tbuckley/cabot-search huggingface dataset:
Abstract 3741: Antimetastatic activity of ISTH0047, a potent and selective TGF-beta 2 antisense oligonucleotide, in syngeneic lung metastatic model of mouse 4T1 mammary carcinoma
Authors: Katja Wosikowski, Kathy Hasenbach, Jutta Petschenka, Diana Barea Roldan, Sebastian Kreiter, Ugur Sahin, Guillaume Serin, Julie-Orlane Redon, Marc Hillairet de Boisferon, Francis Bichat, Hanna Kohonen, Michel Janicot
Journal: Cancer Research (2016)

Abstract Transforming growth factor beta (TGF-β) isoforms are the primary mediators for TGF-β signaling via TGF-β receptors and downstream phosphorylation/dephosphorylation cascade. TGF-β is associated with a wide range of biological processes in oncology, including tumor cell invasion, migration, angiogenesis, immunosuppression, as well as regulation of tumor stem cell properties. Mouse 4T1 mammary carcinoma cell line is a transplantable tumor cell line that is highly tumorigenic and invasive and, unlike most tumor models, can spontaneously metastasize from the primary tumor in the mammary gland to multiple distant sites including lymph nodes, blood, liver, lung, brain, and bone. Considering rather challenging preclinical evaluation of antitumor activity in tumor models, mouse 4T1 mammary carcinoma model has been widely used in the literature for evaluation of TGF-β antagonists. In this report, we describe the efficacy of ISTH0047 - a potent and selective TGF-β2 antisense oligonucleotide - in murine 4T1 primary tumors and lung metastasis following tumor cell injection into the mammary fat pad (orthotopic tumor model) of syngeneic Balb/c mice. Consistent with literature data generated with other classes of TGF-β antagonists (e.g., small-molecule kinase inhibitors, antibodies or TGF-β trap agents), although limited antitumor activity was demonstrated on primary tumor growth, marked and statistically significant decrease of lung metastasis number was observed upon subcutaneous administrations of ISTH0047. In addition, side by side comparison with murine surrogates of CTLA-4 or PD-1 antibodies indicated similar efficacy of all test items on lung metastasis in this model. Taken together, these encouraging results pave the way for in-depth preclinical evaluation of both ‘seed and soil’ theory and efficacy of combination regimen (immunomodulation) for better clinical outcome. Citation Format: Katja Wosikowski, Kathy Hasenbach, Jutta Petschenka, Diana Barea Roldan, Sebastian Kreiter, Ugur Sahin, Guillaume Serin, Julie-Orlane Redon, Marc Hillairet de Boisferon, Francis Bichat, Hanna Kohonen, Michel Janicot. Antimetastatic activity of ISTH0047, a potent and selective TGF-beta 2 antisense oligonucleotide, in syngeneic lung metastatic model of mouse 4T1 mammary 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 3741.
Abstract LB-063: A high-resolution, quantitative proteomic map of human prostate cancer cells
Authors: Bo Zhou, Michael R. Freeman, Wei Yang
Journal: Cancer Research (2016)

Abstract Prostate cancer is the second leading cause of cancer death in American men. Despite remarkable progress in the past decade, the molecular basis of prostate cancer development and progression remains incompletely understood. Owing to the rapid advancement of next generation sequencing technologies, whole-genome and -transcriptome sequencing have been increasingly applied to analyze prostate cancer. In comparison, whole-proteome sequencing of prostate cancer remains very challenging. Here, by applying three different endoproteinases (i.e., trypsin, Glu-C and Asp-N) and two-dimensional liquid chromatography-tandem mass spectrometry, we generated a high-resolution and quantitative proteomic map for DU145, a widely used human prostate cancer cell line. A total of 11,759 non-redundant protein groups were identified with a false discovery rate of 1%, corresponding to 10,561 genes. The absolute abundance of each identified protein was computed, ranging from 110 million to several copies (median = 35,700 copies). In addition, a recent RNA-Seq analysis of DU145 cells suggested that only 10,964 genes have FPKM values of ? 1, indicating that our proteomic profiling covers almost the entire proteome. Among the 10,561 identified genes, at least 904 (e.g., BRAF, BRCA1, EZH2, FGFR1, HNF1B, and STAT3) express two to eight different protein isoforms, some of which have not been characterized before. In addition, proteogenomic analysis identified over 40 aberrant proteins derived from alternative splicing and site mutation as well as translation from 5’UTR, long non-coding RNAs, and pseudogenes. In conclusion, we generated the first near-complete quantitative proteomic map for prostate cancer cells, which may guide the discovery of prostate cancer-specific protein biomarkers. Citation Format: Bo Zhou, Michael R. Freeman, Wei Yang. A high-resolution, quantitative proteomic map of human prostate cancer 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 LB-063.
Transplantation of HLA-Mismatched Stem Cell Transplantation without T Cell Depletion for the Treatment of Malignant Hematological Disease.
Authors: Xiao jun Huang, Daihong Liu, Kai Yan Liu, Lan ping Xu, Huan Chen, Wei Han, Yu Hong Chen, Jing zhi Wang, Zhi yong Gao, Yao Chen Zhang, Qian Jiang, Hong xia Shi, Dao pei Lu
Journal: Blood (2005)
T-cell receptor (TCR) repertoire in metastatic renal cell carcinoma (RCC) patients treated with first-line vascular endothelial growth factor receptor blockade.
Authors: Thai Huu Ho, Robert Charles Gagnon, Yuan Liu, F. Stephen Hodi, Sabina Signoretti, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2016)

501 Background: Reports have demonstrated an inverse relationship between suppression of immune surveillance mechanisms and activation of the vascular endothelial growth factor receptor (VEGFR) pathway suggesting that T cell repertoires may impact response to VEGFR blockade. We evaluated the association between clinical outcomes and T cell repertoire in metastatic RCC patients receiving a front-line anti-VEGFR, pazopanib. Methods: Pre-treatment RCC tumors were analyzed from VEG105192, a phase III study of mRCC patients randomized (2:1) to pazopanib (paz) 800 mg daily vs placebo (pbo) for TCR gamma (TCRG) and TCR beta (TCRB) CDR3 regions. Using the Adaptive Biotechnologies immunoSEQ Assay, we assessed TCR clonality, a measure of total repertoire represented by expanded clones, and entropy, a measure of evenness and diversity. PD-L1 was evaluated by immunohistochemistry (IHC) H-Scores. The goal of the study was to determine if the repertoire of T cell clones was associated with progression-free survival as a clinical endpoint. Results: In the cohort with available tissue, the median PFS was 10.8 and 5.5 months (mos) for paz and pbo, respectively. TCRB (n = 114) and TCRG (n = 43 pbo, 109 paz) clonality ranged from 0-0.31 and 0-0.98, and entropy from 1-12.1 and 0-10.37, respectively. TCRB and TCRG entropy were highly correlated (Spearman’s R = 0.92, n = 114). Samples from the pbo-treated group with higher TCRG entropy, defined as the top 25 th percentile, were associated with an improved median PFS (12.8 months) when compared to the lower 75 th percentile (3.1 months, P = 0.023); similar trends were seen for TCRB entropy. Neither entropy nor clonality was associated with maximal reduction in tumor volume in the paz-treated group. PD-L1 H-scores were not associated with entropy or clonality (P &gt; 0.05). Conclusions: Our data suggests that RCC samples with higher entropy are associated with a favorable prognosis. Identification of tumors with restricted TCRB/G chain usage and less diverse repertoire, as represented by lower entropy and higher clonality, may impact responses to VEGFR blockade and requires further study. Clinical trial information: NCT00334282.
Abstract 1142: E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma by promoting ubiquitination-mediated degradation of RARa
Authors: Qian Zhou, Meidan Ying, Bo Yang, Qiaojun He
Journal: Cancer Research (2016)

Abstract Objective: All-trans retinoic acid (ATRA) is a widely-used differentiation drug that can effectively induce osteogenic differentiation of osteosarcoma cells, but the underlying mechanism remains elusive, which limits the clinical application for ATRA in osteosarcoma patients. In this study, we identified E2F1 as a novel regulator involved in ATRA induced osteogenic differentiation of osteosarcoma cells. Methods: Osteosarcoma cell lines were used as our research models. (1) Protein levels were detected by Western blotting; (2) The interactions between E2F1 and RARalpha were determined by immunofluorescence, immunoprecipitation and GST pull-down assay; (3) The mRNA levels were determined by RT-PCR; (4) Related proteins and genes were investigated via transfection; (5) RARE activity were detected by luciferase reporter assay. (6) Alkaline phosphatase activity was assessed by colorimetric assay using BCIP/NBT Alkaline Phosphatase Color Development kit. Results: We observed that osteosarcoma cells are coupled with individual differences in the expression levels of E2F1 in patients, and E2F1 impairs ATRA-induced differentiation of osteosarcoma cells. Moreover, remarkable anti-proliferative and differentiation-inducing effects of ATRA treatment are only observed in E2F1 low to negative expressed primary osteosarcoma cultures. These results strongly suggested that E2F1 may serve as a potent indicator for the effectiveness of ATRA treatment in osteosarcoma. Interestingly, E2F1 is found to down-regulate retinoic acid receptor (RAR), a key factor determines the effectiveness of ATRA. E2F1 specifically binds to RAR and promotes its ubiquitination-mediated degradation; as a consequence, RAR-mediated differentiation is inhibited in osteosarcoma. Conclusion: E2F1 may serve as a potent biomarker as well as a therapeutic target for ATRA-based differentiation therapeutics, and raise the hope of using differentiation-based approaches for osteosarcoma patients. Citation Format: Qian Zhou, Meidan Ying, Bo Yang, Qiaojun He. E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma by promoting ubiquitination-mediated degradation of RARa. [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 1142.
Abstract 658: Elucidation of cellular origin of mouse intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion
Authors: Tsuneo Ikenoue, Yumi Terakado, Kiyoshi Yamaguchi, Yoichi Furukawa
Journal: Cancer Research (2016)

Abstract Regarding the carcinogenesis of intrahepatic cholangiocarcinoma (ICC), growing interest has been focused on its cellular origin, namely cholangiocytes, progenitor cells, or hepatocytes. We have recently established a novel mouse model of ICC by introducing liver-specific Kras activation and Pten deletion using Alb-Cre mice, in which Cre/loxP-mediated gene recombination was achieved in hepatoblasts and mature hepatocytes. To elucidate the cellular origin of ICC in this mouse model, we utilized hepatocyte or cholangiocyte-lineage specific gene engineering using a tamoxifen (TMX) inducible-Cre/loxP system. The mice carrying Kras activation and Pten deletion by Alb-CreERT2 mice with the TMX treatment at eight weeks of age developed hepatocellular carcinoma and hepatocyte dysplasia within three months. Fluorescence microscopy analyses disclosed that the Cre/loxP-mediated gene recombination was specifically observed in hepatocytes in the mice. In contrast, the mice carrying Kras activation and Pten deletion by Alb-CreERT2 mice at ten days of age induced ICC alone within two months. The gene recombination occurred in cholangiocytes as well as hepatocytes. Expectedly, ICCs were developed in the mice carrying cholangiocyte-specific Kras activation and Pten deletion by K19CreERT mice treated with TMX at 8 weeks after birth. TMX-induced, Cre/loxP-mediated recombination was achieved in epithelia of various organs including intrahepatic bile ducts in these mice. These results suggest that the cellular origin of ICC in mice carrying liver-specific Kras activation and Pten deletion was cholangiocytes but not hepatocytes. This mouse model should be useful for better understanding of human ICC of cholangiocyte-origin and the development of new therapeutic strategies for the disease. Citation Format: Tsuneo Ikenoue, Yumi Terakado, Kiyoshi Yamaguchi, Yoichi Furukawa. Elucidation of cellular origin of mouse intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion. [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 658.
Skin Cancer—The Importance of Prevention
Authors: Eleni Linos, Kenneth A. Katz, Graham A. Colditz
Journal: JAMA Internal Medicine (2016)

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Abstract 1408: Tumor-targeting Salmonella typhimurium A1-R promotes CD8+ T cell infiltration in pancreatic cancer in an orthotopic syngeneic mouse model
Authors: Takashi Murakami, Yukihiko Hiroshima, Yong Zhang, Ming Zhao, Tasuku Kiyuna, Ryusei Matsuyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman
Journal: Cancer Research (2016)

Abstract The effect of tumor-targeting Salmonella typhimurium A1-R on CD8+ cell infiltration was determined on Pan02 murine pancreatic adenocarcinoma cells implanted orthotopically on the pancreatic tail of C57BL/6 mice. Three weeks after orthotopic implantation, mice were randomized into G1: untreated control group (n = 8); and G2: Salmonella typhimurium A1-R treatment group (n = 8, 1 × 107 CFU/body, iv, weekly, 3 weeks). On the 22nd day from initial treatment, all mice were sacrificed and tumors were harvested. The tumor volume ratio was defined as ratio of tumor volume at the 1st day to the 22nd day. H&amp;E staining was performed to evaluate tumor destruction which was classified into 4 categories according to the Evans grading system: Grade I; 0-9% destruction, Grade IIA; 10-50% destruction, Grade IIB; 51-90% destruction, Grade III; few (&amp;lt;10%) viable cancer cells. Immunohistochemical staining using anti-mouse CD8+ antibody was performed to count tumor infiltrating CD8+ cells. The tumor volume ratio was significantly lower in G2 (3.0 ± 2.8) than G1 (39.9 ± 30.7, p &amp;lt; 0.01). Six mice in G1 had peritoneal dissemination whereas no mice showed peritoneal dissemination in G2 (p &amp;lt; 0.01). Significant tumor destruction was observed in G2 (Grade I: 0, Grade IIA: 1, Grade IIB: 6, Grade III: 1) compared to G1 (Grade I: 5, Grade IIA: 3, Grade IIB: 0, Grade III: 0, p &amp;lt; 0.01). Tumor infiltrating CD8+ cells per high-magnification field were significantly higher in G2 (133.5 ± 32.2) than G1 (45.1 ± 19.4, p &amp;lt; 0.001). Strong tumor destruction correlated with higher numbers of tumor-infiltrating CD8+ cells per high-magnification field (Grade I: 35.5 ± 18.3, Grade IIA: 77.3 ± 32.8 Grade IIB and III: 134.7 ± 34.8). The present study demonstrates that Salmonella typhimurium A1-R promotes CD8+ T cell infiltration in a syngeneic pancreatic cancer mouse model. Citation Format: Takashi Murakami, Yukihiko Hiroshima, Yong Zhang, Ming Zhao, Tasuku Kiyuna, Ryusei Matsuyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Tumor-targeting Salmonella typhimurium A1-R promotes CD8+ T cell infiltration in pancreatic cancer in an orthotopic syngeneic mouse 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 1408.
Abstract 2903: Nuclear localization of a secretion protein NAG-1/GDF15
Authors: Kyung-Won Min, Gabriel Silva, Seung J. Baek
Journal: Cancer Research (2016)

Abstract Nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1, also known as GDF15) is a divergent member of the transforming growth factor-beta (TGF-β) superfamily, which exert their biological activity by binding to membrane receptors as a secretion protein. Abnormal regulation of TGF-β signaling can contribute to various diseases such as cancer. Although there is sequence similarity between NAG-1 and other TGF-β superfamily members, NAG-1 does not bind to the TGF-β receptors; therefore the biological consequence of NAG-1 remains to be elucidated. Here, we report that NAG-1 has two putative non-canonical nuclear localization signals (NLSs) that mediate NAG-1 nuclear localization. Nuclear import assay shows that NAG-1 enters the nucleus through nuclear pore complex (NPC) in the presence of ATP, indicating nuclear entry of NAG-1 is active transport. Furthermore, we found the nuclear export signal (NES) recognized by CRM1 at near N-terminal region of NAG-1, that is conserved across various mammalian species. Impeding NES via chemical or genetic approaches promotes nuclear accumulation of NAG-1. We also found that nuclear NAG-1 dampens TGF-β-mediated cell migration and invasion via the inhibition of DNA binding of Smads complex. Overall, our data suggest that nuclear NAG-1 affects TGF-β-induced metastasis activity in cancer cells. Grant support: This work was supported by grant from the University of Tennessee Center of Excellence in Livestock Diseases and Human Health. K Min, Current address: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA Citation Format: Kyung-Won Min, Gabriel Silva, Seung J. Baek. Nuclear localization of a secretion protein NAG-1/GDF15. [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 2903.
Live tweeting: a tool for learning and reflection
Authors: Dermot G McGuckin
Journal: BMJ (2016)

Twitter, as discussed by Groves,1 is integral to the Social Media And Critical Care (SMACC) academic conference,2 where audience members tweet comments and questions directly to speakers. Several weeks after this year’s conference, held in Dublin in June, Twitter continues to stimulate international discussion, education, and reflection.

Live tweeting provides incredible potential for …
Abstract 1977: Interaction between long noncoding RNA EZR-AS1 and SMYD3 promotes EZR expression in ESCC cells
Authors: Xiaodan Zhang, Guo-Wei Huang, Lian-Di Liao, Lin Long, En-Min Liao, Li-Yan Xu
Journal: Cancer Research (2016)

Abstract EZR, a member of the ezrin-radixin-moesin (ERM) family, is involved in multiple aspects of cell migration by acting both as crosslinkers between the membrane, receptors and the actin cytoskeleton, and as regulators of signalling molecules that are implicated in cell adhesion, cell polarity and migration. SMYD3 (SET and MYND Domain-containing protein 3), an H3K4 histone methyltransferase, plays important roles in EZR gene transcription activity. However, the molecular mechanisms of how to recruit this epigenetic modifier to the EZR locus still remain ill-defined. In this study, we identify a natural antisense transcript (NAT) EZR antisense AS1 (EZR-AS1), which is transcribed from the opposite strand on the EZR gene locus, is involved in the SMYD3-mediated transcription of EZR. We find that EZR-AS1 is expressed in esophageal squamous cell carcinoma (ESCC) cells and is positive correlated with EZR expression in both ESCC cells and human ESCC tissues. Silenced EZR-AS1expression decreased EZR expression at both RNA and protein levels, resulting in an apparent inhibitory effect on cell motility. Overexpression of EZR in the EZR-AS1 depleted cells partly restored the mobility of cells. Through RNA-binding protein immunoprecipitation (RIP) assay and RNA pull down assay, we further demonstrate EZR-AS1 directly interacts with SMYD3, and it depends on an RNA/DNA hybrid formation. EZR-AS1 knockdown led to a significant decrease in both SMYD3 occupancy and histone H3K4me3 at the EZR promoter region, whereas EZR-AS1 overexpression results the opposite effects. Together, our results suggest a novel mechanism of interaction between a NAT EZR-AS1 and SMYD3 drives the EZR transcription in ESCC cells. Citation Format: Xiaodan Zhang, Guo-Wei Huang, Lian-Di Liao, Lin Long, En-Min Liao, Li-Yan Xu. Interaction between long noncoding RNA EZR-AS1 and SMYD3 promotes EZR expression in ESCC 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 1977.
Chronic disease outcomes after severe acute malnutrition in Malawian children (ChroSAM): a cohort study
Authors: Natasha Lelijveld, Andrew Seal, Jonathan C Wells, Jane Kirkby, Charles Opondo, Emmanuel Chimwezi, James Bunn, Robert Bandsma, Robert S Heyderman, Moffat J Nyirenda, Marko Kerac
Journal: The Lancet Global Health (2016)

Tackling severe acute malnutrition (SAM) is a global health priority. Heightened risk of non-communicable diseases (NCD) in children exposed to SAM at around 2 years of age is plausible in view of previously described consequences of other early nutritional insults. By applying developmental origins of health and disease (DOHaD) theory to this group, we aimed to explore the long-term effects of SAM.
Use of the NOD/SCID/γcnull Mouse Model To Assess the Hepatocyte-Producing Ability of Human Hematopoietic Cells.
Authors: Hisanori Fujino, Hidefumi Hiramatsu, Atsunori Tsuchiya, Haruyoshi Noma, Mitsutaka Shiota, Katsutsugu Umeda, Momoko Yoshimoto, Toshio Heike, Mamoru Ito, Tatsutoshi Nakahata
Journal: Blood (2005)