tbuckley/cabot-search huggingface dataset:
Abstract 5264: Selective toxicity of MX-106-4C, a survivin inhibitor, in P-glycoprotein-mediated multidrug resistant colon cancer
Authors: Zi-Ning Lei, Zhongzhi Wu, Qiu-Xu Teng, Min Xiao, Wei Li, John N. Wurpel, Zhe-Sheng Chen
Journal: Cancer Research (2020)

Abstract One of the major challenges in colon cancer chemotherapy is multidrug resistance (MDR), which is typically mediated by the overexpression of ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp, ABCB1, MDR1). A number of P-gp inhibitors have been developed, however, none of these compounds have improved chemotherapeutic efficacy due to undesirable pharmacokinetic profiles or adverse effects, resulting in limited clinical success. Therefore, alternative approaches are urgently needed to circumvent MDR cancer. In previous study, a series of synthesized analogs of MX-106, as anti-cancer drugs targeting survivin, exhibited collateral sensitivity (CS) effect to P-gp overexpressing MDR colon cancer cells as well as ABCB1 gene transfected cells, reflected by more than 10-fold cytotoxic effect in P-gp positive MDR cell lines compared to drug sensitive cell lines. Among the analogs, MX-106-4C was identified as the leading compound with the most potent selective toxicity to P-gp overexpressing cells. MX-106-4C-induced CS effect was observed in both intrinsic and acquired P-gp overexpressing colon cancer cells, which was only partially reversed with the presence of a P-gp inhibitor. Nevertheless, this CS effect was abolished in ABCB1-knockout cells, indicating that the selective cytotoxicity was P-gp expression dependent, but only partially related to P-gp function. Furthermore, we found that MX-106-4C did not significantly affect P-gp ATPase activity or drug accumulation and efflux in P-gp-overexpressing cells. In P-gp overexpressing colon cancer cells, short-term (up to 72 h) incubation of MX-106-4C significantly down regulated P-gp expression at transcriptional level but not protein level, whereas long-term (14 d) incubation of MX-106-4C significantly down regulated P-gp protein expression and re-sensitized MDR colon cancer cells to doxorubicin. These findings suggested an indirect interaction and regulation between MX-106-4C and P-gp. Further study revealed that the selective cytotoxic effects of MX-106-4C were associated with cell cycle arrest at G1 phase and apoptosis through the downregulation of CDK4. Overall, this study demonstrates that MX-106-4C selectively kills P-gp positive MDR colon cancer cells and indirectly regulates P-gp, which provides a clue for CS compound design and a novel strategy to obviate P-gp-mediated colon cancer MDR by re-sensitizing heterogeneous tumors with CS agents. Citation Format: Zi-Ning Lei, Zhongzhi Wu, Qiu-Xu Teng, Min Xiao, Wei Li, John N. Wurpel, Zhe-Sheng Chen. Selective toxicity of MX-106-4C, a survivin inhibitor, in P-glycoprotein-mediated multidrug resistant colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5264.
Abstract 6265: Combining arsenic and topoisomerase inhibitors synergistically inhibit gastric cancer
Authors: Ting Kang, Maolin Ge, Shumin Lu, Qing Wang, Shouhai Zhu, Chuanying Zhu, Leizhen Zheng, Han Liu, Siyu Chen
Journal: Cancer Research (2020)

Abstract Objectives: Arsenic compounds have cytotoxic activities in gastric cancer cells, however, the underlying mechanism is unclear and the clinical potential need to be explored. This study was aimed to investigate the mechanism of arsenic on gastric cancer and find a novel regimen for the treatment of gastric cancer. Methods: Gastric cancer cell lines were treated with arsenics and/or chemotherapeutic drugs. MTT assay, FACS, Western blotting, q-RT-PCR and CHIP were used to detect proliferation, modulation of proteins and genes. Results: We previously showed that NFATc3 was a target of Arsenic sulfide and its inhibition blocks gastric cancer growth. Here we show that the NFATc3 expression is critically important for the growth and survival of gastric cancer cells because knockdown of NFATc3 resulted in DNA damage and cell cycle arrest. Arsenic sulfide can target NFATc3 in gastric cancer cells and cause cell double-strand DNA breaks (DSB). However, overexpression of NFATc3 can block the DNA damage. Abolishing NFATc3 expression, whether by shRNA-induced silencing or Arsenic sulfide treatment, directly upregulated recombination activating gene 1 (RAG1, an endonuclease which is essential for immunoglobulin V(D)J recombination), leading to fatal DSB. NFATc3 targets the promoter of RAG1 for transcriptional inhibition. Moreover, we find that Arsenic sulfide and topoisomerase inhibitors (Irinotecan and Epirubicin, Doxorubicin, Etoposide and SN38) synergistically inhibit gastric cancer. Arsenic sulfide, as well as Arsenic Trioxide, enhanced the cytotoxic effect of Irinotecan and they synergistically induced NFATc3 degradation, resulted in disability of DNA repair system, as reflected by the decrease in the phosphorylated ATM/CHK2/CHK1 protein level and the dramatic increase in the phosphorylated H2AX protein level. More inspiring, a patient with advanced gastric cancer with liver and lymph-node metastasis who failed in first-line treatment achieved PR with 2 months treatment of Irinotecan combined with Realgar-Indigo Naturalis Formula, the main component of which is Arsenic sulfide. The progression-free survival was 4 months with no additional adverse event. Conclusions: Our research links arsenic compounds to the regulation of DNA damage repair and RAG1 expression as a mechanism for the cytotoxic effect. The combination of arsenic with topoisomerase inhibitors may represent a novel regimen for the treatment of gastric cancer and warrants further studies. Citation Format: Ting Kang, Maolin Ge, Shumin Lu, Qing Wang, Shouhai Zhu, Chuanying Zhu, Leizhen Zheng, Han Liu, Siyu Chen. Combining arsenic and topoisomerase inhibitors synergistically inhibit gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6265.
Abstract 5259: HSPA6 may be a new target by thyraquinone inhibiting migration and invasion of breast cancer cells
Authors: Shiyi Shen, Ting Xiao, Ju Zhou, Chunli Wei, Junjiang Fu
Journal: Cancer Research (2020)

Abstract Background and Objective: Breast cancer is the malignant tumor with the highest incidence and the second highest mortality among women, and the incidence of breast cancer in China is increasing year by year. The treatment of breast cancer includes radiotherapy, chemotherapy, endocrine therapy, biological targeted therapy and traditional Chinese medicine adjuvant therapy; but the efficacy still needs to be further improved to benefit the patients. Thymoquinone (TQ) is a key component of black grass seed oil and has anti-cancer properties in a variety of tumors. Preliminary studies in our laboratory demonstrated that TQ has a significant inhibitory effect on the migration and invasion of triple negative breast cancer cells. Methods: To find the new target genes for the inhibition of migration and invasion of breast cancer cells by TQ, RNA-sequencing (RNA-seq) was conducted with and without TQ in human breast cancer cell line BT-549 with high invasion and migration characteristics. Quantitative and semi-quantitative RT-PCR was used to further verify the genes regulated by TQ, and then Western Blotting was used to compare the changes of the genes regulated by TQ at the protein level. Finally, the molecular mechanism of TQ inhibiting migration and invasion of human breast cancer cells was investigated by increasing or decreasing the expression of these genes. Results: Eighteen differentially expressed genes, which were closely related to the carcinomas in the experimental group and the control group, were obtained by RNA-seq. HSPA6 gene changed significantly, and showed an up-regulation after adding TQ, which was consistent with the results of RNA-seq. By RT-PCR and Western Blotting from different cell lines (BT549, MCF-7, ZR-75-30, SiHa, Caski), we found that the expression of HSPA6 in the experimental group was higher than that in the control group. The subsequent TQ treatment after knockdown / over-expression will be completed for HSPA6 protein functional effects by TQ. Conclusion: HSPA6 may be a new target gene for TQ to inhibit the migration and invasion of breast cancer cells. The success of this study will provide a new candidate target for clinical treatment of breast cancer. Funding support: National Natural Science Foundation of China (Grant No. 81672887, 81172049) Citation Format: Shiyi Shen, Ting Xiao, Ju Zhou, Chunli Wei, Junjiang Fu. HSPA6 may be a new target by thyraquinone inhibiting migration and invasion of breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5259.
An Unexpectedly Complex Mitoribosome in <i>Andalucia godoyi</i>, a Protist with the Most Bacteria-like Mitochondrial Genome
Authors: Matus Valach, José Angel Gonzalez Alcazar, Matt Sarrasin, B Franz Lang, Michael W Gray, Gertraud Burger
Journal: Molecular Biology and Evolution (2020)

Abstract The mitoribosome, as known from studies in model organisms, deviates considerably from its ancestor, the bacterial ribosome. Deviations include substantial reduction of the mitochondrial ribosomal RNA (mt-rRNA) structure and acquisition of numerous mitochondrion-specific (M) mitoribosomal proteins (mtRPs). A broadly accepted view assumes that M-mtRPs compensate for structural destabilization of mt-rRNA resulting from its evolutionary remodeling. Since most experimental information on mitoribosome makeup comes from eukaryotes having derived mitochondrial genomes and mt-rRNAs, we tested this assumption by investigating the mitochondrial translation machinery of jakobids, a lineage of unicellular protists with the most bacteria-like mitochondrial genomes. We report here proteomics analyses of the Andalucia godoyi small mitoribosomal subunit and in silico transcriptomic and comparative genome analyses of four additional jakobids. Jakobids have mt-rRNA structures that minimally differ from their bacterial counterparts. Yet, with at least 31 small subunit and 44 large subunit mtRPs, the mitoriboproteome of Andalucia is essentially as complex as that in animals or fungi. Furthermore, the relatively high conservation of jakobid sequences has helped to clarify the identity of several mtRPs, previously considered to be lineage-specific, as divergent homologs of conserved M-mtRPs, notably mS22 and mL61. The coexistence of bacteria-like mt-rRNAs and a complex mitoriboproteome refutes the view that M-mtRPs were ancestrally recruited to stabilize deviations of mt-rRNA structural elements. We postulate instead that the numerous M-mtRPs acquired in the last eukaryotic common ancestor allowed mt-rRNAs to pursue a broad range of evolutionary trajectories across lineages: from dramatic reduction to acquisition of novel elements to structural conservatism.
Abstract 3094: Development of a prognostic and predictive 32 gene signature for gastric cancer
Authors: Sunho Park, Jae-Ho Cheong, Sam C. Wang, ChangJin Hong, Matthew Porembka, Tae Hyun Hwang
Journal: Cancer Research (2020)

Abstract Clinical staging at initial cancer diagnosis guides the use and timing of chemotherapy and radiation. However, current pretreatment stratification modalities for gastric cancer (GC) are inadequate and improved tools are needed. In addition, while adjuvant chemotherapy after surgery improves survival of resectable gastric cancer, few predictive biomarkers exist to select patients who might benefit from the current standard chemotherapy. To develop prognostic and/or predictive signatures that are clinically relevant for GC patients, we performed a pan-cancer analysis of somatic mutation of 6,681 patients with 19 different cancer types using the machine learning algorithm NTriPath and identified a 32-gene GC signature. To determine clinical utility of the 32-gene GC signature, we used expression of the 32-gene GC signature from 567 GC patients to discover genetic subtypes. We found that the 32-gene GC signature are prognostic and predictive of response to adjuvant 5-fluorouracil and platinum doublet and pembrolizumab. We further validated the preditive value of the 32-gene GC signature using an independent cohort with metastatic GC treated with Immune Checkpoint Blockades. Finally, we built a genetic-subtype based risk-scoring model to predict overall survival that was validated in three independent cohorts (n = 976). The risk score accurately predicted survival as a continuous function and was significantly associated with survival independent of TNM stage, age, tumor location and Lauren type. Taken together, the 32-gene driven genetic subtype and the genetic-subtype based risk score can guide the use of the current standard of care adjuvant chemotherapy regimen and/or immunotherapy for gastric cancer patients and should be confirmed in prospective clinical trials. Citation Format: Sunho Park, Jae-Ho Cheong, Sam C. Wang, ChangJin Hong, Matthew Porembka, Tae Hyun Hwang. Development of a prognostic and predictive 32 gene signature for gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3094.
Abstract 3938: Anti-angiogenic therapy combination with hypoxia-regulating agent leads to improved tumor regression in a murine model or renal carcinoma
Authors: Imane Nafia, Assia Chaibi, Doriane Bortolotto, Christophe Rey, Alban Bessede
Journal: Cancer Research (2020)

Abstract Background: While antiangiogenic therapies have been shown effective in preclinical and clinical trials, tumors can acquire resistance conferring them the ability to survive and grow under hypoxic conditions, even, induced by antiangiogenic drugs themselves. Methods: This study investigated the effects of an antiangiogenic strategy and hypoxia-regulating agent, each alone and in combination. Here, we have tested the synergistic activity of the anti-angiogenic agent Sunitinib and the mTOR inhibitor Everolimus in murine syngeneic renal cancer model - renal carcinoma being known as angiogenesis-dependent and hypoxia-driven malignancy. Anti-tumor effects were investigated on tumor growth and survival. Flow cytometry-based immunoprofiling was performed at the peripheral level - blood and spleen - while immunohistofluorescence and quantitative image analysis served to characterize and evaluate tumor immune cell infiltrate, tumor hypoxia, and tumor vascular density/features. Results: While Sunitinib and more importantly Everolimus led to a significant tumor growth inhibition as single agents, their combination was more effective on tumor regression. At the peripheral level, Sunitinib, but also Everolimus, led each to declines in circulating and splenic myeloid-derived suppressor cells (MDSCs) - depicted as CD11b+/Gr1+, an event that was further optimized upon combination of both agents. In addition, tumor sections analyses showed decreased microvessel density under Sunitinib and combination treatment. Differential modulations of correlative endothelium/pericytes staining and hypoxia degree were also observed upon the different treatments. This study confirms the preclinical efficacy of Sunitinib and a hypoxia regulator in renal tumor model and suggests that limitation of Sunitinib-induced hypoxia through mTOR targeting or with hypoxia regulators represents a suitable strategy to enhance effect of anti-angiogenic agent thereby limiting tumor growth. Citation Format: Imane Nafia, Assia Chaibi, Doriane Bortolotto, Christophe Rey, Alban Bessede. Anti-angiogenic therapy combination with hypoxia-regulating agent leads to improved tumor regression in a murine model or renal carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3938.
Abstract 5868: Cell barcoding, genetic screens and expression profiling at a single-cell level
Authors: Alex Chenchik, Mikhail Makhanov, Russell Darst, Debbie Deng, Donato Tedesco, Paul Diehl, Lester Kobzik
Journal: Cancer Research (2020)

Abstract Novel single-cell methods for profiling clonal composition and phenotypes of genetically modified cancer cells may improve understanding of tumorigenesis and guide the development of new anti-cancer drugs. To facilitate these studies, we developed a panel of lentiviral barcoded sgRNA libraries to label and monitor cancer cells in time-course experiments in vitro and in mouse xenograft models. The sgRNA effectors and cellular barcodes are transcribed from lentiviral constructs and can be detected by NGS in a single-cell RNA expression profiling assay, allowing characterization of the subpopulation of cells descended from a single, barcoded knockout progenitor cell. To scale up genetic analysis, cell barcodes were incorporated in conjunction with sgRNA effector libraries to identify clonal phenotypic changes induced by specific genetic disruptions in progeny cells derived from a single progenitor cell. However, effective single-cell genetic screening designed for even only a few hundred genes requires expression profiling of one hundred thousand cells (or more) and is not practical using currently available instrumentation. Data will be presented showing how genetic screen technology combined with targeted RNA expression profiling of barcoded knockout cells can be applied for large-scale genetic screens and significantly improve phenotyping of distinct cell populations in several cancer model systems. Preliminary studies demonstrate the assay to have unparalleled throughput, sensitivity, and improved cost-effectiveness for high-throughput drug target discovery applications. Citation Format: Alex Chenchik, Mikhail Makhanov, Russell Darst, Debbie Deng, Donato Tedesco, Paul Diehl, Lester Kobzik. Cell barcoding, genetic screens and expression profiling at a single-cell level [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5868.
Abstract 3961: Influence of hyaluronic acid in tumor microenvironment on glioblastoma (GBM) invasive behavior
Authors: Itay Solomon, Alireza Sohrabi, Stephanie K. Seidlits
Journal: Cancer Research (2020)

Abstract Glioblastoma invasion is mediated by distinct interactions between tumor cells and the extracellular matrix. Engineered biomaterial platforms allow for systemic examination of the influence of the microenvironment HA content on GBM cell activity. In this study, high molecular weight hyaluronic acid (700 kDa) was photopolymerized within three-dimensional (3D) polyethylene-glycol (PEG) hydrogels and patient-derived, primary GBM cell migration in the HA-hydrogels was investigated. Hydrogel polymerization conditions were tuned to achieve orthogonal control of HA content in a series of hydrogels (0.1 - 0.75 wt% HA) with conserved poroelastic properties (i.e. storage moduli and diffusivity). GBM cell migration was strongly influenced by microenvironment HA content. Knockdown of HA-dependent cell surface receptors (CD44 and RHAMM) modulated GBM cell activity. Our results demonstrate that alterations in microenvironment HA content and inhibition of HA-dependent signaling produced distinct molecular and phenotypic differences in GBM migratory behavior. These results demonstrate the differential effect of tumor microenvironment HA content on the invasive phenotype of GBM in a physiologically relevant 3D culture environment. Citation Format: Itay Solomon, Alireza Sohrabi, Stephanie K. Seidlits. Influence of hyaluronic acid in tumor microenvironment on glioblastoma (GBM) invasive behavior [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3961.
Fragmentation, Care Models, and Improving Outcomes in Inflammatory Bowel Disease
Authors: David I. Fudman, Jason K. Hou
Journal: JAMA Network Open (2020)

Shirley Cohen-Mekelburg, MD, MS; Sameer D. Saini, MD, MS; Sarah L. Krein, PhD; Timothy P. Hofer, MD, MSc; Beth I. Wallace, MD, MS; John M. Hollingsworth, MD; Julie P. W. Bynum, MD; Wyndy Wiitala, PhD; Jennifer Burns, MS; Peter D. R. Higgins, MD, PhD, MPH; Akbar K. Waljee, MD, MSc
Abstract 3571: Oxidative stress and the ovarian surface epithelium: TGF-β1 stimulation of IOSE cell lines reveals novel upregulation of NADPH oxidase 4, a membrane bound hydrogen peroxide producing enzyme
Authors: Jennifer L. Meitzler, Becky A. Diebold, Smitha Antony, Yongzhong Wu, Agnes Juhasz, Iris Dahan, Guojian Jiang, Jiamo Lu, Stephen Wang, Mariam M. Konaté, Krishnendu Roy, James H. Doroshow
Journal: Cancer Research (2020)

Abstract Normal ovarian surface epithelium (OSE) has been widely studied as the origin of ovarian cancer. Repetitive ovulation has been implicated in cancer initiation based on damage and inflammation incurred to the OSE upon continuous cycles of tear and repair. Transforming growth factor-beta (TGF-β) plays a role in this normal ovulatory cycle, having been shown to inhibit human OSE proliferation and induce apoptosis, which may prevent the over-proliferation of cells. NADPH oxidase 4 (NOX4), a membrane-associated hydrogen peroxide-producing enzyme, has previously been shown to be sensitive to TGF-β1, with increased expression stimulated in smooth muscle cells and fibroblasts. Here we describe for the first time TGF-β1 induced upregulation of NOX4 in immortalized OSE (IOSE) cells (IOSE121, IOSE144, IOSE364, IOSE386 and IOSE397). This time-dependent increased expression (&amp;gt;5 fold at 2 ng/ml TGF-β1, 24 h) was simulated by direct overexpression of NOX4 in IOSE397 cells and has demonstrated that increased NOX4, in the absence of further growth factor related effects, affords induction of p18 and p21. In addition, using immunohistochemical evaluation of human ovarian cancers in tissue microarrays (n=17 patients), we observed significantly increased expression of NOX4, suggesting that NOX4 upregulation may contribute to the malignant transformation of ovarian cells. Citation Format: Jennifer L. Meitzler, Becky A. Diebold, Smitha Antony, Yongzhong Wu, Agnes Juhasz, Iris Dahan, Guojian Jiang, Jiamo Lu, Stephen Wang, Mariam M. Konaté, Krishnendu Roy, James H. Doroshow. Oxidative stress and the ovarian surface epithelium: TGF-β1 stimulation of IOSE cell lines reveals novel upregulation of NADPH oxidase 4, a membrane bound hydrogen peroxide producing enzyme [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3571.