tbuckley/cabot-search huggingface dataset:
Abstract 68: Neuroblastoma drug response profiles are associated with gene expression profiles
Authors: Jeffrey P. Bond, Elizabeth VanSickle, Thomas S. Dexhemier, Richard R. Neubig, Giselle L. Sholler
Journal: Cancer Research (2016)

Abstract Background: High risk neuroblastoma patients have a poor response to initial chemotherapy, with 20% unable to achieve a complete response. Genomic studies have identified 6 targeted agents whose pathways have been identified in some high risk neuroblastoma tumors. The low frequency of established driver mutations, along with the variety of molecular mechanisms for cancer pathway dysregulation, suggest development of gene expression-based predictive biomarkers in addition to sequence-based biomarkers. Our platform for developing gene expression-based biomarkers includes primary neuroblastoma cell lines, high throughput quantification of cell survival, exome sequencing, and genome-wide expression profiling. Methods: Cell survival was quantified for each of thirty primary neuroblastoma cell lines in the presence of each of six drugs (bortezomib, crizotinib, dasatinib, lapatinib, sorafenib, and vorinostat) using high throughput cell survival measurements. Titration curves were based on treatment with vehicle as well as sixteen concentrations of each drug (replicated within and between plates). Summary descriptions of the response of each cell line to each drug were obtained using the four parameter logistic model as well as the area under the curve. Exome sequences were obtained using Illumina HiSeq technology. Genome-wide expression profiles were obtained using Affymetrix GeneChip technology. Inference was based on parametric univariate and non-parametric multivariate tests. Results: For three of the drugs (bortezomib, dasatinib, and vorinostat) the variation in response between cell lines was statistically significant (p &amp;lt; 0.05; F ≥3) and assay results were reproducible in the context of the differences between cell lines (for the other three drugs the estimated standard deviation of log10 EC50 ≤ 0.2). Genome-wide expression profiles were associated with variation in drug response between cell lines, for example, high PDGFRB expression indicates sensitivity to dasatinib (p &amp;lt; 0.001). Conclusion: High throughput cell survival measurements provided for identification of predictive biomarkers of neuroblastoma drug sensitivity. These biomarkers are currently being studied in the PEDS-PLAN (Pediatric Precision Laboratory Advanced Neuroblastoma Therapy) clinical trial. Citation Format: Jeffrey P. Bond, Elizabeth VanSickle, Thomas S. Dexhemier, Richard R. Neubig, Giselle L. Sholler. Neuroblastoma drug response profiles are associated with gene expression profiles. [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 68.
Abstract 803: Obesity and associated lifestyles modify the effect of glucose metabolism-related genetic variants on impaired glucose homeostasis among postmenopausal women
Authors: Su Yon Jung, Eric M. Sobel, Jeanette C. Papp, Carolyn J. Crandall, Alan N. Fu, Zuo-Feng Zhang
Journal: Cancer Research (2016)

Abstract Background: Impaired glucose metabolism-related genetic variants likely interact with obesity-modifiable factors in response to glucose intolerance, yet their interconnected pathways have not been fully characterized. We assessed in postmenopausal women whether obesity, physical activity, and high dietary fat intake interact with the single-nucleotide polymorphisms (SNPs)-glucose variations. Methods: We used data from 1,027 postmenopausal participants of the Genomics and Randomized Trials Network study and 15 SNPs associated with glucose homeostasis. We used regression analysis plus stratification and graphic approaches. Results: Fasting levels of glucose, insulin, and homeostatic model assessment-insulin resistance (HOMA-IR) were higher in obese, inactive, and high fat-diet women than in their respective counterparts. Carriers within subgroups differently demonstrated the direction and/or magnitude of the variants’ effect on glucose-relevant traits. Variants in GCKR, GCK, DGKB/TMEM195 (P for interactions = 0.02, 0.02, and 0.01), especially, showed interactions with obesity: obese, inactive, and high fat-diet women had greater increases in fasting glucose, insulin, and HOMA-IR levels. Obese carriers at TCF7L2 variant had greater increases in fasting glucose levels than non-obese carriers (P for interaction = 0.04), whereas active women had greater decreases in insulin and HOMA-IR levels than inactive women (P for interaction = 0.02 in both levels). Conclusions: Our data support the important role of obesity in modifying glucose homeostasis in response to glucose metabolism-relevant variants. These findings may inform research on the role of glucose homeostasis in the etiology of disease, particularly obesity-related cancer, and the development of intervention strategies to reduce risk in postmenopausal women. Citation Format: Su Yon Jung, Eric M. Sobel, Jeanette C. Papp, Carolyn J. Crandall, Alan N. Fu, Zuo-Feng Zhang. Obesity and associated lifestyles modify the effect of glucose metabolism-related genetic variants on impaired glucose homeostasis among postmenopausal women. [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 803.
Abstract 1906: Inhibition of miR-186 and repression of aggressive prostate cancer phenotype using a metastatic cell model
Authors: Dominique Z. Jones, M. Lee Schmidt, Katharine R. Hobbing, Geoffrey Clark, LaCreis R. Kidd
Journal: Cancer Research (2016)

Abstract MicroRNA (miR) dysregulation alters the expression of cancer related genes and contributes to disease states in many cancers. For example, ectopic miR-186 expression leads to enhanced cell proliferation and migration in pancreatic cancer. However, the role of miR-186 in prostate cancer (PCa) remains unclear. Previously, we observed significant upregulation of miR-186-5p in PCa patient serum (stage III/IV) compared to controls. Furthermore, miR-186 was significantly up-regulated in metastatic PCa (PC-3) compared to normal prostate epithelial cells (RWPE1). We hypothesized miR-186 inhibition will reduce aggressive PCa in vitro. Consequently, miR-186 was transiently and stably inhibited in PC-3 cells. Cell proliferation and colony formation were evaluated for 7 and 21 days via Trypan Blue exclusion and soft agar assays. Aberrant gene expression was evaluated in transfected cells to identify miR-186 targets. Candidate miR-186 targets were selected using published reports on ‘miR-186 and cancer’, availability of robust antibodies, and statistical filtering (false discovery ≥0.05 and ±1.2 fold change). Mir-186 inhibition in PC-3 cells significantly repressed proliferation and colony formation by 34-64%. Following miR-186 inhibition in PC-3 cells, 2,343 identified mRNA targets were differentially expressed compared to scramble controls (p &amp;lt; 0.05). The target list was reduced to 11 up-regulated candidates. Predicted miR-186 targets are undergoing validation via qRT-PCR, western blots, and luciferase reporter assays. In addition, other studies are in progress to evaluate the impact of miR-186 on cellular proliferation, migration and invasion. Such efforts may lead to the identification of novel biomarkers to improve detection and clinical management strategies for aggressive PCa. Citation Format: Dominique Z. Jones, M. Lee Schmidt, Katharine R. Hobbing, Geoffrey Clark, LaCreis R. Kidd. Inhibition of miR-186 and repression of aggressive prostate cancer phenotype using a metastatic cell model. [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 1906.
Bona Fide Psychotherapy Models Are Equally Effective for Major Depressive Disorder
Authors: Allan A. Abbass, Joel M. Town
Journal: JAMA Psychiatry (2016)

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Exercise therapy versus arthroscopic partial meniscectomy for degenerative meniscal tear in middle aged patients: randomised controlled trial with two year follow-up
Authors: Nina Jullum Kise, May Arna Risberg, Silje Stensrud, Jonas Ranstam, Lars Engebretsen, Ewa M Roos
Journal: BMJ (2016)

<b>Objective</b>&nbsp;To determine if exercise therapy is superior to arthroscopic partial meniscectomy for knee function in middle aged patients with degenerative meniscal tears. <b>Design</b>&nbsp;Randomised controlled superiority trial. <b>Setting</b>&nbsp;Orthopaedic departments at two public hospitals and two physiotherapy clinics in Norway. <b>Participants</b>&nbsp;140 adults, mean age 49.5 years (range 35.7-59.9), with degenerative medial meniscal tear verified by magnetic resonance imaging. 96% had no definitive radiographic evidence of osteoarthritis. <b>Interventions</b>&nbsp;12 week supervised exercise therapy alone or arthroscopic partial meniscectomy alone. <b>Main outcome measures</b>&nbsp;Intention to treat analysis of between group difference in change in knee injury and osteoarthritis outcome score (KOOS<sub>4</sub>), defined a priori as the mean score for four of five KOOS subscale scores (pain, other symptoms, function in sport and recreation, and knee related quality of life) from baseline to two year follow-up and change in thigh muscle strength from baseline to three months. <b>Results</b>&nbsp;No clinically relevant difference was found between the two groups in change in KOOS<sub>4</sub> at two years (0.9 points, 95% confidence interval −4.3 to 6.1; P=0.72). At three months, muscle strength had improved in the exercise group (P≤0.004). No serious adverse events occurred in either group during the two year follow-up. 19% of the participants allocated to exercise therapy crossed over to surgery during the two year follow-up, with no additional benefit. <b>Conclusion</b>&nbsp;The observed difference in treatment effect was minute after two years of follow-up, and the trial’s inferential uncertainty was sufficiently small to exclude clinically relevant differences. Exercise therapy showed positive effects over surgery in improving thigh muscle strength, at least in the short term. Our results should encourage clinicians and middle aged patients with degenerative meniscal tear and no definitive radiographic evidence of osteoarthritis to consider supervised exercise therapy as a treatment option. <b>Trial registration</b>&nbsp;www.clinicaltrials.gov (NCT01002794).
Abstract 4148: Different immune cell responses are associated with glioblastoma subclassification and typical genetic alterations
Authors: Suvi Luoto, Juha Kesseli, Matti Nykter, Kirsi J. Granberg
Journal: Cancer Research (2016)

Abstract Interactions between various components in the tumor microenvironment and dysregulated immune responses are thought to play important roles in cancer development. To better understand the role of immune cells in tumor pathogenesis and destruction, we computationally model the microenvironment of an aggressive brain tumor glioblastoma multiforme (GBM). We downloaded GBM patient RNA-seq data from the Cancer Genome Atlas (TCGA). Using cluster analysis, we identified 16 clusters, each containing 10 to 933 genes that show a statistical enrichment of immune response related gene ontology terms. Utilizing a panel of RNA-seq data from normal cell types, we constructed global and cluster specific regression models to characterize the expression profiles of GBM samples in the clusters of interest as linear combinations of normal cell and reference GBM expression profiles. Simulated data was used to validate that the regression model coefficients accurately reflect the contributions of normal cell types to the expression profiles of tumor samples. Based on the regression analysis, we were able to uncover high variability in the composition of microenvironment across the TCGA cohort, suggesting diverse immune responses in tumors. The results from global regression analysis were then associated with common genetic alterations in GBM and with GBM subclassification. Especially the estimated macrophage, granulocyte, and CD8+ T lymphocyte proportions show significant differences between different GBM subgroups. Accumulation of immune cells was increased in the mesenchymal and neural subtype compared to other subtypes. Furthermore, estimated immune cell proportions were associated with alterations in EGFR and NF1. Taken together, our analysis provided a characterization of the immunomicroenvironment in GBM and linked immune cell responses to typical GBM alterations and GBM subtypes. More detailed characterization of diverse immune responses will facilitate patient stratification and might provide tools for personalized immunotherapy in the future. Citation Format: Suvi Luoto, Juha Kesseli, Matti Nykter, Kirsi J. Granberg. Different immune cell responses are associated with glioblastoma subclassification and typical genetic alterations. [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 4148.
Comparison of preoperative screening tools predicting postoperative complications in oncogeriatric surgical patients.
Authors: Monique Huisman, Barbara Van Leeuwen, Giampaolo Ugolini, Isacco Montroni, Cesare Stabilini, John Spiliotis, Nicola de'Liguori Carino, Eriberto Farinella, Goran Stanojevic, Milica Nestorovic, Dettie Veering, Abdulazeez Salawu, G. de Bock, Riccardo A. Audisio
Journal: Journal of Clinical Oncology (2013)

9557 Background: In the onco-geriatric surgical population it is important to identify patients at increased risk of adverse post-operative outcome in order to effectively implement preventive measures and to improve outcome in this population. There is need for a time saving and efficient screening tool. Our aim was to determine the predictive ability of the Mini Mental State Examination (MMSE), Brief Fatigue Inventory (BFI) and Timed “Up &amp; Go” (TUG) concerning the occurrence of a major post-operative complication in a series of elderly patients undergoing elective surgery for solid tumors. Methods: In an international cohort, 329 patients ≥70years undergoing elective surgery for solid tumors were prospectively included. Primary endpoint was the incidence of a major complication during the first 30 days after surgery. Pre-operatively the MMSE, BFI and TUG were scored. TUG depicts the time needed to stand up from a chair, walk 3 meters, turn around, walk back and sit down. Data were analyzed using multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95%-CI). Results: The majority of patients underwent major surgery (n=219; 66.6%). A total of 71 (22.1%) patients experienced major complications. TUG, MMSE and BFI, adjusted for center, gender and minor or major surgery, were independent predictors of the occurrence of major post-operative complications (see Table). Conclusions: Screening tools are able to predict major post-operative complications in onco-geriatric surgical patients. TUG is most specific in identifying patients at risk and could be considered to allocate preventive measures effectively. [Table: see text]
p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing
Authors: Wenbo Deng, Jeeyeon Cha, Jia Yuan, Hirofumi Haraguchi, Amanda Bartos, Emma Leishman, Benoit Viollet, Heather B. Bradshaw, Yasushi Hirota, Sudhansu K. Dey
Journal: Journal of Clinical Investigation (2016)

Inflammation and oxidative stress are known risk factors for preterm birth (PTB); however, the mechanisms and pathways that influence this condition are not fully described. Previously, we showed that mTORC1 signaling is increased in mice harboring a uterine-specific deletion of transformation-related protein 53 (p53d/d mice), which exhibit premature decidual senescence that triggers spontaneous and inflammation-induced PTB. Treatment with the mTORC1 inhibitor rapamycin reduced the incidence of PTB in the p53d/d mice. Decidual senescence with heightened mTORC1 signaling is also a signature of human PTB. Here, we have identified an underlying mechanism for PTB and a potential therapeutic strategy for treating the condition. Treatment of pregnant p53d/d mice with either the antidiabetic drug metformin or the antioxidant resveratrol activated AMPK signaling and inhibited mTORC1 signaling in decidual cells. Both metformin and resveratrol protected against spontaneous and inflammation-induced PTB in p53d/d females. Using multiple approaches, we determined that p53 interacts with sestrins to coordinate an inverse relationship between AMPK and mTORC1 signaling that determines parturition timing. This signature was also observed in human decidual cells. Together, these results reveal that p53-dependent coordination of AMPK and mTORC1 signaling controls parturition timing and suggest that metformin and resveratrol have therapeutic potential to prevent PTB.
IDENTIFICATION OF A NOVEL FXR RESPONSE ELEMENT; HUMAN FXR INDUCES SHP EXPRESSION THROUGH DIRECT BINDING TO AN LRH-1 BINDING SITE, INDEPENDENT OF THE PRESENCE OF AN IR-1 AND LRH-1
Authors: Martijn O. Hoeke, Mark Hoekstra, Janette Heegsma, Han Moshage, Klaas Nico Faber
Journal: Hepatology (2011)
Difference between SB4 and reference etanercept in the hepatobiliary disorders not considered to be caused by SB4: response to letter by Scheinberg and Azevedo: Table 1
Authors: Paul Emery, Jiří Vencovský, Jeehoon Ghil, Soo Yeon Cheong, Young Hee Rho
Journal: Annals of the Rheumatic Diseases (2016)

We thank Dr Sheinberg and colleagues'1 for raising the issue of hepatobiliary disorders mentioned in the European Public Assessment Report (EPAR) but not included in the 24-week report.2 This was due to the following reasons. First, the general safety reporting scheme was based on common adverse events (≥2% among reported adverse events, seen in table 2 of the paper), and overall major safety indices such as comparison of total treatment-emergent adverse events and serious adverse events. The groups of adverse events were those that were usually expected (or considered to be expected) to occur with etanercept use, such as serious infections, malignancies or injection site reactions. All of these were discussed in the 24-week paper. The imbalance of system …
Abstract 559: Small molecule T-reg inhibitors for cancer immunotherapy
Authors: Suresh Kumar, Jian Wu, Liquing Wang, Feng Wang, Matthew P. Kodrasov, Saket Agarwal, Ivan Sokirniy, Thomas Yeckley, Joseph Weinstock, Michael R. Mattern, Wayne W. Hancock
Journal: Cancer Research (2016)

Abstract Immune evasion is a hallmark feature of tumors as they employ various strategies to suppress the immune system's ability to recognize and destroy cancer cells. T cell checkpoint inhibitors such as anti-PD1 and anti-CTLA-4 antibodies spearhead the immune response against a variety of tumors. Numerous studies suggest that the complex immunosuppressive milieux require the development of additional therapeutic agents to potentiate active drugs and thereby broaden the utility and increase the therapeutic indices of revolutionary immune-oncology treatment modalities. The presence of immunosuppressive regulatory T cells (Tregs) in tumors, keeping tumoricidal Teffector cells in check, signals poor prognosis. Thus, depletion of Tregs or impairment of Treg function is an attractive therapeutic approach for cancer. USP7, a deubiquitylase enzyme implicated as a critical node in several cancer signaling pathways, has recently emerged as an essential factor in maintaining Treg functions. Progenra identified small molecule USP7 inhibitors and employed them to show that Treg specific inhibition of USP7 results in impairment of Treg function leading to immune activation, commensurate with the ablation of Foxp3, a transcription factor that is a target of USP7 and is essential to Treg activation. This USP7 inhibitor class was subsequently lead optimized, and selected USP7 inhibitors were evaluated in ADME/PK studies and shown to impair Treg functions and to exhibit powerful anti-tumor activity against syngeneic lung tumor models in immunocompetent mice. In addition, Progenra's USP7 inhibitors significantly augmented the antitumor activity of anti-PD1 antibody, CAR T cell therapy, and cancer vaccines. These studies provide a strong rationale for the use of USP7 inhibitors in combination therapy protocols to improve the efficacy of currently approved cancer immunotherapy agents. Citation Format: Suresh Kumar, Jian Wu, Liquing Wang, Feng Wang, Matthew P. Kodrasov, Saket Agarwal, Ivan Sokirniy, Thomas Yeckley, Joseph Weinstock, Michael R. Mattern, Wayne W. Hancock. Small molecule T-reg inhibitors for cancer immunotherapy. [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 559.