tbuckley/cabot-search huggingface dataset:
Abstract 3259: LY3127804, a novel anti-Angiopoietin-2 antibody in combination with an anti-VEGFR2 antibody potently inhibits angiogenesis, tumor growth and metastasis
Authors: Sudhakar R. Chintharlapalli, Johnny E. Croy, Donmienne Leung, Damien Gerald, Jirong Lu, Philip W. Iversen, Linda N. Lee, Lysiane Huber, Jonathan Tetreault, Rowena Almonte-Baldonado, Jianghuai Xu, Bharathi Ramamurthy, Jennifer A. Pereira, Chi-Kin Chow, Axel-Rainer Hanauske, Volker Wacheck, Laura Benjamin, Ling Liu
Journal: Cancer Research (2016)

Abstract Angiopoeitin-2 (Ang2) is released from endothelial cells only in response to stimulus (e.g. wound healing, tumor growth) and facilitates blood vessel sprouting and inhibits pericyte-endothelial cell interaction via Tie2 signaling. Combination of an anti-Ang2 antibody and aflibercept, a VEGF trap, has been shown to inhibit tumor growth and decrease tumor vascularity in mouse xenograft tumor models (Daly et al., Cancer Res (2013) 73(1):108). Multiple investigational anti-Ang2 antibody therapies are currently in clinical trials. LY3127804 is a humanized and engineered IgG4 isotype antibody that selectively binds to Ang2 with high affinity and neutralizes Ang2 induced phospho-Tie2. LY3127804 inhibits sprouting angiogenesis and increases pericyte coverage in a mouse developmental retinal angiogenesis model and in mice bearing PC3 xenograft tumors. Combination of LY3127804 and DC101, a potent anti-VEGFR2 antibody, exhibits enhanced efficacy when compared to monotherapy in multiple patient derived xenograft models including NSCLC and ovarian cancers. Anti-Ang2 antibody monotherapy alone resulted in marginal reduction of tumor growth and improved overall survival, while DC101monotherapy had greater reduction in tumor volume with no survival benefit in MDA-MB-231 breast orthotopic model. Combination of anti-Ang2 antibody with anti-VEGFR2 antibody shows reduction in tumor volume and improved overall survival. This robust pre-clinical evidence supports testing the combination of anti-Ang2 and anti-VEGFR2 antibodies in the clinic. LY3127804 is currently in Phase 1 clinical trials (NCT02597036) Citation Format: Sudhakar R. Chintharlapalli, Johnny E. Croy, Donmienne Leung, Damien Gerald, Jirong Lu, Philip W. Iversen, Linda N. Lee, Lysiane Huber, Jonathan Tetreault, Rowena Almonte-Baldonado, Jianghuai Xu, Bharathi Ramamurthy, Jennifer A. Pereira, Chi-Kin Chow, Axel-Rainer Hanauske, Volker Wacheck, Laura Benjamin, Ling Liu. LY3127804, a novel anti-Angiopoietin-2 antibody in combination with an anti-VEGFR2 antibody potently inhibits angiogenesis, tumor growth and metastasis. [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 3259.
Abstract 315: Potential role of androgen receptor in aromatase inhibitor resistance
Authors: Caleb Hunt, Sarah E. Lock, Cynthia E. Shannon, Nichole M. Varela-Gonzalez, Randolph K. Larsen, Amanda J. Schech
Journal: Cancer Research (2016)

Abstract Clinical assessment of breast cancer tumors has shown that androgen receptor (AR) is expressed in more than 75% of cases, independent of molecular subtype. Specifically, clinical studies have shown that estrogen receptor (ER) and AR discordance correlates with endocrine resistance. Preclinical studies show that downregulation of ER results in a lack of estrogen mediated growth which is concurrent with upregulation of AR and its mediated gene targets. In addition, forced expression of AR was shown to induce resistance to tamoxifen, even when estrogen receptor was still expressed. Furthermore, ER positive breast cancer cells made resistant to tamoxifen express higher levels of AR and show sensitivity to abiraterone acetate. Together, these results implicate AR in endocrine resistance and suggest AR as a potential therapeutic target in a subset of these endocrine resistant cancers. The aim of this study was to better understand the role of AR in aromatase inhibitor (AI) resistance through the use of cell lines made resistant to AI through xenograft mouse modeling. In this study, MCF7 cells, MCF7 cells transfected with the human aromatase gene (MCF7Ca), and their aromatase inhibitor (AI) resistant counterparts, were analyzed for changes in AR and ER expression by qPCR and Western blot. Sensitivity of these cells to AR targeting agents was assessed by MTT assay. MCF7Ca cells displayed decreased expression of AR and increased expression of ER when compared to MCF7 cells. AI-resistant cell lines displayed modulation of ER and AR expression when compared to their AI-sensitive counterparts. Upregulation of AR was accompanied with increased AR transcriptional activity, as demonstrated by increased expression of PSA. Treatment of AI-resistant cells with AR targeting agents displayed increased sensitivity when compared to AI-sensitive cells. Together, these results suggest that upregulation of AR may contribute to AI-resistance, and that targeting AR in AI-resistant breast cancer may have therapeutic relevance. Citation Format: Caleb Hunt, Sarah E. Lock, Cynthia E. Shannon, Nichole M. Varela-Gonzalez, Randolph K. Larsen, Amanda J. Schech. Potential role of androgen receptor in aromatase inhibitor resistance. [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 315.
Abstract 24: Loss of ubiquitin-specific peptidase 18 (USP18) causes cold sensitive mice by destabilizing the critical regulator of thermogenesis: uncoupling protein-1 (UCP-1)
Authors: Xi Liu, Yun Lu, Lin Zheng, David J. Sekula, Sarah J. Freemantle, Ethan Dmitrovsky
Journal: Cancer Research (2016)

Abstract USP18 is the major ISG15 (Interferon-Stimulated Gene 15) deconjugase that removes ISG15 from substrate proteins. We recently reported that USP18 null mice spontaneously develop leiomyosarcomas. Intriguingly, these USP18 null mice are also markedly cold sensitive as compared to their wild-type littermates. When briefly exposed to cold stimuli, USP18 null mice significantly (P &amp;lt; 0.05) decreased their body temperature. In contrast, wild-type mice exposed to the same experimental conditions exhibited transient changes in their body temperature. We sought to elucidate the engaged mechanism. Expression profiles of critical thermogenic regulatory proteins were examined by immunoblot analyses of brown fat tissues of USP18 null mice. Strikingly, UCP-1 expression was substantially reduced in these tissues of USP18 null versus wild-type mice. To independently confirm that reduced UCP-1 expression was caused by loss of USP18, stable knock-down of USP18 was independently achieved in a panel of murine cell lines by use of transfected small hairpin RNAs (shRNAs). The obtained results were compared to that of transfected control vectors. USP18 down-regulation by different shRNAs markedly reduced UCP-1 protein as compared to controls. As expected, engineered gain of USP18 expression in the same murine cell lines stabilized UCP-1 protein. We explored if UCP-1 destabilization was due to its complex formation with the ubiquitin-like protein ISG15. This was the expected experimental outcome since USP18 is the distinct deconjugase that removes ISG15 from complexed proteins. Immunoprecipitation assays were performed to establish this direct association. These studies revealed a complex formed between ISG15 and UCP-1 protein. Thus, engineered loss of USP18 in mice led to cold sensitive mice from repression of UCP-1. As a consequence of its complex with ISG15, the thermogenic regulator UCP-1 was destabilized. Taken together, this study extends prior work by showing a previously unrecognized link between USP18 and regulation of thermogenesis. This defines a novel role for the USP18 protease in metabolism. Citation Format: Xi Liu, Yun Lu, Lin Zheng, David J. Sekula, Sarah J. Freemantle, Ethan Dmitrovsky. Loss of ubiquitin-specific peptidase 18 (USP18) causes cold sensitive mice by destabilizing the critical regulator of thermogenesis: uncoupling protein-1 (UCP-1). [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 24.
Abstract 2310: With a little help from CD4 T cells in adoptive T-cell transfer
Authors: Else M. Inderberg, Sébastien Wälchli, Marit R. Myhre, Kari Lislerud, Gunnar Kvalheim, Gustav Gaudernack
Journal: Cancer Research (2016)

Abstract Adoptive transfer of genetically engineered T cells offers great opportunities in cancer immunotherapy, however until recently, HLA-Class II-restricted TCRs have been largely ignored. We have identified and cloned HLA class II-restricted CD4+ T cells isolated from patients vaccinated with long peptides derived from antigens such as hTERT, survivin and frameshift mutated TGFβRII. Several of these cancer patients demonstrated outstanding clinical responses to peptide- or dendritic cell based cancer vaccines with &amp;gt;10-year survival. In these patients strong T-cell responses against peptides other than those used for vaccination were detected, suggesting epitope spreading. Responses against certain peptides associated with clinical benefit were identified and CD4+ T-cell clones recognizing such peptides were isolated. In depth studies of their specificities lead to the selection of HLA-DR and -DQ restricted T-cells having high functional avidity for the HLA-peptide complexes. We studied tumor cell and/or protein recognition and found one telomerase-specific CD4+ T-cell clone recognizing a melanoma cell line with the corresponding HLA allele. The TCR sequences of the interesting clones were identified. The ribosome skipping 2A sequence technique was used to express these TCRs in an mRNA expression vector or retrovirus. When expanded T cells were electroporated with these TCRs, both redirected CD8+ and CD4+ T cells produced TNF-α, IFN-γ and the degranulation marker (CD107a) following co-incubation with specific peptide-loaded targets. We have demonstrated that choosing highly functional CD4+ T-cell clones specific for tumor-associated or -specific antigens from patients with clinical responses after immunotherapy treatment is a successful method for identifying highly functional HLA class II restricted TCRs for adoptive T-cell transfer. The use of HLA class II-restricted TCRs may be of therapeutic value both in haematopoietic malignancies and in melanoma where tumor cells often express HLA class II. In addition, combining the redirection of T cells with both HLA class I- and class II-restricted TCRs may provide a more powerful therapeutic effect in adoptive T cell therapy. Citation Format: Else M. Inderberg, Sébastien Wälchli, Marit R. Myhre, Kari Lislerud, Gunnar Kvalheim, Gustav Gaudernack. With a little help from CD4 T cells in adoptive T-cell transfer. [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 2310.
Abstract 953: miR-31 targets ARID1A to enhance the progression of oral carcinoma
Authors: Wen-Cheng Lu, Shu-Chun Lin, Kuo-Wei Chang
Journal: Cancer Research (2016)

Abstract miR-31 is an oncogenic microRNA in several malignancies including oral squamous cell carcinoma (OSCC). However, the function of miR-31 in modulating the stem cell properties in OSCC has not yet been explored. AT-rich interacting domain (ARID) containing protein members play pluripotent roles in modulating chromatin accessibility of the transcription machineries for gene expression. ARID1A has been shown suppressive to several malignancies and the driver mutations in ARID1A gene are noted in tumors. In this study, we identified that miR-31 targets ARID1A in OSCC, and a reverse expression between miR-31 and ARID1A was noted in OSCC tumors. Furthermore, the miR-31 induced migration, invasion, CSC cell population and stemness gene expression were rescued by ARID1A expression in OSCC cells. ARID1A suppressed the transcription activity of a panel of stemness markers through its affinity to A-T rich region in the promoters. A reverse correlation between ARID1A and these stem cell markers was also seen in OSCC tumors. miR-31+/ARID1A− OSCC cell subclone exhibited higher potency in sphere formation, as well as tumorigenesis and neck metastasis in nude mice relative to other cell subclones. In addition, tumors carrying high miR-31 expression and low ARID1A expression had the worst survival. In summary, this study provides novel mechanistic clues demonstrating that miR-31 targets ARID1A to enrich the stemness properties for OSCC progression. Citation Format: Wen-Cheng Lu, Shu-Chun Lin, Kuo-Wei Chang. miR-31 targets ARID1A to enhance the progression of oral 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 953.
A comparison with indocyanine green fluorescence imaging method and computed tomography-lymphography in sentinel lymph node identification for early breast cancer patients.
Authors: Hajime Abe, Keiichi Yamazaki, Kohri Yoneda, Atsuko Teramoto, Masao Ogawa, Masayasu Kawasaki, Masao Kameyama
Journal: Journal of Clinical Oncology (2015)

e22206 Background: Sentinel lymph nodes (SLN) biopsy has been established as a standard of care in the treatment of early breast cancer. Recently, SLN identification using computed tomography-lymphography (CTLG) has been reported in Japan. We had reported a new technique of SLN identification using fluorescence imaging of indocyanine green (ICG) injection. This study investigated the comparison with fluorescence imaging method and CTLG. Methods: 177 breast cancer patients without clinical evidence of lymph node metastasis were treated. On the day before the operation, CTLG was performed using 64-row multidetector CT. We performed an intradermal injection of contrast agent. The contrasted lymph flow and SLN were identified in reconstructed three-dimensional imaging. The SLN spot was indicated by CT laser light navigator system. During the operation, fluorescence images were obtained using the fluorescence imaging system, pde-neo (Hamamatsu Photonics Co., Japan). After ICG was injected intradermally in to the periareolar skin, lymphatic drainage was observed with fluorescence images. SLN biopsy was performed referring to the axillary compression technique by plastic device. Results: The median age of patients was 57 (range 28 – 87) years old. CTLG and fluorescence imaging was safely performed in all patients. CTLG could visualize lymphatic flow and accurately identify SLN in 93% (162) and 89% (158), respectively, whereas fluorescence imaging identified successfully lymphatic flow and SLN in all patients. Fluorescence imaging with axillary compression technique was visually easy to identify the location of SLN on the axillary skin even in obese patients. Lymphatic flows of CTLG were completely consistent with those of fluorescence imaging. The number of SLN identified by CTLG was significantly lower than that by fluorescence imaging (1.1 vs. 1.6, p < 0.01). 25 patients (14%) were found to have lymph node metastases pathologically, and seven of them had micrometastases of lymph node. Conclusions: Both of fluorescence imaging and CTLG revealed easy and effective to detect SLN, and fluorescence imaging was more high detection rate of SLN.
Abstract 218: Ewing sarcoma gene, EWS, role in mitochondrial homeostasis
Authors: Jun Hong Park
Journal: Cancer Research (2016)

Abstract Peroxisome proliferator-activated receptor γ coactivator (PGC-1α) is a central regulator of mitochondria biogenesis, function and cellular energy metabolism. PGC-1α protein is intrinsically unstable but the mechanism by which PGC-1α stability is regulated is not well understood. Here, we report that a multifunctional protein EWS (Ewing sarcoma) is critical for PGC-1α protein stability and mitochondrial homeostasis. EWS inactivation results in a rapid degradation of PGC-1α via ubiquitin-dependent proteasome pathway and reduces mitochondrial abundance. Re-introduction of EWS in Ews-deficient cells restores PGC-1α expression and mitochondrial anomalies. In the absence of Ews, expression of E3 ubiquitin ligase, FBXW7 (F-box/WD40 domain protein 7), is increased and depletion of Fbxw7 in Ews-null cells restores PGC-1α expression and mitochondrial density. Consistent with these findings, mitochondrial abundance and activity are significantly reduced in brown fat and skeletal muscles of Ews-deficient mice and expression of slow myosin heavy chain is significantly decreased in skeletal muscles of Ews-/- mice compared to controls. Furthermore, Ews-null mice display reduced expression of mitochondrial biogenesis, respiration and fatty acid β-oxidation genes in the liver and abnormally high serum lactate levels. These results demonstrate a novel role of EWS in mitochondrial and cellular energy homeostasis by controlling PGC-1α protein stability. Citation Format: Jun Hong Park. Ewing sarcoma gene, EWS, role in mitochondrial homeostasis. [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 218.
Abstract 3483: ESR1 gene expression and expression ratio of ESR1 to ESR2 are associated with worse prognosis in papillary thyroid carcinoma
Authors: Jin Wook Yi, Ra-Yeong Song, Hyeong Won Yu, Joon-Hyop Lee, Hyungju Kwon, Young Jun Chai, June Young Choi, Su-jin Kim, Kyu-Eun Lee
Journal: Cancer Research (2016)

Abstract Introduction Expression of estrogen receptor (ER) and progesterone receptor (PR) in breast cancer have been widely studied and used as prognostic markers or therapeutic targets in breast cancer patients. However, clinical and pathologic roles of these hormone receptor genes have not been clearly established in thyroid cancer. Materials and methods To evaluate the relationship between sex hormone receptor gene expressions and clinicopathologic variables, we analyzed ESR1, ESR2, ESR ratio (ESR1/ESR2) and PGR mRNA expression data from The Cancer Genome Atlas (TCGA) RNA sequencing experiment in papillary thyroid carcinoma (PTC). To validate results from TCGA analysis, we additionally analyzed a public microarray data (GSE 54598) from the gene expression omnibus (GEO) database. Results In TCGA data analysis, ESR1, ESR ratio and PGR expression were significantly higher in PTC tissue than in normal thyroid tissue (Mean value of normal versus tumor were 264.045 vs 659.427 in ESR1, 19.064 vs 92,017 in ESR ratio and 58.514 vs 119.792 in PGR, respectively). In female patients, ESR1 and ESR ratio was negatively correlated with advanced age (t-value was -2.257 and -2.949 in linear regression analysis). Expression of ESR1 and ESR ratio were higher in classic type PTC, presentation of lymphovascular invasion and BRAF V600E mutation. Higher expression group of ESR1 and ESR ratio showed worse overall survival in female PTC patients (Hazard ratio was 6.348 in ESR1 and 4.031 in ESR ratio, respectively). In microarray analysis, ESR1 and ESR ratio expressions were higher in tumor than normal, classic than follicular variant and BRAF V600E than wild type. Conclusion Expression of ESR1 and ESR ratio were associated with aggressive prognostic factors and worse overall survival in female PTC patients. These results suggest that higher expression of ESR1 and ESR ratio can be used as prognostic markers to predict survival in female patients. Citation Format: Jin Wook Yi, Ra-Yeong Song, Hyeong Won Yu, Joon-Hyop Lee, Hyungju Kwon, Young Jun Chai, June Young Choi, Su-jin Kim, Kyu-Eun Lee. ESR1 gene expression and expression ratio of ESR1 to ESR2 are associated with worse prognosis in papillary thyroid 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 3483.
Accumulated workloads and the acute:chronic workload ratio relate to injury risk in elite youth football players
Authors: Laura Bowen, Aleksander Stefan Gross, Mo Gimpel, François-Xavier Li
Journal: British Journal of Sports Medicine (2016)

The purpose of this study was to investigate the relationship between physical workload and injury risk in elite youth football players.The workload data and injury incidence of 32 players were monitored throughout 2 seasons. Multiple regression was used to compare cumulative (1, 2, 3 and 4-weekly) loads and acute:chronic (A:C) workload ratios (acute workload divided by chronic workload) between injured and non-injured players for specific GPS and accelerometer-derived variables:total distance (TD), high-speed distance (HSD), accelerations (ACC) and total load. Workloads were classified into discrete ranges by z-scores and the relative risk was determined.A very high number of ACC (≥9254) over 3 weeks was associated with the highest significant overall (relative risk (RR)=3.84) and non-contact injury risk (RR=5.11). Non-contact injury risk was significantly increased when a high acute HSD was combined with low chronic HSD (RR=2.55), but not with high chronic HSD (RR=0.47). Contact injury risk was greatest when A:C TD and ACC ratios were very high (1.76 and 1.77, respectively) (RR=4.98).In general, higher accumulated and acute workloads were associated with a greater injury risk. However, progressive increases in chronic workload may develop the players' physical tolerance to higher acute loads and resilience to injury risk.
Abstract LB-291: Environment or accident? A more stringent bound on environmental contributions to cancerogenesis
Authors: Sven Bilke, Paul S. Meltzer
Journal: Cancer Research (2016)

Abstract Finding the right balance between cancer prevention and early detection is essential for an efficient anti-cancer strategy. Yet, the underlying biological question “how much cancer risk results from chance, how much from environmental factors’’ continues to be controversial. Recently, the “bad luck’’ hypothesis was strengthened based on observing a tight correlation between a tissues cancer risk and its number of stem cell divisions [1]. This interpretation was later challenged by pointing out that certain even drastic changes of environmental risk factors would not affect theat correlation [2]. Based on this argument they derived an estimate of the upper bound of environmental contributions to canceriogenesis. Here we argue that the argument made in [2] did not fully appreciate that typically several mutations are requited before cancer initiation occurs [3]. We show that by incorporating this aspect into the analysis the correlation between the number of stem cell divisions and cancer risk would respond to changes of environmental factors. We re-analyze the data in [1] to derive a slightly more stringent upper bound of the environmental risk contributions for a number of cancers than the ones obtained in [2]. [1] C. Tomasetti, B. Vogelstein, Science 347(6217), 78-81 (2015) [2] S. Wu, S.Powers et al., Nature 529, 43-47 (2015) [3] C. Nordling, British Journal of Cancer 7(1), 68-72 (1953) Citation Format: Sven Bilke, Paul S. Meltzer. Environment or accident? A more stringent bound on environmental contributions to cancerogenesis. [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 LB-291.