tbuckley/cabot-search huggingface dataset:
Parental occupation is a risk factor for childhood wheeze and asthma
Authors: N. Tagiyeva, G. Devereux, S. Semple, A. Sherriff, J. Henderson, P. Elias, J. G. Ayres
Journal: European Respiratory Journal (2009)

The present birth cohort study investigated whether or not childhood wheeze and asthma are associated with parental exposure to occupational sensitisers that cause asthma. Parental occupation, from the Avon Longitudinal Study of Parents and Children (ALSPAC), was related to wheeze, asthma, ventilatory function, airway responsiveness and atopic sensitisation in children aged 0–102 months. Occupation was recorded for 11,193 mothers and 9,473 fathers antenatally, and for 4,631 mothers and 5,315 fathers post-natally. Childhood respiratory outcomes were not associated with parental occupational exposure to diisocyanates, glues/resins, dyes, animal dust, solder, enzymes and wood dust. Maternal post-natal occupational exposure to latex and/or biocides/fungicides increased the likelihood of childhood wheeze and asthma. High levels of latex or biocide/fungicide exposure were associated with an OR (95% CI) of 1.26 (1.07–1.50) and 1.22 (1.02–2.05), respectively, for wheezing up to 81 months. Combined maternal latex and biocide/fungicide exposure increased the likelihood of childhood wheeze (1.22 (1.03–1.43)) and asthma. High paternal occupational flour dust exposure was associated with an increased likelihood of wheeze after 30 months (2.31 (1.05–5.10)) and asthma by 91 months (3.23 (1.34–7.79)). Maternal occupational exposure to latex and/or biocides and paternal exposure to flour dust increases the risk of childhood asthma. Further studies in this area are justified.
Glycogen Synthase Kinase-3β, NF-κB Signaling, and Tumorigenesis of Human Osteosarcoma
Authors: Qing-Lian Tang, Xian-Biao Xie, Jin Wang, Qiong Chen, An-Jia Han, Chang-Ye Zou, Jun-Qiang Yin, Da-Wei Liu, Yi Liang, Zhi-Qiang Zhao, Bi-Cheng Yong, Ru-Hua Zhang, Qi-Sheng Feng, Wu-Guo Deng, Xiao-Feng Zhu, Binhua P. Zhou, Yi-Xin Zeng, Jing-Nan Shen, Tiebang Kang
Journal: JNCI Journal of the National Cancer Institute (2012)

Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, may function as a tumor suppressor or an oncogene, depending on the tumor type. We sought to determine the biological function of GSK-3β in osteosarcoma, a rare pediatric cancer for which the identification of new therapeutic targets is urgent.We used cell viability assays, colony formation assays, and apoptosis assays to analyze the effects of altered GSK-3β expression in U2OS, MG63, SAOS2, U2OS/MTX300, and ZOS osteosarcoma cell lines. Nude mice (n = 5-8 mice per group) were injected with U2OS/MTX300, and ZOS cells to assess the role of GSK-3β in osteosarcoma growth in vivo and to evaluate the effects of inhibitors and/or anticancer drugs on tumor growth. We used an antibody array, polymerase chain reaction, western blotting, and a luciferase reporter assay to establish the effect of GSK-3β inhibition on the nuclear factor-κB (NF-κB) pathway. Immunochemistry was performed on primary tumor specimens from osteosarcoma patients (n = 74) to determine the relationship of GSK-3β activity with overall survival.Osteosarcoma cells with low levels of inactive p-Ser9-GSK-3β formed colonies in vitro and tumors in vivo more readily than cells with higher levels and cells in which GSK-3β had been silenced formed fewer colonies and smaller tumors than parental cells. Silencing or pharmacological inhibition of GSK-3β resulted in apoptosis of osteosarcoma cells. Inhibition of GSK-3β resulted in inhibition of the NF-κB pathway and reduction of NF-κB-mediated transcription. Combination treatments with GSK-3β inhibitors, NF-κB inhibitors, and chemotherapy drugs increased the effectiveness of chemotherapy drugs in vitro and in vivo. Patients whose osteosarcoma specimens had hyperactive GSK-3β, and nuclear NF-κB had a shorter median overall survival time (49.2 months) compared with patients whose tumors had inactive GSK-3β and NF-κB (109.2 months).GSK-3β activity may promote osteosarcoma tumor growth, and therapeutic targeting of the GSK-3β and/or NF-κB pathways may be an effective way to enhance the therapeutic activity of anticancer drugs against osteosarcoma.
The Uremic Myocardium and Ischemic Tolerance
Authors: Ralf Dikow, Stefan E. Hardt
Journal: Circulation (2012)

U remia is associated with an increased prevalence of ischemic heart disease.Already, at the start of dialysis, the prevalence of coronary artery disease is 38%. 1 The frequency of myocardial infarction in renal patients is high and the outcome is poor. 2 Despite significant improvement of therapeutic modalities, the unadjusted 2-year mortality for dialysis patients after acute myocardial infarction (MI) has not changed over the past decades, remaining Ϸ73%. 2,3It is of particular note that the risk of cardiac events is 20-fold higher in young adults starting dialysis in the first 2 decades of life in comparison with an age-matched background population.
Safety of laparoscopy versus laparotomy in early-stage endometrial cancer: a randomised trial
Authors: Marian JE Mourits, Claudia B Bijen, Henriëtte J Arts, Henk G ter Brugge, Rob van der Sijde, Lasse Paulsen, Jacobus Wijma, Marlies Y Bongers, Wendy J Post, Ate G van der Zee, Geertruida H de Bock
Journal: The Lancet Oncology (2010)
Haploinsufficiency of <i>Atp2a2</i>, Encoding the Sarco(endo)plasmic Reticulum Ca2+-ATPase Isoform 2 Ca2+ Pump, Predisposes Mice to Squamous Cell Tumors via a Novel Mode of Cancer Susceptibility
Authors: Vikram Prasad, Gregory P. Boivin, Marian L. Miller, Lynne H. Liu, Christopher R. Erwin, Brad W. Warner, Gary E. Shull
Journal: Cancer Research (2005)

Abstract A null mutation in one copy of the Atp2a2 or ATP2A2 gene, encoding sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), leads to squamous cell tumors in mice and to Darier disease in humans, a skin disorder that also involves keratinocytes. Here, we examined the time course and genetic mechanisms of tumor development in the mutant animals. Atp2a2+/− mice overexpressed keratins associated with keratinocyte hyperactivation in normal forestomachs as early as 2 months of age. By the age of 5 to 7 months, 22% of mutants had developed papillomas of the forestomach, and 89% of mutants older than 14 months had developed squamous cell papillomas and/or carcinomas, with a preponderance of the latter. Tumors occurred in regions that had keratinized epithelium and were subjected to repeated mechanical irritation. The genetic mechanism of tumorigenesis did not involve loss of heterozygosity, as tumor cells analyzed by laser capture microdissection contained the wild-type Atp2a2 allele. Furthermore, immunoblot and immunohistochemical analysis showed that tumor keratinocytes expressed the SERCA2 protein. Mutations were not observed in the ras proto-oncogenes; however, expression of wild-type ras was up-regulated, with particularly high levels of K-ras. Loss of the p53 tumor suppressor gene occurred in a single massive tumor, whereas other tumors had increased levels of p53 protein but no mutations in the p53 gene. These findings show that SERCA2 haploinsufficiency predisposes mice to tumor development via a novel mode of cancer susceptibility involving a global change in the tumorigenic potential of keratinized epithelium in Atp2a2+/− mice.
Galectin-3 mediates bone marrow microenvironment-induced drug resistance in acute leukemia cells via Wnt/β-catenin signaling pathway
Authors: Kaimin Hu, Yanjun Gu, Lixia Lou, Lizhen Liu, Yongxian Hu, Binsheng Wang, Yi Luo, Jimin Shi, Xiaohong Yu, He Huang
Journal: Journal of Hematology & Oncology (2015)

Acute leukemia is currently the major cause of death in hematological malignancies. Despite the rapid development of new therapies, minimal residual disease (MRD) continues to occur and leads to poor outcomes. The leukemia niche in the bone marrow microenvironment (BMM) is thought to be responsible for such MRD development, which can lead to leukemia drug resistance and disease relapse. Consequently further investigation into the way in which the leukemia niche interacts with acute leukemia cells (ALCs) and development of strategies to block the underlying process are expected to improve disease prognosis. Recent studies indicated that galectin-3 (gal-3) might play a pivotal role in this process. Thus we aimed to elucidate the exact role played by gal-3 in this process and clarify its mechanism of action. We used human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) to mimic the leukemia BMM in vitro, and investigated their effects on drug resistance of ALCs and the possible mechanisms involved, with particular emphasis on the role of gal-3. In our study, we demonstrated that hBM-MSCs induced gal-3 up-regulation, promoting β-catenin stabilization and thus activating the Wnt/β-catenin signaling pathway in ALCs, which is critical in cytotoxic drug resistance of leukemia. This effect could be reversed by addition of gal-3 short hairpin RNA (shRNA). We also found that up-regulation of gal-3 promoted Akt and glycogen synthase kinase (GSK)-3β phosphorylation, thought to constitute a cross-bridge between gal-3 and Wnt signaling. Our results suggest that gal-3, a key factor mediating BMM-induced drug resistance, could be a novel therapeutic target in acute leukemia.
Studies on the nature and significance of connective tissue antibodies in adult coeliac disease and Crohn's disease
Authors: A. F. N. Magalhaes, T. J. Peters, W. F. Doe
Journal: Gut (1974)

Sera from 92 patients with adult coeliac disease, 20 patients with Crohn9s disease, and 89 control patients were tested for the presence and immunoglobulin class of anticonnective tissue antibodies. In adult coeliac disease patients taking a normal diet there was a high frequency of sera positive for connective tissue antibodies and the majority were IgA in class. Following gluten withdrawal, IgA class connective tissue antibody activity was strikingly reduced. No such antibody activity was detected in concentrated jejunal fluid collected from 15 patients with adult coeliac disease, seven of whose sera were positive for connective tissue antibody. Connective tissue antibody activity was not absorbed by fractions of gluten. Similarly, preparations of human reticulin and glomerular basement membrane together with elastin and collagen failed to absorb connective tissue antibody.
Effects of Different Doses of Physical Activity on Cardiorespiratory Fitness Among Sedentary, Overweight or Obese Postmenopausal Women With Elevated Blood Pressure
Authors: Timothy S Church, Conrad P Earnest, James S Skinner, Steven N Blair
Journal: JAMA (2007)

ContextLow levels of cardiorespiratory fitness are associated with high risk of mortality, and improvements in fitness are associated with reduced mortality risk. However, a poor understanding of the physical activity–fitness dose response relation remains.ObjectiveTo examine the effect of 50%, 100%, and 150% of the NIH Consensus Development Panel recommended physical activity dose on fitness in women.Design, Setting, and ParticipantsRandomized controlled trial of 464 sedentary, postmenopausal overweight or obese women whose body mass index ranged from 25.0 to 43.0 and whose systolic blood pressure ranged from 120.0 to 159.9 mm Hg. Enrollment took place between April 2001 and June 2005 in the Dallas, Tex, area.InterventionParticipants were randomly assigned to 1 of 4 groups: 102 to the nonexercise control group and 155 to the 4-kcal/kg, 104 to the 8-kcal/kg, and 103 to the 12-kcal/kg per week energy-expenditure groups for the 6-month intervention period. Target training intensity was the heart rate associated with 50% of each woman's peak O2.Main Outcome MeasureThe primary outcome was aerobic fitness assessed on a cycle ergometer and quantified as peak absolute oxygen consumption (O2abs, L/min).ResultsThe mean (SD) baseline O2abs values were 1.30 (0.25) L/min. The mean (SD) minutes of exercising per week were 72.2 (12.3) for the 4-kcal/kg, 135.8 (19.5) for the 8-kcal/kg, and 191.7 (33.7) for the 12-kcal/kg per week exercise groups. After adjustment for age, race/ethnicity, weight, and peak heart rate, the exercise groups increased their O2abs compared with the control group by 4.2% in the 4-kcal/kg, 6.0% in the 8-kcal/kg, and 8.2% in the 12-kcal/kg per week groups (P&lt;.001 for each vs control; P for trend &lt;.001). There was no treatment × subgroup interaction for age, body mass index, weight, baseline O2abs, race/ethnicity, or baseline hormone therapy use. There were no significant changes in systolic or diastolic blood pressure values from baseline to 6 months in any of the exercise groups vs the control group.ConclusionIn this study, previously sedentary, overweight or obese postmenopausal women experienced a graded dose-response change in fitness across levels of exercise training.Trial Registrationclinicaltrials.gov Identifier: NCT00011193
The human antimicrobial peptide dermcidin activates normal human keratinocytes
Authors: F. Niyonsaba, A. Suzuki, H. Ushio, I. Nagaoka, H. Ogawa, K. Okumura
Journal: British Journal of Dermatology (2008)

The skin has evolved an epithelial defence mechanism which is characterized by antimicrobial peptides that inactivate various microorganisms and exhibit stimulatory activities bridging innate and adaptive immunity. Dermcidin (DCD) is a newly isolated antimicrobial peptide produced by the eccrine sweat glands in the skin. Recently, the DCD peptides DCD-1 and DCD-1L have been shown to display in vitro microbicidal activities against bacteria and viruses.Because some skin-derived antimicrobial peptides activate keratinocytes, we investigated whether DCD-1L would also trigger keratinocyte activation.Normal human keratinocytes were used in this study. The ability of DCD-1L to induce the production of cytokines/chemokines by keratinocytes was determined by enzyme-linked immunosorbent assay, and various inhibitors were used to investigate the stimulatory mechanism of DCD-1L. Mitogen-activated protein kinase (MAPK) phosphorylation and NF-kappaB activation were analysed by Western blotting.DCD-1L stimulated keratinocytes to generate cytokines and chemokines including tumour necrosis factor-alpha, interleukin-8 (CXCL8), interferon-inducible protein 10 (CXCL10) and macrophage inflammatory protein-3alpha (CCL20). To determine the molecular mechanism involved, we showed that DCD-1L-mediated cytokine/chemokine production was controlled by both G-protein and MAPK pathways, as evidenced by the inhibitory effects of pertussis toxin and specific inhibitors for p38 and ERK, but not for JNK, on DCD-1L-induced keratinocyte activation. Furthermore, we confirmed that DCD-1L could induce phosphorylation of p38 and ERK, and noticeably upregulated NF-kappaB activation.Taken together, the new activity of DCD-1L to stimulate the production of cytokines/chemokines by keratinocytes provides novel evidence for the implication of DCD, beyond its microbicidal ability, in skin immunity.
<i>In vitro</i> and <i>In vivo</i> Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells
Authors: Miriam Puttini, Addolorata Maria Luce Coluccia, Frank Boschelli, Loredana Cleris, Edoardo Marchesi, Arianna Donella-Deana, Shaheen Ahmed, Sara Redaelli, Rocco Piazza, Vera Magistroni, Federica Andreoni, Leonardo Scapozza, Franca Formelli, Carlo Gambacorti-Passerini
Journal: Cancer Research (2006)

Resistance to imatinib represents an important scientific and clinical issue in chronic myelogenous leukemia. In the present study, the effects of the novel inhibitor SKI-606 on various models of resistance to imatinib were studied. SKI-606 proved to be an active inhibitor of Bcr-Abl in several chronic myelogenous leukemia cell lines and transfectants, with IC(50) values in the low nanomolar range, 1 to 2 logs lower than those obtained with imatinib. Cells expressing activated forms of KIT or platelet-derived growth factor receptor (PDGFR), two additional targets of imatinib, were unaffected by SKI-606, whereas activity was found against PIM2. SKI-606 retained activity in cells where resistance to imatinib was caused by BCR-ABL gene amplification and in three of four Bcr-Abl point mutants tested. In vivo experiments confirmed SKI-606 activity in models where resistance was not caused by mutations as well as in cells carrying the Y253F, E255K, and D276G mutations. Modeling considerations attribute the superior activity of SKI-606 to its ability to bind a conformation of Bcr-Abl different from imatinib.
Maternal milk regulation of cell infiltration and interleukin 18 in the intestine of suckling rat pups
Authors: I A Penttila
Journal: Gut (2003)

<b>Background and aims:</b> In neonates the gastrointestinal tract is exposed to food and bacterial antigens at a time when the gut mucosal immune system has not developed the ability to induce oral tolerance. This increases the risk for an inappropriate immune response to oral antigens. Transforming growth factor β (TGF-β) is an immunoregulatory cytokine present in high concentration in maternal milk. Interleukin 18 (IL-18) is a cytokine that mediates early immune events, and drives T cell development. We assessed the role of TGF-β in mediating mucosal immune development and specifically the effect on endogenous IL-18. <b>Methods:</b> Rat pups were randomly assigned to the following groups, naturally suckled, maternal milk via cannula, and formula fed with and without physiological levels of TGF-β2. A comparison of the immune response profile was then carried out. Cytokine profiles, dendritic cell, intestinal mast cell, and eosinophil numbers were assessed. <b>Results:</b> We show that feeding formula deficient in TGF-β2 resulted in accumulated IL-18 protein release from intestinal epithelial cells and IL-18 mRNA up regulation. A proinflammatory cytokine profile resulted in the gut, along with increased numbers of activated dendritic cells, eosinophils, and mast cells. Supplementation of the formula with TGF-β2 down regulated the proinflammatory cytokine mRNA as well as the number of activated lymphocytes, eosinophils, mast cells, CD80, and CD86 positive dendritic cells. <b>Conclusion:</b> The data suggests an important role for maternal milk, in regulating immune responses after exposure to food antigens, which might otherwise induce deleterious immune responses in the intestine of suckling neonates. This regulation is potentially mediated by milk TGF-β2, as well as endogenous IL-18.
Allergen-induced release of GM-CSF and IL-8 in vitro by nasal polyp tissue from atopic subjects prolongs eosinophil survival
Authors: HS Park, KS Jung, J Shute, K Roberts, ST Holgate, R Djukanovic
Journal: European Respiratory Journal (1997)

Eosinophilia is a feature of nasal polyposis. The aim of this study was to determine the role of cytokines and allergen in maintaining the eosinophilic infiltrate in this condition. Polyp fragments from house dust mite (HDM)-sensitive atopic individuals and nonatopic individuals were cultured in the presence of HDM, or phytohaemagglutinin (PHA) or culture medium alone. Culture supernatants were assayed for interleukins (IL) 3, 5, and 8 and granulocyte macrophage colony stimulating factor (GM-CSF), and eosinophil survival enhancing activity (ESEA) in vitro. Significant ESEA was produced spontaneously. When polyp tissue from atopics, but not from nonatopics, was stimulated with allergen for 2 days there was a further increase in ESEA associated with a median 12 and fourfold increase in IL-8 and GM-CSF, respectively. This increased ESEA was markedly reduced with anti-GM-CSF and, to a lesser extent, anti-IL-8 blocking antibodies. When stimulated with PHA, polyp tissue from atopic subjects also produced increased ESEA, implicating possible T-cell involvement. This was associated with a small (twofold), but significant, increase in IL-8 and a less consistent increase in GM-CSF. However, anti-IL-8 or anti-GM-CSF blocking antibodies failed to reduce the ESEA in these supernatants, suggesting involvement of other mechanisms. This study suggests that in sensitized individuals, allergen may contribute to polyp eosinophilia by stimulating the production of granulocyte/macrophage colony stimulating factor and interleukin 8.
Malignant Liver Tumours.
Authors: E R HOWARD
Journal: Gut (2001)

Malignant Liver Tumours. Edited by P-M Clavien (Pp 363; illustrated; £112.00). USA: Blackwells, 1999. ISBN 0-632-04406-3.

Surgeons, hepatologists, and oncologists involved in the management of malignant tumours of the liver now have a variety of recent books available for reference. Some of these texts are primarily concerned with surgical management, with subsidiary chapters on diagnosis, pathology, and other modes of treatment. Others are written from the point of view of the physician or oncologist. This new book has been edited with a change of emphasis in that it attempts to examine and compare critically all of the current modalities of treatment as well as some of those which may be successful in the future. I was pleased with the emphasis on maintaining the quality of life in patients with incurable disease rather than …
Predictors of Prostate Cancer–Specific Mortality After Radical Prostatectomy or Radiation Therapy
Authors: Ping Zhou, Ming-Hui Chen, David McLeod, Peter R. Carroll, Judd W. Moul, Anthony V. D’Amico
Journal: Journal of Clinical Oncology (2005)

Purpose We evaluated predictors of prostate cancer–specific mortality (PCSM) after prostate-specific antigen (PSA) failure after radical prostatectomy (RP) or radiation therapy (RT). Patients and Methods A total of 1,159 men with clinically localized prostate cancer treated with RP (n = 498) or RT (n = 661) developed PSA failure, and they formed the study cohort. Competing risk regression analyses were used to evaluate whether previously identified predictors of time to metastasis, including post-treatment PSA doubling time (PSA-DT), Gleason score, and interval to PSA failure, could also predict time to PCSM after PSA failure. The cumulative incidence method was used to estimate PCSM after PSA failure. Results A post-RP PSA-DT of less than 3 months (hazard ratio [HR], 54.9; 95% CI, 16.7 to 180), a post-RT PSA-DT of less than 3 months (HR, 12.8; 95% CI, 7.0 to 23.1), and a biopsy Gleason score of 8 to 10 (HR, 6.1; 95% CI, 3.4 to 10.7) for patients treated with RT were significantly associated with PCSM. Post-RP estimated rates of PCSM 5 years after PSA failure were 31% (95% CI, 17% to 45%) v 1% (95% CI, 0% to 2%) for patients with PSA-DT of less than 3 months v ≥ 3 months. Post-RT estimated rates of PCSM 5 years after PSA failure were 75% (95% CI, 59% to 92%) v 35% (95% CI, 24% to 47%) for patients with a biopsy Gleason score of ≥ 8 v ≤ 7, respectively, and PSA-DT of less than 3 months; these rates were 15% (95% CI, 0.8% to 28%) v 4% (95% CI, 1% to 6%), respectively, for patients with a PSA-DT ≥ 3 months. Conclusion Patients at high risk for PCSM after PSA failure can be identified based on post-RP PSA-DT or post-RT PSA-DT and biopsy Gleason score. These parameters may be useful in identifying patients for a randomized trial evaluating hormonal therapy with or without docetaxel.
Clinical Comparison of the Sixth Hour-Early Discharge versus Overnight Observation after Elective Transradial Coronary Intervention: A Randomized Study
Authors: Sinan Dağdelen, Ali Buturak, Şevket Görgülü, Tuğrul Norgaz, Alex Değirmencioğlu, Ahmet Akyol, İlke Sipahi, Yasemin Değirmenci
Journal: Journal of the American College of Cardiology (2013)