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关键词： Rheumatoid Arthritis   Biological Therapy   Economics  

摘要： Objective To compare work loss after starting tumour necrosis factor inhibitors (TNFi), rituximab, abatacept or tocilizumab in patients with rheumatoid arthritis (RA).Methods We used data from the Swedish Rheumatology Quality Register to identify patients aged 19-62 years who were treated with TNFi (n=15 093), rituximab (n=2123), abatacept (n=1877) or tocilizumab (n=1720) between 2007 and 2020. Data on work loss (0-365 days per year) from sick leave and disability pension were retrieved from linkage to the Social Insurance Agency. Patients in the different treatment arms were balanced regarding baseline covariates using inverse probability weighting (IPTW).Results Work loss increased for patients with RA until drug treatment initiation, reached a peak in the month after treatment initiation and then levelled off. Following IPTW, at 3 years before starting the treatment, there were no statistically significant differences in the mean annual adjusted work loss days between rituximab, abatacept or tocilizumab vs TNFi (mean difference vs TNFi: rituximab 1.1 days, 95% CI -4.5 to 6.7;abatacept 3.3, 95% CI -2.6 to 9.2;tocilizumab 1.2, 95% CI -4.9 to 7.3). At 3 years after starting the treatment (latest January 2021), there were also no statistically significant differences in the mean annual adjusted work loss days (mean difference: rituximab -4.8 days, 95% CI -11.3 to 1.7;abatacept 5.3, 95% CI -1.8 to 12.3;tocilizumab -0.6, 95% CI -7.7 to 6.5).Conclusions Taking channelling into account, patients with RA treated with TNFi, rituximab, abatacept or tocilizumab had similar trajectories of work loss from sick leave and disability pension until treatment initiation, and similar trend breaks and plateau 3 years thereafter.

关键词： immunopeptidome   MHC molecules   ncRNA-Derived peptides   extracellular vesicles (EVs)   cancer immunotherapy  

摘要： The immunopeptidome, a diverse set of peptides presented by Major Histocompatibility Complex (MHC) molecules, is a critical component of immune recognition and response. This review article delves into the mechanisms of peptide presentation by MHC molecules, particularly emphasizing the roles of ncRNA-derived peptides and extracellular vesicles (EVs) in shaping the immunopeptidome landscape. We explore established and emerging insights into MHC molecule interactions with peptides, including the dynamics of peptide loading, transport, and the influence of cellular and genetic variations. The article highlights novel research on non-coding RNA (ncRNA)-derived peptides, which challenge conventional views of antigen processing and presentation and the role of EVs in transporting these peptides, thereby modulating immune responses at remote body sites. This novel research not only challenges conventional views but also opens up new avenues for understanding immune responses. Furthermore, we discuss the implications of these mechanisms in developing therapeutic strategies, particularly for cancer immunotherapy. By conducting a comprehensive analysis of current literature and advanced methodologies in immunopeptidomics, this review aims to deepen the understanding of the complex interplay between MHC peptide presentation and the immune system, offering new perspectives on potential diagnostic and therapeutic applications. Additionally, the interactions between ncRNA-derived peptides and EVs provide a mechanism for the enhanced surface presentation of these peptides and highlight a novel pathway for their systemic distribution, potentially altering immune surveillance and therapeutic landscapes.

关键词： Banxia Xiexin Decoction   Polycystic ovarian syndrome   miR-20b-5p   TLR4/IL-6  

摘要： ObjectiveThe study is proposed to uncover the protective effect of Banxia Xiexin Decoction (BXD) on polycystic ovarian syndrome (PCOS).MethodsPCOS in rats was induced by continuous injection of DHEA. BXD was continuously administered, and the pathological changes of the ovarian tissue were observed by HE staining. Cleaved caspase-3, TLR4, and IL-6 were measured by immunohistochemical staining, RT-qPCR, and immunoblotting. The regulatory effects of BXD on serum hormones in PCOS rats were evaluated by ELISA. Granulosa cells (GC) were isolated from ovarian tissues of PCOS rats, and cell viability, apoptosis, and cell cycle progression were evaluated, and Cleaved Caspase-3 and IL-6 expressions were *** effectively improved the damage of ovarian tissue, restored abnormal hormone levels, and inhibited cell proliferation and inflammatory response in PCOS rats. BXD blocked the TLR4/IL-6 axis by up-regulating *** negatively regulates the TLR4/IL-6 axis by up-regulating miR-20b-5p, inhibiting the proliferation and inflammatory response of GC in PCOS.

关键词： Manganese oxide  

摘要： Cancer immunotherapies rely on CD8+ cytolytic T lymphocytes (CTLs) in recognition and eradication of tumor cells via antigens presented on major histocompatibility complex class I (MHC-I) molecules. However, we observe MHC-I deficiency in human and murine urologic tumors, posing daunting challenges for successful immunotherapy. We herein report an unprecedented nanosonosensitizer of one-dimensional bamboo-like multisegmented manganese dioxide@manganese-bismuth vanadate (BMMBV) to boost multiple branches of immune responses targeting MHC-I-deficient tumors. BMMBV markedly augments sonodynamic activity contributed by manganese heteroatoms in the lattice of bismuth vanadate with narrowing bandgaps. Under sonoirradiation, BMMBV enhances tumor antigen spreading and emission of adjuvant signals, which potentiate dendritic cell maturation, thereby eliciting high aptitude of CTLs. This therapy substantially up-regulates MHC expression on tumor cells, which are reversely sensitive to CTLs. Alongside, extensive innate immune cells complement the cytolytic activity of CTLs for eliminating mouse urologic tumors. This study offers a reinforced strategy against antigen-loss immune-evasive tumor.

摘要： Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T-cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T-cells that contribute to the anti-tumor response. We find that mouse Braf -driven anaplastic thyroid cancers (ATC) respond markedly to the RAF + MEK inhibitors dabrafenib and trametinib (dab/tram) and that this is associated with upregulation of MhcII in cancer cells and increased CD4+ T-cell infiltration. A subset of recurrent tumors lose MhcII expression due to silencing of , the master transcriptional regulator of MhcII, despite preserved interferon gamma signal transduction, which can be rescued by EZH2 inhibition. Orthotopically-implanted Ciita and H2-Ab1 ATC cells into immune competent mice become unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+ T-cells, also abrogates response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.

关键词： CLDN4   GP3   IFN-beta   PRRSV   sECL2  

摘要： Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most harmful pathogens in the swine industry. Our previous studies demonstrated that the small extracellular domain (ECL2) of CLDN4 effectively blocks PRRSV infection. In this study, we explored the in vivo administration of swine ECL2 (sECL2) and found that it blocked HP-PRRSV infection and alleviated histopathological changes in organs. Notably, sECL2 stimulated cytokine production in the lungs. We observed that CLDN4 upregulated the expression of IFN-beta at low doses of GP3. While high doses of GP3 inhibited the activity of the IFN-beta promotor, regardless of whether CLDN4 was present. GP3 also downregulated IFN-beta by decreasing the phosphorylation of TBK1 and IRF3. These findings highlight functional differences in GP3 under quantity control, which account for the variations in IFN-beta induction during the early and late stages of infection. Our results indicate that sECL2 is a promising candidate drug for developing treatments to control PRRS.

摘要： A 27-year-old man presented with 6 months of diplopia and unsteadiness. A CT scan suggested glioma, prompting transfer to our tertiary hospital. MRI with spectroscopy revealed a T2 FLAIR hyperintense lesion in the diencephalic-mesencephalic region, extending across the midline, with nodular enhancement, and an increased choline-to-N-acetylaspartate (NAA) ratio was observed (Figure). CSF analysis showed lymphocytic pleocytosis, and the patient tested positive for HLA-B51. © 2024 American Academy of Neurology.

摘要： Cytokines play pivotal roles in anticancer immune response. We previously reported that adenovirus armed with an IL18 variant (DR18) that overcomes IL18BP neutralizing effect displayed powerful therapeutic effects in local and distant tumors when delivered intratumorally. Here, we tested a combined delivery of IL12 and DR18 in tumor models since IL12 and IL18 are known to act synergistically in potentiating IFN gamma production and antitumor immunity. To minimize adverse effects associated with systemic delivery, we constructed oncolytic adenoviruses (oAd) harboring DR18 and IL12 (***18/IL12). IL12 was expressed as a single chain IL12 (scIL12) peptide composed of the IL12/p40 and IL12/p35 subunits. Intratumoral administration of ***18/IL12, oAd-expressing DR18 (***18), or oAd-expressing IL12 (***12) showed antitumor effect in syngeneic colorectal tumor models. Compared to ***18 or ***12, administration of ***18/IL12 improved the antitumor effects as well as increased survival rate in these models. We detected enhanced tumor infiltrating T lymphocytes and NK cells in ***18/IL12-treated mice than those from mock-treated or individually treated groups. Moreover, mice received ***18/IL12 had more robust tumor-specific cytotoxicity. Importantly, mice that had tumor regression after ***18/IL12 treatment established anti-tumor specific immune memory. These results show that adenovirus armed with engineered cytokines boosts tumor specific immunity and antitumor effect.

关键词： CD4+ T cell   immune memory   Tfh   Th1  

摘要： It is not clear how CD4+ memory T cells are formed from a much larger pool of earlier effector cells. We found that transient systemic bacterial infection rapidly generates several antigen-specific T helper (Th)1 and T follicular helper (Tfh) cell populations with different tissue residence behaviors. Although most cells of all varieties had transcriptomes indicative of cell stress and death at the peak of the response, some had already acquired a memory cell signature characterized by expression of genes involved in cell survival. Each Th1 and Tfh cell type was maintained long term by interleukin (IL)-7, except germinal center Tfh cells, which depended on a T cell antigen receptor (TCR) signal. The results indicate that acute infection induces rapid differentiation of Th1 and Tfh cells, a minority of which quickly adopt the gene expression profile of memory cells and survive by signals from the IL-7 receptor or TCR.