tbuckley/cabot-search huggingface dataset:
Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis
Authors: Daryle J DePianto, Sanjay Chandriani, Alexander R Abbas, Guiquan Jia, Elsa N N'Diaye, Patrick Caplazi, Steven E Kauder, Sabyasachi Biswas, Satyajit K Karnik, Connie Ha, Zora Modrusan, Michael A Matthay, Jasleen Kukreja, Harold R Collard, Jackson G Egen, Paul J Wolters, Joseph R Arron
Journal: Thorax (2014)

<h3>Background</h3> There is microscopic spatial and temporal heterogeneity of pathological changes in idiopathic pulmonary fibrosis (IPF) lung tissue, which may relate to heterogeneity in pathophysiological mediators of disease and clinical progression. We assessed relationships between gene expression patterns, pathological features, and systemic biomarkers to identify biomarkers that reflect the aggregate disease burden in patients with IPF. <h3>Methods</h3> Gene expression microarrays (N=40 IPF; 8 controls) and immunohistochemical analyses (N=22 IPF; 8 controls) of lung biopsies. Clinical characterisation and blood biomarker levels of MMP3 and CXCL13 in a separate cohort of patients with IPF (N=80). <h3>Results</h3> 2940 genes were significantly differentially expressed between IPF and control samples (|fold change| &gt;1.5, p&lt;0.05). Two clusters of co-regulated genes related to bronchiolar epithelium or lymphoid aggregates exhibited substantial heterogeneity within the IPF population. Gene expression in bronchiolar and lymphoid clusters corresponded to the extent of bronchiolisation and lymphoid aggregates determined by immunohistochemistry in adjacent tissue sections. Elevated serum levels of MMP3, encoded in the bronchiolar cluster, and CXCL13, encoded in the lymphoid cluster, corresponded to disease severity and shortened survival time (p&lt;10<sup>−7</sup> for MMP3 and p&lt;10<sup>−5</sup> for CXCL13; Cox proportional hazards model). <h3>Conclusions</h3> Microscopic pathological heterogeneity in IPF lung tissue corresponds to specific gene expression patterns related to bronchiolisation and lymphoid aggregates. MMP3 and CXCL13 are systemic biomarkers that reflect the aggregate burden of these pathological features across total lung tissue. These biomarkers may have clinical utility as prognostic and/or surrogate biomarkers of disease activity in interventional studies in IPF.
Human leucocyte antigen class Ib molecules in pregnancy success and early pregnancy loss
Authors: Mette Dahl, Thomas Vauvert F. Hviid
Journal: Human Reproduction Update (2011)

BACKGROUND The human leucocyte antigen (HLA) class Ib molecules, HLA-E, -F and -G, are expressed at the materno-fetal interface. Because of the apparent immunoregulatory functions of these proteins, they may be involved in successful acceptance of the semi-allogenic fetus during pregnancy. METHODS The literature on polymorphisms of the three genes, expression patterns of the proteins, and interactions with immune cell receptors have been evaluated to elucidate whether HLA-E, -F and -G are involved in the pathogenesis of some cases of recurrent miscarriages and unexplained infertility. RESULTS AND CONCLUSIONS The HLA class Ib molecules seem to induce suppression of the maternal immune system, but are not necessarily fundamental factors for pregnancy success. However, evidence points towards low expression of these proteins, especially HLA-G, being associated with reduced fertility. To clarify the functions of HLA-E, -F and -G future studies need to link investigations of the polymorphisms in these genes to measurements of protein levels, and examine the role of these proteins in the complex interplay of immune cells and cytokines at the materno-fetal interface.
Use of intermittent stretch in the prevention of serial sarcomere loss in immobilised muscle.
Authors: P E Williams
Journal: Annals of the Rheumatic Diseases (1990)

After immobilisation of muscle in a shortened position there is a reduction of muscle fibre length due to a loss of serial sarcomeres. Experiments have been carried out to determine whether short, daily periods of stretch prevent sarcomere loss and the resultant loss of range of joint motion. It was found that periods of stretch as short as 1/2 h daily were sufficient not only to prevent loss of sarcomeres but actually to cause an increase in the number of sarcomeres in series. Range of joint motion was normal. Such short periods of stretch were also found to prevent much of the muscle atrophy normally associated with immobilisation in the shortened position.
Cyclosporine Improves Psoriasis in a Double-blind Study
Authors: Charles N. Ellis, David C. Gorsulowsky, Ted A. Hamilton, Julie K. Billings, Marc D. Brown, John T. Headington, Kevin D. Cooper, Ole Baadsgaard, Elizabeth A. Duell, Thomas M. Annesley, Jeremiah G. Turcotte, John J. Voorhees
Journal: JAMA (1986)

In a double-blind trial, 21 patients with severe plaque psoriasis were randomly assigned to receive oral cyclosporine, 14 mg/kg/d, or its vehicle. After four weeks of therapy the 11 cyclosporine recipients had the following response to treatment: two had total clearing and six improved markedly, two moderately, and one minimally; whereas ten vehicle-treated patients showed no change or minimal improvement. Vehicle-treated patients, after a switch to cyclosporine for four weeks, demonstrated impressive improvement similar to that seen in patients who initially received only cyclosporine. Moderate or marked improvement or total clearing was noted in 17 (81%) of 21 and 20 (95%) of 21 after one and four weeks of therapy, respectively. Mitotic figures and leukotriene B4 levels in lesions decreased 86% and 64%, respectively, after seven days of cyclosporine therapy. Mononuclear (including activated T cells) and polymorphonuclear leukocyte infiltrates were markedly reduced in lesions of all patients after seven days of cyclosporine therapy. These results suggest that psoriasis may have an immunologic basis mediated by activated T cells and/or other immune cells; if a long-term regimen with a favorable efficacy-side effect ratio can be determined, cyclosporine would be a significant advance in the treatment of psoriasis.
Rat lymphoid cell lines with human T cell leukemia virus production. I. Biological and serological characterization.
Authors: M Tateno, N Kondo, T Itoh, T Chubachi, T Togashi, T Yoshiki
Journal: The Journal of Experimental Medicine (1984)

Cocultivation of spleen cells, lymph node cells, and thymocytes of female Wistar-King-Aptekman rats with short-term cultured male adult T cell leukemia (ATL) cells in the presence of 5-bromo-2'-deoxyuridine (BrdUrd) resulted in the establishment of rat lymphoid cell lines, TARS-1, TARL-2, and TART-1. Cytogenetic analysis of the three cell lines showed a female rat karyotype with 42 chromosomes. The surface phenotypes of TARS-1 and TART-1 were those of rat T cells. TARL-2 was only positive for rat Ia and leukocyte common antigens. The cell lines continuously produced a type C retrovirus, human T cell leukemia virus (HTLV) and expressed ATL-associated antigens. TARS-1 and TART-1, but not TARL-2 were transplantable into newborn syngeneic rats and nude mice. These results strongly indicate that HTLV not only immortalizes, but also transforms rat T cells in vitro. Adult rats immunized with either TARS-1 or TARL-2 produced antibodies specific for HTLV. The biochemical analysis of the antigens that reacted with rat sera revealed that they are the two HTLV-specific polypeptides, p24 and p28.
Successful Eradication of Established Peritoneal Ovarian Tumors in SCID-Beige Mice following Adoptive Transfer of T Cells Genetically Targeted to the MUC16 Antigen
Authors: Alena A. Chekmasova, Thapi D. Rao, Yan Nikhamin, Kay J. Park, Douglas A. Levine, David R. Spriggs, Renier J. Brentjens
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Most patients diagnosed with ovarian cancer will ultimately die from their disease. For this reason, novel approaches to the treatment of this malignancy are needed. Adoptive transfer of a patient's own T cells, genetically modified ex vivo through the introduction of a gene encoding a chimeric antigen receptor (CAR) targeted to a tumor-associated antigen, is a novel approach to the treatment of ovarian cancer. Experimental Design: We have generated several CARs targeted to the retained extracellular domain of MUC16, termed MUC-CD, an antigen expressed on most ovarian carcinomas. We investigate the in vitro biology of human T cells retrovirally transduced to express these CARs by coculture assays on artificial antigen-presenting cells as well as by cytotoxicity and cytokine release assays using the human MUC-CD+ ovarian tumor cell lines and primary patient tumor cells. Further, we assess the in vivo antitumor efficacy of MUC-CD–targeted T cells in SCID-Beige mice bearing peritoneal human MUC-CD+ tumor cell lines. Results: CAR-modified, MUC-CD–targeted T cells exhibited efficient MUC-CD–specific cytolytic activity against both human ovarian cell and primary ovarian carcinoma cells in vitro. Furthermore, expanded MUC-CD–targeted T cells infused through either i.p. injection or i.v. infusion into SCID-Beige mice bearing orthotopic human MUC-CD+ ovarian carcinoma tumors either delayed progression or fully eradicated disease. Conclusion: These promising preclinical studies justify further investigation of MUC-CD–targeted T cells as a potential therapeutic approach for patients with high-risk MUC16+ ovarian carcinomas. Clin Cancer Res; 16(14); 3594–606. ©2010 AACR.
A global study of pathogens and host risk factors associated with infectious gastrointestinal disease in returned international travellers
Authors: Ashwin Swaminathan, Joseph Torresi, Patricia Schlagenhauf, Karin Thursky, Annelies Wilder-Smith, Bradley A. Connor, Eli Schwartz, Frank vonSonnenberg, Jay Keystone, Daniel P. O'Brien
Journal: Journal of Infection (2009)
Reference values for respiratory system resistance in adults
Authors: Dorothe Burggraf, Marion Heiß-Neumann, Matthias Wjst, Loems Ziegler-Heitbrock
Journal: European Respiratory Journal (2012)

The degree of airway disease is usually determined in spirometry using maneuvers that require quite some effort. i.e. FEV1 and FVC. Bodyplethysmography can assess airway obstruction during tidal breathing by determination of airway resistance. Reference values for resistance are, however, scarce.  Within the emphysema versus airway disease (EvA) study we therefore have determined airway resistance in a population of 261 apparently healthy Caucasian subjects aged 45 to 75 with 163 males and 98 females. These were ex-smokers for more than a year or never smokers (27%) with no evidence of acute or chronic lung disease. We determined total resistance (Rt), inspiratory resistance (Rin), expiratory resistance (Rex) and specific resistance (sR).  Rex for the entire group was 0.22±0.11 kPaxsec/L (95 Percentile = 0.45) for males it was 0.20±0.12 kPaxsec/L and for females it was 0.26±0.12 kPaxsec/L. Rin for the entire group was 0.162±0.07 kPaxsec/L (95 Percentile = 0.29) for males it was 0.15±0.07 kPaxsec/L and for females it was 0.18±0.08 kPaxsec/L.  Rt for the entire group was 0.19±0.09 kPaxsec/L (95 Percentile = 0.34).  The resistance values for the females as compared to males were significantly higher for all 4 types of parameters (p  Supported by EU FP7 project #200506.
Pathomechanisms of Type 2 Diabetes Genes
Authors: Harald Staiger, Fausto Machicao, Andreas Fritsche, Hans-Ulrich Häring
Journal: Endocrine Reviews (2009)

Type 2 diabetes mellitus is a complex metabolic disease that is caused by insulin resistance and β-cell dysfunction. Furthermore, type 2 diabetes has an evident genetic component and represents a polygenic disease. During the last decade, considerable progress was made in the identification of type 2 diabetes risk genes. This was crucially influenced by the development of affordable high-density single nucleotide polymorphism (SNP) arrays that prompted several successful genome-wide association scans in large case-control cohorts. Subsequent to the identification of type 2 diabetes risk SNPs, cohorts thoroughly phenotyped for prediabetic traits with elaborate in vivo methods allowed an initial characterization of the pathomechanisms of these SNPs. Although the underlying molecular mechanisms are still incompletely understood, a surprising result of these pathomechanistic investigations was that most of the risk SNPs affect β-cell function. This favors a β-cell-centric view on the genetics of type 2 diabetes. The aim of this review is to summarize the current knowledge about the type 2 diabetes risk genes and their variants' pathomechanisms.
Points: Under-reporting of adverse drug reactions
Authors: D N Bateman
Journal: BMJ (1985)

authors in proposing trials of adjunctive chemo- therapy after radical hysterectomy in patients at risk of recurrence but must emphasise that the reported efficacy of drug combinations applies only at present to squamous disease.Alberts et al, using cisplatin, vincristine, mito- mycin, and bleomycin showed significant long term responsiveness of recurrent and metastatic squamous cell carcinoma of the cervix.'Personal experience in their department (AC) and in Ireland using this combination, particularly in unirradiated tissues, confirms these and other reported response rates.A prospective randomised clinical trial is under way under the auspices of the Irish Gynaecological Oncology Group using this combination after radical hysterectomy for stage lb squamous carcinoma of the cervix with associated risk factors for recurrence.This brings us to suggest the hitherto-unthink- able.Given those at high risk of residual disease after radical hysterectomy and the increasingly effective chemotherapy regimens, how do we assess the status of the patient after adjunctive chemotherapy?Are we approaching the concept of secondary exploratory laparotomy subsequent to postoperative chemotherapy for squamous cell carcinoma of the cervix?
The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers
Authors: Liyong Zhang, Michael S Anglesio, Maureen O'Sullivan, Fan Zhang, Ge Yang, Renu Sarao, Mai P Nghiem, Shane Cronin, Hiromitsu Hara, Nataliya Melnyk, Liheng Li, Teiji Wada, Peter P Liu, Jason Farrar, Robert J Arceci, Poul H Sorensen, Josef M Penninger
Journal: Nature Medicine (2007)
IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice
Authors: Pamela Gasse, Caroline Mary, Isabelle Guenon, Nicolas Noulin, Sabine Charron, Silvia Schnyder-Candrian, Bruno Schnyder, Shizuo Akira, Valérie F.J. Quesniaux, Vincent Lagente, Bernhard Ryffel, Isabelle Couillin
Journal: Journal of Clinical Investigation (2007)

The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1– and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1β recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1β production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.
Allorestricted cytotoxic T cells specific for human CD45 show potent antileukemic activity
Authors: Persis J. Amrolia, Steven D. Reid, Liquan Gao, Beate Schultheis, Gianpietro Dotti, Malcolm K. Brenner, Junia V. Melo, John M. Goldman, Hans J. Stauss
Journal: Blood (2003)
Cardiopulmonary Resuscitation With Chest Compressions During Sustained Inflations
Authors: Georg M. Schmölzer, Megan O’Reilly, Joseph LaBossiere, Tze-Fun Lee, Shaun Cowan, Sharon Qin, David L. Bigam, Po-Yin Cheung
Journal: Circulation (2013)

Background— Guidelines on neonatal resuscitation recommend 90 chest compressions (CCs) and 30 manual inflations (3:1) per minute in newborns. The study aimed to determine whether CC s during sustained inflations (SIs) improves the recovery of asphyxiated newborn piglets in comparison with coordinated 3:1 resuscitation. Methods and Results— Term newborn piglets (n=8/group) were anesthetized, intubated, instrumented, and exposed to 45-minute normocapnic hypoxia followed by asphyxia. Piglets were randomly assigned to receive either 3:1 resuscitation (3:1 group) or CCs during SIs (SI group) when the heart rate decreased to 25% of baseline. Piglets randomly assigned to the SI group received SIs with a pressure of 30 cm H 2 O for 30 s. During the SI, CCs at a rate of 120/min were provided. SI was interrupted after 30 s for 1 s before a further 30-s SI was provided. CCs were continued throughout SIs. CCs and SI were continued until the return of spontaneous circulation. Continuous respiratory parameters, cardiac output, mean systemic and pulmonary artery pressures, and regional blood flows were measured. Mean (standard deviation) time for return of spontaneous circulation was significantly reduced in SI group versus 3:1 group (32 [11] s versus 205 [113] s, respectively). In the SI group, administration of oxygen and epinephrine was significantly lower, whereas minute ventilation and exhaled CO 2 were significantly increased. The SI group had significantly higher mean systemic and pulmonary arterial pressures during resuscitation in comparison with the 3:1 group (51 [10] versus 31 [5] mm Hg; 41[7] versus 31 [7] mm Hg, respectively; all P &lt;0.05), with improved cardiac output and carotid blood flow. Conclusions— Combining CCs and SIs significantly improved the return of spontaneous circulation with better hemodynamic recovery in asphyxiated newborn piglets in comparison with standard coordinated 3:1 resuscitation.
Prospects for personalizing antiviral therapy for hepatitis C virus with pharmacogenetics
Authors: John E Tavis, Maureen J Donlin, Rajeev Aurora, Xiaofeng Fan, Adrian M Di Bisceglie
Journal: Genome Medicine (2011)

Chronic hepatitis C virus (HCV) infection is a major cause of liver disease worldwide. HCV infection is currently treated with IFNα plus ribavirin for 24 to 48 weeks. This demanding therapy fails in up to 50% of patients, so the use of pharmacogenetic biomarkers to predict the outcome of treatment would reduce futile treatment of non-responders and help identify patients in whom therapy would be justified. Both IFNα and ribavirin primarily act by modulating the immune system of the patient, and HCV uses multiple mechanisms to counteract the antiviral effects stimulated by therapy. Therefore, response to therapy is influenced by variations in human genes governing the immune system and by differences in HCV genes that blunt antiviral immune responses. This article summarizes recent advances in understanding how host and viral genetic variation affect outcome of therapy. The most notable human associations are polymorphisms within the IL28B gene, but variations in human leukocyte antigen and cytokine genes have also been associated with treatment outcome. The most prominent viral genetic association with outcome of therapy is that HCV genotype 1 is much less sensitive to treatment than genotypes 2 and 3, but genetic differences below the genotype level also influence outcome of therapy, presumably by modulating the ability of viral genes to blunt antiviral immune responses. Pharmacogenetic prediction of the outcome of IFN-based therapy for HCV will require integrating the efficacies of the immunosuppressive mechanisms of a viral isolate, and then interpreting the viral resistance potential in context of the genetic profile of the patient at loci associated with outcome of therapy. Direct-acting inhibitors of HCV that will be used in combination with IFNα are nearing approval, so genetic prediction for anti-HCV therapy will soon need to incorporate viral genetic markers of viral resistance to the new drugs.
Five year study of etidronate and/or calcium as prevention and treatment for osteoporosis and fractures in patients with asthma receiving long term oral and/or inhaled glucocorticoids
Authors: I A Campbell
Journal: Thorax (2004)

<b>Background:</b> Glucocorticoids are associated with a reduction in bone density and an increased risk of fracture. Concurrent treatment with bisphosphonates reduces bone loss and may prevent fractures. A randomised study was performed to determine whether treatment with cyclical etidronate and/or calcium for 5 years prevents fractures or reverses/reduces bone loss in patients receiving glucocorticoid treatment for asthma. <b>Methods:</b> A multicentre, randomised, parallel group comparison of etidronate alone, calcium alone, etidronate + calcium, and no treatment, with stratification according to level of glucocorticoid exposure was carried out in 39 chest clinics in the UK. Three hundred and forty nine postmenopausal female and male outpatients with asthma aged 50–70 years were randomised. The main outcome measures were fractures and changes in bone mineral density (BMD). <b>Results:</b> Overall, 8% of the patients experienced symptomatic fractures and 17.5% developed either a symptomatic fracture and/or a semiquantitative vertebral fracture by the end of 5 years There were no significant differences between the four treatment groups. Comparing etidronate with no etidronate, the rates of new fractures were not significantly different for symptomatic fractures (OR 1.07 (95% CI 0.46 to 2.47)) or for any fractures (OR 0.82 (95% CI 0.45 to 1.47)). For the comparison of calcium with no calcium the corresponding ORs were 1.43 (95% CI 0.62 to 3.33) and 0.91 (95% CI 0.50 to 1.63). In post hoc analysis the effect of etidronate was greater in women than in men (interaction p value 0.02) with the fracture incidence roughly halved (OR 0.39, 95% CI 0.14 to 0.99). Etidronate increased BMD at the lumbar spine by 4.1% (p = 0.001) while calcium had no significant effect. At the proximal femur the effects of treatment were not significant (relative increases etidronate 1.6%; calcium 1.1%). The rate of new fractures in patients with fractures at entry (23.7%) was higher than in those without fractures at entry (14.3%): OR 1.87 (95% CI 1.06 to 3.07). No association was found between change in BMD and new fractures. <b>Conclusions:</b> In patients receiving glucocorticoids for asthma etidronate significantly increased BMD over 5 years at the lumbar spine but not at the hip and had little if any protective effect against fractures, except possibly in postmenopausal women. The effects of calcium were not significant. Combination treatment had no advantage but increased unwanted effects.