tbuckley/cabot-search huggingface dataset:
Abstract 4675: Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal growth factor receptor mutation-positive non-small cell lung cancer
Authors: Nobuaki Ochi, Hideko Isozaki, Masami Takeyama, Jack W. Singer, Hiromichi Yamane, Yoshihiro Honda, Katsuyuki Kiura, Nagio Takigawa
Journal: Cancer Research (2016)

Abstract Patients with non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs). However, almost all of the patients eventually develop resistance to EGFR-TKIs within approximately one year. The resistance mechanisms of EGFR-TKIs have not been fully elucidated. We previously established an erlotinib-resistant NSCLC cell line named PC-9/ER3 after continuously exposing PC-9 cells, which harbor an in-frame deletion in EGFR exon 19, to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of pSTAT3, pJAK2 increased in the resistant cells (Cancer Sci 103, 1795-802; 2012). Meanwhile, pacritinib is a novel macrocyclic pyrimidine-based JAK2/FLT3 inhibitor with clinical activity in patients with myelofibrosis and lymphoma, which will be used as a standard therapy for myelofibrosis. In this study, we evaluated the synergistic effect of pacritinib combined with erlotinib on JAK2-medatited EGFR-TKI resistant NSCLC. Drug sensitivity was determined using an MTT assay and the combination index was calculated according to the methods based on the median-effect analysis. The combination of pacritinib with erlotinib showed synergistic effects on JAK2-medated EGFR TKI-resistant PC-9/ER3 cells in some cases. Western blotting showed that the combination treatment markedly suppressed pAKT and pERK although pSTAT3 was equivalent regardless of treatment with the pacritinib, erlotinib, pacritinib plus erlotinib, or control in PC-9/ER3 cells. Receptor tyrosine kinase array profiling demonstrated that pacritinib suppressed MET in the PC-9/ER3 cells. The combined treatment of pacritinib and erlotinib in PC-9/ER3 xenografts showed more tumor shrinkage compared with each drug as monotherapy. Western blotting revealed that pMET in the tumor samples was inhibited. These results suggest MET suppression by pacritinib may play a role in overcoming the EGFR-TKI resistance mediated by JAK2 in the PC-9/ER3 cells. In conclusion, pacritinib combined with EGFR-TKI might be a potent strategy against JAK2-mediated EGFR-TKI resistance. Citation Format: Nobuaki Ochi, Hideko Isozaki, Masami Takeyama, Jack W. Singer, Hiromichi Yamane, Yoshihiro Honda, Katsuyuki Kiura, Nagio Takigawa. Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal growth factor receptor mutation-positive non-small cell lung cancer. [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 4675.
A Phase II Study of Anti PD-1 Antibody Pembrolizumab, Pomalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Ashraf Z. Badros, Mehmet H. Kocoglu, Ning Ma, Aaron P. Rapoport, Emily Lederer, Sunita Philip, Patricia Lesho, Cameron Dell, Nancy M. Hardy, Jean Yared, Olga Goloubeva, Zeba Singh
Journal: Blood (2015)
Implications of neural networks for how we think about brain function
Authors: David A. Robinson
Journal: Behavioral and Brain Sciences (1992)

Abstract Engineers use neural networks to control systems too complex for conventional engineering solutions. To examine the behavior of individual hidden units would defeat the purpose of this approach because it would be largely uninterpretable. Yet neurophysiologists spend their careers doing just that! Hidden units contain bits and scraps of signals that yield only arcane hints about network function and no information about how its individual units process signals. Most literature on single-unit recordings attests to this grim fact. On the other hand, knowing a system's function and describing it with elegant mathematics tell one very little about what to expect of interneuronal behavior. Examples of simple networks based on neurophysiology are taken from the oculomotor literature to suggest how single-unit interpretability might decrease with increasing task complexity. It is argued that trying to explain how any real neural network works on a cell-by-cell, reductionist basis is futile and we may have to be content with trying to understand the brain at higher levels of organization.
Abstract 21: The mTORC2 target Akt is regulated in response to glutamine metabolite levels
Authors: Estela Jacinto, Joseph Moloughney, Peter K. Kim, Nicole M. Vega-Cotto, Chang-Chih Wu, Thomas Lynch, Sisi Zhang, Matthew Adlam, Sai Guntaka, Po-Chien Chou, Joshua D. Rabinowitz, Guy Werlen
Journal: Cancer Research (2016)

Abstract Highly proliferating cells are particularly dependent on glucose and glutamine for bioenergetics and to fuel biosynthesis of macromolecules. The signals that respond to the fluctuations of these nutrients and how they control metabolic pathways remain poorly understood. mTOR, as part of mTOR complex 1 (mTORC1), responds to amino acids and plays a central role in metabolism. On the other hand, little is known on how mTORC2, consisting of the core components mTOR, rictor, SIN1 and mLST8 is regulated and its metabolic functions. The phosphorylation of the mTORC2 substrate, Akt, is enhanced in cancer cells, suggesting that mTORC2 becomes deregulated during tumorigenesis. Here we found that the activity of mTORC2 is enhanced by diminishing glutamine-derived metabolites. mTORC2 activity is required by glutamine-requiring biosynthetic pathways such as the hexosamine biosynthetic pathway (HBP). Acute nutrient withdrawal augments Akt phosphorylation but does not affect GFAT1 expression. However, extreme starvation that eventually depletes intracellular glutamine metabolites inactivates mTORC2 and downregulates GFAT1 expression. Thus, while mTORC1 senses glutamine abundance to promote anabolism, mTORC2 responds to declining glutamine catabolites in order to restore metabolic homeostasis. Our findings uncover the role of mTORC2 in metabolic reprogramming and provide insights on more effective therapeutic strategies for glutamine-dependent tumors. Citation Format: Estela Jacinto, Joseph Moloughney, Peter K. Kim, Nicole M. Vega-Cotto, Chang-Chih Wu, Thomas Lynch, Sisi Zhang, Matthew Adlam, Sai Guntaka, Po-Chien Chou, Joshua D. Rabinowitz, Guy Werlen. The mTORC2 target Akt is regulated in response to glutamine metabolite levels. [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 21.
Abdominal Pain and Bloody Diarrhea
Authors: Arjun Gupta, Lan Peng, Hsiao C. Li
Journal: JAMA Oncology (2016)

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Abstract 5113: CXCL12/CXCR4 and integrin signal activation by cancer-associated fibroblasts enhances the chemoresistance in gastric cancer
Authors: Yuka Tamaoki, Takatsugu Ishimoto, Keisuke Miyake, Daisuke Izumi, Daisuke Kuroda, Tsugio Eto, Kota Arima, Hironobu Shigaki, Junji Kurashige, Masaaki Iwatsuki, Yoshifumi Baba, Yasuo Sakamoto, Naoya Yoshida, Hideo Baba
Journal: Cancer Research (2016)

Abstract Purpose: Gastric cancer (GC) is an aggressive cancer metastasizing with a high propensity for peritoneal dissemination and liver metastasis. Some studies have been shown that not only cancer cells but also their surrounding stroma, especially cancer-associated fibroblasts (CAFs) play an important role in tumor development. Previously, we reported that CXCL12-CXCR4 and integrin β1 signal activation by CAFs co-operates for promoting FAK phosphorylation and enhances the invasiveness of GC cells in extracellular matrix (ECM).On the other hand, a previous study presented that CXCR4 and integrin signaling co-operates in mediating adhesion and chemoresistance in small cell lung cancer cells. Therefore, we hypothesized that CXCL12-CXCR4 and integrin signal activation by CAFs enhances the chemoresistance in GC as well. The aim of current study is to elucidate the significance of CAFs mediating signal activation for chemoresistance in GCs. Experimental Design: We first performed chemo-sensitive assays using GC cells cultured with fresh medium or with CAF-conditioned-medium (CM), and these experiments were conducted on non-coated and Matrigel-coated plates. Next, we examined the CXCL12-CXCR4 and integrin related signaling by western blotting analysis. Furthermore, we investigated the critical molecule for chemoresistance using silencing CXCR4 or integrin β1 in GC cells. Results: Chemo-sensitive assays revealed that GC cells cultured with CAF-CM showed more resistant to cisplatin and reactive oxygen spices (ROS) than those cultured with fresh medium. Moreover, GC cells with CAF-CM on Matrigel-coated plates exhibited remarkable resistance in these assays. On the other hand, western blotting analysis showed that Akt activity in GC cells cultured with CAF-CM was up-regulated in concurrence with FAK phosphorylation. Finally, the chemoresitance induced by CAFs was significantly suppressed by CXCR4 or integrin β1 silencing. Conclusions: These results suggest that CXCL12/CXCR4 and integrinβ1 signal activation by CAFs promoted the chemoresistance through enhancing their interaction with ECM in GC. This mechanism underlying the chemoresistance may provide a novel therapeutic target in advanced GCs. Citation Format: Yuka Tamaoki, Takatsugu Ishimoto, Keisuke Miyake, Daisuke Izumi, Daisuke Kuroda, Tsugio Eto, Kota Arima, Hironobu Shigaki, Junji Kurashige, Masaaki Iwatsuki, Yoshifumi Baba, Yasuo Sakamoto, Naoya Yoshida, Hideo Baba. CXCL12/CXCR4 and integrin signal activation by cancer-associated fibroblasts enhances the chemoresistance in gastric cancer. [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 5113.
Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer
Authors: L. B. Saltz, H.-J. Lenz, H. Hochster, S. Wadler, P. Hoff, N. Kemeny, E. Hollywood, M. Gonen, S. Wetherbee, H. Chen
Journal: Journal of Clinical Oncology (2005)

3508 Background: Cetuximab (Cetux), a monoclonal antibody (mab) that targets the epidermal growth factor receptor (EGFR), has shown antitumor activity both alone and in combination with irinotecan (IRI) in IRI-refractory colorectal cancer (CRC). Bevacizumab (Bev), a mab against vascular endothelial growth factor (VEGF), improved the response rate, PFS, and overall survival in CRC patients treated with first line IFL. We evaluated the safety and efficacy of concurrent administration of these two monoclonal antibodies in patients with metastatic CRC. Methods: This is a randomized phase II study in patients with IRI-refractory CRC. All patients were naive to both bev and cetux. EGFR expression was not required for study entry. Arm A received IRI at the same dose and schedule as last received prior to study, plus Cetux 400 mg/m2 loading dose, then weekly at 250 mg/m2, plus Bev 5 mg/kg given every other week. Arm B received the same Cetux and Bev as arm A, but without IRI. Results: 76 patients have been randomized, 75 of whom received treatment. Median age is 60 (range 25–86). Median number of prior regimens is 3 (range 1–7). Median performance status is ECOG 1 (0–1). Interim toxicity data have been previously presented (ASCO GI Symposium, 1/05). No toxicities were encountered that would not have been expected from the single agents alone. As of 12/04, the median time to tumor progression (TTP) for arm A (Cetux/Bev/IRI) is 5.8 months, with 16 patients currently on treatment. For Arm B (Cetux/Bev) the median TTP was 4.0 months. Response data are shown in the table. Conclusions: The combination of Cetux/Bev, alone or with IRI, is tolerable. The response rates and TTP seen with the addition of Bev to either Cetux or Cetux/IRI appear favorable compared to historical controls of Cetux or Cetux/IRI without Bev. Studies of Cetux/Bev in conjunction with front line combination chemotherapy regimens are warranted and have now been initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Access, Genentech, Pfizer, Roche, Sanofi, Taiho Bristol-Meyers Squibb
Bayesian analysis of gene expression profiles links invasion related genes to poor survival in older glioblastoma patients
Authors: Jeremy N. Rich, Chris Hans, Beatrix Jones, Roger E. McLendon, Ahmed Rasheed, Adrian Dobra, Holly Dressman, Darell D. Bigner, Joe Nevins, Mike West
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

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Despite the strikingly grave prognosis for older patients with glioblastomas, significant variability in patient outcome is experienced. To explore the potential for developing improved prognostic capabilities based on the elucidation of potential biological relationships, we performed analyses of genes commonly mutated, amplified, or deleted in glioblastomas and Affymetrix DNA microarray gene expression data from tumors of 43 glioblastoma patients of age greater than 50 for whom survival is known. No prognostic significance was associated with genetic changes in EGFR, TP53, p16INK4A, or PTEN. Statistical analysis of the gene expression data in connection with survival involved exploration of regression models on small subsets of genes, based on computational search over multiple regression models with cross-validation to assess predictive validity. The analysis generated a set of regression models that, when weighted and combined according to posterior probabilities implied by the statistical analysis, identify patterns in expression of a small subset of genes that are associated with survival and have value in assessing survival risks. The dominant genes across multiple such regression models involve three key genes - secreted protein acidic and rich in cysteine (SPARC, Osteonectin), Doublecortex and Semaphorin 3B (SEMA3B) - that play roles in cellular migration processes. Additional analysis, based on statistical graphical association models constructed using similar computational analysis methods, reveals others genes that support the view that multiple mediators of tumor invasion may be important prognostic factors in glioblastomas in older patients. No previous studies of which we are aware have elucidated conclusive links between expression of specific gene and survival of older glioblastoma patients. Our regression analyses using gene expression as explanatory of survival outcomes revealed that genes whose primary cellular effects may be the regulation of cellular migration appear as candidate markers of poor survival. Together these results suggest that tumor migration may represent an important effector of glioblastoma malignancy and may warrant accelerated development of specific therapies. Future studies will prospectively determine the link between the expression of SPARC, doublecortex, and SEMA3B in gliomas of all grades and patient outcome. This work was supported by a grant from the W.M. Keck Foundation. J.N.R. is a Damon Runyon-Lilly Clinical Investigator and a Sidney Kimmel Cancer Foundation Scholar. This work was also supported by NIH grant NS047409 (J.N.R.).
Meaningless METS: studying the link between physical activity and health
Authors: Philippe Autier, Cécile Pizot
Journal: BMJ (2016)

Future studies must streamline their measurement and reporting for real gains in knowledge

Physical activity is good for health. Few would oppose this contention. But, curiously, we do not definitively know how much the type (occupational, recreational, daily living) and quantity of physical activity reduces the risk of common conditions. This imprecision stems essentially from the myriad different ways physical activity has been appraised in epidemiological studies. Some studies investigated physical activity as a whole, while others concentrated on specific types of activity. Different metrics have been used for quantification from just dummy categories (such as high versus low) to quintiles of hours a week. The metabolic equivalent of tasks (MET) is a standardised metric that expresses the energy spent during a specific activity. The MET is defined as the ratio of the metabolic rate during that activity to the metabolic rate when resting.1 A classification system was developed in 19932 and updated …
Abstract 1032: Characterizing the metabolic dependencies of rhabdomyosarcoma and Ewing's sarcoma cells
Authors: Sameer Issaq, Lee Helman
Journal: Cancer Research (2016)

Abstract Sarcomas represent a diverse group of malignancies with unique molecular and pathological characteristics. In order to improve sarcoma treatment, a better understanding of the alterations associated with specific sarcoma subtypes is critically important. Renewed interest in the altered metabolic properties of cancer cells has led to an exploration of targeting metabolic dependencies as a novel therapeutic strategy. In this study, we have characterized the dependency of rhabdomyosarcoma (RMS) and Ewing's sarcoma (EWS) cells on key metabolic substrates by examining cell proliferation and bioenergetic properties under varying concentrations of glucose and glutamine. We utilized two alveolar RMS cell lines, one embryonal RMS cell line, and five EWS cell lines. While all cell lines tested were completely growth-inhibited by lack of glucose, individual RMS and EWS cell lines were differentially sensitive to removal of glutamine. Furthermore, glutamine deprivation significantly reduced mitochondrial bioenergetic function, as demonstrated by Seahorse metabolic flux analysis. The observed effects of glutamine deprivation on proliferation and mitochondrial bioenergetics were rescued by the re-introduction of glutamine into the culture media. Our findings suggest that metabolic dependencies of RMS and EWS cells should be further investigated in order to identify metabolic vulnerabilities that could be targeted for potential therapeutic benefit. Citation Format: Sameer Issaq, Lee Helman. Characterizing the metabolic dependencies of rhabdomyosarcoma and Ewing's sarcoma cells. [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 1032.
PD1, PDL1, PDL2 tumor tissue (TT) expression as predictors of response to neoadjuvant chemotherapy (NAC) and outcome in bladder cancer (BC).
Authors: Petros Grivas, Hamid Emamekhoo, Paul Elson, Jesse McKenney, Homi Zargar, Cristina Magi-Galluzzi, Kim Schach, Nicole DiBiase Brey, Andrew J. Stephenson, Terri McClanahan, Jennifer Yearley, Wendy Blumenschein, Lakshmanan Annamalai, Brian I. Rini, Jorge A. Garcia
Journal: Journal of Clinical Oncology (2016)

e16023 Background: PD1/PDL1 pathway inhibition has activity in BC. NAC effect on PD1, PDL1, PDL2expression is unknown. We assessed PD1, PDL1, PDL2 TT expression in BC patients (pts) before (pre) & after (post) NAC, and its potential impact on NAC response and progression-free survival (PFS). Methods: 40 pts with surgery after NAC (diagnosed 2006-2013) were identified. Paraffin-embedded TT from pre-NAC (TURBT) and/or post-NAC (cystectomy) was analyzed (IHC: low 1-3 +; high 4/5 +) for PD1, PDL1, PDL2 expression. NanoString (nCounter, custom 800-gene set) was used for TT gene expression profiling. Fisher’s exact test, Cochran-Armitage trend test, and proportional hazards models were used for analysis of IHC data & clinical factors. Correlation between mRNA & protein expression was explored. Results: Median age at diagnosis was 65 (39-82), 92% men, 28% never-smoker; 38 pts had NAC (63% Gem-Cis, 18% dd-MVAC, 8% Gem-Carbo, 8% MVAC, 3% Cis-Etop); 6/40 had pT0, 16/40 downstaged vs TURBT; 7/39 pN+, 12/37 LVI+. Primary histology at cystectomy: 25 pure urothelial carcinomas (UC), 7 UC/squamous features, 1 small cell carcinoma. PD1, PDL1, PDL2 protein was expressed pre- & post-NAC. There was significant correlation between PDL1 & PDL2 pre-NAC (p< .0001), PDL1 & PDL2 post-NAC (p< .0001), PDL1 & PD1 post-NAC (p=.0008), PDL2 & PD1 post-NAC (p=.007), and post vs pre- NAC change in both PDL1 & PDL2 protein expression (p< .0001). 76% of paired tissues had reduction in PD1, 44% in PDL1, and 41% in PDL2 protein post vs pre- NAC. High post-NAC PDL1 correlated with higher pT stage & no downstaging (Table). Post-NAC high PDL1 & PDL2 protein expression correlated with shorter PFS (p= .04, HR=4.26; p= .03, HR=4.65, respectively). There was significant correlation between mRNA & protein expression for PDL1 & PDL2 (not for PD1) but no significant difference in PD1, PDL1, PDL2 mRNA expression post vs pre- NAC. Conclusions: NAC affects PD1, PDL1, PDL2 TT IHC expression; this may impact clinical trial designs; validation is needed. IHC pT0 pTa/ CIS pT1/ 2 pT3/ 4 P Downstage p Yes No Post-NAC PDL1 (N=33) Low (1-3+) 4 7 7 8 14 12 High (4/5+) 0 0 0 7 .006 0 7 .01 Post vs pre- NAC PDL1 (N=25) no change/ higher 1 0 2 11 2 12 lower 1 5 4 1 .004 7 4 .02
Generation and Functional Characterization of T Cells Against Candida albicans as Potential Immunotherapy after Allogeneic Stem Cell Transplantation.
Authors: Thomas Lehrnbecher, Olaf Beck, Ulrike Koehl, Frauke Roeger, Klaus-Peter Hunfeld, Jean Paul Latge, Jaqueline Sarfati, Thomas Klingebiel, Lars Tramsen
Journal: Blood (2006)