This article was written by guest blogger Crystal Woodard, PhD
Can your heart prevent diabetes? Being overweight or obese is currently deemed the single best predictor of type 2 diabetes. With the prevalence of obesity on the rise, estimates suggest that one in three American adults could have type 2 diabetes by 2050. Weight loss is key to preventing this epidemic. At SBP, scientists are investigating how hormones released by the heart may help the body burn more calories to prevent obesity and type 2 diabetes.
What color is your fat? All fat is not created equal. Excess weight is held in energy-storing fat cells called white adipose tissue as well as energy-burning fat cells called brown adipose tissue. Increasing a person’s brown fat could improve the risks associated with obesity.
Two compounds released by the heart in response to high blood pressure—human atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)—have been found to play a direct role in “browning” white adipose tissue. By browning, white fat starts to burn more calories, mimicking what occurs in brown fat. Sheila Collins, PhD, professor in the Integrative Metabolism Program and her research team, are investigating how these natriuretic peptides activate fat browning with the goal of tapping into the process to help promote weight loss and prevent diabetes.
In collaboration with Dr. Richard Pratley at the Florida Hospital – SBP Translational Research Institute for Metabolism and Diabetes, the teams are conducting clinical trials with obese and lean volunteers to test whether BNP can increase energy expenditure and improve glucose tolerance. Since recombinant human BNP is an FDA-approved drug prescribed for acute heart failure patients, the costs, and development and approval times for using BNP for these conditions may be reduced.
How does BNP work? Investigators in Italy almost 20 years ago discovered that binding sites for BNP, called natriuretic peptide receptors (NPRs), were expressed in human adipose tissue. The natriuretic peptide ‘signaling’ receptor, NPRA, binds the natriuretic peptides, while the natriuretic peptide ‘clearance’ receptor, NPRC, removes them from circulation. Since then, several studies have reported that BNP levels are lower in the blood of obese patients compared to their lean counterparts. Additional research suggests BNP can lead to increased release of adiponectin, an insulin-sensitizing hormone produced by fat cells and that low levels of BNP in the bloodstream might contribute to insulin resistance.
According to Collins, “Early studies proposed that increased clearance is responsible for the lower peptide levels observed in obese individuals in comparison to lean individuals; however, there are no definitive studies to actually prove this or not. Important efforts are currently underway to understand how NPRs are regulated and how the peptides can be best used for their fat-burning capacity.”
Dr. Sheila Collins is a professor at Sanford Burnham Prebys Medical Discovery Institute (SBP) in Lake Nona, Fla. and a recipient of an American Diabetes Association research award. Dr. Richard Pratley is a senior investigator at the Florida Hospital – SBP Translational Research Institute, Medical Director of the Florida Hospital Diabetes Institute, and adjunct professor at SBP in Lake Nona. This post was written by Crystal Woodard, PhD, a post-doctoral fellow in Dr. Collins’s lab.
Institute News
Leading cardiometabolic researcher to join SBP
Authordrobison
Date
November 5, 2015
The cardiovascular researcher who pioneered visualizing the function of the human heart using the most powerful magnetic resonance available will soon join SBP’s Florida campus. E. Douglas Lewandowski, PhD, will become professor in the Cardiovascular Metabolism Program and director of Cardiovascular Translational Research starting December 2015. He is among the most preeminent investigators in the world who specialize in the metabolic basis of heart failure, including ischemic heart disease and diabetic cardiomyopathy.
“Doug Lewandowski’s pioneering work has unveiled new concepts and therapeutic strategies aimed at improving the treatment of heart failure, a worldwide health problem. He will continue this work at SBP, leading an innovative bench-to-clinic research program at SBP and the Florida Hospital Translational Research Institute for Metabolism and Diabetes (TRI-MD). His recruitment is transformational for our translational research efforts in the cardiovascular arena,” said Daniel P. Kelly, MD, Tavistock Distinguished Professor and scientific director, Center for Metabolic Origins of Disease at SBP Lake Nona.
Lewandowski’s contributions to understanding metabolic pathways and fuels that may protect against the high-morbidity, -mortality, and economic health burden of heart failure are recognized as among the most rigorous and field-advancing. He is renowned in the use of nuclear magnetic resonance (NMR) spectroscopy to visualize and measure metabolic activity in the intact beating heart in health and disease. His expertise in medical imaging techniques involves manipulation of metabolic activity in the ailing heart with pharmacological agents and targeted gene manipulation.
He will hold a joint appointment at Florida Hospital as senior principal investigator at the TRI-MD. He views the partnership between SBP’s basic research and the TRI’s clinical investigations as an attractive and effective research model that will accelerate the translation of the fundamental mechanisms of heart disease and therapeutic targets toward patient-based studies to identify new treatments, therapeutics, and cures.
“With Lake Nona’s emphasis and existing expertise in cardiometabolic disease, I feel that I can immediately contribute to team science approaches to elucidate fundamental mechanisms of heart and metabolic disease. My focus will be to translate findings in SBP’s laboratories to human studies of the metabolic basis of heart disease at the TRI,” said Lewandowski. “It is this partnership that I anticipate will be a game changer in the way I will be able to implement the translation of my laboratory investigations, and I find this very, very exciting.”
Prior to joining SBP, Lewandowski held the position of professor in the Department of Physiology and Biophysics, in the Department of Medicine, and director of the Program in Integrative Cardiac Metabolism at the University of Illinois at Chicago. Previously, Dr. Lewandowski spent a decade on the faculty at Harvard Medical School with hospital appointments at Massachusetts General Hospital in Boston, Mass.
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Exercise following bariatric surgery provides health benefits
New molecular markers for prostate cancer identified
Authorsgammon
Date
October 9, 2014
A team of scientists led by Sanford-Burnham’s Ranjan J. Perera, PhD, has identified a set of RNA molecules that are detectable in tissue samples and urine of prostate cancer patients, but not in normal healthy individuals. The study sets the stage for the development of more-sensitive and specific non-invasive tests for prostate cancer than those currently available, which could result in fewer unnecessary prostate biopsies with less treatment-related morbidity, according to a new study in The Journal of Molecular Diagnostics.
According to the American Cancer Society, prostate cancer is the second most common type of cancer in American men (behind skin cancer), and the second-leading cause of cancer death in men (after lung cancer). In 2014, more than 230,000 new cases of prostate cancer will be diagnosed. One in seven American men will get prostate cancer during his lifetime, and one in 36 will die from it. Since most men with prostate cancer have indolent (non-aggressive) disease for which conservative therapy or surveillance would be appropriate treatment, the clinical challenge is not only how to identify those with prostate cancer, but also how to distinguish those who would benefit from surgical or other aggressive treatment from those who would not.
Today, prostate cancer is primarily detected and monitored by testing for high concentrations of prostate-specific antigen (PSA) in blood samples. High PSA levels are often followed by a biopsy to confirm the presence of cancer, and whether it’s slow growing or aggressive. “While elevated PSA can be an alert to a lethal cancer, it can also detect less aggressive cancers that may never do any harm,” said Vipul Patel, MD, medical director of the Global Robotics Institute at Florida Hospital in Orlando, and co-author of the study. “Moreover, only 25 percent of men with raised PSA levels that have a biopsy actually have prostate cancer. Prostate cancer needs to be screened for; we just need to find a better marker.”
The researchers believe that they have identified a group of RNA molecules – known as long noncoding RNAs (lncRNAs) – that hold the potential for serving as better prognostic markers for prostate cancer. lncRNAs are noncoding RNA molecules that until recently were dismissed by scientists as non-functional noise in the genome. Now, lncRNAs are thought to regulate normal cellular development and are increasingly reported as contributing to a range of diseases, including cancer.
Detection of lncRNAs in urine
“We have identified a set of lncRNAs that appear to have an important role in prostate cancer diagnostics,” said Perera, associate professor and scientific director of Analytical Genomics and Bioinformatics at our Lake Nona campus. “The findings advance our understanding of the role of lncRNAs in cancer biology and, importantly, broaden the opportunity to use lncRNAs as biomarkers to detect prostate cancer.”
The study profiled the lncRNAs in three distinct groups: (1) human prostate cancer cell lines and normal prostate epithelial cells, (2) prostate adenocarcinoma tissue samples and matched normal tissue samples, (3) urine samples from patients with prostate cancer or benign prostate hypoplasia, and normal healthy individuals. In each case, the lncRNAs were elevated in prostate cancer patient samples, but not in patients with benign prostate hypoplasia or normal healthy individuals.
One advantage of lncRNAs is that the molecules can be detected in urine samples, which are more easily available than blood tests. One lncRNA, PCA3, was recently commercialized as a urine test to identify which men suspected of having prostate cancer should undergo repeat prostate biopsy. However, discrepancies have been found to exist between PCA3 levels and clinicopathologic features, said Perera. In the current study, PCA3 was detected in some, but not all of the study samples, suggesting that reliance on a single biomarker may be insufficient for prostate cancer detection, while combining additional markers may increase the specificity and sensitivity of the test.
“There is a tremendous unmet clinical need for better non-invasive screening tools for early detection of prostate cancer to reduce the overtreatment and morbidity of this disease,” added Patel. “Our findings represent a promising approach to meet this demand.”
Technical details of the study
The goal of the first experiment was to see whether lncRNAs are differentially expressed in prostate cancer by measuring total RNA from prostate cancer cell lines and normal epithelial prostatic cells using NCode human ncRNA array and SurePrint G3 human lncRNA microarrays. Hierarchical clustering revealed distinguishable lncRNA expression profiles. Thirty lncRNAs were up-regulated and the expression levels of three top-ranking candidates [XLOC_007697, LOC100287482, and AK024556 (also known as SPRY4-IT1)] were confirmed in prostate cancer cell lines by quantitative real-time polymerase chain reaction (qPCR) analysis. The SPRY4-IT1 was found to be up-regulated more than 100-fold in PC3 cells compared with prostatic epithelial cells.
In a second experiment, lncRNA expression was compared in pooled prostate cancer tissue samples and matched normal tissues from 10 frozen biopsy specimens. Hierarchical clustering of the differentially expressed lncRNAs was observed and 10 up-regulated lncRNAs were detected using microarrays. An additional set of 18 prostate cancer tissue samples was analyzed by qPCR and five lncRNAs were found to be significantly higher in prostate tumor tissues compared with matched normal tissues.
Researchers used qPCR to analyze total RNA isolated from urine in another experiment. Urine was collected from 13 prostate cancer patients and 14 healthy controls. All six lncRNAs were found to be significantly up-regulated in the urine samples from the prostate cancer patients compared with normal patient controls, while there were no differences between normal and benign prostatic hyperplasia patient samples.
In other studies focused particularly on SPRY4-IT1. Using both qPCR and highly sensitive droplet digital PCR, expression of SPRY-IT1 was found to be increased in 16 of 18 (89 percent) tissue samples from patients with prostatic adenocarcinoma, compared to normal tissue samples. The researchers developed chromogenic in situ hybridization (CISH) techniques to visualize SPRY4-IT1 expression in cancerous and matched normal tissue. Intense staining was seen in all adenocarcinoma samples, but not in normal prostatic tissue. Finally, the investigators showed that reduction of SPRY4-IT1 in prostate cancer cells through the use of small interfering RNA (siRNA) leads to decreased cell viability and cellular invasion as well as increased apoptosis, similar to what is seen in melanoma cells.
About the paper
“Long Noncoding RNAs as Putative Biomarkers for Prostate Cancer Detection,” by Bongyong Lee, Joseph Mazar, Muhammed Nauman Aftab, Feng Qi, John Shelley, Jian-Liang Li, Subramaniam Govindarajan, Felipe Valerio, Inoel Rivera, Tadzia Thurn, Tien Anh Tran, Darian Kameh, Vipul Patel, and Ranjan J. Perera, DOI: http://dx.doi.org/10.1016/j.jmoldx.2014.06.009. Published online ahead of The Journal of Molecular Diagnostics, Volume 16, Issue 6 (November 2014) published by Elsevier.
