tbuckley/cabot-search huggingface dataset:
Abstract 1339: Development of a novel autophagy-inducing multikinase inhibitor for the treatment of castration-resistant prostate cancer
Authors: Yuanyuan Qiao
Journal: Cancer Research (2018)

Abstract Inhibition of the androgen axis has revolutionized the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC continues to be a leading cause of cancer-related deaths in men. Here, we characterized a phase I-cleared multikinase inhibitor, ESK981, in prostate cancer preclinical models. ESK981 was markedly more potent in vitro than other kinase inhibitors, including cabozantinib and crizotinib, that have been evaluated clinically in prostate cancer. Surprisingly, we observed that ESK981 was a potent inducer of cellular vacuolization that was associated with an autophagic response. ESK981-induced autophagy could be blocked by either the depletion of the autophagy vesicle formation gene, atg5, or by autophagy inhibitors such as bafilomycin. ESK981 was further shown to induce autophagy in yeast, which is an evolutionarily conserved core cellular pathway. Moreover, ESK981 triggered prostate cancer cells to release chemokines such as CXCL10 into the cell secretome, thus suggesting that ESK981 may stimulate immune surveillance while exerting its tumor inhibitory effect. Together, ESK981 is a novel and potent autophagy-inducing multikinase inhibitor that effectively inhibits CRPC growth through the activation of the autophagic cascade. Citation Format: Yuanyuan Qiao. Development of a novel autophagy-inducing multikinase inhibitor for the treatment of castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1339.
Dynorphin B Is an Agonist of Nuclear Opioid Receptors Coupling Nuclear Protein Kinase C Activation to the Transcription of Cardiogenic Genes in GTR1 Embryonic Stem Cells
Authors: CarloVentura, ElisabettaZinellu, EmilianaManinchedda, MargheritaMaioli
Journal: Circulation Research (2003)

The cardiac differentiation of embryonic stem (ES) cells was found to involve prodynorphin gene and dynorphin B expression and was associated with the interaction of secreted dynorphin B with cell surface opioid receptors coupled with protein kinase C (PKC) signaling and complex subcellular redistribution patterning of selected PKC isozymes. Here, confocal microscopy revealed the presence of immunoreactive dynorphin B–like material in GTR1 ES cells, suggesting that dynorphin peptides may also act intracellularly. Opioid binding sites were identified in ES cell nuclei, with a single dissociation constant in the low nanomolar range. A significant increase in Bmax for a κ opioid receptor ligand was observed in nuclei isolated from ES-derived cardiomyocytes compared with nuclei from undifferentiated cells. Direct exposure of nuclei isolated from undifferentiated ES cells to dynorphin B or U-50,488H, a synthetic κ opioid receptor agonist, time- and dose-dependently activated the transcription of GATA-4 and Nkx...
Optimal conditioning regimen for haplo-identical stem cell transplantation in adult patients with acquired severe aplastic anemia: Prospective de-escalation study of TBI and ATG dose
Authors: Sung‐Eun Lee, Sung Soo Park, Young‐Woo Jeon, Jae‐Ho Yoon, Byung‐Sik Cho, Ki‐Seong Eom, Yoo‐Jin Kim, Seok Lee, Chang‐Ki Min, Hee‐Je Kim, Seok‐Goo Cho, Dong‐Wook Kim, Jong Wook Lee
Journal: American Journal of Hematology (2018)

This prospective study explored an optimal conditioning regimen to ensure engraftment with minimal toxicity in adult patients with severe aplastic anemia (SAA) who received haplo-identical stem cell transplantation from a related mismatched donor (Haplo-SCT). We explored a safe and sufficient dose of rabbit ATG (Thymoglobulin) in combination with 800 cGy total body irradiation (TBI) and fludarabine (Flu, 30 mg/m2 /day) for 5 days using step-by-step dose de-escalation. The dose of ATG was de-escalated from 10 mg/kg (group 1), to 7.5 mg/kg (group 2), to 5 mg/kg (group 3), and the TBI dose was reduced to 600 cGy (group 4) beginning in October 2014. If one patient developed transplant-related mortality (TRM) with engraftment in a group, we moved to the next lower dose group. Thirty-four patients were enrolled in groups 1-3 (n = 10) and 4 (n = 24). All patients achieved primary engraftment. The incidence of acute GVHD (grade ≥ 2) and chronic GVHD (≥ moderate) was 29.4% and 14.7%, respectively. With a median follow-up of 56.6 and 21.8 months in groups 1-3 and group 4, respectively, the 2-year probability of overall survival (91.7% in group 4 vs 70% in groups 1-3, P = 0.155) and GVHD-free survival (78.4% in group 4 vs 50% in groups 1-3, P = 0.115) was shown tended to be better in group 4. This study explored an optimal conditioning with step-by-step de-escalation dosage of ATG and TBI to reduce TRM with sustained graft function. TBI-600 cGy/Flu/intermediate-dose ATG resulted in feasible outcomes of Haplo-SCT for adult patients with SAA.
Abstract 4551: Thyroid hormone induces PD-L1 expression in oral cancer cells
Authors: Yu-Tang Chin, Kwan-Wei Su, Yee-Tang Lim, Ya-Jung Shih, Yi-Ru Chen, Sheng-Yang Lee, Paul J. Davis, Hung-Yun Lin, Earl Fu
Journal: Cancer Research (2018)

Abstract Oral cancer is a fatal disease, which accounts for the fourth highest incidence of malignancy in males and the seventh highest in the general population of Taiwan. Oral cancer is increasing in Taiwan. About 95% of oral cancer in Taiwan is oral squamous cell carcinoma (OSCC). With the development of cancer molecular biology and immunology, targeted therapy for immune checkpoints of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has shown enormous development prospects for treatment of head and neck cancer. The PD-1/PD-L1 checkpoint is a critical regulator of activated T cell-cancer cell interactions which defend tumor cells against immune surveillance. Thyroid hormone induces PD-L1 expression in human oral cancer cells. Human oral cancer OEC-M1 and SCC-25 cells were treated with different concentrations of T4 (10-8 to 10-6M) for 24 h and cells were harvested and total RNA was extracted. qPCR of PD-L1 revealed that PD-L1 mRNA was significantly induced by thyroid hormone on a concentration-dependent basis. Parallel studies were conducted to study the effect of thyroid hormone on PD-L1 protein accumulation. Cancer cells were treated with different concentrations of T4 for 24 h. Total proteins were extracted and western blot analysis of PD-L1 was conducted. Thyroid hormone-activated ERK1/2 and STAT3 were companied with PD-L1 expression. Inhibition of ERK1/2 and consequently STAT3 activation also blocked PD-L1 induced by thyroid hormone. Knockdown of PD-L1 expression by siRNA also inhibits thyroid hormone-induced proliferation of oral cancer cells which indicated that PD-L1 expression is involved in thyroid hormone-induced cancer growth via an ERK1/2-STAT3 signal transduction pathway in oral cancer cells. Citation Format: Yu-Tang Chin, Kwan-Wei Su, Yee-Tang Lim, Ya-Jung Shih, Yi-Ru Chen, Sheng-Yang Lee, Paul J. Davis, Hung-Yun Lin, Earl Fu. Thyroid hormone induces PD-L1 expression in oral cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4551.
Abstract 1953: Expression and activity of MT1-MMP in endothelial cells is regulated by Semaphorin 4D
Authors: Amr Bugshan, Zaid Khoury, Asma Buhamrah, John R. Basile
Journal: Cancer Research (2018)

Abstract The semaphorins and plexins, originally shown to control axon growth cone guidance, are now known to influence many aspects of cell adhesion and migration. Our group and others have demonstrated that carcinomas over express Semaphorin 4D (S4D), particularly under conditions of hypoxia, for the purpose of supporting tumor-induced angiogenesis. However, S4D is a transmembrane protein that must be proteolytically cleaved to attract endothelial cells into a malignancy, a process that in head and neck squamous cell carcinoma (HNSCC) is controlled by membrane type 1-matrix metalloproteinase (MT1-MMP). We wanted to test the possibility that S4D acts through its receptor, Plexin-B1 (PB1), to enhance activity of endothelial cell MT1-MMP, facilitating extracellular matrix degradation and further promoting angiogenesis. We observed upregulated transcription, expression and cell surface localization of MT1-MMP in endothelial cells treated with S4D, occurring in a PB1, RhoA and NF-κB-dependent manner. We also demonstrated that S4D-induced endothelial cell collagen degradation, migration and capillary tube formation are suppressed when PB1 is silenced or its downstream effectors RhoA and NF-κB are inhibited. Endothelial MT1-MMP contributes to the ability of these cells to digest their way through the basement membrane and extracellular matrix, a requirement for the creation of the vascular networks that supply a developing tumor with oxygen and nutrients and allow it access to the systemic circulation for metastasis. These results demonstrate that S4D promotes angiogenesis at multiple levels, and suggest that it would be a valid target for anti-angiogenic intervention in the treatment of solid malignancies. Citation Format: Amr Bugshan, Zaid Khoury, Asma Buhamrah, John R. Basile. Expression and activity of MT1-MMP in endothelial cells is regulated by Semaphorin 4D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1953.
Abstract 3292: Revisiting TCGA data identifies key genes in lung adenocarcinoma
Authors: Jianxiang Shi, Mengtao Xing, Chenglin Luo, Xiao Wang, Liping Dai, Jianying Zhang
Journal: Cancer Research (2018)

Abstract Although the incidence rate of lung cancer has declined over the past few years, it remains the leading cause of cancer death worldwide. The Cancer Genome Atlas has provided invaluable resources for cancer research. The development of next generation sequencing technology and evolution of data analysis tools make it possible to interpret the underlying mechanism of oncogenesis. In current study, normalized FPKM data from 572 samples derived from patients with lung adenocarcinoma (LUAD) from TCGA was used to do weighted gene co-expression network analysis (WGCNA) to identify gene modules associated with lung adenocarcinoma. Raw counts data was used to identify differentially expressed genes in LUAD by using DESeq2 in R (version 3.4.2). WGCNA results shows that magenta (r = 0.47, p &amp;lt;0.001)), black (r = 0.40, p &amp;lt;0.001)) and yellow (r = -0.88, p &amp;lt;0.001) modules are top 3 modules that associated with LUAD and cancer stage. Gene Ontology over-representation analysis shows that genes in magenta modules are involved with transcript elongation; genes in black modules are enriched in cell meiosis related biological processes, including chromosome segregation, nuclear division, DNA replication and mitotic nuclear division et al; genes in yellow module are enriched in angiogenesis, leukocyte migration and hemostasis. It is noteworthy that genes in magenta and black modules are upregulated and in yellow modules are downregulated. GOLM1 and MUC4 in magenta module play certain roles in cancer development. Several genes in MEGA family, including MAGEA3, MAGEA6, MEGEA16 and MEGEA1, and IGF2BP1 in black module have been reported to be overexpressed in various kinds of tumors. However, whether these in silicon discovered genes can be used to distinguish LUAD from controls still needs to be further evaluated. Keywords: lung adenocarcinoma; TCGA; gene expression analysis; bioinformatics; cancer biomarker Citation Format: Jianxiang Shi, Mengtao Xing, Chenglin Luo, Xiao Wang, Liping Dai, Jianying Zhang. Revisiting TCGA data identifies key genes in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3292.
Abstract 20182: Lymphatic System Mediated With Astrocytic Aquaporin 4 is Associated With Sympathoexcitation in Hypertension
Authors: Takuya Kishi, Keita Saku, Kenji Sunagawa, Hiroyuki Tsutsui
Journal: Circulation (2017)

Introduction: Cerebrospinal fluid (CSF) is transported within a dedicated peri-vascular network facilitating metabolic waste clearance from the central nervous system. A peri-arterial CSF influx pa...
Abstract LB-338: SHP2 inhibition enhances sensitivity to MEK inhibitors in multiple resistant cancer models
Authors: Carmine Fedele, Kwan Ho Tang, Hao Ran, Wei Wei, Brian Diskin, George Miller, Benjamin G. Neel
Journal: Cancer Research (2018)

Abstract Targeting tumors with kinase inhibitors induces complex adaptive programs that enable the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. Most tumors developing resistance to MEK inhibitors upregulate and/or activation of at least one of several different receptor tyrosine kinases (RTKs), which drive resistance. Notably, different RTKs or RTK combinations are upregulated in different cancer cells, even those from the same histotype. SHP2 (encoded by PTPN11) is required for RAS/ERK pathway activation downstream of most RTKs, suggesting that it might provide a common targetable resistance node in multiple resistant cancer cell lines. We show that the addition of a newly identified SHP2 inhibitor, SHP099, to MEK therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cancer models in vitro and in vivo. These effects occurred in a wide range of malignancies, including KRAS mutant pancreas, lung cancer, triple negative breast cancer, and serous ovarian cancer cell lines, as well as in PDX and GEMM models. SHP099 effects were overcome by expressing an SHP2 mutant that loses drug binding but retain catalytic activity and regulation, demonstrating that on target effects of the inhibitor. Mechanistic studies across multiple cellular cancer models suggest that SHP2 inhibition by SHP099 prevents the compensatory RAS and ERK1/2 reactivation in response to MEK therapy and impedes the engagement of the ERK1/2 transcriptional programs (i.e., MYC, ETV1, FOSL1, etc.) and signaling outputs that characterize the drug-tolerant state. Combining full doses of MEK inhibitors and SHP099 causes significant toxicity in mice, but non-toxic, efficacious dosing regimens can be achieved. Our findings suggest that SHP099, in combination with MEK inhibition is a promising therapeutic strategy for enhancing the effectiveness of targeted therapies. Citation Format: Carmine Fedele, Kwan Ho Tang, Hao Ran, Wei Wei, Brian Diskin, George Miller, Benjamin G. Neel. SHP2 inhibition enhances sensitivity to MEK inhibitors in multiple resistant cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-338.
Nitric Oxide Activity Is Deficient in Spasm Arteries of Patients With Coronary Spastic Angina
Authors: KiyotakaKugiyama, HirofumiYasue, KenOkumura, HisaoOgawa, KazuteruFujimoto, KoichiNakao, MichihiroYoshimura, TakeshiMotoyama, YoshitoInobe, HiroakiKawano
Journal: Circulation (1996)

Background Coronary spasm can be induced by acetylcholine, serotonin, ergonovine, or histamine, all of which cause vasodilation when the endothelium is intact by releasing nitric oxide (NO). Coronary spasm is promptly relieved by nitroglycerin, which vasodilates through its conversion to NO. It is thus possible that NO release may be deficient in the spasm arteries in patients with coronary spastic angina (CSA). The aim of this study was to determine whether NO release is deficient in coronary arteries of patients with CSA. Methods and ResultsNG-monomethyl-l-arginine (L-NMMA), an inhibitor of NO synthase, was infused into coronary arteries in 21 patients with coronary spastic angina (CSA) and in 28 control patients. Coronary spasm was induced by intracoronary injection of acetylcholine and was documented angiographically in all patients with CSA. L-NMMA dose-dependently decreased basal luminal diameter of coronary arteries in control patients, whereas it had no effect on basal diameter of the spasm arteri...
Coalescent Analysis of Phylogenomic Data Confidently Resolves the Species Relationships in the Anopheles gambiae Species Complex
Authors: Yuttapong Thawornwattana, Daniel Dalquen, Ziheng Yang
Journal: Molecular Biology and Evolution (2018)

Deep coalescence and introgression make it challenging to infer phylogenetic relationships among closely related species that arose through radiative speciation events. Despite numerous phylogenetic analyses and the availability of whole genomes, the phylogeny in the Anopheles gambiae species complex has not been confidently resolved. Here we extract over 80, 000 coding and noncoding short segments (called loci) from the genomes of six members of the species complex and use a Bayesian method under the multispecies coalescent model to infer the species tree, which takes into account genealogical heterogeneity across the genome and uncertainty in the gene trees. We obtained a robust estimate of the species tree from the distal region of the X chromosome: (A. merus, ((A. melas, (A. arabiensis, A. quadriannulatus)), (A. gambiae, A. coluzzii))), with A. merus to be the earliest branching species. This species tree agrees with the chromosome inversion phylogeny and provides a parsimonious interpretation of inversion and introgression events. Simulation informed by the real data suggest that the coalescent approach is reliable while the sliding-window analysis used in a previous phylogenomic study generates artifactual species trees. Likelihood ratio test of gene flow revealed strong evidence of autosomal introgression from A. arabiensis into A. gambiae (at the average rate of ∼0.2 migrants per generation), but not in the opposite direction, and introgression of the 3 L chromosomal region from A. merus into A. quadriannulatus. Our results highlight the importance of accommodating incomplete lineage sorting and introgression in phylogenomic analyses of species that arose through recent radiative speciation events.
Abstract 2493: Inactivation of ARID1A-SWI/SNF complex alters chromatin compactness at enhancer regions and affects transcription of key tumor signaling circuitry
Authors: Yohan Suryo Rahmanto, Xu Shi, Wenjing Shen, Tsutomu Miyamoto, Yu Yu, Xi Chen, Meng-Horng Lee, Vivek Singh, Michele I. Vitolo, Denis Wirtz, Ronny Drapkin, Jianhua Xuan, Ie-Ming Shih, Tian-Li Wang
Journal: Cancer Research (2018)

Abstract Somatic mutations in ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human cancer and represent an emerging mechanism by which a molecular genetic alteration reprograms epigenomes and propels tumorigenesis. Through comprehensive sequencing of chromatin immunoprecipitation and chromatin accessibility, we found chromatin binding regions for ARID1A/BRG1-containing SWI/SNF remodeling complexes, which were enriched at enhancers and corresponded to euchromatin state. ARID1A deletion caused global re-distribution of BRG1-containing complexes in chromatin. Integrative analyses of ATAC-seq, ChIP-seq, and transcriptome data obtained from endometrial epithelium and human endometrioid carcinomas identified high-confidence ARID1A-regulated genes that participate in myriad key tumor and developmental signaling circuitry tissue. Deletion of Arid1a was found to inactivate the TGF-β pathway and to accelerate tumor progression from pre-cancerous lesions to endometrioid carcinomas. This study provides compelling evidence that Arid1a loss is required for developing endometrial cancer from its precursor. Collectively, targeting epigenomic modifications may hold promise for suppressing invasive behaviors of neoplasms carrying ARID1A mutations. Citation Format: Yohan Suryo Rahmanto, Xu Shi, Wenjing Shen, Tsutomu Miyamoto, Yu Yu, Xi Chen, Meng-Horng Lee, Vivek Singh, Michele I. Vitolo, Denis Wirtz, Ronny Drapkin, Jianhua Xuan, Ie-Ming Shih, Tian-Li Wang. Inactivation of ARID1A-SWI/SNF complex alters chromatin compactness at enhancer regions and affects transcription of key tumor signaling circuitry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2493.
The potential for clinical translation of antibody-targeted nanoparticles in the treatment of acute myeloid leukaemia
Authors: Jianfeng Guo, Xue Luan, Zhongcheng Cong, Yao Sun, Limei Wang, Sharon L. McKenna, Mary R. Cahill, Caitriona M. O'Driscoll
Journal: Journal of Controlled Release (2018)
Abstract 5500: Nitric oxide donor DETA/NO inhibits the growth of endometrial cancer cells by upregulating expression of RASSF1 and CDKN1
Authors: Hannah Taitz, Ana Paucarmayta, Robert Cheng, George L. Maxwell, Chad A. Hamilton, David A. Wink, Viqar Syed
Journal: Cancer Research (2018)

Abstract Nitric oxide (NO), a small signaling molecule, is implicated in several biological processes including cancer progression. At low concentrations, it promotes cell survival and tumor progression, and at high concentrations it causes apoptosis and cell death. To date, the effects of NO donor on human endometrial cancer are largely unknown. Four endometrial cancer cell lines (Ishikawa, AN3CA, KLE and HEC-1B) with varying degrees of genetic complexity were treated with different concentrations (50-500 μM) of DETA/NO for 24 to 120 h. The effects of treatment on cell viability and invasion was determined using MTS, and Boyden chamber assays respectively. Treatment of endometrial cancer cells with DETA/NO induced a dose and time-dependent decrease in cell viability. Ishikawa and AN3CA cells were more responsive to DETA/NO induced growth inhibition compared to HEC-1B and KLE cells. Furthermore, DETA/NO effectively inhibited invasive potential of endometrial cancer cells. To understand the mechanisms by which DETA/NO elicits anti-cancer effects, RNA sequencing (RNA-seq) was used to ascertain alterations in the transcriptomes of human endometrial cancer cells. AN3CA, KLE, Ishikawa, and HEC-1B were treated with DETA/NO for 24 h and RNA was extracted. RNA-seq analysis revealed that of the twenty-one top differentially expressed genes, fourteen were upregulated and seven were downregulated in endometrial cancer cells with DETA/NO. The genes that were upregulated in all four cell lines with DETA/NO were tumor suppressors, RASSF1 and CDKN1A. The expression patterns of these genes were confirmed by Western blotting. Taken together, the results provide the first evidence in support of the anti-cancer effects of DETA/NO in endometrial cancer. Citation Format: Hannah Taitz, Ana Paucarmayta, Robert Cheng, George L. Maxwell, Chad A. Hamilton, David A. Wink, Viqar Syed. Nitric oxide donor DETA/NO inhibits the growth of endometrial cancer cells by upregulating expression of RASSF1 and CDKN1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5500.