Sunday, July 31, 2016

Hybrid treatment hunts down and kills leukemia cells

Researchers at UC Davis and Ionis Pharmaceuticals have developed a hybrid treatment that harnesses a monoclonal antibody to deliver antisense DNA to acute lymphoblastic leukemia (ALL) cells and that may lead to less toxic treatments for the disease.
The study, published in the journal Molecular Medicine, demonstrated that once delivered, the therapeutic DNA reduced levels of MXD3, a protein that helps cancer cells survive. This novel conjugate therapy showed great promise in animal models, destroying ALL cells while limiting other damage.
"We've shown, for the first time, that anti-CD22 antibody-antisense conjugates are a potential therapeutic agent for ALL," said Noriko Satake, associate professor in the Department of Pediatrics at UC Davis. "This could be a new type of treatment that kills leukemia cells with few side effects."
ALL is the most common type of childhood cancer. It is a disease in which the bone marrow makes too many immature lymphocytes, a type of white blood cell. While most children survive ALL, many patients suffer late or long-term side effects from treatment, which may include heart problems, growth and development delays, secondary cancers and infertility.
Antisense oligonucleotides are single strands of DNA that can bind to messenger RNA, preventing it from making a protein. While antisense technology has long shown therapeutic potential, getting the genetic material inside target cells has been a problem.
In the study, researchers attached antisense DNA that inhibits the MXD3 protein to an antibody that binds to CD22, a protein receptor expressed almost exclusively in ALL cells and normal B cells.
Once the antibody binds to CD22, the conjugate is drawn inside the leukemia cell, allowing the antisense molecule to prevent MXD3 production. Without this anti-apoptotic protein, ALL cells are more prone to cell death.
The hybrid treatment was effective against ALL cell lines in vitro and primary (patient-derived) ALL cells in a xenograft mouse model. Animals that received the hybrid therapy survived significantly longer than those in the control group.
Designed to be selective, the treatment only targets cells that express CD22. While it does attack healthy B cells, the therapy is expected to leave blood stem cells and other tissues unscathed.
"You really don't want to destroy hematopoietic stem cells because then you have to do a stem cell transplant, which is an extremely intensive therapy," noted Satake. "Our novel conjugate is designed so that it does not harm hair, eyes, heart, kidneys or other types of cells."
While the study shows the conjugate knocked down MXD3, researchers still have to figure out how this was accomplished. In addition, they will investigate combining this treatment with other therapies. Because it hastens cell death, the conjugate could make traditional chemotherapy drugs more effective. In addition, the approach might work against other cancers.
"You can see this as proof of principle," Satake said. "You could switch the target and substitute the antibody, which could be used to treat other cancers or even other diseases."

Story Source:
The above post is reprinted from materials provided by UC Davis Comprehensive Cancer CenterNote: Materials may be edited for content and length.

Cite This Page:
UC Davis Comprehensive Cancer Center. "Hybrid treatment hunts down and kills leukemia cells." ScienceDaily. ScienceDaily, 28 July 2016. .

Scientists discover new therapeutic target for lung cancer driven by KRAS

UT Southwestern Medical Center researchers have identified a new way to target lung cancer through the KRAS gene, one of the most commonly mutated genes in human cancer and one researchers have so far had difficulty targeting successfully.
Researchers studying the underlying biology of KRAS in lung cancer determined that activity resulting from the ACSL3 gene is essential for these lung cancer cells to survive, and that suppressing ACSL3 causes these lung cancer cells to die.
The findings are significant because genetic mutations of KRAS occur in about 30 percent of lung cancer cases, and they are associated with aggressive, therapy-resistant disease with a poor prognosis. Lung cancer remains the leading cause of cancer-related deaths in the U.S., according to the National Cancer Institute (NCI).
"Despite some recent advances, mutant KRAS remains a very challenging target. There is a dearth of treatment options for tumors initiated by this gene," said senior author Dr. Pier Paolo Scaglioni, Associate Professor of Internal Medicine in the Division of Hematology and Oncology, and a member of the Harold C. Simmons Comprehensive Cancer Center.
The KRAS gene (Kirsten rat sarcoma viral oncogene homolog), produces proteins called K-Ras that influence when cells divide. Mutations in K-Ras can result in normal cells dividing uncontrollably and turning cancerous.
"Mutant KRAS not only promotes the growth of tumors, but also the survival of established lung cancer. Since we have no clinically-relevant effective inhibitors of mutant KRAS at this time, there has been an intense clinical interest in developing a treatment that is proven effective," said Dr. Scaglioni, who leads the Cancer Signaling Laboratory at the Simmons Cancer Center.
The team found that the enzymatic activity of ACSL3 (Acyl-CoA synthetase long-chain family member 3) is needed for the mutant KRAS gene to promote the formation of lung cancer, and further demonstrated that fatty acids, which are the substrates of ACSL3 enzyme, have a critical role in lung cancer.
"There is an urgent need for discovery of additional targets that inhibit lipid metabolism in cancer cells that could lead to targeted therapies: the discovery of the importance of ACSL3 in lung cancer meets this unmet need," said Dr. Mahesh S. Padanad, first author and part of the UT Southwestern team, which also includes postdoctoral fellow Dr. Smita Rindhe, and Dr. Margherita Melegari, research associate.
The study, published in Cell Reports, used several complementary approaches, including cell lines, mice, and human patient tumor samples to understand the biological significance of ACSL3 in lung cancer.

Story Source:
The above post is reprinted from materials provided by UT Southwestern Medical CenterNote: Materials may be edited for content and length.

Journal Reference:
  1. Mahesh S. Padanad, Georgia Konstantinidou, Niranjan Venkateswaran, Margherita Melegari, Smita Rindhe, Matthew Mitsche, Chendong Yang, Kimberly Batten, Kenneth E. Huffman, Jingwen Liu, Ximing Tang, Jaime Rodriguez-Canales, Neda Kalhor, Jerry W. Shay, John D. Minna, Jeffrey McDonald, Ignacio I. Wistuba, Ralph J. DeBerardinis, Pier Paolo Scaglioni. Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis.Cell Reports, 2016; DOI: 10.1016/j.celrep.2016.07.009

Novel drug therapy kills pancreatic cancer cells by reducing levels of antioxidants

Reducing levels of antioxidants in pancreatic cancer cells can help kill them, newly published research reveals, suggesting an entirely new treatment strategy for the notoriously lethal illness, in which less than 5 percent of patients survive 5 years.
Although it has become almost a matter of conventional wisdom in popular culture that raising antioxidant levels in the body tends to keep cancer at bay, a team at Cold Spring Harbor Laboratory (CSHL) demonstrates in a series of sophisticated experiments that in the specific context of pancreatic cells on the road to cancer or already in a malignant state, the last thing one wants to do is to raise antioxidant levels.
Oxidizing and anti-oxidizing agents are created in every cell, and are kept in a very precise balance when cells are healthy. The CSHL team, led by Professor David Tuveson, M.D., Ph.D., who is also director of research for The Lustgarten Foundation, proceeds from the insight that proliferating cancer cells present a special case: more oxidants are being made in malignant cells, but more anti-oxidants are being made, too, countering the impact of rising oxidation. Without commensurately more anti-oxidants, malignant cells will die due to excessive oxidation.
"Of course, that's exactly what we want cancer cells to do -- to burn themselves out," observes Iok In Christine Chio, a postdoctoral investigator in the Tuveson lab who led experiments reported in the journal Cell. "The therapeutic principle our lab is testing is whether, by increasing the level of oxidation in cancer cells, we can cause pre-malignant and malignant cells to die."
Most existing forms of cancer therapy, including ionizing radiation treatments and chemotherapy, depend on the killing power of oxidation. Anti-oxidants do indeed have a role in cellular health; but when it comes to killing cancer cells, they are anathema.
When cells detect excessive oxidation, they literally commit suicide, following a built-in program called apoptosis. One way of increasing oxidation in cancer cells is to decrease levels of antioxidants in those same cells. A question addressed by Tuveson's team was how best to do this -- and do it in a way that does not harm healthy cells. They focused on a protein called NRF2 (pronounced "nerf-2"). Scientists call it a master regulator of redox homeostasis -- by which they mean that it's one of the switches one can tweak to disturb the exquisite balance between oxidation and reduction in cancer cells.
When NRF2 is active, cells synthesize a chemical called glutathione, an important antioxidant. It makes sense, then, to try to reduce NRF2 activity or knock it out of action altogether. This is not possible, for two reasons. One is that it is a transcription factor -- a protein that regulates the activity of other genes. Transcription factors are famously difficult to target with drugs. But "you probably wouldn't want to knock it out, in any case," says Chio, "because in addition to promoting production of glutathione, NRF2 has a role in regulating several hundred different genes." One can't delete it from a cell without impacting many other processes.
Tuveson, Chio and other members of the team arrived at a different strategy after conducting experiments in pancreas cells grown in the lab and testing a number of new therapeutic approaches in an animal model of pancreatic cancer.
Using a panel of pancreas organoids -- spherical agglomerations of pancreas cells sampled from people with pancreatic cancer and from the healthy pancreas -- they were able to observe what happens when NRF2 is completely eliminated. The test was run in normal, pre-malignant and malignant pancreas organoids. The pre-malignant organoids carried cellular mutations in the kras gene, which is aberrant in nearly all human pancreatic cancers. The malignant organoids bore that mutation plus a mutation that inactivated the powerful tumor suppressor gene p53. That mutation along with kras is seen in most human malignancies.
These experiments provided a critical clue: The team saw that when NRF2 is missing, the machinery in cells that translates messages from genes into proteins -- the process of protein synthesis -- is very sensitive to fluctuations in the balance between oxidants and anti-oxidants. Crucially, however, protein synthesis was not impacted in normal pancreas cells. "We were very excited when we saw this, " Chio says. "This meant that if we could find a way of reducing antioxidants, protein synthesis would only be impacted in precancerous and malignant cells, a potentially powerful therapeutic strategy."
This phenomenon is called synthetic lethality. It occurs when a condition affecting both healthy and unhealthy cells is lethal only to the unhealthy cells.
The team came up with a two-drug cocktail, which they delivered to mice that model pancreatic cancer. One of the agents, called an AKT inhibitor, is designed to inhibit the beginning of translation process that leads to protein synthesis. The other agent, called BSO, inhibits the synthesis of glutathione, an antioxidant.
AKT inhibitors, administered alone, have produced only modest survival benefits in both mouse models and human patients. "We hoped that by combining them with BSO we might generate a synergy that would boost its effectiveness," says Chio. In effect, the strategy was to mimic biochemically what would happen if they were able to knock out or reduce levels of NRF2 in cancer cells. It was the rationale for hitching BSO to the AKT inhibitor.
"This is where our pancreas organoid system was so valuable," Chio says. "We were able to test this idea and see that this approach was synthetically lethal -- it did increase the killing power of the AKT inhibitor, but the synergy was not present in the setting of normal pancreas cells," she says. In other words, normal pancreas cells were not harmed by the treatment.
The team's new paper reports a synergistic effect in the mouse model of pancreas cancer, as well, proving the concept of killing more cancer by decreasing cancer cell antioxidant levels. Not fully satisfied with the survival benefit noted -- comparatively small in the mice -- they believe they can optimize the treatment by combining different combinations of translation inhibitors and repressors of antioxidant synthesis. This work is well under way.
The approach is potentially pertinent in other cancers in which kras mutations place cells on the road to malignancy. These include certain types of lung cancer and breast cancer.
Dr. Tuveson, who is director of The Lustgarten Foundation Pancreatic Cancer Research Laboratory as well as director of research for The Lustgarten Foundation and Deputy Director of the CSHL Cancer Center, says he is excited about the research.
"Pancreatic cancer employs NRF2 as one of its henchmen to promote bad behavior, but the details were previously unclear," Dr. Tuveson says. "By developing organoid models, Christine, proteomics expert Darryl Pappin of CSHL and their collaborators pursued the basic biology of NRF2 to unravel the molecular underpinnings of this protein and thereby propose new therapeutic approaches for patients. We plan to translate Christine's findings to early phase clinical trials in the near future."

Story Source:
The above post is reprinted from materials provided by Cold Spring Harbor LaboratoryNote: Materials may be edited for content and length.

Journal Reference:
  1. Iok In Christine Chio, Seyed Mehdi Jafarnejad, Mariano Ponz-Sarvise, Youngkyu Park, Keith Rivera, Wilhelm Palm, John Wilson, Vineet Sangar, Yuan Hao, Daniel Öhlund, Kevin Wright, Dea Filippini, Eun Jung Lee, Brandon Da Silva, Christina Schoepfer, John Erby Wilkinson, Jonathan M. Buscaglia, Gina M. DeNicola, Herve Tiriac, Molly Hammell, Howard C. Crawford, Edward E. Schmidt, Craig B. Thompson, Darryl J. Pappin, Nahum Sonenberg, David A. Tuveson. NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic CancerCell, 2016; DOI: 10.1016/j.cell.2016.06.056

Thursday, July 28, 2016

Gene therapy for metabolic liver diseases shows promise


With a shortage of donor organs, Mayo Clinic is exploring therapeutic strategies for patients with debilitating liver diseases. Researchers are testing a new approach to correct metabolic disorders without a whole organ transplant. Their findings appear in Science Translational Medicine.
The medical research study tested gene therapy in pigs suffering from hereditary tyrosinemia type 1 (HT1), a metabolic disorder caused by an enzyme deficiency. The common treatment for this disease is a drug regimen, but it is ineffective in many patients, and the long-term safety of using the drug is unknown.
"Liver transplant is the only curable option in treating HT1, which is characterized by progressive liver disease," says Raymond Hickey, Ph.D., a Mayo surgical researcher. "Using this novel approach to treat HT1 and other metabolic diseases will allow patients to avoid a liver transplant and save more lives."
Through gene therapy, the corrected liver cells are transplanted into the diseased liver, resulting in enzyme production. "This treatment is a new form of cell transplantation that utilizes the patient's own cells, so it does not require immunosuppressive drugs and, thus, avoids the side effects of those drugs," says Scott Nyberg, M.D., Ph.D., a liver transplant surgeon at Mayo Clinic. This therapy resulted in the improvement of pigs with HT1 and the prevention of liver failure. The use of nuclear imaging enables the researchers to monitor expansion of the corrected cells through a noninvasive imaging process.
"Pediatric patients suffering from inborn errors of metabolism of the liver will benefit most from this therapy," says Dr. Hickey. "More than one-fifth of all pediatric liver transplants are a result of metabolic disease."
The study also examines the use of lentiviral vectors for cell delivery in treating liver diseases, a tool traditionally used in treating blood disorders.

Story Source:
The above post is reprinted from materials provided by Mayo Clinic. The original item was written by Bob Nellis. Note: Materials may be edited for content and length.

Journal Reference:
  1. R. D. Hickey, S. A. Mao, J. Glorioso, F. Elgilani, B. Amiot, H. Chen, P. Rinaldo, R. Marler, H. Jiang, T. R. DeGrado, L. Suksanpaisan, M. K. OConnor, B. L. Freeman, S. H. Ibrahim, K. W. Peng, C. O. Harding, C.-S. Ho, M. Grompe, Y. Ikeda, J. B. Lillegard, S. J. Russell, S. L. Nyberg.Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1Science Translational Medicine, 2016; 

Diabetes prevention programs beneficial in improving cardio-metabolic profiles

A new study by researchers at Emory's Rollins School of Public Health and the Centers for Disease Control and Prevention (CDC) shows that lifestyle modification programs modeled on diabetes prevention programs (DPP) trials not only achieved weight reduction, but also additional metabolic benefits -specifically, reductions in blood sugar, blood pressure, and cholesterol levels. The researchers compiled data from 44 published studies with nearly 9,000 adults participating in DPP conducted in US communities, clinics, and through online media.
Led by Mohammed K. Ali, MD, MSc, MBA, associate professor in the Hubert Department of Global Health at Emory, the study offers an overview of the range of metabolic benefits possible through lifestyle modification programs and the program and participant features that were associated with greater benefit.
"There are a number of studies that have shown that weight loss is achievable through DPP programs," says Ali. "Our study goes further by estimating the aggregate metabolic changes that can be achieved."
Complete findings are available in the July 27th edition of PLOS Medicine.
"Our study has relevance for the Centers for Medicare and Medicaid (CMS) which announced in March 2016 their intention to cover diabetes prevention programs for the Medicare population that are at high risk for diabetes. Though CMS has not indicated an intention to cover Medicaid beneficiaries, these findings may prompt further consideration regarding covering this group," says Ali. "Our findings are also relevant for private payer groups and providers of diabetes prevention services, reinforcing several take home messages, that:
  • Lifestyle modification programs to prevent diabetes can be delivered effectively in non-academic and non-clinical settings;
  • on average, participants in the 44 included studies were similar to participants in the original DPP trial, and achieved less weight loss (3.8 vs. 6.8kg), but similar improvements in glucose, blood pressure, and cholesterol reductions; and
  • programs with a maintenance component (keeping contact with participants even after the core program sessions are complete) were associated with larger benefits."
Diabetes currently affects approximately 29 million Americans, and a further 86 million US adults have prediabetes, putting them at high risk of developing diabetes. Identifying people at risk for diabetes, like those with prediabetes, and enrolling them in programs may be an important public health approach to addressing growing diabetes burdens in the US. By 2050, the prevalence of diabetes is expected to reach 25 percent. Adults with diabetes have two to four times higher rates of death from heart disease or stroke with medical expenses that double those without diabetes.
The authors conclude: "According to our findings, there is no difference in outcomes based on who or where DPP programs are delivered, and improvement in other cardio-metabolic factors suggests the program may be especially cost-effective. These types of interventions can yield great results for diabetes prevention if distributed nationally."

Story Source:
The above post is reprinted from materials provided by Emory Health SciencesNote: Materials may be edited for content and length.

Journal Reference:
  1. Uma Mudaliar, Azadeh Zabetian, Michael Goodman, Justin B. Echouffo-Tcheugui, Ann L. Albright, Edward W. Gregg, Mohammed K. Ali.Cardiometabolic Risk Factor Changes Observed in Diabetes Prevention Programs in US Settings: A Systematic Review and Meta-analysisPLOS Medicine, 2016; 13 (7): e1002095 DOI:10.1371/journal.pmed.1002095

20 minutes of ultrasound to the forearm cuts high blood pressure

Blood pressure can significantly drop by applying 20 minutes of ultrasound to the forearm of type II diabetes patients with treatment-resistant hypertension, according to research from Japan's Tohoku University.
High blood pressure is estimated to cause 7.5 million deaths worldwide and can be difficult to control in some patients with type II diabetes.
Katsunori Nonogaki, of Tohoku University's Department of Diabetes Technology, and colleagues, enrolled 212 type II diabetes patients with treatment-resistant hypertension.
They were divided into four groups. One received 20 minutes of low frequency (800 kHz), low-intensity ultrasound irradiation to the forearm. Another received 500 kHz of low-intensity irradiation for 20 minutes. The other two groups were used as controls, receiving a placebo procedure.
They found that the patients' blood pressure and pulse rates were significantly reduced after both 800kHz and 500kHz irradiation sessions compared to pre-treatment levels. Blood pressure levels were also lower than those of the placebo groups, but significantly so in the case of the 500kHz treatment. No adverse effects were found in either group as a result of the ultrasound treatment.
How ultrasound improves blood pressure in these patients is still unclear, but it might suppress sympathetic nerve activity, responsible for the fight or flight response, by means of nerve pathways from the forearm to the cardiovascular system, the researchers say.
"We do not have specific treatments for resistant hypertension," says Nonogaki. "The cost of anti-hypertensive agents for patients is high. Ultrasound has the advantage of being cheap and non-invasive."

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

Journal Reference:
  1. Katsunori Nonogaki, Tomoe Yamazaki, Mari Murakami, Noriko Satoh, Miki Hazama, Kouji Takeda, Nobuyuki Tsujita, Shuichi Katoh, Nariki Kubota. Low-frequency and very low-intensity ultrasound decreases blood pressure in hypertensive subjects with type 2 diabetes.International Journal of Cardiology, 2016; 215: 147 DOI:10.1016/j.ijcard.2016.04.062

CONSTIPATION CAN KILL YOUR LIFE

Constipation indicates retention of waste materials in the body. The main cause of constipation on a physical level is a eating food that is difficult to digest. Milk Coffee/ Milk Tea in the morning may promote constipation, as they tend to be diuretic.
Short-term effects of constipation include bloating, abdominal pain, small amounts of blood or whitish mucus in the stool and an urgent need to have a bowel movement. Chronic, long-term constipation produces these and other, more harmful effects on our body.

What Do we mean by Proper Nutrition


Wednesday, July 27, 2016

Biological explanation for wheat sensitivity found

A new study may explain why people who do not have celiac disease or wheat allergy nevertheless experience a variety of gastrointestinal and extra-intestinal symptoms after ingesting wheat and related cereals. The findings suggest that these individuals have a weakened intestinal barrier, which leads to a body-wide inflammatory immune response.
Findings from the study, which was led by researchers from Columbia University Medical Center (CUMC), were reported in the journal Gut.
"Our study shows that the symptoms reported by individuals with this condition are not imagined, as some people have suggested," said study co-author Peter H. Green, MD, the Phyllis and Ivan Seidenberg Professor of Medicine at CUMC and director of the Celiac Disease Center. "It demonstrates that there is a biological basis for these symptoms in a significant number of these patients."
Celiac disease is an autoimmune disorder in which the immune system mistakenly attacks the lining of the small intestine after someone who is genetically susceptible to the disorder ingests gluten from wheat, rye, or barley. This leads to a range of gastrointestinal symptoms, including abdominal pain, diarrhea, and bloating.
Researchers have struggled to determine why some people, who lack the characteristic blood, tissue, or genetic markers of celiac disease, experience celiac-like GI symptoms, as well as certain extra-intestinal symptoms, such as fatigue, cognitive difficulties, or mood disturbance, after ingesting foods that contain wheat, rye, or barley. One explanation for this condition, known as non-celiac gluten or wheat sensitivity (NCWS), is that exposure to the offending grains somehow triggers acute systemic immune activation, rather than a strictly localized intestinal immune response. Because there are no biomarkers for NCWS, accurate figures for its prevalence are not available, but it is estimated to affect about 1 percent of the population, or 3 million Americans, roughly the same prevalence as celiac disease.
In the new study, the CUMC team examined 80 individuals with NCWS, 40 individuals with celiac disease, and 40 healthy controls. Despite the extensive intestinal damage associated with celiac disease, blood markers of innate systemic immune activation were not elevated in the celiac disease group. This suggests that the intestinal immune response in celiac patients is able to neutralize microbes or microbial components that may pass through the damaged intestinal barrier, thereby preventing a systemic inflammatory response against highly immunostimulatory molecules.
The NCWS group was markedly different. They did not have the intestinal cytotoxic T cells seen in celiac patients, but they did have a marker of intestinal cellular damage that correlated with serologic markers of acute systemic immune activation. The results suggest that the identified systemic immune activation in NCWS is linked to increased translocation of microbial and dietary components from the gut into circulation, in part due to intestinal cell damage and weakening of the intestinal barrier.
"A systemic immune activation model would be consistent with the generally rapid onset of the reported symptoms in people with non-celiac wheat sensitivity," said study leader Armin Alaedini, PhD, assistant professor of medicine at CUMC. He also holds an appointment in Columbia's Institute of Human Nutrition and is a member of the Celiac Disease Center.
NCWS patients who followed a diet that excluded wheat and related cereals for six months were able to normalize their levels of immune activation and intestinal cell damage markers, the researchers also found. These changes were associated with significant improvement in both intestinal and non-intestinal symptoms, as reported by the patients in detailed questionnaires.
Dr. Alaedini added, "The data suggest that, in the future, we may be able to use a combination of biomarkers to identify patients with non-celiac wheat sensitivity, and to monitor their response to treatment."
The study involved an international collaboration between researchers at CUMC and the University of Bologna, Bologna, Italy. "These results shift the paradigm in our recognition and understanding of non-celiac wheat sensitivity, and will likely have important implications for diagnosis and treatment," said co-author Umberto Volta, MD, professor of internal medicine at the University of Bologna. "Considering the large number of people affected by the condition and its significant negative health impact on patients, this is an important area of research that deserves much more attention and funding."
In future studies of NCWS, Dr. Alaedini and his team plan to investigate the mechanisms responsible for triggering the intestinal damage and breach of the epithelial barrier and to further characterize the immune cell responses.

Story Source:
The above post is reprinted from materials provided by Columbia University Medical CenterNote: Materials may be edited for content and length.

Journal Reference:
  1. Armin Alaedini et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac diseaseGut, July 2016 DOI: 10.1136/gutjnl-2016-311964

Vitamin D levels predict risk of brain decline in Chinese elderly

Research conducted by Duke-NUS Medical School (Duke-NUS) and Duke University has associated low vitamin D levels with increased subsequent risk of cognitive decline and impairment in the Chinese elderly.
Produced primarily in the skin upon exposure to sunlight, Vitamin D is necessary for maintaining healthy bones and muscles. It is now believed to also play a significant role in maintaining healthy brain function. An increased risk of cardiovascular and neurodegenerative diseases has been observed in those with low vitamin D levels, and studies from Europe and North America have linked low vitamin D levels with future cognitive decline.
This study asks similar questions of vitamin D levels and cognition in the Chinese elderly. It is the first large-scale prospective study in Asia to study the association between vitamin D status and risk of cognitive decline and impairment in the Chinese elderly. 1,202 study subjects greater than or equal to 60 years of age from the Chinese Longitudinal Health Longevity Survey took part in this study. Their baseline vitamin D levels were measured at the start of the study, and their cognitive abilities were assessed over 2 years.
Regardless of gender and extent of advanced age, individuals with lower vitamin D levels at the start of the study were approximately twice as likely to exhibit significant cognitive decline over time. In addition, low vitamin D levels at baseline also increased the risk of future cognitive impairment by 2-3 times.
"Although this study was conducted on subjects from China, the results are applicable to regions in Asia where a large proportion of the elderly are ethnically Chinese, like Singapore," said Professor David Matchar, first author of the study and Director of the Health Services and Systems Research Programme at Duke-NUS Medical School.
These findings reinforce the notion that vitamin D protects against neuron damage and loss, and call for more intensive investigations into the effects of vitamin D supplements on cognitive decline. Better understanding of the mechanism by which vitamin D protects neurons may help identify effective interventions to stem the rapidly increasing prevalence of cognitive decline observed in aging populations.

Story Source:
The above post is reprinted from materials provided by Duke-NUS Medical SchoolNote: Materials may be edited for content and length.

Journal Reference:
  1. David B. Matchar, Choy-Lye Chei, Zhao-Xue Yin, Victoria Koh, Bibhas Chakraborty, Xiao-Ming Shi, Yi Zeng. Vitamin D Levels and the Risk of Cognitive Decline in Chinese Elderly People: the Chinese Longitudinal Healthy Longevity SurveyThe Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2016; glw128 DOI:10.1093/gerona/glw128

Gene therapy developed for muscle wasting

A discovery by Washington State University scientist Dan Rodgers and collaborator Paul Gregorevic could save millions of people suffering from muscle wasting disease.
The result of the team's four-year project is a novel gene therapeutic approach. The work was published July 20 in Science Translational Medicine, a journal of the American Association for the Advancement of Science.
"Chronic disease affects more than half of the world's population," said Rodgers, professor of animal sciences and director of the Washington Center for Muscle Biology. "Most of those diseases are accompanied by muscle wasting.
"It occurs with chronic infection, muscular dystrophy, malnutrition and old age," he said. "About half the people who die from cancer are actually dying from muscle wasting and there's not one single therapy out there that addresses it.
Family history inspires search for treatment
"I have a strong motivation to do something about this, to do more than simply publish results," said Rodgers, who teamed with Gregorevic of Baker IDI Heart and Diabetes Institute in Australia. "My father died from cachexia," the wasting disease caused by cancer, "and my nephew has Duchenne muscular dystrophy, an incurable, fatal disease that could claim his life in his teens.
"Others have tried and failed to develop treatments for muscle wasting," Rodgers said, "and some drugs have even caused serious safety problems. Our targeted approach only affects muscle and completely avoids these problems, which is why we think we have a solution."
In the paper, lead author Catherine Winbanks, a postdoctoral fellow of Gregorevic, details how researchers built muscle in healthy mice and prevented the loss of skeletal and heart muscle in mice with tumors.
Hormone's muscle-wasting effect blocked
In cachexia, tumors secrete hormones that cause muscle deterioration; in effect, the body eats its own muscles, causing weakness, frailty and fatigue.
"What kills a lot of people isn't the loss of skeletal muscle but heart muscle," said Rodgers. "The heart literally shrinks, causing heart failure."
Researchers have long sought to stop this process, but failed to find a safe way. That's because the hormones that cause wasting -- in particular, a naturally occurring hormone called myostatin -- play important roles elsewhere in the body.
Rodgers and Gregorevic needed a way to stop myostatin, but only in muscles. Their solution: an adeno-associated virus -- a benign virus that specifically targets heart and skeletal muscle.
The virus delivers a small piece of DNA -- a signaling protein called Smad7 -- into muscle cells. Smad7 then blocks two signaling proteins called Smad2 and Smad3, which are activated by myostatin and other muscle-wasting hormones. By blocking those signals, Smad7 stops the breakdown of muscles.
"Smad7 is the body's natural break and, by inhibiting the inhibitor, you build muscle," Rodgers said.
For cachexia patients, such a therapy could massively increase their chances of survival.
"Instead of having one year to fight cancer, you'd have 10 or 15," Rodgers said.
Startup works to develop commercial drug
In 2015, Rodgers launched AAVogen, a company that will develop this discovery into a commercial drug, AVGN7.
He has been working with Norman Ong, a technology licensing associate at WSU's Office of Commercialization, on patents, startup funding and recruitment for AAVogen. Using the funds from WSU's commercial gap fund award, Rodgers' lab will determine the minimum effective dose for AVGN7.
"We want to turn WSU discoveries into real-world uses that benefit the public," said Ong. "Dan is a very busy scientist, so we're proud to help him and AAVogen connect with the right people."
"I formed this company for one purpose: to move the science into society, to see it applied," Rodgers said. "WSU's Office of Commercialization has been instrumental and invaluable to this endeavor.
"Now we have a company with the potential to save a lot of lives," he said.

Story Source:
The above post is reprinted from materials provided by Washington State University. The original item was written by Seth Truscott. Note: Materials may be edited for content and length.

Journal Reference:
  1. C. E. Winbanks, K. T. Murphy, B. C. Bernardo, H. Qian, Y. Liu, P. V. Sepulveda, C. Beyer, A. Hagg, R. E. Thomson, J. L. Chen, K. L. Walton, K. L. Loveland, J. R. McMullen, B. D. Rodgers, C. A. Harrison, G. S. Lynch, P. Gregorevic. Smad7 gene delivery prevents muscle wasting associated with cancer cachexia in miceScience Translational Medicine, 2016; 8 (348): 348ra98 DOI: 10.1126/scitranslmed.aac4976

Early and late menopause can increase risk of type 2 diabetes

Length of lifetime reproductive cycle can affect risk


Women who begin menopause before age 46 or after 55 have an increased risk of developing type 2 diabetes, according to a study of more than 124,000 women enrolled in the Women's Health Initiative, a large national trial aimed at preventing disease in postmenopausal women.
The study, led by Kaiser Permanente researcher Erin LeBlanc, MD, MPH, was published today in the journal Menopause, the official journal of the North American Menopause Society.
According to the Society, the average age of menopause, or a woman's final menstrual period, is 51.
The study found that women who had their final menstrual period before age 46 were 25 percent more likely to develop type 2 diabetes, compared to women who had their final period between ages 46 and 55. Women who had their final period after age 55 had a 12 percent increased risk of developing diabetes.
After menopause, estrogen levels decline. These low levels of estrogen have been linked to increased body fat and appetite, decreased metabolism and high blood-sugar levels. Previous studies linked early menopause to an increased risk of diabetes, but this study is one of the first to show that later menopause also puts women at higher risk.
"Our study suggests the optimal window for menopause and diabetes risk is between the ages of 46 and 55," said Dr. LeBlanc, lead author and an investigator at the Kaiser Permanente Center for Health Research. "Women who start menopause before or after that window should be aware that they are at higher risk, and should be especially vigilant about reducing obesity, eating a healthy diet and exercising. These lifestyle changes will help to reduce their risk for type 2 diabetes."
Length of reproductive cycle also a factor
The study also found an association between the length of a woman's lifetime reproductive cycle and her risk of developing type 2 diabetes. The lifetime reproductive cycle starts when a woman begins her period and ends when she stops having a period. Women with the shortest lifetime reproductive cycles (less than 30 years) were 37 percent more likely to develop diabetes than those with medium length reproductive cycles (36 to 40 years). Women with the longest reproductive cycles (more than 45 years) were 23 percent more likely to develop diabetes compared to women with medium length reproductive cycles.
The differences in risk were reduced, but remained statistically significant after adjusting for several factors, including age, race, BMI, birth control use, hormone replacement therapy, number of pregnancies, physical activity and alcohol consumption.
Women's Health Initiative
The study participants were part of the Women's Health Initiative, a large national study of postmenopausal women focused on strategies for preventing heart disease, bone fractures, and breast and colorectal cancer.
Women ages 50 to 79 were recruited between 1993 and 1998 at 40 clinical sites and followed for about 12 years. The women completed extensive health questionnaires, including questions about reproductive history, age at first period and age of menopause. Diabetes diagnosis was determined through questions about medical history and medication use.

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

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Kaiser Permanente. "Early and late menopause can increase risk of type 2 diabetes: Length of lifetime reproductive cycle can affect risk." ScienceDaily. ScienceDaily, 27 July 2016. .