tbuckley/cabot-search huggingface dataset:
Diesel Exhaust Particles Activate p38 MAP Kinase to Produce Interleukin 8 and RANTES by Human Bronchial Epithelial Cells and <i>N</i>-Acetylcysteine Attenuates p38 MAP Kinase Activation
Authors: SHU HASHIMOTO, YASUHIRO GON, IKUKO TAKESHITA, KEN MATSUMOTO, ITSURO JIBIKI, HAJIME TAKIZAWA, SHOJI KUDOH, TAKASHI HORIE
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Air pollutants including diesel exhaust particles (DEPs) have been shown to enhance allergic responses. DEPs stimulate airway epithelial cells to produce various cytokines; however, the intracellular signal transduction pathway and the involvement of reduction and oxidation (redox) control in DEP-activated signaling have not been determined. In the present study, we therefore examined the role of p38 mitogen-activated protein (MAP) kinase in DEP-induced interleukin 8 (IL-8) and RANTES production by human bronchial epithelial cells (BECs) in order to clarify the intracellular signal transduction pathway that regulates IL-8 and RANTES production. In addition, we also examined the effect of a thiol-reducing agent, N-acetylcysteine (NAC), on DEP-induced p38 MAP kinase activation and cytokine production in order to clarify the redox control mechanism in DEP-induced p38 MAP kinase activation and IL-8 and RANTES production. The results showed that DEP induced IL-8 and RANTES production and the threonine and tyrosine phosphorylation of p38 MAP kinase, reflecting the activation of p38 MAP kinase in BECs. SB 203580, as the specific inhibitor of p38 MAP kinase activity, inhibited DEP-induced IL-8 and RANTES production. NAC inhibited DEP-induced p38 MAP kinase activation and IL-8 and RANTES production. These results indicate that p38 MAP kinase plays an important role in the DEP-activated signaling pathway that regulates IL-8 and RANTES production by BECs and that the cellular redox state is critical for DEP-induced p38 MAP kinase activation leading to IL-8 and RANTES production.
Phospholamban Ablation Rescues Sarcoplasmic Reticulum Ca <sup>2+</sup> Handling but Exacerbates Cardiac Dysfunction in CaMKIIδ <sub>C</sub> Transgenic Mice
Authors: Tong Zhang, Tao Guo, Shikha Mishra, Nancy D. Dalton, Evangelia G. Kranias, Kirk L. Peterson, Donald M. Bers, Joan Heller Brown
Journal: Circulation Research (2009)

We previously showed that transgenic mice expressing Ca(2+)/calmodulin-dependent protein kinase II delta(C) (CaMKII-TG) develop dilated cardiomyopathy associated with increased ryanodine receptors (RyR2) phosphorylation, enhanced sarcoplasmic reticulum (SR) Ca(2+) leak and lowering of SR Ca(2+) load. We hypothesized that phospholamban (PLN) ablation would restore SR Ca(2+) load and prevent the decreased ventricular contractility, dilation and mortality seen in CaMKII-TG.Our objectives were to generate CaMKII-TG mice lacking PLN, determine whether the maladaptive effects of cardiac CaMKIIdelta(C) expression were corrected, and establish the mechanistic basis for these changes.CaMKII-TG were crossed with PLN knockout (PLN-KO) mice to generate KO/TG mice. Myocytes from wild type (WT), CaMKII-TG, PLN-KO and KO/TG were compared. The decreased SR Ca(2+) load and twitch Ca(2+) transients seen in CaMKII-TG were normalized in KO/TG. Surprisingly the heart failure phenotype was exacerbated, as indicated by increased left ventricular dilation, decreased ventricular function, increased apoptosis and greater mortality. In KO/TG myocytes SR Ca(2+) sparks and leak were significantly increased, presumably because of the combined effects of restored SR Ca(2+) load and RyR2 phosphorylation. Mitochondrial Ca(2+) loading was increased in cardiomyocytes from KO/TG versus WT or CaMKII-TG mice and this was dependent on elevated SR Ca(2+) sparks. Cardiomyocytes from KO/TG showed poor viability, improved by inhibiting SR Ca(2+) release and mitochondrial Ca(2+) loading.Normalizing cardiomyocyte SR Ca(2+) loading in the face of elevated CaMKII and RyR2 phosphorylation leads to enhanced SR Ca(2+) leak and mitochondrial Ca(2+) elevation, associated with exacerbated cell death, heart failure and mortality.
Cellular response to alpha-gliadin in untreated coeliac disease.
Authors: C O'Farrelly, C Feighery, J F Greally, D G Weir
Journal: Gut (1982)

An improved technique for the detection of alpha-gliadin sensitised mononuclear cells in the peripheral blood of untreated coeliac patients is described. This method is a modification of the direct LMIF assay, and involves exposure of lymphocytes to alpha-gliadin and the assay of the resultant lymphokine produced using normal leucocytes as indicator cells. All untreated coeliac patients, 14 of 15 treated patients, and two of 28 controls responded to alpha-gliadin. The direct LMIF assay in comparison is less sensitive, and detected sensitivity to alpha-gliadin in only four out of eight patients with untreated coeliac disease. Use of the indirect LMIF technique demonstrates that in untreated as well as treated coeliac patients there are cells sensitised to alpha-gliadin circulating in the peripheral blood. These findings may have pathogenic and diagnostic significance.
The IOC's endeavour to protect the health of the athlete continues
Authors: Kathrin Steffen, Torbjørn Soligard, Lars Engebretsen
Journal: British Journal of Sports Medicine (2011)

After the 2010 Olympic Games in Vancouver, the International Olympic Committee (IOC) has initiated a new project together with the International Olympic Sports Federations (IFs) and the National Olympic Committees (NOC). The aim of the Health, Safety and Security (HSS) survey was to identify and, in turn, eliminate risk factors which could potentially be harmful for the Olympic athletes. Each Federation shared their data on, athletes' risk exposure, technical development and equipment evolution, venue safety procedures, rule change mechanisms and determination of athlete eligibility. The IOC and the IFs are optimistic that this survey will not only increase the awareness on injury prevention, but also facilitate the introduction of tailored measures to prevent injuries and illnesses in each sport and discipline.

With this objective in mind, the IOC have during recent years developed several new programmes.1 The injury and illness surveillance system, developed in cooperation with IFs and NOCs, was implemented with success in the 2008 Beijing (injury surveillance only)2 and in the 2010 Vancouver Olympics,3 and will be further developed in the 2012 London and 2014 Sochii Olympics. Based on a consensus meeting on Periodic Health Exams (PHE),4 the IOC is developing an Electronic …
Response to: ‘Venous thromboembolic events in systemic vasculitis’ by Novikov<i>et al</i>
Authors: J Antonio Aviña-Zubieta, V M Bhole, N Amiri, E C Sayre, H K Choi
Journal: Annals of the Rheumatic Diseases (2014)

Response to: 'Venous thromboembolic events in systemic vasculitis' by Novikov et al4][5][6] Additionally, we have confirmed the increased risk of VTE in patients with GCA in another sample, and those results will be published soon.We also agree with Dr Moiseev that the risk of VTE varies among SARDs.We have reported that patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis have a higher risk of VTE than those with GCA. 7 It is likely that the interaction between the procoagulant state and each SARD may be different depending on the intrinsic pathogenesis of each disease.It seems that Dr Moiseev is surprised that he did not see an increased risk of VTE in his small cohort of GCA cases; without knowing the characteristics of his cohort, we are unable to comment further on his findings.Dr Moiseev also inquired about cost-effective strategies to prevent VTE and raised concern about which patients should use preventive anticoagulation.In our paper, we proposed that preventative anticoagulation may be indicated only for those at high risk.Dr Moiseev asked who those patients that are at high risk are.This is a research question with no answer yet.We believe such investigation should be conducted urgently as it could result in the prevention of VTE.In our study, we observed only one fatal event in the GCA cohort and nine in the non-GCA cohort.However, the low fatality rate observed does not contradict the use of preventative anticoagulation, given that VTE is associated with significant morbidity.Once we know who is at high risk, a randomised clinical trial should be implemented to test the hypothesis that preventable anticoagulation is cost effective.Until then, we agree that further research needs to be done to confirm our results, and to develop and test screening strategies to identify patients who may benefit from preventative anticoagulation.
Randomized Study to Evaluate the Use of High-Dose Therapy as Part of Primary Treatment for “Aggressive” Lymphoma
Authors: Ulrich Kaiser, Irmgard Uebelacker, Ulrich Abel, Josef Birkmann, Lorenz Trumper, Harald Schmalenberg, Tunca Karakas, Bernd Metzner, Dieter K. Hossfeld, Helge G. Bischoff, Astrid Franke, Marcel Reiser, Peter Muller, Luisa Mantovani, Marc Grundeis, Frank Rothmann, Cay-Uwe von Seydewitz, Rolf M. Mesters, Ernst U. Steinhauer, Dorothea Krahl, Kurt Schumacher, Michael Kneba, Michael Baudis, Norbert Schmitz, Rudiger Pfab, Hubert Koppler, Reza Parwaresch, Michael Pfreundschuh, Klaus Havemann
Journal: Journal of Clinical Oncology (2002)

PURPOSE: This trial of the German High-Grade Non-Hodgkin’s Lymphoma Study Group compares the use of high-dose therapy (HDT) as part of primary treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus etoposide followed by involved-field (IF) radiotherapy in a randomized, multicenter, phase III study. PATIENTS AND METHODS: Three hundred twelve patients with “aggressive” non-Hodgkin’s lymphoma aged ≤ 60 years with elevated serum lactate dehydrogenase levels were included from 1990 to 1997. Patients with at least a minor response after two cycles of CHOEP (CHOP + etoposide 3 × 100 mg/m 2 ) were to receive three further cycles of CHOEP followed by IF radiotherapy (arm A) or one further cycle of CHOEP followed by autologous stem-cell transplantation and IF radiotherapy (arm B). RESULTS: Among 158 patients randomized to arm B, 103 (65%) received HDT. The complete remission rate at the end of treatment was 62.9% in arm A and 69.9% in arm B. With a median observation time of 45.5 months, overall survival for all 312 patients was 63% after 3 years (63% for arm A, 62% for arm B; P = .68). Event-free survival was 49% for arm A versus 59% for arm B (P = .22). Relapse in arm B was associated with a significantly worse survival rate than relapse in arm A (P &lt; .05). Relapse after HDT occurred early (median interval, 3 months). Six patients developed secondary neoplasia, three in arm A and three in arm B. CONCLUSION: Results of the randomized trial comparing CHOP-like chemotherapy with early HDT do not support the use of HDT with carmustine, etoposide, cytarabine, and melphalan following shortened standard chemotherapy.
Mucosal lesions in the human small intestine in shock.
Authors: U Haglund, L Hulten, C Ahren, O Lundgren
Journal: Gut (1975)

Characteristic mucosal lesions in resected small intestinal segments from seven patients are reported. Preoperatively, four patients were in shock and general hypotension while the three remaining cases showed signs of local intestinal hypotension. The microscopic appearance of the mucosal lesions was in all patients identical with that previously observed in the feline and canine small intestine after haemorrhage or local intestinal hypotension. It is proposed that an extravascular short-circuiting of oxygen in the mucosal countercurrent exchanger and an intravascular aggregation of blood cells might produce tissue hypoxia which makes the mucosa vulnerable to enzymatic degradation.
Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci
Authors: Mary Carrington, Sophia Wang, Maureen P. Martin, Xiaojiang Gao, Mark Schiffman, Jie Cheng, Rolando Herrero, Ana Cecilia Rodriguez, Robert Kurman, Rodrigue Mortel, Peter Schwartz, Andrew Glass, Allan Hildesheim
Journal: The Journal of Experimental Medicine (2005)

Killer immunoglobulin-like receptor (KIR) recognition of specific human histocompatibility leukocyte antigen (HLA) class I allotypes contributes to the array of receptor–ligand interactions that determine natural killer (NK) cell response to its target. Contrasting genetic effects of KIR/HLA combinations have been observed in infectious and autoimmune diseases, where genotypes associated with NK cell activation seem to be protective or to confer susceptibility, respectively. We show here that combinations of KIR and HLA loci also affect the risk of developing cervical neoplasia. Specific inhibitory KIR/HLA ligand pairs decrease the risk of developing neoplasia, whereas the presence of the activating receptor KIR3DS1 results in increased risk of disease, particularly when the protective inhibitory combinations are missing. These data suggest a continuum of resistance conferred by NK cell inhibition to susceptibility involving NK cell activation in the development of cervical neoplasia and underscore the pervasive influence of KIR/HLA genetic variation in human disease pathogenesis.
Diffuse endothelial dysfunction is common to ANCA associated systemic vasculitis and polyarteritis nodosa
Authors: A D Filer
Journal: Annals of the Rheumatic Diseases (2003)

<b>Background:</b> Excess cardiovascular mortality complicates systemic rheumatic disease, suggesting an accelerated atheromatous process, which it has been proposed relates to the vascular inflammation common in such diseases. Impaired endothelium dependent vasodilatation is an early marker of atheromatous disease. It has previously been shown that such endothelial cell dysfunction (ECD) occurring in the brachial artery can complicate primary systemic necrotising vasculitis (SNV). <b>Objective:</b> To determine if ECD occurs in a wider spectrum of primary SNV, if it is restricted to the major arteries, and whether vasculitis subgroup, ANCA status, or renal involvement influenced the endothelial responses. <b>Methods:</b> Fifty four patients attending the Birmingham vasculitis clinic, including patients with a range of ANCA and non-ANCA associated primary vasculitides, and a group of age matched controls were recruited. The length of patient follow up and disease activity was variable. Disease activity, damage scores, and cardiovascular risk factors were recorded before assessment of flow mediated brachial artery vasodilatation by high resolution ultrasound. Dermal microvascular responses to acetylcholine were also measured in 32 patients and 21 controls by laser Doppler flowmetry. <b>Results:</b> ECD was demonstrated in all primary SNV subgroups of patients with ANCA associated vasculitis and in polyarteritis nodosa, compared with controls. Significant impairment occurred in both vascular beds, regardless of vessel size targeted in the inflammatory vasculitis, ANCA association and titre, or renal involvement. <b>Conclusions:</b> Diffuse endothelial dysfunction, a predictor of atherosclerotic disease, is found extensively in primary systemic vasculitis. Involvement of different vascular beds is independent of target vessel size or ANCA association, and is unrelated to local disease expression. It is suggested that this results from a systemic response that may be a consequence of primary vasculitis, but is distinct from the local inflammatory vasculitic process.
Tumor Suppressor <i>miR-22</i> Determines p53-Dependent Cellular Fate through Post-transcriptional Regulation of p21
Authors: Naoto Tsuchiya, Masashi Izumiya, Hiroko Ogata-Kawata, Koji Okamoto, Yuko Fujiwara, Makiko Nakai, Atsushi Okabe, Aaron J. Schetter, Elise D. Bowman, Yutaka Midorikawa, Yasuyuki Sugiyama, Hiroyuki Aburatani, Curtis C. Harris, Hitoshi Nakagama
Journal: Cancer Research (2011)

Selective activation of p53 target genes in response to various cellular stresses is a critical step in determining the ability to induce cell-cycle arrest or apoptosis. Here we report the identification of the microRNA miR-22 as a p53 target gene that selectively determines the induction of p53-dependent apoptosis by repressing p21. Combinatorial analyses of the AGO2 immunocomplex and gene expression profiles identified p21 as a direct target of miR-22. Induction of p21 was inhibited by miR-22 after exposure to the genotoxic agent Adriamycin (doxorubicin; Bedford Laboratories), sensitizing cells to p53-dependent apoptosis. Interestingly, the activation of miR-22 depended on the intensity of the stresses that induced cells to undergo apoptosis in the presence of p21 suppression. Our findings define an intrinsic molecular switch that determines p53-dependent cellular fate through post-transcriptional regulation of p21.
From Stem Cells to Viable Autologous Semilunar Heart Valve
Authors: Fraser W.H. Sutherland, Tjorvi E. Perry, Ying Yu, Megan C. Sherwood, Elena Rabkin, Yutaka Masuda, G. Alejandra Garcia, Dawn L. McLellan, George C. Engelmayr, Michael S. Sacks, Frederick J. Schoen, John E. Mayer
Journal: Circulation (2005)

Background— An estimated 275 000 patients undergo heart valve replacement each year. However, existing solutions for valve replacement are complicated by the morbidity associated with lifelong anticoagulation of mechanical valves and the limited durability of bioprostheses. Recent advances in tissue engineering and our understanding of stem cell biology may provide a lifelong solution to these problems. Methods and Results— Mesenchymal stem cells were isolated from ovine bone marrow and characterized by their morphology and antigen expression through immunocytochemistry, flow cytometry, and capacity to differentiate into multiple cell lineages. A biodegradable scaffold was developed and characterized by its tensile strength and stiffness as a function of time in cell-conditioned medium. Autologous semilunar heart valves were then created in vitro using mesenchymal stem cells and the biodegradable scaffold and were implanted into the pulmonary position of sheep on cardiopulmonary bypass. The valves were evaluated by echocardiography at implantation and after 4 months in vivo. Valves were explanted at 4 and 8 months and examined by histology and immunohistochemistry. Valves displayed a maximum instantaneous gradient of 17.2±1.33 mm Hg, a mean gradient of 9.7±1.3 mm Hg, an effective orifice area of 1.35±0.17 cm 2 , and trivial or mild regurgitation at implantation. Gradients changed little over 4 months of follow-up. Histology showed disposition of extracellular matrix and distribution of cell phenotypes in the engineered valves reminiscent of that in native pulmonary valves. Conclusions— Stem-cell tissue-engineered heart valves can be created from mesenchymal stem cells in combination with a biodegradable scaffold and function satisfactorily in vivo for periods of &gt;4 months. Furthermore, such valves undergo extensive remodeling in vivo to resemble native heart valves.
Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma
Authors: S.A. Graf, P.A. Stevenson, L.A. Holmberg, B.G. Till, O.W. Press, T.R. Chauncey, S.D. Smith, M. Philip, J.J. Orozco, A.R. Shustov, D.J. Green, E.N. Libby, W.I. Bensinger, J.M. Pagel, D.G. Maloney, Y. Zhou, R.D. Cassaday, A.K. Gopal
Journal: Annals of Oncology (2015)
Taxotere-Induced Inhibition of Human Endothelial Cell Migration Is a Result of Heat Shock Protein 90 Degradation
Authors: Janice Murtagh, Haiyan Lu, Edward L. Schwartz
Journal: Cancer Research (2006)

Abstract In addition to effects on tumor cell proliferation and apoptosis, microtubule-binding agents are potent inhibitors of angiogenesis. The cancer chemotherapeutic drug Taxotere (docetaxel) inhibited vascular endothelial growth factor (VEGF)–induced human umbilical vein endothelial cell (HUVEC) migration in vitro at concentrations substantially lower than required to cause cell cycle arrest or apoptosis. Here, we show that Taxotere caused the ubiquitination and subsequent proteasomal degradation of heat shock protein 90 (Hsp90) in HUVEC. This prevented signaling from the focal adhesions and VEGF receptors and inhibited integrin activation. Taxotere prevented the VEGF-induced phosphorylation of focal adhesion kinase, Akt, and endothelial nitric oxide synthase (eNOS), all of which are Hsp90 client proteins. Taxotere completely blocked the VEGF-induced increase in eNOS activity, and the addition of a NO donor reversed the inhibitory effect of Taxotere on VEGF-induced migration. A similar reversal occurred with a proteasomal inhibitor of Hsp90 degradation. Furthermore, overexpression of Hsp90 rescued HUVEC from the inhibition of VEGF-induced migration by Taxotere. Previous studies have suggested that tubulin is also a client protein of Hsp90, and immunocytochemical analysis showed that Taxotere caused the dissociation of Hsp90 from tubulin. We suggest that uncomplexed Hsp90 is more susceptible to ubiquitination and subsequent proteasomal degradation than the bound form. Although inhibitors of Hsp90 are currently under clinical investigation as antitumor agents, this seems to be the first account of a drug that reduces Hsp90 function by enhancing its proteasomal degradation. Further, the loss of Hsp90 and the inactivation of Hsp90 client proteins are previously undescribed actions of Taxotere that may contribute to its antiangiogenic activity. (Cancer Res 2006; 66(16): 8192-9)
The EuroPrevall surveys on the prevalence of food allergies in children and adults: background and study methodology
Authors: I. Kummeling, E. N. C. Mills, M. Clausen, R. Dubakiene, C. Farnãndez Pérez, M. Fernández‐Rivas, A. C. Knulst, M. L. Kowalski, J. Lidholm, T.‐M. Le, C. Metzler, T. Mustakov, T. Popov, J. Potts, R. Van Ree, A. Sakellariou, B. Töndury, K. Tzannis, P. Burney
Journal: Allergy (2009)

The epidemiological surveys in children and adults of the EU-funded multidisciplinary Integrated Project EuroPrevall, launched in June 2005, were designed to estimate the currently unknown prevalence of food allergy and exposure to known or suspected risk factors for food allergy across Europe. We describe the protocol for the epidemiological surveys in children and adults. This protocol provides specific instructions on the sampling strategy, the use of questionnaires, and collection of blood samples for immunological analyses.The surveys were performed as multi-centre, cross-sectional studies in general populations. Case-control studies were nested within these surveys. The studies in children aged 7-10 years and adults aged 20-54 years were undertaken in eight centres representing different social and climatic regions in Europe.After a community-based survey collecting basic information on adverse reactions to foods, all those stating they had experienced such reactions, as well as of a random sample of those stating 'no reactions' to foods, completed a detailed questionnaire on potential risks and exposures. Also a blood sample was taken to allow serological analysis to establish patterns of food and aeroallergen sensitization. We also included a questionnaire to schools on their preparedness for dealing with food allergy amongst pupils. Subjects reporting adverse reactions to foods and sensitized to the same food(s) were called in for a full clinical evaluation that included a double blind placebo controlled food challenge (DBPCFC), following a protocol which is described in detail elsewhere.The outcome of these studies will help to improve our understanding of several important aspects of food allergies in the European Community, providing for more well-informed policies and effective measures of disease prevention, diagnosis and management.