tbuckley/cabot-search huggingface dataset:
Sirt7 Increases Stress Resistance of Cardiomyocytes and Prevents Apoptosis and Inflammatory Cardiomyopathy in Mice
Authors: Olesya Vakhrusheva, Christian Smolka, Praveen Gajawada, Sawa Kostin, Thomas Boettger, Thomas Kubin, Thomas Braun, Eva Bober
Journal: Circulation Research (2008)

Sirt7 is a member of the mammalian sirtuin family consisting of 7 genes, Sirt1 to Sirt7, which all share a homology to the founding family member, the yeast Sir2 gene. Most sirtuins are supposed to act as histone/protein deacetylases, which use oxidized NAD in a sirtuin-specific, 2-step deacetylation reaction. To begin to decipher the biological role of Sirt7, we inactivated the Sirt7 gene in mice. Sirt7-deficient animals undergo a reduction in mean and maximum lifespans and develop heart hypertrophy and inflammatory cardiomyopathy. Sirt7 mutant hearts are also characterized by an extensive fibrosis, which leads to a 3-fold increase in collagen III accumulation. We found that Sirt7 interacts with p53 and efficiently deacetylates p53 in vitro, which corresponds to hyperacetylation of p53 in vivo and an increased rate of apoptosis in the myocardium of mutant mice. Sirt7-deficient primary cardiomyocytes show a ≈200% increase in basal apoptosis and a significantly diminished resistance to oxidative and genotoxic stress suggesting a critical role of Sirt7 in the regulation of stress responses and cell death in the heart. We propose that enhanced activation of p53 by lack of Sirt7-mediated deacetylation contributes to the heart phenotype of Sirt7 mutant mice.
Medical Education and Care in People's Republic of China
Authors: E. Grey Dimond
Journal: JAMA (1971)

In a personal visit to the People's Republic of China, as a guest of the China Medical Association (simultaneous invitations were extended to Dr. and Mrs. Paul Dudley White, Dr. and Mrs. Samuel Rosen, Dr. and Mrs. Victor W. Sidel, and my wife, Mary Clark Dimond, and myself) in September 1971, I was asked to list areas in which I had special interest. These were medical education, medical care, and acupuncture. Our hosts did their best to make these areas available. Language is the obvious barrier and one's mobility is defined by the agenda. I was able to visit the following health facilities and in addition have perhaps 30 hours of individual and group discussion with physicians: Kwangtung Provincial People's Hospital, Canton; Hsinhua People's Commune (Hospital, Dispensary, Brigade, Barefoot Doctor), Kwangtung; Tungfanghung Kindergarten (Infirmary, Dispensary), Canton; Canton Deaf-Mute School, Canton; Fu Wai Hospital, Peking; Fan Di Hospital, Peking; Third Teaching Hospital, Peking Medical College, Peking; Peking Medical College (Medicine and Pharmacy), Peking; Textile Mill (Hospital, Dispensary, School, Housing), Peking; Library, China Medical Association, Peking; Library, Chinese Academy of Medical Sciences, Peking; Institute Materia Medica, Chinese Academy of Science, Peking.
The relationship between bronchial immunopathology and hyperresponsiveness in asthma
Authors: LW Poulter, C Power, C Burke
Journal: European Respiratory Journal (1990)

Physiological and Immunopathological parameters were investigated in 15 patients with diagnosed asthma, and 6 non-asthmatics presenting with other chest symptoms. The 15 symptom-free asthmatics expressed bronchohyperresponsiveness with a mean provocative dose producing a 20% fall in forced expiratory volume in one second (PD20FEV1) of 1 mg histamine. None of the non-asthmatics responded to 16 mg histamine. Twenty four hours later bronchoscopy was performed and endobronchial biopsies were obtained. Histological staining of frozen biopsy sections revealed a mononuclear cell infiltrate in all 15 asthmatics, while only 1 of the 6 non-asthmatics showed mild inflammation. Monoclonal antibodies were used to identify subsets of lymphocytes, activation markers, macrophages, and HLA-DR expression within the peribronchial infiltrates. In all samples, activated T-cells and macrophages were identified and HLA-DR expression was found to be raised, but the CD4: CD8 ratio was highly variable. No clear relationship was found between cellular distribution and measured lung function parameters. A highly significant correlation was found between the level of HLA-DR expression on the infiltrating cells (quantified microdensitometrically) and bronchial hyperresponsiveness. These results show for the first time that a chronic T-cell-mediated immune response is present in the bronchial tissue of asymptomatic asthmatics, and that the HLA-DR expression promoted correlates with the hyperresponsive status. These data promote the hypothesis that a T-cell-mediated response contributes to a predisposition to bronchial hyperresponsiveness in asthmatics.
G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4
Authors: Isabelle Petit, Martine Szyper-Kravitz, Arnon Nagler, Meir Lahav, Amnon Peled, Liliana Habler, Tanya Ponomaryov, Russell S. Taichman, Fernando Arenzana-Seisdedos, Nobutaka Fujii, Judith Sandbank, Dov Zipori, Tsvee Lapidot
Journal: Nature Immunology (2002)
Radioisotopic detection of experimental myocardial infarction using mercury derivatives of fluorescein
Authors: P. J. B. Hubner
Journal: Cardiovascular Research (1970)

Journal Article Radioisotopic detection of experimental myocardial infarction using mercury derivatives of fluorescein Get access P. J. B. Hubner P. J. B. Hubner From the M.R.C. Cardiovascular Research Unit, Hammersmith Hospital, London Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 4, Issue 4, October 1970, Pages 509–514, https://doi.org/10.1093/cvr/4.4.509 Published: 01 October 1970 Article history Accepted: 27 February 1970 Published: 01 October 1970
Docetaxel and/or zoledronic acid for hormone-naïve prostate cancer: First overall survival results from STAMPEDE (NCT00268476).
Authors: Nicholas David James, Matthew Robert Sydes, Malcolm David Mason, Noel W. Clarke, David Paul Dearnaley, Melissa Ruth Spears, Robin Millman, Chris Parker, Alastair W S Ritchie, J. Martin Russell, John Staffurth, Robert J. Jones, Shaun P. Tolan, John Wagstaff, Andrew Protheroe, Rajaguru Srinivasan, Alison J. Birtle, Joe M. O'Sullivan, Richard Cathomas, Mahesh M K Parmar
Journal: Journal of Clinical Oncology (2015)

5001 Background: STAMPEDE is a randomised controlled trial using a novel multi-arm multi-stage design. It recruits men (pts) with high-risk locally advanced or metastatic prostate cancer (PCa) starting long-term hormone therapy (HT) for the first time. The trial initially assessed adding 1 or 2 of 3 treatment approaches to standard of care (SOC). We report primary survival results for 3 research comparisons that recruited through all their intermediate analyses: docetaxel (D), zoledronic acid (ZA) & the combination (D+ZA). Methods: SOC was hormone therapy for > = 3yrs; RT was encouraged for N0M0 pts up to Nov-2011, then mandated; RT was optional for N+M0 pts. Stratified randomisation allocated pts 2:1:1:1 to SOC (control), SOC+D, SOC+ZA or SOC+D+ZA. 4mg ZA was given for six 3-weekly cycles then 4-weekly until 2yrs. D was given as 75mg/m2 for six 3-weekly cycles with prednisolone 10mg daily. The primary outcome measure was survival (time from randomisation to death from any cause). Pairwise comparisons to control on survival for each research arm had 90% power at 2.5% 1-sided alpha for a hazard ratio of 0.75 requiring ~400 control arm deaths, accounting for 3 intermediate lack-of-benefit analyses on failure-free survival. Analyses used the Cox model of the logrank test, adjusted for stratification factors. Results: From Oct-2005 to Mar-2013, 2,962 pts were randomised to the 4 arms. The groups were balanced with median age 65yrs; 61% metastatic, 14% N+/XM0, 22% N0M0; 93% diagnosed within 6m of randomisation; median PSA 65ng/ml. Median follow-up was 42m. Grade 3-5 toxicity was reported for 31% SOC, 50% SOC+D, 32% SOC+ZA and 52% SOC+D+ZA.There were 405 deaths on the control arm (84% from PCa). The hazard ratio was 0.76 (95% CI 0.63, 0.91; p = 0.003) for SOC+D vs SOC; 0.93 (95% CI 0.79, 1.11; p = 0.437) for SOC+ZA vs SOC; and 0.81 (95% CI 0.68, 0.97; p = 0.020) for SOC+D+ZA vs SOC. Median survival was increased by 10m from 67m on SOC to 77m on SOC+D. Results in M0 and M1 disease will be shown. Conclusions: Survival data from STAMPEDE show a clinically and statistically significant improvement in survival from adding docetaxel but not from adding zoledronic acid in men starting long-term hormone therapy for the first time. Clinical trial information: NCT00268476.
T Cell Trafficking in Allergic Asthma: The Ins and Outs
Authors: Benjamin D. Medoff, Seddon Y. Thomas, Andrew D. Luster
Journal: Annual Review of Immunology (2008)

T cells are critical mediators of the allergic airway inflammation seen in asthma. Pathogenic allergen-specific T cells are generated in regional lymph nodes and are then recruited into the airway by chemoattractants produced by the asthmatic lung. These recruited effector T cells and their products then mediate the cardinal features of asthma: airway eosinophilia, mucus hypersecretion, and airway hyperreactivity. There has been considerable progress in delineating the molecular mechanisms that control T cell trafficking into peripheral tissue, including the asthmatic lung. In this review, we summarize these advances and formulate them into a working model that proposes that T cell trafficking into and out of the allergic lung is controlled by several discrete regulatory pathways that involve the collaboration of innate and acquired immune cells.
Association of Breast Cancer Outcome With Status of p53 and MDM2 SNP309
Authors: Brenda J. Boersma, Tiffany M. Howe, Julie E. Goodman, Harry G. Yfantis, Dong H. Lee, Stephen J. Chanock, Stefan Ambs
Journal: JNCI Journal of the National Cancer Institute (2006)

A common single-nucleotide polymorphism (SNP) in the promoter region of the MDM2 gene, known as T-309G and referred to as SNP309 for this study, leads to increased expression of Mdm2 protein and attenuated function of the p53 tumor suppressor protein. We investigated whether genetic variants in MDM2 were associated with breast cancer incidence and survival and whether the variant status could interact with the tumor p53 status to modify breast cancer survival.We used multivariable logistic and Cox regression analyses to study the relationship of SNP309 status and the status of a second MDM2 SNP in exon 12 at codon 354 (SNP354) with breast cancer incidence and with disease-specific survival among 293 case patients and 317 cancer-free control subjects. Survival analysis included 248 of the 293 case patients who had known tumor p53 status. All statistical tests were two-sided.We did not observe an association between SNP309 status and breast cancer incidence in the unstratified analysis, but we did find a statistically significant association between SNP354 status and breast cancer incidence (odds ratio = 3.34, 95% confidence interval [CI] = 1.88 to 5.93). We also discovered a statistically significant interaction between SNP309 status and tumor p53 expression for breast cancer survival (P(interaction) = .002). Among homozygous carriers of the common MDM2 SNP309 allele (T/T), a mutant p53 status (risk ratio [RR] of death = 2.33, 95% CI = 1.08 to 5.03) and aberrant p53 protein expression (RR = 2.61, 95% CI = 1.22 to 5.57) in breast tumors were associated with poor survival. Tumor p53 status was not associated with breast cancer survival among carriers of the variant MDM2 SNP309 allele (G/T or G/G), which is consistent with a dominant effect of the variant allele.A strong interaction between SNP309 status and tumor p53 status appears to modify the association between p53 status and breast cancer survival.
A G/C Element Mediates Repression of the SM22α Promoter Within Phenotypically Modulated Smooth Muscle Cells in Experimental Atherosclerosis
Authors: B.R. Wamhoff, M.H. Hoofnagle, A. Burns, S. Sinha, O.G. McDonald, G.K. Owens
Journal: Circulation Research (2004)

A hallmark of smooth muscle cell (SMC) phenotypic switching in atherosclerotic lesions is suppression of SMC differentiation marker gene expression. Yet little is known regarding the molecular mechanisms that control this process. Here we show that transcription of the SMC differentiation marker gene SM22alpha is reduced in atherosclerotic lesions and identify a cis regulatory element in the SM22alpha promoter required for this process. Transgenic mice carrying the SM22alpha promoter-beta-galactosidase (beta-gal) reporter transgene were crossed to apolipoprotein E (ApoE)-/- mice. Cells of the fibrous cap, intima, and underlying media showed complete loss of beta-gal activity in advanced atherosclerotic lesions. Of major significance, mutation of a G/C-rich cis element in the SM22alpha promoter prevented the decrease in SM22alpha promoter-beta-gal reporter transgene expression, including in cells that compose the fibrous cap of the lesion and in medial cells in proximity to the lesion. To begin to assess mechanisms whereby the G/C repressor element mediates suppression of SM22alpha in atherosclerosis, we tested the hypothesis that effects may be mediated by platelet-derived growth factor (PDGF)-BB-induced increases in the G/C binding transcription factor Sp1. Consistent with this hypothesis, results of studies in cultured SMCs showed that: (1) PDGF-BB increased expression of Sp1; (2) PDGF-BB and Sp1 profoundly suppressed SM22alpha promoter activity as well as smooth muscle myosin heavy chain promoter activity through mechanisms that were at least partially dependent on the G/C cis element; and (3) a short interfering RNA to Sp1 increased basal expression and attenuated PDGF-BB induced suppression of SM22alpha. Together, these results support a model whereby a G/C repressor element within the SM22alpha promoter mediates transcriptional repression of this gene within phenotypically modulated SMCs in experimental atherosclerosis and provide indirect evidence implicating PDGF-BB and Sp1 as possible mediators of these effects.
Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2
Authors: Barbro Selander, Ulla Mårtensson, Andrej Weintraub, Eva Holmström, Misao Matsushita, Steffen Thiel, Jens C. Jensenius, Lennart Truedsson, Anders G. Sjöholm
Journal: Journal of Clinical Investigation (2006)

Lectin pathway activation of C3 is known to involve target recognition by mannan-binding lectin (MBL) or ficolins and generation of classical pathway C3 convertase via cleavage of C4 and C2 by MBL-associated serine protease 2 (MASP-2). We investigated C3 activation in C2-deficient human sera and in sera with other defined defects of complement to assess other mechanisms through which MBL might recruit complement. The capacity of serum to support C3 deposition was examined by ELISA using microtiter plates coated with O antigen–specific oligosaccharides derived from Salmonella typhimurium, S. thompson, and S. enteritidis corresponding to serogroups B, C, and D (BO, CO, and DO). MBL bound to CO, but not to BO and DO, and efficiently supported C3 deposition in the absence of C2, C4, or MASP-2. The existence of an MBL-dependent C2 bypass mechanism for alternative pathway–mediated C3 activation was clearly demonstrated using CO, solid-phase mannan, and E. coli LPS. MASP-1 might contribute, but was not required for C3 deposition in the model used. Independent of MBL, specific antibodies to CO supported C3 deposition through classical and alternative pathways. MBL-dependent C2 bypass activation could be particularly important in various inherited and acquired complement deficiency states.
Targeted delivery of cytokine therapy to rheumatoid tissue by a synovial targeting peptide
Authors: Sarah E Wythe, Danielle DiCara, Taher E I Taher, Ciara M Finucane, Rita Jones, Michele Bombardieri, Y K Stella Man, Ahuva Nissim, Stephen J Mather, Yuti Chernajovsky, Costantino Pitzalis
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> The synovial endothelium targeting peptide (SyETP) CKSTHDRLC has been identified previously and was shown to preferentially localise to synovial xenografts in the human/severe combined immunodeficient (SCID) mouse chimera model of rheumatoid arthritis (RA). The objective of the current work was to generate SyETP-anti-inflammatory-cytokine fusion proteins that would deliver bioactive cytokines specifically to human synovial tissue. <h3>Methods</h3> Fusion proteins consisting of human interleukin (IL)-4 linked via a matrix metalloproteinase (MMP)-cleavable sequence to multiple copies of either SyETP or scrambled control peptide were expressed in insect cells, purified by Ni-chelate chromatography and bioactivity tested in vitro. The ability of SyETP to retain bioactive cytokine in synovial but not control skin xenografts in SCID mice was determined by in vivo imaging using nano-single-photon emission computed tomography-computed tomography (nano-SPECT-CT) and measuring signal transducer and activator of transcription 6 (STAT6) phosphorylation in synovial grafts following intravenous administration of the fusion protein. <h3>Results</h3> In vitro assays confirmed that IL-4 and the MMP-cleavable sequence were functional. IL-4-SyETP augmented production of IL-1 receptor antagonist (IL-1ra) by fibroblast-like synoviocytes (FLS) stimulated with IL-1β &nbsp;in a dose-dependent manner. In vivo imaging showed that IL-4-SyETP was retained in synovial but not in skin tissue grafts and the period of retention was significantly enhanced through increasing the number of SyETP copies from one to three. Finally, retention correlated with increased bioactivity of the cytokine as quantified by STAT6 phosphorylation in synovial grafts. <h3>Conclusions</h3> The present work demonstrates that SyETP specifically delivers fused IL-4 to human rheumatoid synovium transplanted into SCID mice, thus providing a proof of concept for peptide-targeted tissue-specific immunotherapy in RA. This technology is potentially applicable to other biological treatments providing enhanced potency to inflammatory sites and reducing systemic toxicity.
Inhalation toxicity and carcinogenicity of 1,3-butadiene in Sprague-Dawley rats.
Authors: P E Owen, J R Glaister
Journal: Environmental Health Perspectives (1990)

A 2-year inhalation study was conducted in Sprague-Dawley rats with 1,3-butadiene. Groups of 110 male and 110 female rats inhaled 1,3-butadiene at 0, 1000, or 8000 ppm for 6hr/day, 5 days/week. Interim clinical pathology, neuromuscular, and histopathology investigations were carried out. The study terminated at 20 to 25% survival (105 weeks for females, 111 weeks for males). Following exposure to 1,3-butadiene there were no effects on hematology, blood chemistry, urine analysis, and neuromuscular function that definitely could be associated with treatment. Treatment was associated with changes in clinical condition, suppression of body weight gain, reduced survival, and increases in certain organ weights and in both common and uncommon tumor types. Although the biological interpretation of the significance of some of the tumor types is equivocal, the evidence suggests that the test article is an oncogen to the rat under the conditions of exposure used in this study, and the mechanism is more likely to be an indirect effect through the endocrine system, rather than a direct effect through the production of reactive metabolites.
Improved survival at low lung function in cystic fibrosis: cohort study from 1990 to 2007
Authors: P. M. George, W. Banya, N. Pareek, D. Bilton, P. Cullinan, M. E. Hodson, N. J. Simmonds
Journal: BMJ (2011)

<b>Objectives</b> To evaluate the survival of patients with cystic fibrosis whose lung function has deteriorated to a forced expiratory volume in one second (FEV<sub>1</sub>) below 30% predicted in the recent treatment era and to explore factors associated with any change in survival. <b>Design </b>Cohort study. <b>Setting</b> Adult cystic fibrosis unit in London. <b>Participants</b> 276 patients (147 (53%) male) whose FEV<sub>1</sub> was first observed to be less than 30% predicted between 1 January 1990 and 31 December 2003. <b>Main outcome measure</b> Survival during follow-up to 31 December 2007 in two year sub-cohorts. <b>Results</b> Median survival improved from 1.2 years in the 1990-1 group to 5.3 years in the 2002-3 group, with a marked improvement in survival from 1994. The use of nebulised recombinant human DNase was significantly associated with a reduced risk of death (hazard ratio 0.59, 95% confidence interval 0.44 to 0.79). Significantly increased risks were associated with a body mass index under 19 (hazard ratio 1.52, 1.10 to 2.10), long term oxygen therapy (3.52, 2.49 to 4.99), and nebulised antibiotics (1.84, 1.05 to 3.22). <b>Conclusion</b> A marked improvement has occurred in the survival of patients with cystic fibrosis with an FEV<sub>1</sub> less than 30% predicted. Secondary analyses suggest that some of this improvement may be due to use of recombinant human DNase.
Effect of Pressure Stress Applied to the Airway on Cough-Reflex Sensitivity in Guinea Pigs
Authors: Johsuke Hara, Masaki Fujimura, Akihito Ueda, Shigeharu Myou, Yoshitaka Oribe, Noriyuki Ohkura, Toshiyuki Kita, Masahide Yasui, Kazuo Kasahara
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

We hypothesized that cough stress of the airway wall results in a self-perpetuating cough-reflex cycle in which antigen-induced increase in cough-reflex sensitivity results in pathologic cough, and the cough in turn further amplifies cough-reflex sensitivity.To examine cough-reflex sensitivity in an experimental animal model.We developed an experimental guinea pig model in which airway collapse similar to that in cough was induced by rapid negative pressure applied to the airway of artificially ventilated animals. We examined the influence of this stimulus on cough-reflex sensitivity to inhaled capsaicin and bronchoalveolar lavage (BAL) cell components. After the termination of artificial ventilation, the number of coughs due to capsaicin was measured, and BAL was performed.Capsaicin cough-reflex sensitivity and the number of BAL neutrophils were increased 6 hours after stimulus application, decreasing to control levels by 24 hours. Cough-reflex sensitivity or BAL cell components were not changed in the absence of stimulus application. The number of BAL neutrophils correlated significantly with the number of coughs. Hydroxyurea inhibited the stimulus-induced increase in the number of coughs and airway neutrophil accumulation.Our findings suggest that cough itself is a traumatic mechanical stress to the airway wall that induces neutrophilic airway inflammation and cough-reflex hypersensitivity. Cough stress to the airway wall results in a self-perpetuating cough-reflex cycle.