tbuckley/cabot-search huggingface dataset:
Abstract 620: Platelet CD40L: a Powerful Leukocyte and Endothelial Cell Activator in Atherosclerosis
Authors: Dirk Lievens, Alma Zernecke, Imke Munnix, Linda Beckers, Erwin Wijnands, Randy J Noelle, Johan W Heemskerk, Christian Weber, Mat J Daemen, Esther Lutgens
Journal: Circulation (2007)

Here we investigated whether platelet CD40L plays a role in atherosclerosis. Platelets were obtained from donor ApoE−/− or CD40L−/− ApoE−/− mice, activated with thrombin, neutralized by hirudin and injected intravenously into n=30 ApoE−/− recipients (3E10 7 platelets) every 5 days. Infusion of activated CD40L−/− platelets in ApoE−/− mice from age 5–17wks caused a decrease in atherosclerosis (predominantly early lesions) in the aortic arch and its major branch points (ApoE−/− platelets 2.01E10 5 ± 3.74E10 4 μm 2 vs CD40L−/−ApoE−/− platelets 1.01E10 5 ± 1.57E10 4 μm 2 ; p&lt;0.05) to levels that were comparable to the sham (NaCl) group (1.17E10 5 ± 1.61E10 4 μm 2 ). To induce advanced atherosclerosis, a silastic non-constrictive collar was placed around both carotid arteries in diet fed mice, and activated platelets were injected every 5 days during 5 wks. Infusion of activated CD40L−/−ApoE−/− platelets caused a 35.4% decrease in plaque volume (ApoE−/− platelets 2.08E10 8 ± 2.55E10 7 μm 3 vs CD40L−/−ApoE−/− platelets 1.36E10 8 ± 3.45E10 7 μm 3 , Sham 1.17E10 8 ± 2.71E10 7 μm 3 p&lt;0.05), indicating an important role for activated platelet CD40L in both early and advanced atherosclerosis. Laminar flow assays showed that activated CD40L−/−ApoE−/− platelets lose their capacity of binding CD40L+/+ApoE−/− leukocytes, especially monocytes, with 30.1% compared to activated ApoE−/− platelets. Moreover, FACS analysis (CD45, CD11b,CD41) showed that activated ApoE−/−platelets bind 24.8% less to CD40−/−ApoE−/− leukocytes, and activated CD40L−/−ApoE−/−platelets bind 40.0% less to CD40−/−ApoE−/− leukocytes, thereby pointing out leukocyte CD40 as the receptor of platelet CD40L. Intravital microscopy in carotid arteries of mice, injected with activated CD40L−/− platelets, showed a 3-fold decrease in leukocyte adhesion. Even more, deficiency of CD40L on platelets causes a 58.4% decrease in thrombus formation compared to wild type. We demonstrate that CD40L on activated platelets plays an important role in atherosclerosis by promoting platelet aggregation, the formation of platelet-leukocyte aggregates, and leukocyte-endothelial interactions. This shows that platelet CD40L has a bridging function between the leukocyte and the endothelium.
Abstract 364: Ottawa Heart Genomic Study: Discovery Of Novel Genes For Coronary Artery Disease By Genome-wide Association Utilizing The 500k SNP Array
Authors: Alexandre F Stewart, Ruth McPherson, Kathryn Williams, Nihan Kavaslar, Julie Rutberg, Heather Doelle, Gwen Ewart, George Wells, Robert Roberts
Journal: Circulation (2007)

Purpose: To identify genes predisposing to Coronary Artery Disease (CAD). Methods: We selected the unbiased approach of using the genome wide scan association case control method. Using the Affymetrix 500K SNP array that that average a marker every 6,000 base pairs, we estimated that to detect a Minor Allele Frequency (MAF) of ≥ 10%, an odds ratio for risk of &gt; 1.3 with 90% power would require 14,000 subjects (9,000 cases and 5,000 controls). Phase I consists of genotyping of 1,000 cases of early onset CAD and 1,000 asymptomatic older controls. Phase II will determine whether SNPs showing an association in Phase 1 are replicated in 8,000 cases and 4,000 controls. The phenotype is confirmed or excluded by coronary arteriograms obtained by catheterization or multi-slice CT. Cases with diabetes mellitus are excluded. Results: Initiated in 2005, over one billion genotypes have been performed and analyzed for 1,054 controls and 997 cases completing Phase I. Starting with data on 500,668 SNPs, control genotypes that were monoallelelic (21,668 SNPs) or not in Hardy Weinberg equilibrium were excluded using a false discovery rate (FDR) Q value &lt;0.001 (1,473 SNPs). Individual SNPs with call rates &lt;95% (30,826 SNPs) in cases and controls were excluded, leaving 446,701 SNPs. Fisher’s exact test was used to compare genotypes between cases and controls (FDR Q value &lt;0.05), identifying 2,819 significant SNPs. SNPs with a MAF &lt; 0.01 in both cases and controls (598 SNPs) were removed leaving 2,221 significant SNPs. 14 SNPs in exons were non-synonymous, i.e. cause amino acid substitutions. 53 clusters of SNPs (defined as ≥3 SNPs) within genes and 45 between genes were identified, including one at 9p21.3 that was replicated in multiple independent populations (McPherson et al., Science Express 2007 - in press). In addition, 13 SNPs were identified on the X chromosome. There was no evidence of stratification in our population. SNPs showing significant association with CAD are being assessed in an independent population during Phase II. Conclusions: This is the first genome wide scan for CAD genes utilizing 500,668 markers. Phase I has identified many genes not previously known to be associated with CAD.
Abstract 2891: Bench-to-bedside development of a novel idiotype vaccine against lymphoma
Authors: Hong Qin, Soungchul Cha, Sheetal S. Rao, Kunhwa Kim, Dongho Gwak, Sung-doo Kim, Sapna R. Parshottam, Sheeba K. Thomas, Larry W. Kwak
Journal: Cancer Research (2014)

Abstract Available therapies for lymphoplasmacytic lymphoma (LPL) provide no survival advantage if started before symptoms of end organ damage develop. Current recommendations are to follow a program of observation while patients are in the asymptomatic phase of disease. In this clinical study we will use idiotypic determinants of B-cell lymphoma surface immunoglobulins as tumor-specific antigens (idiotype) to develop a patient-specific vaccine against LPL. By activating the host immune system through vaccination to eradicate tumor cells, we postulate that disease control of asymptomatic phase lymphoplasmacytic lymphoma can be maintained. This novel 2nd generation idiotype vaccine was initially developed by genetic fusion of idiotype antigen in single-chain format with a pro-inflammatory chemokine. The central hypothesis is that antitumor immunity can be triggered by targeting antigen delivery to antigen-presenting cells in vivo by chemokine receptor-mediated binding, uptake and processing of idiotype antigens for more efficient presentation to T cells. A large body of preclinical data demonstrated that the immunogenecity of the idiotype antigen was considerably enhanced by such a genetic modification by a mechanism of facilitating antigen presentation. As a consequence, vaccine-induced prophylactic and therapeutic antitumor effects were significantly potentiated. To translate our vaccine therapy from bench to bedside, we established a CLP laboratory for vaccine preparation. Furthermore, we developed reliable technology to differentiate lymphoma idiotype antigens from idiotypic cell-surface immunoglobulins on normal B cells. Using this technology, we successfully cloned the cDNA encoding variable regions of heavy and light chains of LPL idiotype, and generated patient-specific plasmid constructs containing LPL idiotype single chain in fusion with macrophage inflammatory protein 3 alpha (MIP3a). All three engineering rounds of down-stream GMP amplification of clinical-grade plasmid DNA have been accomplished, which eventually paves the way for us to take a lab-grown agent to a first-in-human clinical trial. Citation Format: Hong Qin, Soungchul Cha, Sheetal S. Rao, Kunhwa Kim, Dongho Gwak, Sung-doo Kim, Sapna R. Parshottam, Sheeba K. Thomas, Larry W. Kwak. Bench-to-bedside development of a novel idiotype vaccine against lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2891. doi:10.1158/1538-7445.AM2014-2891
Hemolytic uremic syndrome in Belgium: incidence and association with verocytotoxin-producing Eschevichia coli infection
Authors: Denis Piérard, Guy Cornu, Willem Proesmans, Anne Dediste, Frédérique Jacobs, Johan Van de Walke, An Mertens, José Ramet, Sabine Lauwers
Journal: Clinical Microbiology and Infection (1999)
Inhibition of wild‐type p53‐induced phosphatase 1 promotes liver regeneration in mice by direct activation of mammalian target of rapamycin
Authors: Lingling Zhang, Leiming Liu, Zhiyong He, Guangbing Li, Junping Liu, Zhangfa Song, Hongchuan Jin, Karl Lenhard Rudolph, Huayu Yang, Yilei Mao, Lianfeng Zhang, Hongbing Zhang, Zhicheng Xiao, Zhenyu Ju
Journal: Hepatology (2015)

The liver possesses extraordinary regenerative capacity in response to injury. However, liver regeneration (LR) is often impaired in disease conditions. Wild-type p53-induced phosphatase 1 (Wip1) is known as a tumor promoter and enhances cell proliferation, mainly by deactivating antioncogenes. However, in this work, we identified an unexpected role of Wip1 in LR. In contrast to its known role in promoting cell proliferation in extrahepatic tissue, we found that Wip1 suppressed hepatocyte proliferation after partial hepatectomy (PHx). Deletion of Wip1 increased the rate of LR after PHx. Enhanced LR in Wip1-deficient mice was a result of the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway. Furthermore, we showed that Wip1 physically interacted with and dephosphorylated mTOR. Interestingly, inhibition of Wip1 also activated the p53 pathway during LR. Disruption of the p53 pathway further enhanced LR in Wip1-deficient mice. Therefore, inhibition of Wip1 has a dual role in LR, i.e., promoting hepatocyte proliferation through activation of the mTORC1 pathway, meanwhile suppressing LR through activation of the p53 pathway. However, the proregenerative role of mTORC1 overwhelms the antiproliferative role of p53. Furthermore, CCT007093, a Wip1 inhibitor, enhanced LR and increased the survival rate of mice after major hepatectomy.mTOR is a new direct target of Wip1. Wip1 inhibition can activate the mTORC1 pathway and enhance hepatocyte proliferation after hepatectomy. These findings have clinical applications in cases where LR is critical, including acute liver failure, cirrhosis, or small-for-size liver transplantations.
Associations between severity of airflow obstruction and atherosclerosis: A cross-sectional study in Japan
Authors: Hisamitsu Omori, Masako Oda, Ayumi Onoue, Noritaka Higashi, Yasuhiro Ogata, Takahiko Katoh
Journal: European Respiratory Journal (2014)

Objectives:  Limited data exist on an association between COPD and atherosclerosis in Japan. Therefore, we examined associations between severity of airflow obstruction and markers of cardiovascular disease (arterial stiffness, coronary artery calcification (CAC), thoracic aortic calcification (TAC)).   Methods:  This study included 775 subjects (mean age 61.4, SD 12.0 years) , who underwent a comprehensive health screening containing spirometry, brachial-ankle pulse wave velocity (baPWV), thoracic low-dose computed tomography (CT) and blood sampling at a medical check-up in 2009 at Japanese Red Cross Kumamoto Health Care Center. Severity of airflow obstruction (AO) was defined according to GOLD criteria. Arterial stiffness was assessed by measurement of baPWV. Presence of CAC and TAC were assessed by CT.   Results:  Mean (SD) baPWV was significantly greater in subjects with moderate and severe AO (n=66), 1778.4 (465.9) cm/sec, than in subjects with a normal lung function (n=661), 1562.0 (321.6) cm/sec, p 1400cm/sec) (OR, 3.37; 95%CI, 1.59-7.17, p=0.002) and the presence of CAC (OR, 1.94; 95%CI, 1.14-3.31, p=0.015) were significantly associated with subjects with moderate and severe AO compared with subjects with a normal lung function. The presence of TAC was not significantly associated with AO.   Conclusions:  Our study suggested associations between severity of airflow obstruction and atherosclerosis.
Lack of survival benefit in metastatic breast cancer with newer chemotherapy agents: The City of Hope experience
Authors: S. K. Pal, R. Gupta, G. Somlo, A. Hurria, C. T. Chung, T. H. Luu, L. Bernstein, J. Mortimer
Journal: Journal of Clinical Oncology (2008)

17510 Background: Since the approval of paclitaxel in 1994, a number of new chemotherapeutics with activity in metastatic breast cancer (MBC) have become available, yet limited data exist to support a trend towards improved survival with these new agents. Methods: We undertook a retrospective chart review of women with MBC diagnosed between 1985 and 2005 and compared overall survival for two time periods (1985–1994 and 1995–2005). We used survival data for patients with metastatic colorectal cancer (mCRC) treated during the same time intervals as our control. Female patients with MBC and mCRC patients were identified from the City of Hope (COH) Cancer Registry. Tumor characteristics and type and number of chemotherapeutic agents utilized were abstracted. Overall survival (OS) was calculated from the date of diagnosis of MBC to the date of death or last follow-up. Results: A total of 385 cases of MBC were identified with a median overall survival (MS) of 2.4 yrs in 199 cases diagnosed between 1985–1994 and 3.1 yrs in 159 cases diagnosed between 1995–2005 (HR 1.14, 95% CI 0.87–1.50; P=0.26). A trend towards improved survival in women with hormone receptor positive disease was observed; however, no difference in survival was observed between the two time intervals assessed (see table). In the control group, 638 patients with mCRC were identified; MS in 212 patients diagnosed from 1985–1994 and in 426 patients diagnosed from 1995–2005 was 1.2 yrs and 2.0 yrs, respectively (HR 1.69, 95%CI 1.33–195, P<0.0001). Conclusions: In colorectal cancer, the addition of new agents has resulted in an improvement in overall survival. However, despite the addition of a number of new and effective chemotherapeutic agents, a similar improvement in the overall survival for women with MBC was not seen. Survival data for COH registry patients diagnosed with MBC or mCRC between 1985 and 2005. Dx between 1985–1994 (MS in yrs) Dx between 1995–2005 (MS in yrs) Hazard Ratio (95% CI) P value All MBC patients 2.4 3.1 1.14 (0.85-1.50) 0.26 MBC by hormonal status ER(+)/PR(+) 3.7 3.8 0.97 (0.36-1.58) 0.59 ER(+)/PR(−) 2.5 3.6 1.11 (0.22-2.58) 0.83 ER(−)/PR(+) 1.5 1.1 0.72 (0.07-7.35) 0.78 ER(−)/PR(−) 1.9 2.1 1.05 (0.57-1.93) 0.87 All mCRC patients 1.2 2.0 1.69 (1.33-1.95) <0.0001 No significant financial relationships to disclose.
Abstract 11287: Translation of an Anti-Inflammatory Nanomedical Treatment for Atherosclerosis: First Randomized Clinical Trial in Patients With Cardiovascular Disease
Authors: Fleur van der Valk, Diederik van Wijk, Mark Lobatto, Dominik Schulte, Hein Verberne, Gert Storm, Martine Willems, Maarten Van der Laan, Dink Legemate, Claudia Calcagno, Maarten Otten, Maarten Paridaans, Venkatesh Mani, Sarayu Ramachandran, Geesje Dallinga-Thie, Aart Nederveen, Max Nieuwdorp, Zahi Fayad, Willem Mulder, Josbert Metselaar, Erik Stroes
Journal: Circulation (2013)

Introduction: Anti-inflammatory therapeutics for atherosclerosis are lacking predominantly due to fear of immunosuppressive side effects. Nanomedicine holds promise to overcome this hurdle, via selectively targeting atherosclerosis. Here we present a program aimed at translating a nanomedicine-based strategy for cardiovascular patients. Methods: preclinical: Pharmacokinetics and safety of PEGylated liposomal nanoparticle containing prednisolone (LN-PLP) was assessed in rats and rabbits. Efficacy of LN-PLP was evaluated in atherosclerosis rabbit model using dynamic contrast enhanced MRI (DCE-MRI) and positron emission tomography (PET) as readout for arterial wall permeability and inflammation. clinical: Local delivery was evaluated by infusing patients with LN-PLP (3mg/kg) 7 and 3 days prior to vascular surgery (n=7). Double staining for CD68 (macrophage) and PEG (LN-PLP) was performed on macrophages isolated from excised plaque tissue. In a randomized controlled trial, efficacy was evaluated by infusing L...
A Novel Chromosomal Translocation Associated With<i>COL1A2</i>-<i>PDGFB</i>Gene Fusion in Dermatofibrosarcoma Protuberans
Authors: Ikumi Nakamura, Yoshiyuki Kariya, Etsuko Okada, Masahito Yasuda, Shigetaka Matori, Osamu Ishikawa, Hiroshi Uezato, Kenzo Takahashi
Journal: JAMA Dermatology (2015)

Dermatofibrosarcoma protuberans (DFSP) is a rare skin cancer that develops in the deep dermis to subcutaneous adipose tissues. A COL1A1-PDGFB gene fusion, leading to the constitutive expression of PDGFB, is the tumorigenic mechanism in most DFSP cases.To evaluate the specificity of PDGFB expression as a diagnostic marker of DFSP and to determine whether other pathomechanisms (ie, gene fusions) exist in patients with DFSP without the COL1A1-PDGFB fusion gene.All patients with DFSP registered in the pathologic database of the University of the Ryukyus from January 1, 1997, through December 31, 2013, and Gunma University from January 1, 1996, through December 31, 2011, were included in this analysis. Samples were obtained from 30 patients presenting with DFSP tumors. We examined the clinicopathologic characteristics and the expression of PDGFB, PDGFRβ, PDGFRα, CD34, nestin, factor XIIIa, fibronectin, α-smooth muscle actin, S-100 protein, and Ki-67 in 30 DFSP cases and 48 non-DFSP mesenchymal tumor cases by immunohistochemical analysis. We then analyzed tumor tissues for the presence of the COL1A1-PDGFB fusion gene. We also tested whether other genes enriched in fibroblasts formed fusion products with PDGFB by reverse transcription-polymerase chain reaction analysis, using gene-specific primers.We aimed to analyze tumor tissues for the presence of the COL1A1-PDGFB fusion gene to investigate expression of PDGFB in DFSP tumors.PDGFB expression was detected in 28 (93%) of 30 patients with DFSP. PDGFB was not homogenously expressed in DFSP tumor cells, whereas CD34 and nestin were often expressed throughout the tumor mass. In 1 DFSP tumor, the COL1A1-PDGFB fusion gene was not detected even though PDGFB was expressed. We identified a novel COL1A2-PDGFB fusion gene in this tumor.Our findings indicate that PDGFB protein is expressed in most DFSP tumors and may be a useful diagnostic tool when used in conjunction with CD34 and nestin expression analysis. These PDGFB expression data, in addition to our discovery of a novel PDGF fusion gene, strongly support the concept that DFSP is a PDGFB-dependent tumor type.
The effects of smoking on asthmatic children - how can we study this in indoor air quality
Authors: David Bilocca, Christopher Zammit, Chloe Bugeja Fassert, Michael Pace Bardon, Marilyn Rogers, Liberato Camilleri, Stephania Chetcuti Zammit, Martin Balzan, Stephen Montefort
Journal: European Respiratory Journal (2014)

Introduction : The Respira study involved standard respiratory questionnaires, environmental monitoring of homes and clinical exam of cases and controls aged between 11 and 14 years.   Aims and Objectives : To compare the different effects of smoking in asthmatic children (n=65) and controls (n=59) in various phases of their life, and to attempt to identify the presence of smoking related elements in particulate matter (PM2.5) sampled in 45 homes.   Materials and Methods : Parents were given questionnaires and a subgroup of homes were chosen to have indoor air sampling of PM2.5 and this was analysed for various elements.   Results : Children with asthmatic symptoms had greater exposure to daily smoking (n=15/65) than controls (n=5/59) (p=0.0271) and in the first year of life (p=0.00596). There was no statistical significance for smoking during pregnancy (p=0.961), exposure to second hand smoke during pregnancy (p=0.138) or breastfeeding.  The relationship of Cadmium and Thallium levels in PM2.5 was compared to symptoms and the smoking habits. There were marginal differences in cadmium and thallium levels between the asthma (mean 0.439 ng/m 3 ) and control (mean 0.268ng/m 3 ) groups (p=0.254). There was no significant difference in cadmium and thallium levels in homes where there was smoking on a daily basis when compared to smoke-free houses (p=0.254).   Conclusion : Children with asthma had a greater exposure to smoking both in their early years of life and presently. There is no correlation between cadmium and thallium levels in PM2.5 and smoking habits, and therefore there must be other sources for these two elements in PM2.5 in this study.
The comparative efficacy of buspirone and diazepam in the treatment of anxiety
Authors: Harold L. Goldberg, Richard J. Finnerty
Journal: American Journal of Psychiatry (1979)

In this double-blind study, 56 adult psychoneurotic outpatients with a primary diagnosis of anxiety neurosis were randomly assigned to receive buspirone (N = 18), diazepam (N = 20), or placebo (N = 18) over a four-week period. A battery of tests administered weekly indicated that buspirone, a new agent not chemically related to any currently marketed drugs, was as effective an antianxiety agent as diazepam and produced no more and perhaps fewer side effects. Buspirone showed excellent antidepressant effects as well. If further studies confirm the authors' findings and determine that buspirone does not result in tolerance and addiction, it would be more advantageous than the benzodiazepines in the treatment of anxiety.
Vestibular function is also vulnerable
Authors: Barry M Seemungal, Adolfo M Bronstein
Journal: BMJ (2007)

We are concerned to correct a common misconception—namely, that ototoxicity is synonymous with deafness. Except for the rare cases of mitochondrial mutations discussed by Bitner-Glindzicz and Rahman, vestibular function is much more sensitive to aminoglycosides than hearing function.1 Ninety per cent of patients with gentamicin associated vestibular loss will not be deaf.2 …
Plant proteinase inhibitor from crataeva tapia (CrataBl) attenuates inflammation and remodelling induced by elastase in mice
Authors: Edna A. Leick, Leandro Vilela Oliva, Bruno Tadeu Martins Oliveira, Rafael Almeida-Reis, Osmar A. Theodoro, Marlon Vilela de Brito, Carla Máximo Prado, Mílton A. Martins, Maria Luiza Vilela Oliva, Iolanda F.L.C. Tibério
Journal: European Respiratory Journal (2013)

Aims:  To evaluate if a plant Kunitz proteinase inhibitor  CrataBl  modulates inflammatory remodelling alterations induced by elastase.  Methods:  C57Bl6 mice received elastase intratracheal (50μl/animal group) or saline (Ve group). Afterwards, mice were treated with  CrataBl  (2mg/kg) on days 1, 14, 21 after elastase instillation (I-E group) or saline instillation. On day 30 mice were anesthetized and mechanically ventilated. Afterwards, lungs were removed en bloc. By morphometry, we quantified the amount of neutrophils and positive cells for MMP-9, MMP-12 and MAC-2 in distal lung parenchyma.  Results:  In elastase group there was a significant increase in neutrophils, MMP-9, MMP-12, TNF-α and MAC-2 compared to controls (p 4 μm 2 ), the amount of the positive cells for MMP-9 (10.35±0.65/10 4 μm 2 ), MMP-12 (14.15±0.59/10 4 μm 2 ) and for MAC-2 (8.40±0.80/10 4 μm 2 ) compared to E-group (p Conclusions:  This Kunitz proteinase inhibitor  (CrataBl)  attenuated elastase-induced pulmonary inflammatory and extracellular matrix remodeling alterations induced by elastase. Although more studies need to be performed, this inhibitor may contribute as potential therapeutic tool for COPD management.  Financial Support:  FAPESP, CNPq, LIM-20-HC-FMUSP.