tbuckley/cabot-search huggingface dataset:
AB0075 Targeting immune and non-immuno synovitis by 1,3,5-TRIAZINE-THIAZOLE via dual inhibition of NF-KB and EGFR-TKS for possible benefit in rheumatoid arthritis
Authors: UP Singh, JK Shrivastava, A Verma, HR Bhat
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic inflammatory disease which is easily recognised by unrelenting inflammation, joint erosion, joint immobility and severe debilitation. The cause of the disease suggests that, T cells, B cells, macrophages, and dendritic cells gain access to the inflamed synovium causing progression of disease via generation of cytokines and autoantibodies. The current available therapies to treat RA target the immune response which in turn adversely affects the immunity of the patients. <h3>Objectives</h3> The presents study deals with the discovery of 1,3,5-triazine-thiazoles targeting immune and non-immuno synovitis by via dual inhibition of NF-κB and EGFR-TKs for possible benefit in rheumatoid arthritis. <h3>Methods</h3> The 1,3,5-triazine-thiazole hybrid derivatives were synthesized via cascade of nucleophillic and cyclo-condensation reaction. These inhibitors was screened for NF-kB transcriptional activity in RAW264.7 macrophages, whereas, EGFR-TKs inhibitor activity was assessed via kinase inhibition assay kit. The docking study was carried out with 3D-crystal structure of NF-κB and EGFR-TK to explicate the inhibitory action. <h3>Results</h3> The designed hybrid analogues showed excellent inhibitory activity against both NF-κB and EGFR-TK. Particularly, against NF-κB, methyl (5c) containing molecule showed most significant activity (respectively with relative NF-κB activity: 1.82±1.87). Docking study suggests that, 5c was deeply buried in the DNA binding domain of NF-κB interacting with Tyr57, Val58, Cys59, His141, and Val142. In EGFR-TK inhibitory assay, the synthesized molecules showed IC<sub>50</sub> ranging from 4.23–39.32μ M via interacting with Leu788, Met766, Lys745, Glu762 with 3D crystal structure of EGFR-TK. <h3>Conclusions</h3> These results demonstrate the feasibility of 1,3,5-triazine-thiazole as dual inhibitior of NF-κB and EGFR-TKs for the treatment of inflammatory disorders such as rheumatoid arthritis in more efficient way. <h3>References</h3> Collison J. Features of synovium in RA remission revealed. Nat. Rev. Rheumatol. 12, 316 (2016). Singh B, Bhat HR, Kumawat MK, Singh UP. Structure-guided discovery of 1,3,5-triazine-pyrazole conjugates as antibacterial and antibiofilm agent against pathogens causing human diseases with favorable metabolic fate. Bioorg Med Chem Lett. 24, 3321 (2014). Singh UP, Pathak M, Dubey V, Bhat HR, Gahtori P, Singh RK. Design, synthesis, antibacterial activity, and molecular docking studies of novel hybrid 1,3-thiazine-1,3,5-triazine derivatives as potential bacterial translation inhibitor. Chem Biol Drug Des. 80, 572 (2012). <h3>Acknowledgements</h3> Authors are thankfull to SHUATS for providing necessary infrastructural facilities. <h3>Disclosure of Interest</h3> None declared
腫瘍標的蛋白質デリバリーシステムのインテイン媒介部位特異的合成:プロドラッグ様特徴に変えるPEGジレンマ【Powered by NICT】
Authors: Chen Yingzhi, Zhang Meng, Jin Hongyue, Tang Yisi, Wang Huiyuan, Xu Qin, Li Yaping, Li Feng, Huang Yongzhuo
Journal: Biomaterials (2017)
A novel method to simulate complex networks of apoptosis in adenocarcinoma of the lung
Authors: Sterling W. Thomas, Danail Bonchev, Lemont B. Kier, Sophie K. Thompson, Chao-Kun Cheng
Journal: Cancer Research (2006)

1560   This study proceeded from the hypothesis that cellular automata modeling of the complex network of the Bcl2-family proteins could provide useful information on the p53-initiated apoptosis, elucidating the most influential relationships in the survival/apoptosis balance in fighting cancer. A cellular automata (CA) model was created of the interactions between the Bcl2 family proteins Bcl2, Bax, BclX(L), their homo- and heterodimers, and the apoptosis effector (non-Bcl2 member) Cytochrome C (CytC). The model of the complex system included 18 interaction paths of competition between apoptosis inhibition (survival factor) and apoptosis initiation (apoptotic factor). The model system was initially simulated using cellular automata with variegated cells representing discriminating binding sites. Bax, BclX(L), and CytC included one active site and Bcl2 included two such sites. Simulations were performed averaging the steady-state concentrations obtained in each of 100 runs. The modeling started with equal initial concentrations of the basic ingredients varying only the binding probability of discriminating binding sites. A hierarchy of interaction patterns were determined then verified by using initial concentrations based on the protein expression data of 71 patients with primary adenocarcinoma of the lung and varying the binding probability. The 71 patients were pooled in seven categories based on primary tumor size. A comparison with expression from 16 non-cancer samples was also included. Thresholds were identified for the three most important interactions. The thresholds were based on the convergence of the concentrations of survival and apoptotic factors. Linear and non-linear correlation coefficients were determined for Bcl2, Bax, and BclX(L) compared to the thresholds. The results of the CA modeling have shown the existence of a very delicate balance between the factors influencing the survival/apoptosis ratio, the latter varying strongly after relatively small changes in the initial concentration. The three most influential interactions were found to be the BclX(L) direct inhibiting the release of CytC, the BclX(L) indirect inhibiting the imbedding of Bax to the mitochondria, and the Bcl2-BclX complex direct inhibiting the release of CytC. The non-linear correlation coefficients for Bcl2, Bax and BclX(L) were 0.214, -0.133, and -0.821, respectively. The resulting correlation supports our hypothesis by highlighting the importance of BclX(L) in apoptosis. Historically, focus has been on other members of the Bcl2 family, however our study indicates that shifting the focus to BclX(L) may provide better markers of apoptotic activity and new treatment options.
Updated Global Estimates of Respiratory Mortality in Adults ≥30Years of Age Attributable to Long-Term Ozone Exposure
Authors: Christopher S. Malley, Daven K. Henze, Johan C.I. Kuylenstierna, Harry W. Vallack, Yanko Davila, Susan C. Anenberg, Michelle C. Turner, Mike R. Ashmore
Journal: Environmental Health Perspectives (2017)

Background: Relative risk estimates for long-term ozone (O3) exposure and respiratory mortality from the American Cancer Society Cancer Prevention Study II (ACS CPS-II) cohort have been used to estimate global O3-attributable mortality in adults. Updated relative risk estimates are now available for the same cohort based on an expanded study population with longer follow-up. Objectives: We estimated the global burden and spatial distribution of respiratory mortality attributable to long-term O3 exposure in adults ≥30y of age using updated effect estimates from the ACS CPS-II cohort. Methods: We used GEOS-Chem simulations (2×2.5º grid resolution) to estimate annual O3 exposures, and estimated total respiratory deaths in 2010 that were attributable to long-term annual O3 exposure based on the updated relative risk estimates and minimum risk thresholds set at the minimum or fifth percentile of O3 exposure in the most recent CPS-II analysis. These estimates were compared with attributable mortality based on the earlier CPS-II analysis, using 6-mo average exposures and risk thresholds corresponding to the minimum or fifth percentile of O3 exposure in the earlier study population. Results: We estimated 1.04–1.23 million respiratory deaths in adults attributable to O3 exposures using the updated relative risk estimate and exposure parameters, compared with 0.40–0.55 million respiratory deaths attributable to O3 exposures based on the earlier CPS-II risk estimate and parameters. Increases in estimated attributable mortality were larger in northern India, southeast China, and Pakistan than in Europe, eastern United States, and northeast China. Conclusions: These findings suggest that the potential magnitude of health benefits of air quality policies targeting O3, health co-benefits of climate mitigation policies, and health implications of climate change-driven changes in O3 concentrations, are larger than previously thought. https://doi.org/10.1289/EHP1390
Transmembrane BAX Inhibitor motif‐containing 1, a novel anti‐inflammatory approach for nonalcoholic steatohepatitis treatment
Authors: Alexander Wree, Maria Eugenia Inzaugarat, Ariel E. Feldstein
Journal: Hepatology (2017)

1Department of Internal Medicine IIIUniversity Hospital RWTH‐AachenAachenGermany 2Department of Pediatric GastroenterologyUniversity of California San Diego (UCSD), and Rady Children's HospitalSan DiegoCA
HPV cell free DNA as a marker of response to chemoradiation for HPV-positive oropharngeal cancers.
Authors: Daniel S. Higginson, Rama Damerla, Eli D. Scher, Stanley I Gutinov, Christopher Thompson, Cristian Cleary, Sean Matthew McBride, Eric Jeffrey Sherman, Nadeem Riaz, Nancy Y. Lee
Journal: Journal of Clinical Oncology (2016)

6083 Background: Circulating cell free plasma DNA(cfDNA) can be a sensitive biomarker of tumor burden that is accessible by simple phlebotomy. Virally induced cancers present unique advantages for cfDNA technologies in that viral genomes present a cancer-specific, broadly applicable target for assessment by quantitative PCR(qPCR) without any additional DNA processing steps that reduce DNA yield. In this pilot study, we hypothesize that qPCR of HPV16 cfDNA can serve as a marker of disease burden after a course of chemoradiation for HPV-associated oropharyngeal cancer(OPC). Methods: Patients were consented and enrolled on MSKCC specimen protocol #06-107. 8-10 mL of blood was collected in EDTA-lined vacutainer tubes before the first fraction of radiation and after the completion of radiation. Within 30 minutes of phlebotomy, samples were centrifuged at 820g for 10 minutes. The upper plasma layer was further centrifuged at 16,000g for 10 minutes to remove any remaining cell debris. DNA was extracted from the upper plasma layer (1-3mL) using the Qiagen QIAamp Circulating Nucleic Acid kit. Primers for quantitative PCR were selected via alignment of all known sequences of the HPV16 and HPV33 strains. Small amplicons ( < 100bp) were selected to maximize assay sensitivity. Results: 25 head and neck cancer patients were accrued. 22 had HPV-associated OPC defined by ISH and/or p16 immunohistochemistry. Of the 14 HPV+ OPC plasma samples analyzed, 12 exhibited detectable HPV16 cfDNA with copy numbers ranging from 1 to ~10,000 copies per mL of plasma and 1 exhibited HPV33 cfDNA for an overall sensitivity of 13/14 (93%). Of the 7 patients who have also completed chemoradiation therapy, all 7 no longer exhibited any detectable HPV16 cfDNA. None of 5 samples with non-head and neck malignancies had detectable HPV cfDNA. Conclusions: HPV16 or HPV33 cfDNA can be readily identified in almost all HPV-associated OPC patients analyzed to date. The copy numbers of HPV16 cfDNA per mL plasma vary widely, likely due to a differing number of integration events. Additional work is needed to determine if residual HPV16 or HPV33 cfDNA at completion of treatment is prognostic of recurrence.
Abstract 236: Heart Failure Remodeling: Local Endogenous Erythropoietin and Erythropoietin Receptor Expression
Authors: Przemyslaw Leszek, Barbara Sochanowicz, Kamil Brzoska, Walerian Piotrowski, Bozena Danko, Mariusz Kusmierczyk, Jacek Rozanski, Tomasz Rywik, Marcin Kruszewski
Journal: Circulation Research (2012)

Erythropoietin (EPO) via erythropoietin receptor (EPOR) maintains myeloid erythropoiesis, however in a failing heart (FH) it seems to exert cytoprotective, antiapoptotic, proangiogenic effects. Aim: to assess (myocardial) M-EPOR expression and to find out if erythropoietin (M-EPO) is produced in human heart; secondary to elucidate the mechanisms related to M-EPO/M-EPOR expression. Methods: We used 33 explanted FH, compared to 11 non-failing hearts (NFH). Patients characteristics: left ventricle (LV - EF 22±11%), NTproBNP (5464±4825 pg/ml). Serum variables: iron (62±32ug/dl), ferritin (156±122ng/ml), transferrin receptor (3.8±2.6mg/l), EPO (29.5±44.4mIU/ml), HT (39.8±5.3%), Hb (13.2±1.7g/dl), creatinine clearance (CrCl 68±23 ml/min), Na+ (138±5.4 mmol/l). Myocardial assesment: M-EPO, M-EPOR, iron storage protein - ferritin (M-FR), iron acquisition protein transferrin receptor (M-TfR), Iron Regulatory Protein 1 (M-IRP1) - by ELISA - ng/mg protein - expression; myocardial iron load - by Instrumental Neutron Activation Analysis, µg/g. Results: In FH and NFH M-EPO/M-EPOR expression were detected; M-EPO was elevated in failing LV (in FH vs NFH 4.7±1.6 vs 3.7±1.4, p=0.0346; ng/mg protein), no changes in M-EPOR was found. M-EPO correlated with M-EPOR from both ventricles (LV- left r=0.63, p=0.0002; RV - right r=0.42, p=0.0161). With regard to anemia (by WHO), patients were divided into two subgroups: A+ (n=11) and A- (n=22). In A+ vs A- serum EPO (47±23 vs 28±30 mIU/l, p=0.0473) was higher. In myocardium A+ M-TfR was lower than in A- both LV (136±61 vs 218±134; p=0.0446) and RV (130±92 vs 199±143; p=0.0688), however no differences in M-EPO/M-EPOR/M-FR/M-IRP1 and iron load were found. In LV, A+ subgroup, IRP1 correlation with M-EPO (r=0.79, p=0.0107) and M-EPOR (r=0.76, p=0.0184). Conclusions: M-EPO/M-EPOR are synthesized locally in human hearts. In failing LV M-EPO synthesis is significantly increased. M-EPO production correlated with M-EPOR expression. M-EPO/EPOR expression is associated with regulatory protein IRP1. The presence of anemia accompanied by high plasma EPO is not connected with modification of myocardial expression: M-EPO/M-EPOR/M-FR/M-IRP1, iron load, except for M-TfR.
Spatiotemporal Dynamics of Genetic Variation in the Iberian Lynx along Its Path to Extinction Reconstructed with Ancient DNA
Authors: Mireia Casas-Marce, Elena Marmesat, Laura Soriano, Begoña Martínez-Cruz, Maria Lucena-Perez, Francisco Nocete, Antonio Rodríguez-Hidalgo, Antoni Canals, Jordi Nadal, Cleia Detry, Eloísa Bernáldez-Sánchez, Carlos Fernández-Rodríguez, Manuel Pérez-Ripoll, Mathias Stiller, Michael Hofreiter, Alejandro Rodríguez, Eloy Revilla, Miguel Delibes, José A. Godoy
Journal: Molecular Biology and Evolution (2017)

There is the tendency to assume that endangered species have been both genetically and demographically healthier in the past, so that any genetic erosion observed today was caused by their recent decline. The Iberian lynx (Lynx pardinus) suffered a dramatic and continuous decline during the 20th century, and now shows extremely low genome- and species-wide genetic diversity among other signs of genomic erosion. We analyze ancient (N = 10), historical (N = 245), and contemporary (N = 172) samples with microsatellite and mitogenome data to reconstruct the species' demography and investigate patterns of genetic variation across space and time. Iberian lynx populations transitioned from low but significantly higher genetic diversity than today and shallow geographical differentiation millennia ago, through a structured metapopulation with varying levels of diversity during the last centuries, to two extremely genetically depauperate and differentiated remnant populations by 2002. The historical subpopulations show varying extents of genetic drift in relation to their recent size and time in isolation, but these do not predict whether the populations persisted or went finally extinct. In conclusion, current genetic patterns were mainly shaped by genetic drift, supporting the current admixture of the two genetic pools and calling for a comprehensive genetic management of the ongoing conservation program. This study illustrates how a retrospective analysis of demographic and genetic patterns of endangered species can shed light onto their evolutionary history and this, in turn, can inform conservation actions.
3D Miniaturization of Human Organs for Drug Discovery
Authors: Joseph Park, Isaac Wetzel, Didier Dréau, Hansang Cho
Journal: Advanced Healthcare Materials (2017)

Abstract “Engineered human organs” hold promises for predicting the effectiveness and accuracy of drug responses while reducing cost, time, and failure rates in clinical trials. Multiorgan human models utilize many aspects of currently available technologies including self‐organized spherical 3D human organoids, microfabricated 3D human organ chips, and 3D bioprinted human organ constructs to mimic key structural and functional properties of human organs. They enable precise control of multicellular activities, extracellular matrix (ECM) compositions, spatial distributions of cells, architectural organizations of ECM, and environmental cues. Thus, engineered human organs can provide the microstructures and biological functions of target organs and advantageously substitute multiscaled drug‐testing platforms including the current in vitro molecular assays, cell platforms, and in vivo models. This review provides an overview of advanced innovative designs based on the three main technologies used for organ construction leading to single and multiorgan systems useable for drug development. Current technological challenges and future perspectives are also discussed.
Invasion Science: Looking Forward Rather Than Revisiting Old Ground – A Reply to Zenni et al .
Authors: Anthony Ricciardi, Tim M. Blackburn, James T. Carlton, Jaimie T.A. Dick, Philip E. Hulme, Josephine C. Iacarella, Jonathan M. Jeschke, Andrew M. Liebhold, Julie L. Lockwood, Hugh J. MacIsaac, Petr Pyšek, David M. Richardson, Gregory M. Ruiz, Daniel Simberloff, William J. Sutherland, David A. Wardle, David C. Aldridge
Journal: Trends in Ecology & Evolution (2017)
Prospective study on the incidence, prevalence and 5-year pancreatic-related mortality of pancreatic cysts in a population-based study
Authors: Marie-Luise Kromrey, Robin Bülow, Jenny Hübner, Christin Paperlein, Markus M Lerch, Till Ittermann, Henry Völzke, Julia Mayerle, Jens-Peter Kühn
Journal: Gut (2017)

To analyse the prevalence, incidence and clinical relevance of pancreatic cysts detected as incidental finding in a population-based longitudinal study.A total of 1077 participants (521 men, mean age 55.8±12.8 years) of 2333 participants from the population-based Study of Health in Pomerania (SHIP) underwent magnetic resonance cholangiopancreaticography (MRCP) at baseline (2008-2012). MRCP was analysed for pancreatic cysts with a diameter ≥2 mm. 676/1077 subjects received a 5-year follow-up (2014-2016). The prevalence and incidence of pancreatic cysts (weighted for study participation) were assessed in association to age, gender and suspected epidemiological risk factors. Mortality follow-up was performed in 2015 for all SHIP participants (mean follow-up period 5.9 years, range 3.2-7.5 years).At baseline pancreatic cysts had a weighted prevalence of 49.1%, with an average number of 3.9 (95% CI 3.2 to 4.5) cysts per subject in the subgroup harbouring cysts. Cyst size ranged from 2 to 29 mm. Prevalence (p<0.001), number (p=0.001) and maximum size (p<0.001) increased significantly with age. The 5-year follow-up revealed a weighted incidence of 12.9% newly detected pancreatic cysts. 57.1% of the subjects initially harbouring pancreatic cysts showed an increase in number and/or maximum cyst size. Of all subjects undergoing MRCP, no participant died of pancreatic diseases within mortality follow-up.The prevalence of pancreatic cysts in the general population is unexpectedly high, and their number and size increase with age. Overall, no pancreatic cancer was observed in this collective during a 5-year follow-up. Nevertheless, prospective follow-up imaging showed minimal progress in more than 50%. Only about 6% of cysts and 2.5% of the study group initially presented with cysts of more than 1 cm and thus might be clinically meaningful.
Abnormalities of T-cell receptor repertoire in CD4+ regulatory and conventional T cells in patients with RAG mutations: Implications for autoimmunity
Authors: Jared H. Rowe, Brian D. Stadinski, Lauren A. Henderson, Lisa Ott de Bruin, Ottavia Delmonte, Yu Nee Lee, M. Teresa de la Morena, Rakesh K. Goyal, Anthony Hayward, Chiung-Hui Huang, Maria Kanariou, Alejandra King, Taco W. Kuijpers, Jian Yi Soh, Benedicte Neven, Jolan E. Walter, Eric S. Huseby, Luigi D. Notarangelo
Journal: Journal of Allergy and Clinical Immunology (2017)
Intensified Myeloablative Conditioning Regimen without Antithymocytic (ATG) Results in Superior Patient Outcome Compared to Myeloablative Conditioning Regimen for Single-Unit Umbilical Cord Blood Transplantation in Hematological Malignancies
Authors: Zimin Sun, Huilan Liu, Yue Wu, Changcheng Zheng, Baolin Tang, Xiaoyu Zhu, Qifa Liu
Journal: Blood (2016)
Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2
Authors: Yuanyuan Wu, Liwen Hu, Yan Liang, Juan Li, Kai Wang, Xuedan Chen, Hui Meng, Xingying Guan, Kang Yang, Yun Bai
Journal: Molecular Cancer (2017)

Abnormal expression of numerous long non-coding RNAs (lncRNAs) has been reported in esophageal squamous cell carcinoma (ESCC) recently, but the great majority of their roles and mechanisms remain largely unclear. We aim to identify the critical ESCC-associated lncRNAs and elucidate the functions and mechanisms in detail. Microarrays were used to analyze the differentially expressed lncRNAs in ESCC tissues. qRT-PCR was used to verify the result of microarrays. The effects of the most up-regulated lncRNA, cancer susceptibility candidate 9(CASC9), on cell growth, proliferation and cell cycle were investigated by in vivo and in vitro assays. Microarrays and recovery tests were used to discover the regulatory targets of CASC9. RNA FISH and subcellular fractionation assays were used to detect the subcellular location of CASC9. Finally, the mechanism of CASC9 regulating PDCD4 was explored by RIP, RNA-protein pull down and ChIP assays. ESCC tissue microarrays showed that CASC9 was the most up-regulated lncRNA. qRT-PCR analysis indicated that CASC9 expression was positively associated with tumor size and TNM stage, and predicted poor overall survival of ESCC patients. Knockdown of CASC9 inhibited ESCC cell growth in vitro and tumorigenesis in nude mice. Furthermore interfering CASC9 decreased cell proliferation and blocked cell cycle G1/S transition. CASC9-associated microarrays indicated that PDCD4 might be the target of CASC9. Consistent with this, PDCD4 expression was negatively associated with CASC9 expression in ESCC tissues and predicted good prognosis. Manipulating CASC9 expression in ESCC cells altered both PDCD4 mRNA and protein levels and cell cycle arrest caused by CASC9 knockdown could be rescued by suppressing PDCD4 expression. CASC9 located both in the nucleus and cytoplasm. Mechanistically, enhancer of zeste homolog2 (EZH2) could bind to both CASC9 and PDCD4 promoter region. Interfering CASC9 reduced the enrichment of EZH2 and H3K27me3 in the PDCD4 promoter region. Our study firstly demonstrates that lncRNA CASC9 functions as an oncogene by negatively regulating PDCD4 expression through recruiting EZH2 and subsequently altering H3K27me3 level. Our study implicates lncRNA CASC9 as a valuable biomarker for ESCC diagnosis and prognosis.