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Study Determines Efficacy of 2 Drugs to Treat a Form of 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.

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.

Source: http://www.dddmag.com/news/2016/10/study-determines-efficacy-2-drugs-treat-form-leukemia

Date: 10/26/2016

Allison Kalloo, MPH, is a patient recruitment consultant specializing in the dynamic intersection of marketing communications and underrepresented populations. She is the founder and CEO of Clinical Ambassador. She is a graduate of The Madeira School, North Carolina Central University, and Yale School of Public Health.

Minority Inclusion in Clinical Trials: When Diversity Priorities Show

Beyond the critical need for securing more study volunteers across the board in clinical trials, a popular concern in all areas of clinical research is achieving diversity in those trials.

Whether in medical journals, popular press, social media, or at professional conferences, both public and private sectors describe a deeper commitment to diversifying their pool of participants, acknowledging its role in research data integrity and the relevance of it reflecting today’s diverse society.

Many now know that while more than one third of the U.S. population is made up of minorities, only 16.7 percent of participants in any industry-funded trials are minorities, which underscores the high stakes and an urgent need for industry to set higher standards for inclusion.

It makes no sense to develop new treatments for populations of patients who may be fundamentally different from those who will be using them. Simple enough, but making good on diversity has proven more complicated. We have known for decades that disease burden disproportionately affects minorities groups, but more recently, researchers also acknowledge that beyond social determinants of disease, minority underrepresentation in clinical trials also contribute significantly to health disparities.

Population shifts will make minorities the majority by 2050 (now described as “the Browning of America”) and create an urgency to achieve greater diversity among trial participants to ultimately better meet therapeutic needs. Further, President Obama’s Precision Medicine Initiative focuses more attention on cutting-edge research to understand the variability in genes, environment, and lifestyle in an effort toward optimizing individualized treatments. But this initiative depends on successfully building a participant cohort that realistically reflects the diversity of the U.S. population and can offer researchers a greater breadth of understanding on a variety of health questions about both prevalent and rare diseases, many of which disproportionately affect minorities.

Access to this genomic data from a diverse cohort will allow investigation into preventing disease and improving quality of life for more people. Currently, few U.S. biomedical studies sufficiently focus on recruitment efforts that stand a viable chance of achieving real diversity—that which reflects disease prevalence—sabotaging our capacity to answer critical questions about minority health, according to the Institute of Medicine.

The pressures mounting on industry to produce more targeted therapies based on better understanding the pharmacodynamics of all patient subgroups are coming from all sides: policymakers, payers, regulators, providers and patients alike. For the FDA, more attention to bridging gaps in study representation is shifting into higher gear, partially in response to the Security and Innovation Act of 2012 (FDASIA section 907).

Since then, the FDA has required industry to start counting, to effectively collect and report data quantifying their product’s safety and effectiveness by age, gender and race on all new drug applications they submit. Evidence of the ramping up of stricter federal policy also comes from the growing number of cases in which the FDA has sent drug makers’ new drug applications back, requiring minority cohort data that was previously lacking. As oversight intensifies, results are also being reported in the FDA’s Drug Trials Snapshots and reviewed in public meetings.

As pressures mount to diversify clinical trials, recent research by Brown and Moyer in Ethnic Health substantiate a willingness on the part of minorities to participate, despite popular rumors to the contrary. The authors reviewed the decision-making processes of 70,000 research volunteers and established that minorities are just as likely as the majority population to participate in clinical trials when approached about participating.

Despite being three times more likely to subscribe to conspiracy theories about genocide, blacks are more willing to participate in HIV-related studies than whites, effectively debunking prevailing notions about distrust being the primary obstacle to minority participation. In reality, the limiting factor to diversity in clinical trials has proven to be more “whether and how” people of color are invited to participate in the first place.

Being deliberate about study diversity means tackling both overt and subtle issues head-on. Factors within the study’s control are still taken for granted. Too often:

• Basic access—to referral sources and to clinical sites—is inadequate;

• Explanations about patients’ rights that can quell fears go poorly communicated;

• Logistical complications and demands on participants’ time are not sufficiently minimized;

• Patient education that connects the dots to clinical research is rarely provided; and,

• Nuanced cultural and linguistic barriers are not given enough time and attention.

Deliberate resources focused on these details hold the promise of eliminating many of the prevailing roadblocks. Despite dramatic shifts in our culture and the potential of precision medicine on our horizon, the pivot toward enhanced engagement setting the stage for real diversity has yet to take place. Committing to a broader mix of patient stakeholders is the first step to achieving durable inclusion, and it can affect outcomes in both broad strokes and with study specificity. The true value of clinical trial recruitment efforts will ultimately be measured not by the higher numbers of participants enrolled, but by the quality of efforts to make studies inclusive. Metrics meant to tell how well recruitment methods have worked must be replaced by metrics focusing more on tracking deliberate delivery of clarity, transparency and relevance, not just “regardless” of study indication, culture mix, and location, but because of those factors. Efforts will be obvious. Establishing sustainable partnerships with diverse participants is absolutely feasible as well, and will enhance the experience for all stakeholders in clinical trials.

Source: https://www.biospace.com/News/minority-inclusion-in-clinical-trials-when/433730

Date: 10/24/2016

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Colombian Pharmaceutical Market to See Strong Four Year Growth

The pharmaceutical market in Colombia is set to rise from $5 billion in 2015 to $7.1 billion by 2020, registering a compound annual growth rate (CAGR) of 7.3%, according to research and consulting firm GlobalData.

The company’s latest report states that this substantial rise can be attributed to increased drug consumption, caused by a rising disease burden, and government initiatives in the public healthcare sector. In addition, Colombia is fast becoming a hub for clinical trial research, due to low costs, and there has been a sharp increase in the number of clinical trials undertaken in recent years. At present, the five leading pharmaceutical companies in Colombia are Tecnoquimicas, Pfizer, Merck & Co., Roche and Procaps.

Officials of various multinational companies agree that Colombia has become an important center for clinical trials in Latin America, and has started to receive clinical trials that would otherwise have been sent to Argentina or Mexico. The increase in clinical trials can be attributed primarily to highly-trained biomedical researchers and significantly lower costs.

In terms of government initiatives driving growth, Colombia has implemented trade agreements with El Salvador, Guatemala, Chile, Honduras, Switzerland, and Canada in order to positively impact the trade and economy of the country. The government has also signed a trade agreement with the EU and the European Free Trade Association nations, which include Liechtenstein, Norway, and Iceland, and expanded its trade relations with Mexico.

Colombia has a determined trade agenda and has initiated Free Trade Agreement (FTA) negotiations with Turkey, South Korea, Japan, and Panama, and has recently signed an FTA with the US.

The government is largely focused on the promotion of generic drug usage, as it is the smallest segment of the pharmaceutical market but is yet to be explored. The Colombian generic market will attract multinational generic manufacturers to leverage the largely untapped opportunity in this sector, and will also help the government to reduce healthcare spending.

Source: http://www.dddmag.com/news/2016/10/colombian-pharmaceutical-market-see-strong-four-year-growth

Date: 10/21/2016

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Tiny Gold Nanoparticles Could Help Develop New Pancreatic Cancer Therapy

A diagnosis of pancreatic cancer is often a death sentence because chemotherapy and radiation have little impact on the disease. In the U.S. this year, some 53,000 new cases will be diagnosed, and 42,000 patients will die of the disease, according to the National Institutes of Health. But research now being reported in ACS Nano could eventually lead to a new type of treatment based on gold nanoparticles.

Scientists have previously studied these tiny gold particles as a vehicle to carry chemotherapy drug molecules into tumors or as a target to enhance the impact of radiation on tumors. In addition, Priyabrata Mukherjee and colleagues previously found that gold nanoparticles themselves could limit tumor growth and metastasis in a model of ovarian cancer in mice.

Now, the team has determined that the same holds true for mouse models of pancreatic cancer. But interestingly, the new work revealed details about cellular communication in the area surrounding pancreatic tumors. By interrupting this communication — which is partly responsible for this cancer’s lethal nature — the particles reduced the cell proliferation and migration that ordinarily occurs near these tumors. Gold nanoparticles of the size used in the new study are not toxic to normal cells, the researchers note.

Date: 10/20/2016

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Folinic Acid Could Help Children With Autism Communicate Better

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.

Source: http://www.biosciencetechnology.com/news/2016/10/folinic-acid-could-help-children-autism-communicate-better

Date: 10/19/2016

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Neuroscientists Identify Two Neuron Populations That Encode Happy or Fearful Memories

Our emotional state is governed partly by a tiny brain structure known as the amygdala, which is responsible for processing positive emotions such as happiness, and negative ones such as fear and anxiety.

A new study from MIT finds that these emotions are controlled by two populations of neurons that are genetically programmed to encode memories of either fearful or pleasurable events. Furthermore, these sets of cells inhibit each other, suggesting that an imbalance between these populations may be responsible for disorders such as depression and post-traumatic stress disorder.

“The positive memory cells identified by the genetic markers, which counter negative memory cells, promise an opportunity to identify effective molecular targets for treatment of emotional disorders such as depression and PTSD,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and director of the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory.

Tonegawa is the senior author of the study, which appears in the Oct. 17 issue of Nature Neuroscience. Joshua Kim, an MIT graduate student, is the paper’s lead author.

Distinct populations

In 2014, Tonegawa’s lab identified a brain circuit that links memories with positive or negative emotions. This circuit connects neurons in the hippocampus, which remember the memory’s context (what happened and where it happened), with neurons in the basolateral amygdala (BLA), which stores the emotional association of the event.

In that study, the researchers also showed that they could reverse a memory’s emotional associations, in mice. To achieve that, they artificially activated hippocampal cells that had been storing a negative memory, while the mouse was undergoing a happier experience. This weakened the fear association of the original memory and replaced it with a more positive feeling, as indicated by the mouse’s preference for a certain location in its container.

However, the same strategy had no effect on neurons of the BLA, suggesting those neurons are precommitted to encoding either fear or feelings of reward. “They seem fixed in terms of what behaviors they can drive,” Kim says.

In the new study, Tonegawa’s lab set out to identify genetic differences that could be used to distinguish the fear-responsive and reward-responsive populations. After analyzing all of the genes turned on in BLA cells, they came up with one gene that is found in BLA cells that encode positive memories but not in cells that encode negative memories. They also found another that exclusively marks the negative population.

The gene associated with reward neurons, known as ppp1r1b, is a well-known gene whose product is involved in dopamine signaling, which is necessary for feelings of pleasure. The function of the gene associated with fear neurons, rspo2, is unknown.

“We don’t know what they’re doing exactly,” Kim said. “There should theoretically be a connection between the gene and cell function, but we don’t necessarily have to understand what the genes do. We’re just using them to discriminate the two populations.”

Anatomically, the BLA is divided into two sections known as posterior and anterior. It turned out that the markers the researchers identified directly map onto these two populations — the anterior region consists of rspo-expressing, fear-encoding cells and the posterior region contains ppp1r1b-expressing, reward-encoding cells.

Feeling off balance

The researchers then used optogenetics, a technique that allows them to selectively inhibit neurons with light, to confirm the two populations’ roles in memory formation. They found that when rspo2 neurons were inhibited, mice could not form fearful memories, and when ppp1r1b neurons were inhibited, they could not form positive memories.

The researchers also discovered that each population of neurons can inhibit the other: When they stimulated activity in the reward neurons, activity in the fear neurons was suppressed, and vice versa. This suggests that the brain constantly balances activity between these two populations of neurons.

“Ultimately what we have is a seesaw between positive and negative,” Kim said. “It’s highly speculative, but anxiety and depression symptoms may be the result of an imbalance between these two populations.”

For example, it is possible that overexcitable fear neurons or less-excitable reward neurons may lead to abnormally strong feelings of fear or anxiety, such as those experienced by people suffering from post-traumatic stress disorder.

The researchers also explored the targets of the BLA, which sends messages to other parts of the brain to stimulate behavioral responses to fearful or pleasurable events. They found that the fear neurons project to a part of the brain called the nucleus accumbens, while reward neurons project to both the nucleus accumbens and another part of the amygdala, known as the central amygdala. Tonegawa’s lab is now investigating these circuits in more detail.

“These results represent a major advance in our understanding of how emotions are processed within the brain and how the balance between positive and negative emotional responses is resolved,” said Joshua Johansen, a faculty member at the RIKEN Brain Science Institute.

“The identification of molecular markers for the different amygdala cell populations allows, for the first time, targeted genetic access to these opposing emotional networks, opening the door to many future studies of emotional function and dysfunction,” says Johansen, who was not part of the research team.

The research was funded by the National Institutes of Health, the RIKEN Brain Science Institute, the Howard Hughes Medical Institute, and the JPB Foundation.

Source: http://www.biosciencetechnology.com/news/2016/10/neuroscientists-identify-two-neuron-populations-encode-happy-or-fearful-memories

Date: 10/18/2016

Cocoa Beans and Cocoa Fruits on wooden, Cocoa concept.

Cocoa Compound Linked to Some Cardiovascular Biomarker Improvements

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 reveal 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.”

Source: http://www.biosciencetechnology.com/news/2016/10/cocoa-compound-linked-some-cardiovascular-biomarker-improvements

Date: 10/17/2016

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Researchers: It’s Time to Consider Propranolol as Anti-Cancer Drug

Propranolol, a beta-blocker commonly prescribed to treat irregular heart rates and other conditions, has significant anti-cancer properties, say researchers in a new clinical study published in ecancermedicalscience.

The Repurposing Drugs in Oncology (ReDO) project, an international collaboration between the Anticancer Fund, Belgium, and US based GlobalCures, says that existing and widely-used non-cancer drugs may represent a relatively untapped source of novel therapies for cancer.

Historically, pharmaceutical companies devote little time to “repurposing” existing drugs. The ReDO project hopes to change that, raising awareness by publishing a series of articles in ecancer to share evidence for using these therapies in cancer medicine.

Propranolol is the latest in a series of drugs that could offer cheap, safe and effective solutions to cancer. It’s available globally in generic form and is on the WHO List of Essential Medicines – particularly in angiosarcoma, a rare form of heart cancer.

“The evidence to date in angiosarcoma is especially compelling,” says study author Pan Pantziarka, PhD, of the Anticancer Fund, Belgium. “Here is a rare disease with high unmet needs that is unlikely to attract investment from the commercial drug development sector. Propranolol offers these patients evidence of efficacy and with little or no toxicity.”

“Existing animal and human data on the use of propranolol to treat cancer is tantalizing and merits rapid and careful evaluation in a number of tumour types,” adds study author Vikas P. Sukhatme of Global Cures, Harvard Medical School, USA.

The paper also highlights the potential of propranolol to act on multiple points of the metastatic cascade – particularly in the peri-operative setting. Post-surgical metastatic spread is a widespread clinical phenomenon, and tackling this has huge potential to lead to improved outcomes.

“There is good in vivo evidence that propranolol, alone and in combination with other agents, impacts this process,” says Pantziarka. “Reducing metastatic spread ultimately saves lives.”

Gauthier Bouche, Medical Director of the Anticancer Fund, points out that propranolol has already been repurposed to treat childhood benign tumours.

“An effective treatment against infantile hemangioma had existed since the 1960s but we only discovered this in 2008 when careful clinicians found it serendipitously. Every day I ask myself: ‘what else can propranolol offer to patients with unmet needs?’ I think there is a lot, and we shouldn’t have to wait another forty years to find out.”

Source: http://www.dddmag.com/news/2016/10/researchers-its-time-consider-propranolol-anti-cancer-drug

Date: 10/14/2016

novavax

Scientists Identify Potent New Anti-Obesity, Anti-Diabetes Target

It is no secret that losing weight is difficult. Each year brings a new popular diet, “guaranteed” to succeed, yet the explosion of obesity in the United States continues.

Current anti-obesity medications are only partly effective, due to substantial side effects, the temporary nature of the weight loss and the non-responsiveness of a considerable number of patients.

In a recently published series of studies led by TSRI Assistant Professor Anutosh Chakraborty of the Florida campus of The Scripps Research Institute (TSRI), scientists have identified a new therapeutic target—a key protein that promotes fat accumulation in animal models by slowing the breakdown and expenditure of fat and encouraging weight gain.

The studies were published in The International Journal of Biochemistry & Cell BiologyMolecular Metabolism and, most recently, The Journal of Clinical Investigation.

“We found that the protein IP6K1 is a viable target in obesity and type 2 diabetes,” Chakraborty said. “We also discovered that an inhibitor of the protein known as TNP decelerates what is known as diet-induced obesity and insulin resistance.”

In the last few years, enhancing energy expenditure has emerged as an attractive strategy to combat obesity and diabetes, although how this might be accomplished remains something of a mystery simply because the mechanisms by which the body maintains its energy balance, is complex.

The new studies point to IP6k1 (inositol hexakisphosphate kinase-1), specifically its inhibition, as a potentially rich target. Chakraborty and his colleagues found that deleting IP6K1 in fat cells enhanced energy expenditure and protected animal models from diet-induced obesity and insulin resistance.

The expenditure of fat energy is preceded by a process called lipolysis that breaks down stored fat or triglycerides (specifically into free fatty acids and glycerol) to be used as energy in cells. The team discovered that deletion of IP6K1 affects interaction with another regulating protein and enhances the breakdown of fats.

To determine the therapeutic possibilities of the IP6K1 pathway, the team looked at the impact of an IP6K inhibitor known as TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl) purine] on diet-induced obesity in animal models. As it turns out, TNP significantly slows the initiation of diet-induced obesity and insulin resistance.

“In addition, the compound facilitates weight loss and improves metabolic parameters when used in animals that are already obese,” said Chakraborty.

Source: http://www.dddmag.com/news/2016/10/scientists-identify-potent-new-anti-obesity-anti-diabetes-target

Date: 10/13/2016