Category Archives: Transhuman News

March 30, 2017 by Julia Evangelou Strait Credit: Washington University School of Medicine

Natural genetic changes can put some people at high risk of certain conditions, such as breast cancer, Alzheimer's disease or high blood pressure. But in rare cases, genetic errors also can have the opposite effect, protecting individuals with these helpful genetic mistakes from developing common diseases.

A new study of such "beneficial" genetic mutations, led by Washington University School of Medicine in St. Louis, may provide guidance on the design of new therapies intended to reduce the risk of heart attacks.

The study is published March 29 in the Journal of the American College of Cardiology.

The researchers studied members of a family with rare mutations in a gene called ANGPTL3. The gene is known to play important roles in processing lipoproteins, molecules that package and transport fat and cholesterol through the bloodstream. Partial or complete loss of this gene was known to cause low cholesterol and triglyceride levels in the bloodstream. But whether it affects risk of heart attack was unclear.

Three of these family membersthose with a complete loss of this geneshowed extremely low blood cholesterol and no evidence of plaque in their coronary arteries. According to the study authors, it was noteworthy that one of these patients showed no evidence of atherosclerosis despite having high risk factors for it, including high blood pressure and a history of type 2 diabetes and tobacco use.

"The family members with complete loss of ANGPTL3 have extraordinarily low cholesterol," said first author Nathan O. Stitziel, MD, PhD, an assistant professor of medicine and of genetics. "The interesting thing about this family is the individuals with total loss of this gene had siblings with normal copies of the same gene. So we could compare people with differences in the function of this gene who are otherwise closely related genetically and share similar environments. It's an anecdotal study of one family, but we felt it might provide some insight into the effects of blocking ANGPTL3."

While the individuals with nonfunctional copies of the gene showed no coronary plaque, their siblings with working copies of the gene showed evidence of plaque in the coronary arteries, though it was not yet causing symptomsa situation that is common in the general population, according to Stitziel.

To study the gene beyond the experience of a single family, the scientists also analyzed data available from large population studies. In data from one study of about 20,000 patients, the researchers found those with a partial loss of this gene had, on average, 11 percent lower total cholesterol, 12 percent lower LDL cholesterol, and 17 percent lower triglycerides, measured in the blood, than individuals with full gene function.

Analysis of data from other large population studies showed a link between partial loss of the gene and a lower risk of coronary artery disease and an association between lower circulating levels of ANGPTL3 protein and a lower risk of heart attack.

Taken together, these findings provide support for efforts to develop drugs that inhibit ANGPTL3 in order to reduce the risk of coronary artery disease and heart attack. The same reasoning led to the development of a class of drugs known as PCSK9 inhibitors, which have recently been shown to be effective at reducing the risk of heart attack in a large clinical trial of more than 27,000 men and women.

Several years ago, researchers found natural beneficial mutations in the PCSK9 gene that lowered people's cholesterol levels and protected them from coronary artery disease, much as mutations in ANGPTL3 seem to do. Both PCSK9 and ANGPTL3 are important in the body's processing of cholesterol from the diet. Any drugs that inhibit them, then, work differently than commonly prescribed statins, which reduce cholesterol levels in the blood by blocking the body's internal cholesterol manufacturing.

While reducing cholesterol levels in the blood typically is thought to be good for the heart, Stitziel pointed out that there may be dangers to inhibiting the normal function of a gene. Not all genetic mutations that result in low cholesterol in the bloodstream are healthy. For example, there is one genetic disorder in which cholesterol levels in the blood are low because cholesterol gets stuck in the liver, resulting in fatty liver disease.

"We need a better understanding of how cholesterol is processed in individuals with complete loss of ANGPTL3 function before we can fully say what effect inhibiting ANGPTL3 is going to have," Stitziel said. "Studies of people with mutations that completely knock out a gene's function are important because they can provide insight into the potential effectsboth good and badof drugs inhibiting that gene's function."

Explore further: What you need to know about cholesterol

(HealthDay)Cholesterol plays a vital role in your health, so it's important to understand the different types of cholesterol and how to influence their levels, a heart specialist says.

To reduce risk of heart attack, the benefits of a healthy lifestyle are clear. But genetics can still stack the deck. Some people's genes bestow a natural advantageor disadvantagein protecting against heart disease, ...

Rare mutations that shut down a single gene are linked to lower cholesterol levels and a 50 percent reduction in the risk of heart attack, according to new research from Washington University School of Medicine in St. Louis, ...

Heart disease patients taking PCSK9 inhibitors to achieve very low levels of cholesterol do not experience an increase in adverse events, including memory impairment or nervous system disorders, but may have an increased ...

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Fish do it, amphibians do it, so why can't we? Scientists are questioning why human hearts lose the ability to regenerate, while other animals don't.

An online metabolic calculator developed by a University of Virginia School of Medicine doctor and his research partner at the University of Florida predicts patients' risk of developing heart disease and diabetes more accurately ...

Natural genetic changes can put some people at high risk of certain conditions, such as breast cancer, Alzheimer's disease or high blood pressure. But in rare cases, genetic errors also can have the opposite effect, protecting ...

Determining the cause of an ischemic stroke - one caused by an interruption of blood supply - is critical to preventing a second stroke and is a primary focus in the evaluation of stroke patients. But despite that importance, ...

Human heart muscle cells can be created in the lab, but researchers have been unable to grow the immature cells to the point where they could be useful.

Further evidence has been found by Universities of Leicester and Bristol researchers to suggest statins could "significantly reduce" the occurrence of blood clotting in certain parts of the body.

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Genetic errors associated with heart health may guide drug development - Medical Xpress

Ovarian cancer is a common form of cancer and a leading cause of cancer death among women. The genes we inherit affect our chances of developing ovarian cancer, and a new genomic study identifies 12 genetic variants associated with the risk.

The Centers for Disease Control and Prevention (CDC) report that almost 21,000 women in the United States were diagnosed with ovarian cancer in 2013, and more than 14,000 died from the disease.

Early detection of ovarian cancer is crucial in improving the patients' survival rate. If the cancer is diagnosed in the early stages - that is, before it has spread beyond the ovaries - the survival rate is estimated at 92 percent. However, according to the American Cancer Society, only 15 percent of ovarian cancers are diagnosed this early.

New research by an international team of scientists from the United Kingdom, the U.S., and Australia identifies 12 genetic variations that raise the likelihood of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer. It forms in the epithelium (the tissue) that covers the ovaries.

The results of the new genomic study were published in the journal Nature Genetics.

The new study was conducted as part of the OncoArray Consortium - a large genomic study looking at almost 450,000 samples in an attempt to identify the genetic background for most common cancers.

The OncoArray Consortium used a novel genotyping technique that allowed the researchers to identify nearly 500,000 single nucleotide polymorphisms (SNPs), which are the most common type of variation found in the human genome.

The inherited genetic architecture accounts for a significant portion of a woman's risk of developing EOC, the authors explain.

"We know that a woman's genetic makeup accounts for about one third of her risk of developing ovarian cancer. This is the inherited component of disease risk. We are less certain of environmental factors that increase our risk, but we do know that several factors reduce the risk of ovarian cancer, including taking the oral contraceptive pill, having your tubes tied, and having children."

Prof. Paul Pharoah, co-lead author

Mutations in the BRCA1 and BRCA2 genes make up 40 percent of this risk.

These faulty genes are quite rare - occurring in approximately 1 in 300 people - and correlate with a high incidence of ovarian and breast cancer.

Using data from the OncoArray Consortium, the new study examined the DNA of more than 25,000 people diagnosed with EOC, as well as genetic data from a control group of nearly 41,000 healthy individuals.

Additionally, the researchers investigated more than 31,000 people who had the BRCA1 and BRCA2 genetic mutations, almost 4,000 of whom had EOC.

The researchers located 12 new genetic variants associated with EOC risk. Additionally, the new study confirmed 18 previously identified variants that had been linked to the risk of developing EOC.

Overall, 6.5 percent of the inherited genetic risk of developing EOC is now known.

The first author of the study, Dr. Catherine Phelan from the Moffitt Cancer Center in Tampa, FL, explains what this percentage means:

"Ovarian cancer is clearly a very complex disease - even the 30 risk variants that we now know increase risk of developing the disease account for just a small fraction of the inherited component. We believe that there will likely be many more genetic variants involved, each with extremely small effects. Most of these are likely to be common, but some will be rare."

The authors also note that some women will have multiple risk-associated gene variants, but even combined, these still do not account for more than a 2.8 percent chance of developing ovarian cancer in their lifetimes.

To put this number into perspective, patients who are offered the option to have their ovaries surgically removed as a preventive measure most often have a lifetime risk of at least 10 percent.

However, the researchers also note that a combination of these genetic variants and being a carrier of the faulty BRCA1 and BRCA2 genes might sometimes be enough to call for preventive surgery.

"In some ways, the hard work starts now. We really have little idea of the functional effect these variants have at the molecular or cellular level and so there are few clues as to how they might affect risk. If we can understand how they work, we will be in a better position to treat - and possibly prevent - ovarian cancer."

Dr. Simon Gayther, study co-author

Learn how tumor DNA fragments help to predict ovarian cancer outcomes.

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Study finds 12 genetic variants that raise the risk of ovarian cancer - Medical News Today

Miami Herald

Cutting-edge gene therapy provides hope for patients with inherited eye conditions Miami Herald For years, patients who had hereditary retinal diseases didn't really have much hope, said Dr. Byron Lam, a neuro-opthalmologist who specializes in hereditary retinal degenerations at UM's Miller School of Medicine. They were diagnosed, but there ...

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Cutting-edge gene therapy provides hope for patients with inherited eye conditions - Miami Herald

March 30, 2017 by Bob Yirka report Motor neurons from mice that received an experimental ALS treatment (top) displayed lower levels of a newly identified biomarker (brown areas) than observed in untreated animals (bottom). Credit: T.F. Gendron et al., Science Translational Medicine (2017)

(Medical Xpress)A very large team of researchers with members from the U.S., Italy and the Netherlands has found what might be a marker for ALS, which the team suggests could be used as a yardstick for measuring the effectiveness of treatments in clinical trials. In their paper published in the journal Science Translational Medicine, the team describes how they connected a genetic abnormality common in ALS patients with a protein they found in blood cells and cerebrospinal fluid.

Amyotrophic lateral sclerosis (ALS), aka Lou Gehrig's disease, is a disorder that causes nerve degeneration leading to muscle atrophy and eventually death. To date, there is no known cure, though one drug has been found to delay the progression of the disease for a few months. One of the things standing in the way of a cure is a lack of tests that can tell researchers if a treatment under study is having any discernable positive impact. This is because there is no test for the disorder itself. In this new effort, the researchers believe they may have found a marker that could be used to test for the disorder, and more importantly, serve as a means for measuring whether a drug developed to reduce symptoms, or better yet a cure for the disease, actually does what is hoped.

The researchers started by looking at patients with a gene mutation called C9ORF72 which is believed to be behind the onset of most types of genetically caused ALS (and also some types of dementia.) During their research, they discovered that many such patients had more than normal amounts of a protein called polyGP in their cerebrospinal fluid and also in their blood cells. Inspired, they conducted a study comparing patients with polyGP in their cerebrospinal fluid with those that had the mutation and with control groups.

The team reports that they found the protein buildup in 134 people who had the mutation, which included 83 people who had ALS, 27 people who had no symptoms, and 24 people who had other types of diseases. Furthermore, they found that the protein buildup was not found in 120 people who did not have the mutation, including those with different types of ALS.

These findings, the group suggests, mean that testing for polyGP might someday soon be used as a viable way to measure treatment success, which could perhaps one day lead to better therapies or perhaps a cure.

Explore further: Children of patients with C9orf72 mutations are at a greater risk of frontotemporal dementia or ALS at a younger age

More information: Tania F. Gendron et al. Poly(GP) proteins are a useful pharmacodynamic marker for-associated amyotrophic lateral sclerosis, Science Translational Medicine (2017). DOI: 10.1126/scitranslmed.aai7866

Abstract There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNAmediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNAbased therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

2017 Medical Xpress

The most common genetic cause of the brain diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a mutation in the C9orf72 gene. Researchers from VIB and UAntwerp, headed by Prof. Christine Van ...

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(Medical Xpress)A very large team of researchers with members from the U.S., Italy and the Netherlands has found what might be a marker for ALS, which the team suggests could be used as a yardstick for measuring the effectiveness ...

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Possible genetic marker for ALS found might prove useful for measuring effectiveness of treatments - Medical Xpress