Invasion of ovarian cancer cells is induced by PITX2-mediated activation of TGF-β and Activin-A

Background:Most ovarian cancers are highly invasive in nature and the high burden of metastatic disease make them a leading cause of mortality among all gynaecological malignancies. The homeodomain transcription factor, PITX2 is associated with cancer in different tissues. Our previous studies demonstrated increased PITX2 expression in human ovarian tumours. Growing evidence linking activation of TGF-β pathway by homeodomain proteins prompted us to look for the possible involvement of this signalling pathway in PITX2-mediated progression of ovarian cancer. Methods: The status of TGF-β signalling in human ovarian tissues was assessed by immunohistochemistry. The expression level of TGFB/INHBA and other invasion-associated genes was measured by quantitative-PCR (Q-PCR) and Western Blot after transfection/treatments with clones/reagents in normal/cancer cells. The physiological effect of PITX2 on invasion/motility was checked by matrigel invasion and wound healing assay. The PITX2- and activin-induced epithelial-mesenchymal transition (EMT) was evaluated by Q-PCR of respective markers and confocal/phase-contrast imaging of cells. Results: Human ovarian tumours showed enhanced TGF-β signalling. Our study uncovers the PITX2-induced expression of TGFB1/2/3 as well as INHBA genes (p < 0.01) followed by SMAD2/3-dependent TGF-β signalling pathway. PITX2-induced TGF-β pathway regulated the expression of invasion-associated genes, SNAI1, CDH1 and MMP9 (p < 0.01) that accounted for enhanced motility/invasion of ovarian cancers. Snail and MMP9 acted as important mediators of PITX2-induced invasiveness of ovarian cancer cells. PITX2 over-expression resulted in loss of epithelial markers (p < 0.01) and gain of mesenchymal markers (p < 0.01) that contributed significantly to ovarian oncogenesis. PITX2-induced INHBA expression (p < 0.01) contributed to EMT in both normal and ovarian cancer cells. Conclusions: Overall, our findings suggest a significant contributory role of PITX2 in promoting invasive behaviour of ovarian cancer cells through up-regulation of TGFB/INHBA. We have also identified the previously unknown involvement of activin-A in promoting EMT. Our work provides novel mechanistic insights into the invasive behavior of ovarian cancer cells. The extension of this study have the potential for therapeutic applications in future

MicroRNA profiles discriminate among colon cancer metastasis

MicroRNAs are being exploited for diagnosis, prognosis and monitoring of cancer and other diseases. Their high tissue specificity and critical role in oncogenesis provide new biomarkers for the diagnosis and classification of cancer as well as predicting patients' outcomes. MicroRNAs signatures have been identified for many human tumors, including colorectal cancer (CRC). In most cases, metastatic disease is difficult to predict and to prevent with adequate therapies. The aim of our study was to identify a microRNA signature for metastatic CRC that could predict and differentiate metastatic target organ localization. Normal and cancer tissues of three different groups of CRC patients were analyzed. RNA microarray and TaqMan Array analysis were performed on 66 Italian patients with or without lymph nodes and/or liver recurrences. Data obtained with the two assays were analyzed separately and then intersected to identify a primary CRC metastatic signature. Five differentially expressed microRNAs (hsa-miR-21, -103, -93, -31 and -566) were validated by qRT-PCR on a second group of 16 American metastatic patients. In situ hybridization was performed on the 16 American patients as well as on three distinct commercial tissues microarray (TMA) containing normal adjacent colon, the primary adenocarcinoma, normal and metastatic lymph nodes and liver. Hsa-miRNA-21, -93, and -103 upregulation together with hsa-miR-566 downregulation defined the CRC metastatic signature, while in situ hybridization data identified a lymphonodal invasion profile. We provided the first microRNAs signature that could discriminate between colorectal recurrences to lymph nodes and liver and between colorectal liver metastasis and primary hepatic tumor

New perspectives in the use of biomaterials for periodontal regeneration

Periodontitis is a disease with a high prevalence among adults. If not treated, it can lead to loss of teeth. Periodontal therapy aims at maintaining patient's teeth through infection control and correction of non-maintainable anatomies including-when possible-regeneration of lost periodontal tissues. The biological regenerative potential of the periodontium is high, and several biomaterials can be utilized to improve the outcome of periodontal therapy. Use of different natural and synthetic materials in the periodontal field has been studied for many years. The main materials used today in periodontology analyzed in this review are: Resorbable and non-resorbable barrier membranes; autogenous, allogeneic, xenogeneic, and alloplastic bone substitutes; biological agents, such as amelogenins; platelet-derived growth factor; bone morphogenic proteins; rh fibroblast growth factor 2; teriparatide hormone; platelet concentrates; and 3D scaffolds. With the development of new surgical techniques some concepts on periodontal regeneration that were strictly applied in the past seem to be not so critical today. This can have an impact on the materials that are needed when attempting to regenerate lost periodontal structures. This review aims at presenting a rationale behind the use of biomaterials in modern periodontal regeneration

A probabilistic simplified seismic model of masonry buildings based on ambient vibrations

The paper presents a new simplified mathematical model for predicting the structural seismic response of buildings. The model, denominated Seismic Model from Ambient Vibrations (SMAV), is based on the experimental modal parameters identified from ambient vibration and only a few information about the geometry and the structural typology of the building. After a short review of the Multi Rigid Polygons model, recently illustrated and validated in an other paper by some of the authors, that allows to estimate the seismic participation factors of the experimental modes also for buildings characterized by complex shaped plan and structural irregularity along the height, the attention is focused on a new stochastic approach for modeling the seismic response of masonry buildings. In particular this new approach aims to take into account the non linearity occurred during a seismic event so that the nonlinear behaviour of the building is considered by reducing its modal frequencies according to the response amplitude. The reduction of the natural frequencies, extracted by Operational Modal Analysis from ambient vibrations, is computed according to specific probabilistic curves: the Frequency Shift Curves (FSCs). This curves provide the percentage reduction of the natural frequencies as a function of the maximum roof drift reached during the strong motion and they are obtained, for some specific masonry typologies, through a Monte Carlo analysis carried out using a simple mechanical model of a masonry panel with geometric and mechanical parameters that vary according to their probabilistic distributions. The seismic response of the building is then computed through a linear equivalent analysis in which an iterative algorithm updates the resonant frequencies according to the specific FSC curve. The concept of structural serviceability index (IOPS), expressing the probability of the building to remain operational, is also introduced. Finally, a comparison between the seismic response computed by the model and the experimental seismic response of the Pizzoli town hall, a masonry existing building endowed with a permanent accelerometer monitoring system, is illustrated

Endometriosis and obstetrics complications: a systematic review and meta-analysis

Objective To evaluate the effect of endometriosis on pregnancy outcomes. Design Systematic review and meta-analysis. Setting Not applicable. Patient(s) Women with or without endometriosis. Intervention(s) Electronic databases searched from their inception until February 2017 with no limit for language and with all cohort studies reporting the incidence of obstetric complications in women with a diagnosis of endometriosis compared with a control group (women without a diagnosis of endometriosis) included. Mean Outcome Measure(s) Primary outcome of incidence of preterm birth at &lt;37 weeks with meta-analysis performed using the random effects model of DerSimonian and Laird to produce an odds ratio (OR) with 95% confidence interval (CI). Result(s) Twenty-four studies were analyzed comprising 1,924,114 women. In most of them, the diagnosis of endometriosis was made histologically after surgery. Women with endometriosis had a statistically significantly higher risk of preterm birth (OR 1.63; 95% CI, 1.32–2.01), miscarriage (OR 1.75; 95% CI, 1.29–2.37), placenta previa (OR 3.03; 95% CI, 1.50–6.13), small for gestational age (OR 1.27; 95% CI, 1.03–1.57), and cesarean delivery (OR 1.57; 95% CI, 1.39–1.78) compared with the healthy controls. No differences were found in the incidence of gestational hypertension and preeclampsia. Conclusion(s) Women with endometriosis have a statistically significantly higher risk of preterm birth, miscarriage, placenta previa, small for gestational age infants, and cesarean delivery