From Agent to Active Sense : Was there an Augustinianism-Averroisant?

Peer reviewe

Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are β3 Integrin-Dependent and Involve a Ca²⁺/P2X7 Receptor Signaling Axis.

Cancer cell adhesion to the vascular endothelium is an important step in tumor metastasis. Thy-1 (CD90), a cell adhesion molecule expressed in activated endothelial cells, has been implicated in melanoma metastasis by binding to integrins present in cancer cells. However, the signaling pathway(s) triggered by this Thy-1-Integrin interaction in cancer cells remains to be defined. Our previously reported data indicate that Ca <sup>2+</sup> -dependent hemichannel opening, as well as the P2X7 receptor, are key players in Thy-1-α <sub>V</sub> β <sub>3</sub> Integrin-induced migration of reactive astrocytes. Thus, we investigated whether this signaling pathway is activated in MDA-MB-231 breast cancer cells and in B16F10 melanoma cells when stimulated with Thy-1. In both cancer cell types, Thy-1 induced a rapid increase in intracellular Ca <sup>2+</sup> , ATP release, as well as cell migration and invasion. Connexin and Pannexin inhibitors decreased cell migration, implicating a requirement for hemichannel opening in Thy-1-induced cell migration. In addition, cell migration and invasion were precluded when the P2X7 receptor was pharmacologically blocked. Moreover, the ability of breast cancer and melanoma cells to transmigrate through an activated endothelial monolayer was significantly decreased when the β <sub>3</sub> Integrin was silenced in these cancer cells. Importantly, melanoma cells with silenced β <sub>3</sub> Integrin were unable to metastasize to the lung in a preclinical mouse model. Thus, our results suggest that the Ca <sup>2+</sup> /hemichannel/ATP/P2X7 receptor-signaling axis triggered by the Thy-1-α <sub>V</sub> β <sub>3</sub> Integrin interaction is important for cancer cell migration, invasion and transvasation. These findings open up the possibility of therapeutically targeting the Thy-1-Integrin signaling pathway to prevent metastasis

Syndecan-4/PAR-3 signaling regulates focal adhesion dynamics in mesenchymal cells.

Syndecans regulate cell migration thus having key roles in scarring and wound healing processes. Our previous results have shown that Thy-1/CD90 can engage both αvβ3 integrin and Syndecan-4 expressed on the surface of astrocytes to induce cell migration. Despite a well-described role of Syndecan-4 during cell movement, information is scarce regarding specific Syndecan-4 partners involved in Thy-1/CD90-stimulated cell migration. Mass spectrometry (MS) analysis of complexes precipitated with the Syndecan-4 cytoplasmic tail peptide was used to identify potential Syndecan-4-binding partners. The interactions found by MS were validated by immunoprecipitation and proximity ligation assays. The conducted research employed an array of genetic, biochemical and pharmacological approaches, including: PAR-3, Syndecan-4 and Tiam1 silencing, active Rac1 GEFs affinity precipitation, and video microscopy. We identified PAR-3 as a Syndecan-4-binding protein. Its interaction depended on the carboxy-terminal EFYA sequence present on Syndecan-4. In astrocytes where PAR-3 expression was reduced, Thy-1-induced cell migration and focal adhesion disassembly was impaired. This effect was associated with a sustained Focal Adhesion Kinase activation in the siRNA-PAR-3 treated cells. Our data also show that Thy-1/CD90 activates Tiam1, a PAR-3 effector. Additionally, we found that after Syndecan-4 silencing, Tiam1 activation was decreased and it was no longer recruited to the membrane. Syndecan-4/PAR-3 interaction and the alteration in focal adhesion dynamics were validated in mouse embryonic fibroblast (MEF) cells, thereby identifying this novel Syndecan-4/PAR-3 signaling complex as a general mechanism for mesenchymal cell migration involved in Thy-1/CD90 stimulation. The newly identified Syndecan-4/PAR-3 signaling complex participates in Thy-1/CD90-induced focal adhesion disassembly in mesenchymal cells. The mechanism involves focal adhesion kinase dephosphorylation and Tiam1 activation downstream of Syndecan-4/PAR-3 signaling complex formation. Additionally, PAR-3 is defined here as a novel adhesome-associated component with an essential role in focal adhesion disassembly during polarized cell migration. These novel findings uncover signaling mechanisms regulating cell migration, thereby opening up new avenues for future research on Syndecan-4/PAR-3 signaling in processes such as wound healing and scarring

Functional evaluation of mandibular reconstruction with bone free flap. A GETTEC study

peer reviewedObjectives: To assess the functional results of oromandibular reconstruction by free bone flap, in terms of swallowing, speech and esthetics. Materials and methods: A transverse multicenter study included 134 patients reconstructed by free bone flap between 1998 and 2016, with more than 6 months’ follow-up, in 9 centers. A standardized questionnaire collected data on patients and treatment. Study endpoints comprised: weight loss, mouth opening, gastrostomy dependence, type of feeding, and DHI score. The impact of patient baseline characteristics on these functional criteria was explored by uni/multivariate analysis. Results: Ninety of the 134 patients had cancer. Fibula flap was mainly used (80%). 94% of reconstructions were primary successes. 71% of patients had pre- or post-operative radiation therapy. 88% had less than 50% lingual resection. 97% recovered oral feeding. 89% had intelligible speech. 86% judged their esthetic appearance as good/average. 9% had dental prosthetic rehabilitation. Radiation therapy and extensive lingual resection significantly impacted swallowing function (P = 0.04 and P = 0.03, respectively). Radiation therapy and oropharyngeal extension significantly increased gastrostomy dependence (P = 0.04 and P = 0.02, respectively). Conclusion: Oromandibular reconstruction by free bone flap enabled return to oral feeding in most cases. More than 80% of patients were satisfied with their result in terms of speech and esthetics. However, the rate of dental rehabilitation was low and the rate of complications was high. © 202

Identification, replication and characterization of epigenetic remodelling in the aging genome:A cross population analysis

Aging is a complex biological process regulated by multiple cellular pathways and molecular mechanisms including epigenetics. Using genome-wide DNA methylation data measured in a large collection of Scottish old individuals, we performed discovery association analysis to identify age-methylated CpGs and replicated them in two independent Danish cohorts. The double-replicated CpGs were characterized by distribution over gene regions and location in relation to CpG islands. The replicated CpGs were further characterized by involvement in biological pathways to study their functional implications in aging. We identified 67,604 age-associated CpG sites reaching genome-wide significance of FWE

Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer.

Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway

Epigenetic Regulation of Fatty Acid Amide Hydrolase in Alzheimer Disease

OBJECTIVE: Alzheimer disease (AD) is a progressive, degenerative and irreversible neurological disorder with few therapies available. In search for new potential targets, increasing evidence suggests a role for the endocannabinoid system (ECS) in the regulation of neurodegenerative processes. METHODS: We have studied the gene expression status and the epigenetic regulation of ECS components in peripheral blood mononuclear cells (PBMCs) of subjects with late-onset AD (LOAD) and age-matched controls (CT). RESULTS: We found an increase in fatty acid amide hydrolase (faah) gene expression in LOAD subjects (2.30 ± 0.48) when compared to CT (1.00 ± 0.14; *p<0.05) and no changes in the mRNA levels of any other gene of ECS elements. Consistently, we also observed in LOAD subjects an increase in FAAH protein levels (CT: 0.75 ± 0.04; LOAD: 1.11 ± 0.15; *p<0.05) and activity (pmol/min per mg protein CT: 103.80 ± 8.73; LOAD: 125.10 ± 4.00; *p<0.05), as well as a reduction in DNA methylation at faah gene promoter (CT: 55.90 ± 4.60%; LOAD: 41.20 ± 4.90%; *p<0.05). CONCLUSIONS: Present findings suggest the involvement of FAAH in the pathogenesis of AD, highlighting the importance of epigenetic mechanisms in enzyme regulation; they also point to FAAH as a new potential biomarker for AD in easily accessible peripheral cells