Train with Wayne: May 2016

Friday, May 27, 2016

Prepackaged portion-controlled meals can lead to greater weight loss than self-selected portions, research says

Increased portion sizes in Americans' diets is widely recognized as a contributor to the obesity epidemic, and now new research published in Obesity, the scientific journal of The Obesity Society, examines the effect of prepackaged, portion-controlled meals on weight loss. The researchers found that when combined with behavioral counseling as part of a complete weight-loss intervention, a meal plan incorporating portion-controlled, prepackaged, frozen lunch and dinner entrées can promote greater weight loss than a self-selected diet.

"Participants who were prescribed twice-daily prepackaged meals lost about eight percent of their initial weight, compared to participants in the control group -- who could select their own diets -- who only lost about six percent," said Cheryl Rock, PhD, RD, lead researcher and Professor of Family Medicine and Public Health at the University of California San Diego School of Medicine. "What's more, our study found that food satisfaction was comparable among all groups, which is a critical factor that may determine long-term usefulness of this strategy. We believe that removing the complexity of planning and preparing low-calorie meals was beneficial to the participants in the intervention."

To conduct the study, Dr. Rock and colleagues assigned 183 study participants to three groups: one that was prescribed two prepackaged meals per day, one that was prescribed two prepackaged meals per day that were higher in protein (>25% energy), and the control group that was allowed to select their own meals. All participants met with a dietitian for a one- to two-hour personalized counseling session in which they determined their own weight-loss goals, received physical activity recommendations and learned behavioral strategies to help them achieve their goals.

After three months, 74% of the participants eating the prepackaged foods had achieved a 5% weight loss, whereas only 53% of the control achieved that milestone. The greater weight loss also led to a decrease in other cardiovascular disease risk factors like total cholesterol and LDL cholesterol for the participants consuming the prepackaged meals. Additionally, meal satisfaction ratings were similar among all groups, and the groups that consumed the prepackaged meals expressed greater confidence in their ability to follow a meal plan long-term.

"Reduction in energy intake is a key factor to weight loss, but it can be difficult for most individuals with overweight or obesity to put into practice," said Martin Binks, PhD, Associate Professor of Nutritional Sciences at Texas Tech University and spokesperson for The Obesity Society. "This type of strategy is a step toward implementing effective, evidence-based solutions to obesity."

The biggest limitation to the study is the lack of detailed dietary intake data. Longer term studies that carefully measure adherence to this type of program would be beneficial.

Story Source:

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

Journal Reference:

Cheryl L. Rock, Shirley W. Flatt, Bilgé Pakiz, Hava-Shoshana Barkai, Dennis D. Heath, Kim C. Krumhar. Randomized clinical trial of portion-controlled prepackaged foods to promote weight loss.Obesity, 2016; 24 (6): 1230 DOI: 10.1002/oby.21481

Clinical trial demonstrates success of low FODMAP diet

In a first of its kind study in the US, those with IBS overcame symptoms with diet changes compared to control

A change in diet can improve the lives of those diagnosed with a common, but hard-to-treat gut disorder.

A first of its kind US trial shows diet changes helped those with a hard-to-treat gut disorder overcome symptoms of irritable bowel syndrome. The study measured the degree of relief from low FODMAP, a frequently recommended diet, which stands for Fermentable Oligo-Di-Monosaccharides and Polyols.

that's the result of research by the University of Michigan Health System, presented at Digestive Disease Week, that studied for the first time in the United States the result of following a carefully controlled diet to improve the symptoms and quality of life for those with irritable bowel syndrome.

"This is the only methodically rigorous clinical trial to show that diet-based therapy can not only improve symptoms, but also quality of life in patients with IBS," says U-M assistant clinical professor and gastroenterologist Shanti Eswaran, M.D., who researches the role of diet and food in functional bowel diseases such as IBS.

Irritable bowel syndrome can be highly debilitating, if not virtually paralyzing, and affect work, sleep and personal and family relationships.

Most treatments initially rely on medications that are often expensive, usually ineffective and frequently cause unwelcome side effects. And unfortunately there is no cure.

Many practitioners and patients have turned to diet as a possible treatment, but many of the dietary recommendations have not been backed by clinical trials.

The study, the largest of its kind, measured the degree of relief from low FODMAP, a frequently recommended diet, which stands for Fermentable Oligo-Di-Monosaccharides and Polyols.

This diet excludes many compounds found in wheat, certain fruits and vegetables, garlic, onions and sugar substitutes.

Over a six-week process, registered dietitians educated and monitored the progress of more than 90 IBS patients. Roughly half followed a prescribed low FODMAP diet, and half were a control group that used a common-sense regimen, cutting down on large meals, binges and known irritants such as caffeine and alcohol.

The results were impressive: More than 50 percent of the patients on the low FODMAP diet had major improvement of their abdominal pain, compared with 20 percent of the control group.

There was also more improvement of other bothersome symptoms compared to the control group: bloating, diarrhea and stool urgency.

Eswaran collaborated with William Chey, M.D., professor of internal medicine, Kenya Jackson, Sivaram G. Pillai, Samuel W. Chey and Theresa Han-Markey, M.S., R.D., at the University of Michigan on the study abstract published in Gastroenterology.

At four weeks, the proportion of patients with a meaningful improvement in IBS quality of life was significantly higher in the low FODMAP group compared to the control group -- 61 percent versus 27 percent.

While the results are highly encouraging for IBS sufferers, there are a few important caveats, Eswaran says.

Because of the many unknowns about the chemical causes and triggers of IBS, the list of "bad" foods is exhaustive and elusive, and help from a dietician is highly recommended.

"Low-FODMAP is not a new treatment, but we are now convinced that it really works," she says. "Our next step will be to more precisely determine the underlying chemistry of how and why particular foods can yield dramatically different results for different people. Meanwhile, we strongly recommend that IBS patients work with their physician and a registered dietitian to navigate the Low-FODMAP diet to take control of their IBS symptoms."

Story Source:

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

Journal Reference:

Shanti L. Eswaran, William D. Chey, Kenya Jackson, Sivaram G. Pillai, Samuel W. Chey, Theresa Han-Markey. 821 A Low FODMAP Diet Improves Quality of Life, Reduces Activity Impairment, and Improves Sleep Quality in Patients With Irritable Bowel Syndrome and Diarrhea: Results From a U.S. Randomized, Controlled Trial.Gastroenterology, 2016; 150 (4): S172 DOI: 10.1016/S0016-5085(16)30665-5

Women may be able to reduce breast cancer risk predicted by their genes

Women with a high risk of developing breast cancer based on family history and genetic risk can still reduce the chance they will develop the disease in their lifetimes by following a healthy lifestyle, new research led by the Johns Hopkins Bloomberg School of Public Health suggests.

White women who are at high risk but who had a low body mass index (a marker for obesity), who did not drink or smoke and who did not use hormone replacement therapy, had roughly the same risk as an average white women in United States, the researchers found. The average chance that a 30-year-old, white woman will develop breast cancer before she is 80 is about 11 percent.

The researchers found that roughly 30 percent of breast cancer cases could be prevented by modifying known risk factors -- say, by drinking less alcohol, losing weight and not taking hormone replacement therapy. More importantly, the study found that a larger fraction of total preventable cases would occur among women at higher levels because of genetic risk factors, family history and a few other factors that cannot be modified.

The findings, published May 26 in JAMA Oncology, are a first step in understanding how advances in the field of genetics can be used for developing precision prevention strategies to help women improve their odds of avoiding breast cancer. Breast cancer remains the most common form of malignancy diagnosed in women in western developed countries, with an estimated 232,000 new cases diagnosed in the United States in 2014. Roughly 40,000 women die in the United States from breast cancer each year.

The findings could be particularly useful as the price of genetic testing continues to fall and more women are able to afford the tests, which typically are not covered by insurance. They may also help scientists develop better guidelines for when and how frequently women should be screened for breast cancer, a calculation that is currently based on age, but that could be based on individual risk factors for each individual woman.

"People think that their genetic risk for developing cancer is set in stone," says the study's senior author Nilanjan Chatterjee, PhD, a Bloomberg Distinguished Professor in the Department of Biostatistics at the Bloomberg School. "While you can't change your genes, this study tells us even people who are at high genetic risk can change their health outlook by making better lifestyle choices such as eating right, exercising and quitting smoking."

Chatterjee and his colleagues from more than a dozen institutions around the world developed a model predicting risk of breast cancer by analyzing records on more than 17,000 women with breast cancer and nearly 20,000 women without the disease from the Breast and Prostate Cancer Cohort Consortium and about 6,000 women participating in the 2010 National Health Interview Study. The researchers combined individual-level data on risk factors such as age, weight and smoking status with data on almost 100 common gene variations, each of which are known to have a modest association with breast cancer but in combination they can lead to substantially elevated risk. They further combined this information with population incidence rates from the National Cancer Institute-Surveillance, Epidemiology and End Results Program. The findings are currently applicable only to white women because further studies are needed to understand the association of the genetic variants with risk of breast cancer for other ethnic groups.

The common gene variations studied by the researchers are quite different from the well known rare mutations in genes like BRCA1 and BRCA2, where having a single variant can mean a very high risk of developing breast cancer.

Chatterjee says the findings may add to the process of creating better screening models for breast cancer. Current recommendations in the U.S. do not call for routine mammograms for breast cancer until the age of 50, though previous recommendations suggested age 40.

While getting older is the No. 1 risk factor for developing breast cancer, other factors -- such as family history -- already come into play and more specific genetic risks may one day prove to also play a role. The model shows that, for example, 16 percent of 40-year-old women in the population had the risk of an average 50-year-old woman and thus possibly could benefit by screening earlier. At the same time, 32 percent of 50 year olds had the risk of 40 year olds and they should at least be carefully counseled so that they understand there may be harm associated with screening those at low risk of developing the disease.

While mammograms can detect early-stage breast cancers, there are risks of false-positive results which can add potentially unnecessary pain, cost and distress. So finding a way to screen those at the highest risk more often -- and those at lower risk less often -- could be beneficial. "We aren't saying there will be less screening, just smarter screening," Chatterjee says.

The model is still several years from being ready for routine medical use. First, Chatterjee says, the model needs to be validated in other studies. Second, he says, the cost of widespread genetic testing, while falling precipitously over the last decade, is still a little too high. But he sees the costs continuing to fall in coming years to a level where such testing can become commonplace. Also, he says, a model needs to be developed for other ethnic populations and for specific subtypes of breast cancer which may have different causes and prognostic outlooks.

Chatterjee says he hopes that once women understand that their genes do not completely predict their cancer destiny, they will work even harder to make lifestyle changes that can potentially reduce the risk they will develop the deadly disease.

"Everyone should be doing the right things to stay healthy but motivating people is often hard," he says. "These findings may be able to help people better understand the benefits of a healthy lifestyle at a more individualized level."

Story Source:

The above post is reprinted from materials provided by Johns Hopkins Bloomberg School of Public Health. Note: Materials may be edited for content and length.

Journal Reference:

Paige Maas, Myrto Barrdahl, Amit D. Joshi, Paul L. Auer, Mia M. Gaudet, Roger L. Milne, Fredrick R. Schumacher, William F. Anderson, David Check, Subham Chattopadhyay, Laura Baglietto, Christine D. Berg, Stephen J. Chanock, David G. Cox, Jonine D. Figueroa, Mitchell H. Gail, Barry I. Graubard, Christopher A. Haiman, Susan E. Hankinson, Robert N. Hoover, Claudine Isaacs, Laurence N. Kolonel, Loic Le Marchand, I-Min Lee, Sara Lindström, Kim Overvad, Isabelle Romieu, Maria-Jose Sanchez, Melissa C. Southey, Daniel O. Stram, Rosario Tumino, Tyler J. VanderWeele, Walter C. Willett, Shumin Zhang, Julie E. Buring, Federico Canzian, Susan M. Gapstur, Brian E. Henderson, David J. Hunter, Graham G Giles, Ross L. Prentice, Regina G. Ziegler, Peter Kraft, Montse Garcia-Closas, Nilanjan Chatterjee. Breast Cancer Risk From Modifiable and Nonmodifiable Risk Factors Among White Women in the United States. JAMA Oncology, 2016; DOI:10.1001/jamaoncol.2016.1025

How the brain makes, and breaks, a habit

Not all habits are bad. Some are even necessary. It's a good thing, for example, that we can find our way home on "autopilot" or wash our hands without having to ponder every step. But inability to switch from acting habitually to acting in a deliberate way can underlie addiction and obsessive compulsive disorders.

Working with a mouse model, an international team of researchers demonstrates what happens in the brain for habits to control behavior.

The study is published in Neuron and was led by Christina Gremel, assistant professor of psychology at the University of California San Diego, who began the work as a postdoctoral researcher at the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health. Senior authors on the study are Rui Costa, of the Champalimaud Centre for the Unknown in Lisbon, and David Lovinger of the NIAAA/NIH.

The study provides the strongest evidence to date, Gremel said, that the brain's circuits for habitual and goal-directed action compete for control -- in the orbitofrontal cortex, a decision-making area of the brain -- and that neurochemicals called endocannabinoids allow for habit to take over, by acting as a sort of brake on the goal-directed circuit.

Endocannabinoids are a class of chemicals produced naturally by humans and other animals. Receptors for endocannabinoids are found throughout the body and brain, and the endocannabinoid system is implicated in a variety of physiological processes -- including appetite, pain sensation, mood and memory. It is also the system that mediates the psychoactive effects of cannabis.

Earlier work by Gremel and Costa had shown that the orbitofrontal cortex, or OFC, is an important brain area for relaying information on goal-directed action. They found that by increasing the output of neurons in the OFC with a technique called optogenetics -- precisely turning neurons on and off with flashes of light -- they increased goal-directed actions. In contrast, when they decreased activity in the same area with a chemical approach, they disrupted goal-directed actions and the mice relied on habit instead.

"Habit takes over when the OFC is quieted," Gremel said.

In the current study, since endocannabinoids are known to reduce the activity of neurons in general, the researchers hypothesized that endocannabinoids may be quieting or reducing activity in the OFC and, with it, the ability to shift to goal-directed action. They focused particularly on neurons projecting from the OFC into the dorsomedial striatum.

They trained mice to perform the same lever-pressing action for the same food reward but in two different environments that differentially bias the development of goal-directed versus habitual actions. Like humans who don't suffer from neuropsychiatric disorders, healthy mice will readily shift between performing the same action using a goal-directed versus habitual action strategy. To stick with the earlier example of getting home, we can switch the homing autopilot off and shift to goal-directed behavior when we need to get to a new or different location.

To test their hypothesis on the role played by endocannabinoids, the researchers then deleted a particular endocannabinoid receptor, called cannabinoid type 1, or CB1, in the OFC-to-striatum pathway. Mice missing these receptors did not form habits -- showing the critical role played by the neurochemicals as well as that particular pathway.

"We need a balance between habitual and goal-directed actions. For everyday function, we need to be able to make routine actions quickly and efficiently, and habits serve this purpose," Gremel said. "However, we also encounter changing circumstances, and need the capacity to 'break habits' and perform a goal-directed action based on updated information. When we can't, there can be devastating consequences."

The findings may suggest, the authors say, a new therapeutic target for people suffering from OCD or addictions: To stop overreliance on habit and restore the ability to shift from habit to goal-directed action, it may be helpful to treat the brain's endocannabinoid system and so reduce habitual control over behavior. Treatment could be pharmaceutical or might involve behavioral therapy. Further research is needed.

Story Source:

The above post is reprinted from materials provided by University of California - San Diego. The original item was written by Inga Kiderra. Note: Materials may be edited for content and length.

Journal Reference:

Christina M. Gremel et al. Endocannabinoid Modulation of Orbitostriatal Circuits Gates Habit Formation. Neuron, May 2016 DOI:10.1016/j.neuron.2016.04.043

Why malnutrition is an immune disorder

This is a conceptual framework for immune dysfunction as a cause and consequence of malnutrition.

Credit: Bourke et al./Trends in Immunology 2016

Malnourished children are most likely to die from common infections, not starvation. New experimental evidence, reviewed May 26 in Trends in Immunology, indicates that even with a healthy diet, defects in immune system function from birth could contribute to a malnourished state throughout life. Researchers speculate that targeting immune pathways could be a new approach to reduce the poor health and mortality caused by under- and overnutrition.

"That traditional image of malnutrition that we're unfortunately so familiar with--of someone wasting away--that's just the external picture," says Review first author Claire Bourke, a postdoctoral research assistant in the Centre for Genomics and Child Health at Queen Mary University of London. "Those height and weight defects that we see are the tip of the iceberg--there are a whole range of pro-inflammatory conditions, impaired gut function, weakened responses to new infections, and a resulting high metabolic burden underlying them."

The most common form of undernutrition globally is stunting -- where children fail to achieve their full height potential. Despite looking healthy, children in developing countries who are stunted in height may also have stunted immune development, making them more vulnerable to death by common infections.

Only recently have researchers had access to technology that can accurately study immunodeficiency. Even though immune parameters in undernourished children have been looked at for decades, much of that data is outdated. How malnutrition and immune function are related is actually still poorly understood; however, there is wide acceptance that malnutrition comes with a range of immune problems. These include reduced numbers of white blood cells, skin and gut membranes that are easier for pathogens to break through, and malfunctioning lymph nodes.

What's also emerging is that the relationship between malnutrition and immune dysfunction may be a bit "chicken and egg," with both causing and being the consequence of the other. Immune dysfunction results when people consume too few calories because of lack of food or have an excess of fat and sugar in their diet. That dysfunction is recorded in the DNA through epigenetic marks, so that if malnourished people have offspring, their children inherit an altered immune system (even after multiple generations). This altered immune system may then cause malnutrition even if children have an adequate diet.

"It's been thought for a long time that the immune system is driving pathology, but new experimental tools have made it possible to separate out the effects of the immune system from those of the diet alone," says Bourke. "There are new models for environmental enteric dysfunction in mice, a growing interest in microbiota and epigenetics--all of these studies show that the more we look into the immune system, the more it has a role to play in a really wide array of physiological systems. It doesn't just fight infection; it affects metabolism, neurological function, and growth, which are things that are also impaired in malnutrition."

Bourke imagines a future where clinicians could generate individualized immune readouts that can identify young people most susceptible to infection as a result of malnutrition. This could reduce the burden of a leading cause of child mortality by helping those who are most vulnerable get treated more often and sooner with targeted interventions.

Some could argue that the jury is still out on the immune dysfunction-malnutrition connection. There are many studies that need to be done to fully support the case, such as comparing the developing immune systems of undernourished versus healthy children over time or determining whether restoring certain immune functions could improve the outcomes of malnutrition. Although there remain many unanswered questions, the evidence for a causal role for immune dysfunction in malnutrition continues to grow, and the authors hope their paper will encourage questions and discussion.

Story Source:

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

Journal Reference:

Bourke et al. Immune dysfunction as a cause and consequence of malnutrition. Trends in Immunology, 2016 DOI: 1

Thursday, May 26, 2016

Scientists block breast cancer cells from hiding in bones

Scientists at the Duke Cancer Institute have identified a molecular key that breast cancer cells use to invade bone marrow in mice, where they may be protected from chemotherapy or hormonal therapies that could otherwise eradicate them.

Through years of experiments in mice, the scientists have found ways to outmaneuver this stealth tactic by not only preventing breast cancer cells from entering the bone marrow, but also by flushing cancer cells out into the blood stream where they could be targeted for destruction.

The findings provide insight into one of the most devastating tendencies of some breast cancers -- the ability to return after seemingly being vanquished. The researchers hope the findings, if replicated in additional animal and human tests, could eventually lead to new therapies for treating breast cancer.

"Clinical studies have found that breast cancer can be caught early and treated, and patients can have no signs of disease," said Dorothy A. Sipkins, M.D., Ph.D., associate professor in the division of hematological malignancies and cellular therapy at Duke. "And then five, 10 or even 15 years later, a patient can relapse. Most often, the site of the metastasized cancer is in the bone."

In an article published online May 25, 2016 in Science Translational Medicine, the researchers describe how cells from breast cancers that are hormone receptor-positive roam through the blood and tissues of mice. They're hunting for specific blood vessels in bone marrow that contain the molecule E-selectin. With their molecular key -- molecules on their surface that bind to E-selectin -- the cancer cells enter the spongy tissue inside bones, often lying dormant for years.

Hormone receptor-positive breast cancers are the most common type of breast cancer, according to the American Society of Clinical Oncology, and grow by exploiting the body's estrogen or progesterone.

In human patients, these dormant cells can resurge later and create metastatic cancer relapse, for which there is no cure, said Sipkins, who is the paper's senior author. Biopsies of bone marrow in human breast cancer patients have shown that even at very early stages of the cancer, roaming cancer cells, or micrometastases, are making their way out of the breast and into the bone marrow, Sipkins said.

"Now we know how they are getting in," she said. "We also identified an important mechanism that allows them to remain anchored in the bone marrow. In the mouse, our findings could offer new strategies to intervene at the molecular level before dormant cells can take hold and cause relapse."

One strategy is finding a way to inhibit E-selectin, which could limit the cancer's ability to travel into the bone and resurge as metastatic cancer, she said. The scientists used an E-selectin inhibitor called GMI-1271, which is currently in human clinical trials. They found the compound successfully prevented the breast cancer cells from entering the bone marrow in mice.

Because microscopic metastases can spread to the bone marrow before patients are even diagnosed with breast cancer, the researchers also tested a strategy that appears to kick dormant breast cancer cells out of their safe house in the bone marrow and back into circulation. They gave the mice plerixafor, an agent used in human bone marrow donors to push stem cells into the bloodstream for harvesting.

The drug was able to force dormant breast cancer cells out of the bone tissue into the bloodstream. The researchers hypothesize that flushing these dormant cancer cells back into the bloodstream might give the immune system, chemotherapy or hormonal therapy another opportunity at killing them off, Sipkins said. She and colleagues hope to investigate that approach further.

"We are hopeful that by understanding how these breast cancer cells migrate through the body and what their life cycle is, we can discover ways to make them more vulnerable and treatable," Sipkins said. "Our hope is to move forward with additional studies in mice to better understand our approach before moving on to studies in humans."

Story Source:

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

Journal Reference:

T. T. Price, M. L. Burness, A. Sivan, M. J. Warner, R. Cheng, C. H. Lee, L. Olivere, K. Comatas, J. Magnani, H. Kim Lyerly, Q. Cheng, C. M. McCall, D. A. Sipkins. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Science Translational Medicine, 2016; 8 (340): 340ra73 DOI:10.1126/scitranslmed.aad4059

Scientists uncover potential trigger to kill cancer

Melbourne researchers have discovered a new way of triggering cell death, in a finding that could lead to drugs to treat cancer and autoimmune disease.

Programmed cell death, also called apoptosis, is a natural process that removes unwanted cells from the body. Failure of apoptosis can allow cancer cells to grow unchecked or immune cells to inappropriately attack the body.

The protein known as Bak is central to apoptosis. In healthy cells Bak sits in an inert state but when a cell receives a signal to die, Bak transforms into a killer protein that destroys the cell.

Institute researchers Dr Sweta Iyer, Dr Ruth Kluck and colleagues have discovered a novel way of directly activating Bak to trigger cell death. Their findings have just been published in the journal Nature Communications.

The researchers discovered that an antibody they had produced to study Bak actually bound to the Bak protein and triggered its activation.

Dr Kluck said the findings were completely unexpected.

"We were excited when we realised we had found an entirely new way of activating Bak," Dr Kluck said. She hopes to use this discovery to develop drugs that promote cell death.

"There is great interest in developing drugs that trigger Bak activation to treat diseases such as cancer where apoptosis has gone awry," she said. "This discovery gives us a new starting point for developing therapies that directly activate Bak and cause cell death."

The researchers used information about Bak's three-dimensional structure to find out precisely how the antibody activated Bak.

"It is well known that Bak can be activated by a class of proteins called 'BH3-only proteins' that bind to a groove on Bak. We were surprised to find that despite our antibody binding to a completely different site on Bak, it could still trigger activation," Dr Kluck said.

Drugs that target this new activation site could be useful in combination with other therapies that promote cell death by mimicking the BH3-only proteins.

"The advantage of our antibody is that it can't be 'mopped up' and neutralised by pro-survival proteins in the cell, potentially reducing the chance of drug resistance occurring," Dr Kluck said.

The researchers are now working with collaborators to develop their antibody into a drug that can access Bak inside cells.

Story Source:

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

Journal Reference:

Sweta Iyer, Khatira Anwari, Amber E. Alsop, Wai Shan Yuen, David C. S. Huang, John Carroll, Nicholas A. Smith, Brian J. Smith, Grant Dewson, Ruth M. Kluck. Identification of an activation site in Bak and mitochondrial Bax triggered by antibodies. Nature Communications, 2016; 7: 11734 DOI: 10.1038/ncomms11734

Differences in metabolism between androgen-dependent, castration resistant prostate cancer may lead to new therapies

Advanced prostate cancer is usually treated by removing androgen, the male hormone that helps it grow. Although initially effective, this treatment often leads to the tumor becoming castration resistant- a lethal condition. Researchers from Baylor College of Medicine and University of Michigan, along with collaborators in other institutions, have determined that castration resistant prostate cancer (CRPC) has particular metabolic characteristics that may open new possibilities for treatment. The results appear inNature Communications.

"Using an innovative approach to integrate gene expression and metabolomics data, we identified key metabolic pathways that are altered in prostate cancer," said corresponding author Dr. Arun Sreekumar, professor of Molecular and Cellular Biology, the Alkek Center for Molecular Discovery and the Verna and Marrs McLean department of Biochemistry and Molecular Biology at Baylor. "Of these metabolic pathways, the hexosamine biosynthetic pathway (HBP) showed significant alterations."

The researchers discovered that HBP is much less active in castrate resistant than in androgen-dependent prostate cancers. Furthermore, having reduced HBP activity is likely to enhance tumor growth.

"When we experimentally knocked down genes involved in HBP in cells similar to CRPC tumor cells, the cells responded with a marked increase in proliferation, both in cell culture and animal experiments," said Sreekumar. "When the cells with reduced HBP received UDP-N-acetylglucosamine, a product of this metabolic pathway they lacked, the cells slowed down their growth."

When the researchers added UDP-N-acetylglucosamine and a clinically used anti-androgen (i.e., enzalutamide) to the CRPC cells growing in the laboratory, the cells reduced their proliferation further.

"This result is particularly noteworthy because our cells were essentially resistant to enzalutamide alone," said Sreekumar.

These results indicate that studying the metabolic characteristics of tumors resistant to therapy offers the possibility of discovering new targets to treat cancer. In this case, the results identify HBP as a potential therapeutic target for castration resistant prostate cancer, a disease that accounts for close to 30,000 deaths annually in the United States.

Story Source:

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

Journal Reference:

Akash K. Kaushik, Ali Shojaie, Katrin Panzitt, Rajni Sonavane, Harene Venghatakrishnan, Mohan Manikkam, Alexander Zaslavsky, Vasanta Putluri, Vihas T. Vasu, Yiqing Zhang, Ayesha S. Khan, Stacy Lloyd, Adam T. Szafran, Subhamoy Dasgupta, David A. Bader, Fabio Stossi, Hangwen Li, Susmita Samanta, Xuhong Cao, Efrosini Tsouko, Shixia Huang, Daniel E. Frigo, Lawrence Chan, Dean P. Edwards, Benny A. Kaipparettu, Nicholas Mitsiades, Nancy L. Weigel, Michael Mancini, Sean E. McGuire, Rohit Mehra, Michael M. Ittmann, Arul M. Chinnaiyan, Nagireddy Putluri, Ganesh S. Palapattu, George Michailidis, Arun Sreekumar. Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer. Nature Communications, 2016; 7: 11612 DOI: 10.1038/ncomms11612

TIPS FOR WEIGHT TRAINING WITH DIABETES

If you’ve got diabetes, weight training can be a great way to stay healthy, and increase your metabolism. Exercising regularly can also help improve glycemic control and enhance insulin sensitivity. Strength training, as well as cardio, is also a great form of exercise for diabetic patients, as it increases muscle size - and larger muscles are able to burn more calories. Weight training isn’t for everyone, but if you’re interested in getting fit and increasing your metabolism, here are some training tips for those with diabetes.

1. Increase Your Protein Intake
When you weight train, your body drains its protein reserves - so if you want to build muscle, you’ll need to increase your protein intake. Consuming one gram of protein per pound of body weight will help ensure that you’re not draining your reserves while working out. Eating foods such as chicken, tuna, and eggs, before and after you train, will help you maintain a healthy protein level.

After working out, it’s important to eat a meal high in protein and carbohydrates, but people with diabetes need to pay special attention to what they eat. Having diabetes, you’re told that you need to limit your carbohydrate intake to keep your blood sugar under control, and your insulin at healthy levels. But cutting out carbs means that your body will look elsewhere for energy - and dip into your protein reserves.

To combat this, make sure to increase your intake of healthy carbohydrates, such as those found in fruits, vegetables, nuts, and whole grain foods. Avoid foods such as potatoes, pastas, and white bread, which contain simple carbohydrates. Eating foods with a lower glycemic index will help ensure that you’ll have a prolonged release of energy, and retain your protein reserves.

2. Set an Appropriate Workout Intensity
How hard you work is ultimately up to you, but there are a few factors to consider before starting a strength training routine. While developing a plan for weight training, be sure to take into account your age, body weight, and exercise background. If it’s been a long time since you’ve regularly exercised, start out slow to avoid overexerting yourself. You can keep track of the intensity of the workout by monitoring your heart ratefor those just getting back into exercise, maintaining a rate of about 40-60 percent of your maximum heart rate is recommended, before moving up to the standard rate of 60-80 percent.

3. Do the Right Number of Repetitions
When developing any strength training routine, it’s important to start out small and work toward specific goals, rather than just jump into a high-stress lifting routine. If you’re training for strength, start by doing 1-2 sets with a number of repetitions you can perform comfortably, then increase your resistance over a period of time. Resting between 30-60 seconds after each set is also a good rule of thumb if you’re just starting out. Beginning this way will help you track your results, and figure out what works and what doesn’t.

4. Monitor Your Blood Sugar
While working out, it’s very important for those managing diabetes to monitor what’s going on inside their body. Checking your blood glucose levels regularly is extremely important in order to minimize the risk of developing hypoglycemia when exercising. Pump users can find modern insulin pumps with continuous blood glucose monitoring integration that feel like smartphones so they can see their levels at a glance. Even if you aren’t insulin-dependent, it’s important to know the warning signs of when you’re suffering from low blood glucose levels, such as shakiness, lightheadedness, headaches, or fatigue. These symptoms can be masked while you’re working out, which is why it’s so essential to make sure to monitor your glucose levels before, during, and after exercise. In addition to these tips, it’s important to consult a physician before undertaking any type of high-stress exercise routine.

Monday, May 23, 2016

Breaking down cancer cell defenses

The mistaken activation of certain cell-surface receptors contributes to a variety of human cancers. Knowing more about the activation process has led researchers to be able to induce greater vulnerability by cancer cells to an existing first-line treatment for cancers (mainly lung) driven by a receptor called EGFR. The team, led by Eric Witze, PhD, an assistant professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania, published their findings this month in Molecular Cell.

"We found that inhibiting an enzyme that adds the fatty acid palmitate onto proteins creates dependence by cancer cells on EGFR signaling for survival," Witze said. By using a small molecule called 2-bromo-palmitate (2BP) that inhibits these palmitate-adding enzymes, the researchers surmise that cancer patients might be able to one day make their cells more sensitive to cancer-fighting EGFR inhibitors.

Palmitate is the most common fatty acid found in animals, plants, and microbes, although is not well studied. Proteins that have palmitate bound to them are usually associated with the cell membrane. Palmitate allows these proteins to transfer chemical signals from outside the cell to inside via the cell membrane.

EGFR itself is a transmembrane protein associated with palmitate, and by blocking palmitate, EGFR becomes hyperactivated. "We thought that this finding would be 'good' for the cancer, but 'bad' for a cancer patient," Witze said. In cancers not related to EGFR signaling, this relationship is correct; however, in cancers related to EGFR, if the palmitate-adding enzyme is inhibited, EGFR is activated, but cancer cells grow more slowly.

In addition, if genifitib, an inhibitor to EGFR itself on the market for lung cancer, is added to the cell, the cells die. This finding is somewhat counterintuitive with regard to cell growth since EGFR activation functions as a positive growth signal, the researchers note; however, that fact cells die when EGFR is inhibited is not counterintuitive, but shows the cells are now addicted to the EGFR signal.

"It's as if a switch is stuck on," Witze said. "The cell loses control of the growth signal." If no palmitate is associated with EGFR, then it the cell loses control of this signal, and if the EGFR inhibitor is added, cells die."

The research shows that the reversible modification of EGFR with palmitate "pins" the tail of EGFR to the cell, impeding EGFR activation. The researchers think when the tail is no longer able to be pinned to the membrane the switch is stuck in the "on" position.

Currently, the experimental 2BP compound inhibits any enzyme that uses palmitate as a substrate, making it toxic to most cells. "We need to find a compound specific for the palmitate-adding enzyme and or modify 2BP to make it more specific to decrease unwanted side effects." Witze said.

Kristin B. Runkle, Akriti Kharbanda, Ewa Stypulkowski, Xing-Jun Cao, Wei Wang, and Benjamin A. Garcia, all from Penn are co-authors.

This work was funded by the National Institute for Health (R01CA181633, T32-CA-557726-07), the American Cancer Society (RSG-15-027-01, IRG -78-002-34) and the Department of Defense (BC123187P1).

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

Exercise associated with longer life in patients with heart failure

Exercise is associated with a longer life in patients with heart failure, according to research presented today in a late breaking trial session at Heart Failure 2016 and the 3rd World Congress on Acute Heart Failure. The analysis in more than 4000 patients showed a mortality benefit from exercise regardless of heart failure severity, age and gender.

"Patients with heart failure should not be scared of exercise damaging them or killing them," said principal investigator Professor Rod Taylor, chair of health services research and director of the Exeter Clinical Trials Unit at the University of Exeter Medical School in Exeter, UK. "The message for heart failure patients is clear. Exercise is good for you, it will make you feel better, and it could potentially make you live longer."

Professor Taylor and colleagues previously conducted a meta-analysis of randomised trials which showed that heart failure patients who exercised were admitted to hospital less often and had a better quality of life. The effects on all-cause mortality were unclear because of differences between trials in the length of follow up.

Exercise Training Meta-Analysis of Trials in Heart Failure (ExTraMATCH II) is an international collaboration of researchers that has performed an individual patient data meta-analysis of trials randomising heart failure patients to exercise or standard therapy. While a traditional meta-analysis pools trial level data to investigate a question, this method analyses the data at patient level and therefore has stronger statistical power. It allowed the investigators to assess whether exercise had an impact on all-cause mortality and hospitalisations in heart failure patients, and see if the effect was different in particular subgroups.

To conduct the study, the investigators identified 23 randomised trials of exercise that included at least 50 heart failure patients who were followed up for six months or longer. After asking the authors of all 23 studies for individual patient data, they received the information from 20 trials.

The 20 trials included 4043 patients with heart failure. The investigators used the individual patient data to assess the impact of exercise on the time to all-cause mortality and first hospitalisation. They also examined the potential influence of patient characteristics including age, gender, heart failure severity (defined by New York Heart Association class), ischaemic aetiology, baseline left ventricular ejection fraction, and peak oxygen uptake.

The investigators found that exercise was associated with an 18% lower risk of all-cause mortality and an 11% reduced risk of hospitalisation compared with no exercise. Professor Taylor said: "This analysis did in fact show that there is a mortality benefit from doing exercise. In other words, patients who exercised had a lower risk of death than those who didn't."

The effect of exercise on mortality and hospitalisations did not differ according to any of the patient characteristics that were analysed. "There was no evidence that some heart failure patients gain more from exercise than others," said Professor Taylor. "The benefits of exercise are consistent regardless of the severity of heart failure, gender, age, and the other factors we looked at."

He added: "Personalising interventions and targeting resources is a hot topic in healthcare. Our research shows that all patients with heart failure should be encouraged to exercise. Policymakers and clinicians should therefore not deny any heart failure patient the chance to participate in exercise rehabilitation on the basis that it will not work for them."

Exercise may benefit patients with heart disease, including heart failure, in a number of ways. It improves physical fitness, which is an even stronger predictor of survival than blood pressure or smoking. Exercise improves the oxygen supply to the heart and reduces the likelihood of the abnormal rhythms that can cause sudden death. Physical activity also improves circulation in the peripheral vasculature, such as in the leg muscles, which may reduce the workload of the heart and improve patients' ability to function.

Professor Taylor concluded: "If heart failure patients are active we can be pretty sure that they will live longer. The simple advice would not be to take up marathon running. This is about increasing one's routine physical activity -- for example walking for 20 to 30 minutes three times at week at an intensity that makes you feel a little bit breathless but not necessarily symptomatic. Discuss it with your cardiologist or GP with the belief that it's going to benefit you."

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

Cite This Page:

European Society of Cardiology. "Exercise associated with longer life in patients with heart failure: All patients benefited regardless of heart failure severity, age and gender." ScienceDaily. ScienceDaily, 23 May 2016. .

Low-salt diets may not be beneficial for all, study suggests

A large worldwide study has found that, contrary to popular thought, low-salt diets may not be beneficial and may actually increase the risk of cardiovascular disease (CVD) and death compared to average salt consumption.

In fact, the study suggests that the only people who need to worry about reducing sodium in their diet are those with hypertension (high blood pressure) and have high salt consumption.

The study, involving more than 130,000 people from 49 countries, was led by investigators of the Population Health Research Institute (PHRI) of McMaster University and Hamilton Health Sciences.

They looked specifically at whether the relationship between sodium (salt) intake and death, heart disease and stroke differs in people with high blood pressure compared to those with normal blood pressure.

The researchers showed that regardless of whether people have high blood pressure, low-sodium intake is associated with more heart attacks, strokes, and deaths compared to average intake.

"These are extremely important findings for those who are suffering from high blood pressure," said Andrew Mente, lead author of the study, a principal investigator of PHRI and an associate professor of clinical epidemiology and biostatistics at McMaster's Michael G. DeGroote School of Medicine.

"While our data highlights the importance of reducing high salt intake in people with hypertension, it does not support reducing salt intake to low levels.

"Our findings are important because they show that lowering sodium is best targeted at those with hypertension who also consume high sodium diets."

Current intake of sodium in Canada is typically between 3.5 and 4 grams per day and some guidelines have recommended that the entire population lower sodium intake to below 2.3 grams per day, a level that fewer than five per cent of Canadians and people around the world consume.

Previous studies have shown that low-sodium, compared to average sodium intake, is related to increased cardiovascular risk and mortality, even though low sodium intake is associated with lower blood pressure.

This new study shows that the risks associated with low-sodium intake -- less than three grams per day -- are consistent regardless of a patient's hypertension status.

Further, the findings show that while there is a limit below which sodium intake may be unsafe, the harm associated with high sodium consumption appears to be confined to only those with hypertension.

Only about 10 per cent of the population in the global study had both hypertension and high sodium consumption (greater than 6 grams per day).

Mente said that this suggests that the majority of individuals in Canada and most countries are consuming the right amount of salt.

He added that targeted salt reduction in those who are most susceptible because of hypertension and high salt consumption may be preferable to a population-wide approach to reducing sodium intake in most countries except those where the average sodium intake is very high, such as parts of central Asia or China.

He added that what is now generally recommended as a healthy daily ceiling for sodium consumption appears to be set too low, regardless of a person's blood pressure level.

"Low sodium intake reduces blood pressure modestly, compared to average intake, but low sodium intake also has other effects, including adverse elevations of certain hormones which may outweigh any benefits. The key question is not whether blood pressure is lower with very low salt intake, instead it is whether it improves health," Mente said

Dr. Martin O'Donnell, a co-author on the study and an associate clinical professor at McMaster University and National University of Ireland Galway, said: "This study adds to our understanding of the relationship between salt intake and health, and questions the appropriateness of current guidelines that recommend low sodium intake in the entire population."

"An approach that recommends salt in moderation, particularly focused on those with hypertension, appears more in-line with current evidence." The study was funded from more than 50 sources, including the PHRI, the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research.

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

Journal Reference:

Andrew Mente et al. Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies. The Lancet, 2016 DOI: 10.1016/S0140-6736(16)30467-6