Current Therapeutical Approaches Targeting Lipid Metabolism in NAFLD.

Nonalcoholic fatty liver disease (NAFLD, including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH)) is a high-prevalence disorder, affecting about 1 billion people, which can evolve to more severe conditions like cirrhosis or hepatocellular carcinoma. NAFLD is often concomitant with conditions of the metabolic syndrome, such as central obesity and insulin-resistance, but a specific drug able to revert NAFL and prevent its evolution towards NASH is still lacking. With the liver being a key organ in metabolic processes, the potential therapeutic strategies are many, and range from directly targeting the lipid metabolism to the prevention of tissue inflammation. However, side effects have been reported for the drugs tested up to now. In this review, different approaches to the treatment of NAFLD are presented, including newer therapies and ongoing clinical trials. Particular focus is placed on the reverse cholesterol transport system and on the agonists for nuclear factors like PPAR and FXR, but also drugs initially developed for other conditions such as incretins and thyromimetics along with validated natural compounds that have anti-inflammatory potential. This work provides an overview of the different therapeutic strategies currently being tested for NAFLD, other than, or along with, the recommendation of weight loss.

Identification of Overexpressed Genes in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a fatal tumor lacking effective therapies. The characterization of overexpressed genes could constitute a strategy for identifying drivers of tumor progression as targets for novel therapies. Thus, we performed an integrated gene-expression analysis on RNAseq data of 85 MPM patients from TCGA dataset and reference samples from the GEO. The gene list was further refined by using published studies, a functional enrichment analysis, and the correlation between expression and patients' overall survival. Three molecular signatures defined by 15 genes were detected. Seven genes were involved in cell adhesion and extracellular matrix organization, with the others in control of the mitotic cell division or apoptosis inhibition. Using Western blot analyses, we found that ADAMTS1, PODXL, CIT, KIF23, MAD2L1, TNNT1, and TRAF2 were overexpressed in a limited number of cell lines. On the other hand, interestingly, CTHRC1, E-selectin, SPARC, UHRF1, PRSS23, BAG2, and MDK were abundantly expressed in over 50% of the six MPM cell lines analyzed. Thus, these proteins are candidates as drivers for sustaining the tumorigenic process. More studies with small-molecule inhibitors or silencing RNAs are fully justified and need to be undertaken to better evaluate the cancer-driving role of the targets herewith identified.

De Novo Genome Assembly at Chromosome-Scale of Hermetia illucens (Diptera Stratiomyidae) via PacBio and Omni-C Proximity Ligation Technology.

Hermetia illucens is a species of great interest for numerous industrial applications. A high-quality reference genome is already available for H. illucens. However, the worldwide maintenance of numerous captive populations of H. illucens, each with its own genotypic and phenotypic characteristics, made it of interest to perform a de novo genome assembly on one population of H. illucens to define a chromosome-scale genome assembly. By combining the PacBio and the Omni-C proximity ligation technologies, a new H. illucens chromosome-scale genome of 888.59 Mb, with a scaffold N50 value of 162.19 Mb, was assembled. The final chromosome-scale assembly obtained a BUSCO completeness of 89.1%. By exploiting the Omni-C proximity ligation technology, topologically associated domains and other topological features that play a key role in the regulation of gene expression were identified. Further, 65.62% of genomic sequences were masked as repeated sequences, and 32,516 genes were annotated using the MAKER pipeline. The H. illucens Lsp-2 genes that were annotated were further characterized, and the three-dimensional organization of the encoded proteins was predicted. A new chromosome-scale genome assembly of good quality for H. illucens was assembled, and the genomic annotation phase was initiated. The availability of this new chromosome-scale genome assembly enables the further characterization, both genotypically and phenotypically, of a species of interest for several biotechnological applications.

Pooled analysis of the MANTICO2 and MONET randomized controlled trials comparing drug efficacy for early treatment of COVID-19 during Omicron waves.

BACKGROUND: The clinical effectiveness of early therapies for mild-to-moderate COVID-19, comparing antivirals and monoclonal antibodies (mAbs) during the Omicron era, has not been conclusively assessed through a post-approval comparative trial. We present a pooled analysis of two randomized clinical trials conducted during Omicron waves. METHODS: The MANTICO2/MONET trial is a pooled analysis of two multicentric, independent, phase-4, three-arm, superiority, randomized, open-label trials. Nonhospitalized patients with early mild-to-moderate COVID-19 (≤5 days after symptoms' onset) and at least one risk factor for disease progression were randomized 1:1:1 to receive 500 mg of intravenous sotrovimab (SOT) or 600 mg of intramuscular tixagevimab/cilgavimab (TGM/CGM) or oral 5-days course of nirmatrelvir/ritonavir (NMV/r) 300/100 mg BID. Primary outcome was COVID-19-related hospitalization or death within 29 days after randomization. Fisher's exact test for pooled data and incidence of failure was reported as overall and by arm with respective 95% CI. Pairwise comparisons across the arms were conducted using unadjusted exact logistic regression. An analysis by means of a doubly robust marginal model using augmented inverse probability weighting (AIPW) was also conducted to estimate the potential outcomes (Pom) in each treatment group and their difference by the average treatment effect (ATE). Analysis of symptom persistence within 30 days after randomization was performed using a 2-level hierarchical mixed-effects logistic model with a random intercept at the patient's level. Point estimates and 95% confidence intervals were adjusted for age and sex and calculated using ANOVA-like methods for the mixed effects logistic model. These trials are registered with the European Clinical Trials Database, EudraCT2021-002612-31 (MANTICO2) and EudraCT2021-004188-28 (MONET) and ClinicalTrials.gov, NCT05321394 (MANTICO2). FINDINGS: Between March 2022 and February 2023, 991 patients (SOT = 332, TGM/CGM = 327, NMV/r = 332) were enrolled in 15 Italian centers. The overall mean age was 66 years; 482 participants (48.80%) were male, and 856 were vaccinated with at least a primary course (86%). Among the 8/991 hospitalizations observed, one resulted in death. The overall estimate of failure was 0.81% (95%CI; 0.35-1.58%). The odds ratio (OR) for the primary outcome in the NMV/r arm compared to the TGM/CGM and SOT arms was 8.41 (95% CI 1.21 to infinity; p = 0.015) and 2.42 (95% CI 0.19 to infinity; p = 0.499), respectively. No significant difference was observed between SOT and TGM/CGM (OR 0.32; 95% CI 0.032-1.83; p = 0.174). Results were similar when we applied the marginal weighted model accounting for potential residual confounding bias. There was no evidence for a difference in the prevalence of symptoms between treatment groups, except for cough, which was higher in the SOT group compared to the other two groups at the 21-day follow-up (P = 0.039) and a higher prevalence of nausea at the 7-day follow-up in the NMV/r group compared to the mAbs group (p = 0.036). INTERPRETATION: NMV/r was superior to TGM/CGM in reducing hospital admission or death in clinically vulnerable patients with SARS-CoV-2 infection treated within 5 days of symptoms' onset. No significant difference in symptom prevalence over time across the arms was found.