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BackgroundArsenic, cobalt, barium, and other individual metal exposure have been confirmed to be associated with the incidence of kidney stones. However, there are few studies on the association between mixed metal exposure and kidney stones, especially in occupational groups. ObjectiveTo investigate the association between mixed metal exposure and kidney stones in an occupational population from a metal smelting plant. MethodsA questionnaire survey was conducted to collect sociodemographic characteristics, medical history, and lifestyle information of 1158 mixed metal-exposed workers in a metal smelting plant in Guangdong Province from July 2021 to January 2022. Midstream morning urine samples were collected from the workers, the concentrations of 18 metals including lithium, vanadium, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, selenium, strontium, molybdenum, cadmium, cesium, barium, tungsten, titanium, and lead were measured by inductively coupled plasma mass spectrometry, and the urinary mercury levels were measured by cold atomic absorption spectroscopy. Based on predetermined inclusion criteria, a total of 919 mixed metal-exposed workers were included in the study, including 117 workers in the kidney stone group and 802 workers in the non-kidney stone group. With a detection rate of urinary metals greater than 80% as entry criterion, 16 eligible metals were finally included for further analysis. Parametric or non-parametric methods were used to compare the differences between continuous or categorical variables of the non-kidney stone group and the kidney stone group. Logistic regression models were constructed to explore the association between individual metal exposures and kidney stones. Weighted quantile sum (WQS) regression models were used to evaluate the association between mixed metal exposure and kidney stones, as well as the weights of each metal on kidney stones. Then Bayesian kernel machine regression (BKMR) models were used to explore the overall effect of mixed metal exposure on renal calculi and the potential interactions between metals. ResultsWe found that there were significant differences in sex, age, length of service, and body mass Index (BMI) between the non-kidney stone group and the kidney stone group (P

Abstract Background The ultrasonic scalpel is widely used during surgery. It is safe and effective to close the pulmonary artery branch vessels of 7 mm or below with an ultrasonic energy device as reported. However, there have been no multicenter randomized clinical trial to assess the safety and effectiveness of using ultrasonic scalpel to coagulate 5–7 mm blood vessels in thoracic surgery. Methods This is a prospective, multicenter, randomized, parallel controlled, non-inferiority clinical trial. A total of 144 eligible patients planning to undergo lung or esophageal surgery will be randomly allocated to the experimental group and the control group. The investigational product (Disposable Ultrasonic Shears manufactured by Reach Surgical, Inc.) and the control product (Harmonic Ace + 7, 5 mm Diameter Shears with Advanced Hemostasis) will be used in each group. The primary endpoint is the success rate of coagulating target blood vessels during surgery. Secondary endpoints include postoperative rebleeding, intraoperative bleeding volume, drainage volume, surgical duration, etc. Postoperative follow-up before and after discharge will be performed. Discussion This clinical trial aims to evaluate the safety and effectiveness of using the investigational product (Disposable Ultrasonic Shears manufactured by Reach Surgical, Inc.) and that of the control product (Harmonic Ace + 7, 5 mm Diameter Shears with Advanced Hemostasis) to coagulate 5–7 mm blood vessels in thoracic surgery. Trial registration ClinicalTrials.gov: NCT06002737. The trial was prospectively registered on 16 August 2023, https://www.clinicaltrials.gov/study/NCT06002737 .

Summary: Background: The long-term survival and perioperative outcomes of robotic-assisted lobectomy (RAL) and video-assisted lobectomy (VAL) in resectable non-small-cell lung cancer (NSCLC) were found to be comparable in retrospective studies, but they have not been investigated in a randomized trial setting. We conducted the RVlob trial to investigate if RAL was non-inferior to VAL in patients with resectable NSCLC. Methods: In this single-center, open-label, and parallel-arm randomized controlled trial conducted in Ruijin Hospital (Shanghai, China) between May 2017 and May 2020, we randomly assigned patients with resectable NSCLC in a 1:1 ratio to receive either RAL or VAL. One of the primary endpoints was 3-year overall survival. Secondary endpoints included 3-year disease-free survival. The Kaplan–Meier approach was used to calculate overall survival and disease-free survival at 3 years. This study was registered with ClinicalTrials.gov, NCT03134534. Findings: A total of 320 patients were randomized to receive RAL (n = 157) or VAL (n = 163). The baseline characteristics of patients were well balanced between the two groups. After a median follow-up of 58.0 months, the 3-year overall survival was 94.6% (95% confidence interval [CI], 91.0–98.3) in the RAL group and 91.5% (95% CI, 87.2–96.0) in the VAL group (hazard ratio [HR] for death, 0.65; 95% CI, 0.33–1.28; P = 0.21); noninferiority of RAL was confirmed according to the predefined margin of −5% (absolute difference, 2.96%; a one-sided 90% CI, −1.39% to ∞; P = 0.0029 for noninferiority). The 3-year disease-free survival was 88.7% (95% CI, 83.6–94.1) in the RAL group and 85.4% (95% CI, 80.0–91.2) in the VAL group (HR for disease recurrence or death, 0.87; 95% CI, 0.50–1.52; P = 0.62). Interpretation: This study is the first randomized trial to show that RAL resulted in non-inferior overall survival compared with VAL in patients with resectable NSCLC. Based on our results, RAL is an equally oncologically effective treatment and can be considered as an alternative to VAL for resectable NSCLC. Funding: National Natural Science Foundation of China (82072557), National Key Research and Development Program of China (2021YFC2500900), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20172005, the 2nd round of disbursement), program of Shanghai Academic Research Leader from Science and Technology Commission of Shanghai Municipality (20XD1402300), Novel Interdisciplinary Research Project from Shanghai Municipal Health Commission (2022JC023), and Interdisciplinary Program of Shanghai Jiao Tong University (YG2023ZD04).

Abstract Background The presence of lymph node (LN) metastasis directly affects the treatment strategy for lung adenocarcinoma (LUAD). Next‐generation sequencing (NGS) has been widely used in patients with advanced LUAD to identify targeted genes, while early detection of pathologic LN metastasis using NGS has not been assessed. Methods Clinicopathologic features and molecular characteristics of 224 patients from Ruijin Hospital were analyzed to detect factors associated with LN metastases. Another 140 patients from Huashan Hospital were set as a test cohort. Results Twenty‐four out of 224 patients were found to have lymph node metastases (10.7%). Pathologic LN‐positive tumors showed higher mutant allele tumor heterogeneity (p

Arbitrage trading is a common quantitative trading strategy that leverages the long-term cointegration relationships between multiple related assets to conduct spread trading for profit. Specifically, when the cointegration relationship between two or more related series holds, it utilizes the stability and mean-reverting characteristics of their cointegration relationship for spread trading. However, in real quantitative trading, determining the cointegration relationship based on the Engle-Granger two-step method imposes stringent conditions for the cointegration to hold, which can easily be disrupted by price fluctuations or trend characteristics presented by the linear combination, leading to the failure of the arbitrage strategy and significant losses. To address this issue, this article proposes an optimized strategy based on long-short-term memory (LSTM), termed Dynamic-LSTM Arb (DLA), which can classify the trend movements of linear combinations between multiple assets. It assists the Engle-Granger two-step method in determining cointegration relationships when clear upward or downward non-stationary trend characteristics emerge, avoiding frequent strategy switches that lead to losses and the invalidation of arbitrage strategies due to obvious trend characteristics. Additionally, in mean-reversion arbitrage trading, to determine the optimal trading boundary, we have designed an optimized algorithm that dynamically updates the trading boundaries. Training results indicate that our proposed optimization model can successfully filter out unprofitable trades. Through trading tests on a backtesting platform, a theoretical return of 23% was achieved over a 10-day futures trading period at a 1-min level, significantly outperforming the benchmark strategy and the returns of the CSI 300 Index during the same period.

Objective This study aimed to develop and validate robust predictive models for patients with oesophageal cancer who achieved a pathological complete response (pCR) and those who did not (non-pCR) after neoadjuvant therapy and oesophagectomy.Design Clinicopathological data of 6517 primary oesophageal cancer patients who underwent neoadjuvant therapy and oesophagectomy were obtained from the National Cancer Database for the training cohort. An independent cohort of 444 Chinese patients served as the validation set. Two distinct multivariable Cox models of overall survival (OS) were constructed for pCR and non-pCR patients, respectively, and were presented using web-based dynamic nomograms (graphical representation of predicted OS based on the clinical characteristics that a patient could input into the website). The calibration plot, concordance index and decision curve analysis were employed to assess calibration, discrimination and clinical usefulness of the predictive models.Results In total, 13 and 15 variables were used to predict OS for pCR and non-pCR patients undergoing neoadjuvant therapy followed by oesophagectomy, respectively. Key predictors included demographic characteristics, pretreatment clinical stage, surgical approach, pathological information and postoperative treatments. The predictive models for pCR and non-pCR patients demonstrated good calibration and clinical utility, with acceptable discrimination that surpassed that of the current tumour, node, metastases staging system.Conclusions The web-based dynamic nomograms for pCR (https://predict-survival.shinyapps.io/pCR-eso/) and non-pCR patients (https://predict-survival.shinyapps.io/non-pCR-eso/) developed in this study can facilitate the calculation of OS probability for individual patients undergoing neoadjuvant therapy and radical oesophagectomy, aiding clinicians and patients in making personalised treatment decisions.

Abstract The molecular profiles and tumor immune microenvironment (TIME) of multiple primary lung cancers (MPLCs) presenting as concurrent lung adenocarcinoma (ADC) and squamous cell carcinoma (SQCC) remain unknown. We aimed to clarify these factors. We performed whole-exome sequencing (WES), RNA sequencing (RNA-Seq), and multiplex immunohistochemistry (mIHC) for five patients with concurrent ADC and SQCC. We found the genetic mutations were similar between ADC and SQCC groups. RNA-Seq revealed that the gene expression and pathways enriched in ADC and SQCC groups were quite different. Gene set enrichment analysis (GSVA) showed that nine gene sets were significantly differentially expressed between the ADC and SQCC groups (p

Dynamic multi-objective optimization problems have been popular because of its extensive application. The difficulty of solving the problem focuses on the moving PS as well as PF dynamically. A large number of efficient strategies have been put forward to deal with such problems by speeding up convergence and keeping diversity. Prediction strategy is a common method which is widely used in dynamic optimization environment. However, how to increase the efficiency of prediction is always a key but difficult issue. In this paper, a new prediction model is designed by using the rank sums of individuals, and the position difference of individuals in the previous two adjacent environments is defined to identify the present change type. The proposed prediction strategy depends on environment change types. In order to show the effectiveness of the proposed algorithm, the comparison is carried out with five state-of-the–art approaches on 20 benchmark instances of dynamic multi-objective problems. The experimental results indicate the proposed algorithm can get good convergence and distribution in dynamic environments.

Abstract Targeting tumor-infiltrating regulatory T cells (Tregs) is an efficient way to evoke an anti-tumor immune response. However, how Tregs maintain their fragility and stability remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. On the contrary, the decreased IFITM3 expression in STAT1-deficient Tregs indicates that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of tumor-infiltrating Tregs in the tumor model. Overall, our study demonstrates that the perturbation of tumor-infiltrating Tregs through the IFNγ-IFITM3-STAT1 feedback loop is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy.

The multi-point dynamic aggregation problem (MPDAP) that arises in practical applications is characterized by a group of robots that have to cooperate in executing a set of tasks distributed over multiple locations, in which the demand for each task grows over time. To minimize the completion time of all tasks, one needs to schedule the robots and plan the routes. Hence, the problem is essentially a combinatorial optimization problem. The manuscript presented a new MPDAP in which the priority of the task was considered that is to say, some tasks must be first completed before others begin to be executed. When the tasks were located at different priority levels, some additional constraints were added to express the priorities of tasks. Since route selection of robots depends on the priorities of tasks, these additional constraints caused the presented MPDAP to be more complex than ever. To efficiently solve this problem, an improved optimization algorithm, called the multi-strategy genetic algorithm (MSGA), was developed. First of all, a two-stage hybrid matrix coding scheme was proposed based on the priorities of tasks, then to generate more route combinations, a hybrid crossover operator based on 0-1 matrix operations was proposed. Furthermore, to improve the feasibility of individuals, a repair schedule was designed based on constraints. Meanwhile, a $ q $-tournament selection operator was adopted so that better individuals can be kept into the next generation. Finally, experimental results showed that the proposed algorithm is feasible and effective for solving the MPDAP.

Introduction The multicenter CHAMPION study aimed to assess the impact of smoking cessation on post-operative complications (PCs) and smoking cessation patterns in Chinese patients undergoing lung surgery. Methods Patients undergoing elective lung surgery were prospectively enrolled from three major tertiary centers in China. Patients were categorized as smokers or quitters before surgery. Baseline characteristics and smoking status were analyzed. The incidence of PCs and pulmonary PCs (PPCs), smoking relapse rate, and causes within six months post-operatively were investigated. The questionnaire was conducted in all patients and 30 healthcare professionals (HCPs), regarding the awareness and effectiveness of smoking cessation methods. Results Of the 276 enrolled patients, 213 (77.2%) were smokers and 63 (22.8%) were quitters; 76.4% were diagnosed with primary lung cancer. PCs occurred in 13.8% of patients, with similar proportions in smokers (14.1%) and quitters (12.7%). PPCs occurred in 9.8% of patients with no significant differences between smokers and quitters (9.4% vs 11.1%, p=0.70). At six months, 9.2% of patients relapsed, with a lower rate in quitters compared to smokers (3.3% vs 11.0%, p=0.01). HCPs exhibited higher awareness of smoking cessation methods than patients. Perceived effectiveness of smoking cessation methods from the patients were low. Conclusions In patients undergoing lung surgery with a low risk of PCs, active smoking does not significantly increase the risk of PCs or PPCs relative to quitters, suggesting that there is likely no need to postpone lung surgery for those who have not yet quit smoking. However, further large-scale studies are necessary to confirm these findings.

Abstract Background METTL3 plays a significant role as a catalytic enzyme in mediating N6-methyladenosine (m6A) modification, and its importance in tumour progression has been extensively studied in recent years. However, the precise involvement of METTL3 in the regulation of translation in non-small cell lung cancer (NSCLC) remains unclear. Results Here we discovered by clinical investigation that METTL3 expression is correlated with NSCLC metastasis. Ablation of METTL3 in NSCLC cells inhibits invasion and metastasis in vitro and in vivo. Subsequently, through translatomics data mining and experimental validation, we demonstrated that METTL3 enhances the translation of aromatase (CYP19A1), a key enzyme in oestrogen synthesis, thereby promoting oestrogen production and mediating the invasion and metastasis of NSCLC. Mechanistically, METTL3 interacts with translation initiation factors and binds to CYP19A1 mRNA, thus enhancing the translation efficiency of CYP19A1 in an m6A-dependent manner. Pharmacological inhibition of METTL3 enzymatic activity or translation initiation factor eIF4E abolishes CYP19A1 protein synthesis. Conclusions Our findings indicate the crucial role of METTL3-mediated translation regulation in NSCLC and reveal the significance of METTL3/eIF4E/CYP19A1 signaling as a promising therapeutic target for anti-metastatic strategies against NSCLC. Graphical abstract

BackgroundHeavy metal exposure is an important cause of reduced bone mineral density (BMD). Epidemiological studies focusing on the effects of mixed heavy metal exposure on BMD in middle-aged and older people are scarce. In single-metal studies, men and women have shown distinct responses of BMD to environmental metal exposure. This study therefore aimed to elucidate the association between mixed heavy metal exposure and BMD and to investigate whether it is sex-specific.MethodsData from the 2017–2020 National Health and Nutrition Examination Survey were selected for this cross-sectional study. The study used three statistical methods, i.e., linear regression, Bayesian kernel machine regression (BKMR) modeling, and weighted quartiles (WQS) regression, to explore the association between the urinary concentrations of 11 metals (barium, cadmium, cobalt, cesium, manganese, molybdenum, lead, antimony, tin, thallium, and Tungsten), either individually or as a mixture, and total femoral BMD.ResultsA total of 1,031 participants were included in this study. Femoral BMD was found to be higher in men than women. A significant negative correlation between the urinary concentrations of the 10 metals and femoral BMD was found in the overall cohort. Further gender sub-stratified analyses showed that in men, urinary metal concentrations were negatively correlated with femoral BMD, with cobalt and barium playing a significant and non-linear role in this effect. In women, although urinary metal concentrations negatively modulated femoral BMD, none of the correlations was statistically significant. Antimony showed sex-specific differences in its effect.ConclusionThe urinary concentrations of 10 mixed heavy metals were negatively correlated with femoral BMD in middle-aged and older participants, and this effect showed gender differences. These findings emphasize the differing role of mixed metal exposure in the process of BMD reduction between the sexes but require further validation by prospective studies.

Constrained multi-objective optimization problems (CMOPs) are commonly encountered in engineering practice. The key to effectively solving these problems lies in achieving a timely balance between convergence, diversity, and feasibility during iterations. Furthermore, the appropriate utilization of infeasible solutions is crucial for identifying potential feasible regions. In order to accomplish this comprehensive objective, we propose a novel dual-stage constrained multi-objective evolutionary algorithm (CMOEA) called NACMOEA in this paper. It can be characterized by the following features: 1) Introducing a novel niche-based individual selection and infeasible solution utilization strategy to enhance convergence, diversity, and feasibility. 2) Presenting a cooperative search strategy assisted by dual archives to approximate the constrained Pareto front (CPF) from both feasible and infeasible perspectives, thereby improving the efficiency of obtaining the complete CPF. 3) Designing a new stage switch method based on non-dominant coverage rate to ensure proper completion of search stage switching. Extensive experiments demonstrate that NACMOEA exhibits competitive comprehensive performance when compared with other advanced CMOEAs.

Gene delivery therapy has emerged as a popular approach for the treatment of various diseases. However, it still poses the challenges of accumulation in target sites and reducing off-target effects. Aerosol gene delivery for the treatment of pulmonary diseases has the advantages of high lung accumulation, specific targeting and fewer systemic side effects. However, the key challenge is selecting the appropriate formulation for aerosol gene delivery that can overcome physiological barriers. There are numerous existing gene carriers under study, including viral vectors and non-viral vectors. With the development of biomaterials, more biocompatible substances have applied gene delivery via inhalation. Furthermore, many types of genes can be delivered through aerosol inhalation, such as DNA, mRNA, siRNA and CRISPR/Cas9. Aerosol delivery of different types of genes has proven to be efficient in the treatment of many diseases such as SARS-CoV-2, cystic fibrosis and lung cancer. In this paper, we provide a comprehensive review of the ongoing research on aerosol gene delivery therapy, including the basic respiratory system, different types of gene carriers, different types of carried genes and clinical applications.

The multi-point dynamic aggregation problem (MPDAP) comes mainly from real-world applications, which is characterized by dynamic task assignation and routing optimization with limited resources. Due to the dynamic allocation of tasks, more than one optimization objective, limited resources, and other factors involved, the computational complexity of both route programming and resource allocation optimization is a growing problem. In this manuscript, a task scheduling problem of fire-fighting robots is investigated and solved, and serves as a representative multi-point dynamic aggregation problem. First, in terms of two optimized objectives, the cost and completion time, a new bilevel programming model is presented, in which the task cost is taken as the leader's objective. In addition, in order to effectively solve the bilevel model, a differential evolution is developed based on a new matrix coding scheme. Moreover, some percentage of high-quality solutions are applied in mutation and selection operations, which helps to generate potentially better solutions and keep them into the next generation of population. Finally, the experimental results show that the proposed algorithm is feasible and effective in dealing with the multi-point dynamic aggregation problem.

Abstract Background The aim of the study was to analyze the relationship between pretreatment inflammatory biomarkers (IBs) and survival outcomes for patients with esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (neo‐CRT) and pembrolizumab. Methods Clinical variables and IBs (absolute monocyte count [AMC], absolute lymphocyte count [ALC], platelet count [PLT], neutrophil‐to‐lymphocyte ratio [NLR], platelet‐to‐lymphocyte ratio [PLR], lymphocyte‐to‐monocyte ratio [LMR], pan‐immune inflammation value [PIV], systemic immunoinflammatory index [SII], systemic immunoreactivity index [SIRI] and prognostic nutritional index [PNI]) were collected. Univariate and multivariate analysis were performed to identify the independent factors for outcomes of ESCC. Results A total of 51 patients were included. Of these, 35 patients achieved pathological complete response (pCR) after neo‐CRT and pembrolizumab (pCR: 68.6%). With a median follow‐up of 20 months, the two‐year PFS and OS of the cohort was 64% and 91%, respectively. Multivariate logistic regression analysis indicated that ALC (overall response [OR] 4.4, p = 0.051) and PLT (OR 6.7, p = 0.023) were two independent predictors for achieving pCR among ESCC treated with neo‐CRT and pembrolizumab. Multivariate Cox regression analysis showed that ALC (HR 0.27, p = 0.028) and SIRI (HR 3.13, p = 0.048) were two independent predictors associated with PFS. Kaplan Meier analysis demonstrated that the PFS of ESCC with high baseline ALC was significantly better than those with low ALC (2‐year PFS: 77% vs. 47%, p = 0.027), but not for overall survival (2‐year OS: 96% vs. 87%, p = 0.46). Conclusions This retrospective analysis based on a prospective cohort for the first time demonstrates that pretreatment ALC is an independent predictor for achieving pCR and favorable outcomes of ESCC treated with neo‐CRT and pembrolizumab.

The trade-off between exploitation and exploration is a dilemma inherent to particle swarm optimization (PSO) algorithms. Therefore, a growing body of PSO variants is devoted to solving the balance between the two. Among them, the method of self-adaptive multi-strategy selection plays a crucial role in improving the performance of PSO algorithms but has yet to be well exploited. In this research, with the aid of the reinforcement learning technique to guide the generation of offspring, a novel self-adaptive multi-strategy selection mechanism is designed, and then a multi-strategy self-learning PSO algorithm based on reinforcement learning (MPSORL) is proposed. First, the fitness value of particles is regarded as a set of states that are divided into several state subsets non-uniformly. Second, the ε-greedy strategy is employed to select the optimal strategy for each particle. The personal best particle and the global best particle are then updated after executing the strategy. Subsequently, the next state is determined. Thus, the value of the Q-table, as a scheme adopted in self-learning, is reshaped by the reward value, the action and the state in a non-stationary environment. Finally, the proposed algorithm is compared with other state-of-the-art algorithms on two well-known benchmark suites and a real-world problem. Extensive experiments indicate that MPSORL has better performance in terms of accuracy, convergence speed and non-parametric tests in most cases. The multi-strategy selection mechanism presented in the manuscript is effective.

Background Dynamic alterations of the tumor immune microenvironment in esophageal squamous cell carcinoma (ESCC) after different neoadjuvant therapies were understudied.Methods We used mass cytometry with a 42-antibody panel for 6 adjacent normal esophageal mucosa and 26 tumor samples (treatment-naïve, n=12; postneoadjuvant, n=14) from patients with ESCC. Single-cell RNA sequencing of previous studies and bulk RNA sequencing from The Cancer Genome Atlas were analyzed, flow cytometry, immunohistochemistry, and immunofluorescence analyses were performed.Results Poor tumor regression was observed in the neoadjuvant chemotherapy group. Radiotherapy-based regimens enhanced CD8+ T cells but diminished regulatory T cells and promoted the ratio of effector memory to central memory T cells. Immune checkpoint blockade augmented NK cell activation and cytotoxicity by increasing the frequency of CD16+ NK cells. We discovered a novel CCR4+CCR6+ macrophage subset that correlated with the enrichment of corresponding chemokines (CCL3/CCL5/CCL17/CCL20/CCL22). We established a CCR4/CCR6 chemokine-based model that stratified ESCC patients with differential overall survival and responsiveness to neoadjuvant chemoradiotherapy combined with immunotherapy, which was validated in two independent cohorts of esophageal cancer with neoadjuvant treatment.Conclusions This work reveals that neoadjuvant therapy significantly regulates the cellular composition of the tumor immune microenvironment in ESCC and proposes a potential model of CCR4/CCR6 system to predict the benefits from neoadjuvant chemoradiotherapy combined with immunotherapy.

Abstract Lung cancer is the leading cause of cancer-related death across the world. Unlike lung adenocarcinoma, patients with lung squamous cell carcinoma (LSCC) have not benefitted from targeted therapies. Although immunotherapy has significantly improved cancer patients’ outcomes, the relatively low response rate and severe adverse events hinder the clinical application of this promising treatment in LSCC. Therefore, it is of vital importance to have a better understanding of the mechanisms underlying the pathogenesis of LSCC as well as the inner connection among different signaling pathways, which will surely provide opportunities for more effective therapeutic interventions for LSCC. In this review, new insights were given about classical signaling pathways which have been proved in other cancer types but not in LSCC, including PI3K signaling pathway, VEGF/VEGFR signaling, and CDK4/6 pathway. Other signaling pathways which may have therapeutic potentials in LSCC were also discussed, including the FGFR1 pathway, EGFR pathway, and KEAP1/NRF2 pathway. Next, chromosome 3q, which harbors two key squamous differentiation markers SOX2 and TP63 is discussed as well as its related potential therapeutic targets. We also provided some progress of LSCC in epigenetic therapies and immune checkpoints blockade (ICB) therapies. Subsequently, we outlined some combination strategies of ICB therapies and other targeted therapies. Finally, prospects and challenges were given related to the exploration and application of novel therapeutic strategies for LSCC.

Abstract Background Xenotransplantation has been primarily performed using fresh donor tissue to study testicular development for about 20 years, and whether the cultured tissue would be a suitable donor is unclear. In this study, we combined testicular culture and xenotransplantation into an integrative model and explored whether immature testicular tissue would survive and continue to develop in this model. Methods In the new integrative model group, the testes of neonatal rats on postnatal day 8 (PND 8) were cultured for 4 days ex vivo and then were transplanted under the dorsal skin of castrated nude mice. The xenografted testes were resected on the 57th day after xenotransplantation and the testes of rats in the control group were harvested on PND 69. The survival state of testicular tissue was evaluated from morphological and functional perspectives including H&E staining, immunohistochemical staining of 8-OH-dG, immunofluorescence staining, TUNEL assay, ultrastructural study, gene expression and protein analysis. Results (a) We found that complete spermatogenesis was established in the testes in the new integrative model group. Compared with the control in the same stage, the seminiferous epithelium in some tubules was a bit thinner and there were vacuoles in part of the tubules. Immunofluorescence staining revealed some ACROSIN-positive spermatids were present in seminiferous tubule of xenografted testes. TUNEL detection showed apoptotic cells and most of them were germ cells in the new integrative model group. 8-OH-dG immunohistochemistry showed strongly positive-stained in the seminiferous epithelium after xenotransplantation in comparison with the control group; (b) Compared with the control group, the expressions of FOXA3, DAZL, GFRα1, BOLL, SYCP3, CDC25A, LDHC, CREM and MKI67 in the new integrative model group were significantly elevated (P

Abstract. Esophageal cancer (EC) has a high incidence and poor prognosis. The two major histological types, squamous cell carcinoma and adenocarcinoma, differ in their epidemiology and treatment options. Patients with locally advanced EC benefit from multimodal therapy concepts including neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, and perioperative chemotherapy. Currently, immunotherapy for the solid tumor is a hot spot. Treatment with adjuvant immune checkpoint inhibitors (ICIs) is the first immunotherapy for resectable EC listed in the latest National Comprehensive Cancer Network Guidelines for the Esophageal and Esophagogastric Junction Cancers. Recent clinical trials have established ICIs for three treatment models of resectable EC. Their short-term results demonstrated ideal efficacy and tolerable toxicity, though some concerns remain. This review summarizes the novel data on the ICIs for resectable EC and lists the registered related clinical trials. Hopefully, this review can provide a reference for ongoing research on the treatment options for resectable EC.

BackgroundComprehensive analysis of transcriptomic profiles of non-small cell lung cancer (NSCLC) may provide novel evidence for biomarkers associated with response to PD-1/PD-L1 immune checkpoint blockade (ICB).MethodsWe utilized weighted gene co-expression network analysis (WGCNA) to analyze transcriptomic data from two NSCLC datasets from Gene Expression Omnibus (GSE135222 and GSE126044) that involved patients received ICB treatment. We evaluated the correlation of co-expression modules with ICB responsiveness and functionally annotated ICB-related modules using pathway enrichment analysis, single-cell RNA sequencing, flow cytometry and alternative splicing analysis. We built a risk score using Lasso-COX regression based on hub genes from ICB-related modules. We investigated the alteration of tumor microenvironment between high- and low- risk groups and the association of the risk score with previously established predictive biomarkers.ResultsOur results identified a black with positive correlation and a blue module with negative correlation to ICB responsiveness. The black module was enriched in pathway of T cell activation and antigen processing and presentation, and the genes assigned to it were consistently expressed on myeloid cells. We observed decreased alternative splicing events in samples with high signature scores of the blue module. The Lasso-COX analysis screened out three genes (EVI2B, DHX9, HNRNPM) and constructed a risk score from the hub genes of the two modules. We validated the predictive value of the risk score for poor response to ICB therapy in an in-house NSCLC cohort and a pan-cancer cohort from the KM-plotter database. The low-risk group had more immune-infiltrated microenvironment, with higher frequencies of precursor exhausted CD8+ T cells, tissue-resident CD8+ T cells, plasmacytoid dendritic cells and type 1 conventional dendritic cells, and a lower frequency of terminal exhausted CD8+ T cells, which may explain its superior response to ICB therapy. The significant correlation of the risk score to gene signature of tertiary lymphoid structure also implicated the possible mechanism of this predictive biomarker.ConclusionsOur study identified two co-expression modules related to ICB responsiveness in NSCLC and developed a risk score accordingly, which could potentially serve as a predictive biomarker for ICB response.

BackgroundChronic obstructive pulmonary disease (COPD) and lung cancer are leading causes of morbidity and mortality worldwide. Studies have reported molecular alterations in patients with lung cancer and in patients with COPD. However, few investigation has been conducted on the molecular characteristics of lung cancer patients with COPD.Materials and methodsWe performed a retrospective cohort study that included 435 patients with pathologically confirmed lung cancer at the Ruijin Hospital. For patients with documented spirometry, Global Initiative for Chronic Obstructive Lung Disease criteria were used to define COPD. For patients without documented spirometry, chest computed tomography and other clinical information were used to define COPD. Tumor tissue DNA was extracted from formalin-fixed paraffin-embedded samples. DNA mutation analysis, multiplex immunohistochemistry (mIHC), calculation of tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), and predication of neoantigens were performed.ResultsAlthough SNV mutations in lung cancer patients with COPD (G1 group) were generally higher than those in lung cancer patients without COPD (G2 group), the difference in the number of mutations was insignificant between the two groups. Of the 35 mutated genes, the number of them was higher in G1 than in G2, except that of EGFR. PI3K-Akt signaling pathway was enriched from significantly different genes. While TMB and MATH levels were not significantly different, the tumor neoantigen burdenwas markedly higher in G1 than that in G2. The level of CD68+ macrophages was significant higher in the stroma and total areas in the G1 group than in G2 group. The level of CD8+ lymphocytes was markedly higher in the stroma and showed a clear tendency forhigher expression in the G1 group than inthe G2 group. No significant differences were observed for the level of programmed death-ligand 1+ (PD-L1+), programmed death 1+ (PD-1+), and CD68PD-L1 in the stroma, tumor and total areas.ConclusionOur study revealed different genetic aberrations and pathways, higher neoantigen burden, and higher level of CD68+ macrophages and CD8+ T lymphocytes in lung cancer patients with COPD. Our investigation implies that the existence of COPD should be considered and immunotherapy is a potential choice when treating lung cancer patients with COPD.

Abstract Background PI3K-Akt pathway activation and the expression of histone deacetylases (HDACs) are highly increased in esophageal cancer, suggesting that inhibition of such targets may be a viable therapeutic strategy. Herein, we aimed to evaluate the anti-tumor effect of CUDC-907, a dual PI3K-HDAC inhibitor, in esophageal squamous cell carcinoma (ESCC). Methods The anti-tumor effects of CUDC-907 in ESCC were evaluated using cell counting kit-8, flow cytometry, and western blot. mRNA-sequencing was used to explore the mechanism underlying CUDC-907 anti-tumor effects. The relations of reactive oxygen species (ROS), lipocalin 2 (LCN2), and CUDC-907 were determined by flow cytometry, rescue experiments, and western blot. The activation of the IRE1α-JNK-CHOP signal cascade was confirmed by western blot. The in vivo inhibitory effects of CUDC-907 were examined by a subcutaneous xenograft model in nude mice. Results CUDC-907 displayed effective inhibition in the proliferation, migration, and invasion of ESCC cells. Through an mRNA-sequencing and functional enrichment analysis, autophagy was found to be associated with cancer cells death. CUDC-907 not only inhibited the PI3K-Akt-mTOR pathways to result in autophagy, but also induced ROS accumulation to activate IRE1α-JNK-CHOP-mediated cytotoxic autophagy by downregulating LCN2 expression. Consistently, the in vivo anti-tumor effects of CUDC-907 accompanied by the downregulated expression of p-mTOR and LCN2 and upregulated expression of p-IRE1α and LC3B-II were evaluated in a xenograft mouse model. Conclusion Our findings suggested the clinical development and administration of CUDC-907 might act as a novel treatment strategy for ESCC. A more in-depth understanding of the anti-tumor effect of CUDC-907 in ESCC will benefit the clinically targeted treatment of ESCC.

Abstract Background Neoadjuvant chemoradiation followed by esophagectomy has been established as the first-line treatment for locally advanced esophageal cancer. Postoperative enteral nutrition has been widely used to improve perioperative outcomes. However, whether to implement preoperative nutritional intervention during neoadjuvant therapy is yet to be verified by prospective studies. Methods POINT trial is a multicenter, open-labeled, randomized controlled trial. A total of 244 patients with surgically resectable esophageal cancer are randomly assigned to nutritional therapy group (arm A) or control group (arm B) with a 2:1 ratio. Both groups receive neoadjuvant chemotherapy with concurrent radiotherapy based on the CROSS regimen followed by minimally invasive esophagectomy. The primary endpoint is the rate of nutrition and immune-related complications after surgery. Secondary endpoints include completion rate of neoadjuvant chemoradiation and related adverse events, rate of pathological complete response, perioperative outcomes, nutritional status, overall survival, progression-free survival and quality of life. Discussion This trial aims to verify whether immunonutrition during neoadjuvant chemoradiation can reduce the rate of complications and improve perioperative outcomes. Frequent communication and monitoring are essential for a multicenter investigator-initiated trial. Trial registration: ClinicalTrials.gov: NCT04513418. The trial was prospectively registered on 14 August 2020, https://www.clinicaltrials.gov/ct2/show/NCT04513418 .

Objective: The safety and feasibility of preoperative pembrolizumab combined with chemoradiotherapy (PPCT) for resectable esophageal squamous cell carcinoma have been confirmed by the prior Preoperative Anti-PD-1 Antibody combined with Chemoradiotherapy for Locally Advanced Squmous Cell Carcinoma of Esophageus (PALACE)-1 trial. Potential therapeutic benefit was also observed with a pathologic complete response rate of 55.6% after PPCT. We will conduct the multicenter single-arm PALACE-2 study to investigate the efficacy and to further confirm the safety of PPCT (ClinicalTrials.gov ID: NCT04435197). Methods: A total of 143 patients with previously untreated, locally advanced, and surgically resectable esophageal squamous cell carcinoma (T2 through T4a, N0 through N+, M0) will be enrolled in PALACE-2. Main exclusion criteria are autoimmune disease, interstitial lung disease, ongoing immunosuppressive therapy, and having received chemotherapy, radiotherapy, target therapy, or immune therapy for this or any other malignancies. Positive programmed cell death ligand 1 expression is not mandatory for enrollment. Patients will receive PPCT, which includes concurrent pembrolizumab (200 mg on day 1 and day 22), carboplatin (area under the curve = 2, once a week for 5 weeks), nab-paclitaxel (50 mg/m2, once a week for 5 weeks), and radiotherapy (23 fractions of 1.8 Gy, 5 fractions a week). Esophagectomy will be performed within 4 to 6 weeks after the completion of PPCT. Results: The primary end point is the rate of pathologic complete response. Secondary outcome measures are 3-year disease-free survival rate, 3-year overall survival rate, R0 resection rate, and adverse events during neoadjuvant and perioperative periods. Conclusions: PPCT was preliminarily demonstrated to be safe, feasible, and to provide potential therapeutic benefits by the PALACE-1 trial. The subsequent multicenter PALACE-2 study will investigate the efficacy and further confirm the safety of PPCT for locally advanced, resectable esophageal squamous cell carcinoma.

Abstract Background Primary lung acinic cell carcinoma is very rare. Here we report a young female patient who suffered the largest primary lung acinic cell carcinoma with severe mediastinal deviation which has never been reported before. We also reviewed data and features of 20 previously reported cases of primary lung acinic cell carcinoma who underwent lobectomy. Case presentation A 27-year-old female patient presented with recurrent coughing and hemoptysis for more than 10 years came to our hospital. A chest computed tomography (CT) showed a giant space-occupying lesion in the hilum of right lung. After a thorough and detailed preoperative examination, the patient then was performed a radical right pneumonectomy with mediastinal lymph node dissection. The size of the tumor was about 8.6 × 4.5 × 4.4 cm. The pathological results demonstrated a primary acinic cell carcinoma of right lung. The immunohistochemistry of the tumor showed AE1/AE3 (+), Ki-67 (2% +), CK7 (+), Vimentin (+), CK19 (+), α1-ACT (+), AB-PAS (+), S-100 (−), TTF-1 (−). The patient was discharged less than 2 weeks after the operation. So far, the patient has been followed-up for 2 years, and no evidence of tumor recurrence or metastasis was observed. Conclusions The primary acinic cell carcinoma of lung in this case is the biggest one ever reported and also the first case treated with radical right pneumonectomy. In addition, the patient had a very rare condition of severe mediastinal deviation at the same time. After surgical treatment, the patient recovered uneventfully and had stable disease without recurrence and metastasis after 2 years of follow-up. This case together with the reported case indicate that primary acinic cell carcinoma of lung is of low malignancy, the prognosis and therapy effect of surgical treatment are relatively satisfactory.

In the past 20 years, robotic system has gradually found a place in esophagectomy which is a demanding procedure in the deep and narrow thoracic cavity containing crucial functional structures. Ivor Lewis esophagectomy (ILE) is a mainstream surgery type for esophagectomy and is widely accepted for its capability in lymphadenectomy and relatively mitigated trauma. As a minimally invasive technique, robot-assisted Ivor Lewis esophagectomy (RAILE) has been frequently compared with the video-assisted procedure and the traditional open procedure. However, high-quality evidence elucidating the advantages and drawbacks of RAILE is still lacking. In this article, we will review the surgical techniques, both short and long-term outcomes, the learning curve, and explicate the current progress and clinical efficacy of RAILE.

Lung cancer is a malignant tumor with high morbidity and mortality in the world today. Emerging evidence suggests that PIWI-interacting RNAs (piRNAs) are aberrantly expressed in various human cancers, including lung cancer. Despite of the poorly understood mechanism, piRNAs may work as carcinogenic roles or tumor suppressors by engaging in a variety of cancer-associated signaling pathways. Therefore, they might serve as potential therapeutic targets, diagnostic indicators, or prognostic indicators in lung cancer. This review will discuss the new findings of piRNAs, including their biosynthetic processes, mechanisms of gene suppression, and the significance of these piRNAs tested in lung cancer samples to determine their involvement in cancer progression.

ObjectiveAnatomical segmentectomy has been proven to be a viable surgical treatment for small-size peripheral lung nodules. Three-dimensional (3D) reconstruction computed tomography (CT) has been proposed as an effective approach to overcome the challenges of encountering pulmonary anatomical variations when performing segmentectomy. Therefore, to further investigate the usefulness of preoperative 3D reconstruction CT in segmentectomy, we will conduct this prospective, multicenter randomized controlled DRIVATS study to compare the use of 3D reconstruction CT with standard chest CT in video-assisted segmentectomy (ClinicalTrials.gov ID: NCT04004494).MethodsThis study began in July 2019 and a total of 190 patients will be accrued from three clinical centers within 4 years. The main inclusion criteria are patients with a single peripheral nodule 0.8–2 cm with at least one of the following requirements: (i) histology of adenocarcinoma in situ; (ii) nodule has ≥50% ground-glass appearance on CT; (iii) radiologic surveillance confirms a long doubling time (≥400 days). Surgical procedures include segmental resection of the lesion and mediastinal lymph node sampling (subsegmental resection or combined subsegmental resection will not be included in this study). The primary endpoint is operative time. The secondary endpoints include incidence of change of surgical plan, intraoperative blood loss, conversion rate, operative accident event, incidence of postoperative complications, postoperative hospital stay, length of hospitalization, duration of chest tube placement, postoperative 30-day mortality, dissection of lymph nodes, overall survival, disease-free survival, preoperative lung function, and postoperative lung function.DiscussionThis multicenter DRIVATS study aims to verify the usefulness of preoperative 3D reconstruction CT compared with standard chest CT in segmentectomy. If successfully completed, this multicenter prospective study will provide a higher level of evidence for the use of 3D reconstruction CT in segmentectomy.

Background Foxp3+ regulatory T (Treg) cells facilitate tumor immune evasion by forming a suppressive tumor microenvironment. Therefore, immune therapies promoting Treg fragility may greatly enhance immune checkpoint blockade (ICB) efficacy in cancers.Methods We have screened 2640 compounds and identified the gut microbial metabolite gallic acid, which promotes Foxp3 degradation and Treg instability by repressing Usp21 gene transcription. In vivo and in vitro experiments have been performed to explore the roles of Usp21 in Treg cells. Importantly, we treated tumor-bearing mice with gallic acid and anti-PD-1 antibody to explore the potential therapeutic value of gallic acid in clinical cancer immunotherapy.Results Mechanistically, gallic acid prevents STAT3 phosphorylation and the binding of phosphorylated STAT3 to Usp21 gene promoter. The deubiquitinated Usp21 and stabilized PD-L1 proteins boost the function of Treg cells. Combination of gallic acid and anti-PD-1 antibody, in colorectal cancer (CRC) treatment, not only significantly dampen Treg cell function by impairing PD-L1/PD-1 signaling and downregulating Foxp3 stability, but also promote CD8+ T cells’ production of IFN-γ and limited tumor growth.Conclusion Our findings have implications for improving the efficacy of ICB therapy in CRC by inducing T-helper-1-like Foxp3lo Treg cells.

Segmentectomy has played a crucial role in the treatment of early-stage lung cancer after the publication of JCOG0802, which indicated that patients with small-sized peripheral non-small-cell lung cancer could receive better survival from segmentectomy than lobectomy despite a higher local recurrence. The intraoperative identification of the intersegmental plane ensures complete resection of the lesion with sufficient margin so that it is deemed as the critical part of segmentectomy. Diverse methods have been developed to acquire distinguishable and lasting borderline between segments, but none of them is proved perfect. In this review, we searched and classified these techniques that emerged from the beginning when segmentectomy was used for bronchiectasis until now. Comparisons between different ways in mechanisms, facility, and safety were made to depict a comprehensive landscape for surgeons to select fit one. Furthermore, we presented our vision for the future of intersegmental plane identification.

Background and objective Perioperative treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancelation of surgery, additional illness, and even death, and have therefore attracted much attention. The purpose of the clinical recommendations is to form a diagnosis and treatment plan suitable for the current domestic medical situation for the immune-related adverse event (irAE). Methods This recommendation is composed of experts in thoracic surgery, oncologists, thoracic medicine and irAE related departments (gastroenterology, respirology, cardiology, infectious medicine, hematology, endocrinology, rheumatology, neurology, dermatology, emergency section) to jointly complete the formulation. Experts make full reference to the irAE guidelines, large-scale clinical research data published by thoracic surgery, and the clinical experience of domestic doctors and publicly published cases, and repeated discussions in multiple disciplines to form this recommendation for perioperative irAE. Results This clinical recommendation covers the whole process of prevention, evaluation, examination, treatment and monitoring related to irAE, so as to guide the clinical work comprehensively and effectively. Conclusion Perioperative irAE management is an important part of immune perioperative treatment of lung cancer. With the continuous development of immune perioperative treatment, more research is needed in the future to optimize the diagnosis and treatment of perioperative irAE.

Differential evolution (DE) has been applied to solve complex optimization problems. An effective DE algorithm should be convergent and able to jump out of the local optimal solution. Motivated by these considerations, an improved differential evolution is proposed, which is based on the oppositional solution, elite sharing schemes, the heuristic crossover operator and combined with a self-adaptive parameter setting strategy. The algorithm is denoted as SOSESDE. First, in the early stage of evolution, the disturbance oppositional strategy is applied to the worse individuals to increase the search space since the oppositional search strategy will generate redundant offspring by the same genetic operation, which can be avoided by random perturbation. Then, an elite sharing scheme is used for information exchange. In this scheme, the K-means is first used to divide the present population into several subpopulations, and then, the elitist in each subpopulation is taken for mutation operation. In addition, the related parameters $F$ and $CR$ are self-adaptively adjusted based on the results of the Wilcoxon signed-rank test and the probability that a parent is selected for the next generation. Besides, the heuristic crossover operator is constructed by using uniform design method. Finally, 53 benchmark functions are optimized using SOSESDE, and the results are compared with those of various state-of-the-art algorithms. The experiments show that compared to these algorithms, SOSESDE exhibits better performance.

Understanding the tumour microenvironment is essential for the efficacy of immunotherapies. Here the authors describe the immune landscape in esophageal squamous cell carcinoma and suggest several immunosuppressive mechanisms, which upon targeting may restore anti-tumour immune response.

ObjectiveThe novel Coronavirus Disease 2019 (COVID-19) has resulted in a global health crisis since first case was identified in December 2019. As the pandemic continues to strain global public health systems, elective surgeries for thoracic cancer, such as early-stage lung cancer and esophageal cancer (EC), have been postponed due to a shortage of medical resources and the risk of nosocomial transmission. This review is aimed to discuss the influence of COVID-19 on thoracic surgical practice, prevention of nosocomial transmission during the pandemic, and propose modifications to the standard practices in the surgical management of different thoracic cancer.MethodsA literature search of PubMed, Medline, and Google Scholar was performed for articles focusing on COVID-19, early-stage lung cancer, and EC prior to 1 July 2021. The evidence from articles was combined with our data and experience.ResultsWe review the challenges in the management of different thoracic cancer from the perspectives of thoracic surgeons and propose rational strategies for the diagnosis and treatment of early-stage lung cancer and EC during the COVID-19 pandemic.ConclusionsDuring the COVID-19 pandemic, the optimization of hospital systems and medical resources is to fight against COVID-19. Indolent early lung cancers, such as pure ground-glass nodules/opacities (GGOs), can be postponed with a lower risk of progression, while selective surgeries of more biologically aggressive tumors should be prioritized. As for EC, we recommend immediate or prioritized surgeries for patients with stage Ib or more advanced stage and patients after neoadjuvant therapy. Routine COVID-19 screening should be performed preoperatively before thoracic surgeries. Prevention of nosocomial transmission by providing appropriate personal protective equipment (PPE), such as N-95 respirator masks with eye protection to healthcare workers, is necessary.

BackgroundTo compare the efficacy and safety of pembrolizumab combined with neoadjuvant chemotherapy (neoCT) versus neoadjuvant chemoradiotherapy (neoCRT) followed by surgery for locally advanced resectable oesophageal squamous cell carcinoma (ESCC).MethodsThis study is a multicentre, prospective, randomized-controlled, phase III clinical study. Eligible ESCC (staging: cT1N2M0 or cT2-3N0-2M0 (stage II/III, high-risk lesions in T2N0M0)) patients will be randomly assigned to either the experimental group (pembrolizumab with neoCT, n = 228) or the control group (neoCRT, n = 114) at a ratio of 2:1. Within 4–6 weeks after preoperative therapy, the McKeown procedure will be performed. Patients in the experimental group will also receive pembrolizumab alone as adjuvant therapy after surgery until 1 year or until the radiographically confirmed PD or other condition indicated for premature termination is observed. The primary endpoint is event-free survival (EFS). The secondary endpoints are 1-, 3-, and 5-year overall survival (OS) and disease-free survival (DFS), short-term outcomes, and quality of life.DiscussionThis is the first prospectively randomized controlled trial designed to compare pembrolizumab plus chemotherapy and chemoradiotherapy as neoadjuvant therapy for resectable ESCC. According to our hypothesis, preoperative pembrolizumab combined with chemotherapy will result in a better tumour response and prolong the survival of patients, with acceptable toxicity. This study started in December 2021, and the enrolment time is estimated to be 2 years.Trial RegistrationThis prospective study has been registered at ClinicalTrials.gov (NCT04807673), March 2021.

Objective: The aim of this study was to investigate how the tumor immune microenvironment differs regarding tumor genomics, as well as its impact on prognoses and responses to immunotherapy in East Asian patients with non-small cell lung cancer (NSCLC). Methods: We performed an integrated analysis using publicly available data to identify associations between anti-programmed death 1 (PD-1)/ programmed death-ligand 1 (PD-L1) immunotherapy efficacy and classic driver oncogene mutations in East Asian NSCLC patients. Four pooled and clinical cohort analyses were used to correlate driver oncogene mutation status and tumor microenvironment based on PD-L1 and CD8+ tumor-infiltrating lymphocytes (TILs). Immune infiltrating patterns were also established for genomic NSCLC subgroups using the CIBERSORT algorithm. Results: Based on East Asian NSCLC patients, TIDE analyses revealed that for anti-PD-1/PD-L1 immunotherapy, epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged tumors yielded inferior responses; however, although Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant tumors responded better, the difference was not statistically significant (EGFR: P = 0.037; ALK: P < 0.001; KRAS: P = 0.701). Pooled and clinical cohort analyses demonstrated tumor immune microenvironment heterogeneities correlated with oncogenic patterns. The results showed remarkably higher PD-L1- and TIL-positive KRAS-mutant tumors, suggesting KRAS mutations may drive an inflammatory phenotype with adaptive immune resistance. However, the EGFR-mutant or ALK-rearranged groups showed a remarkably higher proportion of PD-L1-/TIL-tumors, suggesting an uninflamed phenotype with immunological ignorance. Notably, similar to triple wild-type NSCLC tumors, EGFR L858R-mutant tumors positively correlated with an inflammatory phenotype, suggesting responsiveness to anti-PD-1/PD-L1 immunotherapy (P < 0.05). Furthermore, the CIBERSORT algorithm results revealed that EGFR-mutant and ALK-rearranged tumors were characterized by an enriched resting memory CD4+ T cell population (P < 0.001), as well as a lack of CD8+ T cells (P < 0.01), and activated memory CD4+ T cells (P = 0.001). Conclusions: Our study highlighted the complex relationships between immune heterogeneity and immunotherapeutic responses in East Asian NSCLC patients regarding oncogenic dependence.

In the engineering and economic management fields, optimisation models frequently involve different decision-making levels. These are known as multi-level optimisation problems. Because the decision-making process of such problems are hierarchical, they are also called a hierarchical optimisation problems. When the problem involves only two-level decision-making, the corresponding optimisation model is referred to as a bilevel programming problem(BLPP). To address the complex nonlinear bilevel programming problem, in this study, we design an evolutionary algorithm embedded with a surrogate model-that it is a approximation method and correlation coefficients. First, the isodata method is used to group the initial population, and the correlation coefficients of the individuals in each group are determined based on the rank of the leader and follower objective functions. Second, for the offspring individuals produced by the evolutionary operator, the surrogate model is used to approximate the solution of the follower's programming problem, during which the points in the population are screened by combining the correlation coefficients. Finally, a new crossover operator is designed by the spherical search method, which diversifies the generated offspring. The simulation experimental results demonstrate that the proposed algorithm can effectively obtain an optimal solution.

Abstract Background Currently, there are three main surgical approaches for resectable esophageal cancer: open transthoracic esophagectomy (OTE), conventional minimally invasive esophagectomy (MIE) and robot-assisted esophagectomy (RAE). Previous studies had demonstrated the better short-term outcomes in MIE or RAE when compared to OTE, respectively. However, to date, no prospective study was designed to compare these two minimally invasive approaches (MIE and RAE). The primary objective of this study is to compare the outcomes on survival, safety and efficacy, quality of life between RAE and MIE in the treatment for resectable esophageal squamous cell carcinoma (ESCC). Methods This study is designed as a multicenter, prospective, randomized, non-inferiority phase III clinical trial, investigating the safety and efficacy of RAE compared with MIE in the treatment of resectable ESCC. Eligible patients are randomly assigned to either RAE (n = 180) or MIE (n = 180) group. The follow-up visits will be scheduled at 3, 6, 9, and 12 months in the first two years, and then every 6 months until the end of the study. During the follow-up period, clinical data and quality of life questionnaires will be examined. The primary endpoint is the 5-year overall survival (OS). The secondary endpoints are 3-year OS, 5-year disease-free survival (DFS), short-term outcomes as well as quality of life. Discussion This is the first prospectively randomized controlled trial designed to compare RAE with MIE as surgical treatment for resectable ESCC. According to our hypothesis, RAE will result in at least similar oncologic outcomes and long-term quality of life, but with a shorter operation time, lower percentage of perioperative complications, lower blood loss, and shorter hospital stay when compared with MIE. This study started in July 2017. Follow-up will terminate after 5 years from the time when the last patient was enrolled. Trial registration ClinicalTrial.gov: NCT03094351 (March 29, 2017). The trial was prospectively registered.

Objective To investigate sex hormone and blood lipid levels in patients with lifelong premature ejaculation (LPE) in China. Methods Sex hormone and blood lipid levels were measured in 156 patients with LPE and 76 healthy controls. The Premature Ejaculation Diagnostic Tool (PEDT) and Chinese Index of Sexual Function for Premature Ejaculation-5 Questionnaires (CIPE-5) were applied to diagnose and grade LPE. Results PEDT and CIPE-5 scores were significantly altered in the LPE group compared with the control group. Free testosterone levels were significantly higher in the LPE group than in the control group. Free testosterone levels were also significantly higher in the mild, moderate, and severe LPE subgroups than in the control group. Total testosterone and prolactin levels tended to be lower in the control group than in the LPE group. Very low-density lipoprotein levels were significantly lower in the LPE group and LPE subgroups than in the control group. Triglyceride levels were highest in controls and decreased with progression of LPE. Conclusions Patients with LPE have higher free testosterone levels and lower very low-density lipoprotein levels than controls. These findings indicate that these factors might be indices for LPE. However, the reasons for these phenomena need to be further investigated.

BackgroundCoronavirus disease 2019 (COVID-19) pandemic has become the most severe global health issue. Abnormal liver functions are frequently reported in these patients. However, liver function abnormality was often overlooked during COVID-19 treatment, and data regarding liver functions after cure of COVID-19 is limited. This study aimed to reveal the changes of liver function tests (LFTs) during hospitalization, and its clinical significance in patients with COVID-19.MethodsIn this retrospective, bi-center study, a total of 158 hospitalized patients diagnosed with COVID-19 in China were included from January 22nd, 2020 to February 20th, 2020. Clinical features, laboratory parameters including LFTs, and treatment data were collected and analyzed. LFTs included alanine transaminase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and total bilirubin. Patients were considered with abnormal LFTs when any value of these tests was higher than upper limit of normal.ResultsOf 158 patients with COVID-19, 67 (42.41%) patients had abnormal LFTs on admission and another 50 (31.65%) patients developed abnormal LFTs during hospitalization. The incidence of LFTs abnormality in severe COVID-19 cases was significantly higher than non-severe cases. All LFTs in COVID-19 patients were correlated with oxygenation index. There was no statistical difference in treatment between the patients with or without liver test abnormalities. By the time of discharge, there were still 64 (40.50%) patients with abnormal LFTs. Logistic regression analysis identified younger age, hypertension and low lymphocyte counts as independent risk factors for persistent abnormal LFTs during hospitalization.ConclusionLiver function tests abnormality was common in COVID-19 patients and was more prevalent in severe cases than in non-severe cases. A substantial percentage of patients still had abnormal LFTs by the time of discharge.

Renal cell carcinoma (RCC) is the most common type of kidney cancer with rising incidence. Long noncoding RNA (lncRNA) LINC01133 is a novel lncRNA that is involved in the development of several types of cancers. However, the role of LINC01133 in RCC has not been reported. Thus, in this study, we investigated the functions of LINC01133 in RCC. The qualitative real-time polymerase chain reaction analysis was performed to examine the levels of LINC01133 in RCC tissues and adjacent tissues, as well as RCC cell lines. The results showed that LINC01133 was highly expressed in RCC tissue specimens and cell lines. Downregulation of LINC01133 significantly inhibited the proliferation, migration, and invasion of RCC cells. Further mechanistic investigations proved that LINC01133 directly interacted with microRNA (miR)-30b-5p and regulated the miR-30b-5p expression in RCC cell lines. Moreover, miR-30b-5p exhibited tumor-suppressive activity in RCC cell lines, which was mediated by targeting Ras-related protein Rab-3D (Rab3D). In vivo study showed that LINC01133 knockdown suppressed tumor growth in the nude mice. Taken together, these findings indicated that LINC01133 might be an oncogene in RCC through regulation of the miR-30b-5p/Rab3D axis. Thus, LINC01133 might serve as a potential therapeutic target for the treatment of RCC.

Regulatory T cells (Treg cells) are essential for maintaining immune tolerance, and the dysfunction of Treg cells may cause autoimmune diseases and tumors. Forkhead box P3 (FOXP3) is the key transcription factor controlling Treg cell development and suppressive function. Mouse double minute 2 homolog (MDM2), an E3 ubiquitin ligase, has been identified as an oncoprotein that mediates the ubiquitination and degradation of tumor suppressor p53; however, whether it has functions in Treg cells remains unknown. Here, we demonstrate that MDM2 positively regulates human Treg cell suppressive function via its mediated ubiquitination and stabilization of FOXP3. Knockdown of MDM2 with shRNA in human primary Treg cells leads to the impaired ability of FOXP3 to regulate the expression levels of downstream genes and the attenuated suppressive capacity of Treg cells, due to FOXP3 instability. Consistently, MDM2 overexpression in human Treg cells enhances FOXP3 stability and Treg cell suppressive capacity. Mechanistically, MDM2 interacts with FOXP3, and mainly mediates monoubiquitination and polyubiquitination of FOXP3, thus stabilizing the protein level of FOXP3. We have also found lysine residues in FOXP3 required for MDM2-mediated ubiquitination. In addition, TCR/CD28 signaling upregulates the expression level of MDM2 and its mediated FOXP3 ubiquitination in human Treg cells. Therefore, our findings reveal that MDM2 in Treg cells could be a potential therapeutic target for treating autoimmune diseases and tumors.

A bilevel programming problem with multiple objectives at the leader's and/or follower's levels, known as a bilevel multiobjective programming problem (BMPP), is extraordinarily hard as this problem accumulates the computational complexity of both hierarchical structures and multiobjective optimisation. As a strongly NP-hard problem, the BMPP incurs a significant computational cost in obtaining non-dominated solutions at both levels, and few studies have addressed this issue. In this study, an evolutionary algorithm is developed using surrogate optimisation models to solve such problems. First, a dynamic weighted sum method is adopted to address the follower's multiple objective cases, in which the follower's problem is categorised into several single-objective ones. Next, for each the leader's variable values, the optimal solutions to the transformed follower's programs can be approximated by adaptively improved surrogate models instead of solving the follower's problems. Finally, these techniques are embedded in MOEA/D, by which the leader's non-dominated solutions can be obtained. In addition, a heuristic crossover operator is designed using gradient information in the evolutionary procedure. The proposed algorithm is executed on some computational examples including linear and nonlinear cases, and the simulation results demonstrate the efficiency of the approach.

Abstract Background Esophageal schwannomas are extremely rare, with few cases reported in the literature. Traditionally, resection of esophageal schwannoma is typically performed using thoracotomy or video-assisted thoracic surgery. However, large, irregular tumors may increase the surgical difficulties of complete enucleation and lead to potential mucosal damage. Moreover, a subtotal esophagectomy cannot be avoided in some conditions. Here, we report the first case of robot-assisted enucleation of a large dumbbell-shaped esophageal schwannoma. Case presentation A 48-year-old woman presenting with a 1-year history of dysphagia was noted to have a homogeneous irregular mass measuring 70 mm in diameter and arising from the submucosal layer of the distal esophagus. A diagnosis of an esophageal submucosal tumor (SMT) was made, most likely leiomyoma. Robot-assisted thoracoscopic excision of the tumor was performed. The da Vinci Surgical System provided delicate dissection in the confined posterior mediastinal space, and the large dumbbell-shaped tumor was completely removed without damage to the mucosal integrity. The operative time was 108 min, and the blood loss was less than 20 ml. The pathology of the tumor was esophageal schwannoma. The patient experienced an unremarkable recovery and was discharged on the fifth day after operation. No symptoms or recurrence were present at the 50-month follow-up postoperatively. Conclusion We present a rare case of large irregular esophageal schwannoma that was excised by robot-assisted surgery. A clear operative field and delicate dissections are critical points for the complete removal of this large esophageal SMT. We demonstrate that robotic treatment of large esophageal schwannoma is minimally invasive and can be successfully applied in such cases.

Abstract Background Few studies have described robotic sleeve resection with pulmonary resection. Here, we report the successful implementation of a completely portal robotic sleeve resection with or without pulmonary resection using a modified suture mode. Methods In total, 339 patients underwent curative robotic pulmonary surgery at Ruijin Hospital between May 2015 and September 2017. Three of these patients underwent robotic sleeve resection (right upper lobe, one; left upper lobe, one; and lingular segmental bronchus, one). Five port incisions were utilized, and a simple continuous running suture combined with two interrupted sutures of the membranous and cartilaginous junction portion was preferred for the anastomosis. Results The postoperative course was uneventful for two patients with squamous cell carcinoma. The lingular segmental bronchus patient without pulmonary resection (a salivary gland tumor) underwent short-term atelectasis. The median operation time was 155 (range 132–230) minutes. The median anastomosis time was 25 (range 23–32) minutes. The median length of postoperative hospital stay was 7 (range 6–10) days. There was no mortality or conversion to thoracotomy for any of the patients. All patients were followed for 3–6 months, and there is no tumour recurrence. Conclusions Our limited experience suggested that robotic sleeve resection for pulmonary disease with or without pulmonary resection may be safe and effective. The anastomosis time can be shortened with more robotic surgery experiences and the modified suture mode.