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关键词： span>Intracerebral hemorrhageCold-inducible RNA-binding proteinsNeuroinflammationMicroglial polarizationTat peptides  

摘要： Chordoma is a special malignant tumor that lacks effective therapeutic targets, which can lead to incomplete treatment and metastasis. Inflammation plays an important role in chordoma progression and malignant phenotype. Inflammatory factors such as NF-kappaB and STAT3 are continuously activated in many tumors and contribute to the malignant phenotype of tumors and are potential therapeutic targets. This study suggest TNF-alpha and NF-kappaB signaling pathways were consistently activated in chordomas. Long-term TNF-alpha treatment induces chordoma resistance to EGFR family inhibitors. The underlying mechanism is realized by the key molecules HS3ST3A and HS3ST3B1. These two enzymes are potential targets for chordoma treatment, as well as for combination drugs treatment. It should be emphasized that the above analysis lacks experimental verification.

关键词： HLA   BCR   NK cells   CDC   ADCC   AMR  

摘要： Donor-specific anti-HLA antibodies (DSAs) bind to donor vascular endothelial cells and mediate allograft rejection (AMR), but a clinical challenge for which targeted therapeutic options remain limited. We used a multiplexed single-antigen bead (SAB) assay to detect anti-human leukocyte antigen (HLA) antibodies. Based on the antigens which patient's antibodies aganist to, we developed bivalent HLA-Fc fusion proteins composed of HLA-derived antigenic domains and human IgG1-Fc effector regions (rA24-Fc and rB13-Fc). Specific binding and functional activity of the HLA-Fc proteins were further validated by flow cytometry, ELISA, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) assays. Our findings demonstrate that the fusion proteins rA24-Fc and rB13-Fc significantly reduced HLA-specific antibody reactivity in vitro. Notably, rA24-Fc and rB13-Fc selectively bound to B-cell hybridomas (e.g., mouse W6/32 cells) expressing membrane immunoglobulins (BCR) which bound to the most HLA class I antigens. Importantly, rA24-Fc and rB13-Fc elicited antigen-specific, Fc-dependent elimination of the specific B-cell hybridomas. This study highlights HLA-Fc fusion proteins as a promising therapeutic strategy for the antigen-specific suppression of depletion of alloreactive B cells through dual cytotoxic mechanisms. This precision targeted to BCR of B cells approach is used to apply to the treatment of antibody-mediated rejection.

关键词： biologics   clinical trial   il-17 inhibitor   off-label   psoriasis  

摘要： In this issue of Blood Advances, Wynn et al demonstrate that, in the setting of double cord blood transplant (DCBT), shared human leukocyte antigen (HLA) mismatches between the patient and the losing cord blood unit (LU) when mismatched with the w...

摘要： BACKGROUND & AIMS:Anti-tumor necrosis factor (anti-TNF) is a mainstay of inflammatory bowel disease (IBD) therapy but fails in many patients. Although TNF has pro-inflammatory effects, depletion of TNF receptor 1 (TNFR1) paradoxically exacerbates chronic colitis. Because colitis induces remodeling of mesenchymal cell populations, which provide a niche for epithelial stem cells involved in mucosal healing, we hypothesized that TNFR1 promotes colonic mesenchymal cell diversity and stem cell niche function. METHODS:Mesenchymal TNFR1 function was studied using TNFR1 , platelet derived growth factor receptor alpha (PDGFRα)-Cre;TNFR1 mice, and mixed-genotype mesenchymal-epithelial co-cultures. Mesenchymal cell diversity and gene function were assessed using single-cell RNA-Seq of primary colonic myofibroblasts (CMFs) and via anti-integrin A6 (ITGA6) antibody treatment and exogenous R-spondin 3 (RSPO3) supplementation. RESULTS:TNFR1 mesenchyme exhibits reduced cell diversity, with specific depletion of specialized TNF- and interferon-signaling pericryptal cell-type. Deletion of TNFR1 in the pericryptal mesenchyme diminished the (PDGFRα)+ CMF population and reduced RSPO3 expression, but increased ITGA6 expression relative to controls (TNFR1 ). Moreover, inhibition of ITGA6 reversed the proliferative and migratory phenotype of TNFR1 CMFs and restored expression of PDGFRα and RSPO3. Co-cultures of colonoids with TNFR1 CMFs resulted in downregulation of stem cell marker expression; this was rescued by supplementation with RSPO3. Supporting the role for mesenchymal TNFR1 in regulating colonic epithelial stem cells, mice deficient for TNFR1 in PDGFRα+ cells showed a 40% loss of Lgr5+ stem cells, consistent with the global TNFR1-deficient mouse. CONCLUSION:TNFR1-mediated signaling regulates specification and function of colonic mesenchyme, performing an integral role in the maintenance of the crypt stem cell population.

摘要： MiR-34a is implicated in aging, cell senescence, inflammation, and neurodegenerative diseases. In order to investigate the role of miR-34a in Alzheimer's disease (AD), we produced an AD mouse model, Tg-SwDI mice, with whole body/constitutive miR-34a knockout (KO). MiR-34a KO improved long-term memory in Tg-SwDI mice, which was associated with decreases in the ratio of insoluble Aβ42 to Aβ40 and with increases in soluble and insoluble Aβ40 in the cerebral cortex. Anti-Iba1 immunofluorescence revealed increases in activated microglia. Bulk RNA-sequencing of the hippocampus followed by a gene set enrichment analysis (Enrichr) identified "cellular response to type I interferon" and "type I interferon signaling pathway" as the most prominent gene sets in miR-34a KO Tg-SwDI mice compared to miR-34a wild-type Tg-SwDI mice. Many interferon-stimulated genes (ISGs) that characterize interferon responsive microglia (IRM) were upregulated in miR-34a KO Tg-SwDI mice. MiR-34a knockdown strongly enhanced ISGs expression in TLR7 ligand-stimulated BV2 microglia. These results suggest that miR-34a inhibits the transition of microglia to the IRM state that may modulate synaptic and cognitive functions in neurodegenerative diseases and aging.

摘要： During double umbilical cord blood transplant (DUCBT), the winning unit (WU) rejects the losing unit (LU) because of WU T cells directed against the LU mismatched HLA. This immune response might protect against relapse, especially when the patient and LU (PT-LU) share the same mismatch with the WU. To validate this hypothesis, a retrospective Eurocord study, conducted on 383 DUCBTs, focused on posttransplant relapse and HLA mismatches between PT-LU and the WU. A PT-LU HLA-A mismatch shared with the WU was associated with a lower 7-year relapse incidence (16% vs 28%;P = .048). In addition, multiple PT-LU shared HLA mismatches were also associated with a lower relapse risk (7% vs 29%;P = .003). In DUCBT with >= 2 HLA mismatches between patient and WU, the number of HLA mismatches between those did not significantly affect relapse incidence, whereas multiple PT-LU shared HLA mismatches remained associated with a lower relapse risk (7% vs 29%;P = .0038). Finally, considering patients who did not develop either grade 2 to 4 acute graft-versus-host disease or chronic graft-versus-host disease, a PT-LU shared HLA-A mismatch as well as multiple PT-LU HLA mismatches shared with the WU remained associated with a significantly lower 7-year relapse incidence. In multivariate adjusted analyses multiple PT-LU shared HLA mismatches remained associated with a significantly reduced 7-year posttransplant relapse risk. Our analysis indicates that, during DUCBT, PT-LU shared HLA mismatches prime an immune response of the WU against leukemia, reducing the long-term risk of posttransplant relapse, and that DCBT has particular utility in those with high-risk leukemia.

关键词： Colorectal Cancer   Non-Small Cell Lung Cancer   Human leukocyte antigen - HLA   Immunotherapy   Adoptive cell therapy - ACT  

摘要： T-cell receptors (TCRs) recognize antigens derived from fragments of somatically expressed proteins that are degraded by the proteasome and presented by specific human leukocyte antigen (HLA) molecules. Recent therapeutic advances using the TCR as a tumor-targeting moiety have focused attention on HLA loss of heterozygosity (LOH) as a potential resistance mechanism. Allele-specific LOH, rather than allele-agnostic, is particularly pertinent, but rarely evaluated. Using a real-world dataset comprising 78,418 cases, we demonstrate that allele-specific LOH occurs at a relatively low frequency (<10%) across all patients with cancer. We observed a modest increase in allele-specific HLA LOH in cancers harboring associated neoantigen driver mutations (eg, KRAS or TP53 mutations), but the overall frequency remained consistently low. Furthermore, using an orthogonal dataset, we integrated clinical outcomes with HLA LOH and identified distinct impacts on overall survival in colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) cohorts. For instance, A*02:01-specific LOH was linked to worse survival in CRC (HR 0.5355, 95% CI 0.2991 to 0.9589, p=0.0094) but showed a trend toward improved survival in NSCLC (HR 1.249, 95% CI 0.7778 to 2.005). These findings underscore the relevance of allele-specific HLA LOH assessments and reveal nuanced differences in its clinical implications, which should be accounted for in the optimization of TCR-based immunotherapies.

关键词： obesity   adipose tissue   Th2 response   IL-4   IL-13  

摘要： The Th2 immune response, associated with allergic diseases and helminth infections, has emerged as a significant modulator of metabolic processes in adipose and liver tissues. Th2 cytokines, such as IL-4, IL-5, and IL-13, regulate energy metabolism, insulin resistance, and obesity-related issues. IL-4 and IL-13 play significant roles, while IL-5 mainly recruits eosinophils in visceral fat. IL-4 influences lipid metabolism via STAT6, promoting adipogenesis, lipolysis, and reducing leptin levels, thereby improving insulin resistance or inducing white adipose browning in the absence of leptin. IL-13 affects glucose metabolism by lowering gluconeogenesis and enhancing glucose control and increases energy expenditure in muscles during exercise via STAT3. Emerging therapies include recombinant cytokines, exosomes, and monoclonal antibodies targeting IL-4/IL-13 or IL-5, which are mostly approved for the treatment of allergic diseases. Their use in metabolic disorders is largely unexplored. Overall, Th2 cytokines are promising targets for obesity and metabolic diseases but require dedicated trials to assess benefits and risks.