Activation of an actin signaling pathway in pre-malignant mammary epithelial cells by P-cadherin is essential for transformation.

Alterations in the expression or function of cell adhesion molecules have been implicated in all steps of tumor progression. Among those, P-cadherin is highly enriched in basal-like breast carcinomas, playing a central role in cancer cell self-renewal, collective cell migration and invasion. To establish a clinically relevant platform for functional exploration of P-cadherin effectors in vivo, we generated a humanized P-cadherin Drosophila model. We report that actin nucleators, Mrtf and Srf, are main P-cadherin effectors in fly. We validated these findings in a human mammary epithelial cell line with conditional activation of the SRC oncogene. We show that, prior to promoting malignant phenotypes, SRC induces a transient increase in P-cadherin expression, which correlates with MRTF-A accumulation, its nuclear translocation and the upregulation of SRF target genes. Moreover, knocking down P-cadherin, or preventing F-actin polymerization, impairs SRF transcriptional activity. Furthermore, blocking MRTF-A nuclear translocation hampers proliferation, self-renewal and invasion. Thus, in addition to sustaining malignant phenotypes, P-cadherin can also play a major role in the early stages of breast carcinogenesis by promoting a transient boost of MRTF-A-SRF signaling through actin regulation.

Gastric cancer screening: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Gastric cancer (GC) screening is recommended in high-risk populations, although screening methods and intervals vary. In intermediate-risk populations, screening through esophagogastroduodenoscopy (EGD) may be considered depending on local resources. The aim of this study was to compare GC screening methods regarding effect on mortality, diagnostic yield and adherence. METHODS: Systematic review and meta-analysis including studies evaluating population-based GC screening. Search was conducted in three online databases (MEDLINE, Scopus and clinicaltrials.gov), along with manual search. RESULTS: Forty-four studies were included. Studies in upper gastrointestinal series (UGIS) demonstrated that GC screening was associated with significantly lower GC mortality rates (OR 0.63, 95% CI 0.55 - 0.73). Benefits on mortality were also found in EGD and serum pepsinogen (PG) studies. EGD was associated with significantly higher GC (0.55%, 95% CI 0.39 - 0.75%) and early-GC (EGC) detection rates (0.48%, 95% CI 0.34 - 0.65%) when compared to UGIS (GC 0.19%, 95% CI 0.10 - 0.31%; EGC 0.08%, 95% CI 0.04 - 0.13%) and PG (GC 0.10%, 95% CI 0.05 - 0.16%; EGC 0.10%, 95% CI 0.04 - 0.19%). Non-invasive methods tended to higher adherence rates when compared to EGD. Regardless of the screening method, individualized recruitment performed better. DISCUSSION: Screening positively impacted GC mortality rates. EGD was associated with higher diagnostic yield, while UGIS and PG tended to higher adherence rates. Screening uptake was predominantly impacted by recruitment strategies independently of the adopted method.

Effect of Low-Intensity Pulsed Ultrasound Stimulation, Extracorporeal Shockwaves and Radial Pressure Waves on Akt, BMP-2, ERK-2, FAK and TGF-ß1 During Bone Healing in Rat Tibial Defects.

An experimental study was conducted to determine whether low-intensity pulsed ultrasound stimulation (LIPUS), extracorporeal shockwave treatment (ESWT) and radial pressure wave treatment (RPWT) modulate Akt, bone morphogenetic protein-2 (BMP-2), extracellular signal-regulated kinase-2 (ERK-2), focal adhesion kinase (FAK) and transforming growth factor-ß1 (TGF-ß1) during bone healing in rat tibial defects. Rat tibial defects were exposed to 500 shots of ESWT delivered at 0.12 mJ/mm2, 500 impulses of RPWT operated at 2.0 bar or to daily 20-min 30 mW/cm2 LIPUS. Following 1, 3 and 6 wk, bones were harvested to determine the expression and activity of Akt, BMP-2, ERK-2, FAK and TGF-ß1. Animals exposed to ultrasound were followed up to 3 wk. Protein expression and activity were unchanged following LIPUS treatment. ESWT increased Akt activity 2.11-fold (p = 0.043) and TGF-ß1 expression 9.11-fold (p = 0.016) at 1 wk and increased FAK activity 2.16-fold (p = 0.047) at 3 wk. RPWT increased FAK activity 2.6-fold (p = 0.028) at 3 wk and decreased Akt expression 0.52-fold (p = 0.05) at 6 wk. In conclusion, the protocols employed for ESWT and RPWT modulated distinct signaling pathways during fracture healing, while LIPUS standard protocol did not change the usual signaling pathways of the proteins investigated. Future studies are required to monitor osteogenesis so that the biologic meaning of our results can be clarified.