Volume 136 · Issue 04 · 2023

Monoclonal antibodies have been successfully incorporated into the current therapeutical landscape of lung cancer in the last decades. Recently, with technological advances, bispecific antibodies (bsAbs) have also shown robust efficacy in the treatment of malignant cancers, including lung cancer. These antibodies target two independent epitopes or antigens and have been extensively explored in translational and clinical studies in lung cancer. Here, we outline the mechanisms of action of bsAbs, related clinical data, ongoing clinical trials, and potent novel compounds of various types of bsAbs in clinical studies, especially in lung cancer. We also propose future directions for the clinical development of bsAbs, which might bring a new era of treatment for patients with lung cancer.

2型糖尿病（T2DM），通常被称为慢性代谢疾病，其特征是胰岛素分泌不足或胰岛素抵抗。由于全球T2DM的增加，减少高血糖引起的并发症、随之而来的发病率和死亡率非常重要。^[1]正常的稳态血糖水平已经成为T2DM预后的重要指标，并且被认为是糖尿病药物治疗的主要结果之一。^[2]本文综述了9种主要类型的抗糖尿病药物及其作用机制，可为T2DM治疗药物的研究和开发提供参考。

Despite the decline in the incidence and mortality rates of gastric cancer (GC), the impact of demographic transition on the global burden of GC remains unclear. The current study aimed to estimate the global disease burden through 2040 by age, sex, and region.

GC data for incident cases and deaths by age group and sex were taken from The Global Cancer Observatory (GLOBOCAN) 2020. The incidence and mortality rates were predicted through 2040 by fitting a linear regression model over the most recent trend period with the Cancer Incidence in Five Continents (CI5) data.

The global population will grow to 9.19 billion by 2040, accompanied by increasing population ageing. The incidence and mortality rates of GC will show a persistent decrease, with an annual percent change of -0.57% for males and -0.65% for females. East Asia and North America will have the highest and lowest age standardized rates, respectively. A slowdown in the growth of incident cases and deaths will be observed worldwide. The proportion of young and middle-aged individuals will decline, while the percentage of the elderly will increase, and the number of males will be almost twice the number of females. East Asia and high human development index (HDI) regions will be heavily burdened by GC. East Asia had 59.85% of the new cases and 56.23% of deaths in 2020; these will increase to 66.93% and 64.37% by 2040, respectively. The interaction between population growth, the change in ageing structure and the decline in incidence and mortality rates will lead to an increased burden of GC.

Ageing and population growth will offset the decline in the incidence and mortality rate of GC, resulting in a substantial increase in the number of new cases and deaths. The age structure will continue to change, especially in high HDI regions, requiring more targeted prevention strategies in the future.

Many studies have emphasized that selective resection of epileptic lesions in temoral lobe is associated with better preservation of cognition function; whether this applies to patients with refractory mesial temporal lobe epilepsy (MTLE) remains unknown. The objective of this study was to evaluate changes in cognitive functions, mood status, and quality of life after anterior temporal lobectomy in patients with refractory MTLE.

This single-arm cohort study assessed cognitive function, mood status, and quality of life, as well as electroencephalography findings, in patients with refractory MTLE who underwent anterior temporal lobectomy at Xuanwu Hospital from January 2018 to March 2019. Pre- and post-operative characteristics were compared to evaluate the effects of surgery.

Anterior temporal lobectomy significantly reduced the frequencies of epileptiform discharges. The overall success rate of surgery was acceptable. Anterior temporal lobectomy did not result in significant changes in overall cognitive functions (P > 0.05), although changes in certain domains, including visuospatial ability, executive ability, and abstract thinking, were detected. Anterior temporal lobectomy resulted in improvements in anxiety and depression symptoms and quality of life.

Anterior temporal lobectomy reduced epileptiform discharges and incidence of post-operative seizures as well as resulted in improved mood status and quality of life without causing significant changes in cognitive function.

Studies suggest seasonal fluctuations of symptoms in Parkinson’s disease (PD) patients in Western countries. However, the association between seasonal change and variation in nonmotor symptoms (NMS) in Chinese PD patients is unclear. Here, we studied whether there is a change rule with annual cycle with severity of NMS for patients with PD in Southeast China.

We studied 1005 PD patients between April 2008 and October 2020. Patients were classified into four seasons according to the 24 Chinese solar terms, based on assessment date. We compared comprehensive NMS scales and polysomnography parameters among groups and conducted further analysis of disease severity.

Among the 1005 patients studied, the mean age was 64.2 ± 9.7 years and 569 (56.6%) of them were men. Relative to the summer group, patients assessed during winter had higher Scales for Outcomes in Parkinson’s disease-Autonomic Dysfunction (SCOPA-AUT) scores (P = 0.045). The sleep efficiency factor scores of Pittsburgh Sleep Quality Index in patients were higher during spring than summer (P = 0.009). Among patients who completed polysomnography during the same period (n = 135), compared with summer follow-ups, we observed a higher percentage of NREMS1 in winter and spring follow-ups (P = 0.042, P = 0.011), a higher NREMS1 time in spring follow-ups (P = 0.0024), a lower NREMS2 time in winter follow-ups (P = 0.007), and a higher percentage of phasic rapid eye movement (REM)-sleep without atonia in autumn and winter follow-ups (P = 0.026 and P = 0.020, respectively). In a subset of patients with PD and REM sleep behavior disorder (RBD; n = 182), those visited during winter had higher scores for RBD questionnaire-Hong Kong and its factor 1 (dream-related sub-score) than those visited during summer (P = 0.034, P = 0.020). We observed similar findings for SCOPA-AUT and sleep efficiency factor scores in early stage patients in subgroup analysis.

PD patients assessed for follow-up during summer showed less severe symptoms of autonomic dysfunction and RBD symptoms than those assessed in winter, and less sleep disturbance than those in spring and winter, suggesting that seasonal change and NMS fluctuation are related, especially in patients with early stage PD.

DOK3 (Downstream of kinase 3) is involved primarily with immune cell infiltration. Recent research reported the role of DOK3 in tumor progression, with opposite effects in lung cancer and gliomas; however, its role in prostate cancer (PCa) remains elusive. This study aimed to explore the role of DOK3 in PCa and to determine the mechanisms involved.

To investigate the functions and mechanisms of DOK3 in PCa, we performed bioinformatic and biofunctional analyses. Samples from patients with PCa were collected from West China Hospital, and 46 were selected for the final correlation analysis. A lentivirus-based short hairpin ribonucleic acid (shRNA) carrier was established for silencing DOK3. A series of experiments involving the cell counting kit-8, bromodeoxyuridine, and flow cytometry assays were performed to identify cell proliferation and apoptosis. Changes in biomarkers from the nuclear factor kappa B (NF-κB) signaling pathway were detected to verify the relationship between DOK3 and the NF-κB pathway. A subcutaneous xenograft mouse model was performed to examine phenotypes after knocking down DOK3 in vivo. Rescue experiments with DOK3 knockdown and NF-κB pathway activation were designed to verify regulating effects.

DOK3 was up-regulated in PCa cell lines and tissues. In addition, a high level of DOK3 was predictive of higher pathological stages and worse prognoses. Similar results were observed with PCa patient samples. After silencing DOK3 in PCa cell lines 22RV1 and PC3, cell proliferation was significantly inhibited while apoptosis was promoted. Gene set enrichment analysis revealed that DOK3 function was enriched in the NF-κB pathway. Mechanism experiments determined that knockdown of DOK3 suppressed activation of the NF-κB pathway, increased the expressions of B-cell lymphoma-2 like 11 (BIM) and B-cell lymphoma-2 associated X (BAX), and decreased the expression of phosphorylated-P65 and X-linked inhibitor of apoptosis (XIAP). In the rescue experiments, pharmacological activation of NF-κB by tumor necrosis factor-α (TNF-α) partially recovered cell proliferation after the knockdown of DOK3.

Our findings suggest that overexpression of DOK3 promotes PCa progression by activating the NF-κB signaling pathway.

Cluster of differentiation 8 (CD8 T) cells play critical roles in eradicating human immunodeficiency virus (HIV)-1 infection, but little is known about the effects of T cells expressing CD8 at low levels (CD8^low) or high levels (CD8^high) on HIV-1 replication inhibition after HIV-1 invasion into individual.

Nineteen patients who had been acutely infected with HIV-1 (AHI) and 20 patients with chronic infection (CHI) for ≥2 years were enrolled in this study to investigate the dynamics of the quantity, activation, and immune responses of CD3⁺CD8^low T cells and their counterpart CD3⁺CD8^high T cells at different stages of HIV-1 infection.

Compared with healthy donors, CD3⁺CD8^low T cells expanded in HIV-1-infected individuals at different stages of infection. As HIV-1 infection progressed, CD3⁺CD8^low T cells gradually decreased. Simultaneously, CD3⁺CD8^high T cells was significantly reduced in the first month of AHI and then increased gradually as HIV-1 infection progressed. The classical activation of CD3⁺CD8^low T cells was highest in the first month of AHI and then reduced as HIV-1 infection progressed and entered the chronic stage. Meanwhile, activated CD38^-HLA-DR⁺CD8^low T cells did not increase in the first month of AHI, and the number of these cells was inversely associated with viral load (r = -0.664, P = 0.004) but positively associated with the CD4 T-cell count (r = 0.586, P = 0.014). Increased programmed cell death protein 1 (PD-1) abundance on CD3⁺CD8^low T cells was observed from the 1st month of AHI but did not continue to be enhanced, while a significant T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif (ITIM) domains (TIGIT) abundance increase was observed in the 12th month of infection. Furthermore, increased PD-1 and TIGIT abundance on CD3⁺CD8^low T cells was associated with a low CD4 T-cell count (PD-1: r = -0.456, P = 0.043; TIGIT: r = -0.488, P = 0.029) in CHI. Nonetheless, the nonincrease in PD-1 expression on classically activated CD3⁺CD8^low T cells was inversely associated with HIV-1 viremia in the first month of AHI (r = -0.578, P = 0.015). Notably, in the first month of AHI, few CD3⁺CD8^low T cells, but comparable amounts of CD3⁺CD8^high T cells, responded to Gag peptides. Then, weaker HIV-1-specific T-cell responses were induced in CD3⁺CD8^low T cells than CD3⁺CD8^high T cells at the 3rd and 12th months of AHI and in CHI.

Our findings suggest that CD3⁺CD8^low T cells play an anti-HIV role in the first month of infection due to their abundance but induce a weak HIV-1-specific immune response. Subsequently, CD3⁺CD8^low T-cell number decreased gradually as infection persisted, and their anti-HIV functions were inferior to those of CD3⁺CD8^high T cells.

Essential tremor (ET) and Parkinson’s disease (PD) are common movement disorders. ET-PD syndrome is characterized by the occurrence of PD in patients with a previous history of ET, which may be an independent phenotype distinct from PD. This study aims to identify clinical characteristics and subtypes in ET-PD.

A total of 93 newly diagnosed ET-PD patients and 93 newly diagnosed PD patients matched for age, sex, education, and disease duration of PD were selected using propensity score matching analysis. The K-means cluster analysis was performed for 11 variables derived from the ET-PD group, and cluster profiles were established through statistical analysis of demographic and clinical variables.

The ET-PD group consisted of a high number of patients with a family history of ET exhibiting evident tremor with milder hypokinesia and postural instability symptoms, as compared to the PD group. Through the cluster analysis, two clusters of ET-PD patients were identified. The ET-PD cluster 1 (n = 34) had a shorter ET duration before PD onset, lower number of patients with a family history of ET, higher unified PD rating scale instability scores, higher non-motor symptoms scores (non-motor symptoms scale D1 scores, Hamilton depression scale scores, Hamilton anxiety scale scores, and PD sleep scale-2 scores), and higher Chinese version of the PD questionnaire-39 scores relative to the ET-PD cluster 2 (n = 59).

ET-PD patients had significantly different characteristics for motor symptoms as compared to PD patients, and may be distinctly divided into two clinical subtypes, namely, the ET-PD complex type and the ET-PD simple type.

Electroacupuncture (EA) has been shown to attenuate airway inflammation in asthmatic mice; however, the underlying mechanism is not fully understood. Studies have shown that EA can significantly increase the inhibitory neurotransmitter γ-aminobutyric acid (GABA) content in mice, and can also increase the expression level of GABA type A receptor (GABAAR). Furthermore, activating GABAAR may relieve inflammation in asthma by suppressing toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signaling pathway. Therefore, this study aimed to investigate the role of GABAergic system and TLR4/MyD88/NF-κB signaling pathway in asthmatic mice treated with EA.

A mouse model of asthma was established, and a series of methods including Western blot and histological staining assessment were employed to detect the level of GABA, and expressions of GABAAR and TLR4/MyD88/NF-κB in lung tissue. In addition, GABAAR antagonist was used to further validate the role and mechanism of GABAergic system in mediating the therapeutic effect of EA in asthma.

The mouse model of asthma was established successfully, and EA was verified to alleviate airway inflammation in asthmatic mice. The release of GABA and the expression of GABAAR were significantly increased in asthmatic mice treated with EA compared with untreated asthmatic mice (P < 0.01), and the TLR4/MyD88/NF-κB signaling pathway was down-regulated. Moreover, inhibition of GABAAR attenuated the beneficial effects of EA in asthma, including the regulation of airway resistance and inflammation, as well as the inhibitory effects on TLR4/MyD88/NF-κB signaling pathway.

Our findings suggest that GABAergic system may be involved in mediating the therapeutic effect of EA in asthma, possibly by suppressing the TLR4/MyD88/NF-κB signaling pathway.

Exercise, as the cornerstone of pulmonary rehabilitation, is recommended to chronic obstructive pulmonary disease (COPD) patients. The underlying molecular basis and metabolic process were not fully elucidated.

Sprague-Dawley rats were classified into five groups: non-COPD/rest (n = 8), non-COPD/exercise (n = 7), COPD/rest (n = 7), COPD/medium exercise (n = 10), and COPD/intensive exercise (n = 10). COPD animals were exposed to cigarette smoke and lipopolysaccharide instillation for 90 days, while the non-COPD control animals were exposed to room air. Non-COPD/exercise and COPD/medium exercise animals were trained on a treadmill at a decline of 5° and a speed of 15 m/min while animals in the COPD/intensive exercise group were trained at a decline of 5° and a speed of 18 m/min. After eight weeks of exercise/rest, we used ultrasonography, immunohistochemistry, transmission electron microscopy, oxidative capacity of mitochondria, airflow-assisted desorption electrospray ionization-mass spectrometry imaging (AFADESI-MSI), and transcriptomics analyses to assess rectal femoris (RF).

At the end of 90 days, COPD rats’ weight gain was smaller than control by 59.48 ± 15.33 g (P = 0.0005). The oxidative muscle fibers proportion was lower (P < 0.0001). At the end of additional eight weeks of exercise/rest, compared to COPD/rest, COPD/medium exercise group showed advantages in weight gain, femoral artery peak flow velocity (Δ58.22 mm/s, 95% CI: 13.85-102.60 mm/s, P = 0.0104), RF diameters (Δ0.16 mm, 95% CI: 0.04-0.28 mm, P = 0.0093), myofibrils diameter (Δ0.06 μm, 95% CI: 0.02-0.10 μm, P = 0.006), oxidative muscle fiber percentage (Δ4.84%, 95% CI: 0.15-9.53%, P = 0.0434), mitochondria oxidative phosphorylate capacity (P < 0.0001). Biomolecules spatial distribution in situ and bioinformatic analyses of transcriptomics suggested COPD-related alteration in metabolites and gene expression, which can be impacted by exercise.

COPD rat model had multi-level structure and function impairment, which can be mitigated by exercise.

致编辑：在怀孕期间，获得足够的微量营养素对于确保母亲和胎儿的健康至关重要。由于孕妇对微量营养素的需求迅速增加，而这种需求不能通过日常饮食摄入来满足，特别是在资源匮乏的环境中，妊娠期微量营养素缺乏在世界范围内和中国都非常普遍。^[1]中国此前的研究报告称，高比例的孕妇叶酸、维生素和钙摄入不足。^[1]在这些摄入量不足中，缺钙是主要问题。^[2]

致编辑：近视是最常见的屈光不正，也是视力损害的主要原因。近视的患病率在世界范围内不断增加，在亚洲国家尤其高。它影响了东亚和东南亚部分地区80%至90%的年轻人。^[1]高度近视，超过-6.00 D，由于眼轴长度（AL）延长引起的眼部并发症，包括后葡萄膜瘤、视网膜脱离、脉络膜新血管形成等，增加了视力损害的可能性。由此可见，近视防控是备受世界卫生组织和中国政府高度关注的一个棘手而重要的公共卫生问题。

致编辑：急性心力衰竭（AHF）是住院的主要原因。大多数AHF患者表现为缺氧和呼吸困难。这些患者的治疗通常需要通过面罩进行氧合和更密集的呼吸支持方法，包括无创通气(NIV)或通过气管插管进行有创通气。

致编辑：卵巢反应不良的定义相互矛盾，使得所提出的治疗方法的比较变得复杂。以患者为导向的策略，包括个体化卵母细胞数量（POSEIDON）分类^[1]通过详细的分层来指导个体卵巢反应管理。POSEIDON组3和4被定义为低抗苗勒管激素(AMH；<1.2 ng/mL)和/或低窦卵泡计数(AFC；<5).

致编辑：肝细胞癌（HCC）是2020年全球第六大常见肿瘤和第三大癌症死亡原因。^[1]HCC缺乏早期诊断和瘤内异质性高是其高死亡率的重要原因。遗传易感性和环境刺激导致肿瘤团块由具有不同分化特征的混合肿瘤细胞组成。因此，肿瘤内异质性是肿瘤干细胞分化的必然产物。^[2]

致编辑：幽门螺杆菌(幽门螺杆菌）估计影响到世界上大约一半的人口，特别是在大多数发展中国家。^[1]根除幽门螺杆菌已被证实能促进消化性溃疡愈合，降低胃癌发病率。先前的研究报道，中国西北地区具有高幽门螺杆菌感染率为51.8%。^[2]然而，幽门螺杆菌根除率每年都在下降，主要是由于抗生素耐药性增加，特别是克拉霉素，^[3]各种其他因素也可能影响幽门螺杆菌根除。因此，本研究旨在详细阐述幽门螺杆菌并评估根除失败的相关风险因素，以探索可能的解决方案。

致编辑：营养不良与全膝关节置换术（TKA）后并发症风险增加相关，包括持续伤口引流、伤口愈合延迟、浅表手术部位甚至深部假体周围关节感染以及重症监护室入院。^[1]白蛋白（ALB）是人血浆中最丰富的蛋白质，被认为是营养状况和营养不良的可靠和敏感的生物标志物。与营养不良一样，低血清ALB水平不仅与TKA后的各种术后并发症相关，包括肺部感染、肾功能损害、浅表和深部感染、计划外插管，甚至死亡率；而且与治疗费用增加、住院时间延长和再入院风险增加有关。^[2]

致编辑：肺纤维化的特征是细胞外基质积聚和肺间质重塑。尽管肺纤维化已被广泛研究，但目前仍缺乏有效的抗肺纤维化药物。肺纤维化的发病机制涉及许多方面，其中肺巨噬细胞起着特别重要的作用。^[1]据报道，单核细胞/巨噬细胞表型转换的操作可能是许多巨噬细胞介导的炎性疾病的潜在靶点。在我们之前的研究中，暴露于博莱霉素（BLM）的小鼠显示出循环系统，肺泡和间质区室中单核吞噬细胞的动态变化。循环Ly6C数量的快速增加^你好BLM刺激后的单核细胞，随后M2样肺泡巨噬细胞（AM）数量的扩张，与肺部炎症反应和纤维化密切相关。^[2,3]

致编辑：可塑性支气管炎（PB）是一种罕见的肺部疾病，其特征是产生充满气道的分支支气管管型。它在成人中不如在儿童中常见，发生在1%至4%的Fontan手术后。^[1]

致编辑：不孕症影响着全球15%~20%的夫妇，辅助生殖技术（ART）是最有效的治疗策略。除女性年龄外，许多其他因素，如窦卵泡计数（AFC）、基础卵泡刺激素（FSH）水平和抗苗勒管激素（AMH）水平，统称为卵巢储备试验（ORT）的生物标志物，被广泛用于预测卵巢反应和助孕结果。^[1]其中，AMH和FSH水平在接受ART治疗的妇女中有20%~43%不一致，AMH被证明在预测活产率（LBR）方面更优越。^[2]AMH和AFC长期以来被认为本质上是可互换的，在预测卵巢反应方面具有良好的性能，而很少有研究检查它们的不一致性。^[1]近日，张等人^[3]显示16.76%（203/1211）的AMH和AFC水平不一致和AFC低（<7）和AMH水平正常（≥1.1 ng/mL），与AFCs正常和AMH水平降低的患者相比，临床妊娠率较低，但卵巢反应不良（POR）的发生率较高。尽管如此，仍有一些局限性，如样本量相对不足，未能对LBR进行评论，以及考虑潜在周期混杂因素的额外中间结果。为了确定当检测结果不一致时AMH或AFC是否与ART后的妊娠和新生儿结局相关，并为最佳生育咨询提供线索，我们对44,069名接受首次自体卵母细胞ART周期的患者进行了回顾性队列研究。

在最初的文章发表之后，^[1]作者发现了以下错误：