tbuckley/cabot-search huggingface dataset:
Abstract B56: Inactivation of LKB1-AMPK pathway is mediated by inflammation in pancreatic cancer
Authors: Sita Aggarwal, Qingxia Wang, Shailendra Giri, William Hansel
Journal: Cancer Research (2015)

Abstract Goal: The goal of this project is to determine if there is link between cancer cell metabolism and inflammation. LKB1is a known serine/threonine kinase tumor suppressor gene and it functions by sensing changes in cellular energy homeostasis and modulates anabolic and catabolic processes by activating its downstream kinase, AMP-activated protein kinase (AMPK). It is associated with Peutz-Jeghers syndrome, as well as various cancers including pancreatic cancer. Thus; it is a unique link between cell metabolism and inflammation. Hypothesis: Our hypothesis is that LKB1-AMK succumbs to inactivation processes because of increased NF-κB expression in pancreatic cancer cells and is associated with increased pancreatic cancer growth. Results: We tested five pancreatic cancer cells that express constitutive active NF-κB (pp65) and LKB1proteins by western blot analysis. In these cancer cells there was loss of active AMPK, phospho AMK (pAMPK) protein and its substrate pACC protein, suggesting a negative correlation between inflammation and loss of active AMPK. To strengthen this observation, we treated macrophage with LPS/IFNγ to create inflammatory environment and examined the protein levels of pp65, NF-κB regulated inflammatory gene (COX-2), pAMPK and pACC. We found that induction of pp65 and COX-2 are negatively correlated with pAMPK and pACC. To further support this observation we treated the pancreatic cancer cells with Metformin, a known activator of AMPK and our results clearly indicates that Metformin inhibits the proliferation of pancreatic cancer cells in a time-dependent manner. Metformin activates AMPK and ACC in pancreatic cancer cells. These data indicate that, compounds that activates LKB1-AMPK pathway can be beneficial in pancreatic cancer treatment. Citation Format: Sita Aggarwal, Qingxia Wang, Shailendra Giri, William Hansel. Inactivation of LKB1-AMPK pathway is mediated by inflammation in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B56.
Phase I dose-escalation study of sorafenib in combination with bevacizumab (B), paclitaxel (P), and carboplatin (C) for the treatment of advanced nonsquamous non-small cell lung cancer (NSCLC).
Authors: G. R. Blumenschein, J. R. Molina, C. D. Lathia, T. J. Ong, D. Roth, P. Rajagopalan, F. V. Fossella, M. S. Kies, R. S. Marks, A. A. Adjei, P. R. Sundaresan
Journal: Journal of Clinical Oncology (2011)

7565 Background: Sorafenib (S) is an oral multikinase inhibtor. The safety, antitumor activity, and pharmacokinetics of the combination of S with B/P/C were evaluated in chemonaive patients (pts) with advanced NSCLC. Methods: Pts (>18 yo) with Stage IIIB/IV non-squamous NSCLC and ECOG PS 0-1 were eligible for enrollment in this multicenter, phase I trial. In Cohorts 1, 2 and 3, S was administered on d3-19 (Cycle 1) and d2-19 (subsequent cycles) of each 3-week cycle, at a dose of 200 or 400 mg bid. B (5 or 10 mg/kg), P (200 mg/m2), and C (AUC=6) were administered on d1 of each 3-week cycle. In Cohorts 4 and 5, B (5 mg/kg), P (200 mg/m2), and C (AUC=6) were administered on d1 of each 3-week cycle. S was administered as a 5-d on/2-d off schedule in Cohort 4 and as a 2-week on/1-week off schedule in Cohort 5. Tumor response was assessed every 6 weeks using modified RECIST. Pts were assessed for adverse events (AEs) using the NCI-CTCAE v3.0 grading system. Results: Preliminary data from 30 pts who were evaluable for safety and anti-tumor activity are available. There were five confirmed partial responses (PRs) in Cohort 1, and two, one, and three in Cohorts 2, 3 and 4, respectively. To date, PRs have not been reported in Cohort 5. Seven pts received study drug for at least 14 cycles, and one pt in Cohort 4 continues to receive study drug beyond the 27th cycle of treatment. All pts had at least one AE. Twenty-five pts (83%) experienced AEs that were Grade 3 or greater. Of these 25 pts, 22 had AEs that were considered to be study drug-related, including neutropenia, leukopenia, hypertension, hand-foot skin reaction, and thrombocytopenia. These AEs are consistent with the toxicity profiles of S, B, P, and C. Ten pts manifested serious AEs that were attributed to S administration. Conclusions: Preliminary data indicate that S can be combined safely with B/P/C, and is associated with an AE profile consistent with that anticipated from the co-administration of these compounds. Encouraging activity was observed in a subset of pts with NSCLC, who experienced durable responses and extended disease stabilization. Final efficacy, safety, and pharmacokinetic data will be presented.
Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition
Authors: Shigeki Nakagawa, Lan Wei, Won Min Song, Takaaki Higashi, Sarani Ghoshal, Rosa S. Kim, C. Billie Bian, Suguru Yamada, Xiaochen Sun, Anu Venkatesh, Nicolas Goossens, Gretchen Bain, Gregory Y. Lauwers, Anna P. Koh, Mohamed El-Abtah, Noor B. Ahmad, Hiroki Hoshida, Derek J. Erstad, Ganesh Gunasekaran, Youngmin Lee, Ming-Lung Yu, Wan-Long Chuang, Chia-Yen Dai, Masahiro Kobayashi, Hiromitsu Kumada, Toru Beppu, Hideo Baba, Milind Mahajan, Venugopalan D. Nair, Michael Lanuti, Augusto Villanueva, Angelo Sangiovanni, Massimo Iavarone, Massimo Colombo, Josep M. Llovet, Aravind Subramanian, Andrew M. Tager, Scott L. Friedman, Thomas F. Baumert, Myron E. Schwarz, Raymond T. Chung, Kenneth K. Tanabe, Bin Zhang, Bryan C. Fuchs, Yujin Hoshida
Journal: Cancer Cell (2016)
Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion
Authors: Sungguan Hong, Wenjun Zhou, Bin Fang, Wenyun Lu, Emanuele Loro, Manashree Damle, Guolian Ding, Jennifer Jager, Sisi Zhang, Yuxiang Zhang, Dan Feng, Qingwei Chu, Brian D Dill, Henrik Molina, Tejvir S Khurana, Joshua D Rabinowitz, Mitchell A Lazar, Zheng Sun
Journal: Nature Medicine (2016)
Abstract 1268: Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration
Authors: Cassandra Buchheit, Brittany Angarola, Allison Steiner, Kelsey Weigel, Zachary Schafer
Journal: Cancer Research (2015)

Abstract Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Due to the inherent invasive nature of IBC cells, we hypothesized that IBC cells could evade detachment-induced apoptosis (anoikis), and rely on tightly regulated intracellular signaling pathways to do so. Here we demonstrate that in contrast to normal mammary epithelial cells, IBC cells robustly survive in ECM-detached conditions. ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment, suggesting overexpression/hyperactivation of these oncogenes is vital for IBC evasion of anoikis. Downstream of ErbB2 and EGFR, ERK/MAPK signaling was found to protect cells from anoikis by phosphorylating Bim-EL at serine 59. This phosphorylation of Bim-EL results in a physical interaction between Bim-EL, LC8, and Beclin-1 and prevents Bim-EL from localizing to the mitochondria and promoting cell death. Mutation of the serine 59 site results in increased cell death and a diminished capacity to form a protein complex with LC8 and Beclin-1. Bim-EL knockdown also rescued ECM-detachment-induced death in IBC cells, suggesting Bim-EL is necessary for the induction of anoikis in IBC cells. Interestingly, Bim-EL levels were found to be elevated in ECM-detached IBC cells and present in a significant percentage of IBC patient samples, despite their evasion of anoikis. Therefore, the sequestration of Bim-EL away the mitochondria provides a compelling rationale for how IBC cells survive in the presence of high Bim-EL levels. Furthermore, this mechanism provides a unique and novel opportunity for chemotherapeutic approaches aimed at freeing the already elevated Bim-EL levels from sequestration to specifically induce cell death in IBC cells. Citation Format: Cassandra Buchheit, Brittany Angarola, Allison Steiner, Kelsey Weigel, Zachary Schafer. Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1268. doi:10.1158/1538-7445.AM2015-1268
517. Improving CAR T Cell Efficacy for Solid Tumors By Nanogel-Based Delivery of Immunomodulatory Proteins
Authors: Sagar B. Kudchodkar, Li Tang, Emily K. Jeng, Hing C. Wong, Darrell J. Irvine, Marcela V. Maus
Journal: Molecular Therapy (2015)

Adoptive T cell therapies utilizing T lymphocytes transduced to stably express an anti-CD19 chimeric antigen receptor (CAR) have shown remarkable success against refractory B cell malignancies in multiple clinical trials. Studies are underway to adapt this technology towards the treatment of solid tumors, however, the immunosuppressive tumor microenvironment of many solid tumors may represent a significant barrier to CAR T cell efficacy. In this study, we investigate a means to enhance CAR T cell function by loading them with nanogel "backpacks" containing the T and NK cell stimulatory molecule IL-15N72D:IL-15RaSu/Fc superagonist complex (IL-15sa, also referred to as ALT-803 and currently in clinical trials). The IL15sa nanogel is a crosslinked, protein-polyethylene glycol (PEG) complex that breaks down slowly under physiological conditions allowing for pseudoautocrine stimulation of the CAR T cells with the IL15sa cargo. The effects of IL15sa nanogel loading on CAR T cell function were tested in a glioblastoma multiforme tumor model. Human T lymphocytes were lentivirally-transduced with a CAR targeting the epidermal growth factor variant III (EGFRvIII) antigen, as is currently being tested in early human clinical trials. EGFRvIII is expressed in up to 30% of glioblastoma multiforme cells but not on normal cells. EGFRvIII CAR T cells were loaded with a fluorophore-labeled IL15sa nanogel and examined in vitro for nanogel breakdown and effects on CAR T cell functions. The nanogel was detected on labeled cells for up to five days. Nanogels loaded with either control or IL-15sa did not alter antigen-specific cytolytic activity of EGFRvIII CAR T cells towards glioblastoma target cells. EGFRvIII CAR T cells loaded with control nanogel proliferated with the same kinetics as non-loaded CAR T cells upon co-culture with EGFRvIII+ glioblastoma targets. In contrast, IL15sa nanogel loaded CAR T cells had increased proliferation upon co-culture with antigenbearing targets. Additionally, IL15sa nanogel loaded EGFRvIII CAR T cells proliferated more with repeated stimulation of EGFRvIII-expressing glioblastoma cells. Studies are currently underway to test the efficacy of IL15sa nanogel-loaded EGFRvIII CAR T cells in vivo using a xenogeneic murine model of glioblastoma. These results indicate that nanogel loading of T cells can be a viable way of delivering immunostimulatory agents with CAR T cells. Nanogel loading of immune-modulating or tumoricidal drugs coupled to CAR T cells represents a novel platform for enhancing T cell function, and potentially for delivering systemically toxic drugs, into a specific and hostile tumor microenvironment.
GlycoPEGylated Filgrastim XM22 Fixed Dose Demonstrates Similar Activity in Comparison to Pegfilgrastim in Healthy Volunteers after Single Administration.
Authors: Heinz Lubenau, Rolf Pokorny, Luis Lopez-Lazaro, Peter Bias, Bruce Wallin, Walter Hinderer, Anne-Katrin Maly, Michael Seiberling
Journal: Blood (2007)
Safety and immunogenicity of a recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in Sierra Leone: a single-centre, randomised, double-blind, placebo-controlled, phase 2 trial
Authors: Feng-Cai Zhu, Alie H Wurie, Li-Hua Hou, Qi Liang, Yu-Hua Li, James B W Russell, Shi-Po Wu, Jing-Xin Li, Yue-Mei Hu, Qiang Guo, Wen-Bo Xu, Abdul R Wurie, Wen-Juan Wang, Zhe Zhang, Wen-Jiao Yin, Manal Ghazzawi, Xu Zhang, Lei Duan, Jun-Zhi Wang, Wei Chen
Journal: The Lancet (2016)
Fluoropyrimidine-related toxicity in gastrointestinal cancer patients. Assessment of risk factors
Authors: R. Tassi, G. Perrone, M. Brugia, L. Simi, P. Petreni, E. Mori, I. Landini, M. Pazzagli, T. Mazzei, E. Mini, S. Nobili
Journal: Annals of Oncology (2015)
A second-generation microRNA-based assay for diagnosing tumor tissue origin.
Authors: R. T. Aharonov, S. Rosenwald, T. B. Edmonston, I. Barshack, M. Feinmesser, M. Huszar, W. C. Mueller, F. Fogt, H. Shomin, L. Cohen, I. Burnstein, E. Goren, B. St. Cyr, Y. Spector, N. Dromi, E. Meiri
Journal: Journal of Clinical Oncology (2011)

10575 Background: Cancer of unknown primary (CUP) constitutes 3%-5% of all newly diagnosed cancer cases. It presents a major diagnostic challenge as knowing the tumor tissue of origin (ToO) of the cancer is crucial for choosing the optimal treatment. MicroRNAs are a family of non-coding, regulatory RNA genes involved in development and differentiation that were shown to be involved in carcinogenesis. MicroRNAs, highly stable in clinical samples and tissue-specific, serve as ideal biomarkers for cancer diagnosis. Our first generation assay identifies the ToO using a set of 48 microRNAs measured on a qRT-PCR platform and differentiates 25 different tumor types. We present here the development and validation of a second generation clinical assay that can identify 42 different tumor types using a custom array platform. Methods: Over 1300 primary and metastatic tumor formalin-fixed and paraffin-embedded (FFPE) tissue samples were used for the training and development of the assay. High-purity RNA was extracted using proprietary protocols. Expression levels of all known and additional Rosetta’s proprietary microRNAs were profiled using a custom array platform. A combination of a decision tree with a KNN classifier was developed to identify the ToO based on the expression of 64 microRNAs. A validation set of more than 500 independent FFPE tissue samples of primary tumors and metastases was analyzed blindly and classified using the developed assay. Results: The assay is able to identify 42 tumor types that include carcinomas, soft tissue tumors, lymphoma and other malignancies with very high accuracy. Based on the validation set, the sensitivity (positive agreement) for identifying the tumor origin is 85%. In more than 80% of the cases, a single answer is reported, and for these cases, the sensitivity is 90%. Conclusions: Previous studies have highlighted the tissue-specificity of microRNA expression, and have demonstrated their potential use for classification of human malignancies. An enlarged panel of 42 ToO that can be identified with high accuracy promises improved utility for the diagnosis of cancers of unknown/uncertain primary.
Inadequate medical intervention as prognostic factor in osteosarcoma
Authors: S. Specterman, J. M. Lastiri, M. S. Varela, H. Gioseffi, M. E. Lopez Lincuez, G. Z. Beguelin, M. Makiya, E. Dibar, D. L. Muscolo, M. G. Pallotta
Journal: Journal of Clinical Oncology (2004)

9041 Background: Osteosarcoma is an aggressive disease. Survival has been improved to greater than 75% in most of the last trials. This is due to progress in surgical technique, polychemotherapy and fundamentally because of the multidisciplinary work. Inadequate medical intervention (IMI) (mistakes in the biopsy planning, pathological interpretation or surgery) could impair the osteosarcoma evolution. We compare two groups of patients managed with the same standard of care in our multidisciplinary group; one had a previous IMI and the other did not (control group). Methods: Since 11/1989 until 9/2002, 15 patients with diagnosis of osteosarcoma that had initiated treatment in other institutions and had IMI were evaluated. Nine men, median age 21,1 years (SD: 9,36), two with central localization. Overall survival (OS), disease free survival (DFS), limb sparing and relapses of these patients were evaluated. Results: erroneous diagnoses were: aneurysmal bone cist (N=4), giant cell tumor (N=2), osteochondroma (N=2), osteoblastoma (N=2), fibrous dysplasia (N=1), osteomyelitis (N=1). Histological revision made by an experienced pathologist showed high-grade osteosarcoma in 11 patients and low grade in the rest. Erroneous initial diagnosis leaded to insufficient surgeries (intralesional) in 14 patients in other institutions. Limb sparing rate was lower versus our control population (p= 0.03). In the IMI group the local and systemic relapse rates were worse (40% versus 15%, p=0.000; and 60 versus 28.3%, p=0.04 respectively). Five year SV of patients with IMI was 24.9% versus 65.3% of control group (p= 0.02). DFS was lower in the IMI group: 18.5 vs. 72.2 months (p= 0.01). Conclusions: IMI modified evolution of patients with osteosarcoma dramatically. IMI reduces OS, DFS and decreases conservational possibilities. Specialized multidisciplinary teams should treat every patient with osteosarcoma suspicion. No significant financial relationships to disclose.
Abstract LB-135: E-cadherin as a buffer for mutated B-catenin: A genetic comparison of Apc and B-catenin mutations in vivo
Authors: David J. Huels, Rachel A. Ridgway, Owen J. Sansom
Journal: Cancer Research (2015)

Abstract Wnt deregulation is a characteristic of many cancers, especially Colorectal Cancer (CRC). However, only the intestine harbours mutations in the tumour suppressor gene (TSG) Adenomatous Polyposis Coli (APC) which can be found in around ∼80% of CRC patients. Other cancers (e.g. hepatocellular carcinoma, solid pseudopapillary cancer) achieve Wnt deregulation by specific mutations of B-catenin (CTNNB1). Using genetic approaches in the mouse intestine we compared mutations in APC and B-catenin in the level of Wnt activation, their kinetics and their ability to transform the intestinal epithelium in vitro and in vivo. Deregulation of Wnt by mutation of B-catenin is much slower than by loss of APC, and only gradually increases Wnt activity. In contrast to loss of APC, Wnt deregulation by mutation of B-catenin is almost completely restricted to the small intestine of mice, and not the colon. We have evidence that the restriction of the B-catenin phenotype is due to different E-cadherin levels in the small intestine compared to the colon. Mutation of B-catenin in addition to reduction of E-cadherin levels synergises dramatically in vivo and is now able to transform the colon epithelium. We show that E-cadherin at the adherens junctions acts as buffer for the mutated B-catenin and slows down its accumulation in the cytoplasm. These data shows a clear restriction of B-catenin mediated tumor initiation by E-cadherin. Interestingly, the other cancer types (hepatocellular carcinoma, solid pseudopapillary cancer) show a similar negative relationship of B-catenin mutation and E-cadherin expression. Citation Format: David J. Huels, Rachel A. Ridgway, Owen J. Sansom. E-cadherin as a buffer for mutated B-catenin: A genetic comparison of Apc and B-catenin mutations in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-135. doi:10.1158/1538-7445.AM2015-LB-135
Rituximab Combined to ACVBP (R-ACVBP) as a New Inductive Treatment Followed by High-Dose Consolidative Autotransplantation (HDC) for Poor Risk Diffuse Large B-Cell Lymphoma (DLBCL) in First-Line. Preliminary Results on 119 Patients of a GELA Phase II Study.
Authors: Karim Belhadj, Olivier Fitoussi, Corinne Haioun, Nicolas Mounier, Pierre Lederlin, Bertrand Coiffier, Christian Recher, Olivier Casasnovas, Catherine Sebban, Christophe Fermé, Herve Tilly, Christian Gisselbrecht
Journal: Blood (2006)
Artificial Antigen Presenting Cell Can Be Used To Propagate Genetically Modified CD19-Specific T Cells through Chimeric Antigen Receptor.
Authors: Tontanai Numbenjapon, Lisa Marie A. Serrano, Simon Olivares, Wen-Chung Chang, Harjeet Singh, Claudia M. Kowolik, Sergio Gonzalez, Nancy Gonzalez, Laurence J.N. Cooper
Journal: Blood (2005)
Defining a Hospital Volume Threshold for Minimally Invasive Pancreaticoduodenectomy in the United States
Authors: Mohamed Abdelgadir Adam, Samantha Thomas, Linda Youngwirth, Theodore Pappas, Sanziana A. Roman, Julie A. Sosa
Journal: JAMA Surgery (2016)

There is increasing interest in expanding use of minimally invasive pancreaticoduodenectomy (MIPD). This procedure is complex, with data suggesting a significant association between hospital volume and outcomes.To determine whether there is an MIPD hospital volume threshold for which patient outcomes could be optimized.Adult patients undergoing MIPD were identified from the Healthcare Cost and Utilization Project National Inpatient Sample from 2000 to 2012. Multivariable models with restricted cubic splines were used to identify a hospital volume threshold by plotting annual hospital volume against the adjusted odds of postoperative complications. The current analysis was conducted on August 16, 2016.Incidence of any complication.Of the 865 patients who underwent MIPD, 474 (55%) were male and the median patient age was 67 years (interquartile range, 59-74 years). Among the patients, 747 (86%) had cancer and 91 (11%) had benign conditions/pancreatitis. Overall, 410 patients (47%) had postoperative complications and 31 (4%) died in-hospital. After adjustment for demographic and clinical characteristics, increasing hospital volume was associated with reduced complications (overall association P < .001); the likelihood of experiencing a complication declined as hospital volume increased up to 22 cases per year (95% CI, 21-23). Median hospital volume was 6 cases per year (range, 1-60). Most patients (n = 717; 83%) underwent the procedure at low-volume (≤22 cases per year) hospitals. After adjustment for patient mix, undergoing MIPD at low- vs high-volume hospitals was significantly associated with increased odds for postoperative complications (odds ratio, 1.74; 95% CI, 1.03-2.94; P = .04).Hospital volume is significantly associated with improved outcomes from MIPD, with a threshold of 22 cases per year. Most patients undergo MIPD at low-volume hospitals. Protocols outlining minimum procedural volume thresholds should be considered to facilitate safer dissemination of MIPD.