tbuckley/cabot-search huggingface dataset:
Abstract 2360: Deregulated APA and cancer specific APA isoforms
Authors: Oguzhan Begik, Melda Ercan, Harun Cingoz, Tolga Can, Merve Oyken, Ayse Elif Erson-Bensan
Journal: Cancer Research (2018)

Abstract Certain aspects of diagnosis, prognosis, and treatment of cancer patients are still important challenges to be addressed. We developed a pipeline to uncover patterns of alternative polyadenylation (APA), a hidden complexity in cancer transcriptomes, to further accelerate efforts to discover novel cancer genes and pathways. Here, we found a significant shift in usage of poly(A) signals in six common tumor types compared to normal tissues. We further defined specific subsets of APA events to efficiently classify cancer types/subtypes. Triple negative breast cancers, for example, have specific 3'UTR length alterations where the significant majority are shortening events (70%, 113 of 165) of mostly proliferation-related transcripts compared with normal breast tissue. Such shortening events correlate with increased protein levels and relapse free survival of patients, suggesting functional significance of isoform variability. In line with this isoform diversity, we also detected deregulated expression of mRNA polyadenylation complex proteins in breast cancer cells. Of note, APA proteins are responsive to proliferative signals including estrogen and epidermal growth factor, suggesting a potential explanation to 3'-end isoform diversity in cancer cells. Overall, our study offers a computational and experimental approach for use of APA in novel gene discovery and classification in common tumor types, with important implications in basic research, biomarker discovery, and precision medicine approaches. Citation Format: Oguzhan Begik, Melda Ercan, Harun Cingoz, Tolga Can, Merve Oyken, Ayse Elif Erson-Bensan. Deregulated APA and cancer specific APA isoforms [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 2360.
Letter by Govindarajan and Salgado Regarding Article, “Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial”
Authors: RaghavGovindarajan, EfrainSalgado
Journal: Circulation (2012)
Abstract 12176: Higher CHADS2 Score is Associated With Impairment of Coronary Flow Reserve Evaluated by Phase-Contrast Cine Cardiovascular Magnetic Resonance Imaging
Authors: HidekuniKirigaya, ShingoKato, DaikiGyoutoku, NaoYamada, NaokiIinuma, YukaKusakawa, KouheiIguchi, YukoMiki, TatsuyaNakachi, KazukiFukui, KazuoKimura, SatoshiUmemura
Journal: Circulation (2014)

Background: The CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes, prior stroke) score is used to evaluate the risk of ischemic stroke in patients with atrial fibrillation (AF). Recent study showed that the CHADS2 score was associated with higher rate of mortality and stroke in patients with acute coronary syndrome (ACS), irrespective of the presence or absence of AF. Phase contrast (PC) cine magnetic resonance imaging (MRI) allows for non-invasive and accurate assessment of coronary flow reserve (CFR). The hypothesis of this study is that CHADS2 score can predict impairment of CFR in patients with known or suspected coronary artery disease (CAD). Materials and Methods: One hundred forty three patients with known or suspected CAD (mean age 70.3 ± 9.5 years) without significant coronary arterial stenosis on X-ray coronary angiography (CAG) were studied. By using 1.5T MR scanner, breath-hold PC cine MR images of coronary sinus (CS) were obtained to assess the blood flow of CS both at ...
Abstract 17881: Indexed Ventricular End Diastolic Volume, Ejection Fraction, and QRS Duration Can Be Predictive of Future Cardiac Events and Associated With Interventricular Dyssynchrony in the Fontan Patients With Biventricular Heart
Authors: Tatsunori Takahashi, Yumi Shiina, Kei Inai, Michinobu Nagao, Kenji Fukushima, Hiroki Mori, Gen Harada, Eriko Shimada, Seiji Asagai, Mikiko Shimizu, Tetsuko Ishii, Tokuko Shinohara, Hisashi Sugiyama, Hirofumi Tomimatsu, In-Sam Park
Journal: Circulation (2016)

Introduction: The prognostic factors in patients with biventricular heart who underwent Fontan operation remain unclear. Hypothesis: We assessed the hypothesis that ventricular dilatation, ventricu...
Overexpression of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Induces Intramyocardial Vasculopathy in Apolipoprotein E–Null Mice
Authors: KazuhikoInoue, YujiArai, HirokiKurihara, ToruKita, TatsuyaSawamura
Journal: Circulation Research (2005)

Endothelial dysfunction induced by oxidized low-density lipoprotein (OxLDL) has been implicated in the pathogenesis of atherosclerosis and vasculopathy. Increased expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the receptor for OxLDL in endothelial cells, has been demonstrated in the atherosclerotic plaques from experimental atherosclerotic animal models and human clinical samples. In vitro, activation of LOX-1 alters the expression of several endothelial cell genes that are involved in endothelial dysfunction. To investigate the role of LOX-1 in terms of both endothelial dysfunction and resultant vascular changes, we generated mice overexpressing LOX-1 (LOXtg) in C57BL/6 and apolipoprotein E–null mice (apoEKO) backgrounds. We found that the expression of the transgene was prominent in coronary vessels and cardiomyocytes. The enhancement of OxLDL uptake in LOXtg mice was consistent with the expression level of LOX-1. Under hyperlipidemic conditions, both OxLDL and 8-hydroxy-...
The prognostic significance of global aberrant alternative splicing in patients with myelodysplastic syndrome
Authors: Yi-Tsung Yang, Yu-Chiao Chiu, Chein-Jun Kao, Hsin-An Hou, Chien-Chin Lin, Cheng-Hong Tsai, Mei-Hsuan Tseng, Wen-Chien Chou, Hwei-Fang Tien
Journal: Blood Cancer Journal (2018)

Aberrant alternative splicing (AS) is a hallmark of cancer development. However, there are limited data regarding its clinical implications in myelodysplastic syndrome (MDS). In this study, we performed an in-depth analysis of global AS in 176 primary MDS patients with 20 normal marrow transplant donors as reference. We found that 26.9% of the expressed genes genome-wide were aberrantly spliced in MDS patients compared with normal donors. These aberrant AS genes were related to pathways involved in cell proliferation, cell adhesion and protein degradation. A higher degree of global aberrant AS was associated with male gender and U2AF1 mutation, and predicted shorter overall survival and time to leukemic change. Moreover, it was an independent unfavorable prognostic factor irrespective of age, revised international prognostic scoring system (IPSS-R) risk, and mutations in SRSF2, ZRSR2, ASXL1, TP53, and EZH2. With LASSO-Cox regression method, we constructed a simple prognosis prediction model composed of 13 aberrant AS genes, and demonstrated that it could well stratify MDS patients into distinct risk groups. To our knowledge, this is the first report demonstrating significant prognostic impacts of aberrant splicing on MDS patients. Further prospective studies in larger cohorts are needed to confirm our observations.
Novel multi-drug delivery hydrogel using scar-homing liposomes improves spinal cord injury repair
Authors: Qingqing Wang, Hongyu Zhang, Helin Xu, Yingzheng Zhao, Zhengmao Li, Jiawei Li, Haoli Wang, Deli Zhuge, Xin Guo, Huazi Xu, Salazar Jones, Xiaokun Li, Xiaofeng Jia, Jian Xiao
Journal: Theranostics (2018)

Proper selection and effective delivery of combination drugs targeting multiple pathophysiological pathways key to spinal cord injury (SCI) hold promise to address the thus far scarce clinical therapeutics for improving recovery after SCI. In this study, we aim to develop a clinically feasible way for targeted delivery of multiple drugs with different physiochemical properties to the SCI site, detail the underlying mechanism of neural recovery, and detect any synergistic effect related to combination therapy. Methods: Liposomes (LIP) modified with a scar-targeted tetrapeptide (cysteine-alanine-glutamine-lysine, CAQK) were first constructed to simultaneously encapsulate docetaxel (DTX) and brain-derived neurotrophic factor (BDNF) and then were further added into a thermosensitive heparin-modified poloxamer hydrogel (HP) with affinity-bound acidic fibroblast growth factor (aFGF-HP) for local administration into the SCI site (CAQK-LIP-GFs/DTX@HP) in a rat model. In vivo fluorescence imaging was used to examine the specificity of CAQK-LIP-GFs/DTX binding to the injured site. Multiple comprehensive evaluations including biotin dextran amine anterograde tracing and magnetic resonance imaging were used to detect any synergistic effects and the underlying mechanisms of CAQK-LIP-GFs/DTX@HP both in vivo (rat SCI model) and in vitro (primary neuron). Results: The multiple drugs were effectively delivered to the injured site. The combined application of GFs and DTX supported neuro-regeneration by improving neuronal survival and plasticity, rendering a more permissive extracellular matrix environment with improved regeneration potential. In addition, our combination therapy promoted axonal regeneration via moderation of microtubule function and mitochondrial transport along the regenerating axon. Conclusion: This novel multifunctional therapeutic strategy with a scar-homing delivery system may offer promising translational prospects for the clinical treatment of SCI.
45 New-onset diabetes after transplant (NODAT): incidence, risk analysis and impact on survival
Authors: Y Abbas, K Nawaz, N Ullah, M Salih, S Saadat
Journal: Gut (2017)

Background  Orthotopic liver transplant has become the standard of care for end-stage liver disease and hepatocellular cancer. Better immunosuppressant paved way for improved survival rates post-transplant. But with this longevity comes a higher prevalence of chronic diseases such as New Onset Diabetes After Transplant (NODAT), Hypertension, metabolic syndrome etc. which have a negative impact on graft function and patient survival.  Aim  To study the incidence of NODAT, factors predictive of NODAT and impact of NODAT on mortality and post-transplant survival.  Method  It was a retrospective cohort study of 283 living donor liver transplant recipients from 29/4/2011 till 26/4/2016. Data was collected from records. Simple means and standard deviation was calculated for continuous variables while frequency statistics were calculated for categorical ones. Risk factors were assessed using binary logistic regression analysis.  Results  A total of 130 post liver transplant patients were analysed after exclusion. NODAT was present in 41/130 (31.5%) patients, while 19/130 (14.6%) patients had impaired fasting glycaemia.  Acute cellular rejection and Post-transplant Hyperglycemia showed increased odds of acquiring NODAT post-transplant.  NODAT had significant association with mortality and decreased survival (p=0.05).  Conclusions  This cohort showed that NODAT is an important post-transplant entity with significant impact on mortality and survival. Early identification of at-risk patients is suggested.
Abstract 3897: Pharmacogenomic landscape of long non-coding RNAs in human cancers
Authors: Aritro Nath, R. Stephanie Huang
Journal: Cancer Research (2018)

Abstract Extensive efforts in recent large-scale drug screens have enabled identification of protein-coding genes (PCGs) as biomarkers for anti-cancer agent sensitivity, but information on the role of long-non coding RNAs (lncRNAs) in drug response is sparse. Lower abundance, difficulty in expression profiling and limited functional knowledge have so far hindered global analysis of lncRNAs in drug screens. However, lncRNAs represent nearly 60% of the human genome (vs. 3% for PCGs) and contain a vast majority of pharmacogenomic SNPs. Thus, it is critically important to evaluate the role of lncRNAs in drug sensitivity. Here, we perform a comprehensive reanalysis of large-scale drug screens using novel computational methods to create a landscape of pharmacogenomic interactions of lncRNAs in human cancers. We developed an algorithm to accurately impute the lncRNA transcriptome using PCG expression. This approach allowed us to generate lncRNA transcriptome in high throughput drug screening data sets and enabled systematic evaluation of lncRNAs for hundreds of drugs. For example, we applied our method to the Genomics of Drug Sensitivity in Cancer (GDSC) study, where sensitivity to 265 anti-cancer agents were quantified in 963 cancer cell lines. Sparse regression analysis showed lncRNA transcriptome were similar in accuracy at predicting drug response compared to PCGs (P = 0.9), indicating lncRNAs may be equally important biomarkers. Subsequently, we identified drug-specific lncRNA biomarkers using ANOVA while adjusting for tissue type. Our analysis recapitulated literature-verified lncRNAs associated with drug response, e.g. HOTAIR expression with cisplatin resistance (FDR &amp;lt; 0.05). In addition, we identified several compelling novel lncRNA associations for specific drugs along with previously uncharacterized multi-drug response predictors. We next identified lncRNAs that may serve as biomarkers for drug response while controlling for known cancer functional events. As an example, we analyzed EGFR-inhibitors (erlotinib, gefitinib, pelitinib) while controlling for EGFR somatic point mutations and amplification status and identified an anti-sense lncRNA overlapping UGT1A locus that may be a potential regulator of erlotinib metabolism. These findings reveal important lncRNAs that predict response independent of known cancer functional events and are currently being evaluated in non-small cell lung cancer patients. In conclusion, our comprehensive analysis has generated unprecedented insights into the role of lncRNAs in anti-cancer drug response and will be an invaluable resource for researchers studying drug response in various cancer types. Citation Format: Aritro Nath, R. Stephanie Huang. Pharmacogenomic landscape of long non-coding RNAs in human cancers [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 3897.
Opioids vs Nonopioids for Chronic Back, Hip, or Knee Pain—Reply
Authors: Erin E. Krebs, Amy Gravely, Siamak Noorbaloochi
Journal: JAMA (2018)

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Abstract 5657: Use of a novel immunofluorescence multiplexing technology, InSituPlex™, for the simultaneous detection of immune cells in multiple cancer types
Authors: Sean Downing, Katir Patel, Jamie Buell, Courtney Hebert
Journal: Cancer Research (2018)

Abstract Introduction: The field of immuno-oncology has enthusiastically adopted multiplexed immunohistochemistry (IHC) techniques to establish the spatial relationships between various immune cells in tumor biology. Multiplexing enables researchers to gain a deeper understanding and insight into the tumor microenvironment. Unfortunately, many of the multiplexing technologies currently utilized in the immuno-oncology field face a number of challenges. These challenges include complicated and difficult assay optimizations for high-level multiplexing and the need of specialized imaging instrumentation. In addition, harsh stripping methods and irreversible staining techniques compromise the integrity of precious tissue samples that ultimately can no longer be used for additional forms of testing. InSituPlex™ is a new method of multiplexed IHC that relies on the detection of a unique DNA barcode conjugated to primary antibodies. This technology removes the need to perform multiple, harsh stripping methods to perform multiplexed IHC and allows for higher order of multiplexing in less time than currently available multiplexing techniques, all the while maintaining tissue integrity for use in downstream analyses. Methods: InSituPlex was used to perform a multiplexed IHC assay on 5 samples from 4 tumor types (breast, lung, colon, and melanoma). The assay consisted of the following markers: CD4, CD8, CD20, CD68, PD1, Ki67, FoxP3, and a tumor marker; pan-cytokeratin (CK) for breast, colon, and lung carcinomas and Sox10 for melanoma. Staining was performed using the Leica BOND RX autostainer, imaging was performed on various platforms including the Leica VERSA whole slide scanner, and image analysis was performed using HALO from Indica Labs. Data: All markers were detected utilizing the InSituPlex technology across all tumor types. Data indicates a range of phenotypes for infiltrating immune cells in tumor types from highly inflamed to “immune deserts”. The panel provided for analysis of many phenotypic subtypes, (e.g., CD4+/PD1+, CD8+/Ki67+, and Ki67+/CK+), cell densities, proliferative indexes, and spatial analysis (e.g., CD8+ to tumor cells). Conclusion: InSituPlex technology is proficient in maintaining tissue integrity and detecting a range of immune cell phenotypes in multiple tumor types. InSituPlex can be implemented by any lab possessing a standard fluorescent microscope and does not rely on the purchase of, nor access to, more expensive platforms. Citation Format: Sean Downing, Katir Patel, Jamie Buell, Courtney Hebert. Use of a novel immunofluorescence multiplexing technology, InSituPlex™, for the simultaneous detection of immune cells in multiple cancer types [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 5657.
Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension
Authors: ElisabethMarcos, ElieFadel, OlivierSanchez, MarcHumbert, PhilippeDartevelle, GeraldSimonneau, MichelHamon, SergeAdnot, SaadiaEddahibi
Journal: Circulation Research (2004)

Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of pulmonary hypertension (PH). Serotonin (5-HT) is involved in the hyperplasia through its interactions with specific receptors and internalization by a specific plasma membrane transporter. We investigated the expression and role of the 5-HT transporter (5-HTT) and 5-HT1B, 5-HT2A, and 5-HT2B receptors in lungs and isolated PA-SMCs from patients with primary PH (n=14), pulmonary veno-occlusive disease (n=4), or secondary PH (SPH, n=8) and nonpulmonary hypertensive control subjects. Whereas strong immunostaining for the three receptor types and 5-HTT was seen in remodeled pulmonary vessels from patients in all PH categories, only 5-HTT expression was increased in lungs and cultured PA-SMCs from patients versus controls. The increased growth response of PA-SMCs from patients with primary PH, pulmonary veno-occlusive disease, or SPH to 5-HT or serum was entirely attributable to 5-HTT overexpression, because 5-HT...
Long-Term Stimulation of Adenosine A2b Receptors Begun After Myocardial Infarction Prevents Cardiac Remodeling in Rats
Authors: MasakatsuWakeno, TetsuoMinamino, OsamuSeguchi, HidetoshiOkazaki, OsamuTsukamoto, Ken-ichiroOkada, AkioHirata, MasashiFujita, HiroshiAsanuma, JiyoongKim, KazuoKomamura, SeijiTakashima, NaokiMochizuki, MasafumiKitakaze
Journal: Circulation (2006)

Background— Adenosine inhibits proliferation of cardiac fibroblasts and hypertrophy of cardiomyocytes, both of which may play crucial roles in cardiac remodeling. In the present study, we investigated whether chronic stimulation of adenosine receptors begun after myocardial infarction (MI) prevents cardiac remodeling. Methods and Results— MI was produced in Wistar rats by permanent ligation of the left anterior descending coronary artery. One week after the onset of MI, animals were randomized into 8 groups: vehicle, dipyridamole (DIP; the adenosine uptake inhibitor, 50 mg/kg), 2-chroloadenosine (CADO; the stable analogue of adenosine, 2 mg/kg), and CADO in the presence of the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline (8-SPT) or the selective antagonist for adenosine A1, A2a, A2b, or A3 receptor. Three weeks after treatment, hemodynamic and echocardiographic parameters in the DIP and CADO groups were significantly improved compared with the vehicle group. These hemodynamic and e...
Endothelin-1–Dependent Nuclear Factor of Activated T Lymphocyte Signaling Associates With Transcriptional Coactivator p300 in the Activation of the B Cell Leukemia-2 Promoter in Cardiac Myocytes
Authors: TeruhisaKawamura, KohOno, TatsuyaMorimoto, MasaharuAkao, EriIwai-Kanai, HiromichiWada, NaoyaSowa, ToruKita, KojiHasegawa
Journal: Circulation Research (2004)

Endothelin-1 (ET-1) is a potent survival factor that protects cardiac myocytes from apoptosis. ET-1 induces cardiac gene transcription and protein expression of antiapoptotic B cell leukemia-2 (bcl-2) in a calcineurin-dependent manner. A cellular target of adenovirus early region 1A (E1A) oncoprotein, p300 also activates bcl-2 transcription in cardiac myocytes and is required for their survival. p300 acts as a calcineurin-regulated nuclear factors of activated T lymphocytes (NFATc), downstream targets of calcineurin. In addition, the bcl-2 promoter contains multiple NFAT consensus sequences. These findings prompted us to investigate the role of NFATc in ET-1–dependent and p300-dependent bcl-2 transcription in cardiac myocytes. In primary cardiac myocytes prepared from neonatal rats, mutation of 2 NFAT sites within the bcl-2 promoter completely abolished the ET-1– and p300-induced increases in the activity of this promoter. We show here that p300 markedly potentiates the binding of NFATc1 to the bcl-2 NFAT...
Prevalence of Kingella kingae oropharyngeal carriage and predominance of type a and type b polysaccharide capsules among French young children
Authors: R. Basmaci, K. Deschamps, C. Levy, V. Mathy, F. Corrard, F. Thollot, S. Béchet, E. Sobral, P. Bidet, R. Cohen, S. Bonacorsi
Journal: Clinical Microbiology and Infection (2018)
The Role of Glucagon Hypersecretion in the Pathogenesis of Hyperglycemia Following Acute Myocardial Infarction
Authors: Shlomolaniado, Pesachsegal, Barryesrig
Journal: Circulation (1973)

In a group of nondiabetic patients, postinfarction hyperglycemia was found to be closely associated with high levels of plasma immunoreactive glucagon (IRG). It is proposed that, in certain cases, hyperglycemia following acute myocardial infarction may be related to a temporary and uninhibited rise in plasma glucagon levels, probably stimulated by the major stress of acute myocardial infarction.