tbuckley/cabot-search huggingface dataset:
Abstract 5702: A targeted re-sequencing assay for molecular profiling of somatic mutations from plasma cell-free dna (cfdna) for bladder cancers
Authors: Liqin Dong, Pramit Khetrapal, Simon Rodney, Wei Shen Tan, Sheida Rezaee, Patricia de Winter, John Kelly, Andrew Feber
Journal: Cancer Research (2017)

Abstract Bladder cancer (BC) is the 5th most common cancer in Western societies with a rising global incidence. The major challenge to improving patient outcomes is to better identify patients at risk for recurrence, progression, and metastasis, and to monitor treatment response. A non-invasive monitoring assay is needed in order to interrogate the molecular features and clinical tumor heterogeneity of bladder cancers, which will potentially lead to better stratified patient management. We developed a targeted amplicon-based re-sequencing workflow for detecting and tracking genomic mutations in cfDNA using dual molecular indexed primers for specific amplification of a panel of 20 of known (TERT, FGFR3, PIK3CA, HRAS) and novel BC mutations. Only 3hr time is needed for the total workflow for the library generation and followed by next generation sequencing (NGS) performed on Illumina MiSeq sequencing platform. Data analysis and variants calling was performed. After a thorough test, optimization, and validation of the targeted panel and the workflow on selected samples of matched bladder tumor-blood pairs and controls, 45 samples were included for testing the workflow, which includes samples of 16 matched bladder tumor-blood pairs, technical duplicates of cfDNA DNA Reference Standards (Horizon Discovery) with mutations at known allelic frequencies. Technical duplicates of cfDNA extracted from blood from patients with metastatic BC (pre and post chemotherapy) were also included in this study. Somatic variants from matched tumor-blood pairs were detected. We showed that detection sensitivity at 1.0% allelic frequency was achieved. Our preliminary results demonstrated that we were able to detect mutation burden from cfDNA samples and track mutation burden change in response to chemotherapy for patients with metastatic BC. Here we developed a sensitive, non-invasive targeted NGS workflow to detect somatic mutations for bladder cancers from both tumor DNA and cfDNA samples. Our early results demonstrated that we can detect and track mutational changes from patients with metastatic BC. Citation Format: Liqin Dong, Pramit Khetrapal, Simon Rodney, Wei Shen Tan, Sheida Rezaee, Patricia de Winter, John Kelly, Andrew Feber. A targeted re-sequencing assay for molecular profiling of somatic mutations from plasma cell-free dna (cfdna) for bladder cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5702. doi:10.1158/1538-7445.AM2017-5702
Abstract 4340: RHBDF2 in stromal fibroblasts mediates TGF-β signaling and enhances gastric cancer cell invasion via intercellular crosstalk
Authors: Takatsugu Ishimoto, Keisuke Miyake, Masakazu Yashiro, Tsugio Eto, Daisuke Izumi, Kota Arima, Yoshifumi Baba, Masayuki Watanabe, Kosei Hirakawa, Hideo Baba, Patrick Tan
Journal: Cancer Research (2017)

Abstract Background: Cancer-associated fibroblasts (CAFs) have been reported to promote various types of tumor through secretion of soluble factors. However, there have been no systematic studies of CAFs in diffuse-type gastric cancers (DGCs). We investigated the characteristics and functional roles of CAFs in DGCs using comprehensive genomic approach. Methods: We established primary fibroblasts, normal fibroblasts (NFs) and CAFs from more than 100 tissue samples from GC patients. NFs/CAFs were subjected to Exome and RNA sequencing, and the possible candidates for functional assay were selected from among the acquired comprehensive data. The candidate molecules were examined the functional roles for GC tumor progression by in vitro assays. Results: CAFs exhibited an invasive molecular pattern and acquired motility in extracellular matrix (ECM). We identified RHBDF2 as a mediator of TGF-β signaling and an enhancer of CAF motility. RHBDF2 silencing in CAFs significantly decreased their motility stimulated by TGF-β1 in ECM, whereas NFs transfected with the RHBDF2 expression vector displayed a greater motility in ECM than did control NFs. RHBDF2 silencing also decreased type I TGF-β receptor (TβRI) cleavage through tumor necrosis factor (TNF)-α converting enzyme (TACE) activity and attenuated the invasive molecular pattern of CAFs. Consequently, high-motility CAFs confer on DGC cells the ability to invade the ECM. Furthermore, simultaneous treatment with interleukin (IL)-1α, IL-1β and TNF-α resulted in a strong induction of RHBDF2 expression in NFs. The expression of these cytokines in GC tissues was associated with poor prognosis in GC patients. Conclusion: These findings highlight the underlying mechanism whereby DGC cells take advantage of CAFs to acquire invasiveness. Citation Format: Takatsugu Ishimoto, Keisuke Miyake, Masakazu Yashiro, Tsugio Eto, Daisuke Izumi, Kota Arima, Yoshifumi Baba, Masayuki Watanabe, Kosei Hirakawa, Hideo Baba, Patrick Tan. RHBDF2 in stromal fibroblasts mediates TGF-β signaling and enhances gastric cancer cell invasion via intercellular crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4340. doi:10.1158/1538-7445.AM2017-4340
Abstract 11: The oncolytic peptide LTX-315 enhances T cell clonality and induces synergy with chemotherapy
Authors: Ketil André Camilio, Meng Yu Wang, Janne Nestvold, Gunhild Mælandsmo, Baldur Sveinbjørnsson, Øystein Rekdal
Journal: Cancer Research (2017)

Abstract LTX-315, a novel oncolytic peptide is effective against both drug-resistant and drug-sensitive cancer cells with lower toxicity towards normal cells. Intratumoral treatment with LTX-315 results in growth inhibition, complete regression and long lasting tumor-specific immune responses. The oncolytic effect of LTX-315 involves perturbation of the plasma membrane and distortion of intracellular organelles including the mitochondria with subsequent release of Damage-Associated Molecular Pattern molecules (DAMPs) such as ATP, cytochrome c and HMGB1. LTX-315 effectively induces necrosis within the tumor followed by the release of tumor antigens as demonstrated by a greater increase in tumor infiltrating CD8+ T cells, expansion of T cell clonality, and number of clones within the tumor microenvironment. LTX-315`s ability to modify the tumor microenvironment makes it ideal as a combination partner for other cancer therapies, including chemotherapy and immune checkpoint inhibitors. In preclinical tumor models, combination of LTX-315 and chemotherapeutic agents such as cyclophosphamide and doxorubicin demonstrates significant synergy. Citation Format: Ketil André Camilio, Meng Yu Wang, Janne Nestvold, Gunhild Mælandsmo, Baldur Sveinbjørnsson, Øystein Rekdal. The oncolytic peptide LTX-315 enhances T cell clonality and induces synergy with chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 11. doi:10.1158/1538-7445.AM2017-11
Venous thromboembolism in prostate cancer patients treated with robot-assisted radical prostatectomy and pelvic lymph nodes dissection.
Authors: Shadi E. Hamdan, Olga N. Kozyreva, Ingolf Tuerk, Shachi Gupta
Journal: Journal of Clinical Oncology (2012)

e15123 Background: Cancer and cancer treatment increases the risk of venous thromboembolism (VTE). Pelvic lymph nodes dissection (PLND) during radical prostatectomy increases the risk of VTE. Robot-assisted radical prostatectomy (RARP) is becoming increasingly popular, yet VTE data are not well reported. The aim of the study is to assess the rate of VTE in prostate cancer patients who underwent RARP with and without PLND. Methods: The records of 768 patients who underwent RARP by a single surgeon from 2008-2011 were reviewed for postoperative venous thromboembolism. Patient demographics, Gleason score, clinical stage, PSA, surgical approach and other operative variables were collected by prospective prostate cancer database. Information obtained from patient visit 6-8 weeks after the surgery was included in the database. VTE diagnosis was retrieved from inpatient and outpatient medical records. Fisher's exact test was used to determine the association between RARP with PLND and the occurrence of postoperative VTE. Results: Of the 768 patients who underwent RARP (mean age was 59.8 years, range: 40-77 years), 419 (54%) underwent PLND. Compared to patients who underwent RARP alone, patients who underwent RARP with PLND had higher PSA (mean PSA 7.3 vs. 5.3 p=0.0002), rate of Gleason score ≥ 7 (82% vs. 13% p=&lt;0.0001) and more advanced tumor stage pT3 (39% vs. 12% p=&lt;0.0001). Venous thromboembolism occurred in 5 of 419 (1.2%) patients who underwent RARP with PLND, and in 1 of 349 (0.28%) patients who underwent RARP (p=0.22). The lymph node metastasis rate was 7%. Conclusions: The incidence of VTE in prostate cancer patients treated with RARP is low. PLNDis not associated with a significantly increased risk of venous thromboembolism as compared to RARP alone.
Abstract 1779: Chronic NSAID use increases survival inPIK3CA-altered head and neck squamous cell carcinoma
Authors: Matthew Louis Hedberg, Noah Peyser, William Gooding, Hua Li, Toni Brand, Victor Olivas, Trever Bivona, Simion Choisea, Lin Wang, Jonas Johnson, Uma Duvvuri, Robert Ferris, Daniel Johnson, Patrick Ha, Julie Bauman, Jennifer Grandis
Journal: Cancer Research (2017)

Abstract Background: PIK3CA is the most commonly altered oncogene in head and neck squamous cell carcinoma (HNSCC). Chronic non-steroidal anti-inflammatory (NSAID) use has been shown to reduce mortality in PIK3CA-mutated colorectal cancer through an unknown mechanism. In this retrospective cohort analysis, we evaluated the impact of NSAIDs on HNSCC survival, and sought a biologically plausible explanation for the observed effect. Methods: The PIK3CA status of tumor tissue was determined by FISH and next generation sequencing for 266 HNSCC patients treated at the University of Pittsburgh Cancer Institute. Cox joint proportional hazards models were used to generate multivariate projections of disease-specific (DSS) and overall survival (OS). Prostaglandin E2 (PGE2) secretion and NSAID sensitivity were then assessed in HNSCC cell lines with or without PIK3CA mutation. Results: Chronic NSAID use (≥2 days/week for ≥6 months) was associated with greater disease-specific (HR 0.24; 95% CI, 0.09 - 0.62; p = 0.0032) and overall survival (HR 0.31; 95% CI, 0.14 - 0.69; p = 0.0043) in patients whose tumors harbor PIK3CA mutation and/or amplification. Survival was unchanged by chronic NSAID use in patients with wild-type, unamplified PIK3CA. Chronic NSAID users with PIK3CA-altered tumors had an increase in estimated 5-year DSS from 25% to 72% and in OS from 45% to 78%. Benefit was independent of age, stage, and human papillomavirus (HPV) status; all of which were controlled for in the model. HNSCC cells with endogenous or engineered PIK3CA mutation secreted higher levels of PGE2 and were more sensitive to growth inhibition by NSAID treatment. Conclusions: Chronic NSAID use was associated with markedly improved survival in patients with PIK3CA-altered HNSCC, but not in those with wild-type, unamplified PIK3CA. Preclinical studies implicate the PI3K-COX-PGE2 signaling axis as a potential mediator of NSAID response. A prospective, randomized controlled trial of NSAIDs in patients with PIK3CA-altered HNSCC is warranted. Citation Format: Matthew Louis Hedberg, Noah Peyser, William Gooding, Hua Li, Toni Brand, Victor Olivas, Trever Bivona, Simion Choisea, Lin Wang, Jonas Johnson, Uma Duvvuri, Robert Ferris, Daniel Johnson, Patrick Ha, Julie Bauman, Jennifer Grandis. Chronic NSAID use increases survival in PIK3CA-altered head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1779. doi:10.1158/1538-7445.AM2017-1779
Abstract 345: PTEN tumor suppressive effects in glioblastoma are partly mediated by MET downregulation via a p53-miR-34a axis
Authors: Fadilla Guessous, Nichola A. Cruickshanks, Ying Zhang, David Schiff, Jann Sarkaria, Roger Abounader
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) is the most common and most lethal primary malignant brain tumor. Two common alterations in GBM are loss of the tumor suppressor PTEN and upregulation of the oncogenic receptor tyrosine kinase MET. We uncovered a new connection between PTEN and MET expressions and functions in GBM. We found that PTEN expression in GBM cell lines (U87, U373, A172, LNZ-308) and primary cells (GBM8) inhibits MET expression. We uncovered the molecular basis and functional significance of this connection. Based on our previous work and published literature, PTEN stabilizes p53, p53 induces miR-34a expression, and miR-34a inhibits MET expression. We therefore hypothesized that PTEN inhibits MET by regulating p53 and miR-34a and that the PTEN tumor suppressive effects are partly mediated by MET downregulation. To verify the hypothesis, we first showed that PTEN restoration leads to miR-34a upregulation in GBM cells. We then showed that this latter effect is p53-dependent as p53 knockdown with a specific shRNA partly reversed PTEN induction of miR-34a. We also showed that PTEN-induced downregulation of MET expression can be rescued by inhibition of miR-34a with an anti-miR3a. We therefore established a new molecular cascade that links PTEN, p53, miR-34a and MET in GBM. To determine the functional relevance of this cascade, we assessed the effects of PTEN on GBM cell death and invasion also in the settings of shRNA-mediated knockdown of p53 and anti-miR-mediated inhibition of miR-34a. PTEN strongly induced GBM cell death (measured by Annexin V/7AAD flow cytometry) and inhibited transwell invasion though a collagen IV matrix. The PTEN effects on cell death and invasion were partly reduced by p53 knock-down and miR-34a inhibition. This demonstrates that the tumor suppressive effects of PTEN in GBM are partly mediated by the PTEN/p53/miR-34a/MET cascade. In ongoing experiments, we are investigating the expressions of PTEN, MET, p53 and miR-34a in human GBM tissues to determine if there are potential correlations that are consistent with our above findings. Altogether, this study establishes a new molecular and functional link between PTEN and MET that involves p53 and miR-34a in GBM. Citation Format: Fadilla Guessous, Nichola A. Cruickshanks, Ying Zhang, David Schiff, Jann Sarkaria, Roger Abounader. PTEN tumor suppressive effects in glioblastoma are partly mediated by MET downregulation via a p53-miR-34a axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 345. doi:10.1158/1538-7445.AM2017-345
Abstract 3470: The promyelocytic leukemia (PML) protein modulates rate and localization of homologous recombination in human cell lines with the alternative lengthening of telomeres (ALT) pathway
Authors: Walter Barry, Christopher Heaphy, Alan Meeker
Journal: Cancer Research (2017)

Abstract The promyelocytic leukemia protein (PML) is tightly associated with a defining feature of the cancer specific, telomerase-independent telomere-maintenance pathway known as alternative lengthening of telomeres (ALT); therefore, PML is an important potential target for chemotherapeutics. Cells running ALT contain large accumulations of telomeric DNA and RNA in the nucleoplasm that are frequently coated in a polymer shell of PML protein. These structures are known as ALT-associated PML bodies (APBs). APBs have been postulated to be major sites of the telomeric sequence homologous recombination believed to be the basis of telomere maintenance in ALT. A CRISPR based strategy was used to knock out the PML gene in two widely used ALT positive osteosarcoma-derived human cell lines; U2OS, and SAOS2. Knockout clones from both cell lines continued to proliferate past passage 90 without crisis, and knockouts were validated at the genetic and protein levels by Sanger sequencing and western blotting, respectively. Chromosome orientation fluorescent in situ hybridization (COFISH) was carried out to determine the number of telomere sequence exchanges occurring in a single cell cycle in these knockouts. A twofold increase in telomere-specific exchanges, presumably telomere sister chromatid exchanges (T-SCE), over the parental line was detected. Intrachromosomal exchanges not specific to telomeres were also analyzed by the harlequin chromosome staining method. A significant increase in these types of exchanges was also observed. In conclusion, the presence of PML is not required for ALT to continue to function, and may be acting to modulate homologous recombination frequency and location in ALT positive cells. Citation Format: Walter Barry, Christopher Heaphy, Alan Meeker. The promyelocytic leukemia (PML) protein modulates rate and localization of homologous recombination in human cell lines with the alternative lengthening of telomeres (ALT) pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3470. doi:10.1158/1538-7445.AM2017-3470
Abstract 2389: LINE-1 tumor hypomethylation is associated with shorter recurrence-free survival in localized clear-cell renal cell carcinoma
Authors: Gabriel G. Malouf, Roger Mouawad, Frederick Allanic, Eva Compérat, Morgan Roupret, David Khayat, Jean-Philippe Spano
Journal: Cancer Research (2017)

Abstract Background: Cancer cells are characterized by alterations of DNA methylation patterns involving global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Global DNA hypomethylation is thought to play a role in genetic instability and tumor aggressiveness. Long interspersed nucleotide element-1 (L1/LINE-1) repetitive elements represent 40% of the genome and their methylation is a good indicator of the global DNA methylation level. Although LINE-1 methylation has been previously shown to be associated with prognosis of patients with cancer, the value of LINE-1 methylation in predicting recurrence of patients with localized clear-cell renal cell carcinomas remains unknown. Material and Methods: We quantified the LINE-1 methylation using bisulfite pyrosequencing in cohort of 200 patients with resected clear-cell renal cell carcinomas (AJCC stage I-III). LINE-1 methylation of adjacent normal kidney was also assessed in 128 cases. Threshold of tumor LINE-1 hypomethylation was defined as LINE-1 methylation in normal samples minus three standard deviation. Results: Median methylation of tumor samples was 59.01% versus 61.61% for normal adjacent kidney samples (p&amp;lt;10-5). LINE-1 methylation level of normal adjacent kidney was associated with tumor size (Spearman R=0.21, P=0.02) but not with age (p=0.24) or Leibovitch score (p=0.05). Tumor LINE-1 hypomethylation was observed in 20 samples (n=10%). Strikingly, those were enriched for tumors occurring in female (60% versus 27.7%) (p=0.005); of note, no association was found between LINE-1 tumor hypomethylation and tumor grade (p=0.31), stage (p=1), age (p=0.24) and Leibovitch score (p=0.82). In multivariate analysis, only Leibovitch score and LINE-1 hypomethylation were independently associated with poor recurrence-free survival. Conclusion: LINE-1 hypomethylation is associated with shorter recurrence-free survival in patients with resected clear-cell renal cell carcinomas, suggesting the possibility of using it as predictive biomarker of recurrence. Citation Format: Gabriel G. Malouf, Roger Mouawad, Frederick Allanic, Eva Compérat, Morgan Roupret, David Khayat, Jean-Philippe Spano. LINE-1 tumor hypomethylation is associated with shorter recurrence-free survival in localized clear-cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2389. doi:10.1158/1538-7445.AM2017-2389
Sports injury and illness incidence in the Rio de Janeiro 2016 Olympic Summer Games: A prospective study of 11274 athletes from 207 countries
Authors: Torbjørn Soligard, Kathrin Steffen, Debbie Palmer, Juan Manuel Alonso, Roald Bahr, Alexandre Dias Lopes, Jiri Dvorak, Marie-Elaine Grant, Willem Meeuwisse, Margo Mountjoy, Leonardo Oliveira Pena Costa, Natalia Salmina, Richard Budgett, Lars Engebretsen
Journal: British Journal of Sports Medicine (2017)

To describe the pattern of injuries and illnesses sustained during the Games of the XXXI Olympiad, hosted by Rio de Janeiro from 5 to 21 August 2016.We recorded the daily incidence of athlete injuries and illnesses (1) through the reporting of all National Olympic Committee (NOC) medical teams and (2) in the polyclinic and medical venues by the Rio 2016 medical staff.In total, 11 274 athletes (5089 women, 45%; 6185 men, 55%) from 207 NOCs participated in the study. NOC and Rio 2016 medical staff reported 1101 injuries and 651 illnesses, equalling 9.8 injuries and 5.4 illnesses per 100 athletes over the 17-day period. Altogether, 8% of the athletes incurred at least one injury and 5% at least one illness. The injury incidence was highest in BMX cycling (38% of the athletes injured), boxing (30%), mountain bike cycling (24%), taekwondo (24%), water polo (19%) and rugby (19%), and lowest in canoe slalom, rowing, shooting, archery, swimming, golf and table tennis (0%-3%). Of the 1101 injuries recorded, 40% and 20% were estimated to lead to ≥1 and >7 days of absence from sport, respectively. Women suffered 40% more illnesses than men. Illness was generally less common than injury, with the highest incidence recorded in diving (12%), open-water marathon (12%), sailing (12%), canoe slalom (11%), equestrian (11%) and synchronised swimming (10%). Illnesses were also less severe; 18% were expected to result in time loss. Of the illnesses, 47% affected the respiratory system and 21% the gastrointestinal system. The anticipated problem of infections in the Rio Olympic Games did not materialise, as the proportion of athletes with infectious diseases mirrored that of recent Olympic Games (3%).Overall, 8% of the athletes incurred at least one injury during the Olympic Games, and 5% an illness, which is slightly lower than in the Olympic Summer Games of 2008 and 2012.
Pemetrexed in Nonsquamous Non–Small Cell Lung Cancer
Authors: Bishal Gyawali, Vinay Prasad
Journal: JAMA Oncology (2017)

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