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Find video protocols related to scientific articles indexed in Pubmed.
Genomic rearrangements in prostate cancer.
Curr Opin Urol
PUBLISHED: 11-12-2014
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Genomic instability is a fundamental feature of human cancer, leading to the activation of oncogenes and inactivation of tumor suppressors. In prostate cancer (PCA), structural genomic rearrangements, resulting in gene fusions, amplifications, and deletions, are a critical mechanism effecting these alterations. Here, we review recent literature regarding the importance of genomic rearrangements in the pathogenesis of PCA and the potential impact on patient care.
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Insights into the mechanism of organ-specific cancer metastasis.
Cancer Discov
PUBLISHED: 11-05-2014
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Lucas and colleagues nominate transmembrane serine protease type II (TMPRSS2) as an important player in the initiation of epithelial-mesenchymal transition (EMT) in prostate cancer. Cancer cells maintain androgen receptor-regulated cytoplasmic TMPRSS2 expression, which facilitates EMT invasion and metastasis in model systems through hepatocyte growth factor and c-MET signaling. In addition to providing a rationale for potentially targeting this organ-specific enabler of metastatic disease progression, this study also highlights the importance of understanding how organ/tissue-specific genes are co-opted in the context of cancer. Cancer Discov; 4(11); 1262-4. ©2014 AACR. See related article by Lucas et al., p. 1310.
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Individual differences in individualism and collectivism predict ratings of virtual cities' liveability and environmental quality.
J Gen Psychol
PUBLISHED: 10-11-2014
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ABSTRACT. The present research investigated individual differences in individualism and collectivism as predictors of people's reactions to cities. Psychology undergraduate students (N = 148) took virtual guided tours around historical cities. They then evaluated the cities' liveability and environmental quality and completed measures of individualism and collectivism. Mediation analyses showed that people who scored high in self-responsibility (individualism) rated the cities as more liveable because they perceived them to be richer and better resourced. In contrast, people who scored high in collectivism rated the cities as having a better environmental quality because they perceived them to (1) provide a greater potential for community and social life and (2) allow people to express themselves. These results indicate that people's evaluations of virtual cities are based on the degree to which certain aspects of the cities are perceived to be consistent with individualist and collectivist values.
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Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer.
Science
PUBLISHED: 10-02-2014
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Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.
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Carbon Monoxide Protects Against Hemorrhagic Shock and Resuscitation-Induced Microcirculatory Injury and Tissue Injury.
Shock
PUBLISHED: 09-23-2014
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Traumatic injury is a significant cause of morbidity and mortality worldwide. Microcirculatory activation and injury from hemorrhage contributes to organ injury. Many adaptive responses occur within the microcirculatory beds to limit injury including up regulation of heme oxygenase (HO) enzymes, the rate limiting enzymes in the breakdown of heme to carbon monoxide (CO), iron, and biliverdin. Here we tested the hypothesis that CO abrogates trauma induced injury and inflammation protecting the microcirculatory beds.
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Consensus statement with recommendations on active surveillance inclusion criteria and definition of progression in men with localized prostate cancer: the critical role of the pathologist.
Virchows Arch.
PUBLISHED: 09-01-2014
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Active surveillance (AS) is an important management option for men with low-risk, clinically localized prostate cancer. The clinical parameters for patient selection and definition of progression for AS protocols are evolving as data from several large cohorts matures. Vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for AS. These findings need to be reproducible and consistently reported by surgical pathologists. This report highlights the importance of accurate pathology reporting as a critical component of these protocols.
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Unraveling the clonal hierarchy of somatic genomic aberrations.
Genome Biol.
PUBLISHED: 08-26-2014
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Defining the chronology of molecular alterations may identify milestones in carcinogenesis. To unravel the temporal evolution of aberrations from clinical tumors, we developed CLONET, which upon estimation of tumor admixture and ploidy infers the clonal hierarchy of genomic aberrations. Comparative analysis across 100 sequenced genomes from prostate, melanoma, and lung cancers established diverse evolutionary hierarchies, demonstrating the early disruption of tumor-specific pathways. The analyses highlight the diversity of clonal evolution within and across tumor types that might be informative for risk stratification and patient selection for targeted therapies. CLONET addresses heterogeneous clinical samples seen in the setting of precision medicine.
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Biomarker analyses from a randomized, placebo-controlled, phase IIIb trial comparing bevacizumab with or without erlotinib as maintenance therapy for the treatment of advanced non-small-cell lung cancer (ATLAS).
J Thorac Oncol
PUBLISHED: 08-15-2014
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ATLAS compared bevacizumab plus erlotinib (B+E) with bevacizumab plus placebo (B+P) as maintenance therapy after first-line bevacizumab plus chemotherapy (B+C) for advanced non-small-cell lung cancer (NSCLC). Prespecified biomarkers were prospectively evaluated.
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The critical role of the pathologist in determining eligibility for active surveillance as a management option in patients with prostate cancer: consensus statement with recommendations supported by the College of American Pathologists, International Society of Urologic
Arch. Pathol. Lab. Med.
PUBLISHED: 08-05-2014
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Prostate cancer remains a significant public health problem. Recent publications of randomized trials and the US Preventive Services Task Force recommendations have drawn attention to overtreatment of localized, low-risk prostate cancer. Active surveillance, in which patients undergo regular visits with serum prostate-specific antigen tests and repeat prostate biopsies, rather than aggressive treatment with curative intent, may address overtreatment of low-risk prostate cancer. It is apparent that a greater awareness of the critical role of pathologists in determining eligibility for active surveillance is needed.
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Evidence for molecular differences in prostate cancer between African American and Caucasian men.
Clin. Cancer Res.
PUBLISHED: 07-23-2014
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The aim of this study was to compare the frequency of ERG rearrangement, PTEN deletion, SPINK1 overexpression, and SPOP mutation in prostate cancer in African American and Caucasian men.
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The long road--and the high road--to successful implementation of OncoEMR.
Oncology (Williston Park, N.Y.)
PUBLISHED: 07-10-2014
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We believe that no matter where a practice currently is in the EMR process--vetting products or companies to determine what will best meet its needs, implementing the new product just selected, or trying to take maximum advantage of the product already in use--we hope these suggestions, based on our experience, will contribute to your anticipated success. It is not uncommon for practices to become overwhelmed in the choice, implementation, and utilization of their EMR. What distinguishes those practices that are successful in their use of the EMR is their commitment to the product and their recognition that it is the central element in the treatment of their patients. Consistently exploring better ways to use OncoEMR, staying educated about the changes that occur, and taking full advantage of its best features will keep it simple and actionable for your practice.
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Prostate cancer with Paneth cell-like neuroendocrine differentiation has recognizable histomorphology and harbors AURKA gene amplification.
Hum. Pathol.
PUBLISHED: 06-26-2014
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Aurora kinase A (AURKA) gene amplification has been documented in 67% of hormone-naive prostate cancer cases that progress to a highly aggressive variant of castrate-resistant disease, clinically referred to as "neuroendocrine" prostate cancer, "small cell" prostate carcinoma, or "anaplastic" prostate cancer. Therefore, AURKA amplification is a potential prognostic biomarker that may help to identify patients with prostate cancer who are at high risk for developing castrate-resistant disease with clinical features of small cell carcinoma. Furthermore, AURKA inhibitors are currently being tested in clinical trials. In a previous study, we found AURKA amplification in 6 cases of prostate cancer with Paneth cell-like cells. This morphologic pattern has been suggested to represent low-grade neuroendocrine differentiation (NED) with generally favorable prognosis. We sought to investigate the frequency of AURKA amplification and the histologic characteristics of prostate cancer with Paneth cell-like NED. Twenty-five cases from 172 prostatectomies were evaluated for the presence of 18 morphologic features and AURKA amplification. Most prostate cancers with Paneth cell-like NED had macronucleoli (92%), basophilic appearance (88%), perineural invasion (72%), and nuclear stratification (76%). The frequency of AURKA amplification was 45%, present throughout the examined tumor nodule including areas without Paneth cell-like cells. When histologically similar cases with and without AURKA amplification were compared, this gene alteration was associated with larger extent of Paneth cell-like NED identified at magnification ×20 (P = .015), higher percentage of Paneth cell-like NED throughout the tumor nodule (P = .033), ductal features (P = .02), and higher overall Gleason grade (P = .039). AURKA amplification was not associated with age, serum prostate specific antigen, or tumor stage. The high frequency of AURKA amplification (45%) in localized prostate cancer with Paneth cell-like NED and its potential prognostic significance warrant further investigation.
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MYB-NFIB gene fusion in adenoid cystic carcinoma of the breast with special focus paid to the solid variant with basaloid features.
Hum. Pathol.
PUBLISHED: 06-03-2014
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Adenoid cystic carcinomas (ACCs) from various anatomical sites harbor a translocation t(6;9)(q22-23;p23-24), resulting in MYB-NFIB gene fusion. This gene fusion is not well studied in mammary ACCs, and there are no studies examining this abnormality in solid variant of ACC with basaloid features (SBACC), a high-grade variant thought to behave more aggressively than ACCs with conventional histologic growth. Our aim was to investigate the frequency of MYB-NFIB gene fusion in mammary ACCs with a focus paid to SBACC. MYB rearrangement and MYB-NFIB fusion were assessed by fluorescence in situ hybridization and reverse-transcription polymerase chain reaction, respectively. Histologic features and the presence of MYB rearrangement were correlated with clinical outcome. MYB rearrangement was present in 7 (22.6%) of 31 mammary ACCs (5/15 [33.3%] ACCs with conventional growth; 2/16 [12.5%] SBACCs). One patient with conventional ACC developed distant metastasis, and no patients had axillary lymph node involvement by ACC (mean follow-up, 34 months; range, 12-84 months). Two patients with SBACC had axillary lymph node involvement at initial surgery, and 2 additional patients experienced disease recurrence (1 local, 1 distant; mean follow-up, 50 months; range, 9-192 months). MYB-NFIB fusion status did not correlate with clinical outcome in studied patients. We confirm that MYB-NFIB gene fusion is observed in mammary ACCs and that a subset lacks this abnormality. This study is the first to confirm the presence of MYB rearrangement in SBACC. Additional validation with long-term follow-up is needed to determine the relationship, if any, between MYB-NFIB gene fusion and clinical outcome.
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Correcting age-related changes in the face by use of injectable fillers and neurotoxins.
Semin Cutan Med Surg
PUBLISHED: 06-01-2014
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Many patients seeking rejuvenation treatment have readily apparent age-related changes in facial features. Others exhibit more subtle changes that nonetheless can be corrected to achieve a more youthful appearance. In the following article, four specialists in aesthetic dermatology discuss how injectable hyaluronic acid-based fillers and neurotoxins can achieve rejuvenation without surgery.
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Organoid cultures derived from patients with advanced prostate cancer.
Cell
PUBLISHED: 04-14-2014
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The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and therapy response. Using a 3D organoid system, we report success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells. The first seven fully characterized organoid lines recapitulate the molecular diversity of prostate cancer subtypes, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss. Whole-exome sequencing shows a low mutational burden, consistent with genomics studies, but with mutations in FOXA1 and PIK3R1, as well as in DNA repair and chromatin modifier pathways that have been reported in advanced disease. Loss of p53 and RB tumor suppressor pathway function are the most common feature shared across the organoid lines. The methodology described here should enable the generation of a large repertoire of patient-derived prostate cancer lines amenable to genetic and pharmacologic studies.
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Aggressive variants of castration-resistant prostate cancer.
Clin. Cancer Res.
PUBLISHED: 04-11-2014
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A subset of patients with advanced castration-resistant prostate cancer may eventually evolve into an androgen receptor (AR)-independent phenotype, with a clinical picture associated with the development of rapidly progressive disease involving visceral sites and hormone refractoriness, often in the setting of a low or modestly rising serum prostate-specific antigen level. Biopsies performed in such patients may vary, ranging from poorly differentiated carcinomas to mixed adenocarcinoma-small cell carcinomas to pure small cell carcinomas. These aggressive tumors often demonstrate low or absent AR protein expression and, in some cases, express markers of neuroendocrine differentiation. Because tumor morphology is not always predicted by clinical behavior, the terms "anaplastic prostate cancer" or "neuroendocrine prostate cancer" have been used descriptively to describe these rapidly growing clinical features. Patients meeting clinical criteria of anaplastic prostate cancer have been shown to predict for poor prognosis, and these patients may be considered for platinum-based chemotherapy treatment regimens. Therefore, understanding variants within the spectrum of advanced prostate cancer has important diagnostic and treatment implications.
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Proposed morphologic classification of prostate cancer with neuroendocrine differentiation.
Am. J. Surg. Pathol.
PUBLISHED: 04-08-2014
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On July 31, 2013, the Prostate Cancer Foundation assembled a working committee on the molecular biology and pathologic classification of neuroendocrine (NE) differentiation in prostate cancer. New clinical and molecular data emerging from prostate cancers treated by contemporary androgen deprivation therapies, as well as primary lesions, have highlighted the need for refinement of diagnostic terminology to encompass the full spectrum of NE differentiation. The classification system consists of: Usual prostate adenocarcinoma with NE differentiation; 2) Adenocarcinoma with Paneth cell NE differentiation; 3) Carcinoid tumor; 4) Small cell carcinoma; 5) Large cell NE carcinoma; and 5) Mixed NE carcinoma - acinar adenocarcinoma. The article also highlights "prostate carcinoma with overlapping features of small cell carcinoma and acinar adenocarcinoma" and "castrate-resistant prostate cancer with small cell cancer-like clinical presentation". It is envisioned that specific criteria associated with the refined diagnostic terminology will lead to clinically relevant pathologic diagnoses that will stimulate further clinical and molecular investigation and identification of appropriate targeted therapies.
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SPOP mutations in prostate cancer across demographically diverse patient cohorts.
Neoplasia
PUBLISHED: 02-25-2014
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Recurrent mutations in the Speckle-Type POZ Protein (SPOP) gene occur in up to 15% of prostate cancers. However, the frequency and features of cancers with these mutations across different populations is unknown.
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A comparative study of ERG status assessment on DNA, mRNA, and protein levels using unique samples from a Swedish biopsy cohort.
Appl. Immunohistochem. Mol. Morphol.
PUBLISHED: 02-13-2014
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The ERG rearrangement is identified in approximately 50% of prostate cancer screened cohorts and is known to be highly specific. This genetic aberration, most commonly leading to the TMPRSS2-ERG fusion, but also SLC45A3-ERG or NDRG1-ERG fusions, all leading to an overexpression of a truncated ERG protein. Most studies have applied in situ hybridization (FISH) methods or mRNA-based assays to investigate the ERG status. Recently, studies showed that ERG protein levels assessed by ERG antibodies can be used as a surrogate marker for ERG rearrangement. In the current study, we investigate ERG status on a series of diagnostic biopsies using DNA-based, mRNA-based, and protein-based assays. We formally compared 3 assay results (ie, FISH, fusion mRNA, and immunohistochemistry) to identify which method could be most appropriate to use when having limited amount of tissue. ERG rearrangement was found in 56% of the cases. Comparing ERG rearrangement status by FISH with ERG overexpression and TMPRSS2-ERG fusion transcript we found 95.1% (154/162, Fisher exact test 9.50E-36) and 85.2% (138/162, Fisher exact test 7.26E-22) concordance, respectively. We show that the ERG antibody highly correlates with the ERG rearrangement with high sensitivity and specificity. We also identified the most common TMPRSS2-ERG isoform in the majority of ERG rearranged cases. These results provide compelling evidence that the ERG antibody can be used to further investigate the role of ERG in prostate cancer.
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Recurrent prostate cancer genomic alterations predict response to brachytherapy treatment.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-10-2014
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This study aimed to evaluate the association of recurrent molecular alterations in prostate cancer, such as ERG rearrangements and phosphatase and tensin homolog gene (PTEN) deletions, with oncologic outcomes in patients with prostate cancer treated with brachytherapy.
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Antibody-independent targeted quantification of TMPRSS2-ERG fusion protein products in prostate cancer.
Mol Oncol
PUBLISHED: 01-29-2014
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Fusions between the transmembrane protease serine 2 (TMPRSS2) and ETS related gene (ERG) represent one of the most specific biomarkers that define a distinct molecular subtype of prostate cancer. Studies of TMPRSS2-ERG gene fusions have seldom been performed at the protein level, primarily due to the lack of high-quality antibodies suitable for quantitative studies. Herein, we applied a recently developed PRISM (high-pressure high-resolution separations with intelligent selection and multiplexing)-SRM (selected reaction monitoring) strategy for quantifying ERG protein in prostate cancer cell lines and tumors. The highly sensitive PRISM-SRM assays provided confident detection of 6 unique ERG peptides in both TMPRSS2-ERG positive cell lines and tissues, but not in cell lines or tissues lacking the TMPRSS2-ERG rearrangement, clearly indicating that ERG protein expression is significantly increased in the presence of the TMPRSS2-ERG gene fusion. Significantly, our results provide evidence that two distinct ERG protein isoforms are simultaneously expressed in TMPRSS2-ERG positive samples as evidenced by the concomitant detection of two mutually exclusive peptides in two patient tumors and in the VCaP prostate cancer cell line. Three peptides, shared across almost all fusion protein products, were determined to be the most abundant peptides, providing "signature" peptides for detection of ERG over-expression resulting from TMPRSS2-ERG gene fusion. The PRISM-SRM assays provide valuable tools for studying TMPRSS2-ERG gene fusion protein products in prostate cancer.
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PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer.
Cancer Res.
PUBLISHED: 01-28-2014
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Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to small-molecule inhibitors of PARP1. These effects reflected a posttranscriptional repression of the BRCA2 3'UTR by PCAT-1. Our observations thus offer a novel mechanism of "BRCAness" in sporadic cancers.
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Diagnostic utility of MYC amplification and anti-MYC immunohistochemistry in atypical vascular lesions, primary or radiation-induced mammary angiosarcomas, and primary angiosarcomas of other sites.
Hum. Pathol.
PUBLISHED: 01-25-2014
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Breast cancer patients who receive radiation therapy or develop chronic lymphedema following axillary dissection can develop secondary mammary angiosarcomas (ASs) and, additionally, atypical vascular lesions (AVLs) in the former group. Recently, MYC amplification by fluorescence in situ hybridization (FISH) has been identified in secondary mammary AS but not in AVL and most primary mammary AS as well as AS of other sites. We studied MYC amplification and MYC protein expression in 7 radiation-induced AVLs, 9 secondary mammary ASs, 17 primary mammary ASs, and 20 primary ASs of other sites by FISH analysis and immunohistochemistry. All 9 secondary mammary ASs showed gene amplification and protein expression, whereas neither was found in any of 7 AVLs. No MYC amplification or protein expression was identified in any of the 17 primary mammary ASs. Among primary ASs of other sites, 1 cardiac AS and 1 skin AS showed gene amplification and protein expression. The remaining 18 did not show amplification (90%), but some demonstrated protein expression (39%). We conclude that MYC amplification by FISH is present in secondary mammary AS but not in AVL. We also found MYC amplification in 1 primary skin AS and 1 primary cardiac AS. There was 100% concordance between MYC amplification and protein expression in all AVL, primary mammary AS, and secondary mammary AS, whereas only 65% concordance was found in AS of other sites. MYC protein expression in AS can be helpful in certain diagnostic scenarios in the breast but not in other sites.
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The lethal clone in prostate cancer: redefining the index.
Eur. Urol.
PUBLISHED: 01-02-2014
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Determining the specific primary prostate cancer focus leading to metastatic disease has implications for treatment, including application of focal therapy. A recent report in the Journal of Clinical Investigation shows that molecular characteristics, rather than size and grade alone, may point to the lethal clone in prostate cancer.
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Efficacy of a reduced electroencephalography electrode array for detection of seizures.
Neurohospitalist
PUBLISHED: 01-02-2014
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The expertise required for proper electroencephalography (EEG) setup can make the 10-20 array unwieldy in the hospital setting. There may be a role for an EEG array with reduced leads to improve the efficiency of inpatient practice.
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The use of telemedicine in the management of acute stroke.
Neurosurg Focus
PUBLISHED: 01-02-2014
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Cerebrovascular disease, including acute ischemic stroke, remains a major public health problem in the US and throughout the world. There has been a concerted effort to apply evidence-based practices to stroke care to improve primary and secondary prevention as well as poststroke outcomes. Geography and workforce shortages contribute to a disparity in stroke care, however, among the substantial proportion of the US population that lives outside the reach of an acute stroke-ready hospital or a primary or comprehensive stroke center. In an attempt to combat the rural-to-urban disparity and expand the availability of best stroke practices, Levine and Gorman proposed the development of telemedical outreach for acute stroke evaluation and management, which they called "telestroke." Since then, the practice of telestroke has been found to have a high interrater agreement with a bedside assessment of the National Institutes of Health Stroke Scale score, to enhance correct thrombolysis decision making as compared with telephone-only consultation, and to be cost-effective. In light of these findings and the perception of benefit by acute stroke providers and patients, there has been growing interest in and a rapid expansion of telestroke networks in the US and internationally. There are legal and financial barriers to more widespread use of telemedicine in general, including telestroke. Further research is needed to understand the potential merits of telestroke infrastructure for the many phases of stroke care including poststroke hospitalization, prevention of complications, enhancing secondary prevention, and education of patients and providers.
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Asymptomatic carotid stenosis: What we can learn from the next generation of randomized clinical trials.
JRSM Cardiovasc Dis
PUBLISHED: 01-01-2014
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Stroke remains an exceedingly incident and prevalent public health burden across the globe, with an estimated 16 million new strokes per annum and prevalence over 60 million, and extracranial internal carotid artery atherosclerotic disease is an important risk factor for stroke. Randomized trials of surgical treatment were conducted (North American Symptomatic Carotid Endarterectomy Trial, European Carotid Surgery Trial) and demonstrated efficacy of carotid endarterectomy for secondary prevention of stroke in patients with cerebrovascular events (e.g. ipsilateral stroke, transient ischemic attack, and/or amaurosis fugax) attributable to a diseased artery with 50-99% stenosis. Therapeutic clarity, however, proved elusive with asymptomatic carotid artery disease. Asymptomatic Carotid Atherosclerosis Study (ACAS), Asymptomatic Carotid Surgery Trial, and Veterans Affairs Cooperative Study (VACS) suggested only modest benefit from surgical intervention for primary stroke prevention and the best medical therapy at the time of these trials is not comparable to modern medical therapy. ACT-1, Asymptomatic Carotid Surgery Trial-2, Stent-Protected Angioplasty in asymptomatic Carotid artery stenosis versus Endarterectomy Trial-2, European Carotid Surgery Trial-2, Carotid Revascularization Endarterectomy Versus Stenting Trial-2 are trials that are recent, ongoing, or in development that include diverse populations across Europe and North America, complementary trial designs, and a collaborative spirit that should provide clinicians with evidence that informs best clinical practice for asymptomatic carotid artery disease.
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High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development.
Cancer Res.
PUBLISHED: 12-19-2013
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Standardized and reproducible pre-clinical models that recapitulate the dynamics of prostate cancer (PCa) are urgently needed. We established a bank of transplantable patient-derived PCa xenografts that capture the biological and molecular heterogeneity currently confounding prognostication and therapy development. Xenografts preserved the histopathology, genome architecture, and global gene expression of donor tumours. Moreover, their aggressiveness matched patient observations, and their response to androgen withdrawal correlated with tumor subtype. The panel includes the first xenografts generated from needle biopsy tissue obtained at diagnosis. This advance was exploited to generate independent xenografts from different sites of a primary site: enabling functional dissection of tumor heterogeneity. Prolonged exposure of adenocarcinoma xenografts to androgen withdrawal led to castration-resistant PCa, including the first-in-field model of complete transdifferentiation into lethal neuroendocrine PCa. Further analysis of this model supports the hypothesis that neuroendocrine PCa can evolve directly from adenocarcinoma via an adaptive response, and yielded a set of genes potentially involved in neuroendocrine transdifferentiation. We predict that these next-generation models will be transformative for advancing mechanistic understanding of disease progression, response to therapy and personalized oncology.
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TMPRSS2:ERG Gene Fusion Predicts Subsequent Detection of Prostate Cancer in Patients With High-Grade Prostatic Intraepithelial Neoplasia.
J. Clin. Oncol.
PUBLISHED: 12-02-2013
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High-grade prostatic intraepithelial neoplasia (HGPIN) is considered a precursor lesion of prostate cancer (PCa). The predictive value of ERG gene fusion in HGPIN for PCa was interrogated as a post hoc analysis in the context of a randomized clinical trial.
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Novel post-treatment care after ablative and fractional CO2 laser resurfacing.
J Cosmet Laser Ther
PUBLISHED: 11-18-2013
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Objective: This study evaluates a topical oxygen emulsion (TOE) to reduce adverse effects after skin rejuvenation with a fully ablative CO2 laser alone and in combination with a fractional ablative CO2 laser. Materials and methods: Patients (n = 100) seeking skin rejuvenation underwent CO2 laser resurfacing. Group A patients (n = 34) received a single deep fractional laser treatment followed by application of Aquaphor(™) immediately after treatment for 24 h and TOE every 6 h for the next 6 days. Group B patients (n = 66) underwent both deep fractional and fully ablative laser resurfacing followed by application of TOE every 6 h for 7 consecutive days. Results: Patients in both groups showed clinical improvement and a 7.1% overall incidence of adverse effects which included milia (5.1% overall) and hyperpigmentation (3.1% overall). For milia, Group A and Group B individual adverse effect rates were 11.8% and 1.5%, respectively; for hyperpigmentation, individual rates were 0.0% and 3.1%, respectively. Conclusion: The elimination of petrolatum products in the post-skin care regimen has significantly reduced the incidence of post-procedure complications when compared with the use of TOE, resulting in the lowest incidence of complications in fully ablative or fractional resurfacing published thus far.
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Systematic review of teleneurology: neurohospitalist neurology.
Neurohospitalist
PUBLISHED: 10-30-2013
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The use of 2-way audiovisual telemedicine technology for the delivery of acute stroke care is well established in the literature and is a growing practice. The use of such technology for neurologic consultation outside the cerebrovascular specialty has been reported to a variable extent across most disciplines within the field of neurology, including that of the neurohospitalist medicine. A systematic review of these reports is lacking. Hence, the main purpose of this study was to conduct a systematic review of the literature on teleneurologic consultation in hospital neurology. The databases Ovid MEDLINE, EMBASE, PsychINFO, CINAHL, and Cochrane were used as data sources and were searched with key words "teleneurology" and its numerous synonyms and cognates. These key words were cross-referenced with subspecialties of neurology. The studies were included for further review only if the title or the abstract indicated that the study made use of 2-way audiovisual communication to address a neurologic indication. This search yielded 6625 abstracts. By consensus between the 2 investigators, 688 publications met the criteria for inclusion and further review. Four of those citations directly pertained to the inpatient hospital neurologic consultation. Each of the 4 relevant articles was scored with a novel rubric scoring functionality, application, technology, and evaluation phase. A subspecialty category score was calculated by averaging those scores. The use of 2-way audiovisual technology for general neurologic consultation of hospital inpatients, beyond stroke-related care, is promising, but the evidence supporting its routine use is weak. Further studies on reliability, validity, safety, efficacy, and cost-effectiveness are encouraged.
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Integrative annotation of variants from 1092 humans: application to cancer genomics.
Science
PUBLISHED: 10-05-2013
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Interpreting variants, especially noncoding ones, in the increasing number of personal genomes is challenging. We used patterns of polymorphisms in functionally annotated regions in 1092 humans to identify deleterious variants; then we experimentally validated candidates. We analyzed both coding and noncoding regions, with the former corroborating the latter. We found regions particularly sensitive to mutations ("ultrasensitive") and variants that are disruptive because of mechanistic effects on transcription-factor binding (that is, "motif-breakers"). We also found variants in regions with higher network centrality tend to be deleterious. Insertions and deletions followed a similar pattern to single-nucleotide variants, with some notable exceptions (e.g., certain deletions and enhancers). On the basis of these patterns, we developed a computational tool (FunSeq), whose application to ~90 cancer genomes reveals nearly a hundred candidate noncoding drivers.
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Identification of Molecular Tumor Markers in Renal Cell Carcinomas with TFE3 Protein Expression by RNA Sequencing.
Neoplasia
PUBLISHED: 08-29-2013
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TFE3 translocation renal cell carcinoma (tRCC) is defined by chromosomal translocations involving the TFE3 transcription factor at chromosome Xp11.2. Genetically proven TFE3 tRCCs have a broad histologic spectrum with overlapping features to other renal tumor subtypes. In this study, we aimed for characterizing RCC with TFE3 protein expression. Using next-generation whole transcriptome sequencing (RNA-Seq) as a discovery tool, we analyzed fusion transcripts, gene expression profile, and somatic mutations in frozen tissue of one TFE3 tRCC. By applying a computational analysis developed to call chimeric RNA molecules from paired-end RNA-Seq data, we confirmed the known TFE3 translocation. Its fusion partner SFPQ has already been described as fusion partner in tRCCs. In addition, an RNA read-through chimera between TMED6 and COG8 as well as MET and KDR (VEGFR2) point mutations were identified. An EGFR mutation, but no chromosomal rearrangements, was identified in a control group of five clear cell RCCs (ccRCCs). The TFE3 tRCC could be clearly distinguished from the ccRCCs by RNA-Seq gene expression measurements using a previously reported tRCC gene signature. In validation experiments using reverse transcription-PCR, TMED6-COG8 chimera expression was significantly higher in nine TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in 24 ccRCCs (P < .001) and 22 papillary RCCs (P < .05-.07). Immunohistochemical analysis of selected genes from the tRCC gene signature showed significantly higher eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) and Contactin 3 (CNTN3) expression in 16 TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in over 200 ccRCCs (P < .0001, both).
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Everolimus in combination with paclitaxel and carboplatin in patients with metastatic melanoma: a phase II trial of the Sarah Cannon Research Institute Oncology Research Consortium.
Melanoma Res.
PUBLISHED: 08-24-2013
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This phase II trial examined the efficacy and toxicity of first-line treatment with everolimus, paclitaxel, and carboplatin in patients with advanced melanoma. Seventy patients with metastatic or locally advanced unresectable melanoma who had been untreated previously with chemotherapy or targeted agents received first-line treatment with everolimus (5 mg, orally, daily), paclitaxel (175 mg/m, intravenous, every 3 weeks), and carboplatin (area under the curve 6.0, intravenous, every 3 weeks). Response to treatment was assessed every 6 weeks; responding and stable patients received six cycles of paclitaxel and carboplatin, and subsequently continued single-agent everolimus until disease progression or unacceptable toxicity. Twelve patients (17%) showed objective responses (all partial); an additional 27 patients showed measurable tumor shrinkage. After a median follow-up of 15 months, the median progression-free survival was 4.0 months (95% confidence interval 2.8-5.0 months); the median survival for the entire group was 10.1 months. Myelosuppression was the most common grade 3/4 toxicity; 70% of patients experienced at least one episode of grade 3/4 toxicity while on study. Although this regimen was active in the first-line treatment of advanced melanoma, there was no suggestion of improved efficacy when compared with previous results with paclitaxel/carboplatin alone. Further study of this combination is not recommended.
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Association of Oncofetal Protein Expression with Clinical Outcomes in Patients with Urothelial Carcinoma of the Bladder.
J. Urol.
PUBLISHED: 08-19-2013
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Oncofetal proteins are expressed in the developing embryo. Oncofetal protein expression correlates with the clinical outcome of nonmuscle invasive UCB. IMP3, MAGE-A, glypican-3 and TPBG are oncofetal proteins that have not been well characterized in urothelial carcinoma of the bladder.
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Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing.
Nat. Biotechnol.
PUBLISHED: 06-24-2013
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As more clinically relevant cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies, raising the challenge of optimization and analytical validation of assays that interrogate millions of bases of cancer genomes altered by multiple mechanisms. Here we describe a test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes from routine formalin-fixed and paraffin-embedded (FFPE) clinical specimens. We implemented a practical validation strategy with reference samples of pooled cell lines that model key determinants of accuracy, including mutant allele frequency, indel length and amplitude of copy change. Test sensitivity achieved was 95-99% across alteration types, with high specificity (positive predictive value >99%). We confirmed accuracy using 249 FFPE cancer specimens characterized by established assays. Application of the test to 2,221 clinical cases revealed clinically actionable alterations in 76% of tumors, three times the number of actionable alterations detected by current diagnostic tests.
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Novel MIR143-NOTCH fusions in benign and malignant glomus tumors.
Genes Chromosomes Cancer
PUBLISHED: 06-19-2013
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Glomus tumors (GT) have been classified among tumors of perivascular smooth muscle differentiation, together with myopericytoma, myofibroma/tosis, and angioleiomyoma, based on their morphologic overlap. However, no molecular studies have been carried out to date to investigate their genetic phenotype and to confirm their shared pathogenesis. RNA sequencing was performed in three index cases (GT1, malignant GT; GT2, benign GT and M1, multifocal myopericytoma), followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired-end RNA-seq data. A gene fusion involving MIR143 in band 5q32 was identified in both GTs with either NOTCH2 in 1p13 in GT1 or NOTCH1 in 9q34 in GT2, but none in M1. After being validated by FISH and RT-PCR, these abnormalities were screened on 33 GTs, 6 myopericytomas, 9 myofibroma/toses, 18 angioleiomyomas and in a control group of 5 sino-nasal hemangiopericytomas. Overall NOTCH2 gene rearrangements were identified in 52% of GT, including all malignant cases and one NF1-related GT. No additional cases showed NOTCH1 rearrangement. As NOTCH3 shares similar functions with NOTCH2 in regulating vascular smooth muscle development, the study group was also investigated for abnormalities in this gene by FISH. Indeed, NOTCH3 rearrangements were identified in 9% of GTs, all present in benign soft tissue GT, one case being fused to MIR143. Only 1/18 angioleiomyomas showed NOTCH2 gene rearrangement, while all the myopericytomas and myofibroma/toses were negative. In summary, we describe novel NOTCH1-3 rearrangements in benign and malignant, visceral, and soft tissue GTs.
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Systematic review of telestroke for post-stroke care and rehabilitation.
Curr Atheroscler Rep
PUBLISHED: 06-14-2013
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Telemedicine for acute stroke care is supported by a literature base. It remains unclear whether or not the use of telemedicine for other phases of stroke care is beneficial. The authors conducted a systematic review of the published literature on telemedicine for the purposes of providing post-stroke care. Studies were included if the title or abstract expressed use of two-way audio/video communication for post-stroke care. From an initial yield of 1,405 potentially eligible hits, two reviewers ultimately identified 24 unique manuscripts to undergo functionality, application, technology, and evaluative (F.A.T.E.) scoring. Each article was classified using a scoring rubric to assess the functionality, application, technology, and evaluative stage. It was found that most post-stroke telemedicine studies evaluated rehabilitation of adults. All primary data manuscripts were small and preliminary in scope and evaluative phase, and median F.A.T.E. score for primary data was 2. The use of telemedicine for post-stroke care is nascent and is primarily focused on post-stroke rehabilitation.
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Role of telemedicine in providing tertiary neurological care.
Curr Treat Options Neurol
PUBLISHED: 06-11-2013
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Remote consultation via telemedicine for neurologic indications is in the mainstream. This holds most true for cerebrovascular concerns such as acute stroke, but its use has extended into most of the breadth of neurologic subspecialty practice. This is ostensibly a major advance for enhancing access to neurologic specialty care and a path toward better outcomes overall. Currently, there is a lack of randomized controlled trials and health economic analyses to support this conclusion. The continued use and expansion of teleneurologic practice is encouraged, so long as it is accompanied by clinical data tracking and leads to more randomized controlled trials. A solid evidence base should be established for its use such that future trials and monetary investments can be made with a better understanding of what teleneurology has to offer patients and society.
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Vascular diseases of the spinal cord.
Neurol Clin
PUBLISHED: 06-01-2013
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Vascular disease affecting the spinal can cause substantial neurologic morbidity. Several vascular spinal cord ailments present as neurologic emergencies, and should thus be recognizable to the practicing neurologist. We review the epidemiology, presentation, management strategies, and prognosis of various pathologies, including infarction, dural arteriovenous fistula, arteriovenous malformation, cavernous malformation, compressive epidural hematoma, vasculitis, and genetic abnormalities.
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Somatic copy number alterations by whole exome sequencing implicates YWHAZ and PTK2 in castration-resistant prostate cancer.
J. Pathol.
PUBLISHED: 04-22-2013
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Castration-resistant prostate cancer (CRPC) is the most aggressive form of prostate cancer (PCa) and remains a significant therapeutic challenge. The key to the development of novel therapeutic targets for CRPC is to decipher the molecular alterations underlying this lethal disease. The aim of our study was to identify therapeutic targets for CRPC by assessing somatic copy number alterations (SCNA) by whole exome sequencing on five CRPC/normal paired formalin fixed paraffin embedded (FFPE) samples using the SOLiD4 next generation sequencing (NGS) platform. Data were validated using fluorescence in-situ hybridization (FISH) on a PCa progression cohort. PTK2 and YWHAZ amplification, mRNA and protein expression were determined in selected PCa cell lines. Effects of PTK2 inhibition using TAE226 inhibitor and YWHAZ knockdown on cell proliferation and migration were tested in PC3 cells in vitro. In a larger validation cohort, the amplification frequency of YWHAZ was 3% in localized PCa and 48% in CRPC, whereas PTK2 was amplified in 1% of localized PCa and 35% in CRPC. YWHAZ knockdown and PTK2 inhibition significantly affected cell proliferation and migration in the PC3 cells. Our findings suggest that inhibition of YWHAZ and PTK2 could delay the progression of the disease in CRPC patients harboring amplification of the latter genes. Furthermore, our validated whole exome sequencing data shows that FFPE tissue could be a promising alternative for SCNA screening using next generation sequencing technologies.
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Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma.
Genes Chromosomes Cancer
PUBLISHED: 04-15-2013
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Conventional epithelioid hemangioendotheliomas (EHE) have a distinctive morphologic appearance and are characterized by a recurrent t(1;3) translocation, resulting in a WWTR1-CAMTA1 fusion gene. We have recently encountered a fusion-negative subset characterized by a somewhat different morphology, including focally well-formed vasoformative features, which was further investigated for recurrent genetic abnormalities. Based on a case showing strong transcription factor E3 (TFE3) immunoreactivity, fluorescence in situ hybridization (FISH) analysis for TFE3 gene rearrangement was applied to the index case as well as to nine additional cases, selected through negative WWTR1-CAMTA1 screening. A control group, including 18 epithelioid hemangiomas, nine pseudomyogenic HE, and three epithelioid angiosarcomas, was also tested. TFE3 gene rearrangement was identified in 10 patients, with equal gender distribution and a mean age of 30 years old. The lesions were located in somatic soft tissue in six cases, lung in three and one in bone. One case with available frozen tissue was tested by RNA sequencing and FusionSeq data analysis to detect novel fusions. A YAP1-TFE3 fusion was thus detected, which was further validated by FISH and reverse transcription polymerase chain reaction (RT-PCR). YAP1 gene rearrangements were then confirmed in seven of the remaining nine TFE3-rearranged EHEs by FISH. No TFE3 structural abnormalities were detected in any of the controls. The TFE3-rearranged EHEs showed similar morphologic features with at least focally, well-formed vascular channels, in addition to a variably solid architecture. All tumors expressed endothelial markers, as well as strong nuclear TFE3. In summary, we are reporting a novel subset of EHE occurring in young adults, showing a distinct phenotype and YAP1-TFE3 fusions.
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The mutational landscape of prostate cancer.
Eur. Urol.
PUBLISHED: 04-08-2013
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Prostate cancer (PCa) is a clinically heterogeneous disease with marked variability in patient outcomes. Molecular characterization has revealed striking mutational heterogeneity that may underlie the variable clinical course of the disease.
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Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 04-04-2013
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The p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2 [nuclear receptor coactivator (NCOA)2], and SRC-3 [amplified in breast cancer 1 (AIB1)/NCOA3] are key pleiotropic "master regulators" of transcription factor activity necessary for cancer cell proliferation, survival, metabolism, and metastasis. SRC overexpression and overactivation occur in numerous human cancers and are associated with poor clinical outcomes and resistance to therapy. In prostate cancer (PC), the p160 SRCs play critical roles in androgen receptor transcriptional activity, cell proliferation, and resistance to androgen deprivation therapy. We recently demonstrated that the E3 ubiquitin ligase adaptor speckle-type poxvirus and zinc finger (POZ) domain protein (SPOP) interacts directly with SRC-3 and promotes its cullin 3-dependent ubiquitination and proteolysis in breast cancer, thus functioning as a potential tumor suppressor. Interestingly, somatic heterozygous missense mutations in the SPOP substrate-binding cleft recently were identified in up to 15% of human PCs (making SPOP the gene most commonly affected by nonsynonymous point mutations in PC), but their contribution to PC pathophysiology remains unknown. We now report that PC-associated SPOP mutants cannot interact with SRC-3 protein or promote its ubiquitination and degradation. Our data suggest that wild-type SPOP plays a critical tumor suppressor role in PC cells, promoting the turnover of SRC-3 protein and suppressing androgen receptor transcriptional activity. This tumor suppressor effect is abrogated by the PC-associated SPOP mutations. These studies provide a possible explanation for the role of SPOP mutations in PC, and highlight the potential of SRC-3 as a therapeutic target in PC.
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Frequent truncating mutations of STAG2 in bladder cancer.
Nat. Genet.
PUBLISHED: 03-19-2013
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Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Our studies suggest that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells. These findings identify STAG2 as one of the most commonly mutated genes in bladder cancer.
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Molecular archeology: unearthing androgen-induced structural rearrangements in prostate cancer genomes.
Cancer Cell
PUBLISHED: 02-16-2013
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In this issue of Cancer Cell, Weischenfeldt and colleagues report on the whole genome sequencing of 11 early-onset prostate cancers. Compared to elderly onset prostate cancer, these tumors demonstrate enrichment for androgen-driven structural rearrangements involving ETS family genes. This study confirms observations that prostate cancer manifests discrete genomic subclasses.
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A systematic review of telestroke.
Postgrad Med
PUBLISHED: 02-09-2013
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The use of 2-way audiovisual (AV) technology for delivery of acute stroke evaluation and management, termed "telestroke," is supported by a rapidly growing literature base. A systematic review that provides a comprehensive, easily digestible overview of telestroke science and practice is lacking.
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Variants at IRX4 as prostate cancer expression quantitative trait loci.
Eur. J. Hum. Genet.
PUBLISHED: 02-06-2013
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Genome-wide association studies (GWAS) have identified numerous prostate cancer-associated risk loci. Some variants at these loci may be regulatory and influence expression of nearby genes. Such loci are known as cis-expression quantitative trait loci (cis-eQTL). As cis-eQTLs are highly tissue-specific, we asked if GWAS-identified prostate cancer risk loci are cis-eQTLs in human prostate tumor tissues. We investigated 50 prostate cancer samples for their genotype at 59 prostate cancer risk-associated single-nucleotide polymorphisms (SNPs) and performed cis-eQTL analysis of transcripts from paired primary tumors within two megabase windows. We tested 586 transcript-genotype associations, of which 27 were significant (false discovery rate ?10%). An equivalent eQTL analysis of the same prostate cancer risk loci in lymphoblastoid cell lines did not result in any significant associations. The top-ranked cis-eQTL involved the IRX4 (Iroquois homeobox protein 4) transcript and rs12653946, tagged by rs10866528 in our study (P=4.91 × 10(-5)). Replication studies, linkage disequilibrium, and imputation analyses highlight population specificity at this locus. We independently validated IRX4 as a potential prostate cancer risk gene through cis-eQTL analysis of prostate cancer risk variants. Cis-eQTL analysis in relevant tissues, even with a small sample size, can be a powerful method to expedite functional follow-up of GWAS.European Journal of Human Genetics advance online publication, 11 September 2013; doi:10.1038/ejhg.2013.195.
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The alien limb phenomenon.
J. Neurol.
PUBLISHED: 02-04-2013
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Alien limb phenomenon refers to involuntary motor activity of a limb in conjunction with the feeling of estrangement from that limb. Alien limb serves as a diagnostic feature of corticobasal syndrome. Our objective was to determine the differential diagnoses of alien limb and to determine the features in a large group of patients with the alien limb with different underlying etiologies. We searched the Mayo Clinic Medical Records Linkage system to identify patients with the diagnosis of alien limb seen between January 1, 1996, and July 11, 2011. One hundred and fifty patients with alien limb were identified. Twenty-two were followed in the Alzheimers Disease Research Center. Etiologies of alien limb included corticobasal syndrome (n = 108), stroke (n = 14), Creutzfeldt Jakob disease (n = 9), hereditary diffuse leukoencephalopathy with spheroids (n = 5), tumor (n = 4), progressive multifocal leukoencephalopathy(n = 2), demyelinating disease (n = 2), progressive dementia not otherwise specified (n = 2), posterior reversible encephalopathy syndrome (n = 1), corpus callosotomy (n = 1), intracerebral hemorrhage (n = 1) and thalamic dementia (n = 1). Ten of 14 cerebrovascular cases were right hemisphere in origin. All cases involved the parietal lobe. Of the 44 patients with corticobasal syndrome from the Alzheimers Disease Research Center cohort, 22 had alien limb, and 73 % had the alien limb affecting the left extremities. Left sided corticobasal syndrome was significantly associated with the presence of alien limb (p = 0.004). These findings support the notion that the alien limb phenomenon is partially related to damage underlying the parietal cortex, especially right parietal, disconnecting it from other cortical areas.
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Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer.
Neoplasia
PUBLISHED: 01-30-2013
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Neuroendocrine prostate cancer (NEPC), also referred to as anaplastic prostate cancer, is a lethal tumor that most commonly arises in late stages of prostate adenocarcinoma (PCA) with predilection to metastasize to visceral organs. In the current study, we explore for evidence that Aurora kinase A (AURKA) and N-myc (MYCN) gene abnormalities are harbingers of treatment-related NEPC (t-NEPC). We studied primary prostate tissue from 15 hormone naïve PCAs, 51 castration-resistant prostate cancers, and 15 metastatic tumors from 72 patients at different stages of disease progression to t-NEPC, some with multiple specimens. Histologic evaluation, immunohistochemistry, and fluorescence in situ hybridization were performed and correlated with clinical variables. AURKA amplification was identified in overall 65% of PCAs (hormone naïve and treated) from patients that developed t-NEPC and in 86% of metastases. Concurrent amplification of MYCN was present in 70% of primary PCAs, 69% of treated PCAs, and 83% of metastases. In contrast, in an unselected PCA cohort, AURKA and MYCN amplifications were identified in only 5% of 169 cases. When metastatic t-NEPC was compared to primary PCA from the same patients, there was 100% concordance of ERG rearrangement, 100% concordance of AURKA amplification, and 60% concordance of MYCN amplification. In tumors with mixed features, there was also 100% concordance of ERG rearrangement and 94% concordance of AURKA and MYCN co-amplification between areas of NEPC and adenocarcinoma. AURKA and MYCN amplifications may be prognostic and predictive biomarkers, as they are harbingers of tumors at risk of progressing to t-NEPC after hormonal therapy.
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Epigenomic alterations in localized and advanced prostate cancer.
Neoplasia
PUBLISHED: 01-28-2013
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Although prostate cancer (PCa) is the second leading cause of cancer death among men worldwide, not all men diagnosed with PCa will die from the disease. A critical challenge, therefore, is to distinguish indolent PCa from more advanced forms to guide appropriate treatment decisions. We used Enhanced Reduced Representation Bisulfite Sequencing, a genome-wide high-coverage single-base resolution DNA methylation method to profile seven localized PCa samples, seven matched benign prostate tissues, and six aggressive castration-resistant prostate cancer (CRPC) samples. We integrated these data with RNA-seq and whole-genome DNA-seq data to comprehensively characterize the PCa methylome, detect changes associated with disease progression, and identify novel candidate prognostic biomarkers. Our analyses revealed the correlation of cytosine guanine dinucleotide island (CGI)-specific hypermethylation with disease severity and association of certain breakpoints (deletion, tandem duplications, and interchromosomal translocations) with DNA methylation. Furthermore, integrative analysis of methylation and single-nucleotide polymorphisms (SNPs) uncovered widespread allele-specific methylation (ASM) for the first time in PCa. We found that most DNA methylation changes occurred in the context of ASM, suggesting that variations in tumor epigenetic landscape of individuals are partly mediated by genetic differences, which may affect PCa disease progression. We further selected a panel of 13 CGIs demonstrating increased DNA methylation with disease progression and validated this panel in an independent cohort of 20 benign prostate tissues, 16 PCa, and 8 aggressive CRPCs. These results warrant clinical evaluation in larger cohorts to help distinguish indolent PCa from advanced disease.
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Lenalidomide in combination with gemcitabine as first-line treatment for patients with metastatic carcinoma of the pancreas: a Sarah Cannon Research Institute phase II trial.
Cancer Biol. Ther.
PUBLISHED: 01-28-2013
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To evaluate the 6-mo overall survival, safety and tolerability of lenalidomide in combination with standard gemcitabine as first-line treatment for patients with metastatic pancreatic cancer.
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V-ets erythroblastosis virus E26 oncogene homolog (avian)/Trefoil factor 3/high-molecular-weight cytokeratin triple immunostain: a novel tissue-based biomarker in prostate cancer with potential clinical application.
Hum. Pathol.
PUBLISHED: 01-25-2013
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Trefoil factor 3 (TFF3) is associated with various cancers and overexpressed in a subset of prostate cancers. Functional studies suggest that v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) down-regulates TFF3 expression in hormone-naïve prostate cancer. To characterize this inverse relationship, we developed a triple immunostain encompassing ERG, TFF3, and high-molecular-weight cytokeratin. Triple stain was performed on 96 tumors and 52 benign cases represented in tissue microarrays. Distinct ERG and TFF3 protein was expressed in 45% (43/96) and 36% (35/96) of prostate cancers, respectively. Coexpression was observed in 5% (5/96) of tumor cases, and 24% (23/96) did not express ERG or TFF3. The inverse expression of ERG and TFF3 was significant (P < .0001), with 57% (30/53) of ERG-negative tumors demonstrating TFF3 expression. Sensitivity and specificity of combined ERG and TFF3 expression in detecting prostate cancer were 76% and 96%, respectively. The feasibility of triple immunostain protocol was validated in a set of 76 needle biopsies. The application of this multiplex in situ biomarker for molecular characterization of prostate cancer and as a supplemental diagnostic and prognostic tool in prostate needle biopsies should be further explored.
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Novel dual-color immunohistochemical methods for detecting ERG-PTEN and ERG-SPINK1 status in prostate carcinoma.
Mod. Pathol.
PUBLISHED: 01-25-2013
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Identification of new molecular markers has led to the molecular classification of prostate cancer based on driving genetic lesions. The translation of these discoveries for clinical use necessitates the development of simple, reliable and rapid detection systems to screen patients for specific molecular aberrations. We developed two dual-color immunohistochemistry-based assays for the simultaneous assessment of ERG-PTEN and ERG-SPINK1 in prostate cancer. A total of 232 cases from 184 localized and 48 metastatic prostate cancers were evaluated for ERG-PTEN and 284 cases from 228 localized and 56 metastatic prostate cancers were evaluated for ERG-SPINK1. Of the 232 cases evaluated for ERG-PTEN, 81 (35%) ERG-positive and 77 (33%) PTEN-deleted cases were identified. Of the 81 ERG-positive cases, PTEN loss was confirmed in 35 (15%) cases by fluorescence in situ hybridization (FISH). PTEN status was concordant in 203 cases (sensitivity 90% and specificity 87%; P<0.0001) by both immunohistochemisty and FISH; however, immunohistochemisty could not distinguish between heterozygous and homozygous deletion status of PTEN. Of the 284 cases evaluated for ERG-SPINK1, 111 (39%) cases were positive for ERG. In the remaining 173 ERG-negative cases, SPINK1 was positive in 26 (9%) cases. SPINK1 expression was found to be mutually exclusive with ERG expression; however, we identified two cases, of which one showed concomitant expression of ERG and SPINK1 in the same tumor foci, and in the second case ERG and SPINK1 were seen in two independent foci of the same tumor nodule. Unlike the homogenous ERG staining in cancer tissues, heterogeneous SPINK1 staining was observed in the majority of the cases. Further studies are required to understand the molecular heterogeneity of cases with concomitant ERG-SPINK1 expression. Automated dual ERG-PTEN and ERG-SPINK1 immunohistochemisty assays are simple, reliable and portable across study sites for the simultaneous assessment of these proteins in prostate cancer.
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Impact of constitutional copy number variants on biological pathway evolution.
BMC Evol. Biol.
PUBLISHED: 01-18-2013
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Inherited Copy Number Variants (CNVs) can modulate the expression levels of individual genes. However, little is known about how CNVs alter biological pathways and how this varies across different populations. To trace potential evolutionary changes of well-described biological pathways, we jointly queried the genomes and the transcriptomes of a collection of individuals with Caucasian, Asian or Yoruban descent combining high-resolution array and sequencing data.
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Punctuated evolution of prostate cancer genomes.
Cell
PUBLISHED: 01-17-2013
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The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term "chromoplexy," frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events along which chromoplexy may drive prostate carcinogenesis.
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Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma.
Genes Chromosomes Cancer
PUBLISHED: 01-09-2013
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Spindle cell rhabdomyosarcoma (RMS) is a rare form of RMS with different clinical characteristics between children and adult patients. Its genetic hallmark remains unknown and it remains debatable if there is pathogenetic relationship between the spindle cell and the so-called sclerosing RMS. We studied two pediatric and one adult spindle cell RMS by next generation RNA sequencing and FusionSeq data analysis to detect novel fusions. An SRF-NCOA2 fusion was detected in a spindle cell RMS from the posterior neck in a 7-month-old child. The fusion matched the tumor karyotype and was confirmed by FISH and RT-PCR, which showed fusion of SRF exon 6 to NCOA2 exon 12. Additional 14 spindle cell (from 8 children and 6 adults) and 4 sclerosing (from 2 children and 2 adults) RMS were tested by FISH for the presence of abnormalities in NCOA2, SRF, as well as for PAX3 and NCOA1. NCOA2 rearrangements were found in two additional spindle cell RMS from a 3-month-old and a 4-week-old child. In the latter tumor, TEAD1 was identified by rapid amplification of cDNA ends (RACE) to be the NCOA2 gene fusion partner. None of the adult tumors were positive for NCOA2 rearrangement. Despite similar histomorphology in adults and young children, these results suggest that spindle cell RMS is a heterogeneous disease genetically as well as clinically. Our findings also support a relationship between NCOA2-rearranged spindle cell RMS occurring in young childhood and the so-called congenital RMS, which often displays rearrangements at 8q13 locus (NCOA2).
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Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium Phase II Trial.
Clin Genitourin Cancer
PUBLISHED: 01-02-2013
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This phase II trial examined the activity and toxicity of second-line treatment with pazopanib after failure of first-line single-agent treatment with sunitinib or bevacizumab in patients with advanced clear cell renal carcinoma.
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Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets.
Cancer Discov
PUBLISHED: 12-15-2011
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Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that most commonly evolves from preexisting prostate adenocarcinoma (PCA). Using Next Generation RNA-sequencing and oligonucleotide arrays, we profiled 7 NEPC, 30 PCA, and 5 benign prostate tissue (BEN), and validated findings on tumors from a large cohort of patients (37 NEPC, 169 PCA, 22 BEN) using IHC and FISH. We discovered significant overexpression and gene amplification of AURKA and MYCN in 40% of NEPC and 5% of PCA, respectively, and evidence that that they cooperate to induce a neuroendocrine phenotype in prostate cells. There was dramatic and enhanced sensitivity of NEPC (and MYCN overexpressing PCA) to Aurora kinase inhibitor therapy both in vitro and in vivo, with complete suppression of neuroendocrine marker expression following treatment. We propose that alterations in Aurora kinase A and N-myc are involved in the development of NEPC, and future clinical trials will help determine from the efficacy of Aurora kinase inhibitor therapy.
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Common structural and epigenetic changes in the genome of castration-resistant prostate cancer.
Cancer Res.
PUBLISHED: 12-07-2011
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Progression of primary prostate cancer to castration-resistant prostate cancer (CRPC) is associated with numerous genetic and epigenetic alterations that are thought to promote survival at metastatic sites. In this study, we investigated gene copy number and CpG methylation status in CRPC to gain insight into specific pathophysiologic pathways that are active in this advanced form of prostate cancer. Our analysis defined and validated 495 genes exhibiting significant differences in CRPC in gene copy number, including gains in androgen receptor (AR) and losses of PTEN and retinoblastoma 1 (RB1). Significant copy number differences existed between tumors with or without AR gene amplification, including a common loss of AR repressors in AR-unamplified tumors. Simultaneous gene methylation and allelic deletion occurred frequently in RB1 and HSD17B2, the latter of which is involved in testosterone metabolism. Lastly, genomic DNA from most CRPC was hypermethylated compared with benign prostate tissue. Our findings establish a comprehensive methylation signature that couples epigenomic and structural analyses, thereby offering insights into the genomic alterations in CRPC that are associated with a circumvention of hormonal therapy. Genes identified in this integrated genomic study point to new drug targets in CRPC, an incurable disease state which remains the chief therapeutic challenge.
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The relationship between the need for closure and deviant bias: an investigation of generality and process.
Int J Psychol
PUBLISHED: 11-03-2011
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The need for closure predicts an evaluative bias against people whose opinions or behaviors deviate from those of other members of their social groups. In the present study, we investigated whether the relationship between the need for closure and deviant bias generalized to nonsocial stimuli, and we examined the process underlying this relationship. Sixty-one undergraduate students completed measures of the need for closure, the need for structure, intolerance for ambiguity, and the ability to be decisive and achieve cognitive structure. They then rated their liking for letters of the Latin alphabet ("A" & "B") whose locations were consistent and inconsistent with relevant categories ("A circle" and "B circle"). Participants liked category-inconsistent letters less than category-consistent letters. Measures related to the need for structure and closed-mindedness correlated positively with this deviant bias, whereas measures related to the ability to be decisive and achieve cognitive structure did not. These results imply that the relationship between the need for closure and deviant bias is a relatively basic and pervasive effect that is not unique to social deviance and is driven by the need for structure and closed-mindedness. Implications for social and nonsocial stimuli are discussed.
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Identification and synthesis of new volatile molecules found in extracts obtained from distinct parts of cooked chicken.
J. Agric. Food Chem.
PUBLISHED: 10-10-2011
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Several chicken parts (skin, fat, juice) were cooked in different ways (roasting, simmering) and investigated separately for their volatile composition. In-depth GC/MS analysis of the separate fractions revealed several unknown molecules. Mass spectra interpretation allowed us to identify nine molecules for the first time in chicken, including cyclic aldehydes, cyclic ketones, and new ?-lactones containing an unsaturated linear chain. Identification was confirmed by chemical synthesis followed by comparison of the mass spectra and linear retention indices. The natural occurrence of five of these molecules is reported here for the first time in a natural product.
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Combined modality treatment with chemotherapy, radiation therapy, bevacizumab, and erlotinib in patients with locally advanced squamous carcinoma of the head and neck: a phase II trial of the Sarah Cannon oncology research consortium.
Cancer J
PUBLISHED: 09-29-2011
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: The aim of the study was to evaluate the feasibility and efficacy of adding bevacizumab and erlotinib to concurrent chemoradiation therapy for first-line treatment of patients with locally advanced squamous carcinoma of the head and neck.
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Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma.
Sci Transl Med
PUBLISHED: 09-03-2011
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Integrating transcriptomic sequencing with conventional cytogenetics, we identified WWTR1 (WW domain-containing transcription regulator 1) (3q25) and CAMTA1 (calmodulin-binding transcription activator 1) (1p36) as the two genes involved in the t(1;3)(p36;q25) chromosomal translocation that is characteristic of epithelioid hemangioendothelioma (EHE), a vascular sarcoma. This WWTR1/CAMTA1 gene fusion is under the transcriptional control of the WWTR1 promoter and encodes a putative chimeric transcription factor that joins the amino terminus of WWTR1, a protein that is highly expressed in endothelial cells, in-frame to the carboxyl terminus of CAMTA1, a protein that is normally expressed only in brain. Thus, CAMTA1 expression is activated inappropriately through a promoter-switch mechanism. The gene fusion is present in virtually all EHEs tested but is absent from all other vascular neoplasms, demonstrating it to be a disease-defining genetic alteration. A sensitive and specific break-apart fluorescence in situ hybridization assay was also developed to detect the translocation and will assist in the evaluation of this diagnostically challenging neoplasm. The chimeric WWTR1/CAMTA1 transcription factor may represent a therapeutic target for EHE and offers the opportunity to shed light on the functions of two poorly characterized proteins.
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Common gene rearrangements in prostate cancer.
J. Clin. Oncol.
PUBLISHED: 08-22-2011
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Prostate cancer is a common heterogeneous disease, and most patients diagnosed in the post prostate-specific antigen (PSA) era present with clinically localized disease, the majority of which do well regardless of treatment regimen undertaken. Overall, those with advanced prostate cancer at time of diagnosis do poorly after androgen withdrawal therapy. Understanding the biologic underpinning of prostate cancer is necessary to best determine the risk of disease progression and would be advantageous for the development of novel therapeutic approaches to impede or prevent disease. This review focuses on the recently identified common ETS and non-ETS gene rearrangements in prostate cancer. Although multiple molecular alterations have been detected in prostate cancer, a detailed understanding of gene fusion prostate cancer should help explain the clinical and biologic diversity, providing a rationale for a molecular subclassification of the disease.
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Validation of a TFE3 break-apart FISH assay for Xp11.2 translocation renal cell carcinomas.
Diagn. Mol. Pathol.
PUBLISHED: 08-06-2011
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Renal cell carcinomas (RCCs) with an Xp11.2 translocation predominantly affect young patients, and can present at an advanced stage. However, more cases in older patients and incidentally detected cancers at earlier stages are also being identified. As the histology of Xp11.2 RCCs overlaps with clear cell and papillary RCCs, it is not infrequent that Xp11.2 RCCs are overlooked and misdiagnosed. The objective of this study was to validate the use of fluorescence in-situ hybridization (FISH) for identifying Xp11.2 RCCs. One hundred fifty-eight consecutive, unselected renal tumors were evaluated in tissue microarrays, including 109 clear cell RCCs, 20 papillary RCCs, 3 RCCs with mixed papillary and clear cell features, 1 Xp11.2 translocation RCC, 8 chromophobe RCCs, 10 oncocytomas, and 7 angiomyolipomas. FISH evaluation was performed blinded to karyotype data, available in about two-thirds of cases. Furthermore, conventional sections of 4 Xp11.2 RCCs, 4 RCCs with mixed papillary and clear cell features, and 4 cases of alveolar soft part sarcoma (the latter for control purposes) were also assessed by FISH. Break-apart signals were homogeneously identified throughout tumor cells in 2 cases from the tissue microarrays including 1 known Xp11.2 RCC and 1 misdiagnosed Xp11.2 RCC. All conventional sections from the Xp11.2 RCC and alveolar soft part sarcoma cases were positive for the TFE3 rearrangement by FISH. All remaining cases were negative. Our study shows the clinical application of FISH in formalin-fixed, paraffin-embedded tissue for detection of Xp11.2 translocation RCCs and other tumors with this genetic aberration.
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Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA.
Sci Transl Med
PUBLISHED: 08-05-2011
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More than 1,000,000 men undergo prostate biopsy each year in the United States, most for "elevated" serum prostate-specific antigen (PSA). Given the lack of specificity and unclear mortality benefit of PSA testing, methods to individualize management of elevated PSA are needed. Greater than 50% of PSA-screened prostate cancers harbor fusions between the transmembrane protease, serine 2 (TMPRSS2) and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) genes. Here, we report a clinical-grade, transcription-mediated amplification assay to risk stratify and detect prostate cancer noninvasively in urine. The TMPRSS2:ERG fusion transcript was quantitatively measured in prospectively collected whole urine from 1312 men at multiple centers. Urine TMPRSS2:ERG was associated with indicators of clinically significant cancer at biopsy and prostatectomy, including tumor size, high Gleason score at prostatectomy, and upgrading of Gleason grade at prostatectomy. TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy. In the biopsy cohorts, men in the highest and lowest of three TMPRSS2:ERG+PCA3 score groups had markedly different rates of cancer, clinically significant cancer by Epstein criteria, and high-grade cancer on biopsy. Our results demonstrate that urine TMPRSS2:ERG, in combination with urine PCA3, enhances the utility of serum PSA for predicting prostate cancer risk and clinically relevant cancer on biopsy.
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AlleleSeq: analysis of allele-specific expression and binding in a network framework.
Mol. Syst. Biol.
PUBLISHED: 07-07-2011
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To study allele-specific expression (ASE) and binding (ASB), that is, differences between the maternally and paternally derived alleles, we have developed a computational pipeline (AlleleSeq). Our pipeline initially constructs a diploid personal genome sequence (and corresponding personalized gene annotation) using genomic sequence variants (SNPs, indels, and structural variants), and then identifies allele-specific events with significant differences in the number of mapped reads between maternal and paternal alleles. There are many technical challenges in the construction and alignment of reads to a personal diploid genome sequence that we address, for example, bias of reads mapping to the reference allele. We have applied AlleleSeq to variation data for NA12878 from the 1000 Genomes Project as well as matched, deeply sequenced RNA-Seq and ChIP-Seq data sets generated for this purpose. In addition to observing fairly widespread allele-specific behavior within individual functional genomic data sets (including results consistent with X-chromosome inactivation), we can study the interaction between ASE and ASB. Furthermore, we investigate the coordination between ASE and ASB from multiple transcription factors events using a regulatory network framework. Correlation analyses and network motifs show mostly coordinated ASB and ASE.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.