tbuckley/cabot-search huggingface dataset:
Abstract 3071: Proteasome subunit composition contributes to unusually poor sensitivity of H727 cells to carfilzomib
Authors: Min Jae Lee, Kyung Bo Kim
Journal: Cancer Research (2016)

Abstract Background: While proteasome inhibitors (PIs) have significantly improved the survival of multiple myeloma (MM) patients, significant subsets of MM patients do not respond to the PI- based therapy. Currently, mechanisms of de novo PI resistance in these patients remain completely unknown. In this study, we aim to identify previously unexplored mechanisms of de novo carfilzomib (Cfz) resistance using H727 cancer cells with poor sensitivity to carfilzomib. Results: Our carfilzomib sensitivity investigation in a panel of 16 cancer cell lines revealed that H727 lung cancer cells are markedly resistant to Cfz compared to other cell lines. H727 cells displayed no detectable P-glycoprotein (P-gp) expression and subsequently were not sensitized by reversin 121 (a P-gp inhibitor) to Cfz, ruling out the involvement of P-gp in the resistance of H727 cells to Cfz. Interestingly, we found that H727 cells are killed by PYR-41 (ubiquitin activating enzyme E1 inhibitor) and WP-1130 (deubiquitinase inhibitor) as effectively as Cfz- sensitive H23 cells, suggesting that ubiquitin-proteasome pathway is essential in H727 cells as in H23 cells. In addition, knock-down of proteasome α7 subunit, a component required for the assembly of a proteasome α-ring and thereby a 20S proteasome complex, resulted in an almost complete cell death, indicating that the proteasome is indispensable for the survival of H727 cells. Intriguingly, despite their poor sensitivity to Cfz, H727 cells were highly sensitive to other structurally distinguished PIs such as bortezomib, epoxomicin, and UK-101. Finally, exposure of H727 cells to interferon-γ (IFN-γ), which has been widely used as a biochemical tool to switch cellular proteasome catalytic subunit composition to the one containing immunoproteasome subunits, sensitized H727 cells to Cfz (Changing IC50 values from 1,355 nM to 185 nM). On the contrary, IFN-γ pretreatment did not affect the sensitivity of H23 cells to Cfz. Conclusion: We report that H727 cells have a poor sensitivity to carfilzomib (or de novo resistance to Cfz), and that previously reported resistance mechanism involving P-gp upregulation does not play a role. Given our data presented here, we conclude that de novo Cfz resistance of H727 cells may be attributed to distinguished proteasome subunit composition. We believe that our investigation using cancer cell line models may provide important insights into understanding the mechanisms of de novo PI resistance in clinic. Citation Format: Min Jae Lee, Kyung Bo Kim. Proteasome subunit composition contributes to unusually poor sensitivity of H727 cells to carfilzomib. [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 3071.
Abstract 5266: Fast and accurate fusion transcript detection using the Trinity Cancer Transcriptome Analysis Toolkit
Authors: Brian Haas, Timothy Tickle, Nathalie Pochet, Jing Sun, Peggy Hsu, Chip Stewart, Carrie Ganote, Ben Fulton, Catherine Wu, Aviv Regev
Journal: Cancer Research (2016)

Abstract Chromosomal rearrangements leading to fusion transcripts represent a class of oncogenic aberrations that are of high interest for understanding cancer biology, treating cancer patients, and as targets for the development of new therapies. Transcriptome sequencing via RNA-Seq coupled with downstream bioinformatics software applications offers an effective method for identifying candidate fusion transcripts, and is more targeted and cost-effective than whole genome sequencing. Although many such fusion detection software tools have recently been made available, they often differ greatly in prediction accuracy, execution times, computational requirements, installation complexity, and in not being readily accessible to non-bioinformatician cancer researchers. Here we present the Trinity Cancer Transcriptome Analysis Toolkit (CTAT), a newly developed suite of RNA-Seq targeted fusion detection tools leveraging a combination of reference genome read-mapping and de novo transcriptome assembly, coupled to in silico fusion transcript validation, annotation, and visualization. We show that components of our Trinity CTAT fusion detection toolkit, including STAR-Fusion and FusionInspector, yield improved accuracy and run times as compared to alternative leading tools. As a demonstration of the utility of Trinity CTAT, we explore fusion transcript discovery in a large cohort of ∼300 chronic lymphocytic leukemia (CLL) patient samples. We identify several novel recurrent fusions that may represent drivers of CLL etiology and provide new avenues to therapies. In addition to fusion transcript identification, Trinity CTAT aims to provide cancer researchers with easy access to methods for analyzing cancer RNA-Seq, including transcript reconstruction, identification of mutations, expression analysis, and tumor heterogeneity. Trinity CTAT is freely available open source software and readily accessible to all cancer researchers via our public Galaxy web portal: https://galaxy.ncgas-trinity.indiana.edu/. Citation Format: Brian Haas, Timothy Tickle, Nathalie Pochet, Jing Sun, Peggy Hsu, Chip Stewart, Carrie Ganote, Ben Fulton, Catherine Wu, Aviv Regev. Fast and accurate fusion transcript detection using the Trinity Cancer Transcriptome Analysis Toolkit. [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 5266.
Abstract 2285: Microsomal PGE2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression
Authors: Sun-Hee Kim, Yuuri Hashimoto, Sung-Nam Cho, Jason Roszik, Denái R. Milton, Fulya Dal, Sangwon F. Kim, David G. Menter, Peiying Yang, Suhendan Ekmekcioglu, Elizabeth A. Grimm
Journal: Cancer Research (2016)

Abstract COX-2 and its product PGE2 enhance carcinogenesis and tumor progression, which has been previously reported in melanoma. As most COX inhibitors cause much toxicity, the downstream microsomal PGE2 synthase-1 (mPGES1) is a consideration for targeting. Human melanoma TMAs were employed for testing mPGES1 protein staining intensity and percentage levels and both increased with clinical stage; employing a different Stage III TMA, mPGES1 intensity (not percentage) associated with reduced patient survival. Our results further show that iNOS was also highly expressed in melanoma tissues with high mPGES1 levels, and iNOS-mediated NO promoted mPGES1 expression and PGE2 production. An mPGES1specific inhibitor (CAY10526) as well as siRNA attenuated cell survival and increased apoptosis. CAY10526 significantly suppressed tumor growth and increased apoptosis in melanoma xenografts. Our findings support the value of a prognostic and predictive role for mPGES1, and suggest targeting this molecule in the PGE2 pathway as another avenue toward improving melanoma therapy. Citation Format: Sun-Hee Kim, Yuuri Hashimoto, Sung-Nam Cho, Jason Roszik, Denái R. Milton, Fulya Dal, Sangwon F. Kim, David G. Menter, Peiying Yang, Suhendan Ekmekcioglu, Elizabeth A. Grimm. Microsomal PGE2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression. [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 2285.
Error in Complementary DNA Nomenclature in “Dermatologic Features of ADA2 Deficiency in Cutaneous Polyarteritis Nodosa”
Authors: Roshini S. Abraham, Lawrence E. Gibson
Journal: JAMA Dermatology (2016)

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Abstract 2940: The p53 mutation R273H contributed to drug resistance of EGFR tyrosine kinase inhibitors
Authors: Yueh-Fu Fang, Chun-Yu Lin, Peichih Lee
Journal: Cancer Research (2016)

Abstract Tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) were the standard first-line treatments for lung cancers with activating EGFR mutations. Emergent drug resistance is the major problem in the patients who received treatment of EGFR TKIs. Second point mutation T790M mutations could be found in 50-60% patients who had drug resistance to EGFR TKIs. Alternative pathway of Met signaling, transformation to small cell lung cancer, over-expression of other HER family receptors or epithelial mesenchymal transit were reported in these patients who had drug resistance to EGFR TKIs. NFKB pathway played a role of early resistance to EGFR TKIs in the patients. The p53 mutation could be found in 70-80% lung adenocarcinoma patients. These mutations could be found in lung cancer patients who had wild type or mutated EGFR. Lung adenocarcinomas with mutated p53 lose tumor suppressor function of wild type p53 and have new function from mutated p53. We thought p53 mutation may have gain of function and result in drug resistance to EGFR TKIs in lung cancer patients. We knocked down p53 in three cancer cell line, MDA-MB-468 (p53 R273H), BT-549 (p53 R249S) and H322 (p53 R248L). We found knockdown of p53 R273H in MDA-MB-468 increased sensitivity to gefitinib. Knockdown of p53 R249S and p53 R248L showed the same response to gefitinib in cancer cell lines BT-549 and H322. Lung cancer cell line HCC827 had EGFR exon 19 deletion and was sensitive to gefitinib. We overexpressed p53 R273H, p53 R157H and p53 R249S in HCC827 lung cancer cell line. Overexpression of p53 R273H increased resistance to gefitinib in HCC827 lung cancer cell line. Overexpression of p53 R157H and p53 R249S did not increased the resistance to gefitinib. Conclusion: Gain of function of p53 R273H increased resistance to EGFR TKIs in cancer cell lines. Further immunohistochemistry staining and gene analysis of mutated p53 will be done in lung adenocarcinoma from lung cancer patients who received EGFR TKIs. Citation Format: Yueh-Fu Fang, Chun-Yu Lin, Peichih Lee. The p53 mutation R273H contributed to drug resistance of EGFR tyrosine kinase inhibitors. [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 2940.
Sunitinib-related macrocytosis in patients with advanced renal cell cancer (RCC)
Authors: J. A. Price, R. Shaarbaf, L. A. Wood
Journal: Journal of Clinical Oncology (2007)

15580 Background: Sunitinib is an oral multi-targeted tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity approved and widely used for the treatment of advanced RCC. Based on a clinical observation that several RCC patients receiving Sunitinib developed macrocytosis, this study was performed to describe and examine macrocytosis in this patient population. Methods: A retrospective review of all patients treated with Sunitinib for RCC from 08/05–11/06 was performed. Data regarding hematologic parameters (e.g. CBC, mean corpuscular volume- MCV), concomitant medications, liver function, and time on therapy (cycle length varied from 4–7 weeks) was recorded. Vitamin B12 and folate levels, iron studies, and thyroid function were recorded if available. A standardized, laboratory-specific MCV was used to define macrocytosis. Results: 43 patients formed the study cohort, receiving a median of 4 cycles (24 weeks) of Sunitinib. Overall 19 (44%) patients developed macrocytosis, at a median of 3 cycles (16 weeks). Of the 31 patients who received &gt; 2 cycles of Sunitinib, 48% developed macrocytosis compared to 33% of the 12 patients receiving =2 cycles. Among all patients with macrocytosis, only 8 (42%) had anemia at the time. Of the 24 patients who did not become macrocytic, 19 (79%) had a continual rise in their MCV during therapy. Other causes of macrocytosis including vitamin B12 and folate deficiency, hypothyroidism, and other medications, did not contribute to the macrocytosis identified in this cohort. On preliminary analysis, it did not appear that macrocytosis was associated with response or toxicity. Conclusions: This is the first study to document the common occurrence of Sunitinib-associated macrocytosis in RCC patients. The risk of macrocytosis increased with duration of treatment. Macrocytosis did not appear to be associated with significant clinical sequelae; however this, as well as the mechanism of macrocytosis, requires further study. No significant financial relationships to disclose.
Distinct Characteristics of e13a2 versus e14a2 BCR-ABL Chronic Myeloid Leukemia under Upfront Treatment with Imatinib – an Analysis of the German CML Study IV,
Authors: Benjamin Hanfstein, Philipp Erben, Susanne Saussele, Michael Lauseker, Ulrike Proetel, Sven Haag, Susanne Schnittger, Claudia Haferlach, Hans-Jochem Kolb, Stefan W. Krause, Christoph Nerl, Dominik Heim, Gabriela M. Baerlocher, Jörg E. A. Schubert, Hermann Einsele, Mathias Hänel, Jolanta Dengler, Christiane Falge, Lothar Kanz, Andreas Neubauer, Michael Kneba, Frank Stegelmann, Michael Pfreundschuh, Cornelius F. Waller, Markus Pfirrmann, Jörg Hasford, Wolf-Karsten Hofmann, Rüdiger Hehlmann, Andreas Hochhaus, Martin C. Müller
Journal: Blood (2011)
Abstract 4068: Role of cytochrome P450 (CYP)1A2 in the molecular regulation of CYP1A1 by the carcinogen, 3-methylcholanthrene (MC) in mouse heptoma cells (hepa-1)
Authors: Sudha Kondraganti, Chun Chu, Bhagavatula Moorthy
Journal: Cancer Research (2016)

Abstract Cytochrome P4501A (CYP1A) enzymes play important roles in the activation of PAHs such as 3-methylcholanthrene (MC) to carcinogenic DNA-binding metabolites. We reported earlier that MC causes persistent induction of hepatic and pulmonary CYP1A1 in mice for several weeks after MC withdrawal, and that the phenomenon of sustained hepatic CYP1A1 induction is lost in Cyp1a2-null mice. In this study, we tested the hypothesis that MC elicits induction of persistent CYP1A1 induction in hepa-1 cells, and that CYP1A2 contributes mechanistically to this phenomenon. Hepa-1 cells were treated with the MC (2.5 μM), or dimethylsulfoxide (DMSO) as control, and at selected time points, CYP1A1 promoter activity, CYP1A1 enzyme activities, contents, and CYP1A1 mRNA levels were studied. A 24 h treatment induced the CYP1A1 promoter activity, CYP1A1 mRNA, and ethoxyresorufin O-deethylase (EROD) activity by 2-, 1000-, and 15-fold, respectively. The induction was sustained for 4-5 days. MC persistently induced CYP1A1 apoprotein level as well. Electrophoretic mobility shift assay indicated that MC induced a nuclear protein that bound to aryl hydrocarbon response elements in the CYP1A1 promoter region. Transfection of CYP1A2 siRNA resulted in knockdown of CYP1A2 mRNA by 70%, but a statistically significant increase of basal CYP1A1 mRNA by 35-40%. The induction of CYP1A1 promoter activity, CYP1A1 mRNA, CYP1A1 protein, and EROD activity by MC were not affected by CYP1A2 siRNA at the 24 h time point, but was significantly attenuated by CYP1A2 siRNA on day 5. These results suggest that CYP1A2, possibly via a metabolite, contributes to the sustained induction of CYP1A1 by MC in hepa-I cells. Further investigations into the mechanisms of persistent induction of CYP1A1 by MC could lead to novel preventative/therapeutic strategies against PAH-mediated carcinogenesis in humans. Citation Format: Sudha Kondraganti, Chun Chu, Bhagavatula Moorthy. Role of cytochrome P450 (CYP)1A2 in the molecular regulation of CYP1A1 by the carcinogen, 3-methylcholanthrene (MC) in mouse heptoma cells (hepa-1). [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 4068.
Abstract 55: Glucose supports EGFR-mutated lung adenocarcinoma survival by sustaining EGFR stability
Authors: Jin Kyung Rho, Yun Jung Choi, Chang-Min Choi, Jae Cheol Lee
Journal: Cancer Research (2016)

Abstract Tumor cells are genetically unstable, driven by genetic mutations that stimulate cancer cell proliferation and survival. These genetic mutations are generally linked to particular types of cancer. Oncogenic epidermal growth factor receptor (EGFR) is frequently mutated in non-small cell lung cancer (NSCLC), which is essential for NSCLC development and growth. However, the precise roles of EGFR in lung cancer metabolism are still unclear. Here we show that glucose (Glc) metabolism is critical for EGFR stability required for tumor growth and survival. EGFR mutation leads to a robust increase in Glc uptake, lactate production and glycolytic flux. Moreover, EGFR-mutated NSCLC cell lines are much more sensitive than EGFR WT to inhibition of Glc metabolism through EGFR degradation, suggesting that EGFR mutant NSCLCs rely more heavily than EFGR WT on aerobic glycolysis. Knockdown of EGFR in EGFR-mutated NSCLCs results in a decrease in expression level of genes that encode glycolysis enzymes, indicating that EGFR mutation leads to an increase in Glc metabolism and Glc dependence for growth and survival. Furthermore, inhibition of Glc metabolism shows a significant decrease in intracellular ATP, oxygen consumption and level of TCA cycle intermediates. Indeed, the addition of pyruvate dramatically rescues apoptotic cell death caused by EGFR degradation upon inhibition of Glc metabolism, suggesting that Glc to fuel the TCA cycle is essential for tumor survival. In addition, the inhibition of Glc metabolism overcomes T790M-mediated resistance to EGFR-TKIs. Together, our data suggest that the EGFR mutation mediates the reprogramming of Glc metabolism and this metabolic alteration represents an attractive target for new therapy of EGFR-mutated NSCLC. Citation Format: Jin Kyung Rho, Yun Jung Choi, Chang-Min Choi, Jae Cheol Lee. Glucose supports EGFR-mutated lung adenocarcinoma survival by sustaining EGFR stability. [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 55.
Ongoing epidemic of Mycoplasma pneumoniae infection in Jerusalem, Israel, 2010 to 2012
Authors: R Nir-Paz, A Abutbul, A E Moses, C Block, C Hidalgo-Grass
Journal: Eurosurveillance (2012)

A substantial epidemic of Mycoplasma pneumonia infection was reported in late 2011 in some European countries. We report here an epidemic of M. pneumonia infection that began in Jerusalem during 2010 and is still ongoing. This report complements current information on what might be a worldwide epidemic of M. pneumoniae infection that might require substantial coordinated international public health intervention.
Therapeutic Strategies For Initial Treatment Of AL Amyloidosis: Implications Of Therapy and Response On Outcome
Authors: Angela Dispenzieri, Morie A Gertz, Macp, Martha Q Lacy, Francis K Buadi, Suzanne R Hayman, Nelson Leung, Arleigh McCurdy, Lisa Hwa, Cnp, David Dingli, Prashant Kapoor, Steven R Zeldenrust, John A Lust, Stephen Russell, S. Vincent Rajkumar, Shaji K Kumar
Journal: Blood (2013)
Abstract 369: Automating recovery of spiked tumor cells from blood
Authors: Mark Sarinana, Ky Truong, Keith Cannon, Antonio Guia
Journal: Cancer Research (2016)

Abstract The isolation and study of circulating tumor cells (CTC) enables personalized medicine solutions, monitoring of therapeutics (theragnostics), and monitoring of minimal residual disease (MRD); culturing these rare cells is a frequent goal in cancer research, however the common methods for their isolation (gradient centrifugation, lysis buffer) are damaging to these cells, and many emerging technologies leave the cells bound in a consumable, bound to a biomarker or in a state that is difficult to use in cell culture. Further, the anuclear cells in blood greatly outnumber nucleated cells and present significant challenges to the study of the nucleated cells, for example, erythrocytes can absorb excitation or emission wavelengths in fluorescence studies, and their shape promotes rouleaux formation which can sequester the cells of interest; platelets also have a tendency to be activated by physical handling and cause aggregation that can also sequester and damage the cells of interest, and these all contain the greatest content of RNA and other markers that increase background noise in many assays. We demonstrate a new technology that automates the depletion of erythrocytes, thrombocytes, and plasma markers from, initially, small volumes of blood, using a micromachined membrane filter. We spiked small counts (10 to 1000 estimated from dilution) of tumor cell lines BT474 (breast cancer), DLD1 (colorectal cancer), and K562 (myelogenous leukemia) and other cell types into aliquots of blood. Using calcein-AM-loading to distinguish the spiked cells from blood cells, the recovery rates were determined in a flow cytometer, indicating an average of 80% ±4% (SE, N = 27) recovery of the rare cells after depletion of anuclear cells and plasma. The technology is amenable to use of beads for initial negative depletion of common nucleated cells by magnetic beads and has a recovery capacity of a few to as much as 3 million cells per specimen. Tumor cell lines alone that were run through this automation process then seeded for cell culture demonstrated growth rates indistinguishable from those seeded in similar counts in a regular cell passage. In further studies we demonstrate depletion of leukocytes with magnetic beads and of anuclear cells by filtration to handle larger blood volumes. The filtration system may be used for automated recovery of nucleated cells or cell clusters from blood or other fluid samples (liquid biopsies) without use of harsh chemicals or centrifugation, removing a common barrier for emerging analytical approaches. Citation Format: Mark Sarinana, Ky Truong, Keith Cannon, Antonio Guia. Automating recovery of spiked tumor cells from blood. [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 369.
Development of a novel 1,25(OH)2-vitamin D3 analog with potent ability to induce HL-60 cell differentiation without modulating calcium metabolism
Authors: JY Zhou, AW Norman, M Akashi, DL Chen, MR Uskokovic, JM Aurrecoechea, WG Dauben, WH Okamura, HP Koeffler
Journal: Blood (1991)