tbuckley/cabot-search huggingface dataset:
Abstract 642: Hypoxia-regulated gene expression explains differences between cell line-derived xenografts and patient-derived xenografts
Authors: Joydeep Bhadury, Berglind O. Einarsdottir, Agnieszka Podraza, Roger Olofsson Bagge, Ulrika Stierner, Lars Ny, Marcela Dávila López, Jonas A. Nilsson
Journal: Cancer Research (2016)

Abstract Cell line-derived xenografts (CDXs) are an integral part of drug efficacy testing during development of new pharmaceuticals against cancer but their accuracy in predicting clinical responses in patients have been debated. Patient-derived xenografts (PDXs) are thought to be more useful for predictive biomarker identification for targeted therapies, including metastatic melanoma, due to their similarities to human disease. Here, tumor biopsies from patients and ten widely-used melanoma cell lines were transplanted into immunocompromised mice to generate PDXs and CDXs, respectively. Gene expression profiles generated from the tumors of these PDXs and CDXs clustered into distinct groups, despite similar mutational signatures. Hypoxia-induced gene signatures and overexpression of the hypoxia-regulated miRNA hsa-miR-210 characterized CDXs. Inhibition of hsa-miR-210 with decoys had little phenotypic effect in vitro but resulted in reduced sensitivity to MEK1/2 inhibition in vivo, suggesting down-regulation of this miRNA could result in development of resistance to MEK inhibitors. Citation Format: Joydeep Bhadury, Berglind O. Einarsdottir, Agnieszka Podraza, Roger Olofsson Bagge, Ulrika Stierner, Lars Ny, Marcela Dávila López, Jonas A. Nilsson. Hypoxia-regulated gene expression explains differences between cell line-derived xenografts and patient-derived xenografts. [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 642.
Factors associated with 12 week case-fatality in Staphylococcus aureus bacteraemia: a prospective cohort study
Authors: P. Braquet, F. Alla, C. Cornu, F. Goehringer, L. Piroth, C. Chirouze, M. Revest, C. Lechiche, X. Duval, V. Le Moing, Catherine Chirouze, Elodie Curlier, Cécile Descottes-Genon, Bruno Hoen, Isabelle Patry, Lucie Vettoretti, Pascal Chavanet, Jean-Christophe Eicher, Marie-Christine Greusard, Catherine Neuwirth, André Péchinot, Lionel Piroth, Marie Célard, Catherine Cornu, François Delahaye, Malika Hadid, Pascale Rausch, Audrey Coma, Florence Galtier, Philippe Géraud, Hélène Jean-Pierre, Vincent Le Moing, Catherine Sportouch, Jacques Reynes, Audrey Coma, Florence Galtier, Philippe Géraud, Hélène Jean-Pierre, Vincent Le Moing, Catherine Sportouch, Jacques Reynes, Audrey Coma, Florence Galtier, Philippe Géraud, Hélène Jean-Pierre, Vincent Le Moing, Catherine Sportouch, Jacques Reynes, Nejla Aissa, Thanh Doco-Lecompte, François Goehringer, Nathalie Keil, Lorraine Letranchant, Hepher Malela, Thierry May, Christine Selton-Suty, Nathalie Bedos, Jean-Philippe Lavigne, Catherine Lechiche, Albert Sotto, Xavier Duval, Emila Ilic Habensus, Bernard Iung, Catherine Leport, Pascale Longuet, Raymond Ruimy, Eric Bellissant, Pierre-Yves Donnio, Fabienne Le Gac, Christian Michelet, Matthieu Revest, Pierre Tattevin, Elise Thebault, François Alla, Pierre Braquet, Marie-Line Erpelding, Laetitia Minary, Michèle Bès, Jérôme Etienne, Anne Tristan, François Vandenesch, Alex Van Belkum, Willem Vanwamel
Journal: Clinical Microbiology and Infection (2016)
Does the duration of adjuvant temozolomide impact survival in glioblastoma patients? A retrospective analysis from an Italian registry (GLIOSTRY).
Authors: Roberta Ruda, Giuseppe Lombardi, Silvia Scoccianti, Francesco Pasqualetti, Antonio Silvani, Matteo Santoni, Andrea Pace, Alfredo Marinelli, Ivan Lolli, Mario Balducci, Mauro Arcicasa, Maurizio Salvati, Andrea Sponghini, Simona Vallarelli, Manuela Caroli, Francesca Imbesi, Domenico Bilancia, Marina Faedi, Alessia Pellerino, Riccardo Soffietti
Journal: Journal of Clinical Oncology (2016)

2047 Background: The Stupp regimen for newly diagnosed glioblastoma (GBM) consists of radiotherapy with concomitant and adjuvant temozolomide (TMZ) up to 6 cycles. A number of Institutions prolong the duration of the adjuvant chemotherapy up to 12 or more cycles, but it is unknown whether the prolongation of the adjuvant phase favorably impacts the length of survival. The aim of this retrospective study was to investigate this issue in an homogeneous population of GBM patients (age 18-70 years), receiving the Stupp regimen and the nitrosourea fotemustine at first relapse. Methods: Patients were collected through a national registry (Gliostry), that was established by the Italian Association for Neuro-Oncology (AINO). The survival of 556 patients receiving up to 6 cycles of TMZ was compared with that of 365 patients receiving more than 6 cycles of TMZ. Results: Median PFS following the Stupp regimen was 8.4 months for the group TMZ ≤ 6 cycles and 14.3 months for the group TMZ ˃ 6 cycles (p < 0.001). The advantage in terms of PFS for patients receiving more than 6 cycles of TMZ was higher among patients with MGMT methylation (p < 0.001) and incomplete surgical resection (p < 0.001). Median OS following the Stupp regimen was 16.7 months for the group TMZ ≤ 6 cycles and 26.3 months for the group ˃ 6 cycles (p < 0.001). The advantage in terms of OS for patients receiving more than 6 cycles of TMZ was higher among patients with MGMT methylation (p < 0.001) and incomplete resection (p < 0.001). The probability of response to salvage fotemustine was not influenced by the duration of adjuvant TMZ. Multivariate analysis of both PFS and OS following the Stupp regimen did not show an independent prognostic value for the duration of adjuvant TMZ. Conclusions: The prolongation of adjuvant TMZ with more than 6 cycles could be advantageous only in patients with MGMT methylation and in those with incomplete resection.
In Vitro Expression Studies of Two Mutations on the Metalloprotease and First Cub Domains of the ADAMTS-13 Gene Leading to Severe ADAMTS-13 Deficiency and Chronic Recurrent TTP.
Authors: Flora Peyvandi, Silvia Lavoretano, Raimondo De Cristofaro, Carla Valsecchi, Giuliana Merati, Antonella Lattuada, Pier M. Mannucci
Journal: Blood (2004)
Extended follow-up results of a phase 1B study (BRIM7) of cobimetinib (C) and vemurafenib (V) in BRAF-mutant melanoma.
Authors: Adil Daud, Anna C. Pavlick, Antoni Ribas, Rene Gonzalez, Karl D. Lewis, Omid Hamid, Thomas Gajewski, Igor Puzanov, Jessie J. Hsu, Daniel O. Koralek, Nicholas W. Choong, Grant A. McArthur
Journal: Journal of Clinical Oncology (2016)

9510 Background: The BRIM7 study (ClinicalTrials.gov ID, NCT01271803) evaluated the safety and preliminary efficacy of C+V (Ribas A et al. Lancet Oncol. 2014;15:954-965.); a subsequent randomized phase 3 trial showed statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) of C+V compared with V. Results of BRIM7 with extended follow-up are presented. Methods: Patients (pts) had advanced BRAFV600-mutated melanoma, ECOG PS 0-1, and either progressed on V (V-PD) or were BRAF inhibitor (BRAFi)–naive. Dose-escalation pts received C at 60, 80, or 100 mg/d for 14 d on/14 d off; 21 d on/7 d off (21/7); or continually in combination with V at 720 or 960 mg twice daily (BID) continually. Two dose levels were expanded: C (60 mg/d 21/7) + V (720 mg/d and 960 mg BID). Results: Characteristics for the 129 C+V–treated were as follows: BRAFi-naive, 49%; stage M1c, 70% and 82%; LDH > ULN, 46% and 62%; median follow-up, 21 and 8 months for BRAFi-naive and V-PD pts, respectively.1In this update (data cutoff, Sept 15, 2015), median follow-up in BRAFi-naive and V-PD pts was 26 and 8 months, respectively. With extended follow-up, adverse event frequency and severity were stable, and the safety profile was consistent with prior reports. Confirmed response rate (RR) in BRAFi-naive pts remained 87%. Two additional BRAFi-naive pts attained complete response (CR) at Cycles 31 and 34, increasing the CR rate from 16% to 19%. Median PFS in BRAFi-naive pts was unchanged at 13.8 months. With extended follow-up, median OS in BRAFi-naive pts was 31.2 months, and landmark OS was 83%, 64%, and 37% at 1, 2, and 3 years, respectively. Of 63 BRAFi-naive pts, 12 remained on C+V at the time of data cutoff. Confirmed RR in V-PD pts remained 15%. Median PFS in V-PD pts was unchanged at 2.8 months, and OS increased to 8.5 months. The 2-year OS was 17% with extended follow-up. Conclusions: C+V demonstrates robust efficacy in BRAFi-naive pts without new safety signals in long-term follow-up. Median OS in BRAFi-naive pts was over 2.5 years. Late CR conversions indicate persistent activity with continued therapy. Clinical trial information: NCT01271803.
Abstract 2679: Induction of β-globin protects circulating tumor cells from oxidative stress during dissemination
Authors: Yu Zheng, David T. Miyamoto, Ben S. Wittner, James P. Sullivan, Nicola Aceto, Nicole Vincent Jordan, Min Yu, Nezihi Murat Karabacak, Valentine Comaills, Robert Morris, Rushil Desai, Niyati Desai, Erin Emmons, Richard J. Lee, Chin-Lee Wu, Lecia V. Sequist, Wilhelm Haas, David T. Ting, Mehmet Toner, Sridhar Ramaswamy, Shyamala Maheswaran, Daniel A. Haber
Journal: Cancer Research (2016)

Abstract Identification of candidate metastasis genes has traditionally resulted from comparison of primary and metastatic tumor specimens. However, Circulating Tumor Cells (CTCs) contain metastatic precursors that are present transiently in the bloodstream and their analysis may reveal additional pathways that are induced for a limited time, as they invade and survive within the vasculature. By comparing transcriptome profiles of CTCs from breast, prostate and lung cancers with their primary tumor of origin, we observed consistent and significant induction of the β-globin gene (HBB) within CTCs. In contrast, expression of α-globin, its binding partner within hematopoietic cells, is not coordinately upregulated. The tumor-specific origin of HBB was further confirmed by analysis of human xenografts-derived CTCs in mice, where human-specific HBB polymorphisms are readily distinguishable in the murine background. In cultured cancer cells, we further demonstrate that induction of HBB is triggered by exposure to reactive oxygen species (ROS), and we identify KLF-family transcriptional regulators that mediate this effect. To investigate the function of aberrant β-globin expression within CTCs, we performed shRNA-mediated knockdown of HBB in breast CTC-derived cultures. Cells with depleted HBB expression displayed elevated intracellular ROS levels, increased sensitivity to hydrogen peroxide, and impaired metastatic potential in mouse models. Taken together, these observations suggest that β-globin, a component of functional hemoglobin in red blood cells, is deregulated in disseminated tumor cells, where it may function as a ROS scavenger, reducing oxidative stress and facilitating cancer metastasis. Citation Format: Yu Zheng, David T. Miyamoto, Ben S. Wittner, James P. Sullivan, Nicola Aceto, Nicole Vincent Jordan, Min Yu, Nezihi Murat Karabacak, Valentine Comaills, Robert Morris, Rushil Desai, Niyati Desai, Erin Emmons, Richard J. Lee, Chin-Lee Wu, Lecia V. Sequist, Wilhelm Haas, David T. Ting, Mehmet Toner, Sridhar Ramaswamy, Shyamala Maheswaran, Daniel A. Haber. Induction of β-globin protects circulating tumor cells from oxidative stress during dissemination. [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 2679.
Abstract 3595: Improved therapeutics for hepatocellular carcinoma
Authors: Jessica A. Zavadil, Christi A. Walter
Journal: Cancer Research (2016)

Abstract Eighty percent of hepatocellular carcinoma (HCC) within the USA is diagnosed late when chemotherapy provides only 2 months increased survival. We fortuitously found that treatment with an alkylating agent, methylnitrosurea (MNU), prior to tumorigenesis reduced tumor prevalence later in life by ∼50% in C3HeB/FeJ male mice, a model of spontaneous HCC. A similar effect was observed with temozolomide (TMZ), a glioblastoma therapy that induces the same DNA damage at similar proportions to MNU. O6-methylguanine-DNA methyltransferase (MGMT) repairs the highly mutagenic and cytotoxic O6-methylguanine lesions induced by TMZ, and MGMT abundance influences therapy response in glioblastoma. MGMT is reduced in 1/3 of human HCC, leading us to hypothesize that TMZ could be effective in treating HCC. We proposed to combine TMZ with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, to maximize efficacy, reasoning that SAHA would allow TMZ greater access to DNA to induce greater levels of damage. We tested this drug combination in two human HCC cell lines, Huh7, with reduced MGMT expression, and SNU398, with higher expression. TMZ and SAHA synergistically reduced cell viability in both cell lines with multiple dose combinations. Based on this outcome, we tested the drugs in tumor-bearing C3HeB/FeJ mice. Surprisingly, DMSO treated solvent control mice showed reduced tumor burden. The DMSO treatment was repeated adding a sham control group and confirmed that DMSO significantly reduces tumor burden. The TMZ cohort also displayed a significantly lower tumor burden compared to the sham cohort, but no significant difference was found with SAHA alone or SAHA+TMZ. We previously showed that a hMGMT transgene protects from hepatocarcinogenesis in C3HeB/FeJ mice, but surprisingly, there is not additional protection when transgenic mice are treated with MNU. These results suggest that the more prevalent cytotoxic lesions induced by MNU and TMZ, e.g. N7-methylguanine, may be more important in HCC than O6-methylguanine. These lesions are recognized by methylpurine-DNA glycosylase (MPG) and repaired through base excision repair. Therefore, we directly tested the role of MPG in TMZ therapy through altered expression of MPG in Huh7 and SNU398 cell lines and showed that it does affect sensitivity to TMZ. Citation Format: Jessica A. Zavadil, Christi A. Walter. Improved therapeutics for hepatocellular carcinoma. [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 3595.
PTU-105 Preoperative ciclosporin therapy and appropriate steroid use does not increase risk of infective complications following colectomy for ulcerative colitis: Abstract PTU-105 Table 1
Authors: L Krupa, P Dave, A Hart, L Igali, R Tighe, M Tremelling
Journal: Gut (2012)

<h3>Introduction</h3> Corticosteroids increase the risk of serious and opportunistic infections, independently and in combination with immunosuppressives. Steroids increase risk of post operative sepsis OR 1.68 in Crohn9s disease.<sup>1</sup> Addition of immunosuppressants in Crohn9s increases the risk of opportunistic infection.<sup>2</sup> In acute severe ulcerative colitis (ASUC) addition of ciclosporin is standard management for patients not responding rapidly to IV steroids alone. Some patients do not respond and require urgent surgery.<sup>3</sup> The risk of preoperative ciclosporin therapy to postoperative complications is not known. <h3>Methods</h3> We conducted a retrospective review of patients undergoing colectomy for UC in 2009–2010 in a large centre. 40 colectomies were identified: 26 for ASUC the remainder for cancer or steroid dependency. Differences in post operative complication rates for all 40 individuals were compared between those who received ciclosporin (cases) and those who did not (controls). Analysis was by logistic regression techniques within STATA correcting for steroid use pre and post operatively. Age, gender ASA grade and diabetes were included as potential confounders. <h3>Results</h3> In our panel there was no increase in post operative wound infections, (OR 0.4, p=0.34) intra-abdominal sepsis (OR 1.32, p=0.74), non-GI serious infections (OR 1.9, p=0.39) or all sepsis (OR 0.47, p=0.29) in ciclosporin treated patients compared with controls. There was also no increase in complication rates in patients given high dose steroids before (OR 0.14, p=0.1) or after admission (OR 1.2, p=0.75). Neither steroid use nor ciclosporin use predicted thromboembolic or bleeding complications or need for HDU. <h3>Conclusion</h3> Used appropriately in accordance with current guidelines<sup>4</sup> neither steroids nor ciclosporin increase the risk of post operative infective complications in patients failing medical therapy for ASUC. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Subramanian V</b>. <i>Am J Gastro</i> 2008;<b>103</b>:2373. 2. <b>Toruner M</b>. <i>Gastro</i> 2008;<b>134</b>:929. 3. <b>Van Assche G</b>. <i>Gastro</i> 2003;<b>125</b>:1025. 4. <b>Travis S</b>. <i>J Crohn9s Colitis</i> 2008;<b>2</b>:24.
Survivorship In AML - Outcomes Of Acute Myelogenous Leukemia (AML) Patients (pts) After Maintaining Complete Remission (CR) For At Least 3 Years
Authors: Aditya Shetty, Hagop M Kantarjian, Richard E Champlin, Gautam Borthakur, Talha Badar, Guillermo Garcia-Manero, Borje S. Andersson, Betul Oran, Stefan O. Ciurea, Marina Konopleva, Michael Andreeff, Steven M. Kornblau, William G. Wierda, Sherry Pierce, Farhad Ravandi, Jorge E. Cortes
Journal: Blood (2013)
Abstract 4421: Molecular features of hepatocellular carcinoma arising from non-alcoholic fatty liver
Authors: Makoto Takeda, Takanori Sakaguchi, Ryouta Kiuchi, Takanori Hiraide, Yasushi Shibasaki, Yoshihumi Morita, Hirotoshi Kikuchi, Mitsutoshi Setou, Hiroyuki Konno
Journal: Cancer Research (2016)

Abstract (Background) The incidence of hepatocellular carcinoma (HCC) arising from non-alcoholic fatty liver (NAFL) has been recently increasing according to increase of patients having metabolic syndrome. HCC, which shows steatosis, cellular ballooning, Mallory-Denk bodies, inflammation and fibrosis in cancer tissue, are recognized as steatohepatitic HCC (SH-HCC). This HCC phenotype is more frequently found in NAFL patients than in viral-hepatitic patients. (Purpose) The purpose of this study is to elucidate molecular features of SH-HCC with NAFL background. (Methods) To profile SH-HCC-related genes, mRNA expression patterns in SH-HCCs were compared with those in viral hepatitis HCCs by RNA array. RNA expression of the identified SH-HCC related gene was analyzed in three human liver carcinoma cell lines (HepG2, Huh7, and HLE) in normal conditioned medium. By mimicking the lipid-rich environment, these cell lines were also cultured in the presence of saturated (palmitic or stearic acid, recognized as endoplasmic reticulum stressors) or unsaturated fatty acids (oleic acid: OA). To address the role of SH-HCC-related gene, cell proliferation and apoptosis were assessed in the presence or absence of fatty acids, by knock-down of the objective gene using siRNA. (Results) (1) Caveolin (cav)-1 and -2 were identified as SH-HCC related genes (1.63 and 1.58 fold expression of cav-1 and -2, respectively) by RNA microarray analysis. (2) HLE and Huh7 showed high and low expression of both cav-1 and -2 mRNA, whereas HepG2 did not express either on qRT-PCR. (3) In the presence of OA, HepG2 and Huh7 did not well proliferate, whereas HLE cell proliferation increased with concentration of OA and culture duration. (4) Knock-down of cav-1 and -2 canceled OA-induced increase of cell proliferation. In the same condition, expression of cleaved caspase 3 was increased, suggesting the promotion of apoptosis. (Consideration) Cav-1 and -2, the important protein for endocytosis and cellular signaling, are highly expressed in SH-HCC. These proteins would increase cell proliferation and inhibit apoptosis in the presence of unsaturated fatty acids, presumably by using these fatty acids as energy source or by caveolae-related anti-apoptotic process. Citation Format: Makoto Takeda, Takanori Sakaguchi, Ryouta Kiuchi, Takanori Hiraide, Yasushi Shibasaki, Yoshihumi Morita, Hirotoshi Kikuchi, Mitsutoshi Setou, Hiroyuki Konno. Molecular features of hepatocellular carcinoma arising from non-alcoholic fatty liver. [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 4421.
Abstract 825: Myc-nick promotes efferocytosis through M2 macrophage polarization
Authors: Xiancai Zhong, Ha-Na Lee, Young-Joon Surh
Journal: Cancer Research (2016)

Abstract Resolution of inflammation is an active process which is important for maintaining or restoring homeostasis in response to inflammatory insult. Failure in resolution results in persistent and chronic inflammation which increases the risk of cancer development. Efferocytosis, an essential part of resolution of inflammation, is defined as phagocytic removal of apoptotic cells, especially neutrophils, at the inflamed site, thereby preventing exposure of tissue to toxic intracellular components. It is carried out by a distinct group of phagocytes including anti-inflammatory macrophages (M2 type). Therefore, M2 macrophages represent a key component of the cellular proresolving mechanism and a potential factor for prevention of inflammation-associated cancer. Dysregulation, often overexpression, of c-Myc drives dedifferentiation of cancer cells to acquire capacity for self-renewal and metastasis, which accounts for poor prognosis in cancer patients. A cytoplasmic N-terminal part of full length c-Myc, termed Myc-nick, has been reported to promote differentiation of myoblasts. In the present study, we investigated whether Myc-nick is involved in M2 macrophage polarization and promotion of efferocytosis. We found that ectopic expression of Myc-nick in mouse bone marrow derived macrophages (BMDM) promoted the M2 macrophage polarization through upregulation of interleukin 10 (IL-10) and peroxisome proliferator activated receptor gamma (PPARγ). Furthermore, overexpression of exogenous Myc-nick in BMDM increased capture of apoptotic cells by BMDM through upregulation of a class of phosphatidyl serine (PS) receptors including T-cell immunoglobulin and mucin domain containing 4 (Timd4). PS constitutes one of ‘eat-me’ signals carried by apoptotic cells. PS receptors present on the surface of macrophages are important to recognize, engulf and finally clear apoptotic cells via phagocytosis. In addition, Myc-nick-induced efferocytosis was found to be tightly associated with K (lysine) acetyltransferase 2A (Kat2a/Gcn5). This may lead to the acetylation of transcription factors that regulate expression of PS receptor proteins. In conclusion, activation of M2 macrophages by Myc-nick facilitates efferocytosis and hence resolution of inflammation, and this may suppress inflammation-associated cancer progression. Citation Format: Xiancai Zhong, Ha-Na Lee, Young-Joon Surh. Myc-nick promotes efferocytosis through M2 macrophage polarization. [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 825.