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Jahed M.,Islamic Azad University at Varamin | Ebadi N.,Islamic Azad University at Varamin | Mivehchi M.,Islamic Azad University at Varamin | Majidizadeh T.,Iran National Institute of Genetic Engineering and Biotechnology | And 5 more authors.
Cancer Biomarkers | Year: 2016

BACKGROUND: Urinary bladder carcinoma is one of the leading causes of death among men, and its high recurrence rates make it one of the most solid tumors to treat. The silencing of the tumor suppressor gene by hypermethylation of the CpG islands and overexpression of proto-oncogene proteins are the main mechanisms in cancers. Here, we investigate methylation status of O6-methylguanine-DNA-methyltransferase (MGMT), a tumor suppressor gene and expression level of BCL-2 a proto-oncogene protein that is frequently observed in bladder carcinoma and its recurrences. MATERIALS AND METHODS: We analyzed the methylation of MGMT in 80 tissue samples of patients suffering from bladder cancer and 80 urine samples of cancer-free individuals by MS-PCR. Additionally, BCL-2 protein expression level was analyzed on these 80 tissue samples by immunohistochemistry. RESULTS: 45% of patients had MGMT methylation, of which this hypermethylation does not have significant association with an increase in grade, but there was significant association in cases with recurrence tumors and metastasis tumors. Among patients with recurrence tumor, 92.5% patients showed MGMT hypermethylation; 66% of these showed BCL-2 overexpression. CONCLUSION: Our data indicate that MGMT hypermethylation and BCL-2 overexpression may have an intense role in superficial bladder cancer recurrences. © 2016 - IOS Press and the authors.

Sharma A.,Pfizer | Huard C.,Pfizer | Vernochet C.,Pfizer | Ziemek D.,Pfizer | And 13 more authors.
PLoS ONE | Year: 2014

Brown adipose tissue (BAT) plays a pivotal role in promoting energy expenditure by the virtue of uncoupling protein-1 (UCP-1) that differentiates BAT from its energy storing white adipose tissue (WAT) counterpart. The clinical implication of "classical" BAT (originates from Myf5 positive myoblastic lineage) or the "beige" fat (originates through trans-differentiation of WAT) activation in improving metabolic parameters is now becoming apparent. However, the inducers and endogenous molecular determinants that govern the lineage commitment and differentiation of classical BAT remain obscure. We report here that in the absence of any forced gene expression, stimulation with bone morphogenetic protein 6 (BMP6) induces brown fat differentiation from skeletal muscle precursor cells of murine and human origins. Through a comprehensive transcriptional profiling approach, we have discovered that two days of BMP6 stimulation in C2C12 myoblast cells is sufficient to induce genes characteristic of brown preadipocytes. This developmental switch is modulated in part by newly identified regulators, Optineurin (Optn) and Cyclooxygenase-2 (Cox2). Furthermore, pathway analyses using the Causal Reasoning Engine (CRE) identified additional potential causal drivers of this BMP6 induced commitment switch. Subsequent analyses to decipher key pathway that facilitates terminal differentiation of these BMP6 primed cells identified a key role for Insulin Like Growth Factor-1 Receptor (IGF-1R). Collectively these data highlight a therapeutically innovative role for BMP6 by providing a means to enhance the amount of myogenic lineage derived brown fat. © 2014 Sharma et al.

Today about 1 in 10 Americans suffer from a rare disease, and half of these patients are children, according to the Global Genes Project. There are some 7,000 known rare disorders ranging from benign abnormalities to life-threatening disease. Many affected children pass away before a diagnosis can be made, leaving families to grieve without knowing what might have been done to help them, or how to avoid additional brothers or sisters being affected. At Boston Children's, investigators at The Manton Center for Orphan Disease Research are focused on diagnosing children with a wide variety of rare genetic conditions. While strides have been made, the interpretation of sequencing results can be a labor-intensive process, presenting an overload of information whose analysis may not always yield a definitive causative variant. In the new collaboration, Watson will be trained in nephrology by reading related medical literature and aggregating information on causative mutations for steroid-resistant nephrotic syndrome (SRNS), a rare genetic form of kidney disease. Then, experts at Boston Children's Hospital intend to feed genomic sequencing data from retrospective patients into Watson to further train the system. The goal is to create a cognitive system that can help clinicians interpret a child's genome sequencing data, compare this with medical literature and quickly identify anomalies that may be responsible for the unexplained symptoms. "Coping with an undiagnosed illness is a tremendous challenge for many of the children and families we see," said Christopher Walsh, MD, PhD, director of the Division of Genetics and Genomics at Boston Children's Hospital. "Watson can help us ensure we've left no stone unturned in our search to diagnose and cure these rare diseases so we can uncover all relevant insights from the patient's clinical history, DNA data, supporting evidence and population health data." Even with a diagnosis, effective treatment for rare conditions can be elusive. For example, SRNS are usually unresponsive to immunosuppressive therapy, and often must go on chronic dialysis or wait for a kidney transplant—only to have their disease frequently recur in the new organ. "One of Watson's talents is quickly finding hidden insights and connecting patterns in massive volumes of data," said Deborah DiSanzo, general manager, IBM Watson Health. "Rare disease diagnosis is a fitting application for cognitive technology that can assimilate different types and sources of data to help doctors solve medical mysteries. For the kids and their families suffering without a diagnosis, our goal is to team with the world's leading experts to create a cognitive tool that will make it easier for doctors to find the needle in the haystack, uncovering all relevant medical advances to support effective care for the child." The kidney project will be done in collaboration with Friedhelm Hildebrandt, MD, chief of the Division of Nephrology at Boston Children's and Claritas Genomics. Following its successful completion, Boston Children's plans to expand the effort into undiagnosed neurologic disorders and other disease areas studied by The Manton Center, improving diagnostic and treatment services for patients nationwide. Boston Children's Hospital is part of the Undiagnosed Diseases Network, a NIH program that aims to solve medical mysteries by integrating genetics, genomics, and rare disease expertise. Boston Children's was also the incubator behind Claritas Genomics, a genetic diagnostic laboratory that offers genetic testing and develops new diagnostic tests and solutions, and organizer of the CLARITY Undiagnosed Challenge, a crowd sourcing competition seeking best practices in clinical genomics. The results and winner of the Challenge will be announced at the Boston Children's Hospital Global Pediatric Innovation Summit on November 10. IBM has been developing Watson's ability to analyze genomic data in collaboration with leading cancer centers around the world. The system is currently being used at 16 cancer institutes to analyze and translate genomic data to help oncologists uncover personalized treatment options. The new project with Boston Children's represents the first time this technology will be applied to help clinicians efficiently identify possible options for rare disease diagnosis and treatment. IBM and Boston Children's are also working together to build OPENPediatrics, an online platform designed to bring life-saving medical knowledge to pediatric caregivers worldwide. In September, the two organizations announced they will integrate Watson's deep and iterative question and answer capability to enhance and scale the OPENPediatrics initiative. Explore further: Project will apply cognitive computing to uncover new patient treatment options

Yao R.,Shanghai JiaoTong University | Wang L.,Institute for Pediatric Research | Yu Y.,Institute for Pediatric Research | Wang J.,Shanghai JiaoTong University | And 3 more authors.
Journal of Dermatology | Year: 2016

Neurofibromatosis 1 (NF1) is a common autosomal dominant condition caused by mutations in the NF1 gene. The appearance of multiple café-au-lait macules is an early sign of the condition, which often alert physicians to follow up and further examine the patient for the possibility of NF1. In order to determine the predictive value of multiple café-au-lait macules at early age for NF1 in Chinese patients, we recruited 19 children who shared the common sign of multiple café-au-lait macules from a general pediatric clinic in Shanghai. All the patients were clinically evaluated following the National Institutes of Health criteria for NF1 and molecular tested for sequence variants and copy number changes. Nine children met the clinical diagnostic criteria of NF1, and molecular tests confirmed all nine patients with pathogenic variants including two genomic deletions, two novel frame-shift variants, four novel nonsense and a splicing variants. In addition, four children who did not meet the diagnostic criteria were also found to carry pathogenic NF1 variants. Overall, 68.4% (13/19) of children with café-au-lait macules and various other clinical presentations were molecularly confirmed with NF1. This study demonstrated that the majority of Chinese children with multiple café-au-lait macules who came to seek for medical attention had NF1. Molecular testing is necessary to be used as an adjunct and sometimes as the main tool for confirming and diagnosing children of NF1 at early age. © 2015 Japanese Dermatological Association.

Kirkpatrick B.E.,Geisinger Health System | Riggs E.R.,Geisinger Health System | Azzariti D.R.,Molecular Partners | Miller V.R.,PatientCrossroads | And 9 more authors.
Human Mutation | Year: 2015

As the utility of genetic and genomic testing in healthcare grows, there is need for a high-quality genomic knowledge base to improve the clinical interpretation of genomic variants. Active patient engagement can enhance communication between clinicians, patients, and researchers, contributing to knowledge building. It also encourages data sharing by patients and increases the data available for clinicians to incorporate into individualized patient care, clinical laboratories to utilize in test interpretation, and investigators to use for research. GenomeConnect is a patient portal supported by the Clinical Genome Resource (ClinGen), providing an opportunity for patients to add to the knowledge base by securely sharing their health history and genetic test results. Data can be matched with queries from clinicians, laboratory personnel, and researchers to better interpret the results of genetic testing and build a foundation to support genomic medicine. Participation is online, allowing patients to contribute regardless of location. GenomeConnect supports longitudinal, detailed clinical phenotyping and robust "matching" among research and clinical communities. Phenotype data are gathered using online health questionnaires; genotype data are obtained from genetic test reports uploaded by participants and curated by staff. GenomeConnect empowers patients to actively participate in the improvement of genomic test interpretation and clinical utility. © 2015 Wiley Periodicals, Inc.

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