tbuckley/cabot-search huggingface dataset:
Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells.
Authors: M Gembal, P Gilon, J C Henquin
Journal: Journal of Clinical Investigation (1992)

Glucose stimulation of insulin release involves closure of ATP-sensitive K+ channels, depolarization, and Ca2+ influx in B cells. Mouse islets were used to investigate whether glucose can still regulate insulin release when it cannot control ATP-sensitive K+ channels. Opening of these channels by diazoxide (100-250 mumol/liter) blocked the effects of glucose on B cell membrane potential (intracellular microelectrodes), free cytosolic Ca2+ (fura-2 method), and insulin release, but it did not prevent those of high K (30 mmol/liter). K-induced insulin release in the presence of diazoxide was, however, dose dependently increased by glucose, which was already effective at concentrations (2-6 mmol/liter) that are subthreshold under normal conditions (low K and no diazoxide). This effect was not accompanied by detectable changes in B cell membrane potential. Measurements of 45Ca fluxes and cytosolic Ca2+ indicated that glucose slightly increased Ca2+ influx during the first minutes of depolarization by K, but not in the steady state when its effect on insulin release was the largest. In conclusion, there exists a mechanism by which glucose can control insulin release independently from changes in K(+)-ATP channel activity, in membrane potential, and in cytosolic Ca2+. This mechanism may serve to amplify the secretory response to the triggering signal (closure of K(+)-ATP channels--depolarization--Ca2+ influx) induced by glucose.
SERUM-GLOBULIN AND DIPHTHERIC ANTITOXIN.—A COMPARATIVE STUDY OF THE AMOUNT OE GLOBULIN IN NORMAL AND ANTITOXIC SERA, AND THE RELATION OF THE GLOBULINS TO THE ANTITOXIC BODIES
Authors: Philip Hanson Hiss, James P. Atkinson
Journal: The Journal of Experimental Medicine (1900)

THE RESULTS OF THE FOREGOING EXPERIMENTS MAY BE BRIEFLY SUMMARIZED AS FOLLOWS: The amount of antitoxic substance obtained by precipitation with magnesium sulphate from the blood-serum of the horse corresponds, as nearly as can be determined by the use of test guinea-pigs, in full to the protective power of the serum from which it is obtained, i. e. the precipitate from 1 cc. of serum will protect against the same amount of toxin as 1 cc. of the serum itself. Equal amounts of the precipitates by magnesium sulphate from immunized and non-immunized horses act differently toward toxin; i. e. the proportion of protective substance to the precipitate from non-immunized serum is exceedingly small as compared with the proportion of antitoxin to the precipitate from sera of immunized horses. The average precipitate from the sera of immunized horses, as obtained by magnesium sulphate, is more abundant than the average precipitate from sera of non-immunized horses. In the case of the same animal before and after immunization, the serum before immunization gives a less abundant precipitate with magnesium sulphate than the serum tested after immunization. The proportion of increase per unit of antitoxic strength for the same or different horses is not constant. This may be due to an increase of inactive substances (in their relation to diphtheric toxin) or to imperfect methods of determination. The precipitates obtained by magnesium sulphate give all the reactions recognized as characteristic of globulins, and as distinguishing them from other albuminous bodies. We are not warranted, then, in the present state of our knowledge, in considering any part of these precipitates as other than globulin. But it does seem warrantable to conclude, from the fact that the globulins of normal serum do not protect, or only in comparatively large amounts, against diphtheric toxin, that new globulins are formed, or rather greatly increased in the serum of immunized horses, and that these globulins protect against the toxin. These increased globulins and the inert globulins (which from obvious causes are a very variable factor) are both precipitated by magnesium sulphate. Every animal has a physiological and pathological history more or less widely diverging from the normal, hence absolute conformity in the results obtained is not to be expected, at least with our present methods of differentiation.
Distinct Regulation of Developmental and Heart Disease–Induced Atrial Natriuretic Factor Expression by Two Separate Distal Sequences
Authors: Thomas Horsthuis, Arjan C. Houweling, Petra E.M.H. Habets, Frederik J. de Lange, Hamid el Azzouzi, Danielle E.W. Clout, Antoon F.M. Moorman, Vincent M. Christoffels
Journal: Circulation Research (2008)

Nppa, encoding atrial natriuretic factor, is expressed in fetal atrial and ventricular myocardium and is downregulated in the ventricles after birth. During hypertrophy and heart failure, Nppa expression is reactivated in the ventricles and serves as a highly conserved marker of heart disease. The Nppa promoter has become a frequently used model to study mechanisms of cardiac gene regulation. Nevertheless, the regulatory sequences that provide the correct developmental pattern and ventricular reactivation during cardiac disease remain to be defined. We found that proximal Nppa fragments ranging from 250 bp to 16 kbp provide robust reporter gene activity in the atria and correct repression in the atrioventricular canal and the nodes of the conduction system in vivo. However, depending on fragment size and site of integration into the genome of mice, the fetal ventricular activity was either absent or present in an incorrect pattern. Furthermore, these fragments did not provide ventricular reactivation in heart disease models. These results indicate that the proximal promoter does not provide a physiologically relevant model for ventricular gene activity. In contrast, 2 modified bacterial artificial chromosome clones with partially overlapping genomic Nppa sequences provided appropriate reactivation of the green fluorescent protein reporter during pressure overload-induced hypertrophy and heart failure in vivo. However, only 1 of these bacterial artificial chromosomes provided correct fetal ventricular green fluorescent protein activity. These results show that distinct distal regulatory sequences and divergent regulatory pathways control fetal ventricular activity and reactivation of Nppa during cardiac disease, respectively.
Robust Classification of Renal Cell Carcinoma Based on Gene Expression Data and Predicted Cytogenetic Profiles
Authors: Kyle A. Furge, Kerry A. Lucas, Masayuki Takahashi, Jun Sugimura, Eric J. Kort, Hiro-omi Kanayama, Susumu Kagawa, Philip Hoekstra, John Curry, Ximing J. Yang, Bin T. Teh
Journal: Cancer Research (2004)

Abstract Renal cell carcinoma (RCC) is a heterogeneous disease that includes several histologically distinct subtypes. The most common RCC subtypes are clear cell, papillary, and chromophobe, and recent gene expression profiling studies suggest that classification of RCC based on transcriptional signatures could be beneficial. Traditionally, however, patterns of chromosomal alterations have been used to assist in the molecular classification of RCC. The purpose of this study was to determine whether it was possible to develop a classification model for the three major RCC subtypes that utilizes gene expression profiles as the bases for both molecular genetic and cytogenetic classification. Gene expression profiles were first used to build an expression-based RCC classifier. The RCC gene expression profiles were then examined for the presence of regional gene expression biases. Regional expression biases are genetic intervals that contain a disproportionate number of genes that are coordinately up- or down-regulated. The presence of a regional gene expression bias often indicates the presence of a chromosomal abnormality. In this study, we demonstrate an expression-based classifier can distinguish between the three most common RCC subtypes in 99% of cases (n = 73). We also demonstrate that detection of regional expression biases accurately identifies cytogenetic features common to RCC. Additionally, the in silico-derived cytogenetic profiles could be used to classify 81% of cases. Taken together, these data demonstrate that it is possible to construct a robust classification model for RCC using both transcriptional and cytogenetic features derived from a gene expression profile.
Hyperlipidaemia, statin use and the risk of developing rheumatoid arthritis
Authors: S S Jick, H Choi, L Li, I B McInnes, N Sattar
Journal: Annals of the Rheumatic Diseases (2008)

Objective: To evaluate whether statins are associated with a protective effect on the development of rheumatoid arthritis (RA). Methods: A nested case–control study was conducted using data from the General Practice Research Database. A study population consisting of three groups of subjects aged 40–89 years was identified: (1) patients exposed to a statin or other lipid-lowering agent (LLA); (2) patients with a diagnosis of hyperlipidaemia in the absence of lipid-lowering drug treatment and (3) a random sample of 25 000 individuals with no diagnosis of hyperlipidaemia nor a prescription for a LLA. From this population incident cases of RA and up to four controls for each case were identified, matched on age, sex, general practice, number of years of recorded history in the database and index date. The independent effects of hyperlipidaemia and statins on the development of RA were evaluated using conditional logistic regression. Results: 313 cases of RA and 1252 matched controls were identified. Compared with patients with untreated hyperlipidaemia, or hyperlipidaemia treated with LLA other than statins, the adjusted odds ratio for patients with no hyperlipidaemia was 0.68 (95% CI 0.50 to 0.91). When those with hyperlipidaemia who received statins were compared with those with hyperlipidaemia who did not use statins (ie, untreated hyperlipidaemia patients or those treated with non-statin LLA) the OR was 0.59 (95% CI 0.37 to 0.96). Conclusion: These data provide evidence to support the hypothesis that statins may be protective against the development of RA in patients with hyperlipidaemia.
Inhibition of rat hepatic lipocyte activation in culture by interferon-γ
Authors: Don C. Rockey, Jacquelyn J. Maher, William R. Jarnagin, Giulio Gabbiani, Scott L. Friedman
Journal: Hepatology (1992)

Hepatic lipocytes (perisinusoidal, Ito cells) are the primary matrix–producing cells in liver fibrosis. During liver injury they undergo activation, a process characterized by cell proliferation and increased fibrogenesis. We and others have established a culture model in which in vivo features of lipocyte activation can be mimicked by cells grown on plastic. Additionally, we recently showed that activation is associated with new expression of smooth muscle-specific α–actin both in vivo and in culture. Although interferon–γ is known to inhibit collagen production in some systems, its action as a general modulator of lipocyte activation has not been examined; this issue forms the basis for our study. In culture–activated lipocytes, interferon–γ (1,000 U/ml) significantly inhibited lipocyte proliferation as assessed by [ 3 H]thymidine incorporation assay and nuclear autoradiography. In time–course studies of activation, it also markedly reduced expression of smooth muscle-specific α–actin and its messenger RNA. In dose–response experiments, maximal inhibitory effects on smooth muscle-specific α–actin mRNA gene expression were achieved with as little as 10 U interferon–γ/ml. Inhibition of cellular activation was reversible; after interferon–γ withdrawal, messenger RNA levels of smooth muscle-specific α–actin returned to untreated control levels. The effect of interferon–γ extended to extracellular matrix gene expression, with reduction of type I collagen, type IV collagen and total fibronectin messenger RNAs to 3%, 24% and 15% of untreated control levels, respectively. In contrast to the marked effects on smooth muscle–specific α–actin and extracellular matrix gene expression, interferon–γ reduced total protein synthesis by only 17.7%. Moreover, maximal doses of interferon–γ had no effect on cell viability as determined by exclusion of propidium iodide. In summary, interferon–γ is a potent inhibitor of lipocyte activation and may prove useful in the treatment of fibrotic liver injury. (Hepatology 1992;16:776-784.)
The effect of transfection of antisense cDNA for procollagen alpha 1 (IV) on stimulated proliferation in rat glomerular endothelial cells.
Authors: A Artishevsky, D R Cha, S Adler, C C Nast, S Feld, R J Glassock, S G Adler
Journal: Journal of the American Society of Nephrology (1997)

Glomerular endothelial cells were stably transfected with a pMAMneo-Blue vector recombinant for procollagen alpha 1 (IV) cDNA in the sense (S) or antisense (AS) orientation utilizing a calcium phosphate precipitation technique. Cellular clones resistant to G418 antibiotic were selected and expanded for further analysis. Immunofluorescence microscopy demonstrated less Type IV collagen in the AS clones (1.0 +/- 0.3) than in control parent (P) and S clones (2.0 +/- 0.4) (P < 0.05). Western analysis showed that the AS clones synthesized 20 +/- 10% of the 205-kd alpha 1 (IV) chain of Type IV collagen compared with P cells (P < 0.05). As transfected clones demonstrated similar basal proliferation rates as control cells when cultured in 0.5% fetal calf serum (FCS), but failed to undergo fetal calf serum (FCS)-stimulated hyperplasia when grown on standard fibronectin-coated surfaces in 40% FCS (P < 0.05, compared with P- and S-transfected control cells). There were significant linear relationships between the presence of Type IV collagen as detected by either immunofluorescence microscopy or alpha 1 (IV) peptide chain quantitation by Western analysis and the ability of cells to undergo FCS-stimulated hyperplasia when grown on fibronectin (P < 0.05). Growth on a surface comprised of fibronectin plus Type IV collagen restored the capacity of AS transfected cells to respond to FCS stimulation (P < 0.001), but had no significant effect on the proliferative behavior of P or S cells. Measurements of AS RNA levels in these cells suggest that the inhibition of stimulated proliferation is determined by the presence of a threshold quantity of cellular AS RNA. These data demonstrate that Type IV collagen plays a critical role in conditioning glomerular endothelial cells to respond to proliferative stimuli.
A Modular Analysis of Breast Cancer Reveals a Novel Low-Grade Molecular Signature in Estrogen Receptor–Positive Tumors
Authors: Kun Yu, Kumaresan Ganesan, Lance D. Miller, Patrick Tan
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Previous reports using genome-wide gene expression data to classify breast tumors have typically used standard unsupervised or supervised techniques, both of which have known limitations. We hypothesized that novel clinically relevant information could be revealed in these data sets by an alternative analytic approach. Using a recently described algorithm, signature analysis (SA), we identified “modules,” comprising groups of tightly coexpressed genes that are conditionally linked to particular tumors, in a series of breast tumor gene expression profiles. Experimental Design and Results: The SA successfully identified multiple breast cancer modules specifically linked to distinct biological functions. We identified a novel module, TuM1, whose presence was not readily discernible by conventional clustering techniques. The TuM1 module is expressed in a subset of estrogen receptor (ER)–positive tumors and is significantly enriched with genes involved in apoptosis and cell death. Clinically, TuM1-expressing tumors are associated with low histopathologic grade, and this association is independent of the inherent ER status of a tumor. We confirmed the robustness and general applicability of TuM1 module by demonstrating its association with low tumor grade in multiple independent breast cancer data sets generated using different array technologies. In vitro, the TuM1 module is down-regulated in ER+ MCF7 cells upon treatment with tamoxifen, suggesting that TuM1 expression may be dependent on active signaling by ER. Initial data is also suggestive that TuM1 expression may be clinically associated with a patient's response to antihormonal therapy. Conclusion: Our results suggest that modular-based approaches toward gene expression data can prove useful in identifying novel, robust, and biologically relevant signatures even from data sets that have been the subject of substantial prior analysis.
The social patterning of exercise behaviours: the role of personal and local resources
Authors: Sally Macintyre
Journal: British Journal of Sports Medicine (2000)

The “inverse care law”—that is, those most in need of services are least well provided with them—is well known as it applies to health care.1 It may, however, be less often considered in relation to local provision for health promoting activities. Much health promotion advice focuses on individuals, and exhorts them to engage in better personal habits, or to encourage their children to do so. It is often noted that such messages are differentially taken up by different social class groups; better off and better educated people are more likely to modify their diets, give up smoking, improve dental hygiene practices, and take up healthy physical activities than are poorer and less well educated people.2 The lower take up of healthy behaviours among lower social class groups is often considered to contribute to their poorer health and mortality experiences, although such health behaviours do not in fact completely explain social class gradients in morbidity or mortality.3 It is often assumed that the barriers to the take up of health promotion messages lie in personal factors such as lack of motivation, fatalism …
Targeting STAT3 in Adoptively Transferred T Cells Promotes Their <i>In Vivo</i> Expansion and Antitumor Effects
Authors: Maciej Kujawski, Chunyan Zhang, Andreas Herrmann, Karen Reckamp, Anna Scuto, Michael Jensen, Jiehui Deng, Stephen Forman, Robert Figlin, Hua Yu
Journal: Cancer Research (2010)

Adoptive cell therapy with engineered T cells to improve natural immune response and antitumor functions has shown promise for treating cancer. However, the requirement for extensive ex vivo manipulation of T cells and the immunosuppressive effects of the tumor microenvironment limit this therapeutic modality. In the present study, we investigated the possibility to circumvent these limitations by engineering Stat3 -deficient CD8(+) T cells or by targeting Stat3 in the tumor microenvironment. We show that ablating Stat3in CD8(+) T cells prior to their transfer allows their efficient tumor infiltration and robust proliferation, resulting in increased tumor antigen-specific T-cell activity and tumor growth inhibition. For potential clinical translation, we combined adoptive T-cell therapy with a Food and Drug Administration-approved tyrosine kinase inhibitor, sunitinib, in renal cell carcinoma and melanoma tumor models. Sunitinib inhibited Stat3 in dendritic cells and T cells and reduced conversion of transferred FoxP3(-) T cells to tumor-associated regulatory T cells while increasing transferred CD8(+) T-cell infiltration and activation at the tumor site, leading to inhibition of primary tumor growth. These data show that adoptively transferred T cells can be expanded and activated in vivo either by engineering Stat3-silenced T cells or by targeting Stat3 systemically with small-molecule inhibitors.
Authors’ response to Walker<i>et al.</i>
Authors: D P Tashkin, N Metzdorf, C Hallmann, I Leimer, T Lee, M Decramer
Journal: Thorax (2013)

The research letter by Walker et al 1 questions the generalisability of the results of the 4-year UPLIFT trial comparing tiotropium versus placebo based on potential eligibility for UPLIFT at time of discharge of a COPD patient population in New Zealand hospitalised for an exacerbation. The authors state that 38% of their study population would have been excluded from UPLIFT. The authors' assertion regarding the limited generalisability of UPLIFT's findings to clinical practice is not valid for several reasons.

First, patients hospitalised for COPD exacerbations are not representative of the general COPD population. An epidemiological analysis from The Netherlands2 reported that 2.1% and 4.4% of COPD patients (mean age, 68 years) starting treatment with HandiHaler and Respimat, respectively, had a COPD-related hospitalisation in the year preceding the analysis. Analysis of an elderly Canadian COPD population3 showed that 9.8% were recently hospitalised for acute respiratory conditions. These epidemiological data suggest that the COPD population studied by Walker et al is not representative of the general COPD population. …
Dystrophin Associates With Caveolae of Rat Cardiac Myocytes
Authors: Donald D. Doyle, Gwen Goings, Judy Upshaw-Earley, S. Kelly Ambler, Alison Mondul, H. Clive Palfrey, Ernest Page
Journal: Circulation Research (2000)

Abstract —The possibility of an interaction between the cytoskeletal protein dystrophin and cell surface caveolae in the mammalian myocardium was investigated by several techniques. Caveolin (cav)-3–enriched, detergent-insoluble membranes isolated from purified ventricular sarcolemma by density-gradient fractionation were found to contain dystrophin and dystroglycan. Further purification of cav-3–containing membranes by immunoprecipitation using anti–cav-3–coated magnetic beads yielded dystrophin but not always dystroglycan. Electron microscopic analysis of precipitated material revealed caveola-sized vesicular profiles that could be double-labeled with anti-dystrophin and anti–cav-3 antibodies. In contrast, immunoprecipitation of membranes with anti-dystrophin–coated beads yielded both cav-3 and dystroglycan. Electron microscopic analysis of this material showed heterogeneous membrane profiles, some of which could be decorated with anti–cav-3 antibodies. To confirm that dystrophin and cav-3 were closely associated in cardiac myocytes, we verified that dystrophin was also present in immunoprecipitated cav-3–containing membranes from detergent extracts, as well as in sonicated extracts of purified ventricular myocytes. Confocal immunofluorescence microscopy of ventricular and atrial cardiac myocytes showed that the cellular distributions of cav-3 and dystrophin partially overlapped. Immuno–electron micrographs of thin sections of rat atrial myocytes revealed a fraction of dystrophin molecules that are in apparently close apposition to caveolae. These results suggest that a subpopulation of dystrophin molecules interacts with cardiac myocyte caveolae in vivo and that some of the dystrophin is engaged in linking cav-3 with the dystroglycan complex.