tbuckley/cabot-search huggingface dataset:
Urinary eicosanoids and preschool wheeze phenotype
Authors: Mubin Ibrahim, Chinedu Nwokoro, Marek Sanak, Hitesh Pandya, Steve Turner, Jonathan Grigg
Journal: European Respiratory Journal (2012)

Rationale:   Preschool wheeze follows two broad clinical patterns; i) multi-trigger wheeze (wheeze both with and between colds) and ii) episodic viral wheeze (wheeze exclusively with colds). Whether these patterns reflect stable, distinct phenotypes with different underlying inflammation remains unclear.   Hypothesis:   We hypothesised that preschool children with multi-trigger wheeze have chronic pulmonary leukotriene activation, and therefore higher baseline urinary eicosanoids, than episodic viral wheezers.   Methods:   Children aged 10 months to 5 years with wheeze and no respiratory comorbidity were recruited from three UK hospitals. Wheezing pattern was obtained from parental history. Urine was collected between viral-triggered attacks and frozen at -70 o C. Samples were analysed using high performance liquid chromatography tandem mass spectrometry for a range of eicosanoids (Table 1).   Results:   There was no significant demographic difference between multi-triggered (n=46) and episodic (n=115) wheezers. There was no significant difference in baseline eicosanoid excretion between the 2 groups (P=NS by unpaired t-test, Table 1).   Conclusions:   We found no evidence that the multi-trigger phenotype is associated with increased baseline eicosanoid activation.  Dedicated to the memory of Prof Andrzej Szczeklik who would have been a co-author.
Consumed by breathlessness - A critical interpretative synthesis
Authors: Samantha Harrison, Lindsay Apps, Mick Steiner, Sally Singh, Noelle Robertson
Journal: European Respiratory Journal (2012)

Background:  COPD is characterised by acute exacerbations (AE) often prompting hospital admission. The application of The Common Sense Model suggests that scrutinising the reported experiences of AE and increasing understanding of appraisals of AE may suggest ways to target interventions.   Methods:  A systematic review was conducted. The terms: exacerbate* OR hospital* AND “Chronic obstructive” OR emphysema OR bronchitis AND interview* OR qualitative were used to search electronic databases. Inclusion criteria included: primary research published in English of the patient9s experience of an AE COPD, using qualitative methodologies. 8 full text papers were included. Data were extracted by 3researchers and constructs elicited by 2researchers via Reciprocal Translational Analysis.   Findings:  Themes reflected 3 stages of understanding an AE: 1.  Acute effect  - intense emotions, somatic awareness, need for rescue. 2.  Recurrent impact  –ongoing beliefs and behaviour, life interrupted. 3.  Systems engagement  - help-seeking, faith in the professional.   Conclusions:  Patients are fearful of their symptoms, this prompts constant vigilance and increased passivity. Targeted interventions that acknowledge intense fear and shape appraisals and acceptance may reduce distress and improve focus of self-management messages.
Intracellular glutathione redox status in human dendritic cells regulates Th1/Th2 balance through IL-12 and IL-27 production
Authors: Kunio Dobashi, Yosuke Kamide, Mitsuyoshi Utsugi, Akihito Ono, Tamotsu Ishizuka, Takeshi Hisada, Yasuhiko Koga, Masatomo Mori
Journal: European Respiratory Journal (2012)

Glutathione redox status, changes in intracellular reduced (GSH) or oxidized (GSSG) glutathione, plays a significant role in cellular function. We examined whether intracellular glutathione redox status in human dendritic cells (DCs) regulates the production of polarizing signals, such as IL-27, IL-12, and Th1/Th2 responses.  Human PBMCs were obtained from healthy adult volunteers, and monocyte-derived DCs (MD-DCs) were generated from PBMCs. MD-DCs treated with glutathione reduced form ethyl ester (GSH-OEt) or L-buthionine-(S,R)-sulfoximine (BSO) were stimulated by LPS, and the levels of Th1 and Th2 cytokines were measured. Then, DCs matured by LPS or TSLP were cocultured with allogeneic CD4(+) naive T cells and Th1/Th2 balance was evaluated.  Monocyte-derived DCs exposed to GSH-OEt and BSO had increased and decreased intracellular GSH contents, respectively. LPS-induced IL-27 and IL-12 production was enhanced by GSH-OEt and suppressed by BSO. Mature GSH-OEt-treated MD-DCs enhanced interferon (IFN)-γ production from CD4(+) T cells compared with nontreated MD-DCs, and siRNA against IL-27 and anti-IL-12 mAb suppressed the effect of GSH-OEt on IFN-γ production. Although human myeloid DCs activated by TSLP (TSLP-DCs) prime naive CD4(+) T cells to differentiate into Th2 cells, treatment of TSLP-DCs with GSH-OEt reduced IL-13 production and enhanced IFN-γ production by CD4(+) T cells. Interleukin-27 p28 siRNAs and anti-IL-12 mAb attenuated the inhibitory effect of GSH-OEt on Th2 polarization.  These results indicate that Th1 and Th2 balance are controlled by intracellular glutathione redox status in DCs through the production of IL-27 and IL-12.
Assessment of inflammatory biomarkers and oxidative stress in pulmonary thromboembolism
Authors: Bilal Halici, Sevinc Sarinc Ulasli, Ersin Gunay, Serkan Nural, Sekan Sen, Olcay Akar, Sefa Celik, Mehmet Unlu
Journal: European Respiratory Journal (2013)

Introduction: Pulmonary thromboembolism (PTE) is a preventable disease charecterized by diagnostic difficulties with high mortality and morbidity rates. Failure in pulmonary circulation cause inflammation and oxidative stress. In the present study we aimed to investigate inflammatory markers, ADMA levels and the oxidant-antioxidant balance in patients with PTE.

Materials&Methods: This study was conducted as prospective case control study. Thirty eight patients with the diagnosis of PTE enrolled to the study. Healthy subjects were selected as control group. Venous blood samples were obtained from PTE patients during initial diagnosis and at the first month of treatment and from control subjects and IL6, TNF-α, TAS, TOS and ADMA levels were measured in biochemistry labarotory. Results of patients and healthy subjects were compared.

Results: Thirty eight patients (F/M: 17/21) with the diagnosis of PTE between 2010 and 2012 followed in our clinic and 38 healthy subjects (F/M: 17/21) were recruited to the study. While we found significant differences between patient and control groups in terms of IL6, TNF-α, TAS, ADMA and OSI values (p=0.001; p=0.038; p=0.008; p=0.028; p=0.024 respectively), TOS values were not different between groups (p=0.65). ADMA, IL6, TNF-α, TAS, TOS and OSI values of patients during initial diagnosis and at first month treatment were not different (p>0.05).

Discussion: The results of this study indicate increased inflammation, endothelial damage and oxidative stress in PTE. No difference at the first month of therapy suggests ongoing processes. We consider that these markers may be useful in the diagnosis of PTE.
Bronchial responsiveness and decline in FEV1 in aluminium potroom workers
Authors: V Soyseth, J Kongerud, H Kjuus, J Boe
Journal: European Respiratory Journal (1994)

We have investigated the relationship between annual decline in forced expiratory volume in one second (delta FEV1) and bronchial responsiveness (BR) in aluminium potroom workers. BR was measured in a cross-sectional study of 337 aluminium potroom workers half-way through a 6 yr follow-up study of lung function. A skin-prick test (SPT) was also performed. During follow-up the mean number of measurements of lung function (FEV1) in each subject was 6.8. Mean delta FEV1 was 21.3 ml.yr-1 (within subject SD = 30.5 ml.yr-1). Mean delta FEV1 was 57.0, 44.5 and 16.6 ml.yr-1 in subjects who had provocative concentration producing a 20% fall in FEV1 (PC20) < or = 8.0, 8.1-32.0 and > 32.0 mg.ml-1, respectively. After adjustment for gender, atopy, smoking habit, FEV1, age and familial asthma the association between BR and delta FEV1 was weakened, and was not statistically significant. A significantly accelerated decline in FEV1 with age was found. The difference in delta FEV1 between smokers and nonsmokers was 39.3 ml.yr-1, and between subjects who had a positive skin-prick test compared to subjects with a negative skin-prick test 39.6 ml.yr-1. In subjects reporting work-related asthmatic symptoms the decline in FEV1 was 43.2 ml.yr-1 greater than in asymptomatic subjects. In asymptomatic subjects, positive skin-prick test was also associated with increased delta FEV1. These data indicate that a single measurement of BR is not a predictor of delta FEV1 in aluminium potroom workers. Smoking, work-related asthmatic symptoms, and positive reaction to skin-prick test in asymptomatic workers were risk factors of increased delta FEV1.
Idiopathic pulmonary upper lobe fibrosis shows distinct features and poor prognosis compared to idiopathic pulmonary fibrosis
Authors: Makoto Shioya, Mitsuo Otsuka, Yasuo Kitamura, Keiki Yokoo, Kimiyuki Ikeda, Hirotaka Nishikiori, Masanori Shiratori, Hiroki Takahashi
Journal: European Respiratory Journal (2013)

Objectives: Idiopathic pulmonary upper lobe fibrosis (IPUF) characterized by its unique distribution of abnormalities occupies a part of idiopathic interstitial pneumonias (IIPs) in spite of being a few. We aimed to clarify the clinical features and prognosis of IPUF in comparison with idiopathic pulmonary fibrosis (IPF).  Methods: We subjected 18 IPUF patients (6 male, 12 female) and 49 IPF patients (40 male, 9 female) who were identified on the basis of the medical records of patients with IIPs in our hospital between 2009-‘12. IPUF was diagnosed in consideration of upper lobe dominant distribution of abnormalities regardless having honeycombing on HRCT. Their clinical data including BMI, PFT, serum markers (SP-A, SP-D, KL-6) and TRPG on echocardiography were analyzed. Survival was calculated by the Kaplan-Meier method.  Results: Nine of 18 IPUF showed honeycombing. There was no difference in mean age between IPUF and IPF. Rate of female was significantly higher in IPUF. IPUF showed significantly lower rate of smoking habitant (44 v.s. 84%), lower BMI (20.8 v.s. 24.4). IPUF showed high incidence of previous pneumothorax (50%). Significantly lower %FVC (63.1 v.s. 80.0%) was shown in IPUF, while there was no significant difference in %DLco. In IPUF, SP-A was significantly lower (63.3 v.s. 84.2 ng/ml), while SP-D trended to be higher than IPF. IPUF complicated pulmonary hypertension (PH; TRPG > 30 mmHg) more often than IPF (59 v.s. 35%). The survival time was significantly shorter in IPUF.  Conclusions: IPUF had different features in many parameters including PFT and serum markers from IPF. Moreover, IPUF had higher incidence of PH and worse outcome than IPF.
Next-Generation Sequencing of Tubal Intraepithelial Carcinomas
Authors: Andrew S. McDaniel, Jennifer N. Stall, Daniel H. Hovelson, Andi K. Cani, Chia-Jen Liu, Scott A. Tomlins, Kathleen R. Cho
Journal: JAMA Oncology (2015)

High-grade serous carcinoma (HGSC) is the most prevalent and lethal form of ovarian cancer. HGSCs frequently arise in the distal fallopian tubes rather than the ovary, developing from small precursor lesions called serous tubal intraepithelial carcinomas (TICs, or more specifically, STICs). While STICs have been reported to harbor TP53 mutations, detailed molecular characterizations of these lesions are lacking.We performed targeted next-generation sequencing (NGS) on formalin-fixed, paraffin-embedded tissue from 4 women, 2 with HGSC and 2 with uterine endometrioid carcinoma (UEC) who were diagnosed as having synchronous STICs. We detected concordant mutations in both HGSCs with synchronous STICs, including TP53 mutations as well as assumed germline BRCA1/2 alterations, confirming a clonal association between these lesions. Next-generation sequencing confirmed the presence of a STIC clonally unrelated to 1 case of UEC, and NGS of the other tubal lesion diagnosed as a STIC unexpectedly supported the lesion as a micrometastasis from the associated UEC.We demonstrate that targeted NGS can identify genetic alterations in minute lesions, such as TICs, and confirm TP53 mutations as early driving events for HGSC. Next-generation sequencing also demonstrated unexpected associations between presumed STICs and synchronous carcinomas, providing evidence that some TICs are actually metastases rather than HGSC precursors.
Immunohistologic Characterization of Major Histocompatibility Antigens and Inflammatory Cellular Infiltrate in Human Breast Cancer&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: A K Bhan, C L DesMarais
Journal: JNCI Journal of the National Cancer Institute (1983)

The presence of major histocompatibility antigens [HLA-A,B,C; beta 2 microglobulin (beta 2)m; la-like] on tumor cells and the nature and distribution of mononuclear cellular infiltrates in benign and malignant human breast tumors were studied by the use of monoclonal antibodies and immunoperoxidase techniques on frozen tissue sections. Although all benign tumors expressed HLA-A,B,C or beta 2m, 20 of 53 primary breast cancers did not react with anti-HLA-A,B,C or anti-beta 2m antibodies. Expression of la-like antigens was rarely encountered on tumor cells. The intensity of the inflammatory mononuclear cellular response did not correlate with the expression of HLA-A,B,C or beta 2m by the tumor cells. Most of the mononuclear cells were identified as T-cells. T-cells with a cytotoxic-suppressor phenotype (T8+) were generally the predominant cell type among those found as single cells in the tumor stroma or invading tumor nests. However, infiltration of tumor nests by lymphocytes was infrequently seen and was usually limited to the periphery of the tumor. In contrast, lymphocytes with a helper-inducer phenotype (T4+, Leu-3a+) predominated in the lymphoid aggregates. Anti-Leu-7 (HNK-1) antibody, which reacts with natural killer cells, stained only a few mononuclear cells in the cellular infiltrate in most cases of breast cancer.
Metabolic and cardiovascular comorbidity in COPD patients classified using the GOLD 2011 assessment framework
Authors: P.W. Jones, G. Nadeau, M. Small, L. Adamek
Journal: European Respiratory Journal (2012)

The GOLD guidelines 2011 proposed a new COPD assessment framework which considers current symptoms and future exacerbation risk of adverse events: (A: less symptoms, low risk; B: more symptoms, low risk; C: less symptoms, high risk; D: more symptoms, high risk). This analysis examined comorbidity rates in patients classified using this method.

View this table:



Data from 1041 EU COPD patients (39% from primary care) in the 2011 Adelphi Disease Specific Programme were used in which medical diagnosis of comorbidity was recorded. The GOLD groups were defined using the CAT ≥10 cut-point between patients with less and more symptoms.

One third (32.9%) of patients (mean age 64.9 years) had ≥2 exacerbations in the previous year; 79.5% had FEV1 ≥50%. The table shows the percentage of patients with metabolic and cardiovascular comorbidities in each GOLD Group. Across the groups there was a significant difference in incidence of comorbidity, except for diagnosed coronary artery disease. With the exception of Group C, where there were too few patients for interpretation, there was a clear trend for higher comorbidity in patients with more symptoms and a higher risk of adverse events.

The new GOLD classification identifies groups of patients with differing incidence of metabolic and cardiovascular comorbidity. This comorbidity rises with worsening GOLD Group, which has implications for clinical practice and an understanding of the pathobiology of the disease.
Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome
Authors: Anna Cariboni, Valentina André, Sophie Chauvet, Daniele Cassatella, Kathryn Davidson, Alessia Caramello, Alessandro Fantin, Pierre Bouloux, Fanny Mann, Christiana Ruhrberg
Journal: Journal of Clinical Investigation (2015)

Individuals with an inherited deficiency in gonadotropin-releasing hormone (GnRH) have impaired sexual reproduction. Previous genetic linkage studies and sequencing of plausible gene candidates have identified mutations associated with inherited GnRH deficiency, but the small number of affected families and limited success in validating candidates have impeded genetic diagnoses for most patients. Using a combination of exome sequencing and computational modeling, we have identified a shared point mutation in semaphorin 3E (SEMA3E) in 2 brothers with Kallmann syndrome (KS), which causes inherited GnRH deficiency. Recombinant wild-type SEMA3E protected maturing GnRH neurons from cell death by triggering a plexin D1–dependent (PLXND1-dependent) activation of PI3K-mediated survival signaling. In contrast, recombinant SEMA3E carrying the KS-associated mutation did not protect GnRH neurons from death. In murine models, lack of either SEMA3E or PLXND1 increased apoptosis of GnRH neurons in the developing brain, reducing innervation of the adult median eminence by GnRH-positive neurites. GnRH neuron deficiency in male mice was accompanied by impaired testes growth, a characteristic feature of KS. Together, these results identify SEMA3E as an essential gene for GnRH neuron development, uncover a neurotrophic function for SEMA3E in the developing brain, and elucidate SEMA3E/PLXND1/PI3K signaling as a mechanism that prevents GnRH neuron deficiency.
Expression profile of apoptosis genes in breast tumors over expressing survivin.
Authors: Frédérique Végran, Romain Boidot, Pierre Fumoleau, Lyse Hahnel, Muriel Cadouot, Sarab Lizard-Nacol
Journal: Clinical Cancer Research (2006)

A82   Molecular profiling of tumors may help devise individualized anticancer therapies. A candidate tumor biomarker is survivin, a member of the Inhibitor of Apoptosis (IAP) gene family over expressed in several human cancer. Survivin expression has often been linked to accelerated relapses, refractory disease and unfavorable outcome. Recent studies indicate that Survivin inhibits apoptosis by blocking pro caspase-9 activation and the mitochondrial apoptosis pathway. Here, we aimed to determine the correlation between survivin and the other apoptotic members. First we analyzed survivin expression in 41 breast tumors by quantitative RT-PCR and then the tumors were classified in two groups according to the median expression of tumors and we studied the main apoptosis gene expression profile on macroarray membranes (Super Array GeHs002). These membranes contained 96 genes belonging to TNF ligand and TNF receptor family, Bcl-2, Caspase, IAP, CARD, Death Domain, Death Effector Domain and CIDE Domain families as well as p53 and ATM pathways. The comparison between the two groups of tumors was performed by the Mann-Whitney U-test.The data showed that the group over expressing survivin has high expression levels for TNFRSF10A ( p= 0.0224), MCL1 belonging to Bcl-2 family ( p= 0.0023), CASP4 ( p= 0.0259), RIPK1 belonging to Death Domain family ( p= 0.0192), CASP8AP2 belonging to Death Effector Domain family ( p= 0.0028), CIDEA and DFFA belonging to CIDE Domain family ( p= 0.0376 and  p= 0.0371) and HUS1 belonging to p53/ATM pathway ( p= 0.008).These results indicate that apoptosis is activated in breast cancer by the receptor pathway, with at least TNFRSF10, RIPK1 and CASP8AP2 up-regulated in order to compensate for apoptosis inhibition by survivin. The validation of macro array results will be performed by quantitative real time PCR. Moreover, the relationship between each gene expression will be investigated.
Protein Tyrosine Phosphatase Nonreceptor Type 2: An Important Regulator of lnterleukin‐6 Production in Rheumatoid Arthritis Synovial Fibroblasts
Authors: Borbala Aradi, Masaru Kato, Maria Filkova, Emmanuel Karouzakis, Kerstin Klein, Michael Scharl, Christoph Kolling, Beat A. Michel, Renate E. Gay, Edit I. Buzas, Steffen Gay, Astrid Jüngel
Journal: Arthritis & Rheumatology (2015)

To investigate the role of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in the pathogenesis of rheumatoid arthritis (RA).Synovial tissue samples from patients with RA and patients with osteoarthritis (OA) were stained for PTPN2. Synovial fibroblasts were stimulated with tumor necrosis factor (TNF) and interleukin-1β (IL-1β), lipopolysaccharide (LPS), TRAIL, or thapsigargin. The expression of PTPN2 in synovial fibroblasts and peripheral blood mononuclear cells (PBMCs) was analyzed by real-time polymerase chain reaction and Western blotting. Cell death, the release of IL-6 and IL-8, and the induction of autophagy were analyzed after PTPN2 silencing. Methylated DNA immunoprecipitation analysis was used to evaluate DNA methylation-regulated gene expression of PTPN2.PTPN2 was significantly overexpressed in synovial tissue samples from RA patients compared to OA patients. Patients receiving anti-TNF therapy showed significantly reduced staining for PTPN2 compared with patients treated with nonbiologic agents. PTPN2 expression was higher in RA synovial fibroblasts (RASFs) than in OASFs. This differential expression was not regulated by DNA methylation. PTPN2 was further up-regulated after stimulation with TNF, TNF combined with IL-1β, or LPS. There was no significant difference in basal PTPN2 expression in PBMCs from patients with RA, ankylosing spondylitis, or systemic lupus erythematosus or healthy controls. Most interestingly, PTPN2 silencing in RASFs significantly increased the production of the inflammatory cytokine IL-6 but did not affect levels of IL-8. Moreover, functional analysis showed that high PTPN2 levels contributed to the increased apoptosis resistance of RASFs and increased autophagy.This is the first study of PTPN2 in RASFs showing that PTPN2 regulates IL-6 production, cell death, and autophagy. Our findings indicate that PTPN2 is linked to the pathogenesis of RA via synovial fibroblasts.