tbuckley/cabot-search huggingface dataset:
<i>KRAS</i>in Non–Small-Cell Lung Cancer—Reply
Authors: Kevin Wood, Thomas Hensing, Ravi Salgia
Journal: JAMA Oncology (2016)

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A Clinicogenetic Risk Model (m7-FLIPI) Prospectively Identifies One-Half of Patients with Early Disease Progression of Follicular Lymphoma after First-Line Immunochemotherapy
Authors: Jurinovic Vindi, Robert Kridel, Annette M Staiger, Monika Szczepanowski, Heike Horn, Martin H. Dreyling, Andreas Rosenwald, German Ott, Wolfram Klapper, Andrew D. Zelenetz, Jonathan W. Friedberg, Stephen Ansell, Laurie H. Sehn, Joseph M Connors, Randy D. Gascoyne, David M. Weinstock, Wolfgang Hiddemann, Michael Unterhalt, Eva Hoster, Oliver Weigert
Journal: Blood (2015)
Validation of a panel of cell-cycle progression genes for improved risk stratification in a contemporary radical prostatectomy cohort.
Authors: Matthew R. Cooperberg, Jeffrey Simko, Janet E. Cowan, Julia E. Reid, Satish Bhatnagar, Alexander Gutin, Jerry S. Lanchbury, Steven Stone, Peter Carroll
Journal: Journal of Clinical Oncology (2012)

10 Background: Using clinical parameters, prostate cancers can be risk-stratified to aid treatment decisions. However, novel biomarkers are needed to predict tumor behavior more accurately. We aimed to validate the ability of a previously described 46-gene expression panel consisting of 31 cell-cycle progression (CCP) genes and 15 “housekeeping” genes to predict recurrence in a contemporary cohort of men undergoing radical prostatectomy (RP). Methods: Patients undergoing RP at UCSF since 1994 with ≥5 years of follow-up were included. RNA was extracted from archival RP tissue, and CCP score was calculated as average expression of the 31 CCP genes. Recurrence was defined as 2 PSAs ≥0.2 ng/ml or any salvage treatment at least 6 months after surgery. CCP score association with recurrence was assessed in univariate survival analysis and adjusted for PSA at diagnosis, pathologic Gleason score, margin status, extracapsular extension, seminal vesicle invasion, lymph node invasion. These variables were considered as separate covariates and as measured by the validated CAPRA-S score. Results: 413 men were included, 82 recurred. Most had low- to intermediate-risk pathology (mean CAPRA-S 2.1 ± 1.8). CCP scores ranged from -1.62 to 2.16; the mean was -0.28 ± 0.63. CCP score was associated with recurrence, HR 2.1 per CCP score unit (95% CI 1.6-2.9), p&lt;0.0001. With adjustment for pathologic variables, patient age, and year of surgery, HR was 2.0 per CCP score unit (1.4-2.9), p&lt;0.0001; and with adjustment for CAPRA-S score, the HR was 1.7 per CCP score unit (1.3-2.3), p&lt;0.001. By likelihood ratio testing, adding the CCP score to the CAPRA-S improved accuracy significantly (LR χ 2 11.4, p&lt;0.0001). Based on Kaplan-Meier analysis, CCP score adds useful discrimination to both the overall cohort and for patients with clinically low-risk disease (CAPRA-S score 0-2). Conclusions: In a contemporary post-RP cohort, the CCP score was validated to have significant prognostic accuracy even when controlling for clinical and pathologic data. The score has potential to substantially improve accuracy of risk-stratification, and lead to better decision-making with respect to timing and intensity of treatment.
Randomized phase II study of abiraterone acetate maintenance in combination with docetaxel after disease progression to abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC): ABIDO SOGUG trial.
Authors: Miguel Angel Climent, Alfredo Sanchez, Begoña Mellado, Carmen Santander, Javier Cassinello, M Isabel Saez, Martin Lázaro Quintela, José Pablo Maroto Rey, María José Méndez-Vidal, Aranzazu Gonzalez del Alba, Enrique Grande, Ignacio Duran, Emilio Esteban, Albert Font, Jose Angel Arranz Arija, Javier Puente, Daniel E. Castellano
Journal: Journal of Clinical Oncology (2014)

TPS5096 Background: Docetaxel (D) is the standard treatment for symptomatic or aggressive disease in mCRPC patients. Abiraterone acetate (AA), a specific inhibitor of CYP17, blocks persistent extragonadal and testicular androgen biosynthesis in mCRPC (Massard C, 2011). AA in combination with prednisone improves OS and rPFS in mCRPC patients after D-failure and for pts with asymptomatic or minimally symptomatic CT naïve (Fizazi K, 2012; Ryan CJ, 2013; ZYTIGA Janssen Biotech, Inc., 2012). This study aims to evaluate efficacy and safety of AA maintenance in combination with D after disease progression to first line AA in mCRPC. Methods: This is a randomized phase II open-label study conducted in chemotherapy naïve mCRPC patients progressing after AA treatment. Primarily, patients will be included for AA treatment (1000 mg/d plus prednisone 10 mg/d) if histologically or cytologically adenocarcinoma of the prostate is confirmed, metastatic disease other than visceral, prostate cancer progression to previous castration treatment documented by PSA (PCWG2), radiographic progression (modified RECIST) or bone scan progression; ECOG PS 0-1, testosterone < 50 ng/dL and adequate, hematologic, hepatic, and renal function. Patients will receive AA until clinical and/or radiographic disease progression. In a second phase patients will be randomized to receive D 75 mg/m2 plus prednisone 10 mg/d combined with AA 1000 mg/d (arm A) or D 75 mg/m2 plus prednisone 10 mg/d (arm B) alone in 21 day cycles. Primary objective is 1 year radiographic PFS. Secondary objectives include OS, PFS (radiographic and PSA), Response Rate (radiographic and PSA), pain, skeletal events, QoL, TTP and safety profile. At least fifty four pts are planned to be included in each arm to assess the treatment efficacy in terms of rPFS. Sample size has been calculated using the Fleming method with α=0.05 and β=80%. This study is planned include 119 pts in 17 sites in Spain and is expected to start in February 2014. Clinical trial information: NCT02036060.
Eular recommendations: An evidence based medicine approach to knee osteoarthritis
Authors: K M Jordan, N K Arden, B Bannwarth, J W Bijlsma, K Gunther, P Dieppe, H J Hauselmann, G Herrero-Beaumont, R Kaklamanis, B Leeb, M Lesquesne, S Lohmander, B Maziere, E Mola, K Pavelka, L Punzi, U Serni, B Swoboda, A Verbruggen, I Zimmermann-Gorska, M Doherty, M Dougados, A Pendleton, F Cluzeau
Journal: Annals of the Rheumatic Diseases (2003)
Abstract 2566: Comprehensive analysis to identify functional basis of prostate cancer risk SNPs
Authors: Mridu Middha, Xing Xu, Riina-Minna Vaananen, James Hayes, Pekka Taimen, Xiaoni Gao, Hans G. Lilja, Kim Pettersson, Robert J. Klein
Journal: Cancer Research (2016)

Abstract Introduction: Genome-wide association studies (GWAS) have identified numerous common single nucleotide polymorphisms (SNPs) associated with the risk of developing prostate cancer. Many of these prostate cancer GWAS hits occur in intergenic regions, distant from any annotated gene. Little is yet known about how these SNPs function to alter an individual's risk of prostate cancer. Here we test the hypothesis that many of these SNPs, or SNPs with which they are correlated, alter regulatory regions and thus gene expression in the prostate. Materials and Methods: To test if prostate cancer risk SNPs are correlated with gene expression changes, we conducted expression quantitative trait locus (eQTL) association analysis. Using genome-wide high-density genotypes and gene expression data from 56 tumor and 58 adjacent normal prostate tissues we asked if any of the prostate cancer risk SNPs correlate with expression changes in nearby genes using linear regression, adjusting gene expression levels for principal components of ancestry and different batches. We also asked if individuals who have a higher genetic risk of prostate cancer based on the genotype of all of their risk SNPs show different gene expression patterns in the prostate than those at lower risk of prostate cancer. Results: We have identified several novel cis-eQTLs in prostate tissue for prostate cancer risk SNPs including rs1933488 with RGS17. We have also replicated several previously known cis-eQTLs, including those for IRX4, PPP1R14A, and FOXP4. Individuals at higher genetic risk of developing prostate cancer have altered expression of 37 genes (p&amp;lt;0.001) in their tumor tissue compared to individuals at lower genetic risk. Conclusions: These data demonstrate that several prostate cancer risk SNPs are associated with expression changes in nearby genes in both pathologically malignant and pathologically benign prostate tissue from patients who underwent radical prostatectomy. Additional genes, including HMOX1, CSGALNACT1, and WDR36 show altered expression in patients with different levels of genetic risk of prostate cancer. Citation Format: Mridu Middha, Xing Xu, Riina-Minna Vaananen, James Hayes, Pekka Taimen, Xiaoni Gao, Hans G. Lilja, Kim Pettersson, Robert J. Klein. Comprehensive analysis to identify functional basis of prostate cancer risk SNPs. [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 2566.
The Prevalence and Use of Walking Loops in Neighborhood Parks: A National Study
Authors: Deborah A. Cohen, Bing Han, Kelly R. Evenson, Catherine Nagel, Thomas L. McKenzie, Terry Marsh, Stephanie Williamson, Peter Harnik
Journal: Environmental Health Perspectives (2016)

Background:Previous studies indicate that the design of streets and sidewalks can influence physical activity among residents. Park features also influence park use and park-based physical activity. Although individuals can walk on streets and sidewalks, walking loops in parks offer a setting to walk in nature and to avoid interruptions from traffic.Objectives:Here we describe the use of walking loops in parks and compare the number of park users and their physical activity in urban neighborhood parks with and without walking loops.Methods:We analyzed data from the National Study of Neighborhood Parks in which a representative sample of neighborhood parks (n = 174) from 25 U.S. cities with > 100,000 population were observed systematically to document facilities and park users by age group and sex. We compared the number of people and their physical activity in parks with and without walking loops, controlling for multiple factors, including park size, facilities, and population density.Results:Overall, compared with parks without walking loops, on average during an hourly observation, parks with walking loops had 80% more users (95% CI: 42, 139%), and levels of moderate-to-vigorous physical activity were 90% higher (95% CI: 49, 145%). The additional park use and park-based physical activity occurred not only on the walking loops but throughout the park.Conclusions:Walking loops may be a promising means of increasing population level physical activity. Further studies are needed to confirm a causal relationship.Citation:Cohen DA, Han B, Evenson KR, Nagel C, McKenzie TL, Marsh T, Williamson S, Harnik P. 2017. The prevalence and use of walking loops in neighborhood parks: a national study. Environ Health Perspect 125:170–174; http://dx.doi.org/10.1289/EHP293
Prognostic significance of early changes in the apparent diffusion coefficient that occurs after treatment of patients with glioblastoma multiforme with bevacizumab
Authors: M. Paldino, A. Desjardins, H. S. Friedman, J. J. Vredenburgh, D. P. Barboriak
Journal: Journal of Clinical Oncology (2009)

2058 Background: To determine the prognostic significance of changes in parameters derived from diffusion tensor imaging (DTI) that occur in response to combination chemotherapy with the antiangiogenesis agent bevacizumab (BEV) in patients with recurrent glioblastoma multiforme (GBM). Methods: 16 patients (10 men, 6 women; age range 38–62 years) with recurrent GBM underwent serial 1.5T MR imaging. Axial single-shot echo planar DTI (TR/TE 6000/100; flip angle 90 degrees; voxel: 1.72 x 1.72 x 5mm; b value of 1000 sec/mm 2 ; 12 directions) was obtained on scans performed 3 days and 1 day prior to and 1 day after initiation of therapy with BEV and irinotecan (CPT-11). Clinical follow-up and survival status was documented up to 20 months after the date of initial MR imaging. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were aligned to whole brain contrast-enhanced 3D FLASH and 3D FLAIR image volumes (1 mm isotropic voxels) using a rigid body normalized mutual information algorithm. Based on two pre-treatment scans, the 95% confidence limits for change (95%CL) in ADC and FA were calculated in volumes of tumor-related contrast-enhancement (TRE) and FLAIR signal abnormality (FSA). A patient was considered to have a change in FA or ADC after therapy if the difference between the pre- and post-treatment values was greater than the 95% CL for that parameter. Progression was defined on contrast-enhanced MRI using MacDonald criteria by neuro-oncologists blinded to the DTI findings. Survival was compared using the log rank test. Results: DTI detected a change in ADC within FSA after therapy in three patients (2 increased, 1 decreased). Patients with a change in ADC within FSA had significantly shorter overall (p &lt; 0.0012) and progression free (p &lt; 0.015) survival than those with no change. Median survival in the patient group with a change in ADC was 24.7 (95% CI [17.3, 39.4]) weeks and 56.4 (95% CI [41.7, 96]) weeks in those patients with no change. Conclusions: In patients with GBM treated with BEV and CPT-11, a change in ADC after therapy in areas of FSA is associated with decreased survival. Parameters derived from DTI may, therefore, potentially serve as early markers of treatment failure in patients with GBM. [Table: see text]
The Novel KLF4/MSI2 Signaling Pathway Regulates Growth and Metastasis of Pancreatic Cancer
Authors: Kun Guo, Jiujie Cui, Ming Quan, Dacheng Xie, Zhiliang Jia, Daoyan Wei, Liang Wang, Yong Gao, Qingyong Ma, Keping Xie
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Musashi 2 (MSI2) is reported to be a potential oncoprotein in cases of leukemia and several solid tumors. However, its expression, function, and regulation in pancreatic ductal adenocarcinoma (PDAC) cases have yet to be demonstrated. Therefore, in the current study, we investigated the clinical significance and biologic effects of MSI2 expression in PDAC cases and sought to delineate the clinical significance of the newly identified Krüppel-like factor 4 (KLF4)/MSI2 regulatory pathway. Experimental Design: MSI2 expression and its association with multiple clinicopathologic characteristics in human PDAC specimens were analyzed immunohistochemically. The biological functions of MSI2 regarding PDAC cell growth, migration, invasion, and metastasis were studied using gain- and loss-of-function assays both in vitro and in vivo. Regulation of MSI2 expression by KLF4 was examined in several cancer cell lines, and the underlying mechanisms were studied using molecular biologic methods. Results: MSI2 expression was markedly increased in both PDAC cell lines and human PDAC specimens, and high MSI2 expression was associated with poor prognosis for PDAC. Forced MSI2 expression promoted PDAC proliferation, migration, and invasion in vitro and growth and metastasis in vivo, whereas knockdown of MSI2 expression did the opposite. Transcriptional inhibition of MSI2 expression by KLF4 occurred in multiple PDAC cell lines as well as mouse models of PDAC. Conclusions: Lost expression of KLF4, a transcriptional repressor of MSI2 results in overexpression of MSI2 in PDACs, which may be a biomarker for accurate prognosis. A dysregulated KLF4/MSI2 signaling pathway promotes PDAC progression and metastasis. Clin Cancer Res; 23(3); 687–96. ©2016 AACR.
Abstract 195: Defining the role of PAK7 variants in melanoma
Authors: Kyle M. LaPak, Michael A. Gross, Denny C. Vroom, Greg B. Lesinski, William E. Carson, Christin E. Burd
Journal: Cancer Research (2016)

Abstract Melanoma mortality is directly linked to its profoundly metastatic nature and inherent resistance to conventional chemotherapy. For this reason, increased understanding of the molecular mechanisms driving melanoma progression is of utmost importance. The p21-activated serine/threonine kinases (PAKs) are frequently mutated or overexpressed in cancer and have recently been implicated in tumor metastasis, proliferation, and apoptotic resistance. This observation has inspired drug discovery efforts to limit PAK activity; yet, mechanistic understanding of how PAKs (especially Type II PAKs) contribute to tumor initiation and progression is still evolving. PAK7, a type II PAK, is mutated in 16-18% of all melanomas. Melanoma-associated PAK7 mutations occur throughout the gene and have unknown biochemical and physiological consequences. The objective of this study was to determine how tumor-associated PAK7 variants mechanistically contribute to melanoma initiation and progression. First, we characterized PAK7 protein expression in a panel of 39 melanoma cell lines and primary melanocyte cultures. PAK7 levels were similar in both tumorigenic and non-tumorigenic cells and failed to correlate with the status of common melanoma driver mutations (e.g. NRASQ61, BRAFV600). In an array of 101 human tumor biopsies, PAK7 expression did not significantly change with advancing melanoma stage; however, PAK7 levels were higher in regional lymph node biopsies when compared to primary skin lesions. Since mutation is the predominant mechanism affecting PAK7 in melanoma, we investigated the biochemical and physiological consequences of common PAK7 variants. 11 distinct PAK7 mutations were stably expressed at low levels in VMM39 (melanoma) and NCI-H441 (lung) cells. Using these clones, changes in the phosphorylation of downstream PAK7 targets associated with cellular migration (p120), proliferation (CRAF), and apoptotic resistance (BAD, MDM2) were examined. In addition, we defined phenotypic alterations in cellular morphology, proliferation, migration, and apoptotic resistance associated with the expression of each mutant. These data allowed us to classify PAK7 variants of unknown significance into groups associated with specific cellular outcomes. To our knowledge, this is the first study to functionally characterize a wide variety of melanoma-associated PAK7 mutations and represents a critical first step in understanding how this kinase contributes to tumor initiation and progression. Citation Format: Kyle M. LaPak, Michael A. Gross, Denny C. Vroom, Greg B. Lesinski, William E. Carson. Defining the role of PAK7 variants in melanoma. [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 195.
Abstract 3736: Schlafen 11 (SLFN11) blocks RNA synthesis upon replicative damage, a novel mechanism for killing cancer cells in response to DNA damaging agents
Authors: Junko Murai, Sai-wen Tang, Yves Pommier
Journal: Cancer Research (2016)

Abstract The putative DNA/RNA helicase, SLFN11, is a recently discovered determinant of response to DNA damaging agents including topoisomerase inhibitors (camptothecin, irinotecan, topotecan, doxorubicin and etoposide) and cisplatin. SLFN11 is inactivated in approximately 40% of cancer cell lines (NCI-60 and CCLE). Until now, the molecular mechanisms of SLFN11 action in response to DNA damage have been unknown. Using isogenic SLFN11-knockout cells as well as SLFN11-overexpressing cells, we will show that SLFN11 irreversibly arrests cells in S-phase without cell cycle recovery under camptothecin treatment, whereas SLFN11-negative cells continue cell cycle progression. Notably, the action of SLFN11 is independent of ATR-mediated S-phase checkpoint. Co-immunostaining of 5-Ethynyl Uridine (EU) and gamma-H2AX revealed that SLFN11 blocks RNA synthesis upon replicative damage. Comprehensive analysis of cell cycle genes revealed that genes that drive S-phase progression are selectively turned-off in SLFN11-positive cells, whereas p53-dependent genes remain induced by camptothecin. Accordingly, critical proteins for S-phase progression such as cyclin A, cyclin B, CDK1 and CDK2 were suppressed in SLFN11-positive but not in SLFN11-negative cells, which causality links SLFN11-mediated S-phase arrest in camptothecin-treated cells with inactivation of cell cycle-driving pathways. This mechanism is supported by the fact that the CDK inhibitor roscovitine recapitulates the S-phase arrest even in SLFN11-deficient cells. Finally, by contrast to normal SLFN11, overexpression of SLFN11 helicase-dead mutant failed to block RNA synthesis and to kill camptothecin-treated cells, indicating that the helicase activity of SLFN11 is necessary for its RNA synthesis regulatory function. Our study reveals a novel cell cycle regulation mechanism by SLFN11 that links DNA damage and transcriptional responses in cancer cells with replicative DNA damage. Citation Format: Junko Murai, Sai-wen Tang, Yves Pommier. Schlafen 11 (SLFN11) blocks RNA synthesis upon replicative damage, a novel mechanism for killing cancer cells in response to DNA damaging agents. [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 3736.
PTLD post liver transplantation: Early survival rates not maintained at 5 years in patients from a large monocentric LT cohort
Authors: Phaedra M. Tachtatzis, Shameem Mahmood, Anil Dhawan, Dino Hadzic, Nigel Heaton, Michael A. Heneghan, Abid Suddle, Varuna Aluvi Hare, John G. O'Grady, Robert Marcus, Kosh Agarwal
Journal: Hepatology (2012)
Development Of a Novel Small Molecule Inhibitor Of The Mer Tyrosine Kinase For Treatment Of Acute Lymphoblastic Leukemia
Authors: Deborah DeRyckere, Xiaodong Wang, Amanda A Hill, Weihe Zhang, Michael A Stashko, Susan Sather, Christopher E Cummings, William P Janzen, Stephen V Frye, H. Shelton Earp, Douglas K. Graham
Journal: Blood (2013)