tbuckley/cabot-search huggingface dataset:
A limited CpG-containing oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway inflammation in mice
Authors: John D Campbell, Sariah A Kell, Heather M Kozy, Jeremy A Lum, Rosemary Sweetwood, Mabel Chu, Cameron R Cunningham, Hugh Salamon, Clare M Lloyd, Robert L Coffman, Edith M Hessel
Journal: Thorax (2014)

<h3>Background</h3> CpG-containing oligodeoxynucleotides (CpG-ODNs) are potent inhibitors of T helper 2 mediated allergic airway disease in sensitised mice challenged with allergen. A single treatment has transient effects but a limited series of treatments has potential to achieve clinically meaningful sustained inhibition of allergic airway disease. <h3>Objective</h3> To optimise the treatment regimen for sustained efficacy and to determine the mechanisms of action in mice of an inhaled form of CpG-ODN being developed for human asthma treatment. <h3>Methods</h3> We set up a chronic allergic-asthma model using ragweed-sensitised mice exposed weekly to intranasal ragweed. Using this model, the effects of a limited series of weekly intranasal 1018 ISS (CpG-ODN; B-class) treatments were evaluated during treatment and for several weeks after treatments had stopped but weekly allergen exposures continued. Treatment efficacy was evaluated by measuring effects on lung T helper 2 cytokines and eosinophilia, and lung dendritic cell function and T-cell responses. <h3>Results</h3> Twelve intranasal 1018 ISS treatments induced significant suppression of bronchoalveolar lavage eosinophilia and interleukin 4, 5 and 13 levels. This suppression of allergic T helper 2 parameters was maintained through 13 weekly ragweed exposures administered after treatment cessation. Subsequent experiments demonstrated that at least five treatments were required for lasting suppression. Although CpG-ODN induced moderate T helper 1 responses, suppression of allergic airway disease did not require interferon γ but was associated with induction of a regulatory T-cell response. <h3>Conclusions</h3> A short series of CpG-ODN treatments results in sustained suppression of allergic lung inflammation induced by a clinically relevant allergen.
Quantitative DNA Methylation Analysis of <i>FOXP3</i> as a New Method for Counting Regulatory T Cells in Peripheral Blood and Solid Tissue
Authors: Georg Wieczorek, Anne Asemissen, Fabian Model, Ivana Turbachova, Stefan Floess, Volker Liebenberg, Udo Baron, Diana Stauch, Katja Kotsch, Johann Pratschke, Alf Hamann, Christoph Loddenkemper, Harald Stein, Hans Dieter Volk, Ulrich Hoffmüller, Andreas Grützkau, Alexander Mustea, Jochen Huehn, Carmen Scheibenbogen, Sven Olek
Journal: Cancer Research (2009)

Abstract Regulatory T-cells (Treg) have been the focus of immunologic research due to their role in establishing tolerance for harmless antigens versus allowing immune responses against foes. Increased Treg frequencies measured by mRNA expression or protein synthesis of the Treg marker FOXP3 were found in various cancers, indicating that dysregulation of Treg levels contributes to tumor establishment. Furthermore, they constitute a key target of immunomodulatory therapies in cancer as well as transplantation settings. One core obstacle for understanding the role of Treg, thus far, is the inability of FOXP3 mRNA or protein detection methods to differentiate between Treg and activated T cells. These difficulties are aggravated by the technical demands of sample logistics and processing. Based on Treg-specific DNA demethylation within the FOXP3 locus, we present a novel method for monitoring Treg in human peripheral blood and solid tissues. We found that Treg numbers are significantly increased in the peripheral blood of patients with interleukin 2–treated melanoma and in formalin-fixed tissue from patients with lung and colon carcinomas. Conversely, we show that immunosuppressive therapy including therapeutic antibodies leads to a significant reduction of Treg from the peripheral blood of transplantation patients. In addition, Treg numbers are predictively elevated in the peripheral blood of patients with various solid tumors. Although our data generally correspond to data obtained with gene expression and protein-based methods, the results are less fluctuating and more specific to Treg. The assay presented here measures Treg robustly in blood and solid tissues regardless of conservation levels, promising fast screening of Treg in various clinical settings. [Cancer Res 2009;69(2):599–608]
Genetic control of the immune response to nuclease. V. Genetic linkage and strain distribution of anti-nuclease idiotypes.
Authors: C G Fathman, D S Pisetsky, D H Sachs
Journal: The Journal of Experimental Medicine (1977)

Rat antisera raised against anti-nuclease antibodies from mouse strains A/J and SJL detect strain-specific idiotypic determinants related to the antigen-combining site. These antisera have been used to investigate the genetic linkage and strain distribution of the anti-nuclease idiotypes. Despite the existence of an H-2-linked immune response gene controlling the humoral response to nuclease, expression of the A/J anti-nuclease idiotype has been shown to be independent of genes in the H-2 region: the A/J idiotype was present in immune sera from strains A/J (H-2a) and A.BY (H-2b) but absent in sera from strains B10 (H-2b) and B10.A (H-2a). An analysis of the segregation of the A/J idiotype in offspring of the backcross (A/J x B10.A) x B10.A demonstrated linkage to the Ig-1e heavy chain allotype markers. In a small sample of backcross animals a very high apparent recombination frequency was observed, but further backcross analyses and progeny testing of putative recombinant animals will be required to substantiate this observation. Analysis of the A/J and SJL anti-nuclease idiotype markers in the BALB/c, CB.20, and BAB.14 strains indicate that these idiotypic markers may permit mapping of distinct variable region genes.
Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation
Authors: Kithiganahalli N. Balaji, Norbert Schaschke, Werner Machleidt, Marta Catalfamo, Pierre A. Henkart
Journal: The Journal of Experimental Medicine (2002)

The granule exocytosis cytotoxicity pathway is the major molecular mechanism for cytotoxic T lymphocyte (CTL) and natural killer (NK) cytotoxicity, but the question of how these cytotoxic lymphocytes avoid self-destruction after secreting perforin has remained unresolved. We show that CTL and NK cells die within a few hours if they are triggered to degranulate in the presence of nontoxic thiol cathepsin protease inhibitors. The potent activity of the impermeant, highly cathepsin B-specific membrane inhibitors CA074 and NS-196 strongly implicates extracellular cathepsin B. CTL suicide in the presence of cathepsin inhibitors requires the granule exocytosis cytotoxicity pathway, as it is normal with CTLs from gld mice, but does not occur in CTLs from perforin knockout mice. Flow cytometry shows that CTLs express low to undetectable levels of cathepsin B on their surface before degranulation, with a substantial rapid increase after T cell receptor triggering. Surface cathepsin B eluted from live CTL after degranulation by calcium chelation is the single chain processed form of active cathepsin B. Degranulated CTLs are surface biotinylated by the cathepsin B-specific affinity reagent NS-196, which exclusively labels immunoreactive cathepsin B. These experiments support a model in which granule-derived surface cathepsin B provides self-protection for degranulating cytotoxic lymphocytes.
Updated Definitions of Healthy Ranges for Serum Alanine Aminotransferase Levels
Authors: Daniele Prati, Emanuela Taioli, Alberto Zanella, Emanuela Della Torre, Sonia Butelli, Emanuela Del Vecchio, Luciana Vianello, Francesco Zanuso, Fulvio Mozzi, Silvano Milani, Dario Conte, Massimo Colombo, Girolamo Sirchia
Journal: Annals of Internal Medicine (2002)

Background: Serum alanine aminotransferase (ALT) activity, the variable most commonly measured to assess hepatic disease, fails to identify many patients with hepatic injury. Current standards for "normal" ALT level were defined by using populations that included persons with subclinical liver disease. Objective: To update definitions of healthy ranges for serum ALT level. Design: Retrospective cohort study. Setting: A university hospital in Milan, Italy. Participants: 6835 persons who were first-time blood donors from 1995 through 1999, were negative for anti–hepatitis C virus (HCV), and had no contraindications to donation and 209 persons who attempted to donate blood from 1990 through 1999 but were found to have anti–HCV antibodies. Of the latter group, 131 had HCV viremia. Measurements: Univariate and multivariate analyses examined associations between clinical and laboratory factors and ALT levels. Healthy ranges for ALT were computed from the population at lowest risk for liver disease. Sensitivity and specificity of healthy ALT ranges were evaluated in the donors with HCV antibodies, of whom 133 had liver biopsy. Results: Serum ALT activity was independently related to body mass index and to laboratory indicators of abnormal lipid or carbohydrate metabolism. Updated upper limits (for men, 500 nkat/L [30 U/L]; for women, 317 nkat/L [19 U/L]) were lower than current limits (for men, 667 nkat/L [40 U/L]; for women, 500 nkat/L [30 U/L]) and, during 6-month follow-up, showed superior sensitivity in identifying participants with HCV viremia (sensitivity, 76.3% [95 % CI, 69.1% to 83.6%] vs. 55% [CI, 46.4% to 63.5%]). The related tradeoff in specificity was acceptable (88.5% [CI, 79.2% to 94.6%] vs. 97.4% [91% to 99.7%]). The increased sensitivity targeted patients with minimal to mild histologic lesions. Conclusion: In patients with chronic HCV infection or nonalcoholic fatty liver disease, revision of normal limits for ALT level is advisable.
Higher risk of cardiovascular mortality among lean hypertensive individuals in Tecumseh, Michigan.
Authors: W J Carman, E Barrett-Connor, M Sowers, K T Khaw
Journal: Circulation (1994)

A cohort of 2181 men and women, aged 40 to 79 years, without evidence of coronary heart disease or cancer at entry to the Tecumseh Study was evaluated.Subjects were defined as lean if their Metropolitan Life Insurance table relative weight was < 110 (n = 584) and as obese if their relative weight was > or = 120 (n = 1024). There were 688 subjects with hypertension at study entry (systolic blood pressure > or = 160, diastolic blood pressure > or = 95, or treated). The 29-year relative risk (RR) of mortality from ischemic heart disease (IHD) or cardiovascular disease (CVD) associated with systolic blood pressure level was significant for both lean and obese subjects. Among hypertensive subjects, the RR of fatal IHD for lean versus obese hypertensive subjects was 1.87 (95% confidence interval, 1.21 to 2.88) and the RR of fatal CVD was 1.56 (95% confidence interval, 1.10 to 2.20) using a Cox proportional-hazards model to adjust for the independent effects of age and traditional CVD risk factors. The findings are consistent with other studies in men showing lean hypertensive subjects to be at greater risk of IHD or CVD mortality than obese hypertensive subjects. A similar finding is now observed in women.Associations do not prove causality or dictate management. Nevertheless, the unexplained higher mortality in lean versus obese hypertensive subjects has now been reported with sufficient frequency to suggest that the association is real (if unexplained). Determining the reasons for this association may improve targeted prevention and treatment strategies.
Technetium-99m stannous pyrophosphate imaging of experimental infective endocarditis.
Authors: A L Riba, J Downs, M L Thakur, A Gottschalk, V T Andriole, B L Zaret
Journal: Circulation (1978)

Technetium-99m stannous pyrophosphate (99mTc-PYP) cardiac scintigraphy was performed in 15 rabbits with experimental Streptococcus sanguis aortic valve infective endocarditis. The animals were imaged five to seven days after the administration of bacteria, and in each case abnormal accumulation of the tracer was visualized in the region of the aortic valve. Three types of cardiac scintigraphic patterns were demonstrated: focal, multifocal and extensive, each correlating well with the anatomical extent of the lesion as defined by gross pathology. Tissue distribution studies demonstrated a 30 +/- 5.3 (mean +/- SEM) fold excess of radionuclide uptake in the infective endocarditis lesion compared with that of normal myocardium. Imaging of excised hearts from four animals showed an excellent correlation with in vivo imaging as well as gross pathology. Five animals with nonbacterial thrombotic aortic valve endocarditis demonstrated similar scintigraphic and tissue distribution results. In contrast, four normal animals failed to demonstrate abnormal 99mTc-PYP cardiac scintigrams or tissue uptake. This study demonstrates that 99mTc-PYP cardiac scintigraphy is a sensitive technique to detect experimental aortic valve endocarditis.
Influence of exercise and CO2 on breathing pattern in patients with chronic obstructive lung disease (COLD)
Authors: G Scano, F Gigliotti, A van Meerhaeghe, A De Coster, R Sergysels
Journal: European Respiratory Journal (1988)

In ten eucapnic patients with chronic obstructive lung disease (COLD) we evaluated the breathing pattern during induced progressive hypercapnia (CO2 rebreathing) and progressive exercise on an ergometric bicycle (30 W/3 min). The time and volume components of the respiratory cycle were measured breath by breath. When compared to hypercapnia, the increase in ventilation (VE) during exercise was associated with a smaller increase in tidal volume (VT) and a greater increase in respiratory frequency (fR). Plots of tidal volume (VT) against both inspiratory time (TI) and expiratory time (TE) showed a greater decrease in both TI and TE during exercise than with hypercapnia. Analysis of VE in terms of flow (VT/TI) and timing (TI/TT) showed VE to increase by a similar increase to that in VT/TI during both exercise and hypercapnia, while TI/TT did not change significantly. When the patients were matched for a given VE (28 l.min-1), exercise induced a smaller increase in VT (p less than 0.05), a greater increase in fR (p less than 0.025); TI (p less than 0.025) and TE (p less than 0.01) were found to be smaller during exercise than hypercapnia. The change in the off-switch mechanism during exercise and hypercapnia could account for our results.
Fatty Acid-Binding Protein in Small Intestine IDENTIFICATION, ISOLATION, AND EVIDENCE FOR ITS ROLE IN CELLULAR FATTY ACID TRANSPORT
Authors: Robert K. Ockner, Joan A. Manning
Journal: Journal of Clinical Investigation (1974)

A soluble fatty acid-binding protein (FABP), mol wt ∼ 12,000 is present in intestinal mucosa and other tissues that utilize fatty acids, including liver, myocardium, adipose, and kidney. This protein binds long chain fatty acids both in vivo and in vitro.
Persistence of respiratory syncytial virus (RSV) infection and development of RSV-specific IgG1 response in a guinea-pig model of acute bronchiolitis
Authors: A Dakhama, TZ Vitalis, RG Hegele
Journal: European Respiratory Journal (1997)

Acute respiratory syncytial virus (RSV) bronchiolitis in children can result in sequelae of recurrent wheezing and asthma and production of RSV-specific immunoglobulin E (IgE), but the pathogenesis of these sequeleae is poorly understood. Guinea-pigs experimentally inoculated with human RSV show histological evidence of acute bronchiolitis and chronic persistence of viral antigens and genome in the lungs; whether this persistence is due to infectious replicating virus, and whether infected animals develop RSV-specific immunoglobulin G1 (IgG1) (the main class of antibody involved in guinea-pig allergic responses) is unknown. Guinea-pigs were inoculated intranasally with human RSV or with uninfected cell culture supernatant. At times ranging 1-60 days postinoculation, the viral titre in the lung was determined by immunoplaque assay (a method combining viral culture and immunocytochemistry). Serum titres of RSV-specific IgG1 antibodies were determined by enzyme-linked immunosorbent assay. Bronchiolar inflammation was assessed on coded lung sections, by using a semiquantitative, histological scoring system based on features of human acute bronchiolitis. Infectious RSV was cultured from the lungs of infected animals on all study days, with maximal viral replication observed on Day 3. RSV-specific IgG1 antibodies were detected in all RSV-inoculated animals from Day 7 onward, with the highest antibody titre measured on Day 28. RSV-inoculated guinea-pigs had maximal bronchiolar inflammation on Day 7, and had significantly increased polymorphonuclear cell infiltrates on Days 28 and 60. Respiratory syncytial virus chronically persists as infectious virus in the guinea-pig lung. Infected animals develop an anti-respiratory syncytial virus immunoglobulin G1 antibody response, histological evidence of acute bronchiolitis, and chronic airway inflammation. Persistent respiratory syncytial virus lung infection may be important in the pathogenesis of postbronchiolitis wheezing and asthma in children.
Effect of withdrawal of co-proxamol on prescribing and deaths from drug poisoning in England and Wales: time series analysis
Authors: K. Hawton, H. Bergen, S. Simkin, A. Brock, C. Griffiths, E. Romeri, K. L Smith, N. Kapur, D. Gunnell
Journal: BMJ (2009)

<b>Objective</b> To assess the effect of the UK Committee on Safety of Medicines’ announcement in January 2005 of withdrawal of co-proxamol on analgesic prescribing and poisoning mortality. <b>Design</b> Interrupted time series analysis for 1998-2007. <b>Setting</b> England and Wales. <b>Data sources</b> Prescribing data from the prescription statistics department of the Information Centre for Health and Social Care (England) and the Prescribing Services Unit, Health Solutions Wales (Wales). Mortality data from the Office for National Statistics. <b>Main outcome measures</b> Prescriptions. Deaths from drug poisoning (suicides, open verdicts, accidental poisonings) involving single analgesics. <b>Results</b> A steep reduction in prescribing of co-proxamol occurred in the post-intervention period 2005-7, such that number of prescriptions fell by an average of 859 (95% confidence interval 653 to 1065) thousand per quarter, equating to an overall decrease of about 59%. Prescribing of some other analgesics (co-codamol, paracetamol, co-dydramol, and codeine) increased significantly during this time. These changes were associated with a major reduction in deaths involving co-proxamol compared with the expected number of deaths (an estimated 295 fewer suicides and 349 fewer deaths including accidental poisonings), but no statistical evidence for an increase in deaths involving either other analgesics or other drugs. <b>Conclusions</b> Major changes in prescribing after the announcement of the withdrawal of co-proxamol have had a marked beneficial effect on poisoning mortality involving this drug, with little evidence of substitution of suicide method related to increased prescribing of other analgesics.
Value of Early Referral to Fertility Preservation in Young Women With Breast Cancer
Authors: Sanghoon Lee, Sinan Ozkavukcu, Elke Heytens, Fred Moy, Kutluk Oktay
Journal: Journal of Clinical Oncology (2010)

To determine whether early referral to reproductive specialists improves fertility preservation (FP) outcomes and reduces delay in adjuvant treatment in young women with breast cancer.A secondary analysis of a prospective database of patients with breast cancer undergoing ovarian stimulation (OS) for FP by oocyte or embryo cryopreservation was performed.Of the 154 patients, 93 met the inclusion criteria (mean age, 35.2 ± 4.4 years). Thirty-five of the 93 patients were referred before breast surgery (PreS), and 58 patients were referred after surgery (PostS). The time periods from initial diagnosis (ID) to initiation of OS (42.6 ± 27.7 days for PreS v 71.9 ± 30.7 days for PostS; P < .001) and from ID to initiation of chemotherapy (83.9 ± 24.3 days for PreS v 107.8 ± 42.9 days for PostS; P = .045) were significantly shorter for the PreS group versus the PostS group. Nine (25.7%) of 35 patients in the PreS group versus one (1.7%) of 58 patients in the PostS group were able to undergo two FP cycles (P < .001), resulting in an increased yield of oocytes in the PreS group (18.2% [93 of 511 oocytes] v 0.6% [five of 800 oocytes], respectively; P < .001) and embryos (17.2% [40 of 233 embryos] v 0.6% [two of 357 embryos], respectively; P < .001). Patients who had an oocyte retrieval within 5 weeks of the surgery were able to complete a second cycle within 9 weeks of the surgery.FP referral before breast surgery enables earlier initiation of cryopreservation cycles and chemotherapy and, when appropriate, multiple FP cycles. Women who can undergo multiple cycles may be at advantage for FP because of a larger number of oocytes or embryos cryopreserved. This is the first study demonstrating the benefit of early FP referral in patients with cancer.
Prognostic Significance of Transcription Factor E2F-1 in Bladder Cancer: Genotypic and Phenotypic Characterization
Authors: F. Rabbani
Journal: JNCI Journal of the National Cancer Institute (1999)

We sought to identify and characterize potential alterations in E2F-1, a transcription factor that binds to the retinoblastoma protein (pRB), in bladder neoplasms and to elucidate a possible role for E2F-1 as an oncogene or a tumor suppressor gene.Tumor samples from 133 evaluable patients with bladder cancer were analyzed for E2F-1 gene mutations by use of polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis and DNA sequencing. In addition, tumors were studied for E2F-1 and pRB protein expression by use of immunohistochemistry. Results from the above analyses were correlated with clinicopathologic parameters and outcome. All P values are two-sided.A polymorphism, consisting of a nucleotide change at amino acid codon 393 in exon 7 (GGC-->AGC [Gly-->Ser]), was identified in seven of 133 case patients, being present in both tumor and corresponding normal tissues. No bandshifts were identified in the nuclear-localization or DNA-binding domains on PCR-SSCP analysis. On immunohistochemical analysis, E2F-1 nuclear reactivity was observed in less than 5% of the cells from 53 tumors and in 5%-75% of the cells from the remaining 80 tumors. The pattern of E2F-1 protein expression was not altered in relation to the identified polymorphism. pRB nuclear reactivity greater than 20% (of tumor cells stained) was present in 66% of the samples. E2F-1 nuclear reactivity correlated inversely with the percentage of cells showing pRB reactivity (Kendall tau(b) = -0.18; P = .019). On multivariate analysis, patients with lower E2F-1 reactivity had statistically significantly increased risks of progression to metastases (P = .001) and death (P = .02).E2F-1 alterations occur at the phenotypic level, rather than at the genotypic level, in bladder cancer. The adverse outcome for patients whose tumors exhibit low E2F-1 nuclear expression suggests a possible tumor suppressor role for E2F-1 in bladder cancer.