Fibrous dysplasia (FD) and hyperparathyroidism-jaw tumor syndrome (HPT-JT) are well-characterized benign bone fibro-osseous lesions. The intracellular mechanism leading to excessive deposition of fibrous tissue and alteration of differentiation processes leading to osteomalacia have not yet been fully clarified. Tissue Microarray (TMA)-based immunohistochemical expression of β-catenin, CK-AE1/AE3, Ki-67, cadherins and P-Runx2 were analyzed in archival samples from nine patients affected by FD and HPT-JT and in seven controls, with the aim of elucidating the contribution of these molecules (β-catenin, cadherins and P-Runx2) in the osteoblast differentiation pathway. β-catenin was strongly upregulated in FD, showing a hyper-cellulated pattern, while it was faintly expressed in bone tumors associated with HPT-JT. Furthermore, the loss of expression of OB-cadherin in osteoblast lineage in FD was accompanied by N-cadherin and P-cadherin upregulation (p < 0.05), while E-cadherin showed a minor role in these pathological processes. P-Runx2 showed over-expression in six out of eight cases of FD and stained moderately positive in the rimming lining osteoblasts in HPT-JT syndrome. β-catenin plays a central role in fibrous tissue proliferation and accompanies the lack of differentiation of osteoblast precursors in mature osteoblasts in FD. The study showed that the combined evaluation of the histological characteristics and the histochemical and immunohistochemical profile of key molecules involved in osteoblast differentiation are useful in the diagnosis, classification and therapeutic management of fibrous-osseous lesions.

Early-Onset Schizophrenia (EOS) is a very rare mental disorder that is a form of schizophrenia occurring before the age of 18. EOS is a brain disease marked by an early onset of positive and negative symptoms of psychosis that impact development and cognitive functioning. Clinical manifestations commonly include premorbid features of Autism Spectrum Disorder (ASD), attention deficits, Intellectual Disability (ID), neurodevelopmental delay, and behavioral disturbances. After the onset of psychotic symptoms, other neuropsychiatric comorbidities are also common, including obsessive-compulsive disorder, major depressive disorder, expressive and receptive language disorders, auditory processing, and executive functioning deficits. With the purpose to better gain insight into the genetic bases of this disorder, we developed a pilot project performing whole exome sequencing of nine trios affected by EOS, ASD, and mild ID. We carried out gene prioritization by combining multiple bioinformatic tools allowing us to identify the main pathways that could underpin the neurodevelopmental phenotypes of these patients. We identified the presence of variants in genes belonging to the Wnt, cadherin and cholecystokinin receptor signaling pathways.

OBJECTIVE: Thoracic aortic aneurysm (TAA) is characterized by the dilation of the aorta and is associated with poor prognosis if not diagnosed and treated early. In this context, the identification of biomarkers regarding the TAA diagnosis, monitoring and prognosis is crucial. The purpose of the current study was to investigate the differential gene expression profile of the cadherin 5 (CDH5 or VE-Cadherin) gene network in patients with TAA, to propose novel biomarkers.
METHODS: In silico techniques were used to construct the interactome of the CDH5 network, identify the differentially expressed genes (DEGs) in TAA as compared to healthy controls, and uncover the related molecular functions and the regulating miRNAs.
RESULTS: Transcriptomic data of one microarray dataset were included, incorporating 43 TAA and 43 control samples. Eight DEGs were identified; 7 were up-regulated and 1 was down-regulated. A molecular signature of 8 genes (CDH5; Calcitonin Receptor-Like Receptor-CALCRL; Activin A Receptor-Like Type 1-ACVRL1, Tryptophanyl-TRNA Synthetase 1-WARS; Junction Plakoglobin-JUP, Protein Tyrosine Phosphatase Receptor Type J-PTPRJ, Purinergic Receptor P2X 4-P2RX4, Kinase Insert Domain Receptor-KDR) were identified as biomarkers associated with TAA. PTPRJ was associated with excellent discrimination and calibration in predicting TAA presentation. Positive correlations were reported regarding the expression of CDH5-CALCRL, CDH5-ACVRL1, CDH5-WARS and CDH5-PTPRJ. Finally, gene set enrichment analysis indicated the molecular functions and miRNA families (hsa-miR-296-5p, hsa-miR-6836-5p, hsa-miR-6132, hsa-miR-27a-5p and hsa-miR-6773-5p) relevant to the 8 biomarkers.
CONCLUSIONS: These outcomes propose an 8-gene molecular panel associated with TAA.

Epithelial cells migrate as multicellular units. The directionality and speed of these units are determined by actively moving leader cells. It is important to understand how external cues affect the appearance of these leader cells in physiological and pathological processes. However, the impact of extracellular matrices (ECMs) is still controversial, because physically-adsorbed ECM proteins are amenable to protein remodeling, and uncontrolled cluster geometry can vary migration phenotypes. Here, we demonstrate a photoactivatable substrate, which we used to study the impact of a cyclic Arg-Gly-Asp (cRGD) ligand on leader cell formation in MDCK cells. This robust platform allowed us to investigate the effect of cRGD density on leader cell formation, in any given cluster geometry, with minimized ECM remodeling. Our results show a biphasic response of leader cell appearance upon reducing the surface cRGD density. The increase, in leader cell appearance, within the higher density range, is not only associated with the weakening of circumferential actomyosin belts, but also reduction of cellular mechanical tension and intercellular junctional E-cadherin. These results indicate that cRGD-mediated cell-ECM interactions positively regulate mechanical and biochemical coupling within cell clusters; both are critical for the coordination of cell collectives and eventual reduction in the appearance of leader cells.

Cell lines have been use extensively for the study of the mode of action of different pore forming toxins produced by different bacterial species. Bacillus thuringiensis Cry toxins are not the exception and their mechanism of action has been analyzed in different cell lines. Here we review the data obtained with different cell lines, including those that are naturally susceptible to the three domain Cry toxins (3d-Cry) and other non-susceptible cell lines that have been transformed with 3d-Cry toxin binding molecules cloned from the susceptible insects. The effects on Cry toxin action after expressing different insect gut proteins, such as glycosyl-phosphatidyl-inositol (GPI) anchored proteins (like alkaline phosphatase (ALP) aminopeptidase (APN)), or trans-membrane proteins (like cadherin (CAD) or ATP-binding cassette subfamily C member 2 (ABCC2) transporter) in cell lines showed that, with few exceptions, expression of GPI-anchored proteins do not correlated with increased susceptibility to the toxin, while the expression of CAD or ABCC2 proteins correlated with induced susceptibility to Cry toxins in the transformed cells lines. Also, that the co-expression of CAD and ABCC2 transporter induced a synergistic effect in the toxicity of 3d-Cry toxins. Overall the data show that in susceptible cell lines, the 3d-Cry toxins induce pore formation that correlates with toxicity. However, the intracellular responses remain controversial since it was shown that the same 3d-Cry toxin in different cell lines activated different responses such as adenylate cyclase-PKA death response or apoptosis. Parasporins are Cry toxins that are toxic to cancer cell lines that have structural similarities with the insecticidal Cry toxins. They belong to the 3d-Cry toxin or to MTX-like Cry toxin families but also show important differences with the insecticidal Cry proteins. Some parasporins are pore-forming toxins, and some activate apoptosis. In this review we summarized the results of the different studies about the Cry toxins mode of action using cultured cell lines and discuss their relation with the studies performed in insect larvae.