Tag: Pharmacology

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Insecticide treatment of cattle to kill sand flies and combat leishmaniasis

With an estimated 500,000 human infections and 50,000 deaths annually, visceral leishmaniasis (VL) is the second most prevalent parasitic killer, behind malaria. Leishmania parasites are transmitted through the bite of phlebotomine sand flies. A study published in PLOS Neglected Tropical Diseases makes the case that fighting the insects by treating cattle with the long-lasting insecticide, fipronil, could substantially reduce VL in areas where people and cattle live in close proximity.

Two-thirds of VL cases occur on the Indian subcontinent, and 90% of the Indian VL cases are reported in the densely populated and impoverished state of Bihar. Female sand flies there primarily bite humans and cattle (mostly at night), and after sand fly eggs hatch, the larvae feed on organic matter, the most abundant source being cow patties. At present, control of sand flies in India involves indoor residual spraying with pyrethroid insecticides, but Bihari villagers regularly sleep outdoors during the hot summer months.

Fipronil is an insecticide with a long half-life. The insecticide remains in the system of animals for several weeks to several months, dependent on the concentration administered. Fipronil does not harm mammals at low concentrations, but when fed to cattle at low concentrations in drug form, can kill adult blood-feeding sand flies and sand fly larvae that feed on the cattle feces. Fipronil-based sand fly control could therefore last for several months following a single treatment — and complement the practice of indoor spraying.

David Poché, from Texas A&M University in College Station, USA, and colleagues set out to explore the insecticide’s potential to control sand flies. The researchers developed a mathematical model that describes the effects of fipronil-induced mortality on a sand fly population within a village in Bihar. They describe the model and evaluate its performance based on known parameters. Then they use the model to simulate fipronil-based control schemes with different treatment timing and frequency, and compare their effect on reductions in sand fly populations during spring and summer (June, July, and August are the period of peak human exposure).

Single annual treatments applied in March, May, June, or July noticeably reduced the population peaks that occurred over the 30 to 60 days following treatment, but populations recovered relatively quickly. Treatments applied 3 times per year at 2-month intervals were most effective when initiated in March, reducing the population peaks in April through August by roughly 90% relative compared with no treatment. Treatments applied 6 times per year at 2-month intervals were most effective when initiated in January, reducing population peaks in June through August by over 95%. Monthly treatments resulted in eradication of the sand fly population within 2 years.

Overall, the simulation results suggest that the success of fipronil treatment depends not only on the frequency of applications but also on the timing relative to the sand fly lifecycle. Maintaining high drug levels in cattle feces during the period of high larval abundance seems particularly important.

As the researchers discuss, “while more frequent applications obviously are more efficacious, they also are more expensive and more difficult logistically. Thus, the ability to assess not only efficacy of treatment schemes per se but also their cost-effectiveness and their logistical feasibility is of paramount importance.” In this context, they mention an estimated cost of $1 per cow per treatment, as well as the fact that milk production per cow is estimated to increase by $0.50 per day, thus offering an incentive to villagers to treat their animals.

Further evaluation of sand fly control through the use of fipronil-based drugs in cattle, the researchers say, ideally would involve a field trial in Bihar. Such a trial could provide data on the actual proportion of adult sand flies that obtain their blood meal from cattle and the proportion of eggs laid in organic matter containing cattle feces; numbers that are currently unknown and therefore force the researchers to make assumptions that cause uncertainty in the model predictions.

Suggesting that their model could be adapted to settings where donkeys, dogs, rabbits, or rodents are the main animal targets of blood-thirsty sand flies, the researchers hope that it “will prove useful in the a priori evaluation of the potential role of treatment schemes involving the use of fipronil-based drugs in the control of leishmaniasis on the Indian Subcontinent and beyond.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160818145936.htm  Original web page at Science

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Novel compounds arrested epilepsy development in mice

A team led by Nicolas Bazan, MD, PhD, Boyd Professor and Director of LSU Health New Orleans’ Neuroscience Center of Excellence, has developed neuroprotective compounds that may prevent the development of epilepsy. The findings will be published online in Scientific Reports, a Nature journal, on July 22, 2016.

In this study in an experimental model of epilepsy in mice, the compounds prevented seizures and their damaging effects on dendritic spines, specialized structures that allow brain cells to communicate. In epilepsy, these structures are damaged and rewire incorrectly, creating brain circuits that are hyper-connected and prone to seizures, an important example of pathological plasticity.

“In the current study, preservation of dendritic spines and subsequent protection from seizures, were observed up to 100 days post-treatment, suggesting the process of epilepsy development has been arrested,” notes Dr. Nicolas Bazan, Director of the LSU Health New Orleans Neuroscience Center of Excellence.

Dr. Bazan and Professor Julio Alvarez-Builla Gomez, a medicinal chemist from the University of Alcala in Spain, discovered and patented the LAU compounds, named for the inventors in Louisiana and the Spanish university. A number of LAU compounds were studied in this research, which blocked a neuroinflammatory signaling receptor, protecting dendritic spines and lessening seizure susceptibility and onset, as well as hyper-excitability.

According to the National Institutes of Health, the epilepsies are a spectrum of brain disorders ranging from severe, life-threatening and disabling, to ones that are much more benign. In epilepsy, the normal pattern of neuronal activity becomes disturbed, causing strange sensations, emotions, and behavior or sometimes convulsions, muscle spasms, and loss of consciousness. It is not uncommon for people with epilepsy, especially children, to develop behavioral and emotional problems in conjunction with seizures. Issues may also arise as a result of the stigma attached to having epilepsy, which can lead to embarrassment and frustration or bullying, teasing, or avoidance in school and other social settings. For many people with epilepsy, the risk of seizures restricts their independence (some states refuse drivers licenses to people with epilepsy) and recreational activities. Epilepsy can be a life-threatening condition. Some people with epilepsy are at special risk for abnormally prolonged seizures or sudden unexplained death in epilepsy. There is currently no cure.

The research was supported by the National Institute of General Medical Sciences of the National Institutes of Health. “Future clinical studies would evaluate the potential application of the compounds that we have developed and/or the mechanisms that we have discovered that are targeted by these compounds in the development of epilepsy,” concludes Dr. Bazan. “Most of the anti-epileptic drugs currently available treat the symptom – seizures- not the disease itself. Understanding the potential therapeutic usefulness of compounds that may interrupt the development process may pave the way for disease-modifying treatments for patients at risk for epilepsy.”

The research is part of an ongoing effort in Dr. Bazan laboratory to understand the critical role of brain plasticity which underlies many aspects of health and disease, from developmental disorders like dyslexia to aging, retinal degeneration, neurotrauma (concussions, TBI), stroke, Parkinson’s and Alzheimer’s disease.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160722092930.htm Original web page at Science Daily

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Modifying a living genome with genetic equivalent of ‘search and replace’

Researchers including George Church have made further progress on the path to fully rewriting the genome of living bacteria. Such a recoded organism, once available, could feature functionality not seen in nature. It could also make the bacteria cultivated in pharmaceutical and other industries immune to viruses, saving billions of dollars of losses due to viral contamination.

Finally, the altered genetic information in such an organism wouldn’t be able to contaminate natural cells because of the code’s limitations outside the lab, researchers say, so its creation could stop laboratory engineered organisms from genetically contaminating wildlife. In the DNA of living organisms, the same amino acid can be encoded by multiple codons — DNA “words” of three nucleotide letters.

Here, building on previous work that demonstrated it was possible to use the genetic equivalent of “search and replace” in Escherichia coli to substitute a single codon with an alternative, Nili Ostrov, Church and colleagues explored the feasibility of replacing multiple codons, genome-wide.

The researchers attempted to reduce the number of codons in the E. coli code from 64 to 57 by exploring how to eradicate more than 60,000 instances of seven different codons. They systematically replaced all 62,214 instances of these seven codons with alternatives. In the recoded E.coli segments that the researchers assembled and tested, 63% of all instances of the seven codons were replaced, the researchers say, and most of the genes impacted by underlying amino acid changes were expressed normally.

Though they did not achieve a fully operational 57-codon E. coli, “a functionally altered genome of this scale has not yet been explored,” the authors write. Their results provide critical insights into the next step in the genome rewriting arena — creating a fully recoded organism.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160818145954.htm  Original web page at Science Daily

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* Scientists test nanoparticle drug delivery in dogs with osteosarcoma

At the University of Illinois, an engineer teamed up with a veterinarian to test a bone cancer drug delivery system in animals bigger than the standard animal model, the mouse. They chose dogs — mammals closer in size and biology to humans — with naturally occurring bone cancers, which also are a lot like human bone tumors.

In clinical trials, the dogs tolerated the highest planned doses of cancer-drug-laden nanoparticles with no signs of toxicity. As in mice, the particles homed in on tumor sites, thanks to a coating of the drug pamidronate, which preferentially binds to degraded sites in bone. The nanoparticles also showed anti-cancer activity in mice and dogs.

The researchers report their results in the Proceedings of the National Academy of Sciences.

These findings are a proof-of-concept that nanoparticles can be used to target bone cancers in large mammals, the researchers said. The approach may one day be used to treat metastatic skeletal cancers, they said.

The dogs were companion animals with bone cancer that were submitted for the research trials by their owners, said U. of I. veterinary clinical medicine professor Dr. Timothy Fan, who led the study with materials science and engineering professor Jianjun Cheng. All of the dogs were 40 to 60 kilograms (88 to 132 pounds) in weight, he said.

“We wanted to see if we could evaluate these drug-delivery strategies, not only in a mouse model, but also at a scale that would mimic what a person would get,” Fan said. “The amount of nanoparticle that we ended up giving to these dogs was a thousand-fold greater in quantity than what we would typically give a mouse.”

Using nanoparticles with payloads of drugs to target specific tissues in the body is nothing new, Cheng said. Countless studies test such approaches in mice, and dozens of “nanopharmaceuticals” are approved for use in humans. But the drug-development pipeline is long, and the leap from mouse models to humans is problematic, he said.

“Human bone tumors are much bigger than those of mice,” Cheng said. “Nanoparticles must penetrate more deeply into larger tumors to be effective. That is why we must find animal models that are closer in scale to those of humans.”

Mice used in cancer research have other limitations. Researchers usually inject human or other tumor cells into their bodies to mimic human cancers, Fan said. They also are bred to have compromised immune systems, to prevent them from rejecting the tumors.

“That is one of the very clear drawbacks of using a mouse model,” Fan said. “it doesn’t recapitulate the normal immune system that we deal with every day in the person or in a dog.”

There also are limitations to working with dogs, he said. Dogs diagnosed with bone cancer often arrive at the clinic at a very advanced stage of the disease, whereas in humans, bone cancer is usually detected early because people complain about the pain and have it investigated.

“On the flip side of that, I would say that if you are able to demonstrate anti-cancer activity in a dog with very advanced disease, then it would be likely that you would have equivalent or better activity in people with a less advanced stage of the disease,” Fan said.

Many more years of work remain before this or a similar drug-delivery system can be tested in humans with inoperable bone cancer, the researchers said.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160725192351.htm Original web page at Science Daily

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* Common colon cancer tumor type blocked in mice

A new scientific study has identified why colorectal cancer cells depend on a specific nutrient, and a way to starve them of it. Over one million men and women are living with colorectal cancer in the United States. The National Cancer Institute estimates 4.5% of all men and women will be diagnosed with the cancer during their lifetime, making it the third most common non-skin cancer.

In the study published online in Nature Communications, researchers showed how certain colorectal cancer cells reprogram their metabolism using glutamine, a non-essential amino acid. Many cancer cells rely on glutamine to survive. How they become so dependent on the molecule is hotly debated in the field.

Researchers studied a subset of colorectal cancer cells containing a genetic mutation called PIK3CA. This mutation is located in a gene critical for cell division and movement, and is found in approximately one third of all colorectal cancers. The mutation is also the most commonly identified genetic mutation across all cancers, making the results of the study universally appealing.

Researchers were interested in determining whether or not the common PIK3CA mutation contributes to changes in cancer cell metabolism, such as how nutrients like glutamine are processed. Normally, glutamine is broken down by cancer cells into several other molecules with the help of specific enzymes. This complicated system helps produce adenosine triphosphate, the energy currency of all cells, and other molecules critical for colorectal cancer cell growth.

The researchers found that colorectal cells with the PIK3CA mutation broke down significantly more glutamine than cells without the mutation. The researchers identified several enzymes involved in the process that are more active in the mutant cancer cells than in other cell types, explaining the increased need for glutamine. These enzymes become overactive in the mutant cancer cells due to a cascade of signals led by the protein encoded by mutant PIK3CA gene. This finding represents a novel and important link between the common PIK3CA mutation and altered glutamine metabolism in cancer cells.

Zhenghe John Wang, PhD, professor of genetics and genome sciences and co-leader of the Cancer Genetics Program at Case Western Reserve University School of Medicine helped lead the study. “In layman’s terms, we discovered that colon cancers with PIK3CA oncogenic mutations are addicted to glutamine, a particular nutrient for cancer cells. We also demonstrated that these cancers can be starved to death by depriving glutamine with drugs.”

When the researchers lowered the amount of glutamine available to mutant cancer cells growing in laboratory dishes, the cancer cells died. This discovery led the team to investigate the effects of blocking glutamine availability in mice with colorectal cancer tumors containing the common PIK3CA mutation. Wang and colleagues found that exposing these mice to a compound that blocks glutamine metabolism consistently suppressed tumor growth. They did not observe the same effect on tumors without the mutation. Together, these results provide a promising new therapeutic avenue to suppress growth of colorectal tumors with the PIK3CA mutation. The researchers have filed a patent application based on the unique mechanism of tumor suppression they have identified and the work is available for licensing.

“This study provides the basis for a colon cancer treatment clinical trial that will be started in the summer at the University Hospitals Seidman Cancer Center,” according to Neal Meropol, MD, Dr. Lester E. Coleman, Jr. Professor of Cancer Research and Therapeutics, chief of the division of hematology and oncology, and principal investigator for the trial. The phase I/II study will test the effects of a glutamine metabolism inhibitor in patients with advanced colorectal tumors.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160720215322.htm  Original web page at Science Daily

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Financial cycles of acquisition and ‘buybacks’ threaten public access to breakthrough drugs

New research on the financial practices surrounding a ‘wonder drug’ with a more than 90% cure rate for hepatitis C — a blood-borne infection that damages the liver over many years — shows how this medical breakthrough, developed with the help of public funding, was acquired by a major pharmaceutical company following a late-stage bidding war.

The research shows how that company more than doubled the drug’s price over original pricing estimates, calculating “how much health systems could bear” according to researchers, and channelled billions of dollars in profits into buying its own shares rather than funding further research.

In this way, the company, Gilead Sciences, passed significant rewards on to shareholders while charging public health services in the US up to $86k per patient, and NHS England almost £35k per patient, for a three month course of the drug.

The high prices have contributed to a rationing effect: many public systems across the US and Europe treat only the sickest patients with the new drug, despite its extraordinary cure rate, and the fact that earlier treatment of an infectious disease gives it less opportunity to spread.

Gilead’s strategy of acquisitions and buybacks is an example of an industry-wide pattern, say the researchers. Many big pharmaceutical companies now rely on innovation emerging from public institutes, universities, and venture-capital supported start-ups — acquiring the most promising drug compounds once there is a level of “certainty,” rather than investing in their own internal research and development.

The researchers, from Cambridge University’s Department of Sociology, say this effectively leaves the public “paying twice”: firstly for the initial research, and then for patent-protected high priced medications. A summary of their research has been commissioned by the British Medical Journal (BMJ) and is published today.

“Large pharmaceutical companies rarely take a drug from early stage research all the way to patients. They often operate as regulatory and acquisition specialists, returning most of the subsequent profits to shareholders and keeping some to make further acquisitions,” said lead researcher Victor Roy, a Cambridge Gates Scholar.

The study’s senior author, Prof Lawrence King, said: “Drug research involves trial and error, and can take years to bear fruit — too long for companies that need to show the promise of annual growth to investors, so acquisitions are often the best way to generate this growth.”

There are an estimated 150 million people worldwide chronically infected with hepatitis C. It disproportionately affects vulnerable groups such as drug users and HIV sufferers, and can ultimately lead to liver failure through cirrhosis if left untreated.

Roy and King’s article tells the story of the curative drug Sofosbuvir. The compound was developed by a start-up that emerged from an Emory-based laboratory that received funding from the US National Institutes of Health and the US Veterans Administration.

The start-up, Pharmasset, eventually raised private funding to develop sofosbuvir. When Phase II trials proved more promising than Gilead’s in-house hepatitis C prospects, it acquired Pharmasset for $11bn following a bidding war — the final weeks of which saw Pharmasset’s valuation rocket by nearly 40%.

“The cost of this late stage arms race for revenues has become part of the industry justification for high drug prices,” write Roy and King.

Once Sofosbuvir was market-ready in 2013, Gilead set a price of $84k. A US Senate investigation later revealed that Pharmasset had initially considered a price of $36k.

By the first quarter of 2016, Gilead had accumulated over $35bn in revenue from hepatitis C medicines in a little over two years — nearly 40 times Gilead and Pharmasset’s combined reported costs for developing the medicines.

Last year, Gilead announced that a lion’s share of those profits — some $27bn — will go towards ‘share buybacks’: purchasing its own shares to increase the value of the remaining ones for shareholders. By contrast, between 2013 and 2015 Gilead increased research investment by $0.9bn to $3bn total.

“Share buybacks are a financial manoeuvre that emerged during the early 1980s due to a change in rules for corporations by the Reagan administration. The financial community now expects companies to reward shareholders with buybacks, but directing profit into buybacks can mean cannibalising innovation,” said Roy.

A further example they cite is that of Merck, who spent $8.4bn in 2014 to acquire a drug developer specialising in staph infections. The next year they closed the developer’s early stage research unit, laying off 120 staff. Three weeks after that, Merck announced an extra $10bn in share buybacks.

In the BMJ article, the researchers set out a number of suggestions to counter the consequences of the current financial model. These include giving health systems greater bargaining power to negotiate deals for breakthrough treatments, and limiting share buybacks.

Roy and King also highlight a possible future model that uses a mix of grants and major milestone prizes to “push” and “pull” promising therapies into wider application, and, crucially, uncouples drug prices from supposed development costs, including those added by shareholder expectations. They write that this approach may be attempted for areas of major public health concern.

“The treatments for Hepatitis C may portend a future of expensive therapies for Alzheimer’s to many cancers to HIV/AIDS. Health systems and patients could face growing financial challenges,” said King.

“We need to recognise what current business models around drug development might mean for this future.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160727194358.htm  Original web page at Science Daily

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* Human nose holds novel antibiotic effective against multiresistant pathogens

A potential lifesaver lies unrecognized in the human body: Scientists at the University of Tübingen and the German Center for Infection Research (DZIF) have discovered that Staphylococcus lugdunensis which colonizes in the human nose produces a previously unknown antibiotic. As tests on mice have shown, the substance which has been named Lugdunin is able to combat multiresistant pathogens, where many classic antibiotics have become ineffective. The research results will be published on 27 July in the scientific journal Nature.

Infections caused by antibiotic-resistant bacteria — like the pathogen Staphylococcus aureus (MRSA) which colonizes on human skin — are among the leading causes of death worldwide. The natural habitat of harmful Staphylococcus bacteria is the human nasal cavity. In their experiments, Dr. Bernhard Krismer, Alexander Zipperer and Professor Andreas Peschel from the Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT) observed that Staphylococcus aureus is rarely found when Staphylococcus lugdunensis is present in the nose.

“Normally antibiotics are formed only by soil bacteria and fungi,” says Professor Andreas Peschel. “The notion that human microflora may also be a source of antimicrobial agents is a new discovery.” In future studies, scientists will examine whether Lugdunin could actually be used in therapy. One potential use is introducing harmless Lugdunin-forming bacteria to patients at risk from MRSA as a preventative measure.

Researchers from the Institute of Organic Chemistry at the University of Tübingen closely examined the structure of Lugdunin and discovered that it consists of a previously unknown ring structure of protein blocks and thus establishes a new class of materials.

Antibiotic resistance is a growing problem for physicians. “There are estimates which suggests that more people will die from resistant bacteria in the coming decades than cancer,” says Dr. Bernhard Krismer. “The improper use of antibiotics strengthens this alarming development” he continues. As many of the pathogens are part of human microflora on skin and mucous membranes, they cannot be avoided. Particularly for patients with serious underlying illnesses and weakened immune systems they represent a high risk — these patients are easy prey for the pathogens. Now the findings made by scientists at the University of Tübingen open up new ways to develop sustainable strategies for infection prevention and to find new antibiotics — also in the human body.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160729093039.htm  Original web page at  Science Daily

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Why is cocaine so addictive? Study using animal model provides clues

Scientists at Wake Forest Baptist Medical Center are one step closer to understanding what causes cocaine to be so addictive. The research findings are published in the current issue of the Journal of Neuroscience.

Cocaine addiction is a debilitating neurological disorder that affects more than 700,000 people in the United States alone, according to the Substance Abuse and Mental Health Services Administration. With repeated use, tolerance may develop, meaning more of the drug is required to achieve the same euphoric effect. Cocaine addiction can be characterized by repeated attempts at abstinence that often end in relapse.

“Scientists have known for years that cocaine affects the dopamine system and dopamine transporters, so we designed our study to gain a better understanding of how tolerance to cocaine develops via the dopamine transporters,” said Sara R. Jones, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist and lead author of the study.

“Currently there isn’t any effective treatment available for cocaine addiction so understanding the underlying mechanism is essential for targeting potential new treatments.”

Using an animal model, the research team replicated cocaine addiction by allowing rats to self-administer as much cocaine as they wanted (up to 40 doses) during a six-hour period. Six-hour-a-day access is long enough to cause escalation of intake and tip animals over from having controlled intake to more uncontrolled, binge-like behavior, Jones said.

Following the five-day experiment, the animals were not allowed cocaine for 14 or 60 days. After the periods of abstinence, the researchers looked at the animals’ dopamine transporters and they appeared normal, just like those in the control animals that had only received saline.

However, a single self-administered infusion of cocaine at the end of abstinence, even after 60 days, fully reinstated tolerance to cocaine’s effects in the animals that had binged. In the control animals that had never received cocaine, a single dose did not have the same effect.

These data demonstrate that cocaine leaves a long-lasting imprint on the dopamine system that is activated by re-exposure to cocaine, Jones said. This ‘priming effect,’ which may be permanent, may contribute to the severity of relapse episodes in cocaine addicts.

“Even after 60 days of abstinence, which is roughly equivalent to four years in humans, it only took a single dose of cocaine to put the rats back to square one with regard to its’ dopamine system and tolerance levels, and increased the likelihood of binging again,” Jones said. “It’s that terrible cycle of addiction.”

Jones added that hope is on the horizon through preclinical trials that are testing several amphetamine-like drugs for effectiveness in treating cocaine addiction.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160801163906.htm Original web page at Science Daily

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Beware of antioxidant supplements, warns scientific review

The lay press and thousands of nutritional products warn of oxygen radicals or oxidative stress and suggest taking so-called antioxidants to prevent or cure disease. Professor Pietro Ghezzi at the Brighton and Sussex Medical School and Professor Harald Schmidt at the University of Maastricht have analyzed the evidence behind this. The result is a clear warning: do not take these supplements unless a clear deficiency is diagnosed by a healthcare professional.

Humans depend on oxygen to produce energy, but oxygen also has the potential to generate so-called oxygen radicals, which may cause oxidative stress and disease. Markers of oxidative stress have been correlated with cardiovascular disease, cancer, diabetes, and other conditions. Because of these associations, antioxidant supplements are taken by millions of people; however, none of the antioxidants tested in randomized clinical trials have demonstrated any benefit. On the contrary, some of them may cause harm.

This is because oxygen radicals not only trigger disease but also perform many important functions in the body, such as for immune defense and hormone synthesis. Thus anti-oxidants will interfere with both healthy and disease-triggering oxygen molecules.

“Oxidative stress could be important in some conditions and only in a small proportion of patients,” said Prof. Ghezzi. “It can be targeted in a totally different manner, with drugs targeted only at those sources of oxygen molecules that are triggers of disease and leave the healthy ones alone,” added Prof. Schmidt. The review is published the British Journal of Pharmacology.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160719094130.htm  Original web page at Science Daily

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* Stem cells for Snoopy: pet medicines spark a biotech boom

Many pets are treated like family members — and that is often reflected in the veterinary care that they receive.

Little Jonah once radiated pain. The 12-year-old Maltese dog’s body was curled and stiff from the effort of walking with damaged knees. But after Kristi Lively, Jonah’s veterinary surgeon, enrolled him in a clinical trial of a therapeutic antibody to treat pain, his owner returned to the Village Veterinary Medical Center in Farragut, Tennessee, with tears in her eyes. Her tiny companion trotted easily alongside her. “I got my dog back,” she said.

Such cutting-edge treatments were once reserved for humans. But in recent years, the changing nature of pet ownership has sparked a boom in sophisticated therapies for animals — and many are now approaching the market. On 9 June, the company that sponsored the antibody trial, Nexvet of Dublin, presented its results at the American College of Veterinary Internal Medicine Forum in Denver, Colorado. Other companies are working on bone-marrow transplants, sophisticated cell therapies and cancer vaccines.

“When I was a child and just wanted to be a veterinarian, certainly I didn’t imagine I’d be doing what I’m doing now,” says Heather Wilson-Robles, a veterinary oncologist at Texas A&M University in College Station, who is engineering canine immune cells to fight cancer.

Cancer, arthritis and other diseases associated with old age are becoming more common as pets live longer, thanks in part to better treatment by their owners. “A generation ago, as beloved as Snoopy was, he lived in the backyard in the doghouse,” says Steven St. Peter, president of Aratana Therapeutics, a pet-therapy company in Leawood, Kansas. Now, pets are considered family members, often sharing beds with owners who are willing to pay hefty veterinary bills.

Many standard pet treatments are human drugs given at lower doses to account for animals’ smaller size. But antibodies and cell therapies generally cannot be used across species without provoking an unwanted immune response. And some human treatments simply will not work in pets: many common pain medications are toxic to cats.

Nexvet, which has raised more than US$80 million from investors since it was founded in 2011, takes antibodies that have been approved as human medicines and alters their structures to make them effective in cats or dogs. Moving from a drug lead to safety testing takes about 18 months, says chief executive Mark Heffernan, who estimates that Nexvet’s antibody therapies for pain will cost around $1,500 a year. The company is now looking into developing antibodies that block a protein called PD-1, thereby unleashing the immune system to fight cancer. This approach has shown tremendous promise for treating cancer in people.

Aratana is also developing antibody therapies for pets, and has applied for regulatory approval of a cancer vaccine that uses a bacterium to target malignant cells. The company hopes to move into cell therapies, and to develop a way to manufacture stem cells from fat for use against joint pain. St. Peter wants his company to be the first to win approval from the US Food and Drug Administration for a stem-cell therapy — ahead of firms developing such treatments for people.

Other forms of cell therapy could also result in new veterinary remedies. Last July, veterinary oncologist Colleen O’Connor founded a cancer-treatment company in Houston, Texas, called CAVU Biotherapies. To treat lymphoma, CAVU aims to isolate a sick dog’s immune cells, rejuvenate them in culture, and then infuse them back into the dog’s blood to stimulate an immune response. O’Connor used a similar approach in 2011 to treat Dakota, a bichon frise that belonged to then-US Senator Kent Conrad (Democrat, North Dakota). The dog, a Capitol Hill fixture known as the ‘101st senator’, entered remission but later died of cancer.

For many pet owners, cost is no object. Steven Suter, a veterinary oncologist at North Carolina State University in Raleigh, runs a bone-marrow transplant clinic for dogs that claims to cure 33% of lymphomas. Suter’s clinic was booked solid after it opened in 2008, despite offering treatment that can cost a dog owner up to $24,000. Still, Suter has worked to drive down the cost of care: to filter stem cells from blood, his clinic uses second-hand machines that were donated by a physician with a soft spot for schnauzers. Earlier this year, several major pet-insurance companies added bone-marrow transplants to the lists of procedures that they will pay for.

But when it comes to the latest pet treatments, some animals might be more equal than others. Cats are “physiologically finicky”, Suter says, noting that they may be too small to allow bone-marrow transplants using his usual machines. And O’Connor notes that cats’ immune systems also differ wildly from those of both humans and dogs — meaning that more basic research must be done before sophisticated immunotherapies can be deployed against feline ailments.

At Lively’s clinic, many dog and cat owners were grateful that their animals could participate in Nexvet’s clinical trial. But about a month after the trial ended, the effects of the antibody therapy began to fade. Jonah’s owner was among the clients who called Lively, desperate for a way to access the treatment again. “It’s tough,” Lively says. “They’ll have to wait until this product comes to market.”

Nature 534, 303–304 (16 June 2016) doi:10.1038/534303a

http://www.nature.com/ Nature

http://www.nature.com/news/stem-cells-for-snoopy-pet-medicines-spark-a-biotech-boom-1.20087 Original web page at Nature

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Compound shown to reduce brain damage caused by anaesthesia in early study

An experimental drug prevented learning deficits in young mice exposed repeatedly to anaesthesia, according to a study led by researchers from NYU Langone Medical Center and published June 22 in Science Translational Medicine.

The study results may have implications for children who must have several surgeries, and so are exposed repeatedly to general anaesthesia. Past studies have linked such exposure to a higher incidence of learning disabilities, attention deficits and hyperactivity.

Specifically, the research team found that the experimental drug CX456, part of the AMPAkine class in clinical trials for several neurological conditions, counters for the dampening effect of anaesthesia on nerve signaling. The treatment bolstered nerve cell activity as well as learning ability in mice recovering from repeated exposure to general anaesthesia.

“Each year, in the United States alone, more than a million children under age four undergo surgical procedures that require anaesthesia, and the numbers are growing,” says the study’s senior investigator Guang Yang, PhD, assistant professor of anaesthesiology at NYU Langone. “There are currently no effective treatments to combat potential toxicity linked to repeated anaesthesia, and we would like to change that.”

Yang’s group took advantage of genetically engineered young mice that have protein markers which glow in response to changes in nerve function. Researchers then used advanced microscopy to visualize activity in their brains, comparing nerve signaling activity in those exposed to anaesthesia to those who were not.

The research team found that anaesthesia exposure resulted in a prolonged reduction of signal transmission among nerve cells following anaesthesia. They also observed that CX456 treatment enhances this transmission, along with learning and memory in mice exposed to anesthesia.

The team studied the anaesthetic ketamine, which blocks NMDA (N-methyl-D-aspartate) receptor proteins that enable charged particles like calcium to flow into nerve cells, like electric switches that trigger and shape messages. In contrast, CX546 increases nerve cell activity and calcium influx into nerve cells by enhancing the activity of proteins called AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors.

“We were able to counter anaesthesia-induced deficits in the formation of connections between nerve cells and related learning problems,” says Yang. “This work is an important proof-of-principle study, and opens the door to a new direction for preventing long-term neurocognitive deficits.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160622144816.htm  Original web page at Science

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Antibody-based drug helps ‘bridge’ leukemia patients to curative treatmen

In a randomized Phase III study of the drug inotuzumab ozogamicin, a statistically significant percentage of patients with acute lymphoblastic leukemia (ALL) whose disease had relapsed following standard therapies, qualified for stem cell transplants.

Inotuzumab ozogamicin, also known as CMC-544, links an antibody that targets CD22, a protein found on the surface of more than 90 percent of ALL cells. Once the drug connects to CD22, the ALL cell draws it inside and dies.

The study, which revealed complete remission rates of nearly 81 percent and significantly longer progression-free and higher overall survival rates than with standard therapies, was conducted at The University of Texas MD Anderson Cancer Center. Study findings were reported in the June 12 online issue of the New England Journal of Medicine.

“Forty-one percent of ALL patients in the study were able to proceed to transplant after receiving inotuzumab ozogamicin compared with the 11 percent we have seen qualify through standard chemotherapy,” said Hagop Kantarjian, M.D., chair of Leukemia. “Given that stem cell transplant is considered the only curative treatment option, the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging.”

Donor stem cell transplants generally are considered curative for this aggressive form of leukemia with more than 6,500 American adults expected to be diagnosed with the disease in 2016. However, patients must be in complete remission before they are eligible for transplant.

Current therapies for adults with newly diagnosed B-cell ALL result in complete remission rates (CR) of 60 to 90 percent. However, many of those patients will relapse and only about 30 to 50 percent will achieve long-term, disease-free survival lasting more than three years.

“Standard chemotherapy regimens result in complete remission in 31 to 41 percent of patients who relapse earlier, and just 18 to 25 percent in those who relapse later,” said Kantarjian. “Patients in the inotuzumab ozogamicin study had remission rates of 58 percent, higher than previously reported, possibly due to patients being treated later in the disease course.”

The study reported moderate side effects, the most common being cytopenia, a disorder that reduces blood cell production, and liver toxicity. Funding was provided by Pfizer, Inc.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160612105823.htm Original web page at Science Daily

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New material kills E. coli bacteria in 30 seconds

Every day, we are exposed to millions of harmful bacteria that can cause infectious diseases, such as the E. coli bacteria. Now, researchers at the Institute of Bioengineering and Nanotechnology (IBN) of Agency for Science, Technology and Research (A*STAR), Singapore, have developed a new material that can kill the E. coli bacteria within 30 seconds. This finding has been published in the peer-reviewed journal, Small.

“The global threat of drug-resistant bacteria has given rise to the urgent need for new materials that can kill and prevent the growth of harmful bacteria. Our new antimicrobial material could be used in consumer and personal care products to support good personal hygiene practices and prevent the spread of infectious diseases,” said IBN Executive Director, Professor Jackie Y. Ying.

Triclosan, a common ingredient found in many products such as toothpastes, soaps and detergents to reduce or prevent bacterial infections, has been linked to making bacteria resistant to antibiotics and adverse health effects. The European Union has restricted the use of triclosan in cosmetics, and the U.S. Food and Drug Administration is conducting an on-going review of this ingredient.

Driven by the need to find a more suitable alternative, IBN Group Leader Dr Yugen Zhang and his team synthesized a chemical compound made up of molecules linked together in a chain. Called imidazolium oligomers, this material can kill 99.7% of the E. coli bacteria within 30 seconds aided by its chain-like structure, which helps to penetrate the cell membrane and destroy the bacteria. In contrast, antibiotics only kill the bacteria without destroying the cell membrane. Leaving the cell structure intact allows new antibiotic-resistant bacteria to grow.

“Our unique material can kill bacteria rapidly and inhibit the development of antibiotic-resistant bacteria. Computational chemistry studies supported our experimental findings that the chain-like compound works by attacking the cell membrane. This material is also safe for use because it carries a positive charge that targets the more negatively charged bacteria, without destroying red blood cells,” said Dr Zhang.

The imidazolium oligomers come in the form of a white powder that is soluble in water. The researchers also found that once this was dissolved in alcohol, it formed gels spontaneously. This material could be incorporated in alcoholic sprays that are used for sterilization in hospitals or homes.

E. coli is a type of bacteria found in the intestines of humans and animals, and some strains can cause severe diarrhea, abdominal pain and fever. Such infection is contagious and can spread through contaminated food or water, or from contact with people or animals. Good hygiene practices and proper food handling can prevent contamination.

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https://www.sciencedaily.com/releases/2016/06/160606101404.htm  Original web page at Science Daily

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Resistance mechanism of aggressive brain tumors revealed

Brain tumors subject to therapy can become resistant to it through interactions with their tumor microenvironment rather than because of anything intrinsic about the tumor itself, a new study in mice suggests.

The resistance mechanism outlined in the study involves a particular enzyme and can be overcome using other drugs that target this newly identified signaling pathway. Glioblastoma multiforme (GBM) is a common and aggressive type of adult brain tumor; current standard treatment only minimally prolongs survival.

Macrophages, types of white blood cell that ingest debris, are found in abundance in GMB tumors, and tend to express high levels of colony stimulating factor-1 (CSF-1).

Daniela Quail et al. showed that inhibiting CSF-1 with a drug called BLZ945 caused tumor regression in mice; however, the majority of GBM tumors ultimately developed resistance to BLZ945, a phenomenon of interest as cancer drugs targeting CSF-1 are currently in clinical trials in multiple settings.

Further investigation revealed that GMB recurrence correlated with elevated activity of a tumor enzyme called PI3-K, which was in turn driven by an environmental influence, macrophage-secreted IGF-1. Mice that were treated with BLZ945 plus a PI3-K or IGF-1 inhibitor benefited from significantly longer survival than control mice, the researchers showed.

By implanting BLZ945-resistant tumors into naïve mice, Quail et al. demonstrated that GBM tumors use this this PI3-K/IGF-1 mechanism to manipulate the surrounding microenvironment to their advantage.

Thus, they say, tumors can also develop resistance through microenvironment-dependent mechanisms, independent of the tumor itself. Whether the findings will translate to a human model of glioma remains to be seen.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160519144538.htm  Original web page at Science Daily

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Hundreds of antibiotics built from scratch

Erythromycin is a broad-spectrum antibiotic often used to treat infections of the skin, chest, throat and ears.

A 64-year-old class of antibiotics that has been a cornerstone of medical treatment has been dramatically refreshed by dogged chemists searching for ways to overcome antibiotic-resistant bacteria.

In work described today in Nature, a team of chemists built molecules similar to the drug erythromycin, a key member of the macrolide class, from scratch. In doing so, they were able to generate more than 300 variations on erythromycin that would not have been feasible by merely modifying the original drug — the way that scientists would normally search for new variants of existing antibiotics.

The process generated several variants on erythromycin that can kill bacteria that are resistant to the antibiotic. Although much testing remains before any of the molecules could be used in people, many of them show promise, says chemist Phil Baran of the Scripps Research Institute in La Jolla, California. He adds that the work holds potential for the future of antibiotics: “The fact that you can now make deeply modified analogues in a practical way with chemical synthesis opens the door to a whole host of derivatives that could never have been dreamt of before.”

Erythromycin was first isolated in 1952 from a bacterium in a soil sample taken from the Philippines. But natural erythromycin is a poor drug: although it can kill bacteria, it is unstable in the acidic environs of the stomach, and rearranges there to form a toxic compound. Chemists quickly became experts at modifying erythromycin to make it more stable and less toxic.

Over time, researchers had another reason to develop analogues of the molecule: the rise of erythromycin-resistant bacteria. But after decades of chemically altering the antibiotic, chemists were beginning to run out of options. “Chemists over the past 60 years have been incredibly inventive, but it’s extremely challenging to modify a molecule as complicated as erythromycin,” says Andrew Myers of Harvard University in Cambridge, Massachusetts. “And that’s all we’ve had for a long time.”

Myers and his team decided to go about the problem another way: by synthesizing variations of erythromycin from scratch. The work took five years and led to the discovery of new ways to manufacture molecules.

The team screened 305 of its macrolides against several bacterial strains. Most of the compounds had some antibiotic activity: 83% of them were active against Streptococcus pneumoniae, a bacterium that is susceptible to macrolide antibiotics. Some were also effective against strains that are resistant to multiple antibiotics.

The compounds have not yet been tested in animals, and additional chemical tweaks may be necessary to enhance their potency as well as their safety. Myers has founded a company called Macrolide Pharmaceuticals in Watertown, Massachusetts, to develop the compounds further.

But Baran, who calls the approach “daring” and “fearless” because it started from scratch, says that the success is a testament to the power of organic chemistry. “It shows the power of synthesis to revitalize what is one of the oldest classes of antibiotics.”

Nature doi:10.1038/nature.2016.19946

http://www.nature.com/news/  Nature

http://www.nature.com/news/hundreds-of-antibiotics-built-from-scratch-1.19946  Original web page at Nature

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Changes in ‘microbiome’ during canine atopic dermatitis could lead to antibiotic-free therapies for human, canine disease

Atopic dermatitis (AD), a chronic inflammatory skin condition and the most common form of eczema, is estimated to afflict as much as 10 percent of the U.S. population, and is much more common now than it was 50 years ago. Veterinary clinical estimates also show that approximately 10 percent of dogs have atopic dermatitis. How AD arises isn’t yet fully understood, but a new study from researchers from the Perelman School of Medicine at the University of Pennsylvania and Penn’s School of Veterinary Medicine, have uncovered important insights about the association of AD in dogs compared to humans. The study appears online in the Journal of Investigative Dermatology.

To a greater extent than mouse models, canine AD shares important features of the human version. For example, in both humans and dogs AD has been linked to abnormal blooms of Staphyloccocus bacteria on the skin — mostly Staphyloccocus aureus in humans, and Staphyloccocus pseudintermedius in dogs.

In the study, the research team, comprised of veterinary dermatologists, microbiologists, pathologists, and primary scientists, tracked the bacterial populations, or “microbiomes,” on dogs’ skin, and key properties of the skin’s barrier function during an occurrence of AD, and again after standard treatment with antibiotics. During the flare, researchers observed a sharp decrease in the diversity of the skin bacterial population as certain bacterial species proliferated, along with a decrease in the skin’s protective barrier. With antibiotic therapy, both measures returned to normal levels.

“In both canine and human atopic dermatitis we hypothesize there is a similar relationship among skin barrier function, the immune system, and microbes, even if the individual microbe species aren’t identical,” said senior author Elizabeth A. Grice, PhD, an assistant professor of Dermatology and Microbiology at the Perelman School of Medicine at the University of Pennsylvania. “The hope is that insights gained from this study and others like it will enable us one day to treat this condition by altering the skin’s microbiome without antibiotics.”

Thirty-two dogs (15 with canine AD, and 17 without) from Penn Vet’s Ryan Hospital were enrolled in the study. On three occasions — first during AD flares in the affected dogs, then after 4-6 weeks of targeted antibiotics, and finally 4-6 weeks after treatment concluded — the team took swabs from several areas of skin on the affected dogs. They surveyed the microbiomes of these samples by amplifying and sequencing copies of a key bacterial gene whose DNA sequence is distinct for different bacterial species.

Samples from the dogs with ongoing AD had almost ten times the proportion of Staphylococcus species, compared to the control dogs. Corynebacterium species also rose, as they typically do in humans with AD. A standard measure of the diversity of the dogs’ skin microbiomes also decreased sharply, indicating that the abnormal bacterial proliferation — chiefly from S. pseudintermedius — had crowded out other, harmless or potentially beneficial bacterial species.

At the second visit, immediately following completion of antibiotic therapy, the abundance of Staphyloccocus and Corynebacterium on the skin of affected dogs and the diversity of their skin microbiome had returned almost to the levels seen in the control dogs. Those measures remained largely the same in the third visit, after antibiotic therapy was finished.

Impairment in the skin’s ability to work as a “barrier” to keep moisture in and harmful bacteria out is considered a possible factor in triggering or advancing AD. Under the guidance of Elizabeth Mauldin, DVM DACVP, DACVD, an associate professor of Dermatopathology in Penn’s School of Veterinary Medicine, the researchers also tested skin barrier function in the dogs at each of their three visits. Results showed that the low-bacterial-diversity state of AD flares — corresponding to lesions of AD on the skin — correlated with impairments in the skin barrier, as indicated by a standard test of the water loss rate through the skin (TEWL).

“We don’t know if the bacterial overgrowth is weakening the skin’s barrier function or a weakening of the barrier is enabling the bacterial overgrowth, but we do know now that they’re correlated, and that’s a novel finding,” Grice said.

The research team is now conducting further studies of the microbiome in canine atopic dermatitis, in particular to determine how antimicrobial therapy promotes bacterial resistance.

“This investigation is a prime example of the One Health approach to research, a recognition that we’re dealing with the same disease processes in animals and in humans,” said lead author Charles Bradley, VMD, DACVP, a lecturer and dermatopathologist of pathobiology in Penn’s School of Veterinary Medicine. “The findings highlight the importance of dogs as a model for human dermatitis and help lay the groundwork for new therapeutic strategies, for example involving microbiome transplants to compete with the harmful bacterial overgrowth, as an alternative to antibiotic therapy.”

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https://www.sciencedaily.com/releases/2016/04/160425192814.htm  Original web page at Science Daily

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Superbug infections tracked across Europe

For the first time, scientists have shown that MRSA (methicillin-resistant Staphylococcus aureus) and other antibiotic-resistant ‘superbug’ infections can be tracked across Europe by combining whole-genome sequencing with a web-based system. In mBio, researchers at Imperial College London and the Wellcome Trust Sanger Institute worked with a European network representing doctors in 450 hospitals in 25 countries to successfully interpret and visualise the spread of drug-resistant MRSA.

MRSA and other superbugs are a life-threatening problem for all hospitals across Europe with an estimated 400,000 cases per year and 25,000 deaths from resistant, hospital-acquired infections.

To enable infection control teams across Europe to easily share information and to form a dynamic picture of the rise and spread of antibiotic-resistant bacteria, the scientists from the newly formed Centre for Genomic Pathogen Surveillance developed Microreact.org, a web-based visualisation and mapping tool.

Dr David Aanensen, head of the Centre for Genomic Pathogen Surveillance and joint lead author on the paper said: “Drug resistance is a growing problem both in Europe and across the world and doctors need fast and accurate information to stop epidemics. Our study demonstrates the potential for combining whole-genome sequencing with internet-based visualisation tools to enable public health workers and doctors to see how an epidemic is spreading and make swift decisions to end it.”

The research team read the whole genomes of S. aureus samples to identify which bugs are related to each other, and which are resistant to antibiotics. Using this approach, the scientists were not only able to show the rise and spread of MRSA across Europe, but also provide a quicker way to identify new hotspots of resistance.

Professor Hajo Grundmann, principal investigator on the study and Head of the Institute of Infection Prevention and Hospital Hygiene at the University Medical Centre Freiburg in Germany said: “One of the problems is that these bacteria not only spread within and between hospitals, but they also change their genetic properties due to evolutionary processes over time. Microreact.org allows us to look at their evolution within the context of how they are spreading across Europe.”

In the paper, the scientists show that combining the drug-resistance profile of a bacteria with its whole-genome DNA sequence allowed them to build up a series of drug-resistance ‘DNA photofits’ for resistance to specific drugs. In the future, such an approach may help doctors decide on the best treatments more quickly and help bring drug-resistant outbreaks to an end.

Professor Ed Feil, joint lead author from the Milner Centre for Evolution, at the University of Bath, said: “We’ve developed user-friendly analysis software that demonstrates how whole genome sequence data can be a powerful tool for pan-European surveillance of MRSA and other important pathogens.

Being able to track the spread of outbreaks across the whole continent allows policymakers to identify potential risks to public health and implement appropriate prevention and control strategies.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160505135015.htm Original web page at Science Daily

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Targeted missiles against aggressive cancer cells

Targeted missiles that can enter cancer cells and deliver lethal cell toxins without harming surrounding healthy tissue. This has been a long-standing vision in cancer research, but it has proved difficult to accomplish. A research group at Lund University in Sweden has now taken some crucial steps in this direction.

“For several years, we tried to elucidate which target proteins on the cancer cells’ surface can be used to help these ‘missiles’ to gain entry into cells. Developing this method has been complicated, and we feel pleased to finally have succeeded,” says Professor of Clinical Oncology Mattias Belting. His research group recently published this new method in Nature Communications.

Mattias Belting describes the interior of a cancer tumour as a hostile environment. The rapid cell division of the tumour leads to oxygen deficiency, low pH levels, and nutrient deprivation. In this environment, some cells die spontaneously, while others can be destroyed with the help of radiation, chemo- or immunotherapy. However, the cells that adapt and survive are particularly aggressive.

“We call them stressed cells, and they are known to be more aggressive and insensitive to regular cancer treatments. These are the ones we must find new ways to fight against,” explains Mattias Belting.

The Lund researchers have mapped the thousands of proteins that exist on the surfaces of regular cancer cells, and cells that are stressed due to lack of oxygen. They also found a special protein (caveolin-1) that serves as a gatekeeper, and prevents many of the surface proteins from entering stressed cancer cells.

The researchers continued with identifying some 30 targeted proteins that exist in large quantities on the surfaces of stressed cancer cells, and which also have the ability to effectively pass the “gatekeeper” and be transported into the cells. Against one of these proteins, they have successfully managed to target a toxin-conjugated missile, in the form of an antibody connected to a certain cell toxin, which was able to enter and kill stressed cells, while leaving other cells unharmed.

“The most important aspect of our results is not only that we have identified the proteins that exist on the stressed cancer cells, but also which of them can be used as targets for delivering drugs into the cells,” says first author of the study Erika Bourseau-Guilmain.

There has already been considerable interest in the group’s research. Their method and some of the target proteins are described in detail in the article in Nature Communications, enabling other researchers to build on the foundation laid by the research group from Lund.

“We want to continue to study other target proteins that were identified. We are currently studying other types of stress to find additional, potential target proteins for drug development,” says Mattias Belting.

The Lund researchers worked with cells from e.g. glioblastoma — a type of brain tumour that is difficult to treat. However, they believe that the “missile method” can be used not only against this type, but against many, if not all, types of solid cancers, as stressed cancer cells exist in all types of aggressive tumours.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/04/160420090110.htm  Original web page at Science Daily

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Vitamin stops the aging process of organs

Nicotinamide riboside (NR) is pretty amazing. It has already been shown in several studies to be effective in boosting metabolism. And now a team of researchers at EPFL’s Laboratory of Integrated Systems Physiology (LISP), headed by Johan Auwerx, has unveiled even more of its secrets. An article written by Hongbo Zhang, a PhD student on the team, was published today in Science and describes the positive effects of NR on the functioning of stem cells. These effects can only be described as restorative.

As mice, like all mammals, age, the regenerative capacity of certain organs (such as the liver and kidneys) and muscles (including the heart) diminishes. Their ability to repair them following an injury is also affected. This leads to many of the disorders typical of aging.

Hongbo Zhang wanted to understand how the regeneration process deteriorated with age. To do so, he teamed up with colleagues from ETH Zurich, the University of Zurich and universities in Canada and Brazil. Through the use of several markers, he was able to identify the molecular chain that regulates how mitochondria — the “powerhouse” of the cell — function and how they change with age. The role that mitochondria play in metabolism has already been amply demonstrated, “but we were able to show for the first time that their ability to function properly was important for stem cells,” said Auwerx.

Under normal conditions, these stem cells, reacting to signals sent by the body, regenerate damaged organs by producing new specific cells. At least in young bodies. “We demonstrated that fatigue in stem cells was one of the main causes of poor regeneration or even degeneration in certain tissues or organs,” said Hongbo Zhang.

This is why the researchers wanted to “revitalize” stem cells in the muscles of elderly mice. And they did so by precisely targeting the molecules that help the mitochondria to function properly. “We gave nicotinamide riboside to 2-year-old mice, which is an advanced age for them,” said the researcher. “This substance, which is close to vitamin B3, is a precursor of NAD+, a molecule that plays a key role in mitochondrial activity. And our results are extremely promising: muscular regeneration is much better in mice that received NR, and they lived longer than the mice that didn’t get it.”

Parallel studies have revealed a comparable effect on stem cells of the brain and skin. “This work could have very important implications in the field of regenerative medicine,” said Auwerx. “We are not talking about introducing foreign substances into the body but rather restoring the body’s ability to repair itself with a product that can be taken with food.” This work on the aging process also has potential for treating diseases that can affect — and be fatal — in young people, like muscular dystrophy (myopathy).

So far, no negative side effects have been observed following the use of NR, even at high doses. But caution remains the byword when it comes to this elixir of youth: it appears to boost the functioning of all cells, which could include pathological ones. Further in-depth studies are required.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/04/160428152124.htm  Original web page at Science Daily

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Dressed to kill: Tailoring a suit for tumor-penetrating cancer medications

For more than a decade, biomedical researchers have been looking for better ways to deliver cancer-killing medication directly to tumors in the body. Tiny capsules, called nanoparticles, are now being used to transport chemotherapy medicine through the bloodstream, to the doorstep of cancerous tumors. But figuring out the best way for the particles to get past the tumor’s “velvet rope” and enter the tumor is a challenge scientists are still working out. Drexel University researchers believe that the trick to gaining access to the pernicious cellular masses is to give the nanoparticles a new look — and that dressing to impress will be able to get them past the tumor’s biological bouncers.

Targeted cancer therapy is most effective when the medication is released as close as possible to the interior of a tumor, to increase its odds of penetrating and killing off cancerous cells. The challenge that has faced cancer researchers for years is making a delivery vehicle that is sturdy enough to safely get the medication through the bloodstream to tumors — which is no smooth ride — but is also lithe enough to squeeze through the tumor’s dense extra cellular space — a matrix stuffed with sugars called hyaluronic acid.

In research recently published in the journal Nano Letters, lead author Hao Cheng, PhD, an assistant professor with an appointment in Drexel’s College of Engineering, and affiliation with School of Biomedical Engineering, Science and Health Systems; reports that the way to get past the tumor’s front door has everything to do with how the tiny particle is suited up for the journey.

“What we’ve reported here is a strategy to overcome biological barriers that plague delivery of medication, such as nonvehicle clearance in the bloodstream by the host immune system, and ineffective diffusion in the extracellular matrix of tumor cells,” Cheng said. “It’s a unique strategy that involves the decoration of nanovehicles with enzymes known to break down hyaluronic acid, which is a main barrier in the extracellular space, and the addition of an extra layer of polyethylene glycol to partially cover the enzymes.”

In the paper entitled “Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy,” the group reports that their method is four times more effective at sending nanoparticles into a solid tumor than one of the best strategies currently in use. When cancer medication is loaded in the tiny particle, it has been shown to inhibit the growth of a type of aggressive breast cancer.

The team, which also included researchers Wilbur Bowne, MD, an associate professor in Drexel’s College of Medicine; Dimitrios Arhontoulis, an undergraduate in Drexel’s School of Biomedical Engineering, Science and Health Systems; lead author Hao Zhou and Zhiyuan Fan, doctoral candidates, Junjie Deng, PhD, postdoctoral researchers, and Pelin Lemons, a graduate student, all in the Materials Science and Engineering Department in the College of Engineering, created its nanoparticle suit by starting with one that is common in this area of cancer research and making some key alterations.

“In the general design of nanoparticles, bioactive molecules — not limited to enzymes — were attached on the outermost layer of particles,” Cheng said. “These enzymes can degrade the extra cellular matrix and enhance the nanoparticle’s ability to penetrate solid tumors.”

But in the body, this extra cargo can cause problems. One issue is that attaching enzymes to nanoparticles could cause them to come up short of the tumor and be cleared by the bloodstream before delivering the medication. There’s also a chance that the trip through the bloodstream could render the enzymes inert.

To counter these issues and keep the nanoparticles on course, the team decided to add an extra layer that not only protects the precious payload, but also positions the enzymes for maximum impact.

“The novelty of our design is that we partially embedded the hyaluronidase enzymes in a second polyethylene glycol layer to form the outer shell of the nanoparticle,” Cheng said. “This design dramatically reduces the enzymes’ effect on slowing the particle’s circulation and allows enzymes to maintain their function after the particle diffuses into the tumor.”

Embedding the enzymes in the layers of polyethylene glycol (PEG) ensures that the nanoparticle’s appearance tricks the immune system into leaving it alone during its trip to the tumor, yet and still allows the particle to deal with any hyaluronic acid it encounters on its penetration of the tumor. Other researchers have tested a theory that exposes tumors to the enzymes first, and then to nanoparticles, but this is not nearly as effective as Cheng’s method, because the nanoparticles developed at Drexel retain the enzymes through the duration of their diffusion into tumors, minimizing unnecessary hyaluronic acid degradation.

“The degradation of hyaluronic acid removes the barrier for nanoparticles to diffuse and allows them to access more cancer cells,” Cheng said. “The enhanced diffusion also increases the accumulation of nanoparticles in tumors, and the more nanoparticles that get into tumors the more effective they are at reducing its size.”

As part of the research, the team tested their nanoparticle against competitors that did not have a second layer of polyethylene glycol and ones that did not have the ECM-degrading enzymes. It was no surprise that their nanoparticle performed better in both penetrating tumors and accumulating in the cancerous cells.

“This exciting, novel nanoparticle drug delivery system will improve delivery of anti-cancer agents, enhancing anti-cancer activity to improve patient outcomes,” said Bowne. He foresees enormous potential for this strategy in the neoadjuvant and adjuvant setting for a number difficult to treat cancers such as locally advanced breast, pancreatic and mucin-producing gastrointestinal cancers.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/04/160408163824.htm  Original web page at Science Daily

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New proteins discovered that link obesity-driven diabetes to cancer

For the first time, researchers have determined how bromodomain (BRD) proteins work in type 2 diabetes, which may lead to a better understanding of the link between adult-onset diabetes and certain cancers.

The findings, which appear in PLOS ONE, show that reducing levels in pancreatic beta cells of individual BRDs, called BET proteins, previously shown to play a role in cancer, may also help patients who are obese and diabetic.

The research was led by Gerald V. Denis, PhD, associate professor of pharmacology and medicine at Boston University School of Medicine, who was the first to show that BET protein functions are important in cancer development.

Adult-onset diabetes has been known for decades to increase the risk for specific cancers. The three main members of the BET protein family, BRD2, BRD3 and BRD4, are closely related to each other and often cooperate. However at times, they work independently and sometimes against each other.

According to the researchers new small molecule BET inhibitors have been developed that block all three BET proteins in cancer cells, but they interfere with too many functions.

“The BET proteins provide a new pathway to connect adult-onset diabetes with cancer, so properly targeting BET proteins may be helpful for both,” explained Denis, who is the corresponding author of the study.

He believes this discovery shows the need for deeper analysis of individual BET proteins in all human cell types, starting with boosting insulin and improving metabolism in the pancreas of adults who are obese.

“Without better targeted drugs, some ongoing cancer clinical trials for BET inhibitors are premature. These new results offer useful insight into drug treatments that have failed so far to appreciate the complexities in the BET family.”

https://www.sciencedaily.com/   Science Daily

https://www.sciencedaily.com/releases/2016/03/160323151852.htm  Original web page at Science Daily

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Novel small-molecule antiviral compound protects monkeys from deadly Ebola virus

Rhesus monkeys were completely protected from Ebola virus when treated three days after infection with a compound that blocks the virus’s ability to replicate. These encouraging preclinical results suggest the compound, known as GS-5734, should be further developed as a potential treatment, according to research findings published in the journal Nature.

Ebola virus causes severe hemorrhagic fever in humans and nonhuman primates with high mortality rates and continues to emerge in new geographic locations, including Western Africa, the site of the largest outbreak to date. Since December 2013, over 28,600 cases have been reported in Guinea, Liberia and Sierra Leone, with over 11,300 deaths, according to the World Health Organization. Although several clinical trials have been conducted or are currently underway, there are no licensed vaccines or therapies against Ebola virus.

Travis Warren, Ph.D., a principal investigator at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) and first author of the paper, said the work published is the result of continuing collaborations between USAMRIID and Gilead Sciences of Foster City, Calif. Scientists at the Centers for Disease Control and Prevention (CDC) also contributed by performing initial screening of the Gilead Sciences compound library to find molecules with promising antiviral activity.

That initial work identified the precursor to GS-5734, a small-molecule antiviral agent, which led to the effort by Gilead and USAMRIID to further refine, develop and profile the compound. Led by USAMRIID Science Director Sina Bavari, Ph.D., the paper’s senior author, the research team used cell culture and animal models to demonstrate the compound’s antiviral activity against several pathogens, including Ebola virus.

In animal studies, treatment initiated on day 3 post-infection with Ebola virus resulted in 100 percent survival of the monkeys. The animals also exhibited a substantial reduction in viral load and a marked decrease in the physical signs of disease.

“GS-5734 is a novel nucleotide analog prodrug. It inhibits Ebola virus by blocking the virus’s ability to replicate its own genetic material,” said Warren. “With this process inhibited, the virus can’t make copies of itself. Additionally, we saw no evidence from genetic sequence analyses that the virus was able to generate resistance to GS-5734.”

In cell culture studies, led at USAMRIID by Veronica Soloveva, Ph.D., GS-5734 was active against a broad spectrum of viral pathogens. These included Middle East Respiratory Syndrome (MERS) virus, Marburg virus, and multiple variants of Ebola virus, including the Makona strain causing the most recent outbreak in Western Africa.

“GS-5734 has several favorable characteristics for potential treatment of Ebola virus disease in humans. It is made using well-controlled chemical synthesis procedures, is stable, and can be made on a large scale,” Bavari commented. “It shows substantive post-exposure protection against Ebola virus in nonhuman primates, even when treatments were started after virus had spread to the blood in some animals.”

Taken together, the robust therapeutic efficacy observed in primates, the favorable drug-like properties, and the potential for broad-spectrum antiviral activity suggest that further development of GS-5734 for the treatment of Ebola virus and other viral infections is warranted, Bavari said.

According to Tomas Cihlar, Ph.D., of Gilead Sciences, the company is currently conducting a series of phase I clinical studies in healthy human volunteers to establish the safety and pharmacokinetic profile of GS-5734. The compound also has been provided for compassionate use to treat two patients with Ebola virus infection, both of whom were discharged from the hospital. One of them was the Scottish nurse with recrudescent disease and the other was an acutely infected newborn, thus far the last identified case of Ebola virus infection in Guinea.

“With the hope that the West African outbreak will remain under control, we are exploring alternative options for the development path of GS-5734, including potential use of the animal efficacy rule,” Cihlar said. The animal rule is a regulatory mechanism under which the U.S. Food and Drug Administration may consider efficacy findings from adequate and well-controlled animal studies of a drug in cases where it is not feasible or ethical to conduct human trials.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/03/160303120644.htm  Original web page at Science Daily

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Investigators trace emergence and spread of virulent salmonella strain

Since it first emerged more than half a century ago, a particular strain of multidrug-resistant Salmonella has spread all over the world. Now researchers have figured out why this strain, Salmonella Typhimuriam DT104, has been so successful. This new knowledge could prove valuable in combating other successful pathogens, according to the authors. The study is published ahead of print March 4th in Applied and Environmental Microbiology, a journal of the American Society for Microbiology.

In order to construct the history of this strain, the investigators performed whole-genome sequencing of samples of DT104 that had been collected from patients over more than 40 years, from 1969 to 2012, in 21 countries, on six continents. Very tiny changes in the genome that took place over time enabled them to construct the strain’s family tree (which scientists call a phylogenetic tree). The sequences have also made it easy to estimate roughly when the pathogen acquired the resistance genes.

DT104’s success was due in no small part to its resistance to at least five antibiotics, including ampicillin, chloramphenicol, streptomycin, sulphonamide, and tetracycline, said corresponding author, Pimlapas Leekitcharoenphon, PhD.

Further abetting its spread, unlike other strains of DT Salmonella, DT104 was able to infect numerous livestock species, including cattle, poultry, pigs, and sheep, said Leekitcharoenphon. “Having multiple hosts increases the chances of dissemination,” she explained. Leekitcharoenphon is a postdoctoral researcher at the Research Group for Genomic Epidemiology, National Food Institute, Technical University of Denmark, Lyngby.

Using a program that took into account the rate of mutations in DT104, the investigators estimated that it first emerged in 1948 as an antibiotic susceptible pathogen. It is not clear exactly when DT104 first acquired the multidrug resistance-containing transposon. Transposons are mobile genetic elements that can carry antibiotic resistance genes, and that can jump from one genome to another. In the case of DT104, transposons have been identified as the sources of the resistance genes. The study suggests that the first acquisition of antibiotic resistance may have happened in 1972. However, multidrug-resistant DT104 was first reported in 1984 in the United Kingdom.

The new results also illuminated, for the first time, the results of a program in Denmark to eradicate all pigs infected with DT104, which had begun in 1996, but was stopped in 2000 due to financial pressures. It turns out that program was quite successful.

“If we know and understand the past, we might be able to solve the current resistance problems and prevent future ones,” said Leekitcharoenphon.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/03/160304163407.htm  Original web page at Science Daily

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Engineers grow 3-D heart, liver tissues for better drug testing

Researchers at U of T Engineering have developed a new way of growing realistic human tissues outside the body. Their “person-on-a-chip” technology, called AngioChip, is a powerful platform for discovering and testing new drugs, and could eventually be used to repair or replace damaged organs.

Professor Milica Radisic (IBBME, ChemE), graduate student Boyang Zhang and the rest of the team are among those research groups around the world racing to find ways to grow human tissues in the lab, under conditions that mimic a real person’s body. They have developed unique methods for manufacturing small, intricate scaffolds for individual cells to grow on. These artificial environments produce cells and tissues that resemble the real thing more closely than those grown lying flat in a petri dish.

The team’s recent creations have included BiowireTM — an innovative method of growing heart cells around a silk suture — as well as a scaffold for heart cells that snaps together like sheets of Velcro™. But AngioChip takes tissue engineering to a whole new level. “It’s a fully three-dimensional structure complete with internal blood vessels,” says Radisic. “It behaves just like vasculature, and around it there is a lattice for other cells to attach and grow.” The work is published today in the journal Nature Materials.

Zhang built the scaffold out of POMaC, a polymer that is both biodegradable and biocompatible. The scaffold is built out of a series of thin layers, stamped with a pattern of channels that are each about 50 to 100 micrometres wide. The layers, which resemble the computer microchips, are then stacked into a 3D structure of synthetic blood vessels. As each layer is added, UV light is used to cross-link the polymer and bond it to the layer below.

When the structure is finished, it is bathed in a liquid containing living cells. The cells quickly attach to the inside and outside of the channels and begin growing just as they would in the human body.

“Previously, people could only do this using devices that squish the cells between sheets of silicone and glass,” says Radisic. “You needed several pumps and vacuum lines to run just one chip. Our system runs in a normal cell culture dish, and there are no pumps; we use pressure heads to perfuse media through the vasculature. The wells are open, so you can easily access the tissue.”

Using the platform, the team has built model versions of both heart and liver tissues that function like the real thing. “Our liver actually produced urea and metabolized drugs,” says Radisic. They can connect the blood vessels of the two artificial organs, thereby modelling not just the organs themselves, but the interactions between them. They’ve even injected white blood cells into the vessels and watched as they squeezed through gaps in the vessel wall to reach the tissue on the other side, just as they do in the human body.

AngioChip has great potential in the field of pharmaceutical testing. Current drug-testing methods, such as animal testing and controlled clinical trials, are costly and fraught with ethical concerns. Testing on lab-grown human tissues would provide a realistic model at a fraction of the cost, but this area of research is still in its infancy. “In the last few years, it has become possible to order cultures of human cells for testing, but they’re grown on a plate, a two-dimensional environment,” says Radisic. “They don’t capture all the functional hallmarks of a real heart muscle, for example.”

A more realistic platform like AngioChip could enable drug companies to detect dangerous side effects and interactions between organ compartments long before their products reach the market, saving countless lives. It could also be used to understand and validate the effectiveness of current drugs and even to screen libraries of chemical compounds to discover new drugs. Through TARA Biosystems Inc., a spin-off company co-founded by Radisic, the team is already working on commercializing the technology.

In future, Radisic envisions her lab-grown tissues being implanted into the body to repair organs damaged by disease. Because the cells used to seed the platform can come from anyone, the new tissues could be genetically identical to the intended host, reducing the risk of organ rejection. Even in its current form, the team has shown that the AngioChip can be implanted into a living animal, its artificial blood vessels connected to a real circulatory system. The polymer scaffolding itself simply biodegrades after several months.

The team still has much work to do. Each AngioChip is currently made by hand; if the platform is to be used industrially, the team will need to develop high-throughput manufacturing methods to create many copies at once. Still, the potential is obvious. “It really is multifunctional, and solves many problems in the tissue engineering space,” says Radisic. “It’s truly next-generation.”

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https://www.sciencedaily.com/releases/2016/03/160307112950.htm  Original web page at Science Daily

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Teaching neurons to respond to placebos as potential treatment for Parkinson’s

They found that it is possible to turn a neuron which previously hasn’t responded to placebos (placebo ‘non-responder’ neuron) into a placebo ‘responder’ by conditioning Parkinson patients with apomorphine, a dopaminergic drug used in the treatment of Parkinson’s disease (PD).

When a placebo (saline solution) was given for the first time, it induced neither clinical benefit nor associated neuronal changes in the thalamus, a brain region known to be involved in PD. However, if repeated administrations of apomorphine were performed before placebo administration, a placebo was capable of increasing thalamus neuronal activity along with clinical improvement (reduction of muscle rigidity). Interestingly, the higher the previous administrations of apomorphine was, the larger the neuronal changes and the clinical improvement. When apomorphine was administered for 4 days in a row, the subsequent administration of a placebo induced a response that was as large as the one induced by apomorphine. These changes lasted for 24 hours.

The researchers administered apomorphine, either 1, 2, 3 or 4 days before the surgical implantation of electrodes for deep brain stimulation, which is an effective treatment for PD. During surgery, they replaced apomorphine with a placebo and recorded from single neurons in the thalamus along with the assessment of muscle rigidity of the arm.

Fabrizio Benedetti, from the Department of Neuroscience at University of Turin Medical School, Italy and first author of the study, explained, ‘These findings show that is possible to teach neurons in the thalamus to respond to placebos, so that a placebo non-responder can be turned into a placebo responder. These findings may have profound implications and applications, because we can reduce drug intake by exploiting these learning mechanisms. Since this study shows that there is a memory for drug action, the alternate administration drug-placebo-drug- placebo etc. means people would need to take less medication but yet obtain the same clinical benefit.

‘If a placebo is given after four previous administrations of apomorphine, the placebo response can be as large as the drug response, and this effect lasts up to 24 hours. Therefore, a future challenge will be to see whether this effect can be extended beyond 24 hours.’

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http://www.sciencedaily.com/releases/2016/02/160209221142.htm  Original web page at Science Daily

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Researchers create ‘mini-brains’ in lab to study neurological diseases

Researchers at the Johns Hopkins Bloomberg School of Public Health say they have developed tiny “mini-brains” made up of many of the neurons and cells of the human brain — and even some of its functionality — and which can be replicated on a large scale.

The researchers say that the creation of these “mini-brains,” which will be discussed at the American Association for the Advancement of Science conference in Washington, DC on Feb. 12 at a press briefing and in a session on Feb. 13, could dramatically change how new drugs are tested for effectiveness and safety, taking the place of the hundreds of thousands of animals used for neurological scientific research in the United States. Performing research using these three-dimensional “mini-brains” — balls of brain cells that grow and form brain-like structures on their own over the course of eight weeks — should be superior to studying mice and rats because they are derived from human cells instead of rodents, they say.

“Ninety-five percent of drugs that look promising when tested in animal models fail once they are tested in humans at great expense of time and money,” says study leader Thomas Hartung, MD, PhD, the Doerenkamp-Zbinden Professor and Chair for Evidence-based Toxicology at the Bloomberg School. “While rodent models have been useful, we are not 150-pound rats. And even though we are not balls of cells either, you can often get much better information from these balls of cells than from rodents.

“We believe that the future of brain research will include less reliance on animals, more reliance on human, cell-based models.”

Hartung and his colleagues created the brains using what are known as induced pluripotent stem cells (iPSCs). These are adult cells that have been genetically reprogrammed to an embryonic stem cell-like state and then are stimulated to grow into brain cells. Cells from the skin of several healthy adults were used to create the mini-brains, but Hartung says that cells from people with certain genetic traits or certain diseases can be used to create brains to study various types of pharmaceuticals. He says the brains can be used to study Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and even autism. Projects to study viral infections, trauma and stroke have been started.

Hartung’s mini-brains are very small — at 350 micrometers in diameter, or about the size of the eye of a housefly, they are just visible to the human eye — and hundreds to thousands of exact copies can be produced in each batch. One hundred of them can grow easily in the same petri dish in the lab. After cultivating the mini-brains for about two months, the brains developed four types of neurons and two types of support cells: astrocytes and oligodendrocytes, the latter of which go on to create myelin, which insulates the neuron’s axons and allows them to communicate faster.

The researchers could watch the myelin developing and could see it begin to sheath the axons. The brains even showed spontaneous electrophysiological activity, which could be recorded with electrodes, similar to an electroencephalogram, also known as EEG. To test them, the researchers placed a mini-brain on an array of electrodes and listened to the spontaneous electrical communication of the neurons as test drugs were added.

“We don’t have the first brain model nor are we claiming to have the best one,” says Hartung, who also directs the School’s Center for Alternatives to Animal Testing. “But this is the most standardized one. And when testing drugs, it is imperative that the cells being studied are as similar as possible to ensure the most comparable and accurate results.”

Hartung is applying for a patent for the mini-brains and is also developing a commercial entity called ORGANOME to produce them. He hopes production can begin in 2016. He says they are easily reproducible and hopes to see them used by scientists in as many labs as possible. “Only when we can have brain models like this in any lab at any time will we be able to replace animal testing on a large scale,” he says.

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https://www.sciencedaily.com/releases/2016/02/160212163901.htm  Original web page at Science Daily

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New experimental test detects signs of Lyme disease near time of infection

When it comes to early diagnosis of Lyme disease, the insidious tick-borne illness that afflicts about 300,000 Americans annually, finding the proverbial needle in the haystack might be a far easier challenge — until now, perhaps. An experimental method developed by federal and university researchers appears capable of detecting the stealthy culprit Lyme bacteria at the earliest time of infection, when currently available tests are often still negative.

The team suggests the approach might also be useful for early detection of other elusive bacterial infections. The collaborators — from the National Institute of Standards and Technology (NIST), Institute for Bioscience and Biotechnology Research, and Johns Hopkins School of Medicine — recently reported the successful first trial of their new method.

“Our hypothesis was that Lyme bacteria shed vesicle-like particles — or fragments — derived from the cell wall of the bacteria circulating in the serum of individuals. These particles would contain membrane proteins that can be detected to provide a unique indicator of infection,” explains NIST research chemist Larik Turko.

The challenge was to detect these bacterial membrane proteins among the far, far more plentiful proteins normally present in serum, the watery, cell-free component of blood. The researchers speculated that running serum samples through a high-speed centrifuge — a standard step in chemistry labs — might selectively concentrate the larger, heavier fragments containing the bacterial membrane proteins into pellets. In effect, they predicted, this step would separate the wheat — the sparse target proteins — from the chaff — the much more abundant human serum proteins.

The new method’s promise was demonstrated in tests on serum samples drawn from three patients with undetected Lyme disease at the time of their initial doctor visit. By customizing standard analytical techniques for determining the types and amounts of chemicals in a sample, the team detected extremely small amounts of the target protein in all three samples. For chemistry buffs, the protein in enriched samples was present at a level of about four billionths of a millionth of a mole, the standard unit for amount of substance.

In one patient, the experimental method detected the bacteria three weeks before infection was confirmed with the standard blood tests now used. For the other two, infection was detected simultaneously by the two methods.

“The complexity of Lyme disease, combined with lack of biomarkers to measure infection, has slowed progress,” study collaborator John Aucott, head of the Johns Hopkins Lyme Disease Clinical Research Center.. “Now, thanks to recent advances in technology, the tiniest concentration of blood molecules can now be detected, molecules that were previously ‘invisible’ to scientists.”

Aucott will feature the joint study as an example in his 2016 AAAS Annual Meeting presentation, Big Data Clinical Realities and the Human Dimensions of Interoperable Data.

The current standard blood test for Lyme disease exposes the infection only after antibodies have accumulated to detectable levels, which can take up to 4 to 6 weeks. If patients exhibit a telltale bull’s-eye rash, diagnosis and treatment can begin earlier. But the rash does not occur in 20 to 30 percent of Lyme disease patients, according to the Centers for Disease Control and Prevention.

Rather than waiting for an infected person’s immune system to produce noticeable amounts of antibodies, the team chose to home in on the bacteria itself — specifically, proteins the bug sheds when attacked by the body’s defenses.

“From many candidates, we chose one that is both easily distinguished from human serum proteins and an unambiguous indicator of the bacteria,” Turko says. “This protein, which resides on the outer surface of membranes, became the target of our search in serum samples.”

But finding that target required an important preliminary step to ensure the accuracy of their measurements: making a reference sample that contained ample amounts of the target protein. With the reference sample, the team established the unmistakable signature the bug’s outer-surface membrane protein would yield when they examined samples drawn from patients. As a result of these steps, the team could detect the copies of the target protein, even though human proteins were 10 million times more plentiful.

“We believe that this approach may be universally applicable to detection of other bacterial infections in humans,” the researchers write.

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https://www.sciencedaily.com/releases/2016/02/160212163919.htm  Original web page at Science Daily

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Drug prevents key age-related brain change in rats

As brain cells age they lose the fibers that receive neural impulses, a change that may underlie cognitive decline. Researchers at the University of California, Irvine recently found a way to reverse this process in rats. The study was published Feb. 3, 2016 in The Journal of Neuroscience. Researchers caution that more studies are needed, but the findings shed light on the mechanisms of cognitive decline and identify potential strategies to stem it.

“There’s a tendency to think that aging is an inexorable process, that it’s something in the genes and there’s nothing you can do about it,” said study co-author Gary Lynch. “This paper is saying that may not be true.”

The researchers studied dendrites — the branch-like fibers that extend from neurons and receive signals from other neurons — in rats. Evidence from other studies in rodents, monkeys, and humans indicates that dendrites dwindle with age and that this process — called dendritic retraction — occurs as early as middle age.

The team, led by Lynch, Julie Lauterborn, and Linda Palmer, wanted to know whether dendritic retraction was already underway in 13-month-old or “middle-aged” rats and, if it was, could they reverse it by giving rats a compound called an ampakine. Ampakines had previously been shown to improve age-related cognitive deficits in rats as well as increase production of a key growth factor, brain-derived neurotrophic factor (BDNF) in the brain.

The researchers housed 10-month-old male rats in cages with enriched environments. Unlike standard cages, these enhanced cages provided ample space, a large running wheel, and several objects for the rats to explore. Eleven rats received an oral dose of the ampakine each day for the next three months while the other 12 rats received a placebo. During this three-month window the researchers conducted behavioral testing by monitoring the rats’ activity as they explored an unfamiliar environment. After three months the researchers examined an area of the rats’ brains associated with learning and memory, the hippocampus, and compared that with the hippocampi of two-and-a-half-month-old or “adolescent” rats.

“Middle-aged” rats given the placebo had shorter dendrites and fewer dendritic branches than the younger rats. The brains of rats given the ampakine, however, were mostly indistinguishable from the young rats — dendrites in both were similar in length and in the amount of branching. What’s more, the researchers also found that treated rats had significantly more dendritic spines, the small projections on dendrites that receive signals from other neurons, than either the untreated rats or the young rats.

The researchers found that anatomical differences between the rats also correlated with differences in a biological measure of learning and memory: the treated rats showed enhanced signaling between neurons — a phenomenon called long-term potentiation.

Finally, differences between treated rats and untreated rats appeared in behavioral testing. Typically, rats placed in a new environment spend a lot of time randomly exploring. As they become more familiar, they settle into predicable patterns of activity. Rats receiving ampakine settled into predictable patterns in a foreign play arena by the second day of testing whereas the placebo group of rats continued randomly exploring.

“The treated rats had better memory of the arena and developed strategies to explore,” Lynch said, pointing out that they had in effect reversed the effects of aging in the brain.

“The importance of optimizing cognitive function across the lifespan cannot be overstated,” said Carol Barnes, a neuroscientist at the University of Arizona who studies the effects of aging on the brain and was not involved in the study. This study “is particularly interesting because the drug effect was selective in the brain functions and behaviors that were changed. This is the kind of specificity that could make translation to the clinic possible,” she added.

However, the researchers caution that much work remains to be done before the drug is tested in people. “The next step is to repeat the study,” Lynch said, noting there are a lot of implications associated with this research and they need to proceed with care. The researchers would also want to explore how many days of treatment are necessary to see the same results and whether the drug would also work in older rats and females as well as males.

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http://www.sciencedaily.com/releases/2016/02/160202174005.htm  Original web page at Science Daily

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* Rooting out doping in racehorses

Doping in the horseracing industry has spurred regulations banning performance-enhancing drugs, as well as calls for an anti-doping agency in the U.S. But as in human sports, testing for certain kinds of prohibited substances has been a challenge. Now scientists report in ACS’ journal Analytical Chemistry a new detection method that could help anti-doping enforcers determine whether a horse has received certain substances.

To give their animals an edge on the track, some horse trainers and veterinarians might administer a single substance, a cocktail of hormones, hormone-mimicking compounds or other drugs. Most are prohibited in the racing world, but catching violators can in some cases be difficult with conventional methods. Existing techniques directly test for the original compounds administered to an animal or their unique metabolites or byproducts. But some of these substances can get processed and eliminated by the animal quickly, making the window for detection very short. George Ho Man Chan, Terence See Ming Wan and colleagues are currently investigating unconventional ways to increase the chances of catching cheaters.

The researchers have identified seven biomarkers in urine that potentially indicate whether a horse has been given aromatase inhibitors, a class of compounds also used by bodybuilders to help regulate hormones and get an edge on the competition. Testing for the changes in these naturally-occurring biomarkers in horse urine could reveal the administration of the substances for about 95 to 195 hours after injection. That’s 2 to 2.5 times longer than conventional screening methods. Being able to find evidence for the administration of these drugs for two or more days longer than before could increase the chances that rule-violators will be caught. With further validation studies, this method could be developed into a useful screening tool for detecting the use of aromatase inhibitors in horses.

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http://www.sciencedaily.com/releases/2016/01/160113132809.htm  Original web page at Science Daily

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Bacillus cereus is able to resist certain antibiotic therapies

The pathogenic bacterium Bacillus cereus causes vomiting and diarrhea as well as systemic and local infections. A team of researchers has reported for the first time that B. cereus, following contact with certain antibiotics, can switch into a special slowed-down mode. The bacteria then form small colony variants (SVCs) that are difficult to diagnose and almost impossible to treat with certain antibiotics. This discovered mechanism may provide an alternative explanation for antibiotic resistance.

The bacterium B. cereus had so far been considered to be exclusively endospore-forming. In response to harsh conditions, the bacteria form protective endospores enabling them to remain dormant for extended periods. When conditions are more favourable, the endospores reactivate to become fully functioning bacteria.

Elrike Frenzel, Markus Kranzler and Monika Ehling-Schulz of the Institute of Microbiology at the University of Veterinary Medicine Vienna have now shown for the first time that B. cereus has an alternative lifestyle in the form of so called small colony variants (SCVs). In B. cereus these SCVs form in response to exposure with aminoglycoside antibiotics. SCVs grow slower than the original form of B. cereus. They have an altered metabolism and are resistant to those antibiotics which triggered this state, namely aminoglycosides.

“The bacterium protects itself against the harmful effects of the antibiotics by forming these Small Colony Variants. But B. cereus is usually treated with exactly those antibiotics which induce the SCV state. If an antibiotic triggers the formation of SCVs, it also triggers resistance,” first author Frenzel explains.

The mechanism discovered by Frenzel, Kranzler and Ehling-Schulz is of enormous significance in clinical practice. Traditional diagnostic methods are based on the identification of metabolic features of B. cereus. These tests will not detect SCVs, however, as they have a slower, altered metabolism. This may result in incorrect antibiotic therapies or even failed diagnoses. Study author Frenzel sees molecular-based diagnostics as the only way to diagnose this form of B. cereus.

Treating B. cereus infections using only aminoglycoside antibiotics could bear the risk of a prolonged infection. SCVs grow more slowly, but they still produce toxins that are harmful to the body. “In this case, a combination therapy with other antibiotic groups is advisable,” Frenzel recommends.

One species of bacteria that has been known for years to be a multiresistant hospital pathogen and which poses a life-threatening risk for immunocompromised individuals in particular is Staphylococcus aureus. Those bacteria also form SCVs, but unlike B. cereus they are capable of reverting to its original state. For B. cereus, the adaptation to a small colony variant appears to be final. “We believe that the SCV formation in B. cereus functions differently than in S. aureus,” says study author Ehling-Schulz.

“The ability to form SCVs appears to be of environmental significance for the bacteria,” Frenzel believes. “This alternative lifestyle allows the bacteria to avoid threatening stress factors such as antibiotic exposure. B. cereus are soil-dwelling, and other microorganism in the soil produce antibiotics. Here, too, the formation of SCVs would be an advantage for the bacteria.”

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http://www.sciencedaily.com/releases/2015/12/151228124703.htm  Original web page at Science Daily