National Institutes of Health

NIH study shows schizophrenia’s genetic rising to a new level

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The largest genomic dragnet of any psychiatric disorder to date has unmasked 108 chromosomal sites harboring inherited variations in the genetic code linked to schizophrenia, 83 of which had not been previously reported. By contrast, the “skyline” of such suspect variants associated with the disorder contained only 5 significant peaks in 2011. By combining data from all available schizophrenia genetic samples, researchers supported by the National Institutes of Health (NIH) powered the search for clues to the molecular basis of the disorder to a new level.

“While the suspect variation identified so far only explains only about 3.5 per cent of the risk for schizophrenia, these results warrant exploring whether using such data to calculate an individual’s risk for developing the disorder might someday be useful in screening for preventive interventions,” explained Thomas R. Insel, M.D., director of the NIH’s National Institute of Mental Health, one funder of the study. “Even based on these early predictors, people who score in the top 10 per cent of risk may be up to 20-fold more prone to developing schizophrenia.”

The new found genomic signals are not simply random sites of variation, say the researchers. They converge around pathways underlying the workings of processes involved in the disorder, such as communication between brain cells, learning and memory, cellular ion channels, immune function and a key medication target.

The Schizophrenia Working Group of the Psychiatric Genomic Consortium (PGC) External Web Site Policy reports on its genome-wide analysis of nearly 37,000 cases and more than 113,000 controls in the journal Nature, July 21, 2014. The NIMH-supported PGC represents more than 500 investigators at more than 80 research institutions in 25 countries.

Prior to the new study, schizophrenia genome-wide studies had identified only about 30 common gene variants associated with the disorder. Sample sizes in these studies were individually too small to detect many of the subtle effects on risk exerted by such widely shared versions of genes. The PGC investigators sought to maximize statistical power by re-analyzing not just published results, but all available raw data, published and unpublished. Their findings of 108 illness-associated genomic locations were winnowed from an initial pool of about 9.5 million variants.

A comparison of the combined study data with findings in an independent sample of cases and controls suggest that considerably more such associations of this type are likely to be uncovered with larger sample sizes, say the researchers.

There was an association confirmed with variation in the gene that codes for a receptor for the brain chemical messenger dopamine, which is known to be the target for antipsychotic medications used to treat schizophrenia. Yet evidence from the study supports the view that most variants associated with schizophrenia appear to exert their effects via the turning on and off of genes rather than through coding for proteins.

The study found a notable overlap between protein-related functions of some linked common variants and rare variants associated with schizophrenia in other studies. These included genes involved in communication between neurons via the chemical messenger glutamate, learning and memory, and the machinery controlling the influx of calcium into cells.

“The overlap strongly suggests that common and rare variant studies are complementary rather than antagonistic, and that mechanistic studies driven by rare genetic variation will be informative for schizophrenia,” say the researchers.

Among the strongest associations detected, as in in previous genome-wide genetic studies, was for variation in tissues involved in immune system function. Although the significance of this connection for the illness process remains a mystery, epidemiologic evidence has long hinted at possible immune system involvement in schizophrenia.

Findings confirm that it’s possible to develop risk profile scores based on schizophrenia-associated variants that may be useful in research – but for now aren’t ready to be used clinically as a predictive test, say the researchers.

They also note that the associated variations detected in the study may not themselves be the source of risk for schizophrenia. Rather, they may be signals indicating the presence of disease-causing variation nearby in a chromosomal region.

Researchers are following up with studies designed to pinpoint the specific sequences and genes that confer risk. The PGC is also typing genes in hundreds of thousands of people worldwide to enlarge the sample size, in hopes of detecting more genetic variation associated with mental disorders. Successful integration of data from several GWAS studies suggests that this approach would likely be transferrable to similar studies of other disorders, say the researchers.

“These results underscore that genetic programming affects the brain in tiny, incremental ways that can increase the risk for developing schizophrenia,” said Thomas Lehner, Ph.D., chief of NIMH’s Genomics Research Branch. “They also validate the strategy of examining both common and rare variation to understand this complex disorder.”

About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure.

Source: PharmaBiz

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New cancer immunotherapy methods effective against a wide range of cancers: NIH study

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A new method for using immunotherapy to specifically attack tumour cells that have mutations unique to a patient’s cancer has been developed by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health. The researchers demonstrated that the human immune system can mount a response against mutant proteins expressed by cancers that arise in epithelial cells which can line the internal and external surfaces (such as the skin) of the body. These cells give rise to many types of common cancers, such as those that develop in the digestive tract, lung, pancreas, bladder and other areas of the body.

The research provides evidence that this immune response can be harnessed for therapeutic benefit in patients, according to the scientists. The study appeared May 9, 2014, in the journal Science.

“Our study deals with the central problem in human cancer immunotherapy, which is how to effectively attack common epithelial cancers,” said Steven A. Rosenberg, managing director, chief of the Surgery Branch in NCI’s Centre for Cancer Research. “The method we have developed provides a blueprint for using immunotherapy to specifically attack sporadic or driver mutations, unique to a patient’s individual cancer.”

All malignant tumours harbor genetic alterations, some of which may lead to the production of mutant proteins that are capable of triggering an antitumour immune response. Research led by Rosenberg and his colleagues had shown that human melanoma tumours often contain mutation-reactive immune cells called tumour-infiltrating lymphocytes, or TILs. The presence of these cells may help explain the effectiveness of adoptive cell therapy (ACT) and other forms of immunotherapy in the treatment of melanoma.

In ACT, a patient’s own TILs are collected, and those with the best antitumour activity are grown in the laboratory to produce large populations that are infused into the patient. However, prior to this work it had not been clear whether the human immune system could mount an effective response against mutant proteins produced by epithelial cell cancers. These cells comprise more than 80 per cent of all cancers. It was also not known whether such a response could be used to develop personalised immunotherapies for these cancers.

In this study, Rosenberg and his team set out to determine whether TILs from patients with metastatic gastrointestinal cancers could recognise patient-specific mutations. They analyzed TILs from a patient with bile duct cancer that had metastasised to the lung and liver and had not been responsive to standard chemotherapy. The patient, a 43-year-old woman, was enrolled in an NIH trial of ACT for patients with gastrointestinal cancers (Clinical trial number NCT01174121).

The researchers first did whole-exome sequencing, in which the protein-coding regions of DNA are analysed to identify mutations that the patient’s immune cells might recognise. Further testing showed that some of the patient’s TILs recognised a mutation in a protein called ERBB2-interacting protein (ERBB2IP). The patient then underwent adoptive cell transfer of 42.4 billion TILs, approximately 25 per cent of which were ERBB2IP mutation-reactive T lymphocytes, which are primarily responsible for activating other cells to aid cellular immunity, followed by treatment with four doses of the anticancer drug interleukin-2 to enhance T-cell proliferation and function.

Following transfer of the TILs, the patient’s metastatic lung and liver tumors stabilised. When the patient’s disease eventually progressed, after about 13 months, she was re-treated with ACT in which 95 per cent of the transferred cells were mutation-reactive T cells, and she experienced tumor regression that was ongoing as of the last follow up (six months after the second T-cell infusion). These results provide evidence that a T-cell response against a mutant protein can be harnessed to mediate regression of a metastatic epithelial cell cancer.

“Given that a major hurdle for the success of immunotherapies for gastrointestinal and other cancers is the apparent low frequency of tumor-reactive T cells, the strategies reported here could be used to generate a T-cell adoptive cell therapy for patients with common cancers,” said Rosenberg.

The National Cancer Institute (NCI) leads the National Cancer Programme and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers.

Source: PharmaBiz

USFDA Alerts – Medications for High Blood Pressure

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blood-pressure2

Nearly one in three adults in the United States has high blood pressure, also called hypertension. High blood pressure is dangerous because it increases the risk of stroke, heart attack, heart failure, kidney failure, death.

“High blood pressure is often called the ‘silent killer’ because it usually has no symptoms until it causes damage to the body,” says Douglas Throckmorton, M.D., Deputy Director of FDA’s Center for Drug Evaluation and Research. Many studies have shown that lowering the blood pressure with drugs decreases that damage.

A Lifelong Condition

Blood is carried from the heart to all parts of the body in vessels called arteries. Blood pressure is the force of the blood pushing forward through the body and against the walls of the arteries. The higher the blood pressure, the greater the risk of stroke, heart attack, heart failure, kidney failure, and death.

Blood pressure is made up of two numbers:

  • The “top” number is the systolic blood pressure—the pressure while the heart is pumping blood out. According to the National Institutes of Health (NIH), this number should be less than 120 to be in the normal range.
  • The “bottom” number is the diastolic blood pressure—the pressure while the heart is filling up with blood, getting ready to pump again. According to NIH, this number should be less than 80 to be in the normal range.

It was once believed that only diastolic pressure (the “bottom” number) was important, but this is not true. Elevated systolic pressure alone, particularly common in older people, is just as dangerous as elevations of both systolic and diastolic pressure.

Blood pressure is elevated for two main reasons:

  • too high blood volume
  • too narrow blood vessels.

Most of the time, the cause of a person’s high blood pressure is unknown. Once it develops, high blood pressure usually lasts the rest of the person’s life. But it is treatable.

Some people can lower blood pressure by losing weight, limiting salt intake, and exercising, but for most people, these steps are not enough. Most people need medication for blood pressure control, and will probably need it all their lives.

Types of Medications

FDA has approved many medications to treat high blood pressure, including

  • Diuretics, or “water pills,” which help the kidneys flush extra water and salt from your body and decrease blood volume
  • Angiotensin converting enzyme (ACE) inhibitors and Angiotensin II receptor blockers (ARBs), reduce blood pressure by relaxing blood vessels
  • Beta blockers, which also cause the heart to beat with less force
  • Drugs that directly relax the blood vessels. These include calcium channel blockers (CCBs) and other direct dilators (relaxers) of blood vessels
  • Alpha blockers, which reduce nerve impulses that tighten blood vessels
  • Nervous system inhibitors, which control nerve impulses from the brain to relax blood vessels

Many people with high blood pressure may need more than one medication to reach their goal blood pressure. Your health care provider can tell you if you should be on medication and, if so, which drug(s) may be best for you.

Tips for Consumers

Controlling your blood pressure is a lifelong task. Blood pressure is only one of a number of factors that increase your risk of heart attack, stroke, and death. High cholesterol and diabetes are other risk factors. Lifestyle changes—such as weight loss, a healthy diet, and physical activity—can affect all three risk factors, but many people will also need medications.

Take your medicines and monitor your blood pressure. Take the medications prescribed for you regularly and don’t stop them except on the advice of your health care provider. Hypertension tends to worsen with age and you cannot tell if you have high blood pressure by the way you feel, so have your health care provider measure your blood pressure periodically. You may also want to buy a home blood pressure monitor, available in many drug stores, to measure your blood pressure more frequently. Your health care provider or pharmacist can help you choose the right device. Many drug stores also have blood pressure measuring devices you can use in the store.

Tell your health care provider about any side effects you are having. Some side effects may go away over time, others may be avoided by adjusting the dosage or switching to a different medication.

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FDA discourages use of laparoscopic power morcellation for removal of uterus or uterine fibroids

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Procedure poses risk of spreading undetected cancerous tissue in women with unsuspected cancer

NFC-Fibroids

In a safety communication notice, the U.S. Food and Drug Administration discouraged the use of laparoscopic power morcellation for the removal of the uterus (hysterectomy) or uterine fibroids (myomectomy) in women because, based on an analysis of currently available data, it poses a risk of spreading unsuspected cancerous tissue, notably uterine sarcomas, beyond the uterus.

Laparoscopic power morcellation is one of several available treatments for fibroids. It is a procedure that uses a medical device to divide the uterine tissue into smaller pieces or fragments so it can be removed through a small incision in the abdomen, such as during laparoscopy.

Uterine fibroids are non-cancerous growths that originate from the smooth muscle tissue in the wall of the uterus. According to the National Institutes of Health, most women will develop uterine fibroids at some point in their lives. While most uterine fibroids do not cause problems, they can cause symptoms, such as heavy or prolonged menstrual bleeding, pelvic pressure or pain, and frequent urination, sometimes requiring medical or surgical therapy.

Based on an analysis of currently available data, the FDA has determined that approximately 1 in 350 women who are undergoing hysterectomy or myomectomy for fibroids have an unsuspected type of uterine cancer called uterine sarcoma. If laparoscopic power morcellation is performed in these women, there is a risk that the procedure will spread the cancerous tissue within the abdomen and pelvis, significantly worsening the patient’s likelihood of long-term survival.

“The FDA’s primary concern as we consider the continued use of these devices is the safety and well-being of patients,” said William Maisel, M.D., M.P.H., deputy director for science and chief scientist at the FDA’s Center for Devices and Radiological Health. “There is no reliable way to determine if a uterine fibroid is cancerous prior to removal. Patients should know that the FDA is discouraging the use of laparoscopic power morcellation for hysterectomy or myomectomy, and they should discuss the risks and benefits of the available treatment options with their health care professionals.”

A number of additional treatment options are available for women with symptomatic uterine fibroids, including traditional surgical hysterectomy (performed either vaginally or abdominally) and myomectomy, and laparoscopic hysterectomy and myomectomy without morcellation, as well as other non-surgical options.

The FDA will convene a public meeting of the Obstetrics and Gynecological Medical Devices Panel to discuss information related to laparoscopic power morcellation.

“Input from clinical and scientific experts will help provide valuable information and perspectives to clarify the proper clinical role for these devices,” said Maisel. “We anticipate the discussion will include whether a boxed warning related to the risk of cancer spread should be added to the product labeling for laparoscopic power morcellators to ensure patients and health care professionals are adequately informed of the risks.”

In the interim, the agency has instructed manufacturers of power morcellators used during laparoscopic hysterectomy and myomectomy to review their current product labeling for accurate risk information for patients and health care professionals.

Based on currently available information, the FDA’s recommendations for health care professionals include:

  • Be aware that the FDA discourages the use of laparoscopic power morcellation during hysterectomy or myomectomy for the treatment of women with uterine fibroids.
  • Do not use laparoscopic uterine power morcellation in women with suspected or known uterine cancer.
  • Carefully consider all the available treatment options for women with symptomatic uterine fibroids.
  • Discuss the benefits and risks of all treatments with patients.

After carefully weighing the risks and benefits of the procedure, if a health care professional nonetheless determines that laparoscopic power morcellation is the best therapeutic option for his or her patient, the health care professional should:

  • Inform patients that their fibroid(s) may contain unexpected cancerous tissue and that laparoscopic power morcellation may spread the cancer, significantly worsening their prognosis.
  • Be aware that some clinicians and medical institutions now advocate using a specimen “bag” during morcellation in an attempt to contain the uterine tissue and minimize the risk of cancer spread in the abdomen and pelvis.

FDA’s recommendations for women include:

  • Discuss all the options available to treat your condition, including the risks and benefits of each with your health care professional.
  • If laparoscopic hysterectomy or myomectomy is recommended, ask your health care professional if power morcellation will be performed during your procedure and why it is the best treatment option for you.
  • If you have already undergone a hysterectomy or myomectomy for fibroids, tissue removed during the procedure is typically tested for the presence of cancer. If you were informed these tests were normal and you have no symptoms, routine follow-up with your physician is recommended. Patients with persistent or recurrent symptoms or questions should consult their health care professional.

Source: PharmaBiz

NIH study shows obesity may lead to colorectal cancer

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childhood obesity

Obesity, rather than diet, causes changes in the colon that may lead to colorectal cancer, according to a study in mice by the National Institutes of Health. The finding bolsters the recommendation that calorie control and frequent exercise are not only key to a healthy lifestyle, but a strategy to lower the risk for colon cancer, the second leading cause of cancer-related death in the United States.

Paul Wade, Ph.D., and Thomas Eling, Ph.D., scientists at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, led a collaborative team that made the discovery. The study appeared online April 1 in the journal Cell Metabolism.

A large body of scientific literature says people who are obese are predisposed to a number of cancers, particularly colorectal cancer, Eling said. To better understand the processes behind this link, he and his colleagues fed two groups of mice a diet in which 60 per cent of the calories came from lard. The first group of mice contained a human version of a gene called NAG-1, which has been shown to protect against colon cancer in other rodent studies. The second group lacked the NAG-1 gene.

The NAG-1 mice did not gain weight after eating the high-fat diet, while mice that lacked the NAG-1 gene grew plump.

The researchers noticed another striking difference between the two groups of animals.

“The obese mice exhibited molecular signals in their gut that led to the progression of cancer, but the NAG-1 mice didn’t have those same indicators,” Eling said.

The researchers looked for molecular clues, by isolating cells from the colons of the mice and analyzing a group of proteins called histones. Histones package and organize DNA in a cell’s nucleus, and sometimes undergo a process known as acetylation, in which chemical tags bind to their surface. The pattern of acetylation varies depending on the chemical processes taking place in the cell.

Wade explained that the acetylation patterns for the obese mice and the thin NAG-1 mice were drastically different. Patterns from the obese mice resembled those from mice with colorectal cancer. The additional weight they carried also seemed to activate more genes that are associated with colorectal cancer progression, suggesting the obese mice are predisposed to colon cancer.

“Any preexisting colon lesions in these animals are more likely to evolve rapidly into malignant tumors,” Wade said. “The same thing may happen in humans.”

Wade and Eling want to find out exactly how obesity prompts the body to develop colorectal cancer. Wade said that the likely candidates for triggering tumor growth in the colon are fat cells, but there are many more possibilities. Finding these cellular switches may give rise to production of medications to keep people from getting colorectal cancer.

“Once we identify the signaling pathways and understand how the signal is transduced, we may be able to design ways to treat colorectal cancer in obese patients,” Wade said.

Source: PharmaBiz