2023年 · 第136卷第04期

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.

Type 2 diabetes mellitus (T2DM), more commonly known as chronic metabolic disease, is characterized by insufficient insulin secretion or insulin resistance. Due to the rise of T2DM globally, it is of great importance to decrease the number of complications, consequential morbidity, and mortality stemming from hyperglycemia.^[1]The normal steady-state blood glucose level has become an important metric for T2DM prognosis and is recognized as one of the major results of drug therapies for diabetes.^[2]This review outlines nine major types of antidiabetic drugs, relevance to functional mechanisms, which could provide a reference for the research and development of T2DM treatment drugs.

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.

To the Editor: During pregnancy, it is critical to obtain adequate micronutrients to ensure maternal and fetal health. Due to the rapidly increasing demand for micronutrients among pregnant women and that the demand is not being fulfilled by daily dietary intake, especially in resource-poor settings, micronutrient deficiency during pregnancy is very common worldwide and in China.^[1]Previous studies in China reported that a high proportion of pregnant women had insufficient intakes of folate, vitamins, and calcium.^[1]Of these insufficient intakes, calcium deficiency was the leading problem.^[2]

To the Editor: Myopia is the most common refractive error and a major reason for visual impairment. The prevalence of myopia is increasing worldwide and is particularly high in Asian countries. It affects 80% to 90% of young people in some parts of East and Southeast Asia.^[1]High myopia, which is more than -6.00 D, increases the possibility of visual impairment due to ocular complications caused by extended axial length (AL), which include posterior uveioma, retinal detachment, choroidal new vascularization, and so on. Thus, the prevention and control of myopia is a difficult and important public health issue that has attracted great attention from the World Health Organization and the Chinese government.

To the Editor:Acute heart failure (AHF) is a leading cause of hospitalization. Most patients with AHF present with hypoxia and dyspnea. Treatment of these patients often requires oxygenation via facemask and more intensive respiratory support methods, including non-invasive ventilation (NIV) or invasive ventilation through endotracheal intubation.

To the Editor: The conflicting definition of poor ovarian response has complicated the comparison of proposed treatments. The Patient Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) classification^[1]was formulated to guide individual ovarian response management through detailed stratification. POSEIDON groups 3 and 4 were defined as patients with low anti-Müllerian hormone (AMH; <1.2 ng/mL) and/or low antral follicle count (AFC; <5).

To the Editor: Hepatocellular carcinoma (HCC) is the sixth most common tumor and the third leading cause of cancer death globally in 2020.^[1]The lack of early diagnosis and high intratumoral heterogeneity in HCC are important reasons for its high mortality. Genetic susceptibility and environmental stimuli lead to a tumor mass consisting of mixed tumor cells with different differentiation characteristics. Thus, intratumoral heterogeneity is the inevitable product of the differentiation of tumor stem cells.^[2]

To the Editor: Helicobacter pylori(H. pylori) is estimated to affect approximately half of the world’s population, especially in most developing countries.^[1]Eradication ofH. pylorihas been proven to promote peptic ulcer healing and reduce the incidence of gastric cancer. Previous studies have reported that the northwest region of China has a highH. pyloriinfection rate of 51.8%.^[2]However, theH. pylorieradication rate is declining every year, primarily due to increasing antibiotic resistance, notably clarithromycin,^[3]and various other factors may also impactH. pylorieradication. Consequently, this study was conducted to elaborate on the situation ofH. pylorieradication in Northwest China and evaluate the related risk factors for eradication failure to explore possible solutions.

To the Editor:Malnutrition is associated with an increased risk of complications after total knee arthroplasty (TKA), including persistent wound drainage, delay of wound healing, superficial surgical site and even deep periprosthetic joint infections, and intensive care unit admission.^[1]Albumin (ALB) is the most abundant protein in human plasma and is considered a reliable and sensitive biomarker of nutritional status and malnutrition. Like malnutrition, low serum ALB levels are not only associated with various post-operative complications following TKA including pulmonary infection, renal impairment, superficial and deep infections, unplanned intubation, and even mortality; but also associated with increased treatment costs, longer length of stay and higher risk of readmission.^[2]

To the Editor: Lung fibrosis is characterized by extracellular matrix accumulation and remodeling of the lung interstitium. Although lung fibrosis has been extensively studied, there is still a lack of effective anti-pulmonary fibrosis drugs at present. The pathogenesis of lung fibrosis involves many aspects in which the lung macrophages play a particularly important role.^[1]It has been reported that the manipulation of the monocyte/macrophage phenotype switch might be a potential target for many macrophage-mediated inflammatory disorders. In our previous study, mice that were exposed to bleomycin (BLM) showed a dynamic change of mononuclear phagocytes in the circulating system, lung alveoli, and interstitial compartments. The rapid increase of the number of circulating Ly6C^himonocytes after BLM stimulation, followed by the expansion of M2-like alveolar macrophages (AMϕ) numbers, is closely associated with lung inflammatory response and fibrosis.^[2,3]

To the Editor:Plastic bronchitis (PB) is a rare pulmonary disease characterized by the production of branching bronchial casts that fill the airways. It is less common in adults than in children, and occurs after 1% to 4% of Fontan surgeries.^[1]

To the Editor: Infertility affects 15% to 20% of couples worldwide, and assisted reproductive technology (ART) is the most effective treatment strategy. In addition to female age, many other factors, such as antral follicle count (AFC), basal follicle-stimulating hormone (FSH) level, and anti-Mullerian hormone (AMH) level, collectively known as biomarkers for ovarian reserve tests (ORTs), are widely used to predict ovarian responses and assisted-pregnancy outcomes.^[1]Among them, AMH and FSH levels were discordant in 20% to 43% of women undergoing ART treatment, and AMH was proven to be superior in predicting live birth rate (LBR).^[2]AMH and AFC have long been considered essentially interchangeable and have good performance in predicting ovarian response, while few studies have examined their discordance.^[1]Recently, Zhanget al^[3]showed that 16.76% (203/1211) of individuals with discordant AMH and AFC levels, and with low AFCs (<7) and normal AMH (≥1.1 ng/mL) level, showed a lower clinical pregnancy rate but a higher incidence of poor ovarian response (POR) than those with normal AFCs and decreased AMH level. Still, there are some limitations, such as a relatively insufficient sample size, failure to comment on LBR, and additional intermediate outcomes with consideration of potential cycle confounders. To determine whether AMH or AFC is associated with pregnancy and neonatal outcomes after ART when the test results are discordant, and to provide clues for optimal fertility counseling, we performed a retrospective cohort study on 44,069 patients who underwent their first autologous oocyte ART cycles.

Following the original article’s publication,^[1]the authors identified the following errors: