Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma.

During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described in liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes in a murine HCC model. Our data confirmed inflammasome activation after both TKI treatments, sharing a similar pattern of increased gene expression. According to human database results, transcriptional increase of inflammasome genes is associated with poorer prognosis for male liver cancer patients, suggesting a sex-dependent role for inflammasome activation in HCC therapy. In biopsies of HCC and its surrounding tissue, we detected durable increases in the inflammasome activation pattern after sorafenib or regorafenib treatment in male patients. Further supporting its involvement in sorafenib action, inflammasome inhibition (MCC950) enhanced sorafenib anticancer activity in experimental HCC models, while no direct in vitro effect was observed in HCC cell lines. Moreover, activated human THP-1 macrophages released IL-1ß after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1ß addition, pointing to the liver microenvironment as a key player in inflammasome action. In summary, our results unveil the inflammasome pathway as an actionable target in sorafenib or regorafenib therapy and associate an inflammasome signature in HCC and surrounding tissue with TKI administration. Therefore, targeting inflammasome activation, principally in male patients, could help to overcome sorafenib or regorafenib resistance and enhance the efficacy of TKI treatments in HCC.

Sex-based differences in natural killer T cell-mediated protection against diet-induced steatohepatitis in Balb/c mice.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is prevalent in Western countries, evolving into metabolic dysfunction-associated steatohepatitis (MASH) with a sexual dimorphism. Fertile women exhibit lower MASLD risk than men, which diminishes post-menopause. While NKT-cell involvement in steatohepatitis is debated, discrepancies may stem from varied mouse strains used, predominantly C57BL6/J with Th1-dominant responses. Exploration of steatohepatitis, encompassing both genders, using Balb/c background, with Th2-dominant immune response, and CD1d-deficient mice in the Balb/c background (lacking Type I and Type II NKT cells) can clarify gender disparities and NKT-cell influence on MASH progression. METHODS: A high fat and choline-deficient (HFCD) diet was used in male and female mice, Balb/c mice or CD1d-/- mice in the Balb/c background that exhibit a Th2-dominant immune response. Liver fibrosis and inflammatory gene expression were measured by qPCR, and histology assessment. NKT cells, T cells, macrophages and neutrophils were assessed by flow cytometry. RESULTS: Female mice displayed milder steatohepatitis after 6 weeks of HFCD, showing reduced liver damage, inflammation, and fibrosis compared to males. Male Balb/c mice exhibited NKT-cell protection against steatohepatitis whereas CD1d-/- males on HFCD presented decreased hepatoprotection, increased liver fibrosis, inflammation, neutrophilic infiltration, and inflammatory macrophages. In contrast, the NKT-cell role was negligible in early steatohepatitis development in both female mice, as fibrosis and inflammation were similar despite augmented liver damage in CD1d-/- females. Relevant, hepatic type I NKT levels in female Balb/c mice were significantly lower than in male. CONCLUSIONS: NKT cells exert a protective role against experimental steatohepatitis as HFCD-treated CD1d-/- males had more severe fibrosis and inflammation than male Balb/c mice. In females, the HFCD-induced hepatocellular damage and the immune response are less affected by NKT cells on early steatohepatitis progression, underscoring sex-specific NKT-cell influence in MASH development.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver condition today. In its more advanced form, called metabolic dysfunction-associated steatohepatitis (MASH), adult men are more often affected than women, though this difference vanishes after menopause. Various factors contribute to MASH, including a specific immune cell type called NKT cells, which has not been deeply researched yet. To explore the role of NKT cells in steatohepatitis, we used male and female mice with or without NKT cells (CD1d^−/− mice), feeding them a high-fat diet that induces steatohepatitis. Our findings revealed that female mice had less severe steatohepatitis compared to males. Interestingly, we observed a protective role of NKT cells during steatohepatitis, as male mice without these cells had more damage, inflammation, and fibrosis than those with NKT cells. However, in females, even though those lacking NKT cells showed more liver damage and immune alterations, NKT did not seem to play a major role in early steatohepatitis progression. Notably, females had much fewer NKT cells in their livers compared to males, possibly explaining this difference. In conclusion, NKT cells seem to slow down steatohepatitis progression, especially in male mice. In females, their impact on early steatohepatitis advance appears more limited.

Hepatocellular Carcinoma: Molecular Pathogenesis and Therapeutic Advances.

Hepatocellular carcinoma (HCC), the most common form of liver cancer, continues to be a serious medical problem with poor prognosis, without major therapeutic improvement for years and increasing incidence. Fortunately, advances in systemic treatment options are finally arriving for HCC patients. After a decade of sorafenib as a standard therapy for advanced HCC, several tyrosine kinase inhibitors (TKIs), antiangiogenic antibodies, and immune checkpoint inhibitors have reached the clinic. Although infections by hepatitis B virus and hepatitis C virus remain principal factors for HCC development, the rise of non- alcoholic steatohepatitis from diabetes mellitus or metabolic syndrome is impeding HCC decline. Knowledge of specific molecular mechanisms, based on the etiology and the HCC microenvironment that influence tumor growth and immune control, will be crucial for physician decision-making among a variety of drugs to prescribe. In addition, markers of treatment efficacy are needed to speed the movement of patients towards other potentially effective treatments. Consequently, research to provide scientific data for the evidence-based management of liver cancer is guaranteed in the coming years and discussed here.

Process for disinfection of N95 respirators during COVID-19 utilizing sterile processing department: A single center acute care hospital.

During the COVID-19 crisis, disposable N-95 filtering face piece respirators became a critical supply in many health care institutions. Infection preventionists nationwide struggled with ensuring their facilities had personal protective equipment available while utilizing crisis capacity strategies. Many facilities began using US Centers for Disease Control and Prevention and US Food and Drug Administration guidance to disinfect and reprocess N95 respirators for extended use. N95 respirators are collected for all clinical units on a scheduled basis by the sterile processing department (SPD) in individually labeled bins. Bins are checked into SPD and logged into electronic system to track mask volumes by unit. Masks are inspected by SPD team members, packaged in sterile peel packs on the decontamination side and sent to the clean side of the department. Masks are then reprocessed in the appropriate equipment based on the US Food and Drug Administration Emergency Use Authorization guidelines. The facility was able to provide a consistent method of N95 reprocessing throughout the facility. Utilizing an interdisciplinary team to include the operating room, infection preventionist, SPD, and nursing leadership to troubleshoot and identify barriers on a routine basis was key to making the program a success for the many months of the COVID-19 pandemic.