tbuckley/cabot-search huggingface dataset:
Repeated nationwide point-prevalence surveys of antimicrobial use in Swedish hospitals: data for actions 2003–2010
Authors: Gunilla Skoog, Johan Struwe, Otto Cars, Håkan Hanberger, Inga Odenholt, Mårten Prag, Katarina Skärlund, Peter Ulleryd, Mats Erntell
Journal: Eurosurveillance (2016)

This study sought to analyse antimicrobial pressure, indications for treatment, and compliance with treatment recommendations and to identify possible problem areas where inappropriate use could be improved through interventions by the network of the local Swedish Strategic Programme Against Antibiotic Resistance (Strama) groups. Five point-prevalence surveys were performed in between 49 and 72 participating hospitals from 2003 to 2010. Treatments were recorded for 19 predefined diagnosis groups and whether they were for community-acquired infection, hospital-acquired infection, or prophylaxis. Approximately one-third of inpatients were treated with antimicrobials. Compliance with guidelines for treatment of community-acquired pneumonia with narrow-spectrum penicillin was 17.0% during baseline 2003-2004, and significantly improved to 24.2% in 2010. Corresponding figures for quinolone use in uncomplicated cystitis in women were 28.5% in 2003-2004, and significantly improved, decreasing to 15.3% in 2010. The length of surgical prophylaxis improved significantly when data for a single dose and 1 day were combined, from 56.3% in 2003-2004 to 66.6% in 2010. Improved compliance was possibly the effect of active local feedback, repeated surveys, and increasing awareness of antimicrobial resistance. Strama groups are important for successful local implementation of antimicrobial stewardship programs in Sweden.
Prognostic significance of DNA damage repair (DDR) mutations in patients with urothelial carcinoma (UC) and associations with tumor infiltrating lymphocytes (TILs).
Authors: Russell Bailey McBride, Vaibhav G. Patel, Ana Collazo Lorduy, Mireia Castillo-Martin, Eugene K. Cha, Michael F. Berger, Li Wang, William K. Oh, Jun Zhu, Carlos Cordon-Cardo, David B. Solit, John P. Sfakianos, Matt D. Galsky
Journal: Journal of Clinical Oncology (2016)

4538 Background: Somatic mutations in DDR genes have been associated with improved outcomes in patients with muscle-invasive bladder cancer post-cystectomy, even in the absence of perioperative chemotherapy. This counterintuitive finding has been hypothesized to result from the accumulation of missense mutations encoding antigens that trigger anti-tumor immunity. We sought to validate whether DDR mutations in UC were associated with improved outcomes, and to test whether this association is mediated by TILs. Methods: We performed immunohistochemical staining for CD8 (Dako) and hybridization-based next-generation sequencing (MSK-IMPACT) of all exons and selected introns of 26, previously identified DDR genes in 77 cystectomy specimens (MSH cohort). Mutation rates per case were dichotomized (any vs. none). TILs were measured using an intensity weighted H-Score of CD8+ expression. Clinical information was complete on 63 cases and included age, sex, TNM stage, and neo-adjuvant therapy. Progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) were estimated using proportional hazard models. Statistical analyses were performed using SAS 9.3. Results: At least one DDR mutation was found in 32/63 (50.8%) of the cases. The most common mutations were BRCA1 (7.9%), BRCA2 (6.3%), and ATRX (6.3%). Patients with vs. without DDR mutations did not differ by age, sex, TNM stage, or neoadjuvant therapy. The mean CD8+ H-score was numerically higher in those with DDR mutations (20.2) than in non-mutants (15.9) (Wilcoxon 2-sided p-value = 0.10). Patients with DDR mutations had roughly half the risk of recurrence (HR = 0.53 95% CI [0.26-1.11], p = 0.09) or disease-specific death (HR = 0.51 95% CI [0.24-1.09], p = 0.08). Conclusions: DDR mutations were associated with improved outcomes in patients with UC post-cystectomy, though our sample size was inadequate to reach statistical significance. We also identified a non-significant association between CD8+ tumor expression and DDR mutations. Prospective validation of the association of DDR mutations with clinical outcomes and proposed mechanisms are indicated.
Factors predicting renal function after partial nephrectomy: A multi-institutional analysis of data from the SIB working group.
Authors: Brian R. Lane, Michael Klingler, Georgios Hatzichristodoulou, Alexander Kutikov, Francesco Sanguedolce, Bulent Akdogan, Umberto Capitanio, Marco Roscigno, Alessandro Volpe, Martin Marszalek, Riccardo Campi, Robert G. Uzzo, Alessandro Antonelli, Hans Langenhuijsen, Andrea Minervini
Journal: Journal of Clinical Oncology (2016)

e16063 Background: Despite earlier work suggesting that ischemia plays a dominant role in renal functional decline after partial nephrectomy (PN), more recent evidence indicates that parenchyma preserved plays a central role. It remains unclear whether factors such as tumor complexity, type of resection, ischemia type and time, and blood loss have an effect on renal function after PN after accounting for surgeon assessment of volume preservation (SAVP). We evaluated the impact of these factors on postop GFR in a multi-institutional cohort. Methods: Data were collected from 336 patients who underwent PN for suspected renal tumors at 12 centers in the US and Europe. Tumor size and complexity (RENAL & PADUA) were based on preop CT scan. SIB score described the type of resection, ranging from pure enucleation (0-1) to complete resection (5). Surgeons recorded blood loss, ischemia type and time, SIB and postop SAVP after PN. Linear regression analyses were used to assess the impact of each factor on postop GFR. Results: Median tumor size was 3.0 cm (IQR:2.4-4.3) and tumor complexity was moderate (median RENAL: 6 and PADUA:8). Ischemia was used in 85% of PN with median time of 16 min (IQR:14-21.5). In univariate analyses, the predictors of postop GFR included age (p < .0001), blood loss (p < .0001), tumor size (p = 0.03), use of ischemia (p = 0.035), and GFR adjusted for SAVP (p < .0001). In multivariate analyses, age (p = 0.03), blood loss (p = 0.02), use of ischemia (p = 0.0003) and GFR-SAVP ( < .0001) remained significant predictors of postop GFR (R2= .712). There was no association observed between ischemia time, RENAL, PADUA, or SIB scores and postop GFR (p = 0.11, 0.88, 0.82, 0.45, respectively). Conclusions: The size and complexity of renal tumors, resection technique, and ischemia time, appear to have minimal impact on postoperative renal function. The volume of parenchyma preserved during surgery appears to be of paramount importance in maintaining renal function after PN, along with use of an ischemic technique and minimization of bleeding.
Head Trauma Is the Major Risk Factor for Cerebral Sinus-Vein Thrombosis
Authors: Ornit Giladi, David Steinberg, Kobi Peleg, David Tanne, Adi Givon, Ehud Grossman, Yoram Klein, Shirli Avigdori, Gal Grinberg, Rachel Katz, Varda Shalev, Ophira Salomon
Journal: Blood (2015)
First report of Candida auris in America: Clinical and microbiological aspects of 18 episodes of candidemia
Authors: Belinda Calvo, Analy S.A. Melo, Armindo Perozo-Mena, Martin Hernandez, Elaine Cristina Francisco, Ferry Hagen, Jacques F. Meis, Arnaldo Lopes Colombo
Journal: Journal of Infection (2016)
O027 : The expression of tumor suppressor PTPRD is down-regulated in the liver of patients with HCV infection and in tumor lesions of patients with hepatocellular carcinoma
Authors: N. Van Renne, F.H.T. Duong, C. Gondeau, D. Calabrese, N. Fontaine, A. Ababsa, S.C. Durand, P. Pessaux, M.H. Heim, T.F. Baumert, J. Lupberger
Journal: Journal of Hepatology (2015)
The Dual Inhibition of RNA Pol I Transcription and PIM Kinase as a New Therapeutic Approach to Treat Advanced Prostate Cancer
Authors: Richard J. Rebello, Eric Kusnadi, Donald P. Cameron, Helen B. Pearson, Analia Lesmana, Jennifer R. Devlin, Denis Drygin, Ashlee K. Clark, Laura Porter, John Pedersen, Shahneen Sandhu, Gail P. Risbridger, Richard B. Pearson, Ross D. Hannan, Luc Furic
Journal: Clinical Cancer Research (2016)

The MYC oncogene is frequently overexpressed in prostate cancer. Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. In addition, PIM kinases activate MYC signaling and mRNA translation in prostate cancer and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer.The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective, and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription, has been successfully exploited therapeutically but only in models of hematologic malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in prostate cancer cell lines, in Hi-MYC- and PTEN-deficient mouse models and in patient-derived xenografts (PDX) of metastatic tissue obtained from a patient with castration-resistant prostate cancer.CX-5461 inhibited anchorage-independent growth and induced cell-cycle arrest in prostate cancer cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced TP53 expression and activity and reduced proliferation (MKI67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN-null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of prostate cancer.Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of prostate cancer. Clin Cancer Res; 22(22); 5539-52. ©2016 AACR.
Abstract 2179: Macrolide toxin Mycalolide B is a potent inhibitor of HER2 cancer cell invasion and is the basis of actin targeted therapy for metastatic cancers
Authors: Rodette N. Williams, Andrew W. Craig, John S. Allingham
Journal: Cancer Research (2016)

Abstract Breast and ovarian cancers are among the leading causes of cancer related deaths in women worldwide. Human epidermal growth factor receptor 2 (HER2) is highly expressed in a subset of these cancers that show high rates of progression to metastatic disease. Metastasis is driven by filamentous actin (F-actin) based protrusions that penetrate and degrade extracellular matrix (ECM) to facilitate tumor invasion. In this study, we tested an actin-depolymerizing macrolide toxin Mycalolide B, as a potential suppressor of highly metastatic HER2+ breast and ovarian cancer cell models. Dose responses with Mycalolide B in SKBR3 breast cancer and SKOV3 ovarian cancer cells resulted in similar cytotoxicity (∼65 nM IC50) profiles. In addition, Mycalolide B doses well below the IC50 showed potent suppression of leading edge protrusions, and motility in SKBR3 and SKOV3 cancer cells. This also correlated with reduced ECM degradation and Transwell invasion at low nanomolar doses of Mycalolide B. In contrast, other F-actin based processes such as endocytosis of HER2 and EGFR, were less sensitive to Mycalolide B treatment. However, Mycalolide B treatment did skew the size of endocytic vesicles, which may reflect defects in F-actin based vesicle motility or maturation. Given that HER2 cancers have been effectively targeted by Trastuzumab and Trastuzumab-based antibody-drug conjugates, we are currently testing the compatibility of combined treatments with Mycalolide B and Trastuzumab, for their effects on F-actin based invasion of HER2+ cancers. This strategy may yield a novel class of antibody-drug conjugate, and lead to new HER2 targeted therapies that suppress tumor metastasis by disrupting early steps that are dependent on efficient F-actin polymerization. Citation Format: Rodette N. Williams, Andrew W. Craig, John S. Allingham. Macrolide toxin Mycalolide B is a potent inhibitor of HER2 cancer cell invasion and is the basis of actin targeted therapy for metastatic cancers. [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 2179.
Abstract SY04-01: The in vivo gain-of-function activities of mutant p53
Authors: Guillermina Lozano
Journal: Cancer Research (2016)

Abstract The p53 tumor suppressor is the most often altered gene in human cancers with missense mutations in the DNA binding domain accounting for approximately 70% of alterations. Mutant p53 proteins have gain-of-function activates that contribute to more aggressive tumors with increased metastatic properties. Mechanisms by which mutant p53 exerts its gain of function will be discussed. In addition, I will discuss the generation of a novel mouse model that allows Cre-mediated expression of mutant p53 in specific cell types leaving the surrounding stroma and immune system wild type for p53 as occurs in human somatic tumors. Citation Format: Guillermina Lozano. The in vivo gain-of-function activities of mutant p53. [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 SY04-01.
BRCA1 loses the ring but lords over resistance
Authors: Simon N. Powell
Journal: Journal of Clinical Investigation (2016)

Germline breast cancer 1 (BRCA1) variants are associated with a high risk of breast and ovarian cancers. Many BRCA1-mediated cancers are initially responsive to platinum-based therapy; however, resistance commonly develops. The BRCA1185delAG mutation is common in the Ashkenazi Jewish population and has been thought to result in loss of function due to the introduction of a stop codon in the 5′ region of the BRCA1 transcript. Two studies in this issue of the JCI reveal that the BRCA1185delAG mutation results in the production of BRCA1 that lacks the N-terminal really interesting new gene (RING) domain. RING-less BRCA1 was shown to directly mediate chemoresistance, while maintaining some homologous recombination function. These results provide important insight into BRCA1 function and indicate that other truncated proteins could arise through similar alterations in codon usage.
Association of androgen receptor variant 9 (<i>AR-</i>V9) mRNA expression levels in metastatic tissue with resistance to abiraterone acetate/prednisone (AA/P).
Authors: Manish Kohli, David W. Hillman, Liguo Wang, Ying Li, Hugues Sicotte, Rachel Carlson, Winston Tan, Kevin Wu, Patrick W Eiken, Rafael E. Jimenez, Joseph Cernigliaro, Fernando Quevedo, Brian Addis Costello, Henry C. Pitot, Timothy Jerome Moynihan, Thai Huu Ho, Alan H. Bryce, Liewei Wang, Scott Dehm
Journal: Journal of Clinical Oncology (2016)

5036 Background: AA/P is an approved treatment for metastatic castrate resistant prostate cancer (mCRPC), for which there are no validated resistance/response markers. We conducted a prospective trial to evaluate if Androgen Receptor (AR) or AR variants (AR-Vs) mRNA expression in tissue metastases can predict early resistance to AA/P. Methods: Metastatic sites of CRPC stage patients (pts) initiating pre-chemo AA/P were serially biopsied twice, prior to (pre-AA/P) and after 12 weeks of treatment (post-AA/P). Composite response at 12 weeks (primary endpoint) was evaluated with PSA, RECIST, imaging and symptoms (per PCWG2). Pre-AA/P metastases mRNA expression levels {for AR, AR-Vs (AR-V3, AR-V7, AR-V9, AR23, AR45), Chromogranin-A (CHGA); and four cell cycle division genes}; Serum PSA, testosterone, CHGA levels; Gleason Score (GS) at initial diagnosis; high V/s low volume disease; time on hormone therapy to mCRPC stage were all included in a logistic regression model for predicting AA/P resistance at 12 weeks. A final multivariate analysis (MVA) model fitted only those factors thought to be clinically relevant or with an entry threshold of p ≤ 0.2 in univariate analysis. Results: Between 6/2013 & 8/2015 of 92 pts enrolled, 78 had complete gene expression & outcome data at the time of analysis (12/2015). Gene expression at pre and post AA/P was available for 65/78 pts. Median pre-AA/P PSA was 14.6 ng/ml (IQR: 8.0 - 45.6). Progression at 12 weeks was observed in 32/78 pts. At the univariate level elevated pre-AA/P expression of AR-V3 (p = 0.03), AR-V7 (p = 0.17), AR-V9 (p = 0.02), AR-V7/FL ratio (p = 0.05), AR-V9/FL ratio (p = 0.03) and cell division cycle gene CDC45 (p = 0.11) met the threshold for inclusion into MVA. Elevated AR-V9 expression alone was associated with progression at 12 weeks in the MVA (OR: 4.0; CI 1.31 – 12.2; C-Index: 0.62). Additionally pts with elevated AR-V9 expressions at either biopsy time point (pre or post-AA/P 12-week) were more likely to progress on AA/P (OR: 3.3; 95% CI: 1.11 – 9.92; p = 0.03; C-index: 0.63). Conclusions: Elevated AR-V9 mRNA expression in metastases is associated with early progression on AA/P and could serve as a biomarker of resistance. Clinical trial information: NCT# 0195364.
Distinct Pattern Of Genomic Changes Associated With Smoking In Patients With Myelodysplastic Syndromes (MDS)
Authors: David J. Seastone, Sudipto Mukherjee, Zaher K. Otrock, Paul Elson, Michael K. Keng, Bartlomiej Przychodzen, Hideki Makishima, Brittney Dienes, Sean Hobson, Kristin Dodd, Tracy Cinalli, Ramon V Tiu, Yogen Saunthararajah, Jaroslaw P. Maciejewski, Mikkael A. Sekeres
Journal: Blood (2013)
Abstract 965: Exosome-derived microRNAs contributes to prostate cancer chemoresistance
Authors: JIng Li, Xiaozhen Xu, Hao Guan, Atsushi Mizokami, Evan T. Keller, Xin Yang, Xia Liu, Jiyong Tan, Longyuan Hu, Yi Lu, Jian Zhang
Journal: Cancer Research (2016)

Abstract Accumulating evidence has demonstrated that certain miRNAs play important roles in cancer cell chemoresistance. However, the pleotropic functions of exosome-derived miRNAs on developing chemoresistance remain unknown. In this study, we aimed to build potential networks of miRNAs, which derived from the exosome of chemoresistant prostate cancer (PCa) cells, with their known target genes using miRNA expression profiling and bioinformatic tools. Global miRNA expression profiles were measured by microarray. Twelve miRNAs were initially selected and validated by qRT-PCR. Known targets of deregulated miRNAs were utilized using DIANA-TarBase database v6.0. The incorporation of deregulated miRNAs and target genes into KEGG pathways were utilized using DIANA-mirPath software. To construct potential miRNA regulatory networks, the overlapping parts of two selected KEGG pathways were visualized by Cytoscape software. We identified 29 deregulated miRNAs, including 19 up and 10 down, in exosome samples derived from two kinds of paclitaxel resistance PCa cells (PC3-TXR and DU145-TXR) compared with their parental cells (PC3 and DU145). The enrichment results of deregulated miRNAs and known target genes showed that a few pathways were correlated with several critical cell signaling pathways. We found that hub hsa-16-5p, hsa-miR-3915, hsa-miR-488-3p, hsa-miR-5004-5p, hsa-miR-23c, hsa-miR-3673, hsa-miR-3654, and hsa-miR-32-5p were potential targets to hub androgen receptor (AR) and phosphatase and tensin homolog (PTEN). Hub TCF4 target genes were mainly regulated by hub hsa-miR3176, hsa-miR-141-3p, hsa-miR-606, hsa-miR381, and hsa-miR-429 miRNAs. These results may provide a linkage between PCa chemoresistance and exosome regulatory networks and thus lead us to propose that PTEN and TCF4 genes may be the important genes which regulated by exosome miRNAs in chemoresistance cancer cells. Supported by NSFC Key Project 81130046; NSFC Project 81171993 and NSFC81272415; Guangxi Key Projects 2013GXNSFEA053004 and 2012GXNSFCB053004; Guangxi Ministry of Education grants 201202ZD022 and 201201ZD004. Citation Format: JIng Li, Xiaozhen Xu, Hao Guan, Atsushi Mizokami, Evan T. Keller, Xin Yang, Xia Liu, Jiyong Tan, Longyuan Hu, Yi Lu, Jian Zhang. Exosome-derived microRNAs contributes to prostate cancer chemoresistance. [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 965.
Abstract 1751: Coffee and tea intake and risk of endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2)
Authors: Marta Crous-Bou, Immaculata De Vivo
Journal: Cancer Research (2016)

Abstract Background: Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Well-known risk factors for EC include obesity and elevated levels of estrogen and insulin. Coffee and tea are the most widely consumed beverages in the world, after water. Both are a complex mixture of chemicals with potential antimutagenic and antioxidant properties. Previous studies have reported an inverse association between coffee consumption and circulating levels of estrogen and C-peptide, a marker of insulin secretion, both involved in endometrial carcinogenesis. The presence of antioxidants and other chemopreventive compounds in coffee and tea may have an anticarcinogenic effect. Thus, coffee and tea drinking may decrease the risk of EC. Objective: To examine the association between coffee and tea intake and endometrial cancer risk. Patients and Methods: We combined individual-level data from 24 epidemiologic studies (10 Cohort studies, 14 Case-Control studies) from the Epidemiology of Endometrial Cancer (E2C2) Consortium and performed a pooled analysis of 11,424 endometrial cancer cases and 28,388 controls. Logistic regression models were used to calculate ORs and the corresponding 95% CI. All models were adjusted for potential confounders. Results and Conclusions: Increased coffee consumption was associated with a reduced risk of endometrial cancer: compared to non-coffee drinkers, the pooled OR for those who drank more than 1 cup of coffee per day was 0.79 (95%CI = 0.71-0.87, p = 5.48×10−6). The association is mainly observed in cohort studies and remains significant after adjusting for potential confounders. We found no association between tea consumption and endometrial cancer risk. Citation Format: Marta Crous-Bou, Epidemiology of Endometrial Cancer Consortium (E2C2), Immaculata De Vivo. Coffee and tea intake and risk of endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2). [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 1751.
A High Throughput Experimental Approach to Identify miRNA Target Genes in Hodgkin Lymphoma.
Authors: Lu Ping Tan, Erwin Seinen, Gerben Duns, Debora Jong, Rikst Nynke Schakel, Geert Harms, Ody Sibon, Klaas Kok, Sibrand Poppema, Bart-Jan Kroesen, Anke van den Berg
Journal: Blood (2008)