tbuckley/cabot-search huggingface dataset:
Abstract 3490: Interrogation of small RNA-seq data for small noncoding RNA in human colon cancer
Authors: Srinivas V. Koduru, Angelique Nyinawabera, Dino J. Ravnic, Amit K. Tiwari
Journal: Cancer Research (2017)

Abstract Genomic analysis of the human transcriptome has been made possible only in last decade by next generation sequencing (NGS). Recent advancements in NGS has further allowed us to look into small non-coding RNAs (sncRNAs) such as microRNAs (miRNAs), Piwi-interacting-RNAs (piRNAs), long non-coding RNAs (lncRNAs) &amp; small nuclear/nucleolar RNAs (sn/snoRNAs). Recently, the roles of sncRNAs in biological processes have been implicated in biomarker development for diagnosis, prognosis &amp;therapy. In the present study, 50 colon cancer patient’s small RNA sequencing raw data was downloaded from NIH bioproject (PRJNA266667; 7 TNM stage II &amp; 43 TNM stage III) which contained 27 female &amp; 23 male samples. 24 samples had metachronous metastasis (MM) &amp; 26 non-metachronous metastasis (NMM). The small RNA-seq data was analyzed using PartekFlow. In depth analysis showed aberrant expression of 48 miRNAs (all upregulated) in TNM-III vs TNM-II specimens &amp; 20 miRNAs (17 upregulated &amp; 3 downregulated) in MM vs NMM. Further investigation of dysregulated miRNA through pathway analysis confirmed that the majority of the miRNAs were involved in cancer signaling pathways. Analysis of piRNA found unusual expression of 60 piRNAs (57 upregulated &amp; 3 downregulated) in TNM-III vs TNM-II &amp; 31 piRNAs (28 upregulated &amp; 3 downregulated) in MM vs NMM. Further analysis of long non-coding RNAs, we found 77 lncRNAs were significantly expressed in TNM-III vs TNM-II &amp;18 lncRNAs in MM vs NMM. We also, investigated small nuclear/nucleolar RNAs (sn/snoRNAs), miscRNAs &amp; mtRNAs, we identified 37 snRNAs, 105 snoRNAs, 28 miscRNAs &amp; 5 mtRNAs in TNM-III vs TNM-II whereas 2 snRNAs, 11 snoRNAs, 57 miscRNAs &amp; 8 mtRNAs in MM vs NMM were identified. In summary, our comprehensive analysis on publicly available small RNA-seq data identified multiple small non-coding RNAs that need to be further explored for their use in the prognosis, diagnosis &amp; therapy of colon cancer. Citation Format: Srinivas V. Koduru, Angelique Nyinawabera, Dino J. Ravnic, Amit K. Tiwari. Interrogation of small RNA-seq data for small noncoding RNA in human colon 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 3490. doi:10.1158/1538-7445.AM2017-3490
Abstract 4633: Crosstalk between MDSCs and Th17
Authors: Brijendra Singh
Journal: Cancer Research (2017)

Abstract Expansion of myeloid-derived suppressor cells (MDSCs) within the tumor is a known barrier to successful cancer immunotherapy. MDSCs are heterogeneous population of immature myeloid cells with potent immunosuppressive activity. Emerging evidences in the recent years define the role of immunosuppressive activity of MDSCs on different subsets of CD4+ T cells, however the exact effect of MDSCs on inflammatory Th17 cells during tumor progression is not clear. Here we demonstrate the immunosuppressive effect of MDSCs on Th17 cells. We further show that the interaction between MDSCs and Th17 is not unilateral and reveal that Th17 cells can promote the immunosuppressive effect of MDSCs. MDSCs, either isolated from tumor bearing mice or generated in vitro from bone marrow (BM-derived MDSCs), can both suppress IL-17A expression. Our data also demonstrate that IFNg, produced by Th17 cells is essential for the immunosuppressive activity of BM-derived MDSCs on IL-17A expression and further that the IFNgR1-driven signaling is important for Nos2-mediated immunosuppressive effect of BM-derived MDSCs on IL-17A expression. Understanding the molecular mechanism of the interplay between MDSCs and Th17 cells may help to develop more specific targeted therapy for cancer immunotherapy and improve therapeutic efficacy of the existing therapies against cancer. Note: This abstract was not presented at the meeting. Citation Format: Brijendra Singh. Crosstalk between MDSCs and Th17 [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 4633. doi:10.1158/1538-7445.AM2017-4633
Abstract 443: Lymphatic endothelium protects breast cancer cells from death by inducing metabolic adaptations
Authors: Mirela Berisa, Simona Podgrabinska, Brandon Nicolay, Raul Mostoslavsky, Jerry Chipuk, Mihaela Skobe
Journal: Cancer Research (2017)

Abstract The lymphatic vasculature is an important pathway for breast cancer dissemination, yet it is not understood whether and how the lymphatic vessel microenvironment influences cancer metastasis. We demonstrate that lymphatic endothelial cells (LECs) promote survival of triple-negative breast cancer cells (TNBCs) under stress by improving mitochondrial function and inducing metabolic shift to promote cellular energy production. LECs protected TNBCs from death in vitro induced by the loss of attachment and nutrient deprivation. Cell death was preceded with a sharp increase in reactive oxygen species (ROS), strong up-regulation of Nrf2-mediated oxidative stress response genes and a rapid decline of mitochondrial activity. LECs lowered ROS levels, decreased mitochondrial superoxide formation and enhanced mitochondrial activity in TNBCs. RNAseq transcriptome analysis identified key regulator of mitochondrial metabolism and cellular bioenergetics, peroxisome proliferator-activated receptor gamma coactivator (PPARGC1A/PGC-1α, to be specifically up-regulated in breast cancer cells by LEC-derived factors. Inhibition studies demonstrated that the TNBC survival was dependent on pentose phosphate pathway (PPP) activity. Notably, LECs induced a metabolic shift from glycolysis to fatty-acid oxidation (FAO) and oxidative phosphorylation to maintain ATP and sustain cell viability. These data demonstrate that lymphatic endothelium promotes survival of breast cancer cells by regulating energy production and maintaining redox homeostasis. Our findings suggest that lymphatic endothelium may facilitate metastasis by promoting survival of breast cancer cells within the lymphatic vasculature. Citation Format: Mirela Berisa, Simona Podgrabinska, Brandon Nicolay, Raul Mostoslavsky, Jerry Chipuk, Mihaela Skobe. Lymphatic endothelium protects breast cancer cells from death by inducing metabolic adaptations [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 443. doi:10.1158/1538-7445.AM2017-443
FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious <i>BRCA</i> Mutation–Associated Advanced Ovarian Cancer
Authors: Sanjeeve Balasubramaniam, Julia A. Beaver, Sara Horton, Laura L. Fernandes, Shenghui Tang, Hisani N. Horne, Jinzhong Liu, Chao Liu, Sarah J. Schrieber, Jingyu Yu, Pengfei Song, William Pierce, Kim J. Robertson, Todd R. Palmby, Haw-Jyh Chiu, Eunice Y. Lee, Reena Philip, Robert Schuck, Rosane Charlab, Anamitro Banerjee, Xiao Hong Chen, Xing Wang, Kirsten B. Goldberg, Rajeshwari Sridhara, Geoffrey Kim, Richard Pazdur
Journal: Clinical Cancer Research (2017)

On December 19, 2016, the FDA granted accelerated approval to rucaparib (RUBRACA; Clovis Oncology, Inc.) for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)-associated advanced ovarian cancer who have been treated with two or more chemotherapies. The FDA also approved the FoundationFocus CDx BRCA test (Foundation Medicine, Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious BRCA1 and/or BRCA2 mutations in tumor tissue. Rucaparib's approval was based primarily on efficacy data from 106 patients with BRCA mutation-associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 patients with ovarian cancer treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% [57/106; 95% confidence interval (CI), 44-64], and median duration of response was 9.2 months (95% CI, 6.6-11.7). The approved companion diagnostic verified tumor BRCA mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparib's accelerated approval. Clin Cancer Res; 23(23); 7165-70. ©2017 AACRSee related commentary by Kohn et al., p. 7155.
Abstract 676: Nuclear expression of insulin receptor (InsR) adds prognostic information in primary breast cancer patients with high BMI
Authors: Sofie Björner, Ann H. Rosendahl, Maria Simonsson, Andrea Markkula, Karin Jirström, Signe Borgquist, Carsten Rose, Christian Ingvar, Helena Jernström
Journal: Cancer Research (2017)

Abstract Aim and introduction The aim of this study was to elucidate the prognostic importance of nuclear expression of the insulin receptor (nucInsR) in primary breast cancer. The InsR is important for the metabolism, for the insulin-like growth factor (IGF) signaling network and is implicated in breast cancer. Insulin and InsR are interlinked with obesity and body mass index (BMI), which are also associated with breast cancer. The InsR is present both in the membrane and cytoplasm and can additionally translocate to the nucleus. The role of nucInsR is not well understood and the prognostic importance is unclear. Methods The tumor-specific expression of nucInsR was evaluated by immunohistochemistry on invasive breast cancer tissue microarrays from 984 primary breast cancer patients included in a population-based cohort in Sweden. Patients were followed for up to 11 years, the median follow-up for patients still at risk was five years. nucInsR in relation to prognosis was analyzed using Cox regression, adjusted for age, invasive tumor size, axillary lymph node involvement, histological grade, estrogen receptor (ER) status, BMI, tumor storage time, and treatment. Results Status for nucInsR was available for 900 patients (91.5%). nucInsRpos staining was present in 214 patients (23.8%) and was associated with lower age (P=0.004), and lower waist-to-hip ratio (P=0.006), but not with BMI, ER or PR status. During follow-up, 107 patients had a first breast cancer event. nucInsR had no prognostic significant impact among all patients. However, there was a significant effect modification of BMI on nucInsR regarding event-free survival (Pinteraction=0.006). Patients with nucInsRpos-expressing tumors and higher BMI (≥25 kg/m2) had lower risk for any breast cancer event, adjusted HR (0.49; 95% CI 0.26-0.93), while patients with nucInsRpos-expressing tumors and normal BMI (&amp;lt;25 kg/m2) were associated with a non-significant higher risk of events, adjusted HR (1.72; 95% CI 0.93-3.17). Conclusions These results indicate that nucInsR status may add prognostic information in primary breast cancer depending on BMI. Citation Format: Sofie Björner, Ann H. Rosendahl, Maria Simonsson, Andrea Markkula, Karin Jirström, Signe Borgquist, Carsten Rose, Christian Ingvar, Helena Jernström. Nuclear expression of insulin receptor (InsR) adds prognostic information in primary breast cancer patients with high BMI [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 676. doi:10.1158/1538-7445.AM2017-676
Abstract 5910: Influence of 3D- cultured prostate cancer and stromal cells on drug response
Authors: Dominique N. Gales, Sonni Miller, Temesgen Samuel, Clatyon Yates
Journal: Cancer Research (2017)

Abstract Background: Response to chemotherapeutic drugs presents a significant challenge to effective treatment of advanced prostate cancer. Exploration of therapeutic response has focused largely on the tumor cell. However, evidence suggests mechanisms that involve the tumor microenvironment mediate response to therapeutics. Therefore, it is imperative to mimic the in vivo tumor microenvironment, to bridge the gap between in vitro studies and the development of therapeutics. The concept of three-dimensional (3D) cell culture and co-culture of multiple cell types is critical to predict therapeutic efficacy and outcome. Thus, these studies sought to determine the distinct responses to anti-cancer drugs in 3D cell spheroids. Methods: In this study, we utilized metastatic prostate cancer cells (PC3) and fluorescently labeled prostate bone stromal cell line (HS27a) to generate tumor spheroids. Tumor spheroid viability was measured at 72 and 120 h using the CellTiter-Glo 3D assay after treatment with three common anti-cancer drugs, Docetaxel (4ηM), Enzalutamide (30μM), and Bicalutamide (30μM).Treatments were compared with spheroids originated from HS27a and PC3 cells alone and in co-culture. The cell viability percentage was normalized using the untreated cells as 100% cell survival. Results: Spheroid formation increased resistance to Docetaxel, Enzalutamide, and Bicalutamide. However, PC3 spheroid cells was significantly higher compared to HS27a and co-culture spheroids. For all three spheroids, as the size of the spheroids increase, cellular resistance to anti-cancer and hormone drugs increased. Conclusion: The findings in this study demonstrated that the use for 3D-cell cultures influence many aspects of PCa behavior including, proliferation rates, and response to chemotherapeutics. Note: This abstract was not presented at the meeting. Citation Format: Dominique N. Gales, Sonni Miller, Temesgen Samuel, Clatyon Yates. Influence of 3D- cultured prostate cancer and stromal cells on drug response [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 5910. doi:10.1158/1538-7445.AM2017-5910
Abstract 477: Down-regulated miR-23a contributes to invasion and metastasis of cutaneous melanoma by promoting autophagy
Authors: Weinan Guo, Huina Wang, Yuqi Yang, Sen Guo, Weigang Zhang, Tao Zhao, Lin Liu, Zhe Jian, Ling Liu, Gang Wang, Tianwen Gao, Qiong Shi, Chunying Li
Journal: Cancer Research (2017)

Abstract Background: The occurrence of invasion and metastasis is the major cause of mortality in melanoma. Recent studies suggest that dysregulated miRNAs play critical roles in this procedure, but the underlying mechanism remains elusive. Here, we show that down-regulated miR-23a can promote invasion-metastasis cascade through autophagy in melanoma.Methods: The role of miR-23a in prognosis was assessed in a cohort of melanoma patients (n = 192) with Kaplan-Meier analysis. The effects of miR-23a overexpression were investigated using assays of invasion, migration and in a xenograft model (n = 10 mice per group). Autophagy-related target of miR-23a was confirmed by bioinformatics analysis, luciferase assays and immunoblotting. Molecular studies were performed to determine the downstream cellular and molecular mechanisms. All statistical tests were two-sided.Results: Serum miR-23a level was significantly down-regulated in melanoma patients (P&amp;lt; .001) and was highly correlated with poor clinical outcomes (P = .027, log-rank test). In addition, miR-23a level was remarkably decreased in metastatic melanoma tissues and cell lines (P&amp;lt;.05, P&amp;lt;.01). Moreover, miR-23a overexpression prevented the invasion and migration in vitro and lung and liver metastasis in vivo (both P&amp;lt; .05), by targeting ATG12 and inhibiting autophagy. Mechanically, miR-23a-ATG12 axis attenuated invasion and migration through autophagy-mediated AMPK-RhoA pathway. Finally, the down-regulation of miR-23a in metastatic melanoma was caused by RUNX2 in a transcriptional repression-manner. Conclusion: MiR-23a can act as a crucial epigenetic repressor of melanoma invasion and metastasis in an autophagy-dependent way, which indicates that miR-23a-mediated autophagy inhibition can be exploited to restrain invasion-metastasis cascade in melanoma treatment. Note: This abstract was not presented at the meeting. Citation Format: Weinan Guo, Huina Wang, Yuqi Yang, Sen Guo, Weigang Zhang, Tao Zhao, Lin Liu, Zhe Jian, Ling Liu, Gang Wang, Tianwen Gao, Qiong Shi, Chunying Li. Down-regulated miR-23a contributes to invasion and metastasis of cutaneous melanoma by promoting autophagy [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 477. doi:10.1158/1538-7445.AM2017-477
Review of Alfonso Gómez-Lobo With John Keown, <i>Bioethics and the Human Goods: An Introduction to Natural Law Bioethics</i>
Authors: Christopher Tollefsen
Journal: The American Journal of Bioethics (2017)

"Review of Alfonso Gómez-Lobo With John Keown, Bioethics and the Human Goods: An Introduction to Natural Law Bioethics." The American Journal of Bioethics, 17(8), pp. W3–W4
Abstract 2336: Novel regulatory mechanisms for Bcl2-related Ovarian Killer (BOK) expression in breast cancer
Authors: Benjamin Chidi Onyeagucha, Panneerdoss Subbarayalu, Subapriya Rajamanickam, Nourhan Abdelfattah, Santosh Timilsina, Rosa M. Guzman, Carla Zeballos, Vijay Eedunuri, Sanjay Bansal, Hima Bansal, Tabrez A. Mohammad, Yidong Chen, Manjeet K. Rao
Journal: Cancer Research (2017)

Deregulation of apoptosis is central to cancer progression and a major obstacle to effective treatment. The Bcl-2 gene family members play important roles in the regulation of apoptosis and are frequently altered in cancers. One such member is Bcl-2-related Ovarian Killer (BOK), which is a pro-apoptotic protein. Despite its critical role in apoptosis, the regulation of BOK expression is poorly understood in cancers. Here, we discovered that miR-296-5p, regulates BOK expression by binding to its 3’UTR in breast cancers. Furthermore, we show that depletion of BOK by either miR-296-5p or siRNA against BOK protected breast cancer cells from undergoing paclitaxel-induced apoptosis. Interestingly, miR-296-5p also regulates the expression of Mcl-1, which is an anti-apoptotic protein and is highly expressed in breast cancers. Our results reveal that Mcl-1 is important for suppression of BOK function as ectopic BOK expression induced Mcl-1, while silencing of BOK resulted in reduced Mcl-1 levels in breast cancer cells. In addition, we show that specific silencing of Mcl-1 reduced the long-term growth of breast cancer cells, whereas BOK inhibition didn’t have any effect on the growth of breast cancer cells. Surprisingly, silencing of both Mcl-1 and BOK rescued the effect of Mcl-1 silencing on breast cancer cell growth, suggesting that BOK is important for attenuating cell growth in the absence of Mcl-1, and also showing a tight feedback regulatory loop between BOK and Mcl-1 in breast cancer cells. Furthermore, we demonstrated that BOK protein level is regulated post-translationally by GSK3α and to some extent GSK3β as GSK3 inhibitor (CHIR99021) or silencing of GSK3 significantly increased BOK protein levels in breast cancer cells. Notably, we found that Mcl-1 interacts with GSK3α/β and silencing of Mcl-1 using siRNA significantly attenuated endogenous GSK3α/β levels in breast cancer cells. Taken together, our results suggest that fine tuning (either post-transcriptionally by miR-296-5p or post-translationally by GSK3) of the levels of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 decide the fate of cancer cells to either undergo Apoptosis or proliferation.Citation Format: Benjamin Chidi Onyeagucha, Panneerdoss Subbarayalu, Subapriya Rajamanickam, Nourhan Abdelfattah, Santosh Timilsina, Rosa M. Guzman, Carla Zeballos, Vijay Eedunuri, Sanjay Bansal, Hima Bansal, Tabrez A. Mohammad, Yidong Chen, Manjeet K. Rao. Novel regulatory mechanisms for Bcl2-related Ovarian Killer (BOK) expression in 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 2336. doi:10.1158/1538-7445.AM2017-2336
Abstract 3671: Anti-PD-1 treatment may potentiate the radiation-induced lung injury
Authors: Jianxin Xue, Shisuo Du, You Lu, Adam Dicker, Bo Lu
Journal: Cancer Research (2017)

Abstract Purpose: Combination of radiation therapy and anti-PD1 immunotherapy has been investigated both in the lab and in the clinic. Pneumonitis is a rare but potentially fatal toxicity of ant-programmed death-1 (PD-1) monoclonal antibodies (mAbs). The purpose of our study is to address whether anti-PD-1 mAbs will potentiate radiation-induced lung toxicity and mortality in a murine model using Small Animal Radiation Research Platform (SARRP) for lung-targeting irradiation (IR). Methods: Both lungs of male C57bl/6 mice were targeted for 20Gy using the SARRP. Mice were stratified into 4 treatment groups receiving IgG, anti-PD1, IR + IgG, or IR + anti-PD1. IgG or anti-PD-1 mAbs administrated via i.p. injection, with a dosage of 10mg/kg, twice per week for five doses. Acute lung injury was assessed by H&amp;E staining and flow cytometry to measure CD4 or CD8 positive T lymphocytes. A duplicate study (n=10) was performed to determine long-term survival following lung irradiation. Results: 30 days following lung irradiation, lung tissues exhibited abnormal alveoli, with exudates and inflammatory cells in the alveolar septa (H&amp;E staining). The extent of these changes was more prominent in IR+anti-PD-1 group. Moreover, there were significantly (2.1 fold increase; p&amp;lt;0.05) more CD8+ cytotoxic T lymphocytes, rather than CD4+ cells lymphocytes, in the irradiated lung tissues in the group of IR+anti-PD1 compared to that of IR+IgG. Up to 120 days post IR, 90% mice survived in the group of IR+IgG while 70% mice survived in the IR+anti-PD-1 group (p=0.657). Conclusions: Anti-PD-1 mAbs potentiates the radiation-induced pneumonitis, likely mediated by increased CD8+ cytotoxic T lymphocytes. Anti-PD-1 mAbs may increase the radiation-related mortality although it was not statistically significance at the day 120 following IR. Care should be taken for excessive lung toxicities in ongoing clinical trials of combining thoracic RT and anti-PD1 therapy. We will collaborate with NRG to further investigate clinical lung toxicities from combining thoracic radiotherapy with Nivo in the ongoing RTOG 3505 though analyzing the collected biospecimens. Note: This abstract was not presented at the meeting. Citation Format: Jianxin Xue, Shisuo Du, You Lu, Adam Dicker, Bo Lu. Anti-PD-1 treatment may potentiate the radiation-induced lung injury [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 3671. doi:10.1158/1538-7445.AM2017-3671