to: future operating results, financial position and liquidity, the direct and indirect impact of COVID-19 on our business, financial condition and operations, including on our expenses, supply chain, strategic partners, research and development costs, clinical trials and employees; our expectation about timing and execution of anticipated milestones, responses to regulatory authorities, expected nomination of a second product candidate and timing thereof, and our ability to use study data to advance the development of STK-001; the ability of STK-001 to treat the underlying causes of Dravet syndrome; and the ability of TANGO to design medicines to increase protein production and the expected benefits thereof. These forward-looking statements may be accompanied by such words as aim, anticipate, believe, could, estimate, expect, forecast, goal, intend, may, might, plan, potential, possible, will, would, and other words and terms of similar meaning. These forward-looking statements involve risks and uncertainties, as well as assumptions, which, if they do not fully materialize or prove incorrect, could cause our results to differ materially from those expressed or implied by such forward-looking statements. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: our ability to develop, obtain regulatory approval for and commercialize STK-001 and future product candidates; the timing and results of preclinical studies and clinical trials; the risk that positive results in a clinical trial may not be replicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; risks associated with clinical trials, including our ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates; the occurrence of adverse safety events; failure to protect and enforce our intellectual property, and other proprietary rights; failure to successfully execute or realize the anticipated benefits of our strategic and growth initiatives; risks relating to technology failures or breaches; our dependence on collaborators and other third parties for the development, regulatory approval, and commercialization of products and other aspects of our business, which are outside of our full control; risks associated with current and potential delays, work stoppages, or supply chain disruptions caused by the coronavirus pandemic; risks associated with current and potential future healthcare reforms; risks relating to attracting and retaining key personnel; failure to comply with legal and regulatory requirements; risks relating to access to capital and credit markets; environmental risks; risks relating to the use of social media for our business; and the other risks and uncertainties that are described in the Risk Factors section of our most recent annual or quarterly report and in other reports we have filed with the U.S. Securities and Exchange Commission. These statements are based on our current beliefs and expectations and speak only as of the date of this press release. We do not undertake any obligation to publicly update any forward-looking statements.

Financial Tables Follow

2020

2019

$

201,930

$

222,471

3,528

3,281

77

9

281

$

205,544

$

226,033

205

205

1,642

2,823

2,512

$

210,214

$

228,750

$

904

$

751

4,901

3,350

$

5,805

$

4,101

1,009

221

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Stoke Therapeutics Reports Second Quarter Financial Results and Provides Business Updates - Business Wire

What happened

Shares of Editas Medicine (NASDAQ:EDIT) and Beam Therapeutics (NASDAQ:BEAM) rose as much as 23% and 29%, respectively, today after the pair were rumored to be considering a merger. Although investors shouldn't invest based on speculation, a merger would make sense on multiple fronts.

The duo already have an agreement in place to collaborate on genetic medicines, but the struggling pipeline of Editas Medicine could receive a significant boost from Beam Therapeutics. It would also allow Editas shareholders to avoid many of the technical pitfalls of first-generation CRISPR gene-editing tools, which have yet to be adequately reflected in stock prices. Of course, the flip side is that the merger doesn't make as much sense for Beam Therapeutics.

As of 12:50 p.m. EDT, both small-cap stocks had settled to gains of about 14%.

Image source: Getty Images.

There are multiple reasons a merger makes sense. Consider that:

There's not much to the report that Editas Medicine and Beam Therapeutics are considering a merger. Only one digital publication mentions "chatter" without providing any follow-up details. The rumors are at least plausible given the ties to the Broad Institute and overlap of the scientific founders, but investors simply don't have much to go on. That said, a merger would make more sense for Editas Medicine than Beam Therapeutics, as the latter has a much stronger technical foundation to lean on for the long haul.

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Here's Why Shares of Editas Medicine and Beam Therapeutics Are Soaring Today - Motley Fool

Weill Cornell Medicines Clinical and Translational Science Center (CTSC) has been awarded a grant from the National Institutes of Health to investigate the role of social and biological factors in determining COVID-19 severity and outcomes in New York City patients.

The two-year, $1.5 million grant will fund projects led by Dr. Julianne Imperato-McGinley, director of the CTSC and The Abby Rockefeller Mauz Distinguished Professor of Endocrinology in Medicine at Weill Cornell Medicine.

The projects co-leaders are Dr. Olivier Elemento, director of the Englander Institute for Precision Medicine and professor of computational genomics in pathology and laboratory medicine at Weill Cornell; and Dr. Said Ibrahim, professor of health care policy and research and senior associate dean for diversity and inclusion at Weill Cornell.

Black and Latino populations have suffered a significantly higher proportion of infection and death from COVID-19 in New York City and across the country. Social determinants of health including lack of access to adequate medical care, crowded housing and exposure from ones occupation can influence the likelihood of acquiring COVID-19.

Co-morbidities such as obesity, diabetes and lung and heart disease that put people at risk for severe illness are also more common in Black and Latino populations.

To assess how socioeconomic factors have contributed to the racial and ethnic disparities, the investigators will compare rates of hospitalization, intensive care unit admissions and deaths from COVID-19 in affluent versus lower income communities within New York City. They will also use data from patients across the NewYork-Presbyterian Hospital system to study patterns in demographics, laboratory results and biospecimens to determine if theres a link between genetic variability, race and ethnicity and severity of COVID-19.

The project builds on Weill Cornell Medicines vision of a clinical research program that combines clinical care, investigation into social determinants of health and basic science research. Leveraging CTSC infrastructure, this approach brings together sources like census and other government data, electronic health records and the institutions newly created biobank of COVID-19 patient specimens.

The team plans to use its findings to build a model to predict who is most susceptible to the disease, which can help shape prevention and treatment strategies and bring precision medicine to COVID-19 patients. The team also aims to expand its work to regional and national analyses, tapping into a database of clinical data from COVID-19 patients that is being assembled by the Clinical and Translational Science Award program national network.

Bridget Kuehn is a freelance writer for Weill Cornell Medicine.

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Grant will fund study into COVID outcome disparities in NYC - Cornell Chronicle