背景：非结核分枝杆菌（NTM）与慢性且具有挑战性的感染相关，尤其是肺部疾病（非结核分枝杆菌肺病，NTM-PD）。虽然临床指南为最常见的致病菌种提供了治疗建议，但在处理治疗失败方面提供的指导有限。本研究旨在制定一个基于共识的决策框架，以解决NTM-PD的治疗失败问题。 方法：一个由16名国际专家组成的小组采用电子德尔菲法来解决NTM-PD管理方面的差距。初始陈述源自一份开放式问卷，并得到先前系统评价的支持。进行了多轮专家评估，直至就治疗失败的定义、决策标准、治疗策略和支持性护理措施达成共识。 结果：共识将治疗失败定义为在进行6个月适当的抗分枝杆菌治疗后仍未实现培养转阴，而临床和影像学恶化被视为额外但非强制性的标准。治疗强化或降级决策基于患者偏好、临床状况、合并症、疾病严重程度、抗生素耐受性、耐药模式和既往治疗史。治疗强化突出了个性化多药抗生素方案的必要性。降级策略侧重于提供最佳的、以患者为中心的支持性护理，同时通过选择简化的抗生素方案、用于症状控制的间歇性抗生素疗程或停止抗菌治疗来尽量减少药物不良反应。 结论：本研究提供了一种结构化方法来管理NTM-PD的治疗失败问题，涉及患者选择、治疗强化、降级和支持性护理，同时倡导个性化策略。未来的研究应集中于验证治疗反应的预测因素、优化治疗方案以及研究宿主导向疗法以改善患者预后。
鼠尾草精油生产过程会产生一种经水蒸馏后剩余的植物生物质残渣，以及数量不等的富含高附加值和生物活性水溶性化合物的废水。本研究的目的是使用经大肠杆菌脂多糖（LPS）刺激的小鼠巨噬细胞Raw 264.7和暴露于大肠杆菌的人肠上皮Caco-2细胞，研究鼠尾草水蒸馏废水的体外抗炎作用。通过高效液相色谱-质谱分析鉴定了废水中的多酚类化合物，证实了有机酸（特别是羟基肉桂酸）、黄酮和黄酮醇的存在。这种植物复合物通过减少核因子κB的核转位及其转录活性（白细胞介素[IL]-6、IL-8和肿瘤坏死因子-α信使核糖核酸水平），保护Raw 264.7细胞免受大肠杆菌LPS诱导的炎症。此外，该废水降低了受大肠杆菌攻击的Caco-2细胞中环氧合酶-2蛋白的表达。有趣的是，暴露于大肠杆菌会导致Caco-2细胞的跨上皮电阻值显著降低，这反映了屏障完整性受损，而鼠尾草废水可使其恢复，且这种作用与紧密连接蛋白-1和闭合蛋白的恢复有关，这对维持肠道屏障功能至关重要。目前的数据证实了鼠尾草水蒸馏废水对大肠杆菌诱导的炎症具有保护作用，表明其在预防和/或治疗肠道炎症方面具有潜在应用价值。
衰老细胞（SC）的命运与衰老、多种病症和疾病以及身体机能障碍相关。衰老细胞溶解剂是一类能选择性清除30%-70%衰老细胞的药物，其作用方式是短暂地使衰老细胞抗凋亡途径（SCAPs）失活，这些途径可保护那些具有促凋亡和促炎特性的衰老细胞免受其自身衰老相关分泌表型（SASP）的影响。与此相符的是，一种JAK/STAT抑制剂鲁索替尼，它可减弱衰老的人类前脂肪细胞的促炎SASP，却导致这些细胞变得“抗衰老细胞溶解”。给肥胖小鼠施用衰老细胞溶解剂可选择性地减少具有促炎特性的衰老细胞亚群的数量。在细胞培养中，30%-70%对衰老细胞溶解剂有抗性的人类衰老前脂肪细胞或人脐静脉内皮细胞（HUVECs）（分别对达沙替尼或槲皮素有抗性），其p16、p21、衰老相关β-半乳糖苷酶（SAβgal）、γH2AX水平升高，且增殖停滞，这与整个衰老细胞群体（包括对衰老细胞溶解剂敏感和有抗性的衰老细胞）相似。然而，对衰老细胞溶解剂有抗性的衰老细胞的SASP产生的促炎/凋亡因子较少，在非衰老细胞中诱导的炎症较少，且在生长/纤维化因子方面相当或更丰富。对衰老细胞溶解剂有抗性的衰老细胞释放的线粒体DNA（mtDNA）较少，且抗炎免疫逃逸信号糖蛋白非黑色素瘤-B（GPNMB）的表达更高。将对衰老细胞溶解剂有抗性的衰老细胞腹腔移植到年轻小鼠体内，比移植整个衰老细胞群体引起的身体机能障碍更少。由于鲁索替尼可减弱衰老细胞释放促凋亡SASP因子，而病原体相关分子模式因子（PAMPs）可迅速放大这些因子的释放（充当“衰老细胞敏化剂”），对衰老细胞溶解剂有抗性和敏感的衰老细胞似乎是可以相互转化的。
白细胞介素（IL）-32是一种多功能细胞因子，参与炎症调节、免疫反应和肿瘤生物学过程。IL-32基因由八个外显子组成，并通过可变剪接产生九种不同的异构体。IL-32最初在活化的T细胞和自然杀伤细胞中被发现，其表达可被多种刺激因素上调，包括微生物、丝裂原和炎性细胞因子。IL-32在人体多种组织中广泛表达，包括脾脏、胸腺、肺、肝脏和肠道。其在免疫细胞中的表达尤为突出，在调节细胞生长、代谢和免疫反应中发挥关键作用，并与多种炎性疾病（如类风湿性关节炎、炎症性肠病、特应性皮炎、传染病和代谢综合征）及恶性肿瘤（如食管癌、肝细胞癌、胃癌、肺癌、乳腺癌、胰腺癌、结直肠癌和淋巴瘤）相关。据报道，根据其异构体和细胞环境，IL-32可通过调节核因子κB（NF-κB）、信号转导和转录激活因子（STAT）3以及丝裂原活化蛋白激酶（MAPK）等主要信号通路来促进或抑制炎症反应和肿瘤发展。然而，对IL-32在癌症和炎性疾病中的异构体特异性作用及分子机制的全面了解仍不完整。因此，在本综述中，我们旨在总结关于IL-32在炎性疾病和癌症发展中功能的现有文献，并通过新兴的大数据分析讨论针对IL-32的潜在治疗策略。
背景：间质性肺疾病（ILD）是结缔组织病（CTD）的常见表现，与高发病率和死亡率相关。制定关于CTD-ILD筛查、诊断、治疗及随访的临床实践指南对于优化患者护理至关重要。 方法：一个由肺科医生、风湿科医生、病理学家、放射科医生、方法学家和患者代表组成的欧洲呼吸学会和欧洲风湿病协会联盟特别工作组委员会，基于PICO（患者、干预措施、对照、结局）问题制定建议，并根据GRADE（推荐分级、评估、制定和评价）方法对证据进行分级，同时考虑两个学会共同认可的补充叙述性问题。对于PICO问题和叙述性问题，均采用证据到决策框架来制定建议。 结果：特别工作组委员会针对25个PICO问题和28个叙述性问题得出了建议，涉及系统性硬化症、类风湿关节炎（RA）、特发性炎性肌病、干燥综合征（SjD）、系统性红斑狼疮（SLE）和混合性结缔组织病（MCTD）背景下的ILD。在关于MCTD、SjD和SLE中ILD进展风险筛查和评估的4个叙述性问题以及关于除RA-ILD外CTD-ILD中吡非尼酮的1个PICO问题上，特别工作组没有足够证据支持建议。基于这些建议和常规临床实践制定了筛查、诊断、监测和治疗算法。 结论：我们为每种CTD的临床医生提供基于证据的实用指南。在许多情况下，证据的确定性较低或缺乏证据，我们鼓励进一步研究以填补这些空白。
背景：癌症是导致残疾人和非残疾人死亡率差距的一个主要但未得到充分认识的因素。我们的研究旨在量化这些不平等现象，为减少差距的癌症控制工作提供信息。 方法和结果：我们使用全国性关联数据（2011 - 2022年）构建了一个超过1000万年龄在25 - 74岁的澳大利亚成年人队列。残疾情况通过2011年人口普查中核心日常活动需要协助来衡量，癌症相关死亡通过国家死亡登记确定。我们估计了年龄标准化和特定年龄的癌症死亡率，以及残疾人和非残疾人之间的绝对和相对死亡率不平等（率差和率比）。该研究包括10414951人。在5403503名女性中，185801人（3.4%）报告有残疾；在5011448名男性中，183594人（3.7%）报告有残疾。在超过93940222人年（平均9.2年）的时间里，发生了219257例癌症相关死亡。年龄标准化后，每10万人年，残疾女性的癌症相关死亡人数比非残疾女性多314人（95%置信区间[CI]：301，328），残疾男性比非残疾男性多410人（95%CI：394，427）（分别高出1.96[95%CI：1.92，2.00]倍和1.83[95%CI：1.80，1.87]倍）。女性和男性中绝对不平等最大的是肺癌（每10万人年分别多67例[95%CI：60，73]和103例[95%CI：95，111]死亡），其次是女性乳腺癌（多54例[95%CI：49，60]死亡）、男性前列腺癌（多31例[95%CI：26，36]死亡）以及男女结直肠癌（女性多30例[95%CI：25，34]死亡，男性多44例[95%CI：38，49]死亡）。按5岁年龄组划分，肺癌是35岁及以上女性和男性绝对不平等的主要原因。在女性中，在大多数年龄组中，乳腺癌是绝对不平等的第二大原因，其次是结直肠癌。在男性中，在大多数年龄组中，结直肠癌是第二大原因，前列腺癌在55岁及以上人群的绝对不平等中起很大作用。在女性和男性的大多数年龄组中，残疾人和非残疾人之间癌症相关死亡的很大一部分差异是由与吸烟、肥胖和饮酒相关的癌症导致的。我们发现男女因个别癌症导致的死亡中，残疾人和非残疾人之间的相对不平等程度相似。该研究的主要局限性在于残疾状况是在单一时间点测量的。 结论：残疾人总体上以及与特定癌症相关的癌症死亡率高于非残疾人。为了缩小差距，应优先在整个癌症控制途径中针对残疾人开展有效的干预措施。
目的 以往研究提示血小板与淋巴细胞比值与重症肌无力的疾病活动度之间可能存在关联。然而，这种关联背后的免疫机制仍未得到充分阐明。 方法 分析了229例重症肌无力患者的回顾性队列以及一个单细胞RNA测序数据集，以研究血小板与淋巴细胞比值和疾病严重程度之间的关系。使用美国重症肌无力基金会分类和多变量逻辑回归评估临床关联，同时整合单细胞RNA测序数据以表征与血小板与淋巴细胞比值升高相关的免疫改变。 结果 重症肌无力严重患者的病程更长，延髓症状、胸腺瘤和重复神经刺激阳性的发生率更高（均p<0.001）。虽然血小板与淋巴细胞比值的中位数在各组间未显示出显著差异（p=0.108），但多变量分析证实，血小板与淋巴细胞比值升高与更高的重症肌无力严重程度独立相关（调整优势比=1.027，95%置信区间：1.003-1.052，p=0.034）。单细胞RNA测序显示血小板与淋巴细胞比值高的患者存在免疫失调，其特征为血小板和中性粒细胞增加、自然杀伤细胞减少，以及血小板活化、细胞间粘附和整合素介导的信号通路上调，表明向先天免疫激活转变且免疫协调受损。 结论 血小板与淋巴细胞比值升高独立预测重症肌无力严重程度，可能反映了导致疾病进展和神经肌肉接头功能障碍免疫失调。
邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种普遍存在的环境增塑剂，可通过饮食摄入、吸入和皮肤接触在人体中被检测到。流行病学证据将尿中DEHP代谢物（如MEHHP和MEOHP）与心血管功能障碍联系起来，包括心率变异性降低和内皮功能损害，这些都是心肌梗死（MI）的关键危险因素。然而，DEHP加重特定细胞类型中MI发病机制的细胞类型特异性分子机制仍不清楚。本研究旨在通过整合机器学习（ML）、单细胞RNA测序（scRNA-seq）和分子对接（MD）方法，识别和验证免疫细胞中DEHP特异性分子机制，该机制将暴露与MI发病机制联系起来。整合转录组数据集（GSE66360、GSE60993、GSE61144、GSE48060和GSE141512），通过加权基因共表达网络分析（WGCNA）和联合差异表达分析筛选MI相关基因。同时，使用ChEMBL、PharmMapper和SwissTargetPrediction预测DEHP靶点。然后通过交集分析鉴定共享的DEHP-MI靶点，并通过11种ML算法的集合对其进行优先级排序。随后，通过CIBERSORT分析免疫细胞浸润情况，scRNA-seq数据（GSE269269）在空间上验证了核心基因的细胞类型特异性表达模式。最后，通过MD模拟评估DEHP-靶点结合稳定性。交集分析确定了56个共享的DEHP-MI靶点，并与先天免疫激活和趋化作用有关。六个核心基因（SLC2A3、MMP9、AKR1C3、DAPK2、MAP3K8和TRIB1）被优先作为诊断生物标志物（AUC = 0.981），SHAP表明SLC2A3和MMP9是MI预测的主要驱动因素。这些基因与促炎中性粒细胞/M0巨噬细胞浸润相关（*r* = 0.585 - 0.772），同时抑制适应性免疫细胞。scRNA-seq揭示了细胞类型特异性致病机制：MMP9和SLC2A3定位于炎症引发的CD14单核细胞，AKR1C3在细胞毒性NK细胞中富集。MD证实DEHP与所有核心靶点具有高亲和力结合（ΔG < -5.0 kcal/mol），在结构上支持它们作为破坏者的作用。DEHP通过直接结合SLC2A3和MMP9加重MI。这通过细胞类型特异性致病机制激活促炎免疫失调潜能。富含单核细胞的SLC2A3/MMP9驱动中性粒细胞募集和M0巨噬细胞极化（*r* = 0.585 - 0.772），而NK细胞定位的AKR1C3破坏细胞毒性调节。本研究通过空间分辨的炎症-免疫网络解读了DEHP心脏毒性，并为环境心血管干预提供了新的治疗靶点。
憩室病在西方国家很常见，60岁人群中的患病率高达70%。憩室病这一术语包括历史上已确认的憩室病、非复杂性憩室炎、复杂性憩室炎和憩室出血；还包括越来越被认可的有症状的非复杂性憩室病。有症状的憩室病的诊断需要病史、体格检查、实验室评估和影像学检查。在非复杂性憩室炎中，可能不需要抗生素治疗和住院。在复杂性憩室炎和憩室出血中，可能需要咨询胃肠病学家或外科医生进行内镜检查，以排除恶性肿瘤并控制憩室出血。此外，对于有脓肿、瘘管形成或穿孔的患者以及病情不稳定的患者，可能需要进行外科会诊。
本病例报告了一项新颖且成功的尝试，即通过内镜超声引导下的经胃干预和套扎器夹闭术，对一名解剖结构为Roux-en-Y且病情不稳定的患者进行大规模上消化道出血的识别与治疗。在内镜超声引导下定位残胃，并通过放置管腔吻合金属支架建立胃胃吻合术来进入残胃。识别病变后，通过注射肾上腺素和部署套扎器夹闭术实现止血。患者在门诊随访时病变愈合，完全康复。该方法可为未来改善胃肠道解剖结构改变患者的微创治疗方式铺平道路。
慢性呼吸道疾病，包括慢性阻塞性肺疾病（COPD）、哮喘、尘肺病、间质性肺疾病（ILD）和肺结节病，是全球死亡和发病的主要原因。尽管新冠疫情对急性呼吸道健康产生了影响，但其对慢性呼吸道疾病的影响仍不明确。我们利用《2023年全球疾病负担研究》估算了1990年至2023年全球、区域和国家层面慢性呼吸道疾病的负担，包括风险因素，并评估了在新冠疫情期间这些负担是如何变化的。2023年，慢性呼吸道疾病导致5.692亿例（95%不确定区间（UI），5.088 - 6.398亿例）病例和420万例（360 - 510万例）死亡。尽管ILD和肺结节病有所增加，但从1990年到2023年，全球年龄标准化死亡率下降了25.7%。年轻男性的死亡率下降，尤其是哮喘患者，而老年人的ILD和肺结节病发病率有所上升。吸烟是COPD的主要风险因素，而高体重指数和接触二氧化硅是哮喘和尘肺病的关键风险因素。在疫情期间，慢性呼吸道疾病的发病率略有上升，但死亡率的下降变得更加明显，这凸显了全球需要持续关注并采取行动来应对其长期负担。
This study investigates the genetic diversity and evolutionary mechanisms driving polymyxin resistance in Klebsiella pneumoniae, a critical priority pathogen. By analysing mgrB, phoPQ and pmrAB genes in susceptible (PM-S) and resistant (PM-R) populations through neutrality tests (Tajima D, Fu & Li's D) we uncovered polygenic adaptation and positive selection as a key driver of resistance. High genetic diversity was observed across all loci, with mgrB insertions dominating PM-R populations. Negative Tajima and Fu & Li's D values and excess rare alleles revealed recent population expansions linked to the reintroduction of polymyxins in the 2010s. Positive selection via selective sweeps was detected in PM-R isolates, exemplified by the rapid spread of haplotype 27, which presents mgrB insertions, the major determinant of LPS modification pathway hyperactivation. The expansion of this haplotype suggests that horizontal gene transfer accelerates resistance dissemination. The elevated genetic diversity observed in the phoPQ and pmrAB systems among isolates harbouring mgrB alterations may reflect reduced adaptive fitness costs, enabling the preservation of genomic variability despite sustained selective pressures. Our results demonstrate that polymyxin resistance arises through polygenic adaptation and positive selection, combining de novo mutations, recombination and selection-driven sweeps. These dynamics threaten to exacerbate resistance in hospital environments, emphasising the need for genomic surveillance and alternative therapies. This study bridges molecular evolution and clinical epidemiology, offering insights into the resilience of K. pneumoniae and the ecological drivers of antimicrobial resistance.
免疫检查点阻断（ICB）通过缓解免疫抑制和恢复效应T细胞的细胞毒性，彻底改变了肿瘤治疗。然而，其临床应用受到低反应率和获得性耐药的限制。肿瘤相关中性粒细胞（TANs）是肿瘤免疫调节的关键参与者，已成为ICB反应性和耐药性的关键介质，凸显了将TAN靶向策略与免疫检查点抑制剂（ICIs）联合使用的治疗潜力。本综述从几个维度系统地综合了目前关于中性粒细胞在ICB耐药中的知识：（1）中性粒细胞的临床指标，如中性粒细胞与淋巴细胞比值（NLR）和组织TANs丰度，作为ICI反应和患者预后的预测指标；（2）TAN参与的多方面耐药机制，包括直接抑制T细胞、损害抗原呈递、调节其他免疫细胞功能、促进肿瘤血管生成以及提高肿瘤突变负荷（TMB）；（3）针对TAN生成/耗竭、募集、表型极化、激活、促血管生成功能和中性粒细胞胞外陷阱（NETs）的联合治疗策略，以及相关临床试验的进展。将TAN靶向治疗与ICIs相结合的联合方法有望通过重塑免疫微环境来克服耐药性。阐明中性粒细胞介导的耐药机制并优化联合策略将为精准肿瘤免疫治疗铺平道路。要点：TANs通过抗肿瘤免疫重塑、促进血管生成和提高肿瘤突变负荷来驱动ICI耐药。中性粒细胞生物标志物（如NLR、TAN丰度）对ICI反应和预后具有很强的预测价值。靶向TAN募集、极化、功能和NETosis是克服ICI耐药的一种有前景的策略。许多临床试验正在评估针对中性粒细胞的联合疗法以提高免疫治疗疗效。
Sex-based disparities in the incidence, prevalence and disease manifestations have been observed across various medical conditions, including type 1 diabetes (T1D). Differences in glycaemic control and quality of life between men and women have been reported, with women experiencing lower rates of glycaemic targets and a higher risk for long-term complications, particularly cardiovascular disease. Additionally, women face a greater economic and mental health burden related to T1D. This narrative review explores the challenges that complicate glycaemic management in women living with T1D, including hormonal influences during puberty, pregnancy and the (peri-) menopausal period. We also summarize current available evidence on the safety and efficacy of the MiniMed™ 780G (MM780G) system in addressing these challenges for women living with T1D. Finally, recent real-world data are reported on the absence of significant sex-related differences in glycaemic outcomes of over 280 000 real-world users of the MM780G, across various age groups from childhood and adolescence to the (peri-) menopausal period.
Traditional 2D cell cultures and animal models have served as the foundations of biomedical research. These have significant limitations in modeling human physiology and predicting outcomes of therapy. Recent developments in 3D organoids and organ-on-chip technologies have shifted the field by enabling human relevant dynamic and scalable platforms for disease modeling and drug discovery and toxicity evaluation. Organoids derived from either stem cells or patient samples accurately recreate complex cellular structure and function found in human organs. The combination of organoids with organ-on-chip systems, or micro-engineered devices that closely simulate the interactions between distinct organ types including tissue to tissue as well as fluids and mechanical forces, allows researchers to continually monitor and manipulate the immediate environment of cells. The focus of this study will be on the underlying technologies for the manufacture and use of these systems as well as the main applications of these systems. Future research will include the development of multi-organ chips, artificial intelligence (AI), and biosensors. This study also illustrates how organoids and organ-on-chip technologies will enable the modeling and mimicking of common neurological, liver, gut, heart, cancer, and infectious diseases, as well as their application for high-throughput drug screening and nanotoxicology applications which could potentially help to lessen our reliance on animals for preclinical drug testing. The combined use of CRISPR gene editing, multi-omics profiling, and machine-learning technology is accelerating the transition to personalized medicine. In spite of issues surrounding the standards associated with the use of organoid and organ-on-chip technology, ethical issues, and the magnitude of scalability, there continues to be ongoing technical advances and government support for this quickly developing technology. Organoids and organ-on-chip technologies represent a fundamental shift in the practice of biomedical research and may allow us to more closely and accurately simulate authentic human physiology while providing more efficient and safer platform for drug discovery to be conducted.
Globally, the burden of dementia profoundly affects low- and middle-income countries (LMICs), with a greater burden and risk for late-life women than men. Structural and social determinants of health, crucial constructs conferring risk and protection from later-life dementia, are relatively understudied, yet essential in LMICs. Typical neuroscience studies have historically been small, with highly selected samples that do not generalize well to target populations in LMICs. To better understand gender and sex differences in dementia risk in LMICs, this Perspective lays out a guiding framework for a global dementia research plan-the Population Neuroscience-Dementia Syndemics Framework. Population neuroscience considers the brain in a multilevel context, from a lifecourse perspective, using tools to enhance internal and external validity, while syndemics suggest that diseases and social conditions may cluster and interact in populations with syndemic risk factors-sociocultural, political, economic, and environmental factors that promote stress pathways and disease.
The Wnt signaling pathway deeply participates in multiple physiological and pathological processes. Its activity is intricately regulated by a diverse network of modulators, reflecting the pathway's structural and functional complexity. Dysregulation of Wnt signaling leads to cellular dysfunction and is associated with a wide spectrum of diseases, among which tissue fibrosis represents a major pathological outcome, characterized by activation of myofibroblasts and subsequent excessive deposition of extracellular matrix in response to injury. Wnt signaling is a central driver of fibrotic progression across multiple tissues and organs; however, effective therapeutic strategies directly targeting Wnt signaling in fibrosis remain scarce. In this review, we provide a comprehensive overview of Wnt pathway components, regulatory mechanisms, and therapeutic approaches. We systematically examine how Wnt signaling governs both developmental processes and pathological conditions, with particular emphasis on its role in fibrosis while also extending discussion to other diseases. Special attention is devoted to the secreted frizzled-related proteins (SFRPs) family, soluble regulators with biphasic, context-dependent effects that are especially relevant in fibrosis. Finally, we summarize insights from preclinical and clinical studies, review advances and challenges in the development of small-molecule compounds targeting Wnt components, highlighting the vital role of SFRPs as promising targets for antifibrotic intervention.
据估计，结核病（TB）每年导致125万人死亡，是艾滋病毒感染者（PWH）的主要死因（1）。CD4 + T辅助（Th）细胞群在对结核分枝杆菌（Mtb）的保护性免疫中发挥重要作用，并且是HIV发病机制的重要宿主。PWH血液和胃肠道黏膜中的新证据表明，在Th细胞中，Th17和Th22可能在HIV感染期间优先耗竭。HIV对Th17和Th22细胞的靶向作用可能给合并感染的患者控制Mtb带来重要且尚未完全了解的风险。Mtb驱动的Th17和Th22免疫激活也可能有助于HIV的增殖和持续存在。我们采用了一种合并感染的人源化小鼠模型，以评估由于感染HIV、Mtb或两者而导致的Th17和Th22频率及功能的变化。在感染的小鼠中，Th17细胞是脾脏中HIV的主要宿主，并被证明是肺结核肉芽肿中HIV复制的来源。在患有结核病或结核-艾滋病毒的小鼠肺中，Th17细胞增加。相反，在患有艾滋病毒或结核-艾滋病毒的小鼠中，Th22细胞减少。Mtb感染增加了合并感染小鼠肺部的病毒载量，而HIV抑制了肺部Th17家族细胞因子对Mtb的反应，包括IL-6、IL-22、IL-23和IL-1β。差异转录组评估表明，HIV合并感染破坏了Mtb在肺中激活的Th17途径。总体而言，这些结果表明，在Mtb和HIV合并感染的情况下，HIV可能损害Th22免疫，并利用Th17细胞促进病毒发病机制。
The thoracic duct (TD) is the largest vessel of the lymphatic system, transporting interstitial fluid, macromolecules, and immune cells into the venous circulation via the lymphovenous junction. Respiratory and circulatory forces have been proposed as key drivers of TD lymph propulsion; however, the literature reports inconsistent findings. This study systematically reviews the effects of respiration and circulation on TD lymph flow and pressure in humans and non-human mammals. A systematic review was conducted in accordance with PRISMA guidelines using MEDLINE, Embase, and Google Scholar databases. Studies published up to August 2025 were included with no language or past date restrictions. Twenty-three human and animal studies met the inclusion criteria. Respiratory activity influenced TD flow and/or pressure in 5/6 human and 12/17 animal studies. Circulatory influences were reported in 3/6 human and 8/17 animal studies. Intrinsic TD contractility was described in 3/6 human and 6/17 animal studies and was identified as an independent contributor to lymph propulsion. Overall, reported effects ranged from absent to highly synchronous physiological coupling. Evidence regarding respiratory and circulatory influences on TD lymphodynamics remains inconsistent, reflecting methodological heterogeneity. Findings should be considered hypothesis-generating and highlight the need for modern imaging and standardized physiological protocols.
BACKGROUND: Sepsis-associated acute respiratory distress syndrome (ARDS) is a severe inflammatory lung disorder with high mortality. Bruceine A (BA), a quassinoid from Brucea javanica, exhibits anti-inflammatory and immunomodulatory activities, but its role in ARDS is unclear. OBJECTIVES: This study evaluated the protective effects of BA in lipopolysaccharide (LPS)-induced ARDS and explored its underlying mechanisms. METHODS: Thirty-six C57BL/6 mice were randomized into four groups: Control, LPS, LPS+BA and LPS+dexamethasone (Dex). Lung injury was assessed by histopathology, wet/dry weight ratio and TUNEL assay. Cytokine levels (TNF-α, IL-6, IL-1β, IL-10) were measured by ELISA. Macrophage polarization markers (iNOS, COX-2, Arg-1, YM1, CD206) and NF-κB pathway proteins were evaluated using immunohistochemistry and Western blotting. RESULTS: BA significantly alleviated LPS-induced lung injury, reducing edema, tissue damage and alveolar apoptosis. It suppressed proinflammatory cytokines while enhancing IL-10. BA shifted macrophage polarization from proinflammatory M1 toward anti-inflammatory M2 phenotypes. Furthermore, BA inhibited NF-κB activation, evidenced by reduced phosphorylated p65 and restored IκBα levels. These effects were comparable to Dex. CONCLUSION: BA protects against LPS-induced ARDS in mice by modulating cytokine release, promoting M2 macrophage polarization and suppressing NF-κB activation. These findings suggest BA as a promising natural immunomodulatory agent for inflammatory lung diseases.
引言：与淀粉样β蛋白（Aβ）纤维相互作用的蛋白质可能是阿尔茨海默病（AD）中斑块形成的关键因素，并且代表潜在的生物标志物和治疗靶点。以往使用显微切割斑块进行的蛋白质组学研究可能捕获到了非特异性成分，而非真正的Aβ相互作用蛋白。 方法：将生物素化的Aβ40或Aβ42肽诱导形成纤维，以 scrambled肽作为对照，并与AD和对照前额叶皮质组织的蛋白质提取物孵育。下拉分析结合无标记蛋白质组学鉴定纤维相互作用蛋白。通过蛋白质印迹、免疫荧光、免疫细胞化学、免疫组织化学和计算机分析评估失调和定位情况。 结果：我们鉴定出185种与Aβ40相关的蛋白质和874种与Aβ42相关的蛋白质，其中78种是共享的。包括蛋白激酶Cγ型（PRKCG）在内的16种在AD中表达改变的蛋白质，在体外被确认为实际的相互作用蛋白和斑块成分。值得注意的是，PRKCG的调节影响纤维形成。 讨论：本研究扩展了Aβ斑块相关蛋白质组，鉴定了新的相互作用蛋白，并突出了PRKCG作为AD淀粉样蛋白生成的可药物靶向调节因子。 亮点：全面的蛋白质组学分析允许鉴定与Aβ40和Aβ42纤维相互作用的蛋白质，包括许多新的相互作用蛋白。16种蛋白质在体外和体内被确认为真正的Aβ斑块成分。在AD脑和细胞模型中证实了关键相互作用蛋白的表达失调。PRKCG活性的调节改变了Aβ纤维的形成和进程。研究结果扩展了Aβ相关蛋白质组，并突出了AD生物标志物和治疗开发的新靶点。
背景：TROP2是一种关键的细胞表面致癌信号转导分子，与难治性转移性结直肠癌（CRC）及其他实体瘤的联系日益紧密。转移微环境中乳酸的大量积累与病理转移性进展相关。抗TROP2抗体药物偶联物（ADCs）已在临床应用，但在晚期转移性CRC中疗效有限。阐明TROP2信号如何协调分子和细胞程序以促进CRC转移进展，将有助于改善转移治疗。 方法：组织芯片、免疫组化和蛋白质印迹法明确了TROP2在CRC肝转移（CRLM）中的病理作用。代谢组学分析了TROP2介导的代谢效应。蛋白质印迹法检测TROP2反应性乳酸化位点。细胞衍生异种移植（CDX）、脾内注射模型和患者衍生异种移植（PDX）验证了TROP2或TROP2诱导的H3K18乳酸化（H3K18la）在CRLM发病机制和吖啶黄治疗反应中的作用。通过染色质免疫沉淀测序（ChIP-seq）进行全基因组H3K18la分析。 结果：在此，我们在CRC细胞中发现了H3K18la与TROP2之间的自我强化正反馈环，该环驱动CRC转移进展。我们发现，在CRC转移过程中TROP2水平升高，肝转移中高TROP2水平预示着两个不同队列中治疗后复发增加。我们发现，CRC细胞中H3K18la水平随TROP2表达水平上调。TROP2通过YBX1-HIF-1α信号轴促进大量乳酸生成。靶向糖酵解通量可降低H3K18乳酸化，并抑制TROP2驱动的CRLM定植和进展。从机制上讲，ChIP-seq检测显示H3K18la沉积在一组促转移基因启动子上，促进其表达。至关重要的是，发现TROP2诱导的H3K18la反过来维持TROP2表达，形成正反馈环，进一步加速转移进展。使用一种旧的FDA批准药物吖啶黄进行药理学HIF-1α抑制，可在多个临床前模型中抑制TROP2高表达的CRLM进展。 结论：总体而言，我们确定H3K18la是TROP2介导的CRLM进展的关键表观遗传驱动因素，并提出破坏H3K18la-TROP2反馈环可提供一种针对CRC转移的新治疗策略。 关键点：H3K18la在CRC细胞中因TROP2信号而特异性增加，并驱动TROP2介导的CRLM进展 全基因组分析显示H3K18la在促进转移基因的启动子处沉积，驱动其在TROP2高表达的CRC中的表达 乳酸通过H3K18la维持CRC细胞中TROP2的表达 吖啶黄通过靶向H3K18la/TROP2反馈环抑制TROP2驱动的CRLM
Timely diagnosis of type 1 diabetes (T1D), especially in high-risk populations, is crucial for preventing serious health complications. T1D is a chronic progressive autoimmune disease that has presymptomatic stages that can be identified through the detection of islet autoantibodies. Given that T1D is associated with other autoimmune diseases, having either those diseases or a family history of them will represent a risk of T1D. From a search of the literature conducted in August 2024, we review here the evidence for the risk of either T1D or the development of T1D in association with other autoimmune diseases or a family history of those diseases. Increased risk of subsequent T1D development was identified for individuals with autoimmune diseases, including coeliac disease, autoimmune thyroid disease, autoimmune Addison's disease, juvenile idiopathic arthritis, primary biliary cholangitis, ulcerative colitis, vitiligo, and myasthenia gravis. Increased prevalence of diabetes-associated autoantibody positivity was found among non-diabetic individuals with coeliac and autoimmune thyroid diseases compared with individuals without these autoimmune diseases. Increased risk of T1D was also found for individuals with a family history of autoimmune diseases, including coeliac disease, thyroid disease, Addison's disease, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, autoimmune liver disease, pernicious anaemia, inflammatory bowel disease, multiple sclerosis, and granulomatosis with polyangiitis. This review highlights how certain individuals at risk of T1D can be identified to offer them islet autoantibody screening and, thereby, early detection of T1D.
Aortic dissection is a life-threatening cardiovascular emergency with limited pharmacological options. This study focuses on elucidating the multi-target and multi-pathway mechanisms through which morusin mitigates aortic dissection progression, integrating network pharmacology, single-cell transcriptomics and experimental validation. Multi-database analysis identified 281 morusin targets and 1741 ad-related genes, with 84 overlaps. Enrichment analyses highlighted IL-17, HIF-1 and MAPK signalling pathways as potential regulatory hubs. Protein-protein interaction network analysis identified seven key targets, all showing high binding affinity to morusin in molecular docking. Single-cell transcriptomics revealed cell-type-specific dysregulation, notably MAPK8 upregulation in fibroblasts and immune cells. In vitro, morusin dose-dependently inhibited AngII-induced vascular smooth muscle cell proliferation and modulated IL-17 pathway gene expression. In vivo, morusin attenuated aortic dilation and reduced morbidity and mortality in a BAPN-induced AD mouse model. These findings suggest that morusin mitigates AD progression by targeting key inflammatory and apoptotic pathways, supporting its potential as a multi-target therapeutic candidate.
Ferroptosis, an iron-dependent regulated necrosis driven by redox imbalance, plays a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Kaempferol (KF), a bioactive flavonoid from Polygonati Rhizoma, exhibits anti-ferroptotic properties in lipid peroxidation disorders, yet its molecular mechanism against cigarette smoke extract (CSE)-induced ferroptosis in human bronchial epithelial cells (BEAS-2B) remains to be fully elucidated. Using in vitro models of CSE-induced injury, we observed that KF restored cell viability and attenuated cytotoxicity by restoring redox equilibrium-significantly elevating glutathione (GSH) while reducing malondialdehyde (MDA) and labile iron pool (Fe) levels. Mechanistically, KF suppressed ferritinophagy via nuclear receptor coactivator 4 (NCOA4) inhibition and rescued glutathione peroxidase 4 (GPx4) activity, thereby blocking lipid peroxidation cascades. These effects were mediated through Nrf2-dependent transcriptional activation, counteracting CSE-triggered Nrf2 pathway dysregulation. Our findings reveal that KF mitigates COPD progression by coordinately targeting the Nrf2/NCOA4/GPx4 axis to inhibit ferroptosis, providing a novel therapeutic strategy for oxidative stress-driven pulmonary diseases.
肺腺癌（LUAD）是非小细胞肺癌的主要亚型，发病率和死亡率都很高。放射治疗是LUAD的关键治疗方式，但其疗效常因放疗抵抗而受到影响。（-）-表儿茶素（EC）是一种从金荞麦中提取的天然黄烷醇，据报道可增强多种癌症的放射敏感性。然而，其在LUAD放疗抵抗中的具体作用及潜在机制仍不清楚。在本研究中，我们通过用梯度剂量的X射线反复照射A549和NCI-H520细胞，建立了放疗抗性细胞系A549R和NCI-H520R。此外，通过将A549R细胞皮下接种到裸鼠的左背部区域构建了异种移植肿瘤模型。结果表明，叉头框M1（FOXM1）——一种与肺癌增殖、侵袭及治疗抵抗相关的关键癌蛋白——在LUAD组织和放疗抗性A549R细胞中显著上调。敲低FOXM1可增强A549R细胞的放射敏感性，促进辐射诱导的细胞凋亡，并抑制细胞增殖。EC在体外有效增强了A549R细胞的放疗反应，减弱了放疗抵抗，同时在体内抑制了肿瘤生长。机制上，EC下调了ALKBH5，这是一种已知通过调节mRNA去甲基化参与癌症生物学过程的m6A去甲基化酶，从而促进FOXM1 mRNA的m6A甲基化，随后抑制FOXM1表达，最终减轻LUAD的放疗抵抗。本研究揭示了EC通过ALKBH5/FOXM1轴增强LUAD放射敏感性的新机制，为克服LUAD的放疗抵抗提供了一种潜在的治疗策略。
Transdermal peptides, Engineered from bioactive peptides through rational sequence modification and structural optimization, transdermal peptides have emerged as a transformative strategy for enhancing the transdermal delivery of macromolecular drugs, proteins, and nucleic acids. This review outlines the structural classifications of bioactive peptides, including short, linear, cyclic, cationic, anionic, and neutral peptides, as well as their diverse biological sources. It focuses on the design principles and penetration mechanisms of transdermal peptides. These peptides interact dynamically with skin constituents, such as lipids and keratins, by fine-tuning the hydrophilic-hydrophobic balance, molecular weight, and conformational stability. This transiently disrupts the stratum corneum barrier and facilitates drug permeation via endocytosis and receptor-mediated pathways. They find applications in various pharmaceutical domains, including localized anticancer and antimicrobial therapies, as well as in cosmetics for whitening, anti-aging, and moisturizing. They are also being explored in innovative areas such as hair regeneration and wound healing. When combined with advanced delivery platforms, such as nanocarriers, microneedles, and microfluidic systems, transdermal peptides can significantly improve targeting efficacy and enable controlled release. Despite challenges related to peptide immunogenicity and scalable synthesis, the future integration of smart, stimuli-responsive technologies and artificial intelligence promises to Bioactive peptides, Skin permeation mechanisms, Skin transmission, Transdermal peptidesadvance personalized transdermal therapeutics.
BACKGROUND: Regeneration has emerged as a key concept in aesthetic medicine as the field evolves from predominantly volumetric correction toward biologically oriented strategies aimed at improving tissue quality, function, and long-term structural integrity. However, the widespread use of the term "regenerative" has often been used without biological precision, leading to conceptual overlap with repair, remodeling, and biostimulation. A critical evaluation of the biological basis and clinical evidence supporting regenerative claims is needed. OBJECTIVE: To critically synthesize current biological, translational, and clinical evidence related to skin regeneration in aesthetic medicine, with emphasis on extracellular matrix remodeling, immune modulation, mechanotransduction, and dermal-hypodermal integration, and to contextualize the regenerative potential and limitations of commonly used biomaterials. METHODS: A narrative review was conducted based on experimental studies, translational research, narrative and systematic reviews, and clinical investigations cited in the reference set. Evidence was qualitatively analyzed focusing on mechanisms of action, tissue-level interactions, immune responses, extracellular matrix dynamics, involvement of subcutaneous adipose compartments, and durability of clinical outcomes. RESULTS: Cutaneous regeneration is a multilevel functional process driven by coordinated extracellular matrix reorganization, controlled inflammation, mechanotransduction, angiogenesis, and dermal-hypodermal crosstalk. Particulate collagen biostimulators (poly-l-lactic acid, poly-d,l-lactic acid, calcium hydroxyapatite, and polycaprolactone) demonstrate the most consistent evidence for sustained functional remodeling, with poly-l-lactic acid showing the strongest longitudinal and histological support. Hyaluronic acid-based fillers and skinboosters primarily act as microenvironmental modulators with limited regenerative depth. Polydioxanone threads induce localized mechanobiological remodeling that is highly technique dependent. Biological bioregenerators, including polynucleotides, polydeoxyribonucleotides, and extracellular vesicles, show strong mechanistic plausibility but limited and heterogeneous clinical evidence. CONCLUSION: Regeneration in aesthetic medicine should be defined by biological mechanism, functional integration, and durability rather than by transient morphological change. A biologically accountable and evidence-based framework is essential for responsible clinical application.
Oncology patients receiving cytostatic therapy used to be at high risk of HBV infection when HBV screening measures were less reliable. Infections acquired under these conditions often persist, like those acquired perinatally or during early infancy. We studied the long-term clinical outcomes, viral characteristics, and virus-specific T-cell immunity of chronic HBV infection acquired during chemotherapy. We examined 16 chronically HBV-infected former paediatric oncology patients who were infected during cytostatic treatment in the 1980s. Patients underwent physical examination, laboratory liver function testing, non-invasive measurement of liver stiffness, and determination of HBV serology and DNA levels. If the material was sufficient, HBV sub-genotype, drug resistance and immune escape mutations, and mutations associated with HBeAg negativity were analysed. The frequency of HBV core-specific CD8+ T cells was measured after in vitro antigen-specific expansion. All but one patient were chronically infected with detectable HBsAg but were HBeAg-negative, mostly with low viraemia. Four patients were under ongoing effective antiviral therapy, and four required treatment initiation due to high viraemia or advanced liver disease. Hepatic effects were predominantly observed in highly viraemic patients. No drug resistance or immune escape mutations were observed. In two highly viraemic patients, basal core promoter and precore region mutations reducing HBeAg expression were identified. HBV core-specific CD8+ T cells were detected in all patients, but their frequency was low. In conclusion, more than 30 years after primary HBV infection was acquired during chemotherapy, the course of infection still resembles that of perinatally acquired infections.
BACKGROUND AND OBJECTIVE: Although calcitonin gene-related peptide (CGRP) has emerged as a promising therapeutic target in migraine management, current clinical evidence regarding its dynamic variations in paediatric migraine populations remains inconclusive. We conducted a meta-analysis to explore the relationship between blood CGRP levels and paediatric migraine. DATABASES AND DATA TREATMENT: We systematically searched for observational studies that reported CGRP levels in paediatric migraine published in English from the PubMed, Web of Science, and Embase electronic databases, or in Chinese from the Chinese National Knowledge Infrastructure and the WanFang Med database. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the included studies. The quality of evidence for each outcome was assessed according to the Grading of Recommendations, Assessment, Development, and Evaluation guidelines. RESULTS: Of the 1134 identified studies, eight were eligible for inclusion. There was a 'Moderate' level of evidence demonstrating significantly elevated CGRP levels in children with migraine compared to controls (standardised mean difference [SMD] = 1.44, 95% CI 0.61-2.31). Stratification analysis showed the 'Low' level of evidence revealed higher levels during both ictal (SMD = 2.39, 95% CI 0.59-4.19) and interictal phases (SMD = 1.27, 95% CI 0.54-1.99). 'Very low' quality of evidence supported paediatric migraine patients with (SMD = 1.47, 95% CI 0.67-2.27) and without (SMD = 1.11, 95% CI 0.50-1.72) aura had higher CGRP levels than non-migraine controls. CONCLUSIONS: Our findings suggest that CGRP levels may be a potential diagnostic biomarker and prophylactic therapeutic target for paediatric migraine, but need high-quality longitudinal studies to validate. SIGNIFICANCE STATEMENT: This systematic review and meta-analysis provides significant evidence that CGRP levels serve as a potential diagnostic biomarker for migraine in children and adolescents. Future research should further explore the diagnostic value of CGRP levels in this population. However, the current evidence does not confirm CGRP as an acute-phase therapeutic target for pediatric and adolescent migraine, necessitating validation through higher-quality studies. TRIAL REGISTRATION: PROSPERO number: CRD42025635332.
Globally, wetlands can sequester and store large amounts of soil carbon over the long term due to high primary productivity and slow decomposition. Yet centuries of drainage for agriculture and development have turned many of these carbon sinks into greenhouse gas (GHG) sources. Restoring degraded wetlands, particularly in peat-rich landscapes, is increasingly promoted as a nature-based solution for climate change mitigation. However, the trajectory and timing of recovery remain uncertain, especially given the complex interplay among vegetation dynamics, hydrology, and GHG fluxes. In this study, we analyzed 44 site-years of continuous eddy covariance measurements of carbon dioxide (CO) and methane (CH) fluxes from restored wetlands in California's Sacramento-San Joaquin Delta. Our findings reveal substantial interannual variability in GHG exchange across sites, driven by differences in restoration design, water management, and vegetation establishment. While rapid vegetation growth, especially dense stands of macrophytes, can enhance CO uptake, it often elevates CH emissions and complicates predictions of when wetlands become net GHG sinks. Crucially, wetlands with delayed vegetation establishment due to high or inconsistent water levels (e.g., significant drawdown) remained persistent GHG sources, even years after restoration. Conversely, sites with tailored planting or natural and rapid recolonization exhibited earlier transitions to net sink status, including earlier shifts towards net negative radiative forcing since the restoration. The study highlights the importance of adaptive, site-specific restoration strategies and long-term monitoring to capture switchover dynamics from sources to sinks. As global investment in wetland restoration grows, our findings underscore the need to balance climate mitigation goals with ecological realities and the self-designing processes of vegetation succession.
血管内血栓切除术是缺血性中风的标准治疗方法，缺血性中风是全球致残的主要原因。过去十年的随机试验扩大了纳入标准，以涵盖更广泛的患者群体，如大面积缺血性核心中风患者。然而，尽管大血管再灌注率很高，许多患者的预后仍然很差，这突出表明需要采取超越恢复大血管血流的策略。动脉内溶栓和细胞保护剂因其在血管内血栓切除术中及术后减少继发性并发症的潜力而正在接受研究。这些策略针对微血管阻塞、兴奋性毒性、氧化应激和炎症等关键机制。它们的有效性取决于使作用机制与患者潜在的病理生理学相匹配。尽管多年来在细胞保护试验中取得了有希望的结果，但由于临床转化受限，最近的试验提供了希望和见解，有助于确定转化成功的关键因素。将这些经验教训纳入完善的纳入标准和未来研究中，有可能改变我们对临床结局最差风险最大的患者（包括严重残疾或死亡患者）的护理方法。
目的：中国西北甘青地区的齐家文化（公元前2300 - 1500年）促进了东亚与欧亚草原之间的史前交流，但其人口起源和人口动态仍不明确。我们研究齐家人的母系遗传多样性、祖先来源及区域影响，以阐明他们在东亚史前人口迁移中的作用。 材料与方法：我们分析了29个与齐家文化相关个体的完整线粒体基因组，通过单倍群分类、系统发育分析和群体遗传统计，将其与古代和现代欧亚人群的综合数据集进行比较。 结果：齐家人群呈现出双重祖先结构，分别源自黄河中游的粟作农耕群体（石峁/仰韶/龙山文化）和东亚欧亚草原的游牧群体。值得注意的是，尽管有文化交流的考古证据，但我们的分析显示几乎没有检测到来自西亚的贡献。关键单倍群，特别是F1g和D4j1b，将齐家人与现代藏缅语族使用者（如藏族和羌语族群）联系起来，支持了通过藏彝走廊向南迁移的模式。南方单倍群F1a1a的存在可能表明该地区有有限的向北基因流动。 讨论：齐家文化可能充当了一个基因“熔炉”以及后续的源人群体，说明了不同于单纯文化传播的人口过程。其双重起源反映了中原农业扩张与北方游牧民族迁徙的交汇。此外，它与藏缅语族群体的深厚遗传联系凸显了其在中国西南现代人群基因格局形成中的持久影响。
背景：尽管关于预后的数据较少，但在新辅助化疗后前哨淋巴结阳性的患者中，腋窝淋巴结清扫术（ALND）越来越多地被省略，尤其是那些残留病灶较小的患者。我们研究了接受或未接受ALND治疗的乳腺癌患者及前哨淋巴结有残留微转移患者的肿瘤学结局。 方法：OPBC-07/microNAC是一项回顾性队列研究，使用从30个国家84个癌症中心的机构数据库中获取的数据。纳入年龄在18岁及以上、诊断为临床T1-4、N0-3期乳腺癌且接受新辅助化疗后于2013年1月1日至2023年5月31日期间接受手术的患者，这些患者在冰冻切片或最终石蜡切片上经前哨淋巴结活检确定有残留微转移（转移灶直径>0·2 mm或>200个细胞，大小不超过2·0 mm），或接受了靶向腋窝清扫术（单示踪剂或双示踪剂定位的前哨淋巴结活检加影像引导下对最初活检证实并标记的淋巴结进行定位），或接受了放射性碘籽标记腋窝淋巴结（MARI）手术。主要终点是按腋窝手术类型分层的5年任何腋窝复发率（孤立性或合并局部或远处复发）。鉴于中位随访时间，我们在此报告3年复发率及探索性的5年估计值。本研究已在ClinicalTrials.gov注册，注册号为NCT06529302。 结果：对1585例ypN1mi期女性患者进行了分析，其中804例（50·7%）接受了ALND，781例（49·3%）未接受。在1585名女性中，238名（15·0%）自认为是亚洲人，65名（4·1%）是黑人，200名（12·6%）是西班牙裔，968名（61·1%）是白人，114名（7·2%）种族和族裔未知。1585名女性中有925名（58·4%）患有cT2肿瘤，1054名（66·5%）为淋巴结阳性，1267名（79·9%）接受了淋巴结放疗。中位随访时间为3·1年（四分位间距1·8 - 5·2年）。整个队列的3年任何腋窝复发率（孤立性或合并局部或远处复发）为2·0%（95%置信区间1·3 - 2·9），腋窝手术范围未发现统计学差异。然而，未接受ALND的三阴性疾病患者的任何腋窝复发率显著高于接受ALND的女性（8·7% [95%置信区间4·4 - 15·0] 对2·4% [95%置信区间0·7 - 6·5]，p = 0·018）。多变量分析显示，三阴性乳腺癌（风险比3·83 [95%置信区间1·72 - 8·52]）和未进行淋巴结放疗（2·62 [1·19 - 5·73]）而非未进行ALND（0·86 [0·37 - 2·00]）与任何腋窝复发风险增加独立相关。 解读：总体而言，这些结果不支持对所有接受淋巴结放疗且前哨淋巴结活检为ypN1mi的患者进行ALND；然而，在考虑省略ALND时应考虑肿瘤生物学特性。 资助：美国国立卫生研究院，国家癌症研究所。
BACKGROUND: Lenvatinib resistance (LR) represents a significant obstacle in hepatocellular carcinoma (HCC) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) is involved in tumour metabolic reprogramming; however, its role in LR remains unclear. METHODS: Bioinformatics analyses of public databases were integrated and validated in established LR HCC cell lines. Functional assays (CCK-8, flow cytometry and Seahorse XF analysis) were performed to assess proliferation, apoptosis and aerobic glycolysis. Post-translational modifications of AKR1B10 were characterized using co-immunoprecipitation, mass spectrometry and western blot. RESULTS: AKR1B10 was identified as a critical driver of resistance by establishing a metabolic positive feedback loop. Bioinformatics analyses and experimental validation demonstrated that AKR1B10 upregulation correlates with therapeutic resistance. Functional studies indicated that AKR1B10 promotes resistance by enhancing aerobic glycolysis. Mechanistically, alanyl-tRNA synthetase 1 mediates lactylation modification at AKR1B10 lysine 173 (K173), stabilizing AKR1B10 by blocking ubiquitin (Ub)-proteasomal degradation. Stabilized AKR1B10 interacts physically with lactate dehydrogenase A (LDHA), promoting LDHA phosphorylation at Y10 and accelerating glycolytic lactate production. The increased lactate subsequently induces histone H3K18 lactylation (H3K18la), which transcriptionally upregulates LDHA expression. Thus, a self-reinforcing AKR1B10-lactate-LDHA amplification circuit is formed. Clinical analyses confirmed elevated AKR1B10 expression in LR HCC patient tissues. Importantly, targeting this axis with the AKR1B10 inhibitor epalrestat (EPA) synergized with lenvatinib, overcoming resistance in xenograft mouse models and patient-derived xenograft models. CONCLUSIONS: These findings establish AKR1B10 as both a biomarker and a therapeutic target in HCC. They reveal a novel lactylation-driven glycolytic adaptation mechanism and support the clinical translation of combined EPA-lenvatinib therapy. KEY POINTS: AKR1B10 confers lenvatinib resistance by enhancing aerobic glycolysis in HCC cells. AKR1B10 undergoes AARS1-mediated lactylation at K173, stabilizing it by antagonizing ubiquitin-proteasomal degradation. AKR1B10 promotes LDHA Y10 phosphorylation, boosting lactate production, which drives H3K18la-mediated transcriptional upregulation of LDHA, creating a feed-forward loop. Targeting AKR1B10 with epalrestat synergizes with lenvatinib to overcome resistance in preclinical models.
Mitophagy, an evolutionarily conserved quality-control process, selectively removes damaged mitochondria to maintain cellular homeostasis. Recent advances in our understanding of the molecular machinery underlying mitophagy - from receptors and stress-responsive triggers to lysosomal degradation - illustrate its key role in maintaining mitochondrial integrity and adapting mitochondrial function to ever-changing physiological demands. In this review, we outline the fundamental mechanisms of mitophagy and discuss how dysregulation of this pathway disrupts mitochondrial function and metabolic balance, driving a wide range of disorders, including neurodegenerative, cardiovascular, metabolic, and immune-related diseases, as well as cancer. We explore the dual role of mitophagy as both a disease driver and a therapeutic target, highlighting the efforts and challenges of translating mechanistic insights into precision therapies. Targeting mitophagy to restore mitochondrial homeostasis may be at the center of a large range of translational opportunities for improving human health.
背景：传统上，与机械通气机相比，基于文丘里原理的流量发生器通过头盔（h-CPAP）提供持续气道正压（CPAP）。最近，现代涡轮驱动呼吸机（TDV）在提供 h-CPAP 方面表现出安全有效。我们旨在比较文丘里装置和 TDV 在提供 h-CPAP 时的压力稳定性，并评估高效空气颗粒（HEPA）过滤器对其性能的影响。 方法：我们在限制呼吸条件下的人工肺模拟器上进行了一项台架研究，模拟了有无 HEPA 过滤器介入的两种不同水平的患者努力（高和低）。我们计算了气道压力曲线（PTPinsp）上测量的最小（Pmin）、最大（Pmax）和平均（Pmean）气道压力以及时间乘积的平均值。我们将压力摆动（Pswing）定义为 Pmax - Pmin，将压力下降（Pdrop）定义为呼气末压力 - Pmin。 结果：在所有测试设备中，CPAP 水平的压力摆动差异很大。在“低努力”期间，文丘里装置和 TDV 之间的 Pswing 和 Pdrop 没有差异；在高努力期间，TDV 中的 Pswing（p<0.001）和 Pdrop（p<0.001）明显高于文丘里装置，但 PTPinsp 较低（1.50 SD 0.54 与 1.67 SD 0.55，p<0.001）。HEPA 过滤器的添加几乎使 Pswing 和 PTPinsp 增加一倍（p<0.001），但文丘里装置和 TDV 系统之间的差异仍未改变，后者更为有利（p<0.001）。 结论：在台架设置中，TDV 在提供稳定的正压水平方面优于文丘里系统。
简介和目的：人类先天性中枢性通气不足综合征（CCHS）是由 PHOX2B（成对样同源框 2B）基因突变引起的。基因工程改造的 PHOX2B 啮齿动物表现出脑干Retrotrapezoid 核（RTN）发育缺陷，RTN 是一种对控制呼气肌募集至关重要的二氧化碳敏感结构。这与运动通气反应迟钝有关。这种情况是否可以推断到人类 CCHS 尚不清楚，这也是本研究的目的。 材料和方法：13 名成年 CCHS 患者和 13 名健康参与者进行了递增症状限制的循环心肺运动测试。使用指南方法（通气 V'、潮气量 V、呼吸频率、耗氧量、二氧化碳产生量）分析反应，并辅以呼吸模式分析（即呼气和吸气储备量，ERV 和 IRV）。 结果：两组研究对象均出现通气反应，具体如下：CCHS 患者的 V'和 V 在 40 W 之前增加，然后减少，而健康参与者则没有观察到这种情况（<0.001）。在后一组中，与运动相关的 ERV 和 IRV 减少证明了同时存在呼气和吸气募集。在 CCHS 患者中，虽然发生了吸气募集，但没有证据表明存在呼气募集（没有任何 ERV 减少，<0.001）。 结论：假设人类和啮齿动物的呼吸节律发生机制相似，我们在 CCHS 患者中观察到的与运动相关的呼气募集缺乏与 PHOX2B 相关的神经结构缺陷是一致的，这种缺陷类似于啮齿动物的 RTN。如果得到证实，ERV 募集可以作为纠正 CCHS 呼吸控制的研究中的生理结果。
介绍和目的：过敏性肺炎（HP）是一种具有多种临床特征的间质性肺病，在遗传易感性个体中可表现出类似于特发性肺纤维化（IPF）的纤维化表型。虽然已经发现了几个单核苷酸多态性（SNP）与 IPF 相关，但导致纤维化 HP（fHP）的遗传因素仍知之甚少。本研究调查了葡萄牙 fHP 患者中 和 变体与易感性、临床表现和生存的关联。 材料和方法：进行了一项病例对照研究，共纳入 97 例 fHP 患者和 112 名对照。分析了位于 和 基因中的 6 个 SNP 及其单倍型。通过比较患者和对照，探讨了它们与 fHP 的风险、生存以及临床、放射学和病理学特征的关联。 结果：rs35705950 和三个相邻的 变体（rs3750920、rs111521887 和 rs5743894）与 fHP 的易感性增加相关。fHP 患者的等位基因频率高于对照组（40.7%比 12.1%，<0.0001；52.6%比 40.2%， = 0.011；22.7%比 13.4%， = 0.013；23.2%比 12.9%， = 0.006，分别）。由这些变体形成的单倍型也与 fHP 的易感性相关。此外，特定单倍型（G-T-G-C）的携带者的生存率显著降低（调整后的危险比 6.92，95%置信区间 1.73-27.64， = 0.006）。还发现 rs111521887 和 rs5743894 变体与基线时肺功能下降以及 SNP 和放射学特征之间存在关联，进一步强调了遗传因素在 fHP 中的影响。 结论：这些发现表明 和 MUC5B 变体和单倍型可能是纤维化过敏性肺炎风险评估和预后的有价值工具，有助于对患者进行分层，并深入了解影响该疾病临床过程的遗传因素。
简介：矽肺主要发生在高矽暴露的工人中，可能伴随着肺结核、癌症或自身免疫性疾病等各种疾病的发展。矽肺合并结核病一词描述的是同时患有矽肺和结核病的个体的一种情况。本系统评价和荟萃分析研究旨在评估矽肺患者和接触二氧化硅粉尘的个体患结核病的风险。 方法：我们对截至 2022 年 9 月 6 日的相关研究进行了系统检索，使用了 PubMed/Medline 和 Embase，在标题或摘要中使用了以下关键词：“矽肺”或“矽肺”或“尘肺”或“尘肺”和“肺结核”。包含矽肺患者结核病感染相关和原始信息的队列研究和病例对照研究被纳入进一步分析。由于真实效应大小的异质性估计，使用随机效应模型评估矽肺患者与无矽肺患者相比结核病感染的相对风险的汇总估计值和 95%置信区间（CI）。 结果：在 5352 篇潜在相关文章中，有 7 项研究符合系统评价的条件，其中 4 项队列研究被纳入荟萃分析。所有研究的总人群为 5884 人，其中 90.63%为男性。参与者的平均年龄为 47.7 岁。我们的荟萃分析显示，汇总风险比为 1.35（95%CI 1.18-1.53，I ：94.30%），这意味着矽肺患者和接触二氧化硅的个体患结核病感染的风险增加。 结论：矽肺和二氧化硅暴露会增加患结核病的风险。因此，我们建议长期接触二氧化硅的个体，如矿工，应定期考虑同时进行矽肺和结核病筛查计划。
背景：持续气道正压通气（CPAP）常用于院外环境中治疗急性呼吸衰竭患者。与面罩相比，头盔对患者有诸多优势，但需要至少60 L/min的气体流量以避免二氧化碳重复吸入。本实验台研究的目的是评估连接到单个氧气瓶的四种文丘里装置在提供具有临床相关气体流量、吸入氧分数（FiO）和呼气末正压（PEEP）值的头盔式CPAP时的性能。 方法：使用双流量计将三个双入口文丘里系统（EasyVent、Ventuplus、Compact-HAR）连接到满5升氧气瓶上，并测试它们达到不同设置（流量60 - 80 L/min；FiO 0.4 - 0.5 - 0.6，PEEP 7.5 - 10 - 12.5 cmH₂O）所需的氧气量。第四个文丘里系统（O₂-MAX）直接连接到气瓶上，记录在预设FiO 0.3和0.6时输送的流量和FiO。评估气瓶的运行时间。 结果：EasyVent、Ventuplus和O₂-MAX在连接到单个氧气瓶时能够提供具有临床实用设置的头盔式CPAP，而Compact-HAR则不能。根据预设流量和FiO，气瓶的运行时间在28至60分钟之间。随着气瓶压力下降，输送的气体流量缓慢且线性下降，直至气瓶耗尽。 结论：可以使用连接到氧气瓶的便携式文丘里系统提供头盔式CPAP，但并非所有系统都能做到。当使用双入口文丘里系统时，使用双流量计可实现高流量和高FiO的输送。由于在气瓶消耗过程中观察到流量下降，启动头盔式CPAP时应设置流量>60 L/min。考虑到流量下降现象，在规划患者转运时，气瓶运行时间的估计值可在安全范围内使用。
背景：无创头盔式呼吸支持适用于多种临床情况。在最近的冠状病毒大流行期间，配备高效空气过滤器（HEPA）的连续流头盔式持续气道正压通气（CPAP）系统变得很受欢迎。然而，HEPA过滤器会在设定的呼气末正压（PEEP）之上产生超压。 方法：使用肺模拟器来模拟患者的呼吸力学和用力情况。与室内空气自主呼吸相比，在不同的连续流速率（30 - 150升/分钟）、PEEP水平（5、10、12.5厘米水柱）和呼吸频率（15、20、25、30次/分钟）下，记录有和没有在出口端口使用HEPA过滤器时，头盔式CPAP引起的额外吸气用力（ΔPmusHelmet）。 结果：吸气期间头盔压力波动在很大程度上解释了ΔPmusHelmet的变化（p<0.001，Spearman相关系数=0.964）。在流速为90升/分钟时，经常记录到最低的ΔPmusHelmet水平（0.2 [0; 0.4]厘米水柱）（>70%）。当连续流低于吸气峰值流速时，记录到更高的ΔPmusHelmet水平（3.7 [3.1; 5.6]厘米水柱，p<0.001），或者使用HEPA过滤器时也是如此（2.7 [2.2; 3.5]，p<0.001）。增加流速会导致更高的超压水平，特别是使用HEPA过滤器时（p<0.001）。超压水平与ΔPmusHelmet相关（p<0.001，Spearman相关系数=0.598）。 结论：低于PEEP的头盔压力波动会导致额外的吸气用力。HEPA过滤器起到了流动阻力器的作用，产生超压导致呼吸用力增加。连续流速率应滴定到足够高，以略微超过吸气峰值流速；然而，不建议进一步增加流速，因为这会导致超压增加以及低于PEEP的头盔压力波动增加。
背景：慢性阻塞性肺疾病全球倡议（GOLD）1期（轻度）慢性阻塞性肺疾病（COPD）患者的呼吸结局是否比肺功能正常者更差尚不清楚。 方法：对于本系统评价和荟萃分析，我们检索了截至2023年3月1日发表在PubMed、Embase和Web of Science上的所有文献。纳入比较轻度COPD与肺功能正常者死亡率的研究。采用随机效应模型估计合并效应量及其95%置信区间（CI）。主要结局是全因死亡率。将呼吸系统疾病相关死亡率作为次要结局进行研究。 结果：在识别出的5242篇文献标题中，纳入了12篇出版物。轻度COPD患者的全因死亡率高于肺功能正常者（支气管扩张剂使用前：风险比[HR]=1.21，95%CI：1.11-1.32，I²=47.1%；支气管扩张剂使用后：HR=1.19，95%CI：1.02-1.39，I²=0.0%）。漏斗图显示研究分布对称，未提示发表偏倚。在逐一剔除法敏感性分析中，轻度COPD全因死亡率增加的风险保持一致。每次重复荟萃分析并剔除一项研究时，HR及相应的95%CI均>1。轻度COPD患者的呼吸系统疾病相关死亡率也更高（HR=1.71，95%CI：1.03-2.82，I²=0.0%）。 结论：我们的结果表明，与肺功能正常者相比，轻度COPD与全因死亡率和呼吸系统疾病相关死亡率增加有关。需要进一步研究以确定早期干预和治疗对轻度COPD是否有益。
背景：既往研究表明，重度或极重度气流受限的慢性阻塞性肺疾病（COPD）患者胸肌面积（PMA）减小，这与死亡率相关。然而，轻度或中度气流受限的COPD患者PMA是否也减小尚不清楚。此外，关于PMA与呼吸症状、肺功能、计算机断层扫描（CT）成像、肺功能下降及急性加重之间的关联，现有证据有限。因此，我们开展本研究以评估COPD患者中PMA减小的情况，并阐明其与上述相关变量之间的关联。 方法：本研究基于2019年7月至2020年12月纳入早期慢性阻塞性肺疾病（ECOPD）研究的受试者。收集包括问卷、肺功能及CT成像在内的数据。使用预先定义的-50至90亨氏单位衰减范围，在主动脉弓水平的全吸气CT上对PMA进行定量。进行多变量线性回归分析，以评估PMA与气流受限严重程度、呼吸症状、肺功能、肺气肿、气体潴留及肺功能年下降之间的关联。采用Cox比例风险分析和泊松回归分析，在调整后评估PMA与急性加重之间的关系。 结果：我们纳入了1352名基线受试者（667名肺量计检查正常，685名肺量计检查确诊为COPD）。校正混杂因素后，随着COPD气流受限严重程度的增加，PMA呈单调下降（与肺量计检查正常者相比；慢性阻塞性肺疾病全球倡议组织[GOLD]1级：β=-1.27，P=0.028；GOLD 2级：β=-2.29，P<0.001；GOLD 3级：β=-4.88，P<0.001；GOLD 4级：β=-6.47，P=0.014）。校正后，PMA与改良英国医学研究理事会呼吸困难量表（β=-0.005，P=0.026）、COPD评估测试评分（β=-0.06，P=0.001）、肺气肿（β=-0.07，P<0.001）及气体潴留（β=-0.24，P<0.001）呈负相关。PMA与肺功能呈正相关（均P<0.05）。胸大肌面积和胸小肌面积也发现了类似的关联。1年随访后，PMA与支气管扩张剂后第1秒用力呼气容积占预计值百分比的年下降相关（β=0.022，P=0.002），但与急性加重年发生率或首次急性加重时间无关。 结论：轻度或中度气流受限的患者存在PMA减小。PMA与气流受限严重程度、呼吸症状、肺功能、肺气肿及气体潴留相关，提示测量PMA有助于COPD评估。
引言与目的：量化非插管患者的呼吸努力很重要但也很困难。我们旨在开发两种模型来估计接受高流量氧疗患者的呼吸努力。 患者与方法：我们分析了先前研究中260例接受高流量氧疗患者的数据。他们的呼吸努力通过食管压力的最大偏移量（ΔPes）来衡量。我们开发了一个多变量线性回归模型来估计ΔPes（单位为cmH₂O），以及一个多变量逻辑回归模型来预测ΔPes＞10 cmH₂O的风险。候选预测因素包括年龄、性别、2019冠状病毒病（COVID-19）诊断、呼吸频率、心率、平均动脉压、动脉血气分析结果，包括碱剩余浓度（BEa）和动脉血氧分压与吸入氧分数之比（PaO₂:FiO₂），以及COVID-19与PaO₂:FiO₂之间的乘积项。 结果：我们发现可以根据是否患有COVID-19、BEa、呼吸频率、PaO₂:FiO₂以及COVID-19与PaO₂:FiO₂之间的乘积项来估计ΔPes。调整后的R²为0.39。可以根据BEa、呼吸频率和PaO₂:FiO₂预测ΔPes＞10 cmH₂O的风险。受试者工作特征曲线下面积为0.79（0.73 - 0.85）。我们将这两个模型称为BREF，其中BREF代表呼吸努力（BReathing EFfort）以及三个常见预测因素：BEa（B）、呼吸频率（RE）和PaO₂:FiO₂（F）。 结论：我们开发了两种模型来估计接受高流量氧疗患者的呼吸努力。我们的初步研究结果很有前景，表明这些模型值得进一步评估。
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