Daily Archives: June 8, 2017

Heart disease kills more than 600,000 Americans every year, which translates to more than one in every four deaths. Although lifestyle choices contribute to the disease, genetics play a major role. This genetic facet has remained largely mysterious. But new research by scientists at the University of Maryland School of Medicine (UMSOM) has identified what may be a key player: a mutated gene that leads to irregular heartbeat, which can lead to a dangerously inefficient heart.

The findings were published June 7 in the journal Science Advances. The senior author of the study, Aikaterini Kontrogianni-Konstantopoulos, PhD, is a professor of biochemistry and molecular biology at UMSOM.

The study is the first to illuminate details of how this particular gene, which is called OBSCN, works in heart disease. The gene produces proteins known as obscurins, which seem to be crucial to many physiologic processes, including heart function.

University of Maryland School of Medicine Professor Aikaterini Kontrogianni-Konstantopoulos, PhD, studies the OBSCN gene and obscurin proteins.

This study gives us new information about the involvement of obscurins in the mechanics of heart disease, said Kontrogianni-Konstantopoulos. It suggests that people carrying a mutated version of OBSCN may develop heart disease.

For almost two decades, Kontrogianni-Konstantopoulos has been studying the OBSCN gene and obscurin proteins. Research has found that the gene is often mutated; some of these mutations may play a role in heart disease and certain cancers. She and her colleagues have recently shown that one mutation may play a role in the development of congenital heart disease. However, the cell processes that are affected by the OBSCN mutation have remained largely a mystery.

In this latest study, Kontrogianni-Konstantopoulos and her team unraveled this question. They focused on a mutation that has been linked to an enlarged heart, also known as hypertrophic cardiomyopathy. In this condition, the heart muscle becomes thickened and scarred, and has trouble pumping blood. She created a strain of mouse that carries the mutation, and then divided the animals into three groups: a group that experienced no stress, one that experienced moderate stress, and one that experienced significant stress.

She found that animals in the no-stress group developed irregular heartbeat, also known as arrhythmia. The mildly stressed animals developed thickened hearts, and the severely stressed animals developed hearts that were scarred and ineffective.

Kontrogianni-Konstantopoulos is one of several scientists who first discovered OBSCN in 2001. Prior to that it was all but unknown, hence its name. Since then, she has studied the gene, focusing on its role in both heart disease and cancer. She currently has several other ongoing studies of its effects in both heart disease and cancer.

It is not clear exactly how the mutated OBSCN gene causes heart problems. Her study is the first one to examine this question in relation to the obscurin mutations. She and her colleagues found evidence that the particular mutation they focused on may affect the ability of a protein called phospholamban to regulate the movement of calcium in heart muscle cells; this movement plays a crucial role in controlling how the heart contracts and relaxes. If this process goes awry, the heart does not function properly.Kontrogianni-Konstantopoulos says this work could eventually lead to targeted therapies for people who have OBSCN mutations.

Heart disease is one of our most urgent national health issues, said UMSOM Dean E. Albert Reece, MD, PhD, MBA, who is also the vice president for medical affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor. Dr. Kontrogianni-Konstantopoulos has elucidated this new aspect of the molecular basis of at least some cardiovascular illness. I look forward to seeing what she and others do to further build on this new discovery.

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Study: Mutated Gene Tied to Irregular Heartbeat - UMB News

MONDAY, June 5, 2017 (HealthDay News) -- Two drugs that target genetic flaws are giving people with specific types of advanced lung cancer a chance to live longer and better, a pair of new clinical trials finds.

A newly approved drug called alectinib (Alecensa) works twice as long as the current standard medication in halting cancer growth in patients with ALK-positive non-small cell lung cancer, results from a new global clinical trial show.

ALK is a gene that produces a protein that helps cancer cells grow and spread, according to the American Cancer Society (ACS).

In another study, an experimental drug called dacomitinib delayed cancer growth by about half in non-small cell lung cancer patients who had a mutation of the epidermal growth factor receptor (EGFR) that caused cancer cells to grow faster, a second trial reported. Non-small cell lung cancers comprise most lung cancer cases.

EGFR is a substance normally found on cells that helps them grow and divide, the ACS says.

The drugs, alectinib in particular, will let people live months or years longer just by taking a daily pill, said Dr. Bruce Johnson, chief clinical research officer at Dana-Farber Cancer Institute in Boston. Johnson is also incoming president of the American Society of Clinical Oncology (ASCO).

Alectinib works more than a year longer than crizotinib (Xalkori), which itself supplanted chemotherapy a few years back because it proved more effective with fewer side effects, Johnson said.

"This is kind of a game changer, because the drug itself works at least for two years, plus there are other treatments" that can be substituted when it ultimately becomes ineffective, Johnson said of alectinib. "We used to have to tell these patients 10 or 15 years ago that you've got eight months to a year. Now they most likely have years."

Both of these genetically driven forms of lung cancer are more common in nonsmokers, the ACS says.

The studies were both funded by the drug manufacturers. Hoffmann-La Roche funded the alectinib study. Pfizer and SFJ Pharmaceuticals Group funded the dacomitinib study.

The first clinical trial revealed that alectinib halts lung cancer growth for about 26 months on average. That compared to about 10 months on average for crizotinib, the drug now used as front-line treatment for ALK-positive patients.

Alectinib also works 84 percent better than crizotinib at preventing spread of advanced lung cancer to the brain, because it is better able to penetrate into the brain and kill cancer cells there, said lead researcher Dr. Alice Shaw, director of thoracic oncology at Massachusetts General Hospital Cancer Center in Boston.

About 5 percent of non-small cell lung cancer cases are ALK-positive. That means they have a genetically abnormal protein that fuels cancer growth. In the United States, about 12,500 people are diagnosed with ALK-positive non-small cell lung cancer each year, researchers said in background information.

Alectinib already is approved in the United States as a treatment for ALK-positive patients who no longer respond to crizotinib, Shaw said.

The results should "establish alectinib as the new standard of care" for ALK-positive lung cancer patients, rather than crizotinib, Shaw said.

ASCO expert Dr. John Heymach agreed, calling the clinical trial a "watershed moment."

Not only did the drug work better and longer, but it also produced fewer side effects in patients, noted Heymach, chair of thoracic/head and neck oncology for the University of Texas MD Anderson Cancer Center in Houston.

The most common side effects for alectinib were fatigue, constipation, muscle aches and swelling, while crizotinib patients most often suffered from gastrointestinal problems and liver enzyme abnormalities, according to the researchers.

The second clinical trial compared a new drug, dacomitinib, to the current standard targeted drug gefitinib (Iressa) in treating EGFR-positive lung cancer.

Each year about 15,000 people in the United States are diagnosed with EGFR-positive lung cancer, which involve mutations that increase the growth of cancer cells, researchers said in background notes.

Dacomitinib blocked EGFR mutations more effectively than first-generation drug gefitinib, providing a 41 percent lower chance of cancer progression or death, researchers found. On average, dacomitinib halted cancer growth for 14.7 months in patients, compared with 9.2 months with gefitinib.

"From the perspective of doctors who treat lung cancer daily, this is really a substantial advance," Heymach said, noting that the results put the drug "at the front of the pack in terms of efficacy."

However, dacomitinib also created more side effects, including acne in about 14 percent of patients and diarrhea in 8 percent of patients. Doctors wound up reducing the dosage in about 66 percent of patients as a result of side effects, said lead researcher Dr. Tony Mok, chair of clinical oncology at the Chinese University of Hong Kong.

Heymach said the side effects are "not life-threatening toxicities."

"These are toxicities that doctors who treat this for a living become accustomed to managing," Heymach said.

"At the end of the day, I think we now have one additional choice" in treating EGRF-positive non-small cell lung cancer, Mok concluded, adding that dacomitinib should be considered as a new first-line alternative treatment. The drug has not received FDA approval.

Neither of the tested drugs will be cheap. "Almost all these targeted drugs are thousands of dollars per month," Johnson said.

The results of both trials were scheduled to be presented Monday at ASCO's annual meeting, in Chicago. The findings were also being published June 6 in the New England Journal of Medicine.

More here:
Gene-Targeted Drugs Fight Advanced Lung Cancers - Montana Standard

June 8, 2017 Hair thinning in a human patient and mouse with inherited loss of function mutations in WNT10A is shown. Credit: Michael Passanante and Mingang Xu, PhD

It is almost axiomatic in medicine that the study of rare disorders informs the understanding of more common, widespread ailments. Researchers from the Perelman School of Medicine at the University of Pennsylvania who study an inherited disorder of skin, hair follicles, nails, sweat glands, and teeth called hypohidrotic ectodermal dysplasia (HED) have identified a mechanism that may also be disrupted in male pattern baldness, a more common condition. They published their findings this week in Nature Communications.

About one in 5,000 to 10,000 people are thought to have HED, although this may be an underestimate of its actual prevalence as this condition is not always diagnosed correctly. HED is most frequently caused by mutations in the EDA, EDAR, EDARRAD and WNT10A genes. In addition to its association with HED, mutations in WNT10A are the most common genetic defect observed in people who are born missing one or more teeth, but do not display other characteristics of the disease. These milder WNT10A mutations occur surprisingly frequently, in about 1 to 2 percent of the population. Interestingly, a variant of the WNT10A gene associated with lower levels of its protein's expression has been linked to a greater likelihood of male pattern baldness, according to a recent genome-wide association study.

"By analyzing mice with the WNT10A mutation, as well as tissues from human patients with WNT10A mutations, we found that WNT10A regulates the proliferation, but not the maintenance, of stem cells in hair follicles," said Sarah Millar, PhD, vice chair for Basic Research in the Department of Dermatology. "Together with a previously published genome-wide association study, our findings suggest that lower levels of WNT10A may contribute to male pattern baldness in some individuals."

The team made mouse models for WNT10A-associated HED by deleting the Wnt10a gene. The mutant mice displayed the same symptoms as HED patients with severe loss of function mutations in the WNT10A gene. Long-term absence of WNT10A leads to miniaturization of hair follicle structures and enlargement of the associated sebaceous glands, a phenomenon that is also observed in male pattern baldness.

Millar's group and her clinical collaborators, including Emily Chu, MD, PhD, an assistant professor of Dermatology and John McGrath, MD, from King's College, London, also discovered that cracking and scaling of palm and foot sole skin in WNT10A patients is due to decreased expression of a structural protein called Keratin 9, which is specifically expressed in these regions of skin and contributes to its mechanical integrity.

"Our studies took us back and forth between human patients and our mouse model," said Millar. "Our goal was to find what happened to cellular components affected by the WNT10A mutation to make better treatments."

Millar's group showed that decreased proliferation and Keratin 9 expression in the absence of WNT10A resulted from failure of signaling through a well-characterized pathway that stabilizes a protein called beta-catenin, allowing it to enter the cell nucleus and activate gene transcription.

These findings indicate that small molecule drugs that activate the beta-catenin pathway downstream of WNT10A could potentially be used to treat hair thinning and palm and sole skin defects in WNT10A patients. These agents may also be useful for preventing hair loss in a subgroup of people with male pattern baldness.

Explore further: Study of 52,000 men uncovers the genetics underlying male pattern baldness

A genomic study of baldness identified more than 200 genetic regions involved in this common but potentially embarrassing condition. These genetic variants could be used to predict a man's chance of severe hair loss. The ...

UT Southwestern Medical Center researchers have identified the cells that directly give rise to hair as well as the mechanism that causes hair to turn gray findings that could one day help identify possible treatments ...

A pathway known for its role in regulating adult stem cells has been shown to be important for hair follicle proliferation, but contrary to previous studies, is not required within hair follicle stem cells for their survival, ...

By the time they turn 50, half of European men have some degree of hair loss. For many, it will begin far earlier than that, and yet male pattern baldness is poorly understood.

In experiments in mice, UC San Francisco researchers have discovered that regulatory T cells (Tregs; pronounced "tee-regs"), a type of immune cell generally associated with controlling inflammation, directly trigger stem ...

It is almost axiomatic in medicine that the study of rare disorders informs the understanding of more common, widespread ailments. Researchers from the Perelman School of Medicine at the University of Pennsylvania who study ...

Heart disease kills more than 600,000 Americans every year, which translates to more than one in every four deaths. Although lifestyle choices contribute to the disease, genetics play a major role. This genetic facet has ...

Our DNA influences our ability to read a person's thoughts and emotions from looking at their eyes, suggests a new study published in the journal Molecular Psychiatry.

Mice have a reputation for timidity. Yet when confronted with an unfamiliar peer, a mouse may respond by rearing, chasing, grappling, and bitingand come away with altered sensitivity toward future potential threats.

Researchers at Queen's University have published new findings, providing a proof-of-concept use of genetic editing tools to treat genetic diseases. The study, published in Nature Scientific Reports, offers an important first ...

Yale scientists have discovered the cause of a disfiguring skin disorder and determined that a commonly used medication can help treat the condition.

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Inherited, rare skin disease informs treatment of common hair disorders, study finds - Medical Xpress

Certain polymorphisms in mannose-binding lectin (MBL) and toll-like receptors (TLRs), genes that have a role in the innate immune system, promote susceptibility to or protection against respiratory and rhinovirus infections and acute otitis media (AOM), according to a study in Finnish infants.

Researchers followed 923 children from birth to age 2 years for respiratory infections, relying primarily on daily parental diaries. When respiratory symptoms developed, investigators obtained nasal swabs, on which polymerase chain reaction and antigen tests were performed to detect respiratory viruses. Nasal swabs also were collected during scheduled visits at 2, 13, and 24 months, and blood samples were obtained when the infants were 2 months old. Investigators recorded almost 4000 episodes of acute respiratory infections, with rhinovirus the sole agent in 59%.

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Of the study children, about one-third had variant types of MBL; more than half had variants of TLR3 and TLR8, with smaller proportions having variants of TLR2, TLR4, and TLR7. The MBL polymorphisms were associated with an increased number of days per year with symptoms of respiratory infection and with an increased risk of rhinovirus-associated AOM. The TLR8 polymorphisms were tied to an increased risk of recurrent rhinovirus and the TLR2 variants with recurrent AOM, whereas TLR7 polymorphisms decreased the risk of recurrent rhinovirus infections (Toivonen L, et al. Pediatr Infect Dis J. 2017;36[5]:e114-e122).

Thoughts from Dr Burke

Dr Barton Childs, the late, legendary Johns Hopkins geneticist, was well known for asking at every case conference: Why does this child have this condition at this time? Studies like this one bring us closer to being able to answer Dr Childs question.

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Gene variants relate to risk of respiratory infections and AOM - ModernMedicine