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Screening for Genetic High Cholesterol (Familial Hypercholinesterolemia) Could Help Patients and Families Avoid Heart Attack

Genetic high cholesterol is underdiagnosed and undertreated, according to research presented on September 1, 2019 at the ESC (European Society of Cardiology) Congress 2019 together with the World Congress of Cardiology in Paris, France (August 31-September 4). The presentation abstract was titled "Prevalence and Severity of Coronary Disease In Patients with Familial Hypercholesterolemia Hospitalized for an Acute Myocardial Infarction: Data from the RICO Survey.” Screening could identify patients and family members affected by the condition so that lifestyle changes and treatments can be started to prevent heart attack and stroke. Heterozygous familial hypercholesterolaemia (FH) is a life-threatening genetic condition linked with a high risk of premature cardiovascular disease, including heart attack and stroke. FH is one of the most common potentially fatal family disorders, with a prevalence estimated at 1/250 to 1/200, corresponding to 3.6 to 4.5 million individuals in Europe. Patients with FH have high levels of "bad" cholesterol (low-density lipoprotein; LDL) due to a mutation in genes that clear cholesterol from the body. LDL particles accumulate in the blood and can ultimately build up in the coronary artery walls. Children of patients with heterozygous FH have a 50% chance of inheriting the disorder. As LDL cholesterol levels are elevated as early as birth, the risk of heart attack in patients with FH is 10 to 13 times greater than that of the general population. Elevated LDL cholesterol plus family or personal history of early heart disease are key criteria for diagnosis, which may be confirmed by genetic testing. Management of FH includes a healthy lifestyle and medication.

Lung Cancer in Dogs Is Associated with HER2 Gene Mutation Seen In Human Breast Cancer; Clinical Trial of Drug (Neratinib) Effective in Human Breast Cancer Now Being Planned for Dogs with Lung Cancer; Possible Implications for Humans Who Have Never Smoked

Despite those velvet paintings of poker-playing dogs smoking pipes, cigars, and cigarettes, our canine friends really do not use tobacco. But, like many humans who have never smoked, dogs still get lung cancer. And, as many women who develop a particular type of breast cancer, the same gene -- HER2 -- also appears to be the cause of lung cancer in many dogs, according to a promising new study of pet dogs led by the Translational Genomics Research Institute (TGen), an affiliate of the City of Hope (California), and The Ohio State University. Published online on August 20, 2019 in the journal Clinical Cancer Research, this study could have significant implications, not only for dogs, but also for people who have never smoked. The article is titled “Identification of Recurrent Activating HER2 Mutations in Primary Canine Pulmonary Adenocarcinoma.” TGen and Ohio State found that neratinib -- a drug that has successfully been used to battle human breast cancer -- might also work for many of the nearly 40,000 dogs in the U.S. that annually develop the most common type of canine lung cancer, known as canine pulmonary adenocarcinoma (CPAC). Neratinib inhibits a mutant cancer-causing form of the gene HER2, which is common to both CPAC and HER2-positive human breast cancer patients. "With colleagues at Ohio State, we found a novel HER2 mutation in nearly half of dogs with CPAC. We now have a candidate therapeutic opportunity for a large proportion of dogs with lung cancer," said Will Hendricks, PhD, an Assistant Professor in TGen's Integrated Cancer Genomics Division, Director of Institutional Research Initiatives, and the study's senior author. Based on the results from this study, a clinical trial using neratinib is planned for dogs with naturally occurring lung cancer that have the HER2 mutation.

UW-Madison Leads Effort to Associate Multiple Maladies with FMR1 Premutation That Many Thought Harmless in Carriers; Full Mutation Causes Fragile X Syndrome; Landmark Study Demonstrates Power of Keeping & Mining Electronic Health Records

It was long believed that the so-called FMR1 premutation — an excessive number of trinucleotide repeats (55-200 repeats; normal number of repeats is 5 to 40) in the FMR1 gene — had no direct effect on the people who carry it. Until recently, the only recognized effect on the carriers of the flawed gene was the risk of having offspring with fragile X syndrome (>200 of the trinucleotide repeats), a rare but serious form of developmental disability. In recent years, however, at least two clinical conditions have been well documented in the carriers themselves: an age-dependent neurodegenerative disorder and, in female carriers, early menopause. Now, a team of researchers from the University of Wisconsin (UW)–Madison and Wisconsin’s Marshfield Clinic has found that there may be a much broader health risk to carriers, with potentially dozens of clinical conditions that can be ascribed directly to carrying the premutation. The researchers employed machine learning, a form of artificial intelligence (AI), to mine decades of electronic health records (EHRs) of nearly 20,000 individuals in order to make this landmark discovery. In a study published online on August 21, 2019 in Science Advances, the team led by Marsha Mailick (photo), PhD, a researcher and Professor at UW–Madison’s Waisman Center, and Emeritus Vice Chancellor for Research and Graduate Education at UW-Madison, together with UW–Madison graduate student Arezoo Movaghar, provides a better understanding of the previously disputed relationship between this well-known genetic premutation and a wide range of clinical conditions. At the same time, the interdisciplinary study richly illustrates the power of data-driven discovery.

Protein (FLRT3) with Roles In Neuron Development & Cell Adhesion May Be a Key Factor in Generation of Neuropathic Pain; Blocking FLRT3 Activity May Offer Possible Avenue to Reducing Such Pain

Researchers from Japan's Osaka University have made an important leap in our understanding of how chronic pain conditions develop. In a study published online on July 25, 2019 in the Journal of Neuroscience, the team explains how a protein previously implicated in neuron growth and cell adhesion is also critical for the development of pain sensitization (see image below). The article is titled “Increased Expression of Fibronectin Leucine-Rich Transmembrane Protein 3 in the Dorsal Root Ganglion Induces Neuropathic Pain in Rats.” Neuropathic pain is a chronic condition arising from previous nerve injury or certain diseases, including diabetes, cancer, and multiple sclerosis. Affected patients often display hypersensitivity to normally non-painful stimuli such as touch or repetitive movement, with pain commonly manifesting as shooting burning sensations, numbness, or pins and needles. In many cases, the pain cannot be relieved with analgesics. In humans, the spinal cord dorsal horn acts as a sorting station for pain stimuli. Signals coming in from peripheral areas of the body are processed and then transmitted via secondary neurons to the brain. Importantly, this is a key region in the development of neuropathic pain; studies have linked the condition to abnormal neuronal excitability in the spinal cord dorsal horn. However, what causes these neurons to become overly excited remains a mystery. FLRT3 (fibronectin leucine-rich transmembrane protein-3) is a protein commonly found in both embryonic and adult nervous systems. And while researchers don't know exactly what role it plays in adult tissues, FLRT3 has been implicated in synapse formation and cell adhesion in the developing brain.

Phase 1 Trial Will Evaluate Combination of Fecal Transplant & Immunotherapy in Treating Melanoma

According to an August 16, 2019 press release, a multidisciplinary team at Lawson Health Research Institute in Canada is exploring whether fecal transplants can improve outcomes in melanoma patients treated with immunotherapy. Immunotherapy drugs stimulate a person's immune system to attack and destroy cancer. While these immunotherapy drugs can significantly improve survival outcomes in those with melanoma, they are only effective in 40 to 50 per cent of patients. Preliminary research has suggested that the human microbiome - the diverse collection of microbes in our body - may play a role in whether or not a patient responds. "The gut microbiome helps establish immunity from an early age. It makes sense that a healthy gut could improve response to immunotherapy," explains Dr. Jeremy Burton, a Lawson Scientist who specializes in human microbiome research. "This led us to consider the potential of fecal transplants." Fecal transplants involve collecting stool from a healthy donor, preparing it in a lab, and transplanting it to the patient. The goal is to transplant the donor's microbiome so that healthy bacteria will colonize in the patient's gut. In a phase I clinical trial, the research team at Lawson is the first in Canada to study the use of fecal transplants to alter a cancer patient's microbiome and improve their response to anti-PD1 immunotherapy drugs. Research participants will be 20 melanoma patients recruited from the London Regional Cancer Program (LRCP) at London Health Sciences Centre (LHSC) in London, Ontario, Canada. Each patient will undergo a fecal transplant at St. Joseph's Hospital, a part of St. Joseph's Health Care London, followed by immunotherapy at LRCP. The transplant will consist of taking a number of specially-prepared oral capsules.

Variant of Peptide Now in Trials for Wound Therapy Could Limit “Bystander Effect” Damage in Heart Attacks; Group Hopes to Develop Exosome-Based Approach to Delivery of Potentially Protective Peptide

Imagine there were a drug that you could take soon after a heart attack that could reduce damage by protecting healthy heart muscle tissue. "Cardiologists say that when a heart attack occurs, time is muscle," said Robert Gourdie (photo), PhD, Director of the Fralin Biomedical Research Institute at VTC (Virginia Tech Carilion) Center for Heart and Reparative Medicine Research. Without oxygen supplied by blood flow, heart cells die -- quickly. But while a heart attack may only reduce blood and oxygen to an isolated section of heart cells -- causing what's called hypoxic ischemic injury -- those dying cells send signals to their neighbors. "The problem is that the area of dying tissue is not quarantined. Damaged heart cells start to send out signals to otherwise healthy cells, and the injury becomes much bigger," said Dr. Gourdie, who is also the Commonwealth Research Commercialization Fund Eminent Scholar in Heart Regenerative Medicine Research and Professor in the Department of Biomedical Engineering and Mechanics in the Virginia Tech College of Engineering. Scientists sometimes call this spread of injury signals to nearby healthy tissues a "bystander effect." But what if there were a way to keep the injury localized to the group of cells that are directly affected by the hypoxic ischemic injury, while allowing the nearby heart muscle cells to remain intact? A study published online on August 19, 2019 in the Journal of the American Heart Association reveals that a new molecule developed by a team of researchers led by Dr. Gourdie could help preserve heart tissue during -- and even after -- a heart attack. The open-access article is titled “Interaction of α Carboxyl Terminus 1 Peptide with the Connexin 43 Carboxyl Terminus Preserves Left Ventricular Function After Ischemia‐Reperfusion Injury.” Nearly a decade ago, Dr.

Non-Invasive Brain Imaging During Visual Test Identifies Autism with 87% Accuracy & Correctly Indicates Clinically Determined Severity; New Test Has Potential for Early Diagnostic Screening

A Dartmouth-led research team has identified a non-verbal, neural marker of autism. This marker shows that individuals with autism are slower to dampen neural activity in response to visual signals in the brain. This first-of-its kind marker was found to be independent of intelligence and offers an objective way to potentially diagnose autism in the future. The results were published online on August 15, 2019 in Current Biology. The open-access article is titled “Slower Binocular Rivalry in the Autistic Brain.” "Autism is hard to screen for in children, when the first signs are present. A trained clinician may be able to detect autism at 18-months or even younger; yet, the average age of a diagnosis of autism in the US is about four years old," explains lead author Caroline Robertson, PhD, an Assistant Professor of Psychological and Brain Sciences at Dartmouth, and Director of the Dartmouth Autism Research Initiative (https://sites.dartmouth.edu/autismresearchcenter/). "We need objective, non-invasive screening tools that don't depend on assessing a child's behavior. One of the big goals of the field is to develop objective neural markers of autism that can work with non-verbal individuals. This neural marker is just that," she added. People with autism have long been thought to have differences in inhibiting the neural signals in the brain. This is thought to underpin symptoms in autism, such as hypersensitivity to sensory input, which includes differences in processing visual information. When the human brain is presented with two different images at the same time, the images rock back and forth in awareness, toggling between the left and right eye. Prior research led by Dr.

Oxygen-Sensing Mechanism Based on Small RNA (sRNA) Is Key to E. coli Locating Region of Colon in Which to Set Up Most Threatening Infections; Discovery May Ultimately Enable Avoidance of These Food-Borne Infections

A pair of University of Virginia (UVA) School of Medicine scientists has revealed how E. coli seeks out the most oxygen-free crevices of the colon to cause the worst infection possible. The discovery could one day let doctors prevent the infection by allowing E. coli to pass harmlessly through the body. The new discovery shows just how the food-borne pathogen knows where and when to begin colonizing the colon on its way to making you sick. By recognizing the low-oxygen environment of the large intestine, the dangerous bacterium gives itself the best odds of establishing a robust infection - one that is punishing for the host. "Bacterial pathogens typically colonize a specific tissue in the host. Therefore, as part of their infection strategies, bacterial pathogens precisely time deployment of proteins and toxins to these specific colonization niches in the human host. This allows the pathogens to save energy and avoid detection by our immune systems and ultimately cause disease," said researcher Melissa Kendall (left in photo), PhD, of UVA's Department of Microbiology, Immunology, and Cancer Biology. "By knowing how bacterial pathogens sense where they are in the body, we may one day be able to prevent E. coli, as well as other pathogens, from knowing where it is inside a human host and allow it (the E. coli) to pass through the body without causing an infection." The UVA research was published in the July 9, 2019 issue of PNAS. The article is titled “The sRNA DicF Integrates Oxygen Sensing to Enhance Enterohemorrhagic Escherichia coli Virulence via Distinctive RNA Control Mechanisms.” E. coli naturally lives in our colons, and most strains do us no harm. But there are several strains that can cause cramps, diarrhea, vomiting, even kidney failure and death. Children are at particular risk. As such, E.

From the Tiny Testes of Flies, Rockefeller Scientists Derive Insights into How New Genes Arise

In the battle of the sexes, males appear to have the innovative edge--from a genetic standpoint, at least. Scientists are finding that the testes are more than mere factories for sperm; these organs also serve as hotspots for the emergence of new genes, the raw material for the evolution of species. Using fruit flies, a Rockefeller University team has gained key insight into how nature's attempts at innovation play out during the development of sperm. In research published online on August 16, 2019 in eLife, they mapped the presence of mutations to DNA at the single-cell level, and the activity of new genes arising from such changes. The open-access article is titled “Testis Single-Cell RNA-Seq Reveals the Dynamics of De Novo Gene Transcription and Germline Mutational Bias in Drosophila.” "Our work offers an unprecedented perspective on a process that enables living things to adapt and evolve, and that ultimately contributes to the diversity of life on Earth," says Rockefeller Assistant Professor Li Zhao, PhD, who led the research. In recent years, studies in animals from flies to humans have turned up a number of young genes that originated in the testes. These and other discoveries suggest that the testes rank among the most productive sites in the body--male or female--for genetic innovation. This mass production of genetic novelties comes with significant risks, however. In humans, for example, a father's sperm acquires two to three times more new mutations than do a mother's eggs in the course of normal development, leaving the sperm riddled with genetic mistakes. In some cases, such mistakes may harm the faather’s offspring, or even derail the prospect of fatherhood altogether.

FDA Approves New Drug (Pretomanid) for Treatment-Resistant Forms of Tuberculosis That Affects the Lungs; Approval Signals FDA’s Continued Focus on Facilitating Development of New Treatments to Fight Antimicrobial-Resistant Infections

On August 14, 2019, the U.S. Food and Drug Administration announced approval of Pretomanid Tablets, in combination with bedaquiline and linezolid, for the treatment of a specific type of highly treatment-resistant tuberculosis (TB) of the lungs. “The threat of antimicrobial-resistant infections is a key challenge we face as a public health agency,” said FDA Principal Deputy Commissioner Amy Abernethy, MD, PhD. “The bacterium that causes tuberculosis can develop resistance to the antibiotics used to treat it. Multidrug-resistant TB and extensively drug-resistant TB are public health threats due to limited treatment options. New treatments are important to meet patient national and global health needs. That’s why, among our other efforts to address antimicrobial resistance, we’re focused on facilitating the development of safe and effective new treatments to give patients more options to fight life-threatening infections. This approval also marks the second time a drug is being approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, a pathway, advanced by Congress, to spur development of drugs targeting infections that lack effective therapies. We hope we continue to see more development of antibacterial drugs for treating serious or life-threatening infections in limited populations of patients with unmet medical needs.” Pretomanid (image shows structure), in combination with bedaquiline and linezolid, is approved for treating a limited and specific population of adult patients with extensively drug-resistant, treatment-intolerant or nonresponsive multidrug resistant pulmonary TB. Multidrug-resistant TB and extensively drug-resistant TB are difficult to treat due to resistance to available therapies.

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