tbuckley/cabot-search huggingface dataset:
Abstract 15990: Disturbed Shear Stress Facilitates Caveolae-Mediated oxLDL Uptake Leading to Increased Endothelial Stiffness
Authors: ElizabethLeMaster, ShanSun, DavidEddington, MichaelCho, RichardMinshall, IrenaLevitan
Journal: Circulation (2014)

Introduction: Oxidized low density lipoprotein (oxLDL) is a key risk factor in the formation of atherosclerotic plaques, which are primarily located at vessel bifurcations that exhibit bidirectional recirculating disturbed shear stress (DSS) patterns. It is also well known that while DSS patterns are pro-atherogenic, laminar shear stress (LSS) is atheroprotective. Hypothesis: OxLDL uptake into endothelial cells (ECs) is caveolin-1 (Cav-1) protein dependent and increases under DSS conditions leading to increased cellular stiffness. Methods: To address these questions, a microfluidic channel with a step barrier was designed, tested and fabricated to generate both unidirectional LSS and recirculating DSS patterns onto an endothelial monolayer for 48 hours. EC stiffness was assessed using atomic force microscopy. Results: Our results show a 40% increase in endothelial oxLDL uptake in DSS vs. LSS regions (n=4, p<0.05), which was significantly diminished (50% less) in cells lacking Cav-1, the main protein in ca...
Diagnosis and management of rheumatoid arthritis in adults: summary of updated NICE guidance
Authors: Alex Allen, Serena Carville, Frank McKenna
Journal: BMJ (2018)

### What you need to know

Rheumatoid arthritis is a chronic, disabling autoimmune disease characterised by synovitis of small and large joints causing swelling, stiffness, pain, and progressive joint destruction. About 1% of the UK population have rheumatoid arthritis, and approximately 15% of these people have severe disease. It affects roughly three times as many women as men. People tend to develop rheumatoid arthritis between 40 and 60 years of age, although it can arise at any age. The early signs of rheumatoid arthritis are often encountered in primary care, where people present with joint pain and swelling. Fast and accurate referral to rheumatology services is important to achieve early remission and prevent or reduce disability.1

This article summarises the update of the National Institute for Health and Care Excellence (NICE) guideline for the diagnosis and management of rheumatoid arthritis in adults.2 The management of rheumatoid arthritis has evolved in the nine years since the previous NICE guideline on rheumatoid arthritis was published, with greater emphasis on a treat-to-target strategy rather than specific drug regimens,3 and debate about the merit of initiating treatment with combination drug therapy.4 Technologies such as ultrasound have been increasingly used for diagnosis and monitoring of synovitis where it is unclear from clinical examination.5 These aspects of management were investigated by the Guideline Committee, and …
Abstract P300: Cardiovascular Risk Inequality in Subjects with Chronic Kidney Disease by Age, Race and Ethnicity in the United States
Authors: LongjianLiu
Journal: Circulation (2014)

Objectives: Adults with chronic kidney disease (CKD) carry an extraordinarily excess risk for cardiovascular disease (CVD). The present study aimed to test two hypotheses: (1) Non-Hispanic black (NHB) with CKD have significantly higher CVD risk profiles than non-Hispanic white (NHW). (2) This difference significantly contributes to the excess risk of CVD in NHB versus NHW. Methods: A total of 3,939 participants aged 21-74 years old in the baseline Chronic Renal Insufficiency Cohort Study, a multiethnic population-based study supported by the National Institute of Diabetes and Digestive and Kidney Diseases, were analyzed. CKD was classified using estimate glomerular filtration rate. A sum weighted CVDRisk score was developed from multiple CVD risk factors. Differences in CVDRisk score by race/ethnicity were tested using quantile regression (QR), a novel data mining approach to identify distribution of risk factors and outcomes. Results: The prevalence of CVD was 30.7 and 38.2% in NHW and NHB with CKD (p<0....
Distinct Effects of Leukocyte and Cardiac Phosphoinositide 3-Kinase γ Activity in Pressure Overload–Induced Cardiac Failure
Authors: FedericoDamilano, IreneFranco, CinziaPerrino, KatrinSchaefer, OrnellaAzzolino, DanielaCarnevale, GiuseppeCifelli, PierluigiCarullo, RiccardoRagona, AlessandraGhigo, AlessiaPerino, GiuseppeLembo, EmilioHirsch
Journal: Circulation (2011)

Background—Signaling from phosphoinositide 3-kinase γ (PI3Kγ) is crucial for leukocyte recruitment and inflammation but also contributes to cardiac maladaptive remodeling. To better understand the translational potential of these findings, this study investigates the role of PI3Kγ activity in pressure overload–induced heart failure, addressing the distinct contributions of bone marrow–derived and cardiac cells. Methods and Results—After transverse aortic constriction, mice knock-in for a catalytically inactive PI3Kγ (PI3Kγ KD) showed reduced fibrosis and normalized cardiac function up to 16 weeks. Accordingly, treatment with a selective PI3Kγ inhibitor prevented transverse aortic constriction–induced fibrosis. To define the cell types involved in this protection, bone marrow chimeras, lacking kinase activity in the immune system or the heart, were studied after transverse aortic constriction. Bone marrow–derived cells from PI3Kγ KD mice were not recruited to wild-type hearts, thus preventing fibrosis and ...
Abstract 3075: Type IIB DNA topoisomerase is downregulated by trastuzumab and doxorubicin to synergize cardiotoxicity
Authors: Jiangsong Jiang, Nishant Mohan, Yukinori Endo, Yi Shen, Wen Jin Wu
Journal: Cancer Research (2018)

Abstract Despite heightened risk of cardiotoxicity associated with combination therapy of anthracyclines and trastuzumab in HER2-positive breast cancer patients, little research effort has been invested in exploring the molecular mechanisms of cardiotoxicity induced by this combination therapy. Using human primary cardiomyocytes as a model, we demonstrate that trastuzumab downregulates both gene and protein expressions of type IIB DNA topoisomerase/DNA topoisomerase IIB (TOP2B), a major intracellular target mediating doxorubicin-induced cardiotoxicity. This downregulation of TOP2B in turn induces DNA damage activity and DNA double strand breaks. However, unlike doxorubicin, trastuzumab alone does not induce apoptosis. Further investigation discovers that concurrent or sequential treatment of doxorubicin and trastuzumab significantly reduces protein levels of TOP2B, enhances apoptosis induced by doxorubicin, and inhibits cell growth. Furthermore, treatment of cardiomyocytes with doxorubicin and trastuzumab in either concurrent or sequential setting also enhances production of reactive oxidative and nitrative species as compared to either trastuzumab or doxorubicin treatment in cardiomyocytes. Our data reveal that doxorubicin treatment increases the cellular level of ErbB2/HER2 protein and enhances downstream signaling activity of this pathway. Consequently, this may render cardiomyocytes more sensitive to trastuzumab treatment after doxorubicin exposure. This study provides molecular basis for significantly increased cardiotoxicity in cancer patients treated with anthracyclines and trastuzumab-based combination regimens. Citation Format: Jiangsong Jiang, Nishant Mohan, Yukinori Endo, Yi Shen, Wen Jin Wu. Type IIB DNA topoisomerase is downregulated by trastuzumab and doxorubicin to synergize cardiotoxicity [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 3075.
Abstract 17254: Molecular Mechanism of the Natural Flavone Acacetin in Cardioprotection Against Hypoxia-Reoxygenation Injury
Authors: Wei-Yin Wu, Yu-Kai Cui, Yun-Da Li, Gang Li, Yao Wu, Yan Wang, Gui-Rong Li
Journal: Circulation (2017)

Introduction: Ischemic cardiomyopathy induced by ischemia/reperfusion injury is a major cause of morbidity and mortality around the world; therefore it is important to seek the new strategy that can reduce myocardial ischemia/reperfusion injury. Our recent study reported that the natural flavone acacetin effectively protected myocardium against ischemia/reperfusion injury; however, the detailed mechanism was poorly understood. The present study investigates the potential molecular mechanism of acacetin in myocardioprotection against ischemia/reperfusion injury. Methods: An in vitro hypoxia/reoxygenation (H/R) model was established in primary cultured neonatal rat cardiomyocytes and H9C2 cardiomyoblasts, and potential molecular targets of acacetin in cardioprotection against H/R injury were determined in multiple biochemical and molecular biological approaches. Results: It was found that acacetin (0.3-3 μM) significantly decreased the apoptosis and ROS production induced by H/R injury in both cardiomyocyte...
Abstract 1223: Significance of GSTM1 and GSTT1 gene polymorphism to breast cancer susceptibility in Nigerian women
Authors: Olubanke O. Ogunlana, Omaghomi Ortiseweyinmi, Sadiq Ajoke, Omolara Fatiregun, Solomon O. Rotimi, Bose E. Adegboye, Emeka E. Iweala, Angie O. Igbinoba-Adebayo
Journal: Cancer Research (2018)

Abstract Human glutathione-S-transferases play a key role in the metabolism of drugs and environmental chemicals. There have been conflicting reports on the association of breast cancer susceptibility with null genotypes of glutathione-S-transferase (GST) classes of mu and theta (GSTM1 and GSTT1). However, this is the first report of the association of null genotypes of GSTs with breast cancer patients from Nigerian population. By multiplex PCR, we examined the null genotypes of GSTM1 and GSTT1 in relation to breast cancer risk in Nigerian women. The case-control study included 56 clinically diagnosed breast cancer patients and age-matched control participants. Odds ratio (OR) and 95% confidence interval (Cl) from conditional logistic regression model were used to estimate the association between GSTM1 and GSTT1 subtypes and breast cancer risk. The frequencies of GSTM1 and GSTT1 null genotypes in breast cancer (BC) patients differed from healthy controls (HC) (61% in BC vs. 39% in HC and 66% in BC vs. 34% in HC for GSTM1 and GSTT1 respectively). GSTM1 and GSTT1 null genotypes and their combinations were associated with increased breast cancer risk [OR = 3.06 (95% Cl 0.98-9.48)], [OR = 14.06 (95% Cl 3.02-70.6)] and [OR = 6.98 (95% Cl = 0.11-16.5)] respectively. The study showed an increased breast cancer risk in patients with GSTT1 homozygous gene deletions with relative risk (RR) value of 5.6 than those with GSTM1 (RR = 1.77). In conclusion, the data from our work provide evidence of increased risk of breast cancer associated with GSTM1 and GSTT1 homozygous gene deletions in women from Nigeria. Citation Format: Olubanke O. Ogunlana, Omaghomi Ortiseweyinmi, Sadiq Ajoke, Omolara Fatiregun, Solomon O. Rotimi, Bose E. Adegboye, Emeka E. Iweala, Angie O. Igbinoba-Adebayo. Significance of GSTM1 and GSTT1 gene polymorphism to breast cancer susceptibility in Nigerian women [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 1223.
Perinatal Maternal Depressive Symptoms as an Issue for Population Health
Authors: Michael J. Meaney
Journal: American Journal of Psychiatry (2018)

The importance of maternal depression for child outcomes is well established, and impairments in psychosocial function and parenting are as severe in women with high subsyndromal levels of depressive symptoms as they are in women with clinical depression. The author conducted a systematic review that explored the association between maternal depressive symptoms and child neurodevelopmental outcomes, including in neuroimaging studies. The results strongly suggest that the influences of maternal depressive symptoms operate across a continuum to influence child outcomes, implying that maternal depression may appropriately be considered an issue of population health. This conclusion is strengthened by recent findings that reveal distinct influences of positive maternal mental health on parenting and child outcomes. [AJP AT 175: Remembering Our Past As We Envision Our Future April 1851: Fleetwood Churchill, "On the Mental Disorders of Pregnancy and Childbed" "Women affected with any degree of mental derangement during pregnancy are more disposed than others to puerperal mania. But the serious character of these attacks is even deepened by the fact, abundantly established, that the evil is not limited to the mother. Not only may organic diseases of the body be transmitted to the infant, but a predisposition to insanity, thus multiplying the distress in a most alarming ratio." (Am J Psychiatry 1851; 7:297-317 )].
Abstract 4192: C-terminal HSP90 inhibitor, L80, targets cancer stem cell (CSC)-like property and suppresses metastasis via JAK/STAT3 inactivation in triple-negative breast cancer
Authors: Tae-Min Cho, Eunhye Oh, Daeil Sung, Yoon-Jae Kim, Seojin Jang, Jeewoo Lee, Ji Young Kim, Jae Hong Seo
Journal: Cancer Research (2018)

Abstract Purpose: Triple-negative breast cancer (TNBC) harbors high level of cancer stem cell (CSC)-like populations, which is associated with aggressive phenotype leading to tumor cell dissemination and poor clinical outcomes. Therefore, new drugs that effectively target both CSCs and tumor bulk cells are needed to improve clinical outcomes. The 90-kDa molecular chaperone heat-shock protein, HSP90 has been implicated in cancer progression and metastasis by modulating the stabilization and maturation of many oncogenic proteins. Our objective was to investigate the effects of L80 on cancer stem-like characteristics, cell proliferation and metastasis in TNBC in vitro and in vivo. Experimental Design: The effect of L80 on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis and mammosphere-forming ability and expression of JAK/STAT3 signaling-related factors. An orthotopic injection model with 4T1 mammospheres with self-renewability was used to examine the effect of L80 on tumor growth, angiogenesis and metastasis. Results: L80 treatment caused a significant induction of apoptosis, accompanied by caspase-3/-7 activation and the dysregulation of JAK/STAT3 activation in TNBC cells. The latter phenomenon was associated with impairment of cancer stem-like trait, concomitant with a significant suppression of mammosphere formation. To confirm the physiological relevance of our in vitro findings, we examined the impact of L80 on allografted tumor growth, angiogenesis and metastasis in vivo. L80 administration impedes tumor growth and subsequently suppresses angiogenesis, as evidenced by a marked reduction in number of CD31-positive microvessels in the L80-treated groups compared to their counterparts. L80 administration leads to a significant reduction in lung and liver metastases, coinciding with decreased MMP-2 and MMP-9 levels in circulating blood. These responses were intimately associated with dysregulation of JAK/STAT3 activation. Conclusion: C-terminal HSP90 inhibitor, L80 suppresses tumor growth and metastasis via suppression of JAK/STAT3 activity and CSC-like property. These findings suggest that HSP90 could be a promising target for treatment of metastatic TNBC. Citation Format: Tae-Min Cho, Eunhye Oh, Daeil Sung, Yoon-Jae Kim, Seojin Jang, Jeewoo Lee, Ji Young Kim, Jae Hong Seo. C-terminal HSP90 inhibitor, L80, targets cancer stem cell (CSC)-like property and suppresses metastasis via JAK/STAT3 inactivation in triple-negative breast 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 4192.
Abstract 208: Multi-omics analysis in primary cell cultures reveals the genomic basis of phenotypic diversity within tumors
Authors: Sixue Liu, Zuyu Yang, Guanghao Li, Yanting Luo, Qiang Gong, Xin Wu, Tao Li, Zhiqian Zhang, Baocai Xing, Xiaolan Xu, Xuemei Lu
Journal: Cancer Research (2018)

Abstract To uncover the functionally essential variations related to tumorigenesis and tumor progression from large amount of cancer genomics data is still challenging due to the genetic diversity between patients, and extensive inter- and intra-tumor heterogeneity at the genomic, epigenomic, and transcription levels. Multiple primary cultures derived from phenotypically distinct subpopulations of a single patient may not only represent the diversity and heterogeneity of tumor cell types and states (such as metastasis and drug-resistant), but also narrow the analysis in genomic basis of phenotypic diversity down to the relatively small number of variations between subpopulations with the same genetic background. Performing multi-omics sequencing, we identified variations in single nucleotide, copy number, DNA methylation and gene expression among four primary cell cultures from primary and recurrent tumors in a hepatocellular carcinoma patient. We observed the discrepancy between the phylogenetic relationships revealed by single nucleotide variations (SNVs) and transcriptional profiles in the four cell cultures. The differences in gene expression, which indicated the distinct cellular characteristics and tumorigenic capability in one of the two recurrent cell clones, were correlated to the copy number alterations (CNAs) and DNA methylation variation in gene body and confirmed by the characterization of cellular phenotype. Our multi-omics analysis in heterogeneous clones derived from an individual revealed that CNAs and epigenomic changes, rather than SNVs, dominantly contribute to the phenotypic diversity among subpopulations in tumors, which could shed light on developing new cancer diagnosis and treatment strategies based on gene dosage and epigenetic modification Citation Format: Sixue Liu, Zuyu Yang, Guanghao Li, Yanting Luo, Qiang Gong, Xin Wu, Tao Li, Zhiqian Zhang, Baocai Xing, Xiaolan Xu, Xuemei Lu. Multi-omics analysis in primary cell cultures reveals the genomic basis of phenotypic diversity within tumors [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 208.
Abstract 12239: Efficacy and Safety of the Non-vitamin K Antagonist Oral Anticoagulants (NOACs) in Japan: A Retrospective Cohort Study Using the National Database of Health Insurance Claim
Authors: Masahiro Inoue, Yoshinori Miyamoto, Kotaro Yasuda, Shunya Ikeda, Masakazu Nishigaki, Kazuhiro Takamatsu, Michiyoshi Sato, Masaru Kuriyama, Yoshiki Yagita
Journal: Circulation (2015)

Objective: Examine efficacy and safety of anticoagulation (AC) treatment in Japanese Acute hospitals Methods: Insurance claim data of 66, 693 patients who received anticoagulant treatment were extracted from 352 (20%) of hospitals of all 1580 hospitals enrolled in national database of health insurance, Diagnosis Procedure Combination (DPC) database. All the patients received anticoagulant treatment using warfarin and/or non-vitamin K antagonist oral anticoagulants (NOAC) during 10/1/2012 and 9/30/2014. NOACs in this study are: dabigatran, rivaroxaban, and apixaban. We observed incidence of ischemic stroke as efficacy related outcome. We also observed following unfavorable events: intracranial hemorrhage, gastrointestinal hemorrhage, and all-cause death. Outcomes were compared between group of warfarin-treated patients and NOACs-treated patients. Findings: Of 66,693 patients treated with anticoagulants, 50,523(77.3%) were treated with Warfarin, 16,170(24.8%) were with NOACs. Among 66,693 patients, 1,378 patients (2.1%) who were treated with both drugs were excluded for the analysis. The event rate of ischemic stroke was similar between warfarin-treated group and NOACs-treated group 849 (1.68%) vs 245 (1.52%), respectively (p=0.16). On the other hands, unfavorable events were observed significantly more frequently in warfarin-treated group than NOACs-treated group: all-cause death, 4,875(9.6%) vs 724(4.5%), respectively (p&lt;0.001); intracranial hemorrhage, 685(1.4%) vs 94(0.6%), respectively (p&lt;0.001); gastrointestinal hemorrhage, 883 (1.74%) vs 157 (0.97%), p&lt;0.001). Conclusions: This retrospective study based on large-scale national database revealed that efficacy of warfarin and NOACs were equivalent. However, risk of all-cause death and unfavorable bleeding events was higher in warfarin-treated patients than NOACs-treated patients. This study demonstrates that NOACs contribute a beneficial effect on anticoagulation treatment for the patients with atrial fibrillation in the real world.
Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab
Authors: Patrick M. Brunner, Ana B. Pavel, Saakshi Khattri, Alexandra Leonard, Kunal Malik, Sharon Rose, Shelbi Jim On, Anjali S. Vekaria, Claudia Traidl-Hoffmann, Giselle K. Singer, Danielle Baum, Patricia Gilleaudeau, Mary Sullivan-Whalen, Judilyn Fuentes-Duculan, Xuan Li, Xiuzhong Zheng, Yeriel Estrada, Sandra Garcet, Huei-Chi Wen, Juana Gonzalez, Israel Coats, Inna Cueto, Avidan U. Neumann, Mark G. Lebwohl, James G. Krueger, Emma Guttman-Yassky
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 3285: COSMIC-3D: Impacts of cancer mutations on protein structure, function, and druggability
Authors: Harry C. Jubb, Harpreet K. Saini, Marcel L. Verdonk, Simon A. Forbes
Journal: Cancer Research (2018)

Abstract In recent years there has been an explosion in cancer genomic data that has enabled understanding of the incidence and patterns of mutations in cancer patients. The challenge is to translate this vast resource of genomic research and data into precision medicines that target specific mutations in patient populations and improve clinical outcomes. Delivering personalised cancer medicines requires greater understanding of how cancer mutations impact the structure, function, and druggability of known and potential protein drug targets. In this study we annotate each missense mutation in COSMIC, via COSMIC-3D (http://cancer.sanger.ac.uk/cosmic3d), with protein structural features derived from the wwPDB, and rich functional features derived from the UniProt protein database. The structural features include small molecule binding sites (including drug binding sites), protein-protein interaction interfaces, protein-nucleic acid interactions, solvent inaccessible protein “core” versus solvent exposed areas, and predicted small-molecule druggability. The UniProt-derived functional features represent high quality functional site annotations, including post-translational modification sites, functional domains and motifs, and regions of biological interest. In addition, we explore the relationship between mutation occurrence in protein structural and functional sites, and recurrence in cancer. We found that recurrent missense mutations are significantly enriched in specific structural and functional environments, including small-molecule binding sites and predicted druggable pockets. These results provide promising hypotheses that recurrent, cancer driving mutations may be targeted by small-molecule drugs. We posit that further characterisation of the structure-function implications of each mutation in COSMIC-3D will increasingly aid mutation-guided target discovery and drug design. Citation Format: Harry C. Jubb, Harpreet K. Saini, Marcel L. Verdonk, Simon A. Forbes. COSMIC-3D: Impacts of cancer mutations on protein structure, function, and druggability [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 3285.