Category Archives: Molecular Genetics

Newswise A $53.6 million grant from the National Institutes of Health will aid brain scientists, including a researcher from The University of Texas Health Science Center at Houston (UTHealth), in studying the role of incidental white matter lesions, or WMLs, in dementia among diverse people with cognitive complaints.

The study is led by UC Davis School of Medicine in partnership with UTHealth. It is a new and critical part of the NIHsVascular Contributions to Cognitive Impairment and Dementia(VCID) research program.

Co-principal investigator isMyriam Fornage, PhD, professor of genetics at theBrown Foundation Institute of Molecular Medicine for the Prevention of Human Diseasesat McGovern Medical School at UTHealth. Fornage is a leading researcher on the molecular genetics of cerebrovascular disease.

Our team has been at the forefront of genetic studies of WMLs for two decades, Fornage said. Through the genetic risk profiles we will develop, we will have an opportunity to apply what we have discovered and improve the precision with which we identify patients with a higher prior probability of cognitive impairment and dementia. At the same time, we will be contributing new resources for dementia research everywhere.

The principal investigator isCharles DeCarli, MD, professor of neurology, director of theUC Davis Alzheimers Disease Centerand the nations foremost expert on the role of subcortical cerebrovascular disease in cognitive decline. In the last few years, DeCarli has been awarded national and state research grants exceeding $33 million.

The magnitude of this NIH grant underscores UC Davis Alzheimers Disease Centers national prominence and research leadership, said UC Davis School of Medicine Dean Allison Brashear,MD, a neurologist nationally known for her groundbreaking research in movement disorders. This multiyear research award will enable us to make game-changing advancements in our understanding and treatment of dementia.

WMLs occur when tissue deep in the brain becomes injured, often due to changes in small blood vessels. They are common and often found on brain MRIs of people who have concerns about their brain health.

Why or how WMLs are associated with cognitive decline is not known. Questions surround whether certain WML characteristics, such as size and location, make them greater risk factors for dementia. It also isnt clear how comorbidities additional health conditions such as heart disease or diabetes together with WMLs increase risk for cognitive decline. Defining these connections is essential to improving outcomes for the 5.7 million people in the U.S. affected by cognitive impairment and dementia.

DeCarli and Fornages landmark research is expected to answer these questions and lead to standards for assessing, diagnosing, and treating individuals with WML-related cognitive problems.

This grant gives us the chance to study WMLs from every angle and definitively understand their roles in age- and disease-related cognitive decline and risk for future dementia, DeCarli said. Its the culmination of our three decades of research that has given us great directions, but no final answers yet.

DeCarli and Fornage will conduct a study of patients with WMLs on their MRIs and concerns about cognitive symptoms, but no dementia diagnosis. It will be the first large study of a diverse population on the long-term effects of these lesions on thinking and dementia risk.

Beginning September 2021, study participants will be recruited at UC Davis Health and at least 10 other locations throughout the U.S. They will be from a variety of backgrounds, so the researchers can identify how WML outcomes differ by race, ethnicity, and sex, better representing those at risk for dementia.

Our ultimate goals are to develop a risk profile that identifies the likelihood of WML-related cognitive impairment and dementia over the course of five to 10 years and to identify clear targets for interventional trials, DeCarli said.

Resources to advance all dementia research

Another exciting part of the grant, according to the researchers, is the chance to fund additional studies aimed at refining diagnostic and predictive tools and methods for dementia. The outcomes will enhance dementia research and clinical care worldwide.

Data and samples from these studies will be shared with the wider research community via theNational Alzheimers Coordinating Center at the University of Washingtonand theNational Centralized Repository for Alzheimers Disease and Related Dementias at Indiana University. Images will be shared through theLaboratory of Neuro Imaging at the University of Southern California.

DeCarli and Fornage also participate in theMarkVCID Consortium, supported by the NIHsNational Institute of Neurological Disorders and Stroke. The consortium was established in 2016 to identify biological markers of vascular cognitive impairment and dementia.

This award is co-sponsored by the NIHs National Institute of Neurological Disorders and Stroke andNational Institute on Agingthrough grant 1U19NS120384.

The Brown Foundation Institute of Molecular Medicine (IMM) for the Prevention of Human Diseases is part of McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth). The IMM is focused on studying and preventing diseases at the genetic, cellular, and molecular levels using DNA and protein technologies and animal models. The IMM is part of the Texas Therapeutics Institute, a multi-institutional collaboration encouraging drug discovery. For more information, visitwww.uth.edu/imm/mission.htm.

The UC Davis Alzheimers Disease Research Center is one of only31 research centers designated and funded by the NIHs National Institute on Aging. The center's goal is to translate research advances into improved diagnosis and treatment for patients while focusing on the long-term goal of finding a way to prevent or cure Alzheimers disease and other dementias. The center also allows researchers to study the effects of the disease on a uniquely diverse population. For more information, visithealth.ucdavis.edu/alzheimers.

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Researchers receive more than $53 million to study role of white matter lesions in dementia - Newswise

It was Saturday, February 22, 1997, and Scottish researchers Ian Wilmut and Keith Campbell were expecting a final moment of calm before the results of their unprecedented scientific experiment were announced to the world.

The team had kept the breakthrough under wraps for seven months while they waited for their paper to be published in the prestigious journal Nature. Confidential press releases had gone out to journalists with the strict instruction not to leak the news before February 27.

But that night, the team was tipped off that journalist Robin McKie was going to break the story the very next day in the British newspaper The Observer.

Wilmut and Campbell raced to the lab at the Roslin Institute on Sunday morning as McKie's story hit the media like a thunderbolt. International news outlets had already started swarming at the institute for access to Wilmut and Campbell's creation: Dolly the sheep, the world's first mammal successfully cloned from a single adult cell. Shielded from the general public, she stuck her nose through the fence and munched calmly on the hay in her pen, unperturbed by the horde of news photographers. Dolly, a woolly, bleating scientific miracle, looked much like other sheep, but with a remarkable genetic difference.

By the end of that Sunday, February 23, nearly every major newspaper in the world carried headlines about Dolly the sheep.

Born on July 5, 1996, Dolly was cloned by Wilmut and Campbell's team at the Roslin Institute, a part of the University of Edinburgh, and Scottish biotechnology company PPL Therapeutics. The scientists cloned Dolly by inserting DNA from a single sheep mammary gland cell into an egg of another sheep, and then implanting it into a surrogate mother sheep. Dolly thus had three mothersone that provided the DNA from the cell, the second that provided the egg, and the third that carried the cloned embryo to term. Technically, though, Dolly was an exact genetic replica of only the sheep from which the cell was taken.

Following the announcement, the Roslin Institute received 3000 phone calls from around the world. Dolly's birth was heralded as one of the most important scientific advances of the decade.

But Dolly wasn't science's first attempt at cloning. Researchers had been exploring the intricacies of cloning for almost a century. In 1902, German embryologists Hans Spemann and Hilda Mangold, his student, successfully grew two salamanders from a single embryo split with a noose made up of a strand of hair. Since then, cloning experiments continued to become more sophisticated and nuanced. Several laboratory animal clones, including frogs and cows, were created before Dolly. But all of them had been cloned from embryos. Dolly was the first mammal to be cloned from a specialized adult cell.

Embryonic stem cells, which form right after fertilization, can turn into any kind of cell in the body. After they modify into specific types of cells, like neurons or blood cells, they're call specialized cells. Since the cell that gave rise to Dolly was already specialized for its role as a mammary gland cell, most scientists thought it would be impossible to clone anything from it but other mammary gland cells. Dolly proved them wrong.

Many scientists in the '90s were flabbergasted. Dollys advent showed that specialized cells could be used to create an exact replica of the animal they came from. It means all science fiction is true, biology professor Lee Silver of Princeton University told The New York Times in 1997.

The Washington Post reported that "Dolly, depending on which commentator you read, is the biggest story of the year, the decade, even the century. Wilmut has seen himself compared with Galileo, with Copernicus, with Einstein, and at least once with Dr. Frankenstein."

Scientists, lawmakers, and the public quickly imagined a future shaped by unethical human cloning. President Bill Clinton called for review of the bioethics of cloning and proposed legislation that would ban cloning meant ''for the purposes of creating a child (it didn't pass). The World Health Organization concluded that human cloning was "ethically unacceptable and contrary to human integrity and morality" [PDF]. A Vatican newspaper editorial urged governments to bar human cloning, saying every human has "the right to be born in a human way and not in a laboratory."

Meanwhile, some scientists remained unconvinced about the authenticity of Wilmut and Campbells experiment. Norton Zinder, a molecular genetics professor at Rockefeller University, called the study published in Nature "a bad paper" because Dolly's genetic ancestry was not conclusive without testing her mitochondriaDNA that is passed down through mothers. That would have confirmed whether Dolly was the daughter of the sheep that gave birth to her. In The New York Times, Zinder called the Scottish pair's work ''just lousy science, incomplete science." But NIH director Harold Varmus toldthe Times that he had no doubt that Dolly was a clone of an adult sheep.

Because she was cloned from a mammary gland cell, Dolly was nameddad joke alertafter buxom country music superstar Dolly Parton. (Parton didnt mind the attribution.) Like her namesake, Dolly the sheep was a bona fide celebrity: She posed for magazines, including People; became the subject of books, journal articles, and editorials; had an opera written about her; starred in commercials; and served as a metaphor in an electoral campaign.

And that wasn't all: New York Times reporter Gina Kolata, one of the first journalists to give readers an in-depth look at Dolly, wroteClone: The Road to Dolly, and the Path Ahead and contrasted the animal's creation with the archetypes in Frankenstein and The Island of Dr. Moreau. American composer Steve Reich was so affected by Dolly's story that he featured it in Three Tales, a video-opera exploring the dangers of technology.

The sheep also became an inadvertent political player when the Scottish National Party used her image on posters to suggest that candidates of other parties were all clones of one another. Appliance manufacturer Zanussi used her likeness for a poster with her name and the provocative caption "The Misappliance of Science" (the poster was later withdrawn after scientists complained). In fact, so widespread was the (mis)use of her name that her makers eventually trademarked it to stop the practice.

Following Dolly, many larger mammals were cloned, including horses and bulls. Roslin Biomed, set up by the Roslin Institute to focus on cloning technology, was later sold to the U.S.-based Geron Corporation, which combined cloning technology with stem cell research. But despite her popularityand widespread fearDolly's birth didn't lead to an explosion in cloning: Human cloning was deemed too dangerous and unethical, while animal cloning was only minimally useful for agricultural purposes. The sheep'sreal legacy is considered to be the advancement in stem cell research.

Dollys existence showed it was possible to change one cells gene expression by swapping its nucleus for another. Stem cell biologist Shinya Yamanaka told Scientific American that Dollys cloning motivated him to successfully develop stem cells from adult cells. He later won a Nobel Prize for his results, called induced pluripotent stem cells (iPS) because they're artificially created and can have a variety of uses. They reduced the need for embryonic stem cells in research, and today, iPS cells form the basis for most stem cell research and therapies, including regenerative medicine.

Dolly had sixoffspring, and led a productive, sociable life with many human fans coming to visit her. In 2003, a veterinary examination showed that Dolly had a progressive lung disease, and she was put down. But four clonescreated from the same cell line in 2007 faced no such health issues and aged normally.

Dolly is still a spectacle, though, nearly 25 years after her creation: Her body was taxidermied and puton display at the National Museum of Scotland in Edinburgh.

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Dolly the Sheep: '90s Media Sensation - Mental Floss

Ohio State students with disabilities are adjusting to new accommodations for virtual learning. Credit: Mackenzie Shanklin | Assistant Photo Editor

Online classes are decreasing commute times, allowing students to rewatch live lectures and keeping the university community safe from COVID-19; however, for students with disabilities, the technological interface and isolation pose difficulties they dont face in a typical semester.

As a majority of Ohio State courses have moved to distance learning, Scott Lissner, the universitys Americans with Disabilities Act coordinator, said his office is working to provide students with disabilities a comprehensive education while also keeping them safe during the pandemic. For some of those accommodations, online learning is making the process easier.

If everybody is [taking classes] online, it removes a lot of challenges and simplifies things. We know how to integrate captioning in Zoom. We know how to integrate ASL interpreting into Zoom, Lissner said.

CarmenZoom offers captioning of class and lecture recordings, but did not offer live, automated captioning until recently.

Amy Shuman, a professor in the Department of English and former director of disability studies in the department, said although she records all her classes and uploads the videos with transcripts to make them more accessible, she hasnt seen a widespread shift toward the practice.

Ive talked to some of the older faculty who have hearing aids, and theyre frustrated by the lack of the closed captioning, Shuman said.

Lissner said in an email that Zoom tested live, automated captioning over the summer and Ohio State evaluated the system before releasing it Friday. A Friday press release from Ohio States IT department stated that live captioning is a setting Zoom meeting hosts must manually enable for their classes.

Lindsay Rogers, a first-year in molecular genetics who is hearing impaired, said online classes are easier for her than in-person classes because professors can talk directly into her hearing implants via Bluetooth, but shes had difficulty getting accommodations she typically gets each semester.

I requested [note taking assistance] for this semester, and no one contacted me about getting any sort of note taking assistance, Rogers said.

Lissner said students who do not have proper technology for their classes such as small monitors or devices that cannot connect to hearing aids via Bluetooth are sometimes able to borrow devices from the university. The university has screen-reader compatible monitors, for example, and high-quality speakers that can play sound at higher volumes.

Lissner said these loans are offered on a case-by-case basis depending on students specific disabilities. Students with disabilities are encouraged to participate in live class sessions and are provided with the materials necessary to successfully take part, he said.

We work with faculty and students to make sure accessible versions of whatever is being presented on the shared screen are distributed to students who need them prior to class. So they can either open it up in another window or have a dual monitor setup, Lissner said.

Hybrid courses and discussion-based courses can be difficult to replicate for students who require accommodations, but the ADA office tries to make students feel included while working virtually, Lissner said.

For example, if a student needs ADA accommodations in a hybrid class and is unable to attend in-person sessions, monitors can be set up in a circle around the student, with a wide angle camera used in the physical classroom. This creates an environment closer to that of an in-person class.

Isaac Meisner, a second-year in environmental policy and decision making, said having mostly online courses presents challenges with their mental illnesses.

When youre having classes that are completely online, it makes my mental disorders more difficult to handle just because I need that interaction with other people, and Im not really getting it outside of where I live, Meisner said.

Kayden Gill, a third-year in health sciences and co-president of Buckeyes for Accessibility, said as a wheelchair user and someone with a visual impairment, online courses present both positives and negatives. One of the main cons, Gill said, is it is harder to find ways to exercise without traveling across campus.

From a visual disability standpoint, its a lot easier not to have to worry about finding the place in the lecture hall that you can see, or just always having something as large as your screen can make it is nice, Gill said.

Students can register for accommodations on the Student Life Disability Services website.

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Students with disabilities, university accommodations adapt to virtual learning - OSU - The Lantern

Fluorescent image shows chromosomes (green) segregating in two developing eggs. In each egg, one chromosome (the largest green one) has too many crossovers and is having problems segregating. The image was taken on a deconvolution fluorescent microscope. Credit: Image courtesy of Diana Libuda

University of Oregon and Northwestern University biologists show that too many crossover events can increase infertility.

The exchange of DNA between chromosomes during the early formation of sperm and egg cells normally is limited to assure fertility.

But when there are too many of these genetic exchanges, called crossover events, the segregation of chromosomes into eggs is flawed, biologists have learned in a project done across three labs at the University of Oregon and Northwestern University.

In a paper published online in September 2020 in the journal PLOS Genetics, researchers documented how the disruptions, as seen in basic research with microscopic roundworms (Caenorhabditis elegans), lead to a range of meiotic defects as the chromosomes are subjected to improper spindle forces.

Inaccurate chromosome segregation in humans is associated with Down syndrome and miscarriages. Such segregation defects as seen in the research can result in increased infertility, said UO biologist Diana E. Libuda, the studys principal investigator.

Over the past century, research has focused on making sure enough crossovers are made during sperm and egg development, said Libuda, a professor in the UOs Department of Biology and Institute of Molecular Biology. It was known that developing sperm and eggs had ways to make sure that not too many crossovers are made, but it was unclear why.

The research team identified two mechanisms that help counteract defects triggered by excess crossover activity in developing eggs and, thus, assist the coordination of the process that helps assure genomic integrity in new generations.

Libuda had reported in the October 9, 2013, issue of Nature the discovery of a mechanism that inhibits the overproduction of crossovers in roundworms. However, Libuda said, it was not possible at that time to study the downstream effects in cases where too many crossovers did occur. Since then, her lab developed a way to generate extra crossovers on a single chromosome.

That ability led to a National Institutes of Health-funded collaboration with Sadie Wignall of Northwestern University, an expert on high-resolution imaging of structures involved in segregation of chromosomes into developing eggs. What Wignall found led Libuda back to Bruce Bowermans UO lab to take a look at chromosome segregation in live developing eggs.

Overall, it was a great joining of scientific strengths to take a multipronged approach to answer this important question, Libuda said.

The research provides fundamental insights that can guide research in other organisms to better understand the mechanisms and, eventually, lead to potential clinical applications.

The same proteins that we are studying in C. elegans are also in humans, Libuda said. In fact, most proteins required for fertility are used across organisms that include yeast, fruit flies, nematodes, zebrafish, mice and humans. Research using these microscopic worms has been shown in numerous contexts to have relevance in human health.

Reference: Excess crossovers impede faithful meiotic chromosome segregation in C. elegans by Jeremy A. Hollis, Marissa L. Glover, Aleesa J. Schlientz, Cori K. Cahoon, Bruce Bowerman, Sarah M. Wignall and Diana E. Libuda, 4 September 2020, PLOS Genetics.DOI: 10.1371/journal.pgen.1009001

Co-authors with Libuda, Bowerman and Wignall on the paper were: Jeremy A. Hollis, a technician in Wignalls lab; former UO biology undergraduate student Marissa L. Glover, now a doctoral student at the University of California, Santa Cruz; Aleesa J. Schlientz, who earned a doctorate from the UO this year; and Cori K. Cahoon, a postdoctoral researcher working in Libudas lab under a fellowship from the Jane Coffin Childs Memorial Fund for Medical Research.

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Over-Exchange of DNA in Sperm and Eggs Results in Chromosome Defects That Can Increase Infertility - SciTechDaily

https://research-highlights.keio.ac.jp/

On 21 May, 2020, the Joint Research Coronavirus Task Force was launched in Japan to promote the development of a mucosal vaccine for COVID-19 based on advanced genomic analysis.

"We will analyze 600 blood samples taken from Japanese COVID-19 patients located in approximately 100 hospitals throughout Japan," explains Takanori Kanai of the Keio University School of Medicine, who leads the task force. "One of the goals of the research is to try to understand why the mortality rate due to COVID-19 has remained significantly lower in Japan than the United States and European countries. We think it may be related to genetic differences. We want to resolve this issue and share our results with our colleagues around the world."

Background and goals

This research is being undertaken by experts affiliated with Keio University, Tokyo Medical and Dental University, Osaka University, the Institute of Medical Science at the University of Tokyo, the National Center for Global Health and Medicine, the Tokyo Institute of Technology, Kitasato University, and Kyoto University.

"Our research team includes specialists in infectious diseases as well as other fields such as molecular genetics, computational science, and gastroenterology, which is my area of expertise, and is not directly related to epidemiology or infectious diseases," says Kanai. "This project was conceived by a small group of medical doctors and researchers without experience of handling infectious diseases. But the actual project is interdisciplinary, with members including ICU and medical care staff at university hospitals, community healthcare practitioners, immunologists, and even members of the general public. Ultimately, we want to contribute to society through medicine and science."

Working hypotheses for possible reasons for fewer COVID-19 deaths in Japan and Asia

The members of the task force compiled the following list of potential reasons for the low mortality rate in Japan: Japan's world-class medical system; a history of regular face mask use and attention to hygiene (including hand washing) in daily life; a culture of avoiding physical contact akin to social distancing; low expression of virus receptors; BCG vaccination; and differences in immune response due to differences in racial HLA and other polymorphisms.

Gathering samples and genetic information

The task force's goals are to establish a medical response system to predict who is at risk of contracting severe COVID-19 and develop a vaccine using proprietary technology. Genomic analysis technology is being employed to elucidate the genetic basis of the mechanisms that trigger COVID-19 infections to worsen, and thereby develop methods to fight the disease and develop a mucosal vaccine.

The team is focusing on the fact that the number of COVID-19 deaths per capita is far smaller in the Japanese population than it is in Western countries. The 600 blood samples are being studied by methods including high-resolution HLA analysis, SNP array and whole-genome sequence analysis, and T-cell repertoire analysis.

"Our analysis is being used to compare severe cases with mild and asymptomatic cases to identify genes that may be responsible for the exacerbation of COVID-19 in Japanese patients," explains Kanai. "Regarding vaccine development, predicting the target epitope is a major challenge. We are planning to use supercomputer simulations to identify potential antigens for SARS-CoV-2 based on our results for determining the genes that lead to severe cases of COVID-19 in Japanese patients."

Initial findings will be announced in September 2020

The task force plans to announce the initial findings of their research in September 2020. This will include the identities of the genes associated with triggering severe cases of COVID-19 among Japanese people that could be used to predict potential severity during early diagnostics.

"We want to use our results to produce guidelines to mitigate the dangers of overloading the medical care system during potential second or possibly third waves of COVID-19," says Kanai. "Furthermore, our immunological genetic information will be valuable for designing potential vaccines for SARS-CoV-2 for many Japanese people. We will share our results with colleagues in other countries so that they can use them to develop strategies to combat COVID-19 for their own populations."

About the researcher

Takanori Kanai Professor

Department of Gastroenterology and Hepatology, School of Medicine

Takanori Kanai graduated from the Keio University School of Medicine in 1988. Between 1989 and 2003 he held teaching positions at the Keio University School of Medicine, Keio Cancer Center, and Tokyo Medical and Dental University (TMDU). He has also held distinguished positions including as a committee member of the Harvard Medical Institute Educational Program at TMDU; Section Editor of the journal Inflammatory Bowel Diseases; Associate Editor of Journal of Gastroenterology; Editorial Board Member, American Journal of Physiology and Gastrointestinal and Liver Physiology; and Clinical Professor of Medicine (Visiting), TMDU. At the Keio University School of Medicine, he was appointed as an associate professor in 2007 and a professor in 2013, and he has been serving as a vice dean since 2017.

Links

COVID-19 taskforce https://www.covid19-taskforce.jp/en/home/

Takanori Kanai informationhttps://k-ris.keio.ac.jp/html/100002919_en.html

Further informationKeio UniversityOffice of Research Development and Sponsored Projects2-15-45 Mita, Minato-ku, Tokyo 108-8345 JapanE-mail: [emailprotected]

WebsitesKeio Universityhttps://www.keio.ac.jp/en/

Keio Research Highlightshttps://research-highlights.keio.ac.jp/

About Keio University

Keio University is a private, comprehensive university with six major campuses in the Greater Tokyo area along with a number of affiliated academic institutions. Keio prides itself on educational and research excellence in a wide range of fields and its state-of-the-art university hospital.

Keio was founded in 1858, and it is Japan's first modern institution of higher learning. Over the last century and a half, it has evolved into and continues to maintain its status as a leading university in Japan through its ongoing commitment to producing leaders of the future. Founder Yukichi Fukuzawa, a highly respected educator and one of the most important intellectuals of modern Japan, aspired for Keio to be a pioneer of new discoveries and contribute to society through learning.

SOURCE Keio University

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Keio University Research: Combating COVID-19: Nationwide genomic analysis to study possible reasons for the low COVID-19 mortality rate in Japan -...

Media Advisory

Thursday, September 24, 2020

New findings by scientists at the National Institutes of Health and their collaborators help explain why some people with COVID-19 develop severe disease. The findings also may provide the first molecular explanation for why more men than women die from COVID-19.

The researchers found that more than 10% of people who develop severe COVID-19 have misguided antibodiesautoantibodiesthat attack the immune system rather than the virus that causes the disease. Another 3.5% or more of people who develop severe COVID-19 carry a specific kind of genetic mutation that impacts immunity. Consequently, both groups lack effective immune responses that depend on type I interferon, a set of 17 proteins crucial for protecting cells and the body from viruses. Whether these proteins have been neutralized by autoantibodies orbecause of a faulty genewere produced in insufficient amounts or induced an inadequate antiviral response, their absence appears to be a commonality among a subgroup of people who suffer from life-threatening COVID-19 pneumonia.

These findings are the first published results from the COVID Human Genetic Effort, an international project spanning more than 50 genetic sequencing hubs and hundreds of hospitals. The effort is co-led by Helen Su, M.D., Ph.D., a senior investigator at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH; and Jean-Laurent Casanova, M.D., Ph.D., head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University in New York. Major contributions were made by Luigi Notarangelo, M.D., chief of the NIAID Laboratory of Clinical Immunology and Microbiology (LCIM); Steven Holland, M.D., director of the NIAID Division of Intramural Research and senior investigator in the NIAID LCIM; clinicians and investigators in hospitals in the Italian cities of Brescia, Monza and Pavia, which were heavily hit by COVID-19; and researchers at the Uniformed Services University of the Health Sciences in Bethesda, Maryland.

The wide variation in the severity of disease caused by SARS-CoV-2, the virus behind COVID-19, has puzzled scientists and clinicians. SARS-CoV-2 can cause anything from a symptom-free infection to death, with many different outcomes in between. Since February 2020, Drs. Su and Casanova and their collaborators have enrolled thousands of COVID-19 patients to find out whether a genetic factor drives these disparate clinical outcomes.

The researchers discovered that among nearly 660 people with severe COVID-19, a significant number carried rare genetic variants in 13 genes known to be critical in the bodys defense against influenza virus, and more than 3.5% were completely missing a functioning gene. Further experiments showed that immune cells from those 3.5% did not produce any detectable type I interferons in response to SARS-CoV-2.

Examining nearly 1,000 patients with life-threatening COVID-19 pneumonia, the researchers also found that more than 10% had autoantibodies against interferons at the onset of their infection, and 95% of those patients were men. Biochemical experiments confirmed that the autoantibodies block the activity of interferon type I.

Q Zhang et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science DOI: 10.1126/science.abd4570 (2020).

P Bastard et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science DOI: 10.1126/science.abd4585 (2020).

NIAID Director Anthony S. Fauci, M.D., NIAID Senior Investigator Helen C. Su, M.D., Ph.D., and Luigi Notarangelo, M.D., chief of the NIAID Laboratory of Clinical Immunology and Microbiology, are available for interviews.

To schedule interviews, please contact NIAID Office of Communications, (301) 402-1663, NIAIDNews@niaid.nih.gov.

NIAID conducts and supports research at NIH, throughout the United States, and worldwide to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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Scientists discover genetic and immunologic underpinnings of some cases of severe COVID-19 - National Institutes of Health

Toronto scientists have mapped the genes allowing cancer cells to avoid getting killed by the immune system in a finding that paves the way for the development of immunotherapies that would be effective for larger patient populations and across different tumour types.

"Over the last decade, different forms of immunotherapy have emerged as really potent cancer treatments but the reality is that they only generate durable responses in a fraction of patients and not for all tumour types," says Jason Moffat, a professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto who led the work.

The study also revealed the need for new therapy to take into account the genetic composition of tumours because of mutations in the cancer cells that can potentially make the disease worse in response to treatment, often referred to as cancer resistance mutations.

"It's very important to understand at the molecular level how cancer develops resistance to immunotherapies in order to make them more broadly available. Advances in systematic genetic approaches have let us key in on genes and molecular pathways that are commonly involved in resistance to therapy," says Moffat, who holds Canada Research Chair in Functional Genomics of Cancer.

In immunotherapy, a patient's own immune cells, known as T killer cells, are engineered to find and destroy cancer. But treatment resistance has precluded its use in most patients, especially those with solid tumours.

"It's an ongoing battle between the immune system and cancer, where the immune system is trying to find and kill the cancer whereas the cancer's job is to evade that killing," says Keith Lawson, a co-lead author completing a PhD in Moffat's lab as part of his medical training in the Surgeon-Scientist Program at U of T's Faculty of Medicine.

Tumour heterogeneity--genetic variation in tumour cells within and across individuals that can impact therapy response--further complicates things.

"It's important to not just find genes that can regulate immune evasion in one model of cancer, but what you really want are to find those genes that you can manipulate in cancer cells across many models because those are going to make the best therapeutic targets," says Lawson.

The team, including collaborators from Agios Pharmaceuticals in Cambridge, Massachusetts, looked for genes that regulate immune evasion across six genetically diverse tumor models derived from breast, colon, kidney and skin cancer. The cancer cells were placed in a dish alongside the T cells engineered to kill them, where the ensuing onslaught served as a baseline. The researchers next deployed the gene editing tool CRISPR to switch off one-by-one every gene in the cancer cells and measured the resulting deviations from the killing baseline.

They identified 182 "core cancer intrinsic immune evasion genes" whose deletion makes the cells either more sensitive or more resistant to T cell attack. Among the resisters were all the genes known to develop mutations in patients who stopped responding to immunotherapy, giving the researchers confidence that their approach worked.

Many of the found genes had no previous links to immune evasion.

"That was really exciting to see, because it means that our dataset was very rich in new biological information", says Lawson.

Genes involved in autophagy, a process when cells ramp up recycling their components to mitigate damage following stress, came up as key for immune evasion. This raises a possibility that cancer's susceptibility to immunotherapy could be boosted by targeting its autophagy genes.

But as the researchers delved deeper, they found that deleting certain autophagy genes in pairs rendered the cells resistant to T cell killing. It means that if a tumour already harbors a mutation in one autophagy gene, a treatment that combines immunotherapy with a drug targeting another autophagy gene could make the disease worse in that patient.

"We found this complete inversion of gene dependency", says Moffat. "We did not anticipate this at all. What it shows us is that genetic context, what mutations are present, very much dictates whether the introduction of the second mutations will cause no effect, resistance or sensitivity to therapy".

As more research explores combinatorial effects of mutations across different types of cancer cells, it should become possible to predict from a tumour's DNA what type of therapy will be most effective.

Reference: Lawson KA, Sousa CM, Zhang X, et al.Functional genomic landscape of cancer-intrinsic evasion of killing by T cells. Nature, 2020. doi:10.1038/s41586-020-2746-2

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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182 Genes Identified That Regulate Interactions Between Cancer Cells and T Cells - Technology Networks

On a beautiful early September day, Ken Gierhart hiked a trail familiar since boyhood to Music Pass in the Sangre de Cristo mountains above Westcliffe. As he dropped off the saddle toward the Sand Creek lakes, he noticed people heading the opposite direction with fishing poles.

Hows the fishing? he asked one woman.

Theyre all dead, she replied, saying nothing more as she passed.

Puzzled, Gierhart came upon another woman heading away from the lakes and tried his question again.

There is no fishing, she said. Theyre all dead.

This time, the angler paused to explain that Colorado Parks and Wildlife, according to signs posted in the area, had used a chemical called rotenone to kill all the fish in the lakes and Sand Creek, which meanders south down the mountain before veering west to eventually disappear, after 13 miles, into the depths of the Great Sand Dunes.

The project is part of a long-planned strategy to restore the native Rio Grande cutthroat trout to waters where its numbers have dwindled toward the edge of extinction.

Increasingly scarce in a dwindling native range and hybridized with other species like non-native cutthroats, which had been stocked alongside it many years ago, the Rio Grande cutthroat eventually will be reintroduced to the mountain lakes and streams where it once thrived. But the process can be disconcerting especially to an unsuspecting hiker like Gierhart.

It wasnt until he got closer to Lower Sand Creek Lake that he saw the informational signs for himself. Then he headed toward the upper lake, following the trail that crosses the creek several times along the way. He said piles of dead earthworms filled seemingly every crevice in the rocks. And then it got worse.

It was horrifying at that level to see what had been done to the lake, Gierhart said. When I got to the lake I saw fish belly-up, carcasses on the bank where animals or birds had pulled them out.

Gierhart, a 54-year-old wholesale tree grower, hadnt heard anything about the fish management plan, and he stewed all the way back to his home in Westcliffe. There, he fired up his Facebook account and vented in a post that estimated thousands of dead fish and that attracted nearly 100 comments, most expressing concern over an undertaking they, too, seemed unaware of.

Ive always been preservation conscious, Gierhart said, still steamed a couple weeks later, but to see aquatic life dead like that, I started thinking about the watershed, the lasting effects, side effects.

The rant and its response caught the attention of CPW officials, who expressed frustration over response to a broad regional project that has been years in the making and which framed its intent in a compact signed in 2003 and renewed in 2013 by six federal entities, state agencies in Colorado and New Mexico and three American Indian tribal agencies. The agreement also received non-signatory support from two Trout Unlimited groups.

The Sand Creek drainage was officially listed in a 2013 strategy document.

In 2019, meetings on both the Westcliffe and Alamosa sides of the mountain yielded no opposition other than concern over the temporary loss of fishing and little public comment. The project moved ahead, though a year later than originally scheduled due to a late fish spawn.

Its something we need to do, said John Alves, the Durango-based senior aquatic biologist for CPWs Southwest Region. With only 11% of its historic range left, the Rio Grande cutthroat trout is always susceptible to petitions to list it as endangered, and also to extrication if there are events like fire. Its a constant process for us.

Joe Lewandowski, spokesman for CPWs Southwest Region, which includes the Sand Creek drainage, notes that the state agency has done similar projects before and will do more of them throughout Colorado.

We dont get a great deal of pleasure having to poison a stream, but it is necessary to restore native species, he said in an email to The Colorado Sun. This has been done in waters to restore the Rio Grande, greenback and the Colorado River cutthroat; and these projects will continue.

We know people are not happy to see dead fish, and it is confusing. Its very difficult often impossible to explain to the general public why we have to do these projects.

The intersection of history, science and politics of wildlife management can be complex. And while in this case the ultimate goal to restore the Rio Grande cutthroat to its native range is mostly a shared interest, the path to achieving it can be challenging.

After the 2003 conservation agreement, federal and state authorities started doing reconnaissance in 2004 to determine if the drainage could be restored. Geography that essentially isolated water flow, and therefore fish migration, proved fortuitous.

Its an ideal situation in a lot of regards, because its a closed system, said Fred Bunch, chief of resources management for the Great Sand Dunes National Park and Preserve, which takes in the Sand Creek drainage. The creeks have their headwaters high in the Sangres, they flow into those lakes and the lakes flow out to the dunes. Thirty-four square miles of sand is a pretty substantial fish barrier.

Bunch points to several reasons why reintroduction of the Rio Grande cutthroat looms important. First, theres federal policy that favors native species in national parks and preserves. Another has to do with the essential characteristics of a wilderness area. A third is for preservation of the species.

This is an ideal opportunity to restore 13 miles of habitat for the Rio Grande cutthroat trout, he said.

The stakeholders who signed the conservation agreement meet annually to discuss the status of its efforts. The key thing, Bunch said, is to prevent the listing of the Rio Grande cutthroat as an endangered species and ensure it has robust habitat.

And thats where politics can come in.

The Center for Biological Diversity, a nonprofit organization that claims roots in the fear that government authority alone will not always protect flora and fauna when powerful business interests can exert political leverage. (The timber industry was its founders nemesis.) Now, it contests threats to biodiversity on a range of levels, from climate change to encroachment of off-road vehicles.

The group has petitioned multiple times to place the Rio Grande cutthroat trout on the endangered species list, including one case thats still pending an appeal.

From the standpoint of state wildlife managers like Alves, who shares the groups desire to see the native species rebound, the fishs presence on the list represents another potential layer of bureaucracy that state workers on the ground would have to contend with.

Once a species is listed by the U.S. Fish and Wildlife Service, local agencies dont make decisions, he said. Theyre made by the federal government. For years, since the late 90s, there have been petitions to list the Rio Grande cutthroat trout. (The Center for Biological Diversity) sees listing as a way to get timber and mining off public lands.

That is true, said Noah Greenwald, the centers Portland, Oregon-based endangered species director.

Those things present a real threat to their habitat and to the species, so we want to make sure those things are done in a careful way or theres avoidance of trout habitat or, to the extent that theres damage, theres mitigation which is what the Endangered Species Act requires.

Aside from territorial concerns stemming from listing the species, both the center and the state agree on some key issues. The center supports and applauds the effort to repopulate the Sand Creek drainage with the native fish. But Greenwald also claims that his organizations petitions to list the Rio Grande trout spurred the state to take action to conserve them more than they were before.

We havent succeeded in putting them on the protected list, but weve pressured the state to do more for them, which is a benefit for the species, he said. Theyve done a tremendous amount of surveys and used staffing resources in an effort to avoid listing them. We dont think thats the right tradeoff. It makes more sense to list them and work for recovery.

The center doesnt even have problems with the kill-to-restock method, or the rotenone compound used to achieve it.

Greenwald calls the CPW a credible messenger with regard to the safety of rotenone.

We dont love having to use poisons, he said. But theres been a lot of work done on this issue, and there are not other effective means. As chemicals go, rotenone is pretty specific to fish. We definitely think it needs to be done carefully and we dont relish the thought of poison being used. But its the only way.

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Although the battle over listing the fish persists, all sides celebrate the ideas that in the case of the Sand Creek drainage, the area could become a refugium for the species, where the fish could naturally multiply and be used as a source for future stocking or restoration if some other habitat experiences problems say, from wildfire.

So were doing it for many things, Bunch said. One is the philosophy of land managers, but theres also the species itself. Also theres a recreational piece. Its a great situation where a hiker can backpack in and catch native fish. Thats a pretty great situation to have, and thats what were shooting for.

From the start, the effort to restore the species has been a multipartner project, including federal, state and county agencies and even private groups like Trout Unlimited. Some of the early upfront money came from the National Park Service but functionally, the reintroduction process is a CPW project done in a national preserve. Cost of a helicopter, boats and other equipment is covered mostly by the state.

This year, phase one of the process got underway. But before fish and wildlife authorities took any action, they needed to know exactly how many different species they were dealing with in those waters that stretch from the Sand Creek lakes to the sand dunes.

And thats where science played a big role.

John Wood founded Pisces Molecular more than 20 years ago, just a few years before efforts began in earnest to restore the Rio Grande cutthroat trout.

Though it has just four people on staff, the Boulder-based biotech lab has clients all over the world, not to mention right in its backyard. Woods lab has worked with Colorado Parks and Wildlife on multiple different fish projects, including when in 2007, in conjunction with University of Colorado post-doc Jessica Metcalf, it discovered that CPWs stock of supposed greenback cutthroat trout which happens to be Colorados state fish were actually Colorado River cutthroat trout.

How do scientists figure out what species are in a waterway? One method is simply catching a sample of fish, clipping off the tiniest bits of their fins, and sending the material to a lab for DNA sequencing. Wood notes that can be laborious and difficult to get an accurate representation of the species makeup of a waterway.

The other option is environmental DNA testing. Just as humans regularly shed skin, hair, saliva and other sources of DNA, so do fish. Field researchers can collect a sample of water, filter out all the bits from the water, and send the gunked-up, DNA-laden filter to the lab for testing. These results will indicate the presence of species upstream of where the sample was taken.

Regardless of the type of sample, once it gets to the lab, Woods team uses polymerase chain reactions, also known as PCR, to check for species-specific genetic markers. For reference, this is the same kind of procedure used in the SARS-CoV-2 coronavirus test; Wood says its become a very sexy technique since the patent on PCR expired in the 2000s. And its remarkably precise; if one-tenth of a drop of a fishs DNA solution were mixed into an Olympic-sized swimming pool, Wood said, we would pick it up.

The only technical field that is changing as fast as computers is molecular genetics, so the sort of techniques that we use now are incredibly more sophisticated than when I was in graduate school, and I find that really fun, Wood said.

Theoretically, this could happen all in the field, but Wood says that it requires a lot of coordination, because you dont keep wild fish outside of their water body for very long. More often, its an iterative process between the lab and the wildlife managers testing the waterway, analyzing the results for the percent purity for individual fish or the population at large, then removing or restocking fish as needed, and doing it all over again.

Though Pisces was not directly involved with last months rotenone treatment, it has generally worked on identifying species in the Upper Sand Creek Lake drainage. In 2015, Woods team found evidence that the drainage had native Rio Grande cutthroat trout that were hybridizing with other subspecies, including Yellowstone cutthroat, greenback cutthroat and Colorado River cutthroat.

Wood called CPWs attitude on restoring native species enlightened, especially when compared to previous practices. Much of the 20th century was spent stocking the states waterways with outside fish such as rainbow trout, which are especially susceptible to whirling disease; when that struck the state in the 1990s, the rainbow trout population quickly spread it to other fish species, including native cutthroats. And this wasnt just in one or two rivers; in the process of moving fish around from waterway to waterway, stocking and other efforts inadvertently introduced the disease to 15 of the 17 hydrographic drainages in the state.

Along Sand Creek, the CPW found ponds on private property that harbored the parasites that transmit whirling disease. But the ponds were removed with stimulus funds during the Great Recession. Since they qualified as gravel pits, they could be remediated as abandoned mines. The whirling disease went away and the reintroduction plans moved forward.

Humans, when we mess with ecology, we generally make a mess, Wood said. So its probably philosophically better to do less interventions and strive to maintain whats there than presume that were smarter than Mother Nature.

That said, its not like leaving the river to rebound on its own would work. Part of it has to do with the different life cycles of fish species: brook trout, for example, spawn in the fall, giving them a full six months head start to grow before cutthroats spawn in the spring. And while rainbow trout spawn in the spring, like cutthroats, Wood notes that the jurys still out as to the impact of the two species interbreeding freely.

In other words: humans made this mess, and only humans can clean it up.

We now know more about genetics, we can discern finer level details, we have a longer history of how our attempts to alter ecologies tend not to work very well, so lets see if we can remediate some of the damage that weve done, Wood said.

In June, weeks before implementation of the first phase of the Rio Grande cutthroat project began, the CPW declared a fish emergency public salvage in the Sand Creek drainage. That tactic, which allows anglers to catch an unlimited number of fish from the waterways, has been used more times this summer, for a variety of reasons, than in the past 10 years.

On this occasion, the CPW wanted to let anglers help make best use of the fish before the chemical rotenone was administered to kill any that remained.

Alves, of the CPWs Southwest Region, noted that removing the bag limit seemed to be a particularly effective strategy in the lakes.

Get enough anglers out there, he said, they do a pretty good job.

The rest is left to rotenone, a plant-based compound effective only on gill-breathing organisms primarily fish and insects. The CPW workers secured the necessary permissions and trained to use it. During the first week of September, they began the process in the two high mountain lakes and the creeks below up to a point where waterfalls along Sand Creek provide a natural barrier to fish migration. Phase 2 of the operation will involve clearing Sand Creek from below the waterfalls to the Great Sand Dunes.

A helicopter from the Colorado Division of Fire Protection and Control had been busy fighting wildfires, but eventually was freed up to transport boats, motors, pumps and the 5-gallon buckets of rotenone itself to the lakes. Workers mixed the chemical with water. It was administered from a boat throughout the lake, in volumes dictated by the waters depth. The mixture shaded the water slightly white, a change that diminishes within several hours.

To apply rotenone to streams, workers spread out drips that added the rotenone/water solution to the flow every 15 seconds. A four-hour drip produced the desired solution throughout the streams.

The chemical works quickly. At one of the drip stations, Alves noticed that as soon as the organic green dye marker reached him from a drip point upstream, fish started dying. Workers also sprayed backwaters where fish might be lurking.

Rotenone, though extremely toxic to fish and some insects, is harmless to man and all warmblooded vertebrates, according to the journal Nature. Alves notes that it breaks down quickly in streams, but in lakes, at a water temperature of 50 degrees, takes about 28 days to decompose.

Then, the waiting begins. The dead fish decompose and, if all goes perfectly, the waterways will be clear for stocking. First, the water is tested environmental DNA sampling comes in handy here to make sure no fish survived that could taint the reintroduction of the native Rio Grande.

Youve got to wait and see,Alves said. Well do a lot of sampling, electrofishing in the streams, gill netting in the lakes, probably use environmental DNA, and test to see if there are genetic markers. We use that as a confirming tool.

If any fish remain, CPW will come back and repeat the process.

If theres zero live fish, Alves said, well start to restock in the fall.

Typically, CPW uses airplanes to stock the high mountain lakes. Workers on foot or on horseback, and sometimes by helicopter, stock the streams. By stocking fish in a variety of age groups, managers can hasten the turnaround.

The Sand Creek drainage, with its hiking trails and beautiful vistas, is a highly used area, Alves said. Though remote, its only about an hour-and-a-half hike in from the trail head. What he wants people to understand is that what the CPW is doing is definitely the right thing. Yes, the fish are all gone but thats only temporary.

As soon as we can, well put in Rio Grande cutthroat trout, really a pretty fish, growing to the same size theyre used to catching, a 15- or 16-inch fish, he said. So theyre temporarily losing their opportunity, but itll come back. I predict within five years, theyll see really good cutthroat trout in the lakes.

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Kill fish to save fish: Behind Colorado's effort to revive the Rio Grande cutthroat trout - The Colorado Sun

Molecular Biomarkers Market Overview 2020 2025

This has brought along several changes in This report also covers the impact of COVID-19 on the global market.

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Key Competitors of the Global Molecular Biomarkers Market are: , Alere, Atossa Genetics, Biophysical, Abbott, BioCept, BioTheranostics, DiagnoCure, GenomeDx, Genomic Health, Gen-Probe, Life Technologies, 20/20 GeneSystems, Cynvenio, Dako (Agilent), Epic Sciences, Foundation Medicine, Genomic Health, Molecular Response, Nodality, PGD

Historical data available in the report elaborates on the development of the Molecular Biomarkers on national, regional and international levels. Molecular Biomarkers Market Research Report presents a detailed analysis based on the thorough research of the overall market, particularly on questions that border on the market size, growth scenario, potential opportunities, operation landscape, trend analysis, and competitive analysis.

Major Product Types covered are:GenomicsProteomicsOthers

Major Applications of Molecular Biomarkers covered are:MedicineBiologyOthers

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The report further highlights the development trends in the global Molecular Biomarkers market. Factors that are driving the market growth and fueling its segments are also analyzed in the report. The report also highlights on its applications, types, deployments, components, developments of this market.

Highlights following key factors:

:-Business descriptionA detailed description of the companys operations and business divisions.:-Corporate strategyAnalysts summarization of the companys business strategy.:-SWOT AnalysisA detailed analysis of the companys strengths, weakness, opportunities and threats.:-Company historyProgression of key events associated with the company.:-Major products and servicesA list of major products, services and brands of the company.:-Key competitorsA list of key competitors to the company.:-Important locations and subsidiariesA list and contact details of key locations and subsidiaries of the company.:-Detailed financial ratios for the past five yearsThe latest financial ratios derived from the annual financial statements published by the company with 5 years history.

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Market share assessments for the regional and country level segments. Market share analysis of the top industry players. Strategic recommendations for the new entrants. Market forecasts for a minimum of 9 years of all the mentioned segments, sub segments and the regional markets. Market Trends (Drivers, Constraints, Opportunities, Threats, Challenges, Investment Opportunities, and recommendations). Strategic recommendations in key business segments based on the market estimations. Competitive landscaping mapping the key common trends. Company profiling with detailed strategies, financials, and recent developments. Supply chain trends mapping the latest technological advancements.

Access full Report Description, TOC, Table of Figure, Chart, etc. @ https://reportsinsights.com/industry-forecast/Molecular-Biomarkers-Market-66212

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Reports Insights is the leading research industry that offers contextual and data-centric research services to its customers across the globe. The firm assists its clients to strategize business policies and accomplish sustainable growth in their respective market domain. The industry provides consulting services, syndicated research reports, and customized research reports.

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Molecular Biomarkers Market Incredible Possibilities, Growth Analysis and Forecast To 2026 |112233 - The Daily Chronicle

Urothelial carcinoma of the bladder (UCB) exhibits significant sexual dimorphism in the incidence, etiology, and response to intravesical immunotherapy. Environmental factors such as tobacco use and clinical management issues such as delayed presentation have widely been associated with sex differences in UCB outcomes. Emerging findings from immune checkpoint blockade trials are suggestive of differential outcomes in females compared with males. Sex-specific differences in the way immune system functions and responds to pathogenic insults are well established. As such, an in-depth understanding of the genetic and epigenetic factors contributing to sex-associated differences in response to immunomodulatory therapies is needed urgently for improved management of UCB.

To review the associations between patient sex and clinical outcomes, with a focus on the incidence, host intrinsic features, and response to therapies in UCB.

Using the PubMed database, this narrative review evaluates published findings from mouse model-based and clinical cohort studies to identify factors associated with sex and clinical outcomes in bladder cancer. A scoping review of the key findings on epidemiology, genetic, hormonal, immune physiology, and clinical outcomes was performed to explore potential factors that could have implications in immunomodulatory therapy design.

Sex-associated differences in UCB incidence and clinical outcomes are influenced by sex hormones, local bladder resident immune populations, tumor genetics, and bladder microbiome. In the context of therapeutic outcomes, sex differences are prominent in response to bacillus Calmette-Gurin immunotherapy used in the treatment of non-muscle-invasive bladder cancer. Similarly, with respect to tumor molecular profiles in muscle-invasive bladder cancer, tumors from females show enrichment of the basal subtype.

Among proposed tumor/host intrinsic factors that may influence response to immune-based therapies, patient sex remains a challenging consideration that deserves further attention. Evidence to date supports a multifactorial origin of sexual dimorphism in the incidence and outcomes of UCB.

In this review, we highlight the sex-associated host and tumor intrinsic features that may potentially drive differential disease progression and therapeutic response in urothelial carcinoma of the bladder.

European urology oncology. 2020 Sep 20 [Epub ahead of print]

Madhuri Koti, Molly A Ingersoll, Shilpa Gupta, Christa M Lam, Xue Li, Ashish M Kamat, Peter C Black, D Robert Siemens

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Department of Obstetrics and Gynecology, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada; Department of Urology, Queen's University, Kingston, Ontario, Canada. Electronic address: ., Department of Immunology, Institut Pasteur, Paris, France., Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA., Department of Urology and Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Department of Urology, Division of Surgery, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Department of Urology, Queen's University, Kingston, Ontario, Canada.

PubMed http://www.ncbi.nlm.nih.gov/pubmed/32967818

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Sex Differences in Bladder Cancer Immunobiology and Outcomes: A Collaborative Review with Implications for Treatment. - UroToday