2024年 · 第137卷第02期

The annual incidence of amyloid light-chain (AL) amyloidosis is 3–5/million, and the incidence in men is slightly higher than that in women. Approximately, 70% of patients with newly diagnosed AL amyloidosis have cardiac involvement.

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.

Diagnostic methods for urothelial carcinomas (UCs) are often invasive or have suboptimal accuracy. Methylation of exfoliated cell DNA or cell-free DNA in urine has shown great promise in the diagnosis of UCs. However, most current studies have focused on bladder cancer (BCa), and only a few high-plex methylated DNA panels based on large-volume urine have been reported to exhibit both high sensitivity and specificity.^[1,2]The purpose of this study was to identify universal biomarkers for BCa and upper tract urothelial carcinoma (UTUC) using a small volume of urine. We developed a dual-target diagnostic panel comprising the novel markerAL021918.2and the well-known BCa biomarker Vimentin (VIM). This panel can accurately detect UCs using only 1.8 mL of full-voided urine.

To the Editor:Colorectal cancer (CRC) is a major cause of cancer-related death worldwide, and several pathogens with carcinogenic potential, such asSchistosoma, have been associated with an increased risk of CRC. As a frequently mutated gene in CRC patients, kirsten rat sarcoma viral oncogene homolog (KRAS) helps to determine the selection of CRC therapies. Therefore, we aimed to elucidate the association amongSchistosomainfection,KRASmutation status, and the prognosis of CRC in this study.

To the Editor: Chronic kidney disease (CKD) is a critical health threat. An elevated urinary albumin-creatinine ratio (UACR) is a marker of impaired renal function and is a key risk factor for cardiovascular disease. The rate-pressure product (RPP)^[1]and pressure rate quotient (PRQ) are widely used as methods to quantify cardiac load and hemodynamic response to exercise in clinical practice. Therefore, to better predict CKD, it is of great significance to explore the relationships between RPP or PRQ and UACR.

To the Editor: With an aging global population, the incidences of community-acquired pneumonia (CAP) and chronic obstructive pulmonary disease (COPD) have significantly increased.^[1]Previous studies have confirmed that COPD and asthma are independently associated with the prevalence of CAP. The use of inhaled corticosteroid (ICS), the cornerstone of treatment for asthma, COPD with frequent acute exacerbations, and asthma-COPD overlap (ACO) may induce changes in the local lung microbiome and abnormal lung immunity, ultimately, causing a significantly increased risk of pneumonia. However, in cases of pneumonia, the effect of the use of ICS on CAP mortality remains controversial. While data from one study favored the prior use of ICS, which was associated with a significantly lower short-term mortality rate,^[2]other studies have identified no impact on mortality. To date, data on the impact of the use of ICS on mortality, prehospitalization or during hospitalization, are scarce, particularly in the older population. Therefore, this multicenter, retrospective study explored the association between the use of ICS during hospitalization and short-term mortality in older patients with CAP and those with chronic pulmonary disease (CPD).

To the Editor: Type 1 diabetes mellitus (T1DM) is a progressive disease caused by severe islet β-cell function impairment, resulting in high glucose variability (GV) in patients.^[1]While intensive insulin treatment enabled T1DM patients to achieve near-normal glucose, reflected by reduced hemoglobin A1c (HbA1c) levels, stricter HbA1c targets were associated with an increased risk of hypoglycemia, which would compromise patients’ quality of life and survival.^[2]Recent studies suggest that GV reflects hypoglycemia better than HbA1c alone, and continuous glucose monitoring (CGM) provides a more comprehensive glycemic profile for better glucose indices assessment.^[3]Therefore, we aimed to explore the relationship between the coefficient of variability (CV) of blood glucose and hypoglycemia in T1DM patients with different HbA1c levels and to identify the optimal cut-off values of CV for reducing the hypoglycemia risk in Chinese T1DM patients.

To the Editor: Dermatomyositis (DM) is a rare autoimmune disease characterized by specific cutaneous manifestations and proximal muscle weakness, in which abnormalities of nailfold capillary (NFC) and serum levels of vascular biomarkers are common. Dynamic changes in vascular lesions play an important role in the occurrence and development of DM and reflect the disease activity and treatment efficacy. Due to the diversity of clinical manifestations in DM patients, vascular involvement is often under-evaluated, causing the treatment of refractory vascular damage challenging. This review aims to explore the mechanisms, clinical manifestations, and treatment options of vasculopathy in DM to achieve early recognition and improve prognosis.

To the Editor: Acute pancreatitis (AP) is the most common gastrointestinal condition that leads to acute hospitalization.^[1]The incidence of AP has increased in recent decades, with a current global incidence of 34/100,000, probably due to a rising trend of obesity and gallstone disease. AP is associated with remarkable pain, reduced quality of life (QoL), and even death, thus posing a heavy socioeconomic burden. In addition, approximately 22% of AP patients experience recurrent AP (RAP) and 10% of AP patients progress to chronic pancreatitis.^[2]Petrov and Yadav^[3]have, therefore, argued that AP should not be considered as an acute and self-limiting disease. Treatment and long-term care after AP have drawn widespread attention, which has improved patients’ physical and mental health.

Following the original article’s publication,^[1]the authors informed us of the following errors. The third panel (c) inFigure 2and the sham panel inFigure 7are incorrect. The corrected Figures are shown below. The errors do not affect the results and conclusions of the article. The authors sincerely apologize for the errors.