tbuckley/cabot-search huggingface dataset:
Abstract 716: STAT1 expression in the tumor-stroma microenvironment is influenced by loss of PTEN in prostate cancer
Authors: Thiago Vidotto, Clarissa G. Picanço-Albuquerque, Fabiano P. Saggioro, Rodolfo Borges dos Reis, David Robert Siemens, Madhuri Koti, Jeremy A. Squire
Journal: Cancer Research (2016)

Abstract The prostate cancer (PCa) microenvironment is an admixture of stromal cells, such as lymphocytes, fibroblasts, myofibroblasts and blood vessel endothelium. The reactive stromal microenvironment of PCa facilitates tumor growth through cytokine and chemokine-mediated cell signaling. STAT1, a transcription factor, induces cell cycle arrest, apoptosis and modulates immune and inflammatory response through IFN-á/ã cytokine activation. IFN-á/ã may be secreted in response to PI3K/AKT activation, since this pathway is associated with JAK/STAT signaling. In addition, the PI3K/AKT pathway can become activated when the PTEN prognostic biomarker is deleted in PCa. The rationale for this project is that the immediate stromal microenvironment of PCa may become pro-tumorigenic as a result of induction of inflammatory cytokines caused by PTEN deletions and activation of PI3K/AKT. We performed FISH analysis of the PTEN gene on 172 cores on a PCa tissue microarray (TMA) derived from 43 patients with intermediate risk disease. Analysis of cytoplasmic and nuclear STAT1 in both the tumor and stromal compartments was performed on each TMA core using immunohistochemistry (IHC) to determine whether the tumor PTEN deletion status was associated with STAT1 expression. In each core, tumor and stromal cell histologies were evaluated independently to estimate the percentage area that was stained positive by IHC. The staining was graded as percentage of positive cells with 0 (negative), 1 (less than 10%), 2 (11% to 50%), and 3 (more than 51%). We found that STAT1 expression in stroma was increased when the PTEN gene in the adjacent tumor was homozygously deleted (p = 0,04). We also showed that mean STAT1 expression in benign tissue cores was reduced when compared to the average score from tumor tissue with one (p = 0.01) or two copies (p = 0.03) of the PTEN gene. STAT1 expression and PTEN gene copy numberPTEN copy numberMean STAT1 in StromaMean STAT1 in Tumor&amp;gt;2 copies0.410.822 copies0.510.651 copy0.600.700 copies0.850.85 These results suggest that the STAT1 pathway may be influenced by PTEN loss in this tumor, suggesting that the JAK/STAT inflammatory pathway may have future clinical applications in PCa. Citation Format: Thiago Vidotto, Clarissa G. Picanço-Albuquerque, Fabiano P. Saggioro, Rodolfo Borges dos Reis, David Robert Siemens, Madhuri Koti, Jeremy A. Squire. STAT1 expression in the tumor-stroma microenvironment is influenced by loss of PTEN in prostate 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 716.
Surveillance des infections à VHC aux Pays-Bas
Authors: S. S. Chaves, M-A. Widdowson, A. Bosman
Journal: Eurosurveillance (2003)

Les Pays-Bas ont deux systemes de surveillance des infections dues au virus de l’hepatite C (VHC). Les donnees agregees de laboratoire sont disponibles depuis 1990, et en 1999, la declaration de l'hepatite C est devenue obligatoire. Les resultats montrent que le nombre de cas declares est stable, avec une predominance des cas de sexe masculin (66 %), âges de 15 a 54 ans. L’utilisation de drogues injectables etait le principal mode de transmission (64 %). Le systeme de declaration devrait inclure plus de donnees cliniques pour permettre de mieux depister les changements des modes de transmission.
PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors
Authors: Adrian M. Seifert, Shan Zeng, Jennifer Q. Zhang, Teresa S. Kim, Noah A. Cohen, Michael J. Beckman, Benjamin D. Medina, Joanna H. Maltbaek, Jennifer K. Loo, Megan H. Crawley, Ferdinand Rossi, Peter Besmer, Cristina R. Antonescu, Ronald P. DeMatteo
Journal: Clinical Cancer Research (2016)

Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumors (GISTs) but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GISTs.We analyzed tumor and matched blood samples from 85 patients with GISTs and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in KitV558Δ/+ mice that develop GISTs.The inhibitory receptors PD-1, lymphocyte activation gene 3, and T-cell immunoglobulin mucin-3 were upregulated on tumor-infiltrating T cells compared with T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFNγ-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Δ/+ mice, imatinib downregulated IFNγ-related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition.PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GISTs. Collectively, our results provide the rationale to combine these agents in human GISTs. Clin Cancer Res; 23(2); 454-65. ©2016 AACR.
Knockdown of Plakophilin 2 Downregulates miR-184 Through CpG Hypermethylation and Suppression of the E2F1 Pathway and Leads to Enhanced Adipogenesis In Vitro
Authors: Priyatansh Gurha, Xiaofan Chen, Raffaella Lombardi, James T. Willerson, Ali J. Marian
Journal: Circulation Research (2016)

PKP2, encoding plakophilin 2 (PKP2), is the most common causal gene for arrhythmogenic cardiomyopathy.To characterize miRNA expression profile in PKP2-deficient cells.Control and PKP2-knockdown HL-1 (HL-1(Pkp2-shRNA)) cells were screened for 750 miRNAs using low-density microfluidic panels. Fifty-nine miRNAs were differentially expressed. MiR-184 was the most downregulated miRNA. Expression of miR-184 in the heart and cardiac myocyte was developmentally downregulated and was low in mature myocytes. MicroRNA-184 was predominantly expressed in cardiac mesenchymal progenitor cells. Knockdown of Pkp2 in cardiac mesenchymal progenitor cells also reduced miR-184 levels. Expression of miR-184 was transcriptionally regulated by the E2F1 pathway, which was suppressed in PKP2-deficient cells. Activation of E2F1, on overexpression of its activator CCND1 (cyclin D1) or knockdown of its inhibitor retinoblastoma 1, partially rescued miR-184 levels. In addition, DNA methyltransferase-1 was recruited to the promoter region of miR-184, and the CpG sites at the upstream region of miR-184 were hypermethylated. Treatment with 5-aza-2'-deoxycytidine, a demethylation agent, and knockdown of DNA methyltransferase-1 partially rescued miR-184 level. Pathway analysis of paired miR-184:mRNA targets identified cell proliferation, differentiation, and death as the main affected biological processes. Knockdown of miR-184 in HL-1 cells and mesenchymal progenitor cells induced and, conversely, its overexpression attenuated adipogenesis.PKP2 deficiency leads to suppression of the E2F1 pathway and hypermethylation of the CpG sites at miR-184 promoter, resulting in downregulation of miR-184 levels. Suppression of miR-184 enhances and its activation attenuates adipogenesis in vitro. Thus, miR-184 contributes to the pathogenesis of adipogenesis in PKP2-deficient cells.
Care and Outcomes of Patients With Cancer Admitted to the Hospital on Weekends and Holidays: A Retrospective Cohort Study
Authors: Lauren Lapointe-Shaw, Hani Abushomar, Xi-Kuan Chen, Katerina Gapanenko, Chelsea Taylor, Monika K Krzyzanowska, Chaim M Bell
Journal: Journal of the National Comprehensive Cancer Network (2016)

Patients admitted to the hospital on weekends experience worse outcomes than those admitted on weekdays. Patients with cancer may be especially vulnerable to the effects of weekend care. Our objective was to compare the care and outcomes of patients with cancer admitted urgently to the hospital on weekends and holidays versus those of patients with cancer admitted at other times.This was a retrospective study of all adult patients with cancer having an urgent hospitalization in Canada from 2010 to 2013. Patients admitted to hospital on weekends/holidays were compared with those admitted on weekdays. The primary outcome was 7-day in-hospital mortality. We also compared performance of procedures in the first 2 days of hospital admission and admission to critical care after the first 24 hours.290,471 hospital admissions were included. Patients admitted to hospital on weekends/holidays had an increased risk of 7-day in-hospital mortality (4.8% vs 4.3%; adjusted odds ratio [OR], 1.13; 95% CI, 1.08-1.17), corresponding to 137 excess deaths per year compared with the weekday group. This risk persisted after restricting the analysis to patients arriving by ambulance (7.1% vs 6.4%; adjusted OR, 1.11; 95% CI, 1.04-1.18). Among those who had procedures in the first 4 days of admission, fewer weekend/holiday-admitted patients had them performed in the first 2 days, for 8 of 9 common procedure groups. There was no difference in critical care admission risk after the first 24 hours.Patients with cancer admitted to the hospital on weekends/holidays experience higher mortality relative to patients admitted on weekdays. This may result from different care processes for weekend/holiday patients, including delayed procedures. Future research is needed to identify key outcome-driving procedures, and ensure timely access to these on all days of the week.
Abstract 192: Targeting the protein kinase Hunk in HER2+ resistant breast cancer
Authors: Joelle Zambrano, Kendall Phelps-Polirer, Melissa Abt, Elizabeth Yeh
Journal: Cancer Research (2016)

Abstract Despite the initial success of common HER2 inhibitors used in the clinic, including trastuzumab and lapatinib, HER2 positive (HER2+) breast cancer cells often acquire resistance through mechanisms that continue to remain poorly understood. A number of signaling molecules, which act downstream of HER2, including PI3K, Akt, JNK, and Hormonally-Upregulated Neu-associated Kinase (Hunk), are thought to contribute to resistance. Our recent studies indicate that targeting Hunk via shRNA in HER2+breast cancer cells that are sensitive to HER2 inhibitors (BT474) and cells that are resistant (JIMT) leads to increased caspase-3 activity in vitro and impaired tumor growth in vivo. In addition, we find that targeting Hunk not only sensitizes HER2+ cells to apoptosis, but also impairs autophagy, as indicated by decreased LC3BII expression, the lipidated form of LC3B which signifies active autophagy. Because elevated Hunk protein expression correlates with poorer prognosis, and since Hunk knockdown impairs autophagy, it is possible that Hunk acts to upregulate autophagy thereby contributing to the development of resistance. We have also found that the kinase JNK plays a role in resistance in HER2+ breast cancer cells, and demonstrate that JNK inhibition via a pan-JNK inhibitor impairs tumor growth of JIMT cells. We further show that co-targeting of JNK and HUNK results in greater cell death and significantly reduced tumor growth than either individual treatment in the JIMT-1, HER2+ resistant cell line, as well as a HER2+ line that was engineered to be lapatinib resistant, BT474-LR. Overall, our results indicate that targeting Hunk in HER2+ breast cancer not only alters autophagy and impairs tumor growth, but that co-targeting Hunk and JNK shows greater therapeutic effects on reducing tumor growth and inducing cell death. Citation Format: Joelle Zambrano, Kendall Phelps-Polirer, Melissa Abt, Elizabeth Yeh. Targeting the protein kinase Hunk in HER2+ resistant breast 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 192.
Abstract 4332: Discovery of BAY 1163877 - A pan-FGFR inhibitor: De novo structure-based design and lead optimization of benzothiophenyl-pyrrolotriazines
Authors: Marie-Pierre L. Collin, Mario Lobell, Walter Huebsch, Dirk Brohm, Mélanie Héroult, Klemens Lustig, Sylvia Gruenewald, Ulf Boemer, Rolf Jautelat, Holger Hess-Stump, Stefan Jaroch, Michael Brands, Karl Ziegelbauer
Journal: Cancer Research (2016)

Abstract Fibroblast growth factors (FGFs) orchestrate a variety of cellular functions by binding to their transmembrane tyrosine-kinase receptors (FGFR1-4) and activating downstream signaling pathways. Alterations in FGFR encoding genes are frequently observed in a variety of solid tumors including lung, gastric, breast and urothelial cancer. Therefore, targeting FGFRs using selective FGFR inhibitors is an attractive therapeutic approach to treat cancer patients. BAY 1163877 is an orally active, highly potent and selective small molecule FGFR-1, -2 and -3 kinase inhibitor. We disclose for the very first time its discovery and chemical structure. BAY 1163877 was derived from a de novo structure-based design approach and medicinal chemistry optimization. Data on the structure activity relationship and the pharmacokinetic profile of the benzothiophenyl-pyrrolotriazine structure class will be presented. Based on its favorable preclinical profile, BAY 1163877 is currently being investigated in a Phase 1 clinical trial (NCT01976741). Citation Format: Marie-Pierre L. Collin, Mario Lobell, Walter Huebsch, Dirk Brohm, Mélanie Héroult, Klemens Lustig, Sylvia Gruenewald, Ulf Boemer, Rolf Jautelat, Holger Hess-Stump, Stefan Jaroch, Michael Brands, Karl Ziegelbauer. Discovery of BAY 1163877 - A pan-FGFR inhibitor: De novo structure-based design and lead optimization of benzothiophenyl-pyrrolotriazines. [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 4332.
Abstract 2238: Understanding immune phenotypes and their spatial relationships to breast adenocarcinoma in FFPE tissues
Authors: Yi Zheng, Pallavi Thuse, Linying Liu, Edward C. Stack, Michael Campisano, Kent Johnson, Darryn Unfricht, Nara Narayanan, Clifford Hoyt, Milind Rajopadhye
Journal: Cancer Research (2016)

Abstract The relationship between elements of the immune system and breast tumors in situ requires an approach that leverages multiplexed immunohistochemistry (mIHC) with multispectral imaging to facilitate precise image analyses. To achieve this, we developed a novel 7-color mIHC assay, based on tyramide signal amplification, that allowed us to reliably interrogate CD3, CD4, CD8, FoxP3, CD68, and cytokeratin, in formalin-fixed, paraffin-embedded (FFPE) samples of human breast cancer. Imaging was performed using the multispectral Mantra system and inForm image analysis software. Using this specific mIHC panel and the cell segmenting and phenotyping tools in inForm, we were able to reliably identify cytotoxic T cells (CD3+ CD8+), helper T cells (CD3+ CD4+), regulatory T cells (CD3+ CD4+ FoxP3+), tumor associated macrophages (CD68+) and breast tumor cells (CK+). With cell phenotypes within the tumor microenvironment determined based on specific colocalized staining combinations, we then employed spatial point pattern analyses to examine spatial relationships between specific phenotypes. With this analysis, we were able to describe distances between cytotoxic T cells and regulatory T cells, cytotoxic T cells and tumor associated macrophages, as well as cytotoxic T cells and breast tumor cells. With this combined mIHC, multispectral imaging and advanced image analysis, we demonstrate a novel method that allows for unique tumor microenvironment assessments within in breast cancer. Through the preservation of tumor architecture available in archival FFPE tissues, these methods can advance our understanding of unique tumor microenvironment interactions, and could provide the ability to stratify responses to immunotherapies. Citation Format: Yi Zheng, Pallavi Thuse, Linying Liu, Edward C. Stack, Michael Campisano, Kent Johnson, Darryn Unfricht, Nara Narayanan, Clifford Hoyt, Milind Rajopadhye. Understanding immune phenotypes and their spatial relationships to breast adenocarcinoma in FFPE tissues. [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 2238.
Lacking Of Missing Killer-Immunoglobulin-Like Receptor Ligand In Recipients Can Predict Better Prognosis After HLA-Mismatched/Haploidentical Transplantation Without T Cells Depletion In Vitro In Chronic Myeloid Leukemia Patients
Authors: Xiangyu Zhao, Yingjun Chang, Ling-Ling Xu, Mingrui Huo, Xiaosu Zhao, Lanping Xu, Daihong Liu, Kaiyan Liu, Dan Li, Xiaojun Huang
Journal: Blood (2013)
Abstract 3538: Effects of oral chloroquine administration on a preclinical mouse model of PTEN/p53-deficient prostate cancer
Authors: Marco A. De Velasco, Koichi Sugimoto, Yurie Kura, Yuji Hatanaka, Yutaka Yamamoto, Takashi Oki, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2016)

Abstract Autophagy is cellular process that can promote tumor survival during periods of metabolic and therapeutic stress. Inhibition of autophagy can promote senescence resulting in decreased tumor growth. Genetic alterations of PTEN and p53 are frequently present in advanced human prostate cancer and are associated with poor prognosis. In mouse models, the inactivation of PTEN leads to the development of prostate tumors that progress slowly, in part due to the induction of PTEN-(loss)-induced cellular senescence. Concomitant inactivation of both PTEN and P53 in prostate leads to the development of an aggressive cancer phenotype that can overcome PTEN-(loss)-induced cellular senescence and is characterized with accelerated growth, metastatic development and decreased survival. Published findings show that in some cancer models, the effects of autophagy inhibition are dependent on p53 status. In this study we assessed the effects of pharmacological inhibition of autophagy with chloroquine (CQ) on the growth and progression of mouse prostate tumors driven by the concomitant inactivation of PTEN and p53. CQ is a lysosomotropic agent that has widely used to impede autophagy and inhibit the growth of human tumor cells in vitro and in vivo. Genetically engineered mice with the conditional inactivation of PTEN and p53 were used to evaluate the antitumor effects and therapeutic benefit of CQ in a drug intervention model of prostate cancer. Twenty-seven-week-old PTEN/p53 double knockout mice bearing prostate tumors were randomized to control and oral CQ (100 mg/kg in drinking water) treatment groups. Progression-free survival was 145 days versus 161 days (P = 0.703) for control and CQ treated mice, respectively. Median overall survival was 170 days versus 147 days (P = 0.523) for control and CQ treated mice, respectively. Tumor burden assed by the median genitourinary tract weight was 2.42 grams versus 2.19 grams (P = 0.645) for control and CQ treated mice, respectively. Our molecular assays revealed that CQ failed to consistently inhibit autophagy in tumors at the present dose. Overall, our findings show that CQ alone did not provide treatment benefit in mouse prostate cancer with loss of p53. Citation Format: Marco A. De Velasco, Koichi Sugimoto, Yurie Kura, Yuji Hatanaka, Yutaka Yamamoto, Takashi Oki, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Effects of oral chloroquine administration on a preclinical mouse model of PTEN/p53-deficient prostate 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 3538.
A new method of polyglycolic acid sheet placement in the stomach after endoscopic submucosal dissection
Authors: Ken Kumagai, Satoru Iwamoto, Naoki Esaka, Yoshinori Mizumoto
Journal: Endoscopy (2016)

Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for early gastric cancer. Further efforts are needed to decrease the complications associated with ESD, such as bleeding and perforation. A polyglycolic acid (PGA) sheet (NEOVEIL; Gunze Co., Kyoto, Japan) has the potential to prevent post-ESD bleeding because it covers post-ESD ulcers [1]. The PGA sheet is a soft, non-woven, bioabsorbable fabric that is already used clinically in respiratory and pharyngolaryngeal surgery [2]. However, difficulties are associated with the delivery of PGA sheets to the ulcer floor by endoscopy because the sheet easily sticks to itself under wet conditions. As a result, several strips of the PGA sheet need to be sequentially arranged [3]. We report a new method for PGA sheet placement in the stomach using monofilament sutures (polydioxanone: PDS II; Ethicon US LLC, Cincinnati, Ohio, USA). We have named it "the framing method."
Abstract 2805: Protein oxidation in pancreatic neoplasia and cancer
Authors: Michelle Schultz, Andrew Diaz, Sharon Smite, Brian DeCant, David Bentrem, Paul Grippo
Journal: Cancer Research (2016)

Abstract Rationale- Peroxiredoxin-1 (Prdx1) is overexpressed in pancreatic cancer patient serum and correlates with worse prognosis. Prdx1 is an important antioxidant protein whose deletion causes the formation of malignant lesions in mice. Prdx1's redox function depends on its reduction by two other Thioredoxin system members, Thioredoxin (Txn) and Sulfiredoxin (Srxn). Prdx1 may also contribute to tumorigenesis by oligomerizing and becoming a nuclear chaperone when it's overoxidized and its redox function is inhibited. Objective- Our objective was to investigate disruptions in the Txn system during pancreatic neoplasia and to determine how that affects phosphorylation of Kras effectors. Findings- Prdx1 expression was elevated and Srxn expression was reduced in pancreatic lesions of El-Kras, Pdx1-Cre/LSL-Kras (KC-Pdx1), and P48-Cre/LSL-Kras (KC-P48) mice. Txn was absent in lesions of KC-Pdx1 and KC-P48 mice but present and differentially located in EL-Kras lesions. In primary pancreatic acinar cells, oxidation of the Txn system with auranofin increased ERK and AKT phosphorylation in EL-Kras mice, but not in KC-P48 mice, indicating differential regulation of the Txn system in KC-P48 mice. This could be due to the presence of a higher molecular weight Prdx1 being present in KC-p48 mice and not in EL-Kras mice. This suggests that the effect of mutant Kras on the thioredoxin system in these two models may be different. Prdx1 and (p)ERK also interacted in vitro and inhibition of ERK and AKT phosphorylation modified the expression of Txn and Srxn in pancreatic cell lines. We also found that in human pancreatic cancer patient tissue, Prdx1 was overexpressed in pancreatic cancer as compared to adjacent normal tissue. Conclusions- The Txn system is disrupted during pancreatic neoplasia and may be associated with modified ERK and AKT regulation in Kras mutant pancreatic tissue. Citation Format: Michelle Schultz, Andrew Diaz, Sharon Smite, Brian DeCant, David Bentrem, Paul Grippo. Protein oxidation in pancreatic neoplasia and 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 2805.