Molecular analysis of FOXC1 in subjects presenting with severe developmental eye anomalies

PURPOSE: Haploinsufficiency through mutation or deletion of the forkhead transcription factor, FOXC1, causes Axenfeld-Rieger anomaly, which manifests as a range of anterior segment eye defects and glaucoma. The aim of this study is to establish whether mutation of FOXC1 contributes toward other developmental eye anomalies, namely anophthalmia, microphthalmia, and coloboma. METHODS: The coding sequence and 3;-UTR of FOXC1 was analyzed in 114 subjects with severe developmental eye anomalies by bidirectional direct sequencing. RESULTS: Four coding FOXC1 variations (two novel missense variations, one insertion, and one novel deletion) were identified in the cohort. Two noncoding variations were also identified in the 3'-UTR. The missense mutations were c.889C_T and c.1103C_A, resulting in p.Pro297Ser and p.Thr368Asn, respectively. The c.889C_T transition was identified in 19 of the 100 unaffected control samples. The c.1103C_A transversion resulted in a conservative substitution in an unconserved amino acid and was deemed unlikely to be pathogenic. A c.1142_1144insGCG change resulting in p.Gly380ins, which was previously associated with kidney anomalies, was identified in 44 of the 114 affected individuals. This variation was also present in 29 of the 87 unaffected controls and is therefore likely to be a polymorphism. A c.91_100delCGGCGGCCG deletion resulting in p.Ala31_33del was identified in one individual. This deletion segregated with the moderately affected mother and unaffected maternal grandfather of the proband. This deletion was identified in one of the 307 unaffected controls. CONCLUSIONS: Our data suggests a potential susceptibility role for FOXC1 in generating severe eye pathologies. However, on the basis of these results, it is unlikely that FOXC1 mutation is a major causative factor of anophthalmia, microphthalmia, and coloboma

The Association of Non Viral Liver Diseases from NAFLD to NASH to HCC with the Pandemic of Obesity, Type 2 Diabetes, or Diabesity & Metabolic Syndrome Etiopathogenetic Correlation along with Utilization for Diagnostic & Therapeutic Purposes-A Systematic Review

Earlier we have been reviewing the etiopathogenesis (EP) of obesity, type2 Diabetes mellitus (T2DM), Metabolic Syndrome (MetS), Non Alcoholic Fatty Acid Liver Disease (NAFLD) non alcoholic steatohepapititis (NASH), along with its propagation to Hepatocellular carcinoma (HCC) in addition to their therapies exhaustively. T2DM continues to be a major health issue with reaching epidemic to pandemic proportions. Liver disease includes a spectrum of liver injury varying from isolated steatosis known as Non Alcoholic Fatty Acid Liver Disease (NAFLD) to HCC. Clinically it has been observed that the coexistence of NAFLD as well as T2DM is prevalent. T2DM aids in the biological events that results in escalation of robustness of NAFLD that constitutes the primary etiology of chronic liver diseases. In the past 2 decades the incidence of nonviral NAFLD/NASH, obtained HCC has been escalating at a fast pace. In view of no appropriate agents for therapy of NAFLD/NASH, a thiazolidenedione group of drug pioglitazone used for T2DM therapy is utilized occasionally.Thus here we conducted a systematic review utilizing search engine pubmed, google scholar; web of science; embase; Cochrane review libraryutilizingtheMeSHterms like T2DM; MetS; NAFLD; NASH; HCC;WAT; BAT; VisceralAT; Obesity; BMI; Adipocytokines; adiponectin;leptin; resistin; visfatin; irisin; Hepatokines; angiopoietin like protein 2; hepatosscin; retinol binding protein 4; treatment like pioglitazone;liraglutide; elafibranor CVC (cerviciroc); obeticholic acid; aramchol;selonosertib; simtuzumab; Oxidative stress(OS); insulin resistance (IR) from 1980’s to 2021 till date. We found a total of 1050 articles out of which we selected 236 articles for this review. No meta-analysis was done. Hence diagnosis avoidance in addition to treatment of the generation as well as propagation of NAFLD/NASH are significant areas needing tackling. Thus here we have summarized the EP of NAFLD/NASH, as well as NAFLD/NASH, obtained HCC along with the present advantageous therapies under trial,for NAFLD/NASH. Moreover how adipocyte obtained adipokines along with liver obtained hepatokines might work as both diagnostic in addition to therapeutic targets from NAFLD to HCC

Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the QUASAR 2 clinical trial and an Australian community-based series

Background Several relatively large studies have assessed molecular indicators of colorectal cancer (CRC) prognosis, but most analyses have been restricted to a handful of markers. Methods In stage II/III CRCs from the QUASAR2 clinical trial and from an Australian community-based series, we assessed gene panels for somatic driver mutations and overall mutation burden. We determined molecular pathways of tumorigenesis, and analysed associations with treatment response and prognosis. Findings In QUASAR2 (N=511), TP53, KRAS, BRAF and GNAS mutations were independently associated with shorter relapse-free survival, whereas total somatic mutation burden was associated with longer survival, even after excluding mismatch repair-deficient (MSI+) and POLE-mutant tumours. We successfully validated these associations in the Australian sample set (N=296). In an extended analysis of 1,752 QUASAR2 and Australian CRCs for which KRAS, BRAF and MSI status was available, we found that KRAS and BRAF mutations were specifically associated with poor prognosis in MSI- cancers. This association was not present in MSI+ cancers, and MSI+ tumours with KRAS or BRAF mutation actually had better prognosis than MSI- cancers that were wildtype for KRAS or BRAF. New rare molecular pathways were also uncovered: mutations in the genes NF1 and NRAS from the MAP kinase pathway co-occurred, mutations in TP53 and ATM appeared to be alternative ways of inactivating the DNA damage response pathway. Interpretation A multi-gene panel has identified two previously unreported prognostic associations in CRC involving both TP53 mutation and total mutation burden, and confirmed associations with KRAS and BRAF. We conclude that even a modest-sized gene panel can provide important information for use in clinical practice and out-perform MSI-based models.</p