tbuckley/cabot-search huggingface dataset:
Long-Term Cardiovascular Risk of Nonsteroidal Anti-Inflammatory Drug Use According to Time Passed After First-Time Myocardial Infarction
Authors: Anne-Marie Schjerning Olsen, Emil L. Fosbøl, Jesper Lindhardsen, Fredrik Folke, Mette Charlot, Christian Selmer, Jonas Bjerring Olesen, Morten Lamberts, Martin H. Ruwald, Lars Køber, Peter R. Hansen, Christian Torp-Pedersen, Gunnar H. Gislason
Journal: Circulation (2012)

Background— The cardiovascular risk after the first myocardial infarction (MI) declines rapidly during the first year. We analyzed whether the cardiovascular risk associated with using nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with the time elapsed following first-time MI. Methods and Results— We identified patients aged 30 years or older admitted with first-time MI in 1997 to 2009 and subsequent NSAID use by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. We calculated the incidence rates of death and a composite end point of coronary death or nonfatal recurrent MIs associated with NSAID use in 1-year time intervals up to 5 years after inclusion and analyzed risk by using multivariable adjusted time-dependent Cox proportional hazards models. Of the 99 187 patients included, 43 608 (44%) were prescribed NSAIDs after the index MI. There were 36 747 deaths and 28 693 coronary deaths or nonfatal recurrent MIs during the 5 years of follow-up. Relative to noncurrent treatment with NSAIDs, the use of any NSAID in the years following MI was persistently associated with an increased risk of death (hazard ratio 1.59 [95% confidence interval, 1.49–1.69]) after 1 year and hazard ratio 1.63 [95% confidence interval, 1.52–1.74] after 5 years) and coronary death or nonfatal recurrent MI (hazard ratio, 1.30 [95% confidence interval,l 1.22–1.39] and hazard ratio, 1.41 [95% confidence interval, 1.28–1.55]). Conclusions— The use of NSAIDs is associated with persistently increased coronary risk regardless of time elapsed after first-time MI. We advise long-term caution in the use of NSAIDs for patients after MI.
Abstract 4860: A novel class of small-molecule inhibitors of galectin-1 for prostate cancer therapy
Authors: Ruiwu Liu, Tsung-Chieh Shih, Sophie Kiss, Xiaocen Li, Ting Wang, Jonathan S. Huynh, Chun-Te Wu, Yong Duan, Paramita M. Ghosh, Kit S. Lam
Journal: Cancer Research (2018)

Abstract Galectin-1 (Gal-1) is a multifunctional carbohydrate-binding protein and plays a key role in cancer cell proliferation, apoptosis, cell cycle, tumor angiogenesis and evasion of immune responses. It is also directly involved in the process of angiogenesis and tumor immune escape. An elevated level of Gal-1 has been found in many cancers, including prostate cancer. We show by immunohistochemistry in human prostate tissue that Gal-1 expression level was very low in all non-tumor samples and highly expressed in prostate cancer tissues. In addition, Gal-1 was progressively upregulated from low- , intermediate- to high-grade prostate cancer. Taken together, Gal-1 is an excellent therapeutic target against cancer. Yet, no inhibitors against Gal-1 have been approved by the FDA for cancer treatment due to lack of potent, specific and in vivo effective molecules. We recently discovered a novel small-molecule inhibitor of Gal-1, named LLS2, through a high-throughput one-bead two-compound combinatorial library approach. LLS2 exhibits cytotoxic activity against prostate cancer and ovarian cancer cells. We synthesized a series of LLS2 analogs and performed structure-activity relationship studies, leading to a more potent inhibitor LLS30 that induced apoptosis in castration-resistant prostate cancer cells expressing high levels of Gal-1. Molecular modeling study showed LLS30 bound to the sugar-binding groove of Gal-1. In enzalutamide (ENZ)-resistant 22Rv1 prostate cancer cells expressing high levels of Gal-1 and androgen receptor (AR) splice variants, LLS30 could inhibit expression of AR splice variants and sensitize the cells to ENZ in a dose-dependent manner. Downregulation of Gal-1 by siRNA prevented the expression of alternatively spliced AR variants. More importantly, LLS30 showed potent in vivo antitumor efficacy and synergistic activities with docetaxel and ENZ against PC-3 and 22Rv1 prostate cancer models, respectively. Blood chemistry test from the treated animal showed minimum effect of LLS30 on the liver and kidney functions, implying low toxicity. LLS30 is an excellent drug candidate for preclinical development as a novel prostate cancer therapeutic. Citation Format: Ruiwu Liu, Tsung-Chieh Shih, Sophie Kiss, Xiaocen Li, Ting Wang, Jonathan S. Huynh, Chun-Te Wu, Yong Duan, Paramita M. Ghosh, Kit S. Lam. A novel class of small-molecule inhibitors of galectin-1 for prostate cancer therapy [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 4860.
The roles of hypoxia, PTEN, and Rad51 in mediating metastatic prostate cancer cells' responses to PARP inhibitor and topoisomerase 1 inhibitor.
Authors: Jingsong Zhang, Minghui Wu, Xue Wang
Journal: Journal of Clinical Oncology (2012)

e13564 Background: With the recent success of poly (ADP-ribose) polymerase inhibitor (PARPi) in the treatment of BRCA1 or BRCA2 mutated cancers, there is increasing interest to explore synthetic lethality in cancers with defective DNA repair pathways. Rad51 is an essential protein in the homologous recombination repair (HRR) of DNA double strand breaks. Previous studies with non metastatic prostate cancer (mCaP) cells have reported low Rad51 levels in cells with loss of PTEN or under hypoxia, which then led to their sensitivity to PARPi. Given intra tumor hypoxia and loss of PTEN is common in mCaP, we test PAPRi, ABT888 and DNA damaging topoisomerase I inhibitor, CPT11, either alone or in combination in mCaP preclinical models. Methods: mCaP cell lines with functional PTEN (DU145) and loss of PTEN (PC3) were grew under normoxia (21% O2) or hypoxia (0.2% O2). DNA damage, HRR, apoptosis were assessed with comet assay, western blot, immunofluorescence and flowcytometry. The regulation of RAD51 was studied with quantitative RT-PCR and RAD51 promoter reporter assay. PC3 xenograft was used for in vivo study. Results: Despite of its low levels of expression under hypoxia, up regulation of Rad51 was observed soon after treating hypoxic PC3 and Du145 cells with ABT888 or SN38, an active metabolite of CPT11. Such Rad51 up regulation led to less DNA damage and apoptosis under hypoxia compared to normoxia. Inhibiting RAD51 expression with siRNA overcame PC3 and Du145’s resistance to SN38. Furthermore, ABT888 enhanced the activities of SN38 as detected by clonogenic assay and flowcytometry under both normoxia and hypoxia. Consistent with the in vitro data, ABT888 by itself had limited anti-tumor activities despite the loss of PTEN in PC3 xenografts. The anti-tumor activity of single agent CPT11 was significantly improved with the ABT888 and CPT11 combination (P&lt;0.008). Conclusions: neither loss of PTEN nor hypoxia sensitized mCaP cells to PARPi or DNA damaging drugs. Such resistance under hypoxia was at least partly due to up regulation of Rad51. Combining ABT888 with CPT11 overcame the resistance to CPT11 under hypoxia and enhanced its anti-tumor activities both in vitro and in vivo.
A basic insight into aptamer-drug conjugates (ApDCs)
Authors: Wenjing Xuan, Yongbo Peng, Zhengyu Deng, Tianhuan Peng, Hailan Kuai, Yingying Li, Jiaxuan He, Cheng Jin, Yanlan Liu, Ruowen Wang, Weihong Tan
Journal: Biomaterials (2018)
Outcomes of Eyes Lost to Follow-up with Proliferative Diabetic Retinopathy That Received Panretinal Photocoagulation versus Intravitreal Anti–Vascular Endothelial Growth Factor
Authors: Anthony Obeid, Daniel Su, Samir N. Patel, Joshua H. Uhr, Durga Borkar, Xinxiao Gao, Mitchell S. Fineman, Carl D. Regillo, Joseph I. Maguire, Sunir J. Garg, Jason Hsu
Journal: Ophthalmology (2018)
Peripheral Vascular Spasm as a Prodrome of Herpes Zoster
Authors: Leonblumberg, Albertbehrend
Journal: Circulation (1956)

A case of severe vascular spasm involving the major arterial circulation of the lower extremity has been reported. The unusual feature of this case is the fact that the arterial spasm apparently was a prodrome of herpes zoster, the cutaneous manifestations of which appeared 72 hours after the onset of vasospasm. Response of the vasospastic symptoms to non-operative therapy was good; the herpes zoster required roentgen therapy for relief.
A Maximum-Likelihood Approach to Estimating the Insertion Frequencies of Transposable Elements from Population Sequencing Data
Authors: Xiaoqian Jiang, Haixu Tang, Wazim Mohammed Ismail, Michael Lynch
Journal: Molecular Biology and Evolution (2018)

Transposable elements (TEs) contribute to a large fraction of the expansion of many eukaryotic genomes due to the capability of TEs duplicating themselves through transposition. A first step to understanding the roles of TEs in a eukaryotic genome is to characterize the population-wide variation of TE insertions in the species. Here, we present a maximum-likelihood (ML) method for estimating allele frequencies and detecting selection on TE insertions in a diploid population, based on the genotypes at TE insertion sites detected in multiple individuals sampled from the population using paired-end (PE) sequencing reads. Tests of the method on simulated data show that it can accurately estimate the allele frequencies of TE insertions even when the PE sequencing is conducted at a relatively low coverage (=5X). The method can also detect TE insertions under strong selection, and the detection ability increases with sample size in a population, although a substantial fraction of actual TE insertions under selection may be undetected. Application of the ML method to genomic sequencing data collected from a natural Daphnia pulex population shows that, on the one hand, most (>90%) TE insertions present in the reference D. pulex genome are either fixed or nearly fixed (with allele frequencies >0.95); on the other hand, among the nonreference TE insertions (i.e., those detected in some individuals in the population but absent from the reference genome), the majority (>70%) are still at low frequencies (<0.1). Finally, we detected a substantial fraction (∼9%) of nonreference TE insertions under selection.
Abstract 4505: Silencing connexin 43 induces cell cycle entry and invasion in non-neoplastic mammary epithelial cells
Authors: Sabreen F. Fostok, Dana Bazzoun, Sophie A. Lelievre, Mirvat El-Sibai, Rabih S. Talhouk
Journal: Cancer Research (2018)

Abstract Studies demonstrated loss of connexin 43 (Cx43) expression in breast cancer cells in-vitro and in-vivo. Our previous studies have shown that silencing Cx43 in HMT-3522 S1 cells, non-neoplastic human mammary epithelial cells (S1 cells), altered apical polarity and mitotic spindle orientation under 3-dimensional (3-D) culture conditions. The purpose of this study is to investigate the effects of Cx43 loss on proliferation and invasion of non-neoplastic breast epithelium. Cx43 shRNA-transfected and control S1 cells were cultured under 2-D and 3-D conditions. Cx43-knockdown S1 cells exhibited enhanced proliferation both in 2-D and 3-D throughout the culture period, as shown by the increased cell counts and acinar size, respectively. In addition, cell cycle entry was enhanced, as indicated by the increased percentages of cells in S and G2/M phases and the reduced percentage of cells in G0/G1 phase. Cx43-silenced S1 cells upregulated the expression of proliferation genes, c-Myc and cyclin D1, in 2-D and 3-D, but maintained β-catenin levels. Furthermore, immunoprecipitation studies showed that Cx43 associated with β-catenin and ZO-2 in 2-D and 3-D cultures of S1 cells, and co-localized with β-catenin in 3-D, suggesting assembly of gap junction complexes in S1 cells. The loss of Cx43 caused mis-localization of β-catenin in 3-D cultures of S1 cells, suggesting involvement of the Wnt/β-catenin pathway downstream of Cx43 signaling. β-Catenin primarily exhibited apico-lateral distribution in S1 cells and re-localized to basolateral membrane domains in Cx43 knockdown cells. Silencing Cx43 enhanced migration of S1 cells by 40%, as shown by time-lapse imaging. In addition, Cx43-silenced S1 cells exhibited loss of the characteristic spheroid morphology and acquired a migratory phenotype in acini. Matrigel-invasion and MMP-9 activity were also enhanced. Cx43-silenced S1 cells were capable of invading the matrigel by two-fold compared to control cells. This was concomitant with enhanced expression and activity levels of Rho GTPases (RhoA, Rac1 and Cdc42), suggesting that Cx43 regulates non-canonical Wnt signaling, as a mechanism to induce migration and invasion. We propose a role for Cx43 loss in triggering proliferation and invasion events in non-neoplastic breast epithelium downstream of disrupted Wnt signaling. Citation Format: Sabreen F. Fostok, Dana Bazzoun, Sophie A. Lelievre, Mirvat El-Sibai, Rabih S. Talhouk. Silencing connexin 43 induces cell cycle entry and invasion in non-neoplastic mammary epithelial cells [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 4505.
Response to: ‘Role of tubulointerstitial injury in ANCA-associated vasculitis is underestimated’ by Moiseev <i>et al</i>
Authors: Liang Wu, Min Chen
Journal: Annals of the Rheumatic Diseases (2018)

We thank Dr Moiseev et al 1 for their letter about the role of tubulointerstitial injury in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), as a response to our recently published article ‘Urinary epidermal growth factor predicts renal prognosis in antineutrophil cytoplasmic antibody-associated vasculitis’.2 

Histologically, the typical feature in the kidneys of patients with AAV is pauci-immune necrotising crescentic glomerulonephritis with little immunoglobulin and complement deposition in the glomerular capillary walls.3 Theoretically, glomerular injury is the ‘upstream’ in ANCA glomerulonephritis, and tubulointerstitial injury is commonly thought to be the ‘downstream’ of glomerular injury. Therefore, current biomarkers …
Abstract 13609: Prognostic Impact of Pulmonary Vascular Resistances Estimated by Cardiac Magnetic Resonance in Chronic Heart Failure With Reduced Ejection Fraction
Authors: ÓscarFabregat-Andrés, JordiEstornell-Erill, FranciscoRidocci-Soriano, AndresCubillos-Arango, BrunoBochard-Villanueva, PilarGarcía-González, LorenzoFacila, RafaelPayá-Serrano, SalvadorMorell, JulioCortijo
Journal: Circulation (2014)

Introduction: Pulmonary hypertension is an indicator of worse prognosis in chronic heart failure (HF). As reported in recent years, pulmonary vascular resistances (PVR) could be accurately estimated by cardiac magnetic resonance (CMR). Hypothesis: We sought to assess the prognostic utility of noninvasive calculation of PVR in patients with systolic HF. Methods: Prospective registry of patients with left ventricular ejection fraction (LVEF) <40% and admitted for acute decompensated HF from July 2011 to April 2014. Readmission for HF and all-cause mortality were considered as primary endpoint at follow-up. Results: 105 patients (65.7 years, LVEF 26.0%, ischemic 46%) were included. Patients with primary event had higher PVR: 6.93±1.9 vs. 4.67±1.7 Wu [Wood units] (p<0.001). In multivariate Cox regression analysis, PVR ≥5.2 Wu (cutoff point according ROC curve) was independently associated with increased risk of primary event at 10 months follow-up (HR 4.1 [95% CI 1.5-11.2], p=0.007)(see Table). Kaplan-Meier c...
Abstract 821: B7-H3 is a potential antibody drug conjugate target for the treatment of prostate cancer
Authors: Gareth C. Davies, Kelli Ryan, Alison J. Smith, Chris Lloyd, Ravinder Tammali, Noel Monks, Arthur Lewis, Robert W. Wilkinson
Journal: Cancer Research (2018)

Abstract B7-H3 is a member of the B7 family of immune-regulatory ligands and has been reported to be overexpressed in a broad range of human cancers. In order to understand more comprehensively the expression of B7-H3 on both normal tissues and on tumors, we developed an immunohistochemistry (IHC) assay for the detection of human B7-H3. Using this, we confirmed a restricted normal tissue expression pattern and demonstrated expression of B7-H3 in a range of solid tumors. In particular, a high proportion of prostate cancer samples showed strong homogenous B7-H3 expression. This low normal tissue expression and upregulation in cancer makes B7-H3 an attractive target for an antibody drug conjugate (ADC). To evaluate this approach, antibodies to B7-H3 were isolated by screening a phage display library for binding to B7-H3. These antibodies specifically bind to and are internalised by B7-H3 expressing cancer cells. ADCs were generated by site-specific conjugation of either a DNA-damaging pyrrolobenzodiazepine dimer or a microtubule-disrupting tubulysin payload. These ADCs selectively inhibited the growth of B7-H3 expressing cell lines including androgen-insensitive prostate cancer cell lines such as LNCAP-AI in vitro. Furthermore, these ADCs caused durable tumour regression in human tumor xenograft models in vivo. Together, these data suggest that an ADC targeting B7-H3 may have potential to be used for the treatment of a range of solid tumors including prostate cancer. Citation Format: Gareth C. Davies, Kelli Ryan, Alison J. Smith, Chris Lloyd, Ravinder Tammali, Noel Monks, Arthur Lewis, Robert W. Wilkinson. B7-H3 is a potential antibody drug conjugate target for the treatment of prostate 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 821.
Vascular Structural and Functional Changes in Type 2 Diabetes Mellitus
Authors: IanSchofield, RayazMalik, AshleyIzzard, ClareAustin, AnthonyHeagerty
Journal: Circulation (2002)

Background— To further investigate vascular morphology and function in type 2 (non–insulin-dependent) diabetes mellitus (type 2D), small arteries were examined in vitro from carefully defined cohorts of patients with or without concomitant hypertension and the results compared with those from selected normotensive nondiabetic control subjects and a group of untreated patients with essential hypertension (EH). Methods and Results— Blood vessels were studied through the use of pressure myography to determine vascular morphology, mechanics, and myogenic responsiveness, together with testing of constrictor and dilator function. Small arteries from patients with EH demonstrated eutrophic inward remodeling and an increased distensibility. Vessels from type 2D patients demonstrated hypertrophy, a further increase in distensibility, and a highly significant loss of myogenic responsiveness compared with patients with EH and control patients. Vasoconstrictor function to norepinephrine was normal in patients with ty...
Abstract 11383: Reversal of Post-stroke Cerebral Microvascular Dysfunction by Neuroprotective and Hyperdynamic Therapy for Experimental Subarachnoid Hemorrhage
Authors: Tatsushi Mutoh, Kazumasu Sasaki, Tomoko Mutoh, Kazuhiro Nakamura, Yasuyuki Taki, Tatsuya Ishikawa
Journal: Circulation (2016)

Introduction: Early brain injury characterized by microvascular dysfunction in cerebral vessels may play an important role in the development of delayed cerebral ischemia (DCI) or vasospasm after subarachnoid hemorrhage (SAH). However, little is known as to the microcirculatory mechanism(s) to treat post-SAH DCI. Hypothesis: To clarify the utility of neuroprotective and hyperdynamic therapy in relieving cerebral microcirculatory dysfunction affected by vasospasm after experimental SAH. Methods: Male C57BL/6 mice were subjected to SAH by endovascular perforation and minocycline for antibiotic and anti-inflammatory use was started. Closed cranial bone window was then made over the left somatosensory cortex. In vivo real-time imaging was performed using 2-photon laser-scanning microscopy at postoperative day 3 to record alterations on the level of cerebral microvessels and the effects of dobutamine hyperdynamic therapy at clinical dose were evaluated. Comparison was made with a group without minocycline administration. Results: According to the 3-dimentional observation, &gt;50% of pial and penetrating arteries constricted moderately (25-50%) from day 2 to 3 after SAH, which was greater in number in a group without minocycline pretreatment (p&gt;0.05). In areas close to the microvasospasm, blood cell flow as measured by line scan increased by 24% (range, from 7 to 39%) following dobutamine infusion. Reversal of flow stagnation by dobutamine was more prominently observed in animals with minocycline pretreatment in pial and penetrating arteries (1.2 ± 0.5 vs. 1.8 ± 1.0 mm/s, p&lt;0.05). Diameters of the microvessels or location of microthrombi in precapillary arterioles were not affected in any of the groups (p&gt;0.05). Conclusions: The data suggest that early neuroprotection followed by inotropic hemodynamic therapy can improve microcirculation in specific areas affected by microvasospasm, which may in part, explain novel therapeutic targets for the early treatment of DCI after SAH.
Glycoprotein 130 Regulates Cardiac Myocyte Survival in Doxorubicin-Induced Apoptosis Through Phosphatidylinositol 3-Kinase/Akt Phosphorylation and Bcl-xL/Caspase-3 Interaction
Authors: ShinjiNegoro, HidemasaOh, EirohTone, KeitaKunisada, YasushiFujio, KennethWalsh, TadamitsuKishimoto, KeikoYamauchi-Takihara
Journal: Circulation (2001)

Background—We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown. Methods and Results—We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. A...
Relatedness disequilibrium regression estimates heritability without environmental bias
Authors: Alexander I. Young, Michael L. Frigge, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Gyda Bjornsdottir, Patrick Sulem, Gisli Masson, Unnur Thorsteinsdottir, Kari Stefansson, Augustine Kong
Journal: Nature Genetics (2018)
Esophageal High-Resolution Manometry in Gastroesophageal Reflux Disease
Authors: Amit Patel, Shai Posner, C. Prakash Gyawali
Journal: JAMA (2018)

A 22-year-old man with a 10-year history of gastroesophageal reflux disease (GERD)–like symptoms and taking 20 mg/d of omeprazole had a normal esophagogastroduodenoscopy (EGD) and was diagnosed with achalasia following a high-resolution manometry (HRM) study. What would you do next?