PARP inhibitor prolongs progression-free survival in patients with recurrent ovarian cancer

 

The PARP inhibitor niraparib significantly improves the outcome of platinum-sensitive recurrent ovarian cancer, according to full data from the ENGOT-OV16/NOVA trial presented for the first time at the ESMO 2016 Congress in Copenhagen and published in the New England Journal of Medicine (NEJM). The trial met its primary endpoint, with niraparib considerably prolonging progression-free survival compared to placebo.

"There are limited treatment options in recurrent ovarian cancer," said lead author Dr Mansoor Raza Mirza, chief oncologist, Rigshospitalet, Copenhagen University Hospital, Denmark and medical director of the Nordic Society of Gynaecological Oncology (NSGO). "Cumulative toxicity with platinum-based chemotherapy and lack of additional benefit limits its use. We then pause treatment until the next relapse and start combination chemotherapy."

"The current options for maintenance therapy in the EU are bevacizumab, which can only be given once and improves progression-free survival by just a few months, and the PARP inhibitor olaparib, which is only approved in patients with a germline BRCA mutation (about 10-15% of ovarian cancer patients). No maintenance therapy is approved outside the EU," he continued.

This phase III trial was performed in collaboration with European Network of Gynaecological Oncology Trial groups (ENGOT). The ENGOT-OV16/NOVA trial evaluated the efficacy and safety of the PARP inhibitor niraparib as maintenance therapy in patients with recurrent ovarian cancer who respond to platinum-based chemotherapy. Patients were assigned to cohorts by BRCA mutation status and randomised 2:1 to receive niraparib 300 mg or placebo once daily.

The trial included 553 patients, of whom 203 had the germline BRCA mutation and 350 did not. Niraparib significantly improved the primary endpoint of progression-free survival compared to placebo in both cohorts, as well as in all subgroups.

Median progression-free survival with niraparib compared to placebo was 21.0 vs 5.5 months in the germline BRCA mutation group (hazard ratio [HR] 0.27, 95% confidence interval [CI] 0.173 to 0.410, p<0.0001), 9.3 months vs 3.9 months in the non-germline BRCA mutation group (HR 0.45, 95% CI 0.338 to 0.607, p<0.0001), and 12.9 vs 3.8 months in a subgroup of the non-mutation cohort who had homologous recombination DNA repair deficiencies (HRD) (HR 0.38, 95% CI 0.243 to 0.586, p<0.0001).

More than 10% of patients had grade 3/4 adverse events following treatment with niraparib, of whom 28% had thrombocytopaenia, 25% had anaemia, and 11% had neutropaenia. These were resolved with dose adjustments and patients could continue their treatment. Patient-reported outcomes were similar with niraparib and placebo. Patients on niraparib maintained symptom control and had a quality of life comparable to those on placebo.

Significant improvements were also observed in all secondary endpoints. Compared to placebo, niraparib significantly prolonged the second progression-free survival, time to first subsequent treatment, and chemotherapy-free interval in the mutation and mutation-free groups, and in the HRD subgroup.

"This is a breakthrough for patients with ovarian cancer," said Mirza. "We have never seen such large benefits in progression-free survival in recurrent ovarian cancer. Niraparib significantly improved all endpoints across a broad patient population representing 70% of all ovarian cancer patients. These landmark results could change the way we treat this disease."

He concluded: "Once it is approved by the regulatory authorities, I'll consider niraparib for all my patients with recurrent ovarian cancer who respond to platinum regardless of BRCA status."

Commenting on the results, Dr Andrés Poveda, head of the Gynaecological Cancer Clinic, Oncology Foundation Institute Valencia, Spain, said: "This study more than doubles the population of patients who benefit from a PARP inhibitor."

"Personalised medicine has arrived in high grade serous ovarian cancer," he continued. "This was the first trial to use HRD to select patients for treatment and showed that it is a useful strategy. We also know that PARP inhibitors benefit patients with BRCA mutations."

Poveda concluded: "Future studies are needed to unravel which patients with HRD are not responders to PARP inhibitors and why, and which patients are long responders and why. We also need to know if there are other non-HRD factors, such as cyclin E positivity, that predict which patients will respond to treatment.

Combination treatment for myocardial infarction shows no added benefit compared to ASA monotherapy

The drug ticagrelor has been approved since February 2016 for adults who had a myocardial infarction a year or more ago and are at a high risk of a new myocardial infarction or stroke. Ticagrelor is used together with low-dose acetylsalicylic acid (ASA). In its dossier assessment published in early July 2016, the German Institute for Quality and Efficiency in Health Care (IQWiG) determined an indication of a minor added benefit of ticagrelor in comparison with the administration of ASA alone.

 acetylsalicylic acid(ASA)   Ticagrelor

On the inclusion of additional analyses that the drug manufacturer provided in the commenting procedure conducted by the Federal Joint Committee (G-BA), the Institute now came to a different conclusion, however: An added benefit is not proven because positive effects are called into question by negative effects.

Non-severe bleeding notably more common

The dossier had only contained data on severe bleeding. There were no data on non-severe bleeding that are clinically relevant. The results of the analyses subsequently submitted by the manufacturer were to the disadvantage of ticagrelor: Since these bleeding events were notably more common than under ASA monotherapy, IQWiG determined proof of greater harm with the extent "considerable".

No data on quality of life

In addition, there were no data on quality of life. Particularly in coronary heart disease (CHD), this is a very important outcome criterion however, which is even more important in view of side effects such as dyspnoea. "Disease-related quality of life" is the first treatment goal listed in the recently published revised version of the National Care Guideline for Coronary Heart Disease.

Since, on the one hand, greater harm was proven for an additional outcome, and, on the other, no data on quality of life were available, the positive effects, including the ones regarding mortality and late complications, were called into question by the negative effects. In the overall consideration, no added benefit of ticagrelor plus ASA in comparison with ASA monotherapy could be derived from the data.

Dandelion tea touted as possible cancer killer

Researchers hope to test dandelion tea on patients at a Windsor, Ont., clinic after it was found the roots of the weed killed cancer cells in the laboratory.

The promising research is being led by a University of Windsor oncologist, in association with the Windsor Regional Cancer Centre.

Dr. Caroline Hamm said dandelion root extract is unique, and is one of the only things found to help with chronic myelomonocytic leukemia.

"It was really unusual to find a product that had efficacy in that area," said Hamm.

Some patients swear by it

John DiCarlo, 72, was admitted to hospital three years ago with leukemia. Even after aggressive treatment, he was sent home to put his affairs in order with his wife and four children.

The cancer clinic suggested he try the tea. Four months later, he returned to the clinic in remission. He has been cancer free for three years.

He said his doctor credits the dandelions.

"He said, 'You are doing pretty good, you aren't a sick man anymore'," DiCarlo told CBC News.

The roots of the common dandelion were ground up and made into tea. According to researchers, early results show that the tea kills cancer cells in the lab.

Using dandelion tea extract to treat leukemia is not a new idea. The Memorial Sloan-Kettering Cancer Center in the U.S., among other research sites, has been looking at the plant since at least 2010.

John DiCarlo, 72, says dandelion tea saved his life, after other medical treatments for his leukemia failed. (Steven Bull/CBC)

Hamm said the tea doesn't work for everyone and they need to find out why. The first phase of the trials will attempt to determine the right dose to administer.

Hamm was convinced that the weed contains an active ingredient, but warned "it can harm as well as benefit." She said taking dandelion extract tea could interfere with regular chemotherapy, and she urged patients not to mix the natural remedy with other cancer drugs without speaking to a doctor first.

The researchers have filed an application with Health Canada. If it's approved, Hamm expected to start the first phase of the trials in about two to three months.

Phase 1 involves 21 cancer patients where the standard of care is not working. Hamm said it would include patients with a wide variety of cancer types. The first phase should last six to eight months, she said.

Phase 2 will look at which types of cancer dandelion extract works best on, based on the results of Phase 1.

Fruits, Veggies Powerful Rx for Kidney Disease: Study

Kidney disease patients who eat three to four more servings of fruits and vegetables every day could lower their blood pressure and nearly halve their medication costs, new research suggests.

The findings stem from the multi-year tracking of a small group of patients, in which standard medical treatment was compared with the simple nutritional intervention.

The goal: to see which approach did a better job at driving down both blood pressure and drug expenses.

The result on both fronts showed a clear win for healthy food.

Study author Dr. Nimrit Goraya described the links seen between increased fruit and vegetable intake, kidney disease control and lower medication expenses as "huge." And "the impact was visible from the very first year," she said.

"This study has been done over five years, but every year since the therapy with fruits and vegetables began, we were able to lower medications," she noted.

Goraya is program director for nephrology with Baylor Scott & White Healthcare in Temple, Texas.

She and her colleagues are scheduled to present their findings this week at an American Heart Association meeting on blood pressure, in Orlando, Fla.

High blood pressure is the second leading cause of kidney failure. The kidneys and the circulatory system depend on each other for good health, according to the heart association.

In all, 108 kidney disease patients were enlisted in the study, all of whom were taking similar doses of blood pressure drugs.

Patients were divided into three groups. One group was treated with sodium bicarbonate (baking soda), the standard treatment designed to neutralize the lingering acid that kidney patients typically struggle to excrete. Failure to excrete can lead to abnormally high acid levels, a condition known as "metabolic acidosis."

A second group was not prescribed sodium bicarbonate, but instead was provided three to four servings of fruits and vegetables a day. These patients were not instructed to alter their usual diet beyond consuming their new fruit and vegetable allotment.

A third group was not treated in any way.

The result: After five years, systolic blood pressure (the top number in a reading) was pegged at 125 mm Hg among the fruit and vegetable group, compared with 135 mm Hg and 134 mm Hg, respectively, among the medication and no treatment groups.

What's more, those in the food group were taking considerably lower doses of daily blood pressure medication than those in the other groups, the study authors said.

This translated into a near halving of the food group's total expenditure on such drugs, down to roughly $80,000 over five years compared with an average total of more than $153,000 among each of the other two groups.

As to the exact mechanisms by which an increased intake of fruits and vegetables appears to promote kidney disease control, Goraya pointed to a variety of things that are set in motion whenever nutrition improves.

"I think that the benefit is not singular," she said. Goraya suggested that kidney disease control is likely triggered not only by the protective benefits of healthier foods but also by a corresponding reduction in fast-food consumption, a lowering of salt intake, and perhaps even weight loss.

Those looking for more ways to achieve some measure of kidney disease control without medication might look to the findings of a new Brazilian study also presented at the Orlando meeting that highlighted the potential benefits of exercise.

After reviewing 28 studies involving more than 1,000 patients on dialysis, researchers at the University of Sao Paulo Medical School found that those who routinely engaged in both aerobic exercise and resistance (strength) training significantly lowered their blood pressure.

Lona Sandon is program director in the department of clinical nutrition at the School of Health Professions at UT Southwestern, in Dallas. "It is remarkable what fruits and vegetables can do, along with a little exercise," she said.

"Blood pressure meds come with many side effects that may leave people feeling sluggish, or other problems," Sandon explained. "The side effects of fruits and vegetables and exercise is better health."

The bottom line: "When people have access to healthy foods, they can change their health," said Sandon. "And especially when they eat the recommended amounts that were provided to them in the study."

The findings of studies presented at medical meetings should be viewed as preliminary until published in a peer-reviewed journal.

New study to examine effectiveness of orally administered drug in treating stuttering

Stuttering, an interruption in the flow of speech, affects about three million Americans. It begins most often in childhood, affecting four men for every woman. A precise cause of this complex communicative disorder is not known.

A genetically influenced condition, stuttering appears to originate when various aspects of a young child's development interact, and is best addressed with early intervention. No cure for it has been found, but behavioral treatment options are available. Currently, no Food and Drug Administration (FDA)-approved drug treatments are available.

In an attempt to find a new medicine, a research team at the School of Medicine at the University of California, Riverside, in partnership with the speech pathology laboratory at the University of Redlands, will conduct a study at CITrials in Riverside, Calif., to determine how effective ecopipam, an orally administered medication, is as treatment against stuttering.

Ten volunteers will be selected to participate in the FDA-approved clinical trial. The study, scheduled to begin next month, is seeking volunteers, although space is limited. People interested in participating in the study may contact Gerald Maguire, M.D., the chair of psychiatry and neuroscience at UC Riverside and the associate dean for graduate medical education, who is leading the study: gerald.maguire@medsch.ucr.edu.

"The study is exploratory," Maguire said. "We are the only site in the world conducting this trial; ecopipam has never been tested for stuttering. It has been tested for treatment of tics in Tourette syndrome, a neurological disease, with some encouraging results. Stuttering shares some similarities to the vocal changes seen in subjects with Tourette syndrome. We are hopeful ecopipam will yield beneficial effects in stuttering."

Ecopipam is a first-in-class drug that selectively blocks the actions of the neurotransmitter dopamine at its receptor. Dopamine receptors can be broadly classified into two families based on their structures: D1 receptors and D2 receptors. Ecopipam blocks dopamine only at D1 receptors, and thus acts differently than other commercially available medications. This mechanism explains why ecopipam is being tested as a potential treatment for stuttering.

The 10 patients selected for the clinical trial next month will undergo a physical examination and their medical history will be recorded. To ensure that their stuttering symptoms are sufficiently severe, their speech patterns will be analyzed by Professor Lisa LaSalle, a speech pathologist at the University of Redlands, and co-investigator on the study. Each patient will receive ecopipam for a limited time.

"We believe we could have results from our analysis in as soon as nine months," Maguire said. "A placebo-controlled clinical trial may then follow, pending approval. If ecopipam is found to be effective in controlling stuttering, we may have a viable solution for a disorder that can be traced back centuries."

TSRI scientists shed light on molecular workings of MS drug

In continuation of my update on Tecfidera

A study by scientists at The Scripps Research Institute (TSRI) has helped to de-mystify the molecular workings of the multiple sclerosis (MS) drug Tecfidera®. The drug is the most widely prescribed pill-based therapy for MS, but its biological mechanism remains mysterious.

Using a new TSRI technology that can quickly reveal a drug's protein targets, the scientists showed that Tecfidera® interacts with multiple T cell proteins, in some cases inhibiting their activity, and helping to suppress the T cell activation that is a key feature of MS flare-ups.

"This new technology has given us insights into the therapeutic modulation of the immune system that we could not have obtained with standard approaches," said co-senior author John R. Teijaro, an assistant professor at TSRI.

The study was reported recently in Science Signaling.

Treatment for an Autoimmune Disease

MS is an autoimmune disease of the brain featuring damage to nerve fibers and producing a range of symptoms, including tingling in the extremities, muscle weakness, muscle spasms, visual problems and mood instability. About 400,000 people in the United States and about 2.5 million worldwide have MS, mostly in a form with intermittent flare-ups of symptoms—which can start to worsen inexorably.

Two large clinical trials published in 2012 found that Tecfidera® is almost twice as effective as an older standard MS drug at reducing the rate of flare-ups. It also appears to slow the disease's progression. But how the drug works has never been clear.

Despite its recent (2013) US Food and Drug Administration approval for MS, the drug is neither new nor high-tech. It is a relatively simple organic compound, dimethyl fumarate (DMF), that has been in the biomedical literature for decades. It was once used in Europe to prevent mold growth in sofas during storage and shipping, although the European Union banned it from consumer products in 2009 after it was linked to severe allergic skin reactions. It has proved more useful as a pharmaceutical: since the 1990s it has been an effective treatment—as the main ingredient in the drug Fumaderm®—for the autoimmune skin disease psoriasis. Success against psoriasis led to its investigation as a potential MS drug.

Until recently, the leading theory was that DMF works against MS primarily by unleashing the activity of a protein called Nrf2, which helps protect the brain from autoimmune damage by marshaling a powerful anti-oxidant response and which may also reduce immune system activation. Studies published in the past year have suggested, however, that DMF works principally by reducing immune system activity and does so independently of Nrf2. In recent years, there have also have been several reports among patients taking Fumaderm® or Tecfidera® of a potentially fatal viral brain infection called progressive multifocal leukoencephalopathy, which normally occurs only in people whose immune systems have been seriously weakened.

Study shows maritime pine bark extract may be effective in limiting muscle loss due to aging

In continuation of my update on Pycnogenol....

A new peer-reviewed, published study shows French maritime pine bark extract, Pycnogenol®, may be effective in curbing muscle loss that occurs with aging – a natural process that leads to sarcopenia, a common condition affecting adults as early as age 65. The study, published in the September 2016 Journal on Orthopedics and Traumatology, revealed that daily supplementation with Pycnogenol® helps to stabilize muscles through this natural process and supports muscular function and endurance.

 

According to the National Library of Medicine, physically inactive individuals can lose as much as eight percent of muscle mass each decade after 30. Those who are physically active can maintain more muscle mass yet are still affected by muscle loss due to aging.

"Muscle loss due to aging can affect even the most active individuals and can result in feelings of weakness and frustrating fatigue which can interfere with our daily activities. This natural process is why opening a jar of pickles gets harder as we get older. We have less muscle to work with, so our muscles must work harder and, thus, we get tired faster," said nationally-known natural nutrition expert Dr. Fred Pescatore.

"This new study builds on a body of research connecting Pycnogenol® to healthy aging," said Dr. Pescatore. "As we age, muscle loss starts to impact the daily activities we tend to take for granted like climbing stairs, lifting groceries or enjoying walks without getting tired. This research shows that Pycnogenol can help alleviate the symptoms of sarcopenia and can support muscle function as we age."

In the study, participants between ages 70 - 78 and exhibiting symptoms of muscle loss, sarcopenia and fatigue but otherwise healthy, reported feeling increased muscle endurance in completing daily tasks such as walking and stair climbing, and improved overall muscular function by more than 40 percent. After just 8 weeks of taking 150 mg of Pycnogenol® the study results showed:

"What I found really compelling is the measurable effect Pycnogenol® had on the participants in relation to completing daily tasks -- the research shows that Pycnogenol® can play a role in helping you stay active with greater muscular stability and maintain muscle function as you age," Dr. Pescatore noted.

While experts recommend adequate amounts of sleep, in addition to diet and daily exercise to maintain physical fitness in later years, the study results are encouraging for those looking for an added boost in muscle function overall.

Ref : http://www.webmd.com/vitamins-supplements/ingredientmono-1019-pycnogenol.aspx?activeingredientid=1019

Experimental drug may prevent development of multiple sclerosis in mice

The experimental drug laquinimod may prevent the development or reduce the progression of multiple sclerosis (MS) in mice, according to research published in the September 21, 2016, online issue of Neurology® Neuroimmunology & Neuroinflammation, a medical journal of the American Academy of Neurology.

"These results are promising because they provide hope for people with progressive MS, an advanced version of the disease for which there is currently no treatment," said study author Scott Zamvil, MD, PhD, of the University of California, San Francisco and a Fellow of the American Academy of Neurology.

In a proper immune response, T cells and B cells help the body develop immunity to prevent infection. But in MS, an immune and neurodegenerative disorder, those cells can help create antibodies that attack and destroy myelin, the protective, fatty sheath that insulates nerves in the brain and spinal cord.

For this research, the investigators studied mice that develop a spontaneous form of MS. Mice were either given daily oral laquinimod or a placebo (water). The number of T cells and B cells were then examined.

In one study of 50 mice, only 29 percent of the mice given oral laquinimod developed MS as opposed to 58 percent of the mice given the placebo, evidence the drug may prevent MS. Plus, there was a 96-percent reduction in harmful clusters of B cells called meningeal B cell aggregates. In people, such clusters are found only in those with progressive MS.

In a second study of 22 mice, researchers gave laquinimod after mice developed paralysis and observed a reduction in progression of the disease. When compared to the control, mice given the drug showed a 49-percent reduction in dendritic cells that help create special T cells called T follicular helper cells, a 46-percent reduction in those T cells and a 60-percent reduction in harmful antibodies.

"This study has given us more insight into how laquinimod works," Zamvil said. "But because this was an animal study, more research needs to be done before we know if it could have similar results in people."

Oral antidiabetic drug modulates the body's nitrogen and urea metabolism

In continuation of my updates on metformin

The most frequently prescribed oral antidiabetic drug metformin significantly affects metabolic pathways. This was reported by scientists from the Helmholtz Zentrum München together with colleagues from the German Diabetes Center (DDZ) in Düsseldorf. The underlying study was conducted with further scientists of the German Center for Diabetes Research (DZD). These results have now been published in the journal 'Diabetes'.

Metformin is a widespread oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). According to a number of studies, it additionally reduces the risk of cardiovascular complications. Last year, a team led by Dr. Rui Wang-Sattler discovered that metformin intake lowers the levels of the harmful LDL cholesterol by activating the AMPK protein complex. Dr. Wang-Sattler is head of the "Metabolism" research group in the Research Unit of Molecular Epidemiology at the Institute of Epidemiology II at the Helmholtz Zentrum München. Her group aims to understand the molecular mechanisms that underlie the activity of metformin.

Metformin intake changes metabolite profiles in population-based KORA study

In the present work, the interdisciplinary team of scientists was able to explain a further feature of the drug: "Our results show that metformin also modulates the body's nitrogen and urea metabolism," first author Jonathan Adam summarizes.

In close collaboration with Dr. Stefan Brandmaier and other colleagues, he examined the metabolite profiles (353 small molecules) of KORA participants. The researchers compared T2D patients treated with metformin (a total of 74) with those not being treated with metformin (115) and looked for differences in the distribution of metabolites in the blood. They subsequently confirmed the findings in samples of more than 1500 participants.

Amino acid levels provide a crucial hint

Changes in the amino acid citrulline concentration caused by metformin intake were particularly significant. The amino acid citrulline (named after Citrullus vulgaris, the watermelon, where it is found in large quantities) showed significantly lower levels in samples of T2D patients treated with metformin than in untreated ones. The researchers propose that this is a further consequence of metformin's AMPK activation. "Our analysis indicates that the activation of the AMPK pathway by metformin affects nitrogen and urea metabolism through a further enzyme, which thus lowers the citrulline levels", reports Rui Wang-Sattler.

Accordingly, the scientists suspect that the additional intake of citrulline could have a positive effect on the cardiovascular system in patients being treated with metformin. As a follow-up study, the team plans to analyze the metformin-associated effects on other central metabolic pathways, such as the citric acid cycle.

Supplement of polyunsaturated fatty acids may improve reading skills in children

Supplement of omega-3 and omega-6 fatty acids may improve reading skills of mainstream schoolchildren, according to a new study from Sahlgrenska Academy, at the University of Gothenburg, Sweden. Children with attention problems, in particular, may be helped in their reading with the addition of these fatty acids.

The study included 154 schoolchildren from western Sweden in grade 3, between nine and ten years old. The children took a computer-based test (known as the Logos test) that measured their reading skills in a variety of ways, including reading speed, ability to read nonsense words and vocabulary.

The children were randomly assigned to receive either capsules with omega-3 and omega-6, or identical capsules that contained a placebo (palm oil) for 3 months. The children, parents and researchers did not learn until the study was completed which children had received fatty acids and which had received the placebo. After three months, all children received real omega-3/6 capsules for the final three months of the study.

"Even after three months, we could see that the children's reading skills improved with the addition of fatty acids, compared with those who received the placebo. This was particularly evident in the ability to read a nonsense word aloud and pronounce it correctly (phonologic decoding), and the ability to read a series of letters quickly (visual analysis time)," says Mats Johnson, who is chief physician and researcher at the Gillberg Neuropsychiatry Centre at Sahlgrenska Academy, University of Gothenburg.

No children diagnosed with ADHD were included in the study, but with the help of the children's parents, the researchers could identify children who had milder attention problems. These children attained even greater improvements in several tests, including faster reading already after three months of receiving fatty acid supplements.

Polyunsaturated fats important for the brain

Polyunsaturated fats and their role in children's learning and behavior is a growing research area.

"Our modern diet contains relatively little omega-3, which it is believed to have a negative effect on our children when it comes to learning, literacy and attention," says Mats Johnson. "The cell membranes in the brain are largely made up of polyunsaturated fats, and there are studies that indicate that fatty acids are important for signal transmission between nerve cells and the regulation of signaling systems in the brain."

Previous studies in which researchers examined the effect of omega-3 as a supplement for mainstream schoolchildren have not shown positive results, something Mats Johnson believes may depend on how these studies were organized and what combination and doses of fatty acids were used. This is the first double-blind, placebo-controlled study showing that omega-3/6 improves reading among mainstream schoolchildren.

"Our study suggests that children could benefit from a dietary supplement with a special formula. To be more certain about the results, they should also be replicated in other studies," says Mats Johnson.

Supplement of polyunsaturated fatty acids may improve reading skills in children

Liquid crystal technique could be new way to control drug delivery process

In continuation of my update on liquid crystals..

Liquid crystals are strange substances, both fish and fowl. They can flow like a liquid, but have the orderly molecular structure of a crystalline solid. And that internal structure can be changed by small cues from outside.

A group of scientists at the University of Chicago's Institute for Molecular Engineering has found a way to exploit this property to turn liquid crystals into a tool to manipulate the shape of synthetic cell membranes. The technique has potential for use in biology, medicine, and advanced materials development. The team reported its findings in the Aug. 10, 2016 edition of Science Advances.

"What we've done is reproduced the beginnings of cell division in a synthetic system," said Juan de Pablo, Liew Family Professor in Molecular Engineering, who headed the group. When a cell divides, the spherical cell membrane stretches into an elliptical form, develops a waist in the middle, and then splits into two spherical cells. The scientists built sophisticated models that produced this behavior on the computer and then reproduced it in the real world, testing the model's predictions.

"It's the first time that this has been done," said de Pablo. "It's a system that has been engineered at the molecular level using computer models."

Cellular stand-ins

Standing in for cells in the experiments were capsules, or "vesicles," a few microns in diameter (a fraction the width of a human hair) made of some of the same phospholipids that make up real cell membranes. These were immersed in a bath of liquid crystal oil whose molecules are slightly elongated rather than round. At temperatures above about 97 degrees Fahrenheit the oil behaves like any other oil. But when the temperature is lowered slightly, the molecules of the oil pack tightly against one another like cigarettes and align along a single direction.

"When that happens, the liquid crystal presses on the vesicle more in one direction than in the other, so the vesicle becomes elongated," de Pablo said. "If you squash it more and more, it becomes an ellipsoid and the two ends become pointier and pointier. There is a point when the molecules around those points separate from one another and create a little gap in the membrane through which things could be squeezed out."

Lipid vesicles are in current use for drug delivery. De Pablo envisions using the liquid crystal technique as a cunning way to control that process.

"What we find intriguing is that we have a mechanism that will allow us to take vesicles loaded with something interesting, and by changing the temperature a little bit, we could deform the vesicle and have it squeeze out whatever it has inside without our ever touching the vesicle. And then as we restore the temperature to the original value, the vesicle becomes spherical again."

Calculations indicate that squeezing more or less would alter the size of the gap, allowing for the release of contents of varying sizes. "But that's something that we still have to demonstrate," said de Pablo.

Ref : http://advances.sciencemag.org/content/2/8/e1600978

Cone snail venom could hold key to efficient therapies for diabetes

New research has found that venom extracted from a species of marine cone snail could hold the key to developing 'ultra-fast-acting' insulins, leading to more efficient therapies for diabetes management.

Researchers from Australia and the US have successfully determined the three-dimensional structure of a cone snail venom insulin, revealing how these highly efficient natural proteins called Con-Ins G1 can operate faster than human insulin.

The teams also discovered that Con-Ins G1 was able bind to human insulin receptors, signifying the potential for its translation into a human therapeutic.

Associate Professor Mike Lawrence from Melbourne's Walter and Eliza Hall Institute of Medical Research led a collaborative study between the University of Utah, the Monash Institute of Pharmaceutical Sciences, La Trobe University and Flinders University in Australia.

Associate Professor Lawrence, a specialist in the structure of insulins and their receptors, said the teams utilised the Australian Synchrotron to create and analyse the three-dimensional structure of this cone snail venom insulin protein with exciting results.

"We found that cone snail venom insulins work faster than human insulins by avoiding the structural changes that human insulins undergo in order to function -- they are essentially primed and ready to bind to their receptors, " Associate Professor Lawrence said.

Associate Professor Lawrence said human insulins could be considered 'clunky' by comparison.

"The structure of human insulins contain an extra 'hinge' component that has to open before any 'molecular handshake' or connection between insulin and receptor can take place.

"By studying the three-dimensional structure of this snail venom insulin we've found how to dispense with this 'hinge' entirely, which may accelerate the cell signalling process and thus the speed with which the insulin takes effect." Associate Professor Lawrence said.

Published today in Nature Structural and Molecular Biology, the team's findings build on earlier studies from 2015, when the University of Utah reported that the marine cone snail Conus geographus used an insulin-based venom to trap its prey. Unsuspecting fish prey would swim into the invisible trap and immediately become immobilised in a state of hyperglycaemic shock induced by the venom.

Dr Helena Safavi-Hemami from the University of Utah said it was fascinating to uncover how the cone snail insulin was able to have such a rapid effect on its prey and, furthermore, that the peptide had therapeutic potential in humans. "We were thrilled to find that the principles of cone snail venom insulins could be applied to a human setting," Dr Safavi-Hemami said.

"Our Flinders University colleagues have shown that the cone snail insulin can 'switch on' human insulin cell signalling pathways, meaning the cone snail insulin is able to successfully bind to human receptors," Dr Safavi-Hemami said.

"The next step in our research, which is already underway, is to apply these findings to the design of new and better treatments for diabetes, giving patients access to faster-acting insulins," she said.

Ref : http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.3292.html

Study provides insight into how weight-loss drug acts in the brain

In continuation of  my update on lorcaserin

A weight-loss drug dampened the response to food cues in regions of the brain associated with attention and emotion, leading to decreases in caloric intake, weight and body mass index (BMI), a team led by scientists at Beth Israel Deaconess Medical Center (BIDMC) reported. In the first study of the drug lorcaserin in the human brain, the research revealed the mechanism underlying the drug's efficacy and provides insight into which individuals may benefit most from the medication. The paper was published today in the journal Diabetes, the journal of the American Diabetes Association.

"Human feeding behaviors involve areas of the brain responsible for cognitive control and decision-making," said Christos S. Mantzoros, MD, Director of the Human Nutrition Unit in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and Professor of Medicine at Harvard Medical School. "We wanted to find out if lorcaserin was acting on these brain regions and, if so, where and how. One-third of the U.S. population is obese, and another one-third is overweight. This is a huge burden on individuals and the health care system. In addition, it increases the risk of diabetes, cardiovascular disease and many types of cancer. We need to continue to develop safe and effective therapies to combat this epidemic."

Approved by the FDA in 2012, the generic drug lorcaserin is a medication prescribed for obese or overweight adults who also have weight-related health complications such as diabetes. Several studies have shown the drug helps about half of the people who take it lose more than 5 percent of their body mass within a year, but there's a great deal of variability in individual results, and the mechanism underlying its effect was previously unknown.

To determine how the drug works in the human brain, Mantzoros and colleagues observed 48 obese men and women - half taking the drug, half taking a placebo - over the course of a four-week experiment. Participants came into the clinic on four occasions for blood work, physical exams, measurements and weight-loss counseling with a registered dietician. They were also expected to keep records of the food they ate during the study.

On three visits - before receiving any medication (Week 0), after a week of medication (Week 1), and after four weeks of medication (Week 4) - exams were followed by two brain scans: one after the patients had fasted for at least 12 hours, the other after they had eaten a meal. The scans were taken using functional magnetic resonance imaging (fMRI) to measure changes in blood flow in an active brain, which suggests which regions play a role during a given task. During each scan, participants were shown 150 images of foods generally considered highly desirable, such as cake and onion rings; foods generally considered less desirable like vegetables; and nonfood items like rocks and trees.

At Week 1, the fMRI scans in the fasting state revealed that people taking the drug showed decreased brain activity in response to images of highly desirable foods in the attention-related parietal and visual cortices. At Week 4, the lorcaserin group in the fed state showed less activity in the parietal cortex - which is responsible for integrating sensory information - when looking at any of the food images.

The data also revealed that subjects who had the strongest brain responses to food prior to taking lorcaserin saw the most success with the weight-loss medication.

"Decreases in caloric intake, weight, and BMI were linked to strong responses to food cues in the areas of the brain related to emotion, pleasure and attention prior to taking the weight-loss drug, which suggests that lorcaserin could prove to be of particular benefit to 'emotional eaters,' " Mantzoros said.Lorcaserin targets only a very specific serotonin receptor (known as 5-HT2c), shown in animal studies to play a role in abnormal food consumption. A previous generation of weight loss drugs was linked to this receptor, but because their scope was broader, those products also had dire cardiac side effects including pulmonary hypertension and valve problems. Lorcaserin could produce weight loss without these cardiac risks, the authors noted.

"In addition, the different mechanism of action in comparison to other drugs for obesity creates an opportunity for combination drugs for the treatment of obesity," Mantzoros said. "This might create more powerful solutions and is something that remains to be explored."

New drug holds potential for treating advanced mastocytosis

In continuation of my update on Midostaurin 

Most people have never heard of mastocytosis. It's a rare, sometimes deadly, immune disorder. Now new research may help those with advanced mastocytosis and possibly many more people, too. "This is the first drug that's shown to be effective in this very rare disease," says Tracy George, MD, at the University of New Mexico Comprehensive Cancer Center. George was part of the international team that recently published the results of its study on mastocytosis in the New England Journal of Medicine.

"Mast cells are normal cells in the body that mediate the body's allergic and inflammatory responses," says George. "But people with mast cell disease have too many mast cells and they're abnormal." Too many abnormal mast cells can cause allergic reactions and inflammation. Different subtypes of the disease differ in the how serious these responses are.

People with indolent mastocytosis may have mild symptoms and lead normal lives. Others with indolent mastocytosis may have flushing and diarrhea and other symptoms severely enough that they can't hold a job or do things that most people can do. People with other subtypes of the disease can have life-threatening reactions, such as anaphylactic shock and organ damage. And people with advanced mastocytosis — the most deadly subtype is called mast cell leukemia — live less than six months after their diagnosis.

The Food and Drug Administration has approved only one drug, called imatinib, to treat advanced mastocytosis. Imatinib blocks the action of a cellular protein called a tyrosine kinase receptor. But people with a mutation in a gene called D816V KIT do not respond to imatinib. The D816V KIT gene codes for a tyrosine kinase receptor, says George. And, she says, most people with advanced mastocytosis have the D816V KIT mutation.

Research on the new treatment began at Stanford University, where George worked with a colleague, Jason Gotlib, MD, whose patient had mast cell leukemia. They gave that woman a drug called midostaurin under the FDA's compassionate use policy. "Midostaurin is a multi-kinase inhibitor," says George. "Midostaurin was being evaluated in a clinical trial for a different disease, acute myeloid leukemia. And this lady with mast cell leukemia remarkably improved within weeks, within days."

 Midostaurin 

Gotlib and George began a small clinical trial to test midostaurin in people with advanced mastocystosis. That clinical trial expanded into an international clinical trial after Gotlib and George shared their preliminary results at an international conference. George brought the clinical trial to UNM when she joined the Pathology department and the UNM Comprehensive Cancer Center.

The clinical trial included treatment for three subtypes of advanced mastocytosis. Still, it took years to enroll enough people because the disease is so rare. Mastocytosis affects only about one person in 10,000. In comparison, breast cancer affects more than 12 times as many people and prostate cancer affects more than 13 times as many, according to the American Cancer Society. But even though the clinical trial was small, the results were astounding.

People with advanced mastocytosis on the clinical trial lived an average of 28 months longer. This average includes the 40 percent of people who did not respond to midostaurin. The 60 percent who did respond, though, responded within two or three months of starting treatment. Responders had mild side effects like diarrhea, vomiting and nausea, if they had any at all.

Sixteen people in the clinical trial had mast cell leukemia. "For those patients who did respond," says George, "their median survival has not been reached. So that means [some are] still living, which is unbelievable."

The clinical trial has spurred more research. Scientists around the world are now studying how midostaurin affects mast cells and how to combine it with other drugs to create an even more potent treatment. Novartis, the maker of midostaurin, and other drug companies are investing in research on multi-kinase inhibitors. Clinical trials to test midostaurin for controlling symptoms in people with indolent mastocytosis have opened. And more research into using midostaurin to treat asthma, skin diseases and allergies is in the planning stages.

George, who is the American expert in mastocytosis pathology, says, "I do think this [mastocytosis] is under-diagnosed. Even though patients with advanced mastocytosis are rare, indolent [mastocytosis] is more common. And there are lots of diseases for which unhappy mast cells are a pathogenesis." Now, with the potential for a treatment, people with unhappy mast cells may feel better.

New drug holds potential for treating advanced mastocytosis