2024年 · 第137卷第04期

近年来，内窥镜领域经历了显著的技术进步。这些发展促进了内窥镜检查的有效使用，用于各种病变的精确检查和微创治疗。内窥镜诊断和治疗期间考虑的一个关键参数是病变的大小。在结肠息肉切除术中，息肉的大小与恶性肿瘤的可能性和并发症的可能性有关。类似地，在早期胃癌的情况下，较大的肿瘤通常与淋巴结转移的可能性增加相关，并且是否进行内镜粘膜下剥离（ESD）部分取决于病变的大小。因此，病变大小的准确测量可能会显著影响患者的诊断和治疗计划。然而，目前在内镜检查过程中还没有标准化的定量测量方法。这种通用技术的缺乏阻碍了临床指南提供精确治疗建议的能力。

Aging is a significant risk factor for various diseases, including asthma, and it often leads to poorer clinical outcomes, particularly in elderly individuals. It is recognized that age-related diseases are due to a time-dependent accumulation of cellular damage, resulting in a progressive decline in cellular and physiological functions and an increased susceptibility to chronic diseases. The effects of aging affect not only the elderly but also those of younger ages, posing significant challenges to global healthcare. Thus, understanding the molecular mechanisms associated with aging in different diseases is essential. One intriguing factor is the aryl hydrocarbon receptor (AhR), which serves as a cytoplasmic receptor and ligand-activated transcription factor and has been linked to the aging process. Here, we review the literature on several major hallmarks of aging, including mitochondrial dysfunction, cellular senescence, autophagy, mitophagy, epigenetic alterations, and microbiome disturbances. Moreover, we provide an overview of the impact of AhR on these hallmarks by mediating responses to environmental exposures, particularly in relation to the immune system. Furthermore, we explore how aging hallmarks affect clinical characteristics, inflammatory features, exacerbations, and the treatment of asthma. It is suggested that AhR signaling may potentially play a role in regulating asthma phenotypes in elderly populations as part of the aging process.

Gliomas tend to have a poor prognosis and are the most common primary malignant tumors of the central nervous system. Compared with patients with other cancers, glioma patients often suffer from increased levels of psychological stress, such as anxiety and fear. Chronic stress (CS) is thought to impact glioma profoundly. However, because of the complex mechanisms underlying CS and variability in individual tolerance, the role of CS in glioma remains unclear. This review suggests a new proposal to redivide the stress system into two parts. Neuronal activity is dominant upstream. Stress-signaling molecules produced by the neuroendocrine system are dominant downstream. We discuss the underlying molecular mechanisms by which CS impacts glioma. Potential pharmacological treatments are also summarized from the therapeutic perspective of CS.

As pancreatic cancer (PC) is highly malignant, its patients tend to develop metastasis at an early stage and show a poor response to conventional chemotherapies. First-line chemotherapies for PC, according to current guidelines, include fluoropyrimidine- and gemcitabine-based regimens. Accumulating research on drug resistance has shown that biochemical metabolic aberrations in PC, especially those involving glycolysis and glutamine metabolism, are highly associated with chemoresistance. Additionally, lipid metabolism is a major factor in chemoresistance. However, emerging compounds that target these key metabolic pathways have the potential to overcome chemoresistance. This review summarizes how PC develops chemoresistance through aberrations in biochemical metabolism and discusses novel critical targets and pathways within cancer metabolism for new drug research.

Artificial intelligence (AI) technology represented by deep learning has made remarkable achievements in digital pathology, enhancing the accuracy and reliability of diagnosis and prognosis evaluation. The spatial distribution of CD3⁺ and CD8⁺ T cells within the tumor microenvironment has been demonstrated to have a significant impact on the prognosis of colorectal cancer (CRC). This study aimed to investigate CD3_CT (CD3⁺ T cells density in the core of the tumor [CT]) prognostic ability in patients with CRC by using AI technology.

The study involved the enrollment of 492 patients from two distinct medical centers, with 358 patients assigned to the training cohort and an additional 134 patients allocated to the validation cohort. To facilitate tissue segmentation and T-cells quantification in whole-slide images (WSIs), a fully automated workflow based on deep learning was devised. Upon the completion of tissue segmentation and subsequent cell segmentation, a comprehensive analysis was conducted.

The evaluation of various positive T cell densities revealed comparable discriminatory ability between CD3_CT and CD3-CD8 (the combination of CD3⁺ and CD8⁺ T cells density within the CT and invasive margin) in predicting mortality (C-index in training cohort: 0.65 vs. 0.64; validation cohort: 0.69 vs. 0.69). The CD3_CT was confirmed as an independent prognostic factor, with high CD3_CT density associated with increased overall survival (OS) in the training cohort (hazard ratio [HR] = 0.22, 95% confidence interval [CI]: 0.12–0.38, P <0.001) and validation cohort (HR = 0.21, 95% CI: 0.05–0.92, P = 0.037).

We quantify the spatial distribution of CD3⁺ and CD8⁺ T cells within tissue regions in WSIs using AI technology. The CD3_CT confirmed as a stage-independent predictor for OS in CRC patients. Moreover, CD3_CT shows promise in simplifying the CD3-CD8 system and facilitating its practical application in clinical settings.

Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism.

We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments.

The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 (ERAP1) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1. The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes.

The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1.

No. NCT00454519 (https://clinicaltrials.gov/)

Risk assessment and treatment stratification for three-vessel coronary disease (TVD) remain challenging. This study aimed to investigate the prognostic value of left atrial volume index (LAVI) with the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score II, and its association with the long-term prognosis after three strategies (percutaneous coronary intervention [PCI], coronary artery bypass grafting [CABG], and medical therapy [MT]) in patients with TVD.

This study was a post hoc analysis of a large, prospective cohort of patients with TVD in China, that aimed to determine the long-term outcomes after PCI, CABG, or optimal MT alone. A total of 8943 patients with TVD were consecutively enrolled between 2004 and 2011 at Fuwai Hospital. A total of 7818 patients with available baseline LAVI data were included in the study. Baseline, procedural, and follow-up data were collected. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), which was a composite of all-cause death, myocardial infarction (MI), and stroke. Secondary endpoints included all-cause death, cardiac death, MI, revascularization, and stroke. Long-term outcomes were evaluated among LAVI quartile groups.

During a median follow-up of 6.6 years, a higher LAVI was strongly associated with increased risk of MACCE (Q3: hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.06-1.37, P = 0.005; Q4: HR 1.85, 95%CI 1.64-2.09, P <0.001), all-cause death (Q3: HR 1.41, 95% CI 1.17-1.69, P <0.001; Q4: HR 2.54, 95%CI 2.16-3.00, P <0.001), and cardiac death (Q3: HR 1.81, 95% CI 1.39-2.37, P <0.001; Q4: HR 3.47, 95%CI 2.71-4.43, P <0.001). Moreover, LAVI significantly improved discrimination and reclassification of the SYNTAX score II. Notably, there was a significant interaction between LAVI quartiles and treatment strategies for MACCE. CABG was associated with lower risk of MACCE than MT alone, regardless of LAVI quartiles. Among patients in the fourth quartile, PCI was associated with significantly increased risk of cardiac death compared with CABG (HR: 5.25, 95% CI: 1.97-14.03, P = 0.001).

LAVI is a potential index for risk stratification and therapeutic decision-making in patients with three-vessel coronary disease. CABG is associated with improved long-term outcomes compared with MT alone, regardless of LAVI quartiles. When LAVI is severely elevated, PCI is associated with higher risk of cardiac death than CABG.

Genetic variants of dopaminergic transcription factor-encoding genes are suggested to be Parkinson’s disease (PD) risk factors; however, no comprehensive analyses of these genes in patients with PD have been undertaken. Therefore, we aimed to genetically analyze 16 dopaminergic transcription factor genes in Chinese patients with PD.

Whole-exome sequencing (WES) was performed using a Chinese cohort comprising 1917 unrelated patients with familial or sporadic early-onset PD and 1652 controls. Additionally, whole-genome sequencing (WGS) was performed using another Chinese cohort comprising 1962 unrelated patients with sporadic late-onset PD and 1279 controls.

We detected 308 rare and 208 rare protein-altering variants in the WES and WGS cohorts, respectively. Gene-based association analyses of rare variants suggested that MSX1 is enriched in sporadic late-onset PD. However, the significance did not pass the Bonferroni correction. Meanwhile, 72 and 1730 common variants were found in the WES and WGS cohorts, respectively. Unfortunately, single-variant logistic association analyses did not identify significant associations between common variants and PD.

Variants of 16 typical dopaminergic transcription factors might not be major genetic risk factors for PD in Chinese patients. However, we highlight the complexity of PD and the need for extensive research elucidating its etiology.

Hypertension and non-alcoholic fatty liver disease (NAFLD) share several pathophysiologic risk factors, and the exact relationship between the two remains unclear. Our study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 and Mendelian randomization (MR) analyses.

Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES 2017-2018. Subsequently, a two-sample MR study was performed using the genome-wide association study (GWAS) summary statistics to identify the causal association between hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and NAFLD. The primary inverse variance weighted (IVW) and other supplementary MR approaches were conducted to verify the causal association between hypertension and NAFLD. Sensitivity analyses were adopted to confirm the robustness of the results.

A total of 3144 participants were enrolled for our observational study in NHANES. Weighted multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk (odds ratio [OR] = 1.677; 95% confidence interval [CI], 1.159-2.423). SBP ≥130 mmHg and DBP ≥80 mmHg were also significantly positively correlated with NAFLD. Moreover, hypertension was independently connected with liver steatosis (β = 7.836 [95% CI, 2.334-13.338]). The results of MR analysis also supported a causal association between hypertension (OR = 7.203 [95% CI, 2.297-22.587]) and NAFLD. Similar results were observed for the causal exploration between SBP (OR = 1.024 [95% CI, 1.003-1.046]), DBP (OR = 1.047 [95% CI, 1.005-1.090]), and NAFLD. The sensitive analysis further confirmed the robustness and reliability of these findings (all P >0.05).

Hypertension was associated with an increased risk of NAFLD.

To perform anatomical anterior cruciate ligament reconstruction (ACLR), tunnels should be placed relatively higher in the femoral anterior cruciate ligament (ACL) footprint based on the findings of direct and indirect femoral insertion. But the clinical results of higher femoral tunnels (HFT) in double-bundle ACLR (DB-ACLR) remain unclear. The purpose was to investigate the clinical results of HFT and lower femoral tunnels (LFT) in DB-ACLR.

From September 2014 to February 2016, 83 patients who underwent DB-ACLR and met the inclusion and exclusion criteria were divided into HFT-ACLR (group 1, n = 37) and LFT-ACLR (group 2, n = 46) according to the position of femoral tunnels. Preoperatively and at the final follow-up, clinical scores were evaluated with International Knee Documentation Committee (IKDC), Tegner activity, and Lysholm score. The stability of the knee was evaluated with KT-2000, Lachman test, and pivot-shift test. Cartilage degeneration grades of the International Cartilage Repair Society (ICRS) were evaluated on magnetic resonance imaging (MRI). Graft tension, continuity, and synovialization were evaluated by second-look arthroscopy. Return-to-sports was assessed at the final follow-up.

Significantly better improvement were found for KT-2000, Lachman test, and pivot-shift test postoperatively in group 1 (P >0.05). Posterolateral bundles (PL) showed significantly better results in second-look arthroscopy regarding graft tension, continuity, and synovialization (P <0.05), but not in anteromedial bundles in group 1. At the final follow-up, cartilage worsening was observed in groups 1 and 2, but it did not reach a stastistically significant difference (P >0.05). No statistically significant differences were found in IKDC subjective score, Tegner activity, and Lysholm score between the two groups. Higher return-to-sports rate was found in group 1 with 86.8% (32/37) vs. 65.2% (30/46) in group 2 (P = 0.027).

The HFT-ACLR group showed better stability results, better PL, and higher return-to-sports rate compared to the LFT-ACLR group.

致编辑：银屑病关节炎(PsA)是一种高度异质性的炎性关节炎。它发生在高达30%的银屑病患者中，并可对外部关节、脊柱、肌腱插入和手指产生严重影响。^[1]影像学进展是目前评估PsA结构损伤的首选方法。^[2]PsA的生物治疗选择包括肿瘤坏死因子-α抑制剂(TNFi)、白细胞介素-12/23抑制剂和白细胞介素-17(IL-17)抑制剂。IL-17抑制剂对结构损伤的治疗效果在多项试验中并不一致。因此，对现有的随机对照试验（RCT）进行了系统综述和荟萃分析，以量化IL-17抑制剂对PsA结构损伤的总体影响。本研究在PROSPERO注册（编号CRD42022301774）。

致编辑：寻常痤疮（AV）是一种常见的炎症性皮肤病。基于人群的流行病学研究报道了饮食习惯、生活方式因素、家族史与痤疮的发生和发展之间的关联。^[1,2,3,4]本研究采用设计的电子问卷调查了AV患者的护肤行为和对诱发因素的认知。

致编辑：异基因造血干细胞移植（allo-HSCT）是治疗血液病最有效的选择之一。然而，同种异体HSCT治疗会导致严重的并发症。移植后肾损害是一种重要的并发症。在这项研究中，我们回顾性分析了同种异体HSCT后肾病综合征（NS）的频率，并比较了单倍体相合供体（HID）和匹配供体（MD）HSCT（包括匹配的同胞供体[MSD]和无关供体[URD]）之间NS的频率和临床特征。

致编辑：1型糖尿病（T1D）患者的血糖控制具有挑战性，需要多维评估和精确管理。糖化血红蛋白（HbA1c）是目前评估血糖控制和预测糖尿病预后的金标准。然而，它在准确性方面表现出局限性，这受到临床因素的影响，^[1]以及它不能反映关于低血糖和血糖变异性的信息。^[2]连续血糖监测（CGM）通过引入超越传统参数的新型血糖变量，彻底改变了血糖概况评估，并为改善血糖控制的关键领域提供了见解。

致编辑：正常眼压性青光眼（NTG）是一种进行性视神经病变，其特征是眼内压（IOP）（≤21 mmHg）具有统计学正常的不可逆性失明，^[1,2]这使得临床实践中的早期诊断变得困难。NTG的病理生理学途径包括血管失调、毒性代谢物积聚和经椎板筛压差升高（TLCPD）。^[3]虽然各种小动物模型已经提供了不同病理生理机制的证据，但复杂的临床表型无法被继发性疾病模型完全模仿，啮齿动物和人类之间的差距削弱了它们的翻译潜力。因此，与NTG相关的病理变化仍不清楚。

致编辑：肿瘤免疫微环境在乳腺癌发生、进展中起着关键作用，决定了乳腺癌患者的长期生存。最近的数据显示，癌症免疫疗法的应用具有一些局限性，包括由于免疫刺激剂向免疫细胞的递送不足而产生微弱的免疫应答。^[1]因此，目前的临床努力主要集中在开发可以将无应答者转化为应答者的基于免疫的化疗。^[2]免疫原性细胞死亡(ICD)是一种足以激活适应性免疫应答的调节性细胞死亡形式。ICD通常可由某些化疗药物、溶瘤病毒、物理化学疗法和放疗引发。^[3]值得注意的是，作为一类生物标志物，ICD的显著优势在于它整合了几种免疫相关途径，包括危险信号传导和T细胞浸润/活性。为确定ICD参数的预后价值而进行的一些研究产生了相互矛盾的结果，这可能是因为患者数量有限和ICD参数有限。在这项研究中，确定了重要的ICD相关生物标志物，并获得了ICD相关特征，以估计免疫细胞的浸润、对免疫治疗的反应和乳腺癌的预后。此外，构建了基于独立临床病理因素和ICD风险评分的诺模图来预测乳腺癌患者的长期生存率，这可能有助于改善乳腺癌患者的临床管理。

致编辑：自从Popescu首次对端粒细胞（TCs）进行分类以来，已经过去了18年等人^[1]2005年。基于其超微结构和免疫组织化学特征，将TCs分为Cajal（ICC）型间质细胞，其类似于间充质细胞。^[2]在随后的十年中，TCs被发现在三维结构、免疫生物标志物、基因组学和多种功能方面具有自己鲜明的特征。有趣的是，在人类和动物的多个器官中，TCs肯定不同于成纤维细胞、间充质干细胞和内皮细胞。^[3]它们具有特定的细胞体和显著不同数量的端足（TP），这被认为是与经典成纤维细胞和内皮细胞相比的特征。^[4]Tps形成念珠状图案，由薄节段（足体）和小的扩张区域（足体）组成。免疫组织化学生物标志物分析和透射电子显微镜扫描以及扫描电子显微镜(SEM)测定的组合已成为区分TC与其他间质细胞的“金标准”方案。^[5]在SEM成像下，TCs及其互连的TP显示出构建完整和复杂网络的三维结构，表明它们与实质细胞、免疫细胞和癌细胞相互作用的能力。^[6]

致编辑：内镜超声引导细针穿刺（EUS-FNA）已经取代了其他高风险的侵入性方法，成为胃肠道周围组织采集的首要方法。^[1]为了进一步提高EUS-FNA的有效性和安全性，病理学家可能会进行快速现场细胞学评估（ROSE），但这一过程需要病理学家在场。宏观现场评估（MOSE）因其解决病理学家资源短缺而受到关注。^[2]内窥镜医生可以实时检查组织核心，并评估穿刺材料的充分性。在这项研究中，我们进行了一项单中心和单臂探索性研究，以探索MOSE在基于放大镜的EUS-FNA期间评估标本质量的价值，并确认EUS-FNA的可见组织核心（VTC）的截止长度，以帮助超声内镜医师独立预测穿刺标本的充分性。VTC被定义为从具有相对完整的组织学结构的局灶性病变获得的白色或肉色组织核心。

致编辑：空气污染可导致呼吸系统和心血管疾病（CVDs），对人体健康的影响非常显著。小于0.1µm的空气颗粒可穿过血脑屏障，到达大脑，进入中枢神经系统，引起生理和病理变化。一项研究表明，长期接触细颗粒物_2.5）将增加中国居民CVD的风险。^[1]另一项研究发现，短时间接触低浓度空气污染物也可能导致急性冠脉综合征在1小时内发病。^[2]一项基于7个数据库的荟萃分析显示，环境空气污染与血压升高和高血压呈正相关。^[3]越来越多的证据表明，空气污染会导致心脑血管疾病，进一步影响人类健康。

致编辑：妊娠期糖尿病(GDM)是一种在妊娠期出现不同程度的葡萄糖不耐受和胰岛素抵抗的病理状况。患有GDM的妇女出现不良母体和胎儿结局的几率更高。有GDM病史的患者在随后的妊娠中GDM复发的风险显著增加。我们之前和其他一些研究发现，复发性GDM孕妇围产期不良结局的发生率增加。^[1]到目前为止，鉴于现有数据有限，不建议有GDM病史的妇女避免随后怀孕。那些有复发性GDM病史的女性呢？是否应该建议复发性GDM的女性避免进一步怀孕？目前，关于复发性GDM妇女围产期结局及其预后因素的研究非常罕见。因此，本回顾性队列研究旨在探讨复发性GDM孕妇的围产期结局及其预后因素。