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Proteolysis Targeting Chimera (PROTAC) is an emerging and evolving technology based on targeted protein degradation (TPD). Small molecule PROTACs have shown great efficacy in degrading disease-specific proteins in preclinical and clinical studies, but also showed various limitations. In recent years, new technologies and advances in TPD have provided additional optimized strategies based on conventional PROTACs that can overcome the shortcomings of conventional PROTACs in terms of undruggable targets, bioavailability, tissue-specificity, spatiotemporal control, and degradation scope. In addition, some designs of special targeting chimeras and applications based on multidisciplinary science have shed light on novel therapeutic modalities and drug design. However, each improvement has its own advantages, disadvantages and application conditions. In this review, we summarize the exploration of PROTAC elements, depict a landscape of improvements and derived concepts of PROTACs, and expect to provide perspectives for technological innovations, combinations and applications in future targeting chimera design., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

We aimed to investigate the genomic and tumor microenvironmental (TME) profiles in non-muscle invasive bladder cancer (NMIBC) and explore potential predictive markers for Bacillus Calmette-Guérin (BCG) treatment response in high-risk NMIBC patients (according to European Association of Urology (EAU) risk stratification). 40 patients with high-risk NMIBC (cTis-T1N0M0) who underwent en bloc resection followed by BCG instillation were retrospectively enrolled. Surgical samples were subjected to Next Generation Sequencing (NGS) and multiplex immunofluorescence (mIF) assay. Genomic profiling revealed high prevalences of alterations in TERT (55%), KDM6A (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%) and ARID1A (20%). TME analysis showed different proportions of macrophages, NK cells, T cells subsets in tumoral and stromal compartment. Multivariate analysis identified TERT C228T and alteration in KDM6A as two independent factors associated with inferior RFS. The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment., (© 2024. The Author(s).)

Since silver nanoparticles (AgNPs) and polystyrene microplastics (PS-MP) share common environmental niches, their interactions can modulate their hazard impacts. Herein, we assessed the developmental toxicity of 1 mg/L PS-MP, 0.5 mg/L AgNPs and the mixtures of AgNPs and PS-MP on embryo-larval zebrafish. We found that AgNPs co-exposure with PS-MP remarkably decreased mortality rates, malformation rates, heart rates and yolk sac area, while it increased hatching rates and eye size compared to the AgNPs group. These phenomena revealed that the cell cycle, oxidative stress, apoptosis, lipid metabolism, ferroptosis and p53 signalling pathway were obviously affected by single AgNPs exposure at 96 hpf (hours post fertilization). Interestingly, all these effects were effectively ameliorated by co-exposure with PS-MP. The combination of transcriptomic and metabolomic analyses showed that the imbalance of DEGs (differentially expressed genes) and DEMs (differentially expressed metabolites) (PI, phosphatidylinositol and TAG-FA, triacylglycerol-fatty acid) disturbed both the cell cycle and lipid metabolism following single AgNPs exposure and co-exposure with PS-MP. These findings suggest that PS-MP attenuates the developmental toxicity of AgNPs on embryo-larval zebrafish. Overall, this study provides important insight into understanding the transcriptional responses and mechanisms of AgNPs alone or in combination with PS-MPs on embryo-larval zebrafish, providing a reference for ecological risk assessment of combined exposure to PS-MP and metal nanoparticles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Prostate cancer (PCa) is a prevalent malignant tumor affecting the male reproductive system and there are mainly three widely accepted PCa surgery types in current clinical treatment: open radical prostatectomy (ORP), laparoscopic radical prostatectomy (LRP) and robot-assisted radical prostatectomy (RARP). Here, we aimed to evaluate the clinical effect of RARP for PCa patients compared with ORP and LRP based on the context of PCa encompass two dimensions: oncological outcomes (biochemical recurrence (BCR) and positive surgical margin (PSM)) and functional outcomes (urinary continence and recovery of erectile function) in this network meta-analysis (NMA). PubMed, Embase and Cochrane databases were systematically searched in January 7, 2024. 4 randomized controlled trials (RCTs) and 72 non-RCTs were included. RARP displayed significant positive effect on lower BCR and better recovery of erectile function but no significant differences existed among three surgery types for PSM and urinary continence., Competing Interests: Declaration of Competing Interest All authors declare no financial and personal relationships., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Image-guided surgery (IGS) refers to surgery navigated by medical imaging technology, helping doctors better clarify tumor boundaries, identify metastatic lymph nodes and preserve surrounding healthy tissue function. Recent studies have provided expectable momentum of the application of IGS in prostate cancer (PCa). The authors aim to comprehensively construct a bibliometric analysis of the application of IGS in PCa., Method: The authors searched publications related to application of IGS in PCa from 2013 to 2023 on the web of science core collection (WoSCC) databases. VOSviewer, CiteSpace, and R package 'bibliometrix' were used for bibliometric analysis., Results: Two thousand three eighty-nine articles from 75 countries and 2883 institutions led by the United States were included. The number of publications related to the application of IGS in PCa kept high in the last decade. Johns Hopkins University is the top research institutions. Journal of Nuclear Medicine has the highest popularity as the selection of journal and co-cited journal. Pomper Martin G. had published the most paper. Ali Afshar-Oromieh was co-cited most frequently. The clinical efficacy of PSMA-PET/CT in PCa diagnosis and treatment are main topics in this research field, with emerging focuses on the use of fluorescence imaging guidance technology in PCa. 'PSMA' and 'PET/CT' are the main keywords as long-term research hotspots., Conclusion: This study is the first bibliometric analysis of researches on application of IGS in PCa with three recognized bibliometric software, providing an objective description and comprehensive guidance for the future relevant investigations., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Enhanced cellular therapy has emerged as a novel concept following the basis of cellular therapy. This treatment modality applied drugs or biotechnology to directly enhance or genetically modify cells to enhance the efficacy of adoptive cellular therapy (ACT). Drugs or biotechnology that enhance the killing ability of immune cells include immune checkpoint inhibitors (ICIs) / antibody drugs, small molecule inhibitors, immunomodulatory factors, proteolysis targeting chimera (PROTAC), oncolytic virus (OV), etc. Firstly, overcoming the inhibitory tumor microenvironment (TME) can enhance the efficacy of ACT, which can be achieved by blocking the immune checkpoint. Secondly, cytokines or cytokine receptors can be expressed by genetic engineering or added directly to adoptive cells to enhance the migration and infiltration of adoptive cells to tumor cells. Moreover, multi-antigen chimeric antigen receptors (CARs) can be designed to enhance the specific recognition of tumor cell-related antigens, and OVs can also stimulate antigen release. In addition to inserting suicide genes into adoptive cells, PROTAC technology can be used as a safety switch or degradation agent of immunosuppressive factors to enhance the safety and efficacy of adoptive cells. This article comprehensively summarizes the mechanism, current situation, and clinical application of enhanced cellular therapy, describing potential improvements to adoptive cellular therapy., (© 2024. The Author(s).)

The emergence of resistance to prostate cancer (PCa) treatment, particularly to androgen deprivation therapy (ADT), has posed a significant challenge in the field of PCa management. Among the therapeutic options for PCa, radiotherapy, chemotherapy, and hormone therapy are commonly used modalities. However, these therapeutic approaches, while inducing apoptosis in tumor cells, may also trigger stress-induced premature senescence (SIPS). Cellular senescence, an entropy-driven transition from an ordered to a disordered state, ultimately leading to cell growth arrest, exhibits a dual role in PCa treatment. On one hand, senescent tumor cells may withdraw from the cell cycle, thereby reducing tumor growth rate and exerting a positive effect on treatment. On the other hand, senescent tumor cells may secrete a plethora of cytokines, growth factors and proteases that can affect neighboring tumor cells, thereby exerting a negative impact on treatment. This review explores how radiotherapy, chemotherapy, and hormone therapy trigger SIPS and the nuanced impact of senescent tumor cells on PCa treatment. Additionally, we aim to identify novel therapeutic strategies to overcome resistance in PCa treatment, thereby enhancing patient outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Xia, Sun, Liu, An, Xu, Zhang, Zhong, Zeng, Ma, He, Wang and Xia.)

Pyroptosis is a type of programmed cell death and plays a dual role in distinct cancers. It is elusive to evaluate the activation level of pyroptosis and to appraise the involvement of pyroptosis in the occurrence and development of diverse tumors. Accordingly, we herein established an indicator to evaluate pyroptosis related gene transcription levels based on the expression level of genes involved in pyroptosis and tried to elaborated on the association between pyroptosis and tumors across diverse tumor types. We found that pyroptosis related gene transcription levels could predict the prognosis of patients, which could act as either a favorable or a dreadful factor in diverse cancers. According to signaling pathway analyses we observed that pyroptosis played a significant role in immune regulation and tumorigenesis and had strong links with other forms of cell death. We also performed analysis on the crosstalk between pyroptosis and immune status and further investigated the predictive potential of pyroptosis level for the efficacy of immunotherapy. Lastly, we manifested that pyroptosis status could serve as a biomarker to the efficacy of chemotherapy across various cancers. In summary, this study established a quantitative indicator to evaluate pyroptosis related gene transcription levels, systematically explored the role of pyroptosis in pan-cancer. These results could provide potential research directions targeting pyroptosis, and highlighted that pyroptosis may be used to develop a novel strategy for the treatment of cancer., (© 2023. Springer Nature Limited.)

Background: The high recurrence rate of non-muscle-invasive bladder cancer (NMIBC) after tumor resection brings huge physical and financial burdens for patients. Several predictive models that predict the recurrence of patients with NMIBC have drawbacks in clinical practice. With the rapid development of therapeutic methods, more factors should be taken into consideration when constructing predictive model., Methods: We retrospectively enrolled 90 patients who were diagnosed as intermediate- or high-risk NMIBC and received a Thulium laser resection of bladder tumor (TmLRBT) or transurethral resection of bladder tumor (TURBT) followed by BCG instillation. Univariate Cox regression analysis and multivariate Cox regression analysis were performed to screen out the independent prognostic factors of recurrence free survival (RFS). A nomogram and risk index were constructed using these prognostic factors., Results: In this study, 22 patients suffered recurrence; 37 patients (41%) received TmLRBT, and over 90% patients completed intravesical BCG instillation for one year. The univariate Cox regression showed that surgery (TURBT vs TmLRBT), previous bladder tumor, tumor number, pathological stage, post-operative catheterization and number of BCG therapy were associated with RFS. The multivariate Cox regression revealed that surgery (TURBT vs TmLRBT) (HR = 3.16, 95%CI [1.02 - 9.83]); previous bladder tumor (HR = 4.03, 95%CI [1.41 - 11.54]); number of BCG therapy (HR = 0.89, 95%CI [0.84 - 0.95]) were independent prognostic factors. A nomogram was constructed and exhibited excellent capability in predicting the RFS with an AUC of 0.789, 0.848, 0.806 at 6-, 12- and 24-months respectively and a c-index of 0.822. Also, the calibration curve and decision curve analysis were performed to verify the predictive efficacy. The risk index was derived from the nomogram and also exhibited favorable capability in predicting the progression free survival (PFS) of patients., Conclusions: Patients who received TmLRBT, without previous bladder tumor history and had more intravesical BCG instillations are likely to have better RFS. The nomogram and the risk index which were constructed to predict the RFS and PFS of patients may help urologists to make clinical decisions and aid in precision medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer YZ declared a shared affiliation with the authors to the handling editor at the time of review., (Copyright © 2023 Sun, An, Xu, Liu, Xu, Xia and Wang.)

Objective: To investigate the expressions of Notch1 and Hes1 in diffuse large B-cell lymphoma (DLBCL), and their correlations with clinical features., Methods: Immunohistochemistry (IHC) was performed on DLBCL samples (54 cases) and lymphadenitis tissues (20 cases) to evaluate the expressions of Notch1 and Hes1, and analyze their correlations with clinical characteristics of patients. Based on Oncomine database, the expressions of Notch1 and Hes1 mRNA and DNA were also explored., Results: IHC result showed that the positive expression rates of Notch1 and Hes1 in DLBCL patients were significantly higher than those in the control group ( P <0.05). In DLBCL patients, the expression of Notch1 was closely associated with B symptoms, Ann Arbor stage, lymphocyte count and the level of lactate dehydrogenase ( P <0.05), while the expression level of Hes1 was significantly higher in patients with B symptoms ( P <0.05). Notch + /Hes1 + expression was found in 21 DLBCL tissues (38.9%), and there was a correlation between Notch1 and Hes1 expression ( r =0.296, P <0.05). Bioinformatics analysis (Oncomine database) showed that the mRNA expressions of Notch1 and Hes1 in the Brune dataset were significantly higher than those in the control tissues ( P <0.05)., Conclusion: The expressions of Notch1 and Hes1 in DLBCL are significantly higher than those in lymphadenitis, and correlated with B symptoms and Ann Arbor stage, suggesting that Notch1 and Hes1 play important roles in the occurrence and development of DLBCL.

Background: Cereblon (CRBN) has emerged as a vital E3 ubiquitin ligase for Proteolysis-targeting chimera (PROTAC) design. However, few studies focus on the physiological mechanism of CRBN, and more studies are needed to explore the influence of CRBN on tumorigenesis. This pan-cancer analysis aims to explore the prognostic and immunologic roles of CRBN, and provide new insight for CRBN into cancer treatment and PROTAC design., Methods: The TCGA database, TIMER 2.0 database, and TISIDB database were used to analyze the role of CRBN in pan-cancer. Multiple bioinformatic methods (ssGSEA, Kaplan-Meier, univariate cox regression, ESTIMATE, CIBERSORT) were applied to investigate the CRBN expression status, gene activity, prognostic values, and its correlation with immune scores, immune infiltration, immune-related functions, HALLMARKs functions, and response to immunotherapy in pan-cancer., Results: In most cancer types, the expression and activity of CRBN in tumor groups were lower compared with normal groups. Upregulated CRBN expression may indicate a better prognosis for cancer patients. The Immune score, stromal score, and tumor purity varied greatly among different cancer types. GSEA analysis showed that high CRBN expression was correlated with the downregulation of tumor-promoting signaling pathways. The level of CRBN was associated with Tumor mutation burden (TMB), Microsatellite instability (MSI), objective response rate (ORR), and immune cell infiltration in a few cancer types., Conclusion: Pan-cancer analysis reveals the potential role of CRBN as a prognostic biomarker and versatile immunologic roles in different cancer types. Upregulated expression of CRBN may be beneficial to CRBN-related immunotherapy and PROTAC design., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: T cell immunoglobulin and ITIM domain (TIGIT) is a widely concerned immune checkpoint, which plays an essential role in immunosuppression and immune evasion. However, the role of TIGIT in normal organ tissues and renal clear cell carcinoma is unclear. We aim to identify the critical role of TIGIT in renal clear cell carcinoma and find potential targeted TIGIT drugs., Materials and Methods: Data retrieved from the GTEX database and TCGA database was used to investigate the expression of TIGIT in normal whole-body tissues and abnormal pan-cancer, then the transcriptome atlas of patients with kidney renal clear cell carcinoma (KIRC) in the TCGA database were applied to distinguish the TIGIT related features, including differential expression status, prognostic value, immune infiltration, co-expression, and drug response of sunitinib an anti-PD1/CTLA4 immunotherapy in KIRC. Furthermore, we constructed a gene-drug network to discover a potential drug targeting TIGIT and verified it by performing molecular docking. Finally, we conducted real-time polymerase chain reaction (PCR) and assays for Transwell migration and CCK-8 to explore the potential roles of TIGIT., Results: TIGIT showed a moderate expression in normal kidney tissues and was confirmed as an essential prognostic factor that was significantly higher expressed in KIRC tissues, and high expression of TIGIT is associated with poor OS, PFS, and DSS in KIRC. Also, the expression of TIGIT was closely associated with the pathological characteristics of the tumor, high expression of TIGIT in KIRC was observed with several critical functions or pathways such as apoptosis, BCR signaling, TCR signaling et al. Moreover, the expression of TIGIT showed a strong positive correlation with infiltration of CD8+ T cells and Tregs and a positive correlation with the drug sensitivity of sunitinib simultaneously. Further Tide ips score analysis and submap analysis reveal that patients with high TIGIT expression significantly show a better response to anti-PD1 immunotherapy. Following this, we discovered Selumetinib and PD0325901 as potential drugs targeting TIGIT and verified the interaction between these two drugs and TIGIT protein by molecular docking. Finally, we verified the essential role of TIGIT in the proliferation and migration functions by using KIRC cell lines., Conclusions: TIGIT plays an essential role in tumorigenesis and progression in KIRC. High expression of TIGIT results in poor survival of KIRC and high drug sensitivity to sunitinib. Besides, Selumetinib and PD0325901 may be potential drugs targeting TIGIT, and combined therapy of anti-TIGIT and other treatments show great potential in treating KIRC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xia, Li, Sun, Liu, Xu, An, Xu, Zhang, Zhong, Zeng, Ma, He, Zhang, Guan, Li and Wang.)

Introduction: Renal cell carcinoma (RCC) is one of the most common urinary tumors. The risk of metastasis for patients with RCC is about 1/3, among which 30−40% have lymph node metastasis, and the existence of lymph node metastasis will greatly reduce the survival rate of patients. However, the necessity of lymph node dissection is still controversial at present. Therefore, a new predictive model is urgently needed to judge the risk of lymph node metastasis and guide clinical decision making before operation. Method: We retrospectively collected the data of 189 patients who underwent retroperitoneal lymph node dissection or enlarged lymph node resection due to suspected lymph node metastasis or enlarged lymph nodes found during an operation in Tongji Hospital from January 2016 to October 2021. Univariate and multivariate logistic regression and least absolute shrinkage and selection operator (lasso) regression analyses were used to identify preoperative predictors of pathological lymph node positivity. A nomogram was established to predict the probability of lymph node metastasis in patients with RCC before surgery according to the above independent predictors, and its efficacy was evaluated with a calibration curve and a DCA analysis. Result: Among the 189 patients, 54 (28.60%) were pN1 patients, and 135 (71.40%) were pN0 patients. Three independent impact factors were, finally, identified, which were the following: age (OR = 0.3769, 95% CI = 0.1864−0.7622, p < 0.01), lymph node size according to pre-operative imaging (10−20 mm: OR = 15.0040, 95% CI = 1.5666−143.7000, p < 0.05; >20 mm: OR = 4.4013, 95% CI = 1.4892−7.3134, p < 0.01) and clinical T stage (cT1−2 vs. cT3−4) (OR = 3.1641, 95% CI = 1.0336−9.6860, p < 0.05). The calibration curve and DCA (Decision Curve Analysis) showed the nomogram of this predictive model had good fitting. Conclusions: Low age, large lymph node size in pre-operative imaging and high clinical T stage can be used as independent predictive factors of pathological lymph node metastasis in patients with RCC. Our predictive nomogram using these factors exhibited excellent discrimination and calibration.

Introduction: Bladder cancer (BCa) is the 10th most common type of cancer worldwide, and human papillomavirus (HPV) is the most common sexually transmitted infection. However, the relationship between HPV infection and the risk of BCa is still controversial and inconclusive., Methods: This systematic review and meta-analysis were conducted following the PRISMA 2020 reporting guideline. This study searched four bibliographic databases with no language limitation. The databases included PubMed (Medline), EMBASE, Cochrane Library, and Web of Science. Studies evaluating the interaction between HPV infection and the risk of BCa from inception through May 21, 2022, were identified and used in this study. This study estimated the overall and type-specific HPV prevalence and 95% confidence intervals (95% CI) using Random Effects models and Fixed Effects models. In addition, this study also calculated the pooled odds ratio and pooled risk ratio with 95% CI to assess the effect of HPV infection on the risk and prognosis of bladder cancer. Two-sample mendelian randomization (MR) study using genetic variants associated with HPV E7 protein as instrumental variables were also conducted., Results: This study retrieved 80 articles from the four bibliographic databases. Of the total, 27 were case-control studies, and 53 were cross-sectional studies. The results showed that the prevalence of HPV was 16% (95% CI: 11%-21%) among the BCa patients, most of which were HPV-16 (5.99% [95% CI: 3.03%-9.69%]) and HPV-18 (3.68% [95% CI: 1.72%-6.16%]) subtypes. However, the study found that the prevalence varied by region, detection method, BCa histological type, and sample source. A significantly increased risk of BCa was shown for the positivity of overall HPV (odds ratio [OR], 3.35 [95% CI: 1.75-6.43]), which was also influenced by study region, detection method, histological type, and sample source. In addition, the study found that HPV infection was significantly associated with the progression of BCa (RR, 1.73 [95% CI: 1.39-2.15]). The two-sample MR analysis found that both HPV 16 and 18 E7 protein exposure increased the risk of BCa (HPV 16 E7 protein: IVW OR per unit increase in protein level = 1.0004 [95% CI: 1.0002-1.0006]; p = 0.0011; HPV 18 E7 protein: IVW OR per unit increase in protein level = 1.0003 [95% CI: 1.0001-1.0005]; p = 0.0089)., Conclusion: In conclusion, HPV may play a role in bladder carcinogenesis and contribute to a worse prognosis for patients with BCa. Therefore, it is necessary for people, especially men, to get vaccinated for HPV vaccination to prevent bladder cancer., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: With the growth and aging of population, the incidence of prostate cancer will increase year by year, which is bound to bring greater economic burden to the society. There has been greater interest in the anticancer effects of statin in recent years. It is controversial whether statin use is associated with the risk of prostate cancer (PCa). Thus, we conducted a meta-analysis and systematic review to explore the effects of statin use and their duration and cumulative dose on the overall incidence of PCa., Method: The study was conducted according to the latest guidelines for PRISMA 2020. We searched PubMed and other databases for studies about the association of statin use with the risk of incident prostate cancer between January 1, 1990, and April 11, 2022. Two independent researchers extracted data and evaluated the quality of the studies. R x64 4.1.2 and random-effects model were used for data statistics. Relative risk (RR) and odds ratio (OR) effective values with a 95% confidence interval (95% CI) were used to assess the main results., Results: The results of 6 RCT and 26 cohort studies showed that statins did not significantly associate with the incidence of PCa (RR = 0.94, 95% CI: 0.82-1.08). The similar results were obtained from 9 case-control studies (OR = 1.03, 95% CI: 0.99-1.07). However, statins were associated with a lower risk of Pca (RR = 0.44, 95% CI: 0.28-0.70) when the cumulative defined daily dose (cDDD) was high. Using statins for more than five years could be associated with a reduced incidence of Pca (RR = 0.47, 95% CI: 0.23-0.97). There was a significant heterogeneity in these studies (RCT and cohort study: I 2  = 98%, P  < 0.01; case-control study: I 2  = 72%, P  < 0.01)., Conclusion: We concluded that statins had a neutral association with the overall risk of PCa. High cDDD and long duration were associated with a lower risk of PCa., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Meng-Yao Xu et al.)

Objective: Although the prognostic effect of statins on patients with prostate cancer (PCa) has been frequently evaluated, a consistent result is still lacking. We aimed to evaluate the association between statin use and mortality among patients with PCa after definite therapies., Methods: A systematic search of PubMed and other databases for cohort studies about the effect of statins on patients with PCa was performed until April 2022. Meta-analysis was performed using R software version 4.1.2., Results: 24 cohort studies involving 369, 206 participants were finally included. We found statin use significantly reduced the risk of prostate cancer-specific mortality (PCSM) with a pooled hazard ratio (pHR) = 0.76 (95% CI: 0.69-0.84, 18 studies), especially for postdiagnostic statin users: pHR = 0.81 (95% CI: 0.77-0.85) and patients who accepted androgen deprivation therapy (ADT): pHR = 0.69 (95% CI: 0.59-0.81). Statin use was also associated with a 24% reduction in the risk of all-cause mortality (ACM): pHR = 0.76 (95% CI: 0.68-0.85, 17 studies), especially for postdiagnostic statin users: pHR = 0.81 (95% CI: 0.78-0.85) and patients treated with ADT: pHR = 0.72 (95% CI: 0.63-0.82) or radiotherapy (RT): pHR = 0.68 (95% CI: 0.50-0.93)., Conclusion: In conclusion, the use of statins could promote the prognosis of patients with PCa, especially for postdiagnostic users. For patients who received either ADT or radical prostatectomy (RP), statin use could decrease the PCSM. As for those who received either ADT or RT, statin use could decrease the ACM., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Ye An et al.)

Background: Tertiary lymphoid structures (TLSs) are emerging as a potential predictor of prognosis and response to immunotherapy in some solid tumors. However, the comprehensive role of TLSs in bladder cancer remains unclear., Methods: Eighteen bladder cancer (BCa) datasets were downloaded from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), ArratyExpress and IMvigor210. Based on 39 validated TLS signature genes (TSGs), we evaluated the TLS patterns in all patients, and correlated the TLS patterns with prognosis and tumor microenvironment (TME) cell-infiltrating characteristics. The cox regression model and principal component analysis (PCA) algorithms were used to construct the TLS score, which helps to quantify the TLS pattern in individuals., Results: The landscape of 39 validated TSGs in BCa was assessed first. Five distinct TLS patterns and four gene clusters were determined. TLS cluster C2 and gene cluster A were thought to be characterized by mature TLSs and showed better prognosis and higher immune cells infiltration than other clusters. The TLS score was discovered to be tightly correlated with the infiltration level of immune cells, and could predict the maturation status of TLSs to some extent. We found TLS score was an excellent predictor for prognosis in patients with BCa independent of tumor mutation burden (TMB), and low TLS score was related to better prognosis than high TLS score. Besides, low TLS score was correlated with a better response to immune checkpoint blockade (ICB) immunotherapy and commonly used chemotherapy drugs., Conclusions: Our work demonstrated the characteristics of TLSs in BCa. By using the TLS score, we could evaluate the TLS pattern in individuals. Better understanding of TLS pattern and the usage of TLS score could help instruct clinical strategy and precision medicine for BCa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 An, Sun, Xu, Xu, Ma, Liu, Liu, Wang and Xia.)

Background: Bladder cancer is one of the most common malignancies of the urinary system with an unfavorable prognosis. More and more studies have suggested that lipid metabolism could influence the progression and treatment of tumors. However, there are few studies exploring the relationship between lipid metabolism and bladder cancer. This study aimed to explore the roles that lipid metabolism-related genes play in patients with bladder cancer., Methods: TCGA&#95;BLCA cohort and GSE13507 cohort were included in this study, and transcriptional and somatic mutation profiles of 309 lipid metabolism-related genes were analyzed to discover the critical lipid metabolism-related genes in the incurrence and progression of bladder cancer. Furthermore, the TCGA&#95;BLCA cohort was randomly divided into training set and validation set, and the GSE13507 cohort was served as an external independent validation set. We performed the LASSO regression and multivariate Cox regression in training set to develop a prognostic signature and further verified this signature in TCGA&#95;BLCA validation set and GSE13507 external validation set. Finally, we systematically investigated the association between this signature and tumor microenvironment, drug response, and potential functions and then verified the differential expression status of signature genes in the protein level by immunohistochemistry., Results: A novel 6-lipidmetabolism-related gene signature was identified and validated, and this risk score model could predict the prognosis of patients with bladder cancer. In addition, the prognostic model was tightly related to immune cell infiltration and tumor mutation burden. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) showed that mTOR signaling pathway, G2M checkpoint, fatty acid metabolism, and hypoxia were enriched in patients in the high-risk score groups. Furthermore, 3 therapies specific for bladder cancer patients in different risk scores were identified., Conclusion: s. In conclusion, we investigated the lipid metabolism-related genes in bladder cancer through comprehensive bioinformatic analysis. A novel 6-gene signature associated with lipid metabolism for predicting the outcomes of patients with bladder cancer was conducted and validated. Furthermore, the risk score model could be utilized to indicate the choice of therapy in bladder cancer., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yuan-Yuan Yang et al.)

Bladder cancer (BCa) is the 10th most commonly diagnosed cancer worldwide, and cellular senescence is defined as a state of permanent cell cycle arrest and considered to play important roles in the development and progression of tumor. However, the comprehensive effect of senescence in BCa has not ever been systematically evaluated. Using the genome-wide CRISPR screening data acquired from DepMap (Cancer Dependency Map), senescence genes from the CellAge database, and gene expression data from The Cancer Genome Atlas (TCGA), we screened out 12 senescence genes which might play critical roles in BCa. A four-cell-senescence-regulator-gene prognostic index was constructed using the least absolute shrinkage and selection operator (LASSO) and multivariate COX regression model. The transcriptomic data and clinical information of BCa patients were downloaded from TCGA and Gene Expression Omnibus (GEO). We randomly divided the patients in TCGA cohort into training and testing cohorts and calculated the risk score according to the expression of the four senescence genes. The validity of this risk score was validated in the testing cohort (TCGA) and validation cohort (GSE13507). The Kaplan-Meier curves revealed a significant difference in the survival outcome between the high- and low-risk score groups. A nomogram including the risk score and other clinical factors (age, gender, stage, and grade) was established with better predictive capacity of OS in 1, 3, and 5 years. Besides, we found that patients in the high-risk group had higher tumor mutation burden (TMB); lower immune, stroma, and ESTIMATE scores; higher tumor purity; aberrant immune functions; and lower expression of immune checkpoints. We also performed gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) to investigate the interaction between risk score and hallmark pathways and found that a high risk score was connected with activation of senescence-related pathways. Furthermore, we found that a high risk score was related to better response to immunotherapy and chemotherapy. In conclusion, we identified a four-cell-senescence-regulator-gene prognostic index in BCa and investigated its relationship with TMB, the immune landscape of tumor microenvironment (TME), and response to immunotherapy and chemotherapy, and we also established a nomogram to predict the prognosis of patients with BCa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Liu, Xu, An, Xu, Zhong, Zeng, Ma, He, Zhang, Wang and Xia.)

Background: The postoperative sepsis is a latent fatal complication for both flexible ureteroscopy (fURS) and percutaneous nephrolithotomy (PNL). An effective predictive model constructed by readily available clinical markers is urgently needed to reduce postoperative adverse events caused by infection. This study aims to determine the pre-operative predictors of sepsis in patients with unilateral, solitary, and proximal ureteral stones after fURS and PNL., Methods: We retrospectively enrolled 910 patients with solitary proximal ureteral stone with stone size 10-20 mm who underwent fURS or PNL from Tongji Hospital's database, including 412 fURS cases and 498 PNL cases. We used the least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression analysis to identify the risk factors for sepsis. Finally, a nomogram was assembled utilizing these risk factors., Results: In this study, 49 patients (5.4%) developed sepsis after fURS or PNL surgery. Lasso regression showed postoperative sepsis was associated with gender (female), pre-operative fever, serum albumin (<35 g/L), positive urine culture, serum WBC (≥10,000 cells/ml), serum neutrophil, positive urine nitrite and operation type (fURS). The multivariate logistic analysis indicated that positive urine culture (odds ratio [ OR ] = 5.9092, 95% CI [2.6425-13.2140], p < 0.0001) and fURS ( OR = 1.9348, 95% CI [1.0219-3.6631], p = 0.0427) were independent risk factors of sepsis and albumin ≥ 35g/L ( OR = 0.4321, 95% CI [0.2054-0.9089], p = 0.0270) was independent protective factor of sepsis. A nomogram was constructed and exhibited favorable discrimination (area under receiver operating characteristic curve was 0.78), calibration [Hosmer-Lemeshow (HL) test p = 0.904], and net benefits displayed by decision curve analysis (DCA)., Conclusions: Patients who underwent fURS compared to PNL or have certain pre-operative characteristics, such as albumin <35 g/L and positive urine culture, are more likely to develop postoperative sepsis. Cautious preoperative evaluation and appropriate operation type are crucial to reducing serious infectious events after surgery, especially for patients with solitary, unilateral, and proximal ureteral stones sized 10-20 mm., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Xu, Liu, Xun, Lu, Xu, An, Hu, Li, Xia and Wang.)

Background: SUMOylation is an important component of post-translational protein modifications (PTMs), and bladder cancer (BCa) is the ninth most common cancer around the world. But the comprehensive role of SUMOylation in shaping tumor microenvironment (TME) and influencing tumor clinicopathological features and also the prognosis of patients remains unclear., Methods: Using the data downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), we comprehensively evaluated the SUMOylation patterns of 570 bladder cancer samples, and systematically correlated these SUMOylation patterns with TME immune cell infiltrating characteristics. The SUMO score was constructed to quantify SUMOylation patterns of individuals using principal component analysis (PCA) algorithms., Results: Two distinct SUMOylation patterns and gene clusters were finally determined. Significant differences in the prognosis of patients were found among two different SUMOylation patterns and gene clusters, so were in the mRNA transcriptome and the landscape of TME immune cell infiltration. We also established a set of scoring system named SUMO score to quantify the SUMOylation pattern of individuals with BCa, which was discovered to be tightly connected with tumor clinicopathological characteristics and could predict the prognosis of patients with BCa. Moreover, SUMO score was a considerable predictive indicator for the survival outcome independent of tumor mutation burden (TMB) and low SUMO score was related to better response to immunotherapy using PD-1 blockade. We also found that there existed a significant relationship between sensitivity to commonly used chemotherapy drugs and SUMO score. Finally, a nomograph based on five features, namely, SUMO score, age, gender, T category, and M category was constructed to predict the survival probability of patients with BCa in 1, 3, and 5 years, respectively., Conclusions: Our work demonstrated and overviewed the complicated regulation mechanisms of SUMOylation in bladder cancer, and better understanding and evaluating SUMOylation patterns could be helpful in guiding clinical therapeutic strategy and improving the prognosis of patients with BCa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xia, Sun, Xun, Xiao, Liu, Xu, An, Xu, Liu, Wang and Hu.)

Background: Ferroptosis is a unique iron-dependent form of cell death and bladder cancer (BCa) is one of the top ten most common cancer types in the world. However, the role of ferroptosis in shaping the tumor microenvironment and influencing tumor clinicopathological features remains unknown. Methods: Using the data downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we comprehensively evaluated the ferroptosis patterns of 570 BCa samples based on 234 validated ferroptosis genes reported in the FerrDb database and systematically correlated these ferroptosis patterns with tumor microenvironment (TME) cell-infiltrating characteristics. The ferroptosis score was constructed to quantify ferroptosis patterns of individuals using principal component analysis (PCA) algorithms. Results: Four distinct ferroptosis patterns and two gene clusters were finally determined. Significant differences in clinical characteristics and the prognosis of patients were found among different ferroptosis patterns and gene clusters, so were in the mRNA transcriptome and the landscape of TME immune cell infiltration. We also established a set of scoring system to quantify the ferroptosis pattern of individual patients with BCa named the ferroptosis score, which was discovered to tightly interact with clinical signatures such as the TNM category and tumor grade and could predict the prognosis of patients with BCa. Moreover, tumor mutation burden (TMB) was positively correlated to the ferroptosis score, and the low ferroptosis score was related to a better response to immunotherapy using PD-1 blockade. Finally, we also found there existed a positive correlation between the sensitivity to cisplatin chemotherapy and ferroptosis score. Conclusions: Our work demonstrated and interpreted the complicated regulation mechanisms of ferroptosis on the tumor microenvironment and that better understanding and evaluating ferroptosis patterns could be helpful in guiding the clinical therapeutic strategy and improving the prognosis of patients with BCa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xia, Sun, Liu, Xu, An, Xu, Liu, Hu and Wang.)

This study investigated the effect of rhein(RH) on the apoptosis and autophagy of human umbilical vein endothelial cells(HUVECs) induced by hydrogen peroxide(H&#95;2O&#95;2) and its underlying mechanism. The oxidative damage model in HUVECs was established and the cells were divided into different treatment groups. Cell survival rate was detected by MTT assay, apoptosis by Annexin V-FITC/PI double staining and Hoechst 33258 fluorescence staining, autophagy by Ad-mCherry-GFP-LC3 B adenovirus transfection, and protein expression by Western blot. The results showed that RH could protect cells by increasing the cell survival rate in a dose-dependent manner, decreasing the expression of apoptosis-related proteins(Bax and cleaved caspase-3) and the ratio of Bax/Bcl-2, elevating the expression of Bcl-2, up-regulating the expression of microtubule-associated protein 1 light chain 3(LC3)-Ⅱ, and down-regulating the expression of p62. Adenovirus transfection results showed that RH could increase the green and red spots, as well as the yellow spots. However, after the addition of autophagy inhibitor 3-MA, autophagy was reduced and apoptosis was increased. RH could enhance the expression of silent information regulator 2 related enzyme 1(SIRT1). The addition of SIRT1 inhibitor EX-527 reduced the protective effect of RH and cell viability. The addition of 3-MA had no effect on the expression of SIRT1 protein, but the expression of SIRT1 and LC3-Ⅱ proteins decreased and the expression of p62 increased after the addition of EX-527. After RH treatment, the phosphorylation of adenosine monophosphate-activated protein kinase(AMPK) increased, while that of the mechanistic target of rapamycin(mTOR) decreased in a dose-dependent manner. Moreover, this effect could be weakened by the AMPK inhibitor compound C. RH may enhance autophagy through SIRT1/AMPK/mTOR pathway to reduce H&#95;2O&#95;2-induced apoptosis of HUVECs.

Objective: To observe the change of neovascular morphology and angiogenesis related factors in the ischemic cerebral area after cerebral infarction and the intervention effect of electroacupuncture (EA)., Methods: Wistar rats were randomly divided into model group( n =90), EA group( n =90), sham operation group( n =90) and control group( n =10). The first three groups were further divided into 1 h, 3 h, 6 h, 9 h, 12 h, 24 h, 3 d, 7 d and 12 d subgroups( n =10 in each subgroup). The cerebral infarction model was established by middle cerebral artery occlusion(MCAO). EA(15 Hz, 2 mA) was applied to "Shuigou"(GV26) for 20 min in the EA group. The 1, 3, 6, 9, 12, 24 h subgroups were treated immediately after modeling, the 3, 7, 12 d subgroups were treated once daily for 3, 7 or 12 days. The neovascular endothelial cells were displayed by immunofluorescence double labeling staining. Quantitive real-time PCR and Western blot were applied to detect the changes of basic fibroblast growth factor (bFGF), angiogenin (Ang) -1, 2, platelet-derived growth factor b (PDGF-b) in ischemic brain tissue, respectively., Results: After modeling, CD31 and Ki67 positive cells were first observed at 24 h in the model group, and reached the peak at 3 d, decreased at 7 d. While in the EA group, the CD31 and Ki67 positive cells were first observed at 12 h, and reached the peak at 3 d, and gradually decreased until 12 d. Compared with the control group, the mRNA expressions of bFGF at 9 h-12 h, Ang-1 at 12 h-12 d, Ang-2 at 1 h-12 d and PDGF-b at 1 h, 6 h, 9 h, 24 h-12 d were increased in the model group( P <0.01, P <0.05). After EA, the mRNA expressions of bFGF at 24 h-12 d, Ang-1 at 3 d-12 d, Ang-2 at 3 h-24 h and PDGF-b at 3 h, 6 h, 3 d-12 d were increased( P <0.05, P <0.01). In comparison with the control group, the proteins of bFGF at 24 h, Ang-1 at 6 h-12 d, Ang-2 at 1 h-12 d and PDGF-b at 1 h-7 d were increased in the model group( P <0.05, P <0.01). After EA, the proteins of bFGF at 3 d-12 d, Ang-1 at 3 d-12 d, Ang-2 at 3 h-12 h and PDGF-b at 6 h, 3 d-12 d were increased compared with the model group( P <0.05, P <0.01)., Conclusion: EA can up-regulate the expression of angiogenesis-related factors in MCAO rats, which has an important role in the establishment of blood vessel regeneration and collateral circulation, and thus promote the recovery of neurological function.

Objective: To select the optimized treatment plan of acupuncture for lateral femoral cutaneous neuritis by using multiple indexes decision-making method based on the clinical evidence., Methods: The randomized control trials (RCTs) regarding acupuncture for lateral femoral cutaneous neuritis in the CNKI database, CBM database, WANFANG database, VIP database, PubMed, Cochrane Library and Embase published before December 31, 2017 were comprehensively collected. The modified Jadad scale was used to evaluate the quality of the RCTs. Then the evaluation indexes were selected and the dimensions of evaluation indexes were standardized by using extreme difference transformation method. The weight of each index was determined by using relative comparison method and the standardized matrix was weighted. Thus, the ideal solution and the negative ideal solution were obtained, and the relatively degree of each treatment plan to the ideal solution was calculated to propose the optimized plan of acupuncture for lateral femoral cutaneous neuritis., Results: A total of 18 RCTs were included, the optimized plan of acupuncture for lateral femoral cutaneous neuritis was using thin fire needle to rapidly prick the abnormal skin region with fast needle insertion-withdrawal technique; the fire needle was applied repeatedly; intensive pricking to form a treatment area; the treatment was given once every 5 days., Conclusion: Based on the current clinical evidence, the optimized plan of acupuncture for lateral femoral cutaneous neuritis is using thin fire needle to prick the abnormal skin region; the multiple methods of plum-blossom needling met the characteristic of lateral femoral cutaneous neuritis and is suitable for clinical selection. The main acupoints are ashi points in the abnormal skin area or the acupoints in the foot- yangming meridian and foot- shaoyang meridian, combined with lumbar Jiaji (EX-B2) points.