Volume 136 · Issue 06 · 2023

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.

致编辑：结外自然杀伤/T细胞淋巴瘤(ENKTCL)是一种高度侵袭性的淋巴瘤，与EB病毒(EBV)感染密切相关。通过使用放疗（RT）和基于天冬酰胺酶的化疗的组合，超过70%的早期ENKTCL患者已经被治愈。^[1]然而，在新诊断的晚期或复发/难治性ENKTCL患者中存在巨大挑战。噬血细胞性淋巴组织细胞增多症（HLH）是一种以持续发热、血细胞减少、肝脾肿大和多器官功能障碍为特征的致命综合征。先前的一项研究表明，同时患有HLH和ENKTCL的患者的6个月总生存率（OS）仅为34.4%。^[2]因此，迫切需要新的治疗方案来改善晚期疾病患者的预后，尤其是那些同时患有HLH的患者。在这项研究中，我们报告了一种新的吉西他滨、培门冬酶、依托泊苷和地塞米松（GPED）的联合化疗方案，GPED被证明是有效的和良好的耐受性，值得在未来的前瞻性临床试验中验证。

致编辑：自身免疫性肝病是一种慢性免疫介导的肝病。术语“重叠综合征”(OS)用于描述患者同时或连续出现原发性胆汁性胆管炎(PBC)或原发性硬化性胆管炎和自身免疫性肝炎(AIH)特征的病症。^[1]PBC-AIH OS最常被描述，^[2]在患有纯PBC或AIH的成年患者中，患病率约为8%至20%。

致编辑：强直性脊柱炎（AS）是一种引起脊柱和骶髂关节骨性融合，导致脊柱活动受限和畸形的慢性炎症性疾病。在中国，AS的患病率约为0.29%，男女比例约为3：1，大多数病例发生在青春期。^[1]我国AS患者误诊率>50%，平均诊断延迟时间>7年。如不规范治疗，AS患者3年致残率可达45.5%，5年致残率可达70%。目前，中国登记在册的低收入人群中约有10万AS人群，其中中重度AS约2万人。由于缺乏及时正确的治疗，每年有近一半的患者出现不同程度的残疾，大多数患者因经济条件放弃治疗，导致终身瘫痪。10.5%的男性AS患者作为家庭的“养家糊口者”，因工作能力下降、治疗缺位、治疗费用难以承受而失业，给患者、家庭和社会造成严重影响。^[2]因此，解决发展中地区中重度AS人群的贫困和返贫是一个重要的社会健康问题。

致编辑：胎儿肺动脉闭锁伴室间隔完整（PA/IVS）或临界肺动脉狭窄（CPS）是一种从妊娠中期诊断到出生的进行性疾病。右心室（RV）后负荷升高导致RV肥大和顺应性降低，以及缺乏通过心脏右侧的血流，这导致进行性RV和三尖瓣生长停滞，以及RV心肌的继发性损伤。研究表明，三尖瓣大小、三尖瓣Z-评分、三尖瓣反流（TR）、右心室依赖性冠状动脉循环（RVDCC）、主动脉瓣下狭窄均与双心室产后策略有关。^[1]大多数患有PA/IVS或CPS伴右心发育不全综合征（HRHS）的胎儿将存活至出生，但在出生后生活中发病率和死亡率很高。^[2]在患者的一生中，严重的右心室发育不良可能需要多种复杂的手术策略或其他干预。^[3]

致编辑：急性坏死性脑病（ANE）是一种罕见但往往具有破坏性的儿童神经系统疾病。^[1]遗传易感性和细胞因子风暴在ANE发病机制中起重要作用，^[2,3]但具体的分子生物学机制尚不清楚。ANE患儿的死亡率约为30%，大多数存活患者留下不同程度的神经系统后遗症。^[1,4]

致编辑：胶质瘤是一种由胶质或前体细胞突变引起的高度侵袭性和致死性的异质性疾病。约占儿童肿瘤的50%，占恶性肿瘤的80%。^[1]核苷酸切除修复(NER)途径是涉及许多蛋白质的顺序组装的过程，包括切除修复交叉互补组1(ERCC1)和着色性干皮病互补组F(XPF，也称为ERCC4)。它们在修复由紫外线和螺旋扭曲加合物引起的DNA损伤中起着关键作用。ERCC1-XPF形成二聚体以产生DNA修复所必需的多功能核酸内切酶。^[2]没有DNA修复，DNA损伤聚集并发展为神经胶质瘤。参与DNA修复途径的基因的单核苷酸多态性（SNPs）可能是改变神经胶质瘤风险的潜在靶点。目前，这两个基因的多态性与胶质瘤的关系还很少被描述。

致编辑：间隔子宫是指苗勒管融合后中线间隔异常吸收引起的子宫畸形，可分为完全性和不完全性。它影响了2%的育龄妇女，导致不良的生育结果。^[1]然而，这种畸形子宫环境，尤其是子宫成形术后子宫环境对胎儿发育的不利影响尚不清楚。

致编辑：肌肉减少症被定义为骨骼肌质量和力量与年龄相关的损失，在>60岁的人群中发病率为5%至13%。^[1]肌肉减少症被认为是老年人虚弱的主要原因，据报道虚弱与老年人的不良结局相关。肌肉减少症还会增加跌倒和骨折的风险，导致生活质量下降、其他相关疾病，甚至死亡。因此，建议老年人对肌肉减少症进行早期筛查。普遍接受的肌肉减少症的诊断标准包括肌肉质量、肌肉力量和肌肉功能的测量。^[2]在肌肉质量测量方法中，磁共振成像、计算机断层扫描和双能X线吸收法因成本高或辐射暴露而难以推广。生物电阻抗分析（BIA）是一种非侵入性、便携和经济的方法；然而，其结果会受到各种因素的影响，如水合状态、食物摄入和脂肪分布。上述缺陷限制了其在肌肉减少症筛查中的应用；因此，迫切需要一种基于易于获得和可靠的临床因素的多参数筛查工具。

致编辑：玻璃体切除术后玻璃体出血（PVH）是玻璃体切除术最常见的并发症之一。^[1,2,3]不幸的是，还没有关于如何对PVH采取保守方法的研究。我们描述了一种无需前往手术室并机械加速PVH去除的方法。