tbuckley/cabot-search huggingface dataset:
Abstract 4603: TCF7L1 constrains Wnt/β-catenin signaling and tumor growth in pancreatic cancer
Authors: Kathleen M. Kershaw, Michael D. Arensman, Bridgette Ho, Anna R. Lay, Nicole A. Dawson, David W. Dawson
Journal: Cancer Research (2016)

Abstract Wnt/β-catenin signaling plays important roles in pancreatic adenocarcinoma (PDA) tumor initiation and progression through its promotion of various pro-tumorigenic phenotypes. While RNF43 mutations increase Wnt signaling activity and confer Wnt growth-dependency in a subset of PDA, other key driver mutations in the Wnt pathway are only rarely encountered in PDA. To gain additional insights into alternative mechanisms contributing to increased Wnt pathway activity in PDA, we examined the expression and activity of LEF/TCF family members, the key transcriptional binding partners for β-catenin in canonical Wnt signaling. Luciferase-based β-catenin-activated reporter (BAR) assays demonstrated variable Wnt activity across a large panel of PDA cell lines, which was used to dichotomize cell lines into groups with high or lower β-catenin/TCF-dependent transcription. Supervised analysis of PDA cell line microarray data and parallel western blot analyses identified distinct patterns of TCF/LEF expression, including increased TCF7 and TCF7L2 (aka TCF4) expression in high BAR lines and increased TCF7L1 (aka TCF3) expression in low BAR lines. RNAi-mediated knockdown of individual or combinations of TCF/LEFs in PDA lines revealed TCF7L1 and TCF7L2 both function to repress β-catenin-activated reporter activity. TCF7L1 protein was also found to be targeted for rapid downregulation following Wnt pathway activation by treatment with either Wnt3A ligand or GSK3β inhibitor. RNAi knockdown of TCF7L1 in PDA lines increased anchorage-independent growth and tumor cell migration in vitro and increased in vivo PDA growth in an orthotopic xenograft tumor model. In summary, differential patterns of TCF/LEF expression are correlated with and functionally responsible for differences in Wnt pathway activation and function in PDA. Furthermore, these data implicate abrogation of TCF7L1 growth suppressive phenotypes via β-catenin-mediated downregulation of TCF7L1 as a potentially important mechanism through which Wnt signaling promotes pancreatic tumorigenesis. Citation Format: Kathleen M. Kershaw, Michael D. Arensman, Bridgette Ho, Anna R. Lay, Nicole A. Dawson, David W. Dawson. TCF7L1 constrains Wnt/β-catenin signaling and tumor growth in pancreatic 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 4603.
DACH1 inhibited androgen receptor transactivation and prostate cancer cellular proliferation
Authors: Kongming Wu, Xiaoming Ju, Agnes Witkiewicz, Anping Li, Ming Jin, Richard Pestell
Journal: Cancer Research (2008)

1215   The  Drosophila dachshund  ( dac ) gene is the founding member of the DACH subfamily of nuclear proteins which conduct an essential role in promoting differentiation of the  Drosophila  eye and limb. The  dac  gene functions with  eyeless (eya/Pax6) ,  sine oculis (So, Six) , and  eyes absent  (eya/Eya) in  retinal determination (RD) signaling pathway in  Drosophila . Although the RD gene network is best known for its role in eye specification, these genes contribute to the diverse developmental process in many cell types. Our recent studies of human breast cancer demonstrated that the loss in expression of a cell-fate determination factor, DACH1, was associated with particularly poor prognosis. Induced expression of DACH1 inhibited breast tumor cell proliferation, DNA synthesis and tumor growth  in vivo.  In Drosophila,  dachshund (dac)  is differently expressed in the male and female genital discs and is required for the appropriate differentiation of both male and female genital structure. DACH1 is expressed in normal prostate epithelium and decreased expression was found in prostate cancer. In the human prostate cancer cell line LNCaP, DACH1 expression is regulated by DHT and BMP signals.  To further study the function of DACH1 in hormone signaling and prostate oncogenesis, we established an LNCaP cell line in which expression of DACH1 is regulated by deoxycycline. DACH1 inhibited DNA synthesis, S phase progression and colony formation, as determined by H 3 -thymidine incorporation, FACS and soft agar analyses. In CV-1 and 293T cells, DACH1 inhibited DHT-dependent AR transactivation using either PSA Luc or MMTV-Luc reporter assay. The repression by DACH1 was abolished upon deletion of a DS-domain mutant. DACH1 also inhibited activation of mutated androgen receptors identified in patients with androgen-independent prostate cancer. DACH1 inhibited the AR-coactivation by ARA70, SRC-1 and Tip60. DACH1 and the AR interaction was demonstrated in mammalian two-hybrid analysis. Immunoprecipitation-western blot assay demonstrated that DACH1 complexed with AR associated with HDAC1, HDAC3, NCoR, p300 and pCAF. Confocal microscopy demonstrated the co-localization of DACH1 with AR upon stimulation by DHT. Immunohistochemical stain of 36 paried prostate cancer tissues with corresponding normal tissues demonstrated the significantly decreased expression of DACH1 in cancer. Our data support a model in which DACH1 binds to the AR and inhibits AR signaling through co-repressor binding. This study is the first to demonstrate a role for a cell fate determination factor DACH1 in regulating hormone signaling and prostate cancer cellular proliferation.
A New Prognostic Evaluation of Patients with Acute ST-Elevation Myocardial Infarction Undergoing Primary Angioplasty: Combined Zwolle and Syntax Score
Authors: Şeref Kul, Huseyin Uyarel, Murat Turfan, Gokhan Ertas, Mehmet Akif Vatankulu, Okkes Taha Kucukdagli, Mehmet Ergelen, Hatice Betul Erer, Tolga Sinan Guvenc, Omer Goktekin
Journal: Journal of the American College of Cardiology (2013)
Eating more unsaturated fats and less carbohydrate reduces blood glucose, study finds
Authors: Susan Mayor
Journal: BMJ (2016)

Eating more unsaturated fats, especially polyunsaturated fatty acids, and eating less carbohydrate and saturated fat reduces blood glucose levels and improves insulin resistance and secretion, a large meta-analysis of randomised controlled trials has shown.

Researchers systematically searched for randomised controlled trials investigating the effects that macronutrients in the diet have on blood glucose, insulin, …
Abstract 513: Standardization of technologies for CTC, ctDNA and miRNA enrichment, isolation and analysis for liquid biopsies during the first year of IMI's CANCER-ID
Authors: Thomas Schlange, Nikolas Stoecklein, Rui P. Neves, Sabrina Pleier, Sebastian Bender, Nora Brychta, Merlin V. Luetke-Eversloh, Kiki Andree, Leon Terstappen, Thomas Krahn, Thomas Krahn
Journal: Cancer Research (2016)

Abstract Within the European Innovative Medicines Initiative (IMI) consortium CANCER-ID (www.cancer-id.eu), scientists at academic, clinical and industrial sites across Europe and in the US joined forces to evaluate innovative technologies in the field of liquid cancer biopsies. This project aims at implementing standard operating procedures (SOPs) for pre-analytical sample handling, enrichment, isolation and analysis of Circulating Tumor Cells (CTCs), circulating free tumor DNA (ctDNA) and microRNAs (miRNAs) as novel blood-based biomarkers, with a focus on Non-Small Cell Lung Cancer (NSCLC) and HER2-treatment refractory breast cancer. In order to determine sensitivity and specificity of different technologies for CTC isolation and analysis (e.g. detection of mutations, amplifications, protein phosphorylation), complex samples comprising a mixture of NSCLC or breast cancer cell lines spiked in healthy donor blood were distributed to different CANCER-ID partner sites. These cell lines have been selected based on their molecular/genetic properties to reflect clinically relevant subtypes of the disease and have been further characterized in terms of cell-surface marker expression and cell size distribution. The use of complex spiked samples better models the heterogeneity of real-life patient material. Furthermore, healthy donor and patient derived plasma samples are investigated using different technology platforms to validate tumor-specific miRNA or ctDNA profiles that might characterize molecular tumor subtypes. To this end, differences in exosome-derived versus free circulating miRNAs are of special interest. As for CTCs the development of ctDNA and miRNA standards that can be used to compare and validate different technologies are in the focus of this effort. In summary, our results pave the way for the next phase of CANCER-ID, which includes the analysis of cancer patient samples in clinical studies using different technologies and thereby advance the concept of liquid biopsy particularly in indications in which conventional tissue biopsies are difficult to obtain. Citation Format: Thomas Schlange, Nikolas Stoecklein, Rui P. Neves, Sabrina Pleier, Sebastian Bender, Nora Brychta, Merlin V. Luetke-Eversloh, Kiki Andree, Leon Terstappen, Thomas Krahn, Thomas Krahn. Standardization of technologies for CTC, ctDNA and miRNA enrichment, isolation and analysis for liquid biopsies during the first year of IMI's CANCER-ID. [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 513.
Abstract 3180: Deletions of 18q characterizes a subset of aggressive prostate cancers with metastatic potential
Authors: Claudia Hube-Magg, Martina Kluth, Maximilian Graunke, Christina Koop, Steuber Thomas, Markus Graefen, Stefan Steurer, Thorsten Schlomm, Guido Sauter, Ronald Simon
Journal: Cancer Research (2016)

Abstract Large chromosomal deletions and rearrangements of the TMPRSS:ERG locus are hallmarks of prostate cancer. Deletion of 18q is recurrently found in prostate cancer, but the prevalence and clinical significance of this alteration have not been studied in detail as to yet. We took advantage of our large prostate cancer prognosis tissue microarray (TMA) containing more than 12,000 prostate cancers with clinical follow-up data and performed fluorescence in situ hybridization (FISH) analysis using an 18q21 probe. A total of 6,881 prostate cancers were interpretable by FISH. Deletion of 18q was found in 7.5% of cancers, and was linked to advanced tumor stage (p&amp;lt;0.0001), high Gleason grade (p = 0.0013) and biochemical recurrence (BCR, p&amp;lt;0.0001). Comparison with data from TMPRSS:ERG fusion and ERG protein expression revealed that deletions of 18q were only marginally related to an ERG-fusion negative phenotype (p = 0.0063). Multivariate analysis showed that the prognostic value of 18q deletion was independent from the established prognostic factors in all cancers (p = 0.0004) as well as in the subsets of ERG-fusion negative (p = 0.0148) and ERG-fusion positive cancers (p = 0.0264). From the clinical data attached to our TMA, we defined additional clinical endpoints beyond BCR, which represent the four hallmarks (local, local invasive, occult systemic and metastatic) of tumor growth and dissemination in prostate cancer. Deletion of 18q was linked to unfavorable outcome also according to these alternative clinical endpoints. For example, the fraction of cancers with occult systemic or metastatic dissemination increased from 33.6% in patients whose tumors lacked 18q deletion to 41.8% in patients with tumors harboring 18q deletion (p = 0.0458). In summary, the results of our study demonstrate a pivotal role of 18q deletions for prognosis in prostate cancer independent of the established prognosticators. Citation Format: Claudia Hube-Magg, Martina Kluth, Maximilian Graunke, Christina Koop, Steuber Thomas, Markus Graefen, Stefan Steurer, Thorsten Schlomm, Guido Sauter, Ronald Simon. Deletions of 18q characterizes a subset of aggressive prostate cancers with metastatic potential. [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 3180.
From the authors:
Authors: A. Aliverti, A. Lo Mauro, M.G. D'Angelo
Journal: European Respiratory Journal (2010)

We thank P. Wijkstra and co-workers for their interest and comments regarding our paper, ''Abdominal volume contribution to tidal volume as an early indicator of respiratory impairment in Duchenne muscular dystrophy'' [1].They wonder if our findings of progressive drop of abdominal contribution to tidal volume in Duchenne muscular dystrophy (DMD) are somewhat related to: 1) differences in forced vital capacity (FVC) between sitting and supine position; and 2) nocturnal hypercapnia.These questions are of great interest and they deal with three key aspects regarding the prognosis and the management of patients with DMD and other primary neuromuscular diseases, namely the noninvasive assessment of diaphragm function, the evaluation of sleep disordered breathing and the choice of the correct timing for the introduction of nocturnal noninvasive mechanical ventilation.
Emerging aspergillosis by azole-resistant Aspergillus fumigatus at an intensive care unit in the Netherlands, 2010 to 2013
Authors: Judith van Paassen, Anne Russcher, Astrid WM in 't Veld - van Wingerden, Paul E Verweij, Eduard J Kuijper
Journal: Eurosurveillance (2016)

The prevalence of invasive aspergillosis (IA) at the intensive care unit (ICU) is unknown and difficult to assess since IA also develops in patients lacking specific host factors. In the Netherlands, increasing azole-resistance in Aspergillus fumigatus complicates treatment of patients with IA. The aim of this study was to determine the prevalence of IA by azole-resistant A. fumigatus at the ICU among patients receiving antifungal treatment and to follow their clinical outcome and prognosis. A retrospective cohort study was conducted in a university hospital ICU from January 2010 to December 2013. From all patients who received antifungal treatment for suspected IA, relevant clinical and microbiological data were collected using a standardised questionnaire. Of 9,121 admitted ICU-patients, 136 had received antifungal treatment for suspected IA, of which 38 had a positive A. fumigatus culture. Ten of the 38 patients harboured at least one azole-resistant isolate. Resistance mechanisms consisted of alterations in the cyp51A gene, more specific TR 34 /L98H and TR 46 /T289A/Y121F. Microsatellite typing did not show clonal relatedness, though isolates from two patients were genetically related. The overall 90-day mortality of patients with IA by azole-resistant A. fumigatus and patients with suspicion of IA by azole-susceptible isolates in the ICU was 100% (10/10) vs 82% (23/28) respectively. We conclude that the changing pattern of IA in ICU patients requires appropriate criteria for recognition, diagnosis and rapid resistance tests. The increase in azole resistance rates also challenges a reconsideration of empirical antifungal therapy.
Abstract 2537: Role of N-cadherin in connexin 43 mediated gap junctional formation between dormant breast cancer cells and bone marrow mesenchymal and stromal cells
Authors: Garima Sinha
Journal: Cancer Research (2016)

Abstract Breast cancer (BC) remains a clinical problem. This is partly due to the existence of dormant BC cells (BCCs) in the bone marrow (BM) that could resurge decades after cancer remission. Cancer stem cells (CSCs) establish themselves in cycling quiescence within the BM microenvironment by forming gap junctional intercellular communication (GJIC) with mesenchymal stem cells (MSCs) and the hematopoietic supporting stroma. MiRNAs can be exchanged between the CSCs and other BM cells through the gap junction to impart cycling quiescence of the CSCs. Although the CSCs express several members of the connexin (Cx) family of proteins, GJIC between CSCs and BM cells requires Cx43. Preventing the formation of GJIC between CSCs and endogenous BM cells enhanced cycle of the BCCs with enhanced chemosensitivity. Since Cx43 is also involved in hematopoietic regulation, in order to identify targets to reverse dormancy, this study investigated the molecular mechanisms by which Cx43 is regulated, including the role of N-cadherin as a facilitator of GJIC between CSCs and BM cells. CSCs are epithelial-mesenchymal cells (EMT) and therefore express N-cadherin. In other studies Cx43 has been shown to interact with N-cadherin to facilitate the movement of Cx43 to the cell membrane. To this end, we hypothesize that the intracellular complex formed by N-cadherin and Cx43 in CSCs is regulated by the chemokine CXCL-12. MDA-MB-231, MDA-MB-468 and T47D were stimulated with different levels of CXCL12. At different times, the expression of N-cadherin was studied by real time PCR, confocal microscopy and flow cytometry. The results showed CXCL12 regulated both N-cadherin and Cx43. However, the outcome on their expression depended on the invasiveness of the tumor. Direct interaction between N-cadherin and Cx43 was demonstrated by time-line tracking for co-localization, molecular modeling and immunoprecipitation. In summary, this study showed that co-localization of N-cadherin and Cx43 is controlled by low level of CXC12. Ongoing studies are investigating how these findings affect GJIC between CSCs and BM stroma/MSCs. Citation Format: Garima Sinha. Role of N-cadherin in connexin 43 mediated gap junctional formation between dormant breast cancer cells and bone marrow mesenchymal and stromal 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 2537.
P0883 : Treatment for hepatitis C virus infection among people who inject drugs in the opioid substitution setting: The ethos study
Authors: M. Alavi, J. Grebely, M. Micallef, A. Dunlop, A. Balcomb, C. Day, C. Treloar, N. Bath, P. Haber, G. Dore
Journal: Journal of Hepatology (2015)
Prevention as Precipitant
Authors: Aaron W. Aday, Arturo P. Saavedra, Bruce D. Levy, Joseph Loscalzo
Journal: New England Journal of Medicine (2016)

Two days after undergoing uncomplicated bilateral total knee arthroplasties, a 72-year-old man had a temperature of 101°F and a pruritic, erythematous rash that originated on his trunk and spread peripherally to his arms and upper thighs over the course of 24 hours.
Abstract 1971: BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian cancer
Authors: Garrett W. Rhyasen, Yi Yao, Austin Dulak, Lillian Castriotta, Kelly Jacques, Maureen Hattersley, Gordon B. Mills, Michael Zinda, Stephen Fawell, Paul Lyne, Edwin Clark, Huawei Chen
Journal: Cancer Research (2016)

Abstract The bromodomain and extra-terminal (BET) protein, BRD4 functions as a transcriptional co-activator through recruitment of regulatory complexes to acetylated chromatin. Among all malignancies, the most focal, and recurrent BRD4 gene amplification occurs in high-grade serous ovarian cancer (HGSOC). Despite the elucidation of BRD4 dependencies in cancer, it is unclear whether BRD4 gene amplification can result in oncogenic activity, and hence serve as a patient selection strategy for BET bromodomain inhibitors. To assess the oncogenic potential of BRD4 amplification in HGSOC, we assayed enforced BRD4 expression in non-transformed immortalized surface ovarian cells (IOSE). Physiologically relevant expression of either long or short BRD4 spliced isoforms in IOSE (BRD4-IOSE) resulted in marked phenotypic changes indicative of cellular transformation, including altered growth kinetics, chromatin reorganization, and acquisition of colony formation potential. Transcriptional profiling of BRD4-IOSE and BRD4-amplified HGSOC patients revealed shared expression patterns, including enriched MYC, E2F1, and VEGF gene signatures. Interrogation of BRD4 inhibitor pharmacodynamic markers, and transcripts upregulated through enforced BRD4 expression uncovered Neuregulin-1 as a critical BRD4 transcriptional effector. RNAi-mediated Neuregulin-1 depletion was capable of abolishing the oncogenic activity of BRD4-IOSE, and exogenous Neuregulin-1 was sufficient to transform IOSE without BRD4. A novel BRD4-SWI/SNF interaction was required for driving the oncogenic activity of BRD4-IOSE through maintaining NRG1 expression. The sensitivity of patient-derived HGSOC xenografts to a novel clinical candidate BRD4 inhibitor, AZD5153, correlated with BRD4 amplification and a pharmacodynamic NRG1 response. This study demonstrates the oncogenic potential of BRD4 amplification, defines a relationship between BRD4 and NRG1, and further establishes HGSOC as an appropriate patient population in which to test the therapeutic potential of BET bromodomain inhibitors. Citation Format: Garrett W. Rhyasen, Yi Yao, Austin Dulak, Lillian Castriotta, Kelly Jacques, Maureen Hattersley, Gordon B. Mills, Michael Zinda, Stephen Fawell, Paul Lyne, Edwin Clark, Huawei Chen. BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian 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 1971.
High Expression of Multidrug Resistance-Associated Proteins Predicts Prognosis in Acute Lymphoblastic Leukemia in Children and Adults.
Authors: Sabine L.A. Plasschaert, Eveline S.J.M. de Bont, Marike Boezen, Dorina M. van der Kolk, Simon M.J.G. Daenen, Klaas Nico Faber, Willem A. Kamps, Elisabeth G.E. de Vries, Edo Vellenga
Journal: Blood (2004)
Polymorphisms and Lack of or Aberrant Expression of HLA Class I and II May Influence Antigen Presentation in Classical Hodgkin Lymphoma.
Authors: Arjan Diepstra, Sibrand Poppema, Gerard te Meerman, Marijke Niens, Ilja Nolte, Edo Vellenga, Gustaaf van Imhoff, Joost Kluiver, Anke van den Berg
Journal: Blood (2005)
Acute Megakaryoblastic Leukemia in Children without Down’s Syndrome.
Authors: Dirk Reinhardt, Sylke Diekamp, Joerg Ritter, Claudia Langebrake, Gudrun Fleischhack, Michael Dworzak, Jan Stary, Jochen Harbott, Wolf-Dieter Ludwig, Ursula Creutzig
Journal: Blood (2004)
Ultrafast Magnetic Resonance Imaging for Iron Quantification in Thalassemia Participants in the Developing World
Authors: Amna Abdel-Gadir, Yongkasem Vorasettakarnkij, Hataichanok Ngamkasem, Sabrina Nordin, Emmanuel A. Ako, Monravee Tumkosit, Pranee Sucharitchan, Noppacharn Uaprasert, Peter Kellman, Stefan K. Piechnik, Marianna Fontana, Juliano L. Fernandes, Charlotte Manisty, Mark Westwood, John B. Porter, J. Malcolm Walker, James C. Moon
Journal: Circulation (2016)