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关键词： ABO   HLA   matching   platelet provision   selection  

摘要： BackgroundA large, retrospective study was designed to interrogate current NHS Blood and Transplant (NHSBT) HLA matching strategies for the provision of HLA selected platelets (HLA SP) and to determine whether additional factors such as ABO blood group matching, patient diagnosis, patient and/or donor age, sex, ethnicity, age of platelet unit at transfusion and possibly seasonal variation also play a role in transfusion *** and MethodsData for 56 640 HLA SP transfusions over a 3-year period were collected. Transfusions with missing data for any factor under consideration were excluded, resulting in a cohort of 13 044 transfusions for analysis. Univariable and multivariable regression models were used to determine if any factors influenced an increase in platelet count of >= 10 x 109/L. A stepwise logistic regression was applied, such that each influential factor was adjusted for effects on other factors included in the *** match grade was confirmed as a significant factor in transfusion efficacy, with ABO mismatched units 20% less likely to give an adequate platelet increment (>= 10 x 109/L). Platelet donor age, gender and ethnicity were not significant. Conversely, patient diagnosis, ethnicity, gender and age showed significant associations with platelet increments. Some seasonal variation in efficacy of platelet transfusion was also *** study has demonstrated the efficacy of HLA SP transfusions in refractory patients with a wide range of diagnoses, the importance of HLA match grade, plus the marginal effect of ABO matching. A wide range of donor-related factors was excluded, while a number of patient-related factors were identified, requiring more extensive investigation in ongoing and independent studies, with implications for donor registry, clinical and laboratory practices.

关键词： Leptomeningeal metastasis   Non-small-cell lung cancer (NSCLC)   Intrathecal injection   IL-2   Anti-PD-1   Nivolumab  

摘要： Objectives: Leptomeningeal metastasis (LM) is a serious complication of advanced non-small-cell lung cancer (NSCLC). Intrathecal administration of nivolumab or interleukin-2 (IL-2) has demonstrated efficacy in this setting. Preclinical and limited clinical evidence suggest that combining IL-2 with anti-PD1 therapy may synergistically enhance anti-tumor immunity. However, clinical data on the efficacy and safety of intrathecal co-administration of nivolumab and IL-2 are lacking. Materials and Methods: We describe a case of NSCLC with LM, refractory to multiple EGFR tyrosine kinase inhibitors and previous intrathecal therapies, treated with intrathecal nivolumab and IL-2. Single-cell RNA sequencing (scRNA-seq) was performed on cerebrospinal fluid (CSF) samples collected before and after treatment. Results: This is the first reported case of intrathecal nivolumab plus IL-2 in NSCLC with LM resistant to standard systemic and intrathecal therapies. The patient experienced marked clinical improvement, including substantial remission of intracranial metastases, neurological symptom relief, and a reduction in tumor marker levels, without notable treatment-related adverse events. scRNA-seq analysis of CSF revealed a post-treatment decrease in malignant cell populations and a concomitant increase in immune effector cells, particularly CD8+ T cells and NK cells. Malignant cells exhibited upregulated antigen presentation and apoptosis. Cell-cell interaction analysis indicated enhanced NK cell-mediated cytotoxicity via FASL-FAS signaling and reduced immunosuppressive interactions between regulatory CD4+ T cells and effector memory CD8+ T cells. Conclusions: This case report provides preliminary evidence supporting the feasibility, safety, and potential efficacy of intrathecal nivolumab and IL-2 in treating NSCLC-associated LM. These findings warrant further investigation in prospective clinical studies.

关键词： Alzheimer's disease sequencing project (ADSP)   HLA-DQ alleles   Blood and brain sample exomes   AD and the adaptive immune system   Tau  

摘要： Although many studies have investigated the influence of HLA on the risk of Alzheimer's Disease (AD), there have been inconsistent results. Part of this problem has been attributed to limitations of a clinical assessment in the absence of histopathological confirmation or other quantitative assessments. This study employed a subset of the AD Sequencing Project, representing 2663 cases with histopathological confirmation of AD and confirmation of 881 cognitively normal cases. Two HLA allelic subtypes, DQB1*02:01 and DQB1*02:02, were associated with lower Braak staging, a measure of tauopathy in the brain. These HLA subtypes were also associated with a later age of onset. There was a lower occurrence of HLA-DQB1*02:01 and HLA-DQB1*02:02 in AD cases compared to cognitively normal cases. For all of the above results, replicative sets were confirmatory. The above results were also maintained for both HLA-DQB1*02:01 and HLA-DQB1*02:02 when removing the effect of APOE4 or APOE2. Interestingly, the HLA-DQB1*02 allele binds tau better than all other HLA-DQB1 alleles tested, per an in silico assessment, raising the question of whether deletion of tau binding, auto-reactive T-cells in the thymus could reduce the likelihood of the onset of AD?

关键词： COVID-19 complications   Long COVID   Network pharmacology   NRICM101   Respiratory tract disease   Taiwan Chingguan Yihau  

摘要： The emergence of new SARS-CoV-2 variants with a higher contagious capability and faster transmissible speed has imposed an incessant menace on global health and the economy. The SARS-CoV-2 infection might reoccur and last much longer than expected. Thence, there is a high possibility that COVID-19 can cause long-term health problems. This condition needs to be investigated thoroughly, especially the post-COVID-19 complications. Respiratory tract disorders are common and typical complications after recovery. Until now, there has been a lack of data on specialized therapeutic medicine for post-COVID-19 complications. The clinical efficacy of NRICM101 has been demonstrated in hospitalized COVID-19 patients. This herbal medicine may also be a promising therapy for post-COVID-19 complications, thanks to its phytochemical constituents. The potential pharmacological mechanisms of NRICM101 in treating post-COVID-19 respiratory complications were investigated using network pharmacology combined with molecular docking, and the results revealed that NRICM101 may exert a beneficial effect through the three primary pathways: PI3K/AKT, HIF-1, and TNF signaling pathways. Flavonoids (especially quercetin) have a predominant role and synergize with other active compounds to produce therapeutic effectiveness. Most of the main active compounds exist in three chief herbal ingredients, including Liquorice root (Glycyrrhiza glabra), Scutellaria root (Scutellaria baicalensis), and Mulberry leaf (Morus alba). To our knowledge, this is the first study of the NRICM101 effect on post-COVID-19 respiratory complications. Our findings may provide a better understanding of the potential mechanisms of NRICM101 in treating SARS-CoV-2 infection and regulating the immunoinflammatory response to improve post-COVID-19 respiratory complications.

关键词： antibodies   cross-match   HLA   renal   transplantation  

摘要： Single antigen bead assays have revolutionised the identification and definition of HLA-specific antibodies and HLA-specific antibody profiles present in patients awaiting transplantation are routinely characterised to inform organ allocation. For highly sensitised patients with a lower likelihood of finding a compatible donor, de-listing of unacceptable antigens is an option to release organ offers. In this study, 164 serum samples from 106 potential renal transplant recipients were tested using HISTO SPOT HLA AB in parallel with testing by LABScreen Single Antigen (One Lambda) and cross-matching by both CDC and flow cytometry. The results were analysed to assess the ability of HISTO SPOT HLA AB to predict a cross-match result and to understand the relative sensitivity of this test compared with other available assays. 136 samples analysed were positive for donor-specific antibodies (DSAs) using HISTO SPOT HLA AB. Of these, 17 (12.5%) were CDC positive, and 82 (60.3%) were positive by flow cytometry. A total of 28 sera which were negative for DSAs using HISTO SPOT HLA AB were negative by CDC and 25 (89.3%) were also flow cytometry cross-match negative. In this early study, HISTO SPOT HLA AB has a 100% negative predictive value for CDC and 89.3% for flow cytometry cross-matching. HISTO SPOT may therefore prove a useful additional tool to inform de-listing strategies and to facilitate transplantation in highly sensitised patients.

摘要： HLA class I (HLA-I) molecules present intracellular antigenic peptides to CD8+ T cells during immune surveillance. In donors with type 1 diabetes, hyperexpression of HLA-I occurs in islets with residual insulin-producing beta-cells as a hallmark of the disease. HLA-I hyperexpression is frequently detected beyond the islet boundary, forming a "halo." We hypothesized that this halo may reflect the diffusion of soluble forms of HLA-I (sHLA-I) from the islets to the surrounding pancreatic parenchyma. To verify this, we assessed the expression of total, cell surface, and sHLA-I in beta-cell lines and isolated human islets after treatment with interferon-alpha (IFN-alpha) and IFN-gamma. Consistent with the expression patterns of HLA-I in situ, the beta-cell lines and cultured human islets dramatically upregulated total and surface HLA-I when exposed to IFNs. Concomitantly, sHLA-I release was significantly increased. HLA-I released within extracellular vesicles and cleaved forms of HLA-I did not significantly contribute to the sHLA-I pool. Rather, IFNs upregulated mRNA splice variants lacking the transmembrane domain. Our findings suggest that beta-cells respond to IFNs by upregulating cell-associated and soluble forms of HLA-I. Soluble HLA-I may play a role in modulating islet inflammation during the autoimmune *** Highlights Hyperexpression of cell-associated HLA class I (HLA-I) induced by interferons is a hallmark feature of the residual insulin-containing pancreatic islets of people with type 1 diabetes. Soluble forms of HLA-I have also been described and are increased in the blood of individuals with viral infections and autoimmune disease, including type 1 diabetes. We assessed whether beta-cells release soluble HLA-I (sHLA-I) in response to interferons. We confirm that human beta-cells release significant levels of sHLA-I, demonstrate that this increases after interferon exposure, and define the release mechanism. We propose that sHLA-I may affect the act

关键词： HLA-DQB1*03:01:01:75   HLA-genotyping   Illumina   next generation sequencing   novel allele  

摘要： The HLA-DQB1*03:01:01:75 allele differs from HLA-DQB1*03:01:01:03 by a single nucleotide substitution in intron 2.

关键词： IRF3   Transcription factor   IFN   NMR resonance assignment  

摘要： The Interferon Regulatory Factor (IRF) family of transcription factors is well known for its anti-viral activity in vertebrates. The IRF family comprises nine members (IRF1-9) which have the ability to induce the Interferon beta (IFN beta) promotor. The IRF3 and IRF7 are the key family members involved in the production of type I and type III IFN. IRF3 and IRF7 both comprise of a DNA binding domain (DBD) which binds to its cognate interferon responsive element (IRE) on its target gene promoters. Here, we report near complete backbone and partial side-chain resonance assignments of the DBD domain of the IRF3 subunit of the IRF family. The predicted secondary structure using the backbone chemical shifts largely conforms with that obtained from the crystal structure, with the TALOS-N predicted secondary structures showing slightly elongated beta-strands.

关键词： RNF128   Colitis   Colorectal cancer   Inflammatory damage   IL-6-STAT3  

摘要： Introduction: Intestinal immune dysregulation is strongly linked to the occurrence and formation of tumors. RING finger protein 128 (RNF128) has been identified to play distinct immunoregulatory functions in innate and adaptive systems. However, the physiological roles of RNF128 in intestinal inflammatory conditions such as colitis and colorectal cancer (CRC) remain controversial. Objectives: To elucidate the function and mechanism of RNF128 in colitis and CRC. Methods: Animal models of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSSinduced CRC were established in WT and Rnf128-deficient mice and evaluated by histopathology. Coimmunoprecipitation and ubiquitination analyses were employed to investigate the role of RNF128 in IL-6-STAT3 signaling. Results: RNF128 was significantly downregulated in clinical CRC tissues compared with paired peritumoral tissues. Rnf128-deficient mice were hypersusceptible to both colitis induced by DSS and CRC induced by AOM/DSS or APC mutation. Loss of RNF128 promoted the proliferation of CRC cells and STAT3 activation during the early transformative stage of carcinogenesis in vivo and in vitro when stimulated by IL-6. Mechanistically, RNF128 interacted with the IL-6 receptor a subunit (IL-6Ra) and membrane glycoprotein gp130 and mediated their lysosomal degradation in ligase activity-dependent manner. Through a series of point mutations in the IL-6 receptor, we identified that RNF128 promoted K48-linked polyubiquitination of IL-6Ra at K398/K401 and gp130 at K718/K816/K866. Additionally, blocking STAT3 activation effectively eradicated the inflammatory damage of Rnf128-deficient mice dur-ing the transformative stage of carcinogenesis. Conclusion: RNF128 attenuates colitis and colorectal tumorigenesis by inhibiting IL-6-STAT3 signaling, which sheds novel insights into the modulation of IL-6 receptors and the inflammation-to-cancer transition. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of Cairo Univ