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关键词： 压应力   骨折愈合   细胞因子   骨形态发生蛋白   成纤维细胞生长因子   血小板衍生生长因子   血管内皮生长因子   白细胞介素   肿瘤坏死因子α  

摘要： 背景:骨折愈合是一个非常复杂的生理过程,受多种因素的影响。近年来运用生物力学因素在骨折愈合中展开研究是骨科领域的重点,骨折断端周围的机械应力环境对骨折愈合具有重要调控作用。其中,压应力学微环境对骨折断端细胞因子的影响机制研究是骨相关研究工作者们关注的的热点。目的:总结近年来压应力在骨折愈合中对细胞因子作用机制的研究现状和最新进展。方法:以“压应力,骨折愈合,细胞因子,骨形态发生蛋白,成纤维细胞生长因子,血小板衍生生长因子,血管内皮生长因子,白细胞介素,肿瘤坏死因子α”为中文关键词检索CNKI、万方数据库,以“Compressive stress,Fracture healing,Cytokine,Bone morphogeneticprotein,Fibroblast growth factor,Platelet-derived growth factor,Vascular endothelial growth factor,Interleukin,Tumour necrosisfactor-alpha”为英文关键词检索PubMed、Web of Science数据库,共检索到506篇文献,经筛选后对符合标准的94篇文献进行归纳分析。结果与结论:目前的研究发现,压应力在骨折愈合过程中对不同细胞因子产生不同影响,主要可通过影响细胞信号传导、基因表达调控以及细胞行为的调节等方式实现。其中,压应力可与骨形态发生蛋白、成纤维细胞生长因子、血小板衍生生长因子、血管内皮生长因子、白细胞介素、肿瘤坏死因子α等细胞因子产生作用联系,这一过程涉及到细胞的增殖分化与迁移、炎症反应应答、断端环境营养条件变化等,都是影响骨折愈合的关键因素。全文总结了细胞因子作用机制的复杂性,压应力的调控作用机制需进一步展开深入研究,并对研究中存在的问题和局限性进行思考和未来展望。

关键词： B细胞血液恶性肿瘤   嵌合抗原受体T细胞   免疫疗法   治疗靶点   长期疗效   毒副作用   复发  

摘要： 背景:嵌合抗原受体T(chimeric antigen receptor T,CAR-T)细胞疗法是治疗B细胞血液恶性肿瘤的前沿方法,其能高效且特异性地识别并杀伤肿瘤细胞,不受主要组织相容性复合体限制。目的:旨在梳理CAR-T细胞的结构、发展历程及上市产品进展,总结CAR-T细胞治疗B细胞血液恶性肿瘤的长期疗效,并探讨治疗后的毒副作用、复发性及解决策略,同时综述潜在靶点治疗B细胞血液恶性肿瘤的进展。方法:以“嵌合抗原受体T细胞,B细胞恶性肿瘤,毒副作用,免疫疗法”为中文检索词,以“CAR-T、B cell hematological malignancies,Toxic side effects,Immunotherapy”为英文检索词在中国知网、万方数据库、PubMed数据库检索CAR-T细胞相关靶点治疗B细胞恶性肿瘤的文献。结果与结论:①美国食品药品监督管理局和中国国家药品监督管理局共批准11款CAR-T细胞产品,主要针对B细胞血液恶性肿瘤的CD19和B细胞成熟抗原靶点;②长期随访数据显示,CAR-T细胞治疗为B细胞血液恶性肿瘤患者带来高缓解率和持久反应,但存在抗原丢失或下调导致的复发问题;③CAR-T细胞治疗存在高毒副作用、高复发率和耐药性等问题,限制了其广泛应用;④未来研究的方向包括开发新的靶点、联合治疗等策略,以提高CAR-T细胞的持久性和抗肿瘤活性。

关键词： 急性淋巴细胞白血病   异基因移植   费城染色体   BCR/ABL基因   酪氨酸激酶抑制剂   微小残留病   早期干预   复发  

摘要： 背景:BCR/ABL基因是Ph染色体阳性急性淋巴细胞白血病的特异性基因,其表达水平已经成为异基因造血干细胞移植前后微小残留病监测的敏感指标。然而,移植前BCR/ABL基因表达水平是否影响移植疗效,移植后如何指导酪氨酸激酶抑制剂进行复发的早期干预尚无定论。目的:探讨Ph染色体阳性急性淋巴细胞白血病患者行亲缘间、异基因造血干细胞移植前后BCR/ABL基因表达与复发的关系。方法:选择2015年1月至2022年12月期间华北理工大学附属医院收治的24例达到血液学完全缓解后行亲缘间异基因造血干细胞移植的Ph染色体阳性急性淋巴细胞白血病患者,应用实时荧光定量聚合酶链反应动态监测治疗期间BCR/ABL基因表达水平,以此代表微小残留病。依据BCR/ABL基因表达,移植前给予酪氨酸激酶抑制剂联合化疗,选择异基因造血干细胞移植时机;移植后评估疾病状态,指导酪氨酸激酶抑制剂的应用,制定早期干预复发的方案。结果与结论:随访至2023年12月,中位随访时间为49(12-82)个月,8例血液学复发,复发的中位时间为14(8-39)个月,累积复发率为33%(8/24)。单因素分析显示,异基因造血干细胞移植后血液学复发与性别、年龄、髓外并发症、诊断至移植时间、HLA配型、急性移植物抗宿主病、慢性移植物抗宿主病无明显相关性(P>0.05);与移植前缓解疗程及微小残留病水平有明显相关性,移植前第2次血液学完全缓解、微小残留病阳性患者有更高的血液学复发率(P<0.05)。预期移植后3年累积复发率、无病生存率、总生存率分别为27%,63%,74%;5年累积复发率、无病生存率、总生存率分别为38%,57%,74%。结果表明,异基因造血干细胞移植前BCR/ABL基因阳性Ph染色体阳性急性淋巴细胞白血病患者有更高的复发率;移植后BCR/ABL基因表达可指导酪氨酸激酶抑制剂应用,做为早期干预复发的依据。

关键词： Psoriasis   biologic therapy   TNF inhibitors   interleukin inhibitors   IL-23  

摘要： IntroductionPsoriasis (PsO) is a common chronic, inflammatory, immune-mediated disease. In 2023, a 4.4% prevalence of PsO was reported in Portugal. Currently, Tumor Necrosis Factor inhibitors (TNFi) are the recommended first-line (1 L) biologic agents in Portugal given their lower cost. However, TNFi may not be suitable for several patients. In these patients, interleukin inhibitors (ILi) should be considered as they provide more effective outcomes and a better safety *** interviews with PsO experts were conducted to identify PsO biologic treatment needs, resulting in an online survey to explore clinical cases focused on subpopulations of PsO. A delphi study evaluated consensus on clinical criteria to initiate non-TNFi therapy in seven predefined subpopulations of *** study highlights the benefit of starting non-TNFi therapy in all PsO predefined subpopulations. Patients with infection risk, mild heart failure and associated comorbidities, autoimmune diseases and family history of demyelinating disease consensually benefit from starting non-TNFi therapy in 1 L. Several risks associated with latent tuberculosis, advanced age and oncological disease were also *** the existence of various risks associated with TNFi usage, this clinical perspective overview of Portuguese experts in PsO treatment emphasizes the need for a tailored therapeutic framework in the management of PsO.

关键词： Cancer   clinical trials   cytokine   High-dose IL-2 (HD IL-2)   IL-2 receptor (IL-2R)   IL-2R agonist   immunotherapy   Interleukin-2 (IL-2)  

摘要： Immune checkpoint blockade (ICB) has significantly improved the survival for many patients with advanced malignancy. However, fewer than 50% of patients benefit from ICB, highlighting the need for more effective immunotherapy options. High-dose interleukin-2 (HD IL-2) immunotherapy, which is approved for patients with metastatic melanoma and renal cell carcinoma, stimulates CD8+ T cells and NK cells and can generate durable responses in a subset of patients. Moreover, HD IL-2 may have potential efficacy in patients whose disease has progressed following ICB and plays a vital role in expanding tumor-infiltrating lymphocyte (TIL) in TIL therapy. Despite its potential, the use of HD IL-2 is limited by severe toxicities such as hypotension and vascular leak syndrome. Additionally, only a few patients achieve a good outcome after HD IL-2 therapy. To address these challenges, numerous next-generation IL-2 receptor (IL-2 R) agonists have been developed to exhibit treatment effects while minimizing adverse events. This review will explore IL-2 biology, the clinical application of HD IL-2 therapy, and the development of novel IL-2 R agonists for cancer immunotherapy.

关键词： Fusobacterium   novel species   pangenome   comparative genomics   intestinal microbiota   colorectal cancer  

摘要： Cancerous tissue is a largely unexplored microbial niche that provides a unique environment for the colonization and growth of specific bacterial communities, and with it, the opportunity to identify novel bacterial species. Here, we report distinct features of a novel Fusobacterium species, F. sphaericum sp. nov. (Fs), isolated from primary colon adenocarcinoma tissue. We acquire the complete closed genome and associated methylome of this organism and phylogenetically confirm its classification into the Fusobacterium genus, with F. perfoetens as its closest neighbor. Fs is phenotypically and genetically distinct, with morphological analysis revealing its coccoid shape, that while similar to F. perfoetens is rare for most Fusobacterium members. Fs displays a metabolic profile and antibiotic resistance repertoire consistent with other Fusobacterium species. In vitro, Fs has adherent and immunomodulatory capabilities, as it intimately associates with human colon cancer epithelial cells and promotes IL-8 secretion. An analysis of the prevalence and abundance of Fs in > 20,000 human metagenomic samples shows that it is a rarely detected member within human stool with variable relative abundance, found in both healthy controls and patients with colorectal cancer (CRC). Our study sheds light on a novel bacterial species isolated directly from the human CRC tumor niche and given its in vitro interaction with cancer epithelial cells suggests that its role in human health and disease warrants further investigation.

关键词： Myocardial ischemia/reperfusion injury   caspase-1   IL-1 beta   pyroptosis   mitochondrial homeostasis   cardiomyocyte injury  

摘要： BackgroundPyroptosis is a novel kind of programmed cell death and Caspase-1 plays key roles in driving pyroptosis. The current study aims to elucidate the molecular mechanism affecting cardiomyocyte pyroptosis in myocardial ischemia/reperfusion (I/R) injury, both in vivo and in *** murine model of myocardial I/R injury was established and then treated with lentivirus-mediated shRNA targeting Caspase-1 to evaluate the effect of Caspase-1 on myocardial I/R injury. Further, Caspase-1 was silenced in the cardiomyocytes following hypoxia-reoxygenation (H/R) to detect the function of Caspase-1 in mitochondrial homeostasis and cardiomyocyte *** of Caspase-1 inhibited the secretion of interleukin-1 beta (IL-1 beta), improved cardiac dysfunction and decreased pyroptosis in vivo. The cardio-protective effect was verified in the H/R-induced cardiomyocyte model. Recombinant IL-1 beta protein reversed the inhibitory effect of Caspase-1 knockdown on ***, activating the Caspase-1/IL-1 beta axis by myocardial I/R injury causes mitochondrial homeostasis imbalance, pyroptosis, and the consequent cardiomyocyte injury.

关键词： Escherichia coli   lymphostatin   Chlamydia   inhibition   lymphocyte   IFN gamma  

摘要： Pathogens frequently produce proteins to evade or inhibit host immune responses. One such protein is lymphostatin from attaching and effacing Escherichia coli (also known as lymphocyte inhibitory factor A;LifA), which influences intestinal colonization and inhibits mitogen- and antigen-activated proliferation of T lymphocytes and pro-inflammatory cytokine synthesis. Here, we report the cloning, purification and characterization of a LifA homologue from Chlamydia pecorum. The predicted 382 KDa protein (CPE2_0552) exhibited 36% identity and 55% similarity over 3171 amino acids to lymphostatin from enteropathogenic E. coli strain E2348/69. CPE2_0552 shares glycosyltransferase and cysteine protease motifs required for lymphostatin activity, including similarity in the tertiary structure of these domains predicted by AlphaFold 3. Purified CPE2_0552 did not share the L-shaped globular structure of lymphostatin when analyzed by transmission electron microscopy. CPE2_0552 inhibited concanavalin A-stimulated proliferation of bovine T cells in a concentration-dependent manner, with an inhibitory dose 50 (ID50) of 812 pg/mL. This was 38-fold higher than the ID50 of E. coli E2348/69 lymphostatin tested in parallel on T cells from the same donors (21 pg/mL), but was similar to another LifA homologue from E. coli O157:H7 (ToxB). Moreover, CPE2_0552 inhibited the secretion of interferon gamma (IFN gamma), a key cytokine that influences the outcome of Chlamydia infections. At the concentrations at which CPE2_0552 inhibited T lymphocyte proliferation and IFN gamma secretion, negligible cytotoxicity was observed after 72 h of stimulation. Our study indicates that E. coli lymphostatin belongs to a wider family of lymphocyte-inhibitory molecules that exist in distantly related bacterial pathogens.

关键词： cGAS-STING pathway   porcine   apoptosis   interferon   autophagy   caspase  

摘要： The innate immune cGAS-STING signalling pathway recognizes double-stranded DNA and induces the interferon (IFN) response, autophagy and apoptosis, exerting a broad antiviral effect. However, the mechanisms and interrelationship between STING induced downstream IFN, autophagy, and apoptosis in livestock have not been fully elucidated. Our previous study defined porcine STING (pSTING) induced IFN, autophagy and apoptosis, and showed that IFN does not affect autophagy and apoptosis, whereas autophagy inhibits both IFN and apoptosis, likely by promoting pSTING degradation. In this study, we further explored the underlying mechanism of pSTING induced apoptosis and the regulation of IFN and autophagy by apoptosis. First, pSTING induces endoplasmic reticulum (ER) stress and mitochondrial damage to activate caspases 9, 3, and 7, which drive intrinsic apoptosis. Second, pSTING triggered apoptosis inhibits the IFN response by activating caspase 7, which cleaves pIRF3 at the species specific D197/D198 site. Third, pSTING activated apoptotic caspases 9, 3, and 7 reduce the expression of ATG proteins, and cleave the ATG5-ATG12L1 complex, effectively inhibiting autophagy. Fourth, knockout of pSTING activated apoptosis heightens the IFN response and autophagy, while suppressing the replication of Herpes Simplex Virus type 1 (HSV-1), Vesicular Stomatitis Virus (VSV) and Pseudorabies Virus (PRV). This study sheds light on the molecular mechanisms of innate immunity in pigs.