tbuckley/cabot-search huggingface dataset:
Tumor endothelial interaction, CD44+/CD24- stem cell signature, and prognosis in early-stage breast cancer
Authors: M. Buess, M. Rajski, B. Vogel, R. Herrmann, C. Rochlitz
Journal: Journal of Clinical Oncology (2009)

503 Background: The effects of tumor-endothelial interaction on global gene expression in breast cancer are not yet well characterized. We hypothesized that gene expression signatures induced by tumor-endothelial interaction might be of clinical relevance. Methods: To this aim we set up an ex vivo co-culture model with human benign and a panel of 6 malignant breast epithelial cells in combination with human venous and microvascular endothelial cells and determined associated gene expression changes with cDNA microarrays. Pretreatment gene expression profiles of 295 early stage breast cancers from the Netherlands Cancer Institute with a median follow up of 12.6 years allowed evaluating in vitro effects in vivo. Results: The most prominent response to co-culture was the induction of a set of “M-phase cell cycle” genes in a subset of breast cancer co-cultures, which were absent in co-cultures with normal breast epithelial cells. While in monoculture tumor cells containing the stem cell like CD44+/CD24- signature showed a lower expression of the “M-phase cell cycle” genes than the CD44-/CD24+ cells, in the co-cultures with CD44+/CD24- cells these genes were induced. Interestingly, these tumor cells co- expressed a set of angiogenic factors such as VEGF, PTN, and FGF12 mRNA at significantly higher levels. In vivo, the expression of the gene set derived from the co-culture was remarkably coherent providing a basis for segregation of tumors into two groups. In a univariate analysis, early stage tumors with high expression levels (n= 137) of “M-phase cell cycle” genes had a significantly lower distant metastasis-free survival (p=1.8e-5) (50 % at 10 years) and overall survival rate (p= 5e-9) (52 % at 10 years) than tumors with low expression levels (n= 158) (metastasis-free survival: 73 %; overall survival: 84 % at 10 years). Conclusions: Our results suggest that the interaction of tumor cells expressing the CD44+/CD24- stem cell like signature, implicating a low proliferative potential, with endothelial cells might explain the unexpected and paradoxical association of the CD44+/CD24- signature with highly proliferative tumors with an unfavorable prognosis. Multiple co-expressed angiogenic factors represent potentially interesting additional therapeutic targets. No significant financial relationships to disclose.
PTH-008 Endoscopic Resection of Large Colorectal Polyps in A UK Tertiary Referral Unit
Authors: A Emmanuel, S Gulati, M Burt, B Hayee, A Haji
Journal: Gut (2016)

<h3>Introduction</h3> Whilst the extensive experience of endoscopic resection of large colorectal polyps in Japan has resulted in clear and consistent indications for various techniques depending on polyp size and morphology, practise in western Europe is less well defined. We report the results of a prospective series of endoscopic resections using a variety of techniques from one of only a few tertiary referral centres in the UK providing advanced interventional endoscopy. The patients in this series present some unique challenges, for example the high proportion of patients referred with deeply scarred lesions after previous failed attempts at resection, and the large mean polyp size. <h3>Methods</h3> A prospective series of colorectal endoscopic resections form a tertiary referral centre in the UK. Surveillance endoscopy was performed at 3 months and 12 months after resection. <h3>Results</h3> 363 polyps with a mean size of 56 mm were resected in 326 patients who had a mean age of 71 years: 309 by EMR, 38 by ESD and 16 by hybrid procedures involving ESD. The mean follow up was 12.2 months. Almost all patients were referred after their polyps were at least biopsied and 38% of polyps were deeply scarred from previous intervention. Despite this, adenoma recurrence occurred in only 9.7% of patients, 17% of which were diminutive. 6 patients with recurrence required surgery, 2 right hemicolectomies, 1 TEMS and 1 anterior resection and 2 declined surgery. 67% of patients with recurrence were treated successfully endoscopically with no further recurrence. Of those patients without invasive cancer at their first endoscopic resection, 95% were free from recurrence and had avoided surgery at last follow up. There was only one clinically significant perforation. 2 patients were admitted with post-procedure bleeding, 1 managed conservatively and 1 with endoscopic clips. <h3>Conclusion</h3> These data demonstrate the effectiveness of a tertiary interventional endoscopy unit in a western setting in treating large and complex colorectal polyps, with low recurrence rates and very few significant complications. In contrast to practise in the east, more education is required to prevent multiple attempted interventions before referral to a highly specialised unit. <h3>Disclosure of Interest</h3> None Declared
Cellular and Molecular Events Underlying the Interaction of Hematopoietic Stem and Progenitor Cells with Mesenchymal Stem Cells.
Authors: Nicola Bauer, Ana-Violeta Fonseca, Daniel Freund, Sabine Boxberger, Joachim Oswald, Carsten Werner, Gerhard Ehninger, Martin Bornhaeuser, Denis Corbeil
Journal: Blood (2005)
Abstract 3712: Incidence trend of NPC using age-period-cohort analysis from1987 to 2011 in Sihui County, southern China
Authors: Qing Liu, Sumei Cao, Qihong Huang, Lifang Zhang, Yanhua Li, Shanghang Xie
Journal: Cancer Research (2015)

Abstract In the past several decades, declining incidence rates of NPC have been observed in Chinese populations in Hong Kong, Taiwan, Los Angeles, and Singapore.However, the incidents rates in southern China have remained stable.This study describes the incidence trend of nasopharyngeal carcinoma (NPC) using age-period-cohort (APC) analysis from 1987 to 2011 in Sihui County, southern China. Age-standardized incidence rates compared with the world standard population were examined in both males and females. A Joinpoint regression analysis was conducted to quantify the changes in incidence trends. A Poisson regression APC model was used to assess the age, period, and birth cohort effects on incidence. Age-standardized incidence rates during the study period were 30.29 and 13.09 per 100,000 for males and females, respectively. The incidence rates of NPC remained stable with a non statistical significant average annual percentage change of 0.2% for males and -1.6% for females throughout the entire period. A statistically significant increase (estimated annual percentage change, 6.8%; 95% confidence interval, 0.1%-14.0%) was observed from 2003 to 2009 for males. The incidence of NPC increased with advancing age up to ages 50-59 and decreased at ages &amp;gt;60 years. The curves of NPC incidence by period were virtually flat for males and females. The curve for males by birth cohort showed an increase from the 1922 to 1952 cohort and a decrease thereafter. In females, there was an undulating increase in relative risks from the 1922 to 1972 cohort. In conclusion, the incidence trends for NPC remained generally stable in Sihui from 1987 to 2011, with an increase during 2003-2009. The relative risks of NPC increased in younger female cohorts, the underlying reason of which is expected to be further explored. Note: This abstract was not presented at the meeting. Citation Format: Qing Liu, Sumei Cao, Qihong Huang, Lifang Zhang, Yanhua Li, Shanghang Xie. Incidence trend of NPC using age-period-cohort analysis from1987 to 2011 in Sihui County, southern China. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3712. doi:10.1158/1538-7445.AM2015-3712
589. SENP1 Knockdown Inhibits Hepatocyte Growth Factor-Induced Migration and Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma
Authors: Wenwen Zhang, Huiyan Sun, Chunping Cui, Hua Wang, Fengjun Xiao, Chutse Wu, Xiaozhong Guo, Lisheng Wang
Journal: Molecular Therapy (2015)

The hepatocyte growth factor (HGF)/c-Met signaling aberrations are implicated in the pathogenesis and progress of hepatocellular carcinoma (HCC). However, the epigenetic regulators and their roles in modulating HGF-induced epithelial-mesenchymal transition (EMT), invasion and metastasis of HCC cells are less explored. SUMO/sentrin specific protease 1 (SENP1) is the cysteine protease that regulates SUMO pathways by deconjugating sumoylated proteins. Using real-time PCR we identified increased expression of SENP1 and c-Met in HCC tumors compared to adjacent noncancerous tissues (p<0.05, n=20). We further demonstrated that SENP1 overexpression is associated with HGF/c-Met signals in HCC. Treatment of HCC cells with HGF results in upregulation of SENP1 in a stat5 dependent manner. To explore the role of SENP1 in regulation of characteristics of HCC cells, we knocked down SENP1 in HCC cells lines using lentiviral vectors pLKO. 1-GFP-Senp1-shRNA. HCC-LM3 cells transduced with this vector demonstrated 77% decreased expression of SENP1 compared to cells transduced with a control vector. Lentivirus-mediated SENP1 knockdown triggers apoptosis (from control with 7.68% to Senp1 shRNA with 20.4%), cell cycle arrest and inhibits proliferation (80.6% inhibition, p<0.01) of HCC cells. SENP1 silence reduces HGF-induced migration of HCC cells (66.7% inhibition, p<0.01). Importantly, SENP1 inhibition increases E-cadherin and ZO-1 expression, and decrease fibronectin and N-cadherin expression in HCC cells. A series of transcription factors are involved in regulation of EMT processes. Zeb1 is a zinc finger transcription factor which induces an EMT and confers a metastatic phenotype on carcinomas. We predicted the sumoylation sites of Zeb1 by using a site-specific predictor of SUMOsp 2.0. This prediction was further validated by using Zeb-1 immunoprecipitation and Sumo2 antibody blot. HGF treatment also induced the expression of zeb1. SENP1 knockdown increased Zeb1 desumoylation, leading to reduce its protein level in HCC cells. Our results indicate that SENP1 is frequently over-expressed and associated with HGF/C-met in HCC. SENP1 plays a key role in HGF-induced proliferation, migration and epithelial-mesenchymal transition, suggesting it may be a potential new therapeutic target for HCC.
Abstract 87: Loss of Mir-155 Attenuates Sepsis Induced Cardiac Dysfunction
Authors: Hui Wang, Yihua Bei, Jing Shi, Wei Sun, Peipei Huang, Hui Liu, Xinli Li, Junjie Xiao, Xiangqing Kong
Journal: Circulation Research (2015)

Objective: Sepsis induced cardiac dysfunction is featured by inflammation and metabolic repression. miR-155 is a typical multifunctional miRNA and loss of miR-155 has been shown to protect the heart from pathological cardiac hypertrophy while increased miR-155 could promote the formation of foam cell in atherogenesis. However, the role of miR-155 in sepsis induced cardiac dysfunction is unclear. Methods: E.coli lipopolysaccharide (LPS) (5mg/kg) was administered to C57BL/6 mice to create a sepsis-induced cardiac dysfunction model. Cardiac function was assessed by echocardiography 5-6 h post-LPS administration. Heart tissues were collected within 7-9 h after LPS treatment for the analysis of gene expressions. Tail vein injection of miR-155 antagomir (80mg/kg/d) or miR-155 agomirs (30mg/kg/d) for 3 consecutive days were used to decrease or increase miR-155 expressions in heart. Results: LPS induced a reduction of 15% in fractional shortening (%FS) and 25% in ejection fraction (%EF). Expression of miR-155 was increased by 2 fold in sepsis-induced cardiac dysfunction mouse model. Over-expression of miR-155 agomirs led to a decrease of 5% in FS and 10% in EF as compared to scramble controls. Aggravation of LPS induced cardiac dysfunction by miR-155 agomir was not associated with alteration in inflammation or cardiac metabolism. However, miR-155 agomir increased LPS- induced myocardium apoptosis and also elevated the ratio of Bax/Bcl-2 at the protein level. Intravenous injection of cholesterol-modified antisense oligonucleorides antagomirs of miR-155 markedly rescued the LPS induced heart failure and apoptosis. Western bloting indicated that miR-155 overexpression in vivo led to a significant inhibition of Pea15a while miR-155 knock-down caused a significant upregulation of Pea15a, indicating that Pea15a was a potential target gene of miR-155. Interestingly, plasma miR-155 levels were also found to be significantly increased in critically ill patients with sepsis compared to healthy controls. Conclusion: This study demonstrates that miR-155 regulates sepsis induced cardiac dysfunction and Pea15a is a potential targer gene of miR-155. Loss of miR-155 represents a novel therapeutic method for sepsis induced cardiac dysfunction
Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer
Authors: J.C. Osorio, A. Ni, J.E. Chaft, R. Pollina, M.K. Kasler, D. Stephens, C. Rodriguez, L. Cambridge, H. Rizvi, J.D. Wolchok, T. Merghoub, C.M. Rudin, S. Fish, M.D. Hellmann
Journal: Annals of Oncology (2016)
Alterations in Insulin-Signaling and Coagulation Pathways in Platelets During Hyperglycemia-Hyperinsulinemia
Authors: A. Koneti Rao, Robert Freishtat, Gauthami Jalagadugula, Anamika Singh, Guangfen Mao, Andrew Wiles, Peter Cheung, Guenther Boden
Journal: Blood (2012)
Abstract 450: Suppression of innate and adaptive immune responses in the human lung tumor microenvironment via microRNA-183
Authors: Melba Marie Tejera, Melba Marie Tejera, Sarah S. Donatelli, Jun-Min Zhou, Danielle L. Gilvary, Xianghong Chen, Erika A
Journal: Cancer Research (2015)

Abstract Innate and adaptive immunity plays a critical role in defense against cancer but can be undermined by the tumor microenvironment. To understand the underlying mechanism, we set out to analyze the molecular and cellular basis for natural killer (NK) and CD8 T cell suppression by human lung tumor cells. We found that transforming growth factor-beta (TGFb), abundantly produced by tumor cells, effectively reduced tumoricidal function in activated NK cells and CD8 T cells by specifically targeting a key adaptor protein, DAP12, which is required for surface anchoring of multiple NK receptors, including NKp44. For proof of the TGFb-miR-183-DAP12 circuit, flow cytometric analysis demonstrated that TGFb reduced surface levels of NKp44 on activated primary human NK and CD8 T cells, but western blot analysis demonstrated their intact presence in the cytoplasm. This was due to loss of DAP12, which is critical for surface expression of NKp44 and for downstream signaling to mobilize lytic granules to kill tumor cells. Mechanistically, TGFb readily induced miR-183 expression in both primary human NK cells and T cells which could bind specifically to the 3′UTR of human DAP12 to inhibit transcription and translation. Only miR-183 but not miR-185 or control (CT) transfection repressed luciferase activity of DAP12 3′UTR luciferase reporter constructs transferred into HELA cells. Moreover, we overexpressed lentiviral miR-183 in either primary NK and T cells and found that such expression effectively reduced DAP12 levels in both cell types. Flow cytometric analysis of these same cells indicated that loss of DAP12 was accompanied by loss of NKp44 surface expression and by loss of cytotoxic function against tumor cells. As further proof, we showed that lentiviral anti-sense miR-183 transfection into NK cells and T cells prevented TGFb from suppressing DAP12 expression. Thus, we have uncovered a seminal TGFb-miR-183-DAP12 pathway utilized by tumor cells to silence infiltrating NK and T cells, constituting the first report of miR control of an adaptor protein to control both NK and T cell immune function. Citation Format: Melba Marie Tejera, Melba Marie Tejera, Sarah S. Donatelli, Jun-Min Zhou, Danielle L. Gilvary, Xianghong Chen, Erika A.. Suppression of innate and adaptive immune responses in the human lung tumor microenvironment via microRNA-183. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 450. doi:10.1158/1538-7445.AM2015-450
Putative biomarkers in malignant pleural mesothelioma.
Authors: V. Agarwal, D. Ranatunge, K. Beaumont, A. Campbell, M. J. Lind, L. Cawkwell
Journal: Journal of Clinical Oncology (2011)

e21008 Background: Malignant pleural mesothelioma (MPM) is associated with chronic inflammation due to asbestos exposure. The expression of inflammatory biomarkers associated with oncogenesis, e.g. cyclooxygenase-2 (COX2), 5-Lipoxygenase (5-LOX) and 12-LOX, may be of clinical relevance in MPM. In addition the PTEN/PI3K/AKT/MTOR signal transduction pathway may be aberrant in MPM. Loss of PTEN expression may lead to constitutive activation of AKT, resulting in cell survival and proliferation. In this study we aimed to assess the clinical relevance of 5-LOX, 12-LOX and PTEN protein expression in a large series of MPM samples. Methods: Immunohistochemical analysis was performed in 93 archival MPM tissue samples (48 epithelial, 27 biphasic, 18 sarcomatoid) to determine the expression of the PTEN, 5-LOX and 12-LOX proteins. Survival data were available for all 93 patients and prognostic factors were assessed using univariate and multivariate analyses. Results: Positive 5-LOX expression was seen in 73% (65/88) of samples and this was associated with improved survival (median overall survival 8.3 months versus 4.6 months; p=0.006). However, when histological subtype was taken into consideration, multivariate Cox regression analysis demonstrated that 5-LOX expression was not an independent prognostic variable (p=0.074). Positive 12-LOX expression was seen in 83% (69/83) of samples, but this was not associated with survival (p=0.455). Correlating this LOX expression data with our previously published COX2 expression results in the same cohort (Eur J Cancer 41:1645-8; 2005) revealed significant correlations. Positive 5-LOX expression correlated with positive COX2 expression (p=0.002). Positive 12-LOX expression correlated with 5-LOX co-expression (p=0.006). The expression of PTEN was lost in 27% (23/86) of samples and this was not associated with survival (p=0.223). Conclusions: We have demonstrated that 5-LOX and 12-LOX are expressed in a significant proportion of MPM samples and therefore may be novel therapeutic targets. Loss of PTEN expression was seen in 27% of samples. This research may lead to novel therapeutic strategies for patients with MPM.
Efficacy and safety of extended antithrombotic prophylaxis in elderly medically ill patients
Authors: Francesco Dentali, Nicola Mumoli, Andrea Fontanella, Matteo Nicola Dario Di Minno
Journal: European Respiratory Journal (2016)

Compelling evidence suggests that the risk of pulmonary embolism and deep-vein thrombosis (DVT) persists after hospital discharge in acutely ill medical patients [1]. However, results of available studies did not support the routine use of extended-duration thromboprophylaxis in this setting [2–5]. Extended antithrombotic prophylaxis beyond hospitalisation may be beneficial in elderly, medically ill patients <http://ow.ly/udyj304QvNo>
Abstract 3308: Enhanced expression of galectin-3 isassociated with the alternative activation of macrophages and development oflung fibrosis following radiation
Authors: Weiling Zhao, Jing-Hua Zhang, Ingrid J. Lopes
Journal: Cancer Research (2015)

Abstract Radiotherapy is a major treatment approach to non-operable lung cancer patients. Unfortunately, radiation-induced lung injury occurs in 5-20% of lung cancer patients following radiotherapy. Radiation-induced lung fibrosis contributes to an increased risk of death or a decreased quality of life. The mechanism(s) for the development of radiation-induced lung fibrosis is not fully understood, and no interventions to prevent/ameliorate it have proven successful. Macrophages are the first line of defense for airways and alveolar surfaces and play a key role in the initiation and orchestration of inflammatory responses. Two distinct macrophage subsets have been identified; classically activated macrophages (M1) and alternatively activated macrophages (M2). Increased numbers of activated M2 macrophages have been seen in human fibrotic conditions and rodent models of fibrosis. However, the mechanism(s) driving the persistent activation of M2 macrophages and how this leads to the development of fibrosis remains undefined. Recent studies indicate that galectin-3 (gal-3) is potentially a key regulator of M2 macrophage activation; inhibition of gal-3 expression prevents M2 macrophage activation. In this paper, we show elevated numbers of Ym-1 positive alveolar macrophages in the irradiated lung. Increased expression of gal-3 cells was found in the fibrotic lung, which was associated with fibrotic lesions. M2 macrophages were the majority of cells that expressed gal-3. In our in vitro studies, we found that knocking-down gal-3 using Mission lentiviral transduction particles prevented radiation-induced increases in the expression of YM-1 in Raw 264.7 macrophage. Mouse recombinant gal-3 stimulated mouse lung fibroblast cell proliferation and expression of α-SMA. These data suggest that gal-3 appears to regulate alternative activation of M2 macrophage and play an important role in the development of radiation-induced lung injury. Citation Format: Weiling Zhao, Jing-Hua Zhang, Ingrid J. Lopes. Enhanced expression of galectin-3 isassociated with the alternative activation of macrophages and development oflung fibrosis following radiation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3308. doi:10.1158/1538-7445.AM2015-3308