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In clinical practice, the limited efficacy of standard comprehensive therapy for advanced bladder cancer and the lack of targeted treatment options are well recognized. Targeting abnormal epigenetic modifications in tumors has shown considerable potential in cancer therapy. Through drug screening in tumor organoids, we identified that ML324, a histone lysine demethylase 4A (KDM4A) inhibitor, exhibits potent antitumor effects in both in vitro and in vivo cancer models. Mechanistically, Kdm4a demethylates H3K9me3, leading to chromatin opening and increased accessibility of Gabpa to the squalene epoxidase (Sqle) gene promoter, resulting in transcriptional activation. Inhibition of Kdm4a downregulates Sqle transcription, blocking cholesterol synthesis and causing squalene (SQA) accumulation. This process induces reactive oxygen species (ROS) clearance and suppresses JNK/c-Jun phosphorylation, ultimately inducing apoptosis. Furthermore, ML324 treatment significantly inhibited tumor growth in bladder cancer patient-derived xenograft (PDX) models. Our findings reveal the presence of a Kdm4a-Sqle-ROS-JNK/c-Jun signaling axis that regulates oxidative stress balance, offering a novel strategy for targeted therapy in bladder cancer.

Abstract. Background:. Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a micro-barrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells. Methods:. The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin β8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. Results:. Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts. Conclusions:. The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

Scandium is very expensive and limits the application potential of Sc containing alloys. A novel high-strength Al–Mg–Mn-Sc-Zr alloy was designed for reducing Sc. Multiple strengthening mechanisms were utilized for designing this alloy, especially for the solid solution strengthening which benefits from ultrahigh cooling. With the addition of Mn and Si, the strength of our alloy reaches comparable level of similar alloys while the Sc content is 40–60 % less than them. The effect of Mn addition on microstructure and mechanical properties were carefully studied. Near full-dense samples with relative density >99.88 % were obtained with the help of overlapping prediction model. The continuous Mg2Si network was observed with Si introduction and broken up with increasing Mn content. According to the tensile experiment results and corresponding calculations, it was considered that the thermal stability and the effect of precipitate strengthening was slightly deteriorated. However, obvious improvement of the tensile strength was observed with increasing Mn addition, and the ductility maintains in a certain range. After aging at 280 °C for 4 h, the sample of 1.4 wt% Mn exhibits the highest ultimate strength of 497.08 ± 7.22 MPa, and possesses a considerable ductility of 8.01 ± 0.34 %. The Portevin-Le Chatelier (PLC) effect was observed in stress-strain curves, which reflects a dynamic strain aging of mobile dislocations and solute atoms. After aging, the stress amplitude and waiting time of serration flow decrease obviously, because of the introduction of bypassing precipitates and reduction of diffusion time. Compared with other similar alloys, our alloy exhibited comparable yield strength and elongation, but considerable advantages in material costs resulting from lower Sc content. It will offer not only an idea for alloy design utilizing the ultra-high solid solubility of elements, but also a feasible way to further expand application field of high-strength Al-based alloys through reducing the material costs.

Summary: Activation of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome complex is an essential innate immune signaling mechanism. To reveal how human NLRP3 inflammasome assembly and activation are controlled, in particular by components of the ubiquitin system, proximity labeling, affinity purification, and RNAi screening approaches were performed. Our study provides an intricate time-resolved molecular map of different phases of NLRP3 inflammasome activation. Also, we show that ubiquitin C-terminal hydrolase 1 (UCH-L1) interacts with the NACHT domain of NLRP3. Downregulation of UCH-L1 decreases pro-interleukin-1β (IL-1β) levels. UCH-L1 chemical inhibition with small molecules interfered with NLRP3 puncta formation and ASC oligomerization, leading to altered IL-1β cleavage and secretion, particularly in microglia cells, which exhibited elevated UCH-L1 expression as compared to monocytes/macrophages. Altogether, we profiled NLRP3 inflammasome activation dynamics and highlight UCH-L1 as an important modulator of NLRP3-mediated IL-1β production, suggesting that a pharmacological inhibitor of UCH-L1 may decrease inflammation-associated pathologies.

PANoptosis pathway gene sets encompassing pyroptosis, apoptosis, and necroptosis were identified from the MSigDB database. We analyzed the perturbations and crosstalk in the PANoptosis pathway in prostate adenocarcinoma (PRAD), including gene mutation, transcription, methylation, and clinical features. By constructing a PANoptosis signature, we accurately predicted the prognosis and immunotherapeutic response of PRAD patients. We further explored the molecular features and immunological roles of the signature, dividing patients into high- and low-score groups. Notably, the high-score group correlated with better survival outcomes and immunotherapeutic responses, as well as a higher mutation frequency and enrichment score in the PANoptosis and HALLMARK pathways. The PANoptosis signature also enhanced overall antitumor immunity, promoted immune cell infiltration, upregulated immune checkpoint regulators, and revealed the cold tumor characteristics of PRAD. We also identified potential drug targets based on the PANoptosis signature. These findings lead the way in identifying novel prognostic markers and therapeutic targets for patients with PRAD.

The HIV-1 pandemic, spanning four decades, presents a significant challenge to global public health. This study aimed to understand the molecular transmission characteristics of newly reported HIV infections in Taiyuan, Shanxi Province, China, to analyze the characteristics of subtypes and the risk factors of the transmission network, providing a scientific basis for precise prevention and intervention measures. A total of 720 samples were collected from newly diagnosed HIV-1 patients residing in Taiyuan between 2021 and 2023. Sequencing of partial genes of the HIV-1 pol gene resulted in multiple sequence acquisitions and was conducted to analyze their subtypes and molecular transmission networks. Out of the samples, 584 pol sequences were obtained, revealing 17 HIV-1 subtypes, with CRF07_BC (48.29%), CRF01_AE (31.34%), and CRF79_0107 (7.19%) being the dominant subtypes. Using a genetic distance threshold of 1.5%, 49 molecular transmission clusters were generated from the 313 pol gene sequences. Univariate analysis showed significant differences in the HIV transmission molecular network in terms of HIV subtype and household registration (p < 0.05). Multivariate logistic regression analysis showed that CRF79_0107 subtype and its migrants were associated with higher proportions of sequences in the HIV transmission network. These findings provide a scientific foundation for the development of localized HIV-specific intervention strategies.

Abstract. Background:. Studies have classified muscle-invasive bladder cancer (MIBC) into primary (initially muscle-invasive, PMIBC) and secondary subtypes (initially non-muscle-invasive but progresses, SMIBC), for which controversial survival outcomes were demonstrated. This study aimed to compare the survival outcomes between PMIBC and SMIBC patients in China. Methods:. Patients diagnosed with PMIBC or SMIBC at West China Hospital from January 2009 to June 2019 were retrospectively included. Kruskal–Wallis and Fisher tests were employed to compare clinicopathological characteristics. Kaplan–Meier curves and Cox competing proportional risk model were used to compare survival outcomes. Propensity score matching (PSM) was employed to reduce the bias and subgroup analysis was used to confirm the outcomes. Results:. A total of 405 MIBC patients were enrolled, including 286 PMIBC and 119 SMIBC, with a mean follow-up of 27.54 and 53.30 months, respectively. The SMIBC group had a higher proportion of older patients (17.65% [21/119] vs. 9.09% [26/286]), chronic disease (32.77% [39/119] vs. 22.38% [64/286]), and neoadjuvant chemotherapy (19.33% [23/119] vs. 8.04% [23/286]). Before matching, SMIBC had a lower risk of overall mortality (OM) (hazard ratios [HR] 0.60, 95% confidence interval [CI] 0.41–0.85, P = 0.005) and cancer-specific mortality (CSM) (HR 0.64, 95% CI 0.44–0.94, P = 0.022) after the initial diagnosis. However, higher risks of OM (HR 1.47, 95% CI 1.02–2.10, P = 0.038) and CSM (HR 1.58, 95% CI 1.09–2.29, P = 0.016) were observed for SMIBC once it became muscle-invasive. After PSM, the baseline characteristics of 146 patients (73 for each group) were well matched, and SMIBC was confirmed to have an increased CSM risk (HR 1.83, 95% CI 1.09–3.06, P = 0.021) than PMIBC after muscle invasion. Conclusions:. Compared with PMIBC, SMIBC had worse survival outcomes once it became muscle-invasive. Specific attention should be paid to non-muscle-invasive bladder cancer with a high progression risk.

The economic operation of hydropower stations has the potential to increase water use efficiency. However, there are some challenges, such as the fixed and unchangeable flow characteristic curve of the hydraulic turbines, and the large number of variables in optimal load distribution, which limit the progress of research. In this paper, we propose a new optimal method of the economic operation of hydropower stations based on improved Long Short-Term Memory neural network (I-LSTM) and Random Forest (RF) algorithm. Firstly, in order to accurately estimate the water consumption, the LSTM model’s hyperparameters are optimized using improved particle swarm optimization, and the I-LSTM method is proposed to fit the flow characteristic curve of the hydraulic turbines. Secondly, the Random Forest machine learning algorithm is introduced to establish a load-distribution model with its powerful feature extraction and learning ability. To improve the accuracy of the load-distribution model, we use the K-means algorithm to cluster the historical data and optimize the parameters of the Random Forest model. A Hydropower Station in China is selected for a case study. It is shown that (1) the I-LSTM method fits the operating characteristics under various working conditions and actual operating characteristics of hydraulic turbines, ensuring that they are closest to the actual operating state; (2) the I-LSTM method is compared with Support Vector Machine (SVM), Extreme Learning Machine (ELM) and Long Short-Term Memory neural network (LSTM). The prediction results of SVM have a large error, but compared with ELM and LSTM, MSE is reduced by about 46% and 38% respectively. MAE is reduced by about 25% and 21%, respectively. RMSE is reduced by about 27% and 24%, respectively; (3) the RF algorithm performs better than the traditional dynamic programming algorithm in load distribution. With the passage of time and the increase in training samples, the prediction accuracy of the Random Forest model has steadily improved, which helps to achieve optimal operation of the units, reducing their average total water consumption by 1.24%. This study provides strong support for the application of intelligent low-consumption optimization strategies in hydropower fields, which can bring higher economic benefits and resource savings to renewable energy production.

Abstract Background Bisphenol A (BPA) exposure and its structural analogs (BPS and BPF) might cause endocrine alterations and adverse physiological effects. Few studies to date have directly explored the association between its structural analogs (BPS, BPF) and sex hormones in adult male participants. Therefore, we aimed to assess the associations between BPA, BPS, BPF, and sex hormones in American adult men. Methods We used data from the U.S. National Health and Nutrition Examination Survey 2011–2016. We excluded participants without data available on sex hormones and urinary bisphenols. Furthermore, participants consuming sex hormone medications were excluded. Multivariable regression models were performed to assess the association between bisphenols and sex hormones. Results In this study, 2367 participants were included. Of 2367, in 1575 participants, the data on BPS and BPF were available. We found that a per unit increase in BPF was associated with 0.575 ng/dL higher total testosterone (TT) (Model 2: 95% CI: 0.047, 1.103, P = 0.033). However, there was no significant association between BPA or BPS and TT. Furthermore, increased BPA and BPS levels were associated with higher levels of sex hormone-binding globulin (SHBG) (Model 2: β = 0.364, 95% CI: 0.158, 0.571; β = 0.25, 95% CI: 0.071, 0.429, respectively). Additionally, participants in the highest BPA exposure quartile (quartile 4) had 4.072 nmol/L higher levels of SHBG than those in quartile 1 (Model 2: 95% CI: 0.746, 7.397, P = 0.017; P for trend =0.005). Both BPA and BPS were negatively associated with free testosterone (FT, nmol/L) after full adjustment (Model 2, β = − 0.01%, P = 0.0211, P = 0.0211; Model 2, β = − 0.01%, P = 0.0258, respectively). However, BPF was positively associated with FT (Model 2, β = 0.0029%, P = 0.0028). Conclusion Our study indicated that exposure to both BPA and its substitutions could alter sex hormone levels. This finding supports the possibility that human exposure to bisphenols at environmental levels might affect the endogenous hormone balance.

Abstract Perturbations of the circadian clock are linked to multiple diseases, including cancers. Pharmacological activation of REV-ERB nuclear receptors, the core components of the circadian clock, has antitumor effects on various malignancies, while the impact of SR9009 on prostate cancer (PCa) remains unknown. Here, we found that SR9009 was specifically lethal to PCa cell lines but had no cytotoxic effect on prostate cells. SR9009 significantly inhibited colony formation, the cell cycle, and cell migration and promoted apoptosis in PCa cells. SR9009 treatment markedly inhibited prostate cancer subtype 1 (PCS1), the most lethal and aggressive PCa subtype, through FOXM1 pathway blockade, while it had no impacts on PCS2 and PCS3. Seven representative genes, including FOXM1, CENPA, CENPF, CDK1, CCNB1, CCNB2, and BIRC5, were identified as the shared genes involved in the FOXM1 pathway and PCS1. All of these genes were upregulated in PCa tissues, associated with worse clinicopathological outcomes and downregulated after SR9009 treatment. Nevertheless, knockdown or knockout of REV-ERB could not rescue the anticancer effect of SR9009 in PCa. Further analysis confirmed that it was LXRα rather than REV-ERBs which has been activated by SR9009. The expression levels of these seven genes were changed correspondingly after LXRα knockdown and SR9009 treatment. An in vivo study validated that SR9009 restrained tumor growth in 22RV1 xenograft models and inhibited FOXM1 and its targeted gene expression. In summary, SR9009 can serve as an effective treatment option for highly aggressive and lethal PCS1 tumors through mediating the LXRα/FOXM1 pathway independently of REV-ERBs.

BackgroundThe benefits of vitamin E (VE) for multiple health outcomes have been well evaluated in many recent studies.ObjectiveThe purpose of this umbrella review was to conduct a systematic evaluation of the possible associations between VE intake and various health outcomes.MethodsWe systematically searched various databases, such as PubMed, Embase, and the Web of Science, to identify related meta-analyses of observational studies and randomized trials. We estimated the effect size of each association by using the random or fixed effects models and the 95% confidence intervals. We used standard approaches to evaluate the quality of the articles (AMSTAR) and classified the evidence into different levels of quality (GRADE).ResultsA total of 1,974 review articles were searched, and 27 articles with 28 health outcomes were yielded according to our exclusion criteria. The intake of VE was inversely associated with the risk of breast cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, kidney cancer, bladder cancer, cervical neoplasms, cardiovascular disease, Parkinson's disease, depression, age-related cataracts, metabolic syndrome, and fracture. Overall, most of the quality of the evidence was low or very low. Three outcomes (stroke, age-related cataracts, obesity) were identified as having a “moderate” level of quality. The AMSTAR scores for all health outcomes ranged from 5 to 10.ConclusionOur study revealed that VE intake is beneficially related to multiple health outcomes. However, future studies on recommended doses and recommended populations of VE are also needed.Systematic review registrationhttp://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022339571.

During the load distribution of hydropower units, the frequent crossing of vibration zones as well as large output fluctuations affect the stability of the power station. A multi-objective double-layer intelligent nesting model that considers the constraint of the output fluctuation of units is proposed to address these problems. The nonlinear constraint unit commitment optimization model layer is built based on outer dynamic programming, and the load distribution optimization model layer is constructed based on the improved biogeography-based optimization algorithm. Simultaneously, the unit output fluctuation constraint is established based on whether the unit combination changes in order to limit the unit output fluctuation. The results of this model indicate that compared with traditional load allocation models, the application of the method proposed in this paper can reduce the fluctuation range of unit output by 85.01%. In addition, except for the inevitable vibration zone crossings during startup and shutdown processes, the unit does not cross the vibration zone during operation, which greatly improves the unit’s vibration isolation and optimization capabilities. The multi-objective double-layer intelligent nested model proposed in this paper has significant advantages in the field of load allocation for hydropower units. It effectively improves the stability and reliability of unit operation, and this method can be applied to practical load allocation processes. It is of great significance for the research on load allocation optimization of hydropower units.

Highlights 1. klotho deficiency linked to multiple premature-aging syndromes and a short lifespan 2. Proinflammatory cytokines, including TNF-α, IFN-γ, and IL-6, downregulate α-Klotho gene expression 3. Dietary Inflammatory Index was developed as a tool to determine the inflammatory potential of diet 4. We found that there was a dose–response relationship between DII and circulating concentrations of klotho in a nationally representative population of American adults.

Abstract Current treatment strategy for kidney renal clear cell carcinoma (KIRC) is limited. Tumor-associated antigens, especially neoantigen-based personalized mRNA vaccines represent new strategies and manifest clinical benefits in solid tumors, but only a small proportion of patients could benefit from them, which prompts us to identify effective antigens and suitable populations to facilitate mRNA vaccines application in cancer therapy. Through performing expression, mutation, survival and correlation analyses in TCGA-KIRC dataset, we identified four genes including DNA topoisomerase II alpha (TOP2A), neutrophil cytosol factor 4 (NCF4), formin-like protein 1 (FMNL1) and docking protein 3 (DOK3) as potential KIRC-specific neoantigen candidates. These four genes were upregulated, mutated and positively associated with survival and antigen-presenting cells in TCGA-KIRC. Furthermore, we identified two immune subtypes, named renal cell carcinoma immune subtype 1 (RIS1) and RIS2, of KIRC. Distinct clinical, molecular and immune-related signatures were observed between RIS1 and RIS2. Patients of RIS2 had better survival outcomes than those of RIS1. Further comprehensive immune-related analyses indicated that RIS1 is immunologically “hot” and represent an immunosuppressive phenotype, whereas RIS2 represents an immunologically “cold” phenotype. RIS1 and RIS2 also showed differential features with regard to tumor infiltrating immune cells and immune checkpoint-related genes. Moreover, the immune landscape construction identified the immune cell components of each KIRC patient, predicted their survival outcomes, and assisted the development of personalized mRNA vaccines. In summary, our study identified TOP2A, NCF4, FMNL1 and DOK3 as potential effective neoantigens for KIRC mRNA vaccine development, and patients with RIS2 tumor might benefit more from mRNA vaccination.

Abstract Prostate adenocarcinoma (PRAD) is a leading cause of death among men. Messenger ribonucleic acid (mRNA) vaccine presents an attractive approach to achieve satisfactory outcomes; however, tumor antigen screening and vaccination candidates show a bottleneck in this field. We aimed to investigate the tumor antigens for mRNA vaccine development and immune subtypes for choosing appropriate patients for vaccination. We identified eight overexpressed and mutated tumor antigens with poor prognostic value of PRAD, including KLHL17, CPT1B, IQGAP3, LIME1, YJEFN3, KIAA1529, MSH5 and CELSR3. The correlation of those genes with antigen-presenting immune cells were assessed. We further identified three immune subtypes of PRAD (PRAD immune subtype [PIS] 1–3) with distinct clinical, molecular, and cellular characteristics. PIS1 showed better survival and immune cell infiltration, nevertheless, PIS2 and PIS3 showed cold tumor features with poorer prognosis and higher tumor genomic instability. Moreover, these immune subtypes presented distinguished association with immune checkpoints, immunogenic cell death modulators, and prognostic factors of PRAD. Furthermore, immune landscape characterization unraveled the immune heterogeneity among patients with PRAD. To summarize, our study suggests KLHL17, CPT1B, IQGAP3, LIME1, YJEFN3, KIAA1529, MSH5 and CELSR3 are potential antigens for PRAD mRNA vaccine development, and patients in the PIS2 and PIS3 groups are more suitable for vaccination.

BackgroundIncreasing evidence has emerged to reveal the correlation between genomic instability and long non-coding RNAs (lncRNAs). The genomic instability-derived lncRNA landscape of prostate cancer (PCa) and its critical clinical implications remain to be understood.MethodsPatients diagnosed with PCa were recruited from The Cancer Genome Atlas (TCGA) program. Genomic instability-associated lncRNAs were identified by a mutator hypothesis-originated calculative approach. A signature (GILncSig) was derived from genomic instability-associated lncRNAs to classify PCa patients into high-risk and low-risk groups. The biochemical recurrence (BCR) model of a genomic instability-derived lncRNA signature (GILncSig) was established by Cox regression and stratified analysis in the train set. Then its prognostic value and association with clinical features were verified by Kaplan–Meier (K-M) analysis and receiver operating characteristic (ROC) curve in the test set and the total patient set. The regulatory network of transcription factors (TFs) and lncRNAs was established to evaluate TF–lncRNA interactions.ResultsA total of 95 genomic instability-associated lncRNAs of PCa were identified. We constructed the GILncSig based on 10 lncRNAs with independent prognostic value. GILncSig separated patients into the high-risk (n = 121) group and the low-risk (n = 121) group in the train set. Patients with high GILncSig score suffered from more frequent BCR than those with low GILncSig score. The results were further validated in the test set, the whole TCGA cohort, and different subgroups stratified by age and Gleason score (GS). A high GILncSig risk score was significantly associated with a high mutation burden and a low critical gene expression (PTEN and CDK12) in PCa. The predictive performance of our BCR model based on GILncSig outperformed other existing BCR models of PCa based on lncRNAs. The GILncSig also showed a remarkable ability to predict BCR in the subgroup of patients with TP53 mutation or wild type. Transcription factors, such as FOXA1, JUND, and SRF, were found to participate in the regulation of lncRNAs with prognostic value.ConclusionIn summary, we developed a prognostic signature of BCR based on genomic instability-associated lncRNAs for PCa, which may provide new insights into the epigenetic mechanism of BCR.

Insulin-like growth factor binding protein-7 (IGFBP7) was recently reported to be a ligand of CD93, a potential target to normalize vasculature and attenuate immunotherapy. However, its role in the tumor microenvironment (TME) and immunotherapy response of bladder cancer (BLCA) remains unclear. We comprehensively evaluated the correlation between IGFBP7 and multiple immunological characteristics of BLCA across The Cancer Genome Atlas (TCGA) and two external cohorts. Importantly, the response of IGFBP7-grouped BLCA patients to immunotherapy was predicted and validated by five real-word immunotherapy cohorts. Finally, we developed an IGFBP7-based immune risk model validated by five independent cohorts. IGFBP7 modulated the TME across pan-caners. In BLCA, high expression of IGFBP7 was correlated with more aggressive clinical features. IGFBP7 was positively associated with immunomodulators and promoted tumor-infiltrating lymphocyte trafficking into the tumor microenvironment. However, T cells recognition and tumor cell killing were lower in the high-IGFBP7 group. In addition, high expression of IGFBP7 displayed lower enrichment scores for most pro-immunotherapy pathways. Clinical data from IMvigor210 and GSE176307 indicated that IGFBP7 negatively correlated with the BLCA immunotherapy response. The same trend was also observed in a renal cell carcinoma (RCC) cohort and two melanoma cohorts. Notably, urothelial and luminal differentiation were less frequently observed in the high-IGFBP7 group, while neuroendocrine differentiation was more frequently observed. Mechanistically, high IGFBP7 was associated with an enriched hypoxia pathway and higher expression of key genes in ERBB therapy and antiangiogenic therapy. Furthermore, our IGFBP7-based immune risk model was able to predict the prognosis and response to immunotherapy with good accuracy (5-year AUC = 0.734). Overall, IGFBP7 plays a critical role in the immunoregulation and TME of BLCA and may serve as a novel potential target for combination treatment with immunotherapy for BLCA.

Objective: To evaluate the oncological outcomes of ductal adenocarcinoma of the prostate (DAC) managed with radical prostatectomy (RP) or radiotherapy (RT) and optimize the proper treatment modality to DAC comprehensively. Methods: The cohorts included a total of 528 patients from the Surveillance, Epidemiology and End Results (SEER) database, 354 receiving RP and 174 receiving RT. Cox proportional hazards regressions were performed to assess cancer specific mortality (CSM) and overall mortality (OM) between treatment groups. A competing risk analysis was further conducted. Subgroup analyses by age and level of prostate-specific antigen (PSA) were performed. Propensity score matching was implemented. Results: Patients managed with RP had lower risks of CSM and OM compared with RT (before matching: Hazard ratio [HR]=0.24, 95% confidence interval [CI] 0.13–0.47 and HR=0.26, 95% CI 0.17–0.40, respectively; after matching: HR=0.18, 95% CI 0.04–0.82 and HR=0.28, 95% CI 0.11–0.70, accordingly). Subgroup analyses demonstrated that patients in the middle tertile of the age or with lower tertile PSA level managed with RP took lower risks of OM significantly (HR=0.18, 95% CI 0.06–0.57, p

Abstract The purpose of this study was to evaluate the association between dietary inflammatory index (DII) and urinary incontinence (UI) among a representative sample of the US women. We performed a cross-sectional analysis of women younger than 65 years using the 1999 to 2016 NHANES (National Health and Nutrition Examination Survey) populations. DII were calculated based on baseline dietary intake using 24-h dietary recalls. UI was determined and categorized by self-reported questions. Multivariable logistic regression models were used to assess the association between DII and UI. Stratified linear regression models were applied to test for interaction in prespecified subgroup of interest. A total of 13,441 women age between 20 and 65 years were included in the final analysis. Of these participants 3230 (24.03%) complained of urgency UI, 5276 (39.25%) complained of stress UI and 2028 (15.09%) complained of mixed UI. On multivariate analysis, analysis with DII categorized as quartiles revealed significantly increase odds of urgency UI in the most pro-inflammatory quartile compared to the most anti-inflammatory quartile (OR 1.24, 95% CI 1.07–1.44, P = 0.004 for trend) in full adjustment model. Similar results were observed in SUI (OR 1.14, 95% CI 1.00–1.30, P = 0.021 for trend) and MUI (OR 1.20, 95% CI 1.02−1.43, P = 0.022 for trend). More pro-inflammatory diets, as presented by higher DII scores are associated with an increased likelihood of UI in American women younger than 65 years. Further studies are needed to explore the possible physiological mechanism and evaluate the potential therapeutic implications.

Abstract Background Personal lifestyle is an important cause of prostate cancer (PCa), hence establishing a corresponding knowledge graph (KG) and a chatbot is a convenient way for preventing and assessing risks. The chatbot based on a KG of PCa‐associated lifestyles will be helpful to PCa management, then save health care resources in the ageing society. Results Based on our established knowledge base, we define entities and corresponding relationships to construct the PCa‐associated lifestyles KG for visualization by importing the triples into the Neo4j graph server. The dialogue system uses the Flask framework to determine the classification of questions through entity recognition and relationship extraction and later uses the query template to search the answers from the PCa‐associated lifestyles KG. The PCa‐associated lifestyles KG contains 11 types of entities and 14 types of relationships, the total number of nodes and links is 21 546 and 66 493, respectively. Also, the entity “Lifestyle”, “Paper”, “Baseline” and “Outcome” contain multiple attributes. The established chatbot can answer 12 types of basic questions and predict the probability of a certain lifestyle resulting in a certain PCa. The chatbot is available at http://sysbio.org.cn:5000/Pca/chatbot. Conclusion A chatbot based on PCa‐associated lifestyles KG was constructed to help researchers, physicians or patients learn more about PCa lifestyle management interactively.

Abstract Background Controversy remains despite several studies have discussed the role of bariatric surgery in improving male’s sexual function. This study aims to evaluate the efficacy of bariatric surgery in promoting male’s erectile function. Methods PubMed, EMbase, The Cochrane Library, CNKI and Clinical Trails.gov were searched from database inception to May 2019. The language of publication was limited in English. The International Index of Erectile Function (IIEF) score and Brief Male Sexual Function Inventory (BSFI) score were set as the primary outcome. Results Eleven studies with a total of 370 patients were enrolled in this meta-analysis. The results showed significant improvement in the IIEF score (erectile function: MD = 5.33, 95% CI 4.12–6.54; intercourse satisfaction: MD = 2.57, 95% CI 1.19–3.94; orgasmic function: MD = 0.50, 95%CI 0.60–0.94; overall satisfaction: MD = 1.67, 95% CI 0.78–2.56; sexual desire: MD = 1.27, 95% CI 0.61–1.93; total erectile function: MD = 7.21, 95% CI 4.33–10.10) and the BSFI score (erection: MD =2.53, 95% CI 2.39–2.67; ejaculation: MD = 1.40, 95% CI 1.28–1.51; desire: MD =1.40, 95% CI 1.32–1.49; problem assessment: MD = 2.20, 95% CI 2.06–2.34; sexual satisfaction: MD = 0.70, 95% CI 0.60–0.76) in obese individuals after bariatric surgery. Conclusions This systematic review and meta-analysis indicated that bariatric surgery could be effective in promoting males’s sexual function for obese individuals.

BackgroundControversial evidence about the association between cancer risk and metabolic status among individuals with obesity has been reported, but pooled data remain absent. This study aims to present pooled data comparing cancer risk between patients with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO).MethodsThe current study systematically searched pieces of literature on January 4, 2021, of prospective cohorts that compare the incidence of cancer between MHO and MUO. The quality of included studies was assessed using Newcastle–Ottawa scale, and publication bias was evaluated using funnel plots.ResultsEleven high-quality studies were eventually selected. Quantitative analysis indicates that a lower cancer incidence exists for MHO phenotype than that for MUO (odds ratio [OR], 0.71; 95% confidential interval [CI], 0.61–0.84). Consistent outcomes are presented by subgroup analyses, which are grouped by cohort region (western population: [OR, 0.84; 95% CI, 0.75–0.93]; Asian population: [OR, 0.64; 95% CI, 0.54–0.77]); definition of metabolic unhealthiness (≥3 metabolic abnormalities: [OR, 0.62; 95% CI, 0.54–0.71]; ≥1 metabolic abnormality: [OR, 0.76; 95% CI, 0.62–0.94]); and definition of obesity (body mass index (BMI), ≥30 kg/m2: [OR, 0.84; 95% CI, 0.73–0.98]; BMI, ≥25 kg/m2: [OR, 0.53; 95% CI, 0.52–0.55]).ConclusionIn conclusion, this study suggests a reduced cancer risk for MHO compared to MUO regardless of population heterogeneity, or the definitions of obesity and metabolic status.

Background: Studies have demonstrated the significance of multiple biomarkers for bladder cancer. Here, we attempt to present biomarkers potentially predictive of the prognosis and immunotherapy response of muscle-invasive bladder cancer (MIBC).Method: Immune and stromal scores were calculated for MIBC patients from The Cancer Genome Atlas (TCGA). Core differential expression genes (DEGs) with prognostic value were identified and validated using an independent dataset GSE31684. The clinical implications of prognostic genes and the inter-gene correlation were presented. The distribution of tumor-infiltrating immune cells (TICs), the correlation with tumor mutation burden (TMB), and the expression of eight immune checkpoint–relevant genes and CD39 were accordingly compared. Two bladder cancer cohorts (GSE176307 and IMvigor210) receiving immunotherapy were recruited to validate the prognostic value of LCK and CD3E for immunotherapy.Results: 361 MIBC samples from TCGA revealed a worse overall survival for higher stromal infiltration (p = 0.009) but a better overall survival for higher immune infiltration (p = 0.042). CD3E and LCK were independently validated by TCGA and GSE31684 to be prognostic for MIBC. CD3E was the most correlative gene of LCK, with a coefficient of r = 0.86 (p < 0.001). CD8+ T cells and macrophage M1 are more abundant in favor of a higher expression of CD3E and LCK in MIBC and across pan-cancers. Immune checkpoints like CTLA4, CD274 (PD-1), and PDCD1 (PD-L1) were highly expressed in high-CD3E and high-LCK groups for MIBC and also for pan-cancers, except for thymoma. LCK and CD3E had a moderate positive correlation with CD39 expression. Importantly, high-LCK and high-CD3E groups had a higher percentage of responders than the low-expression groups both in GSE176307 (LCK: 22.73vs. 13.64%, CD3E: 22.00 vs. 13.16%) and IMvigor210 cohorts (LCK: 28.19 vs. 17.45%, CD3E: 25.50 vs. 20.13%).Conclusion: CD3E and LCK were potential biomarkers of MIBC. CD3E and LCK were positively correlated with several regular immunotherapy biomarkers, which is supported by real-world outcomes from two immunotherapy cohorts.

Introduction: We aimed to develop an easy-to-use individual survival prognostication tool based on competing risk analyses to predict the risk of 5-year cancer-specific death after radical prostatectomy for patients with prostate cancer (PCa).Methods: We obtained the data from the Surveillance, Epidemiology, and End Results (SEER) database (2004–2016). The main variables obtained included age at diagnosis, marital status, race, pathological extension, regional lymphonode status, prostate specific antigen level, pathological Gleason Score. In order to reveal the independent prognostic factors. The cumulative incidence function was used as the univariable competing risk analyses and The Fine and Gray's proportional subdistribution hazard approach was used as the multivariable competing risk analyses. With these factors, a nomogram and risk stratification based on the nomogram was established. Concordance index (C-index) and calibration curves were used for validation.Results: A total of 95,812 patients were included and divided into training cohort (n = 67,072) and validation cohort (n = 28,740). Seven independent prognostic factors including age, race, marital status, pathological extension, regional lymphonode status, PSA level, and pathological GS were used to construct the nomogram. In the training cohort, the C-index was 0.828 (%95CI, 0.812–0.844), and the C-index was 0.838 (%95CI, 0.813–0.863) in the validation cohort. The results of the cumulative incidence function showed that the discrimination of risk stratification based on nomogram is better than that of the risk stratification system based on D'Amico risk stratification.Conclusions: We successfully developed the first competing risk nomogram to predict the risk of cancer-specific death after surgery for patients with PCa. It has the potential to help clinicians improve post-operative management of patients.

Immunotherapy has been a milestone for muscle-invasive bladder cancer (MIBC), but only a small portion of patients can benefit from it. Therefore, it is crucial to develop a robust individualized immune-related signature of MIBC to identify patients potentially benefiting from immunotherapy. The current study identified patients from the Cancer Genome Atlas (TCGA) and immune genes from the ImmPort database, and used improved data analytical methods to build up a 45 immune-related gene pair signature, which could classify patients into high-risk and low-risk groups. The signature was then independently validated by a Gene Expression Omnibus (GEO) dataset and IMvigor210 data. The subsequent analysis confirmed the worse survival outcomes of the high-risk group in both training (p < 0.001) and validation cohorts (p = 0.018). A signature-based risk score was proven to be an independent risk factor of overall survival (p < 0.001) and could predict superior clinical net benefit compared to other clinical factors. The CIBERSORT algorithm revealed the low-risk group had increased CD8+ T cells plus memory-activated CD4+ T-cell infiltration. The low-risk group also had higher expression of PDCD1 (PD-1), CD40, and CD27, and lower expression of CD276 (B7-H3) and PDCD1LG2 (PD-L2). Importantly, IMvigor210 data indicated that the low-risk group had higher percentage of “inflamed” phenotype plus less “desert” phenotype, and the survival outcomes were significantly better for low-risk patients after immunotherapy (p = 0.014). In conclusion, we proposed a novel and promising prognostic immune-related gene pair (IRGP) signature of MIBC, which could provide us a panoramic view of the tumor immune microenvironment of MIBC and independently identify MIBC patients who might benefit from immunotherapy.

Background: Urolithiasis is the most common complication of horseshoe kidney (HK), which can be treated by extracorporeal shock wave lithotripsy (ESWL), flexible ureteroscopy (FURS), and percutaneous nephrolithotomy (PCNL). When comparing treatments of ESWL and FURS, it is unclear which is more efficient and safe. The objective of this study was to compare the efficacy and safety of FURS and SWL for the treatment of urolithiasis in HK patients.Methods: A systematic search of the Web of Science, PubMed, and EMBASE was performed in February 2021. Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias in each study.Results: Five studies published between 2008 and 2018 were synthesized in the present meta-analysis. The study revealed that FURS compared with SWL had greater initial and overall stone-free rates (SFRs). Risk ratios (RRs) were 2.46 (P < 0.00001) in initial SFRs, 1.36 (P = 0.02) in overall SFRs. No differences were found in the retreatment ratio, RRs were 0.49 (P = 0.43). In addition, no major complications were encountered, and all the complications were mild to moderate.Conclusion: The study demonstrated that FURS and SWL are effective and safe treatments for patients with HK with stones (

Abstract Background For localized prostate cancer (PCa), radical prostatectomy (RP) and radiotherapy (RT) are two standard interventions to decrease PCa mortality. Contemporary studies contained the elderly people; analyses focusing on patients over 75 years of age were still lacking. Method In the Surveillance Epidemiology and End Results (SEER) database (2004‐2015), people over 75 years of age with cT2 stage were selected in our research. Multivariable Cox proportional hazard models were used to analyze cancer‐specific mortality (CSM) and overall mortality (OM) after adjustment. The propensity score matching was performed to assume the randomization. An instrument variate (IVA) was used to calculate the unmeasured confounders. Results Radical prostatectomy is superior to RT in OM and CSM after adjustment for covariates (HR = 0.54, 95% CI = 0.47‐0.62, P

Abstract Background Lipid profiles are believed to play an important role in the tumorigenesis and progression of prostate cancer (PCa), but research combining those data is lacking. Therefore, this meta-analysis aims to assess the prognostic role of lipid profiles after RP. Method We systematically searched PubMed, Embase, and Cochrane Library Central Register of Controlled Trials for articles evaluating association between lipid profiles and prognosis after RP. Odds ratio (OR) and hazard ratio (HR) of lipid profiles for advanced pathological tumor features and biochemical recurrence (BCR) were extracted and pooled OR and HR were calculated. Newcastle-Ottawa scale was used for study quality assessment and funnel plot was used for evaluating publication bias. Results Twelve articles involving 11,108 patients were eventually selected. We found low HDL was associated with more frequent occurrence of pathological T stage (pT) ≥ T3 (pooled OR = 1.29, 95% CI 1.07–1.56) and Gleason score (GS) ≥8 (pooled OR = 1.32, 95% CI 1.02–1.72) after RP. Hypertriglyceridemia was also linked with higher risk of pT ≥ T3 (pooled OR = 1.20, 95% CI 1.01–1.42) and positive surgical margin (PSM) (pooled OR = 1.36, 95% CI 1.11–1.65). However, no significant association was observed between BCR and abnormal lipid profile levels. Conclusion Low HDL level was associated with more common occurrence of pT ≥ T3 and GS ≥8, and elevated triglycerides level was linked higher risk of pT ≥ T3 and PSM, but none of the lipid subfractions was correlated with biochemical recurrence after RP.

Papillary renal carcinoma (PRCC) is one of the important subtypes of kidney cancer, with a high degree of heterogeneity. At present, there is still a lack of robust and accurate biomarkers for the diagnosis, prognosis and treatment selection of PRCC. Considering the important role of tumor immunity in PRCC, we aim to construct a signature based on immune-related gene pairs (IRGPs) to estimate the prognostic of patients with PRCC. We obtained gene expression profiling and clinical information of patients with PRCC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), which were divided into discovery (n = 287) and validation (n = 28) cohorts, respectively. By univariate analysis, multivariate Cox analysis, and least absolute shrinkage and selection operator (Lasso) analysis, we selected 14 IRGPs with a panel of 22 unique genes to construct the prognostic signature. According to the signature, we stratified patients into high-risk group and low-risk group. In both discovery and validation cohorts, the results of Kaplan-Meier analysis showed that there were significant differences in OS between the two groups (p < 0.001). Combined with multiple clinical and pathological factors, the results of multivariate analyses confirmed that this signature was an independent predictor of OS (HR, 3.548; 95%CI, 2.096-6.006; p < 0.001). The results of immune infiltration analysis demonstrated that the abundance of multiple tumor-infiltration lymphocytes such as CD8 + T cells, Tregs, and T follicular cell helper were significantly higher in the high-risk group. Functional analysis showed that multiple immune-related signaling pathways were enriched in the high-risk group. In conclusion, we successfully established an individualized prognostic IRGPs signature, which can accurately assess and predict the OS of patients with PRCC.

There is a significant heterogeneity in the immunotherapeutic responsiveness of each muscle-invasive bladder cancer (MIBC) patient. In our research, we aimed to identify a novel classification of MIBC based on immunogenomic profiling that may facilitate the reasonable stratification of prognosis and response to immunotherapy. The single-sample gene-set enrichment analysis (ssGSEA) was used to analyze the RNA-seq data of 29 important immune signatures from TCGA. Unsupervised hierarchical clustering was performed to identify an immunogenomic classification of MIBC. Then, we assessed the features of the classification in prognosis, immune infiltration, tumor-infiltration lymphocytes, HLA genes, and PD-L1 expression level. A total of 399 MIBC samples were included and three subtypes named Immunity_High, Immunity_Medium, and Immunity_Low were identified. The Immunity_High had a significant advantage in overall survival over the Immunity_Medium and Immunity_Low (p = 0.046 and p = 0.024). From Immunity_Low to Immunity_High, immune cell infiltration and stromal content showed an upward trend (p < 0.001). Meanwhile, Immunity_High was associated with a significantly higher proportion of TILs including dendritic cells resting, macrophages M1, mast cells resting, T cells CD4 memory activated, and T cells CD8+. And the expression levels of all HLA genes and PD-L1 of Immunity_High were the highest, consistent (p < 0.001). Two hundred ninety eight MIBC patients treated with immunotherapy from the IMvigor210 were included to form an independent validation cohort to verify the robustness of immunogenomic classification and the ability to predict the response to immunotherapy. This classification had potential clinical implications for predicting prognosis and immunotherapeutic responsiveness of MIBC patients.

Abstract The longevity-promoting benefits of lactobacilli were hypothesized as early as 1907. Although the anti-aging effects of lactic acid bacteria (LAB) have been observed in nematodes, rodents and humans for over a century, the mechanisms underlying the effects of probiotics on aging have rarely been assessed. Using the Caenorhabditis elegans (C. elegans) model, various studies have elucidated the role of different signaling cascades, especially the DAF-16 cascade, on lifespan extension by LAB. In this study, the mechanisms through which Bifidobacterium longum strain BB68 affects the longevity of C. elegans were assessed. The lifespan of nematodes increased by 28% after worms were fed BB68, and this extension of lifespan was completely lost in backgrounds containing a mutated DAF-16 gene. High levels of DAF-16 (in the daf-16 (mu86); muIs61 strain) nuclear accumulation and high expression of the SOD-3 gene (a DAF-16-specific target gene) were observed as a result of BB68 treatment. Immunofluorescence microscopy revealed that TIR-1 and JNK-1 are involved in the phosphorylation and activation of DAF-16. Thus, BB68 increased the longevity of nematodes by activating the TIR-1 – JNK-1 – DAF-16 signaling pathway, and the cell wall component of BB68 contributed to longevity.

Combining immune checkpoint inhibitors has shown its efficacy compared to monotherapy in advanced malignancies. We conducted this meta-analysis to provide latest evidence on the objective response rate (ORR) and incidence of treatment-related high-grade adverse events (AEs) during nivolumab and ipilimumab combination treatment and further explore from different drug dose level. PubMed and the 2019 American Society of Clinical Oncology (ASCO) annual meeting abstracts were searched for qualified clinical trials up to June 2019. Of the 23 clinical trials (13 from publications and 11 from ASCO abstracts) included, 2,114 and 2,674 patients were eligible for efficacy and safety analysis, respectively. Pooled analysis suggested that the overall ORR was achieved in 34.5% [95% confidence interval (CI), 29.1–40.4%] of patients. There was no significant difference between nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks (N3I1-Q3W) and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (N1I3-Q3W) arms in ORR [30.8% vs 41%; odds ratio (OR), 0.72; 95% CI, 0.39–1.30; P = 0.275]. Grade 3–4 AEs related to combination therapy occurred in 39.9% (95% CI, 33.5–46.7%) of patients; the most commonly reported grade 3–4 treatment-related AEs were diarrhea (5.28%), colitis (3.96%) and increased alanine aminotransferase (3.51%). Incidence of grade 3–4 AEs were significant lower in N3I1-Q3W arm than in N1I3-Q3W arm (31.3% vs 55.9%; OR 0.52; 95% CI, 0.32–0.87; P = 0.012). Treatment-related death was rare and occurred in 2.0% (95% CI, 1.5–2.7%) of patients. Our comprehensive study provides more precise data on the incidence of treatment-related high-grade AEs and ORR among patients receiving nivolumab and ipilimumab combination regimens. Patients on the N3I1-Q3W arm had comparable ORR and significantly occurred less grade 3–4 AEs than patients on the N1I3-Q3W arm. Our finding is of great importance in assisting clinical trial design and clinical medication choice.

The role of a series of functionalized graphene additives in power cable insulation in suppressing the growth of electrical treeing and preventing the degradation of the polymer matrix has been investigated by density functional theory calculations. Bader charge analysis indicates that pristine, doped or defect graphene could effectively capture hot electrons to block their attack on cross-linked polyethylene (XLPE) because of the π–π conjugated unsaturated structures. Further exploration of the electronic properties in the interfacial region between the additives and XLPE shows that N-doped single-vacancy graphene, graphene oxide and B-, N-, Si- or P-doped graphene oxide have relatively strong physical interaction with XLPE to restrict its mobility and rather weak chemical activity to prevent the cleavage of the C–H or C–C bond, suggesting that they are all potential candidates as effective additives. The understanding of the features of functionalized graphene additives in trapping electrons and interfacial interaction will assist in the screening of promising additives as voltage stabilizers in power cables.

A parameterization modeling method based on finite element mesh to create complex large-scale lattice structures for AM is presented, and a corresponding approach for size optimization of lattice structures is also developed. In the modeling method, meshing technique is employed to obtain the meshes and nodes of lattice structures for a given geometry. Then, a parametric description of lattice unit cells based on the element type, element nodes and their connecting relationships is developed. Once the unit cell design is selected, the initial lattice structure can be assembled by the unit cells in each finite element. Furthermore, modification of lattice structures can be operated by moving mesh nodes and changing cross-sectional areas of bars. The graded and non-uniform lattice structures can be constructed easily based on the proposed modeling method. Moreover, a size optimization algorithm based on moving iso-surface threshold (MIST) method is proposed to optimize lattice structures for enhancing the mechanical performance. To demonstrate the effectiveness of the proposed method, numerical examples and experimental testing are presented, and experimental testing shows 11% improved stiffness of the optimized non-uniform lattice structure than uniform one.