tbuckley/cabot-search huggingface dataset:
Histone Deacetylase 5 Is Overexpressed in Scleroderma Endothelial Cells and Impairs Angiogenesis via Repression of Proangiogenic Factors
Authors: Pei‐Suen Tsou, Jonathan D. Wren, M. Asif Amin, Elena Schiopu, David A. Fox, Dinesh Khanna, Amr H. Sawalha
Journal: Arthritis & Rheumatology (2016)

Objective Vascular dysfunction represents a disease‐initiating event in systemic sclerosis (SSc; scleroderma). Results of recent studies suggest that epigenetic dysregulation impairs normal angiogenesis and can result in abnormal patterns of blood vessel growth. Histone deacetylases (HDACs) control endothelial cell (EC) proliferation and regulate EC migration. Specifically, HDAC‐5 appears to be antiangiogenic. This study was undertaken to test whether HDAC‐5 contributes to impaired angiogenesis in SSc by repressing proangiogenic factors in ECs. Methods Dermal ECs were isolated from patients with diffuse cutaneous SSc and healthy controls. Angiogenesis was assessed using an in vitro Matrigel tube formation assay. An assay for transposase‐accessible chromatin using sequencing (ATAC‐seq) was performed to assess and localize the genome‐wide effects of HDAC5 knockdown on chromatin accessibility. Results The expression of HDAC5 was significantly increased in ECs from patients with SSc compared to healthy control ECs. Silencing of HDAC5 in SSc ECs restored normal angiogenesis. HDAC5 knockdown followed by ATAC‐seq assay in SSc ECs identified key HDAC5 ‐regulated genes involved in angiogenesis and fibrosis, such as CYR61 , PVRL2 , and FSTL1 . Simultaneous knockdown of HDAC5 in conjunction with either CYR61 , PVRL2 , or FSTL1 inhibited angiogenesis in SSc ECs. Conversely, overexpression of these genes individually led to an increase in tube formation as assessed by Matrigel assay, suggesting that these genes play functional roles in the impairment of angiogenesis in SSc. Conclusion Several novel HDAC5 ‐regulated target genes associated with impaired angiogenesis were identified in SSc ECs by ATAC‐seq. The results of this study provide a potential link between epigenetic regulation and impaired angiogenesis in SSc, and identify a novel mechanism for the dysregulated angiogenesis that characterizes this disease.
Statins to Reduce Acute Kidney Injury After Cardiac Surgery—Reply
Authors: Frederic T. Billings, Nancy J. Brown
Journal: JAMA (2016)

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Abstract 176: Development of 1- and 3-phosphohistidine monoclonal antibodies utilized as novel tools to study histidine phosphorylation
Authors: Wayne A. Speckmann, Mark Santos, Reshmie Shea, Sheri Geiman, Arazo Saadat, James Hoberg, Wei Zheng
Journal: Cancer Research (2016)

Abstract Phosphorylation of proteins is one of the most common forms of post-translational modification (PTMs) and is a mechanism for regulating enzyme activity or protein function. There are several amino acids that can be phosphorylated but despite its importance in cancer and tumor metastasis histidine phosphorylation (pHis) has been highly overlooked. One of the key reasons is the inherent challenge associated with studying pHis legitimately, due largely in part to the lack in availability of specific antibodies. Unlike serine, threonine, and tyrosine which all form acid-stable phosphoester (P-O) bonds upon phosphorylation, histidine forms heat and acid-labile phosphoramidate (P-N) bonds. Because of the instability of the P-N bond, it is nearly impossible to assess the prevalence of pHis accurately. Here, we outline the development of selective, sequence independent anti-1-pHis and anti-3-pHis monoclonal antibodies which have addressed this current need for specific antibodies to detect the phosphorylation of histidine. The antibodies developed specifically recognize 1-pHis and 3-pHis and are isomer specific. In addition, they do not cross-react with phospho-tyrosine (pTyr), whereas, the first and second generation “pan-pHis” polyclonal antibodies against 3-pHis have been reported to do so. Moreover, it has been suggested that pHis could be as abundant as pTyr, comprising of approximately 1% of all known phosphorylation in cells, making specific monoclonal antibodies for detection highly desirable. Validation data of the four monoclonal phospho-Histidine antibodies developed (clones SC50-3 and SC1-1 for assessment of 1-pHis activities; clones SC56-2 and SC39-6 for assessment of 3-pHis activities) demonstrate the specificity and broad utility of these monoclonal antibodies when identifying pHis substrates, making them useful tools in a variety of immunological and biological assays. Citation Format: Wayne A. Speckmann, Mark Santos, Reshmie Shea, Sheri Geiman, Arazo Saadat, James Hoberg, Wei Zheng. Development of 1- and 3-phosphohistidine monoclonal antibodies utilized as novel tools to study histidine phosphorylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 176.
A phase I/II study of the vascular disrupting agent BNC105P in combination with gemcitabine-carboplatin in partially platinum-sensitive ovarian cancer patients in first or second relapse: An international collaborative group trial of ANZGOG and HOG.
Authors: Danny Rischin, Daniela Matei, Jeffrey C. Goh, Michelle Margaret Vaughan, Philip James Beale, Meaghan Elizabeth Tenney, Julie Martyn, Dirkje Willemien Sommeijer, Jose Luis Iglesias, David C. Bibby, Jeremy Simpson, Elizabeth E. Doolin, Corinne E. Williams, Martin R. Stockler
Journal: Journal of Clinical Oncology (2013)

TPS5612 Background: BNC105P is a tubulin polymerization inhibitor and a vascular disrupting agent (VDA). In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia, and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells, including ovarian cancer cell lines. Pre-clinical data has demonstrated synergistic activity of BNC105P when combined with platinum or with gemcitabine, supporting the proposed study design. This study will determine the safety and efficacy of BNC105P in ovarian cancer when used in combination with gemcitabine-carboplatin. The target population is women with ovarian or primary peritoneal cancers who progressed 4 to 9 months after first-line platinum based chemotherapy, or 4 to 12 months after second line platinum based chemotherapy. Methods: A single arm phase I will be used to determine the phase II dose for the triplet combination (3-6 subjects per dose level, maximum of 24 subjects). Four dose levels of BNC105P (12-16 mg/m 2 ) and gemcitabine (800-1000 mg/m 2 ) will be assessed. The dose of carboplatin will be set at AUC 4. Enrolment to cohort 2 started in January 2013. The phase II component will consist of a 2-arm, randomized (1:1) study of BNC105P, gemcitabine and carboplatin versus gemcitabine and carboplatin alone. The primary endpoint for the phase II trial is objective response rate (ORR, according to RECIST 1.1 and/or GCIG CA125 criteria. An ORR of 40% or more with the experimental regimen would be considered worthy of further investigation, assuming an ORR of 20% with the control regimen. 110 phase II participants are planned (N = 55/arm). Treatment allocation will be balanced using minimization for the study site, target lesions according to RECIST (present vs. absent), progression free interval from last platinum based chemotherapy regimen (&lt;6 months vs 6 months or more), and first relapse vs. second relapse. Biomarker (tissue and blood-borne) sampling and PK analysis will also be undertaken. Clinical trial information: NCT01624493.
Abstract 4206: A dual-motif CAIX inhibitor, [64Cu]XYIMSR-06, for PET imaging of clear cell renal cell carcinoma
Authors: IL MINN, Soo Min Koo, Hye Soo Lee, Mary Brummet, Steven P. Rowe, Michael A. Gorin, Polina Sysa-Shah, William D. Lewis, Hye-Hyun Ahn, Yuchuan Wang, Sangeeta Ray, Ronnie C. Mease, Sridhar Nimmagadda, Mohamad E. Allaf, Martin G. Pomper, Xing Yang
Journal: Cancer Research (2016)

Abstract Carbonic anhydrase IX (CAIX) is a cell surface enzyme that is over-expressed in approximately 95% of clear cell renal cell carcinomas (ccRCCs), the most common renal cancer. CAIX is also a surrogate marker of hypoxic tumors for various human cancers; however, a clinically viable molecular imaging agent targeting CAIX is not available. We have synthesized and performed in vitro and in vivo evaluation of a dual-motif, low-molecular-weight inhibitor of CAIX, [64Cu] XYIMSR-06, for imaging CAIX expression on ccRCC tumors using positron emission tomography (PET). [64Cu] XYIMSR-06 was synthesized in two steps from reported dual-motif precursor 1. Upon radiolabeling, [64Cu] XYIMSR-06 was evaluated in immunocompromised mice bearing CAIX-expressing SK-RC-52 tumors for in vivo PET imaging and biodistribution. [64Cu] XYIMSR-06 was generated in radiochemical yields of 51.0 ± 4.5% (n = 5) and specific radioactivity of 6.0 GBq/μmol (170Ci/mmol ± 70, n = 5). Tumor could be visualized on PET images by 1 h post-injection with high tumor-to-background levels achieved within 24 h. Biodistribution studies of [64Cu] XYIMSR-06 demonstrated a maximum tumor uptake of 19.3 ± 4.51% injected dose per gram of radioactivity at 4 h. Tumor-to- blood, muscle and kidney ratios were 129.6 ± 18.8, 84.3 ± 21.0 and 2.1 ± 0.26, respectively, at 8 h post-injection. At 24 h, a tumor-to-kidney ratio of 7.1±2.5 was achieved. These findings represent increased tumor-to-background ratios at the indicated times relative to previously reported CAIX-targeted imaging agents. [64Cu] XYIMSR-06 is a promising candidate for PET imaging of CAIX expressing tumors, especially ccRCC. Citation Format: IL MINN, Soo Min Koo, Hye Soo Lee, Mary Brummet, Steven P. Rowe, Michael A. Gorin, Polina Sysa-Shah, William D. Lewis, Hye-Hyun Ahn, Yuchuan Wang, Sangeeta Ray, Ronnie C. Mease, Sridhar Nimmagadda, Mohamad E. Allaf, Martin G. Pomper, Xing Yang. A dual-motif CAIX inhibitor, [64Cu]XYIMSR-06, for PET imaging of clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4206.
Relationship between commonly used HRQOL measures: Correlations and mapping between the UCLA-PCI and EPIC scales.
Authors: Renske MT ten Ham, Jeanette M Broering, Matthew R. Cooperberg, John Kornak, Peter Carroll, Leslie S Wilson
Journal: Journal of Clinical Oncology (2014)

e16037 Background: Treatments available for prostate cancer (PCa) provide similar survival outcomes, so that quality of life becomes more important in treatment decisions. Different general and disease specific questionnaires measure health related quality of life (HRQoL) and it is unknown how they relate. We investigated correlations among the Expanded Prostate Cancer Index 26 (EPIC), UCLA Prostate Cancer Index (PCI), Sexual Health Inventory for Men (SHIM) and International Prostate Symptom Score (IPSS) questionnaires in PCa patients and generated functions to map PCI to the newer EPIC. Methods: 1,853 CaPSURE patients completed HR QoL questionnaires (EPIC, PCI, SHIM, IPSS). Pearson’s correlations compared the relationship between domains. To map PCI items to EPIC scores, the full cohort was randomly divided into a model and a validation cohort. We considered identity, log, square and logit-transformations of the dependent variable. We performed linear and Lowess regressions for each dependent variable transformation. Predicted and observed scores were compared, and R2 and root mean square error (RMSE) calculated. We examined models within disease severity subsets. Results: Correlations between EPIC and PCI were highest for urinary function (0.92) and sexual bother (0.84). Correlation between EPIC bowel and PCI bowel function was 0.64 and with bother 0.68. Correlation between bowel bother scores of EPIC and PCI was 0.69. SHIM’s correlations with PCI sexual function (SF) were higher than EPIC SF, (0.92 and 0.76). Correlation between IPSS (lower is better) and EPIC urinary irritative score was -0.71. The linear model predicted EPIC scores best with EPIC(UB) = 51 + (0.44 * PCI question34). The difference between observed and predicted scores was -0.56 to 1.68, RMSE, 8 to 26% and R2,0.46 to 0.93. Predicted values for severity subsets were overestimated in some ranges with small sample sizes (low scores). Conclusions: High correlations between function and bother scores suggest good agreement between PCI and EPIC scores. Predicted EPIC scores give good predictions across the population, but are less reliable for the few low score patients. The mapping equations allow scores to be updated from PCI to EPIC.
Abstract 34: Monocarboxylate transporters as potential therapeutic targets in human ovarian cancer
Authors: Amy Boyers, Ian Stratford
Journal: Cancer Research (2016)

Abstract Introduction- Cancer cells have the ability to favour glycolysis for the production of lactate even in the presence of sufficient levels of oxygen. This is known as the ‘warburg effect’ or ‘aerobic glycolysis’. As a consequence of this glycolytic switch, there is an accumulation of lactate within cells. Therefore, cells must remove this excess lactate in order to prevent cell death via intracellular acidosis. In order to do this cells use Monocarboxylate Transporters (MCTs), which are responsible for the transport of lactate in and out of cells. MCT1 and MCT4 have been found to be over expressed in many types of human cancers, including ovarian cancer. Aims- The aim of this study was to assess how changing the expression levels of MCT1 and MCT4 effects the growth and response to therapy of four Human Ovarian cancer cell lines (Skov3, Caov3, OV90 and Ovcar3). Methods- Cell lines were stably transfected to either over express MCT1 (Skov3, Caov3, and OV90 cells), MCT4 (OV90 cells) or to contain doxycycline inducible silencing of MCT4 (Skov3, Caov3 and Ovcar3 cells). The effect of changing the expression levels of MCT1 and MCT4 on the function of these cell lines was assessed. Assays to look at changes in cell proliferation, lactate accumulation and release, and the cytotoxicity of Paclitaxel and Carboplatin were determined in both normoxia (21% O2) and hypoxia (0.1/1% O2). Results- Over expressing MCT1 in the three human ovarian cell lines had no effect on cell growth or lactate release in normoxia or hypoxia. Also when MCT1 was over expressed in Skov3 and Caov3 cells there were no changes in their sensitivity to Carboplatin or Paclitaxel. However, when MCT1 was over expressed in OV90 cells, they became slightly more resistant to Paclitaxel. Over expressing MCT4 in OV90 cells also had no effect on cell growth in normoxia, but significantly more lactate was released by these cells. Secondly, when these cells were grown in hypoxia they survived for a greater period of time than wild type cells. This correlated with a much higher amount of lactate being released by these cells. Finally, these cells were more resistant to Paclitaxel than both the MCT1 over expressing cell lines and their wild type counterparts. Conclusions- Changing the expression levels of MCT1 and MCT4 in Human Ovarian cancer cells have an effect on normal cell function. This suggests that MCTs could be potential therapeutic targets in ovarian cancer. Citation Format: Amy Boyers, Ian Stratford. Monocarboxylate transporters as potential therapeutic targets in human ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 34.
Detection of glucocorticoid receptor (GR) expression in circulating tumor cells (CTCs) from patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: David Wise, Jessica Louw, Rachel Krupa, Nicole A. Schreiber, Charles L. Sawyers, Ryan Vance Dittamore, Howard I. Scher
Journal: Journal of Clinical Oncology (2016)

5046 Background: Upregulation of glucocorticoid receptor protein expression in metastatic biopsies from pts with CRPC has previously been shown to correlate with intrinsic and acquired resistance to enzalutamide and has been validated as a therapeutic target in pre-clinical studies. We sought to determine the prevalence of upregulated GR protein expression in CTCs from pts with progressing mCRPC. Methods: Blood samples from 31 pts with progressing mCRPC were subjected to CTC analysis using the EPIC Sciences platform. Samples were examined to identify CK+ (CK+, CD45- cells, with intact nuclei, morph distinct) and CK- (CK-, CD45-, intact nuclei, morph distinct) CTCs for N-terminal GR expression. Prior therapies include: abiraterone acetate (14 pts), enzalutamide (9 pts), docetaxel (11 pts), and ARN-509 (4 pts). 10 pts were treatment-naive. GR upregulation was defined as expression greater than the 95th percentile of GR expression in the LNCAP cell line, a previously established negative control prostate cancer cell line. GR expression in DU145, a prostate cancer cell line with upregulated GR by western blotting, was used as a positive control. Results: Our cohort consisted of 31 pts with detectable and viable CD45-CK+ and CD45-CK- CTCs exhibiting a median CTC count of 13 cells/ml (1 – 441 cells/ml). 17 out of 31 pts (55%) had CTCs with upregulated GR staining with a median of 5 GR+ (CK+ and CK-) cells/ml per patient (range 1 – 135 cells/ml) representing 30% of the CTCs identified in a typical patient (range 5 - 100%). GR upregulation was detected in 40% (4 of 10) of treatment-naïve pts. GR upregulation in CTCs was categorized by treatment history (Table 1). Conclusions: GR protein upregulation in CTCs can be detected in a significant percentage of pts with progressing mCRPC including those without previous exposureto enzalutamide, abiraterone acetate, docetaxel, or ARN-509. These data suggest that detection of GR in patient-derived CTCs may be a useful biomarker to guide GR-directed therapies. Prior Therapy N (%) of patients with GR+ CTCs N/A 4 (40) Enzalutamide 4 (44) Abiraterone 10 (71) Docetaxel 7 (64) ARN-509 4 (100)
Phosphorylation Of GSK3β Is Associated With Inferior Survival In Acute Myeloid Leukemia and Is An Indicator Of AKT Activation In AML Blasts and Bone Marrow Mesenchymal Stem Cells
Authors: Peter P. Ruvolo, Rui-yu Wang, Vivian R Ruvolo, Rodrigo Jacamo, Teresa McQueen, Gautam Borthakur, Yihua Qiu, Kevin R. Coombes, Nianxiang Zhang, Elizabeth J Shpall, Richard E Champlin, Ramiro Garzon, Guido Marcucci, Carlo M. Croce, Marina Konopleva, Michael Andreeff, Steven M. Kornblau
Journal: Blood (2013)
Abstract 4112: Geminin overexpression-dependent recruitment and crosstalk with mesenchymal stem cells enhances aggressiveness in triple-negative breast cancers
Authors: Theresa Bonner, Suryatheja Ananthula, Janene Nordan, Simran Batth, Gailen D. Marshall, Lauren H. Gardner, Yoshiko Shimizu, Wael M. ElShamy
Journal: Cancer Research (2016)

Abstract Introduction: Tumor resident mesenchymal stem cells (MSCs) promote cancer progression. Pathways involved in recruitment of MSCs to breast tumor cells remain largely undefined. We aimed at defining the mechanism whereby geminin overexpressing breast tumor cells recruit and interact with MSCs to increase their own aggressiveness. Experimental Procedures: We used co-culturing assay, immunohistochemistry, in vitro invasion assay with or without cytokines neutralization, western blot analysis, immunoprecipitation, immunofluorescence, ELISA, exposure to hypoxic conditions, cytokines receptor inactivation, in vivo orthotopic tumor formation assay in the presence or absence of inhibitors to the proposed signaling pathways, analysis of publically available data sets for the association of selected factors with overall survival, distant metastasis free survival and recurrent free survival to define the mechanism geminin overexpressing cells employ in vivo to recruit and initiate bi-directional interactions with MSCs in order to enhance their own aggressiveness. Results: Here we show that geminin-dependent acetylation of chromatin HMGB1 (Ac-HMGB1) leads to its release to the extracellular space. Extracellular Ac-HMGB1 promotes geminin overexpressing (GemOE) cells survival by binding to RAGE receptors. Extracellular Ac-HMGB1 also triggers expression and activation of RAGE in the non-expressing MSCs leading to induction of CXCR4 expression and migration of MSCs towards SDF1/CXCL12-expressing GemOE cells. Inhibiting c-Abl, RAGE or CXCR4 prevented MSCs recruitment to GemOE cells in vitro and in vivo. Reciprocal interactions between GemOE cells and MSCs elevate the TIC, basal and EMT traits in GemOE cells leading to enhanced aggressiveness. Indeed, faster, larger and more aggressive tumors develop when GemOE cells are co-injected with MSCs in orthotropic tumor model. Concurrently, inhibiting c-Abl and thus geminin function or RAGE or CXCR4 activity in the in vivo model not only suppressed MSCs recruitment to the orthotopic breast tumors, but also led to decrease in TIC, basal and EMT phenotypes in these tumors. Conclusion: We suggest that GemOE generates metastatic tumors in part through recruiting and interacting with MSCs. Citation Format: Theresa Bonner, Suryatheja Ananthula, Janene Nordan, Simran Batth, Gailen D. Marshall, Lauren H. Gardner, Yoshiko Shimizu, Wael M. ElShamy. Geminin overexpression-dependent recruitment and crosstalk with mesenchymal stem cells enhances aggressiveness in triple-negative breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4112.