tbuckley/cabot-search huggingface dataset:
Induction of IAPP amyloid deposition and associated diabetic abnormalities by a prion-like mechanism
Authors: Abhisek Mukherjee, Diego Morales-Scheihing, Natalia Salvadores, Ines Moreno-Gonzalez, Cesar Gonzalez, Kathleen Taylor-Presse, Nicolas Mendez, Mohammad Shahnawaz, A. Osama Gaber, Omaima M. Sabek, Daniel W. Fraga, Claudio Soto
Journal: The Journal of Experimental Medicine (2017)

Although a large proportion of patients with type 2 diabetes (T2D) accumulate misfolded aggregates composed of the islet amyloid polypeptide (IAPP), its role in the disease is unknown. Here, we show that pancreatic IAPP aggregates can promote the misfolding and aggregation of endogenous IAPP in islet cultures obtained from transgenic mouse or healthy human pancreas. Islet homogenates immunodepleted with anti-IAPP–specific antibodies were not able to induce IAPP aggregation. Importantly, intraperitoneal inoculation of pancreatic homogenates containing IAPP aggregates into transgenic mice expressing human IAPP dramatically accelerates IAPP amyloid deposition, which was accompanied by clinical abnormalities typical of T2D, including hyperglycemia, impaired glucose tolerance, and a substantial reduction on β cell number and mass. Finally, induction of IAPP deposition and diabetic abnormalities were also induced in vivo by administration of IAPP aggregates prepared in vitro using pure, synthetic IAPP. Our findings suggest that some of the pathologic and clinical alterations of T2D might be transmissible through a similar mechanism by which prions propagate in prion diseases.
Abstract 1119: Targeting tankyrases as a therapeutic strategy for triple-negative breast cancer
Authors: Maya Mathew, Loredana Campo, Jung-Lye Kim, Geun-Hyoung Ha, Eun-Kyoung Breuer
Journal: Cancer Research (2017)

Abstract Tankyrases (TNKS1 and TNKS2) are members of the human poly(ADP-ribose) polymerase (PARP) family and catalyze PARsylation by using NAD+ as a substrate to modify various proteins in order to regulate various cellular processes including Wnt/β-catenin signaling. TNKS1 has been shown to be overexpressed and to be correlated with highly aggressive disease and prognosis in various types of human cancers. A small molecule inhibitor of TNKS1, XAV-939 has been proven to be a potent inhibitor of Wnt/β-catenin signaling by stabilizing Axin. However, the effect of tankyrase inhibitors as potential breast cancer therapy is still under investigation. In this study, we found that TNKS1 is highly expressed in breast cancer cell lines, particularly in triple-negative breast cancer (TNBC) cells and that the expression of TNKS1 correlates with anti-proliferative efficacy of tankyrase inhibitors, XAV-939 and JW55. Also, XAV-939 treatment suppressed cell migration and invasion capabilities and epithelial-mesenchymal transition (EMT) signaling in triple-negative breast cancer cell lines. Moreover, XAV-939 reduced expression of stemness markers. It was shown that polo-like kinase 1 (PLK1) functions as a positive regulator of TNKS1 protein stability. Interestingly, we found that combination treatment of XAV-939 with PLK inhibitor GW843682X significantly suppressed cell growth, clonogenic potential, migratory and invasive capabilities of breast cancer cells. The combination of XAV-939 with ionizing radiation (IR) also showed an additional therapeutic effect. Therefore, our findings highlight the important value of TNKS1 as a therapeutic target and suggest the potential for improving the clinical efficacies of tankyrase inhibitors in combination with either PLK inhibitors or radiotherapy for patients with triple-negative breast cancer. Citation Format: Maya Mathew, Loredana Campo, Jung-Lye Kim, Geun-Hyoung Ha, Eun-Kyoung Breuer. Targeting tankyrases as a therapeutic strategy for triple-negative breast 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 1119. doi:10.1158/1538-7445.AM2017-1119
Abstract 3620: RARalpha interactome in breast cancer, the S100 calcium binding protein A3 binds tothe retinoid receptor
Authors: Mineko Terao
Journal: Cancer Research (2017)

Abstract All-trans-retinoic acid (ATRA) is used in the treatment of acute promyelocytic leukemia. ATRA is endowed with promising anti-tumor activity in other tumor types, including breast cancer. In breast cancer, the anti-tumor activity of ATRA is mediated by the retinoid nuclear receptor, RARα (EMBO Mol Med. 2015 7:950-972). RARα is a ligand-dependent transcriptional factor, which is part of nuclear complexes regulating the expression of target genes. To define the RARα interactome in breast cancer cells we took a proteomic approach. We performed mass-spectrometric analysis of RARα immuno-precipitates from nuclear extracts of an ATRA-sensitive breast cancer cell line over-expressing the receptor. We identified 30 proteins differentially interacting with RARα in the absence/presence of ATRA. Three of these proteins FABP5, HSP27 and S100A3 interact with RARα in the absence of ATRA and their binding to the receptor is dramatically reduced upon addition of the retinoid ligand. Binding of the three proteins to RARα was validated by different types of immuno-precipitation experiments. We focused our attention on S100A3, a calcium binding protein whose function is largely unknown. Pull-down and Far-Western experiment indicated that S100A3 binds directly to RARα. Binding is specific to this nuclear receptor isotype as similar interactions with S100A3 are not observed with RARβ, RARγ or RXRα. S100A3 over-expression inhibited RARα ligand-dependent transcriptional activity, suggesting that the calcium-binding protein is a co-repressor. We designed specific shRNAs targeting S100A3 and we are in the process of evaluating their functional effects on ATRA-dependent anti-tumor activity in retinoid sensitive breast cancer cell lines. Citation Format: Mineko Terao. RARalpha interactome in breast cancer, the S100 calcium binding protein A3 binds tothe retinoid receptor [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 3620. doi:10.1158/1538-7445.AM2017-3620
Abstract 2251: Tumor tissue gene expression in association with survival of triple-negative breast cancer
Authors: Shuyang Wang, Qiuyin Cai, Hui Cai, Pingping Bao, Jie Wu, Fei Ye, Wei Zheng, Ying Zheng, Xiao-Ou Shu
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancer (TNBC) is an aggressive type of cancer with limited treatment options. Previous studies have shown that gene expression profiles were associated with TNBC prognosis. Information on specific genes that are predictive of TNBC outcome is limited. Using data and samples from a cohort of 469 TNBC cases from Shanghai Breast Cancer Survival Study (SBCSS), we systematically evaluated expressions of 302 genes in tumor tissue with survival of TNBC. Genes included in the study are PAM50 genes, genes encoding drug metabolizing enzymes and, genes implicated in TNBC biology and progression based on literature reviews. Gene expression levels were measured in total RNA isolated from formalin-fixed paraffin-embedded breast cancer tissues using the NanoString nCounter assay. Cox regression was applied to evaluate disease-free survival (DFS) and overall survival (OS) in association with gene expression. Analysis was adjusted for known predictors of TNBC outcome, including age, disease stage, basal like subtype and DUSP4 gene expression. During a median follow-up of 5.3 years (range: 0.7-8.9 years), 100 deaths and 92 recurrences/breast cancer deaths were documented. Expression levels of 17 genes were significantly associated with OS, and 15 genes with DFS (P&amp;lt;0.05). The top 5 most significant genes are EOMES (Hazard Ratio, HR = 0.88; 95% Confidence Interval, 95% CI: 0.82-0.96), GZMK (HR = 0.91, 95% CI: 0.85-0.97), TUBB3 (HR = 1.12, 95% CI: 1.03-1.21), SIT1 (HR = 0.90, 95% CI: 0.83-0.98) and ZNF224 (HR = 0.89, 95% CI: 0.81-0.97) for OS, and TUBB3 (HR = 1.14, 95% CI: 1.05-1.24), KRT14 (HR = 1.08, 95% CI: 1.02-1.14), BAG1 (HR = 1.19, 95% CI: 1.05-1.35), CD44 (HR = 0.73, 95% CI: 0.58-0.92) and EOMES (HR = 0.89, 95% CI: 0.82-0.97) for DFS. Study is on-going to replicate the findings of this study. Citation Format: Shuyang Wang, Qiuyin Cai, Hui Cai, Pingping Bao, Jie Wu, Fei Ye, Wei Zheng, Ying Zheng, Xiao-Ou Shu. Tumor tissue gene expression in association with survival of triple-negative breast 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 2251. doi:10.1158/1538-7445.AM2017-2251
Abstract 1893: Alpha-tubulin acetyltransferase, MEC-17, regulates cancer cell morphology and migration through epithelial-mesenchymal transition suppression and cell polarity disruption
Authors: Cheng-Che Lee, Chi-Yen Chang, Chi-Min Lin, Jang-Yang Chang
Journal: Cancer Research (2017)

Abstract Acetylation of α-tubulin has characterized as a key process for microtubule stabilization, and it can regulate cell spreading and modulate the dynamics of focal adhesion. MEC-17, a newly identified alpha-tubulin-N-acetyltransferase 1, serves as the major α-tubulin acetyltransferase to promote α-tubulin acetylation in vitro and in vivo. However, the physiological function of MEC-17 in cancer cells and its effect on MT acetylation during cell morphogenesis and migration has remained elusive. In the present study, our results showed that overexpression of MEC-17 induced increment of cell focal adhesion area, suppressed pseudopods formation in three-dimension collagen-embedded cultured environment and inhibited cancer cell migratory and invasive abilities. These changes were further proved to be caused by epithelial-mensenchymal transition (EMT) repression, cell polarity disruption caused by alteration of Golgi orientation and cdc42 activity and the decrease in the phosphorylation of extracellular signal regulatedkinase1/2 (Erk1/2). On the contrary, silencing of endogenous MEC-17 by specific shRNA accelerated the pseudopods formation and EMT process, which lead to facilitating the cell migration. Taken together, these results demonstrated that the important role of MEC-17 in the modulation of intrinsic cellular morphogenesis and migratory and invasive functions through regulation of EMT and polarization. (The study was supported by the following grants: MOST 103-2320-B-006-036-MY3 and MOST 105-2325-B-400-001 from the Ministry of Science and Technology of Taiwan, ROC) Citation Format: Cheng-Che Lee, Chi-Yen Chang, Chi-Min Lin, Jang-Yang Chang. Alpha-tubulin acetyltransferase, MEC-17, regulates cancer cell morphology and migration through epithelial-mesenchymal transition suppression and cell polarity disruption [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 1893. doi:10.1158/1538-7445.AM2017-1893
Abstract 2668: Efficacy study of immuno-checkpoint antibodies in humanized CDX and PDX models
Authors: Feifei Zhang, Yang Yang, Hongkui Chen, Lijun Jia, Kedong Ouyang, Danyi Wen, Taiping Chen
Journal: Cancer Research (2017)

Abstract Immune therapeutic intervention has been accepted widely for many hematopoietic malignancies and solid malignancies in past several years. Preclinical animal models with reconstitution of immune cells and target-expressing tumor cells were urgently needed for prove of concept studies demonstrating stimulatory immune system activation. Here we describe two established models of human PBMC co-transplantation of CDX and PDX. The study design was based on co-inoculation of human PBMC and PD-L1 expressing cell in NOG mice for reconstitution of immuno-checkpoint blockage. A therapeutic anti-PD1 antibody was applied for immune system activation and tumor growth inhibition measurement. After drugs were administrated i.p. for three weeks, 95 % TGI for A375 CDX model were observed. At the termination of the efficacy study at 28 days post therapeutic intervention, tumors of vehicle (tumor only, PMBC only), PD1 Ab treated groups were collected for immunostaining of CD45. Infiltrating T-cell with CD45+ label was found within the tumors when co-inoculated with human PBMC. PBMC humanized PDX models of ovarian cancer was implanted into mice which reconstituted with human PBMC for therapeutic intervention. Results showed that 85% TGI for PBMC humanized ovarian PDX models was observed. In conclusion, the models established here are feasible for immunotherapeutic evaluation and further additional immune therapeutic test articles can be explored with similar approaches. Citation Format: Feifei Zhang, Yang Yang, Hongkui Chen, Lijun Jia, Kedong Ouyang, Danyi Wen, Taiping Chen. Efficacy study of immuno-checkpoint antibodies in humanized CDX and PDX models [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 2668. doi:10.1158/1538-7445.AM2017-2668
Abstract 3805: Pre-diagnostic statin use among breast cancer patients - the relation to HMG-CoA reductase expression and disease-free survival
Authors: Helga Tryggvadottir, Emma Gustbée, Andrea Markkula, Maria Simonsson, Björn Nodin, Karin Jirström, Carsten Rose, Christian Ingvar, Signe Borgquist, Helena Jernström
Journal: Cancer Research (2017)

Abstract Background: The purpose of this study was to investigate whether pre-diagnostic statin use was associated with tumor expression of HMG-CoA reductase (HMGCR) and disease-free survival (DFS) in breast cancer. Previous studies have shown anti-carcinogenic properties of statins and a significantly longer survival among breast cancer patients using statins. We recently showed, that the target of statins, HMGCR, was up-regulated in breast cancer among patients preoperatively treated with statins in a window-of-opportunity trial. Methods: A population-based cohort of primary breast cancer patients in Lund, Sweden was assembled between October 2002 and June 2012. Patients completed a questionnaire including information on medication use. Statin use in relation to DFS was analyzed in 985 patients. Tumor tissue microarrays were constructed and stained with a polyclonal HMGCR antibody to assess HMGCR expression (n=848). Results: Patients were followed for up to 11 years (median follow-up time 5.0 years). In the present study, pre-diagnostic statin use was neither associated with HMGCR expression (P=0.53) nor with DFS (P=0.92), overall or separately in any of the HMGCR expression groups (negative, weak, moderate/strong). Moreover, statin use was not associated with clinical tumor characteristics (tumor size, axillary lymph node involvement, histological grade, hormone receptor status or HER-2 amplification). Conclusion: In contrast to previous studies, the present study did not show any significant association between pre-diagnostic statin use and DFS. It is possible that patients who already used statins have developed tumors that are less dependent on cholesterol metabolism and consequently less influenced by statin treatment. The timing of statin use in relation to breast cancer diagnosis and prognosis should be evaluated in another cohort with preferably longer follow-up time. Citation Format: Helga Tryggvadottir, Emma Gustbée, Andrea Markkula, Maria Simonsson, Björn Nodin, Karin Jirström, Carsten Rose, Christian Ingvar, Signe Borgquist, Helena Jernström. Pre-diagnostic statin use among breast cancer patients - the relation to HMG-CoA reductase expression and disease-free 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 3805. doi:10.1158/1538-7445.AM2017-3805
Pharmacological therapies for opioid induced constipation in adults with cancer
Authors: Jason W Boland, Elaine G Boland
Journal: BMJ (2017)

#### What you need to know

A 75 year old woman with metastatic breast cancer complains of constipation for two weeks. She has been taking regular modified release oral morphine for pain for three weeks. Despite using laxatives, she now opens her bowels with difficulty once or twice a week and complains of abdominal discomfort; these are so severe that she is considering stopping morphine. She has come to discuss treatment options. 

Opioids are commonly prescribed for cancer pain. Constipation reportedly affects around 52% of patients with advanced cancer and 87% of terminally ill patients taking opioids.123 Constipation is often multifactorial in patients with cancer, and opioids may be one cause. The infographic outlines possible contributory factors. Consider opioid induced constipation in people who describe a change in bowel habit after starting opioid therapy that is characterised by reduced frequency, development or worsening of straining, a sense of incomplete rectal evacuation, or harder stool consistency.4Figure 1⇓ illustrates the effects of opioids on the bowel mediated through opioid receptors that can lead to constipation, and in some cases limit opioid use.56



Fig 1  Effect of opioids on the bowel and clinical manifestations. Opioids act on opioid receptors in the gastrointestinal tract, leading to decreased small and large bowel motility with increased intestinal fluid absorption, increased anal sphincter tone, and reduced anorectal sensitivity to distension. These factors together cause dry, hard stools and reduced bowel movements



The infographic shows an approach to assessment and management options. The remainder of this article will …
Abstract 5873: Chaetocin sensitizes GBM cells to TRAIL and BH3 mimetics induced apoptosis
Authors: Ezgi Özyerli, Zeynep Kahya Yeşil, Udo Oppermann, Tuğba Bağcı Önder
Journal: Cancer Research (2017)

Abstract Glioblastoma Multiforme (GBM) is the most common and aggressive brain tumor, which lacks efficient therapy. TRAIL is an antitumor agent that triggers apoptosis selectively on tumor cells, thus can be utilized as therapeutic approach for GBM. However, most GBM cells confer TRAIL resistance and how this resistance is regulated at a molecular level is not completely clear. Epigenetic deregulation has been increasingly recognized as a hallmark of cancer. In this study, we conducted a drug screen against selected chromatin modifiers in U87MG GBM cells and identified Belinostat, Trichostatin A and Chaetocin as potential apoptosis regulators. While Belinostat and Trichostatin A are well-characterized histone deacetylase inhibitors in the context of malignancies, Chaetocin’s role in cancers is less well-known and its relation to TRAIL is novel. Chaetocin is a fungal mycotoxin that inhibits Suv39H1, a histone methyltransferase (HMT) that catalyzes H3K9 methylation. In this study, we investigated how Chaetocin affects the response of GBM cells to apoptotic stimuli by TRAIL. To this end, GBM cell lines U87MG and U373 are treated with varying dose of Chaetocin and cells’ viability and apoptosis responses to varying doses of TRAIL are analyzed. Chaetocin decreased viability down to 11% of control in U87MG cells upon TRAIL treatment, without inducing cellular toxicity and apoptosis by itself. Chaetocin was shown to upregulate the expression of proapoptotic genes while downregulating antiapoptotic gene expression. In addition, elevated Caspase3/7, Caspase8 and Caspase9 activities were detected in U87MG upon Chaetocin treatment together with PARP cleavage as indicator of apoptosis. Chaetocin also sensitized GBM cells to BH3 mimetic ABT263 which indicates that sensitization of GBM cells by Chaetocin is not limited to TRAIL but is rather a general phenomenon for apoptosis. We infer from these findings that Chaetocin plays critical and specific role in apoptotic pathway. Our future work is directed towards examining the changes in gene expression profiling of GBM cells upon Chaetocin treatment and understanding the functional role of H3K9 Methylation in GBM cell apoptosis. To this end, RNAseq analysis is currently being performed and expected to enlighten Chaetocin’s mechanism of action. These findings support our motivation that identifying epigenetic modifier drugs as apoptosis sensitizer may be a promising therapeutic approach for GBM treatment. Note: This abstract was not presented at the meeting. Citation Format: Ezgi Özyerli, Zeynep Kahya Yeşil, Udo Oppermann, Tuğba Bağcı Önder. Chaetocin sensitizes GBM cells to TRAIL and BH3 mimetics induced apoptosis [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 5873. doi:10.1158/1538-7445.AM2017-5873
Abstract 2539: MiR-96-5p functions as an oncogenic miRNA by inhibiting apoptosis in hepatocellular carcinoma
Authors: Naoto Iwai, Kohichiroh Yasui, Akira Tomie, Kei Teasaki, Tomoko Kitaichi, Osamu Dohi, Yasuyuki Gen, Yoshito Ito
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) is one of the most aggressive cancers with high mortality worldwide. MicroRNAs (miRNAs) are small non-coding RNAs that have been used as cancer-related biomarkers and expected to be therapeutic agents. We performed genome-wide miRNA expression profiling of paired HCC tumors and non-tumorous liver tissues from patients with primary HCCs using the miRNA microarray (Agilent). We found that miR-96-5p was most significantly up-regulated in HCC tumors compared to non-tumor tissues. Although miR-96-5p is suggested to be an oncogenic miRNA, the function of miR-96-5p remains largely unknown. We identified the caspase-9 gene (CASP9) as a novel target of miR-96-5p, in addition to the forkhead box O1 gene (FOXO1) which is the known target of it. Caspase-9 protein is thought to play a central role in apoptosis and to be a tumor suppressor. Overexpression of miR-96-5p decreased caspase-9 protein expression and resulted in resistance to apoptosis induced by doxorubicin and UV in HCC cells. Our results suggested that miR-96-5p functions as an oncogenic miRNA by inhibiting apoptosis through decreasing caspase-9 expression in HCC. Citation Format: Naoto Iwai, Kohichiroh Yasui, Akira Tomie, Kei Teasaki, Tomoko Kitaichi, Osamu Dohi, Yasuyuki Gen, Yoshito Ito. MiR-96-5p functions as an oncogenic miRNA by inhibiting apoptosis in hepatocellular carcinoma [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 2539. doi:10.1158/1538-7445.AM2017-2539