tbuckley/cabot-search huggingface dataset:
Abstract 13729: Significant Prognostic Values of Acute Preload Stress Echocardiography by Using Leg-positive Pressure Maneuver in Patients With Severe Aortic Stenosis
Authors: Hiroki Matsuzoe, Kensuke Matsumoto, Hidekazu Tanaka, Hiroki Takada, Fumitaka Soga, Yutaka Hatani, Keiko Hatazawa, Hiroyuki Shimoura, Junichi Ooka, Hiroyuki Sano, Keiko Ryo-Koriyama, Ken-ichi Hirata
Journal: Circulation (2016)

Introduction: Recently, leg-positive pressure (LPP) maneuver, using customized air-bags inflated both lower limbs to maintain a constant loading pressure (90 mmHg for 5 minutes), is reported to be able to apply acute preload stress non-invasively without significant change in either heart rate or blood pressure. Hypothesis: We hypothesized the ability to utilize the Frank-Starling mechanism without significant increase in left ventricular (LV) filling pressure in response to LPP stress could provide additional prognostic capability for patients with aortic stenosis (AS). Methods: We prospectively recruited 48 patients with severe AS. LV stroke volume (SV) was assessed by means of pulsed-wave Doppler, and then normalized by body surface area (SVi). The ratio of transmitral E wave and mitral annular velocity (e’) was calculated to estimate LV filling pressure. These parameters were obtained both at rest and during LPP stress. Event-free survival was then tracked for 136 days. Results: Eight patients developed adverse cardiac events. During acute preload stress, forward SV increased significantly (SVi : 42±9 to 48±9 ml/m 2 , p&lt;0.001) along with minimal change in LV filling pressure (E/e’: 20±8 to 21±11, n.s.) in patients without cardiac events. On the other hand, Frank-Starling mechanism was significantly impaired (SVi: from 41±10 to 38±8 ml/m 2 ), while LV filling pressure increased to the critical level (E/e’:26±7 to 33±7, p&lt;0.01) in patients with cardiac events. When the patients were divided into two subgroups based on the response to LPP stress, patients without preload reserve (ΔSVi&lt;5ml/m 2 ) showed worse event rate than the others (p&lt;0.05). Similarly, patients without diastolic reserve (ΔE/e’ ratio &gt;3) exhibited significantly worse event-free survival (p&lt;0.05). Conclusions: Assessment of preload reserve and diastolic reserve during LPP stress can enhance the predictive capability for cardiovascular outcomes events for patients with AS.
Causality in dietary interventions—building a case for gut microbiota
Authors: Yan Y. Lam, Chenhong Zhang, Liping Zhao
Journal: Genome Medicine (2018)

We provide a conceptual framework to establish a causal link between diet, gut microbiota, and health. Identifying the key strains that mediate microbe–host interactions and understanding the mechanisms involved and the ecology of these strains are critical to translating gut microbiome research into clinical applications and to advancing a new concept of "microbiome nutrition".
Thioredoxin 1 Negatively Regulates Angiotensin II–Induced Cardiac Hypertrophy Through Upregulation of miR-98/let-7
Authors: YanfeiYang, TetsuroAgo, PeiyongZhai, MahaAbdellatif, JunichiSadoshima
Journal: Circulation Research (2011)

Rationale:Thioredoxin (Trx)1 inhibits pathological cardiac hypertrophy. MicroRNAs (miRNAs) are small noncoding RNAs that downregulate posttranscriptional expression of target molecules. Objectives:We investigated the role of miRNAs in mediating the antihypertrophic effect of Trx1 on angiotensin II (Ang II)–induced cardiac hypertrophy. Methods and Results:Microarray analyses of mature rodent microRNAs and quantitative RT-PCR/Northern blot analyses showed that Trx1 upregulates members of the let-7 family, including miR-98, in the heart and the cardiomyocytes therein. Adenovirus-mediated expression of miR-98 in cardiomyocytes reduced cell size both at baseline and in response to Ang II. Knockdown of miR-98, and of other members of the let-7 family, augmented Ang II–induced cardiac hypertrophy, and attenuated Trx1-mediated inhibition of Ang II–induced cardiac hypertrophy, suggesting that endogenous miR-98/let-7 mediates the antihypertrophic effect of Trx1. Cyclin D2 is one of the predicted targets of miR-98. ...
Acute inflammation: endogenous cannabinoids mellow the harsh proinflammatory environment
Authors: Andrew S. Neish
Journal: Journal of Clinical Investigation (2018)

Under normal conditions, there is a paucity of neutrophils within the intestinal mucosa; however, these innate immune cells rapidly infiltrate the mucosa in response to infection and are critical for pathogen control. Unfortunately, these cells can cause extensive damage to the intestine if the initial inflammatory influx is not resolved. Factors that promote resolution of inflammation are of great interest, as they have therapeutic potential for limiting uncontrolled inflammatory damage. In this issue of the JCI, Szabady et al. demonstrate that the multidrug resistance transporter P-glycoprotein (P-gp) secretes endocannabinoids into the intestinal lumen that counteract the proinflammatory actions of the eicosanoid hepoxilin A3, which is secreted into the lumen by the efflux pump MRP2 and serves as a potent neutrophil chemoattractant. Moreover, the antiinflammatory actions of P-gp-secreted endocannabinoids were mediated by peripheral cannabinoid receptor CB2 on neutrophils. Together, the results of this study identify an important mechanism by which endogenous endocannabinoids facilitate the resolution of inflammation; this mechanism has potential to be therapeutically exploited.
Abstract P195: Reproductive History and Subsequent Stroke in Middle-aged African American Women: The Pitt County Study
Authors: DebbieBarrington, ShermanJames
Journal: Circulation (2016)

Introduction: Women with a history of pregnancy loss or delivery of low birth weight (< 2500 grams) and/or preterm (< 37 weeks gestation) (LBW/PTB) infants have an increased subsequent risk for cardiovascular morbidity and mortality. The association between nulliparity and cardiovascular disease has been mixed; some studies reported excess risk among nulliparous women compared to women who had one or two births, while others found decreased risk. Research among African American women is limited regarding whether reproductive history influences risk for cardiovascular disease (e.g., stroke). Hypothesis: We investigated whether a history of pregnancy loss, LBW/PTB delivery and nulliparity increased risk for stroke among middle-aged African American women. Methods: Multiple logistic regression was used to determine the association between LBW/PTB delivery and hypertension among 750 African American female participants (mean baseline age = 35.4 years) in the Pitt County Study, a 13 year (1988-2001) probabilit...
Intracoronary Stenting and Risk for Major Adverse Cardiac Events During the First Month
Authors: HelmutSchühlen, AdnanKastrati, JosefDirschinger, JörgHausleiter, ShpendElezi, AnneWehinger, JürgenPache, MartinHadamitzky, AlbertSchömig
Journal: Circulation (1998)

Background—Our rationale for this study was to analyze the risk for procedural failure of attempted stenting and the risk for major adverse cardiac events (MACE) after success and to develop a risk stratification protocol for successful procedures. Methods and Results—Stenting was attempted in 2894 procedures during the 5-year study period (success in 98.3% of 3815 lesions). After failure, the MACE rate was 42.6%. The risk for failure was higher for lesions in the left circumflex coronary artery or in venous bypass grafts and after an acute occlusion before stenting; it increased with stenosis length or grade and decreased with vessel size and growing institutional experience in stenting. After success, death occurred in 0.8%, death or myocardial infarction in 2.0%, and any MACE in 3.6%. Independent risk factors for MACE were older age, diabetes, acute myocardial infarction, unstable angina, impaired left ventricular function, residual dissections, stent overlap, longer stented segments, and a postprocedu...
Abstract 17197: The Value of Routine Near-patient Haemostasis Testing for Predicting Bleeding After Cardiac Surgery
Authors: Andrew Mumford, Jessica Harris, Zoe Plummer, Veerle Verheyden, Kurtis Lee, Chris Rogers, Barney C Reeves, Gavin J Murphy
Journal: Circulation (2015)

Introduction: Near-patient haemostasis tests assist diagnosis and treatment of blood clotting abnormalities in bleeding patients after cardiac surgery. Aim: To quantify the predictive value of routine near-patient haemostasis tests for coagulopathic bleeding in a large clinical trial. Methods: We performed a prospective cohort study of the patient characteristics and the results of 23 near-patient platelet and viscoelastometry tests in adults undergoing a range of cardiac surgery procedures. The primary outcome was clinical concern about bleeding (CCB), defined as a composite of high blood loss or pro-haemostatic treatment or re-operation for bleeding. A multivariable predictive model for CCB was developed based on the pre-operative characteristics of 1833 patients at a single cardiac centre recruited between March 2010 and August 2012. This model was validated using data for 1611 patients recruited at 16 other UK cardiac surgery centres between July 2009 and February 2013. The additional predictive value of near-patient test results was estimated in the development cohort. Results: CCB occurred in 449 (24.5%) patients in the development cohort. Male sex, absence of diabetes, complex procedure, anti-platelet treatment, short interval since withdrawal of anti-platelet treatment, reduced BMI, reduced pre-operative haematocrit and reduced pre-operative platelet count were independently associated with increased risk of CCB (area under RoC curve (AUR)=0.72 (0.69 to 0.75)). At 75% sensitivity, the specificity of the model was 57%. In the validation cohort, the AUR of the patient characteristics model was 0.63 (0.60 to 0.66). Adding the results of the most predictive near-patient tests performed immediately after surgery improved prediction of CCB in the development cohort (AUR 0.74; 0.72 to 0.77), but at 75% sensitivity this increased the specificity by only 4%. Adding the results of near-patient platelet tests performed before surgery did not further improve prediction of CCB (AUR 0.75; 0.72 to 0.77). Conclusions: Routine near-patient haemostasis tests offer little improvement in the prediction of CCB after cardiac surgery compared to pre-operative patient characteristics alone.
Abstract 1433: Estrogen-related receptor alpha (ERRα) functions to promote prostate cancer cell stemness via its transcriptional regulation of ZIP1 and ACON2 to enhance oxidative phosphorylation
Authors: Taiyang Ma, Zhenyu Xu, Yuliang Wang, Zhu Wang, Weijie Gao, Wenxin You, Leung Franky Chan
Journal: Cancer Research (2018)

Abstract Accumulating evidences suggest that cancer stem-like cells (CSCs) play critical roles in cancer relapse and metastasis, likely due to their strong self-renewal capacity and chemo-radiotherapy resistance. Recent advances also indicate that the energy metabolism status of the CSCs differs greatly from the bulk cancer cells, and that such energy metabolism shift may favor the maintenance of cancer cell stemness. Estrogen-related receptor alpha (ERRα, NR3B1) is a key energy metabolism regulator. In this study, we aim to characterize its role in the energy metabolism regulation in prostate cancer stem-like cells (PCSCs). By analyzing the oxygen consumption and extracellular acidification rates using the Seahorse XF Analyzer, we revealed that the PCSCs, isolated from prostate cancer cell lines (LNCaP, DU145 and PC3) by low attachment 3D-culture, exhibited lower aerobic glycolysis but higher oxidative phosphorylation status. Expression analyses by qPCR and Western blot showed that the isolated PCSCs expressed higher levels of ERRα. Further functional studies showed that overexpression of ERRα could promote the oxidative phosphorylation but lower the glycolysis status, and also enhance the 3-D spheroid formation capacity (stemness) of prostate cancer cells (LNCaP, DU145 and PC3), whereas its knockdown could reverse the effects. Furthermore, we identified by combined chromatin immunoprecipitation (ChIP) and PCR analysis that ERRα could directly regulate two key energy metabolic genes ACON2 (a rate limiting enzyme in TCA cycle) and ZIP1 (a zinc transporter) in PCSCs. Western blot analysis showed that ERRα could up-regulate the ACON2 but repress the ZIP1 expression, whereas its knockdown reverse the expressions of these two proteins in prostate cancer cells. Together, our results show that ERRα can promote the stemness of prostate cancer cells and enhance the cellular energy metabolism towards oxidative phosphorylation in PCSCs via its transcriptional regulation of ACON2 and ZIP1 genes.This study is supported by a General Research Fund from the Research Grants Council of Hong Kong (project code 14107116). Citation Format: Taiyang Ma, Zhenyu Xu, Yuliang Wang, Zhu Wang, Weijie Gao, Wenxin You, Leung Franky Chan. Estrogen-related receptor alpha (ERRα) functions to promote prostate cancer cell stemness via its transcriptional regulation of ZIP1 and ACON2 to enhance oxidative phosphorylation [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 1433.
Abstract 4091: Knockout of genes in the DNA mismatch repair pathway to model colorectal cancer hypermutation
Authors: Abbey Y. Jin, Peter Westcott, Olivia Smith, Amanda Cruz, Mary Clare Beytagh, Tyler Jacks
Journal: Cancer Research (2018)

Abstract Human colorectal cancer (CRC) is characterized by a high burden of somatic mutations, particularly in tumors harboring defects in the DNA mismatch repair (MMR) pathway. However, genetically-engineered mouse models (GEMMs) of cancer to date harbor a very low burden of mutations. Importantly, recent clinical trials have shown that MMR deficient tumors respond favorably to anti-PD-1 immune checkpoint blockade, and it is thought that PD-1 suppression reinvigorates existing T cell clones against neo-antigens associated with hypermutation in these tumors. In order to develop a more clinically relevant GEMM of CRC in which to study the immune response, MMR genes will be knocked out via CRISPR-Cas9 to induce hypermutation. To identify optimal Cas9 single guide RNAs (sgRNAs) against the MMR genes Msh2, Msh3, Msh6, and Mlh1, sgRNAs were designed using the Broad Institute algorithm and knockout efficiency assessed in a reporter cell line by Western blot. In order to induce colon tumors in vivo, colonoscopy-guided submucosal injection was employed to deliver lentivirus encoding sgRNAs against a MMR gene and Apc into mice carrying a constitutive Cas9 allele. Apc is inactivated in over 80% of human CRC, and is an initiating event in CRC in humans and mice. Using a sgMsh2-sgApc dual targeting lentivirus, we were able to efficiently generate colon tumors harboring complete knockout of Apc and near complete knockout of Msh2. Deep sequencing of the targeted loci revealed predominantly loss-of-function frameshift mutations at Apc and Msh2, but also a high degree of polyclonality. Lower titer injections of virus will be explored to induce more clonal tumors. Mlh1, Msh3, and Msh6 will also be targeted in vivo, and the mutational effects of MMR gene loss will be assessed by whole-exome sequencing of tumors. This rapid and flexible GEMM of hypermutant CRC may facilitate a more clinically relevant assessment of the role of the immune system in CRC development, as well as provide improved platforms for testing immunotherapies. Citation Format: Abbey Y. Jin, Peter Westcott, Olivia Smith, Amanda Cruz, Mary Clare Beytagh, Tyler Jacks. Knockout of genes in the DNA mismatch repair pathway to model colorectal cancer hypermutation [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 4091.
Association of IgE-Mediated Allergy With Risk of Complicated Appendicitis in a Pediatric Population
Authors: Martin Salö, Johanna Gudjonsdottir, Erik Omling, Lars Hagander, Pernilla Stenström
Journal: JAMA Pediatrics (2018)

<h3>Importance</h3> Childhood appendicitis is commonly complicated by gangrene and perforation, yet the causes of complicated appendicitis and how to avoid it remain unknown. <h3>Objective</h3> To investigate whether children with IgE-mediated allergy have a lower risk of complicated appendicitis. <h3>Design, Setting, and Participants</h3> This retrospective cohort study included all consecutive patients younger than 15 years (hereinafter referred to as children) who underwent appendectomy for acute appendicitis at a tertiary pediatric surgery center in Sweden between January 1, 2007, through July 31, 2017. Children were stratified between those with and without IgE-mediated allergies. <h3>Main Outcome and Measures</h3> Risk of complicated appendicitis with gangrene or perforation, with occurrence of IgE-mediated allergy as an independent variable and adjusted for age, sex, primary health care contacts, seasonal antigenic exposure, allergy medications, appendicolith, and duration of symptoms. <h3>Results</h3> Of 605 included children (63.0% boys; median age, 10 years; interquartile range, 7-12 years), 102 (16.9%) had IgE-mediated allergy and 503 (83.1%) had no allergy. Complicated appendicitis occurred in 20 children with IgE-mediated allergy (19.6%) compared with 236 with no allergy (46.9%; adjusted odds ratio, 0.33; 95% CI, 0.18-0.59). No significant allergy effect modification by sex, seasonal antigenic exposure, or allergy medication was found. Children with IgE-mediated allergy had a shorter hospital stay (median, 2 days for both groups; interquartile range, 1-2 days vs 1-5 days;<i>P</i> = .004). <h3>Conclusions and Relevance</h3> In this study, children with IgE-mediated allergy had a lower risk of complicated appendicitis. The findings suggest that immunologic disposition modifies the clinical pattern of appendiceal disease. This theory introduces novel opportunities for understanding of the pathogenesis and clinical decision making for one of childhood's most common surgical emergencies.
Microvolt T-Wave Alternans as a Predictor of Ventricular Tachyarrhythmias
Authors: KaoruTanno, SyunshoRyu, NorikazuWatanabe, YoshinoMinoura, MitsuharuKawamura, TakuAsano, YouichiKobayashi, TakashiKatagiri
Journal: Circulation (2004)

Background— Microvolt T-wave alternans (TWA) is reported to be closely associated with sudden cardiac death (SCD) and ventricular tachycardia (VT). Animal experiments revealed that microvolt TWA is highly dependent on heart rate. The purpose of this study was to determine whether patients with TWA at relatively low heart rates have increased vulnerability to ventricular tachyarrhythmias. Methods and Results— Subjects were 248 consecutive patients (158 men, 90 women; mean age, 59±17 years) who underwent electrophysiological study from 1997 to 2000. TWA recording was made in sinus rhythm and at atrial pacing rates of 90, 100, 110, and 120 bpm with the Cambridge Heart CH2000 system. Alternans voltage (Valt) was measured when the alternans ratio was >3 for a period of >1 minute in VM, X, Y, Z, or 2 adjacent precordial leads. Study end point was the first appearance of VT, ventricular fibrillation (VF), appropriate implantable cardioverter-defibrillator therapy with pacing or shocks, or SCD. During the 37±12-m...
Abstract 2184: Enrichment and isolation of tumor cells using a unique flow-sorting approach to decrypt intratumoral heterogeneity in matched samples of squamous cell carcinoma of the lung
Authors: Arthur Krause, Thomas Lorber, Valeria Perrina, Michael T. Barrett, Christian Ruiz, Lukas Bubendorf
Journal: Cancer Research (2018)

Abstract Background: Genomic intratumoral heterogeneity in cancers is a driving force for progression or recurrence. Availability of pure tumor cell material is critical for studying clonal evolution. In general, tumors are highly mixed with benign cells with a mean tumor cell purity of only 49%1 shown in lung squamous cell carcinoma (LSCC). Using a unique flow-sorting based approach enables us to overcome this limitation by highly enriching for tumor cells. Here, we aimed at precisely identifying different tumor populations in primary LSCC and matched distant metastases from 18 patients. Methods: Nuclei from snap-frozen and FFPE tumor specimens were extracted and subjected to flow-sorting using DNA content/ploidy as a parameter. Pan-cytokeratin (pCK) was used to differentiate diploid tumor cell populations from benign diploid stromal cells. DNA has been extracted from these individual tumor cell populations and the mutational profile and copy number status are currently being analyzed using whole exome seqeuencing (WES). Results: We successfully enriched for tumor cells with a purity of higher than 95% using the multi parameter flow-sorting approach. Besides the aneuploid tumors with higher ploidies, we discovered near-diploid tumor populations after enrichment with the pCK antibody. The pCK negative fraction consisting of stromal cells can serve as a germ line control in further downstream analysis as WES. Conclusion: The present study illustrates a unique method that allows high enrichment for tumor cells. Avoiding the dilution of DNA by benign stromal cells, together with the purity of aneuploid tumor cells, the precision of genomic analysis highly increases. At the same time, the diploid and pCK negative stromal cells can serve as a germ line control. Comprehensive genomic profiling of flow-sorted aneuploid and pCK positive diploid tumor populations represent a powerful technique to study intratumoral heterogeneity. References: 1. Zack, T. I. Pan-cancer patterns of somatic copy number alteration. Nature Genetics. 45, 10 (2013). Citation Format: Arthur Krause, Thomas Lorber, Valeria Perrina, Michael T. Barrett, Christian Ruiz, Lukas Bubendorf. Enrichment and isolation of tumor cells using a unique flow-sorting approach to decrypt intratumoral heterogeneity in matched samples of squamous cell carcinoma of the lung [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 2184.