Hepatocellular carcinoma in the noncirrhotic liver: Clinical features and outcomes in Veracruz, Mexico. / Carcinoma hepatocelular en hígado no cirrótico: características clínicas y resultados en Veracruz, México.

INTRODUCTION AND AIM: Hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver. HCC in the noncirrhotic liver accounts for 15-20% of all HCC. Noncirrhotic HCC is a clinically different entity because of the non-neoplastic liver parenchyma involved. Our aim was to describe the presentation, treatment, and predictive survival results of noncirrhotic HCC in Veracruz. MATERIAL AND METHOD: A retrospective study, spanning 13 years, was conducted on patients with noncirrhotic HCC. It analyzed their clinical characteristics, fibrosis/cirrhosis biologic index (NAFLD, MELD, ALBI, APRI, CDS, FIB-4, GUCI, Lok) results, disease treatment, and survival. RESULTS: From a total of 168 cases of HCC, 33 (19.6%) noncirrhotic patients were included in the study. Of those patients, the mean patient age was 67.3 years (51.5% men), 9.1% had hepatitis C virus infection, and 27.3% were alcoholics. Less than 20% of the patients had biologic indexes suggestive of fibrosis/cirrhosis. Mean tumor size was 7.7cm and 42.4% of the patients had alpha-fetoprotein levels>15ng/ml. A total of 52.5% of the tumors were classified as Okuda II and 30.3% of the patients had advanced disease (the Milan criteria). Liver resection was performed on 51.5% of the patients, radiofrequency ablation on 18.2%, and transarterial chemoembolization on 9.1%. The overall 5-year survival rate was 55.4%. Liver resection resulted in the best 5-year survival rate (72.7%). Age>67 years and elevated alpha-fetoprotein levels were associated with poorer survival (P<.05, log-rank). CONCLUSIONS: The characteristics and survival rate of HCC in the noncirrhotic liver were similar to those reported in other studies. Liver resection provided the highest survival rates. The liver fibrosis biologic indexes were not risk factors for survival.

ADAN: a database for prediction of protein-protein interaction of modular domains mediated by linear motifs.

MOTIVATION: Most of the structures and functions of proteome globular domains are yet unknown. We can use high-resolution structures from different modular domains in combination with automatic protein design algorithms to predict genome-wide potential interactions of a protein. ADAN database and related web tools are online resources for the predictive analysis of ligand-domain complexes. ADAN database is a collection of different modular protein domains (SH2, SH3, PDZ, WW, etc.). It contains 3505 entries with extensive structural and functional information available, manually integrated, curated and annotated with cross-references to other databases, biochemical and thermodynamical data, simplified coordinate files, sequence files and alignments. Prediadan, a subset of ADAN database, offers position-specific scoring matrices for protein-protein interactions, calculated by FoldX, and predictions of optimum ligands and putative binding partners. Users can also scan a query sequence against selected matrices, or improve a ligand-domain interaction. AVAILABILITY: ADAN is accessible at http://adan-embl.ibmc.umh.es/ or http://adan.crg.es/.

Point mutations in protein globular domains: contributions from function, stability and misfolding.

Several contrasting hypotheses have been formulated about the influence of functional and conformational properties, like stability and avoidance of misfolding, on the evolution of protein globular domains. Selection at functional sites has been suggested to be detrimental to stability or coupled to it. Avoidance of misfolding may be achieved by discarding misfolding-prone sequences or by maintaining a stable native state and thus destabilizing partially or fully unfolded states from which misfolding can take place. We have performed a hierarchical analysis of a large database of point mutations to dissect the relative contributions of function, stability and misfolding in the evolution of natural sequences. We show that at catalytic sites, selection for function overrules selection for stability but find no evidence for an anticorrelation between function and stability. Selection for stability plays a secondary role at binding sites, but is not fully coupled to selection for function. Remarkably, we did not find a selective pressure against misfolding-prone sequences in globular proteins at the level of individual positions. We suggest that such a selection would compromise native-state stability due to a correlation between the stabilities of native and misfolded states. Stabilization of the native state is the most frequent way in which natural proteins avoid misfolding.