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Abstract Although the initial research focused on glycolysis, mitochondrial oxidative phosphorylation has become a major target of cancer cells. Cytochrome C oxidase assembly factor 6 (COA6) is a conserved assembly factor necessary for complex IV biogenesis. Nevertheless, the clinical predictive value of COA6, especially its correlation with immune cell infiltration in lung adenocarcinoma (LUAD), has not yet been elucidated. COA6 exhibited higher expression levels in LUAD cells and tumor tissues compared to normal tissues. Additionally, heightened COA6 expression was associated with reduced overall survival (OS) and advanced tumor stage. Apart from its role in mitochondrial respiratory processes, COA6 may be involved in the process of antigen binding, immunoglobulin receptor binding. Interestingly, we observed a positive correlation between COA6 expression and tumor mutational burden (TMB), as well as a significant association with decreased immune cell infiltration. COA6 was linked to resistance against gemcitabine and etoposide. We verified that COA6 was highly expressed in LUAD experimentally and cell proliferation was inhibited after COA6 knockdown. Thus, we conclude that the expression of COA6 was correlated with reduced immune cell infiltration. Additionally, COA6 functioned as a biomarker for drug sensitivity and the prognosis of lung adenocarcinoma.

Rechargeable magnesium-ion (Mg-ion) batteries have attracted wide attention for energy storage. However, magnesium anode is still limited by the irreversible Mg plating/stripping procedure. Herein, a well-designed binary Bi2O3-Bi2S3 (BO-BS) heterostructure is fulfilled by virtue of the cooperative interface and energy band engineering targeted fast Mg-ion storage. The built-in electronic field resulting from the asymmetrical electron distribution at the interface of electron-rich S center at Bi2S3 side and electron-poor O center at Bi2O3 side effectively accelerates the electrochemical reaction kinetics in the Mg-ion battery system. Moreover, the as-designed heterogenous interface also benefits to maintaining the electrode integrity. With these advantages, the BO-BS electrode displays a remarkable capacity of 150.36 mAh g−1 at 0.67 A g–1 and a superior cycling stability. This investigation would offer novel insights into the rational design of functional heterogenous electrode materials targeted the fast reaction kinetics for energy storage systems.

BackgroundVolumetric-modulated arc therapy (VMAT) may have the highest overall performance for stereotactic body radiotherapy (SBRT) treatment of inoperable early-stage NSCLC. However, in centers lacking the VMAT technique, the dynamic conformal arc therapy (DCAT) technique is potentially the best option for small and rounded NSCLC-SBRT. Therefore, we will comprehensively analyze the advantages of the DCAT versus the other techniques except VMAT in terms of dosimetry, plan complexity, delivery time, γ-passing rates and the interplay effect.Methods36 patients with early-stage centrally located NSCLC with PTV volumes < 65 cc were enrolled. All patients were redesigned with 50Gy/5f, and 100% of the prescribed dose was normalized to cover 95% of the PTV. The other two delivery techniques compared to the DCAT technique include 3-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT), which use the same parameters for all three techniques.ResultsThe dosimetric parameters of the 3-group plans all met the RTOG 0813 protocol. Unsurprisingly, plan complexity parameters such as segments and MUs were significantly reduced in the DCAT plans by 159.56 and 925.90 compared to the IMRT plans, respectively (all P < 0.001). The delivery time of the DCAT plans was the least of 164.51 s (all P < 0.05). Compared to the IMRT plans, the γ-passing rates were higher in the DCAT plans (P < 0.001), with the most significant difference of 6.01% in the (2%, 1 mm) criteria. As for the interplay effect, the mean dose difference (MDD) in the DCAT plans was as good as the 3DCRT plans at different respiratory amplitudes but better than the IMRT plans (all P < 0.05), and the MDD of DCAT plans did not exceed 3% in all respiratory amplitude.ConclusionIn centers lacking the VMAT technique, implementing SBRT treatment based on the DCAT technique for inoperable early-stage centrally-located NSCLC patients with PTV volumes < 65 cc achieves better treatment efficiency and delivery accuracy while maintaining the plan quality.

Abstract Coal is one of the most important fossil energy sources and is ensuring global energy security. Annual maximum NDVI (Normalized Difference Vegetation Index) data is an important indicator for the research in balancing coal mining and vegetation conservation. However, the existing annual maximum NDVI data displayed lower values with temporally inconsistent and a noticeable mosaic line. Here we propose an algorithm for automatically generating the annual maximum NDVI of China’s coal bases in Google Earth Engine called: Auto-NDVIcb. The accuracy of the Auto-NDVIcb algorithm has been verified with an average RMSE of 0.087 for the 14 coal bases from 2013 to 2022. Based on the proposed Auto-NDVIcb algorithm, an annual maximum NDVI dataset for all 14 coal bases in China from 2013 to 2022 was publicly released. This dataset can be fast and automatically updated online. Hence, the public dataset will continuously serve to monitor the vegetation change induced by coal mining, exploring the mechanism of vegetation degradation, and providing scientific data for developing vegetation protection policies in coal mines.

Objective: Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor characterized by initial sensitivity to chemotherapy, followed by the development of drug resistance. The underlying mechanisms of resistance in SCLC have not been fully elucidated. Aldo-keto reductase family 1 member C3 (AKR1C3), is known to be associated with chemoradiotherapy resistance in diverse tumors. We aim to evaluate the prognostic significance and immune characteristics of AKR1C3 and investigate its potential role in promoting drug resistance in SCLC. Methods: 81 postoperative SCLC tissues were used to analyze AKR1C3 prognostic value and immune features. The tissue microarrays were employed to validate the clinical significance of AKR1C3 in SCLC. The effects of AKR1C3 on SCLC cell proliferation, migration, apoptosis and tumor angiogenesis were detected by CCK-8, wound healing assay, transwell assay, flow cytometry and tube formation assay. Results: AKR1C3 demonstrated the highest expression level compared to other AKR1C family genes, and multivariate cox regression analysis identified it as an independent prognostic factor for SCLC. High AKR1C3 expression patients who underwent chemoradiotherapy experienced significantly shorter overall survival (OS). Furthermore, AKR1C3 was involved in the regulation of the tumor immune microenvironment in SCLC. Silencing of AKR1C3 led to the inhibition of cell proliferation and migration, while simultaneously promoting apoptosis and reducing epithelial-mesenchymal transition (EMT) in SCLC. Conclusion: AKR1C3 promotes cell growth and metastasis, leading to drug resistance through inducing EMT and angiogenesis in SCLC.

Abstract Background Mitochondria, which serve as the fundamental organelle for cellular energy and metabolism, are closely linked to the growth and survival of cancer cells. This study aims to identify and assess Sideroflexin1 (SFXN1), an unprecedented mitochondrial gene, as a potential prognostic biomarker for lung adenocarcinoma (LUAD). Methods The mRNA and protein levels of SFXN1 were investigated based on the Cancer Genome Atlas (TCGA) LUAD dataset, and then validated by real-time quantitative PCR, Western Blotting and immunohistochemistry from our clinical samples. The clinical correlation and prognostic value were evaluated by the TCGA cohort and verified via our clinical dataset (n = 90). The somatic mutation, drug sensitivity data, immune cell infiltration and single-cell RNA sequencing data of SFXN1 were analyzed through public databases. Results SFXN1 was markedly upregulated at both mRNA and protein levels in LUAD, and high expression of SFXN1 were correlated with larger tumor size, positive lymph node metastasis, and advanced clinical stage. Furthermore, SFXN1 upregulation was significantly associated with poor clinical prognosis. SFXN1 co-expressed genes were also analyzed, which were mainly involved in the cell cycle, central carbon metabolism, DNA repair, and the HIF-1α signaling pathway. Additionally, SFXN1 expression correlated with the expression of multiple immunomodulators, which act to regulate the tumor immune microenvironment. Results also demonstrated an association between SFXN1 expression and increased immune cell infiltration, such as activated CD8 + T cells, natural killer cells (NKs), activated dendritic cells (DCs), and macrophages. LUAD patients with high SFXN1 expression exhibited heightened sensitivity to multiple chemotherapies and targeted drugs and predicted a poor response to immunotherapy. SFXN1 represented an independent prognostic marker for LUAD patients with an improved prognostic value for overall survival when combined with clinical stage information. Conclusions SFXN1 is frequently upregulated in LUAD and has a significant impact on the tumor immune environment. Our study uncovers the potential of SFXN1 as a prognostic biomarker and as a novel target for intervention in LUAD.

Introduction This study investigated the relationship between environment support, social support and smoking cessation, to provide suggestions for the construction of environment and social support for tobacco control. Methods This was a secondary analysis based on two cross-sectional surveys of adult smokers who participated in the six-month community smoking cessation intervention projects in Beijing. The study subjects were divided into a successful group (n=159) and an unsuccessful group (n=253). The status of the environment support, community tobacco exposure, and social support were compared between groups. A structural equation model (SEM) was established for Confirmatory Factor Analysis. Results The univariate analysis showed that there were differences in smoking cessation outcomes among smokers with different home tobacco regulations, workplace tobacco regulations and number of smokers in the family. Differences in 6-month smoking reduction were also found with different promotion levels of anti-tobacco messaging and the frequency of smoking events at home. The logistic regression analysis indicated that home tobacco regulations (OR=1.30; 95% CI: 1.00–1.69), workplace tobacco regulations (OR=1.27; 95% CI: 1.05– 1.54), and frequency of smoking events at home (OR=1.15; 95% CI: 1.02–1.29), were associated with smoking cessation. The results of the SEM showed that environment support (β=0.39; 95% CI: 0.05–0.73, p=0.026) and social support (β=0.37; 95% CI: 0.05–0.68, p=0.022) had influence on smoking cessation. Conclusions Environment support and social support are related to smoking cessation. Attention should be paid to the smoking regulations at home and workplace, anti-tobacco messaging, and social support by the family. TRIAL REGISTRATION The study was registered on the official website of the China Clinical Trial Registration Center. Identifier: ChiCTR1900024991

Abstract Background Following external situation reports, individuals perceive risks, experience different emotional reactions, and further change their behaviors. Therefor people’s psychology will also be affected by adjustment of COVID-19 epidemic prevention and control policy, but it remains unknown what kind of coping behaviors will be produced due to psychology. This study defines coping behavior as “medical behavior and irrational consumption behavior after the adjustment of COVID-19 epidemic prevention and control policy in China”, assesses the prevalence of negative emotions in the Chinese population after policy adjustments, and explores how negative emotions affect people’s coping behaviors, conducts baseline research, provides references and suggestions for policy formulation. Methods A cross-sectional online survey was conducted during 21–28 December 2022, included sociodemographic characteristics, COVID-19 infection and irrational purchase behavior, psychological assessment, and opinion polling. Depression and anxiety status are assessed by PHQ-9 and GAD-7. The relationship between anxiety, depression and coping behavior was analyzed by Pearson χ2 test, Fisher’s exact test and logistic regression. Results A total of 3995 infected participants were included in this study, of which 2363(59.1%) and 1194(29.9%) had depression and anxiety. There was a significant difference in clinical treatment and irrational purchase behavior between different level of depression and anxiety. Depression was a risk factor for self- medication (OR = 1.254), seeking professional treatment (OR = 1.215), using online services of medical institutions (OR = 1.320), large-scale purchases of medicines (OR = 1.154) and masks (OR = 1.096). Anxiety was a risk factor for seeking professional treatment (OR = 1.285) and large-scale purchases of masks (OR = 1.168). Conclusion After the adjustment of COVID-19 epidemic prevention and control policy, patient risk perception can increase depression and anxiety. We found that associated with depression, COVID-19 patients are more likely to have medical behaviors such as self- medication, seeking professional treatment, using online services of medical institutions, and storage behaviors of medicines and masks; and anxiety associated with the coping behavior of patients to seek professional treatment and store masks in large quantities. We should improve people’s mental health, and on the other hand, we should give people effective psychological education during the epidemic. Therefore, we should set up psychological outpatient clinics in community health institutions, expanding mental health screening and guidance; relying on the psychological outpatient clinic, establish groups of people with depression or anxiety to carry out COVID-19 health education and peer education, to reduce adverse drug reactions, avoid panic seeking professional treatment and irrational purchase behavior, and protect public mental health. Trial registration This study has been approved by the Medical Ethics Committee of Capital Medical University (2023SY086), and informed consent was obtained from the study subjects before the investigation.

Abstract Despite the benefit with cancer immunotherapies in clinical implication, immunotherapeutic resistance occurred in many patients and the mechanism remains unknown. Increasing evidence has revealed that cell‐intrinsic programmed cell death ligand 1 (PD‐L1) may play a non‐negotiable part in immunotherapeutic resistance. Our present study aimed to elucidate the immune‐independent acquired resistance mechanism to PD‐L1 antibody. We found elevated PD‐L1 expression induced by PD‐L1 antibodies in cancer cell and vascular endothelial cells (VECs) with substantially acquired resistance to PD‐L1 antibodies. Moreover, proliferation of resistant cells was accelerated and the apoptosis was reduced in the absence of immune compared with parental cells. Subsequently, we confirmed that the activation of the PI3K/AKT pathway is involved in the upregulation of PD‐L1 expression. Finally, we found that low dose of anlotinib downregulated PD‐L1 expression only in VECs via inhibiting the PI3K/AKT pathway; however, the same effect was not observed in cancer cells. To sum up, our findings revealed that upregulation of PD‐L1 via activation of the PI3K/AKT signal pathway may promote acquired resistance to PD‐L1 antibodies in an immune‐independent manner. Significance These findings provide new mechanisms of immunotherapeutic resistance and effective evidence of anlotinib combined with immunotherapy.

Introduction We study the relationship between psychological traits of smokers and their smoking cessation effects, and provide more scientific evidence for smoking cessation intervention. Methods The study was conducted as a nested case-control study. Smokers who participated in the community smoking cessation intervention projects in Beijing in 2018–2020, were selected as the research participants and divided into two groups: a successful smoking cessation and unsuccessful smoking cessation group, according to their smoking cessation effects at 6 months. Psychological traits of quitters including smoking abstinence self-efficacy, willingness to quit smoking, and trait coping style, were compared between the two groups, and a structural equation model was established for confirmatory factor analysis to analyze their mechanisms. Results There were differences in smoking cessation results between the successful smoking cessation group and the unsuccessful smoking cessation group in terms of smoking abstinence self-efficacy and willingness to quit smoking. Willingness to quit smoking (OR=1.06; 95% CI: 1.008–1.118) is a risk factor, while smoking abstinence self-efficacy in habit/addiction situations (OR=0.77; 95% CI: 0.657– 0.912) is a protective factor. The results of the structural equation model showed that smoking abstinence self-efficacy (β=0.199, p=0.002) and trait coping style (β= -0.166, p=0.042) could influence smoking cessation effects. The structural equation model was well fitted, which showed that smoking abstinence selfefficacy (β=0.199, p=0.002) and trait coping style (β= -0.166, p=0.042) might have influenced the effect of smoking cessation among smokers. Conclusions Willingness to quit smoking has a positive impact on the smoking cessation effect, while smoking abstinence self-efficacy in habit/addiction situations and negative trait coping style have a negative impact. Smoking abstinence self-efficacy and trait coping styles can significantly affect smoking cessation outcomes. CLINICAL TRIAL REGISTRATION The study has been registered on the official website of the China Clinical Trials Registry. Its registration name is Search for Optimization of Tobacco Dependence Management Model Based on Hospital and Community, and registration number is ChiCTR1900024991.

Abstract Background Laparoscopic surgery (LS) has been increasingly applied in perihilar cholangiocarcinoma (pCCA). In this study, we intend to compare the short-term outcomes of LS versus open operation (OP) for pCCA in a multicentric practice in China. Methods This real-world analysis included 645 pCCA patients receiving LS and OP at 11 participating centers in China between January 2013 and January 2019. A comparative analysis was performed before and after propensity score matching (PSM) in LS and OP groups, and within Bismuth subgroups. Univariate and multivariate models were performed to identify significant prognostic factors of adverse surgical outcomes and postoperative length of stay (LOS). Results Among 645 pCCAs, 256 received LS and 389 received OP. Reduced hepaticojejunostomy (30.89% vs 51.40%, P = 0.006), biliary plasty requirement (19.51% vs 40.16%, P = 0.001), shorter LOS (mean 14.32 vs 17.95 d, P 0.05 for all). After PSM, the short-term outcomes of two surgical methods were similar, except for shorter LOS in LS compared with OP (mean 15.19 vs 18.48 d, P = 0.0007). A series subgroup analysis demonstrated that LS was safe and had advantages in shorting LOS. Conclusion Although the complex surgical procedures, LS generally seems to be safe and feasible for experienced surgeons. Trial registration NCT05402618 (date of first registration: 02/06/2022).

Abstract Neoplasms originating from thymic T-cell progenitors and post-thymic mature T-cell subsets account for a minority of lymphoproliferative neoplasms. These T-cell derived neoplasms, while molecularly and genetically heterogeneous, exploit transcription factors and signaling pathways that are critically important in normal T-cell biology, including those implicated in antigen-, costimulatory-, and cytokine-receptor signaling. The transcription factor GATA-3 regulates the growth and proliferation of both immature and mature T cells and has recently been implicated in T-cell neoplasms, including the most common mature T-cell lymphoma observed in much of the Western world. Here we show that GATA-3 is a proto-oncogene across the spectrum of T-cell neoplasms, including those derived from T-cell progenitors and their mature progeny, and further define the transcriptional programs that are GATA-3 dependent, which include therapeutically targetable gene products. The discovery that p300-dependent acetylation regulates GATA-3 mediated transcription by attenuating DNA binding has novel therapeutic implications. As most patients afflicted with GATA-3 driven T-cell neoplasms will succumb to their disease within a few years of diagnosis, these findings suggest opportunities to improve outcomes for these patients.

Objectives CCL20 is a chemotactic factor that is involved in immune cell recruitment and cancer progression. However, the role of CCL20 in the prognosis of breast cancer remains unclear. This study analyzed correlations between CCL20 expression and immune infiltration, clinicopathological parameters, and prognosis in breast cancer patients. Methods Correlations between CCL20 expression and clinicopathological parameters, prognosis, and immune infiltration in breast cancer were determined using the TIMER, UALCAN, and PrognoScan databases. Furthermore, gene–gene and protein–protein interactions were determined using GeneMANIA and STING network construction, respectively. Results CCL20 expression was significantly upregulated in breast cancer and had significant associations with clinicopathological features, including race, sex, age, menopause status, cancer stage, cancer subclass, and nodal metastasis; moreover, patients with higher CCL20 expression exhibited poor prognosis. Meanwhile, CCL20 expression was significantly correlated with the infiltration of immune cells in breast cancer, including monocytes, neutrophils, tumor-associated macrophages, Th1 cells, regulatory T cells, and exhausted T cells. Moreover, the network of CCL20 expression showed the majority genes and proteins were associated with immune reactions. Conclusions CCL20 is a prognosis-related biomarker in breast cancer on the basis of its correlation with immune infiltration levels and has potential to also be a therapeutic target.

Abstract Background Pancreatic ductal adenocarcinoma is prone to metastasis, resulting in short survival and low quality of life. LncRNAs are pivotal orchestrators that participate in various tumor progress. The underlying role and mechanism of lncRNA FAM83H-AS1 is still unknown in PDAC progression. Methods To address this issue, firstly, we profiled and analyzed the aberrant lncRNA expression in TCGA database and identified FAM83H-AS1 as the most effective one in promoting the migration of pancreatic cancer cells. Then, the expression levels of FAM83H-AS1 in patient’s serum, tumor tissues and PDAC cells were detected using RT-qPCR, and FAM83H-AS1 distribution in PDAC cells was determined by performing FISH and RT-qPCR. Next, a series of in vivo and in vitro functional assays were conducted to elucidate the role of FAM83H-AS1 in cell growth and metastasis in PDAC. The regulatory relationship between FAM83H-AS1 and FAM83H (the homologous gene of FAM83H-AS1) was verified by performing protein and RNA degradation assays respectively. Co-IP assays were performed to explore the potential regulatory mechanism of FAM83H to β-catenin. Rescue assays were performed to validate the regulation of the FAM83H-AS1/FAM83H/β-catenin axis in PDAC progression. Results FAM83H-AS1 was highly expressed in the tumor tissues and serum of patients with PDAC, and was correlated with shorter survival. FAM83H-AS1 significantly promoted the proliferation, invasion and metastasis of PDAC cells, by protecting FAM83H mRNA from degradation. Importantly, FAM83H protein manifested the similar malignant functions as that of FAM83H-AS1 in PDAC cells, and could bind to β-catenin. Specifically, FAM83H could decrease the ubiquitylation of β-catenin, and accordingly activated the effector genes of Wnt/β-catenin signaling. Conclusions Collectively, FAM83H-AS1 could promote FAM83H expression by stabilizing its mRNA, allowing FAM83H to decrease the ubiquitylation of β-catenin, thus resulted in an amplified FAM83H-AS1/FAM83H/β-catenin signal axis to promote PDAC progression. FAM83H-AS1 might be a novel prognostic and therapeutic target for combating PDAC.

Plain English summary The majority of cancer cases and cancer mortality occur in older adults. Aging is a heterogenic process, which results in great diversity in older cancer patients concerning physical, psychological, and social status. There is limited information about the population characteristics and adverse health outcomes of older cancer patients in China, and the magnitude of this problem is unclear, creating challenges in understanding health disparities in geriatric cancer care. In this study, we have described the prevalence of frailty and explored the relationship between frailty and health-related quality of life (HRQoL). This study demonstrated that frailty, not being currently married, advanced cancer stage, and cancer site were significant factors influencing the lower HRQoL. Furthermore, frail individuals had a higher probability belonging to the lowest HRQoL quartile group. This study is considered as the first step in highlighting the importance of staging the aging and assessing quality of life among older cancer patients in China.

BackgroundThere is still a large demand for effective treatments to delay disease deterioration in amyotrophic lateral sclerosis (ALS). Typical symptoms of ALS are considered “flaccidity syndrome” in traditional Chinese medicine (TCM). Huoling Shengji Granule (HLSJ) is a TCM formula used to treat flaccidity syndrome. Results of preclinical tests and a previous clinical study support HLSJ as a novel drug for ALS patients. This trial proposed to examine whether a 48-week course of HLSJ is effective and safe for ALS patients diagnosed with the Chinese medicine syndrome of spleen qi insufficiency and kidney yang deficiency.Methods and analysisIn this phase II, multicenter, randomized, double-blind, riluzole parallel-controlled, superiority-design study, eligible participants had the equal opportunity to be assigned to receive either HLSJ or riluzole randomly. Eleven specialized ALS centers in Mainland China will recruit 144 patients for this trial. The primary and secondary outcomes included the change in the ALSFRS-R score and the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) from baseline to Week 48.DiscussionHere, we endeavored to evaluate TCM for ALS using a standard evidence-based approach for the first time. In addition, the ROADS, a self-report linear-weighted questionnaire, was selected as a secondary outcome measure. We expect to offer a new reference for the outcome evaluation of ALS trials.Clinical trial registration:http://www.Chictr.org.cn, identifier ChiCTR2100044085.

Abstract Background Lung cancer, the primary cause of cancer‐related deaths worldwide, is diagnosed at an advanced stage and has a poor prognosis. Non‐small cell lung cancer (NSCLC) is a major histological type of lung malignancy. This study investigated the effect of ACT001, a novel sesquiterpene lactone derivative, on the proliferation of NSCLC cells and explored the underlying mechanism. Methods The effect of ACT001 on cell proliferation was examined by clone formation and MTT assay. Differentially expressed genes and enrichment pathways were analyzed by RNA‐seq. Flow cytometry and cell cycle‐related protein expression analysis were performed to study the cell cycle. Phosphorylated AKT was detected to explore the mechanism in natural killer cell triggering receptor (NKTR) KD cells with AKT activator and/or inhibitor. The therapeutic effect of ACT001 in vivo was studied in the xenograft tumor model. Results ACT001 inhibited the proliferation and G1/S transition in NSCLC cell lines. By RNA‐seq analysis, NKTR may be the target of ACT001. Moreover, knockdown NKTR promoted cell proliferation and reversed the effects of ACT001. In addition, ACT001 inhibited AKT phosphorylation, but NKTR knockdown promoted AKT phosphorylation. Conclusion Our results suggested NKTR may be the target of ACT001 in NSCLC. ACT001 holds promise as a novel method for the treatment of NSCLC.

Summary: Background: /Objective: As a new immune-nutritional marker, the controlled nutritional status (CONUT) score has been reported to predict the prognosis of cancer patients. We aimed to elucidate the prognostic value of preoperative CONUT score in pancreatic cancer patients undergoing radical surgery, and to construct a nomogram based on CONUT score to predict individual survival. Methods: Preoperative CONUT scores were calculated prospectively in 382 patients with pancreatic cancer who underwent radical surgery. Evaluated the relationship between CONUT score and pancreatic cancer prognosis. Cox proportional hazard models were used to determine predictors of survival and a new nomogram was established to predict pancreatic cancer overall survival (OS). Results: The area under curve of CONUT score was higher than other immune-nutritional indexes. The OS of the high-CONUT group were significantly lower than that of low-CONUT group. Multivariate analysis showed that CONUT score, gender, AJCC stage, complications and reoperation were independent prognostic factors for OS. Nomogram based on these variables has better discriminant ability in predicting survival compared with other traditional staging systems. Conclusions: Preoperative CONUT score is an effective independent predictor of OS in pancreatic cancer patients undergoing radical surgery. This new CONUT based nomogram provides accurate, individualized survival prediction for pancreatic cancer.

Abstract Background Revealing the gene targets of distal regulatory elements is challenging yet critical for interpreting regulome data. Experiment-derived enhancer-gene links are restricted to a small set of enhancers and/or cell types, while the accuracy of genome-wide approaches remains elusive due to the lack of a systematic evaluation. We combined multiple spatial and in silico approaches for defining enhancer locations and linking them to their target genes aggregated across >500 cell types, generating 1860 human genome-wide distal enhancer-to-target gene definitions (EnTDefs). To evaluate performance, we used gene set enrichment (GSE) testing on 87 independent ENCODE ChIP-seq datasets of 34 transcription factors (TFs) and assessed concordance of results with known TF Gene Ontology annotations, and other benchmarks. Results The top ranked 741 (40%) EnTDefs significantly outperform the common, naïve approach of linking distal regions to the nearest genes, and the top 10 EnTDefs perform well when applied to ChIP-seq data of other cell types. The GSE-based ranking of EnTDefs is highly concordant with ranking based on overlap with curated benchmarks of enhancer-gene interactions. Both our top general EnTDef and cell-type-specific EnTDefs significantly outperform seven independent computational and experiment-based enhancer-gene pair datasets. We show that using our top EnTDefs for GSE with either genome-wide DNA methylation or ATAC-seq data is able to better recapitulate the biological processes changed in gene expression data performed in parallel for the same experiment than our lower-ranked EnTDefs. Conclusions Our findings illustrate the power of our approach to provide genome-wide interpretation regardless of cell type.

ObjectiveTo assess the effect of the hospital-community integrated management model of tobacco dependence on smoking cessation among community residents compared with a brief smoking cessation intervention.MethodsOur study recruited 651 smokers who were willing to quit in 19 communities in Beijing and conducted a 6-month smoking cessation intervention. The control group receiving a brief smoking cessation intervention and the pilot group receiving an integrated smoking cessation intervention. Intention-to-treat analysis (ITT) and generalized estimating equations were used to assess the effects of the integrated intervention and smoking cessation medication on average number of cigarettes smoked per day (ACSD) and smoking cessation rate.ResultsSimple effects analysis showed that smokers taking medication had significantly lower ACSD than those not taking medication at follow-up, the control group reduced smoking by 3.270, 4.830, and 4.760 cigarettes in the first, third and sixth months, respectively, while the pilot group reduced by 6.230, 5.820, and 4.100 cigarettes. The integrated intervention significantly reduced ACSD among medication-taking smokers at 1st month (reduced by 3.420, P < 0.05) and 3rd month (reduced by 2.050, P < 0.05), but had no significant effect among non-medication taking smokers. The 3rd month smoking cessation rate among medication-taking smokers was 27.0%, which was significantly higher than the smokers with brief smoking cessation intervention.ConclusionThe integrated hospital-community intervention can significantly promote smoking cessation among smokers taking medication, but the issue of payment for medication and additional labor compensation for medical staff should be addressed before its popularization.

BackgroundCyclin-dependent kinases (CDKs) play a key role in cell proliferation in lung adenocarcinoma (LUAD). Comprehensive analysis of CDKs to elucidate their clinical significance and interactions with the tumor immune microenvironment is needed.MethodsRNA expression, somatic mutation, copy number variation, and single-cell RNA sequencing data were downloaded from public datasets. First, we comprehensively evaluated the expression profile and prognostic characteristics of 26 CDKs in LUAD, and CDK1 was selected as a candidate for further analysis. Then, a systematic analysis was performed to explore the relationships of CDK1 with clinical characteristics and tumor immune microenvironment factors in LUAD.ResultsCDK1 was markedly upregulated at both the mRNA and protein level in LUAD. Moreover, overexpression of CDK1 was related to poor clinical outcomes. CDK1 coexpressed genes were mainly involved in the cell cycle, the DNA repair process, and the p53 signaling pathway. In addition, CDK1 expression was found to be correlated with the expression of multiple immunomodulators and chemokines, which participate in activating and suppressing the immune microenvironment. CDK1 expression was also correlated with increased infiltration of numerous immune cells, including CD4+ T cells and M1 macrophages. Patients with high CDK1 expression tended to have a poor response to immunotherapy but were sensitive to multiple chemotherapies and targeted drugs. The MDK-NCL and SPP1-CD44 ligand−receptor pairs were markedly activated in the intercellular communication network. CDK1 was an independent prognostic factor for LUAD and improved the ability to predict overall survival when combined with tumor stage.ConclusionCDK1 plays an essential role in reshaping the tumor immune microenvironment and might be a prognostic and treatment biomarker in LUAD.

Although sorafenib (Sora) shows improved efficacy in clinical liver cancer therapy, its therapeutic efficacy is still greatly limited due to side effects as well as drug resistance. Thus new drug intervention strategies are imperative. Our research showed the combined application of Dihydroartemisinin (DHA) and Sora had a synergistic inhibitory effect on HepG2 and SW480 cells, and DHA enhanced Sora efficacy on xenograft tumor in nude mice. DHA and Sora significantly inhibited the cell energy metabolism by decreasing the ATP synthesis rate of oxidative phosphorylation and glycolysis rate, and induced ferroptosis by increasing the level of lipid reactive oxygen species (L-ROS), labile iron pool (LIP) as well as malondialdehyde (MDA) and decreasing the level of glutathione (GSH) in HepG2 cells. In addition, DHA and Sora significantly decreased the levels of SLC7A11 (xCT), GCLC, GPX4, and HO-1 protein in HepG2 cells. Importantly, the above-mentioned indicators changed more significantly after the combined application of DHA and Sora as compared with Sora. In conclusion, DHA and Sora had the same mechanism, and the combined application of them could have a synergistic anti-tumor effect by inducing ferroptosis and inhibiting energy metabolism in HepG2 cells.

Recent discoveries have suggested that the F-actin capping protein α1 subunit (CAPZA1) in various human tumors could play a significantly important role in regulating cell proliferation, metastasis, and epithelial–mesenchymal transition. However, the immune-regulating role of CAPZA1 in the initiation and development of lung adenocarcinoma (LUAD) remains unclear. In our research, we first found that CAPZA1 serves as an oncogene in pan-cancers from the TCGA data and higher CAPZA1 expression process unfavorably prognostic value in LUAD based on starBase database, PrognoScan, and LOGpc database. Then, in our analyses, lncRNAs AC026356.1 in LUAD acted as a competitive endogenous RNA (ceRNA) of miR-30d-5p, which might be the possible regulatory miRNA of CAPZA1 based on the starBase database. Finally, we confirmed that CAPZA1 expression had a tightly positive correlation with immune infiltration cells, immune infiltration markers, TMB, MSI, immune score, stromal score, and immune checkpoints, indicating that CAPZA1 was a markedly reliable therapeutic target for immunological antitumor strategies. In conclusion, our investigations revealed that CAPZA1 might function as an immune-associated biomarker in the development and treatment of LUAD, thereby acting as a promising prognostic and therapeutic target against LUAD.

Background and Objective: Indirect hepatotoxicity is a new type of drug-induced hepatotoxicity in which the character of a drug that may induce its occurrence and the underlying mechanism remains elusive. Previously, we proved that Triptolide (TP) induced indirect hepatotoxicity upon LPS stimulation resulting from the deficiency of cytoprotective protein of hepatocyte. However, whether immune cells participated in TP-induced indirect hepatotoxicity and the way immune cells change the liver hypersensitivity to LPS still need to be deeply investigated. In this study, we tried to explore whether and how macrophages are involved in TP-induced indirect hepatotoxicity.Method: Firstly, TP (500 μg/kg) and LPS (0.1 mg/kg) were administrated into female C57BL/6 mice as previously reported. Serum biochemical indicators, morphological changes, hepatic macrophage markers, as well as macrophage M1/M2 markers were detected. Secondly, macrophage scavenger clodronate liposomes were injected to prove whether macrophages participated in TP-induced indirect hepatotoxicity. Also, the ability of macrophages to secrete inflammatory factors and macrophage phagocytosis were detected. Lastly, reverse docking was used to find the target of TP on macrophage and the possible target was verified in vivo and in RAW264.7 cells.Results: TP pretreatment increased the liver hypersensitization to LPS accompanied by the recruitment of macrophages to the liver and promoted the transformation of macrophages to M1 type. Depletion of hepatic macrophages almost completely alleviated the liver injury induced by TP/LPS. TP pretreatment increased the secretion of pro-inflammatory factors and weakened the phagocytic function of macrophages upon LPS exposure. Reverse docking results revealed that MerTK might be the real target of TP.Conclusion: TP disrupts inflammatory cytokines profile and phagocytic function of hepatic macrophages, resulting in the production of massive inflammatory factors and the accumulation of endotoxin in the liver, ultimately leading to the indirect hepatotoxicity of TP. MerTK might be the target of TP on the macrophage, while the binding of TP to MerTK should be investigated in vivo and in vitro.

Background and purposeThe relationship between sleep duration and stroke are inconclusive in China, especially in those individuals with metabolic syndrome. We aimed to investigate the association between sleep duration and incident stroke in participants with metabolic syndrome or its specific components in China.Materials and methodsData were taken from the 2011 and 2015 waves of China Health and Retirement Longitudinal Study (CHARLS). Habitual sleep duration (≤6, 6∼8 [reference], >8 h), daytime napping (0, 1∼60 [reference], and >60 min) were determined by self-reported questionnaires. Metabolic syndrome was defined by blood assessment and biomarkers combined with self-reported doctors’ diagnosis. Incident stroke was determined by reported stroke from 2011 to 2015 wave. Cross-sectional and longitudinal associations between sleep and (incident) stroke at baseline and 4-year follow-up period were tested among the population with metabolic syndrome and its components.ResultsA U-shaped relationship was observed between sleep duration and stroke in cross-sectional analysis. Sleep ≤ 6 h/night had a greater risk of incident stroke (hazard ratio [HR] 1.65; 95% confidence interval [CI] 1.04–2.61) compared with sleep 6∼8 h/night. And the HR of stroke was 1.62 (95%CI, 1.03–2.53) for sleep < 7 h/day compared to 7∼9 h/day. These associations were more evident in the female and individuals aged 45–65 years. Furthermore, the effect of short sleep duration on incident stroke was different in each component of metabolic syndrome, which was more pronounced in participants with elevated blood pressure. And a significant joint effect of sleeping ≤ 6 h/night and no napping on risk of stroke was observed (HR 1.82, 95%CI 1.06–3.12).ConclusionShort sleep duration was an independent risk factor for incident stroke, especially among females, individuals aged 45–65 years, or those with some components of metabolic syndrome, such as hypertension. Napping could buffer the risk of short sleep duration on incident stroke.

Abstract Background Malaria is a fatal disease that presents clinically as a continuum of symptoms and severity, which are determined by complex host-parasite interactions. Clearance of infection is believed to be accomplished by the spleen and mononuclear phagocytic system (MPS), independent of artemisinin treatment. The spleen filters infected red blood cells (RBCs) from circulation through immune-mediated recognition of the infected RBCs followed by phagocytosis. This study evaluated the tolerance of four different strains of mice to Plasmodium berghei strain K173 (P. berghei K173), and the differences in the role of the spleen in controlling P. berghei K173 infection. Methods Using different strains of mice (C57BL/6, BALB/C, ICR, and KM mice) infected with P. berghei K173, the mechanisms leading to splenomegaly, histopathology, splenocyte activation and proliferation, and their relationship to the control of parasitaemia and host mortality were examined and evaluated. Results Survival time of mice infected with P. berghei K173 varied, although the infection was uniformly lethal. Mice of the C57BL/6 strain were the most resistant, while mice of the strain ICR were the most susceptible. BALB/c and KM mice were intermediate. In the course of P. berghei K173 infection, all infected mice experienced significant splenomegaly. Parasites were observed in the red pulp at 3 days post infection (dpi) in all animals. All spleens retained late trophozoite stages as well as a fraction of earlier ring-stage parasites. The percentages of macrophages in infected C57BL/6 and KM mice were higher than uninfected mice on 8 dpi. Spleens of infected ICR and KM mice exhibited structural disorganization and remodelling. Furthermore, parasitaemia was significantly higher in KM versus C57BL/6 mice at 8 dpi. The percentages of macrophages in ICR infected mice were lower than uninfected mice, and the parasitaemia was higher than other strains. Conclusions The results presented here demonstrate the rate of splenic mechanical filtration and that splenic macrophages are the predominant roles in controlling an individual’s total parasite burden. This can influence the pathogenesis of malaria. Finally, different genetic backgrounds of mice have different splenic mechanisms for controlling malaria infection.

BackgroundThe prevalence of cigarette smoking in China is high and the utilization of smoking cessation clinics is very low. Multicomponent smoking cessation interventions involving community and hospital collaboration have the potential to increase the smoking cessation rate. However, the cost-effectiveness of this intervention model is unknown.MethodsWe conducted a smoking cessation intervention trial in 19 community health service centers in Beijing, China. A cost-effectiveness analysis was performed from a societal perspective to compare three strategies of smoking cessation: no intervention (NI), pharmacological intervention (PI), and comprehensive intervention (CI) (PI plus online health promotion). A Markov model, with a time horizon of 20 years, was used to simulate the natural progression of estimated 10,000 male smokers. A cross-sectional survey was conducted to obtain data on costs and quality-adjusted life years (QALYs) by using the five-level EuroQol-5-dimension (EQ-5D-5L) questionnaire. Probabilistic sensitivity analysis was performed to explore parameters of uncertainty in the model.ResultsA total of 680 participants were included in this study, including 283 in the PI group and 397 in the CI group. After 6 months of follow-up, the smoking cessation rate reached 30.0% in the CI group and 21.2% in the PI group. Using the Markov model, compared with the NI group, the intervention strategies of the PI group and the CI group were found to be cost-effective, with an incremental cost-effectiveness ratio (ICER) of $535.62/QALY and $366.19/QALY, respectively. The probabilistic sensitivity analysis indicated that the CI strategy was always the most cost-effective intervention.ConclusionCI for smoking cessation, based in hospital and community in China, is more cost-effective than PI alone. Therefore, this smoking cessation model should be considered to be implemented in healthcare settings.

The gut microbiota is composed of a large number of microorganisms with a complex structure. It participates in the decomposition, digestion, and absorption of nutrients; promotes the development of the immune system; inhibits the colonization of pathogens; and thus modulates human health. In particular, the relationship between gut microbiota and gastrointestinal tumor progression has attracted widespread concern. It was found that the gut microbiota can influence gastrointestinal tumor progression in independent ways. Here, we focused on the distribution of gut microbiota in gastrointestinal tumors and further elaborated on the impact of gut microbiota metabolites, especially short-chain fatty acids, on colorectal cancer progression. Additionally, the effects of gut microbiota on gastrointestinal tumor therapy are outlined. Finally, we put forward the possible problems in gut microbiota and the gastrointestinal oncology field and the efforts we need to make.

BackgroundBevacizumab is the representative drug in antiangiogenic therapy for lung cancer. However, it induced resistance in some neoplasm. Anlotinib, a novel multi-target tyrosine kinase inhibitor which has an inhibitory action on both angiogenesis and malignancy, is possible to reverse the resistance.MethodsTranswell migration and invasion experiments of bevacizumab with or without anlotinib were conducted to verify the activated/inhibited ability of lung adenocarcinoma cells. We sequenced A549 cells with enhanced migration and invasion abilities after bevacizumab treatment, screened out the differentially expressed gene and further confirmed by western blot and q-PCR assays. We also investigated immunohistochemical staining of tumor tissue in mice and human lung adenocarcinoma.ResultsBevacizumab facilitated migration and invasion of lung adenocarcinoma cells. Differentially expressed gene RGC32 was screened out. Bevacizumab upregulated the expression of RGC32, N-cadherin, and MMP2 through ERK-MAPK and PI3K-AKT pathways. Anlotinib downregulated their expression and reversed the effect of bevacizumab on A549 cells. In vivo experiments confirmed that higher-dose bevacizumab facilitated metastasis in tumor-bearing nude mice and upregulated the expression of RGC32, N-cadherin, and MMP2, whereas anlotinib abrogated its effect. Expression of both RGC32 and N-cadherin positively correlated with lymph node metastasis and stage in lung adenocarcinoma was found. Survival analysis revealed that higher expressions of RGC32 and N-cadherin were associated with poor progression-free survival and overall survival.ConclusionsBevacizumab may promote invasion and metastasis of lung adenocarcinoma cells by upregulating RGC32 through ERK-MAPK and PI3K-AKT pathways to promote epithelial–mesenchymal transition, whereas anlotinib reverses the effect. RGC32 and N-cadherin are independent prognostic factors in lung adenocarcinoma.

With the rapid development of industry and economy, the problem of ozone (O3) pollution in China is of increasing concern in recent years. The problem of ozone pollution has become worse in Baicheng City which belongs to the province of Jilin. We analyze the spatial and temporal distribution of surface ozone and its correlation with precursors and meteorological factors during 2015 and 2019 using data from the automatic Atmospheric Environmental Quality Monitoring Station located in Baicheng. Results showed that the daily and monthly mean values of O3 concentration were both single-peak patterns, and interannual variation presented a inverted ‘V’ pattern in Baicheng. The high concentration of O3 in a year generally occurs from May to July, with the highest daily concentration occurring in the afternoon. The total number of days with O3 concentration exceeding the limits was 35 days from 2015 to 2019, among which the number of days exceeding the maximal daily average eight-hour (MDA8) O3 of 100 μg/m3 was the highest in 2018, and the 90th percentile MDA8 showed an overall growth pattern. Seasonal variations in O3 concentration in 2018 and 2019 were not consistent with the three previous years.

Objective: Lymphatic metastasis is one of the leading causes of malignancy dispersion in various types of cancer. However, few anti-lymphangiogenic drugs have been approved for clinical use to date. Therefore, new therapies to block lymphangiogenesis are urgently required. Methods: Immunohistochemistry, immunofluorescence, Western blot, migration assays, and lymphangiogenesis and lymphatic metastasis assays were used. Results: Anlotinib, a receptor tyrosine kinase inhibitor, suppressed the rate of new metastatic lesions (31.82% in the placebo arm and 18.18% in the anlotinib arm) in patients with advanced lung adenocarcinoma who were enrolled in our ALTER-0303 study. D2-40+-lymphatic vessel density was strongly correlated with disease stage, metastasis, and poor prognosis in 144 Chinese patients with lung adenocarcinoma. In mice bearing A549EGFP tumors, tumor lymphatic vessel density, tumor cell migration to lymph nodes, and the number of distant metastatic lesions were lower in the anlotinib group than in the controls. Anlotinib inhibited the growth and migration of human lymphatic endothelial cells (hLECs) and lymphangiogenesis in vitro and in vivo. Treatment of hLECs with anlotinib downregulated phosphorylated vascular endothelial growth factor receptor 3 (VEGFR-3). Conclusions: Anlotinib inhibits lymphangiogenesis and lymphatic metastasis, probably through inactivating VEGFR-3 phosphorylation. The results indicate that anlotinib may be beneficial for treatment in avoiding lymphangiogenesis and distant lymphatic metastasis in lung adenocarcinoma. (Trial registration: ALTER0303; NCT02388919; March 17, 2015.)

Background The clinical benefit of immunotherapy has been limited to a small subset of patients with cancer. Several clinical trials with immune checkpoint inhibitors in multiple cancers have shown some improvement in obese patients. However, how obesity regulates the immune microenvironment remains unclear. Methods Bioinformatic analysis was used to discover immune microenvironmental‐related genes associated with body mass index (BMI). The expression of ICOS in tumor tissues was detected using western blot, immunohistochemistry, quantitative real‐time polymerase chain reaction (RT‐qPCR) and flow cytometry. RT‐qPCR was used to measure the expression of miR‐27a‐3p. The interaction between miR‐27a‐3p and ICOS was confirmed by dual‐luciferase reporter assay. Functional testing of T cells based on proliferation and interferon (IFN)‐gamma secretion was performed using ELISA and flow cytometry. Results ICOS, an immune microenvironment‐related gene, was significantly upregulated in obese patients with lung adenocarcinoma (LUAD). MiR‐27a‐3p showed a negative correlation with ICOS and suppressed the expression of ICOS. We determined that dipocyte‐derived exo‐miR‐27a‐3p could alter the tumor microenvironment by inhibiting ICOS+ T cell proliferation and IFN‐gamma secretion in vitro. Conclusions Adipocyte‐derived exo‐miR‐27a‐3p can inhibit ICOS+ T cell proliferation and IFN‐gamma secretion. The upregulation of ICOS+ T cell functions caused by the downregulation of miR‐27a‐3p in adipose tissue derived exosomes is one of the potential mechanisms for the improved efficacy of immunotherapy in obese LUAD patients.

Objective: Bevacizumab is a recombinant humanized monoclonal antibody that blocks vascular endothelial growth factor (VEGF) with clear clinical benefits. However, overall survival of some cancer types remains low owing to resistance to bevacizumab therapy. While resistance is commonly ascribed to tumor cell invasion induced by hypoxia-inducible factor (HIF), less attention has been paid to the potential involvement of endothelial cells (ECs) in vasculature activated by anti-angiogenic drugs. Methods: Human umbilical vein ECs (HUVECs), bEnd.3 cells, and mouse retinal microvascular ECs (MRMECs) were treated with bevacizumab under conditions of hypoxia and effects on biological behaviors, such as migration and tube formation, examined. Regulatory effects on TGFβ1 and CD105 (endoglin) were established via determination of protein and mRNA levels. We further investigated whether the effects of bevacizumab could be reversed using the receptor tyrosine kinase inhibitor anlotinib. Results: Bevacizumab upregulated TGFβ1 as well as CD105, a component of the TGFβ receptor complex and an angiogenesis promoter. Elevated CD105 induced activation of Smad1/5, the inflammatory pathway and endothelial–mesenchymal transition. The migration ability of HUVECs was enhanced by bevacizumab under hypoxia. Upregulation of CD105 was abrogated by anlotinib, which targets multiple receptor tyrosine kinases including VEGFR2/3, FGFR1-4, PDGFRα/β, C-Kit, and RET. Conclusions: Bevacizumab promotes migration and tube formation of HUVECs via activation of the TGFβ1 pathway and upregulation of CD105 expression. Anlotinib reverses the effects of bevacizumab by inhibiting the above signals.

Abstract Background Vascular endothelial growth factor C (VEGFC), an activator of lymphangiogenesis, is newly identified as an immunomodulator which can regulate the immune system so that tumor cells more easily escape immune surveillance. Evidence has shown programmed cell death‐ligand 1 (PD‐L1) can also suppress the immune response. Nevertheless, the clinical significance of co‐expression of VEGFC and PD‐L1 for predicting outcomes in patients with lung adenocarcinoma has not yet been determined. Methods A total of 114 patients with lung adenocarcinoma who underwent surgeries at Tianjin Medical University Cancer Institute and Hospital between December 2011 and September 2016 were retrospectively reviewed. Tissue specimens were collected for immunohistochemistry of VEGFC and PD‐L1 which were analyzed with an H‐score system. Results In this study, 57 (50.0%) and 47 (41.2%) patients were classified as VEGFC high expression and PD‐L1 high expression. Co‐expression was observed in 33 (28.9%) patients. In addition, a positive correlation was found between VEGFC and PD‐L1 (P = 0.0398, r = 0.1937). In a univariate analysis, both progression‐free survival (PFS) and overall survival (OS) were significantly worse in the VEGFC high expression group and the PD‐L1 high expression group, respectively. Furthermore, VEGFC/PD‐L1 co‐expression showed a worse OS (P = 0.03) and PFS survival (P = 0.01) than the other groups. Conclusions Taken together, these results indicate that VEGFC/PD‐L1 co‐expression can forecast both poor OS and PFS in patients with resected lung adenocarcinoma. Co‐expression of VEGFC and PD‐L1 may serve as a significant prognostic factor for patients with lung adenocarcinoma. Key points VEGFC/PD‐L1 co‐expression forecasts poor survival in patients with resected lung adenocarcinoma. VEGFC/PD‐L1 co‐expression may be used as a prognostic indicator and provide the theoretical possibility to screen the optimal population with a combination of anti‐VEGFC and anti‐PD‐L1 therapy in the clinical treatment.

Abstract Background Kawasaki disease (KD) is a common, yet unknown etiology disease in Asian countries, which causes acquired heart disease in childhood. It is characterized by an inflammatory acute febrile vasculitis of medium-sized arteries, particularly the coronary arteries. High-mobility group box-1 protein (HMGB1) is a non-histone chromosomal-binding protein present in the nucleus of eukaryotic cells, which contains 215 amino acid residues. Although the cellular signal transduction mechanisms of HMGB1 are currently unclear, the important role of the receptor for advanced glycation end-products (RAGE), the main receptor for HMGB1 has been reported in detail. The purpose of our study was to verify the mechanism and clinical significance of HMGB1-RAGE in coronary artery injury of Kawasaki disease. Methods 52 blood samples of patients in KD were collected, and the coronary artery Z score was calculated according to the echocardiographic results. The Z score ≥ 2.0 was classified as coronary artery lesions (CAL); otherwise, it was no-coronary artery lesions (NCAL). In addition, the fever group and control group were set. Among them, the fever group were children with fever due to respiratory tract infection at the same time period as KD (heat peak ≥ 38.5 ℃). The normal group were children at a routine physical examination in the outpatient clinic of Nantong University and the physical examination center of the child care insurance, and there were no infectious diseases and heart diseases. The serum levels of HMGB1, RAGE, and NF-κB in each group were detected by ELISA. The animal model of KD was established using the New Zealand young rabbits. We used RT-qPCR/H&E staining/immunohistochemistry/ELISA and western blot to detect the level of HMGB1/RAGE and NF-κB. Results In this study, we found that the HMGB1/RAGE/NF-κB axis was elevated in the serum of children with KD. In addition, an animal model of KD was subsequently prepared to examine the pathological changes of the coronary arteries. We found that the serum levels of HMGB1/RAGE/NF-κB in rabbits with KD were significantly higher than those of the control group. Moreover, the lumen diameter of the coronary artery was slightly enlarged, and the wall of the tube became thinner and deformed. In addition, the HMGB1/RAGE/NF-κB levels in the coronary artery were higher in the rabbits with KD in the acute phase. Conclusions On the whole, the findings of this study demonstrate that the expression of HMGB1/RAGE/NF-κB is altered at different stages of KD, suggesting that the HMGB1/RAGE/NF-κB signaling pathway plays an important role in vascular injury in KD. The results of this study may have important implications for the early warning of coronary artery lesions in KD.

Introduction Pancreatic cancer is one of the deadliest cancers and pancreaticoduodenectomy (PD) is recommended as the optimal operation for resectable pancreatic head cancer. Minimally invasive surgery, which initially emerged as hybrid-laparoscopy and recently developed into total laparoscopy surgery, has been widely used for various abdominal surgeries. However, controversy persists regarding whether laparoscopic PD (LPD) is inferior to open PD (OPD) for resectable pancreatic ductal adenocarcinoma (PDAC) treatment. Further studies, especially randomised clinical trials, are warranted to compare these two surgical techniques.Methods and analysis The TJDBPS07 study is designed as a prospective, randomised controlled, parallel-group, open-label, multicentre noninferiority study. All participating pancreatic surgical centres comprise specialists who have performed no less than 104 LPDs and OPDs, respectively. A total of 200 strictly selected PD candidates diagnosed with PDAC will be randomised to receive LPD or OPD. The primary outcome is the 5-year overall survival rate, whereas the secondary outcomes include overall survival, disease-free survival, 90-day mortality, complication rate, comprehensive complication index, length of stay and intraoperative indicators. We hypothesise that LPD is not inferior to OPD for the treatment of resectable PDAC. The enrolment schedule is estimated to be 2 years and follow-up for each patient will be 5 years.Ethics and dissemination This study received approval from the Tongji Hospital Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology, and monitor from an independent third-party organisation. Results of this trial will be presented in international meetings and published in a peer-reviewed journal.Trial registration number NCT03785743.

Epigenetic modifications, specifically acetylation of histone plays a decisive role in gene regulation and transcription of normal cellular mechanisms and pathological conditions. The bromodomain and extraterminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT), being epigenetic readers, ligate to acetylated regions of histone and synchronize gene transcription. BET proteins are crucial for normal cellular processing as they control cell cycle progression, neurogenesis, differentiation, and maturation of erythroids and spermatogenesis, etc. Research-based evidence indicated that BET proteins (mainly BRD4) are associated with numeral pathological ailments, including cancer, inflammation, infections, renal diseases, and cardiac diseases. To counter the BET protein-related pathological conditions, there are some BET inhibitors developed and also under development. BET proteins are a topic of most research nowadays. This review, provides an ephemeral but comprehensive knowledge about BET proteins’ basic structure, biochemistry, physiological roles, and pathological conditions in which the role of BETs have been proven. This review also highlights the current and future approaches to pledge BET protein-related pathologies.

Detecting the driver nodes of complex networks has garnered significant attention recently to control complex systems to desired behaviors, where nodes represent system components and edges encode their interactions. Driver nodes, which are directly controlled by external inputs, play a crucial role in controlling all network nodes. While many approaches have been proposed to identify driver nodes of static networks, we still lack an effective algorithm to control ubiquitous temporal networks, where network structures evolve over time. Here we propose an effective online time-accelerated heuristic algorithm (OTaHa) to detect driver nodes of temporal networks. Together with theoretical analysis and numerical simulations on synthetic and empirical temporal networks, we show that OTaHa offers multiple sets of driver nodes, and noticeably outperforms existing methods in terms of accuracy and execution time. We further report that most edges are redundant in controlling temporal networks although the complete instantaneous signal-carrying edges cannot be guaranteed. Moreover, removing edges with high edge betweenness (the number of all-pairs shortest paths passing through the edge) significantly impedes the overall controllability. Our work provides an effective algorithm and paves the way for subsequent explorations on achieving the ultimate control of temporal networks.

Fibrosis is a worldwide public health problem, which typically results from chronic diseases and often leads to organ malfunction. Chronic inflammation has been suggested to be the major trigger for fibrogenesis, yet mechanisms by which inflammatory signals drive fibrogenesis have not been fully elucidated. Total C-21 steroidal glycosides (TCSG) from Baishouwu are the main active components of the root of Cynanchum auriculatum Royle ex Wight, which exert hepatoprotective and anti-inflammation properties. In this study, we established a mouse model with the coexistence of hepatic and renal fibrosis and aimed to investigate the effects of TCSG from Baishouwu on fibrosis and explored the potential mechanisms. The results of biochemical and pathological examinations showed that TCSG from Baishouwu improved liver and kidney function and alleviated hepatic and renal fibrosis by reducing collagen and extracellular matrix deposition in bile duct ligation and unilateral ureteral occlusion (BDL&UUO) mice. According to network pharmacology analysis, the mechanisms underlying the effects of TCSG from Baishouwu on hepatic and renal fibrosis were associated with inflammatory response pathways, including “Signaling by interleukins”, “MAP kinase activation”, “MyD88 cascade initiated on plasma membrane”, and “Interleukin-1 family signaling”. Regression analysis and western blot results revealed that IL-1β/MyD88 inflammation signaling played an essential role in the anti-fibrotic effects of TCSG from Baishouwu. Further data displayed that TCSG from Baishouwu affected inflammatory response and extracellular matrix deposition via suppressing the activation of p38 MAPK/JNK and NF-κB p65 signaling cascades both in the liver and kidney of BDL&UUO mice. Thus, our findings suggest TCSG from Baishouwu as a natural regimen against hepatic and renal fibrosis and provide direct evidence that IL-1β/MyD88 signaling crucially contributes to hepatic and renal fibrosis and modulates liver-kidney crosstalk by maintaining tight control over inflammatory responses.

BackgroundPancreatic head ductal adenocarcinoma (PHDAC) patients with the same tumor-node-metastasis (TNM) stage may share different outcomes after pancreaticoduodenectomy (PD). Therefore, a novel method to identify patients with poor prognosis after PD is urgently needed. We aimed to develop a nomogram to estimate survival in PHDAC after PD.MethodsTo estimate survival after PD, a nomogram was developed using the Tongji Pancreatic cancer cohort comprising 355 PHDAC patients who underwent PD. The nomogram was validated under the same conditions in another cohort (N = 161) from the National Taiwan University Hospital. Prognostic factors were assessed using LASSO and multivariate Cox regression models. The nomogram was internally validated using bootstrap resampling and then externally validated. Performance was assessed using concordance index (c-index) and calibration curve. Clinical utility was evaluated using decision curve analysis (DCA), X-tile program, and Kaplan–Meier curve in both training and validation cohorts.ResultsOverall, the median follow-up duration was 32.17 months, with 199 deaths (64.82%) in the training cohort. Variables included in the nomogram were age, preoperative CA 19-9 levels, adjuvant chemotherapy, Tongji classification, T stage, N stage, and differentiation degree. Harrell’s c-indices in the internal and external validation cohorts were 0.79 (95% confidence interval [CI], 0.76–0.82) and 0.83 (95% CI, 0.78–0.87), respectively, which were higher than those in other staging systems. DCA showed better clinical utility.ConclusionThe nomogram was better than TNM stage and Tongji classification in predicting PHDAC patients’ prognosis and may improve prognosis-based selection of patients who would benefit from PD.

Deriving a successful document representation is the critical challenge in many downstream tasks in NLP, especially when documents are very short. It is challenging to handle the sparsity and the noise problems confronting short texts. Some approaches employ latent topic models, based on global word co-occurrence, to obtain topic distribution as the representation. Others leverage word embeddings, which consider local conditional dependencies, to map a document as a summation vector of them. Unlike the existing works which explore the strategy of utilizing one to help the other, i.e., topic models for word embeddings or vice versa, we propose CME-DMM, a collaboratively modeling and embedding framework for capturing coherent latent topics from short texts. CME-DMM incorporates topic and word embeddings through the attention mechanism and implants them into the latent topic models, which significantly improve the quality of latent topics. Extensive experiments demonstrate that CME-DMM could perceive more coherent topics than other popular methods, resulting in a better performance in downstream NLP tasks such as classification. Besides the interpretable latent topics, the corresponding topic embeddings can describe the meanings of latent topics in the semantic space. The attention vectors, as a by-product of the learning process, can identify the keywords in noisy short texts.

Abstract Background Our objective was to characterize the relationship of anemia and hemoglobin concentrations with cross-sectional cognitive functions and changes in cognitive functions over 2 years in a large sample of Chinese middle aged and elderly. Methods Ten thousand nine hundred eighteen adults aged 45 years or older participating in the China Health and Retirement Longitudinal Study (CHARLS) were used for cross-sectional analyses and 9324 were used for longitudinal analysis. Cognitive functions were assessed by memory recall (episodic memory), mental status (TICS), and global cognitive function at baseline survey (Visit 1) and first follow-up survey (Visit 2). The lower the cognitive test score, the worse the cognitive function. Anemia was defined as hemoglobin concentrations lower than 13 g/dl for men and lower than 12 g/dl for women. Adjusted multivariate regression analyses were used to explore the relationships of different cognitive domains with anemia and hemoglobin concentration. Results Overall, the prevalence of anemia was 12.86% and the mean hemoglobin concentration was 14.37 ± 2.20 g/dl. After adjusting for socio-demographic and health-related covariates, the cross-sectional association between anemia and global cognitive function [β (95%CI) = − 0.49(− 0.69~ − 0.29)], episodic memory [β (95%CI) = − 0.14(− 0.23~ − 0.05)], and TICS [β (95%CI) = − 0.23(− 0.38~ − 0.08)] were significant and did not differ by gender. The hemoglobin concentration was also associated with global cognitive function among the whole sample (P

In several important scientific fields, the efficient numerical solution of symmetric systems of ordinary differential equations, which are usually characterized by oscillation and periodicity, has become an open problem of interest. In this paper, we construct a class of embedded exponentially fitted Rosenbrock methods with variable coefficients and adaptive step size, which can achieve third order convergence. This kind of method is developed by performing the exponentially fitted technique for the two-stage Rosenbrock methods, and combining the embedded methods to estimate the frequency. By using Richardson extrapolation, we determine the step size control strategy to make the step size adaptive. Numerical experiments are given to verify the validity and efficiency of our methods.

Abstract Neural stem/progenitor cells (NPCs) are multipotent stem cells in the central nervous system. Damage to NPCs has been demonstrated to cause adverse effects on neurogenesis and to contribute to neurological diseases. Our previous research suggested that saikosaponin‐d (SSd), a cytostatic drug belonging to the bioactive triterpenoid saponins, exhibited neurotoxicity by inhibiting hippocampal neurogenesis, but the underlying mechanism remained elusive. This study was performed to clarify the role of SSd in cognitive function and the mechanism by which SSd induced damage to hippocampal neurogenesis and NPCs. Our results indicated that SSd caused hippocampus‐dependent cognitive deficits and inhibited hippocampal neurogenesis by reducing the numbers of newborn neurons in mice. RNA sequencing analysis revealed that SSd‐induced neurotoxicity in the hippocampus involved neurotrophin receptor‐interacting MAGE (NRAGE)/neurotrophin receptor interacting factor (NRIF)/p75NTR‐associated cell death executor (NADE) cell signaling activated by the p75 neurotrophin receptor (p75NTR). Mechanistic studies showed that a short hairpin RNA targeting p75NTR intracellular domain reversed SSd‐increased NRAGE/NRIF/NADE signaling and the c‐Jun N‐terminal kinase/caspase apoptotic pathway, subsequently contributing to the survival of NPCs, as well as cell proliferation and differentiation. The addition of recombinant brain‐derived neurotrophic factor (BDNF) ameliorated the SSd‐induced inhibition of BDNF/Tyrosine kinase receptor B (TrkB) neurotrophic signaling, but did not affect SSd‐activated pro‐BDNF/p75NTR signaling. Moreover, the SSd‐induced elevation of cytosolic Ca2+ concentration was responsible for damage to NPCs. The extracellular Ca2+ chelator ethylene glycol‐bis(2‐aminoethylether)‐N,N,N',N'‐tetraacetic acid (EGTA), rather than the intracellular Ca2+ chelator 1,2‐bis(2‐aminophenoxy)ethane‐N,N,N',N'‐tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA/AM), attenuated SSd‐induced cytosolic Ca2+ dysfunction and SSd‐disordered TrkB/p75NTR signaling. Overall, this study demonstrated a new mechanism for the neurotoxic effect of SSd, which has emerging implications for pharmacological research of SSd and provides a better understanding of neurotoxicity induced by cytostatic drugs.

Background: Haploinsufficiency A20 (HA20) is a newly described monogenic disease characterized by a wide spectrum of manifestations and caused by heterozygous mutations in TNFAIP3 which encodes A20 protein. TNFAIP3 mutation leads to disruption of the A20 ovarian tumor (OTU) domain and/or the zinc finger (ZnF) domain. This study aims at exploring the association between the various manifestations of HA20 and different domains disruption of A20.Methods: We reviewed the HA20 cases in previous literature and summarized the clinical features, TNFAIP3 mutation loci and the disrupted domains caused by different sites and patterns of mutations. Patients were classified into three groups according to the A20 domains disruption.Results: A total of 89 patients from 39 families with a genetic diagnosis of HA20 were included. Overall, the age at onset of HA20 was early (median:5.92, IQR:1-10). Patients in the ZnF group showed the earliest onset (median:2.5, IQR:0.6-5), followed by patients in the OTU+ZnF group (median:6, IQR:1-10) and patients in the OTU group (median:10, IQR:8-14). The main manifestations of HA20 patients were recurrent oral ulcers (70%), recurrent fever (42%), gastrointestinal ulcers (40%), skin lesion (38%), genital ulcers (36%), and musculoskeletal disorders (34%). The percentage of patients with musculoskeletal disorders was significantly different among the three groups (p = 0.005). Patients in the OTU+ZnF group and ZnF group were more likely to develop musculoskeletal disorders than patients in the OTU group (p = 0.002 and p = 0.035, respectively). Besides, forty-three percent of HA20 patients were initially diagnosed as Behcet's disease (BD). Compared to the ZnF group, the OTU+ZnF group and OTU group had a higher percentage of patients initially diagnosed as BD (p = 0.006 and p < 0.001, respectively).Conclusion: HA20 is characterized by early-onset and the most common symptoms of HA20 are recurrent oral ulcers, fever and gastrointestinal ulcers. The onset of HA20 in patients with the ZnF domain disruption is earlier than patients with the OTU domain disruption. Compared to the OTU domain, the ZnF domain may be more closely related to musculoskeletal disorders.

BackgroundHepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) has poor prognosis. Sorafenib/lenvatinib is recommended as the first-line therapy in these patients currently, with unsatisfactory response and survival benefit reported. Radiotherapy (RT) is increasingly utilized in advanced HCC and is considered an alternative option for HCC patients with PVTT. Combined treatment of RT and locoregional treatments such as transarterial chemoembolization shows promising results. However, the efficacy and safety for combined treatment of RT and systemic therapy have not been reported and thus warrant further studies. This prospective clinic trial aims at evaluating the efficacy and safety of stereotactic body RT (SBRT) combined with camrelizumab and apatinib in HCC patients with PVTT.MethodsThis multicenter, open-label, randomized controlled trial will enroll 264 HCC patients with PVTT who have not received systemic therapy previously. Stratification of patients will be based on the presence or absence of extrahepatic metastasis and level of AFP (AFP ≥ 400 or

Background Results of several longitudinal cohort studies suggested an association between cerebral small‐vessel disease and depression. Therefore, we performed a meta‐analysis to explore whether cerebral small‐vessel disease imparts increased risk for incident depression. Methods and Results We searched prospective cohort studies relevant to the relationship between cerebral small‐vessel disease and incident depression published through September 6, 2019, which yielded 16 cohort studies for meta‐analysis based on the relative odds ratio (OR) calculated with fixed‐ and random‐effect models. Baseline white matter hyperintensities (WMHs) (pooled OR, 1.37; 95% CI, 1.14–1.65), enlarged perivascular spaces (pooled OR, 1.33; 95% CI, 1.03–1.71), and cerebral atrophy (pooled OR, 2.83; 95% CI, 1.54–5.23) were significant risk factors for incident depression. Presence of deep WMHs (pooled OR, 1.47; 95% CI, 1.05–2.06) was a stronger predictor of depression than were periventricular WMHs (pooled OR, 1.31; 95% CI, 0.93–1.86). What's more, the pooled OR increased from 1.20 for the second quartile to 1.96 for the fourth quartile, indicating that higher the WMH severity brings greater risk of incident depression (25th–50th: pooled OR, 1.20; 95% CI, 0.68–2.12; 50th–75th; pooled OR, 1.42; 95% CI, 0.81–2.46; 75th–100th: OR, 1.96; 95% CI, 1.06–3.64). These results were stable to subgroup analysis for age, source of participants, follow‐up time, and methods for assessing WMHs and depression. Conclusions Cerebral small‐vessel disease features such as WMHs, enlarged perivascular spaces, and cerebral atrophy, especially the severity of WMHs and deep WMHs, are risk factors for incident depression.

Objectives To demonstrate the screening value of echocardiography for portopulmonary hypertension (POPH) in liver transplant candidates. Design Systematic review and meta-analysis. Background POPH is a complication of end-stage liver disease that adversely affects the outcome of orthotopic liver transplant. There are no specific symptoms in the early stage of POPH. POPH reduce the survival rate of patients with end-stage liver disease specially if they are not diagnosed. Therefore, early detection may improve prognosis. The objective of this study is to explore the screening value of echocardiography on liver transplant candidates for screening of POPH compared to right heart catheterization (RHC). Method PubMed, EMBASE and the Cochrane Library were searched by two independent reviewers for potentially eligible studies published up to 30 June 2019 to retrieve data based on per-patient analysis. STATA, Meta-DiSc, and RevMan were applied to perform this meta-analysis. Results Our search yielded 1576 studies, of which 11 satisfied the inclusion criteria. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and area under the summary receiver operating characteristic (SROC) curve (AUC) of echocardiography for POPH were 0.85 (95% CI [0.65–0.94]), 0.83 (95% CI [0.73–0.90]), 4.99 (95% CI [3.03–8.21]), 0.19 (95% CI [0.07–0.46]), and 0.91 (95% CI [0.88–0.93]), respectively. Deeks’ funnel plot did not indicate the existence of publication bias (P = 0.66). Conclusions Echocardiography, a noninvasive modality, provides superior screening for POPH, but the diagnosis of POPH still requires RHC. PROSPERO registration number CRD42019144589.

Large sets of genomic regions are generated by the initial analysis of various genome-wide sequencing data, such as ChIP-seq and ATAC-seq experiments. Gene set enrichment (GSE) methods are commonly employed to determine the pathways associated with them. Given the pathways and other gene sets (e.g., GO terms) of significance, it is of great interest to know the extent to which each is driven by binding near transcription start sites (TSS) or near enhancers. Currently, no tool performs such an analysis. Here, we present a method that addresses this question to complement GSE methods for genomic regions. Specifically, the new method tests whether the genomic regions in a gene set are significantly closer to a TSS (or to an enhancer) than expected by chance given the total list of genomic regions, using a non-parametric test. Combining the results from a GSE test with our novel method provides additional information regarding the mode of regulation of each pathway, and additional evidence that the pathway is truly enriched. We illustrate our new method with a large set of ENCODE ChIP-seq data, using the chipenrich Bioconductor package. The results show that our method is a powerful complementary approach to help researchers interpret large sets of genomic regions.