tbuckley/cabot-search huggingface dataset:
Abstract 1755: PEGylated adenosine deaminase (ADA2) prevents adenosine-mediated increase in tumor growth and improves antitumor immune responses
Authors: Luz Marina Londoño-R, Jessica Cowell, Lin Wang, Qiping Zhao, Lei Huang, Chris Thanos, Michael J. LaBarre, Xiaoming Li, Caglar Cekic
Journal: Cancer Research (2018)

Abstract Adenosine deaminase 2 (ADA2) is a human serum protein that catalyzes the reaction of deamination of adenosine to inosine. Besides catalytic activity, ADA2 has a heparin-binding domain and a growth factor-like domain. Adenosine accumulates in the tumor microenvironment and suppresses anti-tumor immune responses, while promoting tumor cell metastasis. Previously, we showed that treatment of mice with PEGylated forms of ADA2 (PEG ADA2) can decrease the accumulation of tumor-associated adenosine. Here, we analyzed the TCGA RNA-seq database using OncoLnc tool and observed that high expression of the ADA2 gene (CECR1) in certain immunotherapy responsive tumors correlated with increased survival of patients. We then tested different engineered ADA2 variants, using the inactive enzyme variant as a control, for the reversal of adenosine-mediated responses in human T cells, mouse peritoneal macrophages, and mouse and human tumor cell lines. ADA2 variants with higher catalytic activity were able to reverse adenosine-mediated suppression of human T-cell proliferation, cAMP accumulation in tumors and human T cells, and polarization of macrophages into an immunosuppressive, pro-tumor phenotype, whereas the inactive ADA2 variant failed to cause any of these effects. In addition, the variant that lacks the ability to bind to heparin but has improved catalytic activity (PEG NME8058) showed similar responses to those with the catalytically improved variant with intact heparin-binding domain (PEG NME8062). These results suggest that the improved immune cell activity with ADA2 in the presence of adenosine requires the enzyme activity of this molecule. Next, we assessed PEG NME8062 in MC38 and CT26 colon carcinoma syngeneic tumors in C57BL/6 and Balb/c mice, and observed delayed growth in both tumors. Using the inactive enzyme variant, we have shown that anti-tumor effect of PEG NME8062 depends on enzyme activity. Delayed tumor growth was also associated with increased density of key anti-tumor immune cell populations in both tumor models. These data suggest that PEG ADA2 can reduce tumor growth in an enzyme-activity-dependent manner and promote anti-tumor immune responses in vitro and in vivo. These findings have important implications for targeting purinergic signaling for cancer therapy. Citation Format: Luz Marina Londoño-R, Jessica Cowell, Lin Wang, Qiping Zhao, Lei Huang, Chris Thanos, Michael J. LaBarre, Xiaoming Li, Caglar Cekic. PEGylated adenosine deaminase (ADA2) prevents adenosine-mediated increase in tumor growth and improves antitumor immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1755.
Abstract 2643: Increased copy number of <i>EGFR</i> gene is an independent outcome predictor in resected non-small cell lung cancer patients treated by adjuvant chemotherapy
Authors: Vladimira Koudelakova, Radek Trojanec, Jana Potockova, Jiri Drabek, Jana Stranska, Petra Smickova, Pavla Kourilova, Ivona Grygarkova, Vitezslav Kolek, Jozef Skarda, Marian Hajduch
Journal: Cancer Research (2018)

Abstract Background: Lung cancers are the leading cause of cancer-related deaths worldwide. Surgical resection alone remains preferred treatment for early stage patients with non-small cell lung cancer (NSCLC), whereas surgery plus platinum-based adjuvant chemotherapy is recommended for stages II - IIIa. Despite wide spectrum of known genetic alterations, there is a lack of biomarkers predicting response to adjuvant therapy. The aim of our study was to determine the predictive role of selected gene alterations. Methods and patients: Formalin-fixed paraffin embedded tumor samples were obtained from 209 NSCLC patients with stage I to IIIa. Of these, 59 patients were treated by surgical resection only, the follow-up adjuvant chemotherapy was indicated in remaining 150 cases. There were 146 males and 63 females (mean age 66; range 29-82 years), tumor histology revealed 79 adenocarcinomas, 105 squamous cell carcinomas, 21 large cell carcinomas, two adenosquamous carcinomas and two sarcomatoid carcinomas. Fluorescent in situ hybridization (FISH) was used for evaluation of EGFR, CMYC, MET and FGFR1 gene copy numbers and ALK and ROS1 copy numbers and rearrangements, respectively. EGFR, KRAS and BRAF mutations were screened using Cobas EGFR Mutation Test (Roche), TheraScreen: KRAS Mutation kit (Qiagen) and BRAF p.Val600Glu kit (IntellMed). Results: In the group of 150 resectable NSCLC patients treated with platinum-based adjuvant therapy, increased copy number of EGFR gene predicted poor overall survival (OS) (p = 0.00001, hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.32-2.10) as well as disease-free survival (DFS) (p = 0.0001, HR 1.54, 95% CI 1.23-1.91) in univariate analysis. In multivariate analysis adjusted to age and stage, the EGFR copy number was independent predictor of OS (p = 0.001) as well as DFS (p = 0.0004). In the group of 59 patients treated by surgical therapy only, no correlation of tested markers with clinical-pathological data was identified. Conclusions: Increased copy number of EGFR gene was found to be an independent predictor of outcome in NSCLC patients treated by adjuvant platinum-based therapy. Acknowledgment: This work was financially supported by NPU LO1304, TE02000058 and EATRIS-CZ. Citation Format: Vladimira Koudelakova, Radek Trojanec, Jana Potockova, Jiri Drabek, Jana Stranska, Petra Smickova, Pavla Kourilova, Ivona Grygarkova, Vitezslav Kolek, Jozef Skarda, Marian Hajduch. Increased copy number of EGFR gene is an independent outcome predictor in resected non-small cell lung cancer patients treated by adjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2643.
Abstract 18484: Modest Potential Association Between Reductions in Lipoprotein(a) and Major Adverse Cardiovascular Events in the Phase 3 Trials of Alirocumab versus Control
Authors: Kausik K Ray, Henry N Ginsberg, Michael H Davidson, Michael J Louie, Maja Bujas-Bobanovic, Pascal Minini, Robert H Eckel, Christopher P Cannon
Journal: Circulation (2016)

Introduction: Elevated lipoprotein(a) [Lp(a)] levels may be a causal risk factor for cardiovascular (CV) disease. Alirocumab (ALI) reduces both LDL-C and Lp(a). It is unclear if there is a CV outco...
Abstract 3267: Cervical microbiota and the urinary metabolome in patients with high-risk and low-risk HPV infections
Authors: Gilmary Ortiz, Natalyia Chorna, Josefina Romaguera-Agrait, Magaly Martinez-Ferrer, Maria Sanchez, Ana P. Ortiz, Rafael Guerrero-Preston, James R. White, Filipa Godoy-Vitorino
Journal: Cancer Research (2018)

Genital human papillomavirus (HPV) is the world's most commonly diagnosed sexually transmitted infection, and high-risk HPV types are strongly linked to cervical dysplasia and carcinoma. The microbiota of the human cervico-vaginal tract is the interface between the host and environment, and its constituents may act as determinants of susceptibility for HPV infection. There exists the potential for reliable diagnostic biomarkers for cervical cancer in the cervical microbiome as well as in urine, which would be an important biospecimen due to its abundance and non-invasive collection strategy. In this study, we performed comprehensive metabolomic analysis on urine samples from 65 women (54 HPV+, 38 of whom have cervical intraepithelial neoplasia (CIN), and 11 HPV-) and discuss the potential diagnostic implication and metabolic description of high-risk and low-risk HPV infected patients.The experimental procedure employed gas chromatography mass spectrometry (GC-MS) on the urine-derived products and HPV genotyping was determined by reverse hybridization with the HPV SPF10-LiPA25 kit. We further characterized resident cervical bacteria in these patients using Illumina sequencing of the V4 region of the 16S ribosomal RNA with a high-resolution bioinformatics methodology (Resphera Insight v2.2) for species-level taxonomic assignment.The hybridization assay detected 11 low-risk and 10 high-risk HPV types many of them co-occurring in the cervical samples. Lactobacillus iners OTUs were shared by all samples but were significantly more dominant in women with low-risk HPV strains (p-value=0.05), while G. vaginalis, S. sanguinegens and L. jensenii were associated with high-risk strains. CIN1 and CIN3 dysplasic biopsies, detected significant enrichments of Gardnerella vaginalis, L.crispatus and Prevotella amnii (p-values <0.05). Preliminary GC-MS analysis identified elevated levels of palmitic (C16:0) and stearic fatty acids (C18:0) as well as lactic acid, abundant in the HPV+ samples while 5-oxo-proline and Neu5Ac (N-Acetylneuraminic acid) were abundant in the HPV- samples.Our preliminary data identifies possible microbial and metabolic biomarkers associated with oncogenic HPV and cervical intraepithelial neoplasia in women living in Puerto Rico.Citation Format: Gilmary Ortiz, Natalyia Chorna, Josefina Romaguera-Agrait, Magaly Martinez-Ferrer, Maria Sanchez, Ana P. Ortiz, Rafael Guerrero-Preston, James R. White, Filipa Godoy-Vitorino. Cervical microbiota and the urinary metabolome in patients with high-risk and low-risk HPV infections [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3267.
Intensive care support and clinical outcomes of patients with Ebola virus disease (EVD) in West Africa
Authors: Martin Langer, Gina Portella, Stefano Finazzi, Liliane Chatenoud, Simone Lanini, Francesco Vairo, Robert Fowler, Rossella Miccio, Giuseppe Ippolito, Guido Bertolini, Gino Strada
Journal: Intensive Care Medicine (2018)

We investigate the impact on outcome of different levels of supportive treatment in Ebola virus disease (EVD). The NGO EMERGENCY delivered care sequentially at two Ebola Treatment Centres (ETC) in Sierra Leone: first at Lakka (fluids, symptomatic, antibiotic, antimalaria treatment, and hospital level medical care), and thereafter in Goderich, adding organ support in the only African ETC with an equipped and staffed intensive care unit (ETC-ICU).The primary outcome in this retrospective cohort study was in-ETC mortality. Secondarily, we used multivariable logistic regression to investigate the independent impact of the IC on mortality by comparing patients in two ETCs, adjusting for potential confounders, including the viral load (base-10 logarithm in copies/ml) (LVL), modelled as a piecewise linear function. Mortality was plotted versus LVL. Confidence bands were constructed by a bootstrap technique. The number of hospital-free days within 28 was computed to assess the burden of EVD.Data from 229 EVD patients were analysed (123 in Lakka, 106 in Goderich). Crude analysis showed a non-statistically significant difference in mortality (57.7% in Lakka vs 50.0% in Goderich; p = 0.19). Age and LVL were associated with mortality. Adjusted mortality was lower at the Goderich ICU-ETC (p = 0.055). This difference was observed with 80% confidence for patients with LVL between 7.5 and 8.5 copies/ml. Hospital-free days (of 28 days) were greater (7.7 vs 5.5; p = 0.03) for patients treated in the ICU-ETC.Provision of critical care to patients with EVD is feasible in resource-limited settings and was associated with improved survival and less time in hospital.
Abstract 545: NOTCH1 co-expression analysis reveals novel insights underlying its opposing effects as an oncogenic and tumor suppressor in lung cancer
Authors: Sara L. Sinicropi-Yao, David P. Carbone, Kevin R. Coombes, Joseph M. Amann, David Lopez Lopez
Journal: Cancer Research (2018)

Abstract Background: Aberrations in the family of Notch receptors (1, 2, 3, and 4) have been implicated in a range of solid tumors, including lung cancer. NOTCH1 biology is complex where Notch plays an oncogenic and tumor suppressor role in lung adenocarcinoma and lung squamous cell carcinoma, respectively. Although the role of Notch in cancer development and progression has received increased appreciation in recent years, there is still a lack of understanding of the mechanisms underlying these opposing activities in lung cancer. Methods: The Cancer Genome Atlas datasets were used to examine gene co-expression patterns of Notch1 in lung adenocarcinoma and lung squamous cell carcinoma. Biological pathways implicated by gene families were assessed using functional annotation tools (DAVID, ToppGene, and IPA). In vitro and in vivo knockdown studies assessed the functional role of Notch1. Results: This novel co-expression analysis supports the hypothesis that NOTCH1 is co-expressed with different genes in lung adenocarcinoma and squamous cell carcinoma. Knockdown of Notch1 in vitro and in vivo support our in silico finding of opposing effects of NOTCH1. Our analysis implicates genes associated with metabolic pathways, immune pathways, angiogenesis and cell cycle that may underlie the differential role of NOTCH1 in lung adenocarcinoma and squamous cell carcinoma. In vitro and in vivo studies support our bioinformatics analysis. Conclusion: These results demonstrate different NOTCH1 gene co-expression patterns in lung adenocarcinoma and squamous cell carcinoma. These findings provide novel insights underlying the context-dependent role of Notch as an oncogene and tumor suppressor in subtypes of lung cancer. Understanding the similarities and differences in co-expression patterns reveal novel insights, suggesting that tumor intrinsic and extrinsic pathways may underlie the dual role of NOTCH1 in lung cancer. Recognition of the mechanisms underlying NOTCH1 opposing roles in cancer may help direct development of Notch-targeted therapies as a monotherapy or in combination with approaches focusing on the tumor microenvironment. Citation Format: Sara L. Sinicropi-Yao, David P. Carbone, Kevin R. Coombes, Joseph M. Amann, David Lopez Lopez. NOTCH1 co-expression analysis reveals novel insights underlying its opposing effects as an oncogenic and tumor suppressor in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 545.
Rotavirus Vaccination and the Global Burden of Rotavirus Diarrhea Among Children Younger Than 5 Years
Authors: Christopher Troeger, Ibrahim A. Khalil, Puja C. Rao, Shujin Cao, Brigette F. Blacker, Tahmeed Ahmed, George Armah, Julie E. Bines, Thomas G. Brewer, Danny V. Colombara, Gagandeep Kang, Beth D. Kirkpatrick, Carl D. Kirkwood, Jason M. Mwenda, Umesh D. Parashar, William A. Petri, Mark S. Riddle, A. Duncan Steele, Robert L. Thompson, Judd L. Walson, John W. Sanders, Ali H. Mokdad, Christopher J. L. Murray, Simon I. Hay, Robert C. Reiner
Journal: JAMA Pediatrics (2018)

<h3>Importance</h3> Rotavirus infection is the global leading cause of diarrhea-associated morbidity and mortality among children younger than 5 years. <h3>Objectives</h3> To examine the extent of rotavirus infection among children younger than 5 years by country and the number of deaths averted because of the rotavirus vaccine. <h3>Design, Setting, and Participants</h3> This report builds on findings from the Global Burden of Disease Study 2016, a cross-sectional study that measured diarrheal diseases and their etiologic agents. Models were used to estimate burden in data-sparse locations. <h3>Exposure</h3> Diarrhea due to rotavirus infection. <h3>Main Outcomes and Measures</h3> Rotavirus-associated mortality and morbidity by country and year and averted deaths attributable to the rotavirus vaccine by country. <h3>Results</h3> Rotavirus infection was responsible for an estimated 128 500 deaths (95% uncertainty interval [UI], 104 500-155 600) among children younger than 5 years throughout the world in 2016, with 104 733 deaths occurring in sub-Saharan Africa (95% UI, 83 406-128 842). Rotavirus infection was responsible for more than 258 million episodes of diarrhea among children younger than 5 years in 2016 (95% UI, 193 million to 341 million), an incidence of 0.42 cases per child-year (95% UI, 0.30-0.53). Vaccine use is estimated to have averted more than 28 000 deaths (95% UI, 14 600-46 700) among children younger than 5 years, and expanded use of the rotavirus vaccine, particularly in sub-Saharan Africa, could have prevented approximately 20% of all deaths attributable to diarrhea among children younger than 5 years. <h3>Conclusions and Relevance</h3> Rotavirus-associated mortality has decreased markedly over time in part because of the introduction of the rotavirus vaccine. This study suggests that prioritizing vaccine introduction and interventions to reduce diarrhea-associated morbidity and mortality is necessary in the continued global reduction of rotavirus infection.
Extracellular Adenosine Induces Apoptosis of Human Arterial Smooth Muscle Cells via A2b-Purinoceptor
Authors: Marie-LinePeyot, Alain-PierreGadeau, FrédéricDandré, IsabelleBelloc, FrançoiseDupuch, ClaudeDesgranges
Journal: Circulation Research (2000)

Abstract—Apoptosis of arterial smooth muscle cells (ASMCs) could play an important role in the pathogenesis of atherosclerosis and restenosis. Recent studies have demonstrated that extracellular adenosine induces apoptosis in various cell types. Our aim was to delineate the capacity of this nucleoside to induce ASMC apoptosis in arterial diseases. We demonstrate that adenosine dose-dependently triggers apoptosis of cultured human ASMCs. Apoptotic cell death was quantified by analysis of nuclear chromatin morphology and characterized by DNA laddering. The involvement of adenosine receptors was suggested, because neither an adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride, nor an inhibitor of cellular nucleoside transport, dipyridamole, was able to inhibit adenosine-induced ASMC apoptosis. In contrast, an A1/A2-adenosine receptor antagonist, xanthine amine congener, totally inhibited adenosine-induced apoptosis. Furthermore, among more selective inhibitors of P1 purinocepto...
Mobilization of Endothelial Progenitor Cells in Patients With Acute Myocardial Infarction
Authors: SatoshiShintani, ToyoakiMurohara, HisaoIkeda, TakafumiUeno, TomokiHonma, AtsushiKatoh, Ken-ichiroSasaki, ToshifumiShimada, YuichiOike, TsutomuImaizumi
Journal: Circulation (2001)

Background—Endothelial progenitor cells (EPCs) circulate in adult peripheral blood (PB) and contribute to neovascularization. However, little is known regarding whether EPCs and their putative precursor, CD34-positive mononuclear cells (MNCCD34+), are mobilized into PB in acute ischemic events in humans. Methods and Results—Flow cytometry revealed that circulating MNCCD34+ counts significantly increased in patients with acute myocardial infarction (n=16), peaking on day 7 after onset, whereas they were unchanged in control subjects (n=8) who had no evidence of cardiac ischemia. During culture, PB-MNCs formed multiple cell clusters, and EPC-like attaching cells with endothelial cell lineage markers (CD31, vascular endothelial cadherin, and kinase insert domain receptor) sprouted from clusters. In patients with acute myocardial infarction, more cell clusters and EPCs developed from cultured PB-MNCs obtained on day 7 than those on day 1. Plasma levels of vascular endothelial growth factor significantly incre...
춘계학술대회 : 구연 ; 한국인에서 HBeAg 발현을 조절하는 B형 간염 바이러스 유전자 변이들과 임상적 의의
Authors: 김자경, 안상훈, 장혜영, 최용욱, 김지현, 백용한, 이관식, 문병수, 한광협, 전재윤, 문영명
Journal: Clinical and Molecular Hepatology (2005)

배경/목적: 만성 B형 간염 바이러스(HBV) 감염에서 core promoter (CP)와 precore (PreC) 부위의 변이가 HBeAg의 발현에 영향을 주는 것으로 알려져 있다. 하지만 최근 들어 HBeAg을 조절하는 새로운 HBV 변이종들과 이에 따른 임상적 의의가 보고되고 있는데, CP의 염기 서열1809-1812번(Kozak sequence, Gastoenterology 2003 & Hepatology 1999)과 PreC의 1862번(J
Abstract 254: Chemopreventive effects of angiotensin II receptor type 2 agonist on prostate carcinogenesis by the downregulation of the androgen receptor
Authors: Hiroji Uemura, Yusuke Ito, Aya Naiki-Ito, Hiroyuki Kato, Shugo Suzuki, Toshiya Kuno, Satoru Takahashi
Journal: Cancer Research (2018)

Abstract [Background] We previously reported that angiotensin II receptor blockers (ARB), anti-hypertensive drug, have chemopreventive and chemotherapeutic potential against prostate cancer via the reduction of androgen receptor (AR) expression. It is generally known that angiotensin II binds to two kinds of receptors, AT1R and AT2R, and the biological function of AT2R signaling has the opposite effect to that of AT1R signaling in many aspects. We therefore hypothesized that AT2R agonism might attenuate the proliferative activity in prostate cancer cells. In this study, we investigated the effects of the AT2R agonist Compound 21 (C21) designed by Vicore Pharma (Sweden), which is expected to play similar roles to an ARB, on prostate carcinogenesis using the transgenic rat for adenocarcinoma of prostate (TRAP) model previously established in our laboratory. [Materials and Methods] In vitro analyses of the cell growth, Western blotting and PSA-reporter gene assays were performed using LNCaP and 22RV1 cells. TRAP rats at 6 weeks of age were randomly divided into 3 groups of 12 animals each and treated with C21 at 1 or 2 mg/kg/day in drinking water for 12 weeks. They were pathologically examined the classification as prostatic intraepithelial neoplasia and non-invasive adenocarcinoma. The proteins extracted from TRAP prostate glands were examined for Western blotting. [Results] C21 reduced the proliferation activity of prostate cancer cells and down-regulated the PSA promoter activity, medium PSA levels and the AR protein expression. We discovered that C21 inhibited the progression of prostate carcinogenesis in TRAP rats and decreased the incidence of adenocarcinoma in the lateral prostate. A significant increase in the apoptotic index with activation of caspase 3 and 7 were observed by immunohistochemistry and Western blotting analyses. C21 also down-regulated the expression of AR significantly in TRAP rat prostate. C21 decreased the expression of AR and AR-relevant genes reduced the proliferation activity effectively in prostate cancer cells and TRAP rat prostate. [Conclusion] The present study demonstrated that the epoch-making AT2R agonist C21 down-regulated the proliferation activity and the expression of AR both in vitro and in vivo. C21 is a promising drug not only for hypertension but also for human prostate cancer chemoprevention. Citation Format: Hiroji Uemura, Yusuke Ito, Aya Naiki-Ito, Hiroyuki Kato, Shugo Suzuki, Toshiya Kuno, Satoru Takahashi. Chemopreventive effects of angiotensin II receptor type 2 agonist on prostate carcinogenesis by the downregulation of the androgen receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 254.