Walnuts could be key to happier state-of-mind in young healthy men

In continuation of my update on walnuts

College can be a stressful time for young adults as they figure out how to manage intense daily routines that include work, study and play. Eat well, exercise and get plenty of sleep is a familiar mantra to alleviate this stress, but now with the results of his latest study, UNM Nutrition Professor Peter Pribis is able to tell college students that walnuts could be a key to a happier state-of-mind. 

In this first intervention study in humans, Pribis measured the effect of walnut consumption on mood.

"In the past, studies on walnuts have shown beneficial effects on many health outcomes like heart disease, diabetes and obesity," said Pribis. "Our study was different because we focused on cognition, and in this controlled randomized trial (CRT) we measured mood outcomes in males and females."

The participants of the study were 64 students between the ages of 18-25. They represented most ethnic groups: Caucasian, African American, Hispanic and Asian.

The participants were asked to eat three slices of banana bread every day for sixteen weeks--eight weeks of banana bread with walnuts and eight weeks of banana bread without walnuts. The nuts were finely ground into the dough so the two banana breads were similar in taste and appearance. While eating banana bread with walnuts the participants consumed half a cup of walnuts daily.

The mood of the students was measured at the end of each eight-week period.

"We used a validated questionnaire called Profiles of Mood States (POMS)," says Pribis. "It is one of the most widely used and accepted mood scales in studies on cognition. The test has six mood domains: tension, depression, anger, fatigue, vigor, confusion and also provides a Total Mood Disturbance score (TMD). The lower the TMD score the better the mood."

In this double-blind, randomized, placebo controlled, cross-over feeding trial with walnuts for eight weeks, Pribis observed a significant improvement in mood in young, healthy males.

"There was a meaningful, 28 percent improvement of mood in young men," said Pribis. "However we did not observe any improvement of mood in females. Why this is we do not know."

There are several nutrients in walnuts that could be responsible for the improved mood like alpha-Linolenic acid, vitamin E, folate, polyphenols or melatonin. However, this was a whole food study, so in the end it was the synergy and interaction of all the nutrients in the walnuts combined.

For Pribis, the lesson learned from this food study is clear, "Eat more walnuts. This is an easy intervention. They're not only good for your mood, but overall health as well. The recommended amount is one handful per day."

With this knowledge in hand--and hopefully walnuts in the other--young men can happily tackle life's daily stress.

Ref: http://news.unm.edu/news/the-key-to-a-better-mood-for-young-men-is-a-nut




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New drug receives FDA approval to reduce risk of cardiovascular death in adults with diabetes

The U.S. Food and Drug Administration today approved a new indication for Jardiance (empagliflozin) to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and cardiovascular disease.

"Cardiovascular disease is a leading cause of death in adults with type 2 diabetes mellitus," said Jean-Marc Guettier, M.D., C.M., director of the Division of Metabolism and Endocrinology Products in FDA's Center for Drug Evaluation and Research. "Availability of antidiabetes therapies that can help people live longer by reducing the risk of cardiovascular death is an important advance for adults with type 2 diabetes."

According to the Centers for Disease Control and Prevention, death from cardiovascular disease is 70 percent higher in adults with diabetes compared to those without diabetes, and patients with diabetes have a decreased life expectancy driven in large part by premature cardiovascular death.

The FDA's decision is based on a postmarketing study required by the agency when it approved Jardiance in 2014 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Jardiance was studied in a postmarket clinical trial of more than 7,000 patients with type 2 diabetes and cardiovascular disease. In the trial, Jardiance was shown to reduce the risk of cardiovascular death compared to a placebo when added to standard of care therapies for diabetes and atherosclerotic cardiovascular disease.

Jardiance can cause dehydration and low blood pressure (hypotension). Jardiance can also cause increased ketones in the blood (ketoacidosis), serious urinary tract infection, acute kidney injury and impairment in renal function, low blood glucose (hypoglycemia) when used with insulin or insulin secretagogues (e.g. sulfonylurea, a medication used to treat type 2 diabetes by increasing the release of insulin in the pancreas), vaginal yeast infections and yeast infections of the penis (genital mycotic infections), and increased cholesterol.

The most common side effects of Jardiance are urinary tract infections and female genital infections.

Jardiance is not intended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Jardiance is contraindicated in patients with a history of serious hypersensitivity reactions to Jardiance, severe renal impairment, end-stage renal disease, or dialysis.

Arthritis drug increases effectiveness of antidepressants in bipolar patients

In continuation of my updates on celecoxib

Giving severely depressed patients the arthritis drug celecoxib (Celebrex®) dramatically boosted the effectiveness of their antidepressant medication, a Loyola study has found. 

Loyola Medicine psychiatrist Angelos Halaris, MD, PhD, presented the study at the Fifth International Congress on Psychiatry and the Neurosciences in Athens, Greece. Dr. Halaris is a professor in the Department of Psychiatry and Behavioral Neurosciences of Loyola University Chicago Stritch School of Medicine. 

 The eight-week study enrolled bipolar adults, aged 18 to 65, who were in the depressive phase of their disease and had not benefitted from an antidepressant. (Bipolar disorder is marked by alternating periods of elation and depression, with depression typically lasting longer.) Patients were randomly assigned to receive the antidepressant escitalopram (Lexapro®) plus celecoxib or Lexapro plus a placebo. 

Seventy-eight percent of the patients in the celecoxib group experienced at least a 50 percent reduction in their depression scores, with 63 percent reporting their depression had gone away completely. By comparison, only 45 percent of the placebo group recorded a 50 percent or more reduction in depression, with only 10 percent reporting their depression had lifted completely.

It typically takes four to six weeks before an antidepressant begins working. In the Loyola study, patients who took celecoxib began seeing a benefit from their antidepressant within a week.
Fifty-five patients completed the study: 31 in the Lexapro plus celecoxib group and 24 in the Lexapro plus placebo group. 

Previous studies have found that depression revs up the immune system, resulting in chronic inflammation. This inflammatory response affects the normal balance of chemical messengers in the brain called neurotransmitters. Inflammation hinders the function of antidepressants that are designed to restore normal chemical balance. By fighting inflammation, celecoxib appears to make antidepressants more effective, Dr. Halaris said. 

 Celecoxib is used to treat pain, redness, swelling and inflammation from arthritis. It also can manage acute pain and menstrual cramps. By itself, it does not treat depression.

 The study's findings support the hypothesis that inflammation plays a critical role in depression. Reducing inflammation with a drug such as celecoxib "reverses treatment resistance and enhances overall antidepressant response," Dr. Halaris wrote in the study. "Such an intervention, if implemented relatively early in the course of the disease, may arrest the neuroprogressive course of bipolar disorder." 

Scientists modify structure of cancer drug to enhance ability to pass through blood-brain barrier

In efforts to develop new treatments for brain cancer, scientists from Johns Hopkins Drug Discovery and the Kimmel Cancer Center's Bloomberg~Kimmel Institute for Cancer Immunotherapy report they have altered the structure of an experimental drug that seems to enhance its ability to slip through the mostly impermeable blood-brain barrier. Results of their proof-of-concept experiments in monkeys, published Aug. 25 in the Journal of Medicinal Chemistry, show a tenfold better delivery of the drug to the brain compared with the rest of animals' bodies.

The scientists began with an experimental anti-cancer drug cultivated from bacteria found in Peruvian soil more than 70 years ago. Called 6 diazo-5-oxo L norleucine, or DON, the drug blocks the cellular use of the protein building block glutamine. On its own, DON has shrunk tumors in clinical trials of people with a variety of advanced cancers, but its damage to the gastrointestinal system, a glutton for glutamine, ultimately proved too toxic for humans, say the scientists.

"We wondered whether we could make a safer and more tolerable form of DON by enhancing its brain penetration and limiting its exposure to the rest of the body and, thus, toxicity," says Barbara Slusher, Ph.D., professor of neurology, medicine, psychiatry, neuroscience and oncology at the Johns Hopkins University School of Medicine and director of Johns Hopkins Drug Discovery.

Slusher teamed up with Johns Hopkins Kimmel Cancer Center immunologist Jonathan Powell, M.D., Ph.D., who has studied how cancer cells use different metabolic pathways to evade destruction by immune cells.

"A tumor uses aggressive metabolism to grow, sucking up all the surrounding nutrients, which leads to a very oxygen-poor, acidic environment that is not conducive to cancer-killing immune cells," says Powell, who is an associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy.

Powell suspects that using glutamine-blocking drugs to target tumor metabolism could make the environment around a tumor less harsh, slow down its growth and give the immune system a chance to attack the cancer cells. "The hope is to enhance certain immunotherapy drugs by adding such glutamine antagonists," says Powell.

To alter DON, Slusher and her drug discovery team designed and synthesized various derivatives, focused on making the drug more lipid soluble, or lipophillic, a trait known to aid passage through the blood-brain barrier. Once inside the brain, the new derivatives are designed to rapidly metabolize back to DON.

They gave DON and an altered derivative, dubbed 5c, intravenously to two monkeys and, 30 minutes later, measured the amount of the drugs in the monkeys' cerebrospinal fluid and circulating plasma, which is the liquid portion of blood that remains after blood cells, platelets and other cellular components are removed. The monkey that received DON had about seven times less concentration of the drug in its blood than the monkey that received 5c. In the monkey that received 5c, which converts to DON in the brain, the scientists found 10 times more DON in the cerebrospinal fluid than the monkey treated with unaltered DON.

"We showed that we can modify these drugs to have further specificity to target the brain and limit toxicity to the rest of the body," says Slusher. "This strategy can potentially be used to develop tailored drugs for different cancers."

Scientists modify structure of cancer drug to enhance ability to pass through blood-brain barrier:

U.S. FDA panel narrowly backs Cempra's antibiotic solithromycin

A panel of federal health advisers has narrowly recommended approval for an experimental antibiotic from Cempra Inc., a small North Carolina drugmaker.

The Food and Drug Administration's outside experts voted 7-6 in favor of the drug, saying its effectiveness outweighed risks of liver toxicityseen in company studies. The vote is nonbinding but the FDA often follows the advice of its panelists.

Cempra is one of a handful of drugmakers developing new antibiotics amid growing bacterial resistance to decades-old drugs like penicillin.

On Wednesday Cempra shares plunged more than 60 percent after the FDA posted an online review highlighting irregular liver enzyme measurements reported with the drug, called solithromycin. 

U.S. FDA panel narrowly backs Cempra's antibiotic solithromycin

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

A new compound, discovered jointly by international pharmaceutical company Servier, headquartered in France, and Vernalis (R&D), a company based in the UK, has been shown by researchers at the Walter and Eliza Hall Institute and Servier to block a protein that is essential for the sustained growth of up to a quarter of all cancers.

The research presents a new way to efficiently kill these cancerous cells and holds promise for the treatment of blood cancers such as acute myeloid leukemia, lymphoma and multiple myeloma, as well as solid cancers such as melanoma and cancers of the lung and breast. It is published online in the journal Nature.

The Servier compound -- S63845 -- targets a protein of the BCL2 family, called MCL1, which is essential for the sustained survival of these cancer cells.

Institute scientist Associate Professor Guillaume Lessene, who led the Walter and Eliza Hall Institute's research team in Melbourne, Australia, said the work provided the first clear preclinical evidence that inhibiting MCL1 was effective in targeting several cancer types.

"MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body," Associate Professor Lessene said. "Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival."

The institute team of Associate Professor Lessene worked with haematologist Associate Professor Andrew Wei and Dr Donia Moujalled from The Alfred Hospital and Servier scientists, to demonstrate that not only was S63845 effective against several cancer types, but that it could also be delivered at doses that were well tolerated by normal cells.

Dr Olivier Geneste, Director of Oncology Research at Servier, said this preclinical research represented major findings regarding the druggability of MCL1, a valuable and highly challenging target. "S63845 was discovered through collaboration with the fragment and structure based discovery expertise at Vernalis," he said. "As part of the ongoing Servier / Novartis collaboration on this target class, clinical development of a MCL1 inhibitor should be launched in the near future."

Associate Professor Lessene said the research provided further evidence of the usefulness of a new class of anti-cancer drugs called BH3 mimetics. "BH3 mimetics inhibit a group of proteins known as the 'pro-survival BCL-2 proteins'," he said. "MCL1 is a member of this protein family, and inhibiting it activates the process of programmed cell death. Walter and Eliza Hall Institute researchers revealed the role of BCL-2 in cancer more than 28 years ago and the essential role of MCL1 for the survival of malignant cells four years ago."

Ref : 

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models : Nature : Nature Research

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

A new compound, discovered jointly by international pharmaceutical company Servier, headquartered in France, and Vernalis (R&D), a company based in the UK, has been shown by researchers at the Walter and Eliza Hall Institute and Servier to block a protein that is essential for the sustained growth of up to a quarter of all cancers.

The research presents a new way to efficiently kill these cancerous cells and holds promise for the treatment of blood cancers such as acute myeloid leukemia, lymphoma and multiple myeloma, as well as solid cancers such as melanoma and cancers of the lung and breast. It is published online in the journal Nature.

The Servier compound -- S63845 -- targets a protein of the BCL2 family, called MCL1, which is essential for the sustained survival of these cancer cells.

Institute scientist Associate Professor Guillaume Lessene, who led the Walter and Eliza Hall Institute's research team in Melbourne, Australia, said the work provided the first clear preclinical evidence that inhibiting MCL1 was effective in targeting several cancer types.

"MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body," Associate Professor Lessene said. "Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival."

The institute team of Associate Professor Lessene worked with haematologist Associate Professor Andrew Wei and Dr Donia Moujalled from The Alfred Hospital and Servier scientists, to demonstrate that not only was S63845 effective against several cancer types, but that it could also be delivered at doses that were well tolerated by normal cells.

Dr Olivier Geneste, Director of Oncology Research at Servier, said this preclinical research represented major findings regarding the druggability of MCL1, a valuable and highly challenging target. "S63845 was discovered through collaboration with the fragment and structure based discovery expertise at Vernalis," he said. "As part of the ongoing Servier / Novartis collaboration on this target class, clinical development of a MCL1 inhibitor should be launched in the near future."

Associate Professor Lessene said the research provided further evidence of the usefulness of a new class of anti-cancer drugs called BH3 mimetics. "BH3 mimetics inhibit a group of proteins known as the 'pro-survival BCL-2 proteins'," he said. "MCL1 is a member of this protein family, and inhibiting it activates the process of programmed cell death. Walter and Eliza Hall Institute researchers revealed the role of BCL-2 in cancer more than 28 years ago and the essential role of MCL1 for the survival of malignant cells four years ago."

Ref : 

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models : Nature : Nature Research

Combination of two drugs could be effective strategy to target T-cell lymphocytic leukemia

Researchers have determined that two Phase 1 drugs (CX-4945 and JQ1) can work together to efficiently kill T-cell acute lymphoblastic leukemia cells while having minimal impact on normal blood cells.

 JQ1     CX-4945

Although both drugs were previously tested as single agents in clinical trials to treat cancers, the success of the combined actions on cancer cells was previously unknown until now. The findings appear in the journal Haematologica.

Acute lymphoblastic leukemia, also known as acute lymphocytic leukemia or acute lymphoid leukemia, is a form of cancer of the white blood cells, characterized by the overproduction and accumulation of cancerous, immature white blood cells, known as lymphoblasts. Despite treatment improvement, T-cell leukemia remains fatal in 20 percent of pediatric and 50 percent of adult patients. Both CX-4945 and JQ1 are in clinical trials now as single agents to treat solid and hematological cancers.

"Previous studies provided us a rationale to test the combination of CX-4945 and JQ1 on refractory/relapsed T-cell leukemia," said corresponding author Hui Feng, MD, PhD, assistant professor of pharmacology & experimental therapeutics at Boston University School of Medicine (BUSM). "Our findings suggest that the combination treatment of CX-4945 and JQ1 could be an effective strategy to target refractory/relapsed T-cell leukemia," she added.

According to the researchers the efficacy of using a combination of JQ1 and CX-4945 in treating other cancers should also be investigated.

Ref : http://www.haematologica.org/content/early/2016/10/03/haematol.2016.154013

Cranberry extract disrupts communication between bacteria linked to pervasive infections

In continuation of my update on cranberry

Scientists from McGill University and INRS-Institut Armand-Frappier in Canada recently released a novel investigation showing that cranberry extract successfully interrupted the communication between bacteria associated with problematic and pervasive infections. The authors of the data published in Nature's Scientific Reports, Eric Déziel, professor-investigator at INRS-Institut Armand-Frappier and Nathalie Tufenkji, professor at McGill University, state that not only do the results provide insights into how cranberry compounds may work, they also have implications for the development of alternative approaches to control infections.

Previously published work has shown that the American cranberry (Vaccinium macrocarpon L) contains compounds -- such as proanthocyanidins (PACs) -- that provide meaningful antioxidant, anti-adhesion and anti-microbial properties that help fend off illness. Given this, the scientific team hypothesized that cranberries may also have an anti-virulence potential. They wanted to know if these cranberry compounds could help manage bacterial infections. By feeding fruit flies -- a commonly used model for studying human infections -- cranberry extract, the team discovered that cranberry provided flies protection from a bacterial infection and they lived longer than their cranberry-free counterparts. In essence, the cranberry extract reduced the severity of the bacterial infection.

Study author, Dr. Tufenkji, elaborates on what this might mean for humans, as opposed to flies, "This means that cranberries could be part of the arsenal used to manage infections and potentially minimize the dependence on antibiotics for the global public."

To further explain cranberries' impact on bacteria, Dr. Déziel said, "Cranberry PACs interrupt the ability for bacteria to communicate with each other, spread and become virulent -- a process known as quorum sensing. The cranberry extract successfully interferes with the chain of events associated with the spread and severity of chronic bacterial infections."

Added to the evidence of cranberry's role in preventing recurrent urinary tract infections by blocking bacteria from sticking to cell walls, the current study suggests that PACs may help control the virulence or spread of potentially dangerous bacterial infections around the world.

New drug appears to decrease inflammation in the brain linked to Alzheimer's disease

An experimental drug shows promise in treating Alzheimer's disease by preventing inflammation and removing abnormal protein clumps in the brain that are associated with the disease, suggests a study in mice presented at the ANESTHESIOLOGY® 2016 annual meeting.

A key characteristic of Alzheimer's disease is the development of abnormal protein clumps called amyloid plaques and tangled bundles of fibers in the brain. These changes cause inflammation in the brain and damage to the neurons. This progressive damage leads to memory loss, confusion and dementia. The new drug, known as NTRX-07, appears to decrease this inflammation in the brain, while preserving neurons and regenerative cells in the brain.

"This drug may reduce inflammation in the brain, which is linked to Alzheimer's disease," said lead researcher Mohamed Naguib, M.D., a physician anesthesiologist in the Department of General Anesthesiology at the Cleveland Clinic and professor of anesthesiology at the Cleveland Clinic Lerner College of Medicine. "NTRX-07 uses a different mechanism than many other Alzheimer's drugs currently available, as it targets the cause of the disease, not just the symptoms."

The authors discovered NTRX -07's memory-restoring abilities while studying the drug's potential to treat a complex, chronic pain condition called neuropathic pain. "Patients who have neuropathic pain have chronic neuroinflammation," said Dr. Naguib. "This is a compound that blunts that inflammation."

Researchers tested NTRX -07 on mice bred to have similar brain neurodegenerative issues as seen in Alzheimer's. They found that inflammation produced in response to the disease caused changes in the brain's microglia cells - immune cells that typically remove dangerous amyloid plaques (protein clumps) in the brain. As the amyloid plaques accumulated in the mice, the microglia (immune cells) were unable to remove them, leading to inflammation and damage to nerve cells, which caused decreased cognitive ability.

Microglia cells have receptors on the surface called CB2 receptors, which when activated can produce an anti-inflammatory response. NTRX -07 targets CB2 receptors, which leads to decreased inflammation and prevents damage to the brain tissue. The new drug improved removal of abnormal amyloid plaques and improved memory performance and other cognitive skills.

The drug also increased levels of a protein called SOX2, which has been shown to help new brain cells develop and protect the brain in people with Alzheimer's disease. The study found in mice treated with NTRX-07, the levels of SOX2 were restored to normal levels. In contrast, mice treated with a placebo showed decreased levels of SOX2, active inflammation in the brain, poor removal of amyloid plaques, and poor memory performance.

FDA approves new therapy for initial treatment of soft tissue sarcoma

In continuation of my update on Doxorubicin

The U.S. Food and Drug Administration today granted accelerated approval to Lartruvo (olaratumab) with doxorubicin to treat adults with certain types of soft tissue sarcoma (STS), which are cancers that develop in muscles, fat, tendons or other soft tissues. Lartruvo is approved for use with the FDA-approved chemotherapy drug doxorubicin for the treatment of patients with STS who cannot be cured with radiation or surgery and who have a type of STS for which an anthracycline (chemotherapy) is an appropriate treatment.

"For these patients, Lartruvo, added to doxorubicin, provides a new treatment option," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research and acting director of the FDA's Oncology Center of Excellence. "This is the first new therapy approved by the FDA for the initial treatment of soft tissue sarcoma since doxorubicin's approval more than 40 years ago."

The National Cancer Institute estimates that 12,310 new cases of STS and nearly 5,000 deaths are likely to occur from the disease in 2016. The most common treatment for STS that cannot be removed by surgery is treatment with doxorubicin alone or with other drugs. STS includes a wide variety of tumors arising in the muscle, fat, blood vessels, nerves, tendons or the lining of the joints.

Lartruvo is a platelet-derived growth factor (PDGF) receptor-alpha blocking antibody. When stimulated, PDGF receptors cause tumor growth. Lartruvo works by blocking these receptors, which may help slow or stop tumor growth.

The safety and efficacy of Lartruvo were studied in a randomized clinical trial involving 133 patients with more than 25 different subtypes of metastatic STS. Patients received either Lartruvo with doxorubicin or doxorubicin alone. This trial measured the length of time patients lived after treatment (overall survival), the length of time tumors did not grow after treatment (progression-free survival) and the percentage of patients who experienced shrinkage of their tumors (overall response rate). Patients in this trial who received Lartruvo with doxorubicin had a statistically significant improvement in overall survival: the median survival was 26.5 months compared to 14.7 months for patients who received doxorubicin alone. Patients who received Lartruvo with doxorubicin had a median progression-free survival of 8.2 months compared to 4.4 months for patients who received doxorubicin alone. Tumor shrinkage was 18.2 percent for patients who received Lartruvo with doxorubicin and 7.5 percent for those who received doxorubicin alone.

Lartruvo has serious risks including infusion-related reactions and embryo-fetal harm. Infusion-related reactions include low blood pressure, fever, chills and rash. The most common side effects of treatment with Lartruvo are nausea, fatigue, low levels of white blood cells (neutropenia), musculoskeletal pain, inflammation of the mucous membranes (mucositis), hair loss (alopecia), vomiting, diarrhea, decreased appetite, abdominal pain, nerve damage (neuropathy) and headache.

The FDA granted the Lartruvo application fast track designation, breakthrough therapy designation and priority review status because preliminary clinical evidence indicated that it may offer a substantial improvement in effectiveness in the treatment of a serious or life-threatening disease or condition. The FDA is approving Lartruvo under the agency's accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease or condition based on clinical data showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. The sponsor is conducting a larger study, which is currently underway, to further explore the effectiveness of Lartruvo across the multiple subtypes of STS.

Lartruvo also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs intended to treat rare diseases.

New clinical study to examine novel dietary approach for TNBC

A new clinical trial for women with clinically aggressive triple-negative breast cancer (TNBC) will test a novel theory: Will a diet low in an essential nutrient make TNBC cells more vulnerable to cell killing by a new cancer drug?

Women with TNBC have limited treatment options apart from chemotherapy because their tumor cells lack three proteins - estrogen, progesterone and human epidermal growth factor receptors -- commonly targeted with standard treatments. But chemotherapy often fails in these patients, so there is an urgent need to develop new therapies.

Dr. Vince Cryns, who is leading the study along with Dr. Ruth O'Regan, says his team has developed an entirely new approach for TNBC that combines diet with a new cancer drug. This drug, called ONC201, is the first of a new class of cancer drugs that selectively kills tumor cells but not normal cells. It is being developed by the Philadelphia company Oncoceutics.

The clinical trial is based on studies by the Cryns lab showing that a diet low in the essential nutrient methionine make tumor cells more susceptible to cell killing by ONC201. In this phase II trial, funded by the V Foundation for Cancer Research and the Wisconsin Partnership Program, 112 women with metastatic TNBC will be randomized to a diet low in methionine or a regular diet followed by ONC201.

"Our strategy is the first of its kind to use diet to prime TNBC cells to respond to a targeted cancer drug,'' says Cryns.

"I think this will be a really attractive trial to patients, because it is safe and the drug is well-tolerated - it's not like chemotherapy,'' O'Regan says. "Our advisory board of breast-cancer survivors is very excited about this trial." The trial will recruit patients across the state through the Wisconsin Oncology Network, which partners community hospitals with the University of Wisconsin Carbone Cancer Center.

That trial is expected to begin sometime in early 2017.

Before that, Cryns and O'Regan are launching a smaller trial to better understand the effects of the diet on TNBC. In this trial, funded by the Avon Breast Cancer Crusade, 25 women who are newly diagnosed with TNBC will take a low-methionine diet for one to three-weeks before their definitive surgery or chemotherapy. The trial will examine the impact of the low methionine diet on the growth and molecular characteristics of the tumors as well as the effects on body composition and metabolic health.

"A low methionine diet has been shown to reduce body fat and improve metabolic health in rodents so we want to determine whether a short-term reduction in methionine has metabolic benefits in women with TNBC,'' Cryns says. These metabolic effects could be an additional health benefit of this dietary intervention.

Folinic acid treatment could help improve language and communication skills of children with ASD

In continuation of my update on Folinic acid

Prescription doses of folinic acid, which is a reduced form of a B vitamin known as folate, could help improve the language and communication skills of children with autism spectrum disorder (ASD). These are the preliminary findings from a placebo-controlled trial in which children were randomized to receive either high-dose folinic acid or a placebo, says lead author Richard Frye of Arkansas Children's Research Institute in the US. The study, which is published in Springer Nature's journal Molecular Psychiatry, also identified a specific blood marker that can be used to predict which patients have the best chance to respond to the treatment.

Up to two percent of American children are said to experience symptoms that place them on the autism spectrum. Many of these children have difficulty communicating and interacting with others, especially within a social setting. Researchers do not yet fully understand all the reasons behind the development of ASD and, importantly, there are currently no approved treatments that address the core symptoms of this disorder.

"The only currently approved medications for autism are both antipsychotic medications that address non-core symptoms and can lead to unwanted side effects," says John Slattery, a co-author of the study.

Scientific research has linked this disorder to abnormalities in the metabolism of folate as well as genes that are involved in folate metabolism. Certain studies have also shown that the offspring of women who took folate supplements before conception and during pregnancy had a lower risk of having a child with ASD.

About ten years ago a condition, known as cerebral folate deficiency (CFD), was described in which the concentration of folate is below normal in the central nervous system but not in the blood. Many children with CFD had ASD symptoms and responded well to treatment with high-dose folinic acid.

Previously Frye's team could show that folate receptor autoantibodies were found with a high prevalence in children with ASD. In the current study, these researchers found that participants with folate receptor autoantibodies had a more favourable response to the folinic acid treatment. This leads the way to a test that might be useful for clinicians to determine if high-dose folinic acid might be a treatment for a particular child with ASD. The deleterious effects of folate receptor antibodies on brain development and function are now confirmed in a laboratory rat model.

"Improvement in verbal communication was significantly greater in participants receiving folinic acid as compared with those receiving the placebo," says Frye. He adds that the findings should be considered preliminary until the treatment has been assessed further in larger long-term studies.

The researchers indicated they were very pleased with the positive findings of this study, but caution that more research is needed in order to replicate the findings in a larger population.

Study on common bacterium presents new pathway to combat gastric cancers

A common bacterium that more than half of people have in their gut can use hydrogen gas present in the gastrointestinal tract to inject a cancer-causing toxin into otherwise healthy cells, according to a recently published study led by University of Georgia researchers.

The bacterium's reliance on hydrogen presents a pathway to potential new treatment and preventive measures in fighting gastric cancers, which kill more than 700,000 people per year, said corresponding author Robert Maier, Georgia Research Alliance Ramsey Eminent Scholar of Microbial Physiology in the Franklin College of Arts and Sciences.

Previous studies solidified the relationship between stomach ulcers and cancer and certain strains of Helicobacter pylori, a stomach-dwelling bacterium that causes 90 percent of all gastric cancers. Earlier research also found a link between a toxin known as CagA, or cytotoxin-associated gene A, and cancer formation, but the new study exposes how the bacterium uses hydrogen as an energy source to inject CagA into cells, resulting in gastric cancer, Maier said.

"There are many known microbes in the human gut that produce hydrogen and others that use hydrogen. The implications of the study are that if we can alter a person's microflora, the bacterial makeup of their gut, we can put bacteria in there that don't produce hydrogen or put in an extra dose of harmless bacteria that use hydrogen," Maier said. "If we can do that, there will be less hydrogen for H. pylori to use, which will essentially starve this bacteria out and result in less cancer."

Changing the microbial makeup of a person's gut sounds complicated, but scientists are already exploring ways to do so through the use of probiotics, antibiotics, nutritional regimes and even fecal transplants.

Although many people carry the H. pylori bacterium, it can take decades for the infection to develop into cancer, providing an opening for aggressive preventive measures in people who have a high risk of developing tumors, said lead author Ge Wang, a senior research scientist in the Department of Microbiology. The presence of H. pylori strains with both CagA and high hydrogen-utilizing activity within patients can potentially serve as biomarkers for predicting future cancer development.

An earlier study led by Maier, "Molecular Hydrogen as an Energy Source for Helicobacter pylori," published by the American Association for the Advancement of Science in 2002, showed that the presence of hydrogen in the gastric chamber was important for bacterial growth, but it wasn't until the current study that researchers learned of the strong cancer connection: The bacterium harnesses the energy from hydrogen gas, via an enzyme known as hydrogenase, to severely disrupt host cell function, leading to cancer.

"If hydrogen is in the gastric mucosa, of course a bacterium will use it," Maier said. "It's an excellent energy source for many bacteria out in nature. But we didn't realize that pathogens like H. pylori could have access to it inside an animal in a way that enables the bacterium to inject this toxin into a host cell and damage it."

Not all strains of the bacteria cause cancer, but those with CagA are known carcinogens. Using human-derived gastric cells, Wang analyzed the hydrogenase activity in the cells that were infected with different strains — both cancer causing and non-carcinogenic — of H. pylori. He found more activity in the cancer-causing strains. After using genetic engineering to knock out the DNA fragment containing the hydrogenase-inducing genes, which prevented those strains from deriving energy from hydrogen, he found that the strain he created could no longer move the cancer-causing toxin into the gastric cells. Collaborators at Vanderbilt University took Wang's in vitro model and adapted it to test the theory in gerbils, which confirmed the UGA researchers' findings.

Cocoa flavanol consumption linked to improvements in cardiometabolic biomarkers

To the tantalizing delight of chocolate lovers everywhere, a number of recent studies employing various methods have suggested that compounds in cocoa called flavanols could benefit cardiovascular health. Now a systematic review and meta-analysis of 19 randomized controlled trials (RCTs) of cocoa consumption reveals some further pieces of supporting evidence.

The meta-analysis in the Journal of Nutrition, an assessment of the combined evidence from all 19 RCTs, focused on whether consumption of flavanol-rich cocoa products was associated with improvements in specific circulating biomarkers of cardiometabolic health as compared to consuming placebos with negligible cocoa flavanol content. In all, 1,139 volunteers were involved in these trials.

"Our meta-analysis of RCTs characterizes how cocoa flavanols affect cardiometabolic biomarkers, providing guidance in designing large, definitive prevention trials against diabetes and cardiovascular disease in future work," said corresponding author Dr. Simin Liu, professor and director of the Center for Global Cardiometabolic Health at Brown University who worked with epidemiology graduate student and lead author Xiaochen Lin. "We found that cocoa flavanol intake may reduce dyslipidemia (elevated triglycerides), insulin resistance and systemic inflammation, which are all major subclinical risk factors for cardiometabolic diseases."

Liu noted some limitations in the trials. All studies were small and of short duration, not all of the biomarkers tracked in these studies changed for the better, and none of the studies were designed to test directly whether cocoa flavanol consumption leads to reduced cases of heart attacks or type 2 diabetes.

But taking into account some of these heterogeneities across studies, the team's meta-analysis summarizing data from 19 trials found potential beneficial effects of flavanol-rich cocoa on cardiometabolic health. There were small-to-modest but statistically significant improvements among those who ate flavanol-rich cocoa product vs. those who did not.

The greatest effects were seen among trial volunteers who ate between 200 and 600 milligrams of flavanols a day (based on their cocoa consumption). They saw significant declines in blood glucose and insulin, as well as another indicator of insulin resistance called HOMA-IR. They also saw an increase in HDL, or "good," cholesterol. Those consuming higher doses saw some of the insulin resistance benefits and a drop in triglycerides, but not a significant increase in HDL. Those with lower doses of flavanols only saw a significant HDL benefit.

In general, Lin said, where there were benefits they were evident for both women and men and didn't depend on what physical form the flavanol-rich cocoa product was consumed in --dark chocolate vs. a beverage, for example.

"The treatment groups of the trials included in our meta-analysis are primarily dark chocolate -- a few were using cocoa powder-based beverages," Lin said. "Therefore, the findings from the current study apparently shouldn't be generalized to different sorts of chocolate candies or white chocolates, of which the content of sugar/food additives could be substantially higher than that of the dark chocolate."

The authors therefore concluded, "Our study highlights the urgent need for large, long-term RCTs that improve our understanding of how the short-term benefits of cocoa flavanol intake on cardiometabolic biomarkers may be translated into clinical outcomes."