tbuckley/cabot-search huggingface dataset:
Abstract 2421: The role of p53 mutational status and SOX9 suppression in chemotherapy response of ovarian cancer
Authors: Noelle L. Cutter, Matthew Lucito, Ryan Frank, Kimberly Doyle
Journal: Cancer Research (2017)

Abstract Ovarian cancers are highly heterogeneous where platinum based chemotherapy which induces DNA crosslinking resulting in apoptosis of the cell is the preferred treatment. However, many patients are intrinsically resistant or quickly develop resistance. The Sox factors are a large family of transcription factors that play important roles in tumor development and progression in a variety of human malignancies and diverse developmental processes, but their impact in clinical tumorigenesis is still unclear. An analysis of genomic changes in ovarian cancer has provided the most comprehensive and integrated view of cancer genes for any cancer type to date. Ovarian serous adenocarcinoma tumors from 500 patients were examined by The Cancer Genome Atlas (TCGA) Research Network and analyses are reported in a recent issue of Nature. This evidence suggests that epigenetic deregulation, such as methylation, may be a key factor in the onset and maintenance of chemoresistance. Previous microarray analysis results in our lab correctly identified a subset of about 300 genes that when methylated altered the chemoresistance of the ovarian epithelium cells in culture. Of the genes identified in the analysis we further set out to characterize oncogenes and tumor suppressor genes that interact with the guardian of the genome, TP53, to determine if we could elucidate the mechanism by which it increased resistance. Using several in-vitro assays, we determined that the loss of p53 in conjunction with SOX9 decreased the level of apoptosis in response to carboplatin. Furthermore, in cells with mutated p53/SOX9 show an increase in tumorigenesis. Regulation of several pathways with p53 mutations in ovarian cancer might represent a therapy response prediction and could be a future therapeutic target for ovarian cancer. In addition, the crosstalk between p53/SOX9 and epigenetic regulators may present a valid treatment option for increasing carboplatin sensitivity in resistant patients. Note: This abstract was not presented at the meeting. Citation Format: Noelle L. Cutter, Matthew Lucito, Ryan Frank, Kimberly Doyle. The role of p53 mutational status and SOX9 suppression in chemotherapy response of ovarian 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 2421. doi:10.1158/1538-7445.AM2017-2421
Significance of a soft-coagulation system with monopolar electrode for hepatectomy: A retrospective two-institution study by propensity analysis
Authors: Takeomi Hamada, Atsushi Nanashima, Koichi Yano, Yorihisa Sumida, Masahide Hiyoshi, Naoya Imamura, Shuichi Tobinaga, Yuki Tsuchimochi, Shinsuke Takeno, Yoshiro Fujii, Takeshi Nagayasu
Journal: International Journal of Surgery (2017)
Abstract 5604: Novel biomarkers Ly6E/K play important role in drug resistance and tumor immune escape
Authors: Midar A. Hossiny, William R. Frazier, Noriko Steiner, Bhaskar Kallakury, Rakesh Kumar, Geeta Upadhyay
Journal: Cancer Research (2017)

Abstract Stem cell antigen Sca-1 is implicated in murine cancer stem cell biology and breast cancer models, but the role of its human homologs Ly6K and Ly6E in breast cancer are not established. Here we report increased expression of Ly6K/E in human breast cancer specimens correlates with poor overall survival, with an additional specific role for Ly6E in poor therapeutic outcomes. Increased expression of Ly6K/E also correlated with increased expression of the immune checkpoint molecules PDL1 and CTLA4, increased tumor-infiltrating T regulatory cells, and decreased natural killer (NK) cell activation. Mechanistically, Ly6K/E was required for TGFβ signaling and proliferation in breast cancer cells, where they contributed to phosphorylation of Smad1/5 and Smad2/3. Furthermore, Ly6K/E promoted cytokine-induced PDL1 expression and activation and binding of NK cells to cancer cells. Finally, we found that Ly6K/E promoted drug resistance and facilitated immune escape in this setting. Overall, our results establish a pivotal role for a Ly6K/E signaling axis involving TGFβ in breast cancer pathophysiology and drug response, and highlight this signaling axis as a compelling realm for therapeutic invention. Citation Format: Midar A. Hossiny, William R. Frazier, Noriko Steiner, Bhaskar Kallakury, Rakesh Kumar, Geeta Upadhyay. Novel biomarkers Ly6E/K play important role in drug resistance and tumor immune escape [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 5604. doi:10.1158/1538-7445.AM2017-5604
Abstract 5797: Semaphorin 5A preserves epithelial phenotype in pancreatic cancer cells by regulating cross-talk between Wnt and TGF-β signaling
Authors: Sugandha Saxena, Abhilasha Purohit, Surinder K. Batra, Rakesh K. Singh
Journal: Cancer Research (2017)

Abstract Pancreatic cancer (PC) is one of the deadliest forms of cancers. In spite of recent advances, minimal progress has been made in our understanding of PC progression, metastasis, and treatment of PC patients with advanced disease. Striking similarity between the process of cancer metastasis and guidance of neuronal cells to their target sites has generated interest in pharmacologically targeting guidance cue molecules for treatment of metastasis. Among the guidance cue family members, Semaphorin5A (SEMA5A), was found to be involved in organ-specific homing during PC metastasis. With an interest to delineate the function of SEMA5A in PC, we generated SEMA5A knockdown in metastatic PC cell lines. Knock down of SEMA5A expression resulted in loss of cellular differentiation and epithelial phenotype with higher motility as compared to vector control cells. This observation is in accordance with our previous finding that SEMA5A expression was higher in well-differentiated tumors in comparison with undifferentiated pancreatic tumors. Loss of SEMA5A increased TGF-β2 production, decreased expression of E-cadherin, and nuclear translocation of β-catenin. Furthermore, we observed higher Wnt activity and increased expression of the transcription factor SNAIL in SEMA5A knockdown cells in comparison with vector control cells. Higher Wnt signaling along with increased TGF-β2 production explains the loss of differentiation and epithelial markers. Moreover, we observed that non canonical TGF-β2/AKT mediated inhibition of GSK3-β is responsible for increased stability of β-catenin and SNAIL, thereby activating Wnt signaling in SEMA5A knockdown cells. Our observations demonstrate that SEMA5A has a potential role in maintaining the epithelial phenotype in PC cells by keeping cross-talk between Wnt and TGF-β signaling under check. Citation Format: Sugandha Saxena, Abhilasha Purohit, Surinder K. Batra, Rakesh K. Singh. Semaphorin 5A preserves epithelial phenotype in pancreatic cancer cells by regulating cross-talk between Wnt and TGF-β signaling [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 5797. doi:10.1158/1538-7445.AM2017-5797
Association of Estimated Sodium Intake With Adverse Cardiac Structure and Function
Authors: Senthil Selvaraj, Luc Djoussé, Frank G. Aguilar, Eva E. Martinez, Vincenzo B. Polsinelli, Marguerite R. Irvin, Donna K. Arnett, Sanjiv J. Shah
Journal: Journal of the American College of Cardiology (2017)
Abstract 1112: Forced reduction of DSS1, a member of TREX2 complex, highly sensitizes chemotherapy to breast cancer cells in a BRCA2-independent manner
Authors: Kazuhiko Kuwahara, Naomi Gondo, Andri Rezano, Zhenhuan Zhang, Yukari Hato, Kiyotaka Kuzushima, Hiroji Iwata, Tatsuya Toyama, Eisaku Kondo
Journal: Cancer Research (2017)

Abstract [Introduction] DSS1 (deleted in split-hand/split-foot malformation 1) was originally identified as a BRCA2-associated/stabilizing protein. By comparison of DSS1 mRNA level, we reported that the high DSS1 expression groups in breast cancer patients showed worse prognosis in relapse-free survival (RFS); however, DSS1 expression per se was not correlated with other clinical parameters including cellular proliferation or tumor grade, suggesting that the level of DSS1 affected the sensitivity of DNA-damage agents in breast cancer cells (Rezano et al., 2013). It still remains unclear why the expression level of DSS1 is associated with chemosensitivity, because DSS1 has multifunctional properties regulating homologous recombination and RNA-mediated genomic stability. In this study, we investigated if the effect of DSS1 in chemosensitivity is influenced by two representative DSS1-associated molecules, BRCA2 and PCID2. [Methods] We established MCF7 overexpressing DSS1 (MCF7/DSS1) by retroviral transfection. DSS1, BRCA2, or PCID2 knockdown in MCF7 was performed using siRNA transfection. The susceptibility to the cytotoxic chemotherapy such as doxorubicin and paclitaxel in breast cancer cells was evaluated by flow cytometry to detect apoptosis and colony assay. In addition, we compared patient survival by dividing patients into high or low expression group of BRCA2 or PCID2 using cohort studies. [Results] BRCA2 depletion in MCF7/DSS1 did not alter the chemoresistance. Although DSS1 knockdown induced the downregulation of BRCA2, direct depletion of BRCA2 did not show marginal effect to chemosensitivity, suggesting that the enhancement of chemosensitivity by DSS1 knockdown was not related to BRCA2 expression. Importantly, over- and under-expression of PCID2 induced similar effect to chemosensitivity compared to those of DSS1. There was a trend that high PCID2 expression group in breast cancer patients showed worse prognosis in RFS. [Conclusion] DSS1 could be a molecular target to increase chemosensitivity, which is independent of BRCA2 expression. Rather, the transcription-coupled DNA damage induced by impaired TREX2 complex might be associated with induction of chemosensitivity. Citation Format: Kazuhiko Kuwahara, Naomi Gondo, Andri Rezano, Zhenhuan Zhang, Yukari Hato, Kiyotaka Kuzushima, Hiroji Iwata, Tatsuya Toyama, Eisaku Kondo. Forced reduction of DSS1, a member of TREX2 complex, highly sensitizes chemotherapy to breast cancer cells in a BRCA2-independent manner [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 1112. doi:10.1158/1538-7445.AM2017-1112
Abstract 2951: The tumor microenvironment in cholangiocarcinoma is dominated by an immunosuppressive infiltrate
Authors: Nathania M. Figueroa, Brian Belt, Ankit Patel, Booyeon Han, Margaret Hill, William Alexander, Michael O'Dell, Aditi Murthy, Kelli Connolly, Scott A. Gerber, Aram Hezel, David Linehan
Journal: Cancer Research (2017)

Abstract Purpose: To characterize the dynamics of the immune response to cholangiocarcinoma (CCA) in a genetically engineered mouse model of CCA in order to identify immune pathways susceptible to targeted immunotherapies. Experimental Design: Genetically modified mice with targeted Kras activation and loss of p53 (Alb-Cre/LSL-KRASG12D /p53Lox/+) in the liver spontaneously develop CCA recapitulating the histopathologic features of human disease. To evaluate the in vivo immune response to CCA, tumors from Kras-p53 mice and normal livers were excised and processed for histologic examination, flow cytometry, and gene expression analysis. Immunohistochemistry (IHC) and flow cytometry were performed on myeloid and T cell markers to distinguish immune cell subsets. Cell lines established from isolated CCA tumors were used to assess the functional impact between the immune system and tumor cells in co-culture in-vitro studies. Results: Kras-p53 murine hepatic tumors were highly desmoplastic with a heavy fibrotic stromal compartment. IHC analysis demonstrated a prominent inflammatory leukocyte infiltrate compared to normal liver. Flow cytometry of single cell tumor suspensions showed the immune reaction was dominated by CD11b+ monocytic (Ly6C+) and granulocytic (Ly6G+) myeloid cells, and Foxp3+ regulatory T cells (T reg). In vitro studies revealed tumor educated myeloid cells expressed higher levels of genes associated with an immunosuppressive phenotype, including Arginase 1 (p=&amp;lt;0.007). Invasion assays analyzing the migration potential of CCA cell lines co-cultured with CD11b+ cells showed increased invasive properties in these tumor cells when compared to naive controls (p=&amp;lt;0.0001). Additionally, increased tumor-initiating properties were seen by qRT-PCR in tumor cell lines having undergone similar co-culture experiments. These data suggest the immune response to CCA is predominantly immunosuppressive and tumor supportive. Conclusion: CCA tumors from Alb-Cre/LSL-KRASG12D /p53Lox/+ mice have a prominent immunosuppressive infiltrate recapitulating features of the immune reaction in human disease. Thus, Kras-p53 mice provide an ideal model to test targeted immunotherapy for the treatment of CCA. Citation Format: Nathania M. Figueroa, Brian Belt, Ankit Patel, Booyeon Han, Margaret Hill, William Alexander, Michael O'Dell, Aditi Murthy, Kelli Connolly, Scott A. Gerber, Aram Hezel, David Linehan. The tumor microenvironment in cholangiocarcinoma is dominated by an immunosuppressive infiltrate [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 2951. doi:10.1158/1538-7445.AM2017-2951
Abstract LB-136: Characterization of residual Basal Cell Carcinoma after vismodegib treatment
Authors: Brian Biehs, Gerrit J. Dijkgraaf, Bruno Alicke, Franklin Peale, Stephen E. Gould, Frederic J. de Sauvage
Journal: Cancer Research (2017)

Abstract We have generated a mouse model of Superficial Basal Cell Carcinoma (BCC) to study the effect of the Smoothened inhibitor vismodegib in vivo. Despite the potency of vimodegib in blocking Hedgehog (Hh) signaling and efficacy in treatment of BCC, residual disease persists in the mouse model. To better understand the Biology of BCC and the potential mechanisms maintaining BCC during treatment, we profiled isolated untreated as well as residual tumors. We found that treated tumors change their transcriptional program to resemble the cells of skin and hair follicle structures like the Interfollicular Epidermis (IFE) and Isthmus, both of which harbor stem cell compartments. Consistent with these findings, residual disease lacks expression of epidermal differentiation markers and initiates growth upon cessation of treatment. While Wnt signaling is clearly required for BCC initiation in mouse models, we show that Wnt signaling is down-regulated in untreated full-blown disease and subsequently strongly induced in the treated tumors. We hypothesize that re-initiation of the Wnt pathway maintains BCC and study the effect of blocking both Wnt and Hh pathways with combined treatment of vismodegib and Wnt inhibitors. Citation Format: Brian Biehs, Gerrit J. Dijkgraaf, Bruno Alicke, Franklin Peale, Stephen E. Gould, Frederic J. de Sauvage. Characterization of residual Basal Cell Carcinoma after vismodegib treatment [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 LB-136. doi:10.1158/1538-7445.AM2017-LB-136
Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature
Authors: Charles F. Craddock, Aimee E. Houlton, Lynn Swun Quek, Paul Ferguson, Emma Gbandi, Corran Roberts, Marlen Metzner, Natalia Garcia-Martin, Alison Kennedy, Angela Hamblin, Manoj Raghavan, Sandeep Nagra, Louise Dudley, Keith Wheatley, Mary Frances McMullin, Srinivas P. Pillai, Richard J. Kelly, Shamyla Siddique, Michael Dennis, Jamie D. Cavenagh, Paresh Vyas
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML. Experimental Design: We compared outcomes in 259 adults with AML (n = 217) and MDS (n = 42) randomized to receive either AZA monotherapy (75 mg/m2 × 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients. Results: Co-administration of VOR did not increase the overall response rate (P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P = 0.0001), IDH1 (P = 0.004), and TP53 (P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430–40. ©2017 AACR.
Abstract 1927: The significance of calreticulin in pancreatic cancer: a molecule highly expressed in pancreatic cancer stem-like cells
Authors: Satoshi Matsukuma, Kiyoshi Yoshimura, Atsunori Oga, Moeko Inoue, Takuya Fujimtoto, Atsuo Kuramasu, Masanori Fuse, Ryouichi Tsunedomi, Hidetoshi Eguchi, Hiroto Matsui, Shinsuke Kanekiyo, Yukio Tokumitsu, Shinobu Tomochika, Michihisa Iida, Yoshihiro Tokuhisa, Kazuhiko Sakamoto, Nobuaki Suzuki, Tomoko Furuya-Kondo, Hiroshi Itoh, Shigeru Takeda, Shigeru Yamamoto, Shigefumi Yoshino, Shoichi Hazama, Tomio Ueno, Hiroaki Nagano
Journal: Cancer Research (2017)

Abstract Cancer stem-like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P-CSLCs). P-CSLC-enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by two-dimensional electrophoresis and tandem mass spectrometry. The results indicated that a chaperone protein calreticulin (CRT) was significantly upregulated in P-CSLCs compared to parental cells. Flow cytometry analysis demonstrated that CRT was mostly localized to the surface of P-CSLCs and did not correlate with the levels of CD44v9, another P-CSLC biomarker. Furthermore, the side population in CRThigh/CD44v9low population is much higher than that in CRTlow/CD44v9high population. CRT expression was also assessed by immunohistochemistry in pancreatic cancer tissues (n = 80) obtained after radical resection and was found to be associated with patients’ clinicopathological features and disease outcomes in the Cox’s proportional hazard regression model. Multivariate analysis identified CRT as an independent prognostic factor for pancreatic cancer patients, along with age and post-operative therapy. Our results suggest that CRT can serve as a biomarker of P-CSLCs and a prognostic factor associated with poorer survival of pancreatic cancer patients. This novel biomarker can be useful for detecting P-CSLCs independently, which had been detectable by multiple surface markers like CD24, CD44 and ESA. We will present CSLCs properties of CRThigh population in P-CSLCs. Citation Format: Satoshi Matsukuma, Kiyoshi Yoshimura, Atsunori Oga, Moeko Inoue, Takuya Fujimtoto, Atsuo Kuramasu, Masanori Fuse, Ryouichi Tsunedomi, Hidetoshi Eguchi, Hiroto Matsui, Shinsuke Kanekiyo, Yukio Tokumitsu, Shinobu Tomochika, Michihisa Iida, Yoshihiro Tokuhisa, Kazuhiko Sakamoto, Nobuaki Suzuki, Tomoko Furuya-Kondo, Hiroshi Itoh, Shigeru Takeda, Shigeru Yamamoto, Shigefumi Yoshino, Shoichi Hazama, Tomio Ueno, Hiroaki Nagano. The significance of calreticulin in pancreatic cancer: a molecule highly expressed in pancreatic cancer stem-like cells [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 1927. doi:10.1158/1538-7445.AM2017-1927
Ultrasound and PET-CT Correlation in Shoulder Pathology
Authors: Christopher J. Burke, William R. Walter, Ronald S. Adler, James S. Babb, Joseph Sanger, Fabio Ponzo
Journal: Clinical Nuclear Medicine (2017)

To correlate shoulder ultrasound and radiography with F-FDG PET-CT to establish FDG uptake and therefore range of metabolic activity, as defined by SUV analysis, in various symptomatic shoulder pathologies.Retrospective database query was performed for shoulder ultrasound and PET-CT scans between January 2012 and January 2017. Patients who had both studies within 1 year were included. Age- and sex-matched control patients with PET-CT scans only were also included. Retrospective image review determined shoulder pathology, and F-FDG SUVmax was measured using regions of interest placed at the glenohumeral joint, rotator cuff/bursa, and bicipital groove. Glenohumeral and acromioclavicular osteoarthrosis was assessed by radiography using the Kellgren-Lawrence classification system.Thirty-three patients had both imaging studies within 1 year. Ten patients (11 cases) were included, ranging in age from 56 to 90 years (mean, 67.9 years). Control subjects were selected among patients receiving PET-CT within 1 week of symptomatic patients. Glenohumeral osteoarthrosis was mild in 3 (27%), moderate in 2 (18%), and severe in 2 (18%). Six full-thickness rotator cuff tears (55%) were identified. SUVmax means were compared between the pathologic and control groups and were significantly higher in the former: glenohumeral joint (1.96 vs 1.32; P = 0.016), rotator cuff/bursa (2.80 vs 2.0; P = 0.005), and bicipital groove (2.19 vs 1.48; P = 0.007). The highest values were seen in full-thickness rotator cuff tear and severe biceps tenosynovitis.Increased metabolic activity about the shoulder is associated with a spectrum of rotator cuff, glenohumeral joint, and other soft tissue pathology that can be correlated with diagnostic ultrasound findings.