Posts Tagged ‘director’

Understanding, improving body’s fight against pathogens

While they exist in small populations in humans, the large amounts of antibodies secreted by plasma cells make them key to the body’s immune system and its ability to defend itself against pathogens, such as bacteria and viruses. Proper maintenance of a pool of plasma cells is also critical for the establishment of lifelong immunity elicited by vaccination.

Dysregulation of plasma cell production and maintenance could lead to autoimmune diseases and multiple myeloma. Autoimmune diseases occur when the immune system does not distinguish between healthy tissue and antigens, which are found in pathogens. This results in expansion of plasma cells which produce excessive amounts of antibodies leading to destruction of one’s own healthy tissue. The discoveries by scientists in BTI’s Immunology Group have improved understanding of the mechanism by which plasma cells are developed from a major class of white blood cells called B cells.

For the first time, the molecule DOK3 was found to play an important role in formation of plasma cells. While calcium signalling typically controls a wide range of cellular processes that allow cells to adapt to changing environments, it was found to inhibit the expression of the membrane proteins essential for plasma cell formation. These membrane proteins include PDL1 and PDL2, and represent some of the key targets for the development of immunotherapy by pharmaceutical companies. DOK3 was able to promote the production of plasma cells by reducing the effects of calcium signalling on these membrane proteins. The absence of DOK3 would thus result in defective plasma cell formation.

In another study, BTI scientists discovered the importance of SHP1 signalling to the long term survival of plasma cells. While the molecule SHP1 has a proven role in prevention of autoimmune diseases, it was found that the absence of SHP1 would result in the failure of plasma cells to migrate from the spleen where they are generated to the bone marrow, a survival niche where they are able to survive for much longer periods. This could result in a reduction of the body’s immune response and thus, an increased susceptibility to infections and diseases. The scientists in this study also successfully rectified the defective immune response caused by an absence of SHP1 by applying antibody injections, which might advance the development of therapeutics. On the other hand, targeting SHP1 might be a strategy to treat multiple myeloma where the accumulation of cancerous plasma cells in the bone marrow survival niches is undesirable.

Findings hold potential for improved treatment

The discovery of these new targets for modulating the antibody response allows the development of novel therapeutic strategies for patients with autoimmune diseases and cancer.Understanding the mechanism that governs plasma cell differentiation is also critical for the optimal design of vaccines and adjuvants, which are added to vaccines to boost the body’s immune response.

Prof Lam Kong Peng, Executive Director of BTI, said, “These findings allow better understanding of plasma cells and their role in the immune system. The identification of these targets not only paves the way for development of therapeutics for those with autoimmune diseases and multiple myeloma, but also impacts the development of immunological agents for combating infections.”

source : http://www.sciencedaily.com/releases/2014/09/140902115036.htm

Scientists unlock key to blood vessel formation

Professor David Beech, of the School of Medicine at the University of Leeds, who led the research, said: “Blood vessel networks are not already pre-constructed but emerge rather like a river system. Vessels do not develop until the blood is already flowing and they are created in response to the amount of flow. This gene, Piezo1, provides the instructions for sensors that tell the body that blood is flowing correctly and gives the signal to form new vessel structures.

“The gene gives instructions to a protein which forms channels that open in response to mechanical strain from blood flow, allowing tiny electrical charges to enter cells and trigger the changes needed for new vessels to be built.”

The research team is planning to study the effects of manipulating the gene on cancers, which require a blood supply to grow, as well as in heart diseases such as atherosclerosis, where plaques form in parts of blood vessels with disturbed blood flow.

Professor Beech added: “This work provides fundamental understanding of how complex life begins and opens new possibilities for treatment of health problems such as cardiovascular disease and cancer, where changes in blood flow are common and often unwanted.

“We need to do further research into how this gene can be manipulated to treat these diseases. We are in the early stages of this research, but these findings are promising.”

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which part-funded the research, said: “Blood flow has a major effect on the health of the arteries it passes through. Arteries are more likely to become diseased in areas where the flow is disturbed, for example. This is because the endothelial cells lining the arteries are exquisitely sensitive to this flow and their response to changes can lead to disease, where the artery becomes narrowed and can eventually cause a heart attack.

“Until now, very little has been known about the process by which blood flow affects endothelial cells. This exciting discovery, in mice, tells us that a protein in those cells could be critical in detecting and responding to changes in blood flow.

“Through further research, using this knowledge, we hope to see whether a treatment can be developed that targets this process to prevent the development of disease in healthy arteries.”

The research was also funded by the Medical Research Council and the Wellcome Trust and was published in the journal Nature on 10 August 2014.

The researchers conducted the study using mouse models.

source : http://www.sciencedaily.com/releases/2014/08/140810214156.htm

Biomarker for early detection of esophageal cancer developed

Dr. Jobe’s findings were published online in Cancer, a journal of the American Cancer Society.

The four-protein panel, called B-AMP (biglycan, myeloperoxidase, annexin-A6 and protein S100-A9), is a simple, non-invasive, low-cost blood test, that identified esophageal cancer with a high classification accuracy of 87 percent in the study.

The discovery represents a major step forward in not only early detection but also the management of esophageal cancer, said Dr. Jobe, Director of Allegheny Health Network’s Esophageal and Thoracic Institute. The test is already being used at the Institute in a clinical trial setting to monitor the course of esophageal cancer.

“Esophageal cancer patients often have few options available to fight this disease, and five-year survival rates are extremely low at about 15 percent,” said Dr. Jobe. “We’ve made progress in treating and monitoring patients with conditions that can progress to esophageal cancer, such as Gastroesophageal Reflux Disease (GERD), Barrett’s Esophagus and high-grade dysplasia. Yet only a small minority of these patients develop life-threatening esophageal cancer. Better detection techniques are needed.”

The incidence of esophageal cancer is rapidly rising: up to 600 percent higher than in the 1970s. Survival is better when the disease is detected early, but unfortunately most patients do not sense difficulty swallowing until a tumor is advanced.

“We are excited and very optimistic about how this biomarker panel could be used to help patients, from early detection in at-risk patients, to risk-monitoring for patients with conditions that may lead to esophageal cancer, to monitoring the disease course in patients with cancer,” said Ali Zaidi, MD, Director of Research at the AHN Esophageal and Thoracic Institute.

The development of blood-based biomarkers has improved early detection and impacted treatment of cancers such as ovarian and prostate, but development of blood-based esophageal cancer biomarkers has been hampered by the difficulty in identifying a single conserved and universal tracking marker.

Using tissue data from the esophageal cancer progression sequence, biomarkers having known cancer relevance and which are upregulated, were selected for testing in the serum. Followed by novel mathematical modeling, Dr. Jobe’s team was able to combine relevant and strong individual biomarkers into a panel that is accurate and reliable in detecting esophageal cancer.

The team used tissue samples obtained from the Department of Pathology at the University of Pittsburgh, representing patients with Barrett’s Esophagus, high-grade dysplasia and esophageal cancer; for identifying and selecting targets for blood testing using a global proteomics profiling platform. The candidate biomarkers were then tested in blood samples from patients with non-Barrett’s esophagus GERD and esophageal cancer. The findings were validated in an independent but similar cohort assembled at Allegheny Health Network and Roswell Park Cancer Institute in Buffalo.

Out of 3,777 identified tissue proteins, five were shown to have significantly elevated levels in blood of patients with esophageal cancer, as compared to those with non-Barrett’s esophagus GERD, and on mathematical modeling four of those five were shown to have predictive value.

“Dr. Jobe’s research shows the value of our approach to working collaboratively and across the full spectrum of disease,” said David Parda, MD, System Chair, Allegheny Health Network Cancer Institute. “This tour de force research integrates clinical work and advanced biology/informatics to improve prevention, treatment, prognostic and predictive capabilities.”

source : http://www.sciencedaily.com/releases/2014/08/140807145451.htm