Volume 138 · Issue 04 · 2025

Male infertility has become a global concern, accounting for 20-70% of infertility. Dysfunctional spermatogenesis is the most common cause of male infertility; thus, treating abnormal spermatogenesis may improve male infertility and has attracted the attention of the medical community. Mitochondria are essential organelles that maintain cell homeostasis and normal physiological functions in various ways, such as mitochondrial oxidative phosphorylation (OXPHOS). Mitochondrial OXPHOS transmits electrons through the respiratory chain, synthesizes adenosine triphosphate (ATP), and produces reactive oxygen species (ROS). These mechanisms are vital for spermatogenesis, especially to maintain the normal function of testicular Sertoli cells and germ cells. The disruption of mitochondrial OXPHOS caused by external factors can result in inadequate cellular energy supply, oxidative stress, apoptosis, or ferroptosis, all inhibiting spermatogenesis and damaging the male reproductive system, leading to male infertility. This article summarizes the latest pathological mechanism of mitochondrial OXPHOS disorder in testicular Sertoli cells and germ cells, which disrupts spermatogenesis and results in male infertility. In addition, we also briefly outline the current treatment of spermatogenic malfunction caused by mitochondrial OXPHOS disorders. However, relevant treatments have not been fully elucidated. Therefore, targeting mitochondrial OXPHOS disorders in Sertoli cells and germ cells is a research direction worthy of attention. We believe this review will provide new and more accurate ideas for treating male infertility.

This review aimed to provide a comprehensive analysis of the etiology, epidemiology, pathology, and conventional treatment of heterotopic ossification (HO), especially emerging potential therapies. HO is the process of ectopic bone formation at non-skeletal sites. HO can be subdivided into two major forms, acquired and hereditary, with acquired HO predominating. Hereditary HO is a rare and life-threatening genetic disorder, but both acquired and hereditary form can cause severe complications, such as peripheral nerve entrapment, pressure ulcers, and disability if joint ankylosis develops, which heavily contributes to a reduced quality of life. Modalities have been proposed to treat HO, but none have emerged as the gold standard. Surgical excision remains the only effective modality; however, the optimal timing is controversial and may cause HO recurrence. Recently, potential therapeutic strategies have emerged that focus on the signaling pathways involved in HO, and small molecule inhibitors have been shown to be promising. Moreover, additional specific targets, such as small interfering RNAs (siRNAs) and non-coding RNAs, could be used to effectively block HO or develop combinatorial therapies for HO.

Hypotension is a leading cause of age-related cognitive impairment. The available literature evidences that vascular factors are associated with dementia and that hypotension alters cerebral perfusion flow and can aggravate the neurodegeneration of Alzheimer’s disease (AD). Despite the discovery of biomarkers and the recent progress made in neurovascular biology, epidemiology, and brain imaging, some key issues remain largely unresolved: the potential mechanisms underlying the neural deterioration observed in AD, the effect of cerebrovascular alterations on cognitive deficits, and the positive effects of hypotension treatment on cognition. Therefore, further well-designed studies are needed to unravel the potential association between hypotension and cognitive dysfunction and reveal the potential benefits of hypotension treatment for AD patients. Here, we review the current epidemiological, pathobiological, and treatment-related literature on neurovascular changes and hypotension-related cognitive dysfunction and highlight the unsettled but imminent issues that warrant future research endeavors.

The main cause of restenosis after percutaneous transluminal angioplasty (PTA) is the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). Lin28a has been reported to play critical regulatory roles in this process. However, whether CCAAT/enhancer-binding proteins β (C/EBPβ) binds to the Lin28a promoter and drives the progression of restenosis has not been clarified. Therefore, in the present study, we aim to clarify the role of C/EBPβ-Lin28a axis in restenosis.

Restenosis and atherosclerosis rat models of type 2 diabetes (n = 20, for each group) were established by subjecting to PTA. Subsequently, the difference in DNA methylation status and expression of C/EBPβ between the two groups were assessed. EdU, Transwell, and rescue assays were performed to assess the effect of C/EBPβ on the proliferation and migration of VSMCs. DNA methylation status was further assessed using Methyltarget sequencing. The interaction between Lin28a and ten-eleven translocation 1 (TET1) was analysed using co-immunoprecipitation (Co-IP) assay. Student’s t-test and one-way analysis of variance were used for statistical analysis.

C/EBPβ expression was upregulated and accompanied by hypomethylation of its promoter in restenosis when compared with atherosclerosis. In vitro C/EBPβ overexpression facilitated the proliferation and migration of VSMCs and was associated with increased Lin28a expression. Conversely, C/EBPβ knockdown resulted in the opposite effects. Chromatin immunoprecipitation assays further demonstrated that C/EBPβ could directly bind to Lin28a promoter. Increased C/EBPβ expression and enhanced proliferation and migration of VSMCs were observed after decitabine treatment. Further, mechanical stretch promoted C/EBPβ and Lin28a expression accompanied by C/EBPβ hypomethylation. Additionally, Lin28a overexpression reduced C/EBPβ methylation via recruiting TET1 and enhanced C/EBPβ-mediated proliferation and migration of VSMCs. The opposite was noted in Lin28a knockdown cells.

Our findings suggest that the C/EBPβ-Lin28a axis is a driver of restenosis progression, and presents a promising therapeutic target for restenosis.

To evaluate the efficacy and safety of the first cohort of people in China treated with a responsive neurostimulation system (Epilcure^TM, GenLight MedTech, Hangzhou, China) for focal drug-resistant epilepsy in this study.

This multicenter, before-and-after self-controlled study was conducted across 8 centers from March 2022 to June 2023, involving patients with drug-resistant epilepsy who were undergoing responsive neurostimulation (RNS). The study was based on an ongoing multi-center, single-blind, randomized controlled study. Efficacy was assessed through metrics including median seizure count, seizure frequency reduction (SFR), and response rate. Multivariable linear regression analysis was conducted to explore the relationships of basic clinical factors and intracranial electrophysiological characteristics with SFR. The postoperative quality of life, cognitive function, depression, and anxiety were evaluated as well.

The follow-up period for the 19 participants was 10.7 ± 3.4 months. Seizure counts decreased significantly 6 months after device activation, with median SFR of 48% at the 6th month (M6) and 58% at M12 (P <0.05). The average response rate after 13 months of treatment was 42%, with 21% (n = 4) of the participants achieving seizure freedom. Patients who have previously undergone resective surgery appear to achieve better therapeutic outcomes at M11, M12 and M13 (β <0, P <0.05). No statistically significant differences were observed in patients’ scores of quality of life, cognition, depression and anxiety following stimulation when compared to baseline measurements. No serious adverse events related to the devices were observed.

The preliminary findings suggest that Epilcure^TM exhibits promising therapeutic potential in reducing the frequency of epileptic seizures. However, to further validate its efficacy, larger-scale randomized controlled trials are required.

Chinese Clinical Trial Registry (No. ChiCTR2200055247)

G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA).

The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism.

In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (T_regs), an increase in the cluster of differentiation 8 positive (CD8⁺) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8⁺ T cells, and induced the proportion of T_regs. Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells.

Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cells in RA.

Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS.

This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide.

Eighty-two patients were assigned to variant (n = 42) and wild type groups (n = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] µg/mL; wild type, 49.1 [32.0] µg/mL) and area under plasma concentration-time curve over a dosing interval (AUC_tau) (variant, 1731.3 [769.0] µg·h/mL; wild type, 1564.5 [1053.0] µg·h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study.

ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients.

NCT04410965, https://clinicaltrials.gov.

This study aims to compare the efficacy between neoadjuvant immune checkpoint inhibitors (ICIs) plus chemotherapy vs. chemotherapy, and neoadjuvant triplet vs. doublet chemotherapeutic regimens in locally advanced gastric/esophagogastric junction cancer (LAGC).

We included LAGC patients from 47 hospitals in China’s National Cancer Information Database (NCID) from January 2019 to December 2022. Using propensity score matching (PSM), we retrospectively analyzed the efficacy between neoadjuvant ICIs plus chemotherapy vs. chemotherapy alone, and neoadjuvant triplet vs. doublet chemotherapeutic regimens. The primary study result was the pathologic complete response (pCR) rate. The secondary study results were disease-free survival (DFS) and overall survival (OS).

A total of 1205 LAGC patients were included. After PSM, the ICIs plus chemotherapy and the chemotherapy cohorts had 184 patients each, while the doublet and triplet chemotherapy cohorts had 246 patients each. The pCR rate (14.13% vs. 7.61%, χ² = 4.039, P = 0.044), and the 2-year (77.60% vs. 61.02%, HR = 0.67, 95% confidence interval [CI] 0.43-0.98, P = 0.048) and 3-year (70.55% vs. 61.02%, HR = 0.58, 95% CI 0.32-0.93, P = 0.048) DFS rates in the ICIs plus chemotherapy cohort were improved compared to those in the chemotherapy cohort. No significant increase was observed in the OS rates at both 1 year and 2 years. The pCR rates, DFS rates at 1-3 years, and OS rates at 1-2 years did not differ significantly between the doublet and triplet cohorts, respectively. No differences were observed in postoperative complications between any of the group comparisons.

Neoadjuvant ICIs plus chemotherapy improved the pCR rate and 2-3 years DFS rates of LAGC compared to chemotherapy alone, but whether short-term benefit could translate into long-term efficacy is unclear. The triplet regimen was not superior to the doublet regimen in terms of efficacy. The safety after surgery was similar between either ICIs plus chemotherapy and chemotherapy or the triplet and the doublet regimen.

致编辑：复发或难治性（R/R）急性淋巴细胞白血病（ALL）患者预后较差，5年总生存期（OS）为25%~50%，缓解诱导治疗具有挑战性。^[1]异基因造血干细胞移植（HSCT）是R/R ALL患者的金标准治疗。在免疫疗法引入临床实践之前，由于化疗的严重不良事件或无法达到可接受的深度缓解，相当比例的患者无法接受HSCT。包括blinatumomab和嵌合抗原受体T（CAR-T）细胞在内的新型免疫疗法已被证明可增强R/R B-ALL的免疫应答并提高治愈率。然而，缺乏CAR-T细胞和blinatumomab之间的直接治疗比较研究，以及阐明haplo-HSCT和新型免疫疗法对ALL的最佳组合的研究。

致编辑慢性阻塞性肺疾病（COPD）是一个全球性的健康挑战，因为它的高患病率和相关的死亡率。^[1]除了气流阻塞之外，多病是COPD的一个显著特征。从合并症的角度进行评估是COPD综合评估的一部分。本研究的目的是分析COPD住院患者合并症的分布及其对预后的影响。

致编辑：肺癌的特点是发病率和死亡率高，在全球范围内造成重大疾病负担。^[1]在非小细胞肺癌（NSCLC）中，肝转移与较差的临床结局和较短的预期寿命相关。^[2]尽管免疫检查点抑制剂（ICIs）彻底改变了NSCLC的治疗，但现有的预测和预后生物标志物的有效性有限，并带来了临床挑战，特别是对于肝转移患者。白蛋白-胆红素（ALBI）分级系统是一种根据血液白蛋白和胆红素水平计算的肝功能障碍的循证测量，在预测非小细胞肺癌的预后和ICI疗效方面显示出前景。^[3]尽管如此，高体重指数（BMI）与ICI治疗非小细胞肺癌总生存期（OS）的改善独立相关。^[4]鉴于尽管接受ICI治疗，肝转移和低BMI患者的预后较差，我们建议同时评估ALBI评分和BMI可以为接受ICI治疗的非小细胞肺癌和肝转移患者提供有价值的预后信息。这项回顾性多中心研究评估了ALBI-B（一种基于逻辑回归的模型，整合了治疗前ALBI评分和BMI）在预测非小细胞肺癌和肝转移患者ICI临床结局中的效用。

致编辑：胃镜检查被认为是诊断胃部病变的主要方法。^[1]但在白光内镜（WLE）下正确诊断不同的胃部病变可能具有挑战性，因为胃部病变的形态表现多种多样，有些甚至很微妙。由于各地诊断水平参差不齐，缺乏有经验的内镜医师，可能会出现误诊、漏诊。此外，内窥镜医师被繁重的工作负荷所淹没，疲劳可能导致诊断性能进一步下降，即使对于经验丰富的内窥镜医师也是如此。

致编辑：目前，大多数关于脂质、免疫细胞和颅内动脉瘤（IAs）之间关系的研究，包括未破裂颅内动脉瘤（uIAs）和动脉瘤性蛛网膜下腔出血（aSAH），都源于观察性研究。^[1]研究设计中存在不可避免的混杂因素，从而研究结论无法揭示脂质、免疫细胞、IAs之间的因果关系。更重要的是，免疫反应是否介导脂质和IAs之间的关系仍不清楚。因此，我们进行了孟德尔随机化（MR）分析，这是一种可以避免混杂因素干扰并确定正确因果关系的方法。^[2]本研究的目的是：（1）确定基因介导的血脂与IAs之间的因果关系；（2）确定免疫细胞与IAs之间的因果关系；以及（3）研究免疫细胞是否介导脂质和IAs之间的关系。

致编辑：抑郁症是一种常见的精神疾病，影响着全球超过2.6亿所有年龄段的人。^[1]先前调查抗抑郁药使用和中风风险之间关系的研究得出了不一致的结果。^[2,3]因此，尚不清楚各种抗抑郁药类别中的哪一种可能影响中风。因此，合理使用抗抑郁药对于降低卒中风险和复发是重要的，同时提供候选治疗靶点。药物靶点孟德尔随机化（MR）分析使用位于药物靶点基因区域内或附近的遗传变异作为药物作用的代理，是识别药物靶点和疾病之间因果联系的有前途的工具。本研究旨在使用药物靶向MR分析评估抗抑郁药靶基因与卒中及其各种亚型（包括任何卒中[AS]、缺血性卒中[IS]、大动脉粥样硬化性卒中[LAA]、心源性栓塞性卒中[CES]和小血管卒中[SVS]）之间的因果关系。

致编辑重型地中海贫血（TM）是中国南方普遍存在的公共卫生问题，需要异基因造血干细胞移植（allo-HSCT）作为治愈性治疗。只有一小部分TM患者具有同胞相同供体（SID），因此移植中心越来越多地采用替代供体，包括人类白细胞抗原（HLA）匹配的无关供体（MUD）和单倍体相同供体（HID）。尽管早期并发症如移植物抗宿主病(GVHD)在MUD移植中更常见，但近年来有几个中心表明MUD移植在总生存期(OS)或无事件生存期(EFS)方面与SID移植没有区别。^[1]因此，MUD-HSCT是无婴儿猝死综合症的TM患者的合适选择。此外，移植的时机构成了决定HSCT成功的另一个关键因素，因为TM患者遭受由输血和铁积累引起的并发症，导致实质性的疾病负担。因此，HID-HSCT作为一种潜在的解决方案出现，以避免缺乏完全匹配的供体的挑战，从而扩大供体库以包括父母或错配的兄弟姐妹。然而，必须承认接受HID-HSCT的患者会遇到增强的免疫屏障，这会增加GVHD的风险并损害OS。然而，近年来，免疫抑制方案和T细胞耗竭策略取得了重大进展，共同促进了TM患者HID-HSCT总体结局的实质性改善。^[2]迄今为止，使用HID直接比较TM患者HSCT结果的全面大规模临床研究vs.泥浆仍然明显不存在。因此，这两种供体类型对TM患者长期预后的确切影响仍不清楚，值得进一步探索。我们的研究旨在调查尽快接受HID-HSCT或等待MUD是否有益于TM患儿的长期预后。

致编辑：肥胖和2型糖尿病（T2D）在中国是重大的健康问题。尽管中国人的体重指数（身体质量指数）阈值通常低于西方人群，但中国人的中心性肥胖率通常较高，即使在较低的身体质量指数水平下，也会导致代谢风险增加。中国成人T2D患病率估计为11.2%。传统治疗，包括生活方式干预和药物治疗，通常无法在肥胖和T2D患者中实现持续的体重减轻和长期有效的血糖控制。

致编辑：化疗是乳腺癌(BC)患者的主要治疗方法之一，^[1,2]但它通常受到归因于骨髓抑制的剂量限制性毒性的限制。尽管重组人粒细胞集落刺激因子（rhG-CSF）对治疗和预防化疗诱导的中性粒细胞减少症有效，但患者每日给药不方便。^[3,4]

致编辑：致病拷贝数变异（CNVs）与先天性异常和神经发育障碍有关。^[1]然而，一些患有致病性CNVs的胎儿具有结构异常，而其他胎儿表现为表型正常。结构异常胎儿CNVs的产前评估目前依赖于侵入性产前诊断（IPD）。然而，在胎儿没有结构异常的孕妇中缺乏CNV的常规筛查限制了识别具有临床意义的胎儿CNV的能力。

慢性肾脏病（CKD）是影响人类健康的重要疾病，尤其是在CKD患病率和死亡率都很高的发展中国家。^[1]根据最新的CKD流行病学数据，中国人群CKD患病率为8.2%，其中1.8%为CKD 5期（即终末期肾病[ESRD]）患者。^[2]血液透析（HD）是ESRD患者的主要治疗方法。根据中国国家肾脏数据系统（CNRDS），2022年接受HD治疗的人数高达84.4万人。虽然透析可以部分替代肾脏的功能，但透析患者的远处并发症，如心血管疾病（CVD）、肾性骨病和感染，严重影响生活质量和预后。在这些病症中，CVD是透析患者死亡的主要原因。^[3]除了高血压和糖尿病等传统心血管风险因素外，CVD的发展还与肠道微生物群及其代谢物的改变有关。