Breakthrough in brain cancer research

Scientists at Newcastle University, UK, have made a pioneering breakthrough in the understanding of how a fatal brain tumour grows -- which could lead to improved treatments for patients.

Experts have found cells within the malignant brain tumour, glioma, rely on fats to fuel growth. This contradicts previous scientific belief that tumour cells require mainly sugars to make energy.

Glioma is the most common form of primary malignant brain tumour in adults, with approximately four cases per 100,000 people each year. Gliomas remain one of the hardest to treat cancers.

This new discovery provides a unique view of brain cancer cell biology which has significant implications for understanding the behaviour of tumours and improve treatments for this condition.

The study made use of tumour tissue donated by patients undergoing surgery, as well as mouse models of the disease.

Findings of the research are published online today in the journal, Neuro-Oncology.

Dr Elizabeth Stoll, from Newcastle University's Institute of Neuroscience, is lead author of the ground-breaking study.

She said: "Patients with malignant glioma currently receive a poor prognosis, and new interventions are desperately needed to increase the survival and quality of life for patients with the condition.

"Our results provide new insight into the fundamental biochemistry of cancer cells, with exciting implications for patients in the future.

"Most cells within the adult brain require sugars to produce energy and sustain function. Interestingly, we have discovered that malignant glioma cells have a completely different metabolic strategy as they actually prefer to break down fats to make energy.

"Our finding provides a new understanding of brain tumour biology, and a new potential drug target for fighting this type of cancer."

In the study, scientists showed that glioma cells grow more slowly if they are treated with a drug, known as etomoxir, which prevents the cells from making energy with fatty acids.

This discovery provides initial evidence for pursuing new therapeutic avenues to target fatty-acid metabolism in the clinical treatment of brain tumours to slow the progression of the disease.

The team highlight that this study does not address whether nutrition or diet influence tumour growth.

Dr Stoll said: "We tested etomoxir in our animal model, and showed that systemic doses of this drug slow glioma growth, prolonging median survival time by 17%.

"These results provide a novel drug target which could aid in the clinical treatment of this disease for patients in the future."

Stem cells were isolated from brains of mice and mutated to transform them into cancer cells. These mutations were similar to those that normally accumulate to form glioma tumours in people.

The malignant cells were then implanted into mice of the same genetic background as the donor mice, allowing the team to assess the speed of growth of the tumour.

Dr Stoll and her team hope to carry out future studies to develop the drug with clinical partners, so that glioma patients may benefit from this research in the coming years.

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The above post is reprinted from materials provided by Newcastle University. Note: Materials may be edited for content and length.

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Journal Reference:

1. Hua Lin, Shaan Patel, Valerie S. Affleck, Ian Wilson, Douglass M. Turnbull, Abhijit R. Joshi, Ross Maxwell, and Elizabeth A. Stoll. Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells. Neuro-Oncology, 2016 DOI:10.1093/neuonc/now128

Inserting stents through the wrist reduces bleeding, death rates in heart disease patients

Access through the wrist, or radial access, when inserting stents to restore blood flow in heart disease patients has fewer complications and should be the default approach over access through the groin, or femoral access, according to researchers involved in a study in JACC: Cardiovascular Interventions.

Researchers looked at 24 studies, enrolling 22,843 participants to conduct a comprehensive meta-analysis across the spectrum of heart disease and determined there was "strong to very strong" evidence that major bleeding and vascular complications were reduced and "moderate to strong" evidence that all cause death rates were reduced when using radial access versus femoral access.

Researchers concluded that the benefits of radial access support it being the default approach for all heart disease patients needing this procedure.

Radial access is a newer procedure and it involves a longer learning curve to develop the technical skills necessary. However, JACC: Cardiovascular Interventions Editor-in-Chief Spencer King, M.D., MACC, said, "as radial access is increasingly adopted, the benefits seen in trials has been weighed against the learning curve necessary for some operators. This most complete analysis of the value of radial access may convince some doubters to switch."

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The above post is reprinted from materials provided by American College of Cardiology. Note: Materials may be edited for content and length.

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Journal Reference:

1. Marco Valgimigli, MD, PhD et al. Radial Versus Femoral Access for Coronary Interventions Across the Entire Spectrum of Patients With Coronary Artery Disease: A Meta-Analysis of Randomized Trials.JACC: Cardiovascular Interventions, June 2016 DOI:10.1016/j.jcin.2016.04.014

Rate of decline of cardiovascular deaths slows in US

In a study published online by JAMA Cardiology, Stephen Sidney, M.D., M.P.H., of Kaiser Permanente Northern California, Oakland, and colleagues examined recent national trends in death rates due to all cardiovascular disease (CVD), heart disease (HD), stroke, and cancer, and also evaluated the gap between mortality rates from HD and cancer.

With the exception of the flu pandemic years of 1918-1920, heart disease has been the leading cause of death in the United States since 1910, with cancer and stroke among the 5 leading causes of death every year since 1924. During the first decade of the 21st century, HD mortality declined at a much greater rate than cancer mortality and it appeared that cancer would overtake HD as the leading cause of death. The decrease in HD mortality in the U.S. has been attributed to expanded use of evidence-based medical therapies as well as changes in risk factors and lifestyle modifications. For this study, researchers used the data system of the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research to determine national trends in age-adjusted mortality rates due to all CVD, HD, stroke, and cancer from January 2000 to December 2011 and January 2011 to December 2014, overall, by sex, and by race/ethnicity.

The researchers found that the rate of the decline in all CVD, HD, and stroke mortality decelerated substantially after 2011, and the rate of decline for cancer mortality remained relatively stable. The annual rates of decline for 2000-2011 were 3.79 percent, 3.69 percent, 4.53 percent, and 1.49 percent for all CVD, HD, stroke, and cancer mortality, respectively; the rates for 2011-2014 were 0.65 percent, 0.76 percent, 0.37 percent, and 1.55 percent, respectively.

The authors write that if the rates of decline from 2000 to 2011 had persisted, HD mortality in the United States would have been below that of cancer mortality in 2013, but the pattern of HD and cancer being the first and second leading causes of death, respectively, has endured.

"Given the high absolute burden and associated costs of HD and stroke, continued vigilance and innovation are essential in our efforts to address the ongoing challenge of CVD prevention. However, the recent deceleration in the rate of decline in HD mortality is alarming and warrants expanded innovative efforts to improve population-level CVD prevention."

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The above post is reprinted from materials provided by The JAMA Network Journals. Note: Materials may be edited for content and length.

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Journal Reference:

1. Stephen Sidney, M.D., M.P.H. et al. Recent Trends in Cardiovascular Mortality in the United States and Public Health Goals. JAMA Cardiology, June 2016 DOI: 10.1001/jamacardio.2016.1326

Pain killers are worse for you after 3 months.

People who take opioid pain killers have more pain and fatigue after 3 months than non takes.In a study of chronic pain sufferers those taking opioid pain killers had increased diary measures of pain severity, function, and healthcare utilization on crisis and non-crisis diary days, as well as a greater proportion of days in crisis. The patients taking the drugs reported pain levels that were three times greater than those not taking drugs, and had twice as much fatigue.The body has an incredible ability to adapt to any drug as it increases the rate in which it is metabolised and eliminated out of the body. A chronic alcohol drinkers metabolises alcohol much quicker than an occasional alcohol user. the same happens for pain killing drugs.

Little to no association between butter consumption, chronic disease or total mortality

Butter consumption was only weakly associated with total mortality, not associated with cardiovascular disease, and slightly inversely associated (protective) with diabetes, according to a new epidemiological study which analyzed the association of butter consumption with chronic disease and all-cause mortality. This systematic review and meta-analysis, published in PLOS ONE, was led by Tufts scientists including Laura Pimpin, Ph.D., former postdoctoral fellow at the Friedman School of Nutrition Science and Policy at Tufts in Boston, and senior author Dariush Mozaffarian, M.D., Dr.P.H., dean of the School.

Based on a systematic review and search of multiple online academic and medical databases, the researchers identified nine eligible research studies including 15 country-specific cohorts representing 636,151 unique individuals with a total of 6.5 million person-years of follow-up. Over the total follow-up period, the combined group of studies included 28,271 deaths, 9,783 cases of cardiovascular disease, and 23,954 cases of new-onset type 2 diabetes. The researchers combined the nine studies into a meta-analysis of relative risk.

Butter consumption was standardized across all nine studies to 14 grams/day, which corresponds to one U.S. Department of Agriculture estimated serving of butter (or roughly one tablespoon). Overall, the average butter consumption across the nine studies ranged from roughly one-third of a serving per day to 3.2 servings per day. The study found mostly small or insignificant associations of each daily serving of butter with total mortality, cardiovascular disease, and diabetes.

"Even though people who eat more butter generally have worse diets and lifestyles, it seemed to be pretty neutral overall," said Pimpin, now a data analyst in public health modelling for the UK Health Forum. "This suggests that butter may be a "middle-of-the-road" food: a more healthful choice than sugar or starch, such as the white bread or potato on which butter is commonly spread and which have been linked to higher risk of diabetes and cardiovascular disease; and a worse choice than many margarines and cooking oils -- those rich in healthy fats such as soybean, canola, flaxseed, and extra virgin olive oils -- which would likely lower risk compared with either butter or refined grains, starches, and sugars."

"Overall, our results suggest that butter should neither be demonized nor considered "back" as a route to good health," said Mozaffarian. "More research is needed to better understand the observed potential lower risk of diabetes, which has also been suggested in some other studies of dairy fat. This could be real, or due to other factors linked to eating butter -- our study does not prove cause-and-effect."

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The above post is reprinted from materials provided by Tufts University, Health Sciences Campus. Note: Materials may be edited for content and length.

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Journal Reference:

1. Pimpin L, Wu JHY, Haskelberg H, Del Gobbo L, Mozaffarian D. Is Butter Back? A Systematic Review and Meta-Analysis of Butter Consumption and Risk of Cardiovascular Disease, Diabetes, and Total Mortality. PLOS ONE, June 2016 DOI:10.1371/journal.pone.0158118

Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells

Salk Institute scientists have found preliminary evidence that tetrahydrocannabinol (THC) and other compounds found in marijuana can promote the cellular removal of amyloid beta, a toxic protein associated with Alzheimer's disease.

While these exploratory studies were conducted in neurons grown in the laboratory, they may offer insight into the role of inflammation in Alzheimer's disease and could provide clues to developing novel therapeutics for the disorder.

"Although other studies have offered evidence that cannabinoids might be neuroprotective against the symptoms of Alzheimer's, we believe our study is the first to demonstrate that cannabinoids affect both inflammation and amyloid beta accumulation in nerve cells," says Salk Professor David Schubert, the senior author of the paper.

Alzheimer's disease is a progressive brain disorder that leads to memory loss and can seriously impair a person's ability to carry out daily tasks. It affects more than five million Americans according to the National Institutes of Health, and is a leading cause of death. It is also the most common cause of dementia and its incidence is expected to triple during the next 50 years.

It has long been known that amyloid beta accumulates within the nerve cells of the aging brain well before the appearance of Alzheimer's disease symptoms and plaques. Amyloid beta is a major component of the plaque deposits that are a hallmark of the disease. But the precise role of amyloid beta and the plaques it forms in the disease process remains unclear.

In a manuscript published in June 2016's Aging and Mechanisms of Disease, Salk team studied nerve cells altered to produce high levels of amyloid beta to mimic aspects of Alzheimer's disease.

The researchers found that high levels of amyloid beta were associated with cellular inflammation and higher rates of neuron death. They demonstrated that exposing the cells to THC reduced amyloid beta protein levels and eliminated the inflammatory response from the nerve cells caused by the protein, thereby allowing the nerve cells to survive.

"Inflammation within the brain is a major component of the damage associated with Alzheimer's disease, but it has always been assumed that this response was coming from immune-like cells in the brain, not the nerve cells themselves," says Antonio Currais, a postdoctoral researcher in Schubert's laboratory and first author of the paper. "When we were able to identify the molecular basis of the inflammatory response to amyloid beta, it became clear that THC-like compounds that the nerve cells make themselves may be involved in protecting the cells from dying."

Brain cells have switches known as receptors that can be activated by endocannabinoids, a class of lipid molecules made by the body that are used for intercellular signaling in the brain. The psychoactive effects of marijuana are caused by THC, a molecule similar in activity to endocannabinoids that can activate the same receptors. Physical activity results in the production of endocannabinoids and some studies have shown that exercise may slow the progression of Alzheimer's disease.

Schubert emphasized that his team's findings were conducted in exploratory laboratory models, and that the use of THC-like compounds as a therapy would need to be tested in clinical trials.

In separate but related research, his lab found an Alzheimer's drug candidate called J147 that also removes amyloid beta from nerve cells and reduces the inflammatory response in both nerve cells and the brain. It was the study of J147 that led the scientists to discover that endocannabinoids are involved in the removal of amyloid beta and the reduction of inflammation.

Other authors on the paper include Oswald Quehenberger and Aaron Armando at the University of California, San Diego; and Pamela Maher and Daniel Daughtery at the Salk Institute.

The study was supported by the National Institutes of Health, The Burns Foundation and The Bundy Foundation.

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The above post is reprinted from materials provided by Salk Institute. Note: Materials may be edited for content and length.

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Journal Reference:

1. Antonio Currais, Oswald Quehenberger, Aaron M Armando, Daniel Daugherty, Pam Maher, David Schubert. Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids. npj Aging and Mechanisms of Disease, 2016; 2: 16012 DOI:10.1038/npjamd.2016.12

Saved by the sun: Solar-powered oxygen delivery system helps save lives in Uganda

A new twist on the use of renewable energy is saving children's lives in Africa. The innovation--a solar powered oxygen delivery system--is providing concentrated oxygen in hospital for children suffering from severe pneumonia.

The device created by Dr. Michael Hawkes, an assistant professor in the University of Alberta's Division of Pediatric Infectious Diseases, is the focus of a recently published study in The International Journal of Tuberculosis and Lung Disease and is already in use in two hospitals in Uganda.

"Solar-powered oxygen is using freely available resources--the sun and air--to treat children with pneumonia in the most remote settings," says Hawkes. "It's very gratifying for a pediatrician doing research in a lower-resource setting to fill a clinical gap and save lives. It's what our work is all about."

Each year, 900,000 children die of pneumonia worldwide with most deaths taking place in Africa and Asia. Vaccinations and medications exist, but are being rolled out slowly in Africa where diagnostics are poor and chest x-rays are not readily available.

Children with severe pneumonia have infected lungs that need concentrated oxygen until antibiotics begin to work. The concentrated oxygen helps overcome a problem with oxygen exchange caused by the lung infection. In Canada, it is available at the bedside in every hospital room. In developing countries like Uganda, it's harder to come by reliably.

Hawkes worked in Ugandan hospitals in the communities of Kambuga and Jinja for over two years where he quickly recognized a need for a more reliable oxygen source. In low-resource settings, oxygen can be delivered using cylinders, which are often in short supply, or concentrators, which depend on electricity. In Kambuga there were multiple power outages each day, some lasting for up to 48 hours.

"In the hospital you often didn't have access to oxygen cylinders. So the power goes out and you're out of luck. We had children that died in front of our eyes," says Hawkes.

To establish a reliable oxygen source, he and his colleagues came up with the idea of using solar energy. During the day, solar panels supply power to an oxygen concentrator that strips oxygen out of the air. At night, charged batteries from the panels supply the power to the concentrator.

To fund the idea, they received a Grand Challenges Canada grant, a Government of Canada initiative that supports global health research. The funds were used to set up the systems at the Kambuga and Jinja hospitals. "We piloted it on a group of 28 children and it showed that you could use the solar panels and batteries to run the concentrator 24/7. We treated children with pneumonia and the system worked," he says.

Next they conducted a larger randomized controlled trial and showed that solar powered oxygen delivery works just as well as the conventional method of oxygen delivery using cylinders. The trial officially ended in 2015, but after seeing such strong results, the hospitals continue to use the solar powered systems.

Hawkes and his team are now working with the Clinton Health Access Initiative (CHAI) in hopes of soon expanding the system's use to 80 hospitals across Uganda.

"If we could expand it, could you imagine how many children would have access to lifesaving oxygen therapy?" Hawkes wonders. "The challenges are different in these areas of the world, and the innovations need to be different as well."

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Story Source:

The above post is reprinted from materials provided by University of Alberta Faculty of Medicine & Dentistry. Note: Materials may be edited for content and length.

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Journal Reference:

1. H. Turnbull, A. Conroy, R. O. Opoka, S. Namasopo, K. C. Kain, M. Hawkes. Solar-powered oxygen delivery: proof of concept. The International Journal of Tuberculosis and Lung Disease, 2016; 20 (5): 696 DOI: 10.5588/ijtld.15.0796

Ovarian cancer study uncovers new biology

In what is believed to be the largest study of its kind, scientists at The Johns Hopkins University and the Pacific Northwest National Laboratory led a study that examined the proteomes of 169 ovarian cancer patients to identify critical proteins expressed by their tumors.

By integrating their findings with the tumors' genetic data -- the cancer genome -- the investigators report the potential for new insights into the progress of the most malignant form of the disease.

"Correlating our data with clinical outcomes is the first step toward the eventual ability to predict outcomes that reflect patient survival, with potential applications for precision medicine and new targets for pharmaceutical interventions," says Daniel W. Chan, Ph.D., a professor of pathology and oncology who led the team at the Johns Hopkins University School of Medicine. "But just like anything in medicine, clinical validation will be a long and rigorous process."

In a summary of the work published in the advance online edition of Cell on June 29, 2016, the researchers say their achievement illustrates the power of combining genomic and proteomic data to potentially yield a more complete picture of the biology of a cancer that accounts for 3 percent of all cancers in women and is the fifth leading cause of cancer deaths among women in the United States.

"With this knowledge, researchers expect to be better able to identify the biological factors defining the 70 percent of ovarian cancer patients who suffer from the most malignant form of ovarian cancer, called high-grade serous carcinoma," says Chan. Currently, only one in six patients lives five or more years beyond diagnosis.

"Historically, cancer's been looked at as a disease of the genome," says Karin Rodland, Ph.D., chief scientist for biomedical research at the Pacific Northwest National Laboratory. "But that genome has to express itself in functional outcomes, and that's what the proteomic data add, because proteins are what get the actual work of the genome done."

That work starts, Rodland says, when genes are transcribed into RNA, the genetic material that makes protein, the full set of which is referred to as the transcriptome.

The biological complexity of cancer is due in significant part to the fact that not every part of the transcriptome leads to proteins, and not every protein stays stable, with many undergoing changes that affect their impact and interactions with other proteins.

In their effort to better explain ovarian cancer biology, each team studied subsets of 169 high-grade serous carcinoma tissue samples and accompanying genomic and clinical data drawn from The Cancer Genome Atlas (TCGA), a collaborative effort to map cancer's genetic mutations. The task for ovarian cancer was completed in 2011.

The Johns Hopkins team initially selected 122 of the samples based on those tumors' ability to repair damaged DNA -- known as homologous recombination deficiency -- and characterized by changes in genes, including BRCA1, BRCA2 and PTEN, mutations long linked to increased cancer risk and severity.

"We chose to examine these samples because patients with changes in these genes already are benefiting from a specific drug regimen for breast cancer, so if we could find similar changes in ovarian cancer genomes and proteomes, those patients would likely benefit from the same regimen," says Chan.

The Pacific Northwest team initially selected 84 samples based on overall patient survival times. "We examined the data for the shortest-surviving patients and the longest-surviving patients, hoping to pinpoint biological factors associated with extremely short survival or better-than-average, longer survival," says Rodland.

Then, through their participation in the Clinical Proteomic Tumor Analysis Consortium (CPTAC), a program of the U.S. National Cancer Institute that funded both teams, the two teams combined their efforts.

Using protein measurement and identification techniques, such as mass spectrometry, the teams identified 9,600 proteins in all the tumors and pursued study on 3,586 proteins common to all 169 tumor samples.

A hallmark of cancer, and particularly high-grade serous carcinoma, is the appearance of more copies of certain regions of the genome. These so-called copy number alterations can lead to changes in protein abundance. When the researchers compared known regions of copy number alterations, they found that parts of chromosomes 2, 7, 20 and 22 led to changes in abundance of more than 200 proteins. A more careful study of those 200 proteins revealed that many are involved in cell movement and immune system function, both processes implicated in cancer progression, the researchers say.

"By comparing data for overlapping patient samples and finding comparable measurements of protein analysis at both institutions, we think our findings indicate excellent scientific rigor and reproducibility," says Rodland.

This work should give researchers everywhere a wealth of credible information, she continues, because of the number of samples investigated, the number of proteins investigated in each sample, and the ability to cross-reference and correlate the new protein data with the TCGA genome and transcriptome data. "In brief, adding the proteome on top of the genome -- what we call proteogenomics -- provided a new dimension of information that enabled discovery of new biological insights into ovarian cancer while creating a valuable resource for the scientific community," says Rodland.

"High-grade serous carcinoma is such a challenging disease, requiring complex clinical care to achieve long-term survival. This new knowledge gives us new directions to test in the lab and clinic," says Douglas A. Levine, M.D., director of gynecologic oncology at the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center. "This proteogenomic analysis will help us improve patient outcomes and quality of life."

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The above post is reprinted from materials provided by Johns Hopkins Medicine. Note: Materials may be edited for content and length.

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Johns Hopkins Medicine. "Ovarian cancer study uncovers new biology: Proteogenomics provides new inroads to diagnosis, treatment." ScienceDaily. ScienceDaily, 29 June 2016. .

12 benefits of cholesterol

Cholesterol is not the killer it has been made out to be. In fact it is an incredible important structural and functional chemical in your body. One of the most important. No person has ever died from high cholesterol but many now die from low cholesterol. There is no such thing as bad cholesterol just bad medicine and lazy doctors.
Here are some of the benefits of cholesterol
Make hormones to deal with stress
All your sex hormones are made from cholesterol (estrogen, progesterone and testosterone- imagine what happens when you lower this)
Vitamin D is made from cholesterol (for you immune system, healthy bones and so much more)
Bile for digestion
Acts as an antioxidant
In the brain it helps form memories
Helps form serotonin receptors in the brain to feel good
Helps develop healthy brain and nervous system in infants (high in breast milk)
An important structural component of you cell membrane
Repairs damaged arteries by filling the cracks with a soft rubber substance.
Important for your immune system
High LDL cholesterol (the so called bad one) reduces your risk of dying over the age of 60

10 steps to reduce your risk of breast cancer.

Despite what you may read in the media the risk of breast cancer can be dramatically reduced even if you have the breast cancer genes. Inherited genetic factors by themselves contribute relatively little to breast cancer risk. It is not the genes that cause the problem but what we do to the genes. Whether we activate them or not through our diet and lifestyle. The science of epigenetics.

Lose weight to get to your ideal weight
Eat more fruit and vegetables
Be more active. Walking is fine
Stop smoking
Reduce your red meat intake
Reduce your alcohol
Cut out all added sugar
Cut out all added vegetable oils (omega 6, margarine, sunflower, canola etc)
Reduce your stress
Lower your exposure to toxic chemicals (even in make up and shampoos- more on this later).

Strengthening immune defence may be solution for treating tuberculosis

Researchers at Linköping University have made a discovery that could contribute to developing new vaccines and treatment alternatives for tuberculosis in the future. The results have been published in Scientific Reports.

Eight million people suffer from -- and two million die from -- tuberculosis every year. For HIV patients, tuberculosis is the leading cause of death. Antibiotics are currently used against tuberculosis, as no effective vaccine could be developed thus far -- but with growing resistance to antibiotics, the cure for tuberculosis is threatened.

"When the world of research is looking for medicines, finding ways to strengthen immune defense is also now desirable, since medicines that attach the bacteria directly have been shown to lead to the development of resistance to antibiotics. Strengthening the immune defense system can be done through things like what is known as 'stimulated autophagy'. But our research shows that the most common signal path for stimulating autophagy can be immediately dangerous," says Robert Blomgran, research fellow in medicinal microbiology at Linköping University.

Autophagy is an important process that occurs naturally in the body to clean out defective proteins and components that could otherwise damage the cells and cause illness. Making use of this process -- what we call 'stimulated autophagy' -- could be one way of also protecting the body against intracellular microbes. Currently, the most common pharmacological activation of autophagy occurs through what is known as mTORC1 inhibition.

What the researchers discovered was that when the tubercule bacilli are few -- which they are when the illness has not yet broken out -- stimulated autophagy through mTORC1 inhibition is harmful. Instead, the process leads to the tubercule bacilli multiplying within the host cell, which in patients could involve the risk that the tuberculosis worsens.

If the TB patient also has HIV, that illness worsens. This is why the researchers looked more closely at what effects the induction of autophagy has in immune cells infected with both HIV and tuberculosis. The experiments showed that autophagy was then exceptionally dangerous, with an uncontrolled growth of tubercule bacilli as a result.

"How autophagy is stimulated needs to be reviewed so that over the long term it can have the desired effect in patients with tuberculosis, and in the extra sensitive patient group with both tuberculosis and HIV. If this is taken into consideration when new medicines are tested, setbacks could be prevented," Mr Blomgran says.

The research group will now be working further on research concerning other ways to stimulate autophagy and strengthen immune defense cells such as macrophages and dendritic cells, thus controlling the tubercule bacilli.

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Story Source:

The above post is reprinted from materials provided by Linköping Universitet. Note: Materials may be edited for content and length.

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Journal Reference:

1. Anna-Maria Andersson, Blanka Andersson, Christoffer Lorell, Johanna Raffetseder, Marie Larsson, Robert Blomgran. Autophagy induction targeting mTORC1 enhances Mycobacterium tuberculosis replication in HIV co-infected human macrophages. Scientific Reports, 2016; 6: 28171 DOI: 10.1038/srep28171

New cancer immunotherapy drugs linked to arthritis in some patients

Case reports on 13 cancer patients suggest that a small number of cancer patients taking the immunotherapy drugs ipilimumab and nivolumab may be at some higher-than-normal risk of developing autoimmune joint and tissue diseases, including inflammatory arthritis, according to a preliminary study by Johns Hopkins Medicine researchers.

"I don't think anyone is particularly surprised that rheumatologic disorders might be a complication of drugs that boost the immune system," says study author Laura C. Cappelli, M.D., a rheumatologist at the Johns Hopkins University School of Medicine. But the new study, however small in sample size, she says, is believed to be the largest published case series of a link between the drugs and the diseases.

The patients described in the new case report make up only about 1.3 percent of the total patients treated with drugs -- singly or in combination -- at The Johns Hopkins Hospital from 2012 to 2016, Cappelli says, but if further research confirms a cause-and-effect relationship, the rate is likely an underestimation of how common rheumatologic diseases are in patients taking so-called immune checkpoint inhibitors. She notes that patients with only mild joint pain, for instance, or those with already deteriorating health from their cancers may not have been referred to the rheumatology clinic for their symptoms.

"We keep having referrals coming in from our oncologists as more patients are treated with these drugs," says Clifton Bingham, M.D., associate professor of medicine at the Johns Hopkins University School of Medicine and director of the Johns Hopkins Arthritis Center. "In particular, as more patients are treated with combinations of multiple immunotherapies, we expect the rate to go up."

Between 2012 and 2016, 13 patients at the Johns Hopkins Kimmel Cancer Center who were taking one or both drugs to treat their cancers developed new-onset arthritis or sicca syndrome, a set of autoimmune conditions causing dry eyes and mouth, including Sjogren's syndrome. The cases were described online June 15 in Annals of Rheumatic Diseases.

"In 2015, our rheumatology clinic started getting more and more referrals from our oncology department to evaluate patients treated with immunotherapies," says Cappelli. "And the patients we saw had very severe, highly inflammatory arthritis. They needed even higher doses of steroids to control their symptoms compared to what is needed in other forms of inflammatory arthritis, like rheumatoid arthritis."

Ipilimumab and nivolumab -- as well as a growing number of other checkpoint inhibitors now in clinical trials -- are designed to turn off the molecular "checkpoints" that some cancers use to evade the body's natural immune system cells. When the drugs work, they allow the immune system to detect -- and attack -- tumor cells. But because they also turn up the activity of the immune system as a whole, the drugs can trigger immune-related side effects, including so-called autoimmune responses, in which the body attacks its own cells and tissues.

Cappelli notes that clinical trials of ipilimumab and nivolumab found an increased risk of inflammatory bowel diseases, lung inflammation, autoimmune thyroid disease and pituitary gland inflammation. But those trials were designed primarily to determine efficacy against cancer and not to fully examine all features of rheumatologic side effects, she says.

Overall, Cappelli and her colleagues identified 13 patients who had developed previously undiagnosed or reported rheumatologic symptoms after their treatment with the immune checkpoint inhibitors. All were over 18 and had been treated for melanoma, nonsmall-cell lung cancer, small-cell lung cancer or renal carcinoma. Eight were taking a combination therapy with both ipilimumab and nivolumab, while five were only taking one of the two drugs. Nine of the patients developed inflammatory arthritis, and the other four were diagnosed with sicca syndrome. With treatment, all patients were able to get their rheumatologic diseases under control, though not eliminated.

Cappelli says she wants the case report to raise awareness among both patients and clinicians that rheumatologic side effects may occur with the drugs. "It is important when weighing the risk-benefit ratio of prescribing these drugs," she says. "And it's important for people to be on the lookout for symptoms so they can see a rheumatologist early in an effort to prevent or limit joint damage."

Cappelli, Bingham and their rheumatology colleagues are planning further collaboration with Johns Hopkins oncologists to better track the incidence of rheumatologic disease in patients taking immunotherapy drugs and determine whether any particular characteristics put cancer patients at higher risk of rheumatologic complications.

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Story Source:

The above post is reprinted from materials provided by Johns Hopkins Medicine. Note: Materials may be edited for content and length.

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Journal Reference:

1. Laura C Cappelli, Anna Kristina Gutierrez, Alan N Baer, Jemima Albayda, Rebecca L Manno, Uzma Haque, Evan J Lipson, Karen B Bleich, Ami A Shah, Jarushka Naidoo, Julie R Brahmer, Dung Le, Clifton O Bingham.Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Annals of the Rheumatic Diseases, 2016; annrheumdis-2016-209595 DOI: 10.1136/annrheumdis-2016-209595

Disrupted immunity in fetal brain is linked to neurodevelopmental disorders

Findings in mice may help explain how viral infection during pregnancy raises the risk of autism, schizophrenia in offspring

Disrupted fetal immune system development, such as that caused by viral infection in the mother, may be a key factor in the later appearance of certain neurodevelopmental disorders. This finding emerges from a Weizmann Institute study published in Science on June 23, 2016.

The study may explain, among other things, how the mother's infection with the cytomegalovirus (CMV) during pregnancy, which affects her own and her fetus's immune system, increases the risk that her offspring will develop autism or schizophrenia, sometimes years later. This increased risk of neurodevelopmental diseases had been discovered many years ago in epidemiological studies and confirmed in mouse models. The Weizmann study, led by Dr. Ido Amit and Prof. Michal Schwartz, of the Immunology and Neurobiology Departments, respectively, provides a possible explanation for this increase on the cellular and the mechanistic molecular levels.

"Previous studies had shown that the timing of the disruption in the mother's immune system during pregnancy affects the type of brain damage her child may develop. For example, a viral infection in early pregnancy raises the risk of autism, whereas an infection later in the pregnancy raises the risk of schizophrenia," said Amit. "We've set out to examine the mechanisms behind these phenomena, while focusing on the role the immune system plays in brain development."

Orit Matcovitch-Natan, a graduate student in the laboratories of both Amit and Schwartz, and other members of the two teams, studied the sole immune cells present in the brain -- the microglia, which contribute to the brain's development and maintenance. The scientists discovered that the development of these cells in the mouse fetus and in newborn mice proceeds in three distinct stages, parallel to those of the developing brain: early cells that populate the brain of the embryo shortly after its inception, pre-microglia and adult cells. By screening the genomes of these cells and testing them extensively, the scientists were able to define each stage in terms of its activated genes, their control mechanisms and the epigenetic features, that is, the activation of proteins that "package" the DNA and affect gene expression in the course of development. The scientists also characterized the functions of some of these genes in the microglia, which contributed to an in-depth understanding of the developmental processes.

The second stage -- that of the pre-microglia -- proved the most sensitive to disruptions. This stage takes place close to birth and shortly afterwards, just when the developing brain undergoes the vital process of "pruning," in which inappropriate synapses among neurons are lopped off. The pre-microglia play an important role in pruning, helping remove the superfluous neuronal networks, and shaping and strengthening the connections among the remaining neurons. When the scientists exposed the brains of pregnant mice to synthetic materials that mimic a CMV infection, they found that the development of the pre-microglia was disrupted in their offspring. Genes involved in the maturation of these cells were expressed at the wrong time, and the cells proceeded to an adult stage earlier than usual. The offspring later exhibited abnormal behavior, including disturbances in social interaction and behaviors similar to those of people with schizophrenia.

"We've discovered that it's essential for the development of immune cells in the brain to be synchronized with the development of the brain itself," says Schwartz. "Premature shift of the microglia in mice to the adult stage leads to brain malfunction later on." Though these findings have been obtained in mice, the scientists hypothesize that disrupted coordination between the development of the microglia and that of the brain contributes to an increased risk of such neurodevelopmental disorders as autism and schizophrenia in human beings. The scientists believe that the heightened immune response to viral infection in the mother's body may be responsible for disrupting the timing of microglia development.

"Our research has paved the way for studying the effects of other viruses on the mother's immune system in general, and on her offspring's brain development. It can also advance the study of neurodevelopmental disorders and their connection to the immune system," says Orit Matcovitch-Natan.

In yet another series of experiments, the Weizmann scientists established a connection between the development of the microglia in the brains of mice and intestinal microbes -- the microbiome. They found that in newborn mice that were free of any microbes, the maturation of the microglia was delayed. This finding suggests that in human babies, factors that shape the microbiome -- natural ones such as breastfeeding, or therapeutic, such as antibiotics -- may affect the immune cells in the baby's brain and consequently the brain's development. It's still unknown to what extent this research, conducted in mice, is relevant to human beings, but the scientists hope that an improved understanding of this process may in the future help prevent certain neurological disorders in babies, caused by disruptions in the mother's immune system.

Taking part in the study were Dr. Deborah R. Winter, Amir Giladi, Eyal David and Dr. Hadas Keren-Shaul, as well as Dr. Eran Elinav and Christoph Thaiss of the Immunology Department, and Hila Ben-Yehuda, Merav Cohen and Dr. Kuti Baruch of the Neurobiology Department. Matcovitch-Natan and Amit Spinrad, also a graduate student, belonged to both departments. Study participants also included Prof. Michael H. Sieweke of Centre National de la Recherche Scientifique, France.

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Story Source:

The above post is reprinted from materials provided by Weizmann Institute of Science. Note: Materials may be edited for content and length.

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Journal Reference:

1. O. Matcovitch-Natan, D. R. Winter, A. Giladi, S. Vargas Aguilar, A. Spinrad, S. Sarrazin, H. Ben-Yehuda, E. David, F. Zelada Gonzalez, P. Perrin, H. Keren-Shaul, M. Gury, D. Lara-Astaiso, C. A. Thaiss, M. Cohen, K. Bahar Halpern, K. Baruch, A. Deczkowska, E. Lorenzo-Vivas, S. Itzkovitz, E. Elinav, M. H. Sieweke, M. Schwartz, I. Amit. Microglia development follows a stepwise program to regulate brain homeostasis. Science, 2016; DOI: 10.1126/science.aad8670