Two-Drug Combination, Under Certain Circumstances, Can Eliminate Disease

New research conducted by Harvard scientists is laying out a road map to one of the holy grails of modern medicine: a cure for cancer.

As described in a paper recently published in eLife, Martin Nowak, a professor of mathematics and of biology and director of the Program for Evolutionary Dynamics, and co-author Ivana Bozic, a postdoctoral fellow in mathematics, show that, under certain conditions, using two drugs in a "targeted therapy" -- a treatment approach designed to interrupt cancer's ability to grow and spread -- could effectively cure nearly all cancers.

Though the research is not a cure for cancer, Nowak said it does offer hope to researchers and patients alike.

"In some sense this is like the mathematics that allows us to calculate how to send a rocket to the moon, but it doesn't tell you how to build a rocket that goes to the moon," Nowak said. "What we found is that if you have a single point mutation in the genome that can give rise to resistance to both drugs at the same time, the game is over. We need to have combinations such that there is zero overlap between the drugs."

Importantly, Nowak said, for the two-drug combination to work, both drugs must be given together -- an idea that runs counter to the way many clinicians treat cancer today.

"We actually have to work against the status quo somewhat," he said. "But we can show in our model that if you don't give the drugs simultaneously, it guarantees treatment failure."

In earlier studies, Nowak and colleagues showed the importance of using multiple drugs. Though temporarily effective, single-drug targeted therapy will fail, the researchers revealed, because the disease eventually develops resistance to the treatment.

To determine if a two-drug combination would work, Nowak and Bozic turned to an expansive data set supplied by clinicians at New York's Memorial Sloan-Kettering Cancer Center that showed how patients respond to single-drug therapy. With data in hand, they were able to create computer models of how multidrug treatments would work. Using that model, they then treated a series of "virtual patients" to determine how the disease would react to the multidrug therapy.

"For a single-drug therapy, we know there are between 10 and 100 places in the genome that, if mutated, can give rise to resistance," Nowak explained. "So the first parameter we use when we make our calculations is that the first drug can be defeated by those possible mutations. The second drug can also be defeated by 10 to 100 mutations.

"If any of those mutations are the same, then it's a disaster," he continued. "If there's even a single mutation that can defeat both drugs, that is usually good enough for the cancer -- it will become resistant, and treatment will fail. What this means is we have to develop drugs such that the cancer needs to make two independent steps -- if we can do that, we have a good chance to contain it." 

How good a chance?

"You would expect to cure most patients with a two-drug combination," Bozic said. "In patients with a particularly large disease burden you might want to use a three-drug combination, but you would cure most with two drugs."

The trick now, Nowak and Bozic said, is to develop those drugs.

To avoid developing drugs that are not vulnerable to the same mutation, Bozic said, pharmaceutical companies have explored a number of strategies, including using different drugs to target different pathways in cancer's development.

"There are pharmaceutical companies here in Cambridge that are working to develop these drugs," Nowak said. "There may soon be as many as 100 therapies, which means there will be as many as 10,000 possible combinations, so we should have a good repertoire to choose from.

"I think we can be confident that, within 50 years, many cancer deaths will be prevented," Nowak added. "One hundred years ago, many people died from bacterial infections, and now they would be cured. Today, many people die from cancer, and we can't help them, but I think once we have these targeted therapies, we will be able to help many people -- maybe not everyone -- but many people."

Source:Science Daily

R.Sawas

Bacteria Communicate to Help Each Other Resist Antibiotics

New research from Western University unravels a novel means of communication that allows bacteria such as Burkholderia cenocepacia (B. cenocepacia) to resist antibiotic treatment. B. cenocepacia is an environmental bacterium that causes devastating infections in patients with cystic fibrosis (CF) or with compromised immune systems.

Dr. Miguel Valvano and first author Omar El-Halfawy, PhD candidate, show that the more antibiotic resistant cells within a bacterial population produce and share small molecules with less resistant cells, making them more resistant to antibiotic killing. These small molecules, which are derived from modified amino acids (the building blocks used to make proteins), protect not only the more sensitive cells of B. cenocepacia but also other bacteria including a highly prevalent CF pathogen, Pseudomonas aeruginosa, and E. coli. The research is published in PLOS ONE.

"These findings reveal a new mechanism of antimicrobial resistance based on chemical communication among bacterial cells by small molecules that protect against the effect of antibiotics," says Dr. Valvano, adjunct professor in the Department of Microbiology and Immunology at Western's Schulich School of Medicine & Dentistry, currently a Professor and Chair at Queen's University Belfast. "This paves the way to design novel drugs to block the effects of these chemicals, thus effectively reducing the burden of antimicrobial resistance."

"These small molecules can be utilized and produced by almost all bacteria with limited exceptions, so we can regard these small molecules as a universal language that can be understood by most bacteria," says El-Halfawy, who called the findings exciting. "The other way that Burkholderia communicates its high level of resistance is by releasing small proteins to mop up, and bind to lethal antibiotics, thus reducing their effectiveness." The next step is to find ways to inhibit this phenomenon.

The research, conducted at Western, was funded by a grant from Cystic Fibrosis Canada and also through a Marie Curie Career Integration grant.

N.H.Khider

Source: Science Daily

Foods for a Healthy, Happy Stomach

It’s obvious that the foods we eat have a direct impact on our stomachs and other digestive organs. It’s easy to identify when we’ve eaten too much, dined on something that disagrees with us or have gone too long without eating. It’s more difficult to note and easier to overlook, those foods that leave us feeling light and help our digestive system run smoothly.

There are foods guaranteed to keep your stomach healthy and your appetite satisfied:

 Pears

 Pears are a great source of fiber, which helps soften and add weight to stool, moving it through the digestive tract. Pears also contain sorbitol, a sugar that attracts water into the intestines, further softening your stool.

Yogurt

Yogurt helps digestion, improves the immune system and fights off bacterial infections. Within our stomach lining is a healthy bacteria known as probiotics. Yogurt is an excellent and delicious external probiotics source that aid in digestion and help keeps you regular.

Ginger

Ginger is part of the carminatives family; a group of herbs that help soothe the digestive track. It can aid digestion as well as relieve upset stomach, nausea and vomiting. Other herbs in the carminative family include cinnamon, sage and thyme.

For more information on a happy, health digestive system, visit Dr. Oz’s Gut Check Challenge.

Source: DR OZ Show

R.Sawas 

Tired and Edgy? Sleep Deprivation Boosts Anticipatory Anxiety

UC Berkeley researchers have found that a lack of sleep, which is common in anxiety disorders, may play a key role in ramping up the brain regions that contribute to excessive worrying.

Neuroscientists have found that sleep deprivation amplifies anticipatory anxiety by firing up the brain's amygdala and insular cortex, regions associated with emotional processing. The resulting pattern mimics the abnormal neural activity seen in anxiety disorders. Furthermore, their research suggests that innate worriers -- those who are naturally more anxious and therefore more likely to develop a full-blown anxiety disorder -- are acutely vulnerable to the impact of insufficient sleep.

"These findings help us realize that those people who are anxious by nature are the same people who will suffer the greatest harm from sleep deprivation," said Matthew Walker, a professor of psychology and neuroscience at UC Berkeley and senior author of the paper, published June 26 in the Journal of Neuroscience.

The results suggest that people suffering from such maladies as generalized anxiety disorder, panic attacks and post-traumatic stress disorder, may benefit substantially from sleep therapy. At UC Berkeley, psychologists such as Allison Harvey, a co-author on the Journal of Neuroscience paper, have been garnering encouraging results in studies that use sleep therapy on patients with depression, bipolar disorder and other mental illnesses.

"If sleep disruption is a key factor in anxiety disorders, as this study suggests, then it's a potentially treatable target," Walker said. "By restoring good quality sleep in people suffering from anxiety, we may be able to help ameliorate their excessive worry and disabling fearful expectations."

While previous research has indicated that sleep disruption and psychiatric disorders often occur together, this latest study is the first to causally demonstrate that sleep loss triggers excessive anticipatory brain activity associated with anxiety, researchers said.

"It's been hard to tease out whether sleep loss is simply a byproduct of anxiety, or whether sleep disruption causes anxiety," said Andrea Goldstein, a UC Berkeley doctoral student in neuroscience and lead author of the study. "This study helps us understand that causal relationship more clearly."

In their experiments, performed at UC Berkeley's Sleep and Neuroimaging Laboratory, Walker and his research team scanned the brains of 18 healthy young adults as they viewed dozens of images, first after a good night's rest, and again after a sleepless night. The images were either neutral, disturbing or alternated between both.

Participants in the experiments reported a wide range of baseline anxiety levels, but none fit the criteria for a clinical anxiety disorder. After getting a full night's rest at the lab, which researchers monitored by measuring neural electrical activity, their brains were scanned via functional MRI as they waited to be shown, and then viewed 90 images during a 45-minute session.

To trigger anticipatory anxiety, researchers primed the participants using one of three visual cues prior to each series of images. A large red minus sign signaled to participants that they were about to see a highly unpleasant image, such as a death scene. A yellow circle portended a neutral image, such as a basket on a table. Perhaps most stressful was a white question mark, which indicated that either a grisly image or a bland, innocuous one was coming, and kept participants in a heightened state of suspense.

When sleep-deprived and waiting in suspenseful anticipation for a neutral or disturbing image to appear, activity in the emotional brain centers of all the participants soared, especially in the amygdala and the insular cortex. Notably, the amplifying impact of sleep deprivation was most dramatic for those people who were innately anxious to begin with.

"This discovery illustrates how important sleep is to our mental health," said Walker. "It also emphasizes the intimate relationship between sleep and psychiatric disorders, both from a cause and a treatment perspective."

Other co-authors of the study are Stephanie Greer and Jared Saletin at UC Berkeley, and Jack Nitschke at the University of Wisconsin-Madison. The research was funded by the National Institute of Mental Health.

N.H.Khider

Source : Science Daily

Pleasure Response from Chocolate: You Can See It in the Eyes

The brain's pleasure response to tasting food can be measured through the eyes using a common, low-cost ophthalmological tool, according to a study just published in the journal Obesity. If validated, this method could be useful for research and clinical applications in food addiction and obesity prevention.

Dr. Jennifer Nasser, an associate professor in the department of Nutrition Sciences in Drexel University's College of Nursing and Health Professions, led the study testing the use of electroretinography (ERG) to indicate increases in the neurotransmitter dopamine in the retina.

Dopamine is associated with a variety of pleasure-related effects in the brain, including the expectation of reward. In the eye's retina, dopamine is released when the optical nerve activates in response to light exposure.

Nasser and her colleagues found that electrical signals in the retina spiked high in response to a flash of light when a food stimulus (a small piece of chocolate brownie) was placed in participants' mouths. The increase was as great as that seen when participants had received the stimulant drug methylphenidate to induce a strong dopamine response. These responses in the presence of food and drug stimuli were each significantly greater than the response to light when participants ingested a control substance, water.

"What makes this so exciting is that the eye's dopamine system was considered separate from the rest of the brain's dopamine system," Nasser said. "So most people- and indeed many retinography experts told me this- would say that tasting a food that stimulates the brain's dopamine system wouldn't have an effect on the eye's dopamine system."

This study was a small-scale demonstration of the concept, with only nine participants. Most participants were overweight but none had eating disorders. All fasted for four hours before testing with the food stimulus.

If this technique is validated through additional and larger studies, Nasser said she and other researchers can use ERG for studies of food addiction and food science.

"My research takes a pharmacology approach to the brain's response to food," Nasser said. "Food is both a nutrient delivery system and a pleasure delivery system, and a 'side effect' is excess calories. I want to maximize the pleasure and nutritional value of food but minimize the side effects. We need more user-friendly tools to do that."

The low cost and ease of performing electroretinography make it an appealing method, according to Nasser. The Medicare reimbursement cost for clinical use of ERG is about $150 per session, and each session generates 200 scans in just two minutes. Procedures to measure dopamine responses directly from the brain are more expensive and invasive. For example, PET scanning costs about $2,000 per session and takes more than an hour to generate a scan.

N.H.Khider

Source: Science Daily