Positive and negative regulation of the Fcγ receptor–stimulating activity of RNA-containing immune complexes by RNase

The U1RNP complex, Ro/SSA, and La/SSB are major RNA-containing autoantigens. Immune complexes (ICs) composed of RNA-containing autoantigens and autoantibodies are suspected to be involved in the pathogenesis of some systemic autoimmune diseases. Therefore, RNase treatment, which degrades RNA in ICs, has been tested in clinical trials as a potential therapeutic agent. However, no studies to our knowledge have specifically evaluated the effect of RNase treatment on the Fcγ receptor–stimulating (FcγR-stimulating) activity of RNA-containing ICs. In this study, using a reporter system that specifically detects FcγR-stimulating capacity, we investigated the effect of RNase treatment on the FcγR-stimulating activity of RNA-containing ICs composed of autoantigens and autoantibodies from patients with systemic autoimmune diseases such as systemic lupus erythematosus. We found that RNase enhanced the FcγR-stimulating activity of Ro/SSA- and La/SSB-containing ICs, but attenuated that of the U1RNP complex–containing ICs. RNase decreased autoantibody binding to the U1RNP complex, but increased autoantibody binding to Ro/SSA and La/SSB. Our results suggest that RNase enhances FcγR activation by promoting the formation of ICs containing Ro/SSA or La/SSB. Our study provides insights into the pathophysiology of autoimmune diseases involving anti-Ro/SSA and anti-La/SSB autoantibodies, and into the therapeutic application of RNase treatment for systemic autoimmune diseases.Naito R., Ohmura K., Higuchi S., et al. Positive and negative regulation of the Fcγ receptor–stimulating activity of RNA-containing immune complexes by RNase. JCI Insight 8, e167799 (2023); https://doi.org/10.1172/jci.insight.167799

Relevance of the Core 70 and IL-28B polymorphism and response-guided therapy of peginterferon alfa-2a ± ribavirin for chronic hepatitis C of Genotype 1b: a multicenter randomized trial, ReGIT-J study

BACKGROUND: We conducted a multicenter randomized clinical trial to determine the optimal treatment strategy against chronic hepatitis C virus (HCV) with genotype 1b and a high viral load (G1b/high). METHODS: The study subjects included 153 patients with G1b/high. Patients were initially treated with PEG-IFNα-2a alone and then randomly assigned to receive different treatment regimens. Ribavirin (RBV) was administered to all patients with HCV RNA at week 4. Patients negative for HCV RNA at week 4 were randomly assigned to receive PEG-IFNα-2a (group A) or PEG-IFNα-2a/RBV (group B). Patients who showed HCV RNA at week 4 but were negative at week 12 were randomly assigned to receive weekly PEG-IFNα-2a (group C) or biweekly therapy (group D). Patients who showed HCV RNA at week 12 but were negative at week 24 were randomly assigned to receive PEG-IFNα-2a/RBV (group E) or PEG-IFNα-2a/RBV/fluvastatin (group F). RESULTS: Overall, the rate of sustained virological response (SVR) was 46 % (70/153). The total SVR rate in the group (A, D, and F) of response-guided therapy was significantly higher than that in the group (B, C, and E) of conventional therapy [70 % (38/54) versus 52 % (32/61), p = 0.049]. Although IL28-B polymorphism and Core 70 mutation were significantly associated with efficacy, patients with rapid virological response (RVR) and complete early virological response (cEVR) achieved high SVR rates regardless of their status of IL-28B polymorphism and Core 70 mutation. CONCLUSION: In addition to knowing the IL-28B polymorphism and Core 70 mutation status, understanding the likelihood of virological response during treatment is critical in determining the appropriate treatment strategy

Microstructure and conductivity of blacklight‐sintered TiO₂, YSZ, and Li₀.₃₃La₀.₅₇TiO₃

Rapid densification of ceramics has been realized and its merits were demonstrated through multiple approaches out of which UHS and flash sintering attract recent attention. So far, however, scalability remains difficult. A rise in throughput and scalability is enabled by the introduction of blacklight sintering powered by novel light source technology. Intense illumination with photon energy above the bandgap (blacklight) allows high absorption efficiency and, hence, very rapid, contactless heating for all ceramics. While heating the ceramic directly with light without any furnace promises scalability, it simultaneously offers highly accurate process control. For the technology transfer to industry, attainable material quality needs to be assured. Here, we demonstrate the excellent microstructure quality of blacklight‐sintered ceramics observed with ultrahigh voltage electron microscopy revealing an option to tune nanoporosity. Moreover, we confirm that electronic, electron, oxygen, and lithium‐ion conductivities are equal to conventionally sintered ceramics. This gives the prospect of transmitting the merits of rapid densification to the scale of industrial kilns

Sarcopenia and Frailty in Liver Cirrhosis

Skeletal muscle is the largest organ in the body, and skeletal muscle atrophy results from a shift in the balance of protein synthesis and degradation toward protein breakdown. Primary sarcopenia is defined as a loss of skeletal muscle mass and strength or physical function due to aging, and secondary sarcopenia is defined as a loss of skeletal muscle mass and strength or physical function due to underlying diseases. Liver cirrhosis (LC) is one of the representative diseases which can be complicated with secondary sarcopenia. Muscle mass loss becomes more pronounced with worsening liver reserve in LC patients. While frailty encompasses a state of increased vulnerability to environmental factors, there is also the reversibility of returning to a healthy state with appropriate intervention. Several assessment criteria for sarcopenia and frailty were proposed in recent years. In 2016, the Japan Society of Hepatology created assessment criteria for sarcopenia in liver disease. In Japan, health checkups for frailty in the elderly aged 75 years or more started in April 2020. Both sarcopenia and frailty can be adverse predictors for cirrhotic patients. In this review article, we will summarize the current knowledge of sarcopenia and frailty in LC patients

Dysregulation of intracellular pH is a cause of impaired capacitation in Slc22a14-deficient mice

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Cancer Cachexia: Its Mechanism and Clinical Significance

The term “cachexia” is derived from the Greek words kakos (bad) and hexis (habit). Cachexia is a malnutrition associated with chronic diseases such as cancer, chronic heart failure, chronic renal failure, and autoimmune diseases, and is characterized by decreased skeletal muscle mass. Cancer cachexia is quite common in patients with advanced cancer. Weight loss is also a characteristic symptom of cancer cachexia, along with decreased skeletal muscle mass. As nutritional supplementation alone cannot improve cachexia, cytokines and tumor-derived substances have been attracting attention as its relevant factors. Cancer cachexia can be also associated with reduced chemotherapeutic effects, increased side effects and treatment interruptions, and even poorer survival. In 2011, a consensus definition of cachexia has been proposed, and the number of relevant research reports has increased significantly. However, the pathogenesis of cachexia is not fully understood, and there are currently few regulatory-approved standard treatments for cachexia. The main reason for this is that multiple etiologies are involved in the development of cachexia. In this review, we will outline the current status of cachexia, the mechanisms of which have been elucidated in recent years, especially from the perspective of advanced cancer