tbuckley/cabot-search huggingface dataset:
Abstract 1662: Synthesis and biologic evaluation of diethylbenzaldehyde analogues to probe functional activity of aldehyde dehydrogenase activity in cancer
Authors: Ali Ibrahim, Maria Sadiq, Daniela Presa, Ioannis Ntafoulis, Ahmad Alkawi, Fiona Frame, Norman J. Maitland, Zoe Cournia, Paul M. Loadman, Jan Moreb, Klaus Pors
Journal: Cancer Research (2018)

Abstract The human aldehyde dehydrogenases (ALDHs) play a major role in detoxifying highly reactive aldehydes into carboxylic acids. Deregulation of ALDHs has implications in a number of cancers. They play an important role as a cancer stem cell (CSC) marker due to high activity found in CSCs, while high expression is also known to lead to resistance to chemotherapeutic drugs. Although the exact roles of ALDHs are not fully understood, emerging information indicates several isoforms from the ALDH1 family, ALDH3A1 and ALDH7A1, play key roles in several cancer types. To probe the role of ALDH functional activity, we here report on the perturbation of ALDH expression and function using diethylbenzaldehyde (DEAB) analogues. The H1299 lung cancer cell line has negligible amount of ALDH activity, and ALDH-expressing variants were used to study the novel DEAB analogues. H1299 wild-type cells (WT) and cells expressing RFP were used as controls. Expression of the proteins was confirmed by Western blots and ALDH enzymatic activity assay. We used cell culture, colorimetric MTT assay, aldefluor assay and in vitro treatment with DEAB analogues. ALDH-expressing lysates were used to obtain biochemical inhibition data of the DEAB analogues using propionaldehyde as substrate with NAD+ as a co-factor. DEAB has been shown to covalently bind to ALDH7A1, and computational modeling was employed to understand how chemical modifications to DEAB affected the binding mode. Selected ALDH-affinic probe compounds were tested in a panel of colon, lung and prostate cancer cell lines including docetaxel-resistant variant and patient samples to investigate if DEAB analogues had an effect on cell viability as single agents or in combination with docetaxel. In conclusion, the novel DEAB analogues aid us to understand ALDH functional activity and provide a platform for discovering more selective ALDH inhibitors Citation Format: Ali Ibrahim, Maria Sadiq, Daniela Presa, Ioannis Ntafoulis, Ahmad Alkawi, Fiona Frame, Norman J. Maitland, Zoe Cournia, Paul M. Loadman, Jan Moreb, Klaus Pors. Synthesis and biologic evaluation of diethylbenzaldehyde analogues to probe functional activity of aldehyde dehydrogenase activity in 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 1662.
Assessment of Pericardial Inflammation in a Patient With Tuberculous Effusive Constrictive Pericarditis With 18F-2-Deoxyglucose Positron Emission Tomography
Authors: Jong-WonHa, Jong-DooLee, Young-GookKo, MijinYun, Se-JoongRim, NamsikChung, Sang-HoCho
Journal: Circulation (2006)
Special issue: Pharmaceutical innovation
Authors: Pornsak Sriamornsak, Duangratana Shuwisitkul
Journal: Asian Journal of Pharmaceutical Sciences (2018)

“Pharmaceutical innovation” is an interdisciplinary area of the pharmaceutical sciences including drug development with a focus on manufacturing, process control, and technology, among many other subfields of research. In this special issue, we have invited all participants attended the International Conference and Exhibition on Pharmaceutical Sciences and Technology 2018 under the theme of pharmaceutical innovation and translational research for human health, held in Bangkok during January 24–25, 2018, to submit the research papers and after peer-review process, 10 of them were selected.
Abstract LB-357: Transcriptional landscape of stroma progression in the breast tumor microenvironment
Authors: Raditya Utama, Anja Bastian, Narayanan Sadagopan, Ying Jin, Eric Antoniou, Yin Huang, Peter Lee, Gurinder Atwal
Journal: Cancer Research (2018)

Abstract The breast tumor microenvironment of primary and metastatic sites is a complex milieu of differing cell populations. However, the genomic expression landscape of the tumor stroma and its role in mediating cancer progression and informing effective therapies is not well understood. Here we obtained and cultured 52 cell-sorted stromal tissue samples across 37 patients from normal, primary tumor, and metastatic tumor sites. Deep RNA-seq was performed on poly(A)+ transcripts using a multiplexed barcoding sequencing strategy to increase yield and obviate batch effects. A conservative linear model of expression covariates revealed significant (q&amp;lt;0.05) differential expression of protein-coding genes and lncRNAs in the stroma (80 transcripts in normal versus primary and 108 transcripts in primary versus metastatic). The majority of these genes were found to be associated with pattern formation, embryogenesis, and the epithelial-mesenchymal transition. Among the genes that were silenced in the epithelial cells, IHC staining was initially done for C2orf88, ALOX5AP, and UNC5C which are important in PKA binding, immune response, apoptosis, and neural development. Furthermore, survival analyses of 827 luminal breast tumor samples from TCGA demonstrated the predictive power of the stromal gene expression in informing clinical outcome. Together these results highlight the evolution of stromal gene expression in breast tumors and suggest novel therapeutic strategies targeting the microenvironment. Citation Format: Raditya Utama, Anja Bastian, Narayanan Sadagopan, Ying Jin, Eric Antoniou, Yin Huang, Peter Lee, Gurinder Atwal. Transcriptional landscape of stroma progression in the breast tumor microenvironment [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 LB-357.
Overexpressed A1 Adenosine Receptors Reduce Activation of Acetylcholine-Sensitive K+ Current by Native Muscarinic M2 Receptors in Rat Atrial Myocytes
Authors: Marie-CécileWellner-Kienitz, KirstenBender, ThomasMeyer, MoritzBünemann, LutzPott
Journal: Circulation Research (2000)

Abstract—In adult rat atrial myocytes, muscarinic acetylcholine (ACh)-sensitive K+ current activated by a saturating concentration of adenosine (IK(ACh),(Ado)) via A1 receptors (A1Rs) amounts to only 30% of the current activated by a saturating concentration of ACh (IK(ACh),(ACh)) via muscarinic M2 receptors. The half-time of activation of IK(ACh),(Ado) on a rapid exposure to agonist was ≈4-fold longer than that of IK(ACh),(ACh). Furthermore, IK(ACh),(Ado) never showed fast desensitization. To study the importance of receptor density for A1R-IK(ACh),(Ado) signaling, adult atrial myocytes in vitro were transfected with cDNA encoding for rat brain A1R and enhanced green fluorescent protein (EGFP) as a reporter. Whole-cell current was measured on days 3 and 4 after transfection. Time-matched cells transfected with only the EGFP vector served as controls. In ≈30% of EGFP-positive cells (group I), the density of IK(ACh),(Ado) was increased by 72%, and its half-time of activation was reduced. Density and kineti...
Abstract 18179: Application of Machine Learning Algorithm for Early Prediction to Classify Atrial Fibrillation Into Paroxysmal and Non-Paroxysmal by Analysis of fibrillatory Wave on 12-Lead Electrocardiography
Authors: Sungsoo Kim, Sohee Kwon, Sung Hwi Hong, Junyong Kim, Jeong-Eun Yi, Minsuk Kim, Kihwan Kwon, Wook Bum Pyun, Junbeom Park
Journal: Circulation (2017)

Introduction: Fibrillatory (f) wave of Atrial Fibrillation (AF) may have relevant information for classification of AF by analyzing 12-lead ECG. Paroxysmal AF has different treatment strategy and b...
Abstract 4194: Tumor Treating Fields (TTFields) affect invasion properties and cell morphology of various cancer cells in vitro
Authors: Rosa S. Schneiderman, Moshe Giladi, Einav Zeevi, Anna Shteingauz, Tali Voloshin, Yaara Porat, Mijal Munster, Eilon D. Kirson, Yoram Palti
Journal: Cancer Research (2018)

Abstract Tumor Treating Fields (TTFields) therapy is an approved modality for the treatment of glioblastoma. TTFields are delivered via continuous, noninvasive application of low intensity, intermediate frequency alternating electric fields. The antimitotic effects of TTFields have been extensively investigated. We explored other processes that may be affected by TTFields such as cellular invasion. Human glioma, human and mouse melanoma, human breast cancer and human colon cancer cell lines were treated with TTFields using the inovitro system. Invasion assays were performed using a modified Matrigel coated Boyden chamber. TTFields effect on cells size, focal adhesions and stress fibers morphology was studied using immuno-fluorescent confocal microscopy. Invasion was significantly reduced compared to untreated cells in all tested cell lines. Furthermore, the optimal frequency for inhibition of invasion in tested cells was 300 kHz while the optimal anti mitotic frequency leading to glioma cell death is 200 kHz. The inhibitory effect on migration was observed at electric fields intensities of 0.6 V/cm RMS which is below the 1 V/cm RMS threshold previously reported for induction of cell death. Combining TTFields with Bumetanide, an agent that inhibits cellular motility, resulted in further inhibition of glioma cell invasion. TTFields application resulted in an increase in cell size, as well as in focal adhesion size, number and peripheral distribution of the adhesion sites. Also, treated cells adopted a more flattened and spread shape in comparison with control cells. TTFields treated cells exhibit reduction in appearance of stress fibers and a dense meshwork of actin filaments around the entire cell periphery. Our results suggest that cancer cell motility is impaired by exposure to TTFields. The TTFields parameters (intensity and frequency) which led to the maximal inhibition of cellular motility are different from those required for exerting anti-mitotic effects. The alterations in cells morphology during exposure to TTFields may contribute to reduction in cell motility. Further studies are needed to elucidate the mechanism by which TTFields disrupts cellular motility in glioma cancer cells. Citation Format: Rosa S. Schneiderman, Moshe Giladi, Einav Zeevi, Anna Shteingauz, Tali Voloshin, Yaara Porat, Mijal Munster, Eilon D. Kirson, Yoram Palti. Tumor Treating Fields (TTFields) affect invasion properties and cell morphology of various cancer cells in vitro [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 4194.
Pharmacometabolic response to pirfenidone in pulmonary fibrosis detected by MALDI-FTICR-MSI
Authors: Na Sun, Isis E. Fernandez, Mian Wei, Michael Witting, Michaela Aichler, Annette Feuchtinger, Gerald Burgstaller, Stijn E. Verleden, Philippe Schmitt-Kopplin, Oliver Eickelberg, Axel Walch
Journal: European Respiratory Journal (2018)

Idiopathic pulmonary fibrosis (IPF) is a fatal condition that reduces life expectancy and shows a limited response to available therapies. Pirfenidone has been approved for treatment of IPF, but little is known about the distinct metabolic changes that occur in the lung upon pirfenidone administration. Here, we performed a proof-of-concept study using high-resolution quantitative matrix-assisted laser desorption/ionisation Fourier-transform ion cyclotron resonance mass spectrometry imaging (MALDI-FTICR-MSI) to simultaneously detect, visualise and quantify in situ endogenous and exogenous metabolites in lungs of mice subjected to experimental fibrosis and human patients with IPF, and to assess the effect of pirfenidone treatment on metabolite levels. Metabolic pathway analysis and endogenous metabolite quantification revealed that pirfenidone treatment restores redox imbalance and glycolysis in IPF tissues, and downregulates ascorbate and aldarate metabolism, thereby likely contributing to in situ modulation of collagen processing. As such, we detected specific alterations in metabolite pathways in fibrosis and, importantly, metabolic recalibration following pirfenidone treatment. Together, these results highlight the suitability of high-resolution MALDI-FTICR-MSI for deciphering the therapeutic effects of pirfenidone and provide a preliminary analysis of the metabolic changes that occur during pirfenidone treatment in vivo . These data may therefore contribute to improvement of currently available therapies for IPF.
Application of the 2017 Revised McDonald Criteria for Multiple Sclerosis to Patients With a Typical Clinically Isolated Syndrome
Authors: Roos M. van der Vuurst de Vries, Julia Y. Mescheriakova, Yu Yi M. Wong, Tessel F. Runia, Naghmeh Jafari, Johnny P. Samijn, Janet W. K. de Beukelaar, Beatrijs H. A. Wokke, Theodora A. M. Siepman, Rogier Q. Hintzen
Journal: JAMA Neurology (2018)

<h3>Importance</h3> In 2017, the International Panel on Diagnosis of Multiple Sclerosis revised the McDonald 2010 criteria for the diagnosis of multiple sclerosis (MS). The new criteria are easier to apply and could lead to more and earlier diagnoses. It is important to validate these criteria globally for their accuracy in clinical practice. <h3>Objective</h3> To evaluate the diagnostic accuracy of the 2017 criteria vs the 2010 criteria in prediction of clinically definite MS in patients with a typical clinically isolated syndrome (CIS). <h3>Design, Setting and Patients</h3> A total of 251 patients at Erasmus MC, Rotterdam, the Netherlands, in collaboration with several regional hospitals, fulfilled the inclusion criteria. Thirteen patients received another diagnosis early in the diagnostic process and therefore were excluded from the analyses. Nine patients with CIS declined to participate in the study. This left 229 patients who were included between March 2006 and August 2016 in this prospective CIS cohort. Patients underwent a baseline magnetic resonance imaging scan within 3 months after onset of symptoms and, if clinically required, a lumbar puncture was performed. Data were analyzed between December 2017 and January 2018. <h3>Main Outcomes and Measures</h3> Sensitivity, specificity, accuracy, and positive and negative predictive value were calculated after 1, 3, and 5 years for the 2017 vs the 2010 criteria. <h3>Results</h3> Among the 229 patients with CIS, 167 were women (73%), and the mean (SD) age was 33.5 (8.2) years. One hundred thirteen patients (49%) were diagnosed as having CDMS during a mean (SD) follow-up time of 65.3 (30.9) months. Sensitivity for the 2017 criteria was higher than for the 2010 criteria (68%; 95% CI, 57%-77% vs 36%; 95% CI, 27%-47%;<i>P</i> &lt; .001), but specificity was lower (61%; 95% CI, 50%-71% vs 85%; 95% CI, 76%-92%;<i>P</i> &lt; .001). Using the 2017 criteria, more MS diagnoses could be made at baseline (n = 97 [54%]; 95% CI, 47%-61% vs n = 46 [26%]; 95% CI, 20%-32%;<i>P</i> &lt; .001). In the group with at least 5 years of follow-up, 33% of patients who were diagnosed as having MS using the 2017 criteria did not experience a second attack during follow-up vs 23% when using the 2010 criteria. <h3>Conclusions and Relevance</h3> The 2017 revised McDonald criteria are associated with greater sensitivity but less specificity for a second attack than the previous 2010 criteria. The tradeoff is that it leads to a higher number of MS diagnoses in patients with a less active disease course.
Deficiency in ClC-3 Chloride Channels Prevents Rat Aortic Smooth Muscle Cell Proliferation
Authors: Guan-LeiWang, Xue-RongWang, Mo-JunLin, HuaHe, Xiu-JianLan, Yong-YuanGuan
Journal: Circulation Research (2002)

Recent growing evidence suggests that chloride (Cl−) channels are critical to the cell cycle. In cultured rat aortic vascular smooth muscle cells (VSMCs), we have previously found that Cl− channel blockers inhibit endothelin-1 (ET-1)–induced cell proliferation. The present study was designed to further identify the specific Cl− channels responsible for VSMC proliferation. Due to the lack of a specific blocker or opener of any known Cl− channels, we used the antisense strategy to investigate the potential role of ClC-3, a member of the voltage-gated Cl− channel gene family, in cell proliferation of cultured rat aortic VSMCs. With [3H]-thymidine incorporation and immunoblots, we found that ET-1–induced cell proliferation was parallel to a significant increase in the endogenous expression of ClC-3 protein. Transient transfection of rat aortic VSMCs with antisense oligonucleotide specific to ClC-3 caused an inhibition in ET-1–induced expression of ClC-3 protein and cell proliferation of VSMCs in the same conc...
Abstract 5327: DNA methylation loss in late-replicating domains is linked to mitotic cell division
Authors: Wanding Zhou, Huy Q. Dinh, Zachary Ramjan, Daniel J. Weisenberger, Charles M. Nicolet, Hui Shen, Peter W. Laird, Benjamin P. Berman
Journal: Cancer Research (2018)

Abstract DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed Partially Methylated Domains (PMDs). We profiled 39 diverse primary tumors and 8 matched adjacent tissues using Whole-Genome Bisulfite Sequencing (WGBS), and analyzed them alongside 343 additional human and 206 mouse WGBS datasets. We identified a local CpG sequence context associated with preferential hypomethylation in PMDs. Analysis of CpGs in this context (“Solo-WCGWs”) revealed previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increases with age in both fetal and postnatal tissues, appearing to track accumulation of cell divisions beginning early in life. In cancer, the degree of PMD hypomethylation correlates with somatic mutation density and expression of cell-cycle dependent genes, reinforcing its mitotic clock-like role. We propose that late replication leads to progressive methylation loss throughout an individual's lifespan, potentially contributing to the onset of cancer and acting as a biomarker for cellular aging. Citation Format: Wanding Zhou, Huy Q. Dinh, Zachary Ramjan, Daniel J. Weisenberger, Charles M. Nicolet, Hui Shen, Peter W. Laird, Benjamin P. Berman. DNA methylation loss in late-replicating domains is linked to mitotic cell division [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 5327.
Varicose Veins and Deep Venous Thrombosis
Authors: Alok Tiwari, Will Lester, Tjun Yip Tang
Journal: JAMA (2018)

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Capnocytophaga canimorsus as a cause of spontaneous Gram-negative bacilli community-acquired meningitis
Authors: M. Amara, N. Zappella, E. Bruneel, C. Courboulès, N. Ung, P. Bayle, E. Gydé, F. Bruneel, J.-P. Bédos, B. Pangon
Journal: Clinical Microbiology and Infection (2018)
Novel Molecular Mechanism Involving α1D (Cav1.3) L-Type Calcium Channel in Autoimmune-Associated Sinus Bradycardia
Authors: YongxiaQu, GhayathBaroudi, YuankunYue, MohamedBoutjdir
Journal: Circulation (2005)

Background— Congenital heart block (CHB) is an autoimmune disease that affects fetuses/infants born to mothers with anti-Ro/La antibodies (positive IgG). Although the hallmark of CHB is complete atrioventricular block, sinus bradycardia has been reported recently in animal models of CHB. Interestingly, knockout of the neuroendocrine α1D Ca channel in mice results in significant sinus bradycardia and atrioventricular block, a phenotype reminiscent to that seen in CHB. Here, we tested the hypothesis that the α1D Ca channel is a novel target for positive IgG. Methods and Results— Reverse transcription–polymerase chain reaction, confocal indirect immunostaining, and Western blot data established the expression of the α1D Ca channel in the human fetal heart. The effect of positive IgG on α1D Ca current (ICa-L) was characterized in heterologous expression systems (tsA201 cells and Xenopus oocytes) because of the unavailability of α1D-specific modulators. α1D ICa-L activated at negative potentials (between −60 a...
Abstract 3507: Targeting the insulin-like growth factor-1 receptor in MTAP-deleted renal cell carcinomas
Authors: Jihao Xu, Wen-Hsin Chang, Carissa Huang, David Yang, Ching-Hsien Chen
Journal: Cancer Research (2018)

Abstract Renal cell carcinoma (RCC) has emerged as a metabolic disease characterized by dysregulated expression of metabolic enzymes. Patients with metastatic RCC have an unusually poor prognosis and near-universal resistance to all current therapies. To ultimately improve cancer treatment and survival rate, there is an urgent need to reveal the mechanisms by which metabolic enzymes and aberrant pathways regulate oncogenic signaling. Through an integrated two-step analysis of RCC metabolic pathways, we previously identified dysregulated expression of methylthioadenosine phosphorylase (MTAP) in aggressive RCC. An accumulation of cellular methylthioadenosine has been observed in MTAP-deleted cancer cells. Interestingly, we found a decreased of protein-methylation level with concomitant with an increase in tyrosine phosphorylation after MTAP knockout. Next, we performed a phospho-kinase antibody array screen and identified the type 1 insulin-like growth factor-1 receptor (IGF1R) as the top-one candidate with upregulated tyrosine phosphorylation in response to MTAP loss. IGF1R phosphorylation acted upstream of Src and STAT3 signaling in MTAP-knockout RCC cells. Reduction of phospho-IGF1R by a selective inhibitor of IGF-1R, linsitinib, inhibited the cell migration and invasion capability of MTAP-deleted cells. Data from cell viability assays showed that MTAP loss enhanced linsitinib-mediated cytotoxicity in RCC cells. Our data suggest that IGF1R signaling is a driver pathway to confer aggrieves nature of MTAP-deleted renal cell carcinomas. Citation Format: Jihao Xu, Wen-Hsin Chang, Carissa Huang, David Yang, Ching-Hsien Chen. Targeting the insulin-like growth factor-1 receptor in MTAP-deleted renal cell carcinomas [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 3507.