Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis.

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

Capsule-epithelium-fibre unit ultrastructure in the human lens.

This study aimed to investigate the capsule-epithelium-fibre unit ultrastructure of the human lens, particularly the interfaces of the epithelium with the capsule and the epithelium with the fibre cell. A total of 12 lenses from donor humans who died of trauma without systemic and ocular diseases were investigated by transmission electron microscopy (TEM), combined with immunofluorescence staining for localising certain specific proteins. Some of the results were further studied in the anterior lens capsules of cataract patients. Our results revealed capsule protrusion into the epithelium in some areas and potential processing of capsule components. The young elongating fibre cells directly adjacent to the epithelium with a high stain density strongly expressed CD24. Numerous extracellular vesicles could be seen in the space between human lens epithelial cells (HLECs) and between HLECs and the capsule. Mitophagy and autophagy were also observed in the HLECs. Our research may be beneficial in better understanding the function of the human lens.

New technique for removal of perfluorocarbon liquid related sticky silicone oil and literature review.

AIM: To investigate the safety and efficacy of sticky silicone oil (SSO) removal using a 22-gauge vein detained needle and inner limiting membrane (ILM) wrap-and-peel technique. METHODS: This retrospective consecutive case series reviewed the records of patients with a history of retinal detachment who had received silicone oil and perfluorocarbon liquid (PFCL) as intraocular tamponades. Patients were included in the analysis if they exhibited SSO remnants during silicone oil removal. The aspiration of most of the SSO remnants was performed by a 22-gauge vein detained needle. The small amounts of droplets adhered to the macula and epi-macular membrane were subsequently removed by the ILM warp-and-peel technique. The anatomical and functional outcomes, and postoperative complications were recorded. In vitro experiments were performed to simulate the formation of SSO remnants in four groups. RESULTS: Of 711 patients who underwent silicone oil removal during the study period, 9 patients exhibited SSO remnants and underwent follow-up for at least 3mo. Seven eyes (78%) underwent the ILM wrap-and-peel technique to completely remove small droplets of SSO that were glued to the macula and epi-macular membrane. No obvious complications occurred. Postoperative optical coherence tomography revealed normal retinal structure in all patients. In vitro analyses showed that balanced salt solution and prolonged vibration (for 1wk) had the strongest effects on silicone oil and PFCL compound opacities. CONCLUSION: SSO remnants could be removed in an intact manner and without complications, using a vein detained needle-assisted and ILM wrap-and-peel technique. The findings suggest that PFCL and infusion fluid should be completely removed before silicone oil injection to prevent SSO formation.

Mechanism of Precipitate Microstructure Affecting Fatigue Behavior of 7020 Aluminum Alloy.

The effect of different precipitate microstructures obtained by different heat treatments on fatigue behavior of 7020 aluminum alloy was investigated. The fine Guinier Preston I (GPI) zones in the under-aged alloy can be repeatedly sheared by dislocations produced in cyclic loading, making the fatigue crack initiate difficultly and fatigue crack path propagate tortuously. Fatigue strength and fatigue crack propagation resistance of the alloy with shearable precipitates are much higher than those of the alloy with unshearable precipitates. The peak-aged alloy with continuous grain boundary precipitate (GBP) and narrow precipitate free zone (PFZ) is prone to initiate fatigue cracks and reduce fatigue strength. With the growth of unshearable precipitates, the fatigue strength of the alloy firstly increases and then decreases. Precipitates with moderate size in the over-aged alloy improve the roughness-induced crack closure (RICC) effect. Soft matrix with appropriate width between the precipitates can promote the slip reversibility and relax the crack tip stress. The fatigue strength of the moderately over-aged alloy reaches to 122.1 MPa at 107 cycles of loading, and the fatigue crack growth rate (FCGR) is 35.6% slower than that of the peak-aged alloy at ΔK of 10 MPa·m1/2.

Novel risk loci for rheumatoid arthritis in Han Chinese and congruence with risk variants in Europeans.

OBJECTIVE: To investigate differences in genetic risk factors for rheumatoid arthritis (RA) in Han Chinese as compared with Europeans. METHODS: A genome-wide association study was conducted in China with 952 patients and 943 controls, and 32 variants were followed up in 2,132 patients and 2,553 controls. A transpopulation meta-analysis with results from a large European RA study was also performed to compare the genetic architecture across the 2 ethnic remote populations. RESULTS: Three non-major histocompatibility complex (non-MHC) loci were identified at the genome-wide significance level, the effect sizes of which were larger in anti-citrullinated protein antibody (ACPA)-positive patients than in ACPA-negative patients. These included 2 novel variants, rs12617656, located in an intron of DPP4 (odds ratio [OR] 1.56, P = 1.6 × 10(-21) ), and rs12379034, located in the coding region of CDK5RAP2 (OR 1.49, P = 1.1 × 10(-16) ), as well as a variant at the known CCR6 locus, rs1854853 (OR 0.71, P = 6.5 × 10(-15) ). The analysis of ACPA-positive patients versus ACPA-negative patients revealed that rs12617656 at the DPP4 locus showed a strong interaction effect with ACPAs (P = 5.3 × 10(-18) ), and such an interaction was also observed for rs7748270 at the MHC locus (P = 5.9 × 10(-8) ). The transpopulation meta-analysis showed genome-wide overlap and enrichment in association signals across the 2 populations, as confirmed by prediction analysis. CONCLUSION: This study has expanded the list of alleles that confer risk of RA, provided new insight into the pathogenesis of RA, and added empirical evidence to the emerging polygenic nature of complex trait variation driven by common genetic variants.

Genetics of rheumatoid arthritis contributes to biology and drug discovery.

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.