Study explains why COPD patients develop tolerance to roflumilast drug

Roflumilast, a drug recently approved in the United States to treat severe chronic obstructive pulmonary disease (COPD), increases the production of a protein that causes inflammation, which possibly results in patients developing a tolerance to the drug after repeated use and makes the drug less effective, according to researchers at Georgia State University, Kumamoto University and the University of Rochester Medical Center.

The findings, published on March 23 in the Proceedings of the National Academy of Sciences USA, may help explain the development of tolerance to roflumilast and may assist with developing new therapeutics to improve the efficacy of the drug.

COPD is the fourth-leading cause of death worldwide. This progressive disease causes airflow blockage and breathing-related problems, such as coughing that produces large amounts of mucus, wheezing, shortness of breath and chest tightness. Cigarette smoking is the leading cause of COPD, according to the National Heart, Lung and Blood Institute.

Study explains why COPD patients develop tolerance to roflumilast drug

Fourth-line bosutinib ‘appropriate’ after prior CML treatment failure, intolerance

In continuation of my update on bosutinib

A Spanish study suggests that bosutinib can help improve or maintain response in patients with chronic myeloid leukaemia (CML) after treatment failure of three previous tyrosine kinase inhibitors (TKI).

Researcher Juan Luís Steegmann (Hospital Universitario de la Princesa, Madrid, Spain) and colleagues analysed medical records of 30 chronic phase CML patients with Philadelphia chromosome-positive disease given bosutinib under the Spanish Compassionate Use programme after discontinuing imatinib, dasatinib and nilotinib as a result of resistance or intolerance.

Of the 15 patients without a complete cytogenetic response at baseline, defined as after TKI use but before bosutinib initiation, two (13.3%) achieved it following bosutinib treatment.

Fourth-line bosutinib ‘appropriate’ after prior CML treatment failure, intolerance

BCM-95 Curcumin improves chemotherapy's effectiveness in killing chemoresistant cancer cells

The structure of curcumin, officially known as diferuloylmethane, is two ferulic acid moeities bound together with an additional carbon (methane) to abridge the carboxyl groups. It can exist in a enol form (pictured below) or a keto form, which is molecularily symmetrical with two ketone groups on the backbone.

Cancer cell resistance to chemotherapy is a major cause of death in patients with colorectal cancer. In a first-of-its-kind study, BCM-95® Curcumin was found to improve chemotherapy's effectiveness in killing chemoresistant cells via a mechanism not previously identified. [Toden S, Okugawa Y, Jascur T, Wodarz D, Komarova N, Buhrmann C, Shakibaei M, Boland R, and Goel A. Curcumin mediates chemosensitization to 5-flurouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis. 2015; 1-13. Doi:10.1093/carcin/bvg006]

"Chemoresistance occurs when the cancer cell is no longer responding to the cancer-killing effects of chemotherapy. The cancer cell 'learns' how to survive the chemo. It is a huge problem," states Ajay Goel, Ph.D., Director of Center for Gastrointestinal Research, and Director of Epigenetics, Cancer Prevention and Genomics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, lead author of the study.

BCM-95 Curcumin improves chemotherapy's effectiveness in killing chemoresistant cancer cells

Two common antibiotic treatments equally effective against MRSA skin infections

Researchers funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have found that two common antibiotic treatments work equally well against bacterial skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA) acquired outside of hospital settings. Known as community-associated MRSA, or CA-MRSA, these skin infections have been reported in athletes, daycare-age children, students, military personnel and prison inmates, among others, and can lead to hospitalization, surgical procedures, bacteria in the blood, and in severe cases, death. 

Although MRSA is an increasingly common pathogen and the most common cause of skin infection in the United States, there is no standard treatment approach for CA-MRSA. As CA-MRSA emerged in community settings, there were concerns about how to identify the best treatment options and preserve the effectiveness of last-line drugs. Two older antibiotics that are no longer under patent, clindamycin and TMP-SMX, are recommended to treat CA-MRSA. It was unknown whether one antibiotic was associated with better outcomes in patients.

To answer this question, scientists tested clindamycin and TMP-SMX in adults and children with uncomplicated skin infections for 10 days. Of 466 study participants who received either antibiotic, the cure rate was 89.5 percent for clindamycin (below structure)

  

and 88.2 percent for TMP-SMX (Trimethoprim/sulfamethoxazole or co-trimoxazole) -(below structure)...

The side effects of both drugs were comparable. The findings, which appear in the New England Journal of Medicine, suggest that uncomplicated skin infectious acquired outside of hospitals can be treated inexpensively and successfully with either drug, according to the researchers.

Two common antibiotic treatments equally effective against MRSA skin infections

RNA molecule can be manipulated to generate more neurons from neural stem cells

A research team at UC San Francisco has discovered an RNA molecule called Pnky that can be manipulated to increase the production of neurons from neural stem cells.

The research, led by neurosurgeon Daniel A. Lim, MD, PhD, and published on March 19, 2015 in Cell Stem Cell, has possible applications in regenerative medicine, including treatments of such disorders as Alzheimer's disease, Parkinson's disease and traumatic brain injury, and in cancer treatment.

Pnky is one of a number of newly discovered long noncoding RNAs (lncRNAs), which are stretches of 200 or more nucleotides in the human genome that do not code for proteins, yet seem to have a biological function.

The name, pronounced "Pinky," was inspired by the popular American cartoon series Pinky and the Brain. "Pnky is encoded near a gene called 'Brain,' so it sort of suggested itself to the students in my laboratory," said Lim. Pnky also appears only to be found in the brain, he noted.

Co-first authors Alex Ramos, PhD, and Rebecca Andersen, who are students in Lim's laboratory, first studied Pnky in neural stem cells found in mouse brains, and also identified the molecule in neural stem cells of the developing human brain. They found that when Pnky was removed from stem cells in a process called knockdown, neuron production increased three to four times.

"It is remarkable that when you take Pnky away, the stem cells produce many more neurons," said Lim, an assistant professor of neurological surgery and director of restorative surgery at UCSF. "These findings suggest that Pnky, and perhaps lncRNAs in general, could eventually have important applications in regenerative medicine and cancer treatment."

RNA molecule can be manipulated to generate more neurons from neural stem cells

New triple combination therapy shows promise in controlling advanced melanoma

Results of a new study by UCLA researchers has found that a groundbreaking new triple combination therapy shows promising signs of more effectively controlling advanced melanoma than previous BRAF + MEK inhibitor or BRAF inhibitor + immunotherapy combos alone, and with increased immune response and fewer side effects.

An estimated 70,000 new cases of metastatic melanoma are diagnosed each year in the United States, and of those 8,000 will die of the disease. About 50 percent of these men and women (or 35,000 a year) have a mutated protein called a BRAF mutation, which in most cases allows melanoma to eventually build up a resistance to many drug therapies.

In the new study led by UCLA Jonsson Comprehensive Cancer Center member Dr. Antoni Ribas and colleague Dr. Siwen Hu-Lieskovan, UCLA scientists combined targeted therapies utilizing a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) (trametinib)  (dabrafenib)

with immunotherapy. The three together are shown to be more effective treatments by sensitizing the patients' own immune system to enhance immunotherapy, and reduce the probability of the melanoma eventually developing resistance.

New triple combination therapy shows promise in controlling advanced melanoma

Chemical found in stinging nettles and ants could improve cancer drug

A cancer drug could be made 50 times more effective by a chemical found in stinging nettles and ants, new research finds. Researchers at the University of Warwick found that when the chemical, Sodium Formate, is used in combination with a metal-based cancer treatment it can greatly increase its ability to shut down cancer cells.

Developed by Warwick's Department of Chemistry, the drug, a compound of the metal ruthenium called JS07, is capable of exploiting a cancer cell's natural weaknesses and disrupts its energy generation mechanism.

Laboratory tests on ovarian cancer cells have shown that when used in combination with Sodium Formate JS07 is 50 times more effective than when acting alone. Derived from formic acid which is commonly found in a number of natural organisms including nettles and ants, Sodium Formate (E-237) is more commonly used as a food preservative.

The Warwick researchers developed a novel method for binding Sodium Formate with JS07 to form a more potent form of the drug. The researchers subsequently found that the potent form of JS07 acts as a catalyst when it interacts with a cancer cell's energy-generating mechanism. This interaction disrupts the mechanism, causing the cell's vital processes to cease functioning and for the cell to shut down.

Chemical found in stinging nettles and ants could improve cancer drug

Olive ingredients may prevent Alzheimer's disease

It has long been proven that people who follow a Mediterranean diet and keep physically and mentally active are less likely to suffer from dementia. Olives in particular appear to play a key role in this regard. But just what are the substances contained in these small, oval fruit that are so valuable? This is what a Hessen-based group of researchers from the Goethe University Frankfurt, the Technical University (TU) of Darmstadt and Darmstadt company N-Zyme BioTec GmbH intends to find out. The three-year project "NeurOliv" has a project volume of 1.3 million Euros and is funded by the Federal Ministry of Education and Research as part of the high-tech initiative "KMU-innovativ Biochance".

This collaboration combines a number of approaches, the initiative of which came from N-Zyme BioTec GmbH. The aim is to use substances contained in olives to develop new functional food for the ageing society, which will protect against Alzheimer's disease. "We want to test whether olive polyphenols can even help to cure the disease. This is why we believe our products also relate to the pharmaceutical sector", says Dr. Joachim Tretzel, Managing Director of N-Zyme BioTec GmbH. The high-tech initiative of the German government was set up to fund small and medium-sized enterprises.

Olive oil : http://www.oliveoilsource.com/page/what-olive-oil

Olive ingredients may prevent Alzheimer's disease

New anti-clotting therapy no better than established anticoagulants

A novel therapy that would allow doctors to turn the body's blood-clotting ability off and on in a more controlled way was about as effective as established anticoagulants in patients undergoing angioplasty but was associated with higher rates of moderate to severe bleeding, according to an analysis of data from a terminated Phase III trial presented at the American College of Cardiology's 64th Annual Scientific Session. The study was officially halted in August due to an excess of severe allergic reactions, so authors caution that the data should be considered exploratory given the early termination.

Before the trial was stopped, 3,232 patients undergoing angioplasty, a procedure to open blocked coronary arteries, were enrolled in the study at 225 hospitals in 17 countries including North America and Europe. The study was designed to compare the safety and efficacy of the REG1 Anticoagulation System and bivalirudin--a commonly used anticoagulant--in a total of 13,200 patients. Patients were equally randomized to the bivalirudin or REG1 in an open-label fashion and data was collected at three and 30 days.

No differences were found between patients receiving REG1 compared to bivalirudin in terms of the study's primary efficacy endpoint--a composite of all-cause death, heart attack, stroke or urgent revascularization, which was reported in 6.7 percent of patients in the REG1 arm and 6.4 percent of patients receiving bivalirudin three days after angioplasty. Efficacy was still comparable at 30 days.

The REG1 system failed to show a benefit in the primary safety endpoint of bleeding compared to bivalirudin. Using a validated bleeding scale, patients receiving REG1 had a 0.4 percent rate of severe or fatal bleeding compared to 0.1 percent with patients who were given bivalirudin for anticoagulation. Moderate to severe bleeding was significantly higher in the REG1 group compared with bivalirudin.

New anti-clotting therapy no better than established anticoagulants

Viagra can have anti-cancer, anti-Alzheimer's disease effects if used with new drugs

Chaperone proteins play an important role in protein folding in human cells and in bacteria and are promising new targets for drugs to treat cancer and Alzheimer's disease and for novel antiviral drugs and antibiotics. How existing drugs such as Viagra or Cialis and a derivative of the drug Celebrex, for example, can reduce the activity of a specific chaperone protein, with the potential for anti-tumor and anti-Alzheimer's disease effects, is described in a Review article in DNA and Cell Biology, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the DNA and Cell Biology website until April 9, 2015.

In the article "HSPA5/Dna K May Be a Useful Target for Human Disease Therapies", Laurence Booth, Jane Roberts, and Paul Dent, Virginia Commonwealth University, Richmond, provide a comprehensive discussion of the HSPA5/Dna K chaperone protein and the published evidence for its role in various human diseases. The authors describe how OSU-03012, an experimental compound derived from the drug celecoxib (Celebrex) interacts with Viagra or Cialis to reduce levels of chaperone proteins. Reduced levels of HSPA5 and Dna K can interfere with virus replication, promote bacterial cell death, and even make drug-resistant "superbugs" susceptible to existing antibiotics.

"Drugs like Celebrex and Viagra are readily available and generally recognized as safe. This study by Booth and colleagues may lead to new applications of these relatively new medicines," says Carol Shoshkes Reiss, PhD, Editor-in-Chief, of DNA and Cell Biology and Professor, Departments of Biology and Neural Science, New York University, NY. "The potential impact, if the experiments described are translatable to human disease, could be paradigm-shifting. The potential applications are serious antibiotic resistant infections, chemotherapy-resistant cancers, and neurodegenerative disease ranging from Parkinson's disease to Huntington's or Alzheimer's disease."

Viagra can have anti-cancer, anti-Alzheimer's disease effects if used with new drugs

Promising new natural treatment for Alzheimer's disease nears clinical trial

 

A promising new natural treatment for Alzheimer's disease is moving toward clinical trials. This will be a major step forward as there is nothing on the market that slows the progression of Alzheimer's.

Muraleedharan Nair, Michigan State University natural products chemist, has patented a botanical compound, withanamides. His spinoff company, Natural Therapeutics, will begin the trials as soon as funding is in place.

To date, none of the major pharmaceutical companies - Merck, Eli Lilly, Bristol-Myers Squibb - have been able to produce an effective treatment that passed human clinical trials, Nair said.

"This particular research has focused on Ashwagandha, an herbal remedy that's been used in Eastern medicines for centuries," he said. "Our compound withanamides may work to prevent Alzheimer's disease at the onset, and it also could prevent its progression."

While plants cannot be patented, compounds from it can. MSU holds the patent for withanamides, and earlier research revealed that the compound, found in the plants' seeds, proved to be a powerful anti-oxidant - double the strength of what's on today's market. The potent compound has shown that it can protect cells against damaging attacks by a rogue protein ¬- the earliest stage of Alzheimer's.

Alzheimer's begins when a specific protein starts breaking, or cleaving, at the wrong place to produce an unwanted fragment. This bad fragment, called BAP, stresses cells' membranes, sparks plaque formation and eventually kills the cells. This attack begins in the frontal lobe, erasing memories and continuing its unrelenting assault deeper into the brain.

A complicating factor is that the majority of protein cleaving is a natural, healthy process. Pharmaceutical companies, however, have focused their efforts on blocking the tiny faction of bad cleaving of the protein producing BAP.

Promising new natural treatment for Alzheimer's disease nears clinical trial

Naproxen and omeprazole combination effective in preventing bladder cancer

The anti-inflammatory class of drugs NSAIDs have shown great promise in preventing cancers including colon, esophagus and skin. However, they can increase the risks of heart attacks, ulcers and rare but potentially life-threatening bleeds.

A new study suggests there may be ways to reduce these dangerous side effects. Collaborators from the University of Michigan, the National Cancer Institute and the University of Alabama looked at naproxen, which is known to have a lower cardiovascular risk than other NSAIDs. Naproxen, like most NSAIDs and aspirin, does increase the risk for gastric ulcers or bleeding. Here, the researchers used the proton pump inhibitor omeprazole, a commonly used acid inhibitor, in combination with naproxen and tested its effects on cancer prevention in a rat model of bladder cancer.

They found that naproxen reduced the incidence of bladder cancer by 75 percent in rats. Omeprazole by itself did not affect the development of cancer but it also did not interfere with the effect of naproxen at preventing tumors. The rats who received naproxen alone or naproxen with omeprazole developed cancer at similarly low rates, while all rats receiving omeprazole alone or no treatment developed bladder cancer.

Clinical data in humans has previously shown combining omeprazole plus naproxen reduced gastric toxicity roughly 70 percent.

The authors also found that intermittent dosing with naproxen (three weeks on the drugs, followed by three weeks off) was highly effective and likely to reduce gastric toxicity. However, it does not have the clear clinical data supporting reduced gastric toxicity associated with naproxen and omeprazole.

"Our study shows that naproxen works just as well with a proton pump inhibitor as without. This provides proof of principle that this could be a valuable cancer prevention strategy and one hopes it can advance quickly to a clinical trial for those at high risk of colon, esophageal, squamous cell skin cancer or potentially other cancers," says lead study author Ronald A. Lubet, Ph.D., a scientist with the Chemopreventive Agent Development Research Group at the National Cancer Institute.

Naproxen and omeprazole combination effective in preventing bladder cancer

New drug shows promise in driving insulin-producing beta cells to multiply

In a screen of more than 100,000 potential drugs, only one, harmine, drove human insulin-producing beta cells to multiply, according to a study led by researchers at the Icahn School of Medicine at Mount Sinai, funded by JDRF and the National Institutes of Health, and published online today in Nature Medicine.

Diabetes results from too few insulin-producing "beta cells" in the pancreas secreting too little insulin, the hormone required to keep blood sugar levels in the normal range. The disease affects 380 million people worldwide, and leads to major medical complications: heart attack, stroke, kidney failure, blindness and limb amputation.

The Mount Sinai study found that harmine drove the sustained division and multiplication of adult human beta cells in culture, a feat that had eluded the field for years. In addition, harmine treatment tripled the number of beta cells and led to better control of blood sugar in three groups of mice engineered to mimic human diabetes.

"Our results provide a large body of evidence demonstrating that the harmine drug class can make human beta cells proliferate at levels that may be relevant for diabetes treatment," said senior study author Andrew Stewart, MD, Director of the Diabetes, Obesity and Metabolism Institute at the Icahn School of Medicine. "While we still have a lot of work to do in improving the specificity and potency of the harmine and related compounds, we believe these results represent a key step toward more effective future treatment of diabetes."

Loss of insulin-producing beta cells has long been recognized as a cause of Type 1 diabetes, in which the immune system mistakenly attacks and destroys beta cells. In recent years, researchers have concluded that a deficiency of functioning beta cells also contributes importantly to Type 2 diabetes. Thus, developing drugs that can increase the numbers of healthy beta cells is a major priority in diabetes research.

Ref : http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3820.html

New drug shows promise in driving insulin-producing beta cells to multiply

New injectable polymer could strengthen blood clots

In the initial study with rats, 100 per cent of animals injected with PolySTAT survived a typically lethal injury to the femoral artery. Only 20 per cent of rats treated with a natural protein that helps blood clot survived.

“Most of the patients who die from bleeding die quickly,” said co-author Dr. Nathan White, an assistant professor of emergency medicine who teamed with UW bioengineers and chemical engineers to develop the macromolecule. “This is something you could potentially put in a syringe inside a backpack and give right away to reduce blood loss and keep people alive long enough to make it to medical care.”

According to a statement, the UW team was inspired by factor XIII, a natural protein found in the body that helps strengthen blood clots.

Normally after an injury, platelets in the blood begin to congregate at the wound and form an initial barrier. Then a network of specialised fibres called fibrin start weaving themselves throughout the clot to reinforce it.

New injectable polymer could strengthen blood clots

New cancer drug enters phase I clinical trials in humans

"Even though they have elevated levels of procaspase-3, cancer cells never turn the enzyme on. So they keep growing and become tumors," he said. "PAC-1 restores the activity of procaspase-3 and, because the enzyme is elevated in cancer cells, it targets cancer cells over non-cancerous cells."  

A new drug that prompts cancer cells to self-destruct while sparing healthy cells is now entering phase I clinical trials in humans. The drug, called PAC-1, first showed promise in the treatment of pet dogs with spontaneously occurring cancers, and is still in clinical trials in dogs with osteosarcoma.

The compound was discovered and is being developed based on the hypothesis that most cancers have elevated levels of an enzyme called procaspase-3," said University of Illinois chemistry professor Paul Hergenrother, who discovered the anti-cancer effects of PAC-1 more than a decade ago. "Procaspase-3 is an enzyme that, when turned on, kills cells."

Cancer cells, however, override this normal cell-recycling pathway, he said.

Early tests of the drug's effectiveness came when Hergenrother collaborated with U. of I. veterinary clinical sciences professor Timothy Fan, who tested PAC-1 in his canine cancer patients. These clinical trials helped the researchers find the best way to deliver the drug - it is now in pill form for both human and canine patients - and led to new insights into the drug's activity and potential, Fan said.

New cancer drug enters phase I clinical trials in humans