tbuckley/cabot-search huggingface dataset:
Mucosal microbiome dysbiosis in gastric carcinogenesis
Authors: Olabisi Oluwabukola Coker, Zhenwei Dai, Yongzhan Nie, Guijun Zhao, Lei Cao, Geicho Nakatsu, William KK Wu, Sunny Hei Wong, Zigui Chen, Joseph J Y Sung, Jun Yu
Journal: Gut (2017)

Objectives We aimed to characterise the microbial changes associated with histological stages of gastric tumourigenesis. Design We performed 16S rRNA gene analysis of gastric mucosal samples from 81 cases including superficial gastritis (SG), atrophic gastritis (AG), intestinal metaplasia (IM) and gastric cancer (GC) from Xi’an, China, to determine mucosal microbiome dysbiosis across stages of GC. We validated the results in mucosal samples of 126 cases from Inner Mongolia, China. Results We observed significant mucosa microbial dysbiosis in IM and GC subjects, with significant enrichment of 21 and depletion of 10 bacterial taxa in GC compared with SG (q&lt;0.05). Microbial network analysis showed increasing correlation strengths among them with disease progression (p&lt;0.001). Five GC-enriched bacterial taxa whose species identifications correspond to Peptostreptococcus stomatis , Streptococcus anginosus , Parvimonas micra , Slackia exigua and Dialister pneumosintes had significant centralities in the GC ecological network (p&lt;0.05) and classified GC from SG with an area under the receiver-operating curve (AUC) of 0.82. Moreover, stronger interactions among gastric microbes were observed in Helicobacter pylori -negative samples compared with H. pylori -positive samples in SG and IM. The fold changes of selected bacteria, and strengths of their interactions were successfully validated in the Inner Mongolian cohort, in which the five bacterial markers distinguished GC from SG with an AUC of 0.81. Conclusions In addition to microbial compositional changes, we identified differences in bacterial interactions across stages of gastric carcinogenesis. The significant enrichments and network centralities suggest potentially important roles of P. stomatis , D. pneumosintes , S. exigua , P. micra and S. anginosus in GC progression.
Abstract 6: New chk1 inhibitor development &amp; the feasibility of use of chk1 inhibitor with antimetabolite for NSCLC
Authors: Injae Chung
Journal: Cancer Research (2017)

Abstract DNA damaging anticancer agents activate checkpoints that stop the cell cycle to prevent additional DNA replication &amp; mitosis until damaged region has been repaired. One of the important regulatory proteins activated in DNA damage response pathway is Checkpoint kinase 1 (Chk1). Therefore, Chk1 inhibitors have emerged as promising new therapeutics for cancer. In order to find novel Chk1 inhibitor, we have conducted a structure based virtual screening. Several small molecules have shown 75 - 100 % inhibition of Chk1 in the binding affinity assay. Combined with the results of kinase assay with ATP &amp; mechanism based cell assay, hit candidates has been led. Lung cancer is the leading cause of cancer related deaths in Korea. About 85 % of lung cancer is non-small cell lung carcinoma (NSCLC) worldwide. Chemotherapy for NSCLC is often regarded ineffective. To test the feasibility of Chk1 inhibitor to sensitize antimetabolite in NSCLC, growth inhibition induced by gemcitabine plus MK8776 was assessed in A549 &amp; H1129 cells. These cells are insensitive to the MK8776 when treated as a single agent (IC50 &amp;gt;10 μM). In contrast, MK8776 reduced the concentration of gemcitabine required to inhibit H1299 or A540 cell growth by almost 3-30 fold or 6-15 fold, respectively, depending on the concentration used. These results would imply the potential clinical utility of Chk1 inhibitor as an adjuvant for antimetabolite such as gemcitabine for NSCLC. Further studies to evaluate the effectiveness of Chk1 inhibitor including new molecules would be warranted in additional preclinical and clinical settings. [The chemical library used in this study was kindly provided by Korea Chemical Bank &amp; KIST. This study was supported by a grant (2015R1D1A1A01057014) from the National Research Foundation of Korea.] Citation Format: Injae Chung. New chk1 inhibitor development &amp; the feasibility of use of chk1 inhibitor with antimetabolite for NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 6. doi:10.1158/1538-7445.AM2017-6
Abstract 2214: Adaptive dynamic artificial polyligand targeting (ADAPT): a method to identify exosomal proteins from a prostate cancer cell line
Authors: Tassilo Hornung, Stephen Logie, Aniket S. Bondre, Varun Maher, Melissa N. Richards, Jelena Zarkovic, Teresa T. Tinder, Heather A. O'Neill, Mark R. Miglarese, David B. Spetzler
Journal: Cancer Research (2017)

Abstract In the recent years it was demonstrated that a multitude of body fluids contains substantial amounts of exosomes, extracellular vesicles with sizes ranging between 40 and 100 nm. Those vesicles have protein profiles characteristic of their cells of origin. It was shown that exosomes play a role in cell-to-cell communication making them attractive targets to identify early disease stage biomarkers. Cancer heterogeneity is known for a long time to be an important clinical determinant of patient outcome. We developed the highly multiplexed ADAPT platform to capture systems-based biological signatures that may reflect the molecular heterogeneity of various cancer types and help to improve diagnosis of the disease. Exosomes from two prostate cancer cell lines, VCaP and LNCaP, were used to train ssDNA libraries to discriminate them. A highly diverse library of 1012 oligonucleotides (ODNs) was subjected to five rounds of positive and negative selection against exosomes from VCaP and LNCaP prostate cancer cell lines. Individual ODNs that bound preferably to exosomes from VCaP cells were identified by NGS, resynthesized and binding of co-precipitated ODNs to VCaP exosomes was verified by qPCR. LC-MS/MS was used to identify binding partners of ODNs bound to VCaP exosomes. Several of those binding partners (CHMP1b/2a/4b, VPS28, Syntenin-1) were found to be part of the ESCRT machinery, which participates in exosomes biogenesis. It was found that those proteins are overexpressed in human cancers. In addition, we identified the chemokine I-TAC, which is overexpressed in blood and tissue of men with advanced prostate adenocarcinomas. Finally, we found hnRNP-1, a cancer associated splicing factor, and the cold shock proteins RNPL and A18 hnRNP. Knock-down of these cold shock proteins has been shown to enhance chemotherapeutic cell killing of prostate cells. ADAPT is an unbiased profiling platform that identifies cancer associated proteins expressed on exosomes. This platform can be deployed against multiple cancer types and offers broad potential applications in biomarker discovery. Citation Format: Tassilo Hornung, Stephen Logie, Aniket S. Bondre, Varun Maher, Melissa N. Richards, Jelena Zarkovic, Teresa T. Tinder, Heather A. O'Neill, Mark R. Miglarese, David B. Spetzler. Adaptive dynamic artificial polyligand targeting (ADAPT): a method to identify exosomal proteins from a prostate cancer cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2214. doi:10.1158/1538-7445.AM2017-2214
Abstract 1190: Comprehensive high-throughput screen for combination therapies to block acquired resistance to targeted drugs
Authors: Izhak Haviv
Journal: Cancer Research (2017)

Abstract Background - Genetic and epigenetic alterations provide the selective advantage for cancer cell acquired drug resistant (ADR). A bottleneck in implementing drug combination is the challenging task of identifying combinations with acceptable risk benefit ratio. High throughput functional genomic (RNAi) screen is an ideal tool to comprehensively identify double and triple inhibitor combinations to prevent ADR. Unfortunately, most anticancer agents are antagonists (antagonists operate in the same direction as the RNAi), therefore RNAi hits with possible clinical value are the ones that disappear during the screen. Materials and Methods - We use lentiviral-borne shRNA libraries (mainly kinome collection) to transduce the different RNAis into patient-derived cancer cells. The resulting mixed cancer cell population (each lost one gene) is subject to negative screen, to identify mediators of ADR. This process was performed with approved cancer drugs, such as erlotinib, olaparib, pazopanib, etc. We developed a proprietary unique way to identify the RNAi clones that disappear/extinct, specifically in the presence of the investigated drug. RNAi clones are tracked using next generation sequencing, and quantified in treated and untreated cancer cell cultures or xenografts. The resulting drug combinations identified through this screen are tested directly on a platform of patient-derived xenografts. Results - We identified known boosters of the EGFR activity, such as DYRK1 (maintains level of EGFR protein), IKBKE (downstream survival mediator), which when reduced by their RNAi, enhance the response to erlotinib. Consequently, known inhibitors of JAK1, CDK4/6, and PI3K combined to egfr inhibitors generated more durable remissions in egfr positive cells. Remarkably, even tumors without egfr mutations were sensitive to the combinations. A similar discovery of novel combinations were found for olaparib and pazopanib. Mouse harboring patient derived xenografts tolerated combination therapy fairly well. Conclusion - Our findings demonstrate the value of clinically testing the efficacy of drug combinations empirically designed to block ADR. Animal model support our findings with acceptable toxicity. Citation Format: Izhak Haviv. Comprehensive high-throughput screen for combination therapies to block acquired resistance to targeted drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1190. doi:10.1158/1538-7445.AM2017-1190
Abstract 3395: Alternative splicing of the MEAF6 gene promotes neuroendocrine prostate cancer development
Authors: Ahn R. Lee, Yinan Li, Ning Xie, Colin C. Collins, Xuesen Dong
Journal: Cancer Research (2017)

Abstract In response to the selection pressures exerted by potent androgen receptor (AR) pathway inhibitors (ARPI), adenocarcinoma prostate cancer (PCa) cells can undergo an adaptive process of cellular phenotype reprogramming termed neuroendocrine trans-differentiation. With this AR-bypass mechanism of survival emerges a lethal treatment-resistant PCa subtype called treatment-induced neuroendocrine PCa (t-NEPC). t-NEPC is becoming a major clinical issue as it is estimated to affect &amp;gt;25% of advanced-stage PCa patients with the level of incidences predicted to rise as a result of the extensive applications of ARPI in the clinic. This underscores the gravity of our aims to delineate the molecular underpinnings of t-NEPC to inform future therapies that prevent or mitigate t-NEPC development. In this study, we have identified a splice variant of the MYST/Esa1-associated factor 6 (MEAF6) gene, MEAF6-1, that is highly expressed in t-NEPC tumor biopsies as well as neuroendocrine cell lines of prostate and lung cancers. We show that the neuronal RNA splicing factor, SRRM4, stimulates MEAF6-1 splicing. Enhanced MEAF6-1 expression in prostate adenocarcinoma cell lines does not induce neuroendocrine trans-differentiation of these cells. Rather, it stimulates cell proliferation, anchorage-independent cell growth, invasion, and xenograft tumor growth. Gene microarray identified that these MEAF6-1 actions are in part mediated by the ID1 and ID3 genes. These findings suggest that the MEAF6-1 variant does not induce neuroendocrine differentiation of prostate cancer cells, but facilitates t-NEPC progression through accelerating proliferation of cells that have acquired neuroendocrine phenotypes. Citation Format: Ahn R. Lee, Yinan Li, Ning Xie, Colin C. Collins, Xuesen Dong. Alternative splicing of the MEAF6 gene promotes neuroendocrine prostate cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3395. doi:10.1158/1538-7445.AM2017-3395
Abstract 3401: Role of membrane-associated guanylate kinase inverted 2 in advanced and castration-resistant prostate cancers
Authors: Bao Le, Kimberly Hammer, Katya Frantskevich, Irene Ong, Wei Huang, Paul Marker
Journal: Cancer Research (2017)

Abstract Background: Prostate cancer is the most common non-cutaneous malignancy for men in the U.S. Patients with advanced and/or metastatic prostate cancer are commonly treated with androgen deprivation therapy. Unfortunately, incurable castration resistant prostate cancer commonly develops 2-3 years after initial treatment. Methods: To identify candidate cancer genes involved in the development of castration resistance, the Sleeping Beauty (SB) transposon system and androgen-sensitive LNCaP cell line were used in a forward mutagenesis screen designed to model the transition from androgen sensitive to androgen insensitive prostate cancer. MAGI-2 was identified in the screen as a common insertion site gene, potentially involved in the transition to androgen independence. Clinical significance of MAGI-2 in prostate cancer was further supported by human TCGA data. Functional assays were used to confirm the involvement of MAGI-2 in prostate cancer progression. Results: MAGI-2 expression was prognostic for patient survival outcome. Ectopic expression of MAGI-2 in 22Rv1 cells resulted in a decrease in cell proliferation and colony formation in in vitro studies. At the molecular level, overexpression of MAGI2 induced a suppression of known androgen responsive genes. MAGI-2 overexpression also limited the growth of grafts compared to empty vector grafts in in vivo xenograft models. Conclusion: MAGI-2 was identified in a forward mutagenesis screen modeling the development of castration resistant prostate cancer. Human protein expression data from patient tissues supported a possible role for MAGI-2 in prostate cancer. Functional studies confirmed the potential involvement of MAGI-2 in prostate cancer progression. Future studies are seeking to elucidate the functional role and mechanism-of-action for MAGI-2 in prostate cancer. Ultimately, this may identify MAGI-2-regulated signaling pathways as therapeutic targets for prostate cancer. Citation Format: Bao Le, Kimberly Hammer, Katya Frantskevich, Irene Ong, Wei Huang, Paul Marker. Role of membrane-associated guanylate kinase inverted 2 in advanced and castration-resistant prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3401. doi:10.1158/1538-7445.AM2017-3401
Abstract 1879: Transcriptional regulation of KAI1 by p73 in colorectal cancer metastasis
Authors: Woo Kyun Bae, Kyung Hyun Yoo, Keunsoo Kang, Lothar Hennighausen, Ik-Joo Chung
Journal: Cancer Research (2017)

Abstract Background: p73 is a member of the p53 family transcription factors and known tumor suppressor. However, its transcriptional activity is complex owing to its multiple isoforms, and limited information is available regarding the transcriptional and functional regulation of the p73 gene in colorectal cancer. In this study, we examined the role of p73 in colorectal cancer. Methods: We established a TAp73 overexpressing cell line using the Tet-on inducible expression system and analyzed global RNA expression by RNA-sequencing (RNA-seq). We studied the effects of TAp73 expression on the migration, invasiveness, and EMT of colon cancer cells. We conducted experiments in animals with liver metastasis of colorectal cancer. To investigate the roles of p73 in colon cancer, we examined the samples from patients, who had undergone surgical resection for colorectal cancer between 2009 and 2013. mRNA expression of TAp73 and KAI1 was analyzed in 108 colorectal cancer specimen and adjacent non-cancerous tissues by real-time RT-PCR. Results: RNA-seq showed the association between TAp73 and KAI1 expression. Migration and invasiveness of colon cancer cells were reduced by TAp73 expression, but induced by KAI1 knockdown. TAp73 regulates KAI1 expression in colon cancer cell lines. TAp73-induced decrease in invasiveness and epithelial-mesenchymal transition (EMT) was abrogated by KAI1 knockdown in TAp73 overexpressing cells. Migration ability of TAp73 overexpressing cells was recovered by KAI1 knockdown. Hepatic metastases were significantly reduced in mice injected with TAp73 overexpressing cells and increased in those injected with TAp73 overexpressing cells with KAI1 knockdown. mRNA expression of TAp73 and KAI1 was higher in colorectal cancer tissues than in adjacent non-cancerous tissues. Significant correlation between TAp73 and KAI1 mRNA expression was detected in early stage primary colorectal cancer, but not in the advanced stage. Conclusions: This study suggests that p73 (TAp73) acts as a tumor suppressor in the progression of colorectal cancer and regulates the expression of KAI1, which is a key target of p73 in colorectal cancer liver metastases. Note: This abstract was not presented at the meeting. Citation Format: Woo Kyun Bae, Kyung Hyun Yoo, Keunsoo Kang, Lothar Hennighausen, Ik-Joo Chung. Transcriptional regulation of KAI1 by p73 in colorectal cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1879. doi:10.1158/1538-7445.AM2017-1879
Albumin-Gold Nanorod Nanoplatform for Cell-Mediated Tumoritropic Delivery with Homogenous ChemoDrug Distribution and Enhanced Retention Ability
Authors: Hsien-Ting Chiu, Cheng-Kuan Su, Yuh-Chang Sun, Chi-Shiun Chiang, Yu-Fen Huang
Journal: Theranostics (2017)

Recently, living cells with tumor-homing properties have provided an exciting opportunity to achieve optimal delivery of nanotherapeutic agents. However, premature payload leakage may impair the host cells, often leading to inadequate in vivo investigations or therapeutic efficacy. Therefore, a nanoplatform that provides a high drug-loading capacity and the precise control of drug release is required. In the present study, a robust one-step synthesis of a doxorubicin (DOX)-loaded gold nanorod/albumin core-shell nanoplatform (NR@DOX:SA) was designed for effective macrophage-mediated delivery to demonstrate how nanoparticle-loaded macrophages improve photothermal/chemodrug distribution and retention ability to achieve enhanced antitumor effects. The serum albumin shell of these nanoagents served as a drug reservoir to delay the intracellular DOX release and drug-related toxicity that impairs the host cell carriers. Near-infrared laser irradiation enabled on-demand payload release to destroy neighboring tumor cells. A series of in vivo quantitative analyses demonstrated that the nanoengineered macrophages delivered the nanodrugs through tumor-tropic migration to tumor tissues, resulting in the twice homogenous and efficient photothermal activations of drug release to treat prostate cancer. By contrast, localized pristine NR@DOX:SAs exhibit limited photothermal drug delivery that further reduces their retention ability and therapeutic efficacy after second combinational treatment, leading to a failure of cancer therapy. Moreover, the resultant unhealable wounds impair quality of life. Free DOX has rapid clearance and therefore exhibits limited antitumor effects. Our findings suggest that in comparison with pristine nanoparticles or free DOX, the nanoengineered macrophages effectively demonstrate the importance and effect of homogeneous drug distribution and retention ability in cancer therapy.
Abstract 4700: Poly G oligonucleotide enhances anti-tumor immune response among the patients with primary lung cancer
Authors: Nobuaki Kobayashi, Yuji Shibata, Masaki Yamamoto, Takashi Sato, Masaharu Shinkai, Harumi Koizumi, Kenichi Takahashi, Makoto Kudo, Hidekazu Shirota, Takeshi Kaneko
Journal: Cancer Research (2017)

Abstract Synthetic oligonucleotides (ODNs) containing specific sequences have an immunomodulatory effect. It is highly expected that such ODNs can be developed into a novel anti-cancer immunotherapy with these effects. Our past data revealed that a novel poly-G ODN has an anti-tumor immune effect in the tumor-bearing murine model. This effect of poly-G ODN was mediated by T cells in a TLR9 independent manner. Poly-G ODN directly induced the phosphorylation of Lck, thereby enhancing the production of IL-2 and T cell proliferation. Meanwhile, our recent data suggested that the immune effect by poly-G ODN against cancer was different in human. We identified poly-G ODN induced T cell proliferation and production of IFN-gamma through the enhancement of monocyte maturation in human mononuclear cells isolated from peripheral blood or malignant pleural effusion of lung cancer patients. Further studies are continued for the establishment of a novel anti-cancer immune therapy with poly-G ODN. Citation Format: Nobuaki Kobayashi, Yuji Shibata, Masaki Yamamoto, Takashi Sato, Masaharu Shinkai, Harumi Koizumi, Kenichi Takahashi, Makoto Kudo, Hidekazu Shirota, Takeshi Kaneko. Poly G oligonucleotide enhances anti-tumor immune response among the patients with primary lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4700. doi:10.1158/1538-7445.AM2017-4700
Abstract 5252: Quercetin inhibits prostate cancer by modulating ROS and key regulators of apoptosis and cell survival
Authors: Ashley B. Ward, Hina Mir, Neeraj Kapur, Guru Sonpavde, Shailesh Singh
Journal: Cancer Research (2017)

Abstract Long latency and indolent nature of prostate cancer (PCa) provides a window of opportunity for preventive interventions using natural and synthetic agents. Hence, the focus of this study was to ascertain the chemopreventive role of Quercetin, a bioflavonoid, commonly used to treat prostatitis. Human PCa cells (LNCaP, DU145 and PC3) were treated with different concentrations of Quercetin and its effect on cell survival and apoptosis was determined by MTT assay. Human PCa cells treated with Quercetin showed significant reduction in cell viability and proliferation compared with untreated controls, which was dose and time dependent. In addition to this our FACS analysis showed higher percentage of apoptotic cells after Quercetin treatment compared to untreated cells. Quercetin induced apoptosis in PCa cells is a cumulative effect of modulation of key apoptotic proteins, changes in mitochondrial membrane potential and ROS production. Our results demonstrate that Quercetin is a potent chemopreventive agent, which may improve outcomes of PCa by inhibiting mechanisms involved in tumor progression. Citation Format: Ashley B. Ward, Hina Mir, Neeraj Kapur, Guru Sonpavde, Shailesh Singh. Quercetin inhibits prostate cancer by modulating ROS and key regulators of apoptosis and cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5252. doi:10.1158/1538-7445.AM2017-5252