Citations

Transforming growth factor β (TGFβ) family ligands initiate a cascade of events capable of modulating cellular growth and differentiation. The receptors responsible for transducing these cellular signals are referred to as the type I and type II TGFβ receptors. Ligand binding to the type II receptor results in the transphosphorylation and activation of the type I receptor. This heteromeric complex then propagates the signal(s) to downstream effectors. There is presently little data concerning the fate of TGFβ receptors after ligand binding, with conflicting reports indicating no change or decreasing cell surface receptor numbers. To address the fate of ligand-activated receptors, we have used our previously characterized chimeric receptors consisting of the ligand binding domain from the granulocyte/macrophage colony-stimulating factor α or β receptor fused to the transmembrane and cytoplasmic domain of the type I or type II TGFβ receptor. This system not only provides the necessary sensitivity and specificity to address these types of questions but also permits the differentiation of endocytic responses to either homomeric or heteromeric intracellular TGFβ receptor oligomerization. Data are presented that show, within minutes of ligand binding, chimeric TGFβ receptors are internalized. However, although all the chimeric receptor combinations show similar internalization rates, receptor down-regulation occurs only after activation of heteromeric TGFβ receptors. These results indicate that effective receptor down-regulation requires cross-talk between the type I and type II TGFβ receptors and that TGFβ receptor heteromers and homomers show distinct trafficking behavior.

ABSTRACTObjective:Microscopic colitis (MC) is prevalent in adults investigated for chronic watery diarrhea, yet characterization of pediatric MC is limited.Methods:Our pathology database was searched from 1995 to 2011 for pediatric cases of lymphocytic colitis (LC) or collagenous colitis (CC). Those with diarrhea persisting for >2 weeks and visually normal colonoscopy were accepted as cases. Demographics, laboratory results, medication use within 3 months of presentation, medical and family history of autoimmune disease, and response to treatment were abstracted.Results:A total of 27 cases were histologically consistent with MC on biopsy; 5 with concomitant enteric infection or isolated abdominal pain were excluded. Twenty‐two cases of MC (female patients, 59%; median age at diagnosis, 15.3 years) were included (19 LC and 3 CC). Two had type 1 diabetes mellitus, 2 were anti‐nuclear antibody positive, and 2 had common variable immunodeficiency. Of 20 patients who underwent an esophagogastroduodenoscopy, 1 had collagenous sprue and 4 had celiac disease. One presented after the clearance of recurrent Clostridium difficile infection. Previous drug exposures included nonsteroidal anti‐inflammatory drugs (n = 7), proton pump inhibitors (n = 6), and selective serotonin reuptake inhibitors (n = 3). Common symptoms in addition to diarrhea included abdominal pain (77.3%) and weight loss (27.3%). Of 17 patients with follow‐up, all of the 8 treated with steroids had some response: 57.1% (4/7) responded to mesalamine and 42.9% (3/7) responded to bismuth subsalicylate.Conclusions:In this cohort of pediatric patients, LC was much more common than CC. As described in adults, we observed associations with celiac disease, type 1 diabetes mellitus, and medications; we additionally saw an association with immunodeficiency. Our patients showed greater response to steroids than mesalamine or bismuth.

AimVarious factors are underlying for the onset of non‐B, non‐C hepatitis virus‐related hepatocellular carcinoma (NBNC‐HCC). We aimed to investigate the independent risk factors and profiles associated with NBNC‐HCC using a data‐mining technique.MethodsWe conducted a case‐control study and enrolled 223 NBNC‐HCC patients and 669 controls from a health checkup database (n = 176 886). Multivariate analysis, random forest analysis and a decision‐tree algorithm were employed to examine the independent risk factors, factors distinguishing between the case and control groups, and to identify profiles for the incidence of NBNC‐HCC, respectively.ResultsIn multivariate analysis, besides γ‐glutamyltransferase (GGT) levels and the Brinkman index, albumin level was an independent negative risk factor for the incidence of NBNC‐HCC (odds ratio = 0.67; 95% confidence interval = 0.60–0.70; P < 0.0001). In random forest analysis, serum albumin level was the highest‐ranked variable for distinguishing between the case and control groups (98 variable importance). A decision‐tree algorithm was created for albumin and GGT levels, the aspartate aminotransferase‐to‐platelet ratio index (APRI) and the Brinkman index. The serum albumin level was selected as the initial split variable, and 82.5% of the subjects with albumin levels of less than 4.01 g/dL were found to have NBNC‐HCC.ConclusionData‐mining analysis revealed that serum albumin level is an independent risk factor and the most distinguishable factor associated with the incidence of NBNC‐HCC. Furthermore, we created an NBNC‐HCC profile consisting of albumin and GGT levels, the APRI and the Brinkman index. This profile could be used in the screening strategy for NBNC‐HCC.

Cellular senescence is a state of irreversible cell cycle arrest that has been documented to both suppress cancer and promote aging. Although not well understood, extensive nuclear changes, including the remodeling of chromatin, take place as cells become senescent. In this issue, Ivanov et al. (2013. J. Cell Biol. http://dx.doi.org/jcb.201212110) report that chromatin fragments are released from the nuclei of senescent cells and are subsequently targeted for processing through the autophagy/lysosomal pathway.

Background Censoring that is dependent on covariates associated with survival can arise in randomized trials due to changes in recruitment and eligibility criteria to minimize withdrawals, potentially leading to biased treatment effect estimates. Imputation approaches have been proposed to address censoring in survival analysis; while these approaches may provide unbiased estimates of treatment effects, imputation of a large number of outcomes may over- or underestimate the associated variance based on the imputation pool selected. Purpose We propose an improved method, risk-stratified imputation, as an alternative to address withdrawal related to the risk of events in the context of time-to-event analyses. Methods Our algorithm performs imputation from a pool of replacement subjects with similar values of both treatment and covariate(s) of interest, that is, from a risk-stratified sample. This stratification prior to imputation addresses the requirement of time-to-event analysis that censored observations are representative of all other observations in the risk group with similar exposure variables. We compared our risk-stratified imputation to case deletion and bootstrap imputation in a simulated dataset in which the covariate of interest (study withdrawal) was related to treatment. A motivating example from a recent clinical trial is also presented to demonstrate the utility of our method. Results In our simulations, risk-stratified imputation gives estimates of treatment effect comparable to bootstrap and auxiliary variable imputation while avoiding inaccuracies of the latter two in estimating the associated variance. Similar results were obtained in analysis of clinical trial data. Limitations Risk-stratified imputation has little advantage over other imputation methods when covariates of interest are not related to treatment. Risk-stratified imputation is intended for categorical covariates and may be sensitive to the width of the matching window if continuous covariates are used. Conclusions The use of the risk-stratified imputation should facilitate the analysis of many clinical trials, in which one group has a higher withdrawal rate that is related to treatment.

ObjectiveTo determine whether the impact of aging on cardiovascular disease (CVD) risk in patients with rheumatoid arthritis (RA) differs from that in the general population (as estimated by the Framingham Risk Score [FRS]).MethodsA population‐based inception cohort of Olmsted County, Minnesota residents ages ≥30 years who fulfilled the American College of Rheumatology 1987 criteria for RA in 1988–2008 was assembled and followed up until death, migration, or July 1, 2012. Data on CVD events were collected by medical records review. The 10‐year FRS for CVD was calculated. Cox models adjusted for FRS were used to examine the influence of age on CVD risk.ResultsThe study included 563 patients with RA without prior CVD (mean age 55 years, 72% women, and 69% seropositive [i.e., rheumatoid factor and/or anti–citrullinated protein antibody positive]). During a mean followup of 8.2 years, 98 patients developed CVD (74 seropositive and 24 seronegative), but the FRS predicted only 59.7 events (35.4 seropositive and 24.3 seronegative). The gap between observed and predicted CVD risk increased exponentially across age, and the effect of age on CVD risk in seropositive RA was nearly double its effect in the general population, with additional log(age) coefficients of 2.91 for women (P = 0.002) and 2.06 for men (P = 0.027).ConclusionOur findings indicate that age exerts an exponentially increasing effect on CVD risk in seropositive RA, but no increased effect among seronegative patients. The causes of accelerated aging in patients with seropositive RA deserve further investigation.