tbuckley/cabot-search huggingface dataset:
Maintenance and Loss of Duplicated Genes by Dosage Subfunctionalization
Authors: Jean-Francois Gout, Michael Lynch
Journal: Molecular Biology and Evolution (2015)

Whole-genome duplications (WGDs) have contributed to gene-repertoire enrichment in many eukaryotic lineages. However, most duplicated genes are eventually lost and it is still unclear why some duplicated genes are evolutionary successful whereas others quickly turn to pseudogenes. Here, we show that dosage constraints are major factors opposing post-WGD gene loss in several Paramecium species that share a common ancestral WGD. We propose a model where a majority of WGD-derived duplicates preserve their ancestral function and are retained to produce enough of the proteins performing this same ancestral function. Under this model, the expression level of individual duplicated genes can evolve neutrally as long as they maintain a roughly constant summed expression, and this allows random genetic drift toward uneven contributions of the two copies to total expression. Our analysis suggests that once a high level of imbalance is reached, which can require substantial lengths of time, the copy with the lowest expression level contributes a small enough fraction of the total expression that selection no longer opposes its loss. Extension of our analysis to yeast species sharing a common ancestral WGD yields similar results, suggesting that duplicated-gene retention for dosage constraints followed by divergence in expression level and eventual deterministic gene loss might be a universal feature of post-WGD evolution.
Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: A prospective study
Authors: S Bruno, E Silini, A Crosignani, F Borzio, G Leandro, F Bono, M Asti, S Rossi, A Larghi, A Cerino, M Podda, M U Mondelli
Journal: Hepatology (1997)

A prospective study was performed to establish whether infection with specific hepatitis C virus (HCV) genotypes was associated with an increased risk of development of hepatocellular carcinoma (HCC) in cirrhosis. A cohort of 163 consecutive hepatitis C virus antibody (anti– HCV)–positive cirrhotic patients was prospectively evaluated for the development of HCC at 6–month intervals by ultrasound (US) scan and α–fetoprotein (AFP) concentration. HCV genotypes were determined according to Okamoto. Risk factors associated with cancer development were analyzed by univariate and multivariate statistics. At enrollment, 101 patients (62%) were infected with type 1b, 48 (29.5%) were infected with type 2a/c, 2 (1.2%) were infected with type 3a, 1 (0.6%) was infected with type 1a, 3 (1.8%) had a mixed–type infection, and, in 8 patients (4.9%), genotype could not be assigned. After a 5– to 7–year follow–up (median, 68 months), HCC developed in 22 of the patients, 19 infected with type 1b and 3 with type 2a/c (P &lt; .005). Moreover, HCC developed more frequently in males (P &lt; .01), patients with excessive alcohol intake (P &lt; .01), those over 60 years of age (P &lt; .02), and in patients who did not receive interferon treatment (P &lt; .02). Multivariate analysis showed that type 1b was the most important risk factor associated with tumor development (odds ratio 6.14, 1.77–21.37 95% confidence interval). Other independent risk factors were older age and male sex. Cirrhotic patients infected with HCV type 1b carry a significantly higher risk of developing HCC than patients infected by other HCV types. The latter may require a less intensive clinical surveillance for the early detection of neoplasia.
GRK5-Mediated Exacerbation of Pathological Cardiac Hypertrophy Involves Facilitation of Nuclear NFAT Activity
Authors: Jonathan E. Hullmann, Laurel A. Grisanti, Catherine A. Makarewich, Erhe Gao, Jessica I. Gold, J. Kurt Chuprun, Douglas G. Tilley, Steven R. Houser, Walter J. Koch
Journal: Circulation Research (2014)

Rationale : G protein–coupled receptor kinases (GRKs) acting in the cardiomyocyte regulate important signaling events that control cardiac function. Both GRK2 and GRK5, the predominant GRKs expressed in the heart, have been shown to be upregulated in failing human myocardium. Although the canonical role of GRKs is to desensitize G protein–coupled receptors via phosphorylation, it has been demonstrated that GRK5, unlike GRK2, can reside in the nucleus of myocytes and exert G protein–coupled receptor–independent effects that promote maladaptive cardiac hypertrophy and heart failure. Objective : To explore novel mechanisms by which GRK5 acting in the nucleus of cardiomyocytes participates in pathological cardiac hypertrophy. Methods and Results : In this study, we have found that GRK5-mediated pathological cardiac hypertrophy involves the activation of the nuclear factor of activated T cells (NFAT) because GRK5 causes enhancement of NFAT-mediated hypertrophic gene transcription. Transgenic mice with cardiomyocyte-specific GRK5 overexpression activate an NFAT-reporter in mice basally and after hypertrophic stimulation, including transverse aortic constriction and phenylephrine treatment. Complimentary to this, GRK5 null mice exhibit less NFAT transcriptional activity after transverse aortic constriction. Furthermore, the loss of NFATc3 expression in the heart protected GRK5 overexpressing transgenic mice from the exaggerated hypertrophy and early progression to heart failure seen after transverse aortic constriction. Molecular studies suggest that GRK5 acts in concert with NFAT to increase hypertrophic gene transcription in the nucleus via GRK5’s ability to bind DNA directly without a phosphorylation event. Conclusions : GRK5, acting in a kinase independent manner, is a facilitator of NFAT activity and part of a DNA-binding complex responsible for pathological hypertrophic gene transcription.
Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study)
Authors: PM Rothwell, AJ Coull, MF Giles, SC Howard, LE Silver, LM Bull, SA Gutnikov, P Edwards, D Mant, CM Sackley, A Farmer, PAG Sandercock, MS Dennis, CP Warlow, JM Bamford, P Anslow
Journal: The Lancet (2004)
Tolerance to Islet Autoantigens in Type 1 Diabetes
Authors: Jean-François Bach, Lucienne Chatenoud
Journal: Annual Review of Immunology (2001)

Tolerance to beta cell autoantigens represents a fragile equilibrium. Autoreactive T cells specific to these autoantigens are present in most normal individuals but are kept under control by a number of peripheral tolerance mechanisms, among which CD4(+) CD25(+) CD62L(+) T cell-mediated regulation probably plays a central role. The equilibrium may be disrupted by inappropriate activation of autoantigen-specific T cells, notably following to local inflammation that enhances the expression of the various molecules contributing to antigen recognition by T cells. Even when T cell activation finally overrides regulation, stimulation of regulatory cells by CD3 antibodies may reset the control of autoimmunity. Other procedures may also lead to disease prevention. These procedures are essentially focused on Th2 cytokines, whether used systemically or produced by Th2 cells after specific stimulation by autoantigens. Protection can also be obtained by NK T cell stimulation. Administration of beta cell antigens or CD3 antibodies is now being tested in clinical trials in prediabetics and/or recently diagnosed diabetes.
Stress fractures of the pubic rami in rheumatoid arthritis.
Authors: A H Isdale
Journal: Annals of the Rheumatic Diseases (1993)

OBJECTIVE--To draw attention to and detail the features of stress fractures of the pubic rami in patients with rheumatoid arthritis (RA). METHODS--Twenty two cases were collected prospectively over a four year period from patients undergoing active rheumatological surveillance in Leeds. Both old and new fractures were included. Information was obtained from the patients, clinical notes, and radiological investigations. RESULTS--All patients were women (mean age 68.1 years) with longstanding (mean disease duration 24.2 years) seropositive RA. Nineteen (86%) were receiving regular prednisolone treatment and all patients had radiological evidence of osteoporosis, with vertebral crush fractures in 10 (63%) of the 16 who had vertebral x ray examination. There was no biochemical evidence of osteomalacia. Nineteen (86%) presented with pain in the low back, groin, or hip and three were asymptomatic. Pain developed gradually in seven with an acute onset in the remainder. Six gave a history of a fall but only seven were x rayed at the onset of symptoms and initial radiographs were negative in five of these. In eighteen the fracture had either minimal or no effect on their mobility. Fractures affected all four pubic rami and in four all four were fractured. All but one patient (who had multiple fractures) made an uneventful recovery over two to four weeks with conservative management. CONCLUSIONS--Stress fractures of the pubic rami in RA appear to be more common than had been recognised. The low grade nature of symptoms, the minimal effect on mobility, and the absence of significant trauma are typical features and suggest that many more stress fractures may go unrecognised.
The mechanisms of sodium absorption in the human small intestine
Authors: John S. Fordtran, Floyd C. Rector, Norman W. Carter
Journal: Journal of Clinical Investigation (1968)

The present studies were designed to characterize sodium transport in the jejunum and ileum of humans with respect to the effects of water flow, sodium concentration, addition of glucose and galactose, and variations in aniomic composition of luminal fluid. In the ileum, sodium absorption occurred against very steep electrochemical gradients (110 mEq/liter, 5-15 mv), was unaffected by the rate or direction of water flow, and was not stimulated by addition of glucose, galactose, or bicarbonate. These findings led to the conclusion that there is an efficiently active sodium transport across a membrane that is relatively impermeable to sodium. In contrast, jejunal sodium (chloride) absorption can take place against only the modest concentration gradient of 13 mEq/liter, was dramatically influenced by water movement, and was stimulated by addition of glucose, galactose, and bicarbonate. The stimulatory effect of glucose and galactose was evident even when net water movement was inhibited to zero by mannitol. These observations led to the conclusion that a small fraction of jejunal sodium absorption was mediated by active transport coupled either to active absorption of bicarbonate or active secretion of hydrogen ions. The major part of sodium absorption, i.e. sodium chloride absorption, appeared to be mediated by a process of bulk flow of solution along osmotic pressure gradients. The stimulatory effect of glucose and galactose, even at zero water flow, was explained by a model in which the active transport of monosaccharide generates a local osmotic force for the absorption of solution (NaCl and water) from the jejunal lumen, which, in the presence of mannitol, is counterbalanced by a reverse flow of pure solvent (H(2)O) through a parallel set of channels which are impermeable to sodium. Support for the model was obtained by the demonstration that glucose and bicarbonate stimulated the absorption of the nonactively transported solute urea even when net water flow was maintained at zero by addition of mannitol to luminal contents.
Double-stranded RNA induces disproportionate expression of thymic stromal lymphopoietin versus interferon- in bronchial epithelial cells from donors with asthma
Authors: L. Uller, M. Leino, N. Bedke, D. Sammut, B. Green, L. Lau, P. H. Howarth, S. T. Holgate, D. E. Davies
Journal: Thorax (2010)

<h3>Background</h3> Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that strongly activates dendritic cells and can initiate allergic inflammation. Since exposure to rhinovirus or double-stranded (ds) RNA (a surrogate of viral infection) induces TSLP expression in bronchial epithelial cells (BECs), this cytokine may link innate antiviral responses and the type 2 adaptive immune response. <h3>Objective</h3> As BECs from donors with asthma have a deficient interferon (IFN) response to rhinovirus infection, a study was undertaken to test the hypothesis that their antiviral response shows a bias towards TSLP production. <h3>Methods</h3> Primary BECs were grown from subjects with asthma and healthy volunteers. After exposure to dsRNA, interleukin (IL)-8, IFN<i>β</i> and TSLP mRNA and protein expression were measured by RT-qPCR and ELISA, respectively. <h3>Results</h3> dsRNA dose-dependently increased IL-8 expression in BECs with no significant difference between the groups. However, BECs from subjects with asthma expressed less IFN<i>β</i> and more TSLP mRNA and protein in response to dsRNA than BECs from those without asthma (median (IQR) 57 (38–82) pg/ml vs 106 (57–214) pg/ml for IFN<i>β</i> (p&lt;0.05) and 114 (86–143) pg/ml vs 65 (32–119) pg/ml for TSLP (p&lt;0.05) in response to 10 μg/ml dsRNA for 24 h). Induction of TSLP mRNA by dsRNA was blocked by Toll-like receptor 3 or protein kinase inhibitors or by preventing de novo protein synthesis, but not by neutralisation of type I IFN receptors. <h3>Conclusion</h3> BECs from subjects with asthma are biased towards higher TSLP and lower IFN<i>β</i> production in response to dsRNA, suggesting that viral infection in asthma may lead to an altered mediator profile that biases towards a Th2 immune response.
First-line 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) does not impair the feasibility and the activity of second line treatments in metastatic colorectal cancer
Authors: G. Masi, L. Marcucci, F. Loupakis, E. Cerri, C. Barbara, S. Bursi, G. Allegrini, I.M. Brunetti, R. Murr, S. Ricci, S. Cupini, M. Andreuccetti, A. Falcone
Journal: Annals of Oncology (2006)
CYTOLOGIC STUDIES ON RHEUMATIC FEVER
Authors: Currier McEwen
Journal: Journal of Clinical Investigation (1935)

of data for synovialfluid from patients with rheumatic fever-only specimens from joints uncomplicated by previous aspiration are listed DurtionWht Patient Age Sex Joint of ofar-Saeoepr-blood Amouint ter of 0* rm Polys.Lymph-Mono-fren-Othier of rthr o' emer of fluid fluiid synovial cytes ocytes cytes'cls dis-tfiirithrtisue cut fluid e eass 1W.~~~~days das OF. c.c. percent pecent percent percen percent per cen M. M. 23 M
High strain mechanical loading rapidly induces tendon apoptosis: an ex vivo rat tibialis anterior model
Authors: A Scott, K M Khan, J Heer, J L Cook, O Lian, V Duronio
Journal: British Journal of Sports Medicine (2005)

The role of apoptosis, or programmed cell death, has only recently been explored in tendon.To investigate the development of apoptosis after high strain loading of rat tendon.The right tibialis anterior tendons of three rats were prepared for mechanical loading, and left tendons were prepared identically as non-loaded controls. Tendon was loaded with 20% strain for six hours using a 1 Hz longitudinal sine wave signal. The following were used to assess apoptosis: (a) a monoclonal mouse antibody (F7-26) to label single stranded DNA breaks; (b) a rabbit polyclonal antibody that specifically recognises the cleaved form of caspase-3.Light microscopy confirmed that the high strain protocol induced a stretch overload injury. Control tendons showed little or no staining with the F7-26 antibody, but the loaded tendons displayed numerous apoptotic cells. The percentage of apoptotic cells (20%) in the loaded tendon was significantly greater than in the control tendon (1%) (p = 0.000). The labelled cells colocalised with abnormal nuclear morphology, including nuclear fragmentation. The staining against cleaved caspase-3 was positive in loaded tendons only, and localised both to nucleus and cytoplasm.This experiment extends knowledge of human tendon apoptosis by showing that apoptosis can occur in response to short term, high strain mechanical loading. This is the first report of mechanical loading of intact tendon causing excessive apoptosis.
Increased peripheral T cell reactivity to microbial antigens and collagen type II in rheumatoid arthritis after treatment with soluble TNFalpha receptors
Authors: L Berg
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVE</h3> Peripheral T cells from patients with rheumatoid arthritis (RA) are hyporesponsive when stimulated with antigen or mitogen in vitro, possibly owing to increased production of proinflammatory cytokines such as tumour necrosis factor α (TNFα). This study sought to find out if and how RA T cell reactivity is affected during treatment with etanercept (Enbrel), a soluble TNFα receptor. <h3>METHODS</h3> Heparinised blood was collected from patients with RA at baseline, after four and eight weeks of etanercept treatment, and from healthy controls. After density separation spontaneous production of interferon γ (IFNγ), TNFα, interleukin 6 (IL6), and IL10 by peripheral blood mononuclear cells (PBMC) was detected by ELISPOT. For detection of T cell reactivity, PBMC were stimulated in vitro with mitogen (phytohaemagglutinin (PHA)), microbial antigens (purified protein derivative (PPD), influenza), or an autoantigen, collagen type II (CII). Supernatants were analysed for IFNγ and IL2 content by enzyme linked immunosorbent assay (ELISA). <h3>RESULTS</h3> In RA the number of cells spontaneously producing IFNγ was significantly increased after four, but not eight weeks9 treatment with etanercept. T cell reactivity, as measured by IFNγ production to PPD, influenza, and CII was significantly increased after four and sustained after eight weeks9 treatment, whereas IFNγ production induced by PHA remained unchanged. TNFα production was significantly higher in patients with RA than in controls and did not change during etanercept treatment. <h3>CONCLUSION</h3> Treatment of patients with RA with etanercept may lead to increased peripheral T cell reactivity both to microbial antigens and to self antigens such as CII. These findings indicate that TNFα blockade may not only suppress but also stimulate certain aspects of antimicrobial immune defence and autoimmunity.
Vertebral fractures and bone mineral density in idiopathic, secondary and corticosteroid associated osteoporosis in men
Authors: S F Evans
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVE</h3> To investigate bone mineral density (BMD) in men with symptomatic osteoporosis and compare BMD in patients with idiopathic, secondary and corticosteroid associated osteoporosis. <h3>METHODS</h3> Age, number of vertebral fractures at presentation and BMD were investigated in men presenting to a bone metabolism clinic with idiopathic (n=105; group 1), secondary (n=67; group 2) and corticosteroid osteoporosis (n=48; group 3). BMD was measured in 176 healthy men (controls). Osteoporosis was diagnosed if there was ⩾20% vertebral deformity. <h3>RESULTS</h3> Age at peak BMD in controls was 20–29 years at spine (LS-BMD) and femoral neck (FN-BMD). LS-BMD did not change with age but FN-BMD decreased in controls and groups 1 and 2. Mean (SD) age was similar in groups 1 (62.8 (11.5) years, 2 (60.2 (11.0)) years and 3 (62.7 (10.4) years with 45%, 51% and 40% of patients respectively presenting before 60 years. Back pain, present for up to 12 months, was the commonest cause of referral. Vertebral fractures at presentation averaged mean (SD) 2.51 (1.9) in group 1, 2.76 (2.2) in group 2 and 2.48 (1.8) in group 3. LS-BMD Z scores and T scores were more negative in group 1 patients with ⩽3 vertebral fractures compared with FN-BMD suggesting a greater trabecular bone deficit. LS-BMD Z score in group 1 is −1.71, lower than in population studies. LS T score associated with fracture was about −2.4 in all groups. T8, T12 and L1 were the most frequent levels for fracture. <h3>CONCLUSIONS</h3> Men with symptomatic osteoporosis present in middle age, have low BMD with similar T scores irrespective of aetiology and sustain ⩾ 1 fracture.
Randomized Trials in 2466 Patients With Stage I Seminoma: Patterns of Relapse and Follow-up
Authors: G. M. Mead, S. D. Fossa, R. T. D. Oliver, J. K. Joffe, R. A. Huddart, J. T. Roberts, P. Pollock, R. Gabe, S. P. Stenning
Journal: JNCI Journal of the National Cancer Institute (2011)

From July 1, 1989, through March 31, 2001, 2466 patients with stage I seminoma were evaluated in three randomized noninferiority trials: the TE10, TE18, and TE19 trials. We analyzed mature results of these studies. The TE10 trial randomly assigned 478 patients to para-aortic and ipsilateral iliac lymph node (dogleg field) or para-aortic only radiation therapy (total dose = 30 Gy). The TE18 trial randomly assigned 1094 patients to a total dose of 30 or 20 Gy of radiation therapy, predominantly to a para-aortic field. The TE19 trial randomly assigned 1477 patients to radiation therapy or a single injection of carboplatin at a dose of seven times the area under the curve. Time to relapse was determined from Kaplan–Meier curves, and such data were compared by use of Cox regression models. Noninferiority in TE18 and TE19 required the upper limit of the 90% confidence intervals (CIs) (reflecting the one-sided test for noninferiority at a 5% statistical significance level) to exclude a hazard ratio (HR) of greater than 2.0 and a doubling of the 5-year relapse rates observed in the control arm. The TE10 trial was not powered to exclude clinically relevant differences in overall relapse rates but was assessed against the same criteria. Median follow-up times were 6.4–12 years in the three trials. We identified the noninferiority of the following treatments: 20 Gy of radiation therapy in the TE18 trial (HR of relapse = 0.63, 90% CI = 0.38 to 1.04) and carboplatin in the TE19 trial (HR of relapse = 1.25, 90% CI = 0.83 to 1.89). Para-aortic radiation therapy in the TE10 trial was associated with a hazard ratio of relapse of 1.15 (90% CI = 0.54 to 2.44). Relapse occurred after 3 years in only four (0.2%) of all 2466 patients. Computed tomography scans had little impact on the detection of relapse after radiation therapy; seven of the 904 patients allocated radiation therapy in TE19 had a relapse detected by this method. This large and mature dataset from three randomized trials has provided support for the use of either radiation therapy or carboplatin therapy as adjuvant treatment for stage I seminoma.