Tufts University School of Engineering researchers and collaborators from Texas A&M University have published the first research to use computational modelling to predict and identify the metabolic products of gastrointestinal (GI) tract microorganisms. Understanding these metabolic products, or metabolites, could influence how clinicians diagnose and treat GI diseases, as well as many other metabolic and neurological diseases increasingly associated with compromised GI function.

The human GI tract is colonized by billions of bacteria and other microorganisms, belonging to hundreds of species that are collectively termed ‘microbiota.’ Disruptions in the microbiota composition, and subsequently the metabolites derived from the microbiota, are increasingly correlated not only to GI diseases such as inflammatory bowel disease (IBD) and colitis, but also to insulin resistance and Type 2 diabetes.

‘There is increasing evidence that microbiota-derived metabolites play a significant role in modulating physiological functions of the gut,’ said Professor Kyongbum Lee, senior author on the paper and chair of the Department of Chemical and Biological Engineering in Tuft School of Engineering. ‘Emerging links between the GI tract microbiota and many other parts of the body, including the brain, suggest the tantalizing possibility to influence even cognition and behaviour through relatively benign interventions involving diets or probiotics.’

However, to date, only a handful of metabolites principally produced by microbiota—rather than the host organism itself—have been identified. Identifying microbiota-derived metabolites and understanding their effects on specific host functions could open up new avenues of basic and clinical research to develop safe, targeted therapies involving molecules that, by definition, constitute the natural chemical makeup of the host.

‘Current methods of identifying and quantifying these metabolites are unable to distinguish whether the metabolites are produced by the host or the microbiota,’ said Lee.

The newly reported approach models the microbiome as a single, complex network of reactions. By using computational algorithms for network analysis, virtual pathways can be constructed to determine possible metabolic products. Then, these products can be parsed into host-derived or microbiota-derived metabolites.

The research team focused on aromatic amino acids (AAAs) because their metabolites are involved in many of the more than 2,400 distinct reactions expressed in the microbiota as a whole.

‘In addition, we studied AAA-derived metabolites because AAAs can give rise to a variety of bioactive chemicals, such as salicylic acid, an anti-inflammatory compound, and serotonin, which is a neurotransmitter, obviously important in proper brain function,’ said Lee.

Work previously published in the Proceedings of the National Academy of Sciences from Lee’s collaborator Arul Jayaraman, professor in the Artie McFerrin Department of Chemical Engineering at Texas A&M University who holds a master’s from Tufts School of Engineering, had already demonstrated that indole, a bacterial metabolite derived from the aromatic amino acid tryptophan, caused an anti-inflammatory response in the gut and increased resistance to pathogen colonization that could lead to infection

The algorithmic model in the research published today predicted 49 different metabolites would appear as exclusive to the microbiota. In vivo tests on mice then confirmed the presence of more than half of the predicted metabolites, including two novel metabolites, which play a role in the pathways that regulate microbiota metabolism as well as host immune function.

Next steps for the team include identifying microbiota metabolites whose levels are either significantly elevated or depleted during diseases such as IBD or cancer, to find disease-specific markers and explore possible roles for these metabolites in disease progression.

‘Ultimately, the goal is to apply our models to arrive at a mechanistic understanding of the roles microbiota products may play in human physiology, and in turn, diagnose and treat disease,’ said Lee. ‘I think the potential for impact is immense.’ Tufts University

High blood pressure is a leading cause of death around the world, and its prevalence continues to rise. A study shows that a protein in the spleen called placental growth factor (PlGF) plays a critical role in activating a harmful immune response that leads to the onset of high blood pressure in mice. The findings pave the way for the development of more effective treatments for this common and deadly condition.

High blood pressure, also known as hypertension, affects more than 1 billion people worldwide and is a major risk factor for stroke, heart failure, and kidney diseases. Mounting evidence suggests that immune cells such as T cells contribute to the development of hypertension, but the underlying mechanisms have not been clear. Senior study author Giuseppe Lembo of IRCCS Neuromed and his team suspected that PlGF could be the missing link because it plays important roles in both the cardiovascular system and the immune system.

The researchers found support for this idea in the new study. Mice that were genetically engineered to lack PlGF did not develop hypertension after they were infused with angiotensin II–a hormone that normally increases blood pressure. These mice were also protected from hypertension-related heart and kidney damage, unlike genetically normal mice. Moreover, PlGF deficiency prevented T cells from leaving the spleen, entering the blood stream, and infiltrating the vessels and kidneys where hypertension was manifested. Additional experiments revealed that the nervous system controls levels of PlGF in the spleen, and PlGF in the spleen in turn is essential for the activation of T cells and the onset of hypertension.

‘In recent years, anti-PlGF monoclonal antibodies have been developed as a strategy to slow tumor growth and for age-related macular degeneration,’ says lead study author Daniela Carnevale. ‘The ongoing clinical trials testing humanized monoclonal antibodies directed to PlGF opens up the possibility of targeting it in hypertension too.’

‘There is a pressing need for new treatments to control and better target resistant hypertension,’ says Lembo. ‘PlGF is an appealing molecular therapeutic target because clinical tools to target this pathway already exist.’ EurekAlert

Latest figures by the International Diabetes Federation (IDF) have shown that an average 20% of the GCC population and nearly 19% of the UAE population now live with diabetes, with a marked increase in type II diagnoses. Coupled with this rise in disease prevalence, the Health Authority Abu Dhabi (HAAD) is forecasting nearly fourfold increase of healthcare cost for UAE nationals between 2010 and 2030. 
With the pancreas transplantation solution (that involves implanting a healthy pancreas, one that can produces insulin, into an insulin-dependent diabetic patient who is at risk of severe complications) being considered as a more accessible therapy for diabetic patients, the Arab Health Congress, running alongside Arab Health in January 2015 in Dubai, brings together leading practitioners in the field to discuss approaches to address the social and economic burden of the regional rising rate of the disease. 
Commenting on the potentially groundbreaking role of drug discovery and transplantation therapies ahead of his speech at the Arab Health Congress, Dr Mikel Prieto, Surgical Director of the Kidney and Pancreas Transplant Program and Paediatric Kidney Transplantation Medical Director of International Practice Operations at the Mayo Clinic said: “Pancreas transplantation has come of age in the 21st century. The results of this relatively rare type of transplant are outstanding with graft and patient survival rates well above 90 percent. This procedure represents an excellent option for the type of diabetic patients who have significant difficulty controlling their blood sugar or who have developed kidney disease as a consequence of their diabetes. Today, we can offer them a pancreas transplant or a combined pancreas and kidney transplant. This will free them from the need to inject themselves with insulin several times a day.”
World Diabetes Day, which took place on the 14^th of November, was also a reminder of the need for urgent action to fight against the disease in order to prevent the rate of diabetes in the Middle East from doubling in the next 20 years. The IDF estimates the adult population in the MENA region will increase from 375 million in 2013 to 584 million by 2035, with diabetes sufferers rising from 34.6 million to 67.9 million.

www.arabhealthonline.com

A study combining tumour cells from patients with breast cancer with a laboratory model of blood vessel lining provides the most compelling evidence so far that a specific trio of cells is required for the spread of breast cancer. The findings could lead to better tests for predicting whether a woman’s breast cancer will spread and to new anti-cancer therapies. The study was led by researchers at the NCI-designated Albert Einstein Cancer Center and Montefiore Einstein Center for Cancer Care (MECCC).

Maja Oktay, M.D., Ph.D.According to the National Cancer Institute, more than 232,000 American women developed breast cancer last year and nearly 40,000 women died from the disease. It is the most common cancer among women in the United States. Most breast cancer deaths occur because the cancer has spread, or metastasized, which means that cells in the primary tumour have invaded blood vessels and travelled via the bloodstream to form tumours elsewhere in the body.

In earlier studies involving animal models and human cancer cell lines, researchers found that breast cancer spreads when three specific cells are in direct contact: an endothelial cell (a type of cell that lines the blood vessels), a perivascular macrophage (a type of immune cell found near blood vessels), and a tumour cell that produces high levels of Mena, a protein that enhances a cancer cell’s ability to spread. Where these three cells come in contact is where tumour cells can enter blood vessels—a site called a tumour microenvironment of metastasis, or TMEM. Tumours with high numbers of TMEM sites (i.e., they have a high TMEM ‘score’) were more likely to metastasize than were tumours with lower TMEM scores. In addition, the researchers found that cancer tissues high in a form of Mena called MenaINV were especially likely to metastasize. (MenaINV refers to the invasive form of Mena.)

‘Those studies revealed new insights into how cancer might spread, but they didn’t necessarily show what is happening in patients,’ said study leader Maja Oktay, M.D., Ph.D., associate professor of pathology at Albert Einstein College of Medicine of Yeshiva University and attending cytopathologist at Montefiore.

Since then, the scientists have extended their research to include patients with breast cancer. In 2011, they published findings on 40 patients showing a correlation between high MenaINV levels and high TMEM scores. The present study combines results from those 40 patients plus an additional 60 patients. All 100 patients had been diagnosed with invasive ductal carcinoma and were being treated at MECCC. Invasive ductal carcinoma is the most common type of invasive breast cancer, accounting for 80 percent of cases. In this disease, the cancer has grown through the duct walls and into the surrounding breast tissue.
For the subset of more recent patients, the researchers assessed tumour cell behaviour—in particular, cancer cells’ ability to cross the endothelium (inner layer) of blood vessels. They obtained tumour cells using fine needle aspiration and placed them in a novel engineered tissue assay designed to replicate the endothelium of a blood vessel—the barrier that cells must cross so they can spread from a primary tumour to distant sites. Biopsied tumour tissue from all 60 new patients was fixed in formalin and embedded in paraffin so that TMEM sites in the tissue could be counted.
‘It’s critically important to learn more about the metastatic process so we can develop new ways to predict whether cancer will spread and identify new treatments.’

Breast cancer cells able to cross the endothelial layer in this assay were found to have higher MenaINV levels compared with the total population of patients’ aspirated cells. In addition, finding high levels of MenaINV correlated with finding high numbers of TMEM sites in paraffin biopsy specimens from the same patients. The TMEM ‘score’ for each biopsy specimen was calculated by counting the total number of TMEM sites observed within ten 400x magnification fields. Combining the results from all 100 patients showed that the findings were consistent across the three most common clinical subtypes of invasive ductal carcinoma.

‘These results confirm that TMEM sites and MenaINV are essential for the spread of breast cancer in humans,’ said Dr. Oktay. ‘They also imply that MenaINV expression and TMEM score measure related aspects of a commonly used mechanism that human breast cancers use to metastasize.’

Dr. Oktay noted that ‘the outcome for patients with metastatic breast cancer hasn’t improved in the past 30 years despite the development of targeted therapies. It’s critically important to learn more about the metastatic process so we can develop new ways to predict whether cancer will spread and identify new treatments.’ Albert Einstein College of Medicine

After mining the genetic records of thousands of breast cancer patients, researchers from the Johns Hopkins Kimmel Cancer Center have identified a gene whose presence may explain why some breast cancers are resistant to tamoxifen, a widely used hormone treatment generally used after surgery, radiation and other chemotherapy.

The gene, called MACROD2, might also be useful in screening for some aggressive forms of breast cancers, and, someday, offering a new target for therapy, says Ben Ho Park, M.D., Ph.D., an associate professor of oncology in the Kimmel Cancer Center’s Breast Cancer Program and a member of the research team.

The drug tamoxifen is used to treat oestrogen receptor-positive breast cancers. Cells in this type of breast cancer produce protein receptors in their nuclei which bind to and grow in response to the hormone oestrogen. Tamoxifen generally blocks the binding process of the oestrogen-receptor, but some oestrogen receptor-positive cancers are resistant or become resistant to tamoxifen therapy, finding ways to elude its effects. MACROD2 appears to code for a biological path to tamoxifen resistance by diverting the drug from its customary blocking process to a different way of latching onto breast cancer cell receptors, causing cancer cell growth rather than suppression, according to a report by Park and his colleagues.

Specifically, the team’s experiments found that when the gene is overexpressed in breast cancer cells–producing more of its protein product than normal–the cells become resistant to tamoxifen.

One piece of evidence for the gene’s impact was demonstrated when the Johns Hopkins scientists blocked MACROD2’s impact in breast cancer cell cultures by using an RNA molecule that binds to the gene to ‘silence,’ or turn off, the gene’s expression. But the technique only partially restored the cells’ sensitivity to tamoxifen.

To conduct the study, the scientists examined two well-known databases of breast cancer patients’ genetic information, The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium study. Patients who had MACROD2 overexpressed in primary breast cancers at the original breast cancer site had significantly worse survival rates than those who did not, according to an analysis of the patient databases.

With this in mind, the Johns Hopkins scientists suggest that clinicians may be able to look at MACROD2 activity to help them identify aggressive breast cancers at early stages of growth.

The team’s analysis also found that MACROD2 overexpression was present in the majority of metastases in patients with tamoxifen-resistant tumours and in tumour cells that had spread from their original site in the breast. The latter finding, says Park, suggests that tamoxifen resistance caused by the gene might be a process that develops over time as women take the drug.

Finding a small group of a patient’s cancer cells that overexpress MACROD2, he explained, means those cells are likely to be the ‘survivors’ of early treatment with tamoxifen that go on to multiply and cause metastatic tumours. ‘The resultant cells–or the vast majority of them–are now all overexpressing MACROD2, and are the cells that are aggressive and will cause trouble,’ he adds.

Park and his team cautioned that there may be other genetic factors that control tamoxifen resistance, and that nothing in their study should suggest that tamoxifen use should be avoided. EurekAlert