2024年 · 第137卷第02期

淀粉样轻链（AL）淀粉样变性的年发病率为3-5/百万，男性发病率略高于女性。大约70%新诊断的AL淀粉样变性患者有心脏受累。

Small cell lung cancer (SCLC) is a highly malignant tumor with a very poor prognosis; therefore, more effective treatments are urgently needed for patients afflicted with the disease. In recent years, emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology, metastasis, immune microenvironment, and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes. Additionally, advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease. Herein, we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.

Chimeric antigen receptor (CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia (ALL). Measurable/minimal residual disease (MRD) monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy. Common MRD detection methods include flow cytometry (FCM), polymerase chain reaction (PCR), and next-generation sequencing (NGS), and each method has advantages and limitations. It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse. Thus, how to perform prognostic evaluations, stratify risk based on MRD status, and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice. This review assesses the common and novel MRD assessment methods. In addition, we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), as well as other therapeutic strategies to improve treatment effect. Furthermore, this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy.

Highly expressed in various human cancers, circular RNA Protein Kinase C Iota (circPRKCI) has been reported to play an important role in cancer development and progression. Herein, we sought to reveal the prognostic and clinical value of circPRKCI expression in diverse human cancers.

We searched the Pubmed, Web of Science, and the Cochrane Library databases from inception until May 16, 2021. The relationship between circPRKCI expression and cancer patients’ survival, including overall survival (OS) and disease-free survival (DFS), was assessed by pooled hazard ratios (HR) with corresponding 95% confidence interval (CI). The correlation between circPRKCI expression and clinical outcomes was evaluated using odds ratios (OR) with corresponding 95% CI. The data were analyzed by STATA software (version 12.0) or Review Manager (RevMan 5.3).

A total of 15 studies with 1109 patients were incorporated into our meta-analysis. The results demonstrated that high circPRKCI expression was significantly related to poor OS (HR = 1.96, 95% CI: 1.61, 2.39, P <0.001) when compared with low circPRKCI expression in diverse human cancers. However, elevated circPRKCI expression was not associated with DFS (HR = 1.34, 95% CI: 0.93, 1.95, P = 0.121). Furthermore, the patient with a higher circPRKCI expression was prone to have a larger tumor size, advanced clinical stage, and lymph node metastasis, but it was not significantly correlated with age, gender, and distant metastasis.

Elevated circPRKCI expression was correlated with worse OS and unfavorable clinical features, suggesting a novel prognostic and predictive role of circPRKCI in diverse human cancers.

Links between alterations in gut microbiota composition and amyotrophic lateral sclerosis (ALS) have previously been reported. This study aimed to examine the microbiota in the nasal cavity of ALS.

Sixty-six ALS patients and 40 healthy caregivers who live in close proximity with patients were enrolled. High throughput metagenomic sequencing of the 16S ribosomal deoxyribonucleic acid (rDNA) gene V3–V4 region of nasal microbiota was used to characterize the alpha and beta diversity and relative abundance of bacterial taxa, predict function, and conduct correlation analysis between specific taxa and clinical features.

The nasal microbiome of ALS patients showed lower alpha diversity than that of corresponding healthy family members. Genera Gaiella, Sphingomonas, Polaribacter_1, Lachnospiraceae_NK4A136_group, Klebsiella, and Alistipes were differentially enriched in ALS patients compared to controls. Nasal microbiota composition in ALS patients significantly differed from that in healthy subjects (unweighted UniFrac P = 0.001), while Linear discriminant analysis Effect Size (LEfSe) analysis indicated that Bacteroidetes and Firmicutes dominated healthy nasal communities at the phylum level, whereas Actinobacteria was the predominant phylum and Thermoleophilia was the predominant class in ALS patients. Genus Faecalibacterium and Alistipes were positively correlated with ALS functional rating scale revised (ALSFRS-R; r_s = 0.349, P = 0.020 and r_s = 0.393, P = 0.008), while Prevotella-9 and Bacteroides operational taxonomic units (OTUs) were positively associated with lung function (FVC) in ALS patients (r_s = 0.304, P = 0.045, and r_s = 0.300, P = 0.048, respectively). Prevotella-1 was positively correlated with white blood cell counts (WBC, r_s = 0.347, P = 0.021), neutrophil percentage (Neu%, r_s = 0.428, P = 0.004), and neutrophil-to-lymphocyte ratio (NLR, r_s = 0.411, P = 0.006), but negatively correlated with lymphocyte percentage (Lym%, r_s = -0.408, P = 0.006). In contrast, Streptococcus was negatively associated with Neu% (r_s = -0.445, P = 0.003) and NLR (r_s = -0.436, P = 0.003), while positively associated with Lym% (r_s = 0.437, P = 0.003). No significant differences in nasal microbiota richness and evenness were detected among the severe and mild ALS patients.

ALS is accompanied by altered nasal microbial community composition and diversity. The findings presented here highlight the need to understand how dysbiosis of nasal microbiota may contribute to the development of ALS.

Oral anti-coagulants (OAC) are the intervention for the prevention of stroke, which consistently improve clinical outcomes and survival among patients with atrial fibrillation (AF). The main purpose of this study is to identify problems in OAC utilization among hospitalized patients with AF in China.

Using data from the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation (CCC-AF) registry, guideline-recommended OAC use in eligible patients was assessed.

A total of 52,530 patients with non-valvular AF were enrolled from February 2015 to December 2019, of whom 38,203 were at a high risk of stroke, 9717 were at a moderate risk, and 4610 were at a low risk. On admission, only 20.0% (6075/30,420) of patients with a diagnosed AF and a high risk of stroke were taking OAC. The use of pre-hospital OAC on admission was associated with a lower risk of new-onset ischemic stroke/transient ischemic attack among the diagnosed AF population (adjusted odds ratio: 0.54, 95% confidence interval: 0.43–0.68; P <0.001). At discharge, the prescription rate of OAC was 45.2% (16,757/37,087) in eligible patients with high stroke risk and 60.7% (2778/4578) in eligible patients with low stroke risk. OAC utilization in patients with high stroke risk on admission or at discharge both increased largely over time (all P <0.001). Multivariate analysis showed that OAC utilization at discharge was positively associated with in-hospital rhythm control strategies, including catheter ablation (adjusted odds ratio [OR] 11.63, 95% confidence interval [CI] 10.04–13.47; P <0.001), electronic cardioversion (adjusted OR 2.41, 95% CI 1.65–3.51; P <0.001), and anti-arrhythmic drug use (adjusted OR 1.45, 95% CI 1.38–1.53; P <0.001).

In hospitals participated in the CCC-AF project, >70% of AF patients were at a high risk of stroke. Although poor performance on guideline-recommended OAC use was found in this study, over time the CCC-AF project has made progress in stroke prevention in the Chinese AF population.

ClinicalTrials.gov, NCT02309398.

Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for β-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 (CTNNB1), the most frequently altered proto-oncogene in hepatic neoplasms.

Constitutive β-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 (β-catenin^Δ(ex3)/+), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-catenin^Δ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on β-catenin-activated human liver cancer cells were determined in vitro. Immuno-deficient nude mice subcutaneously inoculated with β-catenin wild-type or mutant liver cancer cells and hepatitis B virus (HBV); β-catenin^lox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of β-catenin mutant liver cancer.

MTX was identified and validated as a preferential agent against the proliferation and tumor formation of β-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV; β-catenin^lox(ex3)/+ mice, which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer.

MTX is a promising chemotherapeutic agent for β-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of β-catenin mutant liver cancer.

Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown.

In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl₄), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF.

We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders.

We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.

Atopic dermatitis (AD) affects approximately 10% of adults worldwide. CM310 is a humanized monoclonal antibody targeting interleukin-4 receptor alpha that blocks interleukin-4 and interleukin-13 signaling. This trial aimed to evaluate the efficacy and safety of CM310 in Chinese adults with moderate-to-severe AD.

This multicenter, randomized, double-blind, placebo-controlled, phase 2b trial was conducted in 21 medical institutions in China from February to November 2021. Totally 120 eligible patients were enrolled and randomized (1:1:1) to receive subcutaneous injections of 300 mg CM310, 150 mg CM310, or placebo every 2 weeks for 16 weeks, followed by an 8-week follow-up period. The primary endpoint was the proportion of patients achieving ≥75% improvement in the Eczema Area and Severity Index (EASI-75) score from baseline at week 16. Safety and pharmacodynamics were also studied.

At week 16, the proportion of EASI-75 responders from baseline was significantly higher in the CM310 groups (70% [28/40] for high-dose and 65% [26/40] for low-dose) than that in the placebo group (20%[8/40]). The differences in EASI-75 response rate were 50% (high vs. placebo, 95% CI 31%–69%) and 45% (low vs. placebo, 95% CI 26%–64%), with both P values <0.0001. CM310 at both doses also significantly improved the EASI score, Investigator’s Global Assessment score, daily peak pruritus Numerical Rating Scale, AD-affected body surface area, and Dermatology Life Quality Index compared with placebo. CM310 treatment reduced levels of thymus and activation-regulated chemokine, total immunoglobulin E, lactate dehydrogenase, and blood eosinophils. The incidence of treatment-emergent adverse events (TEAEs) was similar among all three groups, with the most common TEAEs reported being upper respiratory tract infection, atopic dermatitis, hyperlipidemia, and hyperuricemia. No severe adverse events were deemed to be attributed to CM310.

CM310 at 150 mg and 300 mg every 2 weeks demonstrated significant efficacy and was well-tolerated in adults with moderate-to-severe AD.

ClinicalTrials.gov, NCT04805411.

Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.

The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin β8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models.

Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.

The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma.

The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro. A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8⁺ T cells in TME were analyzed by flow cytometry.

Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro. AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1⁺/CD8⁺ T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ)⁺ or Ki67⁺ CD8 T cells and decreasing the levels of CD8⁺ Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8⁺ T cells proliferation, and weakening CD8⁺ T cells depletion.

This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8⁺ T cells in TME.

尿路上皮癌（UCs）的诊断方法通常是侵入性的或具有次优的准确性。尿液中脱落细胞DNA或无细胞DNA的甲基化在UCs的诊断中显示出巨大的前景。然而，目前大多数研究都集中在膀胱癌（BCa）上，只有少数基于大量尿液的高复合甲基化DNA组被报道表现出高灵敏度和特异性。^[1,2]本研究的目的是使用少量尿液鉴定BCa和上尿路上皮癌（UTUC）的通用生物标志物。我们开发了一种包含新型标记的双靶诊断小组AL021918.2和众所周知的BCa生物标志物波形蛋白（维姆).该面板仅使用1.8 mL完全排泄的尿液即可准确检测UCs。

致编辑：结肠直肠癌(CRC)是世界范围内癌症相关死亡的主要原因，并且具有致癌潜力的几种病原体，例如血吸虫与CRC风险增加相关。作为CRC患者中常见的突变基因，kirsten大鼠肉瘤病毒癌基因同源物（克拉斯）有助于确定CRC疗法的选择。因此，我们旨在阐明血吸虫感染，克拉斯突变状态和本研究中结直肠癌的预后。

致编辑慢性肾脏疾病（CKD）是一种严重的健康威胁。尿白蛋白—肌酐比值（UACR）升高是肾功能受损的标志物，也是心血管疾病的关键危险因素。速率-压力乘积^[1]压力和速率商（PRQ）作为定量心脏负荷和血流动力学对运动反应的方法在临床上被广泛使用。因此，探讨RPP或PRQ与UACR的关系对于更好地预测CKD具有重要意义。

致编辑：随着全球人口老龄化，社区获得性肺炎（CAP）和慢性阻塞性肺病（COPD）的发病率显著增加。^[1]既往研究证实COPD和哮喘与CAP患病率独立相关。吸入性皮质类固醇（ICS）是治疗哮喘、频繁急性加重的COPD和哮喘-COPD重叠（ACO）的基石，其使用可能会诱导局部肺部微生物群的变化和肺免疫异常，最终导致肺炎风险显著增加。然而，在肺炎病例中，使用ICS对CAP死亡率的影响仍有争议。虽然一项研究的数据支持先前使用ICS，这与显著较低的短期死亡率相关，^[2]其他研究发现对死亡率没有影响。迄今为止，关于使用ICS对死亡率、住院前或住院期间的影响的数据很少，尤其是在老年人群中。因此，这项多中心、回顾性研究探讨了老年CAP和慢性肺病（CPD）患者住院期间使用ICS与短期死亡率之间的关系。

致编辑：1型糖尿病（T1DM）是一种由严重的胰岛β细胞功能损害引起的进行性疾病，导致患者出现高葡萄糖变异性（GV）。^[1]虽然强化胰岛素治疗使T1DM患者达到接近正常的血糖，反映在血红蛋白A1c(HbA1c)水平降低上，但更严格的HbA1c目标与低血糖风险增加相关，这将损害患者的生活质量和生存率。^[2]最近的研究表明，GV比单独的HbA1c更好地反映低血糖，连续血糖监测（CGM）为更好的血糖指数评估提供了更全面的血糖概况。^[3]因此，我们旨在探讨不同HbA1c水平的T1DM患者血糖变异系数（CV）与低血糖的关系，并确定降低中国T1DM患者低血糖风险的最佳CV临界值。

致编辑：皮肌炎（DM）是一种罕见的自身免疫性疾病，以特定的皮肤表现和近端肌无力为特征，其中甲襞毛细血管（NFC）异常和血管生物标志物的血清水平很常见。血管病变的动态变化在DM的发生发展中起着重要作用，反映了疾病的活动性和治疗疗效。由于DM患者临床表现的多样性，血管受累往往被低估，导致难治性血管损伤的治疗具有挑战性。本文旨在探讨糖尿病血管病变的机制、临床表现和治疗方案，以达到早期识别和改善预后。

致编辑：急性胰腺炎（AP）是导致急性住院的最常见胃肠道疾病。^[1]近几十年来，AP的发病率有所增加，目前全球发病率为34/100,000，这可能是由于肥胖和胆结石疾病的上升趋势。AP与显著的疼痛、生活质量（QoL）下降甚至死亡相关，因此造成了沉重的社会经济负担。此外，大约22%的AP患者经历复发性AP(RAP)，10%的AP患者进展为慢性胰腺炎。^[2]彼得罗夫和亚达夫^[3]因此，我认为AP不应被视为一种急性和自限性疾病。AP后的治疗和长期护理已引起广泛关注，改善了患者的身心健康。

在最初的文章发表之后，^[1]作者告诉我们以下错误。第三个小组(c)图2和假面板图7是不正确的。修正后的数字如下所示。这些错误不影响文章的结果和结论。作者真诚地为错误道歉。