tbuckley/cabot-search huggingface dataset:
Abstract 1799: ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct “alpha-cell signature” subgroup
Authors: Saurabh V. Laddha, Chang S. Chan, Peter Lewis, Matthew Koletsky, Kenneth Robzyk, Edaise Da Silva, Paula J. Torres, Brian Untch, Promita Bose, Timothy Chan, David S. Klimstra, David C. Allis, Laura H. Tang
Journal: Cancer Research (2018)

Abstract Pancreatic neuroendocrine tumors (PanNETs) or islet cell tumors are a rare neuroendocrine malignancy with an annual incidence of less than 1 per 100,000 per year. Current classification scheme for PanNETs include grade and stage. While well-differentiated PanNETs can be successfully treated with surgery, there are few treatments for metastatic PanNETs. A greater understanding of the cells of origin of PanNETs, tumor progression and pathway pathogenesis may guide the development of novel therapeutic options. The most commonly mutated genes in PanNETs are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing (n=33) and Illumina 450K DNA methylation (n=32) analysis on randomly selected PanNETs to reveal two distinct subgroups with one group consisting exclusively of A-D-M mutant PanNETs. Pair-wise correlation of gene expression between all PanNETs, showed A-D-M mutant PanNETs are more homogeneous as a group than A-D-M WT PanNETs. Among A-D-M mutant PanNETs, mutants with the same genotype (mutations in ATRX/DAXX/MEN1) did not show greater gene expression correlation. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature similar to that of alpha cells (pval &amp;lt; 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. We validated our subtype classification and A-D-M mutant panNET alpha signature using two independent PanNETs expression dataset. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells. Citation Format: Saurabh V. Laddha, Chang S. Chan, Peter Lewis, Matthew Koletsky, Kenneth Robzyk, Edaise Da Silva, Paula J. Torres, Brian Untch, Promita Bose, Timothy Chan, David S. Klimstra, David C. Allis, Laura H. Tang. ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct “alpha-cell signature” subgroup [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 1799.
Abstract 12194: Finding Out a Useful Parameter of Sleep Disordered Breathing in Chronic Heart Failure Patients
Authors: TadamitsuNakashima, TomokoOhkusa, TomokoNao, NorikoHarada, YasuakiWada, TakeshiUeyama, ShigekiKobayashi, YasuhiroIkeda, HiroyukiSawatari, AkikoChishaki, Shin-ichiAndo, MasafumiYano
Journal: Circulation (2014)

Background and Purpose: Sleep disordered breathing (SDB) is highly prevalent in patients with chronic heart failure (CHF). Though severity of SDB has been commonly assessed by apnea hypopnea index (AHI) using standard polysomnography (PSG), this method necessitates especially dedicated facilities and trained personnel. Thus, we tried to determine a practical threshold for detecting moderate SDB by investigating all admitted CHF patients with the use of pulse-oximetry data. Methods: Consecutive stable CHF patients (N=136) were prospectively screened for the presence of SDB according to Japanese guideline for treatment of SDB. In patients who were suspected of having SDB from the data showing 3% oxygen desaturation index (ODI), standard PSG was performed. The relationship between parameters obtained by the PSG and pulse-oximetry were investigated. Results: Of the 136 patients (81 male), average NYHA class and left ventricular ejection fraction (LVEF) were 2.2±0.7 and 46.9±17.9%, respectively. In 123 patient...
Multiple myeloma: 2018 update on diagnosis, risk‐stratification, and management
Authors: S. Vincent Rajkumar
Journal: American Journal of Hematology (2018)

Abstract Multiple myeloma accounts for approximately 10% of hematologic malignancies. The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events: CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or &gt;1 focal lesion on magnetic resonance imaging. Patients with del(17p), t(14;16), and t(14;20) have high‐risk multiple myeloma. Patients with t(4;14) translocation and gain(1q) have intermediate‐risk. All others are considered standard‐risk. Initial treatment consists of bortezomib, lenalidomide, dexamethasone (VRd). In high‐risk patients, carfilzomib, lenalidomide, dexamethasone (KRd) is an alternative to VRd. In eligible patients, initial therapy is given for approximately 3‐4 cycles followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT at first relapse. Patients not candidates for transplant are treated with VRd for approximately 8‐12 cycles followed by lenalidomide or lenalidomide plus dexamethasone. After ASCT, lenalidomide maintenance is recommended for standard risk patients, while maintenance with a bortezomib‐based regimen is needed for patients with intermediate or high‐risk disease. Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse. Aggressive relapse with extramedullary plasmacytomas or plasma cell leukemia may require anthracycline containing combination chemotherapy regimens.
Abstract 4417: MicroRNA 181a-5p reprogrammed glucose and lipid metabolism in lung cancer though regulating SIRT1 and ACSL4
Authors: Ji Woong Son, Seul-Gi Kim, In Beom Jeong, Sun Jung Kwon
Journal: Cancer Research (2018)

Abstract Changes in metabolism are key contributors to tumorigenesis and metastasis. Micro RNAs (miRNA) play critical roles in glucose and lipid metabolism. In previous studies, miRNA 181a-5p (miR-181a-5p) was shown to be a significant component in down regulation of lung cancer tissue and mesenchymal-like lung cancer cell lines. To define the role of endogenous miR-181a-5p in cancer metabolism, we performed assays for luciferase, Lactate Dehydrogenase (LDH), glucose uptake and mitochondrial ATP synthase inhibitor. It was demonstrated that miR-181a-5p inhibited aerobic glycolysis and lipid metabolism and overexpression decreased LDH and lipid content in lung cancer. Furthermore, the overexpression of miR-181a-5p diminished invasion and migration by inhibition of Sirtuin 1 (SIRT1) and acyl-CoA synthetase long-chain family member 4 (ACSL4). Together these findings suggest that miR-181a-5p might be involved with reprograming lung cancer metabolism. Citation Format: Ji Woong Son, Seul-Gi Kim, In Beom Jeong, Sun Jung Kwon. MicroRNA 181a-5p reprogrammed glucose and lipid metabolism in lung cancer though regulating SIRT1 and ACSL4 [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 4417.
Endothelial Precursor Cell Migration During Vasculogenesis
Authors: AnnetteSchmidt, KlaraBrixius, WilhelmBloch
Journal: Circulation Research (2007)

Migration of endothelial precursor cells (so-called “angioblasts” in embryos and “endothelial progenitor cells” in adults) during vasculogenesis is a requirement for the formation of a primary vascular plexus. The migration is initiated by the change of endothelial precursors to their migratory phenotype. The endothelial precursor cells are then guided to the position where the primary vascular plexus is formed. Migration is stopped by the reversion of the cells to their nonmigratory phenotype. A combination of regulatory mechanisms and factors controls this process. These include gradients of soluble factors, extracellular matrix–cell interaction and cell–cell interaction. In this review, we give an overview of the regulation of angioblast migration during embryonic vasculogenesis and its relationship to the migration of endothelial progenitors during postnatal vascular development.
Molecular Mechanisms Underlying Ionic Remodeling in a Dog Model of Atrial Fibrillation
Authors: LixiaYue, PeterMelnyk, RaniaGaspo, ZhiguoWang, StanleyNattel
Journal: Circulation Research (1999)

Abstract—The rapid atrial rate during atrial fibrillation (AF) decreases the ionic current density of transient outward K+ current, L-type Ca2+ current, and Na+ current, thereby altering cardiac electrophysiology and promoting arrhythmia maintenance. To assess possible underlying changes in cardiac gene expression, we applied competitive reverse transcriptase–polymerase chain reaction to quantify mRNA concentrations in dogs subjected to 7 (group P7 dogs) or 42 (group P42 dogs) days of atrial pacing at 400 bpm and in sham controls. Rapid pacing reduced mRNA concentrations of Kv4.3 (putative gene encoding transient outward K+ current; by 60% in P7 and 74% in P42 dogs; P<0.01 and P<0.001, respectively, versus shams), the α1c subunit of L-type Ca2+ channels (by 57% in P7 and 72% in P42 dogs; P<0.01 versus shams for each) and the α subunit of cardiac Na+ channels (by 18% in P7 and 42% in P42; P=NS and P<0.01, respectively, versus shams) genes. The observed changes in ion channel mRNA concentrations paralleled ...
Microtubule Involvement in Translational Regulation of Fibronectin Expression by Light Chain 3 of Microtubule-Associated Protein 1 in Vascular Smooth Muscle Cells
Authors: BinZhou, MarleneRabinovitch
Journal: Circulation Research (1998)

Abstract—Our previous studies suggested that enhanced fibronectin mRNA translation in ductus arteriosus compared with aortic smooth muscle cells is related to increased expression of light chain 3 (LC3) of microtubule-associated protein 1, which binds an AU-rich element in the 3′ untranslated region of fibronectin mRNA. We therefore hypothesized that microtubules are involved in LC3-mediated fibronectin mRNA translational regulation. In this study we show that disruption of microtubules by colchicine inhibits fibronectin mRNA translation in cultured ductus arteriosus smooth muscle cells. We proposed that the mechanism might be related to decreased docking of fibronectin mRNA on the translational machinery, ie, membrane-bound polysomes on rough endoplasmic reticulum, and confirmed this by Northern blot analysis. To investigate the mechanism further, we carried out polysome analysis using sucrose gradient centrifugation and fractionation and studied the polysomal distribution of fibronectin mRNA and LC3 pro...
Targeting the IDO1 pathway in cancer: from bench to bedside
Authors: Ming Liu, Xu Wang, Lei Wang, Xiaodong Ma, Zhaojian Gong, Shanshan Zhang, Yong Li
Journal: Journal of Hematology & Oncology (2018)

Indoleamine 2, 3-dioxygenases (IDO1 and IDO2) and tryptophan 2, 3-dioxygenase (TDO) are tryptophan catabolic enzymes that catalyze the conversion of tryptophan into kynurenine. The depletion of tryptophan and the increase in kynurenine exert important immunosuppressive functions by activating T regulatory cells and myeloid-derived suppressor cells, suppressing the functions of effector T and natural killer cells, and promoting neovascularization of solid tumors. Targeting IDO1 represents a therapeutic opportunity in cancer immunotherapy beyond checkpoint blockade or adoptive transfer of chimeric antigen receptor T cells. In this review, we discuss the function of the IDO1 pathway in tumor progression and immune surveillance. We highlight recent preclinical and clinical progress in targeting the IDO1 pathway in cancer therapeutics, including peptide vaccines, expression inhibitors, enzymatic inhibitors, and effector inhibitors.
Good Clinical Practice in Diagnosis of Vulvovaginal Symptoms—Reply
Authors: Caroline M. Mitchell, Susan D. Reed, Katherine A. Guthrie
Journal: JAMA Internal Medicine (2018)

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Effects of Age and Sex on Clinical Outcomes After Percutaneous Coronary Intervention Relative to Coronary Artery Bypass Grafting in Patients With Triple-Vessel Coronary Artery Disease
Authors: KyoheiYamaji, HirokiShiomi, TakeshiMorimoto, KenjiNakatsuma, ToshiakiToyota, KohOno, YutakaFurukawa, YoshihisaNakagawa, KazushigeKadota, KenjiAndo, ShinichiShirai, TomoyaOnodera, HirotoshiWatanabe, MasahiroNatsuaki, RyuzoSakata, MichiyaHanyu, NoboruNishiwaki, TatsuhikoKomiya, TakeshiKimura
Journal: Circulation (2016)

Background—Age and sex are important considerations in the choice between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in daily clinical practice. Methods and Results—Of 25 816 patients enrolled in the multicenter Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto; Cohort-1, n=9877; Cohort-2, n=15 939), the present study population consisted of 5651 patients (men, n=3998; women, n=1653) with triple-vessel coronary artery disease who were considered to be pertinent in comparisons of PCI with CABG (PCI, n=3165; CABG, n=2486). Patients were divided into 3 groups according to the tertiles of age: ≤65 years (n=1972), 66 to 73 years (n=1820), and ≥74 years (n=1859). The excess adjusted mortality risk of PCI relative to CABG was significant in patients ≥74 years of age (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.10–1.79; P=0.006), whereas the risks were neutral in patients ≤65 years of age (HR, 1.05; 95% CI, 0.73–1.53; P=0.78) and in ...
Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome
Authors: Gal Hacohen-Kleiman, Shlomo Sragovich, Gidon Karmon, Andy Y. L. Gao, Iris Grigg, Metsada Pasmanik-Chor, Albert Le, Vlasta Korenková, R. Anne McKinney, Illana Gozes
Journal: Journal of Clinical Investigation (2018)

Previous findings showed that in mice, complete knockout of activity-dependent neuroprotective protein (ADNP) abolishes brain formation, while haploinsufficiency (Adnp+/–) causes cognitive impairments. We hypothesized that mutations in ADNP lead to a developmental/autistic syndrome in children. Indeed, recent phenotypic characterization of children harboring ADNP mutations (ADNP syndrome children) revealed global developmental delays and intellectual disabilities, including speech and motor dysfunctions. Mechanistically, ADNP includes a SIP motif embedded in the ADNP-derived snippet drug candidate NAP (NAPVSIPQ, also known as CP201), which binds to microtubule end–binding protein 3, essential for dendritic spine formation. Here, we established a unique neuronal membrane–tagged, GFP-expressing Adnp+/– mouse line allowing in vivo synaptic pathology quantification. We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment. Adnp+/–mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal). In conclusion, we have connected ADNP-related synaptic pathology to developmental and behavioral outcomes, establishing NAP in vivo target engagement and identifying potential biomarkers. Together, these studies pave a path toward the clinical development of NAP (CP201) for the treatment of ADNP syndrome.
Abstract 2114: 3D co-culture of pancreatic tumor sphroids and stellate cells using minipillar array as a microtumor model of pancreatic ductal adenocarcinoma
Authors: Hyun Ju Hwang, Min-Suk Oh, Seul-Ki Kim, Hyo-Jeong Kuh
Journal: Cancer Research (2018)

Abstract Purpose: Tumor microenvironmental (TME) factors play important roles in cancer progression and chemoresistance by inducing epithelial-mesenchymal transition (EMT) and related mechanisms. Pancreatic stellate cell (PSC) is a highly-enriched cell type in TME of pancreatic ductal adenocarcinoma (PDAC). Three dimensional (3D) tumor spheroids (TS) are considered as an in vivo-like tumor model demonstrating its clinical relevancy. We previously developed a minipillar array histochip for 3D culture and immunohistological analysis of TS in an increased throughput manner. Here, we present a minipillar-based co-culture of TS and PSC as a novel in vitro microtumor model of pancreatic ductal adenocarcinoma. Methods: Minipillar chips were obtained from MBD Co. (Cellvitro™ 55Cryo). 3D TS of Panc-1, human PDAC cells and PSCs (Sciencell) were cultured on minipillars and at the bottom of 96 well plates, respectively, as embedded in type I collagen. Changes in expression of extracellular matrix (ECM) and EMT-related factors in TS were assessed by confocal microscopy following cyrosection preparation. Results: Co-culture condition was optimized for the growth of TS, activation of PSC, and their interaction. Expression of EMT markers such as TGF-β1 and vimentin increased in co-cultured TS than mono-cultured TS. ECM remodeling as indicated by increased matrix deposition (collagen I, fibronectin) and fiber organization was observed in TS co-cultured with PSC compared to mono-cultured TS. Upon drug exposure (gemcitabine and paclitaxel), survival advantage was prominent in TS co-cultured with activated PSC. Conclusions: We established 3D model of PDAC by co-culturing TS and PSC using minipillar histochips. EMT-related changes including ECM remodeling and drug resistance were recapitulated in the model. Overall our results indicate usefulness of the present model not only in studying the role of TME factors and their interactions towards tumor progression but also in the evaluation of therapeutic efficacy of drug candidates and combinations. Citation Format: Hyun Ju Hwang, Min-Suk Oh, Seul-Ki Kim, Hyo-Jeong Kuh. 3D co-culture of pancreatic tumor sphroids and stellate cells using minipillar array as a microtumor model of pancreatic ductal adenocarcinoma [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 2114.
Abstract 5335: A highly efficient targeted bisulfite sequencing method for accurate DNA methylation profiling
Authors: Quan Peng, Daniel Kim, Mohammad Nezami Ranjbar, Sascha Strauss, Scott Winter, Yexun Wang
Journal: Cancer Research (2018)

Abstract Background DNA methylation plays an important role in gene regulation. Bisulfite sequencing (BS), in which unmethylated cytosines are converted to uracil while methylated cytosines remain intact, is considered as the gold standard for DNA methylation detection with single nucleotide resolution. Due to the high cost of whole genome BS and the low throughput of amplicon BS, there remains the need for new targeted bisulfite sequencing methods with high efficiency and flexibility. Results We developed a targeted bisulfite sequencing method, by incorporating single primer enrichment (SPE) and molecular barcoding (UMI) technology. This enables flexible and scalable targeted DNA methylation analysis with high efficiency. We first studied the ability of our assay to detect CpG methylation at various levels in reference materials. We also evaluated its utility in profiling CpG methylation in different cell line DNA, and compared the results with published data from alternative technologies (WBS, RRBS and microarray). Conclusions We demonstrated the successful implementation of SPE and UMI technology on bisulfite converted DNA with high enrichment specificity and low bias. We showed that our method accurately detected CpG methylation at different levels, in concordance with expected titration mixture or published datasets. Comparing to reported amplicon BS, our technology enables much higher multiplexing scale and much simpler workflow. Comparing to probe capture based enrichment, our technology enables much lower DNA input, much higher sequencing efficiency (on-target) and shorter turnaround time. Citation Format: Quan Peng, Daniel Kim, Mohammad Nezami Ranjbar, Sascha Strauss, Scott Winter, Yexun Wang. A highly efficient targeted bisulfite sequencing method for accurate DNA methylation profiling [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 5335.
Abstract 13854: Outcome Analysis of Percutaneous Balloon Mitral Valvotomy Through Vortex Formation Time Index
Authors: Kambiz Ghafourian, Ahmad Falahatpisheh, Steven A Goldstein, Augusto D Pichard, Arash Kheradvar
Journal: Circulation (2011)

BACKGROUND: Transmitral vortex assists effective transfer of blood volume, momentum and energy from left atrium to the aorta via left ventricle (LV), and minimizes the stroke work (Figure 1). Vorte...