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关键词： Colorectal cancer   IL-10   SNP   Genotype   Haplotype   Diplotype   Risk   Survival  

摘要： Background and aim: As the presence of single nucleotide polymorphisms (SNPs) in the interleukin (IL)-10 gene continues to be a major challenge in the development of effective therapies for digestive cancers, this case-control study was conducted to assess the possible influence of genotype, haplotype and diplotype for two SNPs (-1082A/G (rs1800896) and -592A/C (rs1800872)) located in the promoter region of IL-10 gene on the incidence, severity and prognosis of colorectal cancer (CRC) in Tunisians. Methods: IL-10 gene SNPs were analyzed in 130 CRC cases and 165 healthy subjects (HS) using PCR-SSP. Results: For the IL-10 -1082A/G SNP, the comparison of genotype frequencies between cases and HS groups showed that the G allele significantly reduced CRC risk under the recessive model (GG vs. AA + AG: OR [95%CI] = 0.44 [0.21-0.93], p = 0.03). Conversely, a positive association was observed between the codominant model (AG vs. AA + GG) and high susceptibility (OR [95%CI] = 1.65 [1.02-2.63], p = 0.04). After stratification by disease site, the recessive model was also found to reduce susceptibility to colon cancer (OR [95%CI] = 0.18 [0.04-0.72], p = 0 0.01), while the homozygote model (AA vs. GG) was suggested as a risk factor (OR [95%CI] = 5.16 [1.31-23.26], p = 0.02). Furthermore, the codominant model (AG vs. AA + GG) doubled the risk of rectum cancer (OR [95%CI] = 1.98 [1.07-3.70], p = 0.03). For the IL-10 -592A/C SNP, the codominant model (AC vs. AA + CC) has a protective effect against the development of CRC (OR [95%CI] = 0.59 [0.36-0.94], p = 0.03). The IL-10 gene haplotype was not associated with CRC risk. A stratified analysis by disease site demonstrated that the presence of Hap3 (-1082G and -592C alleles) specifically reduced the risk of developing colon cancer (OR [95%CI] = 0.51 [0.32-0.80], p = 0.003). Moreover, homozygous Hap3/Hap3 diplotype significantly reduced susceptibility to CRC (OR [95%CI] = 0.35 [0.14-0.85], p = 0.02). Interestingly, this diplotype has

关键词： Neuro-Behcet's disease   Cerebrospinal fluid   IL-6   Intrathecal production   Blood-brain barrier   Infliximab  

摘要： Highlights•Persistent marked elevation of CSF IL-6 is a characteristic feature of CPNB. •Both intrathecal IL-6 production and BBB dysfunction take place in CPNB. •Infliximab results in rapid decrease in intrathecal IL-6 production in CPNB. •Intrathecal IL-6 production plays a pivotal role in the elevation of CSF IL-6.

关键词： 乳腺癌   单克隆抗体   治疗性抗体   靶向治疗  

摘要： 乳腺癌作为女性最常见的恶性肿瘤之一,仍然是全球范围关注的公共卫生问题.在各种癌症治疗方法中,靶向治疗是减少肿瘤复发、提高患者生存率、增加癌症治疗特异性的常用治疗方法之一.通过靶向特定的标记物,单克隆抗体被认为是最实用和最有前景的方法.在乳腺癌治疗中,单克隆抗体可以发挥多种作用,如靶向癌细胞,帮助定位治疗药物并将其递送到靶标,可直接攻击癌细胞、干预癌细胞的生长和存活等.与其他治疗方法相比,单克隆抗体有多种使用方式,具有一定疗效,因此,其成为治疗乳腺癌的合适候选者.然而,单克隆抗体治疗也会引起各种副作用,如疲劳、颤抖、发烧、头痛、呼吸困难、恶心/呕吐、肌肉疼痛、皮疹和出血等.根据其使用方式,单克隆抗体可分为四种类型:裸单抗、共轭单抗、双特异性和三特异性抗体.本文重点对这几种抗体类药物的研究进展作相应的综述.

关键词： Dapsone   HLA-B*13:01   PCR-SSP   Real-time PCR   Dapsone-induced SCARs  

摘要： Dapsone and co-trimoxazole are potent antibiotics for treating various infections and inflammations. However, several studies reported the strongly association between severe cutaneous adverse drug reactions (SCARs) to both drugs and the HLA-B*13:01 allele. Rapid and reliable screening for the HLA-B*13:01 allele can mitigate the risk of dapsone-induced SCARs. We developed two methods, multiplex sequence-specific primer PCR (PCR-SSP) and real-time PCR (RT-PCR), tailored for different clinical settings. These methods were optimized to minimize false positives among the Thai population. Clinical validation demonstrated excellent reproducibility, with both methods showing 100 % concordance in repeated tests. PCR-SSP achieved a limit of detection as low as 100 pg of genomic DNA, while RT-PCR reached 1 pg. Overall statistical accuracy was 100.00 % (95 % CI: 98.18 %-100.00 %). Screening for drug-related HLA alleles is crucial for reducing mortality from severe cutaneous adverse drug reactions, especially dapsone hypersensitivity syndrome (DHS) and dapsone-induced hypersensitivity reactions (DIHRs). Our screening approach for dapsone can also be extended to co-trimoxazole, representing a significant advancement in personalized medicine and preemptive pharmacogenetic testing for tailored patient care and safety, albeit further validation in diverse ethnic populations is warranted to ensure universal applicability.

关键词： 药物性肠炎   氟尿嘧啶类化疗药物   免疫检查点抑制剂   巨细胞病毒   淋巴细胞  

摘要： 本病例为南京大学医学院附属鼓楼医院收治的1例胃癌术后使用氟尿嘧啶类药物化学治疗和程序性死亡蛋白1抑制剂免疫治疗导致的药物性肠炎合并肠道巨细胞病毒感染患者，就其不同病程时期的临床病理学特点和鉴别诊断要点进行讨论，以加深临床和病理医师对药物性肠炎的认识。

关键词： IL-32 isoform   IL-32 beta   IL-32 secretion mechanism   T cells   exosomes   unconventional secretion pathway   IL-2   cancer  

摘要： IL-32 expression is important for pathogen clearance but detrimental in chronic inflammation, autoimmunity, and cancer. T cells are major IL-32 producers in these diseases and key mediators of pathogen and tumor elimination but also autoimmune destruction. However, their contribution to IL-32 biology during immune responses is hardly understood due to several isoforms with divergent inflammatory properties. Here, we identified IL-32 beta as the predominant isoform in various T cell subsets of healthy individuals and breast cancer patients with the highest levels detected in intratumoral regulatory T cells. We show that IL-32 beta is induced by IL-2 but IL-32 beta release requires T Cell Receptor rather than IL2R stimulation. Using inhibitors of protein secretion pathways and serial (ultra)centrifugation of T cell supernatants, we demonstrate that T cells actively secrete IL-32 beta unconventionally, as a free protein and, to a minor degree, through exosomes. Thus, our data identify activated T cells as major IL-32 beta secretors in health and cancer.

关键词： Aloe-emodin   Inflammatory bowel disease   Intestinal microbiome   IL-4/IL-13 pathway  

摘要： Introduction: Inflammatory bowel disease (IBD) is a global health concern. Aloe-emodin (AE) has diverse pharmacological benefits, including anti-inflammatory effects. However, its role in IBD remains unclear, prompting our investigation of its regulatory effects and mechanisms in an IBD mouse model. Methods: We studied the therapeutic efficacy of AE in alleviating symptoms and modulating cytokine secretion in a murine model of dextran sulfate sodium (DSS)-induced colitis. BALB/c mice were administered DSS to induce colitis and were subsequently treated with varying doses of AE. Changes in body weight, fecal lipocalin-2 (LCN2) levels, colon tissue histology, and serum cytokine concentrations were evaluated to assess the effects of AE treatment. Additionally, 16 S rRNA sequencing was used to analyze alterations in the composition of the gut microbiota following AE intervention. Finally, the database was used to analyze the signaling pathways associated with IBD in AE and to detect the expression levels of interleukin (IL)-4 pathway using real-time quantitative reverse transcription PCR. Exogenous IL-4 was used in rescue experiments to observe its effects on the disease process of IBD under AE regulation. Results: AE treatment resulted in a dose-dependent mitigation of weight loss, reduction in fecal LCN2 levels, and amelioration of histological damage in DSS-induced colitis in mice. The levels of superoxide dismutase and catalase increased, whereas malondialdehyde decreased following AE treatment, indicating a dose-dependent alleviation of colitis symptoms. Furthermore, AE administration attenuated the secretion of pro-inflammatory cytokines, including IL-17, tumor necrosis factor-alpha (TNF-alpha), and chemokine ligand 1, while promoting the expression of antiinflammatory cytokines IL-4 and IL-13. Analysis of the gut microbiota revealed that AE effectively suppressed the overgrowth of colitis-associated bacterial species and restored microbial homeostasis. Finally, w

摘要： Purpose: Cytokine-engineering of chimeric antigen receptor-redirected T cells (CAR T cells) is a promising principle to overcome the limited activity of canonical CAR T cells against solid *** Design: We developed an investigational medicinal product, GD2IL18CART, consisting of CAR T cells directed against ganglioside GD2 with CAR-inducible IL18 to enhance their activation response and cytolytic effector functions in the tumor microenvironment. To allow stratification of patients according to tumor GD2 expression, we established and validated immunofluorescence detection of GD2 on paraffin-embedded tumor ***: Lentiviral all-in-one vector engineering of human T cells with the GD2-specific CAR with and without inducible IL18 resulted in cell products with comparable proportions of CAR-expressing central memory T cells. Production of IL18 strictly depends on GD2 antigen engagement. GD2IL18CART respond to interaction with GD2-positive tumor cells with higher IFN gamma and TNF alpha cytokine release and more effective target cytolysis compared with CAR T cells without inducible IL18. GD2IL18CART further have superior in vivo antitumor activity, with eradication of GD2-positive tumor xenografts. Finally, we established GMP-compliant manufacturing of GD2IL18CART and found it to be feasible and efficient at clinical ***: These results pave the way for clinical investigation of GD2IL18CART in pediatric and adult patients with neuroblastoma and other GD2-positive cancers (EU CT 2022- 501725-21-00). See related commentary by Locatelli and Quintarelli, p. 3361Conclusions: These results pave the way for clinical investigation of GD2IL18CART in pediatric and adult patients with neuroblastoma and other GD2-positive cancers (EU CT 2022- 501725-21-00). See related commentary by Locatelli and Quintarelli, p. 3361

关键词： 猪圆环病毒4型   衣壳蛋白   原核表达   多克隆抗体  

摘要： 以合成的猪圆环病毒4型（PCV4）全基因组为模板，PCR扩增PCV4 Cap和dCap基因序列，并将其克隆至原核表达载体pET-28a中，得到重组质粒pET-28a-PCV4-Cap和pET-28a-PCV4-dCap。经酶切和测序鉴定后，将重组质粒转化至大肠杆菌BL21感受态细胞，经IPTG诱导，成功表达了约28 ku的融合蛋白His-PCV4-dCap，通过镍离子亲和层析法纯化His-PCV4-dCap融合蛋白，皮下多点注射免疫BALB/c小鼠，经3次免疫后获得PCV4 Cap蛋白多克隆抗体。Western-blotting和间接免疫荧光（IFA）结果显示，本研究制备的PCV4 Cap蛋白多克隆抗体与原核以及真核表达的PCV4 Cap蛋白均具有良好的反应性，为建立PCV4检测方法以及研究PCV4 Cap蛋白功能，揭示PCV4感染及致病机制奠定了基础。

关键词： Colorectal cancer   Nilotinib   Anti-PDL1 therapy   MHC-I   CD8(+) T cell  

摘要： Background Although immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, only a minority of colorectal cancer (CRC) patients respond to them. Enhancing tumor immunogenicity by increasing major histocompatibility complex I (MHC-I) surface expression is a promising strategy to boost the antitumor efficacy of ICIs. Methods Dual luciferase reporter assays were performed to find drug candidates that can increase MHC-I expression. The effect of nilotinib on MHC-I expression was verified by dual luciferase reporter assays, qRT-PCR, flow cytometry and western blotting. The biological functions of nilotinib were evaluated through a series of in vitro and in vivo experiments. Using RNA-seq analysis, immunofluorescence assays, western blotting, flow cytometry, rescue experiments and microarray chip assays, the underlying molecular mechanisms were investigated. Results Nilotinib induces MHC-I expression in CRC cells, enhances CD8(+) T-cell cytotoxicity and subsequently enhances the antitumor effects of anti-PDL1 in both microsatellite instability and microsatellite stable models. Mechanistically, nilotinib promotes MHC-I mRNA expression via the cGAS-STING-NF-kappa B pathway and reduces MHC-I degradation by suppressing PCSK9 expression in CRC cells. PCSK9 may serve as a potential therapeutic target for CRC, with nilotinib potentially targeting PCSK9 to exert anti-CRC effects. Conclusion This study reveals a previously unknown role of nilotinib in antitumor immunity by inducing MHC-I expression in CRC cells. Our findings suggest that combining nilotinib with anti-PDL1 therapy may be an effective strategy for the treatment of CRC.