2023年 · 第136卷第06期

Obstructive sleep apnea (OSA) is a common condition that has considerable impacts on human health. Epigenetics has become a rapidly developing and exciting area in biology, and it is defined as heritable alterations in gene expression and has regulatory effects on disease progression. However, the published literature that is integrating both of them is not sufficient. The purpose of this article is to explore the relationship between OSA and epigenetics and to offer better diagnostic methods and treatment options. Epigenetic modifications mainly manifest as post-translational modifications in DNA and histone proteins and regulation of non-coding RNAs. Chronic intermittent hypoxia-mediated epigenetic alterations are involved in the progression of OSA and diverse multiorgan injuries, including cardiovascular disease, metabolic disorders, pulmonary hypertension, neural dysfunction, and even tumors. This article provides deeper insights into the disease mechanism of OSA and potential applications of targeted diagnosis, treatment, and prognosis in OSA complications.

The clinical efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in reducing major cardiovascular adverse events related to atherosclerotic cardiovascular disease (ASCVD) has been well established in recent large randomized outcome trials. Although the cardiovascular and all-cause mortality benefit of PCSK9i remains inconclusive, current cholesterol management guidelines have been modified toward more aggressive goals for lowering low-density lipoprotein cholesterol (LDL-C). Consequently, the emerging concept of "the lower the better" has become the paradigm of ASCVD prevention. However, there is evidence from observational studies of a U-shaped association between baseline LDL-C levels and all-cause mortality in population-based cohorts. Among East Asian populations, low LDL-C was associated with an increased risk for hemorrhagic stroke in patients not on antithrombotic therapy. Accumulating evidence showed that low LDL-C was associated with an enhanced bleeding risk in patients on dual antiplatelet therapy following percutaneous coronary intervention. Additionally, low LDL-C was associated with a higher risk for incident atrial fibrillation and thereby, a possible increase in the risk for intracranial hemorrhage after initiation of anticoagulation therapy. The mechanism of low-LDL-C-related bleeding risk has not been fully elucidated. This review summarizes recent evidence of low-LDL-C-related bleeding risk in patients on antithrombotic therapy and discusses potential measures for reducing this risk, underscoring the importance of carefully weighing the pros and cons of aggressive LDL-C lowering in patients on antithrombotic therapy.

Regulated cell death (RCD), including apoptosis, pyroptosis, necroptosis, and ferroptosis, is regulated by a series of evolutionarily conserved pathways, and is required for development and tissue homeostasis. Based on previous genetic and biochemical explorations of cell death subroutines, the characteristics of each are generally considered distinctive. However, recent in-depth studies noted the presence of crosstalk between the different forms of RCD; hence, the concept of PANoptosis appeared. Cancer, a complex genetic disease, is characterized by stepwise deregulation of cell apoptosis and proliferation, with significant morbidity and mortality globally. At present, studies on the different RCD pathways, as well as the intricate relationships between different cell death subroutines, mainly focus on infectious diseases, and their roles in cancer remain unclear. As cancers are characterized by dysregulated cell death and inflammatory responses, most current treatment strategies aim to selectively induce cell death via different RCD pathways in cancer cells. In this review, we describe five types of RCD pathways in detail with respect to tumorigenesis and cancer progression. The potential value of some of these key effector molecules in tumor diagnosis and therapeutic response has also been raised. We then review and highlight recent progress in cancer treatment based on PANoptosis and ferroptosis induced by small-molecule compounds, immune checkpoint inhibitors, and nanoparticles. Together, these findings may provide meaningful evidence to fill in the gaps between cancer pathogenesis and RCD pathways to develop better cancer therapeutic strategies.

The glucose metabolism is crucial for sustained brain activity as it provides energy and is a carbon source for multiple biomacromolecules; glucose metabolism decreases dramatically in Alzheimer’s disease (AD) and may be a fundamental cause for its development. Recent studies reveal that the alternative splicing events of certain genes effectively regulate several processes in glucose metabolism including insulin receptor, insulin-degrading enzyme, pyruvate kinase M, receptor for advanced glycation endproducts, and others, thereby, influencing glucose uptake, glycolysis, and advanced glycation end-products-mediated signaling pathways. Indeed, the discovery of aberrant alternative splicing that changes the proteomic diversity and protein activity in glucose metabolism has been pivotal in our understanding of AD development. In this review, we summarize the alternative splicing events of the glucose metabolism-related genes in AD pathology and highlight the crucial regulatory roles of splicing factors in the alternative splicing process. We also discuss the emerging therapeutic approaches for targeting splicing factors for AD treatment.

At present, a large number of chronic obstructive pulmonary disease (COPD) patients are undiagnosed in China. Thus, this study aimed to develop a simple prediction model as a screening tool to identify patients at risk for COPD.

The study was based on the data of 22,943 subjects aged 30 to 79 years and enrolled in the second resurvey of China Kadoorie Biobank during 2012 and 2013 in China. We stepwisely selected the predictors using logistic regression model. Then we tested the model validity through P-P graph, area under the receiver operating characteristic curve (AUROC), ten-fold cross validation and an external validation in a sample of 3492 individuals from the Enjoying Breathing Program in China.

The final prediction model involved 14 independent variables, including age, sex, location (urban/rural), region, educational background, smoking status, smoking amount (pack-years), years of exposure to air pollution by cooking fuel, family history of COPD, history of tuberculosis, body mass index, shortness of breath, sputum and wheeze. The model showed an area under curve (AUC) of 0.72 (95% confidence interval [CI]: 0.72-0.73) for detecting undiagnosed COPD patients, with the cutoff of predicted probability of COPD=0.22, presenting a sensitivity of 70.13% and a specificity of 62.25%. The AUROC value for screening undiagnosed patients with clinically significant COPD was 0.68 (95% CI: 0.66-0.69). Moreover, the ten-fold cross validation reported an AUC of 0.72 (95% CI: 0.71-0.73), and the external validation presented an AUC of 0.69 (95% CI: 0.68-0.71).

This prediction model can serve as a first-stage screening tool for undiagnosed COPD patients in primary care settings.

The ideal blood pressure (BP) target for patients with atrial fibrillation (AF) is still unclear. The present study aimed to assess the effect of the baseline BP on all-cause mortality in patients with AF.

This registry study included 20 emergency centers across China and consecutively enrolled patients with AF from 2008 to 2011. All participants were followed for 1 year ± 1 month. The primary endpoint was all-cause mortality.

During the follow-up, 276 (13.9%) all-cause deaths occurred. Kaplan-Meier curves showed that a systolic blood pressure (SBP) ≤110 mmHg or >160 mmHg was associated with a higher risk of all-cause mortality (log-rank test, P = 0.014), and a diastolic blood pressure (DBP) <70 mmHg was associated with the highest risk of all-cause mortality (log-rank test, P = 0.002). After adjusting for confounders, the multivariable Cox regression model suggested that the risk of all-cause mortality was increased in the group with SBP ≤110 mmHg (hazard ratio [HR], 1.963; 95% confidence interval [CI], 1.306-2.951), and DBP <70 mmHg (HR, 1.628; 95% CI, 1.163-2.281). In the restricted cubic splines, relations between baseline SBP or DBP and all-cause mortality showed J-shaped associations (non-linear P <0.001 and P = 0.010, respectively). The risk of all-cause mortality notably increased at a lower baseline SBP and DBP.

Having a baseline SBP ≤110 mmHg or DBP <70 mmHg was associated with a significantly higher risk of all-cause mortality in patients with AF. An excessively low BP may not be an optimal target for patients with AF.

Heterogeneity of tumor cells and the tumor microenvironment (TME) is significantly associated with clinical outcomes and treatment responses in patients with urothelial carcinoma (UC). Comprehensive profiling of the cellular diversity and interactions between malignant cells and TME may clarify the mechanisms underlying UC progression and guide the development of novel therapies. This study aimed to extend our understanding of intra-tumoral heterogeneity and the immunosuppressive TME in UC and provide basic support for the development of novel UC therapies.

Seven patients with UC were included who underwent curative surgery at our hospital between July 2020 and October 2020. We performed single-cell RNA sequencing (scRNA-seq) analysis in seven tumors with six matched adjacent normal tissues and integrated the results with two public scRNA-seq datasets. The functional properties and intercellular interactions between single cells were characterized, and the results were validated using multiplex immunofluorescence staining, flow cytometry, and bulk transcriptomic datasets. All statistical analyses were performed using the R package with two-sided tests. Wilcoxon-rank test, log-rank test, one-way analysis of variance test, and Pearson correlation analysis were used properly.

Unsupervised t-distributed stochastic neighbor embedding clustering analysis identified ten main cellular subclusters in urothelial tissues. Of them, seven urothelial subtypes were noted, and malignant urothelial cells were characterized with enhanced cellular proliferation and reduced immunogenicity. CD8⁺ T cell subclusters exhibited enhanced cellular cytotoxicity activities along with increased exhaustion signature in UC tissues, and the recruitment of CD4⁺ T regulatory cells was also increased in tumor tissues. Regarding myeloid cells, coordinated reprogramming of infiltrated neutrophils, M2-type polarized macrophages, and LAMP3⁺ dendritic cells contribute to immunosuppressive TME in UC tissues. Tumor tissues demonstrated enhanced angiogenesis mediated by KDR⁺ endothelial cells and RGS5⁺/ACTA2⁺ pericytes. Through deconvolution analysis, we identified multiple cellular subtypes may influence the programmed death-ligand 1 (PD-L1) immunotherapy response in patients with UC.

Our scRNA-seq analysis clarified intra-tumoral heterogeneity and delineated the pro-tumoral and immunosuppressive microenvironment in UC tissues, which may provide novel therapeutic targets.

With functionally heterogeneous cells, tumors comprise a complex ecosystem to promote tumor adaptability and evolution under strong selective pressure from the given microenvironment. Diversifying tumor cells or intra-tumor heterogeneity is essential for tumor growth, invasion, and immune evasion. However, no reliable method to classify tumor cell subtypes is yet available. In this study, we introduced the single-cell sequencing combined with copy number characteristics to identify the types of tumor cells in microsatellite stable (MSS) colorectal cancer (CRC).

To characterize the somatic copy number alteration (SCNA) of MSS CRC in a single cell profile, we analyzed 26 tissue samples from 19 Korean patients (GSE132465, the Samsung Medical Center [SMC] dataset) and then verified our findings with 15 tissue samples from five Belgian patients (GSE144735, the Katholieke Universiteit Leuven 3 [KUL3] dataset). The Cancer Genome Atlas (TCGA) cohort, GSE39582 cohort, and National Cancer Center (NCC) cohort (24 MSS CRC patients were enrolled in this study between March 2017 and October 2017) were used to validate the clinical features of prognostic signatures.

We employed single cell RNA-sequencing data to identify three types of tumor cells in MSS CRC by their SCNA characteristics. Among these three types of tumor cells, C1 and C3 had a higher SCNA burden; C1 had significant chromosome 13 and 20 amplification, whereas C3 was the polar opposite of C1, which exhibited deletion in chromosome 13 and 20. The three types of tumor cells exhibited various functions in the tumor microenvironment and harbored different mutations. C1 and C2 were linked to the immune response and hypoxia, respectively, while C3 was critical for cell adhesion activity and tumor angiogenesis. Additionally, one gene (OLFM4) was identified as epithelium-specific biomarker of better prognosis of CRC (TCGA cohort: P = 0.0110; GSE39582 cohort: P= 0.0098; NCC cohort: P= 0.0360).

On the basis of copy number characteristics, we illustrated tumor heterogeneity in MSS CRC and identified three types of tumor cells with distinct roles in tumor microenvironment. By understanding heterogeneity in the intricate tumor microenvironment, we gained an insight into the mechanisms of tumor evolution, which may support the development of therapeutic strategies.

Sirtuin-3 (Sirt3) has been documented to protect against mitochondrial dysfunction and apoptosis. Honokiol (HKL) is a Sirt3 pharmacological activator with reported neuroprotective effects in multiple neurological disorders. The present study aimed to explore the neuroprotective effects of HKL and the role of Sirt3 following intracerebral hemorrhage (ICH).

An in vivo ICH model in rats was established by injecting autologous blood into the right basal ganglia. PC12 cells were stimulated with hemin. For the in vivo investigation, the modified Neurological Severity Scores and the Morris water maze test were performed to assess neurological deficits. Hematoxylin-Eosin and Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining were employed to evaluate the histopathology and apoptosis. Immunohistochemical staining was used to investigate the expression of Sirt3. Adenosine triphosphate (ATP) levels were quantified to assess mitochondrial dysfunction. Cell counting kit-8, lactate dehydrogenase assay, and flow cytometry were used to analyze cell vitality and apoptosis in vitro. Immunofluorescence staining was performed to observe mitochondrial morphology and dynamin-related protein 1 (Drp1) localization to mitochondria. Western blot was applied to quantify the expression of Sirt3, Bax, Bcl-2, cleaved-caspase-3, Drp1, phosphorylation of Drp1 at serine-616, and phosphorylation of Drp1 at serine-637 in vivo and in vitro.

HKL treatment alleviated neurological deficits, attenuated the histopathological damage and cell apoptosis, and restored the decreased ATP levels in ICH rats. HKL improved cell survival rate, reduced cell apoptosis, and inhibited mitochondrial fission in PC12 cells. Moreover, both in vivo and in vitro models showed increased phosphorylation of Drp1 at Ser616, and reduced phosphorylation of Drp1 at Ser637. Meanwhile, immunofluorescence co-localization analysis revealed that hemin increased the overlap of Drp1 and mitochondria in PC12 cells. The phosphorylation and mitochondrial translocation of Drp1 were effectively reversed by HKL treatment. Importantly, the selective Sirt3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine suppressed these effects.

Our findings demonstrated that HKL ameliorated ICH-induced apoptosis and mitochondrial fission by Sirt3, suggesting that HKL has immense prospects for the treatment of ICH.

To the Editor: Extranodal natural killer/T-cell lymphoma (ENKTCL) is a highly aggressive lymphoma, closely associated with Epstein-Barr virus (EBV) infection. By using the combination of radiotherapy (RT) and asparaginase-based chemotherapy, more than 70% of patients with early stage ENKTCL have been cured.^[1]However, great challenges exist among patients at newly diagnosed advanced stage or relapsed/refractory ENKTCL. Hemophagocytic lymphohistiocytosis (HLH) is a fatal syndrome characterized by persistent fever, cytopenia, hepatosplenomegaly, and multi-organ dysfunction. A previous study demonstrated that patients with concurrent HLH and ENKTCL had a 6-month overall survival (OS) rate of merely 34.4%.^[2]Thus, new regimens are urgently needed to improve the prognosis of patients with advanced disease, especially those with concurrent HLH. In this study, we reported a new combination chemotherapy regimen of gemcitabine, pegaspargase, etoposide, and dexamethasone (GPED), and GPED was shown to be effective and well tolerable, which is worthy of validation in future prospective clinical trials.

To the Editor:Autoimmune liver disease is a chronic immune-mediated liver disease. The term "overlap syndrome" (OS) is used to describe the conditions in which patients simultaneously or consecutively present with features of primary biliary cholangitis (PBC) or primary sclerosing cholangitis and autoimmune hepatitis (AIH).^[1]PBC-AIH OS is described most frequently,^[2]with a prevalence of approximately 8% to 20% in adult patients with either pure PBC or AIH.

To the Editor: Ankylosing spondylitis (AS) is a chronic inflammatory disease that causes bony fusion of spine and sacroiliac joints, resulting in restricted spinal movement and deformity. In China, the prevalence of AS is about 0.29% with a male to female ratio of approximately 3:1, and most cases occur in the adolescent period.^[1]The misdiagnosis rate of AS patients in China is >50%, and the average delay time of diagnosis is >7 years. Without standardized treatment, the 3-year disability rate of AS patients can reach 45.5%, and the 5-year disability rate can reach 70%. At present, there are approximately 100,000 AS people among the low-income population registered in China, including about 20,000 people with moderate to severe AS. Lacking timely and correct treatment, nearly half of patients suffer from different degrees of disability every year, and most of them give up treatment for financial conditions, resulting in lifelong paralysis. 10.5% of male AS patients, as the "breadwinners" of family, lose their jobs due to the decline in working ability, absence of treatment, and unaffordable treatment cost, causing a serious impact on the patient, family, and society.^[2]Thus, it is an important social health problem to tackle poverty and return of poverty among people with moderate to severe AS in developing areas.

To the Editor:Fetal pulmonary atresia with intact ventricular septum (PA/IVS) or critical pulmonary stenosis (CPS) is a progressive disease from the time of midgestation diagnosis to birth. Elevated right ventricular (RV) afterload results in RV hypertrophy and reduced compliance, as well as a lack of flow through the right side of the heart, which leads to progressive RV and tricuspid valve growth arrest, and secondary damage of the RV myocardium. Studies have shown that tricuspid valve size, tricuspid valveZ-score, tricuspid regurgitation (TR), right ventricle dependent coronary circulation (RVDCC), and subaortic stenosis are all related to the two-ventricle postnatal strategy.^[1]Most fetuses with PA/IVS or CPS with hypoplastic right heart syndrome (HRHS) will survive until birth, but with high morbidity and mortality during postnatal life.^[2]Significant RV dysplasia may require multiple complex surgical strategies or other interventions during the patient’s lifetime.^[3]

To the Editor:Acute necrotizing encephalopathy (ANE) is a rare but often devastating neurologic disorder in children.^[1]Hereditary susceptibility and cytokine storm play important roles in ANE pathogenesis,^[2,3]but the specific molecular biological mechanism is unclear. The mortality rate among children with ANE is approximately 30%, and most surviving patients are left with various degrees of neurological sequelae.^[1,4]

To the Editor:Glioma is a highly invasive and lethal heterogeneous disease caused by glial or precursor cell mutation. It accounts for about 50% of tumors in children and 80% of malignant tumors.^[1]The nucleotide excision repair (NER) pathway is a process that involves the sequential assembly of many proteins, including excision repair cross complementation group 1 (ERCC1) and xeroderma pigmentosum complementation group F (XPF, also known as ERCC4). They play key roles in repairing DNA damages caused by ultraviolet light and helixdistorting adducts. The ERCC1-XPF forms a dimer to produce a multifunctional endonuclease essential for DNA repair.^[2]Without DNA repair, DNA lesions aggregate and develop into glioma. The single nucleotide polymorphisms (SNPs) of genes involved in the DNA repair pathway may be potential targets for altering the risk of glioma. At present, the relationship between polymorphisms of these two genes and glioma has rarely been described.

To the Editor:Septate uterus is a uterine malformation caused by abnormal resorption of the midline septum after fusion of the Müllerian ducts and it can be classified into the complete and incomplete septum. It affects 2 % of women of reproductive age, leading to poor fertility outcomes.^[1]However, the adverse effects of this malformed uterine environment, especially the postmetroplasty uterine environment, on fetal development are unclear.

To the Editor:Sarcopenia is defined as age-related loss of skeletal muscle mass and strength, with an incidence of 5 % to 13% in persons aged >60 years.^[1]Sarcopenia is considered a major contributor of frailty in the elderly, and frailty is reported to be associated with poor outcomes of older people. Sarcopenia can also increase the risk of falls and fractures, leading to lower quality of life, other related diseases, and even death. Thus, early screening of sarcopenia is recommended for older people. The universally accepted diagnostic criteria of sarcopenia include the measurement of muscle mass, muscle strength, and muscle function.^[2]Among the muscle mass measurement methods, magnetic resonance imaging, computed tomography, and dual-energy X-ray absorptiometry were difficult to popularize because of the high cost or radiation exposure. Bioelectrical impedance analysis (BIA) is a non-invasive, portable, and economical method; however, its results can be affected by various factors such as hydration status, food intake, and fat distribution. The above deficiencies limit its use in the screening of sarcopenia; thus, a multi-parameter screening tool based on easy-to-get and reliable clinical factors is urgently needed.

To the Editor: Post-vitrectomy vitreous hemorrhage (PVH) is one of the most common complications of vitrectomy.^[1,2,3]Unfortunately, there have been no studies on how to adopt a conservative approach to PVH. We describe a method that eliminates the need to go to the operating room and mechanically accelerates the removal of PVH.