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关键词： 甲状腺癌   手术   老年患者   T淋巴细胞   促甲状腺激素  

摘要： 目的探讨促甲状腺激素(TSH)抑制疗法在老年甲状腺癌手术患者中的应用效果。方法根据治疗方式的不同将106例老年甲状腺癌手术患者分为对照组(54例)和观察组(52例),对照组患者采用常规治疗,观察组患者采用TSH抑制疗法。比较两组患者的甲状腺功能[游离三碘甲腺原氨酸(FT3)、游离甲状腺素(FT4)、TSH]、T淋巴细胞(CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))水平及术后2年的复发情况。结果治疗6个月后,两组患者FT3、FT4、CD4^(+)水平及CD4^(+)/CD8^(+)均高于本组治疗前,TSH、CD8^(+)水平均低于本组治疗前,观察组患者FT3、FT4、CD4^(+)水平及CD4^(+)/CD8^(+)均高于对照组,TSH、CD8^(+)水平均低于对照组,差异均有统计学意义(P﹤0.05)。观察组患者术后2年复发率为7.69%,低于对照组患者的22.22%,差异有统计学意义(P﹤0.05)。结论TSH抑制疗法应用于老年甲状腺癌手术患者中,可改善甲状腺功能、调节免疫功能、降低术后复发风险。

关键词： Paralichthys olivaceus   Interleukin-12   Interleukin-12 receptor subunit beta-2   Th1 cells differentiation   Adjuvant  

摘要： Interleukin-12 (IL-12) regulates the differentiation of CD4+ T lymphocytes into Th1 cells by binding to its receptor, thereby promoting cellular immunity. This study characterized IL-12 and its receptor (32 (IL-12R(32) in flounder (Paralichthys olivaceus) and investigated their interaction, effects on T cell proliferation and differentiation, and the adjuvant effects of IL-12. The recombinant IL-12 was successfully expressed, and the IL-12R(32 antibody was confirmed to specifically recognize IL-12R(32. IL-12 bound to IL-12R(32 at the cellular level. IL-12 stimulation increased leukocyte proliferation and the proportion of CD4+/IL-12R(32+ cells. Moreover, blocking IL-12R(32 with antibody reduced Th1 markers (STAT4, T-bet, IFN-y) and increased Th2 markers (JAK3, STAT6, GATA3). Immunization with rOmpV+IL-12 significantly upregulated CD4+/IFN-y+ cells on day seven, peaked the sIgM+ B lymphocyte response in the fourth week, and enhanced survival after Edwardsiella tarda challenge. In conclusion, IL-12 signaling effectively facilitates the differentiation of Th1 cells and negatively impacts the function of Th2 cells in flounder. This study provides new insights into the immune regulation of CD4+ T cells in teleosts and lays the foundation for understanding the cellular immune mechanisms of vaccines in aquaculture.

关键词： Brazil   HLA   HLA-C   new allele   next-generation sequencing   Rio de Janeiro  

摘要： The novel HLA-C*15:02:01:65Q allele was first described in a potential bone marrow donor from Brazil.

关键词： AI   artificial intelligence   ALK   TGF-   β   receptor kinase   AKT   protein kinase b   AMPK   5’ monophosphate-activated protein kinase   Ang-II   angiotensin II   ANGPT   angiopoietin   BCL2   B-cell lymphoma 2   BP   blood pressure   CAF   cancer-associated fibroblast   CANTOS   Canakinumab Anti-Inflammatory Thrombosis Outcome Study   CAR-T   chimeric antigen receptor T cell   CCL   C-C Motif Chemokine ligand   CDK   cyclin-dependent kinases   CHIP   clonal hematopoiesis of indeterminate potential   CREB   cAMP response element   CRP   C reactive protein   CVD   cardiovascular disease   CYP   cytochrome P450   D2-HG   D-2-hydroxyglutarate   DAMPs   damage-associated molecular patterns   DI   drug interaction   DLL   δ   -like ligand   DNMT3A   DNA methyltransferase 3A   EC   endothelial cell   ECM   extracellular matrix   EGF   epithelial growth factor   ELK-1   ETS-like 1 protein   ER   estrogen receptor   ERK1/2   extracellular signal-regulated kinase ½   ETS   erythroblast transformation specific   US FDA   United States Food and Drug Administration   GPCR   chemokine G protein-coupled receptor   GWAS   genome-wide association studies   HER2   human epidermal growth factor 2   HGF   hepatocyte growth factor   HF   heart failure   HIF-1   hypoxia-inducible factor 1   HSPC   hematopoietic stem progenitor cells   HUVEC   human umbilical cord endothelial cell   ICI   immune checkpoint inhibitor   IDH   isocitrate dehydrogenase   IFN-   γ   interferon   γ   IL   interleukin   KLF   rüppel-like factor   LPS   lipopolysaccharides   LV   left ventricular   MAPK   mitogen-activated protein kinase   MAX   Myc-associated factor X   MHC   major histocompatibility complex   MDSC   myeloid-derived suppressor cell   MEK   MAPK kinase   MEKI   MAPK kinase inhibitor   MI   myocardial infarction   MMPs   matrix metalloproteinases   MYC   Myc proto-oncogene protein   NF-κB   nuclear factor kappa-light-chain-enhancer of activated B cells   NK   natural killer   NLRP3   NOD-like receptor protein 3   NOTCH   Neurogenic locus notch homolog protein   PAMP   pathogen-associated molecular patterns   PD   pharmacodynamics   PDGF   platelet-derived growth factor   PD-L1   programmed death-ligand 1   PFKFB3   6-phosphofructokinase/2,6-bisphosphatase 3   PI3K   phosphatidylinositol 3-kinase   PK   ph  

摘要： Cancer and cardiovascular disease (CVD) are the 2 biggest killers worldwide. Specific treatments have been developed for the 2 diseases. However, mutual therapeutic targets should be considered because of the overlap of cellular and molecular mechanisms. Cancer research has grown at a fast pace, leading to an increasing number of new mechanistic treatments. Some of these drugs could prove useful for treating CVD, which realizes the concept of cancer drug repurposing. This review provides a comprehensive outline of the shared hallmarks of cancer and CVD, primarily ischemic heart disease and heart failure. We focus on chronic inflammation, altered immune response, stromal and vascular cell activation, and underlying signaling pathways causing pathological tissue remodeling. There is an obvious scope for targeting those shared mechanisms, thereby achieving reciprocal preventive and therapeutic benefits. Major attention is devoted to illustrating the logic, advantages, challenges, and viable examples of drug repurposing and discussing the potential influence of sex, gender, age, and ethnicity in realizing this approach. Artificial intelligence will help to refine the personalized application of drug repurposing for patients with CVD. Significance Statement: Cancer and cardiovascular disease (CVD), the 2 biggest killers worldwide, share several underlying cellular and molecular mechanisms. So far, specific therapies have been developed to tackle the 2 diseases. However, the development of new cardiovascular drugs has been slow compared with cancer drugs. Understanding the intersection between pathological mechanisms of the 2 diseases provides the basis for repurposing cancer therapeutics for CVD treatment. This approach could allow the rapid development of new drugs for patients with CVDs. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the CC BY-NC license

关键词： Astragaloside IV   Retinal pigment epithelial cell   Cell senescence   FTO   m6A methylation   IL-1 beta  

摘要： Background: Resistance to senescence in retinal pigment epithelial (RPE) cells can delay the progression of agerelated macular degeneration (AMD). However, the mechanisms underlying RPE cell senescence remain inadequately understood, and effective therapeutic strategies are lacking. While astragaloside IV (Ast) has demonstrated anti-aging properties, its specific effects on RPE cell senescence and potential mechanisms are not yet fully clarified. Purpose: This study aimed to explore the impacts of Ast on RPE cell senescence and to uncover the molecular mechanisms involved. Methods: The therapeutic efficacy of Ast was assessed using sodium iodate (NaIO3)-induced adult retinal pigment epithelial cell line 19 (ARPE-19) cell models and an AMD mouse model. To investigate the mechanisms by which Ast mitigated RPE cell senescence, RNA sequencing (RNA-seq), drug affinity responsive target stability-mass spectrometry (DARTS-MS), cellular thermal shift assay (CETSA), reverse transcription quantitative PCR (RTqPCR), as well as western blotting were conducted. Results: Ast significantly inhibited NaIO3-treated ARPE-19 cell senescence and protected against NaIO3-induced AMD in mice. RNA-seq analysis revealed that Ast significantly attenuated inflammation-related signaling pathways and reduced the mRNA levels of interleukin-1 beta (IL-1f)). Specifically, Ast decreased the stability of IL-1f) mRNA while enhancing its N6-methyladenosine (m6A) methylation. Furthermore, Ast directly interacted with fat mass and obesity-associated protein (FTO). Knockdown or pharmacological inhibition of FTO mitigated the senescence and IL-1f) expression in NaIO3-treated ARPE-19 cells. FTO was essential for Ast to inhibit cellular senescence and IL-1f) expression. Additionally, inhibition or knockdown of FTO conferred also provided resistance to AMD in the murine model. Conclusion: Our results indicated that Ast significantly attenuated RPE cell senescence and showed anti-AMD properties. FTO was demon

关键词： Systemic lupus erythematosus   bone marrow mesenchymal stem cells   autophagy   senescence   IL-6   lupus mice  

摘要： BackgroundSystemic lupus erythematosus is a common autoimmune disease. Studies have suggested that defective stem cells could be involved in the pathogenesis of systemic lupus erythematosus, which leads to changes in the function of immune cells. By observing the cell morphology, autophagy, and senescence of bone marrow mesenchymal stem cells (BMSCs) from lupus mice and normal controls, this study investigated the role of IL-6 in autophagy and senescence of BMSCs and explored relevant *** MRL/lpr and C57 mice with similar weights and sizes at 20-22 weeks old were selected. BMSCs were isolated using the whole bone marrow adherent method. Quantitative real-time polymerase chain reaction, beta-galactosidase staining, western blotting, and ELISA were used to detect autophagy and *** with BMSCs from normal mice, BMSCs from lupus mice exhibited low autophagy and premature senescence with a senescence-associated secretory phenotype. The addition of exogenous IL-6 increased the protein levels of p-STAT3 and Bcl-2, and in the IL-6-treated group, the premature senescence of cells increased and autophagy *** biological functions of BMSCs from MRL/lpr lupus mice were impaired. IL-6 prevents autophagy and subsequently promotes the senescence of BMSCs by activating the IL-6/STAT3 pathway.

关键词： HLA-C*08:01:01   HLA-C*08:301   next-generation sequencing  

摘要： The novel HLA-C*08:301 allele has a C -> A substitution in exon 4.

关键词： Tuberculosis   TST   IGRA   TB Resisters   Classical Monocytes   IL-1B  

摘要： Mycobacterium tuberculosis (***) infection can lead to various outcomes, including active tuberculosis or latent tuberculosis infection (LTBI). Household contacts of TB cases have a high risk of acquiring LTBI. However, some contacts exposed to *** remain negative for tuberculin skin test (TST) and interferon-gamma release assay (IGRA) tests and are called 'TB resisters'. Characterization of immune responses in 'TB resisters' may help to understand correlates of protection against ***. Based on the TST and IGRA tests, household contacts were divided into 'LTBI' and 'TB Resisters'. Peripheral blood mononuclear cells (PBMCs) of the study participants were isolated and processed to characterize the monocyte subsets based on CD14 and CD16 expression in flow cytometry. Monocyte intracellular cytokine expression (IL-10, IL-6, TNF-alpha and IL-1B) was assessed after Lipopolysaccharide (LPS) stimulation. LTBI and active TB patients showed a higher frequency of intermediate and non-classical monocyte subsets depicting the infectious stage. Higher frequency of classical monocyte subsets was associated with 'TB resisters'. Marked expression of IL-1B and a higher monocyte to lymphocytes (M/ L) ratio was seen in PTB, LTBI and TB resister groups compared to healthy controls indicating active disease or exposure to ***. Classical Monocytes (CM) were further found to be associated with higher expression of IL-1B and IL-10 in the 'TB resister group', which might help in the clearance of infection at an early stage. LTBI and PTB showed significantly higher TNF-alpha producing monocytes than healthy controls and 'TB Resisters'. IL6producing monocytes were significantly higher in LTBI compared to other study groups. These findings could further be explored with follow-up in cohort of 'TB resisters'. Also, the role of IL-1B and IL10 secreting classical monocytes in early clearance of infection could be explored with in vitro mechanistic studies.

关键词： dapagliflozin   IL-17   NLRP3   secukinumab   sunitinib  

摘要： Sunitinib (SUN) is a chemotherapeutic agent showing renal toxicity that limits its clinical applications. The present research aimed to clarify the potential ameliorative effects of secukinumab (SEC) and dapagliflozin (DAPA) against SUN-induced renal toxicity and the underpinning molecular mechanisms. For this purpose, adult Wistar albino rats were received SUN (25 mg/kg 3 times/week, po) and co-treated with SEC (3 mg/kg/every 2 weeks, subcutaneously) or DAPA (10 mg/kg/day, po) for 4 weeks and compared with age-matched control group (CON). Markers of kidney functions were assessed in serum samples. Kidneys were harvested for biochemical and histological examination. Compared to CON group, SUN-treated rats displayed signs of kidney dysfunction along with renal histological changes that were ameliorated by SEC or DAPA. Both drugs significantly lowered the renal levels of IL-17, but SEC exerted more inhibitory effect than DAPA. Additionally, SUN-subjected rats showed significant increases in the renal expression of NLRP3 inflammasome and the other inflammatory mediators including IL-1 beta, END-1, and MCP-1. This was associated with marked decline of the renal levels of beclin-1. Co-treatment with SEC or DAPA significantly suppressed NLRP3-induced inflammation while enhanced beclin-1-mediated autophagy. The modulatory effect of DAPA on NLRP3 and beclin-1 was superior to that of SEC. Moreover, both drugs significantly and similarly attenuated the enhanced cleaved caspase-3 expression and interstitial fibrosis in renal tissue of SUN-subjected rats. Collectively, these findings may repurpose SEC and DAPA as candidate therapies to alleviate the renal toxicity of SUN and to rescue the renal functionality in SUN-treated cancer cases.

关键词： allogeneic   haplobank   histocompatibility   HLA   iPSC   registry  

摘要： Background: Several countries have either developed or are developing national induced pluripotent stem cell (iPSC) banks of cell lines derived from donors with HLA homozygous genotypes (two identical haplotypes) prevalent in their local populations to provide immune matched tissues and cells to support regenerative medicine therapies. This 'haplobank' approach relies on knowledge of the HLA genotypes of the population to identify the most beneficial haplotypes for patient coverage, and ultimately identify donors or cord blood units carrying two copies of the target haplotype. Aims: A potentially more efficient alternative to a national bank approach is to assess the haplotypes required to provide global patient coverage and to produce a single, global haplobank. Toward that end, we have developed an algorithm to prioritize HLA haplotypes that optimize coverage across the global population. Methods: We analyzed data from eighteen countries participating in the Global Alliance for iPS Therapy (GAiT). A representative pool of HLA genotypes, reflecting the HLA of patients, was derived by sampling from each country's WMDA hematopoietic stem cell donor registry, or surrogate population. An algorithm was created based on HLA-A, -B and -DRB1 haplotype homozygous types with population HLA matching coverage defined by the absence of Host versus Graft (HvG) mismatches at these loci. HLA matching coverage was determined by iteratively selecting HLA haplotypes that provide the largest coverage against patient HLA genotypes sampled from the same population, excluding genotypes compatible with previous iterations. Results: The top 10 haplotypes for each of the 18 countries were identified with patient coverage ranging from 19.5% in Brazil to 63.8% in Japan, with a mean coverage of 33.3%. In a 'global' model, utilizing the 180 most frequent haplotypes across all 18 populations (equivalent to 10 lines per country), the patient coverage ranged from 54.6% in India to 81.7% in Sweden,