Active ingredient of pungent substances slows growth of breast cancer cells

Capsaicin, an active ingredient of pungent substances such as chilli or pepper, inhibits the growth of breast cancer cells. This was reported by a team headed by the Bochum-based scent researcher Prof Dr Dr Dr habil Hanns Hatt and Dr Lea Weber, following experiments in cultivated tumour cells. In the journal "Breast Cancer - Targets and Therapy", the researchers from Ruhr-Universität Bochum presented their findings together with colleagues from the Augusta clinics in Bochum, the hospital Herz-Jesu-Krankenhaus Dernbach and the Centre of Genomics in Cologne.

The experiments were carried out with the SUM149PT cell culture, a model system for a particularly aggressive type of breast cancer, i.e. the triple-negative type. Chemotherapy is currently the only available treatment for this type of cancer. 

Frequently occurring receptor

In the cultivated cells, the team detected a number of typical olfactory receptors. One receptor occurred very frequently; it is usually found in the fifth cranial nerve, i.e. the trigeminal nerve. It belongs to the so-called Transient Receptor Potential Channels and is named TRPV1. That receptor is activated by the spicy molecule capsaicin as well as by helional - a scent of fresh sea breeze.

 (helional)  Capsaicin

In collaboration with Dr Gabriele Bonatz from the Augusta clinics in Bochum (Brustzentrum), Hatt's team confirmed the existence of TRPV1 in tumour cells in nine different samples from patients suffering from breast cancer.

Cancer cells die

The researchers activated the TRPV1 receptor in the cell culture with capsaicin or helional, by adding the substances to the culture for a period of several hours or days. As a result, the cancer cells divided more slowly. Moreover, the treatment caused tumour cells to die in larger numbers. The surviving cells were no longer able to move as quickly as heretofore; this implies that their ability to form metastases in the body was impeded.

"If we could switch on the TRPV1 receptor with specific drugs, this might constitute a new treatment approach for this type of cancer," says Hanns Hatt. An intake via food or inhalation is insufficient for this purpose.

Effective in mice

Earlier studies had demonstrated that the chemical arvanil - with a chemical make-up similar to that of the spicy molecule capsaicin - was effective against brain tumours in mice; it reduces tumour growth in the animals. Due to its side effects, however, this substance is not approved for humans. In addition to capsaicin and helional, the endovanilloids, produced naturally in the body, also activate the TRPV1 receptor.

FDA approves first drug to treat children and adults with spinal muscular atrophy

The U.S. Food and Drug Administration today approved Spinraza (nusinersen), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. Spinraza is an injection administered into the fluid surrounding the spinal cord.

RNA, (2'-0-(2-METHOXYETHYI))(P-THIO)(M5U-C-A-C-M5U-M5U-M5U-C-A-M5UA- A-M5 U-G-C-M5U-G-G)

"There has been a long-standing need for a treatment for spinal muscular atrophy, the most common genetic cause of death in infants, and a disease that can affect people at any stage of life," said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research. "As shown by our suggestion to the sponsor to analyze the results of the study earlier than planned, the FDA is committed to assisting with the development and approval of safe and effective drugs for rare diseases and we worked hard to review this application quickly; we could not be more pleased to have the first approved treatment for this debilitating disease."

SMA is a hereditary disease that causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. There is wide variability in age of onset, symptoms and rate of progression. Spinraza is approved for use across the range of spinal muscular atrophy patients.

The FDA worked closely with the sponsor during development to help design and implement the analysis upon which this approval was based. The efficacy of Spinraza was demonstrated in a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose. Patients were randomized to receive an injection of Spinraza, into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick). Twice the number of patients received Spinraza compared to those who underwent the mock procedure. The trial assessed the percentage of patients with improvement in motor milestones, such as head control, sitting, ability to kick in supine position, rolling, crawling, standing and walking.

The FDA asked the sponsor to conduct an interim analysis as a way to evaluate the study results as early as possible; 82 of 121 patients were eligible for this analysis. Forty percent of patients treated with Spinraza achieved improvement in motor milestones as defined in the study, whereas none of the control patients did.

Additional open-label uncontrolled clinical studies were conducted in symptomatic patients who ranged in age from 30 days to 15 years at the time of the first dose, and in presymptomatic patients who ranged in age from 8 days to 42 days at the time of first dose. These studies lacked control groups and therefore were more difficult to interpret than the controlled study, but the findings appeared generally supportive of the clinical efficacy demonstrated in the controlled clinical trial in infantile-onset patients.

The most common side effects found in participants in the clinical trials on Spinraza were upper respiratory infection, lower respiratory infection and constipation. Warnings and precautions include low blood platelet count and toxicity to the kidneys (renal toxicity). Toxicity in the nervous system (neurotoxicity) was observed in animal studies.

The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a rare pediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive priority review of a subsequent marketing application for a different product. This is the eighth rare pediatric disease priority review voucher issued by the FDA since the program began.

Spinraza is marketed by Biogen of Cambridge, Massachusetts and was developed by Ionis Pharmaceuticals of Carlsbad, California.

Study shows three-drug combination delays recurrence and lengthens life for myeloma patients

In continuation of my update on lenalidomide, bortezomib and dexamethasone

The International Myeloma Foundation (IMF) today announced the publication in The Lancet of the results of a randomized, phase III trial, conducted by SWOG, a publicly funded international cancer clinical trials network, and led by IMF chairman of the board Brian G.M. Durie, MD. This important trial compared the effectiveness of two drug regimens in patients undergoing their first round of treatment for multiple myeloma. The trial shows that a three-drug combination - known as VRd - delays recurrence and lengthens life for myeloma patients, indicating a possible new standard of care.

One regimen used in the study was lenalidomide with dexamethasone, a standard first-line treatment for myeloma patients. The other drug regimen also included bortezomib, a second-line drug typically given to myeloma patients whose cancer progresses after initial therapy. SWOG researchers found that the addition of bortezomib earlier made a difference for myeloma patients, giving them about another year of remission and another year of life compared to the standard two-drug regimen.

"Our results are clear. Using bortezomib in combination with lenalidomide and dexamethasone in front-line treatment - hitting the disease early and hard - makes a meaningful difference for myeloma patients," said study principal investigator Dr. Durie, a physician at Cedars-Sinai Outpatient Cancer Center in Los Angeles. "Our results represent a potential new standard of care."

"This is a landmark study that lends clarity to frontline therapy of myeloma," said Dr. S. Vincent Rajkumar of Mayo Clinic and a co-author of the study. "Newer alternatives to VRd may be more expensive, cumbersome, or toxic. These regimens will therefore need to show superiority over VRd in randomized trials."

Also worth noting, Dr. Rajkumar said, is that the VRd regimen will become even more cost effective as the drugs in this combination become generic over time.

 bortezomib     lenalidomide

  dexamethasone

Patients in the trial receiving bortezomib, along with lenalidomide and dexamethasone, in their first six months of treatment had a median remission time of 43 months compared to a median remission of 30 months for patients who received lenalidomide and dexamethasone alone. Researchers also found that patients who received bortezomib lived a median of 75 months, or about six years, after their initial treatment. Patients who received the standard two-drug treatment lived a median of 64 months, or about five years, after initial treatment.

Celebrating its 60th year, SWOG has conducted more than 1,300 cancer trials that have led to FDA approval of 14 new drugs and led to more than 100 changes to cancer standards of care. SWOG is part of the NCI's National Clinical Trials Network (NCTN), the nation's largest and oldest publicly funded cancer research network. SWOG members and other members in the NCTN enrolled 471 eligible and consented adult patients in the study, known as S0777, between February 2008 and February 2012, at 139 institutions across the US.

Patients ranged in age from 28 to 87, had active myeloma, and had not had a stem-cell transplant or any prior treatment for their disease. Patients were randomized into two groups. One group received the standard two-drug treatment for six cycles over six months. That includes lenalidomide, an immunomodulating therapy marketed as Revlimid by Celegene Corporation. The other group received a three-drug combination that included bortezomib, a proteasome inhibitor marketed as Velcade by Millennium Pharmaceuticals. These patients received the triple combination therapy for eight cycles over six months.

Ancient Chinese medicine for malaria could potentially aid in treatment of tuberculosis

In continuation of my update on Artemisinin

A centuries-old herbal medicine, discovered by Chinese scientists and used to effectively treat malaria, has been found to potentially aid in the treatment of tuberculosis and may slow the evolution of drug resistance.

In a promising study led by Robert Abramovitch, a Michigan State University microbiologist and TB expert, the ancient remedy artemisinin stopped the ability of TB-causing bacteria, known as Mycobacterium tuberculosis, to become dormant. This stage of the disease often makes the use of antibiotics ineffective.

The study is published in the journal Nature Chemical Biology.

"When TB bacteria are dormant, they become highly tolerant to antibiotics," Abramovitch said, an assistant professor in the College of Veterinary Medicine. "Blocking dormancy makes the TB bacteria more sensitive to these drugs and could shorten treatment times."

One-third of the world's population is infected with TB and the disease killed 1.8 million people in 2015, according to the Centers for Disease Control and Prevention.

Mycobacterium tuberculosis, or Mtb, needs oxygen to thrive in the body. The immune system starves this bacterium of oxygen to control the infection. Abramovitch and his team found that artemisinin attacks a molecule called heme, which is found in the Mtb oxygen sensor. By disrupting this sensor and essentially turning it off, the artemisinin stopped the disease's ability to sense how much oxygen it was getting.

"When the Mtb is starved of oxygen, it goes into a dormant state, which protects it from the stress of low-oxygen environments," Abramovitch said. "If Mtb can't sense low oxygen, then it can't become dormant and will die."

Abramovitch indicated that dormant TB can remain inactive for decades in the body. But if the immune system weakens at some point, it can wake back up and spread. Whether it wakes up or stays 'asleep' though, he said TB can take up to six months to treat and is one of the main reasons the disease is so difficult to control.

"Patients often don't stick to the treatment regimen because of the length of time it takes to cure the disease," he said. "Incomplete therapy plays an important role in the evolution and spread of multi-drug resistant TB strains."

He said the research could be key to shortening the course of therapy because it can clear out the dormant, hard-to-kill bacteria. This could lead to improving patient outcomes and slowing the evolution of drug-resistant TB.

After screening 540,000 different compounds, Abramovitch also found five other possible chemical inhibitors that target the Mtb oxygen sensor in various ways and could be effective in treatment as well.

"Two billion people worldwide are infected with Mtb," Abramovitch said. "TB is a global problem that requires new tools to slow its spread and overcome drug resistance. This new method of targeting dormant bacteria is exciting because it shows us a new way to kill it."

Ref : http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.2259.html

Combination therapy holds great promise to clear precancerous skin lesions

A combination of two FDA-approved drugs - a topical chemotherapy and an immune-system-activating compound - was able to rapidly clear actinic keratosis lesions from patients participating in a clinical trial. Standard treatment for this common skin condition, which can lead to the development of squamous cell carcinoma, takes up to a month and can elicit several unpleasant side effects. The report from Massachusetts General Hospital (MGH) investigators has been published online and will appear in the January issue of the Journal of Clinical Investigation.

fluorouracil (5-FU)      Calcipotriol 

"The high tumor clearance rate, short treatment duration and favorable side-effect profile highlight the remarkable effectiveness of this approach, compared with currently available treatments," says Shadmehr Demehri, MD, PhD, of the MGH Center for Cancer Immunology and the Cutaneous Biology Research Center, senior author of the report. "But more importantly, the unprecedented ability of this combination therapy to directly activate the adaptive immune system against skin cancer precursors holds great promise to establish an immune memory within treated skin capable of preventing future cancer development."

Caused by long-term exposure to sunlight, actinic keratosis is characterized by rough, scaly patches on the skin. Very common in older individuals with fair complexions, actinic keratosis is the third most common reason for consulting a dermatologist in the U.S. If untreated, actinic keratosis lesions can progress to squamous cell carcinoma, the second most common form of skin cancer. Current topical treatments for actinic keratosis cause side effects - such as pain, crusting and susceptibility to infection - and need to be applied for up to four weeks.

Calcipotriol, an FDA-approved treatment for psoriasis, induces expression in the skin of an immune system activator called TSLP. While overexpression of TSLP is associated with the allergic inflammation seen in asthma and eczema, it has been noted that individuals with these allergic conditions appear to be less susceptible to skin cancer. Other studies have supported the ability of TSLP to suppress skin cancer development, which led Demehri's team to investigate its potential against actinic keratosis.

Experiments with a mouse model of skin cancer development showed that twice-weekly application of calcipotriol both induced TSLP expression and delayed tumor development. When tumors did develop, they were fewer and smaller than in mice not treated with calcipotriol. An experiment in which calcipotriol was applied to the ears of mice while skin cancer was induced to develop on the backs of the animals resulted in elevated blood levels of TSLP and the suppression of tumor development, implying that brief TSLP-inducing treatment could lead to a lasting systemic antitumor immune response.

Since clinically available concentrations of calcipotriol have had limited effectiveness against actinic keratosis and produced no evidence of immune activation, the MGH team hypothesized that combining the available 0.005 percent calcipotriol ointment with 5 percent fluorouracil (5-FU) cream, a standard treatment for actinic keratosis, might amplify the immune-activating potential of calcipotriol. In a randomized, double-blinded clinical trial, 65 participants with multiple actinic keratosis lesions were treated with a combination of calcipotriol and 5-FU, while 67 received a control preparation of 5-FU mixed with petroleum jelly.

The preparations were applied twice a day to the entire affected sites of participants - face, scalp and arms - and because treatment with 5-FU alone requires seven or more days to have any effect against actinic keratosis, participants were treated for four days only. A day after treatment ended, the treated skin of those receiving calcipotriol plus 5-FU, including areas that did not contain clinically visible lesions, showed clear signs of inflammation, indicating immune system activation. Areas of inflammation were found to have a significant influx of lymphocytes - primarily T cells - at the sites of lesions.

Eight weeks after treatment, participants receiving the combined treatment had a significantly greater reduction in the number and size of actinic keratosis lesions - for example, an average of 88 percent reduction in facial lesions versus 26 percent reduction for those receiving the control preparation. Even participants with large "hypertrophic" lesions, which rarely respond to conventional topical treatments, saw significant reduction in the size of their lesion with combined treatment. Among participants receiving combined treatment who had previously been treated for actinic keratosis, 82 percent found the treatment to be more effective.

"As both medications used in our trial are already available clinically, they could readily be used by dermatologists to treat actinic keratosis, particular in patients for whom conventional treatments have failed," says Demehri, who is an assistant professor of Dermatology at Harvard Medical School. "The ultimate goal of our research is to use patients' own immune systems to prevent cancer, so we are very excited to determine whether our success in activating a T-cell-dominant immune response against a skin cancer precursor will protect the treated skin against future skin cancer development. We're planning to follow the participants in this trial over the coming years to address that important question."

FDA awards accelerated approval to new ovarian cancer drug

In continuation of my update on Rubraca                                         

The U.S. Food and Drug Administration today granted accelerated approval to Rubraca (rucaparib) to treat women with a certain type of ovarian cancer. Rubraca is approved for women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a specific gene mutation (deleterious BRCA) as identified by an FDA-approved companion diagnostic test.

"Today's approval is another example of the trend we are seeing in developing targeted agents to treat cancers caused by specific mutations in a patient's genes," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research and acting director of the FDA's Oncology Center of Excellence. "Women with these gene abnormalities who have tried at least two chemotherapy treatments for their ovarian cancer now have an additional treatment option."

The National Cancer Institute estimates that 22,280 women will be diagnosed with ovarian cancer in 2016 and an estimated 14,240 will die of this disease. Approximately 15 to 20 percent of patients with ovarian cancer have a BRCA gene mutation.

BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including ovarian cancers. Rubraca is a poly ADP-ribose polymerase (PARP) inhibitor that blocks an enzyme involved in repairing damaged DNA. By blocking this enzyme, DNA inside the cancerous cells with damaged BRCA genes may be less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.

Today, the FDA also approved the FoundationFocus CDxBRCA companion diagnostic for use with Rubraca, which is the first next-generation-sequencing (NGS)-based companion diagnostic approved by the agency. The NGS test detects the presence of deleterious BRCA gene mutations in the tumor tissue of ovarian cancer patients. If one or more of the mutations are detected, the patient may be eligible for treatment with Rubraca.

The safety and efficacy of Rubraca were studied in two, single-arm clinical trials involving 106 participants with BRCA-mutated advanced ovarian cancer who had been treated with two or more chemotherapy regimens. BRCA gene mutations were confirmed in 96 percent of tested trial participants with available tumor tissue using the FoundationFocus CDxBRCA companion diagnostic. The trials measured the percentage of participants who experienced complete or partial shrinkage of their tumors (overall response rate). Fifty-four percent of the participants who received Rubraca in the trials experienced complete or partial shrinkage of their tumors lasting a median of 9.2 months.

Common side effects of Rubraca include nausea, fatigue, vomiting, low levels of red blood cells (anemia), abdominal pain, unusual taste sensation (dysgeusia), constipation, decreased appetite, diarrhea, low levels of blood platelets (thrombocytopenia) and trouble breathing (dyspnea). Rubraca is associated with serious risks, such as bone marrow problems (myelodysplastic syndrome), a type of cancer of the blood called acute myeloid leukemia and fetal harm.

The agency approved Rubraca under its accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease or condition based on clinical data showing the drug has an effect on a surrogate (substitute) endpoint that is reasonably likely to predict clinical benefit. The sponsor is continuing to study this drug in patients with advanced ovarian cancer who have BRCA gene mutations and in patients with other types of ovarian cancer. The FDA also granted the Rubraca application breakthrough therapy designation and priority review status. Rubraca also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs intended to treat rare diseases.

Rubraca is marketed by Clovis Oncology, Inc. based in Boulder, Colorado. The FoundationFocus CDxBRCA companion diagnostic is marketed by Foundation Medicine, Inc. of Cambridge, Massachusetts.

Antibiotic gel shows promise in preventing onset of Lyme borreliosis following tick bite

In continuation of my update on azithromycin

An antibiotic gel based on azithromycin, an antibiotic with antibacterial properties, helps to prevent the onset of Lyme borreliosis following a tick bite. That is the finding of a multi-centre international study, in which MedUni Vienna's Department of Clinical Pharmacology played an important part. The study has now been published in the world-leading journal "The Lancet Infectious Diseases" (impact factor 21,372).

 

In addition to the Medical University of Vienna, Austrian partners involved in the Phase II/III study, which now only has to be followed by a verification study in order to be potentially put into clinical use, were the Medical University of Graz (Department of Dermatology), the Medical University of Innsbruck (Department of Dermatology and Venerology), the Elisabethinen Hospital in Linz and the Center for Travel Medicine in St. Pölten. Other study partners come from Germany (Berlin, Würzburg) and Switzerland (Zürich). The antibiotic gel was developed by the Swiss company Ixodes AG.

A total of 1,000 patients with fresh tick bites were treated with the antibiotic gel within 72 hours of being bitten. Says Jilma: "None of the test subjects went on to develop Lyme borreliosis." Conversely, in the control group that received a placebo, there were seven cases of borreliosis.

The advantage of the gel is that it has no side-effects and, according to the promising results, can therefore also be used for children. Moreover, treatment is very simple: the gel has to be applied every 12 hours over a period of three days. "This kills off the borrelia," explains Jilma.

In Austria, there are around 24,000 cases of Lyme disease every year, while in Western Europe the annual figure is more than 200,000 new cases of the world's most common tick-borne infectious disease. If the infection goes untreated, it can attack a person's joints, heart and nervous system and lead to serious complications. Up to 5% of all tick bites result in Lyme disease: around 20% of ticks are infected.

Ref : http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(16)30529-1.pdf

UT Southwestern researchers find new way to combat multidrug-resistant bacteria in burn injuries

A new way to fight multidrug-resistant bacteria by blinding them rather than killing them proved highly effective in a model of burn injuries, UT Southwestern Medical Center research shows.

(A) Carboxy-functionalized polystyrene micro-beads of 1 μm diameter are activated using EDC/NHS, and covalently coupled to GST (control beads) or GST-MAM7 (inhibitor beads) using Sulfo-SMPB. This results in directional coupling of recombinant proteins to the bead surface via the cysteine-containing GST domain. (B) Schematic of GST-MAM7 bead mimicry of bacterial MAM7 presentation.

"In the United States, there are more than 1 million burn injuries and 100,000 hospitalizations annually. Up to 75 percent of the mortality in burn patients is associated with infections, which are particularly common in patients who suffer extensive burns - those that cover 40 percent or more of the body," said Dr. Steven Wolf, Section Chief for Burns and Professor of Surgery at UT Southwestern Medical Center.

Dr. Wolf, one of three senior authors of the study published today in Scientific Reports, is also a former Director of the Burn Center at the U.S. Army Institute of Surgical Research in San Antonio, Texas.

"Rather than killing the bacteria, we blinded them so they could not find the places where they normally stick to the host (body's) cells. If bacteria cannot bind, they cannot grow," said Dr. Wolf, who is also Surgery's Vice Chair for Research and holder of the Golden Charity Guild Charles R. Baxter, M.D. Chair.

The study done in rats targeted one of the most lethal pathogens: multidrug-resistant Pseudomonas aeruginosa, which is found in approximately 33 percent of all burn cases and in 59 percent of extensive burns. The researchers showed that topical application of an engineered adhesion inhibitor molecule - Multivalent Adhesion Molecule 7, or MAM7 - substantially decreased the bacterial levels in wounds in the first 24 hours after administration and prevented the spread of the infection to adjacent tissue for three more days. In addition, the experimental molecule aided wound healing and maintained normal inflammatory responses to the burn, the researchers report.

"Antibiotic-resistant bacteria are an increasingly prevalent problem in the clinic and hospital, so new ways to prevent and treat infections are direly needed. Antibiotics work by killing bacteria, which places microbes under extreme pressure to develop antibiotic resistance," said co-senior author Dr. Kim Orth, Professor of Molecular Biology and Biochemistry at UT Southwestern.

"Our approach doesn't target bacterial survival; rather it targets the microbes' ability to damage the host - its virulence. There is no reason for the bacteria to become resistant to this approach. Being unable to bind to wounded tissue is an inconvenience, and the bacteria move on," Dr. Orth said.

She compared the situation to the search for parking at a shopping mall.

"If all the parking spaces are filled, then the bacteria have no place to park," said Dr. Orth, a Howard Hughes Medical Institute Investigator who also holds the Earl A. Forsythe Chair in Biomedical Science and is a W.W. Caruth, Jr. Scholar in Biomedical Research at UT Southwestern.

The experimental molecule was developed in the Orth laboratory and grew out of the postdoctoral research project of the study's third senior author, Dr. Anne-Marie Krachler, now with the McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth).

When working at UT Southwestern, Dr. Krachler studied a group of adhesion molecules called adhesins that are created by bacteria to bind, or stick to cells in an early and crucial step in causing infection. Although most adhesins are specific to various pathogens, members of the adhesion family she identified - Multivalent Adhesion Molecules, including MAM7 - are used by most gram-negative bacteria, including the type used in this burn study.

In one UTSW experiment, Dr. Krachler detached MAM7 from the bacteria that produce it and showed that the lack of MAM7 made the bacteria much less able to cause infection. In 2013, Dr. Orth gave a UT Southwestern President's Lecture describing the molecular activity of MAM7. Dr. Wolf was in attendance, and approached Dr. Orth about a collaboration to test the efficacy of MAM7 using a fluorescent strain of antibiotic-resistant bacteria in a live animal model.

That led to the multiyear effort to develop the recombinant MAM7 inhibitor attached to a scaffold made of bacteria-sized polymer microbeads that was used in this study. UT Southwestern has an international patent application filed on the molecule.

"We attached lots of copies of MAM7 to the microbeads. In this study, we found that topically applied MAM7-coupled microbeads reach the cells' binding sites first and - for at least four days in this experiment - stay there, without hindering wound healing. The MAM7 adhesion inhibitors remain on the wounds and prevent the bacteria from binding to the tissue," Dr. Orth said.

In addition to burns, Dr. Krachler said, this strategy could work against diabetic ulcers and surgical wounds that can become infected.

"What's exciting about MAM7 is that the agent is so broad-spectrum. Most bacteria have their own specific type of adhesion molecules. For instance Vibrio uses one kind and Salmonella uses a different one and multidrug-resistant bacteria another, but almost all of them want to park in the same place.

"Antibiotics are amazing drugs, and they have saved countless lives since their discovery more than 80 years ago. But there is a challenge - the challenge of antibiotic resistance that has made many antibiotics ineffective. A material that targets virulence instead of killing bacteria could be a way to treat infections that are resistant to antibiotics," she said. "This is a trial in rats. A future goal is to use this strategy in patients."

Following the success of this proof-of-concept study, additional steps include testing whether the anti-adhesion strategy might also block infection of bacteria that can cause lethal infections during surgery, Dr. Orth said.

Ref : http://www.nature.com/articles/srep39341

New Application of Existing Drug Offers Personalized Therapy for Lung Cancer

A subset of lung tumours is exquisitely sensitive to a class of recently approved anti-cancer drugs. Researchers at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna and the Ludwig Institute for Cancer Research in Oxford published this finding in the journal Nature Communications. It opens the way for new clinical trials in a type of cancer considered to be "undruggable" and may lead to a therapy for up to 10% of lung cancer patients.

(Vienna, 6th of December 2016) Lung cancer remains the leading cause of cancer-related deaths worldwide. In contrast to other tumour types, lung tumours present a high number of genomic alterations - this is a consequence of exposure to carcinogenic substances found in tobacco smoke, which is the main cause of lung cancer. About 10% of lung tumours carry mutations in a gene called ATM. However, there are no drugs available in the clinic to treat ATM mutant lung cancer.

With cutting edge high-throughput drug screens that analyse how the genetic makeup of the patient affects their response to drugs, the team of Sebastian Nijman, CeMM Adjunct PI and Group Leader at the Ludwig Institute for Cancer Research in Oxford made a surprising discovery: Cancer cells with ATM mutations are sensitive for drugs that inhibit an enzyme called MEK. The study was published in Nature Communications (DOI: 10.1038/NCOMMS13701)

MEK is part of a biochemical pathway which is responsible for supporting proliferation and survival of the cell, while ATM plays a central role during the DNA damage response. In ATM deficient lung cancer cells, Nijman's team found that MEK inhibition results in cells being unable to keep proliferating and leads to apoptosis. An unexpected finding, as MEK inhibitors have so far been approved for the treatment of a type of skin cancer but not for lung cancer.

"Normally lung cancer cells are resistant to MEK inhibition as they activate compensatory signals," Ferran Fece, one of the two first authors on the study and former PhD student at CeMM, explains. "In contrast, ATM mutant cells fail to do this and subsequently cannot cope with the blocking of MEK and die. We call this type of unexpected drug sensitivity synthetic lethality".

  Trametinib

Michal Smida, the other shared first author on the article and former PostDoc at CeMM, adds: "We knew that cancer mutations can lead to extreme sensitivity to some drugs. But finding these cancer Achilles' heels is very difficult as they are difficult to predict and extremely rare. We screened a large number of gene and drug combinations and got lucky."

The study constitutes a substantial contribution for the development of a future precision medicine: ATM mutations could be used as a potential biomarker to stratify lung cancer patients to receive a MEK inhibitor. ATM is found to be mutated in 8-10% of lung adenocarcinomas - given that this type of tumour is among the most prevalent for both men and women worldwide, a significant number of patients could benefit from a MEK inhibitor based treatment. 


More : http://www.nature.com/articles/ncomms13701

New Application of Existing Drug Offers Personalized Therapy for Lung Cancer

Moderate coffee consumption may offer protection against age-related cognitive decline

A new report from the Institute for Scientific Information on Coffee (ISIC), a not-for-profit organisation devoted to the study and disclosure of science related to coffee and health, highlights the potential role of coffee consumption in reducing the risk of cognitive decline. The report concludes that a moderate intake of coffee (3-5 cups per day) may provide protection against age-related cognitive decline and other neurodegenerative diseases such as Alzheimer's and Parkinson's.

The report provides a summary of the research presented at ISIC's symposium, titled 'Nutrition, Coffee and Age-Related Cognitive Decline', held during the European Union Geriatric Medicine Society's 2016 Congress in Lisbon, Portugal. The findings are particularly relevant given Europe's ageing population: the number of people aged 60 years or over is projected to rise to 217.2 million by 2030, therefore understanding and communicating diet and lifestyle factors that may limit age-related cognitive decline will help to improve the quality of life for this growing demographic.

The symposium speakers whose insights and research contributed to ISIC's report were:

• Professor Lisette de Groot, Professor of Nutrition and Ageing, Division of Human Nutrition at Wageningen University (The Netherlands)
• Professor Rodrigo A. Cunha, Professor at the Faculty of Medicine of the University of Coimbra and Principal Investigator at the Centre for Neuroscience and Cell Biology of the University of Coimbra (CNC) (Portugal)
• Dr Elisabet Rothenberg, Associate Professor of Nutrition at Kristianstad University (Sweden)

Key highlights about coffee from the report include:

• Research published in 2016 suggests that moderate coffee consumption can reduce the risk of developing Alzheimer's by up to 27%. Research has suggested that it is regular, long-term coffee drinking that is key to helping to reduce the risk of Alzheimer's Disease.
• The association between coffee consumption and cognitive decline is illustrated by a 'U-shaped' pattern in recent meta-analyses, with the greatest protection seen at an intake of approximately 3-5 cups of coffee per day.
• Although the precise mechanisms of action behind the suggested association between coffee and age-related cognitive decline are unknown, caffeine is likely to be involved. There are many other compounds in coffee, such as antioxidants and anti-inflammatory agents, which may also play a role. Caffeic acid, for example, is a polyphenol (antioxidant) found in coffee, and research suggests that these may be associated with improved cognitive function.

Professor Rodrigo A. Cunha, Professor at the Faculty of Medicine of the University of Coimbra and Principal Investigator at the Centre for Neuroscience and Cell Biology of the University of Coimbra (CNC), Portugal, commented:

"Healthcare professionals have an important part to play in providing patients with accurate research-based information, to help them to follow a healthy diet and lifestyle, and in turn, reduce their risk of age-related cognitive decline. Moderate coffee consumption could play a significant role in reducing cognitive decline which would impact health outcomes and healthcare spending across Europe."

In its Scientific Opinion on the safety of caffeine, the European Food Safety Authority (EFSA) concluded that intakes of up to 400mg of caffeine (the equivalent of up to 5 cups of coffee per day), from all sources, do not raise any concerns for healthy adults. One cup of coffee provides approximately 75-100mg caffeine.

 

Australian researchers have discovered remarkable evolutionary changes to insulin regulation in two of the nation's most iconic native animal species - the platypus and the echidna - which could pave the way for new treatments for type 2 diabetes in humans.

The findings, now published in the Nature journal Scientific Reports, reveal that the same hormone produced in the gut of the platypus to regulate blood glucose is also surprisingly produced in their venom.

The research is led by Professor Frank Grutzner at the University of Adelaide and Associate Professor Briony Forbes at Flinders University.

The hormone, known as glucagon-like peptide-1 (GLP-1), is normally secreted in the gut of both humans and animals, stimulating the release of insulin to lower blood glucose.

But GLP-1 typically degrades within minutes.

In people with type 2 diabetes, the short stimulus triggered by GLP-1 isn't sufficient to maintain a proper blood sugar balance. As a result, medication that includes a longer lasting form of the hormone is needed to help provide an extended release of insulin.

"Our research team has discovered that monotremes - our iconic platypus and echidna - have evolved changes in the hormone GLP-1 that make it resistant to the rapid degradation normally seen in humans," says co-lead author Professor Frank Grutzner, from the University of Adelaide's School of Biological Sciences and the Robinson Research Institute.

"We've found that GLP-1 is degraded in monotremes by a completely different mechanism. Further analysis of the genetics of monotremes reveals that there seems to be a kind of molecular warfare going on between the function of GLP-1, which is produced in the gut but surprisingly also in their venom," he says.

The platypus produces a powerful venom during breeding season, which is used in competition among males for females.

"We've discovered conflicting functions of GLP-1 in the platypus: in the gut as a regulator of blood glucose, and in venom to fend off other platypus males during breeding season. This tug of war between the different functions has resulted in dramatic changes in the GLP-1 system," says co-lead author Associate Professor Briony Forbes, from Flinders University's School of Medicine.

"The function in venom has most likely triggered the evolution of a stable form of GLP-1 in monotremes. Excitingly, stable GLP-1 molecules are highly desirable as potential type 2 diabetes treatments," she says.

Professor Grutzner says: "This is an amazing example of how millions of years of evolution can shape molecules and optimise their function.

"These findings have the potential to inform diabetes treatment, one of our greatest health challenges, although exactly how we can convert this finding into a treatment will need to be the subject of future research."

GLP-1 has also been discovered in the venom of echidnas. But while the platypus has spurs on its hind limbs for delivering a large amount of venom to its opponent, there is no such spur on echidnas.

"The lack of a spur on echidnas remains an evolutionary mystery, but the fact that both platypus and echidnas have evolved the same long-lasting form of the hormone GLP-1 is in itself a very exciting finding," Professor Grutzner says.

Platypus venom shows potential for new diabetes treatments

New treatment prevents chemotherapy-induced hearing loss in children with cancer

Investigators from Children's Hospital Los Angeles and 37 other Children's Oncology Group hospitals in the U.S. and Canada have determined that sodium thiosulfate prevents cisplatin-induced hearing loss in children and adolescents with cancer. Results of this randomized, controlled, phase 3 study, called ACCL0431, have been published in the early online edition of Lancet Oncology.

"This federally-funded, cooperative group study is the first to show that cisplatin-induced hearing loss can be reduced by about half in children and adolescents being treated for cancer," said David R. Freyer, DO, MS, director of the Survivorship & Supportive Care Program in the Children's Center for Cancer and Blood Diseases at Children's Hospital Los Angeles, who was lead author and chair of the study. "It is an important step toward developing a safe and effective strategy that will greatly improve quality of life for cancer survivors." Freyer is also professor of Clinical Pediatrics and Medicine at the Keck School of Medicine of USC.

Cisplatin is a chemotherapy medication widely used to treat a variety of cancers in both adults and children. Although effective, cisplatin frequently causes permanent hearing loss and tinnitus (ringing in the ears), resulting in functional disability for patients who receive it. For young children in particular, hearing loss is especially serious because it results in impaired language development, learning and social interactions. Preventing ototoxicity, while preserving chemotherapeutic efficacy, has been a long-standing goal of physicians, scientists, parents and survivors. Historically, there have been no proven treatments for preventing cisplatin-induced hearing loss tested under the rigorous conditions of ACCL0431. Without otoprotection, the only way to prevent hearing loss is to delete or decrease cisplatin doses, which could render the cancer treatment less effective.

In ACCL0431, 125 eligible participants between the ages of 1 to 18 years with newly-diagnosed cancer were enrolled over a 4 year period. The cancer diagnoses were hepatoblastoma, germ cell tumor, medulloblastoma, neuroblastoma, osteosarcoma, or other cancer types treated with cisplatin. Study participants were randomized to receive sodium thiosulfate or observation (control) during their chemotherapy. Their hearing was assessed at baseline, following completion of the chemotherapy regimen and 1 year later.

The investigators reported a significant reduction in the incidence of hearing loss in participants who were treated with cisplatin and sodium thiosulfate (29%) compared to those who received cisplatin alone (56%). The greatest benefit was seen in children younger than 5 years of age, who are most susceptible to, and also most affected by, cisplatin-induced hearing loss.

Other effects of sodium thiosulfate were carefully monitored in the study. Overall, sodium thiosulfate was tolerated well without any serious adverse events. Survival from the cancer was not affected by sodium thiosulfate among participants who had localized tumors. However, survival appeared to be lower among those with metastatic disease who received sodium thiosulfate. Additional research is needed to determine what role sodium thiosulfate should have in preventing hearing loss in specific subsets of patients being treated with cisplatin.