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Abstract Background Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that poses a substantial economic burden. The Random forest algorithm is effective in predicting AD; however, the key factors influencing AD onset remain unclear. This study aimed to analyze the key lipoprotein and metabolite factors influencing AD onset using machine-learning methods. It provides new insights for researchers and medical personnel to understand AD and provides a reference for the early diagnosis, treatment, and early prevention of AD. Methods A total of 603 participants, including controls and patients with AD with complete lipoprotein and metabolite data from the Alzheimer’s disease Neuroimaging Initiative (ADNI) database between 2005 and 2016, were enrolled. Random forest, Lasso regression, and CatBoost algorithms were employed to rank and filter 213 lipoprotein and metabolite variables. Variables with consistently high importance rankings from any two methods were incorporated into the models. Finally, the variables selected from the three methods, with the participants’ age, sex, and marital status, were used to construct a random forest predictive model. Results Fourteen lipoprotein and metabolite variables were screened using the three methods, and 17 variables were included in the AD prediction model based on age, sex, and marital status of the participants. The optimal random forest modeling was constructed with “mtry” set to 3 and “ntree” set to 300. The model exhibited an accuracy of 71.01%, a sensitivity of 79.59%, a specificity of 65.28%, and an AUC (95%CI) of 0.724 (0.645–0.804). When Mean Decrease Accuracy and Gini were used to rank the proteins, age, phospholipids to total lipids ratio in intermediate-density lipoproteins (IDL_PL_PCT), and creatinine were among the top five variables. Conclusions Age, IDL_PL_PCT, and creatinine levels play crucial roles in AD onset. Regular monitoring of lipoproteins and their metabolites in older individuals is significant for early AD diagnosis and prevention.

Abstract Family with sequence similarity 20, member A (FAM20A) is a pseudo-kinase in the secretory pathway and is essential for enamel formation in humans. Here we examine if FAM20A is a membrane-associated protein. We show that the full-length FAM20A can be purified from HEK293 cells transfected with a FAM20A-expresing construct. Further, it is only found in the membrane fraction, but not in the soluble fraction, of cell lysate. Consistently, it is not secreted out of the expressing cells. Moreover, it is co-localized with GM130, a cis-Golgi network marker, and membrane topology analysis indicates that it has its C-terminus oriented towards the lumen of the organelle. Our results support that FAM20A is a Type II transmembrane protein within the secretory compartments.

Farmers are considered a high-risk group for intentional and unintentional injuries. This review identified significant risk factors for agricultural injuries in farmers and explored injury prevention countermeasures based on the literature. Therefore, CiteSpace software was used to analyze the relevant literature in this field. Additionally, we identified both key risk factors and countermeasures using the Haddon matrix and the 5 E’s risk reduction strategies conceptual framework, respectively. The risk factors were identified from four categories (host, agent, physical environment, and social environment) corresponding to three phases (pre-event, event, and post-event). Interventions of 5 E’s risk reduction strategies including education, engineering, enforcement, economic, and emergency response have been proven effective in preventing injuries or reducing their severity. Our findings provide a comprehensive foundation and research direction for the study and prevention of injuries among farmers.

Abstract Background Gonorrhea has long been a serious public health problem in mainland China that requires attention, modeling to describe and predict its prevalence patterns can help the government to develop more scientific interventions. Methods Time series (TS) data of the gonorrhea incidence in China from January 2004 to August 2022 were collected, with the incidence data from September 2021 to August 2022 as the validation. The seasonal autoregressive integrated moving average (SARIMA) model, long short-term memory network (LSTM) model, and hybrid SARIMA-LSTM model were used to simulate the data respectively, the model performance were evaluated by calculating the mean absolute percentage error (MAPE), root mean square error (RMSE), and mean absolute error (MAE) of the training and validation sets of the models. Results The Seasonal components after data decomposition showed an approximate bimodal distribution with a period of 12 months. The three models identified were SARIMA(1,1,1) (2,1,2)12, LSTM with 150 hidden units, and SARIMA-LSTM with 150 hidden units, the SARIMA-LSTM model fitted best in the training and validation sets, for the smallest MAPE, RMSE, and MPE. Conclusions The overall incidence trend of gonorrhea in mainland China has been on the decline since 2004, with some periods exhibiting an upward trend. The incidence of gonorrhea displays a seasonal distribution, typically peaking in July and December each year. The SARIMA model, LSTM model, and SARIMA-LSTM model can all fit the monthly incidence time series data of gonorrhea in mainland China. However, in terms of predictive performance, the SARIMA-LSTM model outperforms the SARIMA and LSTM models, with the LSTM model surpassing the SARIMA model. This suggests that the SARIMA-LSTM model can serve as a preferred tool for time series analysis, providing evidence for the government to predict trends in gonorrhea incidence. The model's predictions indicate that the incidence of gonorrhea in mainland China will remain at a high level in 2024, necessitating that policymakers implement public health measures in advance to prevent the spread of the disease.

The aging problem is becoming more and more prominent globally. Attention to the quality of life and related health improvement among the elderly has become an important issue in modern society. This study utilized a tracking survey conducted in 2017-2018, involving 9,327 Chinese older adults, to examine health influencing factors, and applied structural equation modeling to analyze the influencing factors on the self-assessment of life satisfaction among older adults in different regions (cities, counties, and villages) in China. This study revealed that economic status, psychological status, personal situation, life behaviors, and child care are important influences on older people’s self- assessed life satisfaction. There is a positive correlation between economic status, psychological status, child care and the results of the self-assessment of life satisfaction of the elderly. Psychological status and child care have a greater impact on the self-assessment of life satisfaction among the elderly in urban areas compared to villages and towns. The influence of economic status on the self-assessment of life satisfaction of the elderly is lower in urban areas than in rural areas. There is a significant difference in the influence of personal situations on the self-assessment of life satisfaction among the elderly. Additionally, older individuals tend to report higher levels of self-assessment of life satisfaction. Furthermore, female elderly individuals tend to report higher levels of satisfaction compared to males. Findings from this study indicate that improving health self-assessment in older adults requires targeted efforts based on different geographic areas of life and the age stages of older adults, and more attention needs to be paid to men who are just entering old age.

Sustainable economic development is a hot issue in current research, and it is of great significance to analyze the effects of air pollution and population agglomeration on sustainable economic development. This study collects the relevant data released by the Chinese government from 2011–2021, and empirically analyzes the method of constructing an individual one-factor fixed-effects model in order to explore the impacts of SO2 emissions and population agglomeration on sustainable economic development. Through the analysis, it is found that SO2 emissions are negatively correlated with sustainable economic development, and the direction and intensity of its influence are affected by urbanization level, industrial structure, and living standards of residents. The influence of population agglomeration on economic sustainable development is positively correlated. Meanwhile, through the sub-regional study, we further confirmed that the impact of the above influencing factors on the sustainable economic development of different regions is different. Therefore, in order to promote sustainable economic development, it is necessary to further identify the stage of sustainable economic development according to the actual situation of different regions, and to effectively integrate factors including the environment, population, urbanization, industrial structure, etc.

The management of a three-dimensional warehouse is a key part of the upper computer monitoring and management system for three-dimensional warehouses. Currently, there are problems such as unreasonable planning and inability to respond to real-time demands. Therefore, further improvement is needed to optimize the management of storage locations. The main purpose of the research is to achieve better storage stability and improve storage and retrieval efficiency. First, the study constructed a multiobjective mathematical model based on the weight, frequency of use, and category of the goods. Three objective functions were constructed. Therefore, the operational efficiency of the stacker crane and the turnover rate of items were improved. Meanwhile, the overall stability of the shelves was ensured, and the management efficiency of the warehouse was improved. At the same time, the study introduced the GA-PSO algorithm to solve the mathematical model and optimize the goods location planning. These results confirmed that the proposed algorithm had significantly lower iteration times than traditional particle swarm optimization in different warehouse sizes and types of goods. The iteration required to reach the optimal value in Situation 1 was only 80, which was 90 fewer than PSO. Meanwhile, in Situation 2, the optimization results of the proposed algorithm in four objective functions were as high as 42.94%, 26.03%, 30.72%, and 46.15%, respectively, which increased by 1.20%, 8.04%, 5.61%, and 7.38% compared to PSO. The proposed algorithm can achieve more efficient and intelligent warehouse management, improving the efficiency and accuracy of logistics operations. It is significant for logistics industry development and enterprise competitiveness enhancement.

Upon endoplasmic reticulum (ER) stress, inositol-requiring enzyme 1 (IRE1) is activated, which subsequently converts an unspliced X-box binding protein 1 (XBP1U) mRNA to a spliced mRNA that encodes a potent XBP1S transcription factor. XBP1S is essential for relieving ER stress and secretory cell differentiation. We previously established Twist2-Cre;Xbp1CS/+ mice that constitutively expressed XBP1S in the Twist2-expressing cells as well as in the cells derived from the Twist2-expressing cells. In this study, we analyzed the dental phenotype of Twist2-Cre;Xbp1CS/+ mice. We first generated a mutant Xbp1s minigene that corresponds to the recombinant Xbp1Δ26 allele (the Xbp1CS allele that has undergone Cre-mediated recombination) and confirmed that the Xbp1s minigene expressed XBP1S that does not require IRE1α activation in vitro. Consistently, immunohistochemistry showed that XBP1S was constitutively expressed in the odontoblasts and other dental pulp cells in Twist2-Cre;Xbp1CS/+ mice. Plain X-ray radiography and µCT analysis revealed that constitutive expression of XBP1S altered the dental pulp chamber roof- and floor-dentin formation, resulting in a significant reduction in dentin/cementum formation in Twist2-Cre;Xbp1CS/+ mice, compared to age-matched Xbp1CS/+ control mice. However, there is no significant difference in the density of dentin/cementum between these two groups of mice. Histologically, persistent expression of XBP1S caused a morphological change in odontoblasts in Twist2-Cre;Xbp1CS/+ mice. Nevertheless, in situ hybridization and immunohistochemistry analyses showed that continuous expression of XBP1S had no apparent effects on the expression of the Dspp and Dmp1 genes. In conclusion, these results support that sustained production of XBP1S adversely affected odontoblast function and dentin formation.

Abstract Background In recent years, it has become a research focus to accurately extract key genes influencing the occurrence and development of diseases from massive genomic data and study their regulatory mechanisms. Further exploration of these large databases is beneficial for us to identify key regulatory mechanisms in the occurrence and development of diseases, providing direction and theoretical basis for subsequent experimental design and research. Methods By using data from The Cancer Genome Atlas (TCGA) for lung adenocarcinoma (LUAD), the immune cell content of patients was obtained through deconvolution calculations in CIBERSORTx. Combined with Bayesian network inference methods, the impact of key gene expression on the heterocellular network influencing lung cancer was analyzed. Results We found CD36 and ADRA1A genes were identified as two key mRNA genes influencing lung adenocarcinoma. The sensitivity analysis shows that the model performs well on both the testing set (error rate = 4%, AUC = 0.9804), the training set (error rate = 5.637%, AUC = 0.9746) and the verification set (error rate = 28.85%, AUC = 0.8689). The model has excellent predictive capabilities. Conclusion We found that CD36 and ADRA1A genes may influence the development of lung cancer by affecting regulatory T cell and follicular helper T cell populations. Additionally, plasma cells may affect the expression of the CD36 gene. And the mutual information calculated by the model for these two genes is also the highest, indicating their potential as tumour biomarkers. Combining the network model, it can be inferred that CD36 and ADRA1A are likely to influence the occurrence and development of the disease through follicular helper T cells and regulatory T cells.

N6-Methyladenosine (m6A) methylation is one of the most extremely examined RNA modifications. M6A modification evidently impacts cancer development by effecting RNA metabolism. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are involved in multiple essential biological processes by regulating gene expression at the transcriptional and post-transcriptional levels. Accumulated evidences indicated that m6A is involved in regulating the cleavage, stability, structure, transcription, and transport of lncRNAs or miRNAs. Additionally, ncRNAs also play significant roles in modulating m6A levels of malignant cells by participating in the regulation of m6A methyltransferases, the m6A demethylases and the m6A binding proteins. In this review, we systematically summarize the new insight on the interactions between m6A and lncRNAs or miRNAs, as well as their impacts on gastrointestinal cancer progression. Although there are still extensive studies on genome-wide screening of crucial lncRNAs or miRNAs involved in regulating m6A levels of mRNAs and disclosing differences on mechanisms of regulating m6A modification of lncRNAs, miRNAs or mRNAs in cancer cells, we believe that targeting m6A-related lncRNAs and miRNAs may provide novel options for gastrointestinal cancer treatments.

Abstract Immune checkpoint inhibitors (ICIs) are most commonly used for melanoma and non-small cell lung cancer (NSCLC) patients. FAT atypical cadherin 1 (FAT1), which frequently mutates in melanoma and NSCLC. In this study, we aim to investigate the association of FAT1 mutations with ICI response and outcome. We collected somatic mutation profiles and clinical information from ICI-treated 631 melanoma and 109 NSCLC samples, respectively. For validation, a pan-cancer cohort with 1661 patients in an immunotherapy setting was also used. Melanoma and NSCLC samples from the Cancer Genome Atlas were used to evaluate the potential immunologic mechanisms of FAT1 mutations. In melanoma, patients with FAT1 mutations had a significantly improved survival outcome than those wild-type patients (HR: 0.67, 95% CI: 0.46–0.97, P = 0.033). An elevated ICI response rate also appeared in FAT1-mutated patients (43.2% vs. 29.2%, P = 0.032). Associations of FAT1 mutations with improved prognosis and ICI response were confirmed in NSCLC patients. In the pan-cancer cohort, the association between FAT1 mutations and favorable ICI outcome was further validated (HR: 0.74, 95% CI: 0.58–0.96, P = 0.022). Genomic and immunologic analysis showed that a high mutational burden, increased infiltration of immune-response cells, decreased infiltration of immune-suppressive cells, interferon and cell cycle-related pathways were enriched in patients with FAT1 mutations. Our study revealed that FAT1 mutations were associated with better immunogenicity and ICI efficacy, which may be considered as a biomarker for selecting patients to receive immunotherapy.

Abstract Purpose Protein tyrosine phosphatase receptor type T (PTPRT), which is a well‐known phosphatase and mutates frequently in melanoma and non‐small cell lung cancer (NSCLC). Our research aims to elucidate its mutation association with immune checkpoint inhibitors (ICI) efficacy. Methods We integrated whole‐exome sequencing (WES)‐based somatic mutation profiles and clinical characteristics of 631 melanoma samples received ICI agents from eight studies and 109 NSCLC samples from two studies. For validation, 321 melanoma and 350 NSCLC immunotherapy samples with targeted next‐generation sequencing (NGS) were employed. Besides, an independent NSCLC cohort contained 240 samples was also collected for further corroboration. Distinct immune infiltration was evaluated according to the PTPRT mutational status. Results In the WES melanoma cohort, patients with PTPRT mutations harbored a significantly elevated ICI response rate (40.5% vs. 28.6%, p = 0.036) and a prolonged survival outcome (35.3 vs. 24.9 months, p = 0.006). In the WES NSCLC cohort, the favorable response and immunotherapy survival were also observed in PTPRT‐mutated patients (p = 0.036 and 0.019, respectively). For the validation cohorts, the associations of PTRPT mutations with better prognoses were identified in melanoma, NSCLC, and pan‐cancer patients with targeted‐NGS (all p

IntroductionTurner syndrome (TS) is a chromosomal disorder that affects phenotypic females who have one intact X chromosome and complete or partial absence of the second sex chromosome in association with one or more clinical manifestations. However, the immunological profile of TS with different X chromosome origins is incompletely understood.MethodsIn this study, transcriptomic expression profiles of 26 TS (45,X) samples and 10 normal karyotype (46,XX) samples derived from GSE46687 cohort were employed. Differentially expressed immune-related genes (DEIRGs) between monosomy X TS patients with different X chromosome origins and normal females were investigated respectively. Subsequently, functional annotation, protein-protein interaction (PPI) network analysis, immunocyte infiltration evaluation, tissue-specific gene expression and Weighted gene co expression network analysis (WGCNA) were performed to explore the immunological characteristic in TS with different X chromosome origins.Results34 and 52 DEIRGs were respectively identified in 45,Xm and 45,Xp patients compared with normal individuals. The identified DEIRGs in Xm group were significantly enriched in pathways associated with cancer. In Xp TS patients, the most enriched signals were immune response-related. A majority of genes involved in the above pathways were downregulated. PPI analysis identified 4 (FLT3, IL3RA, CSF2RA, PIK3R3) and 6 (PDGFRB, CSF2, IL5, PRL, CCL17 and IL2)hub genes for Xm and Xp groups, respectively. CIBERSORT results showed that the proportion of Tregs in the Xm group and the naive B cells and resting NK cells in the Xp group significantly increased, respectively. Tissue-specific expression results indicated that BDCA4+_dentritic cells and CD19+ B cells were the prominent specific expressed tissues in Xp patients. Results of WGCNA support the above analysis.ConclusionsThis study aims at studying the immunological characteristics of TS with different X chromosome origins. Pathways in cancer in Xm group and immune response in Xp group were suppressed. 4 and 6 hub IRGs were identified as biomarkers for Xm and Xp patients, respectively. B cells played important roles in Xp patients. Further studies are needed to draw more attention to the functional validation of these hub genes and the roles of B cells.

Abstract Background The coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has led to a global pandemic in an unprecedented time frame. Systemic vascular involvement in COVID‐19 has been identified, and SARS‐CoV‐2 has also been found to cause multiple organ ischemia and posterior ocular segment disease in mammals, raising concerns about the human retinal microvascular involvement in SARS‐CoV‐2. Objective To objectively assess the presence of retinal microvascular impairment in COVID‐19 patients by optical coherence tomography angiography (OCTA), so as to facilitate the clinical system management of COVID‐19 patients. Methods We searched PubMed, Cochrane Library, EMBASE, Ovid, CBM to collect eligible studies. The main outcomes included the vessel density (VD), area or perimeter of foveal avascular zone (FAZ), central foveal thickness (CFT), subfoveal choroidal thickness (SCT) in our meta‐analysis. Results We eventually included five studies with a total of 401 participants. Our meta‐analysis showed that nonacute infectious COVID‐19 or post‐COVID‐19 patients presented significantly lower foveal VD of deep capillary plexus (WMD = −4.22, 95% CI [−8.00, −0.43]) and thinner SCT (WMD = −10.33, 95% CI [−19.08, −1.57]) than healthy controls. The foveal VD and parafoveal VD of superficial capillary plexus, parafoveal VD of deep capillary plexus, CFT, area, and perimeter of FAZ showed no significant differences between the groups. Conclusion The patients of nonacute infectious COVID‐19 or post‐COVID‐19 displayed alterations in the retinal microvasculature and choroidal vessels, including a significantly lower foveal VD in deep capillary plexus and thinner SCT. The impairment may be a medium to long‐term process. Close ophthalmic surveillance is necessary for COVID‐19 patients or post‐COVID‐19 patients.

Abstract. Objective:. This study conducted inverse probability of treatment weighting (IPTW) survival analysis to examine survival in pancreatic adenocarcinoma patients. Methods:. In this population-based study, data from the Surveillance, Epidemiology, and End Results program of the United States were analyzed to identify patients diagnosed with adenocarcinoma of the pancreas 2004 to 2014. Differences in survival rates were examined among patients who underwent pancreatectomy alone, radiotherapy alone, and those who had pancreatectomy plus adjuvant radiotherapy. Kaplan–Meier estimates and Cox proportional hazards models with the IPTW were performed to determine the effect of different treatments on overall and cancer-specific survival. This study was approved by the Ethics Review Board of Weifang Medical University. Results:. A total of 8191 patients were included, with 3409 taking pancreatectomy only, 2865 taking radiotherapy only, and 1917 taking pancreatectomy plus adjuvant radiotherapy. Patients who received surgery plus adjuvant radiotherapy had statistically a higher survival rate than those who received the other 2 treatments. Survival analysis with the IPTW for the 3 different groups showed that the difference in median overall survival time among these patient groups was significant. Conclusion:. Using IPTW survival analysis, the present study shows that surgery with adjuvant radiotherapy is significantly associated with improved overall and cancer-specific survival among patients with pancreatic adenocarcinoma.

Abstract Background The COVID-19 has caused a sizeable global outbreak and has been declared as a public health emergency of international concern. Sufficient evidence shows that temperature has an essential link with respiratory infectious diseases. The objectives of this study were to describe the exposure-response relationship between ambient temperature, including extreme temperatures, and mortality of COVID-19. Methods The Poisson distributed lag non-linear model (DLNM) was constructed to evaluate the non-linear delayed effects of ambient temperature on death, by using the daily new death of COVID-19 and ambient temperature data from January 10 to March 31, 2020, in Wuhan, China. Results During the period mentioned above, the average daily number of COVID-19 deaths was approximately 45.2. Poisson distributed lag non-linear model showed that there was a non-linear relationship (U-shape) between the effect of ambient temperature and mortality. With confounding factors controlled, the daily cumulative relative death risk decreased by 12.3% (95% CI [3.4, 20.4%]) for every 1.0 °C increase in temperature. Moreover, the delayed effects of the low temperature are acute and short-term, with the most considerable risk occurring in 5–7 days of exposure. The delayed effects of the high temperature appeared quickly, then decrease rapidly, and increased sharply 15 days of exposure, mainly manifested as acute and long-term effects. Sensitivity analysis results demonstrated that the results were robust. Conclusions The relationship between ambient temperature and COVID-19 mortality was non-linear. There was a negative correlation between the cumulative relative risk of death and temperature. Additionally, exposure to high and low temperatures had divergent impacts on mortality.

Abstract Background At the end of 2019, the outbreak of coronavirus disease 2019 (COVID-19) severely damaged and endangered people’s lives. The public health emergency management system in China has played an essential role in handling the response to the outbreak, which has been appreciated by the World Health Organization and some countries. Hence, it is necessary to conduct an overall analysis of the development of the health emergency management system in China. This can provide a reference for scholars to aid in understanding the current situation and to reveal new research topics. Methods We collected 2247 international articles from the Web of Science database and 959 Chinese articles from the China National Knowledge Infrastructure database. Bibliometric and mapping knowledge domain analysis methods were used in this study for temporal distribution analysis, cooperation network analysis, and co-word network analysis. Results The first international article in this field was published in 1991, while the first Chinese article was published in 2005. The research institutions producing these studies mainly existed in universities and health organizations. Developed countries and European countries published the most articles overall, while eastern China published the most articles within China. There were 52 burst words for international articles published from 1999–2018 and 18 burst words for Chinese articles published from 2003–2018. International top-ranked articles according to the number of citations appeared in 2005, 2007, 2009, 2014, 2015, and 2016, while the corresponding Chinese articles appeared in 2003, 2004, 2009, and 2011. Conclusions There are differences in the regional and economic distribution of international and Chinese cooperation networks. International research is often related to timely issues mainly by focusing on emergency preparedness and monitoring of public health events, while China has focused on public health emergencies and their disposition. International research began on terrorism and bioterrorism, followed by disaster planning and emergency preparedness, epidemics, and infectious diseases. China considered severe acute respiratory syndrome as the starting research background and the legal system construction as the research starting point, which was followed by the mechanism, structure, system, and training abroad for public health emergency management.

Abstract Background There were amounts of previous studies on chronic diseases, but few studies on the prevalence of chronic disease and the healthy lifestyle intervention in recent years, China. This study aimed to investigate the prevalence of chronic disease and the implementation of healthy lifestyle intervention in rural areas of China, so as to put forward health promotion measures to control the chronic diseases effectively. Method A large cross-sectional study (N = 2168) on community diagnosis and chronic disease was carried out in Shandong province, China. The chronic disease questionnaire and the healthy lifestyle intervention questionnaires were recruited to survey the chronic diseases and the implementation of healthy lifestyle intervention. Physical examination and biochemical indicators examination were carried out by the medical staffs and clinical laboratory. Results The current diagnosed prevalence of hypertension, diabetes, hyperlipidemia for total sample, female, male were 24.97, 24.6, 25.5, 7.60, 8.9, 6.0 and 40.27%, 45.9, 33.3% respectively in rural China. The one-year prevalence of myocardial infarction (MI) and stroke of the total sample, female, male were 1.06, 1.0, 1.1 and 2.09%, 2.2, 2.0% respectively. Healthy lifestyles interventions were not effective in rural China. The current active smoking rate and passive smoking rate were 25.68 and 42.65%. 27.86% of the population drunk alcohol within a month and 47.01% of them participated in the actions to control salt daily intake. Only 1.07 and 7.89% of the population participated in medium to high intensity physical exercises. Conclusions The prevalence of common chronic diseases were still high and the implementation of healthy lifestyle intervention were not optimal in rural area, China. Challenges to prevent chronic diseases were still severe, so medical institutes, government and individuals would put forward effective strategies to reduce the prevalence and public health promotion project should be effectively strengthened.

BackgroundImmune checkpoint inhibitor (ICI) therapy dramatically prolongs melanoma survival. Currently, the identified ICI markers are sometimes ineffective. The objective of this study was to identify novel determinants of ICI efficacy.MethodsWe comprehensively curated pretreatment somatic mutational profiles and clinical information from 631 melanoma patients who received blockade therapy of immune checkpoints (i.e., CTLA-4, PD-1/PD-L1, or a combination). Significantly mutated genes (SMGs), mutational signatures, and potential molecular subtypes were determined. Their association with ICI responses was assessed simultaneously.ResultsWe identified 27 SMGs, including four novel SMGs (COL3A1, NRAS, NARS2, and DCC) that are associated with ICI efficacy and well-known driver genes. COL3A1 mutations were associated with improved ICI overall survival (hazard ratio (HR): 0.64, 95% CI: 0.45–0.91, p = 0.012), whereas immune resistance was observed in patients with NRAS mutations (HR: 1.42, 95% CI: 1.10–1.82, p = 0.006). The presence of the tobacco smoking-related signature was significantly correlated with inferior prognoses (HR: 1.42, 95% CI: 1.11–1.82, p = 0.005). In addition, the signature resembling that of alkylating agents and a newly discovered signature both exhibited extended prognoses (both HR

BackgroundDespite the acknowledged sex-related differences in immune response and immune checkpoint inhibitor (ICI) efficacy, little is known about the sex disparities in melanoma of novel genomic determinants for ICI therapies.MethodsPretreatment genomic profiles and clinical characteristics of 631 melanoma patients treated with ICIs (i.e., inhibitors of CTLA-4, PD-1/PD-L1, or both) were comprehensively curated. Genomic factors, i.e., significantly mutated genes (SMGs), mutational signatures, and molecular subtypes were identified, and their associations with ICI treatment efficacy in male and female patients were evaluated.ResultsOf the 15 SMGs identified in this study, three genes (i.e., CFH, DGKG, and PPP6C) were found to exhibit sex differences with respect to ICI efficacy. Among these, CFH mutations exhibited both response rate and survival benefits in male, but not in female patients. A total of four mutational signatures (i.e., signatures 1, 4, 7, and 11) were extracted. Male patients with signature 4 (also known as smoking-related signature) had an inferior ICI response rate and overall survival. However, this association was not significant in females. An immune subtype based on mutational activities was found to be significantly associated with poor ICI survival in female patients.ConclusionWe uncovered several sex-dependent genomic correlates of response to ICI treatment, such as male-biased CFH mutations and signature 4 and the female-biased immune resistance subtype. The findings derived from this research provide clues for exploring different immunotherapeutic approaches in male and female patients with melanoma.

Remarkable clinical benefits in several advanced cancers are observed under the treatment of immune checkpoint inhibitor (ICI) agents. However, only a smaller proportion of patients respond to the treatments. Reelin (RELN) is frequently mutated in the cancer genome. In this study, the RELN mutation association with ICI treatment efficacy in melanoma and non-small cell lung cancer (NSCLC) was elucidated. Data from 631 melanoma and 109 NSCLC patients with both ICI treatment data and pre-treatment mutational profiles were collected. In addition, from the Cancer Genome Atlas (TCGA) project, we also obtained both tumors to explore the immunologic features behind RELN mutations. Melanoma patients with RELN mutations exhibited a favorable ICI survival benefit when compared with wild-type patients (HR: 0.66, 95% CI: 0.51–0.87, p = 0.003). A higher response rate was also noticed in RELN-mutated patients (38.9% vs. 28.3%, p = 0.017). The association of RELN mutations with a preferable immunotherapy outcome and response was further confirmed in NSCLC. Further exploration demonstrated that favorable immunocyte infiltration and immune response signaling pathways were found in patients with RELN mutations. In this study, RELN mutations were identified to connect with a better immune microenvironment and an improved ICI efficacy in melanoma and NSCLC, which provides a potential biomarker for immunological feature evaluation and immunotherapeutic outcome prediction at the molecular level.

Dentin sialophosphoprotein (DSPP) is an extracellular matrix protein that is highly expressed in odontoblasts, but only transiently expressed in presecretory ameloblasts during tooth development. We previously generated a knockin mouse model expressing a mouse equivalent (DSPP, p.P19L) of human mutant DSPP (p.P17L; referred to as “DsppP19L/+”), and reported that DsppP19L/+ and DsppP19L/P19L mice manifested a dentin phenotype resembling human dentinogenesis imperfecta (DGI). In this study, we analyzed pathogenic effects of mutant P19L-DSPP on enamel development in DsppP19L/+ and DsppP19L/P19L mice. Micro-Computed Tomography (μCT) analyses of 7-week-old mouse mandibular incisors showed that DsppP19L/P19L mice had significantly decreased enamel volume and/or enamel density at different stages of amelogenesis examined. Acid-etched scanning electron microscopy (SEM) analyses of mouse incisors demonstrated that, at the mid-late maturation stage of amelogenesis, the enamel of wild-type mice already had apparent decussating pattern of enamel rods, whereas only minute particulates were found in DsppP19L/+ mice, and no discernible structures in DsppP19L/P19L mouse enamel. However, by the time that incisor enamel was about to erupt into oral cavity, distinct decussating enamel rods were evident in DsppP19L/+ mice, but only poorly-defined enamel rods were revealed in DsppP19L/P19L mice. Moreover, μCT analyses of the mandibular first molars showed that DsppP19L/+ and DsppP19L/P19L mice had a significant reduction in enamel volume and enamel density at the ages of 2, 3, and 24weeks after birth. Backscattered and acid-etched SEM analyses revealed that while 3-week-old DsppP19L/+ mice had similar pattern of enamel rods in the mandibular first molars as age-matched wild-type mice, no distinct enamel rods were observed in DsppP19L/P19L mice. Yet neither DsppP19L/+ nor DsppP19L/P19L mice showed well-defined enamel rods in the mandibular first molars by the age of 24weeks, as judged by backscattered and acid-etched SEM. In situ hybridization showed that DSPP mRNA level was markedly reduced in the presecretory ameloblasts, but immunohistochemistry revealed that DSP/DSPP immunostaining signals were much stronger within the presecretory ameloblasts in Dspp mutant mice than in wild-type mice. These results suggest that mutant P19L-DSPP protein caused developmental enamel defects in mice, which may be associated with intracellular retention of mutant DSPP in the presecretory ameloblasts.

In this paper, we focus on training a support vector machine (SVM) online with a single pass over streaming data.Traditional batch-mode SVMs require previously prepared training data; these models may be unsuitable for streaming data circumstances. Online SVMs are effective tools for solving this problem by receiving data streams consistently and updating model weights accordingly. However, most online SVMs require multiple data passes before the updated weights converge to stable solutions, and may be unable to address high-rate data streams. This paper presents OSVM_SP, a new online SVM with a single pass over streaming data, and three budgeted versions to bound the space requirement with support vector removal principles. The experimental results obtained with five public datasets show that OSVM_SP outperforms most state-of-the-art single-pass online algorithms in terms of accuracy and is comparable to batch-mode SVMs. Furthermore, the proposed budgeted algorithms achieve comparable predictive performance with only 1/3 of the space requirement.

BackgroundThe involvement of microRNA-338-5p in modulating NPC pathogenesis is still largely unknown, and this study aimed to investigate this issue.MethodsThe expressions of cancer associated genes were determined by Real-Time qPCR and Western Blot, and cell apoptosis was determined by flow cytometer (FCM). CCK-8 assay and colony formation assay were respectively used to determine cell proliferation and colony formation abilities. Transwell assay was used to evaluate cell migration. The expression levels of Ki67 protein in mice tissues were measured by Immunohistochemistry (IHC) assay.ResultsThe present study found that microRNA-338-5p suppressed NPC progression by degrading its downstream target, Wnt family member 2B (WNT2B). Specifically, microRNA-338-5p tended to be low-expressed in NPC tissues and cell lines, compared to the non-tumor nasopharyngeal mucosa tissues and normal nasopharyngeal cell line (NP69). Upregulation of microRNA-338-5p inhibited proliferation, mobility, and epithelial-mesenchymal transition (EMT) in NPC cells in vitro, while silencing of microRNA-338-5p had opposite effects. Consistently, microRNA-338-5p suppressed tumorigenesis of NPC cells in vivo. In addition, microRNA-338-5p targeted WNT2B for degradation and inhibition, and the inhibiting effects of microRNA-338-5p overexpression on NPC development were reversed by upregulating WNT2B.ConclusionsTaken together, we concluded that microRNA-338-5p targeted WNT2B to hinder NPC development.

Abstract Objective To determine the correlation of displacement of the mediastinal metastatic lymph nodes with adjacent organs in non‐small cell lung cancer using four‐dimensional computed tomography. Methods The displacements of 51 mediastinal metastatic lymph nodes located in the left–right, anterior–posterior, and superior–inferior directions were measured using four‐dimensional computed tomography. Correlation analyses were carried out to determine the association between the displacement of lymph nodes and volumetric change of the lungs and heart. Results A significant correlation of displacement of the left group lymph nodes in left–right and the right group in anterior–posterior directions with volumetric change of the ipsilateral lung was observed. There were significant correlations between displacement of the left group lymph nodes and volumetric change of the heart. Conclusion Displacement of the mediastinal metastatic lymph nodes was relevant to the adjacent organs.

Abstract Aims To perform a dosimetric evaluation of four different simultaneous integrated boost whole brain radiotherapy modalities with hippocampus and inner ear avoidance in the treatment of limited brain metastases. Methods Computed tomography/magnetic resonance imaging data of 10 patients with limited (1–5) brain metastases were used to replan step-and-shoot intensity-modulated radiotherapy (sIMRT), dynamic intensity-modulated radiation therapy (dIMRT), volumetric-modulated arc therapy (VMAT), and helical tomotherapy (Tomo). The prescribed doses of 40–50 Gy in 10 fractions and 30 Gy in 10 fractions were simultaneously delivered to the metastatic lesions and the whole-brain volume, respectively. The hippocampal dose met the RTOG 0933 criteria for hippocampal avoidance (Dmax ≤17 Gy, D100% ≤10 Gy). The inner ear dose was restrained to Dmean ≤15 Gy. Target coverage (TC), homogeneity index (HI), conformity index (CI), maximum dose (Dmax), minimum dose (Dmin) and dose to organs at risk (OARs) were compared. Results All plans met the indicated dose restrictions. The mean percentage of planning target volume of metastases (PTVmets) coverage ranged from 97.1 to 99.4%. For planning target volume of brain (PTVbrain), Tomo provided the lowest average D2% (37.5 ± 2.8 Gy), the highest average D98% (25.2 ± 2.0 Gy), and the best TC (92.6% ± 2.1%) and CI (0.79 ± 0.06). The two fixed gantry IMRT modalities (step and shot, dynamic) provided similar PTVbrain dose homogeneity (both 0.76). Significant differences across the four approaches were observed for the maximum and minimum doses to the hippocampus and the maximum doses to the eyes, lens and optic nerves. Conclusion All four radiotherapy modalities produced acceptable treatment plans with good avoidance of the hippocampus and inner ear. Tomo obtained satisfactory PTVbrain coverage and the best homogeneity index. Trial registration Clinicaltrials.gov, NCT03414944. Registered 29 January 2018

Task offloading and resource allocation are the major elements of edge computing. A reasonable task offloading strategy and resource allocation scheme can reduce task processing time and save system energy consumption. Most of the current studies on the task migration of edge computing only consider the resource allocation between terminals and edge servers, ignoring the huge computing resources in the cloud center. In order to sufficiently utilize the cloud and edge server resources, we propose a coarse-grained task offloading strategy and intelligent resource matching scheme under Cloud-Edge collaboration. We consider the heterogeneity of mobile devices and inter-channel interference, and we establish the task offloading decision of multiple end-users as a game-theory-based task migration model with the objective of maximizing system utility. In addition, we propose an improved game-theory-based particle swarm optimization algorithm to obtain task offloading strategies. Experimental results show that the proposed scheme outperforms other schemes with respect to latency and energy consumption, and it scales well with increases in the number of mobile devices.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in China. This study aimed to develop a hyaluronic acid (HA) decorated, pH sensitive lipid-polymer hybrid nanoparticles (LPH NPs) to co-deliver erlotinib (ERL) and bevacizumab (BEV) (HA-ERL/BEV-LPH NPs) for targeting and suppressing NSCLC. HA contained pH sensitive nano-materials were synthesized by acylation reaction. HA-ERL/BEV-LPH NPs were prepared using a sonication method. To explore the efficiency of the system, we evaluated the physicochemical parameters and performed a release study, a cellular uptake assay, a cytotoxicity evaluation, and several in vivo anti-tumor studies in comparison with free drugs and single drug systems. All LPH NPs samples have particle sizes of about 100−120 nm, polydispersity index values range from 0.12 to 0.15, and negative zeta potentials. HA-ERL/BEV-LPH NPs contained pH sensitive adipic acid dihydrazide (ADH) showed fast drug release at pH 5.5 than pH 7.4. After 21 days, the tumor volume of the HA-ERL/BEV-LPH NPs group (229.2 ± 13.1 mm3) was significantly smaller than 0.9 % NaCl control group (1126.3 ± 39.4 mm3), with a tumor inhibition rate of 79.7 ± 3.2 %. The maximum plasma ERL concentrations, half life period, and area under the curve of HA-ERL/BEV-LPH NPs were 21.6 μg/mL, 7.57 h, and 290.3 mg/L·h). With the highest tumor tissue accumulation concentration (25.3 μg/mL) and low system toxicity, HA-ERL/BEV-LPH NPs. HA-ERL/BEV-LPH NPs could be used as a promising system for the combination therapy of NSCLC.

The three-dimensional flower-like Bi2WO6 was synthesized through a one-step microwave method (the reaction temperature was 434 K and the reaction took 10 min) with the assistance of ethanolamine (EA). The prepared samples were characterized by X-ray diffraction, scanning electron microscopy, Fourier-transform infrared spectroscopy, ultraviolet–visible spectroscopy, PL, X-ray photoelectron spectroscopy and Brunauer–Emmett–Teller analysis. Methyl orange was used as target pollutant to evaluate the photocatalysis property of samples. Furthermore, the influence of the mechanism of EA on the structure and catalytic performance of Bi2WO6 was discussed. The detailed characterizations revealed that the three-dimensional flower-like Bi2WO6 was successfully synthesized with the assistance of EA. The results confirmed that EA significantly influenced the morphology of Bi2WO6 products. The addition of EA can effectively alter the pressure of the reaction and improve the crystal phase and structure of Bi2WO6 photocatalysts, enhancing the photocatalytic activity of samples and improving the photocatalytic efficiency. EA can serve as an assembling agent and structure-directing agent resulting in the formation of flower-like architectures. With the increase of the amount of EA, the as-prepared Bi2WO6 sample gradually forms a flower-like structure, leading to a shorter time of light holes migrating to the surface of the catalyst. It makes the compound rate significantly decreased, and improves the photocatalytic efficiency of the sample.

Background. To compare the survival of Chinese cirrhotic patients with hepatocellular carcinoma (HCC) ≤ 4 cm who underwent radiofrequency ablation (RFA) alone or a combination of RFA with percutaneous ethanol injection (PEI).Material and methods. Retrospective analysis was performed for 681 cases with HCC ≤ 4 cm who were treated with RFA alone or RFA combined with PEI (RFA + PEI) between 2004 and 2011.Results. As a result, 180 patients in each group were selected after propensity score matching (PSM). Higher overall survival (OS) and recurrence-free survival (RFS) rates were achieved by RFA + PEI compared with RFA alone (P = 0.019 and 0.009, respectively). The 1-, 3-, and 5-year cumulative OS rates were 78.0, 44.4, and 30.1% for patients in RFA group and 88.2, 58.0, and 41.1% for patients in RFA + PEI group, respectively. Besides, the 1-, 3-, and 5-year cumulative RFS rates were 77.0, 43.8, and 29.2% in RFA group, and 87.9, 57.6, and 38.4% in RFA + PEI group, respectively. The local recurrence, complete ablation and five-year mortality showed no distinct differences between RFA and RFA + PEI groups in three subgroups classified with tumor size. Moreover, Cox regression multivariate analysis results showed that sex and treatment approach were significantly related to OS, whereas sex, status of HBsAg, local recurrence, and number of tumor nodule were related to RFS.Conclusion. Therefore, the combination of RFA and PEI yielded better OS and RFS rates than RFA alone for Chinese patients with HCC ≤ 4 cm.

To reduce the high risk of radiation toxicity and enhance the quality of life of patients with non-small cell lung cancer (NSCLC), we quantified the metabolic tumor volumes (MTVs) from baseline to the late-course of radiotherapy (RT) by fluorodeoxyglucose positron emission tomography computerized tomography (FDG PET-CT) and discussed the potential benefit of late-course adaptive plans rather than original plans by dose volume histogram (DVH) comparisons. Seventeen patients with stage II-III NSCLC who were treated with definitive conventionally fractionated RT were eligible for this prospective study. FDG PET-CT scans were acquired within 1 week before RT (pre-RT) and at approximately two-thirds of the total dose during-RT (approximately 40 Gy). MTVs were taken as gross tumor volumes (GTVs) that included the primary tumor and any involved hilar or mediastinal lymph nodes. An original plan based on the baseline MTVs and adaptive plans based on observations during-RT MTVs were generated for each patient. The DVHs for lung, heart, esophagus and spinal cord were compared between the original plans and composite plans at 66 Gy. At the time of approximately 40 Gy during-RT, MTVs were significantly reduced in patients with NSCLC (pre-RT 136.2±82.3 ml vs. during-RT 64.7±68.0 ml, p = 0.001). The composite plan of the original plan at 40 Gy plus the adaptive plan at 26 Gy resulted in better DVHs for all the organs at risk that were evaluated compared to the original plan at 66 Gy (p

This is a clinical study to compare noninvasive hypoxia imaging using 18F-fluoroerythronitroimidazole (18F-FETNIM) and 18F-fluoromisonidazole (18F-FMISO) positron emission tomography/computed tomography (PET/CT) in patients with inoperable stages III-IV lung cancer.A total of forty-two patients with inoperable stages III-IV lung cancer underwent 18F-FETNIM PET/CT (n = 18) and 18F-FMISO PET/CT (n = 24) before chemo/radiation therapy. The standard uptake values (SUVs) of malignant and normal tissues depict 18F-FETNIM PET/CT and 18F-FMISO PET/CT uptake. Tumor-to-blood ratios (T/B) were used to quantify hypoxia.All patients with lung cancer underwent 18F-FETNIM PET/CT and 18F-FMISO PET/CT successfully. Compared to 18F-FMISO, 18F-FETNIM showed similar uptake in muscle, thyroid, spleen, pancreas, heart, lung and different uptake in blood, liver, and kidney. Significantly higher SUV and T/B ratio with 18F-FMISO (2.56±0.77, 1.98±0.54), as compared to 18F-FETNIM (2.12±0.56, 1.42±0.33) were seen in tumor, P = 0.022, 5cm groups in 18F-FMISO PET/CT, P = 0.015 (or P = 0.029), whereas no difference was detected in 18F-FMISO PET/CT, P = 0.446 (or P = 0.707). Both 18F-FETNIM and 18F-FMISO showed significantly higher SUVs (or T/B ratios) in stage IV than stage III, P = 0.021, 0.013 (or P = 0.032, 0.02).18F-FMISO showed significantly higher uptake than 18F-FETNIM in tumor/non-tumor ratio and might be a better hypoxia tracer in lung cancer.

To explore the value of a new simple lyophilized kit for labeling PRGD2 peptide (18F-ALF-NOTA-PRGD2, denoted as 18F-alfatide) in the determination of metabolic tumor volume (MTV) with micro-PET in lewis lung carcinoma (LLC) tumor-bearing C57BL/6 mice verified by pathologic examination and compared with those using 18F-fluorodeoxyglucose (FDG) PET.All LLC tumor-bearing C57BL/6 mice underwent two attenuation-corrected whole-body micro-PET scans with the radiotracers 18F-alfatide and 18F-FDG within two days. 18F-alfatide metabolic tumor volume (VRGD) and 18F-FDG metabolic tumor volume (VFDG) were manually delineated slice by slice on PET images. Pathologic tumor volume (VPath) was measured in vitro after the xenografts were removed.A total of 37 mice with NSCLC xenografts were enrolled and 33 of them underwent 18F-alfatide PET, and 35 of them underwent 18F-FDG PET and all underwent pathological examination. The mean ± standard deviation of VPath, VRGD, and VFDG were 0.59±0.32 cm3 (range,0.13~1.64 cm3), 0.61±0.37 cm3 (range,0.15~1.86 cm3), and 1.24±0.53 cm3 (range,0.17~2.20 cm3), respectively. VPath vs. VRGD, VPath vs. VFDG, and VRGD vs. VFDG comparisons were t = -0.145, P = 0.885, t = -6.239, P

Twist1 and Twist2 are highly homologous bHLH transcription factors that exhibit extensive highly overlapping expression profiles during development. While both proteins have been shown to inhibit osteogenesis, only Twist1 haploinsufficiency is associated with the premature synostosis of cranial sutures in mice and humans. On the other hand, biallelic Twist2 deficiency causes only a focal facial dermal dysplasia syndrome or additional cachexia and perinatal lethality in certain mouse strains. It is unclear how these proteins cooperate to synergistically regulate bone formation.Twist1 floxed mice (Twist1(f/f)) were bred with Twist2-Cre knock-in mice (Twist2(Cre/+)) to generate Twist1 and Twist2 haploinsufficient mice (Twist1(f/+); Twist2(Cre/+)). X-radiography, micro-CT scans, alcian blue/alizarin red staining, trap staining, BrdU labeling, immunohistochemistry, in situ hybridizations, real-time PCR and dual luciferase assay were employed to investigate the overall skeletal defects and the bone-associated molecular and cellular changes of Twist1(f/+);Twist2(Cre/+) mice.Twist1 and Twist2 haploinsufficient mice did not present with premature ossification and craniosynostosis; instead they displayed reduced bone formation, impaired proliferation and differentiation of osteoprogenitors. These mice exhibited decreased expressions of Fgf2 and Fgfr1-4 in bone, resulting in a down-regulation of FGF signaling. Furthermore, in vitro studies indicated that both Twist1 and Twist2 stimulated 4.9 kb Fgfr2 promoter activity in the presence of E12, a Twist binding partner.These data demonstrated that Twist1- and Twist2-haploinsufficiency caused reduced bone formation due to compromised FGF signaling.

Family with sequence similarity 20,-member C (FAM20C) is highly expressed in the mineralized tissues of mammals. Genetic studies showed that the loss-of-function mutations in FAM20C were associated with human lethal osteosclerotic bone dysplasia (Raine Syndrome), implying an inhibitory role of this molecule in bone formation. However, in vitro gain- and loss-of-function studies suggested that FAM20C promotes the differentiation and mineralization of mouse mesenchymal cells and odontoblasts. Recently, we generated Fam20c conditional knockout (cKO) mice in which Fam20c was globally inactivated (by crossbreeding with Sox2-Cre mice) or inactivated specifically in the mineralized tissues (by crossbreeding with 3.6 kb Col 1a1-Cre mice). Fam20c transgenic mice were also generated and crossbred with Fam20c cKO mice to introduce the transgene in the knockout background. In vitro gain- and loss-of-function were examined by adding recombinant FAM20C to MC3T3-E1 cells and by lentiviral shRNA-mediated knockdown of FAM20C in human and mouse osteogenic cell lines. Surprisingly, both the global and mineralized tissue-specific cKO mice developed hypophosphatemic rickets (but not osteosclerosis), along with a significant downregulation of osteoblast differentiation markers and a dramatic elevation of fibroblast growth factor 23 (FGF23) in the serum and bone. The mice expressing the Fam20c transgene in the wild-type background showed no abnormalities, while the expression of the Fam20c transgene fully rescued the skeletal defects in the cKO mice. Recombinant FAM20C promoted the differentiation and mineralization of MC3T3-E1 cells. Knockdown of FAM20C led to a remarkable downregulation of DMP1, along with a significant upregulation of FGF23 in both human and mouse osteogenic cell lines. These results indicate that FAM20C is a bone formation "promoter" but not an "inhibitor" in mouse osteogenesis. We conclude that FAM20C may regulate osteogenesis through its direct role in facilitating osteoblast differentiation and its systemic regulation of phosphate homeostasis via the mediation of FGF23.