tbuckley/cabot-search huggingface dataset:
Effect of Prenatal Exposure to Airborne Polycyclic Aromatic Hydrocarbonson Neurodevelopment in the First 3 Years of Life among Inner-City Children
Authors: Frederica P. Perera, Virginia Rauh, Robin M. Whyatt, Wei-Yann Tsai, Deliang Tang, Diurka Diaz, Lori Hoepner, Dana Barr, Yi-Hsuan Tu, David Camann, Patrick Kinney
Journal: Environmental Health Perspectives (2006)

Our prospective cohort study of nonsmoking African-American and Dominican mothers and children in New York City is evaluating the role of prenatal exposure to urban pollutants, including polycyclic aromatic hydrocarbons (PAHs) , environmental tobacco smoke (ETS) , and pesticides, in the pathogenesis of neurobehavioral disorders. We used the Bayley Scales of Infant Development to evaluate the effects on child mental and psychomotor development of prenatal exposure to airborne PAHs monitored during pregnancy by personal air sampling. Behavioral development was assessed by the Child Behavior Checklist. We adjusted for potential confounders including sociodemographic factors and prenatal exposure to ETS and chlorpyrifos. Prenatal exposure to PAHs was not associated with psychomotor development index or behavioral problems. However, high prenatal exposure to PAHs (upper quartile) was associated with lower mental development index at age 3 [beta=-5.69; 95% confidence interval (CI), -9.05 to -2.33; p<0.01]. The odds of cognitive developmental delay were also significantly greater for children with high prenatal exposure (odds ratio=2.89; 95% CI, 1.33 to 6.25; p=0.01). General estimated equation analysis showed a significant age times PAH effect on mental development (p=0.01), confirming the age-specific regression findings. Further adjustment for lead did not alter the relationships. There were no differences in effect sizes by ethnicity. The results require confirmation but suggest that environmental PAHs at levels recently encountered in New York City air may adversely affect children's cognitive development at 3 years of age, with implications for school performance.
Exciting Times beyond the Brain: Metabotropic Glutamate Receptors in Peripheral and Non-Neural Tissues
Authors: Marcela Julio-Pieper, Peter J. Flor, Timothy G. Dinan, John F. Cryan
Journal: Pharmacological Reviews (2011)

Metabotropic glutamate (mGlu) receptors are G-protein-coupled receptors expressed primarily on neurons and glial cells, where they are located in the proximity of the synaptic cleft. In the central nervous system (CNS), mGlu receptors modulate the effects of l-glutamate neurotransmission in addition to that of a variety of other neurotransmitters. However, mGlu receptors also have a widespread distribution outside the CNS that has been somewhat neglected to date. Based on this expression, diverse roles of mGlu receptors have been suggested in a variety of processes in health and disease including controlling hormone production in the adrenal gland and pancreas, regulating mineralization in the developing cartilage, modulating lymphocyte cytokine production, directing the state of differentiation in embryonic stem cells, and modulating gastrointestinal secretory function. Understanding the role of mGlu receptors in the periphery will also provide a better insight into potential side effects of drugs currently being developed for neurological and psychiatric conditions. This review summarizes the new potential roles of mGlu receptors and raises the possibility of novel pharmacological targets for various disorders.
<i>Ebf1</i> or <i>Pax5</i> haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia
Authors: Lynn M. Heltemes-Harris, Mark J.L. Willette, Laura B. Ramsey, Yi Hua Qiu, E. Shannon Neeley, Nianxiang Zhang, Deborah A. Thomas, Thearith Koeuth, Emily C. Baechler, Steven M. Kornblau, Michael A. Farrar
Journal: The Journal of Experimental Medicine (2011)

As STAT5 is critical for the differentiation, proliferation, and survival of progenitor B cells, this transcription factor may play a role in acute lymphoblastic leukemia (ALL). Here, we show increased expression of activated signal transducer and activator of transcription 5 (STAT5), which is correlated with poor prognosis, in ALL patient cells. Mutations in EBF1 and PAX5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL, we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1, but this had little effect on most EBF1 or PAX5 target genes. Only a subset of target genes was deregulated; this subset included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL.
Insulin-Like Growth Factor-I Axis as a Pathway for Cancer Chemoprevention
Authors: Vaqar Mustafa Adhami, Farrukh Afaq, Hasan Mukhtar
Journal: Clinical Cancer Research (2006)

Even as chemoprevention is emerging as a realistic and a sensible modality for cancer control, knowledge on the molecular biomarkers and genetic signatures involved in the process of carcinogenesis will further allow customized targeted development of chemopreventive regimens for individualized
18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) for assessment of enteropathy-type T cell lymphoma
Authors: M Hoffmann
Journal: Gut (2003)

<b>Background and aims:</b> Enteropathy-type T cell lymphoma (ETCL) represents a relatively rare disease, accounting for less than 1% of non-Hodgkin's lymphomas. ETCL is an aggressive lymphoma which may either present de novo or arise in the context of longstanding or untreated coeliac disease (CD). The aim of this study was to evaluate the potential of 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) for imaging of ETCL. Furthermore, we wished to evaluate whether the presence of CD might provide a potential diagnostic obstacle to imaging of lymphoma due to unspecific 18F-FDG uptake and whether accumulation of 18F-FDG within the gut correlates with activity of CD. <b>Patients and methods:</b> We retrospectively analysed patients with ETCL and individuals suffering from CD undergoing 18F-FDG-imaging at our PET unit. Material for histological reassessment by a reference pathologist had to be available for inclusion of patients in the analysis. Whole body 18F-FDG-PET scans were performed 40 minutes following injection of 300–380 MBq of 18F-FDG. Images were reconstructed iteratively. In areas with focally elevated FDG uptake and in case of diffusely elevated intestinal 18F-FDG accumulation, standard uptake values (SUVs) were calculated. <b>Results:</b> During a period of two years, five patients (one male, four female) with a mean age of 56.4 years (range 44–62) with a diagnosis of ETCL underwent 18F-FDG-PET. Four of these patients were imaged before application of cytotoxic treatment while one patient had regular PET scans for follow up. All four patients undergoing pre-therapeutic imaging showed markedly elevated intestinal 18F-FDG uptake, with a maximal SUV of 6.4–8.0 (mean 7.15 (SD 0.82)). The patient imaged following surgery and cytotoxic therapy had no pathologic 18F-FDG uptake which was found to correlate with normal duodenal mucosa, as evidenced by repeated biopsies and conventional imaging methods. During the same time span, 12 patients (five male, seven female) with a mean age of 63.8 years (range 42–82) suffering from CD were imaged. Four of these patients showed no elevated intestinal 18F-FDG uptake while five had minor diffuse intestinal 18F-FDG accumulation with SUVs ranging between 2.2 and 4.6 (mean 3.4 (SD 0.89)). In the remaining three patients with diffuse intestinal 18F-FDG uptake, no SUV could be calculated. SUVs in patients with ETCL were remarkably higher than in patients suffering from CD (p=0.011), irrespective of the activity of CD at the time of imaging. <b>Conclusion:</b> In spite of the relatively small number of patients, our results clearly indicate the potential value of 18F-FDG-PET for diagnosing and imaging ETCL. In addition, the data also suggest that 18F-FDG-PET may lead to early diagnosis in individuals developing ETCL in the context of longstanding CD. This is due to the fact that 18F-FDG does not appear to significantly accumulate in the gut of patients with CD, irrespective of disease activity.
Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial
Authors: PS Burge, Pma Calverley, PW Jones, Sally Spencer, JA Anderson, TK Maslen
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objectives:</b> To determine the effect of long term inhaled corticosteroids on lung function, exacerbations, and health status in patients with moderate to severe chronic obstructive pulmonary disease. <b>Design:</b> Double blind, placebo controlled study. <b>Setting:</b> Eighteen UK hospitals. <b>Participants:</b> 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV<sub>1</sub>) 50% of predicted normal. <b>Interventions:</b> Inhaled fluticasone propionate 500 μg twice daily from a metered dose inhaler or identical placebo. <b>Main outcome measures:</b> Efficacy measures: rate of decline in FEV<sub>1</sub> after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events. <b>Results:</b> There was no significant difference in the annual rate of decline in FEV<sub>1</sub> (P=0.16). Mean FEV<sub>1</sub> after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo (P&lt;0.001). Median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P=0.026). Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate (P=0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25% <i>v</i> 19%, P=0.034). <b>Conclusions:</b> Fluticasone propionate 500 μg twice daily did not affect the rate of decline in FEV<sub>1</sub> but did produce a small increase in FEV<sub>1</sub>. Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status. These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease.
Response to ‘Abatacept in relapsing polychondritis’ by Moulis<i>et al</i>
Authors: Stanford L Peng, Donald Rodriguez
Journal: Annals of the Rheumatic Diseases (2013)

We were pleased to learn of Moulis et al 's update on their experience with abatacept in three patients with relapsing polychondritis, particularly as their disease manifestations reflected the same manifestations suggested in our study to be of greatest interest for abatacept: chondritis and peripheral arthritis.1 Interestingly, one patient achieved a complete, while another achieved only a partial, corticosteroid-sparing response, and …
How to Use a Subgroup Analysis
Authors: Xin Sun, John P. A. Ioannidis, Thomas Agoritsas, Ana C. Alba, Gordon Guyatt
Journal: JAMA (2014)

Clinicians, when trying to apply trial results to patient care, need to individualize patient care and, potentially, manage patients based on results of subgroup analyses. Apparently compelling subgroup effects often prove spurious, and guidance is needed to differentiate credible from less credible subgroup claims. We therefore provide 5 criteria to use when assessing the validity of subgroup analyses: (1) Can chance explain the apparent subgroup effect; (2) Is the effect consistent across studies; (3) Was the subgroup hypothesis one of a small number of hypotheses developed a priori with direction specified; (4) Is there strong preexisting biological support; and (5) Is the evidence supporting the effect based on within- or between-study comparisons. The first 4 criteria are applicable to individual studies or systematic reviews, the last only to systematic reviews of multiple studies. These criteria will help clinicians deciding whether to use subgroup analyses to guide their patient care.
Declining Mortality Rate Among People With Diabetes in North Dakota, 1997–2002
Authors: Edward F. Tierney, Betsy L. Cadwell, Michael M. Engelgau, Larry Shireley, Sherri L. Parsons, Kathy Moum, Linda S. Geiss
Journal: Diabetes Care (2004)

Both the increasing prevalence (1,2) and the high lifetime risk for diabetes (3) have enormous implications for the future; this disease is a major cause of premature mortality, and people with diabetes die at about twice the rate of people without diabetes (4). Efforts to track mortality trends have been difficult because death certificates, as currently structured, are inadequate to assess diabetes mortality, as less than half of diabetic decedents have diabetes listed (4). To improve the tracking of mortality among people with diabetes, North Dakota added a check box to its death certificate in 1992 that asked whether the decedent had diabetes. The period of 1992–1996 has been reported previously (5). In this study, we use the check box to aid in calculating the number of decedents with diabetes and in examining mortality rates among those with diabetes from 1997 through 2002.

We used 1997–2002 North Dakota death certificate data to calculate the number of deaths among individuals with diabetes. A decedent was considered to have diabetes if the underlying cause of death or the contributing causes of death had an ICD-9 or -10 code for diabetes (ICD-9 code 250 in 1997 or 1998; ICD-10 codes E10–E14 in 1999–2002) or if the diabetes check box (responses: yes or no) indicated that the decedent had diabetes. Multiple imputation (6) was used to adjust for missing …
CHOP Compared With CHOP Plus Granulocyte Colony-Stimulating Factor in Elderly Patients With Aggressive Non-Hodgkin’s Lymphoma
Authors: J.K. Doorduijn, B. van der Holt, G.W. van Imhoff, K.G. van der Hem, M.H.H. Kramer, M.H.J. van Oers, G.J. Ossenkoppele, M.R. Schaafsma, L.F. Verdonck, G.E.G. Verhoef, M.M.C. Steijaert, I. Buijt, C.A. Uyl-de Groot, M. van Agthoven, A.H. Mulder, P. Sonneveld
Journal: Journal of Clinical Oncology (2003)

Purpose: To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin’s lymphoma (NHL). Patients and Methods: Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle. Results: In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P = .01) and doxorubicin (median, 95.4% v 93.3%; P = .04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P = .63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P = .76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P = .006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. Conclusion: In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.
Author's reply to Farebrother
Authors: J. Whittle
Journal: BMJ (2014)

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Abstract 4883: CDK8: A new druggable mediator of NFκB activity
Authors: Mengqian Chen, Martina McDermott, Zhengguan Yang, Jiaxin Liang, Gary P. Schools, Chang-uk Lim, Tao Lu, Stark R. George, Deborah K. West, Donald C. Porter, Eugenia V. Broude, Igor B. Roninson
Journal: Cancer Research (2014)

Abstract Cyclin-dependent kinase 8 (CDK8) is a transcription-regulating oncogenic serine kinase, which mediates several cancer-related transcriptional pathways such as beta-catenin, TP53, TGF-beta and HIF1A. We have recently discovered the first selective small-molecule inhibitors of CDK8 and its closely related isoform CDK19 and showed that these inhibitors block chemotherapy-induced tumor-promoting paracrine activities of both tumor and normal cells (Porter et al., PNAS 109, 13799, 2012). Since transcription factor NFκB plays a key role in damage-induced expression of tumor-promoting cytokines, we have tested the effects of a highly selective CDK8/19 inhibitor Senexin A on NFκB-induced transcription. Senexin A treatment or knockdown of CDK8 by shRNA inhibits transcriptional activation of NFκB-responsive promoters and of acutely responsive cytokine genes (such as CXCL1, CXCL2, IL8 and CCL20), by TNFα, a canonical NFκB activator, in several cell lines. CDK8 inhibition did not prevent nuclear translocation of active NFκB proteins. Chromatin immunoprecipitation (ChIP) analysis of HEK293 cells, untreated or treated with TNFα or Senexin A, singly or in combination, showed that CDK8 is recruited to NFκB early-responsive genes upon TNFα treatment, but the CDK8 inhibitor did not prevent the recruitment of NFκB, CDK8 or RNA Polymerase II (Pol II) to the target genes. However, CDK8 kinase activity was found to be required for C-terminal domain phosphorylation (both at S2 and S5 residues) of Pol II associated with the target genes, which is needed for the elongation of their NFκB-initiated transcription. In contrast, Pol II phosphorylation at constitutively expressed genes is not dependent on CDK8 kinase activity. These results suggest that CDK8 inhibitors may exert their effects against the activation of tumor-promoting and pro-inflammatory secreted factors in the tumor microenvironment by preventing transcriptional activation of NFκB-induced genes. Citation Format: Mengqian Chen, Martina McDermott, Zhengguan Yang, Jiaxin Liang, Gary P. Schools, Chang-uk Lim, Tao Lu, Stark R. George, Deborah K. West, Donald C. Porter, Eugenia V. Broude, Igor B. Roninson. CDK8: A new druggable mediator of NFκB activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4883. doi:10.1158/1538-7445.AM2014-4883
Histomorphometric parameters and susceptibility to neutrophil elastase degradation of skin elastic fibres from healthy individuals and patients with Marfan syndrome, Ehlers-Danlos type IV, and pseudoxanthoma elasticum
Authors: M-V. BERTERETCHE, W. HORNEBECK, B. PELLAT, C. BLANCHET BARDON, G. GODEAU
Journal: British Journal of Dermatology (1995)

The morphometric parameters of mid-dermal elastic fibres from the skin of four patients with Marfan syndrome, four patients with Ehlers-Danlos syndrome type IV (EDS IV), and two patients with pseudoxanthoma elasticum (PXE) were determined, and compared with those of healthy individuals of a similar age range. The volume fraction occupied by elastic fibres was significantly reduced in Marfan patients compared with normal controls, and this was independent of age. In contrast, it was significantly increased in PXE patients, whereas the volume fraction occupied by skin elastic fibres varied within the EDS IV group. Dermal elastic fibres from patients with Marfan syndrome. EDS IV and PXE are hydrolysed by human neutrophil elastase in a qualitatively and quantitatively different fashion from those from healthy individuals. Marfan syndrome and EDS IV dermal elastic fibres were found to be more resistant to hydrolysis by human neutrophil elastase, but PXE elastic fibres were hydrolysed at a rate similar to elastic fibres from control skin.
Cytokine production by infrapatellar fat pad can be stimulated by interleukin 1β and inhibited by peroxisome proliferator activated receptor α agonist
Authors: Stefan Clockaerts, Yvonne M Bastiaansen-Jenniskens, Carola Feijt, Luc De Clerck, J A N Verhaar, Anne-Marie Zuurmond, Vedrana Stojanovic-Susulic, Johan Somville, Margreet Kloppenburg, Gerjo J V M van Osch
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Infrapatellar fat pad (IPFP) might be involved in osteoarthritis (OA) by production of cytokines. It was hypothesised that production of cytokines is sensitive to environmental conditions. <h3>Objectives</h3> To evaluate cytokine production by IPFP in response to interleukin (IL)1β and investigate the ability to modulate this response with an agonist for peroxisome proliferator activated receptor α (PPARα), which is also activated by lipid-lowering drugs such as fibrates. <h3>Methods</h3> Cytokine secretion of IPFP was analysed in the medium of explant cultures of 29 osteoarthritic patients. IPFP (five donors) and synovium (six donors) were cultured with IL-1β and PPARα agonist Wy14643. Gene expression of IL-1β, monocyte chemoattractant protein (MCP1), (IL-6, tumour necrosis factor (TNF)α, leptin, vascular endothelial growth factor (VEGF), IL-10, prostaglandin-endoperoxide synthase (PTGS)2 and release of TNFα, MCP1 and prostaglandin E<sub>2</sub> were compared with unstimulated IPFP and synovium explants. <h3>Results</h3> IPFP released large amounts of inflammatory cytokines, adipokines and growth factors. IL-1β increased gene expression of PTGS2, TNFα, IL-1β, IL-6 and VEGF and increased TNFα release in IPFP. MCP1, leptin, IL-10 gene expression and MCP1, leptin and PGE<sub>2</sub> release did not increase significantly. Synovium responded to IL-1β similarly to IPFP, except for VEGF gene expression. Wy14643 decreased gene expression of PTGS2, IL-1β, TNFα, MCP1, VEGF and leptin in IPFP explants and IL-1β, TNFα, IL-6, IL-10 and VEGF in synovium that responded to IL-1β. <h3>Conclusion</h3> IPFP is an active tissue within the joint. IPFP cytokine production is increased by IL-1β and decreased by a PPARα agonist. The effects were similar to effects seen in synovium. Fibrates may represent a potential disease-modifying drug for OA by modulating inflammatory properties of IPFP and synovium.