β-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis

Objective: Deregulation of the Wnt signalling pathway by mutations in the Apc or β-catenin genes underlies colorectal carcinogenesis. As a result, β-catenin stabilises, translocates t

Adenomatous polyposis coli-mediated control of β-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors

Background: During skeletogenesis, protein levels of β-catenin in the canonical Wnt signaling pathway determine lineage commitment of skeletal precursor cells to osteoblasts and chondrocytes. Adenomatous polyposis coli (Apc) is a key controller of β-catenin turnover by down-regulating intracellular levels of β-catenin. Results: To investigate whether Apc is involved in lineage commitment of skeletal precursor cells, we generated conditional knockout mice lacking functional Apc in Col2a1-expressing cells. In contrast to other models in which an oncogenic variant of β-catenin was used, our approach resulted in the accumulation of wild type β-catenin protein due to functional loss of Apc. Conditional homozygous Apc mutant mice died perinatally showing greatly impaired skeletogenesis. All endochondral bones were misshaped and lacked structural integrity. Lack of functional Apc resulted in a pleiotropic skeletal cell phenotype. The majority of the precursor cells lacking Apc failed to differentiate into chondrocytes or osteoblasts. However, skeletal precursor cells in the proximal ribs were able to escape the noxious effect of functional loss of Apc resulting in formation of highly active osteoblasts. Inactivation of Apc in chondrocytes was associated with dedifferentiation of these cells. Conclusion: Our data indicate that a tight Apc-mediated control of β-catenin levels is essential for differentiation of skeletal precursors as well as for the maintenance of a chondrocytic phenotype in a spatio-temporal regulated manner

Predictors of Limb Fat Gain in HIV Positive Patients Following a Change to Tenofovir-Emtricitabine or Abacavir-Lamivudine

Background Antiretroviral treatment (cART) in HIV causes lipoatrophy. We examined predictors of anthropometric outcomes over 96 weeks in HIV-infected, lipoatrophic adults receiving stable cART randomised to tenofovir-emtricitabine (TDF-FTC) or abacavir-lamivudine (ABC-3TC) fixed dose combinations. Methodology/Principal Findings The STEAL study was a prospective trial of virologically suppressed participants randomised to either TDF-FTC (n = 178) or ABC-3TC (n = 179). Anthropometric assessment was conducted at baseline, weeks 48 and 96. The analysis population included those with baseline and week 96 data remaining on randomised therapy. Distribution of limb fat change was divided into four categories (≤0%, \u3e0-10%, \u3e10-20%, \u3e20%). Baseline characteristics [demographics, medical history, metabolic and cardiovascular biomarkers] were assessed as potential predictors of change in percent subcutaneous limb fat using linear regression. 303 participants (85% of STEAL population) were included. Baseline characteristics were: mean (±SD) age 45 (±8) years; thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI) duration 4 (±3) years; limb fat 5.4 (±3.0)kg; body mass index 24.7 (±3.5) kg/m2. Mean (SD) limb fat gain to week 48 and 96 was 7.6% (±22.4) and 13.2% (±27.3), respectively, with no significant difference between groups. 51.5% of all participants had \u3e10% gain in limb fat. Predictors of greater limb fat gain at week 96 were baseline tNRTI (10.3, p = 0.001), glucose \u3e6 mmol/L (16.1, p = 0.04), higher interleukin 6 (IL-6) (2.8, p = 0.004) and lower baseline limb fat (3.8-6.4 kg - 11.2; \u3e6.4 kg - 15.7, p trend\u3c0.001). Conclusions/Significance Modest peripheral fat gain occurred with both TDF-FTC and ABC-3TC. Baseline factors associated with more severe lipodystrophy (lipoatrophy, baseline tNRTI, raised IL6, and glucose) predicted greater limb fat recovery at 96 weeks

Genetic and environmental influences on the stability of withdrawn behavior in children: A longitudinal, multi-informant twin study.

We examined the contribution of genetic and environmental influences on the stability of withdrawn behavior (WB) in childhood using a longitudinal multiple rater twin design. Maternal and paternal ratings on the withdrawn subscale of the Child Behavior Checklist (CBCL) were obtained from 14,889 families when the twins were 3, 7, 10 and 12 years old. A longitudinal psychometric model was fitted to the data and the fit of transmission and common factor models were evaluated for each variance component. WB showed considerable stability throughout childhood, with correlation coefficients ranging from about .30 for the 9-year time interval to .65 for shorter time intervals. Individual differences in WB as observed by the mother and the father were found to be largely influenced by genetic effects at all four time points, in both boys (50–66%) and girls (38–64%). Shared environmental influences explained a small to modest proportion (0–24%) of the variance at all ages and were slightly more pronounced in girls. Non-shared environmental influences were of moderate importance to the variance and slightly increased with age, from 22–28% at age 3 to 35–41% at age 12 years. The stability of WB was largely explained by genetic effects, accounting for 74% of stability in boys and 65% in girls. Shared environmental effects explained 7% (boys) and 17% (girls) of the behavioral stability. Most shared environmental effects were common to both raters, suggesting little influence of rater bias in the assessment of WB. The shared environmental effects common to both raters were best described by a common factor model, indicating that these effects are stable and persistent throughout childhood. Non-shared environmental effects accounted for the remaining covariance over time

A Targeted Constitutive Mutation in the Apc Tumor Suppressor Gene Underlies Mammary But Not Intestinal Tumorigenesis

Germline mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominant hereditary predisposition to the development of multiple colorectal adenomas and of a broad spectrum of extra-intestinal tumors. Moreover, somatic APC mutations play a rate-limiting and initiating role in the majority of sporadic colorectal cancers. Notwithstanding its multifunctional nature, the main tumor suppressing activity of the APC gene resides in its ability to regulate Wnt/β-catenin signaling. Notably, genotype–phenotype correlations have been established at the APC gene between the length and stability of the truncated proteins encoded by different mutant alleles, the corresponding levels of Wnt/β-catenin signaling activity they encode for, and the incidence and distribution of intestinal and extra-intestinal tumors. Here, we report a novel mouse model, Apc1572T, obtained by targeting a truncated mutation at codon 1572 in the endogenous Apc gene. This hypomorphic mutant allele results in intermediate levels of Wnt/β-catenin signaling activation when compared with other Apc mutations associated with multifocal intestinal tumors. Notwithstanding the constitutive nature of the mutation, Apc+/1572T mice have no predisposition to intestinal cancer but develop multifocal mammary adenocarcinomas and subsequent pulmonary metastases in both genders. The histology of the Apc1572T primary mammary tumours is highly heterogeneous with luminal, myoepithelial, and squamous lineages and is reminiscent of metaplastic carcinoma of the breast in humans. The striking phenotype of Apc+/1572T mice suggests that specific dosages of Wnt/β-catenin signaling activity differentially affect tissue homeostasis and initiate tumorigenesis in an organ-specific fashion

Individual risk calculator to predict lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma:a multicenter cohort study

Background Lymph node metastasis (LNM) is possible after endoscopic resection of early esophageal adenocarcinoma (EAC). This study aimed to develop and internally validate a prediction model that estimates the individual risk of metastases in patients with pT1b EAC. Methods A nationwide, retrospective, multicenter cohort study was conducted in patients with pT1b EAC treated with endoscopic resection and/or surgery between 1989 and 2016. The primary end point was presence of LNM in surgical resection specimens or detection of metastases during follow-up. All resection specimens were histologically reassessed by specialist gastrointestinal pathologists. Subdistribution hazard regression analysis was used to develop the prediction model. The discriminative ability of this model was assessed using the c-statistic. Results 248 patients with pT1b EAC were included. Metastases were seen in 78 patients, and the 5-year cumulative incidence was 30.9 % (95 % confidence interval [CI] 25.1 %-36.8 %). The risk of metastases increased with submucosal invasion depth (subdistribution hazard ratio [SHR] 1.08, 95 %CI 1.02-1.14, for every increase of 500 μm), lymphovascular invasion (SHR 2.95, 95 %CI 1.95-4.45), and for larger tumors (SHR 1.23, 95 %CI 1.10-1.37, for every increase of 10 mm). The model demonstrated good discriminative ability (c-statistic 0.81, 95 %CI 0.75-0.86). Conclusions A third of patients with pT1b EAC experienced metastases within 5 years. The probability of developing post-resection metastases was estimated with a personalized predicted risk score incorporating tumor invasion depth, tumor size, and lymphovascular invasion. This model requires external validation before implementation into clinical practice

Lymphovascular invasion quantification could improve risk prediction of lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma

AIM: To quantify lymphovascular invasion (LVI) and to assess the prognostic value in patients with pT1b esophageal adenocarcinoma. METHODS: In this nationwide, retrospective cohort study, patients were included if they were treated with surgery or endoscopic resection for pT1b esophageal adenocarcinoma. Primary endpoint was the presence of metastases, lymph node metastases, or distant metastases, in surgical resection specimens or during follow‐up. A prediction model to identify risk factors for metastases was developed and internally validated. RESULTS: 248 patients were included. LVI was distributed as follows: no LVI (n = 196; 79.0%), 1 LVI focus (n = 16; 6.5%), 2–3 LVI foci (n = 21; 8.5%) and ≥4 LVI foci (n = 15; 6.0%). Seventy‐eight patients had metastases. The risk of metastases was increased for tumors with 2–3 LVI foci [subdistribution hazard ratio (SHR) 3.39, 95% confidence interval (CI) 2.10–5.47] and ≥4 LVI foci (SHR 3.81, 95% CI 2.37–6.10). The prediction model demonstrated a good discriminative ability (c‐statistic 0.81). CONCLUSION: The risk of metastases is higher when more LVI foci are present. Quantification of LVI could be useful for a more precise risk estimation of metastases. This model needs to be externally validated before implementation into clinical practice

Mx Scripts Library: Structural Equation Modeling Scripts for Twin and Family Data

Structural equation modeling (SEM) provides a flexible tool to carry out genetic analyses of family and twin data. The basic model which decomposes the variance between and within families for a particular trait into genetic and non-genetic components can be generalized to multivariate and/ or longitudinal data, incorporate sex differences in parameter estimates, and model the effects of measured environment, candidate genes or DNA marker data. We introduce a web-based library ( http://www.psy.vu.nl/mxbib ) of scripts for uni- and multivariate genetic epidemiological analyses, as well as for linkage and genetic association tests. The scripts are written to be used with the freely available software package Mx and provide a flexible and uniform approach to the analysis of data from relatives. © 2005 Springer Science+Business Media, Inc