37 research outputs found
Defective Gp130-Mediated Signal Transducer and Activator of Transcription (Stat) Signaling Results in Degenerative Joint Disease, Gastrointestinal Ulceration, and Failure of Uterine Implantation
The receptor subunit gp130 transduces multiple cell typeâspecific activities of the leukemia inhibitory factor (LIF)/interleukin (IL)-6 family of cytokines through the signal transducer and activator of transcription (STAT) and src homology 2 domainâbearing protein tyrosine phosphatase (SHP)-2/ras/Erk pathways. To define STAT-dependent physiological responses, we generated mice with a COOH-terminal gp130ÎSTAT âknock-inâ mutation which deleted all STAT-binding sites. gp130ÎSTAT mice phenocopyed mice deficient for IL-6 (impaired humoral and mucosal immune and hepatic acute phase responses) and LIF (failure of blastocyst implantation). However, unlike mice with null mutations in any of the components in the gp130 signaling pathway, gp130ÎSTAT mice also displayed gastrointestinal ulceration and a severe joint disease with features of chronic synovitis, cartilaginous metaplasia, and degradation of the articular cartilage. Mitogenic hyperresponsiveness of synovial cells to the LIF/IL-6 family of cyto-kines was caused by sustained gp130-mediated SHP-2/ras/Erk activation due to impaired STAT-mediated induction of suppressor of cytokine signaling (SOCS) proteins which normally limits gp130 signaling. Therefore, the joint pathology in gp130ÎSTAT mice is likely to arise from the disturbance of the otherwise balanced activation of the SHP-2/ras/Erk and STAT signaling cascades emanating from gp130
Lâanziano attivo. Proposte e riflessioni per la terza e la quarta etĂ
Il problema della senilitĂ si pone ormai in Italia, come in tutte le societĂ avanzate, in termini assai diversi dal passato. I saggi compresi nel presente volume intervengono su tutti gli aspetti della senilitĂ - da quelli psicologici, sanitari e affettivi a quelli assistenziali, economici e giuridici - per suggerire indicazioni operative e possibili soluzioni.- Indice #4- Prefazione, Marcello Pacini #10- Introduzione, Giuliano Urbani #12- Prima parte Per una nuova concezione della condizione anziana #20- LâetĂ del tempo libero, Norberto Bobbio #22- Lâanziano protagonista in una societĂ che cambia, Gian Maria Capuani e Giannino Piana #26- La piccola immortalitĂ , Nando dalla Chiesa #36- Lâanziano come risorsa sociale: il volontariato dopo la pensione, Fausto Melloni #44- Seconda Parte Aspetti sociali della condizione anziana #62- Psicogerontologia: attualitĂ e nuove prospettive, Maria Antonietta Aveni Casucci #64- Lâinvecchiamento della popolazione italiana in un contesto internazionale, Antonio Golini e Agostino Lori #82- Lâanziano e lâinnovazione tecnologica, Francesco Jovane e Roberto Groppetti #114- La tutela giuridica dellâanziano, Luigi Mengoni #128- La salute dellâanziano: valutazione dei meccanismi di plasticitĂ , Renzo Rozzini, Angelo Bianchetti e Marco Trabucchi #140- Lavoratori anziani: ambivalenza e interventi, Harris T. Schrank e Joan M. Waring #156- Il medico e lâanziano, Carlo Vergani #176- La normalitĂ incerta, Virginio Oddone e Fabrizio Fabris #188- Il quadro organizzativo per una corretta assistenza socio-sanitaria alla popolazione anziana, Gaetano Maria Fara #200- Terza Parte Le tendenze della riflessione #216- La condizione degli anziani in Italia, Claudio Calvaruso #218- Anziani attivi: un possibile esempio di nuova centralitĂ del sociale, Vincenzo Cesareo #228- Appendice Un contributo di ricerca #246- Figli adulti e genitori anziani: una nuova relazione tra le generazioni, Giovanna Rossi #24
Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples
Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts
Elevated Dnmt3a activity promotes polyposis in ApcMin mice by relaxing extracellular restraints on Wnt signaling
Background & Aims: Aberrant DNA methylation is a common early event in neoplasia, but it is unclear how this relates to dysregulation of DNA (cytosine-5) methyltransferases (Dnmts). Here we use knock-in transgenic mice to investigate the consequences of intestinal epithelium-specific overexpression of de novo Dnmt3a. Methods: A novel gene targeting strategy, based on the intestinal epithelium-specific, uniform expression of the A33 glycoprotein, is employed to restrict Dnmt3a overexpression in homozygous A33 mutant mice. Results: A33 mice infrequently develop spontaneous intestinal polyps. However, when genetically challenged, tumor multiplicity in A33;Apc compound mice is 3-fold higher than in Apc mice. Although we observe a requirement for spontaneous loss of heterozygosity of the adenomatous polyposis coli (Apc) gene to trigger tumorigenesis in Apc mice, lesions in A33;Apc mice frequently retain the wild-type Apc allele. However, epithelia from normal mucosa and polyps of A33;Apc mice show hypermethylation-mediated transcriptional silencing of the Wnt antagonists Sfrp5, and to a lesser extent, Sfrp1 and increased nuclear ÎČ-catenin alongside activation of the Wnt-target gene Axin2/Conductin. Conversely, enforced Sfrp5 expression suppresses canonical Wnt-signaling more effectively in wild-type than in Apc cells. Conclusions: Aberrant activation of the canonical Wnt pathway, either by mono-allelic Apc loss or transcriptional silencing of Sfrp5 is largely insufficient to promote polyposis, but epistatic interactions between these genetic and epigenetic events enables initiation and promotion of disease. This mechanism is likely to play a role in human colorectal cancer, because we also show that elevated DNMT3A expression coincides with repressed SFRP5 and enhanced AXIN2/CONDUCTIN expression in paired patient biopsies
Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard AnalogâInduced Airway Obstruction
Physiological expression of the PI3K-activating mutation Pik3caH1047R combines with Apc loss to promote development of invasive intestinal adenocarcinomas in mice
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Change in Physical Activity and Sitting Time After Myocardial Infarction and Mortality Among Postmenopausal Women in the Women's Health InitiativeâObservational Study
Background: How physical activity (PA) and sitting time may change after first myocardial infarction (MI) and the association with mortality in postmenopausal women is unknown. Methods and Results: Participants included postmenopausal women in the Women's Health InitiativeâObservational Study, aged 50 to 79 years who experienced a clinical MI during the study. This analysis included 856 women who had adequate data on PA exposure and 533 women for sitting time exposures. Sitting time was selfâreported at baseline, year 3, and year 6. Selfâreported PA was reported at baseline through year 8. Change in PA and sitting time were calculated as the difference between the cumulative average immediately following MI and the cumulative average immediately preceding MI. The 4 categories of change were: maintained low, decreased, increased, and maintained high. The cut points were â„7.5 metabolic equivalent of task hours/week versus <7.5 metabolic equivalent of task hours/week for PA and â„8 h/day versus <8 h/day for sitting time. Cox proportional hazard models estimated hazard ratios and 95% CIs for allâcause, coronary heart disease, and cardiovascular disease mortality. Compared with women who maintained low PA (referent), the risk of allâcause mortality was: 0.54 (0.34â0.86) for increased PA and 0.52 (0.36â0.73) for maintained high PA. Women who had preâMI levels of sitting time <8 h/day, every 1 h/day increase in sitting time was associated with a 9% increased risk (hazard ratio=1.09, 95% CI: 1.01, 1.19) of allâcause mortality. Conclusions: Meeting the recommended PA guidelines preâ and postâMI may have a protective role against mortality in postmenopausal women