Volume 136 · Issue 03 · 2023

Integrins are a family of transmembrane receptors that connect the extracellular matrix and actin skeleton, which mediate cell adhesion, migration, signal transduction, and gene transcription. As a bi-directional signaling molecule, integrins can modulate many aspects of tumorigenesis, including tumor growth, invasion, angiogenesis, metastasis, and therapeutic resistance. Therefore, integrins have a great potential as antitumor therapeutic targets. In this review, we summarize the recent reports of integrins in human hepatocellular carcinoma (HCC), focusing on the abnormal expression, activation, and signaling of integrins in cancer cells as well as their roles in other cells in the tumor microenvironment. We also discuss the regulation and functions of integrins in hepatitis B virus-related HCC. Finally, we update the clinical and preclinical studies of integrin-related drugs in the treatment of HCC.

Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells’ productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.

The lungs are one of the most common extra-articular organs involved in rheumatoid arthritis (RA), which is reported to occur in up to 60% to 80% of RA patients. Respiratory complications are the second leading cause of death due to RA. Although there is a wide spectrum of RA-associated respiratory diseases, interstitial lung disease is the most common manifestation and it impacts the prognosis of RA. There has been progress in understanding the management and progression of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and RA-associated respiratory diseases recently, for example, opportunistic pulmonary infectious diseases and toxicity from RA therapies. From a chest physicians’ perspective, we will update the diagnosis and treatment of RA-associated ILD, methotrexate-associated lung disease, and the complication of Pneumocystis jiroveci pneumonia in RA in this review.

In China, the level of ambient fine particulate matter (PM_2.5) pollution far exceeds the air quality standards recommended by the World Health Organization. Moreover, the health effects of PM_2.5 exposure have become a major public health issue. More than half of PM_2.5-related excess deaths are caused by cardiopulmonary disease, which has become a major health risk associated with PM_2.5 pollution. In this review, we discussed the latest epidemiological advances relating to the health effects of PM_2.5 on cardiopulmonary diseases in China, including studies relating to the effects of PM_2.5 on mortality, morbidity, and risk factors for cardiovascular and respiratory diseases. These data provided important evidence to highlight the cardiopulmonary risk associated with PM_2.5 across the world. In the future, further studies need to be carried out to investigate the specific relationship between the constituents and sources of PM_2.5 and cardiopulmonary disease. These studies provided scientific evidence for precise reduction measurement of pollution sources and public health risks. It is also necessary to identify effective biomarkers and elucidate the biological mechanisms and pathways involved; this may help us to take steps to reduce PM_2.5 pollution and reduce the incidence of cardiopulmonary disease.

Estrogen impacts neural development; meanwhile, it has a protective effect on the brain. Bisphenols, primarily bisphenol A (BPA), can exert estrogen-like or estrogen-interfering effects by binding with estrogen receptors. Extensive studies have suggested that neurobehavioral problems, such as anxiety and depression, can be caused by exposure to BPA during neural development. Increasing attention has been paid to the effects on learning and memory of BPA exposure at different developmental stages and in adulthood. Further research is required to elucidate whether BPA increases the risk of neurodegenerative diseases and the underlying mechanisms, as well as to assess whether BPA analogs, such as bisphenol S and bisphenol F, influence the nervous system.

Epilepsy accounts for a significant portion of the global disease burden. However, little is known about the disease burden of epilepsy in China and its provinces.

We assessed the burden of epilepsy in China and its provinces, municipalities, and autonomous regions from 1990 to 2019. Burden was measured as incidence, prevalence, deaths, years lived with disability, years of life lost, and disability-adjusted life years (DALYs), by age, sex, year, and province. We used the Socio-Demographic Index (SDI) to determine the association between the provincial development level and age-standardized DALY rates of epilepsy from 1990 to 2019.

In 2019, epilepsy caused 1367.51 thousand (95% uncertainty interval [UI]: 979.92–1837.61 thousand) DALYs, and the age-standardized DALY rate was 99.77 (95% UI: 71.33–133.52)/100,000. The age-standardized incidence and prevalence rates for epilepsy in China were 24.65/100,000 and 219.69/100,000, increased by 45.00% (95% UI: 8.03–98.74%) and 35.72% (95% UI: 0.47–86.19%) compared with that in 1990, respectively. From 1990 to 2019, the proportion of DALY caused by epilepsy in the age group under 25 years steadily decreased. The proportion of DALYs caused by epilepsy in people aged 50 years and over increased from 9.45% and 10.22% in 1990 to 29.01% and 32.72% for male and female individuals in 2019, respectively. The highest age-standardized mortality rates were seen in Tibet (4.26 [95% UI: 1.43–5.66]/100,000), Qinghai (1.80 [95% UI: 1.15–2.36]/100,000), and Yunnan (1.30 [95% UI: 0.88–1.62]/100,000), and the lowest mortality rates were in Guangdong (0.48 [95% UI: 0.39–0.64]/100,000), Zhejiang (0.56 [95% UI: 0.44–0.70]/100,000), and Shanghai (0.57 [95% UI: 0.41–0.73]/100,000). The age-standardized DALY rates across the country and in provinces, municipalities, and autonomous regions generally decreased as their SDI increased.

The disease burden of epilepsy is still heavy in China, especially in the western provinces. The incidence and prevalence of epilepsy increased between 1990 and 2019, and the burden of epilepsy in the elderly increases gradually. This study provides evidence on epilepsy prevention and care of different regions in China.

China bears the biggest atrial fibrillation (AF) burden in the world. However, little is known about the incidence and predictors of AF. This study aimed to investigate the current incidence of AF and its electrocardiographic (ECG) predictors in general community individuals aged over 60 years in China.

This was a prospective cohort study, recruiting subjects who were aged over 60 years and underwent annual health checkups from April to July 2015 in four community health centers in Songjiang District, Shanghai, China. The subjects were then followed up from 2015 to 2019 annually. Data on sociodemographic characteristics, medical history, and the resting 12-lead ECG were collected. Kaplan–Meier curve was used for showing the trends in AF incidence and calculating the predictors of AF. Associations of ECG abnormalities and AF incidence were examined using Cox proportional hazard models.

This study recruited 18,738 subjects, and 351 (1.87%) developed AF. The overall incidence rate of AF was 5.2/1000 person-years during an observation period of 67,704 person-years. Multivariable Cox regression analysis indicated age (hazard ratio [HR], 1.07; 95% confidence interval [CI]: 1.06–1.09; P < 0.001), male (HR, 1.30; 95% CI: 1.05–1.62; P = 0.018), a history of hypertension (HR, 1.55; 95% CI: 1.23–1.95; P < 0.001), a history of cardiac diseases (HR, 3.23; 95% CI: 2.34–4.45; P < 0.001), atrial premature complex (APC) (HR, 2.82; 95% CI: 2.17–3.68; P < 0.001), atrial flutter (HR, 18.68; 95% CI: 7.37–47.31; P < 0.001), junctional premature complex (JPC) (HR, 3.57; 95% CI: 1.59–8.02; P = 0.002), junctional rhythm (HR, 18.24; 95% CI: 5.83–57.07; P < 0.001), ventricular premature complex (VPC) (HR, 1.76; 95% CI: 1.13–2.75, P= 0.012), short PR interval (HR, 5.49; 95% CI: 1.36–22.19; P = 0.017), right atrial enlargement (HR, 6.22; 95% CI: 1.54–25.14; P = 0.010), and pacing rhythm (HR, 3.99; 95% CI: 1.57–10.14; P = 0.004) were independently associated with the incidence of AF.

The present incidence of AF was 5.2/1000 person-years in the studied population aged over 60 years in China. Among various ECG abnormalities, only APC, atrial flutter, JPC, junctional rhythm, short PR interval, VPC, right atrial enlargement, and pacing rhythm were independently associated with AF incidence.

There are few data comparing clinical outcomes of complex percutaneous coronary intervention (CPCI) when using biodegradable polymer drug-eluting stents (BP-DES) or second-generation durable polymer drug-eluting stents (DP-DES). The purpose of this study was to investigate the safety and efficacy of BP-DES and compare that with DP-DES in patients with and without CPCI during a 5-year follow-up.

Patients who exclusively underwent BP-DES or DP-DES implantation in 2013 at Fuwai Hospital were consecutively enrolled and stratified into two categories based on CPCI presence or absence. CPCI included at least one of the following features: unprotected left main lesion, ≥2 lesions treated, ≥2 stents implanted, total stent length >40 mm, moderate-to-severe calcified lesion, chronic total occlusion, or bifurcated target lesion. The primary endpoint was major adverse cardiac events (MACE) including all-cause death, recurrent myocardial infarction, and total coronary revascularization (target lesion revascularization, target vessel revascularization [TVR], and non-TVR) during the 5-year follow-up. The secondary endpoint was total coronary revascularization.

Among the 7712 patients included, 4882 (63.3%) underwent CPCI. Compared with non-CPCI patients, CPCI patients had higher 2- and 5-year incidences of MACE and total coronary revascularization. Following multivariable adjustment including stent type, CPCI was an independent predictor of MACE (adjusted hazard ratio [aHR]: 1.151; 95% confidence interval [CI]: 1.017–1.303, P = 0.026) and total coronary revascularization (aHR: 1.199; 95% CI: 1.037–1.388, P = 0.014) at 5 years. The results were consistent at the 2-year endpoints. In patients with CPCI, BP-DES use was associated with significantly higher MACE rates at 5 years (aHR: 1.256; 95% CI: 1.078–1.462, P = 0.003) and total coronary revascularization (aHR: 1.257; 95% CI: 1.052–1.502, P = 0.012) compared with that of DP-DES, but there was a similar risk at 2 years. However, BP-DES had comparable safety and efficacy profiles including MACE and total coronary revascularization compared with DP-DES in patients with non-CPCI at 2 and 5 years.

Patients underwent CPCI remained at a higher risk of mid- to long-term adverse events regardless of the stent type. The effect of BP-DES compared with DP-DES on outcomes was similar in CPCI and non-CPCI patients at 2 years but had inconsistent effects at the 5-year clinical endpoints.

Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, is characterized by synovitis and progressive damage to the bone and cartilage of the joints, leading to disability and reduced quality of life. This study was a randomized clinical trial comparing the outcomes between withdrawal and dose reduction of tofacitinib in patients with RA who achieved sustained disease control.

The study was designed as a multicenter, open-label, randomized controlled trial. Eligible patients who were taking tofacitinib (5 mg twice daily) and had achieved sustained RA remission or low disease activity (disease activity score in 28 joints [DAS28] ≤3.2) for at least 3 months were enrolled at six centers in Shanghai, China. Patients were randomly assigned (1:1:1) to one of three treatment groups: continuation of tofacitinib (5 mg twice daily); reduction in tofacitinib dose (5 mg daily); and withdrawal of tofacitinib. Efficacy and safety were assessed up to 6 months.

Overall, 122 eligible patients were enrolled, with 41 in the continuation group, 42 in the dose-reduction group, and 39 in the withdrawal group. After 6 months, the percentage of patients with a DAS28-erythrocyte sedimentation rate (ESR) of <3.2 was significantly lower in the withdrawal group than that in the reduction and continuation groups (20.5%, 64.3%, and 95.1%, respectively; P < 0.0001 for both comparisons). The average flare-free time was 5.8 months for the continuation group, 4.7 months for the dose reduction group, and 2.4 months for the withdrawal group.

Withdrawal of tofacitinib in patients with RA with stable disease control resulted in a rapid and significant loss of efficacy, while standard or reduced doses of tofacitinib maintained a favorable state.

Chictr.org, ChiCTR2000039799.

Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.

Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL).

A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69–1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension (P < 0.001, P = 0.026 and P = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714–0.787), and CK-18 M30 at Youden’s index maximum was 275.7 U/L. Both sensitivity (55% [52%–59%]) and positive predictive value (59%) were not ideal.

This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.

致编辑：磷酸尿性间充质肿瘤（PMT）是一种罕见的、缓慢进展的、组织形态学上不同的肿瘤实体，可出现在身体的任何部位。^[1]根据世界卫生组织，PMT有良性和恶性两种病理类型。^[2]PMT是由于肿瘤诱导的骨软化症（TIO）而被发现的，并且近年来越来越多地被认为是TIO的主要原因。^[1]然而，大多数已发表的报告集中于PMT的临床病理学、免疫组织化学和分子遗传学研究，而不是放射学检查。^[3,4]因此，本研究的目的是寻找PMT的共同影像学特征，以帮助临床诊断。

致编辑：DL-3-n-丁基苯酞(NBP)是一种基于从种子中提取的成分的合成药物香芹琳恩。（中国芹菜）。据报道，它对肌萎缩侧索硬化（ALS）模型小鼠具有保护作用。^[1]在中国ALS协会19个ALS临床中心进行了一项随机、双盲、安慰剂对照试验。所有患者均提供了书面知情同意书。北京协和医院伦理委员会批准了研究方案（编号S621），所有患者均签署了知情同意书。所有中心都遵循相同的研究方案。

致编辑：与未再入院的慢性阻塞性肺疾病（COPD）患者相比，再入院患者的死亡率显著更高（2.3%vs.13.4%),^[1]这无疑对康复护理和医疗资源造成了社会经济压力。需要确定影响再入院风险的潜在因素。营养不良的发生率在老年COPD患者中经常发生，根据所使用的筛查工具，从20%到45%不等。迷你营养评估（MNA）作为一种实用、经济、有效的评分系统，对评估老年人的营养状况具有重要价值。营养不良是老年人群的一种脆弱状态，与不良的长期预后有关。本研究旨在研究营养状况相关危险因素对再入院的影响，并评估MNA评分系统和更新的肌肉减少症诊断标准在预测老年COPD患者再入院风险中的价值。

致编辑：银屑病是一种常见的慢性丘疹鳞状皮肤病，在世界范围内发生，可在任何年龄出现，并给个人和社会带来巨大负担。白细胞介素（IL）-17A被认为是诱导银屑病炎症和组织损伤的关键效应细胞因子。^[1]Ixekizumab是一种特异性结合并抑制IL-17A的人源化单克隆免疫球蛋白G。ixekizumab在银屑病患者中的疗效和安全性已在多项随机临床试验中得到明确证明，即UNCOVER-1、UNCOVER-2、UNCOVER-3和UNCOVER-J。^[2,3]然而，ixekizumab在中国银屑病患者中的临床研究数据仍然有限。

致编辑：目前，肺移植通常通过横向胸骨切开术或用于双肺移植的胸骨切开术或用于单肺移植的后外侧胸骨切开术进行。然而，这些极具侵入性的方法可能导致术后早期疼痛，延迟伤口愈合，并导致慢性开胸术后神经痛，这可能影响患者的生活质量。^[1,2]有趣的是，报道了几种用于肺移植的微创手术方法。^[3,4]此外，机器人手术系统现在广泛用于胸外科领域。在此，我们报告了一例为终末期慢性阻塞性肺疾病（COPD）患者进行机器人辅助右单肺移植的病例。

到编辑：胆道闭锁（BA）是一种罕见的闭塞性胆管病，发生于婴儿期，伴有破坏性肝脏炎症和肝纤维化。尽管最近研究表明转化生长因子-β（TGF-β)在BA的肝纤维化和炎症中起重要作用，其疾病机制仍知之甚少。环状RNA（circRNAs）是最近发现的一类独特的具有高特异性的调节RNA分子。由于先前的证据将circRNAs与TGF-β炎症信号通路的调节联系起来，我们进一步研究了circRNAs在BA中的潜在调节作用，并发现了对BA发病机制的新见解。BA的特征是受影响肝脏中的破坏性炎症和纤维化，破坏肝外胆管并扰乱胆汁流动。如果不及时治疗，BA会迅速恶化并导致毁灭性的后果。手术干预，即Kasai肝门肠吻合术，是BA患者最常见的治疗选择。不幸的是，在40%至50%的患者中，胆汁引流在手术后未能改善，并且大多数最终需要肝移植。作为炎症反应的关键调节因子和指标，TGF-β在BA婴儿中上调。^[1]因此，了解TGF-β失调可以提供对疾病机制的更好理解，从而为治疗开发提供新的见解。

致编辑：松果体母细胞瘤（PB）是一种罕见的松果体实质起源的胚胎性肿瘤，是儿童和青少年经常诊断的世界卫生组织IV级病变。一项基于文献的研究显示，与>5岁的患者相比，≤5岁的患者预后更差（5年生存率：15%vs.57%,P<0.001).^[1]因此，患有PB的年幼儿童和大龄儿童应分开治疗。对于PB的治疗，建议最大限度地安全手术切除，然后进行颅脊髓放疗和化疗，治疗方案高度依赖于年龄。阿卜杜勒巴基等人^[2]回顾了23例年龄为<在HEAD START I-III试验中进行了6年，发现颅脊髓照射和高剂量诱导化疗，然后进行骨髓消融化疗和自体造血细胞拯救（HDCx/AuHCR）与更好的生存率相关。几项基于人群的研究使用监测、流行病学和最终结果（SEER）数据库的数据评估了儿科和成人患者的预后因素。塞尔瓦纳坦等人^[3,4]包括1990年至2007年间来自SEER数据库的儿科患者和成人患者；他们的结果表明，年龄较大是儿科患者唯一的阳性预后因素，而年龄较小和局限性疾病与成人患者生存率的提高相关。鉴于PB的罕见性、幼儿PB预后不良以及缺乏针对幼儿PB的研究，我们旨在使用SEER数据库的数据确定≤5岁PB患者的预后因素和生存结果。

致编辑：环扎术可降低宫颈功能不全患者的早产率并改善围产期结局。然而，以前关于这个主题的发现是不一致的。许多临床因素影响环扎术的结果。据报道，妊娠32周后出生的新生儿发病率显著降低。^[1]因此，使用胎龄为<分娩时32周作为环扎术的主要疗效指标具有现实意义。

致编辑：腹膜后脂肪肉瘤（RLS）是一种起源于腹膜后的罕见恶性肿瘤。它被评估为腹膜后肉瘤最常见的类型。RLS根据病理分类可分为四种亚型，包括高分化脂肪肉瘤（WDL）、去分化脂肪肉瘤（DDL）、粘液样细胞脂肪肉瘤（MLS）和多形性脂肪肉瘤（PLS）。^[1]巨大RLS是指长直径大于病理肿瘤4期（pT4）类别（≥30 cm）指定长度两倍的RLS美国癌症联合委员会（AJCC）分期手册.^[2]尽管发病率相对较低，但它给患者带来了巨大的健康负担，标准的治疗策略仍有待探索。根据临床经验，巨大RLS有特定的特征。例如，巨大的RLS可以占据几乎整个腹腔，靠近甚至包裹下腔静脉。由于位于腹部深部，患者早期通常症状不典型。只有当肿瘤变得巨大时，才能感觉到明显的体征和症状。这些特征增加了在手术期间实现完全切除和满意的患者结果的难度。此外，对巨大RLS的特点缺乏全面的研究，阻碍了其诊断和靶向治疗的进一步进展。巨大RLS特征的识别在临床实践中可能具有重要意义。在此，我们进行了一项单中心回顾性研究，以揭示巨大RLS患者的临床病理特征和预后。

致编辑：慢性牙周炎已被定义为一种缓慢进展的疾病。在大多数情况下，缩放和根面规划（SRP）提供了令人满意的预后。然而，由于牙龈下复杂的解剖结构，仅靠非手术牙周治疗很难防止菌斑再定植和彻底清除深袋中的牙结石。^[1]近年来，一些研究探讨了吲哚菁绿（ICG）介导的抗菌光动力疗法（aPDT）作为非手术治疗的辅助手段的疗效，但没有一致的结果。