Background: Despite their histological resemblance to colorectal adenocarcinomas, there is little information about the molecular events involved in the pathogenesis of intestinal-type sinonasal adenocarcinomas (ITACs). Aims: To evaluate the possible role of DNA mismatch repair (MMR) gene defects or disruptions of the E cadherin-b catenin complex in ITAC by investigating the immunohistochemical expression of the MMR gene products, b catenin, and E cadherin in a group of sporadic ITACs. Methods: Ten sporadic cases of ITAC were stained with antibodies against MLH1, MSH2, MSH3, MSH6, b catenin, and E cadherin. Results: Nine cases showed strong nuclear expression of MLH1, whereas one case showed moderate staining. All 10 cases were strongly positive for MSH2 and MSH3. MSH6 was strong in nine cases, and moderate in one. Membranous b catenin expression was strong in all 10 cases, and no case showed cytoplasmic or nuclear staining. E cadherin was strong in seven cases, and moderate in three cases. Conclusions: The preserved nuclear expression of MLH1, MSH2, MSH3, and MSH6 suggests that mutations or promoter methylation of MMR genes do not play a role in the pathogenesis of ITAC. The strong membranous staining for E cadherin and b catenin and lack of abnormal cytoplasmic or nuclear expression is in keeping with the preservation of E cadherin-b catenin complexes and b catenin pathways.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disorder of the cardiac muscle characterised by ventricular arrhythmias, cardiac failure and sudden cardiac death. Desmosomes -the intercellular junctions of both epithelial and cardiovascular tissues that connect intermediate filaments of adjacent cells, generating a large and mechanically resilient network -are disordered in ARVC. Here, we exploit new insights into desmoplakin (DP), a critical component of desmosome structures. Indeed, both patient skin and keratinocytes expressing DP mutant construct showed large intercellular aggregates and a decrease in the amount of junctional proteins at areas of cell-cell contact. Moreover, experiments with DP knockout mice indicated that mislocalization of another junctional protein, connexin 43 was ameliorated by b-blocker (beta-blocker), or b-adrenergic receptor blocker -known to interfere with the binding to the receptor of epinephrine and other stress hormones to weaken the effects of stress hormones. Thus, these novel findings fortify the genetic and cellular mechanisms behind the marked heterogeneity of the disease and provide new therapeutic interventions that target intercellular junctions.

Cutaneous ichthyosis (CI) is a collective group of monogenetic disorders of cornification demonstrating epidermal scaling, fissuring, chronic skin inflammation, and increased susceptibility to infection. In healthy individuals the skin microbiome limits growth of pathogenic organisms; however, the microbiome signature in CI is poorly characterized. To rectify this, we investigated the microbiome signature across 7 subtypes of CI in 43 individuals of Southeast Asian ethnicity, of which exome sequencing revealed 20 novel and 31 recurrent pathogenic variants. Microbiome meta-analysis revealed distinct microbial populations, reduced commensal microbiota, and higher colonization by pathogenic species. This correlated with increased production of inflammatory cytokines, including Th17 and JAK/STAT signaling, in peripheral blood mononuclear cells. Moreover, we identified microbiota and inflammation alterations in wounds of CI patients responsible for impaired wound healing. Together, this research enhances our understanding of the microbiological, immunological, and molecular properties of CI patients and provides critical information for improving therapeutic management.