New Molecular Target Identified for Treating Cerebral Malaria

                                                             Mosquito Anopheles

A drug already approved for treating other diseases may be useful as a treatment for cerebral malaria, according to researchers at Harvard T. H. Chan School of Public Health. They discovered a novel link between food intake during the early stages of infection and the outcome of the disease, identifying two molecular pathways that could serve as new targets for treatment.

“We have known for a long time that nutrition can affect the course of infectious disease, but we were surprised at how rapidly a mild reduction in food intake could improve outcome in a mouse malaria model,” said senior author James Mitchell, associate professor of genetics and complex diseases. “However, the real importance of this work is the identification of unexpected molecular pathways underlying cerebral malaria that we can now target with existing drugs.”

The study appears online January 30, 2015 in Nature Communications.

Cerebral malaria — a severe form of the disease — is the most serious consequence of infection by the parasite Plasmodium falciparum, resulting in seizures, coma, and death. Currently there is a lack of safe treatment options for cerebral malaria, particularly for use in children, who represent the majority of cases. Even patients who receive early treatment with standard antimalarial chemotherapeutic agents run a high risk of dying, despite clearance of the parasite. Moreover, around 25% of survivors develop neurological complications and cognitive impairment.

Lead authors Pedro Mejia and J. Humberto Treviño-Villarreal, both researchers at Harvard T.H. Chan School of Public Health, found that leptin—a hormone secreted from fat tissue with roles in suppressing appetite, but also in activating adaptive immune and inflammatory responses—is increased upon infection in a mouse model of cerebral malaria, and turns out to be a major bad actor in promoting neurological symptoms and death. Remarkably, Mejia, Treviño-Villarreal and colleagues showed that reducing leptin using a variety of means, either genetically, pharmacologically, or nutritionally by reducing food intake during the first two days of infection, protected against cerebral malaria.

The researchers also found that leptin acted primarily on cytotoxic T cells by turning on the well-studied mTOR protein, for which pharmacologic inhibitors are readily available. In their animal model, treating mice with the mTOR inhibitor rapamycin protected them against the neurological complications of cerebral malaria. Protection was due in part to a preservation of the blood brain barrier, which prevented the entry of blood cells carrying the parasites into the brain. As rapamycin is already FDA-approved for use in humans, trials in humans for cerebral malaria treatment with this drug may be possible, according to the researchers.

This study was the result of an ongoing collaboration between the Mitchell lab in the Department of Genetics and Complex Diseases and the labs of Manoj Duraisingh and Dyann Wirth in the Department of Immunology and Infectious Diseases. Other Harvard T.H. Chan School of Public Health authors included  Christopher Hine, Eylul Harputlugil, Samantha Lang, Ediz Calay and Rick Rogers.

This study was supported in part by grants from NIH (DK090629 and AG036712) and the Glenn Foundation for Medical Research to J.R.M.; a Harvard T.H. Chan School of Public Health Yerby postdoctoral fellowship to Mejia, and financial support from the Universidad Auto´noma de Nuevo Leo´n to Treviño-Villarreal.

Source: Harvard

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Studying patterns in bacterial organization

credit to Gerard Wong, of the California NanoSystems Institute

Bacterial biofilms, at first glance, may seem to be spontaneous, random phenomena from which we have no power to protect our environment or ourselves.

They’re potentially useful as an aid to wastewater treatment, but they also cause infections that account for $6 billion a year in health care costs. Biofilms are also more resistant to antibiotic drugs, making them difficult to eradicate.

Dr. Kun Zhao, of the California NanoSystems Institute at UCLA, refuses to see biofilms as arbitrary: he emphasizes the fact that biofilms are communities of bacteria in self-produced polymeric matrices of polysaccharides, and using a biophysical approach, he studies the pattern behind their organization.

Central questions in Zhao’s research include how bacterial colonies transition from reversible to irreversible attachment, how they migrate, and how they ultimately disperse. Specifically, Zhao examines the polysaccharide Psl, which poses a positive feedback loop because it is both secreted by moving bacteria and serves as a chemo-attractant for future bacteria movement. The positive feedback creates an inherent pattern, as bacteria are more likely to visit a location they have been to before.

Zhao and colleagues have also discovered that bacterial mutants that cannot produce Psl exhibit more random and uniform movement.

To better quantify bacterial movement,Zhao has created a computer algorithm that shows the full movement history of each individual bacterium on a dish, and that provides a “search engine” allowing researchers to find every bacterium performing specific life cycle activities, like division.

Zhao has postulated a “rich get richer” mechanism for biofilms. He compares bacterial organization to Wall Street because concentrated movement ensures that some cells become extremely enriched. In the future, he hopes to model colloidal structures for biological problems, like the growth of the bacterial cell wall. Zhao currently uses colloids, which in physics are used as models for atomic systems, to observe how shapes affect self-assembly. He also would like to look at cell-substrate interactions, which are implicated in bacterial territoriality and social interactions.

by Olivia Zhu

Source: Duke University

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Drug combo supresses growth of late-stage prostate cancer turmors

By Natalie van Hoose

Low doses of metformin, a widely used diabetes medication, and a gene inhibitor known as BI2536 can successfully halt the growth of late-stage prostate cancer tumors, a Purdue University study finds.

Prostate cancer causes the second-highest number of cancer-related deaths in men in the U.S., and methods of treating advanced prostate cancer are limited.

Xiaoqi Liu (pronounced zhow-CHEE' LEE'-oo), associate professor of biochemistry and cancer research, and fellow researchers found that the drugs metformin and BI2536 can work together to suppress the spread of prostate cancer that resists all other available treatments, potentially prolonging patients' lives.

"We've found a promising way to treat late-stage prostate cancer," Liu said. "By combining low levels of two well-tolerated drugs, the progression of this disease could be significantly delayed. Completely curing the cancer at the advanced stage is pretty much impossible, but this treatment might manage it for a while - that's exciting."

A number of treatments exist for the earlier stages of prostate cancer, which grows slowly compared with many other cancers. Because prostate cancer cells need the male sex hormone androgen to develop, one way to treat the disease is to suppress androgen - a process known as castration. If the cancer continues to spread, the patient often undergoes chemotherapy. As a last resort, drugs that block the synthesis of androgen by prostate cancer cells can be used, but these medications only extend a patient's lifespan for several months.

New approaches to treating the most persistent forms of prostate cancer are "urgently needed," Liu said.

Adding to the challenge is the fact that castration treatment can inadvertently encourage the cancer to get tougher. It can heighten oxidative stress on the prostate gland, which increases the expression of Plk1, a gene that has been linked to many cancers. Over-expression of Plk1 can also trigger the synthesis of androgen.

"The goal of castration is to block androgen synthesis," Liu said. "But cancer cells eventually become 'smart' enough to make androgen anyhow, which is why the cancer continues to grow."

Additionally, castration can disrupt the body's metabolism and lead to insulin resistance, which also can stimulate the production of androgen. The cancer will spread until both of these side effects are stopped, Liu said.

Previous studies showed that metformin - an inexpensive, antidiabetic drug that has been commonly used for more than 40 years - is particularly potent to prostate cancer tumors.

Working with fellow researchers from Purdue, the University of Wisconsin-Madison and the Indiana University School of Medicine, Liu found that a combination of low levels of metformin and BI2536, a drug that stifles the activity of Plk1, could work in tandem to slow the growth of prostate tumors too advanced for current treatments by promoting the self-destruction of cancer cells and preventing androgen synthesis.

The drugs did not impact healthy prostate cells, a "key finding," Liu said. "Ideally, cancer therapy will have minimal effects on normal cells."

Because metformin helps regulate metabolism, it may reverse some of the metabolic damage caused by castration, he said.

The researchers tested the drugs in a classical cell culture assay of prostate cancer cells and in advanced prostate tumors in mice. Low concentrations of the drugs significantly slowed the development of cancer in both trials. The mice tumors were grown from the tumor cells of a late-stage prostate cancer patient, suggesting that the treatment would prove effective in humans.

"Those results were amazing," Liu said. "These are the first data we've generated from a real patient, so I was almost jumping in the air when I saw that it worked."

Liu said that the next step in the research is to test the combination of drugs in clinical trials. Further research is also needed to understand the underlying mechanism of metformin and why it is effective at suppressing prostate cancer

Source: Purdue Univesity

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New Weight Loss Device Makes You Feel Full

People who are obese have a new tool in their arsenal for fighting excess weight.

The U.S. Food and Drug Administration approved a medical device called the Maestro Rechargeable System that is implanted in the stomach and, through an external, adjustable controller, helps obese people lose weight. It is approved for patients 18 and older who have a body mass index of 35 to 45, have a condition related to being obese such as type 2 diabetes, and have not been able to lose weight through traditional means. 

The Maestro Rechargeable System targets nerve pathways between the brain and the stomach that are responsible for making a person feel full. In a clinical trial, patients using the device lost 8.5% more weight than people who received an inactive version of it. About 53% of the patients with the device lost at least 20% of their excess weight, and 38% lost at least 25%.

But compared with bariatric surgery, the trial’s results are not as impressive. Eric T. Volckmann, M.D., who specializes in bariatric surgery at University of Utah Health Care, says that after gastric bypass surgery, patients can expect to lose 60% to 80% of their excess body weight.

Bariatric surgery is a highly invasive procedure. But so is implantation of the Maestro Rechargeable System. 

“Any procedure, no matter how small, is still risky,” Volckmann says.

Furthermore, Volckmann says the long-term effects of the device are not as well understood as those of bariatric surgery. He says more research is needed before he would recommend the Maestro Rechargeable System for a severely obese patient.

In the future, the device may make sense for a patient with a BMI between 30 and 35 who is not responding to medical weight loss measures such as lifestyle modifications.

Source: University of Utah

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New natural supplement relieves canine arthritis

Portrait old dog

Arthritis pain in dogs can be relieved, with no side effects, by a new product based on medicinal plants and dietary supplements that was developed at the University of Montreal's Faculty of Veterinary Medicine. "While acupuncture and electrical stimulation are two approaches that have been shown to have positive effects on dogs, until now a few studies have investigated a plant-based approach to therapy," explained Professor Éric Troncy, senior author of the study. His findings were published in Research in Veterinary Science.

Troncy and his team worked with 32 dogs (and their owners!) who had been diagnosed with arthritis by X-ray and orthopaedic exam, and who all weighed more than 20 kilograms. By drawing on existing rodent studies and working with Pierre Haddad of the university's Department of Pharmacology, Troncy developed two formulas for his trial. These formulas are not currently commercially available.

The first formula, composed of curcumin, devil's claw, black current, Indian frankincense (Salai), willow bark, pineapple bromelaine and camomile, was developed to treat arthritis-induced inflammation. The second included the same ingredients, plus dietary supplements such as omega 3, chondroitin sulfate and glutamine, and was formulated in the hope that it would promote the regeneration of articulations.

Half the dogs received the first formula for four weeks and then the second formula for another four weeks. The other half, acting as the control, received a placebo. The outcomes were tested using three methods. Firstly, the dogs were filmed as they walked at a consistent speed over a special platform that captures the strength of each paw. Secondly, a special electronic collar recorded the dogs' daily activities. And finally, the owners were asked to provide their own evaluations of their dog's behaviour.

The researchers were able to identify an improvement by the fourth week of the trial. "After the eight week course, on average, the strength of the dogs receiving treatment had improved to the equivalent of a kilo of extra strength per paw, which is moreover. None of these dogs saw their health decline, unlike 35.8% of the dogs who were given the placebo," said Maxim Moreau, who was first author of the study.

The improvements were also reflected in the dogs' daily lives. The collars revealed that the dogs receiving treatment maintained their physical activity, and in fact the group average increased from six hours of daily activity to eight. Meanwhile, the dogs receiving the placebo were progressively less active. "In some cases, we recorded the dogs to ensure that the collar was recording actual physical activity rather than movements such as scratching," Troncy explained.

Nonetheless, the ratings from the owners were more mixed. "This third evaluation was more subjective and the contrast between the test group and the control group less stark," Troncy said. "We suspect that the owner may have forgotten what the animal's behaviour was like before it developed arthritis."

The findings raise the possibility of offering a new form of treatment to human beings. "The model of evaluation that we have used is the best for predicting the efficacy of anti-arthritis treatments. We can therefore consider that clinical trials on humans would have a good chance of having positive outcomes," Troncy said.

About this study: This study was funded in part by a grant from ArthroLab Inc., an ongoing New Opportunities Fund grant (#9483) and a Leader Opportunity Fund grant (#24601) from the Canada Foundation for Innovation for the pain/function equipment, a Discovery Grant (#327158-2008; #441651-2013) from the Natural Sciences and Engineering Research Council of Canada for the bio-analyses and salaries, and by the Osteoarthritis Chair of the University of Montreal Hospital Centre, Université de Montréal. Maxim Moreau received a doctoral scholarship from the Canadian Institutes of Health Research (TGF-53914) -- Strategic Training Initiative in Health Research program (MENTOR) and a doctoral scholarship from the Fonds de recherche du Québec-Santé.

Source: Universite de Montreal

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