Category Archives: Genetic Medicine

News Release

Wednesday, November 20, 2019

Studies in cell and animal models reveal insights into cancer cells vulnerability that could lead to new strategies against brain cancers.

Researchers have devised a new plan of attack against a group of deadly childhood brain cancers collectively called diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), thalamic glioma and spinal cord glioma. Scientists at the National Institutes of Health, Stanford University, California, and Dana-Farber Cancer Institute, Boston, identified a drug pair that worked together to both kill cancer cells and counter the effects of a genetic mutation that causes the diseases.

The researchers showed that combining the two drugs panobinostat and marizomib was more effective than either drug by itself in killing DMG patient cells grown in the laboratory and in animal models. Their studies also uncovered a previously unrecognized vulnerability in the cancer cells that scientists may be able to exploit to develop new strategies against the cancer and related diseases. The results were published Nov. 20 in Science Translational Medicine.

DMGs are aggressive, hard-to-treat tumors that represent the leading cause of brain cancer-related death among U.S. children. DMGs typically affect a few hundred children a year between ages 4 to 12; most children die within a year of diagnosis. Most cases of DMG are caused by a specific mutation in histone genes. Histones are protein complexes in the cell nucleus. DNA wraps around histones to form chromatin, which packages DNA in the nucleus. How DNA winds and unwinds around histones is influenced by enzymes, including histone deacetylases. These enzymes add or remove chemical tags, which indirectly controls if genes are turned on or off.

In an earlier study, Stanford neuro-oncologist Michelle Monje. M.D., Ph.D., and her colleagues showed that panobinostat, which blocks key histone deacetylase enzymes, could restore the DIPG histone function to a more normal state. While panobinostat is already in early clinical testing in DIPG patients, its usefulness may be limited because cancer cells can learn to evade its effects. So Monjes team wanted to identify other possible drugs and combinations of them that could affect the cancer.

Very few cancers can be treated by a single drug, said Monje, a senior author of the study who treats children with DIPG and other diffuse midline gliomas. Weve known for a long time that we would need more than one treatment option for DIPG. The challenge is prioritizing the right ones when there are thousands of potential options. Were hopeful that this combination will help these children.

Monje and the National Cancer Institutes Katherine Warren, M.D., now at Dana-Farber Cancer Institute and Boston Childrens Hospital, collaborated with Craig Thomas, Ph.D., and his colleagues at the NIHs National Center for Advancing Translational Sciences (NCATS). Thomas and his team used NCATS drug screening expertise and matrix screening technology to examine drugs and drug combinations to see which ones were toxic to DIPG patient cells.

NCATS robotics-enabled, high-throughput screening technologies enable scientists to rapidly test thousands of different drugs and drug combinations in a variety of ways. Scientists can examine the most promising single drugs and combinations, determine the most effective doses of each drug and learn more about the possible mechanisms by which these drugs act.

The NCATS researchers first studied the effects of single approved drugs and investigative compounds on DIPG cell models grown in the laboratory from patient cells. They focused on agents that could both kill DIPG cells and cross the brains protective blood-brain barrier, a necessity for a drug to be effective against DIPG in patients. The team then tested the most effective single agents in various combinations.

Such large, complex drug screens take a tremendous collaborative effort, said Thomas, also a senior study author. NCATS was designed to bring together biologists, chemists, engineers and data scientists in a way that enables these technically challenging studies.

While there were multiple, promising outcomes from these screens, the team focused on the combination of histone deacetylase inhibitors (like panobinostat) with drugs called proteasome inhibitors (such as marizomib). Proteasome inhibitors block cells normal protein recycling processes. The panobinostat-marizomib combination was highly toxic to DIPG cells in several models, including DIPG tumor cell cultures that represented the main genetic subtypes of the disease and mice with cells transplanted from patient tumors. The combination also reduced tumor size in mice and increased their survival. A similar response was found in spinal cord and thalamic DMG models developed from cells grown in culture from patient cells.

The screening studies also provided important clues to the ways the drugs were working. Building on these data, the collaborative team subsequently conducted a series of experiments that showed the DIPG cells responded to these drugs by turning off a biochemical process in the cells mitochondria that is partly responsible for creating ATP, which provides energy to cells. The drug combination essentially shuts down tumor cell ATP production.

The panobinostat-marizomib drug combination exposed an unknown metabolic vulnerability in DIPG cells, said first author Grant Lin, Ph.D., at Stanford University School of Medicine. We didnt expect to find this, and it represents an exciting new avenue to explore in the development of future treatment strategies for diffuse midline gliomas.

Plans are underway for clinical trials of the drug combination and of marizomib alone.

Many drugs that we test have multiple effects on DIPG cells, said Warren, a senior study author. Panobinostat, for example, inhibits a specific enzyme, but it has other mechanisms working in tumor cells that may contribute to its effectiveness. Were still trying to understand the various Achilles heels in these cancer cells. This work is an important step in translating our preclinical data into patients.

Monje stressed the panobinostat-marizomib combination might be an important component of a multitherapy strategy, including approaches that harness the immune system and those that disrupt factors in the tumor microenvironment that the glioma cells depend on to grow. Like Warren, Monje emphasized the need to better understand how drugs target and impact the DIPG cells vulnerabilities.

Our work with NCATS showed the need to gather more preclinical data in a systematic, high-throughput way to understand and prioritize the strategies and agents to combine, Monje said. Otherwise were testing things one or two drugs at a time and designing clinical trials without preclinical data based on hypothesized mechanisms of action. We want to move past this guesswork and provide preclinical evidence to guide clinical decisions and research directions.

Lin added, The idea is to get as many effective tools as possible to work with that can have an impact on patients.

The research was funded by Alexs Lemonade Stand Foundation, Izzys Infantry Foundation, McKenna Claire Foundation, Unravel Pediatric Cancer, Defeat DIPG Foundation, ChadTough Foundation, N8 Foundation, Kortney Rose Foundation, Cure Starts Now Foundation and the DIPG Collaborative, Sam Jeffers Foundation, Lyla Nsouli Foundation, Abbies Army Foundation, Waxman Family Research Fund, Virginia and D.K. Ludwig Fund for Cancer Research, National Institute for Neurological Disorders and Stroke (R01NS092597) and NIH Directors Common Fund (DP1NS111132), Maternal and Child Health Research Institute at Stanford, the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases, The DIPG All-In Initiative and the NCATS and NCI intramural programs.

About the National Center for Advancing Translational Sciences (NCATS):NCATS conducts and supports research on the science and operation of translation the process by which interventions to improve health are developed and implemented to allow more treatments to get to more patients more quickly. For more information about how NCATS is improving health through smarter science, visithttps://ncats.nih.gov.

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

###

Read the original:
Scientists find promising drug combination against lethal childhood brain cancers - National Institutes of Health

Taller people have an increased risk of developing atrial fibrillation (AFib), an irregular and often rapid heartbeat that can lead to stroke, heart failure and other complications, according to a newPenn Medicinestudy. The research, which reveals a strong link between the genetic variants associated with height and ones risk for AFib, is the among the first to demonstrate that height may be a causalnot correlatedrisk factor for AFib. The findings were presented at theAmerican Heart Associations 2019 Scientific Sessionsin Philadelphia this month.

Researchers found that the risk for AFib climbed as ones height increased, with every one-inch increase in height translating to about a three percent increase in risk of Afibindependent of other clinical factorsas compared to those at average height (5 feet and 7 inches).

Our findings suggest it may be beneficial to incorporate height into risk-prediction tools for AFib, says the studys lead authorMichael Levin, a cardiovascular medicine fellow at Penn. While current guidelines advise against widespread screening for AFib, our findings show that a certain group of patientsspecifically, very tall patientsmay benefit from screening.

Read more at Penn Medicine News.

View post:
Tall people: Your hearts are at risk - Penn: Office of University Communications

In a surprising finding using the standard animal model of Down syndrome (DS), scientists were able to correct the learning and memory deficits associated with the condition the leading genetic cause of cognitive disability and the most frequently diagnosed chromosomal disorder in the U.S. with drugs that target the bodys response to cellular stresses.

In a study published Nov. 14, 2019, in the journal Science, a team led by researchers at UC San Francisco and Baylor College of Medicine show that some of the intellectual impairments associated with DS may be traced to altered protein production in a region of the brain called the hippocampus, which is central to learning and long-term memory formation.

But in the so-called Ts65Dn mouse, engineered to capture genetic, behavioral and cognitive features of human Down syndrome, these changes can be undone. When the researchers administered drugs that target one of the cells key stress response pathways, they were able to bring protein levels back to normal, which caused the cognitive deficits typical of the Ts65Dn mouse to vanish.

Although the cognitive features of DS have generally been thought of as irreversible, the researchers say, these findings indicate that it may be possible to improve cognitive function in human DS using similar compounds.

Because DS is caused by an extra copy of chromosome 21, scientists have generally studied the disease through the lens of genetics, focusing primarily on ways in which the superfluous chromosome disrupts normal gene activity. But in the new study, rather than restricting their efforts to genes and chromosomes, the scientists trained their sights on the largely unexplored role of proteostasis a technical term for the cells protein manufacturing and quality control machinery in DS.

Peter Walter, Ph.D., co-senior author of the study, spearheaded the research to uncover a link between proteostasis defects and DS.

The vast majority of the field has been focusing on individual genes on chromosome 21 to figure out which ones are causally related to Down syndrome and its pathologies. Our approach was different. We were trying to uncover a link between proteostasis defects and DS, said Peter Walter, Ph.D., professor of Biochemistry and Biophysics at UCSF and co-senior author of the new study.

Walter spearheaded the new study with collaborator Mauro Costa-Mattioli, Ph.D., a professor of neuroscience at Baylor College of Medicine who is currently a visiting professor in Walters lab thanks to a UCSF Presidential Chair Award.

To identify proteostasis problems that might contribute to DS, the researchers turned to a common mouse model that captures most of the chromosomal, developmental and cognitive abnormalities that define the human version of the syndrome.

Using polysome profiling, a technique that allows scientists to take a detailed snapshot of the cells protein factories in action, the researchers found that up to 39 percent less protein was being produced in the hippocampus of DS mice, prompting them to ask why extra copies of genes could lead to a decline in protein production.

The researchers discovered that hippocampal cells in DS mice had activated whats known as the integrated stress response (ISR), a biological circuit that detects when somethings awry the presence of an extra chromosome, for example, in the case of DS and engages a protective response that activates machinery to tamp down protein production.

The cell is constantly monitoring its own health. When something goes wrong, the cell responds by making less protein, which is usually a sound response to cellular stress. But you need protein synthesis for higher cognitive functions, so when protein synthesis is reduced, you get a pathology of memory formation, said Walter.

Backing up these results, the scientists also found that the ISR was also activated in postmortem samples of brain tissue from people with DS. And by a stroke of pure luck, the researchers were able to obtain a tissue sample from a person with DS in whom some cells carried the expected third copy of chromosome 21, while others were genetically normal the ISR, however, was only active in the cells with the extra chromosome.

Taken together, these findings strongly suggest that the ISR is involved in, and perhaps even responsible for, certain DS symptoms.

Though the ISR can be activated by four different enzymes, the scientists found that only one of them, named PKR, was involved in activating the ISR in hippocampal cells in DS. By blocking the activity of PKR they were able to prevent ISR activation and reverse the declines in protein production that had been observed in the brains of DS mice. But even more impressive, the researchers found that blocking the ISR significantly improved cognitive function in these mice as well.

The researchers used three different approaches to dial down ISR activity deleting the PKR gene, using a drug that suppresses PKR activity, and finally, using a safe, well-studied drug called ISRIB that activates protein-manufacturing machinery that competes directly with the ISRs efforts to shut off protein production. All three approaches yielded a marked improvement in cognition, as demonstrated by two different memory and learning tests.

We started with a situation that looked hopeless, nobody thought anything could be done. But we may have struck gold.Peter Walter, Ph.D.

Importantly, these changes were physiological as well as behavioral. DS mice that were given ISR inhibitors showed improved function at synapses, sites between nerve cells where changes associated with learning take place. In fact, after ISR activity was blocked, the brains of DS mice were transmitting fewer of the inhibitory signals that can make it harder for the brain to learn and form new long-term memories.

Though the results of the study were extremely promising, Walter cautions that much more in this area remains to be studied. Still, the findings are an important first step toward finding therapies that could improve the lives and overall health of people living with DS, a condition that has generally been considered untreatable.

We started with a situation that looked hopeless, Walter said. Nobody thought anything could be done. But we may have struck gold.

Authors: Additional authors include Ping Jun Zhu, Sanjeev Khatiwada, Ya Cui, Lucas C. Reineke, Sean W. Dooling, Jean J. Kim, and Wei Li of the Baylor College of Medicine. Peter Walter is also a Howard Hughes Medical Institute investigator.

Funding: This study was funded by NIH grants R01NS076708, R01HG007538, R01CA193466 and R01 CA228140, Sammons Enterprises and the Howard Hughes Medical Institute.

Disclosures: Peter Walter is an inventor on U.S. Patent 9708247 held by the Regents of the University of California that describes ISRIB and its analogs. Rights to the invention have been licensed by UCSF to Calico LLC. Wei Li is a consultant for the Chosen Med. The authors declare no other competing interests.

Read the rest here:
In Down syndrome mouse model, scientists reverse intellectual deficits with drugs - University of California

QATAR: The legalized and ethical imputations of using stem cells and artificial intelligence (AI) in medicine were discussed at the new installment of Weill Cornell Medicine Qatars (WCM-Q) Intersection of Law & Medicine series.

Skilled speakers at the event talked about the impact of current advances in stem cell science and AI on the development of medicine in Qatar and explored how the latest legal architecture could be developed to secure the rights and safety of patients in the Mena region.

The all-day-long program was organized by WCM-Q in league with Hamad Bin Khalifa University and the University of Malaya of Kuala Lumpur, Malaysia.

Stem cells are thrilling areas for medical experimentation because they have the capability to restore damaged or diseased tissues in humans with conditions such as Parkinsons disease, type 1 diabetes, stroke, cancer, and Alzheimers disease, and much more.

Stem cells can help the researchers to test new drugs for safety and effectiveness.

Stem cells have the capacity for unlimited or extended self-renewal, and they can differentiate themselves into many different cell types to become tissue- or organ-specific cells with special functions, told Dr. Amal Robay, WCM-Q assistant professor in genetic medicine and director of research compliance.

The central ethical dilemma of stem cell science arises from the fact that embryonic stem cells are derived from human embryos or by cloning, she added.

Bioethics expert Dr. Jeremy Sugarman of Johns Hopkins University in Baltimore, US said that the public image of stem cell research had been damaged by a small number of high-profile cases in which scientists had behaved unethically.

The field had also been hampered by different countries applying different laws to stem cell research, making international collaboration problematic, he added.

While, the implementation of AI in Medicine has the potential to leverage analysis of huge amounts of data to improve patient outcomes, but poses ethical concerns regarding privacy, the variety of data sources, biases and relying on non-human entities for potentially life-changing decisions.

Its very important that we bridge that gap between the professions of law and medicine, and that we understand the fundamental importance of ethicists to the advance of science, toldDr. Barry Solaiman, assistant professor of law in the College of Law and Public Policy at HBKU.

We need to consider how lawyers can help to develop laws to ensure that scientific advances and that it does so in ways that protect everyone involved, he added.

The event, which was co-directed by Dr. Solaiman and Dr. Thurayya Arayssi, professor of clinical medicine and senior associate dean for medical education and continuing professional development at WCM-Q, also participated in other skilled speakers.

Dr Mohamed Firdaus bin Abdul Aziz of the Faculty of Law at the University of Malaya, who talk about stem cell regulations around the world, Dr Faisal Farooq of Qatar Computing Research Institute, who discussed about AI in healthcare, Dr Effy Vayena of the Swiss Institute of Technology on the ethical challenges of using machine learning in medicine, Dr Sharon Kaur of the Faculty of Law at the University of Malaya on global regulation of AI, and Dr Mohamed Ghaly of Qatar Faculty of Islamic Studies on Islamic concept of bioethics in stem cell research.

The visiting professors also contributed in two panel discussions, one examining the law and ethics of stem cell science, managed by Dr. Adeeba Kamarulzaman, dean of medicine at the University of Malaya, and another on AI in healthcare managed by Dr Thurayya Arayssi, professor of clinical medicine and senior associate dean for medical education and continuing professional development at WCM-Q.

Continued here:
New Invention of Artificial intelligence in Medicine with Stem Cells by WCM-Q - Universal News

Since Invitaes inception a decade ago, the firm has been working for the proactive use of genetic information in mainstream medicine. The San Francisco, CA-based company has been using M&A activity to help bring companies under its tent to help make this goal a reality.

On Monday, the genetic-testing specialist made more progress on this front by announcing it would put down $50 million to acquire Clear Genetics, a company that develops digital counseling software.

San Francisco, CA-based Clear Genetics has developed Gia, a chatbot that equips patients with actionable information throughout the genetic testing process and provides guidance for understanding test results.

Invitae said Gia can guide patients regarding consent, personalized risk assessment, insurance benefits, pre/post-test education and understanding their test results, all through an intuitive online conversation. Patients are able to ask Gia questions throughout the process, and the chatbox uses natural language processing to respond with the resources they need. Gia is currently being used by customers in Invitae's direct channel.

In a release, Sean George, co-founder and CEO of Invitae said, For genetics to truly go mainstream, patients and clinicians need automated workflow solutions like those Clear Genetics has created. In working with the Clear Genetics team over the past year, we have first-hand experience with the value of their patient-centric services. With their capabilities, we will greatly enhance our ability to provide a streamlined customer experience, enable scaled clinician education and support, and arm genetics experts with the tools they need to keep up with the exploding demand for genetic information in healthcare.

Taking genetics mainstream is a lofty goal, but through a wide range of acquisitions, Invitae is quickly accomplishing this task. Just a few months ago the company reported it signed an agreement to acquire Singular Bio, a non-invasive prenatal screening (NIPS) specialist for $55 million.

Two years ago, Invitae landed two deals acquiring both Good Start Genetics and CombiMatrix, two companies that specialize in screening prospective parents and newborns. During a 2017 earnings call discussing the deals, George said these acquisitions were the beginning of genetics being broadly available to all and accessible to all in mainstream medicine.

Invitaes 3Q19 earnings paint the picture the companys strategy is significant inroads in reaching this goal. Looking at the numbers, the company generated revenue of $57. million in 3Q19, which represented a 51% increase over 3Q18 revenue of $37.4 million.

Ten years ago, when we started Invitae [we wanted] to get genetic information incorporated into mainstream medical use for everyone around the world in modernized economies, George said during Invitaes 3Q19 earnings call, according to a Seeking Alpha Transcript. While we have many years to go, the transformation of the genetics industry is underway. And we believe our 26th quarter of on average double-digit quarter-over-quarter growth serves as an indication of a new trajectory, a new model for personalized medicine as we move this industry beyond the more than 1.7 million people in the U.S. diagnosed with cancer per year into all of the equally impactful genetic disorders affecting those we serve.

Read the original here:
Deal Helps Bring Genetic Information to Mainstream Medicine - Medical Device and Diagnostics Industry

By Stephanie Miceli | Nov. 13, 2019

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

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

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

Knowledge Is Power

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

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

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

Affordability Is Part of Accessibility

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

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

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

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

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

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

Steps Toward Including All of Us

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

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

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

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

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

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

Integrating Consumer Genomics into Health Care

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

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

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

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