tbuckley/cabot-search huggingface dataset:
Changes in Chromatin Accessibility Across the GM-CSF Promoter upon T Cell Activation Are Dependent on Nuclear Factor κB Proteins
Authors: Adele F. Holloway, Sudha Rao, Xinxin Chen, M. Frances Shannon
Journal: The Journal of Experimental Medicine (2003)

Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a key cytokine in myelopoiesis and aberrant expression is associated with chronic inflammatory disease and myeloid leukemias. This aberrant expression is often associated with constitutive nuclear factor (NF)-κB activation. To investigate the relationship between NF-κB and GM-CSF transcription in a chromatin context, we analyzed the chromatin structure of the GM-CSF gene in T cells and the role of NF-κB proteins in chromatin remodeling. We show here that chromatin remodeling occurs across a region of the GM-CSF gene between −174 and +24 upon T cell activation, suggesting that remodeling is limited to a single nucleosome encompassing the proximal promoter. Nuclear NF-κB levels appear to play a critical role in this process. In addition, using an immobilized template assay we found that the ATPase component of the SWI/SNF chromatin remodeling complex, brg1, is recruited to the GM-CSF proximal promoter in an NF-κB–dependent manner in vitro. These results suggest that chromatin remodeling across the GM-CSF promoter in T cells is a result of recruitment of SWI/SNF type remodeling complexes by NF-κB proteins binding to the CD28 response region of the promoter.
Effect of myo-inositol on cell proliferation and collagen transcription and secretion in proximal tubule cells cultured in elevated glucose.
Authors: F N Ziyadeh, D A Simmons, E R Snipes, S Goldfarb
Journal: Journal of the American Society of Nephrology (1991)

Tubulointerstitial lesions often develop in the kidneys of patients and experimental animals with diabetes mellitus. In an in vitro model of diabetic renal disease, it has been previously demonstrated in this laboratory that elevated glucose levels stimulate procollagen transcription and secretion in proximal tubule cells in culture while inducing cellular hypertrophy and reducing cellular proliferation. Previous experiments in other tissues have suggested that myo-inositol supplementation, probably by reversing a disturbance in cell myo-inositol metabolism related to increased activity of the polyol pathway, reverses the effects of glucose on cell function. We tested the effect of myo-inositol supplementation on proximal tubule cells in culture in the presence of elevated medium glucose level. Incubation in 450 mg/dL of glucose media reduced cell proliferation; 450 mg/dL of glucose plus myo-inositol (800 microM) increased proliferation, returning the value to that seen in cells incubated in 100 mg/dL of glucose. Incubation in 450 mg/dL of glucose media increased type IV and type I procollagen mRNA levels and peptide secretion rates compared with those seen in cells incubated in medium containing 100 mg/dL of glucose. This glucose-induced stimulation of procollagen mRNA levels and procollagen secretion was not observed when the elevated glucose medium was supplemented with 800 microM myo-inositol. On the other hand, myo-inositol supplementation did not prevent the glucose-induced cellular hypertrophy: there was no reduction in the increased leucine incorporation and cellular protein content. Cell incubation in 450 mg/dL of glucose media did not lead to a measurable decrease in total cellular myo-inositol.(ABSTRACT TRUNCATED AT 250 WORDS)
Lack of an association between granuloma annulare and type 2 diabetes mellitus
Authors: C.L. Nebesio, C. Lewis, T-Y. Chuang
Journal: British Journal of Dermatology (2002)

Summary Background Conflicting reports have been published regarding whether a relationship exists between granuloma annulare (GA) and diabetes mellitus (DM). Objectives To evaluate the prevalence of DM in patients with GA using a case–control design. Methods The incidence of DM was determined in 126 patients with GA. Fifty of the 126 patients with GA were further compared with an age‐, sex‐ and race‐matched population of psoriasis patients seen during a similar time period in the same clinical setting. Results Eleven (9%) of 126 GA patients suffered from type 2 DM. In the matched comparison of 50 patients, 11 (22%) GA patients and 10 (20%) psoriasis patients suffered from type 2 DM. Conclusions This case–control study failed to reveal any statistically significant correlation between GA and type 2 DM.
PWE-051 Studies of the psychophysiological markers and the brain processing of nausea in healthy humans using a novel virtual reality video
Authors: K S Ng, S J Coen, Y C Chua, V F Ban, M A Gresty, G J Sanger, S C Williams, G J Barker, P L Andrews, M Imran, Q Aziz
Journal: Gut (2012)

<h3>Introduction</h3> Nausea is a common and complex multi-system sensation. Objective psychophysiological markers of nausea that also predict nausea susceptibility in humans are lacking. The regions of the brain that process the sensation of nausea are also unknown. Using a novel model of motion sickness induced nausea, we aimed to study psychophysiological and brain responses during nausea in healthy human volunteers. <h3>Methods</h3> A 10-min video of motion and a control video of a still image were presented to 98 healthy volunteers (age 26±8 years, 53 male). Validated questionnaires were used for anxiety and nausea assessment. We monitored sympathetic activity [heart rate (HR) and mean, systolic and diastolic blood pressure (MBP, SBP and DBP)]; parasympathetic activity [cardiac vagal tone (CVT), cardiac sensitivity to baroreceptor reflex (CSB)], electrogastrogram (EGG) and blood cortisol. Comparisons of these parameters were made in the 25 most susceptible and the 25 most resistant subjects (nausea VAS). 28 subjects of the 50 (aged 25±5 years, 16 males, 11 nausea resistant) repeated the experiments with Functional MRI to assess brain activity during nausea. <h3>Results</h3> All subjects completed the studies without vomiting. <i>Comparison of motion video (MV) to control:</i> MV raised nausea scores (nausea VAS, +57%±11, pComparison of nausea susceptible (NS) with resistant subjects (NR): the NS subjects showed more parasympathetic withdrawal; larger sympathetic activation and higher cortisol release and trend for higher EGG activity in comparison to NR subjects (Abstract PWE-051 table 1). <i>Brain imaging data</i> (all results had corrected p: There was a positive correlation between brain activity and nausea level in the inferior frontal gyrus; and a negative correlation in declive, culmen, cuneus, and parahippocampal gyrus in NS subjects. Compared to NR subjects, NS volunteers showed increased activity in the substantia nigra; and decreased activity in declive and parahippocampal gyrus during nausea induction. <h3>Conclusion</h3> NS subjects decreased PNS tone and increased SNS tone, anxiety and cortisol suggesting these parameters could be markers of nausea susceptibility. The NS subjects also showed different brain processing patterns compared to NR subjects. Thus, this safe and effective model for inducing nausea without vomiting can be used to study effects of nausea on GI function together with correlations with objective physiological and brain activity markers. The markers identified may help to reduce and refine animal experiments. <h3>Competing interests</h3> None declared.
Crosstalk of lipids and inflammation in atherosclerosis: the PRO of PGRN?
Authors: Saskia C.A. de Jager, Gerard Pasterkamp
Journal: Cardiovascular Research (2013)

This editorial refers to ‘Deletion of progranulin exacerbates atherosclerosis in ApoE knockout mice’ by R. Kawase et al ., doi:10.1093/cvr/cvt178. 

Atherosclerosis is recognized as a chronic inflammatory process that accelerates in the context of high cholesterol levels.1 The unique aspect of atherosclerosis, over other inflammatory diseases, is the major effect of the cholesterol environment. There is accumulating evidence that lipids can influence inflammatory responses and vice versa, but so far the lipid and inflammatory components that initiate atherosclerotic disease have mainly been studied as two separate pathogenic entities. Elucidation of the functional denominators that link immune activation and derailed cholesterol metabolism may facilitate the development of novel therapeutic strategies to treat atherosclerosis.

Evidence is accumulating that supports the relevance of cross-talk of lipid metabolism and the immune responses in vascular pathology. For instance lipid loading induces a distinct, unique gene expression profile in macrophages within the atherosclerotic lesion.2 It also was shown that cholesterol crystals (consequence of extreme cholesterol loading) that are present in early atherosclerotic lesions, can induce inflammasome activation and may thus be considered as a novel initiators of inflammation.3,4

In this issue of cardiovascular research, Kawase et al .5 describe a role for the growth factor progranulin (PGRN) in the pathogenesis of atherosclerosis. Data are presented suggesting that PGRN is a glycoprotein that strongly influences and inhibits detrimental immune responses. PGRN is a protein that may exert a role in the cross-talk of immunity and lipid turnover, as it has both …
The role of metformin in polycystic ovary syndrome: a systematic review
Authors: Etelka Moll, Fulco van der Veen, Madelon van Wely
Journal: Human Reproduction Update (2007)

This meta-analysis evaluated the effectiveness of metformin in subfertile women with polycystic ovary syndrome (PCOS). Only randomized trials investigating the effectiveness of metformin and PCOS definition consistent with the Rotterdam consensus criteria, were eligible. Primary outcome was live birth rate. A literature search identified 27 trials. In therapy naïve women, we found no evidence of a difference in live birth rate when comparing metformin with clomifene citrate (CC) [relative risks (RR) 0.73; 95% confidence interval (CI) 0.51–1.1] or comparing metformin plus CC with CC (RR 1.0; 95% CI 0.82–1.3). In CC-resistant women, metformin plus CC led to higher live birth rates than CC alone (RR 6.4; 95% CI 1.2–35); metformin also led to higher live birth rates than laparoscopic ovarian drilling (LOD) (RR 1.6; 95% CI 1.1–2.5). We found no evidence for a positive effect of metformin on live birth when added to LOD (RR 1.3; 95% CI 0.39–4.0) or FSH (RR 1.6; 95% CI 0.95–2.9), or when co-administered in IVF (RR 1.5; 95% CI 0.92–2.5). In IVF, metformin led to fewer cases of ovarian hyperstimulation syndrome (OHSS) (RR 0.33; 95% CI 0.13–0.80). This meta-analysis demonstrates that CC is still first choice therapy for women with therapy naïve PCOS. In CC-resistant women, the combination of CC plus metformin is the preferred treatment option before starting with LOD or FSH. At present, there is no evidence of an improvement in live birth when adding metformin to LOD or FSH. In IVF, metformin leads to a reduced risk of OHSS.
MspI polymorphism at +83 bp in intron 1 of the human apolipoprotein A1 gene is associated with elevated levels of HDL cholesterol and apolipoprotein A1 in nondiabetic subjects but not in type 2 diabetic patients with coronary heart disease.
Authors: A Pulkkinen, L Viitanen, A Kareinen, S Lehto, M Laakso
Journal: Diabetes Care (2000)

OBJECTIVE: Elevated HDL cholesterol and its principal carrier protein apolipoprotein a1 [apo(a1)] are associated with reduced risk of coronary heart disease (CHD). No studies are available on the impact of the -75-bp and/or +83-bp polymorphisms of the apo(a1) gene on HDL cholesterol and apo(a1) levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We determined the prevalence of the: -75-bp and +83-bp polymorphisms of the apo(a1) gene by restriction fragment length polymorphism analysis among 308 unrelated nondiabetic subjects with CHD and among 251 unrelated patients with type 2 diabetes with CHD and in randomly selected 82 healthy men (CHD-). RESULTS: The rare M1- and M2- allele frequencies of the apo(a1) gene were 23 and 1.8%, respectively, among control subjects; 20 and 1.5%, respectively, among nondiabetic subjects with CHD; and 22 and 2.6%, respectively, among patients with type 2 diabetes and CHD (NS). Nonsmoking nondiabetic subjects with CHD having the M2+- genotype had higher HDL cholesterol (1.48 +/- 0.19 vs. 1.23 +/- 0.02 mmol/l, P &amp;lt; 0.01) and apo(a1) (1.43 +/- 0.10 vs. 1.36 +/- 0.02 g/l, P &amp;lt; 0.05) levels than subjects with the M2++ genotype, even after adjustment for confounding factors. This association was not found among patients with type 2 diabetes and CHD. CONCLUSIONS: We conclude that the +83-bp polymorphism of the apo(a1) gene is associated with elevated HDL cholesterol and apo(a1) levels in Finnish nondiabetic subjects but not in patients with type 2 diabetes.
Oxidized LDL Modulates Apoptosis of Regulatory T Cells in Patients with ESRD
Authors: Pascal Meier, Dela Golshayan, Edouard Blanc, Manuel Pascual, Michel Burnier
Journal: Journal of the American Society of Nephrology (2009)

Increased levels of oxidized low-density lipoproteins (oxLDL) contribute to the increased risk for atherosclerosis, which persists even after adjusting for traditional risk factors, among patients with ESRD. Regulatory T cells (CD4+/CD25+ Tregs), which down-regulate T cell responses to foreign and self-antigens, are protective in murine atherogenesis, but whether similar immunoregulation occurs in humans with ESRD is unknown. Because cellular defense systems against oxLDL involve proteolytic degradation, the authors investigated the role of oxLDL on proteasome activity of CD4+/CD25+ Tregs in patients with ESRD. CD4+/CD25+ Tregs isolated from uremic patients' peripheral blood, especially that of chronically hemodialyzed patients, failed to suppress cell proliferation, exhibited cell-cycle arrest, and entered apoptosis by altering proteasome activity. Treating CD4+/CD25+ Tregs with oxLDL or uremic serum ex vivo decreased the number and suppressive capacity of CD4+/CD25+ Tregs. In vitro, oxLDL promoted the accumulation of p27Kip1, the cyclin-dependent kinase inhibitor responsible for G1 cell cycle arrest, and increased apoptosis in a time- and concentration-dependent manner. In summary, proteasome inhibition by oxLDL leads to cell cycle arrest and apoptosis, dramatically affecting the number and suppressive capacity of CD4+/CD25+ Tregs in chronically hemodialyzed patients. This response may contribute to the immune dysfunction, microinflammation, and atherogenesis observed in patients with ESRD.
Flavopiridol Sensitivity of Cancer Cells Isolated from Ascites and Pleural Fluids
Authors: Christina Richard, Donald Matthews, Wilhelmina Duivenvoorden, Jonathan Yau, Paul S. Wright, John P.H. Th'ng
Journal: Clinical Cancer Research (2005)

Abstract Purpose: We examined the efficacy of flavopiridol, a cyclin-dependent kinase inhibitor that is undergoing clinical trials, on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers. Experimental Design: Metastasized cancer cells were isolated from the pleural fluids (n = 20) or ascites (n = 15) of patients, most of whom were refractory to chemotherapy. These primary cancer cells were used within 2 weeks of isolation without selecting for proliferative capacities. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay was used to characterize the response of these cancer cells to commonly used chemotherapeutic agents, and their response to flavopiridol was compared with rapidly dividing cultured cell lines. Results: The primary cancer cells displayed phenotypes that were different from established cell lines; they had very low replication rates, dividing every 1 to 2 weeks, and underwent replicative senescence within five passages. These primary tumor cells retained their resistance to chemotherapeutic drugs exhibited by the respective patients but did not show cross-resistance to other agents. However, these cancer cells showed sensitivity to flavopiridol with an average LD50 of 50 nmol/L (range, 21.5-69 nmol/L), similar to the LD50 in established cell lines. Because senescent cells also showed similar sensitivity to flavopiridol, it suggests that the mechanism of action is not dependent on the activity of cyclin-dependent kinases that regulate the progression of the cell cycle. Conclusion: Using cancer cells isolated from the ascites or pleural fluids, this study shows the potential of flavopiridol against cancer cells that have developed resistance to conventional chemotherapeutic agents.
Temozolomide and cisplatin versus temozolomide in patients with advanced melanoma: a randomized phase II study of the Hellenic Cooperative Oncology Group
Authors: D. Bafaloukos, D. Tsoutsos, H. Kalofonos, S. Chalkidou, P. Panagiotou, E. Linardou, E. Briassoulis, E. Efstathiou, A. Polyzos, G. Fountzilas, C. Christodoulou, C. Kouroussis, T. Iconomou, H. Gogas
Journal: Annals of Oncology (2005)
Rapidly Progressive Diaphragmatic Weakness and Injury during Mechanical Ventilation in Humans
Authors: Samir Jaber, Basil J. Petrof, Boris Jung, Gérald Chanques, Jean-Philippe Berthet, Christophe Rabuel, Hassan Bouyabrine, Patricia Courouble, Christelle Koechlin-Ramonatxo, Mustapha Sebbane, Thomas Similowski, Valérie Scheuermann, Alexandre Mebazaa, Xavier Capdevila, Dominique Mornet, Jacques Mercier, Alain Lacampagne, Alexandre Philips, Stefan Matecki
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation (MV). Paradoxically, MV itself results in a rapid loss of diaphragmatic strength in animals. However, very little is known about the time course or mechanistic basis for such a phenomenon in humans.Objectives: To determine in a prospective fashion the time course for development of diaphragmatic weakness during MV; and the relationship between MV duration and diaphragmatic injury or atrophy, and the status of candidate cellular pathways implicated in these phenomena.Methods: Airway occlusion pressure (TwPtr) generated by the diaphragm during phrenic nerve stimulation was measured in short-term (0.5 h; n = 6) and long-term (>5 d; n = 6) MV groups. Diaphragmatic biopsies obtained during thoracic surgery (MV for 2–3 h; n = 10) and from brain-dead organ donors (MV for 24–249 h; n = 15) were analyzed for ultrastructural injury, atrophy, and expression of proteolysis-related proteins (ubiquitin, nuclear factor-κB, and calpains).Measurements and Main Results: TwPtr decreased progressively during MV, with a mean reduction of 32 ± 6% after 6 days. Longer periods of MV were associated with significantly greater ultrastructural fiber injury (26.2 ± 4.8 vs. 4.7 ± 0.6% area), decreased cross-sectional area of muscle fibers (1,904 ± 220 vs. 3,100 ± 329 μm2), an increase of ubiquitinated proteins (+19%), higher expression of p65 nuclear factor-κB (+77%), and greater levels of the calcium-activated proteases calpain-1, -2, and -3 (+104%, +432%, and +266%, respectively) in the diaphragm.Conclusions: Diaphragmatic weakness, injury, and atrophy occur rapidly in critically ill patients during MV, and are significantly correlated with the duration of ventilator support.
Intrarenal cells, not bone marrow–derived cells, are the major source for regeneration in postischemic kidney
Authors: Fangming Lin, Ashley Moran, Peter Igarashi
Journal: Journal of Clinical Investigation (2005)

Ischemic injury to the kidney produces acute tubular necrosis and apoptosis followed by tubular regeneration and recovery of renal function. Although mitotic cells are present in the tubules of postischemic kidneys, the origins of the proliferating cells are not known. Bone marrow cells (BMCs) can differentiate across lineages to repair injured organs, including the kidney. However, the relative contribution of intrarenal cells and extrarenal cells to kidney regeneration is not clear. We produced transgenic mice that expressed enhanced GFP (EGFP) specifically and permanently in mature renal tubular epithelial cells. Following ischemia/reperfusion injury (IRI), EGFP-positive cells showed incorporation of BrdU and expression of vimentin, which provides direct evidence that the cells composing regenerating tubules are derived from renal tubular epithelial cells. In BMC-transplanted mice, 89% of proliferating epithelial cells originated from host cells, and 11% originated from donor BMCs. Twenty-eight days after IRI, the kidneys contained 8% donor-derived cells, of which 8.4% were epithelial cells, 10.6% were glomerular cells, and 81% were interstitial cells. No renal functional improvement was observed in mice that were transplanted with exogenous BMCs. These results show that intrarenal cells are the main source of renal repair, and a single injection of BMCs does not make a significant contribution to renal functional or structural recovery.
Relevance of the novel IASLC/ATS/ERS classification of lung adenocarcinoma in advanced disease
Authors: A. D. Campos-Parra, A. Aviles, S. Contreras-Reyes, C. E. Rojas-Marin, R. Sanchez-Reyes, R. J. Borbolla-Escoboza, O. Arrieta
Journal: European Respiratory Journal (2014)

Since the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS) reported a new lung adenocarcinoma (ADC) classification, several groups have validated its association with prognosis in early stage disease. To our knowledge, there are no studies in advanced disease. We reviewed 313 patients with invasive lung ADC who were re-classified using the new IASLC/ATS/ERS criteria. Patients received platinum-based chemotherapy. Clinical characteristics, EGFR mutations, response and progression-free survival (PFS) after chemotherapy and overall survival were analysed. ADCs were classified as lepidic 7.4%, acinar 44.7%, papillary 10.1%, micropapillary 3.5% and solid 34.2%. When patterns were lumped into groups, response rates and PFS to platinum-based chemotherapy were better in high-grade ADC (micropapillary, papillary and solid-predominant) <i>versus</i> intermediate-grade ADC (lepidic and acinar-predominant) (36.9% <i>versus</i> 25.4% p=0.034 and 6.4 <i>versus</i> 5.5 months p=0.009, respectively). Overall survival was better in high-grade ADC (25 <i>versus</i> 16.8; p=0.023). Factors associated with better overall survival were Eastern Cooperative Oncology Group (0-1), EGFR mutations and high-grade ADC. Prognostic differences found with the new classification in early disease may not apply to patients with advanced disease. Unlike in early stages, patients with high-grade ADC have longer overall survival compared with intermediate-grade ADC, probably due to a better response to chemotherapy.