Researchers from LSTM’s Research Centre for Drugs and Diagnostics (RCDD) have found a way of significantly reducing the treatment required for lymphatic filariasis and onchocerciasis from several weeks to seven days. By targeting Wolbachia, a bacterial symbiont that the filarial parasites need to live, the team has discovered a drug synergy that enables effective treatment over a shorter time.
Lymphatic filariasis (LF), which can cause elephantiasis or hydrocele, swelling of the limbs or scrotum and onchocerciasis, also known as river blindness, affect millions of people in some of the world’s poorest communities. Both are caused by filarial parasites for which the bacterial symbiont Wolbachia is essential for development. Filarial Neglected Tropical Diseases are prioritised for elimination, in line with fulfilment of the 2030 United Nations Sustainable Development Goals. A consensus of expert opinion, including the WHO, and major donors, USAID and UK DFID, considers that successful implementation of a macrofilaricidal (curative) or permanent sterilising drug would greatly accelerate the end game elimination of lymphatic filariasis and onchocerciasis. Traditional treatment for these conditions require repetitive, long-term mass drug administrations, and although targeting the symbiont with doxycycline has proved clinically effective, it is programmatically challenging due to the long treatment time and exclusion of pregnant women and children.
In a new paper researchers provide proof-of-concept of a radical improvement to the targeting of Wolbachia via a drug synergy between the anthelmintic drug albendazole and antibiotics. LSTM’s Professor Mark Taylor is senior author on the paper. He said: “As part of the A·WOL programme, we have screened all registered drugs for anti-Wolbachia activity, which has allowed us to look at repurposing existing and registered drugs against these debilitating conditions. The combination of an antibiotic and the anti-worm drug albendazole provided the greatest surprise when they acted synergistically to reduce the treatment time from weeks to days, opening up the opportunity to scale-up this approach at the community level.”
The team believe that their work is of immediate public health importance because the drugs that have been used, rifampicin and albendazole, are already registered. “These drugs can be tested in infected people as soon as possible,” continued Professor Taylor.
The first author on the paper, LSTM’s Dr Joe Turner, added, “the discovery of drug synergy between a common anthelmintic and different classes of antibiotics is also exciting because even more potent synergism may be evident when we combine with our next generation, ‘designer’ anti-Wolbachia drugs currently in development as part of the A·WOL programme. Potentially, we may be in a position to reduce curative treatment time frames down to five days or less for filariasis, with better acceptability and reduced costs for patients and local health systems”
Liverpool School of Tropical Medicine
www.lstmed.ac.uk/news-events/news/new-combination-therapy-of-registered-re-purposed-drugs-dramatically-shortens-anti

Clinicians today have an arsenal of more than 200 drugs at their disposal for treating a range of cancers — 68 drugs were approved between 2011 and 2016 alone. But many chemotherapeutic agents pose stubborn challenges: they cause serious side effects because they kill healthy cells in addition to cancer cells; some forms of cancer develop resistance to drugs; and many such chemotherapies, being poorly water-soluble, demonstrate low bio-availability resulting in sub-optimal drug delivery to cancer cells.
A potential solution lies in the synergistic combination of a chemotherapeutic drug with engineered genetic material designed to neutralize the malevolent genes conferring resistance to that drug, among other functions.
While there are numerous examples of synthetic dual gene and drug delivery vehicles, new hybrid materials developed in the lab at the NYU Tandon School of Engineering use easily modifiable proteins to deliver a chemical one-two punch: they combine a lipid “container” for transfection — the transportation of cargo past a cell membrane — and an easy-to-make protein capsule that can bind both small chemotherapeutic molecules and nucleic acids.
Developed by a team led by NYU Tandon Associate Professor of Chemical and Biomolecular Engineering Jin Kim Montclare — who also serves as an Affiliate Professor of Chemistry at NYU’s College of Arts and Sciences, and an Affiliate Professor of Biomaterials at NYU College of Dentistry, as well as being affiliated with SUNY Downstate as a Professor of Biochemistry — the hybrid lipid-protein material, called a lipoproteoplex, comprises both a coiled supercharged protein macromolecule and a commercially available transfection agent called Lipofectamine 2000.
Lipoproteoplex allows researchers to swap out a supercharged protein or lipid component and any number of siRNA to address a specific cell line and type of drug.
Because the researchers engineered the protein macromolecule with extensive positive charges on the surface and a hydrophobic core, it can be easily festooned with negatively charged short interfering RNA (siRNA) — a powerful tool for suppressing genes that invoke drug resistance and propagate disease states —while also serving as an efficient, and toxicity reducing, carryall for the hydrophobic chemotherapeutic agent doxorubicin.
In research published, the team details how the lipoproteoplex exposed to samples of the MCF-7 breast cancer cell line delivered more doxorubicin to target cells than did Lipofectamine 2000 alone, resulting in a substantial decrease in MCF-7 cell viability. They also demonstrated that the hybrid macromolecule was highly successful at siRNA transfection, silencing the gene by 60 percent.
Montclare said a key benefit of the new lipoproteoplex is ease of modification, an asset to researchers studying cells whose genetically invoked behaviour changes over time and differs by cell line and patient. Rather like a system of mix-and-match components, the lipoproteoplex allows researchers to swap out a supercharged protein or lipid component and any number of siRNA to address a specific cell line and type of drug.
“Unlike other pursuits at producing dual gene and drug delivery systems, this approach doesn’t require tedious chemical synthesis procedures; rather we can biosynthesize any variant of the supercharged protein,” she said. “This allows for substituting different siRNA molecules and chemotherapeutic drugs to suit lab needs.”

New York University Tandon School of Engineering
engineering.nyu.edu/press-releases/2017/08/09/researchers-nyu-tandon-create-new-biomaterial-delivers-drug-gene-silencer

Imagine if doctors could determine, many years in advance, who is likely to develop dementia. Such prognostic capabilities would give patients and their families time to plan and manage treatment and care. Thanks to artificial intelligence research conducted at McGill University, this kind of predictive power could soon be available to clinicians everywhere.
Scientists from the Douglas Mental Health University Institute’s Translational Neuroimaging Laboratory at McGill used artificial intelligence techniques and big data to develop an algorithm capable of recognizing the signatures of dementia two years before its onset, using a single amyloid PET scan of the brain of patients at risk of developing Alzheimer’s disease.
Dr. Pedro Rosa-Neto, co-lead author of the study and Associate Professor in McGill’s departments of Neurology & Neurosurgery and Psychiatry, expects that this technology will change the way physicians manage patients and greatly accelerate treatment research into Alzheimer’s disease.
“By using this tool, clinical trials could focus only on individuals with a higher likelihood of progressing to dementia within the time frame of the study. This will greatly reduce the cost and the time necessary to conduct these studies,” adds Dr. Serge Gauthier, co-lead author and Professor of Neurology & Neurosurgery and Psychiatry at McGill.
Scientists have long known that a protein known as amyloid accumulates in the brain of patients with mild cognitive impairment (MCI), a condition that often leads to dementia. Though the accumulation of amyloid begins decades before the symptoms of dementia occur, this protein couldn’t be used reliably as a predictive biomarker because not all MCI patients develop Alzheimer’s disease.
To conduct their study, the McGill researchers drew on data available through the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a global research effort in which participating patients agree to complete a variety of imaging and clinical assessments.
Sulantha Mathotaarachchi, a computer scientist from Rosa-Neto’s and Gauthier’s team, used hundreds of amyloid PET scans of MCI patients from the ADNI database to train the team’s algorithm to identify which patients would develop dementia, with an accuracy of 84%, before symptom onset. Research is ongoing to find other biomarkers for dementia that could be incorporated into the algorithm in order to improve the software’s prediction capabilities.
“This is an example how big data and open science brings tangible benefits to patient care,” says Dr. Rosa-Neto, who is also director of the McGill University Research Centre for Studies in Aging.
While new software has been made available online to scientists and students, physicians won’t be able to use this tool in clinical practice before certification by health authorities. To that end, the McGill team is currently conducting further testing to validate the algorithm in different patient cohorts, particularly those with concurrent conditions such as small strokes.

McGill Universityhttp://tinyurl.com/y8dd4zda

Researchers at the University of Cincinnati (UC) College of Medicine have shown that a new targeted treatment could benefit patients with certain pancreatic tumours by preventing spread of the cancer and protecting their heart from damage—a direct result of the tumour. Higher levels of serotonin among other tumour secretions can cause injury to the valves of the heart over time, leading to cardiac impairment—a condition referred to as cardiac carcinoid disease—in these patients.
These findings could lead to another targeted treatment for patients and prevent the onset of additional complications from their cancer.
"Pancreatic neuroendocrine tumours—pancreatic NETs, pNETs or islet cell tumours—are tumours that form from the abnormal growth of neuroendocrine cells in the pancreas,” says lead author Hala Elnakat Thomas, PhD, research assistant professor in the Division of Hematology and Oncology, Department of Internal Medicine, and member of the Cincinnati Cancer Consortium and UC Cancer Institute’s Pancreatic Cancer Center. "Most pancreatic NETs are functional, meaning they produce hormones. The overproduction of certain hormones results in a number of symptoms termed carcinoid disease which may impact the patients’ quality of life if not managed appropriately.”
She says mutations in key players of the mTOR pathway, a molecular pathway present and active in several types of cancer, have been identified in pNETs.
"Inhibiting mTOR signalling using everolimus, a targeted therapy, known as a rapalog, for patients with lung and gastroenteropancreatic NETs, has been approved by the FDA. A rapalog inhibits the mTOR protein by preventing it from activating some signals,” she says. "However, patients eventually experience progression of cancer on this treatment, highlighting the need for additional therapies. In this study, we focused on pancreatic NETs (pNETs) and thought that treatment of these tumours upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), could overcome a number of resistance mechanisms in tumours and delay cardiac carcinoid disease.”
Elnakat Thomas’ team and colleagues including Jack Rubinstein, MD, a member of the Heart, Lung and Vascular Institute and an associate professor within the UC College of Medicine, performed preclinical studies using human pNET cells injected into animal models to determine tumour progression and cardiac function in those treated with a rapalog alone or switched to the mTORKi (CC-223) when cancer progression was noticed.
"Our results showed that in the majority of pNETs that progress on rapalog therapy, it is possible to reduce disease progression when switching instead to an mTORKi, such as CC-223,” Elnakat Thomas says. "The mTORKi also may lead to additional cardiac benefit by decreasing valvular fibrosis (damage) when compared with placebo or just the rapalog. The mTORKi also inhibit mTOR but they do it differently than rapalogs, and they are stronger inhibitors of signals, so the inhibition is more complete with an mTORKi than a rapalog. This data warrants further testing of the long-term cardioprotective benefit of an mTORKi in neuroendocrine tumour patients prone to carcinoid syndrome. Altogether, these results are timely as an mTORKi therapy called sapanisertib is currently in phase II clinical trial testing in pNET patients with metastatic cancer or tumours that are not reacting to treatment and cannot be surgically removed.”
University of Cincinnati
healthnews.uc.edu/news/?/29597/

A research team led by investigators from Massachusetts General Hospital (MGH) and collaborators has shown, for the first time, that it may be possible to non-surgically treat or even prevent the damage to a major heart valve that often occurs after a heart attack. In their report the investigators – including co-senior authors at Boston Children’s Hospital and Brigham and Women’s Hospital – describe how treatment with the antihypertension drug losartan reduced mitral valve damage in an animal model of heart attack.
“Our study supports a new concept transforming how we think about heart valves,” says Robert Levine, MD, of the Heart Valve Program and the Cardiac Ultrasound Laboratory in the Corrigan Minehan Heart Center at MGH, co-senior author of the report. “They are not just passive tissue flaps, as previously thought, but are biological battlegrounds where medicines can be used to help patients. Patients with heart valve disease are currently treated with interventions – surgery or implanted devices – late in their illness when the heart is failing. We aim to prevent disease progression at an early stage and keep our patients’ hearts healthy.”
When blockage to a coronary artery causes the death of heart muscle, the body responds by sending immune cells and other inflammatory factors to the site of the damage. Co-lead author Jacob Dal-Bianco, MD, also of the MGH Heart Valve Program, explains, “A heart attack is like a fire in the heart;  inflammation triggered by damage to the heart muscle attracts cells to clear up the damage and form a healed scar. The mitral valve can be caught up as an innocent bystander in this process and become inflamed and scarred, eventually becoming shorter, stiffer and less able to close effectively.”
Located between the left atrium, which receives oxygenated blood from the lungs, and the left ventricle, from which blood is pumped out to the body, a healthy mitral valve keeps blood flowing in the right direction. But if the valve tissues called leaflets don’t close properly after the heart beats, blood can leak back towards the lungs – a process called mitral valve regurgitation – reducing the efficiency of the heart and placing additional stress on the already-damaged organ. While it had been thought that post-heart-attack damage to the mitral valve was caused only by physical forces exerted by the scarring and stretching of damaged heart muscle, recent research by MGH team members found that the valve itself becomes thicker and stiffer, further reducing its ability to close.
Among the factors released by immune cells in an attempt to heal damaged heart muscle is transforming growth factor (TGF)-beta. While it is an important regulator of processes involved in growth, development and the immune response, excess levels of TGF-beta can overactivate other cells, leading to further scarring and stiffening of the mitral valve. Surgical repair of a damaged mitral valve fails within two years in 60 percent of patients, leading to shortness of breath and eventual heart failure.
The hypertension drug losartan is known to inhibit the effects of TGF-beta, and the current study was designed to see whether it could reduce post-heart-attack mitral valve damage in an animal model. For two months, daily doses of the drug were given to sheep in which a heart attack had been surgically induced. A control group of animals that did not receive the drug had surgical mesh sutured to their left ventricular walls to restrict the stretching that typically follows a heart attack and keep the size of the ventricle the same as in the drug-treated animals. At the end of the study period, significantly less inflammation, thickening and scarring had developed in the mitral valves of the losartan-treated animals, compared with the control group. Another study by the same group is investigating whether losartan treatment actually can reduce mitral valve regurgitation.

Massachusetts General Hospital
www.massgeneral.org/about/pressrelease.aspx?id=2141