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Abstract BAP1, BRCA1-Associated Protein 1, serves as a novel tumor suppressor through the deubiquitination of monoubiquitination of H2A and subsequent gene transcriptional regulation. Regulated cell death like apoptosis or ferroptosis is considered an essential mechanism mediating tumor suppression. Previous reports, including ours, have demonstrated that BAP1 could promote apoptosis and ferroptosis to inhibit tumor development. Whether BAP1 regulated additional types of cell death remains unclear. Disulfidptosis is a recently identified novel cell death mode characterized by aberrant accumulation of intracellular disulfide (e.g., cystine) and depletion of NADPH. In this study, we first demonstrated that BAP1 could significantly protect disulfidptosis induced by glucose starvation, which is validated by various cell death inhibitors and the accumulation of disulfide bonds in the cytoskeleton proteins. BAP1 is known to inhibit SLC7A11 expression. We found that the protective effect of BAP1 against disulfidptosis was counteracted when overexpressing SLC7A11 or adding additional cystine. Conversely, BAP1-mediated suppression of disulfidptosis was largely abrogated when SLC7A11-mediated cystine uptake was inhibited by the knockout of SLC7A11 or erastin treatment. Besides, high BAP1 expression showed lower NADP+/NADPH levels, which might confer resistance to disulfidptosis. Consistent with these observations, the expression level of BAP1 was also positively correlated with NADPH-related genes in KIRC patients, though the underlying mechanism mediating NADPH regulation remains further investigation. In summary, our results revealed the role of BAP1 in the regulation disulfidptosis and provided new insights into the understanding of disulfidptosis in tumor development.

BackgroundThe mpox pandemic has caused widespread public concern around the world. The spread of misinformation through the internet and social media could lead to an infodemic that poses challenges to mpox control. ObjectiveThis review aims to summarize mpox-related infodemiology studies to determine the characteristics, influence, prevention, and control measures of the mpox infodemic and propose prospects for future research. MethodsThe scoping review was conducted based on a structured 5-step methodological framework. A comprehensive search for mpox-related infodemiology studies was performed using PubMed, Web of Science, Embase, and Scopus, with searches completed by April 30, 2024. After study selection and data extraction, the main topics of the mpox infodemic were categorized and summarized in 4 aspects, including a trend analysis of online information search volume, content topics of mpox-related online posts and comments, emotional and sentiment characteristics of online content, and prevention and control measures for the mpox infodemic. ResultsA total of 1607 articles were retrieved from the databases according to the keywords, and 61 studies were included in the final analysis. After the World Health Organization’s declaration of an mpox public health emergency of international concern in July 2022, the number of related studies began growing rapidly. Google was the most widely used search engine platform (9/61, 15%), and Twitter was the most used social media app (32/61, 52%) for researchers. Researchers from 33 countries were concerned about mpox infodemic–related topics. Among them, the top 3 countries for article publication were the United States (27 studies), India (9 studies), and the United Kingdom (7 studies). Studies of online information search trends showed that mpox-related online search volume skyrocketed at the beginning of the mpox outbreak, especially when the World Health Organization provided important declarations. There was a large amount of misinformation with negative sentiment and discriminatory and hostile content against gay, bisexual, and other men who have sex with men. Given the characteristics of the mpox infodemic, the studies provided several positive prevention and control measures, including the timely and active publishing of professional, high-quality, and easy-to-understand information online; strengthening surveillance and early warning for the infodemic based on internet data; and taking measures to protect key populations from the harm of the mpox infodemic. ConclusionsThis comprehensive summary of evidence from previous mpox infodemiology studies is valuable for understanding the characteristics of the mpox infodemic and for formulating prevention and control measures. It is essential for researchers and policy makers to establish prediction and early warning approaches and targeted intervention methods for dealing with the mpox infodemic in the future.

Abstract Background Hepatocellular carcinoma (HCC) is a prevalent malignant tumor that poses a major threat to people’s lives and health. Previous studies have found that multiple deubiquitinating enzymes are involved in the pathogenesis of HCC. The purpose of this work was to elucidate the function and mechanism of the deubiquitinating enzyme USP40 in HCC progression. Methods The expression of USP40 in human HCC tissues and HCC cell lines was investigated using RT-qPCR, western blotting and immunohistochemistry (IHC). Both in vitro and in vivo experiments were conducted to determine the crucial role of USP40 in HCC progression. The interaction between USP40 and Claudin1 was identified by immunofluorescence, co-immunoprecipitation and ubiquitination assays. Results We discovered that USP40 is elevated in HCC tissues and predicts poor prognosis in HCC patients. USP40 knockdown inhibits HCC cell proliferation, migration and stemness, whereas USP40 overexpression shows the opposite impact. Furthermore, we confirmed that Claudin1 is a downstream gene of USP40. Mechanistically, USP40 interacts with Claudin1 and inhibits its polyubiquitination to stabilize Claudin1 protein. Conclusions Our study reveals that USP40 enhances HCC malignant development by deubiquitinating and stabilizing Claudin1, suggesting that targeting USP40 may be a novel approach for HCC therapy.

Abstract Background Hepatic ischemia-reperfusion injury (HIRI) is a pathophysiological process during liver transplantation, characterized by insufficient oxygen supply and subsequent restoration of blood flow leading to an overproduction of reactive oxygen species (ROS), which in turn activates the inflammatory response and leads to cellular damage. Therefore, reducing excess ROS production in the hepatic microenvironment would provide an effective way to mitigate oxidative stress injury and apoptosis during HIRI. Nanozymes with outstanding free radical scavenging activities have aroused great interest and enthusiasm in oxidative stress treatment. Results We previously demonstrated that carbon-dots (C-dots) nanozymes with SOD-like activity could serve as free radicals scavengers. Herein, we proposed that C-dots could protect the liver from ROS-mediated inflammatory responses and apoptosis in HIRI, thereby improving the therapeutic effect. We demonstrated that C-dots with anti-oxidative stress and anti-inflammatory properties improved the survival of L-02 cells under H2O2 and LPS-treated conditions. In the animal model, Our results showed that the impregnation of C-dots could effectively scavenge ROS and reduce the expression of inflammatory cytokines, such as IL-1β, IL-6, IL-12, and TNF-α, resulting in a profound therapeutic effect in the HIRI. To reveal the potential therapeutic mechanism, transcriptome sequencing was performed and the relevant genes were validated, showing that the C-dots exert hepatoprotective effects by modulating the hepatic inflammatory network and inhibiting apoptosis. Conclusions With negligible systemic toxicity, our findings substantiate the potential of C-dots as a therapeutic approach for HIRI, thereby offering a promising intervention strategy for clinical implementation.

Abstract Background The aim of this study was to review clinical features of adolescent malignant germ cell tumors (MGCTs) in Beijing and analyze the peculiar characteristics of this age group. Methods Clinical characteristics, pathological presentations, and survival outcomes of 34 patients were analyzed retrospectively. Results Of 34 patients, 12 girls and 22 boys, 18 (52.9%) had an extra‐cranial tumor, including one testicular tumor, five ovarian tumors, one sacrococcygeal tumor, and 11 mediastinal tumors. Histologically, we found immature teratomas (n = 6), yolk sac tumors (n = 5), mixed malignant tumors (n = 5), an embryonic carcinoma (n = 1), and seminoma (n = 1). Three‐year event‐free survival (EFS) and overall survival (OS) were 48.8% and 62.9%, respectively. Another 16 (47.1%) patients had an intracranial tumor, including nine in the pineal region, five in the suprasellar region, one in basal ganglia, and one in cerebellopontine. All patients had localized disease and an excellent outcome with 3‐year EFS and OS of 93.7% and 100%, respectively. Conclusions Adolescent MGCTs are rare with a strong dependence on gender, and the mediastina and pineal region are the most common tumor locations. The prognosis is promising compared with that of other adolescent tumors and MGCTs in other age groups. MGCTs in mediastina have a tendency to companion with other hematological malignancies, and the prognosis is extremely poor in these patients.

Background Chronic obstructive pulmonary disease (COPD) and hyperuricaemia are both characterised by systemic inflammation. Preventing chronic diseases among the population with common metabolic abnormality is an effective strategy. However, the association of hyperuricaemia with the higher incidence and risk of COPD remains controversial. Therefore, replicated researches in populations with distinct characteristics or demographics are compellingly warranted.Methods This cohort study adopted a design of ambispective hospital-based cohort. We used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to minimise the effects of potential confounding factors. A Cox regression model and restricted cubic spline (RCS) model were applied further to assess the effect of serum urate on the risk of developing COPD. Finally, we conducted a two-sample Mendelian randomisation (MR) analysis to explore evidence of causal association.Results There is a higher incidence in the population with hyperuricaemia compared with the population with normal serum urate (22.29/1000 person-years vs 8.89/1000 person-years, p=0.009). This result is robust after performing PSM (p=0.013) and IPTW (p

Abstract Background The immune microenvironment within hepatocellular carcinoma (HCC) is remarkably intricate. Although the combination of an immune checkpoint inhibitor and Lenvatinib can extend the overall survival of HCC patients, the outcome remains suboptimal. Methods We assessed alterations in MEX3C expression during hepatocarcinogenesis by validating multiple databases and subsequently developed a predictive model. Subsequently, we enriched the associated genes of MEX3C to investigate its functional role. We examined the correlation between MEX3C expression levels and immune infiltrating cells. The effects of MEX3C knockdown and Lenvatinib on hepatoma cells were observed by cell function experiments. Results MEX3C expression is elevated in HCC compared to normal tissues, and its high expression correlates with poor prognosis. Immune checkpoint expression was elevated in the high MEX3C expression group, concomitant with heightened myeloid-derived suppressor cell (MDSC) expression. The combination of MEX3C knockdown and Lenvatinib demonstrated a stronger inhibitory effect on HCC cells compared to Lenvatinib alone. Conclusion MEX3C shows promise as a potential therapeutic target for treating HCC. Furthermore, the combination of MEX3C knockdown and Lenvatinib could offer a novel therapeutic avenue for HCC treatment.

ObjectivesThe study aims to analyze factors that affect the postoperative health-related quality of life (HRQOL) of degenerative lumbar scoliosis (DLS) patients and explore the appropriate pelvic incidence minus lumbar lordosis (PI-LL) value for Chinese DLS patients.MethodsDLS patients who met the inclusion and exclusion criteria were included in this study. General information, spino-pelvic parameters, and HRQOL were collected. Correlation analysis was used to explore the spino-pelvic parameters that affect the postoperative HRQOL. Thresholds of each parameter were obtained using the receiver operating characteristic (ROC) curve. Regardless of the effect of age, DLS patients were classified into three groups according to the SRS-Schwab classification: group 0 means PI-LL 20°. Postoperative HRQOL was analyzed using variance methods. The ROC curve was used to measure the appropriate PI-LL threshold. When considering the effect of age, the patients with Oswestry Disability Index (ODI) 0.8, postoperative sagittal vertical axis (SVA) ≤ 5 cm, postoperative T1 pelvic angle (TPA) ≤ 16° and postoperative global tilt (GT) ≤ 22°, respectively. Regardless of the effect of age, there was a statistical difference in postoperative HRQOL between group 0 and group ++. The PI-LL threshold derived from the ROC curve was 14.4°. Compared with the PI-LL > 14° group, the PI-LL ≤ 14° group achieved a lower postoperative ODI score and a higher postoperative SRS-22 score. Considering the influence of age, the equation for ideal PI-LL was PI-LL = 0.52age + 0.38PI-39.4 (R = 0.509, p = 0.001).ConclusionsPI-LL was an important parameter that affects the postoperative HRQOL of DLS patients. Sufficient LL should be restored during the operation (LL ≥ PI-14°). The appropriate PI-LL value was affected by age. Smaller LL needed to be restored as the age increased.

ABSTRACTObjectives There is no meta-analysis about the effects of pegfilgrastim on the occurrence of febrile neutropenia (FN) in pediatric/adolescent cancer patients. The study explored the efficacy of prophylactic pegfilgrastim in preventing FN in children/adolescents with cancer.Methods PubMed, Embase, and the Cochrane Library were searched for studies published before April 7, 2020. The primary outcome was the rate of FN. Effect size (ES) and odds ratio (OR) with 95% confidence intervals (CIs) were used to evaluate the outcome. The ES represented the rate of FN, and the STATA ‘metaprop’ command was used to synthesize the rate.Results Eight studies were included, comprising 167 patients and 550 courses of treatment. There was no difference between pegfilgrastim and filgrastim for the rate of FN in children receiving chemotherapy (OR = 0.68, 95% CI: 0.20–2.23, P = 0.520). In patients receiving pegfilgrastim, the rate of FN was 25.6% (95% CI: 14.9%−36.3%), the rate of grade 4 FN was 38.3% (95% CI: 19.2%−59.5%), the rate of severe neutropenia (SN) was 40.5% (95% CI: 35.1%−46.1%), and the rate of treatment delays due to FN was 4.8% (95% CI: 0.8%−11.3%).Discussion The number of studies that could be included was small; therefore, a specific type of cancer or a specific treatment could be studied. Heterogeneity was high.Conclusion There was no difference between pegfilgrastim and filgrastim for the rate of FN. The use of pegfilgrastim was still associated with rates of FN, grade 4 FN, severe neutropenia, and treatment delays due to FN in pediatric cancer patients.

Abstract Background To summarize the characteristics and treatment, and analyze the prognosis of large number of infants with retinoblastoma (RB) in China through a multicenter, 10-year retrospective analysis. Methods The data of RB infants were collected from multiple centers. The characteristics and survival prognosis were analyzed. The overall survival (OS) rate was estimated by the Kaplan–Meier method. Multivariate Cox survival analysis was to evaluate the independent risk factors affecting the prognosis of RB infants. Results A total of 373 RB infants (202 boys and 171 girls) were included, the median age was 6.22 months (10 days to 11.93 months). The median follow-up time of RB infants was 18.4 (1.02–122.81 months). After excluding the lost to follow-up cases, the OS rate was 97.7% (345/353). Kaplan–Meier survival analysis indicated that 9 cases died and the median survival time was not reached. Univariate analysis of prognostic factors revealed eye affected, presenting signs, left eye stage and recurrence to be poor prognostic factors for OS rate in RB infants (all P

Background: Gastric cancer (GC) is frequently diagnosed at advanced stages, when cancer cells have already metastasized. Therefore, patients with GC have a low survival rate and poor prognosis even after treatment. Methods: We downloaded GC-related RNA sequencing (RNA-Seq) data, copy number variation (CNV) data, and clinical data for bioinformatics analysis to screen prognostic genes of GC. Single-sample gene set enrichment analysis and survival analyses were performed on the RNA-Seq data, and differential and correlation analyses were conducted on the CNV data to obtain CNV-driven differentially expressed genes (DEGs). Prognostic genes were identified through univariate Cox analyses of the CNV-driven DEGs, combined with the clinical data. F2R like thrombin or trypsin receptor 3 (F2RL3) was finally selected for verification after functional and survival analyses of the prognostic genes. Results: F2RL3 expression was lower in paracancer tissue than in GC tissue, and lower in GES-1 gastric epithelial cells than in GC cells. The cell culture supernatants from F2RL3-knockdown GC cells were collected and used to culture human umbilical vein endothelial cells (HUVECs). It was observed that F2RL3 enhanced the activity, metastasis, invasion, and angiogenesis of GC cells; promoted the epithelial–mesenchymal transition (EMT) of GC cells; and impacted the Ras-associated protein 1 (Rap1)/mitogen-activated protein kinase (MAPK) pathway. To further explore the involvement of the Rap1/MAPK pathway in GC development, a pathway activator was added to GC cells with knockdown of F2RL3 expression. This pathway activator not only enhanced the activity, invasion, and migration of GC cells but also promoted the EMT and blood vessel formation. Conclusions: F2RL3 regulates the angiogenesis and EMT of GC cells through the Rap1/MAPK pathway, thus influencing the onset and progression of GC.

Objective: COPD is the most common chronic respiratory disease with complex environmental and genetic etiologies. It was reported that EPAS1 might participate in the occurrence and development of respiratory diseases. However, the association between EPAS1 and COPD was unclear. Methods: First, a case-control study enrolling 1130 COPD patients and 1115 healthy controls in Guangzhou was conducted to clarify the association between EPAS1 polymorphisms and COPD susceptibility. Secondly, a prevalence study recruited 882 participants in Gansu to verify the effect of positive polymorphisms on lung function. Finally, the 10-year absolute risk considering environmental factors and genetic variations was calculated by the method of Gail and Bruzzi. Results: EPAS1 rs13419896 AA genotype reduced COPD risk in southern Chinese (AA vs. GG: adjusted OR = 0.689, 95% CI = 0.498–0.955; AA vs. GG/GA: adjusted OR = 0.701, 95% CI = 0.511–0.962). Further, the rs13419896 A allele was significantly associated with higher pre-FEV1/pre-FVC in both the Guangzhou and Gansu populations (P A were finally retained to develop a relative risk model for males. Smoking status, biomass as fuels, and rs13419896 G > A were retained in the female model. The population-attributable risk of the male or female model was 0.457 (0.283–0.632) and 0.421 (0.227–0.616), respectively. Conclusions: This study first revealed that EPAS1 rs13419896 G > A decreased COPD susceptibility and could be a genetic marker to predict the 10-year absolute risk for COPD.

Abstract Background Mesenchymal stem cells (MSCs) possess the potential to differentiate into chondrocytes, which makes them an ideal source for healing cartilage defects. Here, we seek to identify the essential genes participating in MSCs chondrogenesis. Methods Human MSCs were induced for chondrogenesis for 7, 14, and 21 days using a high-density micromass culture system, and RNA was extracted for RNA-seq. Results A total of 6247 differentially expressed genes (DEGs) were identified on day 7, and 85 DEGs were identified on day 14. However, no significant DEGs was identified on day 21. The top 30 DEGs at day 7, including COL9A3, COL10A1, and CILP2, are closely related to extracellular matrix organization. While the top 30 DEGs at day 14 revealed that inflammation-related genes were enriched, including CXCL8, TLR2, and CCL20. We also conducted protein–protein interaction (PPI) networks analysis using the search tool for the retrieval of interacting genes (STRING) database and identified key hub genes, including CXCL8, TLR2, CCL20, and MMP3. The transcriptional factors were also analyzed, identifying the top 5 TFs: LEF1, FOXO1, RORA, BHLHE41, and SOX5. We demonstrated one particular TF, RORA, in promoting early MSCs chondrogenesis. Conclusions Taken together, our results suggested that these DEGs may have a complex effect on MSCs chondrogenesis both synergistically and solitarily.

Abstract Background Human mesenchymal stem cells (hMSCs) have been proven to have inherent chondrogenic differentiation potential, which appears to be used in cartilage regeneration. Increasing evidence suggests that irisin enhances osteoblast differentiation of MSCs, but little is known about its potential on chondrogenic differentiation. Methods In the study, we investigated the effects of irisin on chondrogenic differentiation of hMSCs using a high-density pellet culture system. The cartilage pellets were evaluated by morphology, and the metabolism of cartilage matrix was detected by qPCR, western blot and immunohistochemistry. Next, RNA-seq was performed to explore the underlying mechanism. Furthermore, using the transduction of plasmid, miRNAs mimics and inhibitor, the activation of Rap1/PI3K/AKT axis, the expression level of SIPA1L2, and the functional verification of miR-125b-5p were detected on day 7 of chondrogenic differentiation of hMSCs. Results Compared with the controls, we found that irisin treatment could significantly enhance the chondrogenic differentiation of hMSCs, enlarge the induced-cartilage tissue and up-regulate the expression levels of cartilage markers. RNA-seq indicated that irisin activated the Rap1 and PI3K/AKT signaling pathway, and the lower expression level of SIPA1L2 and the higher expression level of miR-125b-5p were found in irisin-treated group. Further, we found that irisin treatment could up-regulate the expression level of miR-125b-5p, targeting SIPA1L2 and consequently activating the Rap1/PI3K/AKT axis on the process of chondrogenic differentiation of hMSCs. Conclusions Collectively, our study reveals that irisin can enhance chondrogenic differentiation of hMSCs via the Rap1/PI3K/AKT pathway, suggesting that irisin possesses prospects in cartilage regeneration.

BackgroundHepatocellular carcinoma (HCC) is a common malignant tumor associated with a poor prognosis. Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) has been reported to promote diverse tumors, but little is known about its role in HCC.MethodsExpression levels of UCHL3 in Huh7 and Hep3B cells were measured by qRT-PCR. UCHL3, Vimentin protein levels, and ubiquitination levels were determined by Western blot assay. co-immunoprecipitation, Immunofluorescence, and IHC were used to detect the interaction and expression association between UCHL3 and Vimentin in the cells. Wound healing and Transwell assays were used to measure cell migration. Spheroid formation assay were used to assess stem-like properties.ResultsUCHL3 expression was found to be significantly elevated in HCC and associated with poor prognosis. UCHL3 promoted migration and stem-like properties of HCC cells. Vimentin was identified as a potential de-ubiquitination substrate of UCHL3 and UCHL3 interacted with and promoted the de-ubiquitination of Vimentin, enhancing its stability. Moreover, the suppression of UCHL3 by siRNA or the inhibition by TCID upregulated ubiquitinated Vimentin. Vimentin attenuated the suppression of cell migration caused by knockdown of UCHL3.ConclusionUCHL3 was highly expressed in HCC and functioned as an oncogene. Vimentin is a novel substrate of UCHL3 and its stabilization and de-ubiquitination enhanced HCC cell migration.

BackgroundChronic Obstructive Pulmonary Disease (COPD) is a common and harmful disease that requires an effective tool to early screen high-risk individuals. Gansu has unique environments and customs, leading to the different prevalence and etiology of COPD from other regions. The association between altitude and COPD once attracted epidemiologists' attention. However, the prevalence in Gansu and the role of altitude are still unclarified.MethodsIn Gansu, a multistage stratified cluster sampling procedure was utilized to select a representative sample aged 40 years or older. The questionnaire and spirometry examination were implemented to collect participants' information. The diagnosis and assessment of COPD were identified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion, while post-bronchodilator FEV1/FVC < LLN was for sensitivity analysis. Furthermore, the effect of high altitude on COPD was evaluated by the logistic regression model after propensity score matching (PSM). Finally, the participants were randomly divided into training and validation sets. The training set was used to screen the relative factors and construct a nomogram which was further assessed by the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) in the two sets.ResultsThere were 2,486 eligible participants in the final analysis, of which 1,584 lived in low altitudes and 902 lived in high altitudes. Based on the GOLD criterion, the crude and standardized prevalences in Gansu were 20.4% (18.7–22.0) and 19.7% (17.9–21.6). After PSM, the logistic regression model indicated that high altitude increased COPD risk [PSM OR: 1.516 (1.162–1.978)]. Altitude, age, sex, history of tuberculosis, coal as fuel, and smoking status were reserved for developing a nomogram that demonstrated excellent discrimination, calibration, and clinical benefit in the two sets.ConclusionsCOPD has become a serious public health problem in Gansu. High altitude is a risk factor for COPD. The nomogram has satisfactory efficiency in screening high-risk individuals.

Abstract Background With the widespread use of the posterior surgery, more and more surgeons chose posterior surgery to treat thoracic and lumbar tuberculosis. But others still believed that the anterior surgery is more conducive to eradicating the lesions, and easier to place larger bone pieces for bone graft fusion. We compared the clinical and radiological outcomes of anterior and posterior surgical approaches and presented our views. Methods This study included 52 thoracic and lumbar tuberculosis patients at Sun Yat-sen Memorial Hospital from January 2010 to June 2018. All cases underwent radical debridement, nerve decompression, intervertebral bone graft fusion and internal fixation. Cases were divided into anterior group (24 cases) and posterior group (28 cases). Statistical analysis was used to compare the clinical effectiveness, radiological outcomes, complications and other related information. Results Patients in the anterior group and the posterior group were followed up for an average of 27.4 and 22.3 months, respectively. There were no statistically significant differences between groups in the preoperative, postoperative and last follow-up VAS score, ASIA grade and Cobb angle of local kyphosis. Moreover, there were no statistically significant differences in the improvement of neurological function, loss of kyphotic correction, total incidence of complications, operative time, intraoperative blood loss and hospital stay between the two groups (P > 0.05). But there was greater correction of kyphosis, earlier bone fusion, lower incidence of poor wound healing, less interference with the normal spine and less internal fixation consumables and medical cost in the anterior group (P

Background: The occurrence and development of chronic obstructive pulmonary disease (COPD) are regulated by environmental and genetic factors. In hypoxia, Erythropoietin (EPO) satisfies the body’s need for oxygen by promoting the production of red blood cells. Hypoxia was proven to be a common physiological condition in COPD progression and associated with many complications. Some studies have found that EPO is involved in the development of COPD. But the mechanism has not been fully proven. Methods: We conducted a case-control study enrolled 1095 COPD patients and 1144 healthy controls in Guangdong Province to evaluate the association between EPO polymorphisms (rs1617640 A>C, rs507392 A>G, rs564449 G>T) and COPD susceptibility. 872 participants from southern Gansu Province were recruited to verify the effect of EPO polymorphisms on lung function. Results: EPO rs1617640 C allele reduced COPD susceptibility in southern Chinese significantly (AC vs. AA: adjusted Odds ratio (OR) = 0.805, 95% CI = 0.669–0.969; AC+CC vs. AA: adjusted OR = 0.822, 95% CI = 0.689–0.980). However, there was no association between rs507392 A>G and rs564449 G>T polymorphisms and COPD susceptibility (p > 0.05). We further observed that the rs1617640 C allele was associated with higher FEV1 and FVC in Guangdong and Gansu populations significantly (both p < 0.05). In brief, the level of FEV1 and FVC increased with the C allele number. We modeled the relative risk for men and women, in which the population-attributable risks chances were 0.449 (0.258–0.641) and 0.262 (0.128–0.396) respectively. In this model, smoking status, coal as fuels, education level, and rs1617640 A>C were finally retained for males, while smoking status, biomass as fuels, and1617640 A>C were retained for females. In the end, using the method developed by Gail and Bruzzi, we fitted a 10-year absolute risk model for southern Chinese with different individual relative risks, which was presented as a table. Conclusions: In conclusion, this study found that EPO rs1617640 A>C polymorphism is associated with COPD susceptibility in southern Chinese, and the C allele was associated with better lung function. In addition, it could also be considered a genetic marker associated with environmental factors to predict the absolute 10-year risk of COPD in southern Chinese.

Parkin, an E3 ubiquitin ligase, plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level, but the underlying mechanism is poorly understood. Here, our study demonstrated that inhibition of histone deacetylase (HDAC) by treatment of HDACis activates mitophagy through mediating Parkin acetylation, leading to inhibition of cervical cancer cell proliferation. Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer, indicating the low acetylation level of Parkin. Using mass spectrometry, Parkin is identified to interact with two upstream molecules, acetylase acetyl-CoA acetyltransferase 1 (ACAT1) and deacetylase HDAC2. Under treatment of suberoylanilide hydroxamic acid (SAHA), Parkin is acetylated at lysine residues 129, 220 and 349, located in different domains of Parkin protein. In in vitro experiments, combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1 (PINK1) and the function of Parkin in mitophagy induction and tumor suppression. In tumor xenografts, the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA. Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis, which offers a new mitophagy modulation strategy for cancer therapy.

Abstract Receptor-interacting protein kinase 3 (RIPK3) functions as a central regulator of necroptosis, mediating signaling transduction to activate pseudokinase mixed lineage kinase domain-like protein (MLKL) phosphorylation. Increasing evidences show that RIPK3 contributes to the pathologies of inflammatory diseases including multiple sclerosis, infection and colitis. Here, we identified a novel small molecular compound Salt-inducible Kinases (SIKs) inhibitor HG-9-91-01 inhibiting necroptosis by targeting RIPK3 kinase activity. We found that SIKs inhibitor HG-9-91-01 could block TNF- or Toll-like receptors (TLRs)-mediated necroptosis independent of SIKs. We revealed that HG-9-91-01 dramatically decreased cellular activation of RIPK3 and MLKL. Meanwhile, HG-9-91-01 inhibited the association of RIPK3 with MLKL and oligomerization of downstream MLKL. Interestingly, we found that HG-9-91-01 also trigger RIPK3-RIPK1-caspase 1-caspase 8-dependent apoptosis, which activated cleavage of GSDME leading to its dependent pyroptosis. Mechanistic studies revealed that SIKs inhibitor HG-9-91-01 directly inhibited RIPK3 kinase activity to block necroptosis and interacted with RIPK3 and recruited RIPK1 to activate caspases leading to cleave GSDME. Importantly, mice pretreated with HG-9-91-01 showed resistance to TNF-induced systemic inflammatory response syndrome. Consistently, HG-9-91-01 treatment protected mice against Staphylococcus aureus-mediated lung damage through targeting RIPK3 kinase activity. Overall, our results revealed that SIKs inhibitor HG-9-91-01 is a novel inhibitor of RIPK3 kinase and a potential therapeutic target for the treatment of necroptosis-mediated inflammatory diseases.

Abstract Osteoarthritis (OA) is characterized by cartilage destruction, chronic inflammation, and local pain. Evidence showed that retinoic acid receptor-related orphan receptor-α (RORα) is crucial in cartilage development and OA pathogenesis. Here, we investigated the role and molecular mechanism of RORα, an important member of the nuclear receptor family, in regulating the development of OA pathologic features. Investigation into clinical cartilage specimens showed that RORα expression level is positively correlated with the severity of OA and cartilage damage. In an in vivo OA model induced by anterior crucial ligament transaction, intra-articular injection of si-Rora adenovirus reversed the cartilage damage. The expression of cartilage matrix components type II collagen and aggrecan were elevated upon RORα blockade. RNA-seq data suggested that the IL-6/STAT3 pathway is significantly downregulated, manifesting the reduced expression level of both IL-6 and phosphorylated STAT3. RORα exerted its effect on IL-6/STAT3 signaling in two different ways, including interaction with STAT3 and IL-6 promoter. Taken together, our findings indicated the pivotal role of the RORα/IL-6/STAT3 axis in OA progression and confirmed that RORα blockade improved the matrix catabolism in OA chondrocytes. These results may provide a potential treatment target in OA therapy.

Study DesignRetrospective analysis.ObjectiveTo evaluate bone quality and investigate asymmetrical development of the thoracic vertebral body in adolescent idiopathic scoliosis (AIS) based on Hounsfield unit (HU) measurements obtained from computed-tomography (CT) scans.Summary of Background DataHU value demonstrated higher reliability and accuracy than the traditional method, indicating that they could be used to individually evaluate and effectively assess the bone quality of every vertebra in the CT films.MethodsTotal 30 AIS patients classified as Lenke Type 1A and 30 paired controls were included in this study. Regions of interest for HU value were measured on three horizontal images of the thoracic vertebrae. HU measurements of the whole vertebral body in each vertebra were obtained. Using HU value, we separately measured the concave and convex sides of each vertebral body in patients' group, as well as within the left and right sides in controls.ResultsIn controls, the mean HU value of T1–T12 thoracic vertebral bodies was 240.03 ± 39.77, with no statistical differences among different levels. As for AIS patients, in the structural curve, the apical region had a significantly lower HU compared with the other regions, and asymmetrical change was found between the concave and convex sides, most significantly in the apical region. In the non-structural curve, the average HU value was 254.99 ± 44.48, and no significant difference was found either among the different levels of vertebrae or between the concave and convex sides.ConclusionsAbnormal and asymmetrical changes in bone quality of the thoracic vertebral body in patients with Lenke 1A AIS were indicated. Low bone quality in the convex side of the structural curve indicated stronger internal fixation in surgery to correct the deformity.

In most cancers, forkhead box N3 (FOXN3) acts as a transcriptional inhibitor to suppress tumor proliferation, but in pancreatic cancer, the opposite effect is observed. To confirm and investigate this phenomenon, FOXN3 expression in various carcinomas was determined using GEPIA2 and was found to be highly expressed in pancreatic cancer. Kaplan-Meier plotter was then used for survival analysis, revealing that high FOXN3 expression in pancreatic cancer might be associated with a poor prognosis. Similarly, clinical samples collected for immunohistochemical staining and survival analysis showed consistent results. The RNA-seq data of pancreatic cancer patients from the TCGA were then downloaded, and the differential expression gene set was obtained using R for gene set enrichment analysis (GSEA). The intersection of the above gene sets and FOXN3-related genes was defined as related differentially expressed gene sets (DEGs), and enrichment analysis was performed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, we analyzed the relationship between FOXN3 and immune infiltration in pancreatic cancer. Collectively, our findings reveal that FOXN3 is involved in the occurrence and progression of pancreatic cancer and may be useful as a prognostic tool in pancreatic cancer immunotherapy.

Regulation of ubiquitination is involved in various processes in cancer occurrence and development, including cell cycle arrest, cell proliferation, apoptosis, invasion, metastasis, and immunity. Ubiquitination plays an important role not only at the transcriptional and post-translational levels but also at the protein level. When ubiquitination is in a pathological state, abnormally activated biological processes will not only induce cancer progression but also induce immune evasion. The main function of deubiquitinases (DUBs) is to remove ubiquitin chains from substrates, changing the biological activity of the substrates. It has great potential to improve the prognosis of cancer by targeting DUB to regulate proteome. Ubiquitin-specific peptidase 22 (USP22) belongs to the ubiquitin-specific protease (USP) family of DUBs and has been reported to be related to various physiological and pathological processes. USP22 is abnormally expressed in various malignant tumors such as prostate cancer, lung cancer, liver cancer, and colorectal cancer, which suggests that USP22 may play an important role in tumors. USP22 may stabilize programmed death ligand 1 (PD-L1) by deubiquitination while also regulating T-cell infiltration into tumors. Regulatory T cells (Tregs) are a unique class of immunosuppressive CD4+ T cells that primarily suppress the immune system by expressing the master transcription factor forkhead box protein 3 (FOXP3). USP22 was found to be a positive regulator of stable FOXP3 expression. Treg-specific ablation of USP22 leads to reduced tumor volume in multiple cancer models. This suggests that USP22 may regulate tumor resistance to immunotherapy. In this article, we review and summarize the biological functions of USP22 in multiple signal transduction pathways during tumorigenesis, immune evasion, and drug resistance. Furthermore, we propose a new possibility of combining USP22 with chemotherapeutic, targeted, and immunosuppressive drugs in the treatment of cancer.

Immune rejection is the major limitation for porcine xenograft survival in primate recipients. Proinflammatory cytokines play important roles in immune rejection and have been found to mediate the pathological effects in various clinical and experimental transplantation trials. IL-17 and TNF-α play critical pathological roles in immune disorders, such as psoriasis and rheumatoid arthritis. However, the pathological roles of human IL-17 (hIL-17) and human TNF-α (hTNF-α) in xenotransplantation remain unclear. Here we found that hIL-17 and hTNF-α additively or synergistically regulate the expression of 697 genes in porcine aortic endothelial cells (PAECs). Overall, 415 genes were found to be synergistically regulated, while 282 genes were found to be additively regulated. Among these, 315 genes were upregulated and 382 genes were downregulated in PAECs. Furthermore, we found that hIL-17 and hTNF-α additively or synergistically induced the expression of various proinflammatory cytokines and chemokines (e.g., IL1α, IL6, and CXCL8) and decreased the expression of certain anti-inflammatory genes (e.g., IL10). Moreover, hIL-17 plus hTNF-α increased the expression of IL1R1 and IL6ST, receptors for IL1 and IL6, respectively, and decreased anti-inflammatory gene receptor expression (IL10R). hIL-17 and hTNF-α synergistically or additively induced CXCL8 and CCL2 expression and consequently promoted primary human neutrophil and human leukemia monocytic cell migration, respectively. In addition, hIL-17 and hTNF-α induced pro-coagulation gene (SERPINB2 and F3) expression and decreased anti-coagulation gene (TFPI, THBS1, and THBD) expression. Additionally, hIL-17 and hTNF-α synergistically decreased occludin expression and consequently promoted human antibody-mediated complement-dependent cytotoxicity. Interestingly, hTNF-α increased swine leukocyte antigen (SLA) class I expression; however, hIL-17 decreased TNF-α-mediated SLA-I upregulation. We concluded that hIL-17 and hTNF-α likely promote the inflammatory response, coagulation cascade, and xenoantibody-mediated cell injury. Thus, blockade of hIL-17 and hTNF-α together might be beneficial for xenograft survival in recipients.

Abstract Background To implement the “without the need for a second visit” (WNASV) initiative in our hospital by optimizing the outpatient clinic services via an upgraded information system, in order to increase the quality of outpatient medical services and improve patients’ satisfaction. Methods An Internet-based care delivery approach was developed and applied to improve the delivery of health care services, simplify the treatment process, and reduce patient waiting time. The patient waiting time and consultation time in the outpatient clinics of our hospital during the peak service intervals and the proportions of various payment methods for outpatient services during the period from May 2017 to September 2019 were retrospectively analyzed. Also, the patients’ satisfaction with the outpatient process was surveyed. Results The waiting time for consultation was shortened from 32.25 min to 28.42 min; the consultation time was shortened from 6.52 min to 3.15 min; and the waiting time for payment decreased from 7.40 min to 4.31 min. The proportion of payment via a counter was reduced from 86.80 to 21.79%, the proportion of self-service payment increased from 9.99 to 16.05%, and the proportion of payment during a consultation increased from 3.21 to 61.91%. The scores of the patients’ satisfaction with the outpatient services increased from an average of 89.10 points in 2017 to an average of 90.26 points in 2019. Conclusion The continuous improvement of the service process markedly increases the efficiency of the outpatient services, and effectively improves patient’s satisfaction with the outpatient process, this initiative thus deserves further application.

Abstract Background Little is known about the implications of circRNAs in the effects of melatonin (MEL) on bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoporosis (OP) progression. The aim of our study was to investigate circRNAs in MEL-regulated BMSC differentiation and OP progression. Methods BMSC osteogenic differentiation was measured by qRT-PCR, western blot (WB), Alizarin Red, and alkaline phosphatase (ALP) staining. Differential circRNA and mRNA profiles of BMSCs treated by MEL were characterized by deep sequencing, followed by validation using RT-PCR, Sanger sequencing, and qRT-PCR. Silencing and overexpression of circ_0003865 were conducted for functional investigations. The sponged microRNAs and targeted mRNAs were predicted by bioinformatics and validated by qRT-PCR, RNA pull-down, and dual-luciferase reporter assay. The function of miR-3653-3p and circ_0003865/miR-3653-3p/growth arrest-specific gene 1 (GAS1) cascade was validated for the osteogenic differentiation of BMSCs by CCK-8, qRT-PCR, WB, Alizarin Red, and ALP staining. The effects of circ_0003865 on OP development were tested in murine OP model. Results MEL promoted osteogenic differentiation of BMSCs. RNA sequencing revealed significant alterations in circRNA and mRNA profiles associated with multiple biological processes and signaling pathways. Circ_0003865 expression in BMSCs was significantly decreased by MEL treatment. Silencing of circ_0003865 had no effect on proliferation while promoted osteogenic differentiation of BMSCs. Overexpression of circ_0003865 abrogated the promotion of BMSC osteogenic differentiation induced by MEL, but proliferation of BMSCs induced by MEL had no change whether circ_0003865 was overexpression or not. Furthermore, circ_0003865 sponged miR-3653-3p to promote GAS1 expression in BMSCs. BMSC osteogenic differentiation was enhanced by miR-3653-3p overexpression while BMSC proliferation was not affected. By contrast, miR-3653-3p silencing mitigated the promoted BMSC osteogenic differentiation caused by circ_0003865 silencing, but had no effect on proliferation. Finally, circ_0003865 silencing repressed OP development in mouse model. Conclusion MEL promotes BMSC osteogenic differentiation and inhibits OP pathogenesis by suppressing the expression of circ_0003865, which regulates GAS1 gene expression via sponging miR-3653-3p.

Hypoxia microenvironment, a critical feature of hepatocellular carcinoma, contributes to hepatocarcinogenesis, tumor progression and therapeutic resistance. Hypoxia-inducible factors (HIFs)-activated target genes are the main effectors in hypoxia-induced HCC progression. In this study, we identified ubiquitin E3 ligase ring finger protein 146 (RNF146) as a novel HIFs target gene. Either HIF-1α or HIF-2α knockdown significantly repressed hypoxia-induced RNF146 upregulation in Hep3B and Huh7 cells. TCGA data and our immunohistochemistry analysis consistently revealed the overexpression of RNF146 in HCC tissues. The upregulated expression of RNF146 was also detected in HCC cell lines. The high RNF146 level was correlated with poor clinical features and predicted a shorter overall survival of patients with HCC. RNF146 knockdown suppressed the proliferation, colony formation and glycolysis of HCC cells, but suppressed but RNF146 overexpression promoted these malignant behaviors. Moreover, RNF146 silencing weakened HCC growth in mice. RNF146 inversely regulated phosphatase and tensin homolog (PTEN) protein level, thereby activating the AKT/mechanistic target of rapamycin kinase (mTOR) pathway in HCC cells. MG132 reversed RNF146 overexpression-induced PTEN reduction. RNF146 knockdown decreased the ubiquitination and degradation of PTEN in HCC cells. Therefore, we clarified that PTEN knockdown notably abolished the effects of RNF146 silencing on the AKT/mTOR pathway and Hep3B cells’ proliferation, colony formation and glycolysis. To conclude, our data confirmed that RNF146 was transcriptionally regulated by HIF-1/2α and activated the AKT/mTOR pathway by promoting the ubiquitin proteolysis of PTEN, thereby contributing to HCC progression. RNF146 may be a potential new drug target for anti-HCC.

Here we introduce a case of retroperitoneal liposarcoma, which is characterized by repeated recurrences after surgery, and has undergone a total of 6 operations. The diameter of the tumor was about 26 cm at the time of the patient's diagnosis. The imaging examination revealed that the surrounding organs and blood vessels were invaded, which brought great challenges to radical resection. The postoperative pathology of the patient’s first operation was dedifferentiated liposarcoma, and some areas showed myxofibrosarcoma differentiation. With the recurrence of sarcoma, myxofibrosarcoma dedifferentiated into rhabdomyosarcoma, and malignant fibrous histiocytoma appeared in some areas. How to treat this type of patient after recurrence? How to deal with blood vessels wrapped by sarcoma during surgery? The medical community has not yet reached the same conclusion. We describe the process of treating the patient and the experience of dealing with blood vessels during surgery.

Abstract Importance Cancer is the main cause of death by disease in children. Children experience the highest incidence of cancer in the first year of life. However, there is no comprehensive registration system for children with tumors in China. Objective To summarize the diagnosis and treatment of infant cancer and analyze the status of standardized diagnosis and management among several treatment centers in Beijing, China, thereby providing evidence to guide further clinical research. Methods From January 1, 2010 to December 31, 2019, patients with newly diagnosed infantile malignant solid tumors were admitted to six large tertiary pediatric solid tumor diagnosis and treatment centers in Beijing. The epidemiology, clinical features, and therapeutic effects of tumors in these patients were analyzed retrospectively. All patients were followed up until March 31, 2020. Results In total, 938 patients were enrolled in this study. There were 530 boys (56.5%) and 408 girls (43.5%); the median age was 6.0 months (range, 0–12.0 months). The three most common tumors were retinoblastoma in 366 patients (39.0%), neuroblastoma in 266 patients (28.4%), hepatoblastoma in 133 patients (14.2%), and central nervous system tumors in 52 patients (5.5%). The estimated 5‐year overall survival rate was 81.3% ± 1.8%, and the 5‐year event‐free survival rate was 71.8% ± 2.9%. The 5‐year overall survival rates of non‐rhabdomyosarcoma soft tissue sarcoma, neuroblastoma, and retinoblastoma were 100%, 88% ± 2.2%, and 86.9% ±2.1%, respectively. The 5‐year event‐free survival rates were 81.1% ± 2.7% for neuroblastoma, 81.6% ± 9.8% for non‐rhabdomyosarcoma soft tissue sarcoma, and 72.7% ± 14.1% for extracranial malignant germ cell tumors. Interpretation The three most common infantile malignant solid tumors were retinoblastoma, neuroblastoma, and hepatoblastoma. Multidisciplinary combined diagnosis and treatment is needed for infantile tumors.

Abstract Background The purpose of this study is to analyze the influence of radiation therapy on survival in a historical cohort of 56 pediatric patients with head and neck rhabdomyosarcoma. Methods A historical cohort of 56 pediatric patients with head and neck rhabdomyosarcoma from June 1st, 2013 to June 30th, 2019 was chosen. Clinical data and follow up results were collected including all diagnosis, treatment and prognosis information. Overall survival (OS) and event free survival (EFS) as time-to-event distributions were estimated with Kaplan-Meier method, and univariate analysis was performed with log rank test to detect differences between groups. Multivariate analysis was performed to explore the risk factors for survival with Cox proportional hazard model. Results The media follow up time of all 56 patients was 31.8 months (range 3.5–74.6 months). There were 26 events during follow up, including 14 disease progressions and 12 relapses. The estimated 5-year OS of all patients was 69.9%, and the estimated 5-year EFS was 48.8%. Patients with radiation therapy as a component of the initial treatment plan had better 5-year OS and EFS compared with those without radiation therapy (OS 80.3% vs. 49.7%, p = 0.003 and EFS 63.9% vs. 21.9%, p 5 cm and non-initial radiation therapy were independent risk factors for OS in all patients, non-initial radiation therapy was an independent risk factor for EFS in all patients, and tumor size > 5 cm was an independent risk factor for OS in patients with events. Conclusions Radiation therapy as a component of initial treatment can improve the OS and EFS in pediatric head and neck rhabdomyosarcoma patients by enhancing local control, and non-initial radiation therapy is an independent risk factor for OS and EFS. Salvage radiation therapy still can improve OS in patients with disease progression and relapse. Tumor size > 5 cm is an independent risk factor for OS in pediatric HNRMS patients with or without disease progression/relapse.

To evaluate the short-term prognosis of pediatric hepatoblastoma (HB) in relation to excision repair cross-complementation gene 1 (ERCC1) C118T single nucleotide polymorphism (SNP) and VEGF expression. ERCC1 C118T SNP and VEGF expression were detected and investigated in 31 children with HB undergoing platinum-based chemotherapy, to analyze their relationship with short-term pediatric HB prognosis. CC (38.7%; 12/31), CT (35.5%; 11/31), and TT (25.8%; 8/31) ERCC1 C118T mutation types were identified. The Kaplan-Meier survival curve analysis showed that the CC group had a better short-term prognosis than the CT + TT group (p = 0.010). VEGF was overexpressed in 14 cases (45.2%) and underexpressed in 17 cases (54.8%). The Kaplan-Meier survival curve analysis showed that the high VEGF expression group showed poorer short-term prognosis than the lower VEGF expression group (p = 0.004). In this study, ERCC1 C118T SNP in children with HB was mainly found to be mutant type CT + TT. Compared to wild type CC, children with the mutant type CT + TT exhibited better treatment efficacy and remission with platinum-based chemotherapy as well as better survival rates. Moreover, the short-term prognosis of children with low VEGF expression was better than in those with high expression.

Intervertebral disc degeneration (IDD) is a degenerative disease that is characterized by decreased matrix synthesis and extra degradation, nucleus pulposus cells (NPCs) apoptosis, and infiltration of inflammatory factors. Aloin, a colored compound from aloe plants, has been shown to be effective against skeletal degenerative diseases, but it is unclear whether it is protective against IDD. Herein, we investigated the role of aloin in NPCs. In our study, the upregulation of proinflammatory factors, apoptosis, and unbalanced matrix metabolism were observed in degenerative NP tissues. We found that aloin had a curative effect on extracellular matrix metabolism and apoptosis in TNF-alpha- (TNF-α-) treated NPCs by inhibiting oxidative stress and the proinflammatory factor expression. Further investigation revealed that aloin treatment suppressed the TAK1/NF-κB pathway. Moreover, the expression level of the NLPR3 inflammasome was downregulated after aloin treatment in TNF-α-treated NPCs. In summary, our results demonstrated that aloin treatment can reverse TNF-α-induced unbalanced matrix metabolism and apoptosis of NPCs via the TAK1/NF-κB/NLRP3 axis. This study supports that aloin can be a promising therapeutic agent for IDD.

Windows have a great impact on building energy consumption, and the thermal performance of window frames directly affects its energy-saving potential. In this paper, a novel method is proposed to optimize the thermal performance of commercially available broken-bridge aluminum window frames, by incorporating radiant insulation panels (RIPs) into the window frame cavity. A typical aluminum alloy window frame heat transfer model is theoretically analyzed and validated, and the effects of key design parameters on the equivalent thermal conductivity (ETC) of the cavity radiation heat transfer and the heat transfer coefficient (U-factor) of window frames are quantitatively analyzed by a finite element simulation method using the THERM software. Moreover, the RIP, the insulation material filling, and low surface emissivity on the thermal performance of the window frame are compared and analyzed. The results show that the RIP is better placed in the middle, the width and quantity of RIPs are negatively correlated with the U-factor, while the surface emissivity of RIPs is positively correlated with the U-factor. Adding RIPs in the cavity can reduce the U-factor of the window frame by more than 7.43%, slightly lower than 8.97% for the filling type, but significantly higher than 0.81% for the low-emissivity type. Inserting RIPs is a simple and effective way to reduce the U-factor of the window frame and have a great potential of use.

BackgroundHepatoblastoma (HB) is the most common malignant embryonic liver tumor type in children under 3 years of age. In the present study, the next generation sequencing (NGS) method was used to detect the genotype characteristics of HB and summarize the correlation between the common mutation genotypes noted in this disease and the clinical treatment and prognosis. The results may aid clinical prognosis and the successful application of targeted drugs.MethodsInitially, DNA was extracted from tumor tissue specimens and peripheral blood derived from 19 pediatric patients with HB. Subsequently, DNA panel and NGS methods were used to detect tumor diagnosis and the expression levels of treatment-associated genes, followed by the summary of genotype characteristics. In addition, in order to further assess the application of immunotherapy in HB, immunohistochemical detection of programmed cell death 1 ligand 1 (PDL1) was performed in combination with tumor mutation burden (TMB) and DNA mismatch repair status analysis. Furthermore, the clinical treatment effect and prognosis of the pediatric patients were statistically analyzed according to the characteristics of the genotype. Overall prognosis and prognostic analyses in different groups were performed by Kaplan-Meier and log-rank tests, respectively. Finally, expression validation and diagnostic analysis of commonly reported genes were performed in the GSE75271 dataset, which was obtained from the Gene Expression Omnibus (GEO) database.ResultsIn the present study, certain mutated genes, including nuclear factor erythroid 2-related factor 2 (NFE2L2), catenin β1 (CTNNB1), MYCN, tumor protein p53, axis inhibition protein 1 (AXIN1) and adenomatous polyposis coli (APC) were associated with the pathogenesis of HB. During TMB and DNA mismatch repair status analyses, pediatric patients had a low TMB. All of them did not present with microsatellite instability. The immunohistochemical results indicated lower expression levels of PDL1 in HB. The complete remission (CR) rate of pediatric patients in the gene abnormality group was lower than that of the non-reported disease-associated gene abnormality group. The 2-year overall survival rate and disease-free survival rate of 19 pediatric patients with HB were 72.1% and 42.4%, respectively. Receiver operating characteristic (ROC) analysis demonstrated that CTNNB1, NFE2L2, AXIN1, APC, MYCN and insulin growth factor 2 (IGF2) may be potential biomarkers that could be used for the diagnosis of HB.ConclusionThe genotype changes in HB were more common and the CR rate of the pediatric patients with an altered genotype was lower than that of pediatric patients without an altered genotype. In addition, pediatric patients with HB exhibited lower TMB compared with adult patients. Moreover, the data indicated that CTNNB1, NFE2L2, AXIN1, APC, MYCN and IGF2 may be potential biomarkers that can be used for the diagnosis of HB.

Melatonin (Mlt) confers potential antitumor effects in various types of cancer. However, to the best of our knowledge, the role of Mlt in the giant cell tumor of bone (GCTB) remains unknown. Moreover, further research is required to assess whether Mlt can enhance the therapeutic effect of zoledronic acid (Zol), a commonly used anti-GCTB drug. In this research, we investigated the effects of Mlt, Zol, and the combination of these two drugs on GCTB cells’ characteristics, including cell proliferation, apoptosis, osteogenic differentiation, migration, and invasion. The cell counting kit-8 (CCK-8) assay, colony formation assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay (TUNEL), alkaline phosphatase (ALP) staining, alizarin red staining (ARS), scratch wound healing assay, and transwell experiment were performed, respectively. Our results showed that Mlt could effectively inhibit the proliferation, migration, and invasion of GCTB cells, as well as promote the apoptosis and osteogenic differentiation of tumor cells. Of note, a stronger antitumor effect was observed when Mlt was combined with Zol treatment. This therapeutic effect might be achieved by inhibiting the activation of both the Hippo and NF-κB pathways. In conclusion, our study suggests that Mlt can be a new treatment for GCTB, which could further enhance the antitumor effect of Zol.

Sorafenib a multi-target tyrosine kinase inhibitor, is the first-line drug for treating advanced hepatocellular carcinoma (HCC). Mechanistically, it suppresses tumor angiogenesis, cell proliferation and promotes apoptosis. Although sorafenib effectively prolongs median survival rates of patients with advanced HCC, its efficacy is limited by drug resistance in some patients. In HCC, this resistance is attributed to multiple complex mechanisms. Previous clinical data has shown that HIFs expression is a predictor of poor prognosis, with further evidence demonstrating that a combination of sorafenib and HIFs-targeted therapy or HIFs inhibitors can overcome HCC sorafenib resistance. Here, we describe the molecular mechanism underlying sorafenib resistance in HCC patients, and highlight the impact of hypoxia microenvironment on sorafenib resistance.

Abstract The friction properties of wet clutches are highly dependent on the surface tribofilms formed by automatic transmission fluids (ATFs). Here, four commercial ATFs were evaluated with a disc-on-disc tribometer to study tribofilm formation on steel surfaces and the effects of tribofilms on the friction properties. The chemical composition, stoichiometry, structure, and thickness of the tribofilms were investigated by scanning electron microscopy (SEM), energy dispersive X-ray spectrometry (EDX), secondary ion mass spectrometry (SIMS), and X-ray photoelectron spectroscopy (XPS). Calcium phosphate (CaP) tribofilms form on the friction surface with all ATFs, which contributes to their antishudder characteristics. The thickness and surface coverage of CaP tribofilms are positively correlated with their antishudder properties.

Abstract Background The protective effect of melatonin against bone metabolism imbalance in osteoporosis (OP) induced by drugs such as retinoic acid (RA) is unclear. The aim of this study was to explore the role of melatonin in bone destruction based on a mouse model. Methods RA-induced OP model mice were established. To assess the effect of melatonin on these mice, micro-CT was used to characterize the trabecular structure of normal mice and those treated with RA (model), RA + low-dose melatonin (Mlt-L), RA + high-dose melatonin (Mlt-H), and RA + alendronate sodium (positive control). The shape of the trabecular bone, the length and diameter of the femoral head and the height and diameter of vertebra(L1) of each group were also measured and the number of osteoclasts was determined by Tartrate-resistant acid phosphatase (TRACP) staining. Meanwhile, the expression of alkaline phosphatase (ALP) was evaluated by immunohistochemistry assays. The differences between groups in terms of liver and kidney oxidation–related indexes and serum and urinary indicators related to bone metabolism were also analyzed. Furthermore, qRT-PCR and western blotting were used to evaluate the effect of melatonin on osteogenic and osteoclastic differentiation in MC3T3-E1 and RAW264.7 cells, respectively. Results RA induction led to a decrease in the amount and density of trabecular bone, a decrease in the length and diameter of the femur and height, diameter of the vertebra (L1), a decrease in bone mass and density and the expression of ALP, and an increase in the number of osteoclasts. Melatonin treatment alleviated these effects induced by RA, increasing the amount of trabecular bone in OP mice, improving the microstructure of the femur and vertebra(L1) and increasing bone mass bone density and the expression of ALP, as well as decreasing the number of osteoclasts. Additionally, blood and urinary bone metabolism-related indicators showed that melatonin promoted bone formation and inhibited bone resorption. Determination of oxidant and antioxidant biomarkers in the livers and kidneys of the mice revealed that melatonin promoted the antioxidant level and suppressed the level of oxidant molecules in these organs. In vitro, RA promoted osteoclasts and inhibit osteogenesis by increasing oxidative stress levels in the RAW264.7 and MC3T3-E1 cells, but melatonin reversed this effect. Melatonin may, therefore, play a role in the ERK/SMAD and NF-κB pathways. Conclusions Melatonin can alleviate bone loss in RA-induced OP model mice, repair the trabecular microstructure, and promote bone formation. These effects may be related to reducing oxidation levels in vivo and vitro through the ERK/SMAD and NF-κB pathways.

Abstract Arthrogryposis is a group of phenotypically and genetically heterogeneous disorders characterized by congenital contractures of two or more parts of the body; the pathogenesis and the causative genes of arthrogryposis remain undetermined. We examined a four‐generation arthrogryposis pedigree characterized by camptodactyly, limited forearm supination, and loss of myofibers in the forearms and hands. By using whole‐exome sequencing, we confirmed MET p.Y1234C mutation to be responsible for arthrogryposis in this pedigree. MET p.Y1234C mutation caused the failure of activation of MET tyrosine kinase. A Met p.Y1232C mutant mouse model was established. The phenotypes of homozygous mice included embryonic lethality and complete loss of muscles that originated from migratory precursors. Heterozygous mice were born alive and showed reduction of the number of myofibers in both appendicular and axial muscles. Defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts were proven to be responsible for the skeletal muscle dysplasia of mutant mice. Overall, our study shows MET to be a causative gene of arthrogryposis and MET mutation could cause skeletal muscle dysplasia in human beings.

Abstract Background Hepatocellular carcinoma (HCC) is the most common malignant liver tumor with poor clinical outcomes. Increasing amount of long non-coding RNAs (lncRNAs) have been revealed to be implicated in the carcinogenesis and progression of HCC. However, the expressions, clinical significances, and roles of most lncRNAs in HCC are still unknown. Methods The expression of lncRNA MCM3AP antisense RNA 1 (MCM3AP-AS1) in HCC tissues and cell lines was detected by qRT-PCR and fluorescence in situ hybridization. Immunoblotting, CCK-8, EdU, colony formation and flow cytometry were performed to investigate the role of MCM3AP-AS1 in HCC cell proliferation, cell cycle and apoptosis in vitro. A subcutaneous tumor mouse model was constructed to analyze in vivo growth of HCC cells after MCM3AP-AS1 knockdown. The interactions among MCM3AP-AS1, miR-194-5p and FOXA1 were measured by RNA pull-down, RNA immunoprecipitation and luciferase reporter assay. Results We revealed a novel oncogenic lncRNA MCM3AP-AS1, which is overexpressed in HCC and positively correlated with large tumor size, high tumor grade, advanced tumor stage and poor prognosis of HCC patients. MCM3AP-AS1 knockdown suppressed HCC cell proliferation, colony formation and cell cycle progression, and induced apoptosis in vitro, and depletion of MCM3AP-AS1 inhibited tumor growth of HCC in vivo. Mechanistically, MCM3AP-AS1 directly bound to miR-194-5p and acted as competing endogenous RNA (ceRNA), and subsequently facilitated miR-194-5p’s target gene forkhead box A1 (FOXA1) expression in HCC cells. Interestingly, FOXA1 restoration rescued MCM3AP-AS1 knockdown induced proliferation inhibition, G1 arrest and apoptosis of HCC cells. Conclusions Our results recognized MCM3AP-AS1 as a novel oncogenic lncRNA, which indicated poor clinical outcomes in patients with HCC. MCM3AP-AS1 exerted an oncogenic role in HCC via targeting miR-194-5p and subsequently promoted FOXA1 expression. Our findings suggested that MCM3AP-AS1 could be a potential prognostic biomarker and therapeutic target for HCC.

Innovative mass timber panels, known as composite laminated panels (CLP), have been developed using lumber and laminated strand lumber (LSL) laminates. In this study, strain distributions of various 5-layer CLP and cross-laminated timber (CLT) were investigated by experimental and two modelling methods. Seven (7) different panel types were tested in third-point bending and short-span shear tests. During the tests, the digital imaging correlation (DIC) technique was used to measure the normal and shear strain in areas of interest. Evaluated component properties were used to determine strain distributions based on the shear analogy method and finite element (FE) modelling. The calculated theoretical strain distributions were compared with the DIC test results to evaluate the validity of strain distributions predicted by the analytical model (shear analogy) and numerical model (FE analysis). In addition, the influence of the test setup on the shear strain distribution was investigated. Results showed that the DIC strain distributions agreed well with the ones calculated by the shear analogy method and FE analysis. Both theoretical methods agree well with the test results in terms of strain distribution shape and magnitude. While the shear analogy method shows limitations when it comes to local strain close to the supports or gaps, the FE analysis reflects these strain shifts well. The findings support that the shear analogy is generally applicable for the stress and strain determination of CLP and CLT for structural design, while an FE analysis can be beneficial when it comes to the evaluation of localized stresses and strains. Due to the influence of compression at a support, the shear strain distribution near the support location is not symmetric. This is confirmed by the FE method.

ObjectiveAfter a complete remission to treatment for hepatoblastoma, some children still have recurrence. We identified and explored the factors that influence recurrence after complete remission in a retrospective study.MethodsOf 197 children with hepatoblastoma, 140 (71.1%) achieved initial complete remission and were enrolled in factor analysis. Variables consisted of age, sex, PRE-Treatment EXTent of tumor (PRETEXT) stage, pathologic type, metastatic disease, serum alpha-fetoprotein level, vascular involvement, and surgical margin status. We employed univariate and multivariate analyses to assess the relationship between each factor and tumor recurrence.ResultsOf 140 children who achieved initial complete remission, 42 (30%) had recurrent hepatoblastoma. The 5-year overall survival rates for the non-recurrence and recurrence group were 99.0% and 78.6%, respectively. The overall 1-year, 3-year, and 5-year recurrence-free survival (RFS) rates were 77.8%, 69.8%, and 69.8%, respectively. All recurrences occurred within 2 years from complete remission. The RFS rate was significantly higher in children younger than 3 years and in those with mixed pathological type, PRETEXT II and III, without metastatic disease, without vascular involvement, and microscopic negative margin than in that of children older than 3 years, with epithelial pathological type, PRETEXT IV, metastatic disease, vascular involvement, and macroscopic positive margin (P < 0.001, = 0.020, < 0.001, = 0.004, = 0.002, and < 0.001, respectively). The independent risk factors for recurrence after complete remission were age ≥3 years, PRETEXT IV, and metastatic disease (P < 0.05).ConclusionAge, PRETEXT stage, metastatic disease, vascular involvement, pathologic type, and surgical margin status might be associated with recurrent hepatoblastoma after complete remission; meanwhile, age ≥3 years, PRETEXT IV, and metastatic disease are independent risk factors of recurrence. Further research is needed on the causes of tumor recurrence, which may improve the long-term outcomes of children with hepatoblastoma.

Cross-laminated timber (CLT) is a type of engineered wood product that offers both high in-plane and out-of-plane load-bearing capacity. It is slowly becoming an alternative material for building high-rise structures. However, there is no current standard or regulation for determining the shear modulus of CLT under in-plane loading condition, which is a very important property for its use as structural members. Few methods have been proposed over the last decade to determine the in-plane shear modulus of CLT. Almost all of the methods proposed until now have their strengths and weaknesses. In this paper, some of the prominent methods for determining the in-plane shear modulus of CLT are described and analysed. The descriptions along with the critical discussions will facilitate a better understanding and might pave the way to further enhancements of the method(s) to determine the in-plane shear modulus of CLT.

Intervertebral disc degenerative disease (IDD) is the most common degenerative spine disease, which leads to chronic low back pain and symptoms in the lower extremities. In this study, we found that RORα, a member of the retinoid-related orphan receptor family, is significantly elevated in nucleus pulposus tissue in IDD patients. The elevation of RORα is associated with increased apoptosis of nucleus pulposus (NP) cells. Therefore, we applicated a well-established inverse agonist of RORα, SR3335, to investigate its role in regulating NP cell metabolism and apoptosis. To further investigate the mechanism that SR3335 regulates the pathogenesis of IDD in vitro, tumor necrosis factor alpha (TNF-α) stimulation was used in human NP cells to mimic the hostile environment that leads to degeneration. We found that SR3335 treatment reversed the trend of increased apoptosis in NP cells induced by TNF-α treatment. Next, TNF-α treatment upregulated the expression of type II collagen and aggrecan and downregulated MMP13 (matrix-degrading enzyme matrix metalloproteinase 13) and ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4). However, these effects were reversed after SR3335 treatment. Furthermore, we find that SR3335 mediated the effect in NP cells by regulating the YAP signaling pathway, especially by affecting the phosphorylation state of YAP. In conclusion, the reduction of matrix degradation enzymes and apoptosis upon SR3335 treatment suggests that SR3335 is a promising drug in reversing the deleterious microenvironment in IDD patients.

Abstract Background Autophagy is an intracellular degradation pathway conserved in eukaryotes. ANXA6 (annexin A6) belongs to a family of calcium‐dependent membrane and phospholipid‐binding proteins. Here, we identify ANXA6 as a newly synthesized protein in starvation‐induced autophagy and validate it as a novel autophagy modulator that regulates autophagosome formation. Results ANXA6 knockdown attenuates starvation‐induced autophagy, while restoration of its expression enhances autophagy. GO (gene ontology) analysis of ANXA6 targets showed that ANXA6 interacts with many RAB GTPases and targets endocytosis and phagocytosis pathways, indicating that ANXA6 exerts its function through protein trafficking. ATG9A (autophagy‐related 9A) is the sole multispanning transmembrane protein and its trafficking through recycling endosomes is an essential step for autophagosome formation. Our results showed that ANXA6 enables appropriate ATG9A+ vesicle trafficking from endosomes to autophagosomes through RAB proteins or F‐actin. In addition, restoration of ANXA6 expression suppresses mTOR (mammalian target of rapamycin) activity through the inhibition of the PI3K (phosphoinositide 3‐kinase)‐AKT and ERK (extracellular signal‐regulated kinase) signaling pathways, which is a negative regulator of autophagy. Functionally, ANXA6 expression is correlated with LC3 (microtubule‐associated protein 1 light chain 3) expression in cervical cancer, and ANXA6 inhibits tumorigenesis through autophagy induction. Conclusions Our results reveal an important mechanism for ANXA6 in tumor suppression and autophagy regulation.