tbuckley/cabot-search huggingface dataset:
Abstract 1650: Whole-genome RNAi screen identified BCAS1 as a novel modifier of non-small cell lung carcinoma radioresistance
Authors: Colin O’Leary, Peter Deraska, Alan D’Andrea, David Kozono
Journal: Cancer Research (2016)

Abstract Introduction: Despite optimal chemotherapy, radiotherapy and/or surgery, non-small cell lung carcinoma (NSCLC) remains the leading cause of cancer-related death in the United States. Therefore, there is a need for agents, such as radiosensitizers, that can improve the efficacy of current therapies. Using a whole-genome shRNA screen, we sought to identify and characterize novel gene products that may be involved in NSCLC radioresistance. We hypothesize that these proteins may represent novel targets for NSCLC radiosensitization. Materials and Methods: A whole-genome pooled retroviral shRNA screen was performed using the Hannon-Elledge library of 74,705 distinct shRNAs directed against over 18,000 genes, to identify gene knockdowns that showed cytotoxicity only in cells treated with fractionated radiation given daily Monday-Friday. To confirm targets identified in the whole-genome screen, we treated A549 and NCI-H460 NSCLC cells with siRNAs targeted against the genes of interest and assessed cell viability following irradiation using the CellTiter-Glo assay and clonogenic survival assays. Results: We identified six novel genes (BCAS1, c7orf24, CDC45L, KIAA0101, TCN1 and TNC) whose knockdown sensitized NSCLC cells to radiation. Of the six genes, siRNA knockdown of BCAS1 showed the most consistent increases in sensitivity to ionizing radiation. Analysis of cell viability following radiation revealed that BCAS1 knockdown resulted in a 50% additional decrease in cell viability in A549 and NCI-H460 cells following 8 and 4 Gy of ionizing radiation, respectively. We confirmed these results by clonogenic survival assays. To assess for tumor-specific expression in NSCLC, we compared expression data between matched normal tissue and NSCLC biopsy samples and found that BCAS1 is substantially more highly expressed in tumor tissues. Examination of affinity capture-mass spectroscopy data suggested that BCAS1 interacts with RUVBL2, a RuvB-like AAA ATPase, which has known functions in DNA damage and repair. Conclusions: BCAS1 emerged from a whole-genome RNAi screen as a potential target for improving the efficacy of radiotherapy in NSCLC. We demonstrated that BCAS1 is overexpressed in tumor tissues compared to normal lung, and that its knockdown consistently sensitizes NSCLC cell lines to radiation, validating the screen hit. Ongoing work suggests that BCAS1 may modulate DNA damage repair. Further studies to understand the mechanism by which BCAS1 is involved in radioresistance are necessary. Citation Format: Colin O’Leary, Peter Deraska, Alan D’Andrea, David Kozono. Whole-genome RNAi screen identified BCAS1 as a novel modifier of non-small cell lung carcinoma radioresistance. [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 1650.
Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
Authors: Wouter van Rheenen, Aleksey Shatunov, Annelot M Dekker, Russell L McLaughlin, Frank P Diekstra, Sara L Pulit, Rick A A van der Spek, Urmo Võsa, Simone de Jong, Matthew R Robinson, Jian Yang, Isabella Fogh, Perry Tc van Doormaal, Gijs H P Tazelaar, Max Koppers, Anna M Blokhuis, William Sproviero, Ashley R Jones, Kevin P Kenna, Kristel R van Eijk, Oliver Harschnitz, Raymond D Schellevis, William J Brands, Jelena Medic, Androniki Menelaou, Alice Vajda, Nicola Ticozzi, Kuang Lin, Boris Rogelj, Katarina Vrabec, Metka Ravnik-Glavač, Blaž Koritnik, Janez Zidar, Lea Leonardis, Leja Dolenc Grošelj, Stéphanie Millecamps, François Salachas, Vincent Meininger, Mamede de Carvalho, Susana Pinto, Jesus S Mora, Ricardo Rojas-García, Meraida Polak, Siddharthan Chandran, Shuna Colville, Robert Swingler, Karen E Morrison, Pamela J Shaw, John Hardy, Richard W Orrell, Alan Pittman, Katie Sidle, Pietro Fratta, Andrea Malaspina, Simon Topp, Susanne Petri, Susanne Abdulla, Carsten Drepper, Michael Sendtner, Thomas Meyer, Roel A Ophoff, Kim A Staats, Martina Wiedau-Pazos, Catherine Lomen-Hoerth, Vivianna M Van Deerlin, John Q Trojanowski, Lauren Elman, Leo McCluskey, A Nazli Basak, Ceren Tunca, Hamid Hamzeiy, Yesim Parman, Thomas Meitinger, Peter Lichtner, Milena Radivojkov-Blagojevic, Christian R Andres, Cindy Maurel, Gilbert Bensimon, Bernhard Landwehrmeyer, Alexis Brice, Christine A M Payan, Safaa Saker-Delye, Alexandra Dürr, Nicholas W Wood, Lukas Tittmann, Wolfgang Lieb, Andre Franke, Marcella Rietschel, Sven Cichon, Markus M Nöthen, Philippe Amouyel, Christophe Tzourio, Jean-François Dartigues, Andre G Uitterlinden, Fernando Rivadeneira, Karol Estrada, Albert Hofman, Charles Curtis, Hylke M Blauw, Anneke J van der Kooi, Marianne de Visser, An Goris, Markus Weber, Christopher E Shaw, Bradley N Smith, Orietta Pansarasa, Cristina Cereda, Roberto Del Bo, Giacomo P Comi, Sandra D'Alfonso, Cinzia Bertolin, Gianni Sorarù, Letizia Mazzini, Viviana Pensato, Cinzia Gellera, Cinzia Tiloca, Antonia Ratti, Andrea Calvo, Cristina Moglia, Maura Brunetti, Simona Arcuti, Rosa Capozzo, Chiara Zecca, Christian Lunetta, Silvana Penco, Nilo Riva, Alessandro Padovani, Massimiliano Filosto, Bernard Muller, Robbert Jan Stuit, Ian Blair, Katharine Zhang, Emily P McCann, Jennifer A Fifita, Garth A Nicholson, Dominic B Rowe, Roger Pamphlett, Matthew C Kiernan, Julian Grosskreutz, Otto W Witte, Thomas Ringer, Tino Prell, Beatrice Stubendorff, Ingo Kurth, Christian A Hübner, P Nigel Leigh, Federico Casale, Adriano Chio, Ettore Beghi, Elisabetta Pupillo, Rosanna Tortelli, Giancarlo Logroscino, John Powell, Albert C Ludolph, Jochen H Weishaupt, Wim Robberecht, Philip Van Damme, Lude Franke, Tune H Pers, Robert H Brown, Jonathan D Glass, John E Landers, Orla Hardiman, Peter M Andersen, Philippe Corcia, Patrick Vourc'h, Vincenzo Silani, Naomi R Wray, Peter M Visscher, Paul I W de Bakker, Michael A van Es, R Jeroen Pasterkamp, Cathryn M Lewis, Gerome Breen, Ammar Al-Chalabi, Leonard H van den Berg, Jan H Veldink
Journal: Nature Genetics (2016)
Abstract 4259: Long term cell culture models to identify biomarkers of response
Authors: Usha Warrior, Jonathan Crane, Karen Bernards, Brian Nelson, Katie Snead, Alison Angione, Amber Sherman, Shawn DeVault, Jim Hnilo, jameel Shah.
Journal: Cancer Research (2016)

Abstract In order to test the efficacy of many cancer therapeutics, culturing cells in the presence of compounds for longer than the conventional 72-hr cell growth assay may be necessary. It is shown that the inhibition of many epigenetic targets results in a significantly delayed drug response not revealed by conventional shorter term cell growth assays. OncoPanel™ from Eurofins Pharma Discovery Services is a collection of 300 cell lines with broad cancer type and subtype representation and extensive genomic characterization. We have developed a 10-day assay to test inhibitors of epigenetic targets. Using the EZH2-selective inhibitor, GSK343, we have demonstrated the advantages of cell line profiling under long-term assay conditions when drug response reflects a protracted mechanism of action. We also tested Olaparib, a PARP inhibitor, in this system and showed substancial increased sensitivity against several cell lines versus the 72 hr assay. The significant biomarkers identified from the genomic analysis of the data from both GSK343 and Olaparib substantiate the relevance of long term cell profiling. Citation Format: Usha Warrior, Jonathan Crane, Karen Bernards, Brian Nelson, Katie Snead, Alison Angione, Amber Sherman, Shawn DeVault, Jim Hnilo, jameel Shah. Long term cell culture models to identify biomarkers of response. [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 4259.
The Role of Peroxiredoxin III and Sulfiredoxin for Mitochondrial ROS Production to Arsenic Trioxide in Acute Promyelocytic Leukemia Cells
Authors: Yeung-Chul Mun, Jee-Young Ahn, Eun-Sun Yoo, Kyoung Min Cho, Kyoung Eun Lee, Eunmi Nam, Soon Nam Lee, Hyun Ae Woo, Sue Goo Rhee, Chu-Myong Seong
Journal: Blood (2014)
Abstract PL02-02: Transcriptional regulation by the MAX-like protein MLX is required for adaptive metabolic responses in development and tumorigenesis
Authors: Patrick A. Carroll, Pei-Feng Cheng, Charles H. Muller, Liam Hunt, Fabio Demontis, Don E. Ayer, Robert N. Eisenman
Journal: Cancer Research (2016)

Abstract The MYC transcription factor, together with its obligate dimerization partner, MAX, regulates widespread gene expression and is implicated in the etiology of a broad spectrum of cancers. MYC and MAX are members of the MAX-MLX superfamily of bHLHZ transcription factors (which includes MYC, MAX, MXD, MLX, and MONDO/ChREBP). Members of this highly conserved family respond to environmental cues to modulate gene expression programs and control cellular fate. We recently showed that metabolic reprogramming and survival in MYC-driven cancer cells is coordinately regulated by MYC-MAX and MONDOA-MLX. While knockdown of MONDOA or MLX affected multiple metabolic pathways in MYC-induced tumors, we found that decreased fatty acid synthesis primarily accounted for the loss of viability (Carroll et al. Cancer Cell 27:271, 2015) To explore the physiological role of the MLX branch of the MAX-MLX network we generated mice with targeted deletion of Mlx. Mlx null mice appeared to develop normally; however, we found that Mlx null males are infertile, with strikingly diminished sperm production, viability, and motility. MondoA knockout mice exhibited a similar phenotype. By employing tissue-specific Cre-mediated deletion of Mlx, we uncovered metabolic defects in both Sertoli cells as well as germ cells, including loss of lipogenic enzymes and altered lipid content. Moreover, we found that human male germ cell tumors (MGCTs) overexpress MAX-MLX network proteins and undergo apoptosis upon loss of MONDOA/MLX. Importantly, the same metabolic pathways shown to be crucial for survival of neuroblastoma are also required for survival of MGCTs. Furthermore. we have uncovered a critical role for MLX in myokine production required for myoblast fusion in vitro. Moreover, mice bearing homozygous deletion of Mlx fail to regenerate muscle following cardiotoxin treatment (Hunt et al. Genes Dev. 29:2475, 2015). Taken together, our studies suggest a critical role for the MLX arm of the MAX-MLX network in adaptive metabolic responses in tumorigenesis and development. Funding: NIH grants CA57138 (to RNE) and GM055668 (to DEA); ALSAC of St. Jude Children's Research Hospital, the Ellison Medical Foundation, the Glenn Foundation for Medical Research, and the American Federation for Aging Research (AFAR) (to FD). Citation Format: Patrick A. Carroll, Pei-Feng Cheng, Charles H. Muller, Liam Hunt, Fabio Demontis, Don E. Ayer, Robert N. Eisenman. Transcriptional regulation by the MAX-like protein MLX is required for adaptive metabolic responses in development and tumorigenesis. [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 PL02-02.
Effect of concurrent chemotherapy on overall survival in elderly bladder cancer patients undergoing radiotherapy: A population-based analysis.
Authors: Abhishek Ashok Solanki, Alec Block, Elizabeth Henry, Ellen R. Gaynor, Matthew M. Harkenrider, James Welsh, William Small
Journal: Journal of Clinical Oncology (2016)

e16000 Background: Randomized data demonstrate concurrent chemoradiotherapy (CRT) improves overall survival (OS) compared to radiotherapy alone (RT) in muscle invasive bladder cancer. However, patients ≥ 80 make up a small proportion of CRT trials, and the incremental benefit of CRT in elderly patients is unclear. We analyzed the National Cancer Database to estimate the improvement in OS with CRT compared to RT in this cohort. Methods: Patients ≥ 80 years old with cT2-4 N0-3 M0 muscle invasive bladder transitional cell carcinoma treated with RT or CRT were selected. The chi-squared test was used to compare clinical, treatment, and sociodemographic covariates between both groups. The Kaplan-Meier method was used to estimate OS, and univariate analysis (UVA) was performed using the log rank test to identify the impact of covariates on OS. Multivariable analysis (MVA) was performed using the Cox Proportional Hazards model, and included all covariates with p < 0.1 on UVA. Results: 474 patients treated with radiotherapy from 2004 to 2012 met eligibility criteria, 293 (62%) patients received RT and 181 (38%) patients received CCRT. Median age was 85 years (range: 80-90). CRT patients were younger (p < 0.001), were more likely to have Charlson-Deyo comorbidity score (CDCC) of 0 (p = 0.029) and radiation dose ≥ 60 Gy (p = 0.011). Median follow-up was 17 months. Overall 2-year OS was 40%. UVA revealed CRT (2-year OS 49% vs. 35%; p < 0.001), lower age (p = 0.032), lower t-stage (p = 0.043), lower n-stage (p = 0.037), and radiation dose ≥ 60 Gy (p < 0.001) were associated with improved OS. CDCC was not associated with OS (p = 0.112). MVA revealed CRT (Hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.53 to 0.87; p = 0.002) and RT dose ≥ 60 Gy (HR 0.45; 95% CI, 0.36 to 0.57; p < 0.001) were associated with improved OS. T4 disease was associated with worse OS (HR 1.41; 95% CI, 1.03 to 1.94; p = 0.031). On sensitivity analysis, CCRT was still associated with improved OS when including CDCC in the MVA model. Conclusions: This is the largest series of elderly patients undergoing bladder cancer RT, and revealed that CRT is associated with improved OS, independent of CDCC. When possible, CCRT should be used in this population.
Gastrointestinal malignancies as a subsequent malignant neoplasm in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: T. O. Henderson, J. Whitton, W. Leisenring, J. P. Neglia, A. T. Meadows, K. C. Oeffinger, L. Diller, G. T. Armstrong, L. L. Robison, P. C. Nathan
Journal: Journal of Clinical Oncology (2010)

9520 Background: There is emerging evidence that childhood cancer survivors (CCS) develop gastrointestinal (GI) malignancies more frequently and earlier than the general population. We determined the risk of GI subsequent malignant neoplasms (SMN) and described factors associated with their development to inform surveillance recommendations. Methods: We assessed the risk of GI SMN in a cohort of 14,372 5-year CCS and compared that to population-based data from the Surveillance, Epidemiology and End Results (SEER) program. Multivariate Cox regression models identified associations between key risk factors and GI SMN development. Results: 45 CCS developed GI SMN at a median age of 33.5 years (range: 9.7-44.8) and a median of 22.8 years (range: 5.5-30.2) from their original diagnoses. The 30-year cumulative incidence of a GI SMN was 0.64% (95% confidence interval [CI]: 0.43-0.86). The most frequent SMN locations were colorectal (n=24; 53%), stomach (n=7; 16%), and hepatobiliary system (n=4, 9%). CCS with a GI SMN were more likely to be deceased than those without (51.1 vs. 13.8%, p<0.05). 60.9% of deceased died of their GI SMN. The risk of GI SMN was almost 5-fold higher in CCS than the general population (standardized incidence ratio [SIR]=4.6, 95% CI: 3.5-6.1) with absolute excess risk (AER) of 14 per 100,000 person-years (py). Colorectal SMN SIR was 4.19 (95% CI: 2.78-6.30), EAR was 7/100,000 py. Survivors of Wilms' tumor, Hodgkin's lymphoma and bone tumors were at highest risk. The multivariate model revealed abdominal radiation (RR=5.32, 95% CI: 2.74-10.32), alkylating agents (RR=2.60, 95% CI: 1.06-6.37) and platinum drugs (RR=4.73, 95% CI: 1.49-15.14) increased the risk of GI SMN. Conclusions: While the overall incidence is low, CCS are at increased risk for developing a GI SMN with an associated elevated risk of mortality. Surveillance in at-risk survivors should commence at a younger age than is recommended for the general population. No significant financial relationships to disclose.
Abstract 1717: Circulating tumor cells from in vitro 3D culture systems have tumor-initiating capacity in vivo
Authors: Marina C. Cabrera, Elaine Hurt, Xiaoru Chen, Shi Xiaoqing, Haifeng Bao
Journal: Cancer Research (2016)

Abstract Circulating tumor cells (CTCs) are cells that have detached from the primary tumor and entered the bloodstream with the potential to seed metastatic tumors in distal sites. High CTC numbers correlate with aggressive disease, increased metastasis, and decreased time to relapse. It has also been shown that cancer stem cells (CSCs) represent a proportion of the CTCs present in patients. Given that CSCs are resistant to chemotherapy and are responsible for tumor initiation, it is posited that the CSCs are the seeds of metastasis. However, direct evidence for this hypothesis is limited because there are few methods for culturing and studying these rare cells. We are using a 3D culture chamber system (RealBio D4™) to establish long-term cultures of human-derived breast and pancreatic tumors. We observed that the system's 3D matrix supported culture development and incorporation of tissue organization and microenvironment. Further, the chamber design allowed CTCs generated within the cultures to migrate out of the cell mass into the circulating nutrient medium where they were collected for characterization. The isolated CTCs displayed CSC properties via CellSearch® (CD44+,CD24-; CD44+,CD24+ for breast and pancreas respectively). In addition, these isolated CTCs displayed tumor-initiating capacity when implanted into mice. Future studies will compare CTCs isolated from 3D culture with cells from tumors, blood, and tissue grown on scaffold through RT-PCR, histology, and gene expression assays. Citation Format: Marina C. Cabrera, Elaine Hurt, Xiaoru Chen, Shi Xiaoqing, Haifeng Bao. Circulating tumor cells from in vitro 3D culture systems have tumor-initiating capacity in vivo. [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 1717.
Safety and efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort.
Authors: Neil Howard Segal, Sai-Hong Ignatius Ou, Ani Sarkis Balmanoukian, Matthew G. Fury, Erminia Massarelli, Julie R. Brahmer, Jared Weiss, Patrick Schoffski, Scott Joseph Antonia, Christophe Massard, Dan Paul Zandberg, Samir Khleif, Xia Li, Marlon Rebelatto, Keith Steele, Paul B. Robbins, John A. Blake-Haskins, Marcus O. Butler
Journal: Journal of Clinical Oncology (2015)

3011 Background: Outcomes are poor for patients (pts) with recurrent/metastatic (R/M) SCCHN, and new treatments are needed. An ongoing phase I/II, multicenter, open-label study (NCT01693562) is evaluating the safety and efficacy of MEDI4736 (M), a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity, in multiple solid tumor types including SCCHN. PD-L1 is expressed in SCCHN tumors and may be associated with response to anti-PD-L1 treatment. Methods: Pts with R/M SCCHN, an ECOG of 0 or 1, without prior anti-PD-1/PD-L1 exposure are eligible. M is administered IV every 2 weeks at 10 mg/kg for 12 months. Retreatment is permitted upon progression after 12 months. PD-L1 expression is assessed by IHC using the Ventana SP263 clone. Prior documented HPV status is collected at study entry. Response is based on investigator assessment per RECIST v1.1. Data included represent a larger population with more mature follow up than previously reported (Fury M, et al. Poster presented at ESMO 2014, 988PD). Results: As of 31 Oct 2014, 62 pts (mean age 58 years [range 24–96]; 86% male; 64% current/prior smokers; ECOG 0/1: 38%/62%; HPV pos/neg/unk: 40%/39%/21%), with a median of 3 prior systemic treatments (1–10), received a median of 6 doses (1–26). Drug-related AEs were observed in 60% of pts; the most frequent were fatigue (11%), diarrhea, (8%), and nausea (7%). Grade ≥ 3 related AEs were reported in 7% of pts: rash (2 pts), and increased GGT, fatigue, and tumor inflammation (1 pt each). No drug-related AEs led to discontinuation or death. No colitis or grade ≥ 3 pneumonitis was observed. Overall, 51 pts were evaluable for response with ≥ 24 weeks of follow up; ORR was 12% (25% in PD-L1+ pts), and DCR at 24 weeks was 16% (25% in PD-L1+ pts). Responses are ongoing in 5/6 responding pts, with response durations ranging from 4+ to 43+ weeks. Median duration of response has not been reached. Conclusions: With more mature follow up, the safety profile of M in SCCHN is manageable and consistent with previous reports. Responses are durable; ORR and DCR are higher in PD-L1+ pts. A registration program is underway in pts with SCCHN for M alone and in combination with tremelimumab. Clinical trial information: NCT01693562.
Case 32-1969
Authors: William E. Strole, Benjamin Castleman
Journal: New England Journal of Medicine (1969)

Presentation of Case First admission. A sixty-year-old man was admitted to the hospital because of headaches and diplopia.Twenty-five years previously he had been treated in a military hospital for multiple battle injuries; a seminoma of the right testis was found, radical dissection was performed, and a dose of approximately 5000 R was administered to the para-aortic lymph-node chain. Subsequently, diarrhea occurred, with the passage of 6 to 10 loose stools daily; he had no fever or chills. The diarrhea was treated with aluminum hydroxide gel (Amphojel) or paregoric. During the next twenty years episodes of crampy abdominal pain, bloating . . .
Case 7-1966
Authors: Mitchell T. Rabkin, Benjamin Castleman
Journal: New England Journal of Medicine (1966)

Presentation of Case First admission. A thirty-seven-year-old woman was admitted to the hospital because of edema.She had been well until five weeks previously, when a "pressing" sensation developed in the lumbar region and persisted for half an hour. Dysuria occurred for a week thereafter. During the four weeks before entry she had progressive edema of the ankles. Three weeks before admission a physician prescribed chlorothiazide, but it was without benefit. During the week before entry the abdomen became distended, and periorbital edema developed.There was no history of the passage of dark urine, pyuria, hematuria, urinary frequency, fever or . . .