tbuckley/cabot-search huggingface dataset:
Quality of life and dyspnoea in patients treated with bosentan for idiopathic pulmonary fibrosis (BUILD-1)
Authors: G. Raghu, T. E. King, J. Behr, K. K. Brown, R. M. du Bois, I. Leconte, S. Roux, J. Swigris
Journal: European Respiratory Journal (2009)

No therapy is known to improve health-related quality of life (HRQoL) or dyspnoea in patients with idiopathic pulmonary fibrosis. The present study investigated longitudinal changes in HRQoL and dyspnoea and explored the effects of bosentan on these end-points during the Bosentan Use in Interstitial Lung Disease (BUILD)-1 trial. In total, 154 subjects received oral bosentan (n = 71) or placebo (n = 83). Changes in HRQoL and dyspnoea from baseline to month (M) 6 and up to M12 were measured using the St George’s Respiratory Questionnaire (SGRQ), 36-item short-form health survey (SF-36), Transition Dyspnoea Index and Borg dyspnoea index. Overall, minimal changes occurred in measures of HRQoL and dyspnoea among placebo-treated subjects during the study. The effects of bosentan treatment on HRQoL and dyspnoea in the all-treated population were minimal. However, in the subset of subjects who had undergone surgical lung biopsy for diagnosis of idiopathic pulmonary fibrosis, treatment effects were observed up to M12 in the impact domain of the SGRQ and the physical functioning, general health and role emotional domains of the SF-36. HRQoL and dyspnoea changed minimally during the course of the present study. Observations from exploratory analyses suggested benefits of bosentan on HRQoL among patients who had undergone surgical lung biopsy for diagnosis, and they merit further investigation.
Acute appendicitis in nine British towns.
Authors: D J Barker, A Liggins
Journal: BMJ (1981)

The incidence of acute appendicitis was compared among residents in nine towns in England and Wales, the towns having been chosen so that three were in the north, three in the central latitude band, and three in the south. Each group of three towns comprised one with "better,' one with "intermediate,' and one with "worse' socioeconomic conditions. The data were derived from hospital records for the years 1974-7. Hospital discharge rates for acute appendicitis were higher in the three northern towns in both sexes and all age groups. There was no consistent variation with the socioeconomic state of the towns. The distribution of appendicitis in the nine towns differed from that of other "diseases of Western civilisation' and so weighs against the hypothesis of similar dietary influences in the aetiology of acute appendicitis and these other diseases. These findings are being followed up by dietary surveys in the towns.
Ethnic Differences in Patterns of Suicide Across the Life Cycle
Authors: Steven J. Garlow, David Purselle, Michael Heninger
Journal: American Journal of Psychiatry (2005)

The authors analyzed suicide across the life cycle of different ethnic groups in an urban population equally divided between blacks (44.6%) and whites (48.1%).Two data sets were used: 1) all suicides in Fulton County, Ga., from January 1994 through December 2002 and 2) all U.S. suicides reported by the National Center for Injury Prevention in 1999 and 2000.The population rates for suicide in Fulton County were 1.22 per 100,000 black females, 10.74 per 100,000 black males, 9.89 per 100,000 white females, and 21.04 per 100,000 white males. In Fulton County, age at completed suicide was more than a decade lower in blacks than in whites. The median age of black victims was 32 years, with an interquartile range (IQR) of 23-45, and the median for whites was 44 years (IQR=31-58); the difference was significant. The mean ages of victims who were black (mean=36.1 years, SD=17.0) and of "other" race (mean=35.7, SD=14.3) were significantly lower than the mean for whites (mean=46.2, SD=18.5). The national data were similar, but minorities accounted for an even smaller percentage of suicides. Median age at completed suicide for African Americans nationally was 34 years (IQR=24-45) compared to 44 years (IQR=32-58) for Caucasians.African Americans commit suicide at rates much lower than those for whites, but they do so when much younger and they have a narrow, age-defined window of vulnerability. Age-specific psychopathological processes and protective factors may define suicide risk for each demographic group.
Managing common mental health disorders in primary care: conceptual models and evidence base
Authors: Peter Bower, Simon Gilbody
Journal: BMJ (2005)

Adipose tissue fibrosis is regulated by the chronic and progressive metabolic imbalance caused by differences in caloric intake and energy expenditure. By exploring the cellular heterogeneity within fibrotic adipose tissue, we demonstrate that early adipocyte progenitor cells expressing both platelet-derived growth factor receptor (PDGFR) α and β are the major contributors to extracellular matrix deposition. We show that the fibrotic program is promoted by senescent macrophages. These macrophages were enriched in the fibrotic stroma and exhibit a distinct expression profile. Furthermore, we demonstrate that these cells display a blunted phagocytotic capacity and acquire a senescence-associated secretory phenotype. Finally, we determined that osteopontin, which was expressed by senescent macrophages in the fibrotic environment promoted progenitor cell proliferation, fibrotic gene expression, and inhibited adipogenesis. Our work reveals that obesity promotes macrophage senescence and provides a conceptual framework for the discovery of rational therapeutic targets for metabolic and inflammatory disease associated with obesity.
LSECtin Expressed on Melanoma Cells Promotes Tumor Progression by Inhibiting Antitumor T-cell Responses
Authors: Feng Xu, Jing Liu, Di Liu, Biao Liu, Min Wang, Zhiyuan Hu, Xuemei Du, Li Tang, Fuchu He
Journal: Cancer Research (2014)

Abstract Therapeutic antibodies that target T-cell co-inhibitory molecules display potent antitumor effects in multiple types of cancer. LSECtin is a cell surface lectin of the DC-SIGN family expressed in dendritic cells that inhibits T-cell responses. LSECtin limits T-cell activity in infectious disease, but it has not been studied in cancer. Here we report the finding that LSECtin is expressed commonly in melanomas where it blunts tumor-specific T-cell responses. When expressed in B16 melanoma cells, LSECtin promoted tumor growth, whereas its blockade slowed tumor growth in either wild-type or LSECtin-deficient mice. The tumor-promoting effects of LSECtin were abrogated in Rag1−/− mice or in response to CD4+ or CD8+ T-cell depletion. Mechanistic investigations determined that LSECtin inhibited the proliferation of tumor-specific effector T cells by downregulating the cell cycle kinases CDK2, CDK4, and CDK6. Accordingly, as expressed in B16, tumor cells LSECtin inhibited tumor-specific T-cell responses relying upon proliferation in vitro and in vivo. Notably, LSECtin interacted with the co-regulatory molecule LAG-3, the blockade of which restored IFNγ secretion that was reduced by melanoma-derived expression of LSECtin. Together, our findings reveal that common expression of LSECtin in melanoma cells engenders a mechanism of immune escape, with implications for novel immunotherapeutic combination strategies. Cancer Res; 74(13); 3418–28. ©2014 AACR.
IL-2/IL-2Ab Complexes Induce Regulatory T Cell Expansion and Protect against Proteinuric CKD
Authors: Tania Polhill, Geoff Yu Zhang, Min Hu, Andrew Sawyer, Jimmy Jianheng Zhou, Mitsuru Saito, Kylie E. Webster, Ya Wang, Yiping Wang, Shane T. Grey, Jonathan Sprent, David C.H. Harris, Stephen I. Alexander, Yuan Min Wang
Journal: Journal of the American Society of Nephrology (2012)

Regulatory T cells (Tregs) help protect against autoimmune renal injury. The use of agonist antibodies and antibody/cytokine combinations to expand Tregs in vivo may have therapeutic potential for renal disease. Here, we investigated the effects of administering IL-2/IL-2Ab complexes in mice with adriamycin nephropathy, a model of proteinuric kidney disease that resembles human focal segmental glomerulosclerosis. Injecting IL-2/IL-2Ab complexes before or, to a lesser extent, after induction of disease promoted expansion of Tregs. Furthermore, administration of this complex was renoprotective, evidenced by improved renal function, maintenance of body weight, less histologic injury, and reduced inflammation. IL-2/IL-2Ab reduced serum IL-6 and renal expression of IL-6 and IL-17 but enhanced expression of IL-10 and Foxp3 in the spleen. In vitro, the addition of IL-2/IL-2Ab complexes induced rapid STAT-5 phosphorylation in CD4 T cells. In summary, these data suggest that inducing the expansion of Tregs by administering IL-2/IL-2Ab complexes is a possible strategy to treat renal disease.
Randomized, Controlled Trial of Acupuncture for the Treatment of Hot Flashes in Breast Cancer Patients
Authors: Gary Deng, Andrew J. Vickers, K. Simon Yeung, Gabriella M. D'Andrea, Han Xiao, Alexandra S. Heerdt, Steven Sugarman, Tiffany Troso-Sandoval, Andrew D. Seidman, Clifford A. Hudis, Barrie R. Cassileth
Journal: Journal of Clinical Oncology (2007)

Purpose To determine the immediate and long-term effects of true acupuncture versus sham acupuncture on hot flash frequency in women with breast cancer. Patients and Methods Seventy-two women with breast cancer experiencing three or more hot flashes per day were randomly assigned to receive either true or sham acupuncture. Interventions were given twice weekly for 4 consecutive weeks. Hot flash frequency was evaluated at baseline, at 6 weeks, and at 6 months after initiation of treatment. Patients initially randomly assigned to the sham group were crossed over to true acupuncture starting at week 7. Results The mean number of hot flashes per day was reduced from 8.7 (standard deviation [SD], 3.9) to 6.2 (SD, 4.2) in the true acupuncture group and from 10.0 (SD, 6.1) to 7.6 (SD, 5.7) in the sham group. True acupuncture was associated with 0.8 fewer hot flashes per day than sham at 6 weeks, but the difference did not reach statistical significance (95% CI, −0.7 to 2.4; P = .3). When participants in the sham acupuncture group were crossed over to true acupuncture, a further reduction in the frequency of hot flashes was seen. This reduction in hot flash frequency persisted for up to 6 months after the completion of treatment. Conclusion Hot flash frequency in breast cancer patients was reduced following acupuncture. However, when compared with sham acupuncture, the reduction by the acupuncture regimen as provided in the current study did not reach statistical significance. We cannot exclude the possibility that a longer and more intense acupuncture intervention could produce a larger reduction of these symptoms.
Studies on the role of the host immune response in recovery from Friend virus leukemia. II. Cell-mediated immunity.
Authors: B Chesebro, K Wehrly
Journal: The Journal of Experimental Medicine (1976)

Congenic mouse strains differing only at genes within the H-2 complex were found to have virus-specific cytotoxic effector cells in their spleens during or after recovery from Friend leukemia virus-induced splenomegaly. These effector cells were theta-positive T lymphocytes which functioned in vitro without help or inhibition by B lymphocytes or glass-adherent cells. The antigenic specificities recognized by the effector cells were viral-induced cellular antigens apparently different from those identified by serological techniques.
Circulating interleukin 6 during a continuous infusion of tumor necrosis factor and interferon gamma.
Authors: P Brouckaert, D R Spriggs, G Demetri, D W Kufe, W Fiers
Journal: The Journal of Experimental Medicine (1989)

Plasma samples obtained from patients receiving a 24-h continuous infusion of human recombinant (hr)TNF or a combination of two overlapping, 24-h continuous infusions of hrIFN-gamma and hrTNF were analyzed for IL-6 in a sensitive bioassay. A transient appearance of circulating IL-6 was observed with peak levels between 3 and 6 h after the start of the hrTNF infusion. These peak levels correlated quite well with the dose of hrTNF administered (r = 0.86; p less than 0.001). The maximal value observed was 27.5 ng/ml IL-6 in a sample of a patient receiving 545 micrograms/m2 hrTNF. The combination of hrIFN-gamma (200 micrograms/m2) and hrTNF in the infusions resulted in higher IL-6 levels than a comparable dose of hrTNF alone. A maximal value of 23.5 ng/ml IL-6 was observed in a patient receiving 205 micrograms/m2 hrTNF. No IL-6 was found in the plasma of patients during the 12-h infusion with hrIFN-gamma alone, except for two borderline samples.
Cell Labeling and Tracking Method without Distorted Signals by Phagocytosis of Macrophages
Authors: Sun-Woong Kang, Sangmin Lee, Jin Hee Na, Hwa In Yoon, Dong-Eun Lee, Heebeom Koo, Yong Woo Cho, Sun Hwa Kim, Seo Young Jeong, Ick Chan Kwon, Kuiwon Choi, Kwangmeyung Kim
Journal: Theranostics (2014)

Cell labeling and tracking are important processes in understanding biologic mechanisms and the therapeutic effect of inoculated cells in vivo.Numerous attempts have been made to label and track inoculated cells in vivo; however, these methods have limitations as a result of their biological effects, including secondary phagocytosis of macrophages and genetic modification.Here, we investigated a new cell labeling and tracking strategy based on metabolic glycoengineering and bioorthogonal click chemistry.We first treated cells with tetra-acetylated N-azidoacetyl-D-mannosamine to generate unnatural sialic acids with azide groups on the surface of the target cells.The azide-labeled cells were then transplanted to mouse liver, and dibenzyl cyclooctyne-conjugated Cy5 (DBCO-Cy5) was intravenously injected into mice to chemically bind with the azide groups on the surface of the target cells in vivo for target cell visualization.Unnatural sialic acids with azide groups could be artificially induced on the surface of target cells by glycoengineering.We then tracked the azide groups on the surface of the cells by DBCO-Cy5 in vivo using bioorthogonal click chemistry.Importantly, labeling efficacy was enhanced and false signals by phagocytosis of macrophages were reduced.This strategy will be highly useful for cell labeling and tracking.
Human Eosinophils Express Granzyme B and Perforin: Potential Role in Tumour Killing in Oral Squamous Cancer
Authors: F. Davoine, A. Sim, T. Wierzbicki, C. Leong, L. Puttagunta, T. McGaw, D. Yu, R. Moqbel
Journal: Journal of Allergy and Clinical Immunology (2006)
Prediction of Survival in Multiple Myeloma Based on Gene Expression Profiles Reveals Cell Cycle and Chromosomal Instability Signatures in High-Risk Patients and Hyperdiploid Signatures in Low-Risk Patients: A Study of the Intergroupe Francophone du Myélome
Authors: Olivier Decaux, Laurence Lodé, Florence Magrangeas, Catherine Charbonnel, Wilfried Gouraud, Pascal Jézéquel, Michel Attal, Jean-Luc Harousseau, Philippe Moreau, Régis Bataille, Loïc Campion, Hervé Avet-Loiseau, Stéphane Minvielle
Journal: Journal of Clinical Oncology (2008)

Survival of patients with multiple myeloma is highly heterogeneous, from periods of a few weeks to more than 10 years. We used gene expression profiles of myeloma cells obtained at diagnosis to identify broadly applicable prognostic markers.In a training set of 182 patients, we used supervised methods to identify individual genes associated with length of survival. A survival model was built from these genes. The validity of our model was assessed in our test set of 68 patients and in three independent cohorts comprising 853 patients with multiple myeloma.The 15 strongest genes associated with the length of survival were used to calculate a risk score and to stratify patients into low-risk and high-risk groups. The survival-predictor score was significantly associated with survival in both the training and test sets and in the external validation cohorts. The Kaplan-Meier estimates of rates of survival at 3 years were 90.5% (95% CI, 85.6% to 95.3%) and 47.4% (95% CI, 33.5% to 60.1%), respectively, in our patients having a low risk or high risk independently of traditional prognostic factors. High-risk patients constituted a homogeneous biologic entity characterized by the overexpression of genes involved in cell cycle progression and its surveillance, whereas low-risk patients were heterogeneous and displayed hyperdiploid signatures.Gene expression-based survival prediction and molecular features associated with high-risk patients may be useful for developing prognostic markers and may provide basis to treat these patients with new targeted antimitotics.
Hepatitis C virus induced up-regulation of microRNA-27: A novel mechanism for hepatic steatosis
Authors: Ragunath Singaravelu, Ran Chen, Rodney K. Lyn, Daniel M. Jones, Shifawn O'Hara, Yanouchka Rouleau, Jenny Cheng, Prashanth Srinivasan, Neda Nasheri, Rodney S. Russell, D. Lorne Tyrrell, John Paul Pezacki
Journal: Hepatology (2013)

MicroRNAs (miRNAs) are small RNAs that posttranscriptionally regulate gene expression. Their aberrant expression is commonly linked with diseased states, including hepatitis C virus (HCV) infection. Herein, we demonstrate that HCV replication induces the expression of miR-27 in cell culture and in vivo HCV infectious models. Overexpression of the HCV proteins core and NS4B independently activates miR-27 expression. Furthermore, we establish that miR-27 overexpression in hepatocytes results in larger and more abundant lipid droplets, as observed by coherent anti-Stokes Raman scattering (CARS) microscopy. This hepatic lipid droplet accumulation coincides with miR-27b's repression of peroxisome proliferator-activated receptor (PPAR)-α and angiopoietin-like protein 3 (ANGPTL3), known regulators of triglyceride homeostasis. We further demonstrate that treatment with a PPAR-α agonist, bezafibrate, is able to reverse the miR-27b-induced lipid accumulation in Huh7 cells. This miR-27b-mediated repression of PPAR-α signaling represents a novel mechanism of HCV-induced hepatic steatosis. This link was further demonstrated in vivo through the correlation between miR-27b expression levels and hepatic lipid accumulation in HCV-infected SCID-beige/Alb-uPa mice.Collectively, our results highlight HCV's up-regulation of miR-27 expression as a novel mechanism contributing to the development of hepatic steatosis.
On the mechanism of drug-induced blockade of Na+ currents: interaction of antiarrhythmic compounds with DPI-modified single cardiac Na+ channels.
Authors: M Kohlhardt, H Fichtner, U Fröbe, J W Herzig
Journal: Circulation Research (1989)

In patch-clamped membranes from neonatal rat cardiocytes, elementary Na+ currents were recorded at 19 degrees C for study of the inhibitory influence of several antiarrhythmic drugs including lidocaine, diprafenone, propafenone, and prajmalium on DPI-modified cardiac Na+ channels. Diprafenone (20 mumol/l) and lidocaine (300 mumol/l) induced a voltage- and time-dependent block of reconstructed macroscopic sodium current (INa). The drugs depressed the sustained, noninactivating INa component (which reflects the number and open probability of DPI-modified Na+ channels) effectively, in a voltage- and time-dependent fashion. Once opened, DPI-modified Na+ channels are highly drug-sensitive. Antiarrhythmic drugs (propafenone, diprafenone, and, to a lesser extent, lidocaine) provoke a flicker block, that is, the long-lasting openings are chopped into a large number of short and grouped openings. This indicates rapid transitions between a drug-associated, blocked state and a drug-free, conducting state. The latter has a unitary conductance of 12 pS, very similar to the control value in the absence of antiarrhythmic drugs. The decrease in open time of drug-treated DPI-modified Na+ channels is concentration-dependent. Hill coefficients for propafenone of about 1.0 and for prajmalium of about 0.7 were calculated. A blocking rate constant of 6.1 x 10(7) mol-1sec-1 for propafenone, but of 1.5 x 10(7) mol-1sec-1 for prajmalium was obtained at -30 mV. The unblocking rate constant for propafenone was, also at -30 mV, about twice as large as the unblocking rate constant for prajmalium. The open channel block kinetics are essentially voltage-dependent. The affinity of the channel-associated drug receptor increases on membrane depolarization. The blocking rate constant was inversely related to the number of Na+ ions moving through the open channel. It is concluded that the manifestation of this voltage- and Na+-dependent flicker block is intimately related to removal of fast Na+ inactivation.
Insertion of a self-expandable endotracheal metal stent using topical anaesthesia and a fibreoptic bronchoscope: a comfortable way to offer palliation.
Authors: D Coolen, H Slabbynck, D Galdermans, C Van Schaardenburg, L L Mortelmans
Journal: Thorax (1994)

A self-expandable stent was used to obtain prolonged relief of stridor resulting from tracheal obstruction by extrinsic tumour compression despite prior external irradiation. The stent was inserted in an easy and comfortable procedure with fibreoptic bronchoscopy under local anaesthesia.
Heat shock factor 1 over-expression protects against exposure of hydrophobic residues on mutant SOD1 and early mortality in a mouse model of amyotrophic lateral sclerosis
Authors: Pei-Yi Lin, Sharotka M Simon, Won Kyun Koh, Oluwarotimi Folorunso, C Samuel Umbaugh, Anson Pierce
Journal: Molecular Neurodegeneration (2013)

Abstract Background Mutations in the Cu/Zn superoxide dismutase gene (SOD1) are responsible for 20% of familial forms of amyotrophic lateral sclerosis (ALS), and mutant SOD1 has been shown to have increased surface hydrophobicity in vitro . Mutant SOD1 may adopt a complex array of conformations with varying toxicity in vivo . We have used a novel florescence-based proteomic assay using 4,4’-bis-1-anilinonaphthalene-8-sulfonate (bisANS) to assess the surface hydrophobicity, and thereby distinguish between different conformations, of SOD1and other proteins in situ . Results Covalent bisANS labeling of spinal cord extracts revealed that alterations in surface hydrophobicity of H46R/H48Q mutations in SOD1 provoke formation of high molecular weight SOD1 species with lowered solubility, likely due to increased exposure of hydrophobic surfaces. BisANS was docked on the H46R/H48Q SOD1 structure at the disordered copper binding and electrostatic loops of mutant SOD1, but not non-mutant WT SOD1. 16 non-SOD1 proteins were also identified that exhibited altered surface hydrophobicity in the H46R/H48Q mutant mouse model of ALS, including proteins involved in energy metabolism, cytoskeleton, signaling, and protein quality control. Heat shock proteins (HSPs) were also enriched in the detergent-insoluble fractions with SOD1. Given that chaperones recognize proteins with exposed hydrophobic surfaces as substrates and the importance of protein homeostasis in ALS, we crossed SOD1 H46R/H48Q mutant mice with mice over-expressing the heat shock factor 1 (HSF1) transcription factor. Here we showed that HSF1 over-expression in H46R/H48Q ALS mice enhanced proteostasis as evidenced by increased expression of HSPs in motor neurons and astrocytes and increased solubility of mutant SOD1. HSF1 over-expression significantly reduced body weight loss, delayed ALS disease onset, decreases cases of early disease, and increased survival for the 25 th percentile in an H46R/H48Q SOD1 background. HSF1 overexpression did not affect macroautophagy in the ALS background, but was associated with maintenance of carboxyl terminus of Hsp70 interacting protein (CHIP) expression which declined in H46R/H48Q mice. Conclusion Our results uncover the potential importance of changes in protein surface hydrophobicity of SOD1 and other non-SOD1 proteins in ALS, and how strategies that activate HSF1 are valid therapies for ALS and other age-associated proteinopathies.