tbuckley/cabot-search huggingface dataset:
Abstract 13082: On-Pump Cardiac Surgery in Humans Induces Myocardial Nitric Oxide Synthase Dysfunction via S-Glutathionylation of eNOS
Authors: Raja Jayaram, Nicky Goodfellow, Mei Hua Zhang, Svetlana Reilly, Mark Crabtree, Ravi DeSilva, Rana Sayeed, Barbara Casadei
Journal: Circulation (2014)

Background and Aims: The mechanism responsible for LV dysfunction after cardiac surgery is only partially understood. In isolated rat hearts subjected to a prolonged ischemia-reperfusion protocol, LV dysfunction was associated with uncoupling of endothelial nitric oxide synthase (eNOS) activity secondary to oxidation of the NOS co-factor, tetrahydrobiopterin (BH4). Here we investigated the effect of cardiopulmonary bypass (CPB) and reperfusion on myocardial NOS activity and ROS production in 116 patients who underwent elective cardiac surgery. Results: Paired samples of the right atrial appendages (RAA) were obtained prior to venous cannulation of the right atrium (PRE) and after myocardial reperfusion (POST). Atrial superoxide (O2-) release increased significantly after reperfusion (in RLU/sec/mg: from 37.83 ± 3.71 to 65.02 ± 6.01 in the POST samples; p &lt; 0.001, n = 46 samples from 23 patients) due to uncoupling of NOS activity (D-NAME - L-NAME = ΔO2- in RLU/sec/mg: from - 31.47 ± 9.15 PRE to 40.75 ± 11.84 POST; p &lt; 0.001 in n = 36) and increased mitochondrial and NOX2 oxidase activity (by 309% and 149%, respectively, P&lt;0.001). POST atrial content of BH4 was reduced by 32% (P=0.001), as was the activity of the rate-limiting enzyme in BH4 synthesis, GTP-cyclohydrolase 1 (GTPCH1, by 50%, P&lt;0.001). NOS activity (HPLC detection of 14C L-Arginine to L-Citrulline conversion) decreased significantly after reperfusion (by 60%; p &lt; 0.001) whereas the protein content of NOS isoforms remained unchanged. Surprisingly, the PRE-POST difference in NOS activity was not affected by BH4 supplementation (10 μM) or NOX2 inhibition with the gp-91-ds tat peptide. Instead, we identified increased eNOS s-glutathionylation as the main mechanism responsible for NOS uncoupling after reperfusion. Reversing NOS s-glutathionylation with dithiothreitol (DTT: 100 μM; n=18) completely restored NOS activity after reperfusion (p =0.34). Conclusions: Our findings indicate that NOS s-glutathionylation, rather than BH4 depletion, accounts for NOS dysfunction in patients after cardiac surgery and CPB. Although myocardial NOX2 activity is increased after reperfusion, NOX2 do not appear to be the source of oxidative stress responsible for NOS dysfunction under these conditions.
Prognostic Value of Fasting Versus Nonfasting Low-Density Lipoprotein Cholesterol Levels on Long-Term Mortality
Authors: Bethany Doran, Yu Guo, Jinfeng Xu, Howard Weintraub, Samia Mora, David J. Maron, Sripal Bangalore
Journal: Circulation (2014)

National and international guidelines recommend fasting lipid panel measurement for risk stratification of patients for prevention of cardiovascular events. However, the prognostic value of fasting versus nonfasting low-density lipoprotein cholesterol (LDL-C) is uncertain.Patients enrolled in the National Health and Nutrition Examination Survey III (NHANES-III), a nationally representative cross-sectional survey performed from 1988 to 1994, were stratified on the basis of fasting status (≥8 or <8 hours) and followed for a mean of 14.0 (±0.22) years. Propensity score matching was used to assemble fasting and nonfasting cohorts with similar baseline characteristics. The risk of outcomes as a function of LDL-C and fasting status was assessed with the use of receiver operating characteristic curves and bootstrapping methods. The interaction between fasting status and LDL-C was assessed with Cox proportional hazards modeling. Primary outcome was all-cause mortality. Secondary outcome was cardiovascular mortality. One-to-one matching based on propensity score yielded 4299 pairs of fasting and nonfasting individuals. For the primary outcome, fasting LDL-C yielded prognostic value similar to that for nonfasting LDL-C (C statistic=0.59 [95% confidence interval, 0.57-0.61] versus 0.58 [95% confidence interval, 0.56-0.60]; P=0.73), and LDL-C by fasting status interaction term in the Cox proportional hazards model was not significant (Pinteraction=0.11). Similar results were seen for the secondary outcome (fasting versus nonfasting C statistic=0.62 [95% confidence interval, 0.60-0.66] versus 0.62 [95% confidence interval, 0.60-0.66]; P=0.96; Pinteraction=0.34).Nonfasting LDL-C has prognostic value similar to that of fasting LDL-C. National and international agencies should consider reevaluating the recommendation that patients fast before obtaining a lipid panel.
Effect of Insulin on Acetylcholine-Induced Vasodilation in Normotensive Subjects and Patients With Essential Hypertension
Authors: StefanoTaddei, AgostinoVirdis, PaolaMattei, AndreaNatali, EleFerrannini, AntonioSalvetti
Journal: Circulation (1995)

Background The present study was designed to directly test the vasodilation action of insulin and its relation to endothelium-dependent mechanisms. Methods and Results In 18 normotensive subjects and 27 patients with untreated mild to moderate essential hypertension, we studied the effect of intrabrachial insulin on the changes in forearm blood flow (strain-gauge plethysmography) induced by intrabrachial acetylcholine (at doses of 0.15, 0.45, 1.5, 4.5, and 15 μg · min−1 · dL−1), an endothelium-dependent vasodilator, or sodium nitroprusside (at doses of 1, 2, and 4 μg · min−1 · dL−1), an endothelium-independent vasodilator. Local hyperinsulinemia (deep venous plasma insulin, 48±6 and 51±5 μU/mL in control subjects and hypertensive patients, respectively) did not affect basal forearm blood flow and stimulated forearm glucose extraction (control subjects, 3±1% to 11±2%, P<.001; hypertensive patients, 3±1% to 6±1%, P<.001; P<.01 for the between-group difference). In both normotensive and hypertensive subjects...
Activation of NAD(P)H Oxidase by Tryptophan-Derived 3-Hydroxykynurenine Accelerates Endothelial Apoptosis and Dysfunction In Vivo
Authors: QiongxinWang, MiaoZhang, YeDing, QilongWang, WenchengZhang, PingSong, Ming-HuiZou
Journal: Circulation Research (2014)

Rationale:The kynurenine (Kyn) pathway is the major route for tryptophan (Trp) metabolism in mammals. The Trp–Kyn pathway is reported to regulate several fundamental biological processes, including cell death. Objective:The aim of this study was to elucidate the contributions and molecular mechanism of Trp–Kyn pathway to endothelial cell death. Methods and Results:Endogenous reactive oxygen species, endothelial cell apoptosis, and endothelium-dependent and endothelium-independent vasorelaxation were measured in aortas of wild-type mice or mice deficient for nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase subunits (p47phox or gp91phox) or indoleamine-pyrrole 2,3-dioxygenase 1 with or without angiotensin (Ang) II infusion. As expected, AngII increased plasma levels of Kyn- and 3-hydroxykynurenine–modified proteins in endothelial cells in vivo. Consistent with this, AngII markedly increased the expression of indoleamine-pyrrole 2,3-dioxygenase in parallel with increased expression of interferon...
Abstract 17226: Enhancing the Prediction of 30 Day Readmission after PCI Using Unstructured Data Extracted by Semi-Automated Querying of the Electronic Medical Record
Authors: Jason HWasfy, GauravSingal, CashelO’Brien, Daniel MBlumenthal, Kevin FKennedy, John ASpertus, Robert WYeh
Journal: Circulation (2014)

Background: Models predicting readmission have poor discrimination. We examined if information from the electronic medical record (EMR), abstracted with semi-automated methods, adds incremental predictive information for 30-day readmission after percutaneous coronary intervention (PCI). Methods: We matched readmitted patients to controls 1:2 on a validated readmission risk model, and used a search-assisted chart review to extract data from the EMR, including past need for medical interpretation, albumin level, medical adherence, previous visits to the emergency department, atrial fibrillation and atrial flutter, syncope and presyncope, end-stage liver disease, malignancy, and anxiety. We assessed differences in the rates of these conditions between cases and controls, and estimated their independent association using logistic regression conditioned on matched groups. Results: The 893 cases were matched to 1776 controls. Cases and controls did not differ on predicted risk of readmission (16.3% vs. 16.2%, p...
Abstract 1581: Circulating cell-free DNA for metastatic cervical cancer detection, genotyping and monitoring
Authors: Zhigang Kang, Sanja Stevanović, Christian Hinrichs, Laing Cao
Journal: Cancer Research (2018)

Abstract Purpose: Circulating cell-free (ccf) human papillomavirus (HPV) DNA is a unique tumor marker for metastatic cervical cancers. We developed a method to genotype and quantify circulating HPV DNA in patients with HPV16- or HPV18-positive metastatic cervical cancer for disease monitoring and treatment-related decision making. Patients and Methods: In this retrospective study, HPV ccfDNA was measured in serum samples from metastatic cervical cancer patients by duplex digital droplet (dd) PCR. Nine patients had received tumor-infiltrating lymphocyte (TIL) immunotherapy. ccfDNA data were aligned with the tumor HPV data, drug treatment, and clinical outcome. Results: In blinded tests, HPV ccfDNA was detected in 19/19 (100%) patients with HPV-positive metastatic cervical cancer but not in any of the 45 healthy blood donors. The HPV genotype harbored in the patients' tumors was correctly identified in 87/87 (100%) sequential patient serum samples. In three patients who experienced objective responses after TIL immunotherapy, a transient HPV ccfDNA peak was detected 2-3 days after TIL infusion. Furthermore, a persistent clearance of HPV ccfDNA was observed in only two patients with a complete response (CR) after TIL immunotherapy. Conclusions: HPV ccfDNA represents a promising tumor marker for non-invasive HPV genotyping and may be used in selecting patients for HPV type-specific T-cell-based immunotherapies. It may also have value in detecting the anti-tumor activities of therapeutic agents and in the long-term follow-up of cervical cancer patients in remission. Citation Format: Zhigang Kang, Sanja Stevanović, Christian Hinrichs, Laing Cao. Circulating cell-free DNA for metastatic cervical cancer detection, genotyping and monitoring [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 1581.
Abstract 5634: Eradication of breast carcinoma with bone metastasis by autologous formalin-fixed tumor vaccine (AFTV) combined with radiation and chemotherapy
Authors: Fumito Kuranishi, Yuki Imaoka, Hiroshi Iwako, Yoji Uemae, Takeshi Ishihara, Tsubasa Miyazaki, Tadao Ohno
Journal: Cancer Research (2018)

Abstract No standardized treatment has been established for skeletal metastasis of breast carcinoma which is refractory to intensive chemo-radiation therapy and therefore is assumed impossible to cure. Here we show, however, the 3rd successful case concomitantly treated with the tumor vaccine, AFTV, and chemo-radiation therapy (the 1st and 2nd cases have been presented in AACR2013 and AACR2015, respectively). A 50-year old woman presented 2.5-cm mass of tubular carcinoma in her left breast in a MRI image. The tumor accompanied with no lymph node metastasis was resected in March 2009. We found the tumor was ER(+), PgR(-), and HER2 (-). Four months after the resection, she selected one course of AFTV as the first-line therapy. Response to delayed-type hypersensitivity (DTH) test became strongly positive. We then treated her with the aromatase inhibitor, anastrozole. Six years later, in March 2015, a PET image revealed bone-metastasis to sternum which was confirmed by needle-biopsy and ABC immunostaining as class V metastatic ductal carcinoma. We treated her again with second course of AFTV and palliative radiation therapy (36Gy/12fractions/19days) together with letrozole, bisphosphonate, additional 2 shots of nivolmab (40mg/48kg body) in October and November 2015. She was diagnosed to be complete response by PET imaging in February 2016, August 2016, and August 2017. Alteration of her blood CEA level suggests that the combined treatments eradicated the metastatic breast carcinoma. In conclusion, the present case suggests that AFTV in combination with palliative X-ray irradiation and adjuvant aromatase inhibitors eradicates skeletal metastasis of breast carcinoma with enhancement of a specific anti-tumor immune reactivity. Citation Format: Fumito Kuranishi, Yuki Imaoka, Hiroshi Iwako, Yoji Uemae, Takeshi Ishihara, Tsubasa Miyazaki, Tadao Ohno. Eradication of breast carcinoma with bone metastasis by autologous formalin-fixed tumor vaccine (AFTV) combined with radiation and chemotherapy [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 5634.
Prospective Randomized Study to Assess the Efficacy of Site and Rate of Atrial Pacing on Long-Term Progression of Atrial Fibrillation in Sick Sinus Syndrome
Authors: Chu-PakLau, NgarmukosTachapong, Chun-ChiehWang, Jing-fengWang, HaruhikoAbe, Chi-WoonKong, ReginaldLiew, Dong-GuShin, LuigiPadeletti, You-HoKim, RazaliOmar, KreingkraiJirarojanakorn, Yoon-NyunKim, Mien-ChengChen, CharnSriratanasathavorn, MuhammadMunawar, RuthKam, Jan-YowChen, Yong-KeunCho, Yi-GangLi, Shu-LinWu, ChristopheBailleul, Hung-FatTse
Journal: Circulation (2013)

Background—Atrial-based pacing is associated with lower risk of atrial fibrillation (AF) in sick sinus syndrome compared with ventricular pacing; nevertheless, the impact of site and rate of atrial pacing on progression of AF remains unclear. We evaluated whether long-term atrial pacing at the right atrial (RA) appendage versus the low RA septum with (ON) or without (OFF) a continuous atrial overdrive pacing algorithm can prevent the development of persistent AF. Methods and Results—We randomized 385 patients with paroxysmal AF and sick sinus syndrome in whom a pacemaker was indicated to pacing at RA appendage ON (n=98), RA appendage OFF (n=99), RA septum ON (n=92), or RA septum OFF (n=96). The primary outcome was the occurrence of persistent AF (AF documented at least 7 days apart or need for cardioversion). Demographic data were homogeneous across both pacing site (RA appendage/RA septum) and atrial overdrive pacing (ON/OFF). After a mean follow-up of 3.1 years, persistent AF occurred in 99 patients (25...
Abstract 1527: Splicing factors determine breast cancer cell mitosis through control of sister chromatid cohesion
Authors: Esmee Koedoot, John Martens, Sylvia E. Le Dévédec, Bob van de Water
Journal: Cancer Research (2018)

Abstract Breast cancer is the mostly diagnosed cancer in women worldwide and is also the leading cause of death from cancer in women, mainly due to metastasis formation. Accumulating evidence suggests that RNA splicing is critical in breast cancer progression. To investigate the role of every single component of the splicing machinery (the spliceosome) in this process, we systematically evaluated the effect of siRNA-mediated knockdown of 244 splicing factors on proliferation in two highly proliferative breast cancer cell lines MDA-MB-231 and Hs578T. Hits of the primary screen were validated with single siRNAs and separated based on their effects on migration and proliferation respectively. Knockdown of nine validated proliferation hits, amongst which was SF3B1, a known breast cancer driver gene, resulted for all nine hits in a distinct poly-lobed nuclear phenotype in both cell types, accompanied by increased DNA content and higher number of cells in G1-S transition. Increased levels of phospho-Histone H3 and lack of metaphase alignment suggested a defect in mitosis, which was confirmed by decreased RNA expression of sister chromatid cohesion factors MAU2, ESPL1 and SMC1A and interestingly, increased CDCA5 RNA levels. Upon splicing factor knockdown, CDCA5 intron 1 was retained resulting in decreased CDCA5 protein levels, inaccurate metaphase alignment and finally cell death. To identify the direct partners of the splicing factors that control mitosis, we coupled pull-down of GFP fused splicing factors with mass spectrometry. Seven out of the nine splicing factors that were identified in our screen causing poly-lobed nuclear phenotypes, resided in the same protein complex together with proteins involved in snRNP assembly and some mitosis-related factors. In conclusion, we have identified several splicing factors that are critically determining breast cancer cell proliferation through modulating the expression of chromatid cohesion factors and thereby mediating the successful metaphase alignment and ultimate mitosis. Citation Format: Esmee Koedoot, John Martens, Sylvia E. Le Dévédec, Bob van de Water. Splicing factors determine breast cancer cell mitosis through control of sister chromatid cohesion [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 1527.
Abstract 104: Intra-arrest Mild Hypothermia Following Delayed CPR Did Not Improve Survival in Asphyxial Cardiac Arrest Model in Rats
Authors: JieLiu, MengChen, YueWang, FeiHan
Journal: Circulation (2014)

Introduction: Ischemia/reperfusion injury induced cellular damage and organ dysfunction after prolonged cardiac arrest. Ischemia introduced a susceptibility to damage that may worsen by reperfusion with normal blood. Intra arrest cooling was shown significant benefit by many reports. Hypothesis: We sought to find whether cooling first with delayed CPR by cold blood reperfusion improve survival compared to immediate conventional CPR by warm blood reperfusion and then cooling after ROSC in asphyxial cardiac arrest model in rats. Methods: Thirty-eight male Wistar rats (260 ~ 310 g) were included in the experiment. Cardiac arrest was induced by 8 minutes asphyxia. Rats were divided into 3 groups: (1) normothermia group (N group, n = 12), rectal temperature maintained at 37 ± 0.5°C during cardiac arrest, CPR, and post-ROSC ventilation periods; (2) intra-arrest hypothermia group (I group, n = 12), after 8 minutes of asphyxia, rats were cooled to 33°C in 3 minutes, and then CPR, rectal temperature maintained at ...
Abstract 995: Tumor-stroma IL-1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemo-resistance and is associated with poor prognosis in pancreatic cancer
Authors: Daoxiang Zhang, Lin Li, Hongmei Jiang, Andrea Wang-Gillam, Jinsheng Yu, Richard Head, Jingxia Liu, Marianna B Ruzinova, Kian-Huat Lim
Journal: Cancer Research (2018)

Abstract Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but so far success remains limited in the clinic. Furthermore, preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAFs) carries a risk of accelerating PDAC progression. These concerns underscore the need to concurrently target the key signaling mechanisms that drive the malignant attributes of both CAFs and PDAC cells. We previously reported that inhibition of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) suppresses NF-kB activity and promotes chemotherapy response in PDAC cells. In this study, we show that CAFs in PDAC tumors robustly express activated IRAK4 and NF-kb. The role of IRAK4 and NF-kB in PDAC CAFs has not been reported, and should be clarified before advancing IRAK4 inhibitors to the clinic. Using shRNAs and small molecular inhibitors, we found that IRAK4 is a key driver of NF-kB activity in CAFs. We showed that CAFs utilizes IRAK4 to drive tumor fibrosis, support PDAC cells proliferation, survival and chemo-resistance in vitro and in vivo. From cytokine array analysis of CAFs and microarray analysis of PDAC cells, we identified IL-1b as a key cytokine that activates IRAK4 in CAFs. Targeting IRAK4 or IL-1b renders PDAC tumors less fibrotic and more sensitive to gemcitabine in vivo.Moreover, high IL-1b expression by immunohistochemistry in PDAC samples is strongly associated with poor overall survival. Together, our studies established a tumor-stroma IL-1b-IRAK4 feedforward circuitry that can be therapeutically disrupted to render chemotherapy more effective in PDAC. Citation Format: Daoxiang Zhang, Lin Li, Hongmei Jiang, Andrea Wang-Gillam, Jinsheng Yu, Richard Head, Jingxia Liu, Marianna B Ruzinova, Kian-Huat Lim. Tumor-stroma IL-1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemo-resistance and is associated with poor prognosis in pancreatic 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 995.
Abstract 1770: Morab-202, a folate receptor alpha-targeted antibody-drug conjugate, shows a highly potent activity against a panel of FRA-expressing tumors
Authors: Caroline Mignard, Coralie DURIX, Katherine Rybinski, Xin Cheng, Keiji Furuuchi, Earl Albone, Toshimitsu Uenaka, Marc Hillairet de Boisferon
Journal: Cancer Research (2018)

Abstract Folate receptor alpha (FRA) is a membrane protein with high affinity for binding and transporting folate into cells. Overexpression of FRA may confer a growth advantage to tumors by increasing folate uptake and affecting cell proliferation via alternative cell signaling pathways (1). FRA levels have been found to be elevated in tumors of epithelial origin compared to normal tissue as cancers of the breast (including TNBC (2)), colon, lungs and ovary (3). In this study, we report the development of MORAb-202, an anti-FRA antibody-drug conjugate (ADC), consisting of a FRA-binding antibody (MORAb-003, farletuzumab) with a cathepsin-cleavable form of eribulin (eribulin mesylate, marketed as Halaven®), a highly potent anti-mitotic agent that induces cell-cycle arrest and cell death by targeting microtubules. We first study expression of FRA on a large panel of tumors patient-derived xenograft (PDX) and Cancer Cell Line-derived Xenograft (CDX). Then, we performed in vitro and in vivo anti-proliferation assays and compare antitumor activity of MORAb-202 with free eribulin accordingly to the FRA expression level. FRA expression was found to be determinant in the sensitivity of tumor cells to the cytotoxic effect of the ADC. Moreover, in case of high expression of FRA, MORAb-202 showed a higher antitumor activity compared with free eribulin. These results suggest that FRA expression could be used as a response-predictive biomarker for this targeted therapy. The ability to identify and treat patients with an effective therapy based on the known expression of the tumor marker is a key point in predictive medicine progress. These findings support the clinical development of MORAb-202 ADC as a novel targeted therapy for patients with FRA-expressing tumors. The ADC described in this abstract is investigational, as efficacy and safety have not been established. There is no guarantee that this ADC will be available commercially. 1-Siu MK et al., PLoS One. 2012;7(11) 2-Nacela BM. et al., PLoS One. 2015, 10(3) 3-Cheung A. et al., Oncotarget. 2016 7(32), 52553-52574 4-Arrowsmith J. &amp; Miller P. 2011-2012. Nat. Rev. Drug Discov. 12, 569 (2013). 5-Paul S.M. et al. Nat. Rev. Drug Discov. 9, 203-214 (2010). 6-Hidalgo, M. et al. Cancer Discov. 4, 998-1013 (2014). Citation Format: Caroline Mignard, Coralie DURIX, Katherine Rybinski, Xin Cheng, Keiji Furuuchi, Earl Albone, Toshimitsu Uenaka, Marc Hillairet de Boisferon. Morab-202, a folate receptor alpha-targeted antibody-drug conjugate, shows a highly potent activity against a panel of FRA-expressing 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 1770.