In anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, we analysed the efficacy of a combined immunotherapy protocol consisting of teratoma removal, steroid, intravenous immunoglobulin (IVIG), rituximab and tocilizumab (T-SIRT). This cohort study included seventy-eight consecutive patients treated for anti-NMDAR encephalitis between Jan 2014 and Oct 2019 in a national referral hospital. Detailed 2-year disease time course was analysed using Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores at every 2 weeks for 12 weeks from baseline, every month for the next 3 months and then every 3 months. Treatment regimens at each time point were categorized as SI, SIR, or SIRT with/without teratoma removal (T). Adverse events were classified according to the Common Terminology Criteria for Adverse-Events (CTCAE v5.0), where a severe adverse event was defined as an adverse event with CATAE grade 4. In a linear mixed model analysis, using the SIRT regimen was more effective than SIR or SI regimens in lowering CASE scores (P < 0.001 and P = 0.001, respectively). The presence of teratoma (P = 0.001), refractory status epilepticus (P < 0.001) and a higher CASE score at baseline (P < 0.001) predicted a higher CASE score at each time point. Completion of the (T)-SIRT regimen within 1 month of onset resulted in better 1-year improvements in CASE score (P < 0.001) and modified Rankin scale scores (P = 0.001), compared to those of using other regimens within 1 month or delaying teratoma removal for more than 1 month. Pneumonia was a frequent adverse event (52/78, 66.7%) in the whole study population and neutropenia was frequent during SIRT (11/52, 21.2%), but the regimen was well tolerated in most patients. We concluded that the early application of combined immunotherapy consisting of T-SIRT had better efficacy than was found for delayed or partial application of this combination in anti-NMDAR encephalitis.

Reliable quantification of nanoparticle uptake in mammalian cells is essential to study the effects of nanoparticles in the fields of medicine and environmental science. Most conventional quantification methods, such as...

Despite the worldwide effect of the Coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we show that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. In addition, we confirm increased Th2-biased adaptive immune responses, accompanying overt complement activation, in the critical group. Moreover, enhanced antibody responses and complement activation is associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from six fatal cases, as well as by enhanced hallmark gene set signatures of FcγR signaling and complement activation in myeloid cells of respiratory specimens from critical COVID-19 patients. These results suggest that SARS-CoV-2 infection may drive specific innate immune responses, including eosinophil-mediated inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of critical disease in COVID-19 patients.

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The canonical Wnt signaling pathway, in which ␤-catenin nuclear localization is a crucial step, plays an important role in osteoblast differentiation. Pin1, a prolyl isomerase, is also known as a key enzyme in osteogenesis. However, the role of Pin1 in canonical Wnt signal-induced osteoblast differentiation is poorly understood. We found that Pin1 deficiency caused osteopenia and reduction of ␤-catenin in bone lining cells. Similarly, Pin1 knockdown or treatment with Pin1 inhibitors strongly decreased the nuclear ␤-catenin level, TOP flash activity, and expression of bone marker genes induced by canonical Wnt activation and vice versa in Pin1 overexpression. Pin1 interacts directly with and isomerizes ␤-catenin in the nucleus. The isomerized ␤-catenin could not bind to nuclear adenomatous polyposis coli, which drives ␤-catenin out of the nucleus for proteasomal degradation, which consequently increases the retention of ␤-catenin in the nucleus and might explain the decrease of ␤-catenin ubiquitination. These results indicate that Pin1 could be a critical target to modulate ␤-catenin-mediated osteogenesis.