tbuckley/cabot-search huggingface dataset:
Absent MicroRNAs in Different Tissues of Patients with Acquired Cardiomyopathy
Authors: Christine S. Siegismund, Maria Rohde, Uwe Kühl, Felicitas Escher, Heinz Peter Schultheiss, Dirk Lassner
Journal: Genomics Proteomics & Bioinformatics (2016)

MicroRNAs (miRNAs) can be found in a wide range of tissues and body fluids, and their specific signatures can be used to determine diseases or predict clinical courses. The miRNA profiles in biological samples (tissue, serum, peripheral blood mononuclear cells or other body fluids) differ significantly even in the same patient and therefore have their own specificity for the presented condition. Complex profiles of deregulated miRNAs are of high interest, whereas the importance of non-expressed miRNAs was ignored. Since miRNAs regulate gene expression rather negatively, absent miRNAs could indicate genes with unaltered expression that therefore are normally expressed in specific compartments or under specific disease situations. For the first time, non-detectable miRNAs in different tissues and body fluids from patients with different diseases (cardiomyopathies, Alzheimer's disease, bladder cancer, and ocular cancer) were analyzed and compared in this study. miRNA expression data were generated by microarray or TaqMan PCR-based platforms. Lists of absent miRNAs of primarily cardiac patients (myocardium, blood cells, and serum) were clustered and analyzed for potentially involved pathways using two prediction platforms, i.e., miRNA enrichment analysis and annotation tool (miEAA) and DIANA miRPath. Extensive search in biomedical publication databases for the relevance of non-expressed miRNAs in predicted pathways revealed no evidence for their involvement in heart-related pathways as indicated by software tools, confirming proposed approach.
Study was not designed to measure prevalence
Authors: S. Jones, I. Jones
Journal: BMJ (1996)

Table 1-Comparison of intemal malignancies between patients with multiple basal cell carcinomas and controls Malignancy Cases Controls Haematological* 5 Ot Breast 3 1 Gastrointestinal tract 1 2 Genitournary tract 4 4 Total 13 7*Four patients had non-Hodgkin's lymphoma and one had chronic myeloid leukaemia.tP = 0.
Abstract 482: Atypical expression of βV-tubulin in secretory cells of the fallopian tube as a biomarker for early dysplasia
Authors: Deepti Mathew, Yanhua Wang, Anne Van Arsdale, Susan Band Horwitz, Hayley McDaid
Journal: Cancer Research (2016)

Abstract Class V βeta tubulin isotype (βV-tubulin), was recently found to have a tissue-specific expression pattern in epithelial tissues with secretory function, and deregulated expression in certain tumors. The overall aim of this study was to define the localization of βV-tubulin in the fallopian tube and its expression in pre-malignant dysplasia. Fallopian tube epithelium (FTE) was obtained from patients undergoing salpingectomy for various reasons including familial history that comprised BRCA mutant cases. Additionally, βV-tubulin expression was also examined in serous ovarian neoplasms. Immunohistochemistry, using a novel antibody developed in our lab against human βV-tubulin, was used to evaluate expression in paraffin-embedded sections of the distal fallopian tube (n = 55) and tumors (n = 13), from prospectively selected cases, categorized according to reasons for salpingectomy. Staining with standard markers, Pax-8 and acetylated α-tubulin was done to demarcate the secretory and ciliated cells of the FTE, respectively. Pilot data indicate that in the FTE, βV-tubulin is present in secretory cells and essentially never in ciliated cells. Morphologically “normal” FTE had only rare, scattered βV-tubulin positive cells; whereas, percentage positivity was increased in cases with serous ovarian neoplasms, and BRCA-wildtype familial breast cancer. The highest expression was observed in FTE from patients with BRCA-mutant breast cancers. Four distinct types of FTE atypia were observed in patients with known BRCA mutations. βV-tubulin was highly expressed in serous ovarian neoplasms, with the extent and intensity of staining elevated in high-grade serous carcinomas, compared to serous borderline tumors. In summary, βV-tubulin was localized to secretory cells of the distal FTE and its expression varied according to the clinical diagnosis. The frequency of these cells, and thus expression of βV-tubulin was dramatically enriched in tissue obtained from BRCA mutant cases. BRCA mutants also exhibited pronounced histologic atypia indicative of early dysplasia. Furthermore, elevated expression of βV-tubulin correlated with poor differentiation status in serous ovarian neoplasms. Citation Format: Deepti Mathew, Yanhua Wang, Anne Van Arsdale, Susan Band Horwitz, Hayley McDaid. Atypical expression of βV-tubulin in secretory cells of the fallopian tube as a biomarker for early dysplasia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 482.
Abstract LB-046: Mechanism and consequences of HDAC6 regulation by RanBPM
Authors: Louisa Salemi, Xu Wang, David Hess, Caroline Schild-Poulter
Journal: Cancer Research (2016)

Abstract Ran-binding protein M (RanBPM) has been shown to interact with numerous proteins, implicating it in a variety of cellular processes including cell adhesion, migration, microtubule dynamics, and gene transcription. Work in our laboratory previously identified RanBPM as an activator of apoptosis induced by DNA damage. Our studies have also suggested a tumour suppressor role for RanBPM, as its downregulation not only disrupted apoptotic activation, but lead to loss of growth factor dependence and increased rates of cell migration. Here we show that RanBPM downregulation promotes tumour formation in orthotopic and metastasis mouse models, further suggesting a tumour-suppressive function for RanBPM. Recently, we characterized an interaction between RanBPM and Histone Deacetylase 6 (HDAC6). HDAC6 is a cytoplasmic deacetylase with an important role in cell migration. Its substrates include α-tubulin, cortactin and Hsp90. Increased HDAC6 expression and/or activity has been demonstrated to promote cell migration and tissue invasiveness. HDAC6 has also been shown to be required for oncogenic transformation and tumour formation. Upregulated HDAC6 has been observed in a number of different cancers and recently, specific HDAC6 inhibitors have been found to inhibit cell growth and prevent tumour formation in mouse models. We previously identified that the interaction between RanBPM and HDAC6 mediates the inhibition of HDAC6. Here we demonstrate that the LisH domain of RanBPM specifically, is responsible for the association with HDAC6. RanBPM also interacts with α-tubulin at microtubules and this localization is dependent on HDAC6, whereas HDAC6 localization at microtubules is independent of RanBPM. RanBPM has been identified to be part of a large protein complex, termed the CTLH complex. Components of the complex are conserved from the homologous yeast complex, the Gid complex, which functions as an E3 ubiquitin ligase complex. Here we evaluate HDAC6 regulation by the CTLH complex and asses co-localization of the CTLH complex with microtubules, specifically α-tubulin. Overall, our results suggest that the tumour suppressor functions of RanBPM could stem, at least in part from an inhibition of the oncogenic activities of HDAC6. Citation Format: Louisa Salemi, Xu Wang, David Hess, Caroline Schild-Poulter. Mechanism and consequences of HDAC6 regulation by RanBPM. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-046.
Abstract 1414: Treatment outcome under cetuximab-based therapy and individual ADCC capability in head and neck cancer
Authors: Cristiana Lo Nigro, Laura Lattanzio, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Giuliana Strola, Marco Merlano, Gerard Milano
Journal: Cancer Research (2016)

Abstract Introduction Cetuximab is a IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR) used for head and neck squamous cell carcinoma (HNSCC) treatment. In addition to EGFR targeting, cetuximab is able to develop an antibody-dependent cell-mediated cytotoxicity (ADCC), triggered by Fc receptors (Fcγ-R) on Natural Killer cells, macrophages and polymorphonucleated leukocytes. This prospective study examined the possible prognostic value of cetuximab-mediated ADCC response in a cohort of HNSCC patients. Patients and Methods There were 63 patients treated with curative intent with chemo-radiotherapy (CT-RT), associated (N = 39) or not (N = 24) with cetuximab. Peripheral blood samples were collected at start of therapy. Intrinsic ADCC was evaluated from ex vivo NK-dependent activity measuring LDH release through the Cytotox 96® non radioactive cytotoxicity assay, previously standardized in our laboratory (Crit Rev Oncol Hematol, 2015). EGFR tumoral expression was analyzed by immunohistochemistry. Results Median ADCC response at treatment start for all patients was 56.1% (range 5-99%). Analysing the whole population, patients with ADCC above the median value (high) showed a better OS as compared to patients with ADCC below the median (low), HR = 0.3827 (95% CI, 0.1464 to 1.000), p = 0.05 (Long-rank Mantel-Cox Test). A sub-group analysis confirmed a possible link between high ADCC and a better OS (CT-RT group, p = 0.223 and CT-RT+cetuximab group, p = 0.244). Importantly, considering CT-RT+cetuximab treatment and EGFR tumoral expression (N = 21), patients with EGFR 3+ status and high ADCC showed an improved OS as compared to patients with ADCC below median value, HR = 0.09031 (95% CI, 0.009983 to 0.8170), p = 0.032 (Long-rank Mantel-Cox Test). Median OS values for patients with high EGFR expression were 34.8 months (range 9.1-53.7) and 13.1 months (range 2.1-39.5) for patients with respectively high ADCC and low ADCC. Conclusion ADCC is shown to be a strong driver of cetuximab-based therapy outcome in HNSCC. High tumoral EGFR expression and high ADCC confer a particularly long overall survival. These data suggest an ADCC-based and EGFR expression-based precision therapy under cetuximab in HNSCC and open perspectives for NK boosting. Citation Format: Cristiana Lo Nigro, Laura Lattanzio, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Giuliana Strola, Marco Merlano, Gerard Milano. Treatment outcome under cetuximab-based therapy and individual ADCC capability in head and neck cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1414.
Abstract LB-290: UCSC TumorMap: Exploring cancer signatures on an interactive dynamic landscape
Authors: Yulia Newton, Adam Novak, Teresa Swatlowski, Sahil Chopra, Sofie Salama, Olena Morozova, David Haussler, Joshua Stuart
Journal: Cancer Research (2016)

Abstract Cancer is caused by accumulated changes in a cell's DNA sequence that disrupt the regulation of genetic networks. Mutation type, cell of origin, and tissue microenvironment all influence the initiation and progression of disease. The Cancer Genome Atlas (TCGA) catalogues the molecular changes of thousands of tumor samples of various tumor types using different data modalities including genomic, transcriptomic, proteomic, and epigenomic views. The goal is to find similarities amongst cancers of different tissues and to reveal clinically-relevant subtypes sharing common molecular abnormalities. While various analyses for interpreting these rich datasets exist, few methods are available to enable intuitive global overviews of these rich compendia. There is a need for methods that can tap the statistical power of large cohorts, to aid in analysis of smaller cohorts and of individual patient samples. Patterns present in many tumors may reveal driving genomic aberrations and pathway signatures that inform therapy. Here, we present a TumorMap, a tool that generates a map of cancer samples for interactive exploration, data overlay visualization, and statistical analysis. TumorMap arranges samples on a hexagonal 2-dimensional grid based on sample similarity. Different maps can be made for each distinct platform of data. Herein we demonstrate the utility of TumorMap for revealing commonalities between cancers of different tissue types, and its ability to aid in pan-cancer hypothesis generation. TumorMap maps for various cancer cohorts are available for free online at http://tumormap.ucsc.edu. Citation Format: Yulia Newton, Adam Novak, Teresa Swatlowski, Sahil Chopra, Sofie Salama, Olena Morozova, David Haussler, Joshua Stuart. UCSC TumorMap: Exploring cancer signatures on an interactive dynamic landscape. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-290.
αvβ6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor
Authors: Huimin Lu, Tao Wang, Jing Li, Carmine Fedele, Qin Liu, Jianzhong Zhang, Zhong Jiang, Dhanpat Jain, Renato V. Iozzo, Shelia M. Violette, Paul H. Weinreb, Roger J. Davis, Daniel Gioeli, Thomas J. FitzGerald, Dario C. Altieri, Lucia R. Languino
Journal: Cancer Research (2016)

Abstract Androgen receptor signaling fuels prostate cancer and is a major therapeutic target. However, mechanisms of resistance to therapeutic androgen ablation are not well understood. Here, using a prostate cancer mouse model, Ptenpc−/−, carrying a prostate epithelial-specific Pten deletion, we show that the αvβ6 integrin is required for tumor growth in vivo of castrated as well as of noncastrated mice. We describe a novel signaling pathway that couples the αvβ6 integrin cell surface receptor to androgen receptor via activation of JNK1 and causes increased nuclear localization and activity of androgen receptor. This downstream kinase activation by αvβ6 is specific for JNK1, with no involvement of p38 or ERK kinase. In addition, differential phosphorylation of Akt is not observed under these conditions, nor is cell morphology affected by αvβ6 expression. This pathway, which is specific for αvβ6, because it is not regulated by a different αv-containing integrin, αvβ3, promotes upregulation of survivin, which in turn supports anchorage-independent growth of αvβ6-expressing cells. Consistently, both αvβ6 and survivin are significantly increased in prostatic adenocarcinoma, but are not detected in normal prostatic epithelium. Neither XIAP nor Bcl-2 is affected by αvβ6 expression. In conclusion, we show that αvβ6 expression is required for prostate cancer progression, including castrate-resistant prostate cancer; mechanistically, by promoting activation of JNK1, the αvβ6 integrin causes androgen receptor–increased activity in the absence of androgen and consequent upregulation of survivin. These preclinical results pave the way for further clinical development of αvβ6 antagonists for prostate cancer therapy. Cancer Res; 76(17); 5163–74. ©2016 AACR.
Abstract LB-109: Identification of anaplastic lymphoma kinase fusions in clear cell renal cell carcinoma
Authors: Huafeng Wei, Yang Chen
Journal: Cancer Research (2016)

Abstract As the most common type of renal cancer, clear cell renal cell carcinoma (ccRCC) with advanced stages constitutes a continued major challenge for uro-oncologists where identification of novel driver mutations and development of novel targeted therapies against them remain an unmet need. Aberrations of the anaplastic lymphoma kinase (ALK) gene have been implicated in the pathogenesis of multiple human cancers where ALK represents a rational therapeutic target as demonstrated in lung cancer with ALK rearrangement. In this study, we performed the screening of ALK expression in 87 pathologically defined ccRCC by immunohistochemistry (IHC) using a newly developed rabbit anti-human ALK monoclonal antibody (clones D5F3). Four patients were positive for ALK expression as determined by IHC among which 2 cases were further confirmed by fluorescence in situ hybridization (FISH) assay using the Vysis LSI ALK dual color break-apart probe; furthermore, we detected the presence of EML4-ALK (E13:A20, variant 1) fusion gene in tumors from these two patients by using RACE-coupled PCR sequencing and RT-PCR. Notably, we first showed that enforced EML4-ALK expression significantly promoted the in vitro proliferation, clonogenic colony formation and apoptosis resistance in immortalized normal renal tubal epithelial cell HK2 and their in vivo outgrowth when injected into immunocompromised nude mice, and importantly, this pro-tumorigenic effect could be completely abolished by ALK-specific inhibitor Crizotinib, indicating the potential effectiveness of ALK-specific inhibitors in treating ALK-positive ccRCC patients. Our data show that ALK fusions exist in adult ccRCC, which provides the rationale for ALK inhibitor therapy in selected patients of ccRCC. Citation Format: Huafeng Wei, Yang Chen. Identification of anaplastic lymphoma kinase fusions in clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-109.
Carbapenemase-producing Enterobacteriaceae in Europe: assessment by national experts from 38 countries, May 2015
Authors: Barbara Albiger, Corinna Glasner, Marc J. Struelens, Hajo Grundmann, Dominique L. Monnet
Journal: Eurosurveillance (2015)

In 2012, the European Centre for Disease Prevention and Control (ECDC) launched the 'European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE)' project to gain insights into the occurrence and epidemiology of carbapenemase-producing Enterobacteriaceae (CPE), to increase the awareness of the spread of CPE, and to build and enhance the laboratory capacity for diagnosis and surveillance of CPE in Europe. Data collected through a post-EuSCAPE feedback questionnaire in May 2015 documented improvement compared with 2013 in capacity and ability to detect CPE and identify the different carbapenemases genes in the 38 participating countries, thus contributing to their awareness of and knowledge about the spread of CPE. Over the last two years, the epidemiological situation of CPE worsened, in particular with the rapid spread of carbapenem-hydrolysing oxacillinase-48 (OXA-48)- and New Delhi metallo-beta-lactamase (NDM)-producing Enterobacteriaceae. In 2015, 13/38 countries reported inter-regional spread of or an endemic situation for CPE, compared with 6/38 in 2013. Only three countries replied that they had not identified one single case of CPE. The ongoing spread of CPE represents an increasing threat to patient safety in European hospitals, and a majority of countries reacted by establishing national CPE surveillances systems and issuing guidance on control measures for health professionals. However, 14 countries still lacked specific national guidelines for prevention and control of CPE in mid-2015.
Abstract 3561: Role of bcl-2 family proteins in phorbol ester-induced apoptosis of acute myeloid leukemia cells
Authors: Cassandra Holbert, Jeffrey Forrester, Michael Roberts
Journal: Cancer Research (2016)

Abstract Human acute myeloid cell lines undergo genetic re-programming in response to differentiation inducers. The M3 AML cell line, HL-60, has served as a model system for studying phorbol ester-induced myeloid differentiation into macrophage-like cells. Macrophage differentiation is preceded by cell cycle arrest and followed by apoptosis. Therefore, the system elucidates the changes in the leukemia cell gene expression program necessary to override the genetic alterations driving continuous cell division, preventing myeloid differentiation, and blocking programmed cell death. We hypothesize that defining the evolving transcriptome as AML cells reverse their proliferative, undifferentiated, and pro-survival phenotype will reveal genes regulating these processes and possibly identify new targets for AML treatment. Whole genome exon DNA microarray analyses identifies 1260 genes whose RNA expression levels change significantly during the reprogramming. Among these genes are members of the BCL-2 family that encode both pro- and anti-apoptotic proteins (BBC3, PMAIP1, BID and BCL2, MCL1, BCL2A1, respectively). Myeloid cell leukemia 1 (MCL1) is a BCL-2 family protein defined as an anti-apoptotic protein, however MCL1 increases in expression following phorbol ester treatment in HL-60 cells, as well as other AML lines including THP-1, Kasumi-1, and KG-1. The MCL1 gene can be alternatively spliced to generate a transcript encoding a BH3-only variant (MCL1S) known to exhibit pro-apoptotic function. Western blotting demonstrates the accumulation of MCL1S protein prior to the initiation of apoptosis in phorbol ester treated cells. Here we present evidence for splice variant switching and explore the possibility that reduction in the pro-survival form, MCL1L, and accumulation of MCL1S mediates the p53-independent initiation of apoptosis. Currently, we are evaluating the effects on the leukemic phenotype and apoptotic response to phorbol ester in HL-60 cell lines overexpressing MCL1L, MCL1S, and PMAIP1, as well as HL-60 lines containing CRISPR-Cas9 mediated knockouts of MCL1 and PMAIP1. Citation Format: Cassandra Holbert, Jeffrey Forrester, Michael Roberts. Role of bcl-2 family proteins in phorbol ester-induced apoptosis of acute myeloid leukemia cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3561.
Electronic Health Records Quantify Previously Existing Phenomenon—Physicians Spend Hours Coordinating Care—Reply
Authors: Daniel R. Murphy, Dean F. Sittig, Hardeep Singh
Journal: JAMA Internal Medicine (2016)

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Mitoxantrone, Not Idarubicin, Significantly Improves the Outcome of Children with Relapsed ALL – Result of the International, Randomised ALLR3 Study.
Authors: Catriona Parker, Rachel Waters, Carly Leighton, Jeremy Hancock, Anthony Moorman, Mary Morgan, Philip Ancliff, Nicholas Goulden, Rosemary Sutton, Tamas Revesz, Philip Darbyshire, Sharon Love, Vaskar Saha
Journal: Blood (2009)