Search

List of primers used for cloning and genotyping

Invasive lobular carcinoma (ILC) accounts for 8%–14% of all breast cancer cases. The main hallmark of ILCs is the functional loss of the cell–cell adhesion protein E-cadherin. Nonetheless, loss of E-cadherin alone does not predispose mice to mammary tumor development, indicating that additional perturbations are required for ILC formation. Previously, we identified an N-terminal truncation variant of ASPP2 (t-ASPP2) as a driver of ILC in mice with mammary-specific loss of E-cadherin. Here we showed that expression of t-ASPP2 induced actomyosin relaxation, enabling adhesion and survival of E-cadherin–deficient murine mammary epithelial cells on stiff matrices like fibrillar collagen. The induction of actomyosin relaxation by t-ASPP2 was dependent on its interaction with protein phosphatase 1, but not on t-ASPP2–induced YAP activation. Truncated ASPP2 collaborated with both E-cadherin loss and PI3K pathway activation via PTEN loss in ILC development. t-ASPP2–induced actomyosin relaxation was required for ILC initiation, but not progression. Conversely, YAP activation induced by t-ASPP2 contributed to tumor growth and progression while being dispensable for tumor initiation. Together, these findings highlight two distinct mechanisms through which t-ASPP2 promotes ILC initiation and progression.Significance:Truncated ASPP2 cooperates with E-cadherin and PTEN loss to drive breast cancer initiation and progression via two distinct mechanisms. ASPP2-induced actomyosin relaxation drives tumor initiation, while ASPP2-mediated YAP activation enhances tumor progression.

Criteria for histopathological classification of tumors

GSK-296692 intervention study dosing overview

Supplementary Figures 1-7

Myeloid dysplastic syndrome (MDS) reflects a preleukemic bone marrow (BM) disorder with limited treatment options and poor disease survival. As only a minority of MDS patients are eligible for curative hematopoietic stem cell transplantation, there is an urgent need to develop alternative treatment options. Chronic activation of Wnt/β-catenin has been implicated to underlie MDS formation and recently assigned to drive MDS transformation to acute myeloid leukemia. Wnt/β-catenin signaling therefore may harbor a pharmaceutical target to treat MDS and/or prevent leukemia formation. However, targeting the Wnt/β-catenin pathway will also affect healthy hematopoiesis in MDS patients. The control of Wnt/β-catenin in healthy hematopoiesis is poorly understood. Whereas Wnt/β-catenin is dispensable for steady-state erythropoiesis, its activity is essential for stress erythropoiesis in response to BM injury and anemia. Manipulation of Wnt/β-catenin signaling in MDS may therefore deregulate stress erythropoiesis and even increase anemia severity. Here, we provide a comprehensive overview of the most recent and established insights in the field to acquire more insight into the control of Wnt/β-catenin signaling in healthy and inefficient erythropoiesis as seen in MDS.

International audience; Obesity is a complex disease with many causes, including a possible role for environmental chemicals. Perfluorohexane sulfonate (PFHxS) is one of many per- and polyfluoroalkyl substances (PFASs) frequently detected in humans and it is suspected to be an obesogenic compound. We examined the potential long-term effects of PFHxS on metabolic parameters in rats after developmental exposure to 0.05, 5 or 25 mg/kg bw/day, with or without co-exposure to a background mixture of twelve endocrine disrupting chemicals (EDmix). Both male and female offspring showed signs of lower birth weight following intrauterine exposure. Female offspring exposed to both PFHxS and EDmix had increased body weight in adulthood. The retroperitoneal fat pad was larger in the PFHxS-exposed female offspring when compared to those exposed to EDmix alone. An attempt to detect putative molecular markers in the fat tissue by performing whole transcriptome profiling revealed no significant changes between groups and there were no significant effects on plasma leptin levels in exposed females. Our results show that early life exposure to endocrine disrupting chemicals can influence body weight later in life, but the effect is not necessarily reflected in changed gene expression in the fat tissue.

Bisphenol A (BPA) has been widely reported to exert endocrine disrupting effects, including the induction of adipogenesis in cultured preadipocytes and intact animals. Because of the potential harm to human health, BPA is being substituted by structurally related bisphenols. Whether or not such BPA analogues are safe substitutes, however, remains largely unknown. Here, we investigated the potential of bisphenol B (BPB), bisphenol E (BPE), bisphenol F (BPF), bisphenol S (BPS), and 4-cumylphenol (4-CP) to affect lipid and hormone levels in 3 T3-L1 cells. We found that BPB, BPE, BPF, BPS, and 4-CP all affected lipid accumulation and leptin levels to the same extent and potencies as BPA. Based on these and other results, we conclude that these BPA analogues and 4-CP most likely will elicit similar effects on adipocytes as BPA. Using them to substitute BPA in products should be done with caution.

Invasive lobular carcinoma (ILC) accounts for 8%–14% of all breast cancer cases. The main hallmark of ILCs is the functional loss of the cell–cell adhesion protein E-cadherin. Nonetheless, loss of E-cadherin alone does not predispose mice to mammary tumor development, indicating that additional perturbations are required for ILC formation. Previously, we identified an N-terminal truncation variant of ASPP2 (t-ASPP2) as a driver of ILC in mice with mammary-specific loss of E-cadherin. Here we showed that expression of t-ASPP2 induced actomyosin relaxation, enabling adhesion and survival of E-cadherin–deficient murine mammary epithelial cells on stiff matrices like fibrillar collagen. The induction of actomyosin relaxation by t-ASPP2 was dependent on its interaction with protein phosphatase 1, but not on t-ASPP2–induced YAP activation. Truncated ASPP2 collaborated with both E-cadherin loss and PI3K pathway activation via PTEN loss in ILC development. t-ASPP2–induced actomyosin relaxation was required for ILC initiation, but not progression. Conversely, YAP activation induced by t-ASPP2 contributed to tumor growth and progression while being dispensable for tumor initiation. Together, these findings highlight two distinct mechanisms through which t-ASPP2 promotes ILC initiation and progression. Significance: Truncated ASPP2 cooperates with E-cadherin and PTEN loss to drive breast cancer initiation and progression via two distinct mechanisms. ASPP2-induced actomyosin relaxation drives tumor initiation, while ASPP2-mediated YAP activation enhances tumor progression.

Objective: To examine the effect of the intervention implemented in the ToyBox study on changes observed in age and sex specific BMI percentile and investigate the role of perinatal factors, parental perceptions and characteristics on this change. Design: A multicomponent, kindergarten-based, family-involved intervention with a cluster-randomized design. A standardized protocol was used to measure children’s body weight and height. Information was also collected from parents/caregivers via the use of validated questionnaires. Linear mixed effect models with random intercept for country, socioeconomic status and school were used. Setting: Selected preschools within the provinces of Oost-Flanders and West-Flanders (Belgium), Varna (Bulgaria), Bavaria (Germany), Attica (Greece), Mazowieckie (Poland) and Zaragoza (Spain). Participants: A sample of 6, 268 pre-schoolers aged 3.5-5.5 (51.9% boys). Results: There was no intervention effect on the change in children’s BMI percentile. However, parents’ underestimation of their children’s actual weight status, parental overweight and mothers’ pre-pregnancy overweight/obesity were found to be significantly and independently associated with increases in children’s BMI percentile in multivariate modelling. Conclusion: Before or as part of the implementation of any childhood obesity intervention initiative, it is important to assist parents/caregivers to correctly perceive their own and their children’s weight status. Recognition of excessive weight by parents/caregivers can increase their readiness to change and as such facilitate higher adherence to favourable behavioural changes within the family. © 2021 Lippincott Williams and Wilkins. All rights reserved.

Objective: To examine the effect of the intervention implemented in the ToyBox study on changes observed in age and sex specific BMI percentile and investigate the role of perinatal factors, parental perceptions and characteristics on this change. Design: A multicomponent, kindergarten-based, family-involved intervention with a cluster-randomized design. A standardized protocol was used to measure children’s body weight and height. Information was also collected from parents/caregivers via the use of validated questionnaires. Linear mixed effect models with random intercept for country, socioeconomic status and school were used. Setting: Selected preschools within the provinces of Oost-Flanders and West-Flanders (Belgium), Varna (Bulgaria), Bavaria (Germany), Attica (Greece), Mazowieckie (Poland) and Zaragoza (Spain). Participants: A sample of 6,268 pre-schoolers aged 3.5-5.5 (51.9% boys). Results: There was no intervention effect on the change in children’s BMI percentile. However, parents’ underestimation of their children’s actual weight status, parental overweight and mothers’ pre-pregnancy overweight/obesity were found to be significantly and independently associated with increases in children’s BMI percentile in multivariate modelling. Conclusion: Before or as part of the implementation of any childhood obesity intervention initiative, it is important to assist parents/caregivers to correctly perceive their own and their children’s weight status. Recognition of excessive weight by parents/caregivers can increase their readiness to change and as such facilitate higher adherence to favourable behavioural changes within the family.

E-cadherin (CDH1) is a master regulator of epithelial cell adherence junctions and a well-established tumor suppressor in Invasive Lobular Carcinoma (ILC). Intriguingly, somatic inactivation of E-cadherin alone in mouse mammary epithelial cells (MMECs) is insufficient to induce tumor formation. Here we show that E-cadherin loss induces extrusion of luminal MMECs to the basal lamina. Remarkably, E-cadherin-deficient MMECs can breach the basal lamina but do not disseminate into the surrounding fat pad. Basal lamina components laminin and collagen IV supported adhesion and survival of E-cadherin-deficient MMECs while collagen I, the principle component of the mammary stromal micro-environment did not. We uncovered that relaxation of actomyosin contractility mediates adhesion and survival of E-cadherin-deficient MMECs on collagen I, thereby allowing ILC development. Together, these findings unmask the direct consequences of E-cadherin inactivation in the mammary gland and identify aberrant actomyosin contractility as a critical barrier to ILC formation., E-cadherin is a well-known tumor suppressor albeit loss of E-cadherin alone is insufficient to induce mammary tumorigenesis. Here the authors report that epithelial cells that have lost E-cadherin can survive by extruding to the basal lamina but require rebalancing of actomyosin contractility to drive tumor development.

Percutaneous cholecystostomy is frequently used as a treatment option for acute calculous cholecystitis in patients unfit for surgery. There is sparse evidence on the long-term impact of cholecystostomy on gallstone-related morbidity and mortality in patients with acute calculous cholecystitis. This study describes the long-term outcome of acute calculous cholecystitis following percutaneous cholecystostomy compared to conservative treatment. This was a cohort study of patients admitted at our institution from 2006 to 2015 with acute calculous cholecystitis without early or delayed cholecystectomy. Endpoints were gallstone-related readmissions, recurrent cholecystitis, and overall mortality. The investigation included 201 patients of whom 97 (48.2%) underwent percutaneous cholecystostomy. Patients in the cholecystostomy group had significantly higher age, comorbidity level, and inflammatory response at admission. The median duration of catheter placement in the cholecystostomy group was 6 days. The complication rate of cholecystostomy was 3.1% and the mortality during the index admission was 3.5%. The median follow-up was 1.6 years. The rate of gallstone-related readmissions was 38.6%, and 25.3% had recurrence of cholecystitis. Cox regression analyses revealed no significant differences in gallstone-related readmissions, recurrence of acute calculous cholecystitis, and overall mortality in the two groups. Percutaneous cholecystostomy in the treatment of acute calculous cholecystitis was neither associated with long-term benefits nor complications. Based on the high gallstone-related readmission rates of this study population and todays perioperative improvements, we suggest rethinking the indications for non-operative management including percutaneous cholecystostomy in acute calculous cholecystitis.