tbuckley/cabot-search huggingface dataset:
Abstract 12739: Gap Junction Protein Beta 4 Plays an Important Role In Cardiac Hypertrophy and Cardiac Function in Human and Zebrafish
Authors: Ryuji Okamoto, Itaru Goto, Yuhei Nishimura, Issei Kobayashi, Ryotaro Hashizume, Kaoru Dohi, Norikazu Yamada, Toshio Tanaka, Masaaki Ito
Journal: Circulation (2016)

Introduction: Gap junction protein beta 4 (GJB4) encodes a transmembrane connexin protein (Cx30.3) that is a component of gap junctions. Mutations in this gene remain unknown to be associated with hypertrophic cardiomyopathy (HCM) and cardiac dysfunction. Hypothesis: Our hypothesis is that mutations in GJB4 can cause familial HCM, which can progresses into dilated-phase HCM (d-HCM). Methods: We have previously examined a patient and her elder brother who both presented with complicated severe HCM and whose parents are married cousins. The elder brother had died suddenly as a child and the autopsy demonstrated the development of HCM. The patient was diagnosed with HCM, which progressed to d-HCM during the 20-year follow-up. The patient has recently undergone cardiac transplantation. The parents are healthy. We hypothesized that an autosomal recessive mutation caused their familial HCM. The whole-exome sequencing was performed from each of the three participants. We generated knockout zebrafish of GJB4 and ELP2 by CRISPER/Cas9 system and analysis the volume and function of ventricle at five days post fertilization (dpf). Results: The gene exome analysis showed 34 single nucleotide polymorphisms (SNPs) that caused amino acid change for which the patient was homozygous and both parents were heterozygous after excluding all known common (&gt;10%) SNP gene mutations in the dbSNP. Among them, GJB4 and ELP2 were the identified genes that are possibly associated with cardiac muscle. The PolyPhen-2 scores of mutations in GJB4 and ELP2 were 1.000 and 0.001 respectively. The identified missense mutation was a 981 A&gt;C nucleotide transition in GJB4. The resultant E204A substitution replaces a polar carboxylic glutamate with a nonpolar alanine. The endodiastolic volume was significantly lower in GJB4-KO (94pl, p&lt;0.01) and ELP2-KO (95pl, p&lt;0.01) than in wild type (WT, 145pl) zebrafish at 5 dpf. Furthermore the ventricular ejection fraction was decreased in GJB4 KO (0.66, p&lt;0.01) and unchanged in ELP2-KO (0.80) respectively compared with WT zebrafish (0.82). Conclusions: These results indicate both that mutations in GJB4 and ELP2 can cause a familial form of HCM and that GJB4 especially may be a new target for treatment of cardiac function and hypertrophy.
The frequency of specific contact allergies is reduced in patients with psoriasis
Authors: A. Claßen, T. Buhl, S. Schubert, M. Worm, A. Bauer, J. Geier, S. Molin
Journal: British Journal of Dermatology (2018)

Earlier studies suggested an inverse association between contact allergy and psoriasis, although the results of clinical studies have been inconsistent. Gene expression studies in human contact allergy focusing on immune responses revealed nickel being an inducer of T helper (Th)1/Th17 and some Th22 immune polarization, whereas fragrances were found to promote a Th2‐dominated immune activation. To investigate the epidemiological association between contact allergy and psoriasis in a large multicentre cohort and to analyse the sensitization profile to specific allergens in these patients. Retrospective analysis of patch‐tested patients from 56 departments of dermatology (1996–2015), including 2387 patients with psoriasis and 161 989 control patients. All patients with atopic dermatitis were excluded from both groups. The odds ratio (OR) for contact allergy was calculated to be 0·55 in patients with psoriasis (95% confidence interval 0·50–0·59). Logistic regression analyses with several independent variables indicated a 'protective effect' of having psoriasis for most allergens, independently of age, sex, affected body site and patch test indication. Fragrance mix II (OR 0·36) and lanolin alcohols (OR 0·38) were found to be among the least common allergens in patients with psoriasis. In contrast, the frequency of contact dermatitis to nickel was only marginally affected in patients with psoriasis compared with controls (OR 0·75). The inverse association between psoriasis and allergic contact sensitization is likely to be not exclusively mediated by psoriasis itself. The polarization of the activated immune response by specific allergens may influence the occurrence and significance of contact allergies in underlying immune‐mediated diseases, eventually even beyond the skin.
The Phosphodiesterase Inhibitor Cilostazol Induces Regression of Carotid Atherosclerosis in Subjects With Type 2 Diabetes Mellitus
Authors: NaotoKatakami, Young-SeolKim, RyuzoKawamori, YoshimitsuYamasaki
Journal: Circulation (2010)

Background— Antiplatelet drugs are effective in preventing recurrence of atherosclerosis in type 2 diabetic patients. However, the efficacy and usefulness of 2 different antiplatelet drugs, aspirin and cilostazol, in the progression of carotid intima-media thickening are unknown. Methods and Results— To compare prevention by cilostazol and aspirin of progression of atherosclerosis, we conducted a prospective, randomized, open, blinded end point study in 4 East Asian countries. A total of 329 type 2 diabetic patients suspected of peripheral artery disease were allocated to either an aspirin-treated (81 to 100 mg/d) group or a cilostazol-treated (100 to 200 mg/d) group. The changes in intima-media thickness of the common carotid artery during a 2-year observation period were examined as the primary end point. The regression in maximum left, maximum right, mean left, and mean right common carotid artery intima-media thickness was significantly greater with cilostazol compared with aspirin (−0.088±0.260 versu...
Abstract 5317: JAK2 regulates oxidative damage-induced epigenetic alterations
Authors: Ning Ding, Sam Miller, Heather O'Hagan
Journal: Cancer Research (2018)

Abstract Elevated levels of reactive oxygen species at sites of chronic inflammation cause oxidative DNA damage in epithelial cells, contributing to carcinogenesis. Aberrant silencing of key genes by promoter CpG island DNA hypermethylation occurs in many cancers that form at sites of chronic inflammation. Yet, it is not completely understood how these aberrant DNA methylation alterations are initiated. We hypothesize that the recruitment of epigenetic silencing proteins to sites of oxidative DNA damage is important for initiating DNA methylation. Here we demonstrate that after hydrogen peroxide (H2O2) treatment, mismatch repair proteins MSH2 and MSH6 become localized to sites of oxidative DNA damage, resulting in the recruitment of DNA methyltransferase 1 (DNMT1) and Polycomb repressive complex 2 (PRC2) members to chromatin. This recruitment results in the formation of repressive chromatin in the promoters of tumor-suppressor genes and the concomitant transient reduction in their expression. We sought to further understand the mechanism that drives H2O2-induced MSH2 and MSH6 chromatin binding. Janus kinase 2 (JAK2) is a kinase that is canonically known to be activated by cytokines and growth hormones and phosphorylate the transcription factor signal transducer and activator of transcription (STATs). Here, we demonstrate that in response to treatment with H2O2, but not interleukin 6 (IL-6), JAK2 translocates to the nucleus and interacts with MSH2 and MSH6. Nuclear JAK2 is important for H2O2-induced chromatin interaction of MSH2, MSH6, DNMT1 and PRC2 members. Interestingly, H2O2-induces a global and site-specific increase in trimethylation of histone H3 at lysine 27 (H3K27me3) that is also dependent on JAK2. Furthermore, by analyzing TCGA datasets, we demonstrate high JAK2 mRNA expression correlates with CpG island methylator phenotype (CIMP) status in gastric and colorectal cancer. All together, these findings suggest JAK2 plays a key role in initiating oxidative damage-induced epigenetic alterations during inflammation-driven tumorigenesis. Ultimately, understanding the mechanism of initiation of cancer-specific promoter DNA hypermethylation may lead to treatment strategies to reduce aberrant epigenetic changes induced by chronic inflammation and therefore reduce tumorigenesis. Citation Format: Ning Ding, Sam Miller, Heather O'Hagan. JAK2 regulates oxidative damage-induced epigenetic alterations [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 5317.
Abstract 3827: Bispecific antibodies with an anti-PD-1 backbone for cancer therapy generate enhanced immune activity
Authors: Baiyong Li, Zhaoliang Huang, Xinghua Pang, Tingting Zhong, Na Chen, Max Wang, Xiaoping Jin, Dennis Xia, Peng Zhang, Michelle Yu Xia
Journal: Cancer Research (2018)

Abstract PD-1 antibody combination therapy shows great promise to further enhance clinical efficacy of PD-1 antibody. Bispecific antibody represents an emerging platform that allows simultaneous targeting of multiple pathways employing a single agent. Here we present a series of bispecific antibodies using anti-PD-1 antibody as backbone, including PD-1/CTLA-4 and PD-1/VEGF bispecific antibodies, which target additional immune suppressive pathways to further enhance cancer immunity. These include complementary check point pathway and suppression of dendritic cell maturation and antigen presentation. Clinical candidates for these projects have been selected demonstrating superior immune enhancing activity in preclinical study. These bispecific antibodes are designed based on Akeso Tetrabody platform, which has demonstrated robust developability properties. Akeso PD-1/CTLA-4 bispecific antibody AK104 has entered clinical trial for advanced solid tumors (ClinicalTrials.gov Identifier: NCT03261011). Citation Format: Baiyong Li, Zhaoliang Huang, Xinghua Pang, Tingting Zhong, Na Chen, Max Wang, Xiaoping Jin, Dennis Xia, Peng Zhang, Michelle Yu Xia. Bispecific antibodies with an anti-PD-1 backbone for cancer therapy generate enhanced immune activity [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 3827.
Abstract 49: Over-activation Of Natural Killer Cells Due To Dysfunction Of Cd16-mediated Signaling In Adamts13-deficient Ttp Patients With A History Of Relapse
Authors: Fangzhou, DariseFarris
Journal: Circulation Research (2014)

Thrombotic thrombocytopenic purpura (TTP) is a rare life-threaten vascular autoimmune disease. There is no effective method to treat it in clinical trials since pathogenesis of TTP has not been fully elucidated. Here we investigate the role of NK cells in relapse development of TTP. Our results showed that the frequencies of CD3−CD56dimCD16− and CD3−CD56briCD16− NK cells are increased in TTP patients with a history of relapse. Expression of CD107a, granzyme A and IFN-γ by CD3−CD56dim NK cells following in vitro stimulation with PMA/ionomycin / monensin is improved in the relapse group, compared with those on NK cells derived from TTP patients without relapse development. NK cells isolated from TTP patients with a history of relapse indicated stronger cytotoxicity to target K562 cells than those of NK cells derived from TTP patients without relapse development, suggesting prior activation of NK cells in vivo. Treatment with anti-human CD16 antibody up-regulates cytotoxicity of NK cells derived from TTP pat...
Abstract 5381: Understanding the genesis and oncogenic consequences of tandem duplicator phenotypes in human cancers
Authors: Francesca Menghi, Floris Barthel, Vinod Yadav, Ming Tang, Bo Ji, Gregory Carter, Jos Jonkers, Roel Verhaak, Ralph Scully, Ed Liu
Journal: Cancer Research (2018)

Abstract Genome-scale instability configurations in cancer genomes are commonly found across different types of cancers. We and others have described an enrichment of head-to-tail somatic segmental tandem duplications (TDs) in primarily breast and ovarian cancers, a configuration known as the Tandem Duplicator Phenotype (TDP). Here, we perform a meta-analysis of 2,717 human cancer genomes, representing 30 different tumor types and refine the TDP classification based on the identification of highly specific and recurrent TD span profiles. Overall, we identify the TDP as a highly recurrent chromosomal instability configuration, occurring in 14% of the cancer genomes examined. The TDP is remarkably prevalent in triple negative breast cancer (50%), ovarian cancer (55%), and uterine cancers (45%), but is infrequent in most other cancer types. In TDP tumors, TD span sizes can be classified into three major discrete intervals with modal values of 10 Kb, 230 Kb, and 1.7 Mb. TDPs with a dominant TD modal span size of 10 Kb are strongly associated with conjoint TP53 mutations and BRCA1 deficiency across different tumor types. TDPs with larger span sizes (230 Kb and 1.7 Mb) are associated with CCNE1 pathway activation and CRKRS/CDK12 gene disruptions. We proved the driver role of the conjoint abrogation of the BRCA1 and TP53 genes for the induction of TDP cancers with the 10 Kb predominant span peak by generating mammary cancers with a Tandem Duplicator Phenotype of the ~10 Kb TD span configuration type in genetically modified mouse models harboring deleterious mutations in only these same two genes. Lastly, we describe how heterogeneous combinations of tumor suppressors and chromatin topologically associating domains are disrupted, and oncogene and tissue-specific super enhancers are duplicated as a consequence of TD formation in TDP tumors. In summary, our work unifies a number of observations around a specific cancer genomic signature, shows how a number of genetic drivers converge on creating the tandem duplicator phenotype, and how the downstream consequences of the TDs generate oncogenic diversity that allows for further formation of genetic subgroups. The implications of TDP-based stratification for therapy response are currently under investigation. Citation Format: Francesca Menghi, Floris Barthel, Vinod Yadav, Ming Tang, Bo Ji, Gregory Carter, Jos Jonkers, Roel Verhaak, Ralph Scully, Ed Liu. Understanding the genesis and oncogenic consequences of tandem duplicator phenotypes 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 5381.
Abstract 2060: The pseudogeneFLT1P1functions as a tumor metastasis suppressor in a preclinical model of colorectal cancer
Authors: Xiangcang Ye, Fan Fan, Rajat Bhattacharya, Delphine R. Boulbes, Rui Wang, Ling Xia, Lee M. Ellis
Journal: Cancer Research (2018)

Abstract Chromosome 3p21.3 is one of the unstable genomic loci that are frequently altered by epigenetic modifications or interstitial deletions in human solid tumors. Several genes in 3p21.3 are known to be tumor suppressors. This locus includes a non-coding gene, fms-related tyrosine kinase 1 pseudogene 1 (FLT1P1), of which the role is largely unknown. Our previous published study (Ye et al. MCR, 2015) found that FLT1P1 was transcribed primarily as an antisense that inhibits VEGFR1 protein expression through interaction with miR-520a in human colorectal cancer (CRC) cells. In this study, we showed that the expression of FLT1P1 antisense is silenced by promoter hyper-methylation in xenograft tumors. Our data further showed that the loss of the FLT1P1 antisense not only up-regulated the expression of VEGFR1 and other genes relating to tumor angiogenesis, but also induced the EMT phenotype in tumor cells. Moreover, the FLT1P1 silenced cells demonstrated an increase in the number of metastasis to the liver following spleen injection in a mouse model. These observations suggest that the transcribed FLT1P1 antisense is a tumor metastasis suppressor. Our finding warrants further investigation of the genetic and epigenetic alterations of FLT1P1 and their impact on metastasis of CRC cells. Citation Format: Xiangcang Ye, Fan Fan, Rajat Bhattacharya, Delphine R. Boulbes, Rui Wang, Ling Xia, Lee M. Ellis. The pseudogene FLT1P1 functions as a tumor metastasis suppressor in a preclinical model of colorectal 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 2060.
Abstract 11019: Incidence and Predictors for Late Acquired Stent Malapposition of Drug-Eluting-Stents With Second-Generation Permanent and Biodegradable Polymer-Coatings - A Prospective, Randomized Comparison Using Optical Coherence Tomography
Authors: Christian Roth, Clemens Gangl, Daniel Dalos, Sabine Scherzer, Lisa Krenn, Gerhard Kreiner, Georg Delle-Karth, Thomas Neunteufl, Rudolf Berger
Journal: Circulation (2014)

Introduction: The polymers releasing the drug of first-generation drug-eluting stents (DES) may induce allergic reactions and inflammation, resulting in late-acquired stent malapposition (LASM) with uncoverage of struts, and risk of stent thrombosis. The incidence and predictors of LASM in DES with different polymers designed to improve biocompatibility are unknown. Methods: Fifty patients with 59 lesions of interest were randomized to elective treatment with Everolimus-eluting stents (EES; n=17, 20 lesions)], Zotarolimus-eluting stents (ZES; n=15, 19 lesions), and Biolimus-eluting stents (BES; n=18, 20 lesions) and underwent optical coherence tomography after implantation and after one year. Results: After implantation 29 early stent malappositions (ESM) were documented in 29 lesions (49% of lesions), distributed to 11 lesions treated with EES (55%), 11 with ZES (58%), and 7 with BES (35%; n.s.). After one year 14 late stent malappositions (LSM) in 14 lesions (24%) were detected; nine ESM persisted (EPSM) after one year (1 EES, 6 ZES, 2 BES), whereas 20 ESM resolved. In addition, 9 LASM were documented (5 LASM in early well-apposed Stents, 4 LASM in Stents which also have EPSM). LASM was present in 7 hydrophilic polymer-coated ZESs (37%), in 2 fluoropolymer-coated EESs (10%), and in none of the biodegradable polymer-coated BESs (p=0.003). Independent predictors of LASM were the vessel treated (RCA as vessel with high motion; p&lt;0.022) and type of polymer (biodegradable or permanent; p&lt;0.035). Conclusion: The incidence of ESM and EPSM were similar, whereas the incidence of LASM was different in second-generation DES with different polymers. Biodegradable polymer prevented LASM, stent locations with significant vessel movement (RCA) enhanced LASM.
Abstract P135: Abdominal Obesity is Associated With DNA Methylation in Cardiovascular Health Related Genes Among Adolescents
Authors: Fan He, Arthur Berg, Edward O Bixler, Julio Fernandez-Mendoza, Yuka Imamura Kawasawa, Anna C Salzberg, Eric A Whitsel, Duanping Liao
Journal: Circulation (2017)

Background: Obesity, especially abdominal obesity, is a risk factor for coronary artery disease (CAD) in various populations. Little is known regarding the role of epigenetics in the association between abdominal obesity and cardiovascular health in adolescents. Hypothesis: Abdominal and especially visceral obesity is associated with DNA methylation in genes related to cardiovascular health among adolescents. Methods: We used data from a sample of 263 adolescents participating in the population-based Penn State Child Cohort follow-up exam (N=421). Dual-energy X-ray absorptiometry was used to measure visceral and subcutaneous fat areas (VAT; SAT, in cm 2 ) in each participant. We extracted DNA from peripheral leukocytes and subjected it to enhanced, reduced representation bisulfite sequencing. A high-throughput assay provided single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions. We excluded bases with &lt; 10x coverage or available from &lt; 20 individuals. We analyzed a total of 1,609,424 methylation sites. We used linear regression models to assess the association between site-specific methylation level (expressed as %) and VAT and SAT. We adjusted all models for age, race, sex, and body mass index (BMI) percentile. We used Bonferroni-adjusted statistical tests to identify sites significantly related to VAT and separately, SAT. We mapped the VAT- and SAT-associated sites to the hg19 assembly and subjected them to Ingenuity Pathway Analysis (IPA) wherein mapped gene sets were examined for enrichment of downstream function and diseases. Results: On average, the sample was 55% male, 79% white and aged 16.7 (standard deviation = 2.2) years. VAT and SAT were significantly associated with methylation at 296 sites within 193 genes and 101 sites within 87 genes, respectively. Among them, seven genes related to VAT and five related to SAT were associated with CAD. IPA revealed that CAD-related genes were significantly enriched in both gene sets (for VAT: p=1.97x10 -2 ; SAT: p=9.67x10 -3 ). Genes related to VAT also were significantly enriched in endothelial activation (p=8.16x10 -3 ), fibrogenesis (p=5.01x10 -5 ), and dyslipidemia (p=7.99x10 -3 ). Indeed, higher VAT was associated with hypomethylation of CD14 and hypermethylation of GNMT , while higher SAT was associated with hypermethylation of ADRB1 and hypomethylation of TUBB4A . Conclusion: If externally validated, our data would suggest that (1) abdominal obesity in adolescence is associated with DNA methylation of genes related to cardiovascular health, independent of BMI; and (2) visceral adiposity has a more prominent association with cardiovascular health through DNA methylation of genes with roles in atherogenesis.
Abstract 2236: Metformin and pancreatic cancer risk in Taiwanese patients with type 2 diabetes
Authors: Chin-Hsiao Tseng
Journal: Cancer Research (2018)

Abstract Background: Whether metformin may reduce pancreatic cancer risk is controversial and has rarely been studied in Asian populations. This study evaluated pancreatic cancer risk in type 2 diabetes patients with and without metformin treatment. Methods: An original cohort of 16232 never users and 153408 ever users of metformin who were newly diagnosed of type 2 diabetes between 1999 and 2005 were enrolled from Taiwan's National Health Insurance. A propensity score matched cohort of 16232 ever users and 16232 never users were derived from this original cohort. The patients were followed up until December 31, 2011 and analyses were conducted in both the original cohort and the matched cohort. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using propensity score. Results: In the original cohort, the incidence rate of pancreatic cancer in never users and ever users were 43.59 and 28.85 per 100000 person-years, respectively, with an overall hazard ratio of 0.658 (95% confidence interval: 0.438-0.988, P=0.0436). While compared to never users, the hazard ratio (95% confidence interval) for cumulative duration of metformin use in the first (&amp;lt;22.10 months), second (22.10-46.70 months) and third tertile (&amp;gt;46.70 months) was 1.445 (0.950-2.196), 0.595 (0.384-0.922) and 0.157 (0.094-0.264), respectively. Results in the matched cohort were very similar, with an overall hazard ratio of 0.492 (0.252-0.961) and the hazard ratio in the respective tertile of cumulative duration was 0.900 (0.368-2.198), 0.648 (0.266-1.581) and 0.094 (0.013-0.692). Conclusions: Metformin significantly reduces pancreatic cancer risk in a dose-response pattern. Citation Format: Chin-Hsiao Tseng. Metformin and pancreatic cancer risk in Taiwanese patients with type 2 diabetes [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 2236.