Whole-exome sequencing reveals critical genes underlying metastasis in oesophageal squamous cell carcinoma

Oesophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers, owing to a high frequency of metastasis. However, little is known about the genomic landscape of metastatic ESCC. To identify the genetic alterations that underlie ESCC metastasis, whole-exome sequencing was performed for 41 primary tumours and 15 lymph nodes (LNs) with metastatic ESCCs. Eleven cases included matched primary tumours, synchronous LN metastases, and non-neoplastic mucosa. Approximately 50–76% of the mutations identified in primary tumours appeared in the synchronous LN metastases. Metastatic ESCCs harbour frequent mutations of TP53, KMT2D, ZNF750, and IRF5. Importantly, ZNF750 was recurrently mutated in metastatic ESCC. Combined analysis from current and previous genomic ESCC studies indicated more frequent ZNF750 mutation in diagnosed cases with LN metastasis than in those without metastasis (14% versus 3.4%, n = 629, P = 1.78 × 10–5). The Cancer Genome Atlas data further showed that ZNF750 genetic alterations were associated with early disease relapse. Previous ESCC studies have demonstrated that ZNF750 knockdown strongly promotes proliferation, migration, and invasion. Collectively, these results suggest a role for ZNF750 as a metastasis suppressor. TP53 is highly mutated in ESCC, and missense mutations are associated with poor overall survival, independently of pathological stage, suggesting that these missense mutations have important functional impacts on tumour progression, and are thus likely to be gain-of-function (GOF) mutations. Additionally, mutations of epigenetic regulators, including KMT2D, TET2, and KAT2A, and chromosomal 6p22 and 11q23 deletions of histone variants, which are important for nucleosome assembly, were detected in 80% of LN metastases. Our study highlights the important role of critical genetic events including ZNF750 mutations, TP53 putative GOF mutations and nucleosome disorganization caused by genetic lesions seen with ESCC metastasis.No Full Tex

A DNA Sequence Directed Mutual Transcription Regulation of HSF1 and NFIX Involves Novel Heat Sensitive Protein Interactions

BACKGROUND: Though the Nuclear factor 1 family member NFIX has been strongly implicated in PDGFB-induced glioblastoma, its molecular mechanisms of action remain unknown. HSF1, a heat shock-related transcription factor is also a powerful modifier of carcinogenesis by several factors, including PDGFB. How HSF1 transcription is controlled has remained largely elusive. METHODOLOGY/PRINCIPAL FINDINGS: By combining microarray expression profiling and a yeast-two-hybrid screen, we identified that NFIX and its interactions with CGGBP1 and HMGN1 regulate expression of HSF1. We found that CGGBP1 organizes a bifunctional transcriptional complex at small CGG repeats in the HSF1 promoter. Under chronic heat shock, NFIX uses CGGBP1 and HMGN1 to get recruited to this promoter and in turn affects their binding to DNA. Results show that the interactions of NFIX with CGGBP1 and HMGN1 in the soluble fraction are heat shock sensitive due to preferential localization of CGGBP1 to heterochromatin after heat shock. HSF1 in turn was found to bind to the NFIX promoter and repress its expression in a heat shock sensitive manner. CONCLUSIONS/SIGNIFICANCE: NFIX and HSF1 exert a mutual transcriptional repressive effect on each other which requires CGG repeat in HSF1 promoter and HSF1 binding site in NFIX promoter. We unravel a unique mechanism of heat shock sensitive DNA sequence-directed reciprocal transcriptional regulation between NFIX and HSF1. Our findings provide new insights into mechanisms of transcription regulation under stress

Big Domains Are Novel Ca2+-Binding Modules: Evidences from Big Domains of Leptospira Immunoglobulin-Like (Lig) Proteins

binds to a Big domains, which would provide a novel functional role of the proteins containing Big fold. with dissociation constants of 2–4 µM. Lig A9 and Lig A10 domains fold well with moderate thermal stability, have β-sheet conformation and form homodimers. Fluorescence spectra of Big domains show a specific doublet (at 317 and 330 nm), probably due to Trp interaction with a Phe residue. Equilibrium unfolding of selected Big domains is similar and follows a two-state model, suggesting the similarity in their fold. binding

Signet-ring cell carcinoma of colorectum - current perspectives and molecular biology

Purpose: \ud Colorectal signet-ring cell carcinoma (SRCC) is rare, and very little detailed information on the molecular biology of the disease is available.\ud \ud Methods: \ud The literature on the clinical, pathological and, in particular, the molecular biology of this rare entity was critically reviewed. The reviewed articles take into account a total of 1,817 cases of SRCC, but only 143 cases have molecular data available. The characteristics of two patients with colorectal SRCC were also discussed.\ud \ud Results: \ud Colorectal SRCC mostly occurs in younger patients, is larger and has different site predilection compared with conventional colorectal adenocarcinoma. It can occur as one of the synchronous cancers in the colorectum. The cancer is usually diagnosed at advanced stages because of the late manifestation of symptoms, and aggressive treatment strategy is required. Limited reports in the literature have shown that the variant of colorectal cancer demonstrated a different pattern of genetic alterations of common growth kinase-related oncogenes (K-ras, BRAF), tumour suppressor genes (p53, p16), gene methylation and cell adhesion-related genes related to the Wingless signalling pathway (E-cadherin and beta-catenin) from conventional colorectal adenocarcinoma. Colorectal SRCC also showed high expression of mucin-related genes and genes related to the gastrointestinal system. There was also a higher prevalence of microsatellite instability-high tumours and low Cox-2 expression in colorectal SRCC as opposed to conventional adenocarcinoma.\ud \ud Conclusions: \ud Colorectal SRCC has unique molecular pathological features. The unique molecular profiles in SRCC may provide molecular-based improvements to patient management in colorectal SRCC

The cost effectiveness of a quality improvement program to reduce maternal and fetal mortality in a regional referral hospital in Accra, Ghana

To evaluate the cost-effectiveness of a quality improvement intervention aimed at reducing maternal and fetal mortality in Accra, Ghana.Quasi-experimental, time-sequence intervention, retrospective cost-effectiveness analysis.Data were collected on the cost and outcomes of a 5-year Kybele-Ghana Health Service Quality Improvement (QI) intervention conducted at Ridge Regional Hospital, a tertiary referral center in Accra, Ghana, focused on systems, personnel, and communication. Maternal deaths prevented were estimated comparing observed rates with counterfactual projections of maternal mortality and case-fatality rates for hypertensive disorders of pregnancy and obstetric hemorrhage. Stillbirths prevented were estimated based on counterfactual estimates of stillbirth rates. Cost-effectiveness was then calculated using estimated disability-adjusted life years averted and subjected to Monte Carlo and one-way sensitivity analyses to test the importance of assumptions inherent in the calculations.Incremental Cost-effectiveness ratio (ICER), which represents the cost per disability-adjusted life-year (DALY) averted by the intervention compared to a model counterfactual.From 2007-2011, 39,234 deliveries were affected by the QI intervention implemented at Ridge Regional Hospital. The total budget for the program was $2,363,100. Based on program estimates, 236 (±5) maternal deaths and 129 (±13) intrapartum stillbirths were averted (14,876 DALYs), implying an ICER of$158 ($129-$195) USD. This value is well below the highly cost-effective threshold of $1268 USD. Sensitivity analysis considered DALY calculation methods, and yearly prevalence of risk factors and case fatality rates. In each of these analyses, the program remained highly cost-effective with an ICER ranging from$97-$218.QI interventions to reduce maternal and fetal mortality in low resource settings can be highly cost effective. Cost-effectiveness analysis is feasible and should regularly be conducted to encourage fiscal responsibility in the pursuit of improved maternal and child health