Serum micrornas as novel biomarkers for primary sclerosing cholangitis and cholangiocarcinoma

The diagnosis of primary sclerosing cholangitis (PSC) is difficult due to the lack of sensitive and specific biomarkers, as is the early diagnosis of cholangiocarcinoma (CC), a complication of PSC. The aim of this study was to identify specific serum miRNAs as diagnostic biomarkers for PSC and CC

Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal-7 microRNA

Cholangiopathies are diseases that affect cholangiocytes, the cells lining the biliary tract. Liver stem cells (LSCs) are able to differentiate into all cells of the liver and possibly influence the surrounding liver tissue by secretion of signaling molecules. One way in which cells can interact is through secretion of extracellular vesicles (EVs), which are small membrane-bound vesicles that contain proteins, microRNAs (miRNAs), and cytokines. We evaluated the contents of liver stem cell–derived EVs (LSCEVs), compared their miRNA contents to those of EVs isolated from hepatocytes, and evaluated the downstream targets of these miRNAs. We finally evaluated the crosstalk among LSCs, cholangiocytes, and human hepatic stellate cells (HSCs). We showed that LSCEVs were able to reduce ductular reaction and biliary fibrosis in multidrug resistance protein 2 (MDR2)−/− mice. Additionally, we showed that cholangiocyte growth was reduced and HSCs were deactivated in LSCEV-treated mice. Evaluation of LSCEV contents compared with EVs derived from hepatocytes showed a large increase in the miRNA, lethal-7 (let-7). Further evaluation of let-7 in MDR2−/− mice and human primary sclerosing cholangitis samples showed reduced levels of let-7 compared with controls. In liver tissues and isolated cholangiocytes, downstream targets of let-7 (identified by ingenuity pathway analysis), Lin28a (Lin28 homolog A), Lin28b (Lin28 homolog B), IL-13 (interleukin 13), NR1H4 (nuclear receptor subfamily 1 group H member 4) and NF-κB (nuclear factor kappa B), are elevated in MDR2−/− mice, but treatment with LSCEVs reduced levels of these mediators of ductular reaction and biliary fibrosis through the inhibition of NF-κB and IL-13 signaling pathways. Evaluation of crosstalk using cholangiocyte supernatants from LSCEV-treated cells on cultured HSCs showed that HSCs had reduced levels of fibrosis and increased senescence. Conclusion: Our studies indicate that LSCEVs could be a possible treatment for cholangiopathies or could be used for target validation for future therapies

Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy

BackgroundT cells engineered to target CD19 antigen on neoplastic B cells represent the most striking example of CAR-T cell therapy. The success rate of this therapy is affected by several limitations: target antigen loss, and/or acquisition of a senescent/exhausted phenotype by CAR and non-CAR T cells. Case presentationWe report on a patient affected by refractory Diffuse Large B-cell Lymphoma who was resistant to CAR T-cell therapy and to two cycles post CAR-T of pembrolizumab (PBZ) due to the evolution into a B-cell Hodgkin-like lymphoma. Owing to the CD30 expression and the Hodgkin-like phenotype, the patient was ultimately treated with Brentuximab-Vedotin and finally underwent remission. Upon PBZ treatment, 100% of circulating CAR-T+ cells showed a persistent CD8(+) senescent/exhausted phenotype, while an increase in the percentage of senescent cells was found in the non-CAR CD8(+) T cells compartment. ConclusionsPBZ is not able to reinvigorate exhausted CAR(+) T cells and to confer durable clinical response. We hypothesize that the phenomenon is due to the senescent phenotype of CAR(+) T cells, which did not allow PBZ-induced reactivation and proliferative rescue. The phenomenon, together with the loss of CAR-T target CD19 and the shift of non-CAR CD8(+) T cells towards a senescent phenotype likely contributed to set up an immune landscape with poor antitumor capacity

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Quali effetti hanno avuto le misure di contenimento del COVID-19 sul benessere occupazionale? Uno studio sui lavoratori delle piccole e medie imprese italiane

Introduzione. Le piccole e medie imprese italiane (PMI) sono state duramente colpite dalle misure di contenimento dell’emergenza sanitaria da COVID-19. Ad oggi, non è ancora chiaro quale impatto queste misure possano aver avuto sul benessere occupazionale dei lavoratori impiegati nelle PMI. Obiettivi. Il presente studio si propone di esplorare se e come la chiusura durante il lockdown di alcune PMI, possa aver avuto un impatto sulla percezione della crisi economica e sulla salute psico-fisica dei lavoratori in esse impiegati. Metodo. 101 lavoratori impiegati in PMI localizzate in una provincia del Sud Italia hanno compilato un questionario self-report che includeva: apertura durante il lockdown (1 item), paura della crisi economica (Fear of the Economic Crisis Scale), auto-efficacia percepita nel fronteggiare il COVID-19 (COVID-19-related coping self-efficacy) e salute psico-fisica (General Health Questionnaire). Le analisi dei dati hanno previsto modelli di mediazione e mediazione moderata. Risultati. La chiusura durante il lockdown si associa positivamente con la paura della crisi economica (β=.72, p<.01) che, a sua volta, porta i lavoratori delle PMI a sperimentare sintomi di malessere psico-somatico (β=.20, p<.001). Tuttavia, l’impatto negativo della paura della crisi economica sul loro stato di salute è confermato soltanto per coloro che possiedono bassi (β=.31, p<.001) o moderati (β=.21, p<.001) livelli di auto-efficacia percepita nel fronteggiare il COVID-19, ma non per coloro con elevati livelli di auto-efficacia (β=.08, p=.20). Limiti. Questo studio trasversale si basa esclusivamente su misure self-report e su un campione esiguo di lavoratori provenienti da un’unica provincia italiana. Aspetti innovativi. Analizzando gli effetti di una specifica misura di lockdown sul benessere occupazionale dei lavoratori impiegati nelle PMI, questa ricerca arricchisce la letteratura sugli effetti dell’emergenza sanitaria. Inoltre, individuando nell’auto-efficacia percepita un’importante fattore di protezione, questo studio fornisce supporto circa l’importanza di fornire a tali lavoratori coping effectiveness training

Quali effetti hanno avuto le misure di contenimento del COVID-19 sul benessere occupazionale? Uno studio sui lavoratori delle piccole e medie imprese italiane.

Introduzione. Le piccole e medie imprese italiane (PMI) sono state duramente colpite dalle misure di contenimento dell’emergenza sanitaria da COVID-19. Ad oggi, non è ancora chiaro quale impatto queste misure possano aver avuto sul benessere occupazionale dei lavoratori impiegati nelle PMI. Obiettivi. Il presente studio si propone di esplorare se e come la chiusura durante il lockdown di alcune PMI, possa aver avuto un impatto sulla percezione della crisi economica e sulla salute psico-fisica dei lavoratori in esse impiegati. Metodo. 101 lavoratori impiegati in PMI localizzate in una provincia del Sud Italia hanno compilato un questionario self-report che includeva: apertura durante il lockdown (1 item), paura della crisi economica (Fear of the Economic Crisis Scale), auto-efficacia percepita nel fronteggiare il COVID-19 (COVID-19-related coping self-efficacy) e salute psico-fisica (General Health Questionnaire). Le analisi dei dati hanno previsto modelli di mediazione e mediazione moderata. Risultati. La chiusura durante il lockdown si associa positivamente con la paura della crisi economica (β=.72, p<.01) che, a sua volta, porta i lavoratori delle PMI a sperimentare sintomi di malessere psico-somatico (β=.20, p<.001). Tuttavia, l’impatto negativo della paura della crisi economica sul loro stato di salute è confermato soltanto per coloro che possiedono bassi (β=.31, p<.001) o moderati (β=.21, p<.001) livelli di auto-efficacia percepita nel fronteggiare il COVID-19, ma non per coloro con elevati livelli di auto-efficacia (β=.08, p=.20). Limiti. Questo studio trasversale si basa esclusivamente su misure self-report e su un campione esiguo di lavoratori provenienti da un’unica provincia italiana. Aspetti innovativi. Analizzando gli effetti di una specifica misura di lockdown sul benessere occupazionale dei lavoratori impiegati nelle PMI, questa ricerca arricchisce la letteratura sugli effetti dell’emergenza sanitaria. Inoltre, individuando nell’auto-efficacia percepita un’importante fattore di protezione, questo studio fornisce supporto circa l’importanza di fornire a tali lavoratori coping effectiveness training

Therapeutic Potential of IL-17-Mediated Signaling Pathway in Autoimmune Liver Diseases

Emerging evidence reveals that various cytokines and tissue microenvironments contribute to liver inflammation and autoimmunity, and IL-17 family is one of highlights acknowledged. Although the implication of IL-17 family in most common autoimmune diseases (such as psoriasis, inflammatory bowel disease, and rheumatoid arthritis) has been extensively characterized, the role of this critical family in pathophysiology of autoimmune liver diseases (AILD) still needs to be clarified. In the review, we look into the intriguing biology of IL-17 family and further dissect on the intricate role of IL-17-mediated pathway in AILD. Considering encouraging data from preclinical and clinical trials, IL-17 targeted therapy has shown promises in several certain autoimmune conditions. However, blocking IL-17-mediated pathway is just beginning, and more fully investigation and reflection are required. Taking together, targeting IL-17-mediated responses may open up new areas of potential clinical treatment for AILD