A new bioavailable fenretinide formulation with antiproliferative, antimetabolic, and cytotoxic effects on solid tumors.

Fenretinide is a synthetic retinoid characterized by anticancer activity in preclinical models and favorable toxicological profile, but also by a low bioavailability that hindered its clinical efficacy in former clinical trials. We developed a new formulation of fenretinide complexed with 2-hydroxypropyl-beta-cyclodextrin (nanofenretinide) characterized by an increased bioavailability and therapeutic efficacy. Nanofenretinide was active in cell lines derived from multiple solid tumors, in primary spheroid cultures and in xenografts of lung and colorectal cancer, where it inhibited tumor growth independently from the mutational status of tumor cells. A global profiling of pathways activated by nanofenretinide was performed by reverse-phase proteomic arrays and lipid analysis, revealing widespread repression of the mTOR pathway, activation of apoptotic, autophagic and DNA damage signals and massive production of dihydroceramide, a bioactive lipid with pleiotropic effects on several biological processes. In cells that survived nanofenretinide treatment there was a decrease of factors involved in cell cycle progression and an increase in the levels of p16 and phosphorylated p38 MAPK with consequent block in G0 and early G1. The capacity of nanofenretinide to induce cancer cell death and quiescence, together with its elevated bioavailability and broad antitumor activity indicate its potential use in cancer treatment and chemoprevention

Endovascular repair in atypical traumatic rupture of thoracic aorta

Introduction. The traumatic rupture of thoracic aorta is a surgical emergency with high risk of morbidity and mortality. Case report. We describe the case of an atypical rupture of retrocardiac thoracic aorta with dissection of brachiocephalic trunk and spleen trauma occurred after a road accident. TC scan and perioperative angiography showed an atypical rupture of thoracic aorta. Conclusion. A combined treatment, endovascular for retrocardiac thoracic aorta and surgical for brachiocephalic artery, has been useful to diminish the hemodinamic and organ ischemic problems associated with open surgery

Compliance with the clinical practice guidelines for the management of hepatitis B and C virus-related chronic liver disease: a survey based on hospitalized cirrhotic patients

In recent years, significant progress has been made in furthering our knowledge of chronic liver disease (CLD) and evaluating the therapeutic approaches. These have been updated in the form of recommendations by international scientific societies. Through a retrospective analysis, this study aimed to verify whether these recommendations have been applied in real practice. The study design included data gathered from all patients consecutively hospitalized for decompensated liver cirrhosis during one year. A pre-made master form was used to record data on the patients’ past knowledge of the etiology and management of their liver disease. As expected, hepatitis C virus (HCV) was the most frequent cause of CLD, while 41 cases were cryptogenic. In 69 of 263 patients with HCV infection, viral genotyping had been performed, although only 39 of these cases had been treated. Only 3 of 44 patients suffering from hepatitis B virus (HBV)-related liver cirrhosis had been treated in the past, while 11 patients were still being treated. Among the remaining patients, 15 were not aware that they had CLD and 15 had never been considered for antiviral treatment. In 81 cases, the disease had progressed to hepatocellular carcinoma, but only 19 patients had discovered the tumor following regular ultrasound screening. Thirty-seven patients were receiving specific treatment consistent with the stage of their disease. The management of HBV- and HCV-related CLD in Sicily is far from optimal, and although the natural history and management practices of these diseases are well known, this knowledge is a long way from being applied in our daily practice

Timescales of emergence of chronic nuisance flooding in the major economic centre of Guadeloupe

Chronic flooding, occurring at high tides under calm weather conditions, is occasionally taking place today in the low-lying areas of the Petit-Cul-de-sac marin (Guadeloupe, West Indies, French Antilles). This area includes critical industrial, harbor and major economic infrastructures for the island. As sea level rises, concerns are growing regarding the possibility for repeated chronic flooding events, which would alter the operations at these critical coastal infrastructures without appropriate adaptation. Here, we use information on past and future sea levels, vertical ground motion and tides to assess times of emergence of chronic flooding in the Petit-Cul-de-sac marin. For RCP8.5 (i.e., continued growth of greenhouse gas emissions), the number of flood days is projected to increase rapidly after the emergence of the process, so that coastal sites will be flooded every two days within 2 decades after the onset of chronic flooding. For coastal locations with the smallest altitude, we show that the reconstructed number of floods are consistent with observations known from a previous survey. One key uncertainty of our result is the actual rate of subsidence of the island. However, our satellite interferometric synthetic-aperture radar results show that the local variability of this subsidence is smaller than the uncertainties of the technique, which we estimate between 1 (standard deviation of measurements) and 5\u2009mm/yr (upper theoretical bound). Our results imply that adaptation pathways considering a rapid increase of recurrent chronic flooding are required in the critical port, industrial and commercial center of Guadeloupe, as well as presumably in many low-elevation coastal zones of other tropical islands

An organoid model of colorectal circulating tumor cells with stem cell features, hybrid EMT state and distinctive therapy response profile

Background Circulating tumor cells (CTCs) are responsible for the metastatic dissemination of colorectal cancer (CRC) to the liver, lungs and lymph nodes. CTCs rarity and heterogeneity strongly limit the elucidation of their biological features, as well as preclinical drug sensitivity studies aimed at metastasis prevention. Methods We generated organoids from CTCs isolated from an orthotopic CRC xenograft model. CTCs-derived organoids (CTCDOs) were characterized through proteome profiling, immunohistochemistry, immunofluorescence, flow cytometry, tumor-forming capacity and drug screening assays. The expression of intra- and extracellular markers found in CTCDOs was validated on CTCs isolated from the peripheral blood of CRC patients. Results CTCDOs exhibited a hybrid epithelial-mesenchymal transition (EMT) state and an increased expression of stemness-associated markers including the two homeobox transcription factors Goosecoid and Pancreatic Duodenal Homeobox Gene-1 (PDX1), which were also detected in CTCs from CRC patients. Functionally, CTCDOs showed a higher migratory/invasive ability and a different response to pathway-targeted drugs as compared to xenograft-derived organoids (XDOs). Specifically, CTCDOs were more sensitive than XDOs to drugs affecting the Survivin pathway, which decreased the levels of Survivin and X-Linked Inhibitor of Apoptosis Protein (XIAP) inducing CTCDOs death. Conclusions These results indicate that CTCDOs recapitulate several features of colorectal CTCs and may be used to investigate the features of metastatic CRC cells, to identify new prognostic biomarkers and to devise new potential strategies for metastasis prevention

Characterization of SARS-CoV-2 Variants in Military and Civilian Personnel of an Air Force Airport during Three Pandemic Waves in Italy

We investigated SARS-CoV-2 variants circulating, from November 2020 to March 2022, among military and civilian personnel at an Air Force airport in Italy in order to classify viral isolates in a potential hotspot for virus spread. Positive samples were subjected to Next-Generation Sequencing (NGS) of the whole viral genome and Sanger sequencing of the spike coding region. Phylogenetic analysis classified viral isolates and traced their evolutionary relationships. Clusters were identified using 70% cut-off. Sequencing methods yielded comparable results in terms of variant classification. In 2020 and 2021, we identified several variants, including B.1.258 (4/67), B.1.177 (9/67), Alpha (B.1.1.7, 9/67), Gamma (P.1.1, 4/67), and Delta (4/67). In 2022, only Omicron and its sub-lineage variants were observed (37/67). SARS-CoV-2 isolates were screened to detect naturally occurring resistance in genomic regions, the target of new therapies, comparing them to the Wuhan Hu-1 reference strain. Interestingly, 2/30 non-Omicron isolates carried the G15S 3CLpro substitution responsible for reduced susceptibility to protease inhibitors. On the other hand, Omicron isolates carried unusual substitutions A1803V, D1809N, and A949T on PLpro, and the D216N on 3CLpro. Finally, the P323L substitution on RdRp coding regions was not associated with the mutational pattern related to polymerase inhibitor resistance. This study highlights the importance of continuous genomic surveillance to monitor SARS-CoV-2 evolution in the general population, as well as in restricted communities