tbuckley/cabot-search huggingface dataset:
Naturally Occurring Isothiocyanates Exert Anticancer Effects by Inhibiting Deubiquitinating Enzymes
Authors: Ann P. Lawson, Marcus J.C. Long, Rory T. Coffey, Yu Qian, Eranthie Weerapana, Farid El Oualid, Lizbeth Hedstrom
Journal: Cancer Research (2015)

Abstract The anticancer properties of cruciferous vegetables are well known and attributed to an abundance of isothiocyanates such as benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC). While many potential targets of isothiocyanates have been proposed, a full understanding of the mechanisms underlying their anticancer activity has remained elusive. Here we report that BITC and PEITC effectively inhibit deubiquitinating enzymes (DUB), including the enzymes USP9x and UCH37, which are associated with tumorigenesis, at physiologically relevant concentrations and time scales. USP9x protects the antiapoptotic protein Mcl-1 from degradation, and cells dependent on Mcl-1 were especially sensitive to BITC and PEITC. These isothiocyanates increased Mcl-1 ubiquitination and either isothiocyanate treatment, or RNAi-mediated silencing of USP9x decreased Mcl-1 levels, consistent with the notion that USP9x is a primary target of isothiocyanate activity. These isothiocyanates also increased ubiquitination of the oncogenic fusion protein Bcr-Abl, resulting in degradation under low isothiocyanate concentrations and aggregation under high isothiocyanate concentrations. USP9x inhibition paralleled the decrease in Bcr-Abl levels induced by isothiocyanate treatment, and USP9x silencing was sufficient to decrease Bcr-Abl levels, further suggesting that Bcr-Abl is a USP9x substrate. Overall, our findings suggest that USP9x targeting is critical to the mechanism underpinning the well-established anticancer activity of isothiocyanate. We propose that the isothiocyanate-induced inhibition of DUBs may also explain how isothiocyanates affect inflammatory and DNA repair processes, thus offering a unifying theme in understanding the function and useful application of isothiocyanates to treat cancer as well as a variety of other pathologic conditions. Cancer Res; 75(23); 5130–42. ©2015 AACR.
The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions
Authors: Matthias Nahrendorf, Filip K. Swirski, Elena Aikawa, Lars Stangenberg, Thomas Wurdinger, Jose-Luiz Figueiredo, Peter Libby, Ralph Weissleder, Mikael J. Pittet
Journal: The Journal of Experimental Medicine (2007)

Healing of myocardial infarction (MI) requires monocytes/macrophages. These mononuclear phagocytes likely degrade released macromolecules and aid in scavenging of dead cardiomyocytes, while mediating aspects of granulation tissue formation and remodeling. The mechanisms that orchestrate such divergent functions remain unknown. In view of the heightened appreciation of the heterogeneity of circulating monocytes, we investigated whether distinct monocyte subsets contribute in specific ways to myocardial ischemic injury in mouse MI. We identify two distinct phases of monocyte participation after MI and propose a model that reconciles the divergent properties of these cells in healing. Infarcted hearts modulate their chemokine expression profile over time, and they sequentially and actively recruit Ly-6Chi and -6Clo monocytes via CCR2 and CX3CR1, respectively. Ly-6Chi monocytes dominate early (phase I) and exhibit phagocytic, proteolytic, and inflammatory functions. Ly-6Clo monocytes dominate later (phase II), have attenuated inflammatory properties, and express vascular–endothelial growth factor. Consequently, Ly-6Chi monocytes digest damaged tissue, whereas Ly-6Clo monocytes promote healing via myofibroblast accumulation, angiogenesis, and deposition of collagen. MI in atherosclerotic mice with chronic Ly-6Chi monocytosis results in impaired healing, underscoring the need for a balanced and coordinated response. These observations provide novel mechanistic insights into the cellular and molecular events that regulate the response to ischemic injury and identify new therapeutic targets that can influence healing and ventricular remodeling after MI.
Application of an online team physician survey to the consensus statement on sideline preparedness: the medical bag's highly desired items
Authors: Clayton Everline
Journal: British Journal of Sports Medicine (2010)

Three major duties of the team physician, according to a consensus statement published in 2001, are ‘to plan and train for emergencies during competition and practice, address equipment and supply issues and provide for proper event coverage’. Various medical supplies have been consistently recommended in articles preceding and following the consensus statement while others have not. Nonetheless, there has never been an online survey of team physicians involved with the American Medical Society for Sports Medicine or the American Orthopaedic Society for Sports Medicine covering community, high school, collegiate and professional sporting events that documented the usage of supplies typically found in a team physician's main ‘medical bag’ by consensus standards. The purpose of this study was to document the usage frequencies of supplies listed as ‘highly desirable for the “medical bag” to include’ as well as stocking, storage and inventory maintenance protocols for these events and to compare them with recommendations from the consensus statement as well as some protocols involving prehospital care from a ‘wilderness’ perspective.
Cloning of mouse ptx3, a new member of the pentraxin gene family expressed at extrahepatic sites
Authors: M Introna, VV Alles, M Castellano, G Picardi, L De Gioia, B Bottazzai, G Peri, F Breviario, M Salmona, L De Gregorio, TA Dragani, N Srinivasan, TL Blundell, TA Hamilton, A Mantovani
Journal: Blood (1996)
Hypoxia Enhances Ecto-5′-Nucleotidase Activity and Cell Surface Expression in Endothelial Cells
Authors: S. Ledoux, I. Runembert, K. Koumanov, J.B. Michel, G. Trugnan, G. Friedlander
Journal: Circulation Research (2003)

Extracellular adenosine production by the glycosyl-phosphatidyl-inositol-anchored Ecto-5′-Nucleotidase plays an important role in the defense against hypoxia, particularly in the intravascular space. The present study was designed in order to elucidate the mechanisms underlying hypoxia-induced stimulation of Ecto-5′-Nucleotidase in endothelial cells. For this purpose, aortic endothelial cells (SVARECs) were submitted to hypoxic gas mixture. Hypoxia (0% O 2 for 18 hours) induced a 2-fold increase of Ecto-5′-Nucleotidase activity (V max 19.78±0.53 versus 8.82±1.12 nmol/mg protein per min), whereas mRNA abundance and total amount of the protein were unmodified. By contrast, hypoxia enhanced cell surface expression of Ecto-5′-Nucleotidase, as evidenced both by biotinylation and immunostaining. This effect was accompanied by a decrease of Ecto-5′-Nucleotidase endocytosis, without modification of Ecto-5′-Nucleotidase association with detergent-resistant membranes. Finally, whereas cholesterol content was unmodified, hypoxia induced a time-dependent increase of saturated fatty acids in SVARECs, which was reversed by reoxygenation, in parallel to Ecto-5′-Nucleotidase stimulation. Incubation of normoxic cells with palmitic acid enhanced Ecto-5′-Nucleotidase activity and cell surface expression. In conclusion, hypoxia enhances cell surface expression of Ecto-5′-Nucleotidase in endothelial cells. This effect could be supported by a decrease of Ecto-5′-Nucleotidase endocytosis through modification of plasma membrane fatty acid composition.
Supersensitivity to pentagastrin in diffuse oesophageal spasm
Authors: V. Eckardt, H. Weigand
Journal: Gut (1974)

A 38-year-old patient, complaining of dysphagia and substernal pain of nine months' duration, was found by manometric studies to have diffuse oesophageal spasm. As has similarly been reported for cholinergic agents in achalasia and in some cases of diffuse oesophageal spasm the oesophageal body responded in a hypersensitive fashion to subcutaneous and intravenous injections of pentagastrin. This effect was inhibited by the intravenous administration of atropine and completely abolished by nitroglycerine. When pentagastrin was subcutaneously injected before a barium examination a distortion of the oesophageal contour, described as curling or corkscrew oesophagus, regularly appeared.
Heparin Cofactor II Is a Novel Protective Factor Against Carotid Atherosclerosis in Elderly Individuals
Authors: Ken-ichi Aihara, Hiroyuki Azuma, Nobuyuki Takamori, Yasuhiko Kanagawa, Masashi Akaike, Mitsunori Fujimura, Tomonori Yoshida, Shunji Hashizume, Midori Kato, Hiroshi Yamaguchi, Shuji Kato, Yasumasa Ikeda, Tomoko Arase, Akira Kondo, Toshio Matsumoto
Journal: Circulation (2004)

Thrombin plays a crucial role in atherothrombotic changes. Because heparin cofactor II (HCII) inhibits thrombin actions after binding to dermatan sulfate at injured arterial walls, HCII may negatively regulate thrombin actions in vascular walls. We hypothesized that plasma HCII activity is a preventive factor against atherosclerotic changes, especially in elderly individuals who already have atherosclerotic vascular injuries.Maximum plaque thickness (MPT) in the carotid artery was measured by ultrasonography in 306 Japanese elderly individuals (154 men and 152 women; age, 40 to 91 years; 68.9+/-11.1 years, mean+/-SD). The relevance of cardiovascular risk factors including plasma HCII activity to the severity of MPT was statistically evaluated. Plasma HCII activity decreased with age. Simple linear regression analysis after adjustments for age and sex showed that lipoprotein(a), glycosylated hemoglobin A1c, and presence of diabetes mellitus significantly contributed to an increase in MPT values (r=0.119, P<0.05; r=0.196, P<0.001; and r=0.227, P<0.0001, respectively). In contrast, high-density lipoprotein (HDL) cholesterol and HCII activity were negatively correlated with MPT values (r=-0.117, P<0.05, and r=-0.202, P<0.0005, respectively). Multiple regression analysis revealed that plasma HCII activity and HDL cholesterol independently contributed to the suppression of MPT values and that the antiatherogenic contribution of HCII activity was stronger than that of HDL cholesterol (P<0.001 and P<0.05, respectively).These results suggest that HCII can be a novel and independent antiatherogenic factor. Moreover, HCII is a stronger predictive factor than HDL cholesterol against carotid atherosclerosis in elderly individuals.
Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: A randomized controlled trial
Authors: Peter Alexander Blanch Wark, Michael John Hensley, Nicholas Saltos, Michael James Boyle, Ruth Christine Toneguzzi, Grad Dip Clin Epid, Jodie Louise Simpson, Patrick McElduff, Peter Gerard Gibson
Journal: Journal of Allergy and Clinical Immunology (2003)
Self- and Nonself-Recognition by C-Type Lectins on Dendritic Cells
Authors: Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. 't Hart, Yvette van Kooyk
Journal: Annual Review of Immunology (2004)

Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that collect antigen in body tissues and transport them to draining lymph nodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC) molecules for presentation to naive T cells, resulting in the induction of cellular and humoral immune responses. DCs take up antigen through phagocytosis, pinocytosis, and endocytosis via different groups of receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens. Uptake of antigen by CLRs leads to presentation of antigens on MHC class I and II molecules. DCs are well equipped to distinguish between self- and nonself-antigens by the variable expression of cell-surface receptors such as CLRs and TLRs. In the steady state, DCs are not immunologically quiescent but use their antigen-handling capacities to maintain peripheral tolerance. DCs are continuously sampling and presenting self- and harmless environmental proteins to silence immune activation. Uptake of self-components in the intestine and airways are good examples of sites where continuous presentation of self- and foreign antigens occurs without immune activation. In contrast, efficient antigen-specific immune activation occurs upon encounter of DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors such as TLRs that result in DC maturation and subsequently immune activation. Here we discuss the concept that cross talk between TLRs and CLRs, differentially expressed by subsets of DCs, accounts for the different pathways to peripheral tolerance, such as deletion and suppression, and immune activation.
Hodgkin's Disease Survivors More Fatigued Than the General Population
Authors: Jon Håvard Loge, Arne Foss Abrahamsen, Øivind Ekeberg, Stein Kaasa
Journal: Journal of Clinical Oncology (1999)

To estimate the level of fatigue and frequency of fatigue cases among Hodgkin's disease survivors (HDS) and compare them with normative data from the general population.A cross-sectional follow-up study was done of 557 HDS (age range, 19 to 74 years) treated at the Norwegian Radium Hospital from 1971 to 1991. The sample was approached by mail, and their data were compared with normative data from 2,214 controls (age range, 19 to 74 years) representative of the general Norwegian population. Of the 557 HDS, 459 (82%) responded. The mean age (+/- SD) at the time of study was 44+/-12 years, and the mean observation time was 12+/-6 years. The Fatigue Questionnaire (11 items) measures physical and mental fatigue. Two systems of scoring were used, dichotomized (0, 0, 1, and 1) and Likert (0, 1, 2, and 3). Total fatigue (TF) constitutes the sum of all the Likert scores. Caseness was defined as a total dichotomized score of > or =4 and fatigue that lasted 6 months or longer.The HDS had significantly higher levels of TF than the controls (14.3 v 12.2) (P < .001). Fatigue among the HDS equaled that of the controls in poorest health. More HDS (61%) than controls (31%) reported fatigue symptoms lasting 6 months or longer (P < .001). Fatigue cases were more frequent among HDS (men, 24%; women, 27%) than among the controls (men, 9%; women, 12%) (P < .001). Disease stage/substage IB/IIB predicted fatigue caseness (P = .03). No significant associations were found between treatment characteristics and fatigue.Hodgkin's disease survivors are considerably more fatigued than the general population and report fatigue of a substantially longer duration.
Changing Models of Biomedical Research
Authors: William F. Crowley, James F. Gusella
Journal: Science Translational Medicine (2009)

Thanks to the revolutions in information technology, human "-omics" research, and intricate medical device development, academic health centers (AHCs) now have an unparalleled potential to become translational engines that both generate basic science advances and then translate them into human studies and, ultimately, into improved health care. However, AHC infrastructures have traditionally been optimized to foster basic research. Now modifications must be made to meet these expanded roles of AHCs, from providing fundamental biomedical insights to first-in-human interventions and, if warranted, to larger randomized clinical trials. Eventually, AHCs must integrate these improved treatments into patient care. Challenges to this process have been defined by the Institute of Medicine. Building the appropriate infrastructures for human investigation and stabilizing the careers of young physicians essential to these translational events have become critical needs that will require systemic investments if AHCs are to respond to these biological revolutions and fulfill their promise.
Valvular Heart Disease
Authors: Raffi Bekeredjian, Paul A. Grayburn
Journal: Circulation (2005)

Aortic regurgitation (AR) is characterized by diastolic reflux of blood from the aorta into the left ventricle (LV). Acute AR typically causes severe pulmonary edema and hypotension and is a surgical emergency. Chronic severe AR causes combined LV volume and pressure overload. It is accompanied by systolic hypertension and wide pulse pressure, which account for peripheral physical findings, such as bounding pulses. The afterload excess caused by systolic hypertension leads to progressive LV dilation and systolic dysfunction. The most important diagnostic test for AR is echocardiography. It provides the ability to determine the cause of AR and to assess the severity of AR and its effect on LV size, function, and hemodynamics. Many patients with chronic severe AR may remain clinically compensated for years with normal LV function and no symptoms. These patients do not require surgery but can be followed carefully for the onset of symptoms or LV dilation/dysfunction. Surgery should be considered before the LV ejection fraction falls below 55% or the LV end-diastolic dimension reaches 55 mm. Symptomatic patients should undergo surgery unless there are excessive comorbidities or other contraindications. The primary role of medical therapy with vasodilators is to delay the need for surgery in asymptomatic patients with normal LV function or to treat patients in whom surgery is not an option. The goal of vasodilator therapy is to achieve a significant decrease in systolic arterial pressure. Future therapies may focus on molecular mechanisms to prevent adverse LV remodeling and fibrosis.
Pathologic Characteristics of Transplanted Kidney Xenografts
Authors: Akira Shimizu, Kazuhiko Yamada, Simon C. Robson, David H. Sachs, Robert B. Colvin
Journal: Journal of the American Society of Nephrology (2011)

For xenotransplantation to become a clinical reality, we need to better understand the mechanisms of graft rejection or acceptance. We examined pathologic changes in α1,3-galactosyltransferase gene-knockout pig kidneys transplanted into baboons that were treated with a protocol designed to induce immunotolerance through thymic transplantation (n=4) or were treated with long-term immunosuppressants (n=3). Hyperacute rejection did not occur in α1,3-galactosyltransferase gene-knockout kidney xenografts. By 34 days, acute humoral rejection led to xenograft loss in all three xenografts in the long-term immunosuppression group. The failing grafts exhibited thrombotic microangiopathic glomerulopathy with multiple platelet-fibrin microthrombi, focal interstitial hemorrhage, and acute cellular xenograft rejection. Damaged glomeruli showed IgM, IgG, C4d, and C5b-9 deposition. They also demonstrated endothelial cell death, diffuse endothelial procoagulant activation with high expression of tissue factor and vWF, and low expression of the ectonucleotidase CD39. In contrast, in the immunotolerance group, two of four grafts had normal graft function and no pathologic findings of acute or chronic rejection at 56 and 83 days. One of the remaining kidneys had mild but transient graft dysfunction with reversible, mild microangiopathic glomerulopathy, probably associated with preformed antibodies. The other kidney in the immunotolerance group developed unstable graft function at 81 days and developed chronic xenograft glomerulopathy. In summary, the success of pig-to-primate xenotransplantation may necessitate immune tolerance to inhibit acute humoral and cellular xenograft rejection.
Lysyl Oxidase–Like 2 as a New Poor Prognosis Marker of Squamous Cell Carcinomas
Authors: Héctor Peinado, Gema Moreno-Bueno, David Hardisson, Eduardo Pérez-Gómez, Vanesa Santos, Marta Mendiola, Juan Ignacio de Diego, Manuel Nistal, Miguel Quintanilla, Francisco Portillo, Amparo Cano
Journal: Cancer Research (2008)

Abstract Lysyl oxidase–like 2 (Loxl2) interacts with and stabilizes Snai1 transcription factor, promoting epithelial-mesenchymal transition. Either Loxl2 or Snai1 knock-down blocks tumor growth and induces differentiation, but the specific role of each factor in tumor progression is still unknown. Comparison of the gene expression profiles of the squamous cell carcinoma cell line HaCa4 after knocking-down Loxl2 or Snai1 revealed that a subset of epidermal differentiation genes was specifically up-regulated in Loxl2-silenced cells. In agreement, although both Loxl2- and Snai1-knockdown cells showed reduced in vivo invasion, only Loxl2-silenced cells exhibited a skin-like epidermal differentiation program. In addition, we show that expression of Loxl2 and Snai1 correlates with malignant progression in a two-stage mouse skin carcinogenesis model. Furthermore, we found that increased expression of both LOXL2 and SNAI1 correlates with local recurrence in a cohort of 256 human laryngeal squamous cell carcinomas. We describe for the first time that high levels of LOXL2 are associated with decreased overall and disease-free survival in laryngeal squamous cell carcinomas, lung squamous cell carcinoma, and lymph node–negative (N0) breast adenocarcinomas. Altogether, our results show that LOXL2 can be used as a new poor prognosis indicator in human squamous cell carcinomas promoting malignant transformation by both SNAI1-dependent and SNAI1-independent pathways. [Cancer Res 2008;68(12):4541–50]
Blood pressure responsiveness to obstructive events during sleep after chronic CPAP
Authors: O. Marrone, A. Salvaggio, M.R. Bonsignore, G. Insalaco, G. Bonsignore
Journal: European Respiratory Journal (2003)

The aim of this study was to investigate whether chronic continuous positive airway pressure (CPAP) affects blood pressure (BP) responsiveness to obstructive events occurring on the first night of CPAP withdrawal in obstructive sleep apnoea (OSA) after chronic treatment. Thirteen male subjects with severe OSA underwent nocturnal polysomnography with beat­by­beat BP monitoring before treatment and after 4.9±3.4 months of home CPAP (mean daily use 5.1±1.7 h). Variations in oxyhaemoglobin saturation (Δ S a,O 2 ), systolic (Δ P s ), and diastolic (Δ P d ) BP within nonrapid eye movement apnoeas and hypopnoeas were measured on a sample of pre­ and post­treatment events. In addition, a pretreatment sample was selected for Δ S a,O 2 to match post­treatment events. The higher the mean Δ S a,O 2 was in the full pretreatment sample, the more Δ S a,O 2 , Δ P s and Δ P d were attenuated after treatment. Mean Δ P s decreased from 47.3±8.5 in the full pretreatment sample to 42.2±6.9 in the selected pretreatment sample, to 31.5±5.9 mmHg in the post­treatment sample. The post­treatment value differed significantly from both the pretreatment values. The corresponding values for mean Δ P d were 27.0±3.5, 24.0±3.1 and 19.6±3.7 mmHg, with all values differing significantly from each other. Chronic continuous positive airway pressure is followed by a decrease in apnoea/hypopnoea­related blood pressure swings, possibly secondary to both reduced severity of event­related hypoxaemia and decreased responsiveness to obstructive events secondary to chronic prevention of nocturnal intermittent hypoxaemia.