tbuckley/cabot-search huggingface dataset:
A novel target of formoterol, a dual-specificity phosphatase DUSP4 on regulation of corticosteroid budesonide sensitivity
Authors: Yoshiki Kobayashi, Nicolas Mercado, Anna Miller-Larsson, Peter Barnes, Kazuhiro Ito
Journal: European Respiratory Journal (2011)

Introduction:  We previously reported that formoterol, a long-acting β 2 -adrenoceptor agonist, activated a serine/threonine protein phosphatase PP2A which is involved in the restoration of corticosteroid (CS) sensitivity by formoterol (Kobayashi et al ERJ 2009;34:583s). We explored other phosphatases and identified dual-specificity phosphatase DUSP4 as a possible novel target of formoterol.   Aims:  To confirm that DUSP4 is activated by formoterol and is involved in regulation of CS sensitivity.   Methods:  U937 monocytic cells were incubated with IL-2 and IL-4 for 48 h to induce CS insensitivity. CS sensitivity was determined by the CS budesonide ability to inhibit TNFα-induced IL-8 production and to translocate glucocorticoid receptor (GR) from cell cytoplasm to nucleus. Phosphatase activity of immunopurified DUSP4 was measured by fluorescence-based assay. The nuclear/cytoplasmic GR ratio and phosphorylation levels of GR-Ser 226  and JNK1 kinase were analysed by western-blotting. In some experiments DUSP4 was knocked down by siRNA.   Results:  Formoterol increased DUSP4 activity, which was reduced under IL-2/IL-4 exposure. Knock-down of DUSP4 reduced GR nuclear translocation and CS sensitivity. Knock-down of DUSP4 also abrogated the dephosphorylation of GR-Ser 226  and JNK1 by formoterol - the effects involved in GR nuclear translocation and restoration of CS sensitivity.   Conclusions:  Formoterol regulates sensitivity to budesonide through activation of DUSP4 which dephosphorylates JNK1 and which in turn leads to dephosphorylation of GR-Ser 226 . This novel mechanism by formoterol may contribute to the clinical efficacy of combination of formoterol and budesonide.
The Increasing Visibility of the Threat of Health Care Worker Self-contamination
Authors: Michelle Doll, Gonzalo M. Bearman
Journal: JAMA Internal Medicine (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Short term effects of ambient sulphur dioxide and particulate matter on mortality in 12 European cities: results from time series data from the APHEA project
Authors: K Katsouyanni, G Touloumi, C Spix, J Schwartz, F Balducci, S Medina, G Rossi, B Wojtyniak, J Sunyer, L Bacharova, J P Schouten, A Ponka, H R Anderson
Journal: BMJ (1997)

<h3>Abstract</h3> <b>Objectives:</b> To carry out a prospective combined quantitative analysis of the associations between all cause mortality and ambient particulate matter and sulphur dioxide. <b>Design:</b> Analysis of time series data on daily number of deaths from all causes and concentrations of sulphur dioxide and particulate matter (measured as black smoke or particles smaller than 10 μm in diameter (PM10)) and potential confounders. <b>Setting:</b> 12 European cities in the APHEA project (Air Pollution and Health: a European Approach). <b>Main outcome measure:</b> Relative risk of death. <b>Results:</b> In western European cities it was found that an increase of 50 μg/m<sup>3</sup> in sulphur dioxide or black smoke was associated with a 3% (95% confidence interval 2% to 4%) increase in daily mortality and the corresponding figure for PM10 was 2% (1% to 3%). In central eastern European cities the increase in mortality associated with a 50 μg/m<sup>3</sup> change in sulphur dioxide was 0.8% (-0.1% to 2.4%) and in black smoke 0.6% (0.1% to 1.1%). Cumulative effects of prolonged (two to four days) exposure to air pollutants resulted in estimates comparable with the one day effects. The effects of both pollutants were stronger during the summer and were mutually independent. <b>Conclusions:</b> The internal consistency of the results in western European cities with wide differences in climate and environmental conditions suggest that these associations may be causal. The long term health impact of these effects is uncertain, but today9s relatively low levels of sulphur dioxide and particles still have detectable short term effects on health and further reductions in air pollution are advisable. <h3>Key messages</h3> Evidence is accumulating that air pollution below the levels of national and international standards has adverse short term health effects In this study data from 12 European cities showed that increases in sulphur dioxide and particulate matter are associated with increased total mortality The effects of the two pollutants seem to be independent Associations were stronger and more consistent in western European cities Current low levelsof sulphur dioxide and particles stillaffect health and further reductions in pollution are needed
A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy.
Authors: K Antman, L Ayash, A Elias, C Wheeler, M Hunt, J P Eder, B A Teicher, J Critchlow, J Bibbo, L E Schnipper
Journal: Journal of Clinical Oncology (1992)

The study was designed to determine the duration of complete response (CR) for patients with unresectable or metastatic breast cancer treated with high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) while responding to conventional-dose therapy.Eligibility criteria included histologically documented metastatic or unresectable breast cancer, at least a partial response (PR) to conventional-dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m3, and physiologic age between 18 and 55 years. Patients with inadequate renal, hepatic, pulmonary, and/or cardiac function or tumor involvement of marrow or CNS were excluded. Cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 were given by continuous infusion over 4 days. After recovery, sites of prior bulk disease were to be radiated or resected if feasible.Of 29 registered patients, one died of toxicity (3%; hemorrhage). CRs and PRs continued a median of 16 and 5 months after transplant, respectively (26 and 9 months from initiation of chemotherapy for metastatic disease). Of 10 patients transplanted in CR, four have not progressed at 17 to 31 months after transplantation (25 to 43 months after beginning standard-dose therapy). One of four patients with uptake on bone scan as their only sites of residual disease before transplant and one of three who converted from PR to CR with transplant have not progressed at 27 and 29 months, respectively, after transplant.CTCb is an intensification regimen with a low mortality that delivers a significantly increased dose of agents with known activity at conventional doses in breast cancer. Although the duration of PR is short as expected, CRs appear to be durable.
Radioactive Oxygen <sup>15</sup>O Studies in Cerebral Neoplasms
Authors: C G McKenzie, G L Lenzi, T Jones, S Moss
Journal: Journal of the Royal Society of Medicine (1978)

Methods of diagnosis and anatomical localization of cerebral neoplasms have reached a high level of efficiency. A new method of studying cerebral circulation and metabolism by a simple noninvasive technique of steady-state imaging during the inhalation of radioactive oxygen and radioactive oxygen-labelled CO2 is described. The results of preliminary studies of a group of cerebral neoplasms of various histological types are presented and the implications discussed.
Home Artificial Nutrition in Advanced Cancer
Authors: Loris Pironi, Enrico Ruggeri, Stephan Tanneberger, Stefano Giordani, Franco Pannuti, Mario Miglioli
Journal: Journal of the Royal Society of Medicine (1997)

Attitudes to home artificial nutrition (HAN) in cancer vary greatly from country to country. A 6-year prospective survey of the practice of HAN in advanced cancer patients applied by a hospital-at-home programme in an Italian health district was performed to estimate the utilization rate, to evaluate efficacy in preventing death from cachexia, maintaining patients at home without burdens and distress and improving patients' performance status, and to obtain information about costs. Patients were eligible for HAN when all the following were present: hypophagia; life expectancy 6 weeks or more, suitable patient and family circumstances; and verbal informed consent. From July 1990 to June 1996, 587 patients were evaluated; 164 were selected for HAN (135 enteral and 29 parenteral) and were followed until 31 December 1996. The incidence of HAN per million inhabitants was 18.4 in the first year of activity and 33.2–36.9 in subsequent years, being 4–10 times greater than rates reported by the Italian HAN registers. On 31 December 1996, 158 patients had died because of the disease and 6 were on treatment. Mean survival was 17.2 weeks for those on enteral nutrition and 12.2 weeks for those on parenteral nutrition. Prediction of survival was 72% accurate. 95 patients had undergone 155 readmissions to hospital, where they spent 15–23% of their survival time. Burdens due to HAN were well accepted by 124 patients, an annoyance or scarcely tolerable in the remainder. The frequency of major complications of parenteral nutrition was 0.67 per year for catheter sepsis and 0.16 per year for deep vein thrombosis. Karnofsky performance score increased in only 13 patients and body weight increased in 43. The fixed direct costs per patient-day (in European Currency Units) were 14.2 for the nutrition team, 18.2 for enteral nutrition and 61 for parenteral nutrition. The results indicate that definite entry criteria and local surveys are required for the correct use of HAN in advanced cancer patients, that HAN can be applied without causing additional burdens and distress, and that its costs are not higher than hospital costs.
Expression of CysLT2 receptors in asthmatic lung, and the roles in bronchoconstriction
Authors: Takeshi Nabe, Tomohiko Sekioka, Michiaki Kadode, Masanori Fujii, Takashi Abe, Michiaki Horiba, Shigekatsu Kohno, Kazuhito Kawabata
Journal: European Respiratory Journal (2014)

Background: Expression and functional roles of CysLT2 receptors in asthmatic airways have been unclear.

Objectives: Expression of both CysLT1 and CysLT2 receptors in the lung of asthma patients, and their functional roles in antigen-induced bronchial contraction were comparatively examined, and they were compared with those of non-asthma subjects.

Methods: Expression of CysLT1 and CysLT2 receptors in the airway tissues isolated from asthma and non-asthma subjects were assessed by immunohistochemistry. As assessment of the functional roles, effects of a CysLT2 receptor-specific antagonist, BayCysLT2RA, and a dual CysLT1/2 receptor antagonist, ONO-6950 on antigen-induced bronchial contraction were evaluated in vitro.

Results: Both CysLT1 and CysLT2 receptors were expressed on the smooth muscle and the epithelium of the bronchi, and alveolar leukocytes. Relative expression of CysLT2 receptors to CysLT1 receptors especially in the smooth muscle of the asthmatic lung showed a tendency to be higher than that in non-asthma subjects. CysLT2 receptor-blockade hardly potentiated an inhibitory effect of a CysLT1-specific antagonist, montelukast, on the antigen-induced contraction of bronchi of non-asthma subjects. However, in the bronchus from one of 2 asthma patients, CysLT2 receptor antagonism suppressed the contraction, and both CysLT1 and CysLT2 receptor blockade showed additive inhibitory effects on the anaphylactic contraction.

Conclusions: CysLT2 receptor activation by cysteinyl leukotrienes may play roles in a certain asthma patient, suggesting that CysLT2 receptor antagonists and dual CysLT1/2 receptor antagonists could be new therapeutic agents for asthma.
Peri-natal weight gain and early development of recurrent wheeze and asthma in term children
Authors: Astrid Sevelsted, Hans Bisgaard
Journal: European Respiratory Journal (2011)

Rationale:  Peri-natal growth and asthma may share origins   Objectives:  We explored the association between growth in the peri-natal period and the development of recurrent wheeze and asthma.   Methods:  The analysis included 398 of a birth cohort of 411 Danish neonates born at term of mothers with a history of asthma. The primary end-points were recurrent wheeze and asthma. Atopic dermatitis was also investigated. Algorithm-diagnoses were based on 6-monthly clinical examinations and at acute episodes in a prospective, single-center, birth cohort study.   Measurements and main results:  Birth weight and length and infant growth rate were estimated from the linear regression of z-scores measured at four occasions during the first year of life. Risk was estimated from Cox and logistic regression analysis. Multivariate models were adjusted for gender, gestational age, mothers smoking during pregnancy, and duration of exclusive breastfeeding.  Weight at birth (Z-score) was associated with development of recurrent wheeze and asthma with an adjusted hazard ratio of 1.277 95%CI:[1.025;1.591] (p=.029), while increased growth in infant weight was associated with an adjusted hazard ratio of 1.145 95%CI:[0.997;1.316] (p=.055). Analyses of length and BMI at birth and growth of those showed comparable effects. There were no association between infant size or growth rate and the development of atopic dermatitis.   Conclusions:  Weight gain in the peri-natal period was significantly associated with the development of recurrent wheeze or asthma in young at-risk children born at term suggesting peri-natal mechanisms as a common link.
Combined depletion of cdk2, cdk1 and cdk9 activities induces apoptosis in cancer cells
Authors: Dongpo Cai, Vaughan M. Latham, Xinxin Zhang, Geoffrey I. Shapiro
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4898 

Cyclin-dependent kinases (cdks) are universally overactive in tumor cells and represent potential anti-neoplastic drug targets. However, it remains unclear whether selective vs. pan-cdk inhibition is superior for inducing anti-tumor effects. Recent data have suggested the depletion of cdk2 activity alone does not lead to antiproliferative effects in cancer cells. On the other hand, expression of cdk2 dominant-negative mutants, cdk2 inhibitory peptides and targeted degradation of cyclin A all lead to effects on S/G2 progression and apoptosis. The latter approaches, however, target both cdk2 and cdk1 suggesting potential benefit for combined depletion of these cdks. To investigate these issues further, we have used siRNA technology to inducibly deplete cdk2, cdk1 and both together from NCI-H1299 non-small cell lung cancer and U2OS osteosarcoma cells. Depletion of cdk2 activity alone leads to a subtle antiproliferative defect in NCI-1299 cells, with slowing of G1 progression following release from a nocodazole-induced mitotic block. Cell cycle effects after cdk2 depletion are not evident in U2OS cells, in which rapid compensation by D-cyclin overexpression occurs. Depletion of cdk1 activity alone leads only to a weak G2/M arrest in NCI-H1299 cells, while depletion of both cdk1 and cdk2 together induces a potent G2/M arrest, eventually followed by a small amount of cell death. In contrast, cdk1 depletion results in G2/M arrest and endoreduplication in U2OS cells, while combined cdk2 and cdk1 depletion slows progression through S phase as well, and is accompanied by a dramatic induction of apoptosis. Combined cdk2 and cdk1 depletion in U2OS cells is preceded by reduced expression of the anti-apoptotic protein XIAP, encoded by an mRNA of short half-life that is depleted after inhibition of cdk-mediated phosphorylation of the C-terminal domain of RNA polymerase II. The CTD is phosphorylated by cdks7 and 9, but may be phosphorylated by other cdks as well in some cellular contexts. XIAP depletion is critical to cell death, as combined depletion of cdk2, cdk1 and cdk9 or cdk2, cdk1 and XIAP substantially increases the degree of apoptosis induced in NCI-H1299 cells compared to the combined depletion of cdk2 and cdk1 alone. Similarly, depletion of cdk1 and cdk2 sensitizes NCI-H1299 cells to flavopiridol, used at concentrations only expected to potently inhibit cdk9. Our data indicate that combined depletion of cdk2, cdk1 and cdk9 can induce apoptosis in tumor cells and suggest that these cdks represent a rational subset of the cdk family for drug targeting.
Haematologic parameters and their prognostic impact in malignant pleural mesothelioma
Authors: Catharina Crolow, Torsten Blum, Jens Kollmeier, Sergej Griff, Timo Weiß, Henrik Wurps, Sebastian Thiel, Nicolas Schönfeld, Torsten T. Bauer
Journal: European Respiratory Journal (2014)

Background: Malignant pleural mesothelioma (MPM) is a rare and heterogeneous disease with divergent prognosis and need for an individualized therapy. Haematologic parameters (white and red blood cells, platelets) can be of prognostic value in MPM.

Aim and objectives: To identify the prognosis of patients with MPM in respect to haematologic parameters.

Methods: In a monocentric study all patients with MPM diagnosed between January 2004 and December 2011 were prospectively recorded and evaluated with regard to histology, stage, therapy (surgical resection [RES]: pleurectomy/decortication, extrapleural pleurectomy; chemotherapy [CTX], radiation [RTX]), haematologic parameters on admission (white blood cells, red blood cells, platelets) and survival.

Results: 170 patients (127 men, 43 women); median age 68.7 years. Histological subtypes: epithelial 78.8%, sarcomatoid 8.2% and biphasic 12.9%. Therapy: RES 96 pat. (56.5%), CTX 128 pat. (75.3%), RTX 26 pat. (15.3%), including multimodal therapies. 21 pat. (12.4%) received solely best supportive care. Median overall survival (OS) for all patients was 16.1 months (95% CI 14.3-18.0 months). Median OS showed a negative trend with regard to leukocytosis (>8,4 G/l; p=0.13) and anaemia (Hb  400 G/l) significantly correlated with poorer median OS (p=0.019).

![Figure][1] 



Conclusion: Our data support the prognostic impact of haematologic parameters in MPM.

 [1]: pending:yes
Exercise-related perceptions do not affect exercise response in subjects with OSA
Authors: Giulia Innocenti Bruni, Francesco Gigliotti, Claudia Coli, Barbara Binazzi, Ilenia Presi, Isabella Romagnoli, Barbara Lanini, Loredana Stendardi, Giorgio Scano
Journal: European Respiratory Journal (2011)

Lean and obese subjects have similar exercise capacity and intensity of dyspnea and leg effort. Obese individuals with OSA have a reduced exercise capacity (Vanhecke 2008); if this depends on exercise-related perceptions needs to be defined. Sixteen subjects with OSA, 8 lean (BMI:25.6±2.5) and 8 obese (BMI:40.8±10.1) and 14 subjects without OSA, 8 obese (BMI 44.9±7.5) and 6 lean subjects (25.5±1.9) underwent spirometry, polysomnography, and incremental exercise test. FRC (% pv) was similar in obese with and without OSA (84.4±9.8 vs 88.6±24.2 respectively; p:ns). The severity of OSA (AHI:51.1±24 vs 30.3±10.5; p:ns) was the same in obese and lean subjects. At VO2Peak (l/min: 2.62±0.6; 2.4±0.7; 2.51±0.6; 2.25±0.5 in obese with OSA and non OSA, and lean with OSA and non OSA subjects, respectively; ANOVA: p:ns). VO2peak (ml/kg/min) was similar between obese subjects (OSA vs non OSA) and between lean subjects (OSA vs non OSA). End-expiratory-lung-volume (EELV) decreased in lean subjects with (290±420ml), and without OSA (330±184ml), while increased in Obese with (270±330ml) and without OSA subjects (304±330ml). Peak BORG was similar (ANOVA p:ns) in the four groups (7.5±1.6; 6.25±1.75; 5.9±2.4; 6.8±2.3 for obese OSA and non OSA, and lean OSA and non OSA subjects, respectively). Peak leg effort did not significantly differ in obese and lean subgroups: (8.63±1.69; 7±1.9; 7.1±2.1; 8.5±0.8 for obese with and without OSA, and lean with and without OSA, respectively; ANOVA p:ns). The qualitative difference in EELV response indicates respiratory mechanical limitation during exercise in obese subjects with and without OSA. Exercise-related perceptions do not affect exercise response in obese with OSA.
Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant.
Authors: M J Laughlin, D S McGaughey, J R Crews, N J Chao, D Rizzieri, M Ross, J Gockerman, C Cirrincione, D Berry, L Mills, P Defusco, S LeGrand, W P Peters, J J Vredenburgh
Journal: Journal of Clinical Oncology (1998)

To determine the incidence of myelodysplasia (MDS) and/or acute leukemia (AL) in breast cancer patients after high-dose chemotherapy (HDC) with a single conditioning regimen and autologous bone marrow transplant (ABMT), and analyze the cytogenetic abnormalities that arise after HDC.We retrospectively reviewed the records of 864 breast cancer patients who underwent ABMT at Duke University Medical Center, Durham, NC, from 1985 through 1996 who received the same preparative regimen of cyclophosphamide 1,875 mg/m2 for 3 days, cisplatin 55 mg/m2 for 3 days, and BCNU 600 mg/m2 for 1 day (CPB). Pretransplant cytogenetics were analyzed in all patients and posttransplant cytogenetics were evaluated in four of five patients who developed MDS/AL.Five of 864 patients developed MDS/AL after HDC with CPB and ABMT. The crude cumulative incidence of MDS/AL was 0.58%. The Kaplan-Meier curve shows a 4-year probability of developing MDS/AL of 1.6%. Pretransplant cytogenetics performed on these five patients were all normal. Posttransplant cytogenetics were performed on four of five patients and they were abnormal in all four, although only one patient had the most common cytogenetic abnormality associated with secondary MDS/AL (chromosome 5 and/or 7 abnormality).Whereas MDS/AL is a potential complication of HDC with CPB and ABMT, the incidence in this series of patients with breast cancer was relatively low compared with that reported in patients with non-Hodgkin's lymphoma who underwent ABMT. The cytogenetic abnormalities reported in this group of breast cancer patients were not typical of those seen in prior reports of secondary MDS/AL and appear to have occurred after HDC.