The Involvement of miR-21 in the Molecular Pathogenesis of Richter Transformation

https://openworks.mdanderson.org/sumexp23/1050/thumbnail.jp

Going Circular: History, Present, and Future of circRNAs in Cancer

To date, thousands of highly abundant and conserved single-stranded RNA molecules shaped into ring structures (circRNAs) have been identified. CircRNAs are multifunctional molecules that have been shown to regulate gene expression transcriptionally and post-transcriptionally and exhibit distinct tissue- and development-specific expression patterns associated with a variety of normal and disease conditions, including cancer pathogenesis. Over the past years, due to their intrinsic stability and resistance to ribonucleases, particular attention has been drawn to their use as reliable diagnostic and prognostic biomarkers in cancer diagnosis, treatment, and prevention. However, there are some critical caveats to their utility in the clinic. Their circular shape limits their annotation and a complete functional elucidation is lacking. This makes their detection and biomedical application still challenging. Herein, we review the current knowledge of circRNA biogenesis and function, and of their involvement in tumorigenesis and potential utility in cancer-targeted therapy

DNA Methylation-Based Classifier Differentiates Intrahepatic Pancreato-Biliary Tumours

BACKGROUND: Differentiating intrahepatic cholangiocarcinomas (iCCA) from hepatic metastases of pancreatic ductal adenocarcinoma (PAAD) is challenging. Both tumours have similar morphological and immunohistochemical pattern and share multiple driver mutations. We hypothesised that DNA methylation-based machine-learning algorithms may help perform this task. METHODS: We assembled genome-wide DNA methylation data for iCCA (n = 259), PAAD (n = 431), and normal bile duct (n = 70) from publicly available sources. We split this cohort into a reference (n = 399) and a validation set (n = 361). Using the reference cohort, we trained three machine learning models to differentiate between these entities. Furthermore, we validated the classifiers on the technical validation set and used an internal cohort (n = 72) to test our classifier. FINDINGS: On the validation cohort, the neural network, support vector machine, and the random forest classifiers reached accuracies of 97.68%, 95.62%, and 96.5%, respectively. Filtering by anomaly detection and thresholds improved the accuracy to 99.07% (37 samples excluded by filtering), 96.22% (17 samples excluded), and 100% (44 samples excluded) for the neural network, support vector machine and random forest, respectively. Because of best balance between accuracy and number of predictable cases we tested the neural network with applied filters on the in-house cohort, obtaining an accuracy of 95.45%. INTERPRETATION: We developed a classifier that can differentiate between iCCAs, intrahepatic metastases of a PAAD, and normal bile duct tissue with high accuracy. This tool can be used for improving the diagnosis of pancreato-biliary cancers of the liver

Serum microrna biomarkers for detection of non-small cell lung cancer

Non small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality world-wide and the majority of cases are diagnosed at late stages of disease. There is currently no cost-effective screening test for NSCLC, and the development of such a test is a public health imperative. Recent studies have suggested that chest computed tomography screening of patients at high risk of lung cancer can increase survival from disease, however, the cost effectiveness of such screening has not been established. In this Phase I/II biomarker study we examined the feasibility of using serum miRNA as biomarkers of NSCLC using RT-qPCR to examine the expression of 180 miRNAs in sera from 30 treatment naive NSCLC patients and 20 healthy controls. Receiver operating characteristic curves (ROC) and area under the curve were used to identify differentially expressed miRNA pairs that could distinguish NSCLC from healthy controls. Selected miRNA candidates were further validated in sera from an additional 55 NSCLC patients and 75 healthy controls. Examination of miRNA expression levels in serum from a multi-institutional cohort of 50 subjects (30 NSCLC patients and 20 healthy controls) identified differentially expressed miRNAs. A combination of two differentially expressed miRNAs miR-15b and miR-27b, was able to discriminate NSCLC from healthy controls with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100% in the training set. Upon further testing on additional 130 subjects (55 NSCLC and 75 healthy controls), this miRNA pair predicted NSCLC with a specificity of 84% (95% CI 0.73-0.91), sensitivity of 100% (95% CI; 0.93-1.0), NPV of 100%, and PPV of 82%. These data provide evidence that serum miRNAs have the potential to be sensitive, cost-effective biomarkers for the early detection of NSCLC. Further testing in a Phase III biomarker study in is necessary for validation of these results. © 2012 Hennessey et al

Apophallus microsoma N. SP. from Chicks Infected with Metacercariae from Coho Salmon (Oncorhynchus kisutch ) and Review of the Taxonomy and Pathology of the Genus Apophallus (Heterophyidae)

Metacercariae of an unidentified species of Apophallus Luhe, 1909 are associated with overwinter mortality in coho salmon, Oncorhynchus kisutch (Walbaum, 1792), in the West Fork Smith River, Oregon. We infected chicks with these metacercariae in order to identify the species. The average size of adult worms was 197 x 57 μm, which was 2 to 11 times smaller than other described Apophallus species. Eggs were also smaller, but larger in proportion to body size, than in other species of Apophallus. Based on these morphological differences, we describe Apophallus microsoma n. sp. In addition, sequences from the cytochrome c oxidase 1 gene from Apophallus sp. cercariae collected in the study area, which are likely conspecific with experimentally cultivated A. microsoma, differ by >12% from those we obtained from Apophallus donicus (Skrjabin and Lindtrop, 1919) and from Apophallus brevis Ransom, 1920. The taxonomy and pathology of Apophallus species is reviewed.Keywords: Mortality, St. Lawrence River, Life cycle, Parasite, Perch Perca flavescens, Trematoda, Yellow perch, Brevis, Oregon, Nanophyetus salmincol

ACC/AHA/SCAI/AMA–Convened PCPI/NCQA 2013 Performance Measures for Adults Undergoing Percutaneous Coronary Intervention A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures, the Society for Cardiovascular Angiography and Interventions, the American Medical Association–Convened Physician Consortium for Performance Improvement, and the National Committee for Quality Assurance

Journal of the American College of Cardiology Ó 2014 by the American College of Cardiology Foundation, American Heart Association, Inc., American Medical Association, and National Committee for Quality Assurance Published by Elsevier Inc. Vol. 63, No. 7, 2014 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.12.003 PERFORMANCE MEASURES ACC/AHA/SCAI/AMA–Convened PCPI/NCQA 2013 Performance Measures for Adults Undergoing Percutaneous Coronary Intervention A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures, the Society for Cardiovascular Angiography and Interventions, the American Medical Association–Convened Physician Consortium for Performance Improvement, and the National Committee for Quality Assurance Developed in Collaboration With the American Association of Cardiovascular and Pulmonary Rehabilitation and Mended Hearts Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and Mended Hearts WRITING COMMITTEE MEMBERS Brahmajee K. Nallamothu, MD, MPH, FACC, FAHA, Co-Chair*; Carl L. Tommaso, MD, FACC, FAHA, FSCAI, Co-Chairy; H. Vernon Anderson, MD, FACC, FAHA, FSCAI*; Jeffrey L. Anderson, MD, FACC, FAHA, MACP*; Joseph C. Cleveland, J R , MDz; R. Adams Dudley, MD, MBA; Peter Louis Duffy, MD, MMM, FACC, FSCAIy; David P. Faxon, MD, FACC, FAHA*; Hitinder S. Gurm, MD, FACC; Lawrence A. Hamilton, Neil C. Jensen, MHA, MBA; Richard A. Josephson, MD, MS, FACC, FAHA, FAACVPRx; David J. Malenka, MD, FACC, FAHA*; Calin V. Maniu, MD, FACC, FAHA, FSCAIy; Kevin W. McCabe, MD; James D. Mortimer, Manesh R. Patel, MD, FACC*; Stephen D. Persell, MD, MPH; John S. Rumsfeld, MD, PhD, FACC, FAHAjj; Kendrick A. Shunk, MD, PhD, FACC, FAHA, FSCAI*; Sidney C. Smith, J R , MD, FACC, FAHA, FACP{; Stephen J. Stanko, MBA, BA, AA#; Brook Watts, MD, MS *ACC/AHA Representative. ySociety of Cardiovascular Angiography and Interventions Representative. zSociety of Thoracic Surgeons Representative. xAmerican Association of Cardiovascular and Pulmonary Rehabilitation Representative. kACC/AHA Task Force on Performance Measures Liaison. {National Heart Lung and Blood Institute Representative. #Mended Hearts Representative. The measure specifications were approved by the American College of Cardiology Board of Trustees, American Heart Association Science Advisory and Coordinating Committee, in January 2013 and the American Medical Association–Physician Consortium for Performance Improvement in February 2013. This document was approved by the American College of Cardiology Board of Trustees and the American Heart Association Science Advisory and Coordinating Committee in October 2013, and the Society of Cardiovascular Angiography and Interventions in December 2013. The American College of Cardiology requests that this document be cited as follows: Nallamothu BK, Tommaso CL, Anderson HV, Anderson JL, Cleveland JC, Dudley RA, Duffy PL, Faxon DP, Gurm HS, Hamilton LA, Jensen NC, Josephson RA, Malenka DJ, Maniu CV, McCabe KW, Mortimer JD, Patel MR, Persell SD, Rumsfeld JS, Shunk KA, Smith SC, Stanko SJ, Watts B. ACC/AHA/SCAI/AMA–Convened PCPI/NCQA 2013 perfor- mance measures for adults undergoing percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures, the Society for Cardiovascular Angiography and Interventions, the American Medical Association–Convened Physician Consortium for Performance Improvement, and the National Committee for Quality Assurance. J Am Coll Cardiol 2014;63:722–45. This article has been copublished in Circulation. Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.cardiosource.org) and the American Heart Asso- ciation (http://my.americanheart.org). For copies of this document, please contact Elsevier Inc. Reprint Department, fax (212) 633-3820, e-mail [email protected]. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American College of Cardiology. Requests may be completed online via the Elsevier site (http://www.elsevier.com/authors/obtaining- permission-to-re-use-elsevier-material). This Physician Performance Measurement Set (PPMS) and related data specifications were developed by the Physician Consortium for Performance Improvement (the Consortium), including the American College of Cardiology (ACC), the American Heart Association (AHA), and the American Medical Association (AMA), to facilitate quality-improvement activities by physicians. The performance measures contained in this PPMS are not clinical guidelines, do not establish a standard of medical care, and have not been tested for all potential applications. Although copyrighted, they can be reproduced and distributed, without modification, for noncommercial purposesdfor example, use by health care pro

SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers

Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. SIK2 is required for centrosome splitting and PI3K activation and regulates cancer cell proliferation, metastasis, and sensitivity to chemotherapy. Here, we showed that SIK2 inhibitors sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. SIK2 inhibitors decreased PARP enzyme activity and phosphorylation of class-IIa histone deacetylases (HDAC4/5/7). Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7–associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC

MicroRNA Expression and Regulation in Human Ovarian Carcinoma Cells by Luteinizing Hormone

MicroRNAs have been widely-studied with regard to their aberrant expression and high correlation with tumorigenesis and progression in various solid tumors. With the major goal of assessing gonadotropin (luteinizing hormone, LH) contributions to LH receptor (LHR)-positive ovarian cancer cells, we have conducted a genome-wide transcriptomic analysis on human epithelial ovarian cancer cells to identify the microRNA-associated cellular response to LH-mediated activation of LHR.Human ovarian cancer cells (SKOV3) were chosen as negative control (LHR-) and stably transfected to express functional LHR (LHR+), followed by incubation with LH (0-20 h). At different times of LH-mediated activation of LHR the cancer cells were analyzed by a high-density Ovarian Cancer Disease-Specific-Array (DSA, ALMAC™), which profiled ∼ 100,000 transcripts with ∼ 400 non-coding microRNAs.In total, 65 microRNAs were identified to exhibit differential expression in either LHR expressing SKOV3 cells or LH-treated cells, a few of which have been found in the genomic fragile regions that are associated with abnormal deletion or amplification in cancer, such as miR-21, miR-101-1, miR-210 and miR-301a. By incorporating the dramatic expression changes observed in mRNAs, strong microRNA/mRNA regulatory pairs were predicted through statistical analyses coupled with collective computational prediction. The role of each microRNA was then determined through a functional analysis based on the highly-confident microRNA/mRNA pairs.The overall impact on the transcriptome-level expression indicates that LH may regulate apoptosis and cell growth of LHR+ SKOV3 cells, particularly by reducing cancer cell proliferation, with some microRNAs involved in regulatory roles

Identification of microRNA-mRNA modules using microarray data

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are post-transcriptional regulators of mRNA expression and are involved in numerous cellular processes. Consequently, miRNAs are an important component of gene regulatory networks and an improved understanding of miRNAs will further our knowledge of these networks. There is a many-to-many relationship between miRNAs and mRNAs because a single miRNA targets multiple mRNAs and a single mRNA is targeted by multiple miRNAs. However, most of the current methods for the identification of regulatory miRNAs and their target mRNAs ignore this biological observation and focus on miRNA-mRNA pairs.</p> <p>Results</p> <p>We propose a two-step method for the identification of many-to-many relationships between miRNAs and mRNAs. In the first step, we obtain miRNA and mRNA clusters using a combination of miRNA-target mRNA prediction algorithms and microarray expression data. In the second step, we determine the associations between miRNA clusters and mRNA clusters based on changes in miRNA and mRNA expression profiles. We consider the miRNA-mRNA clusters with statistically significant associations to be potentially regulatory and, therefore, of biological interest.</p> <p>Conclusions</p> <p>Our method reduces the interactions between several hundred miRNAs and several thousand mRNAs to a few miRNA-mRNA groups, thereby facilitating a more meaningful biological analysis and a more targeted experimental validation.</p

Protocol for a population-based Ankylosing Spondylitis (PAS) cohort in Wales

<p>Abstract</p> <p>Background</p> <p>To develop a population-based cohort of people with ankylosing spondylitis (AS) in Wales using (1) secondary care clinical datasets, (2) patient-derived questionnaire data and (3) routinely-collected information in order to examine disease history and the health economic cost of AS.</p> <p>Methods</p> <p>This data model will include and link (1) secondary care clinician datasets (i.e. electronic patient notes from the rheumatologist) (2) patient completed questionnaires (giving information on disease activity, medication, function, quality of life, work limitations and health service utilisation) and (3) a broad range of routinely collected data (including; GP records, in-patient hospital admission data, emergency department data, laboratory/pathology data and social services databases). The protocol involves the use of a unique and powerful data linkage system which allows datasets to be interlinked and to complement each other.</p> <p>Discussion</p> <p>This cohort can integrate patient supplied, primary and secondary care data into a unified data model. This can be used to study a range of issues such as; the true economic costs to the health care system and the patient, factors associated with the development of severe disease, long term adverse events of new and existing medication and to understand the disease history of this condition. It will benefit patients, clinicians and health care managers. This study forms a pilot project for the use of routine data/patient data linked cohorts for other chronic conditions.</p