tbuckley/cabot-search huggingface dataset:
Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: DanielSinnecker, AlexanderGoedel, Karl-LudwigLaugwitz, AlessandraMoretti
Journal: Circulation Research (2013)

Induced pluripotent stem cells offer the possibility to generate patient-specific stem cell lines from individuals affected by inherited disorders. Cardiomyocytes differentiated from such patient-specific induced pluripotent stem cells lines have been used to study the pathophysiology of arrhythmogenic heart diseases, such as the long-QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Testing for unwanted drug side effects or tailoring medical treatment to the specific needs of individual patients with arrhythmogenic disorders may become future applications of this emerging technology.
Hypoxic tumor therapy by hemoglobin-mediated drug delivery and reversal of hypoxia-induced chemoresistance
Authors: Jie Yang, Wei Li, Lihua Luo, Mengshi Jiang, Chunqi Zhu, Bing Qin, Hang Yin, Xiaoling Yuan, Xiaoyi Yin, Junlei Zhang, Zhenyu Luo, Yongzhong Du, Jian You
Journal: Biomaterials (2018)
Abstract 5361: Spatial genome organization as a framework for somatic alterations in human cancer
Authors: Kadir C. Akdemir, Andrew Futreal
Journal: Cancer Research (2018)

Abstract Genomic material within the nucleus is folded into successive layers in order to package and organize the long string of linear DNA. This hierarchical level of folding is closely associated with transcriptional regulation and DNA replication. Recent chromosome conformation studies have revealed that mammalian chromosomes are structured into tissue-invariant topologically associating domains (TADs) where the DNA within a given domain interacts more frequently together than with regions in other domains. Genes within the same TADs represent similar expression and histone-modification profiles. Therefore, regions separating different TADs (boundaries) have important roles in reinforcing the stability of these domain-wide features. Indeed, TAD boundary disruptions in human genetic disorders or human cancers lead to misregulation of certain genes, due to de novo enhancer exposure to promoters. Here, to understand effects and distributions of somatic structural variations across TADs, we utilized single nucleotide variations and genomic rearrangements from 2658 high-coverage whole genome sequencing data across various cancer types with paired normal samples. Our analysis revealed that deletions between repressed and active TADs result in up-regulation of genes on the repressed end of the deletions, whereas active domain genes remain unaffected. Interestingly, we further identified a strong correlation between the mutational distributions in human cancers and the spatial organization of the genome. Transcriptionally active TADs contain less mutation burden compared to inactive TADs, as a result regional mutation rates are drastically different around the boundaries delineating epigenetically distinct domains. However, mutation rates remain similar around the boundaries for samples with the DNA mismatch repair deficiency. Taken together, our analyses reveal new insights about genome architecture, aberrant gene expression and mutational distributions in human cancers. Citation Format: Kadir C. Akdemir, Andrew Futreal. Spatial genome organization as a framework for somatic alterations in human 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 5361.
Bionic Baroreceptor Corrects Postural Hypotension in Rats With Impaired Baroreceptor
Authors: KazuyaHosokawa, TomomiIde, TomoyukiTobushi, KazuoSakamoto, KenOnitsuka, TakafumiSakamoto, TakeoFujino, KeitaSaku, KenjiSunagawa
Journal: Circulation (2012)

Background—Impairment of the arterial baroreflex causes orthostatic hypotension. Arterial baroreceptor sensitivity degrades with age. Thus, an impaired baroreceptor plays a pivotal role in orthostatic hypotension in most elderly patients. There is no effective treatment for orthostatic hypotension. The aims of this investigation were to develop a bionic baroreceptor (BBR) and to verify whether it corrects postural hypotension. Methods and Results—The BBR consists of a pressure sensor, a regulator, and a neurostimulator. In 35 Sprague-Dawley rats, we vascularly and neurally isolated the baroreceptor regions and attached electrodes to the aortic depressor nerve for stimulation. To mimic impaired baroreceptors, we maintained intracarotid sinus pressure at 60 mm Hg during activation of the BBR. Native baroreflex was reproduced by matching intracarotid sinus pressure to the instantaneous pulsatile aortic pressure. The encoding rule for translating intracarotid sinus pressure into stimulation of the aortic depr...
Abstract 3861: 3D ex vivo PDX cell model screening to better predict in vivo outcome
Authors: Xiaoxi Xu, Zhongliang Li, Yan Liu, Fanxiu Meng, Yu Lu, Songling Zhang, Chunlan Dong, Frank Xing, Qian Shi
Journal: Cancer Research (2018)

Abstract Patient-derived xenograft (PDX) models have been highly demanded in preclinical drug discovery and development due to several advantages over conventional 2D cell culture system: 1) reflection of the heterogeneity, molecular and histopathologic signatures of the original tumor than cell lines or genetically engineered mouse models, and 2) certain degree of correlation of their drug-response profiles with clinical response. Certain limitations of using PDX models, however, do exist, including low throughput in candidate drug screening, lack of dose-response curves, high cost and time-consuming studies, and progressive loss of human-derived stromal elements over passages. To overcome these disadvantages, we sought to develop ex vivo 3D assay format on cells isolated from early passage PDX models, and provide genetic mutation information to better interpret results. Moreover, we attempted to incorporate immunotherapy strategy into the 3D system as well. We have recently built up an ex vivo cell bank containing more than 300 frozen ex vivo tumor cells dissociated from freshly isolated PDX tumor tissues. We have collected five panels of such frozen ex vivo cells, each panel representing more than 50 models in a specific tumor type. SOC compounds corresponding to each unique tumor panel were tested, and will be discussed. Moreover, we have established a 3D immune cell and ex vivo somatic tumor cell co-culture system to evaluate drug efficacy of immune checkpoint inhibitors aPD1, aPDL1 and CTLA4 antibodies either as single agent or in combination with small-molecule inhibitors. The data will be presented. In summary, we have developed a robust and reproducible 3D ex vivo assay platform for medium-throughput compound screening with bioinformatics information for data interpretation. Citation Format: Xiaoxi Xu, Zhongliang Li, Yan Liu, Fanxiu Meng, Yu Lu, Songling Zhang, Chunlan Dong, Frank Xing, Qian Shi. 3D ex vivo PDX cell model screening to better predict in vivo outcome [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 3861.
Abstract 721: Development of a therapeutic HPV vaccine based on mass spectrometry-verified target epitopes
Authors: Sebastian Kruse, Maria Bonsack, Sara Becker, Nitya Mohan, Alina Steinbach, Stephanie Hoppe, Renata Blatnik, Angelika B. Riemer
Journal: Cancer Research (2018)

Abstract For rational therapeutic vaccine design, detailed knowledge about target epitopes that are truly presented on cancer cells is essential. Many potential tumor-specific epitopes, such as viral epitopes or mutation-derived neoepitopes, are presented at low abundance. Thus, detection of these epitopes remains a challenge. We have developed a high-sensitivity targeted mass spectrometry (MS) approach for direct detection of low-abundant epitopes. We used human papillomavirus (HPV) as a model system, as high-risk HPVs cause over 600,000 cervical, anogenital and oropharyngeal cancer cases per year. Moreover, the HPV oncoproteins E6 and E7 are essential for the induction and maintenance of the malignant phenotype, and thus are ideal targets for immunotherapy. Potential HPV16 E6 and E7 target epitopes were predicted in silico and their HLA-binding verified in cellular binding assays. HLA-peptide complexes were immunoprecipitated from HPV16-positive cancer cells and the purified peptides were analyzed by MS. Identified HPV epitopes were assessed for immunogenicity in vitro with PBMC from healthy donors and in vivo in the MHC-humanized mouse model A2.DR1. The binding assays resulted in the identification of known and novel HPV16-derived HLA-binding peptides. Furthermore, we used this data to formulate rules on how to optimally use epitope prediction tools to increase the chances of predicting true HLA ligands. 14 HLA-A2-restricted HPV16 epitopes were detected on the surface of CaSki and 866 cervical cancer cells, 9 of which were novel. 13 out of the 14 MS-detected peptides were immunogenic in ELISpot assays. Vaccination of A2.DR1 mice with one selected epitope induced high numbers of specific cytotoxic T-cells, and caused anti-tumor effects in a newly developed HPV16 E6/E7-expressing A2.DR1-compatible tumor model. We conclude that our epitope detection and validation approach is suitable for validating even low-abundant candidate epitopes to be true immunotherapy targets. MS-detection of epitopes appears to be a good predictor of immunogenicity, which makes this approach an attractive platform for determining target epitopes for therapeutic cancer vaccines. Citation Format: Sebastian Kruse, Maria Bonsack, Sara Becker, Nitya Mohan, Alina Steinbach, Stephanie Hoppe, Renata Blatnik, Angelika B. Riemer. Development of a therapeutic HPV vaccine based on mass spectrometry-verified target epitopes [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 721.
Abstract 16518: Does Retrograde Perfusion via the Superior Vena Cava During Deep Hypothermic Circulatory Arrest Reach the Brain? An In-Vivo Study Using S-100β in Humans
Authors: Mario Gaudino, Natalia Ivascu, Melissa Cushing, Christopher Lau, Ivancarmine Gambardella, Leonard N Girardi
Journal: Circulation (2016)

Introduction: The optimal technique of brain perfusion during circulatory arrest remains controversial. Retrograde perfusion (RCP) via the superior vena cava (SVC) has produced good clinical result...
Abstract 12763: The Clinical SYNTAX Score Has an Additive Predictive Value in High Risk Patients
Authors: Jeehoon Kang, Kyung Woo Park, Si-Hyuck Kang, Hae-Young Lee, Hyun-Jae Kang, Bon-Kwon Koo, In-Ho Chae, Tae-Jin Youn, Byung-Hee Oh, Young-Bae Park, Hyo-soo Kim
Journal: Circulation (2014)

Introduction: The SYNTAX score (SS) has been used as an angiographic grading tool to determine the complexity of coronary diseases, and was verified to predict outcomes after revascularization. How...
De novo NAD+ biosynthetic impairment in acute kidney injury in humans
Authors: Ali Poyan Mehr, Mei T. Tran, Kenneth M. Ralto, David E. Leaf, Vaughan Washco, Joseph Messmer, Adam Lerner, Ajay Kher, Steven H. Kim, Charbel C. Khoury, Shoshana J. Herzig, Mary E. Trovato, Noemie Simon-Tillaux, Matthew R. Lynch, Ravi I. Thadhani, Clary B. Clish, Kamal R. Khabbaz, Eugene P. Rhee, Sushrut S. Waikar, Anders H. Berg, Samir M. Parikh
Journal: Nature Medicine (2018)
Abstract 3594: DEK overexpression in breast epithelial tissue creates a pro-oncogenic environment
Authors: Megan Johnstone, Jon Cheek, Lisa M. Privette Vinnedge
Journal: Cancer Research (2018)

Abstract Dense epithelial breast tissue, as detected by mammography, is correlated with a four- to six-fold increased risk for developing breast cancer (BC). It is currently not possible to distinguish dense breast tissue from that which will develop into cancer. Therefore, the need to identify novel markers will improve breast cancer screening and reduce expensive overdiagnosis and overtreatment. Previous research has failed to define reliable diagnostic biomarkers that specify dense breast tissue from that which has the possibility to transform into malignant tissue. DEK, a chromatin binding and DNA repair protein, is upregulated in the majority of solid cancers including breast cancer. Previous publications from our lab demonstrate, in vitro, that DEK overexpression promotes proliferation, increased motility, and epithelial polarization in part through canonical WNT/β-catenin signaling. In vivo experiments with a DEK knockout murine model display a mitigated tumor development response as compared to wild-type mice. Given that DEK is highly expressed in over 60% of BC, we generated a conditional mammary epithelial specific doxycycline-regulated Dek overexpressing (DEK OE) murine model. We find that DEK OE leads to dense epithelial breast tissue, largely due to lobuloalveolar hyperplasia. Longitudinal findings demonstrate that DEK OE results in transformation of mammary epithelial tissue with microtumor development. DEK OE tissue sections display increased transcription of Wnt genes, with upregulation of downstream WNT signaling targets such as AXIN and β-catenin. Conversely, longitudinal repression of DEK OE with doxycycline displays normal tissue morphology and organization. Our data suggest that DEK OE stimulates hyperplasia of mammary epithelium, due to increased proliferation, similar to dense breast tissue as detected by mammography, and may increase risk for spontaneous transformation and BC development later in life. Citation Format: Megan Johnstone, Jon Cheek, Lisa M. Privette Vinnedge. DEK overexpression in breast epithelial tissue creates a pro-oncogenic environment [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 3594.
Cloning and Functional Expression of a Novel Cardiac Two-Pore Background K+ Channel (cTBAK-1)
Authors: DongheeKim, AkikazuFujita, YoshiyukiHorio, YoshihisaKurachi
Journal: Circulation Research (1998)

Abstract—We have cloned from a mouse heart cDNA library a novel K+ channel subunit that has two pore-forming domains and four transmembrane regions. Its amino acid sequence shares 25% identity with mouse TWIK-1, 22% with mouse TREK-1, and 33% with a putative K+ channel of Caenorhabditis elegans (C40C9). Strikingly abundant mRNA for this clone was expressed in the heart. The mRNA was also detected in kidney, brain, skin, testis, lung, skeletal muscle, small intestine, and stomach but not in liver, thymus, or spleen. Reverse transcription–polymerase chain reaction analyses of single cells showed that the mRNA of the clone was expressed in both atrial and ventricular myocytes per se. Xenopus oocytes injected with the cRNA of the clone expressed a Ba2+-sensitive K+-selective current with an almost linear steady-state current-voltage relationship. In cell-attached patches, the expressed channel exhibited short-lasting openings with a mean open time of ≈2 milliseconds and a unitary conductance of ≈16 pS (150 mm...
Endothelial Nitric Oxide Synthase Plays an Obligatory Role in the Late Phase of Ischemic Preconditioning by Activating the Protein Kinase Cε–p44/42 Mitogen-Activated Protein Kinase–pSer-Signal Transducers and Activators of Transcription1/3 Pathway
Authors: Yu-TingXuan, YiruGuo, YanqingZhu, Ou-LiWang, GreggRokosh, RobertoBolli
Journal: Circulation (2007)

Background— The role of endothelial nitric oxide synthase (eNOS) in ischemic preconditioning (PC) and cardioprotection is poorly understood. We addressed this issue using a genetic, rather than pharmacological, approach. Methods and Results— In the nonpreconditioned state, eNOS−/− mice exhibited infarct sizes similar to those of wild-type mice. A sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles (ischemic PC) induced late PC in wild-type mice; genetic deletion of eNOS abrogated the cardioprotection induced by late PC. In wild-type mice, ischemic PC induced membranous translocation of protein kinase C (PKC)e and an increase in pSer-MEK-1/2 and pTyr-p44/42 mitogen-activated protein kinase, nuclear pSer-signal transducers and activators of transcription (STAT)1 and pSer-STAT3, and nuclear STAT1/3 DNA binding activity, followed by upregulation of cyclooxygenase-2 protein and activity 24 hours later. All of these changes were abrogated in eNOS−/− mice. The NO donor diethylenetriamine/NO r...
Patient, Procedure, and Endoscopist Risk Factors for Perforation, Bleeding, and Splenic Injury After Colonoscopies
Authors: Moussa Laanani, Joël Coste, Pierre-Olivier Blotière, Franck Carbonnel, Alain Weill
Journal: Clinical Gastroenterology and Hepatology (2018)

We investigated perforations, bleeding, and splenic injuries after screening or diagnostic colonoscopies to identify patient-, procedure-, endoscopist-, and facility-associated risk factors.We analyzed data from the SNIIRAM-PMSI national claims databases in France. A total of 4,088,799 patients, 30 years or older, undergoing a first screening or diagnostic colonoscopy from 2010 through 2015 were identified. Rates of severe adverse events (SAEs) were estimated using stringent and broad definitions. Risk factors associated with perforations and major bleeding were estimated using multilevel logistic regression models, adjusted for patient, colonoscopy, and endoscopist characteristics.Perforation rates ranged from 3.5 (stringent definition) to 7.3 (broad definition) per 10,000 procedures, bleeding rates ranged from 6.5 to 23.1 per 10,000 procedures, and splenic injury rates ranged from 0.20 to 0.34 per 10,000 procedures. Rates of 30-day mortality were 13.2 per 1000 bleeds, 29.2 per 1000 perforations, and 36.1 per 1000 splenic injuries (stringent definitions). Patient characteristics associated with SAEs were increasing age (especially for perforation), cancer, and cardiovascular comorbidities. Procedure characteristics associated with SAEs included polypectomy-especially of polyps larger than 1 cm with an increased risk of perforation (odds ratio, 4.1; 95% CI, 3.4-5.0) and bleeding (odds ratio, 13.3; 95% CI, 11.7-15.1). Less-experienced endoscopists and endoscopists who performed a smaller number of colonoscopies were independently associated with a risk of SAEs.In an analysis of national claims databases in France, we found SAEs related to screening and diagnostic colonoscopies to be more frequent in older patients, in patients with comorbidities, and with less-experienced endoscopists. Patients at risk of SAE should be identified and colonoscopies should be performed or supervised by experienced endoscopists.
Abstract 364: Differentially methylated super-enhancers regulate gene expression in human papillomavirus-related head and neck squamous cell carcinoma
Authors: Emily L. Flam, Dylan Z. Kelley, Elena Stavrovskaya, Ludmila Danilova, Theresa Guo, Michael Considine, Jiang Qian, Joseph A. Califano, Alexander V. Favorov, Elana J. Fertig, Daria A. Gaykalova
Journal: Cancer Research (2018)

Abstract Human papillomavirus-related head and neck squamous cell carcinoma (HPV+ HNSCC) is characterized by abundant gene expression changes, which cannot be explained by limited genetic alterations alone. We hypothesized that epigenetically regulated super-enhancers (SEs) are the drivers of aberrant gene expression in HPV+ HNSCC. We used integrated analysis of DNA methylation and gene expression data for cancer and noncancer oropharyngeal tissues to discover actionable SEs that regulate expression of target genes in HPV+ HNSCC. Since no SEs are currently defined for any HNSCC samples; we investigated 6196 SE elements that were obtained from the public domain for closely related tissues, including normal and tumor lung, and cervical cancer cell lines. We analyzed the methylation of these elements and gene expression of their nearby genes for 47 HPV+ HNSCC and their 25 noncancer controls. Overall, we found 122 differentially methylated SEs that had putative target (nearby) genes whose expression was correlated with enhancer methylation in HPV+ HNSCC. Of these, 107 were hypermethylated, and 15 were hypomethylated in tumors relative to normal samples. The pathway analysis revealed that the inferred SE-regulated genes were associated with pathways known to regulate carcinogenesis. Our data demonstrate that gene expression in HPV+ HNSCC may be regulated by epigenetic alterations in SE elements of related tissues. Citation Format: Emily L. Flam, Dylan Z. Kelley, Elena Stavrovskaya, Ludmila Danilova, Theresa Guo, Michael Considine, Jiang Qian, Joseph A. Califano, Alexander V. Favorov, Elana J. Fertig, Daria A. Gaykalova. Differentially methylated super-enhancers regulate gene expression in human papillomavirus-related head and neck squamous cell carcinoma [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 364.
What’s in a name? ‘Non-coeliac gluten or wheat sensitivity’: controversies and mechanisms related to wheat and gluten causing gastrointestinal symptoms or disease
Authors: Michael D E Potter, Marjorie M Walker, Simon Keely, Nicholas J Talley
Journal: Gut (2018)

The global population has more than doubled over the past 40 years, supported by the ‘green revolution’ in agriculture producing high-yield grain varieties, including wheat, that are central to the modern diet.1 Wheat covers more than 200 million hectares of land,2 is the third most produced cereal behind rice and maize,3 and is responsible for one-fifth of the world’s calorific input.2 Wheat contains gluten proteins, predominantly made of equal parts of glutenins and gliadins, which are resistant to digestion, and their partially digested epitopes are immunogenic and central to the process that leads to coeliac disease,3 4 an autoimmune condition characterised by an aberrant immune response to ingested gluten in genetically susceptible individuals, which results in small bowel inflammation, enteropathy and potential malabsorption.5 The prevalence of coeliac disease in the past 50 years has risen to approximately 0.7%–2%, a phenomenon attributed to increased awareness and detection, as well as a true increase in prevalence.6 7 The sole and current only curative treatment, a lifelong gluten-free diet, considered central to the management of coeliac disease has also seen increasing popularity in the general population; there is a widespread underlying belief that a gluten-free diet may be ‘healthier’, despite a lack of evidence to support this notion and even evidence that it may be harmful to the non-coeliac population.8 This has seen the gluten-free food industry boom to an estimated US$6 billion per year industry.5 

Gluten, or more generally wheat, has also been associated with other GI disease. In the absence of coeliac disease and under the guise of the increasingly fashionable but controversial label ‘non-coeliac gluten/wheat sensitivity’ (NCG/WS), gluten has been popularised in the press as a potential cause of almost all possible conceivable physiological complaints, ranging from GI to neurological, dermatological, psychological and musculoskeletal …
Abstract 11383: Glucose-Lowering Medications and Angina Burden in Patients With Stable Coronary Disease. Results From the TERISA Trial
Authors: Suzanne V Arnold, Darren K McGuire, John A Spertus, Yan Li, Patrick Yue, Silvio E Inzucchi, Luiz Belardinelli, Bernard R Chaitman, Mikhail Kosiborod
Journal: Circulation (2014)

Background: Different classes of glucose-lowering medications have been associated with varying risks of myocardial infarction and CV death, but their associations with angina severity are unknown....