BACKGROUND:As the only approved oral medication for premature ejaculation (PE), dapoxetine faces a high discontinuation rate, primarily due to lower than expected efficacy. The impact of serum metabolites on PE treatment remains undetermined; therefore, we aimed to identify metabolites associated with dapoxetine efficacy. METHODS:Clinical data and blood samples were collected from 116 patients with lifelong PE before 8 weeks of dapoxetine treatment. Serum was analyzed by untargeted metabolomics profiling. Efficacy was assessed with the Clinical Global Impression of Change (CGIC) scale: scores ≥ 1 were classified as the effective group and ≤ 0 as the ineffective group. Differential serum metabolites between the two groups were identified using the Mann-Whitney U test. Enrichment analysis determined metabolic pathways significantly associated with efficacy. RESULTS:Compared to the ineffective group, indoleacrylic acid and (-)-riboflavin were significantly upregulated in the effective group, while 15-keto-13,14-dihydroprostaglandin A2, dienestrol, hippuric acid, and PC (16:0/16:0) were downregulated. The six metabolites showed a discriminatory ability of 0.646, 0.667, 0.633, 0.645, 0.651, and 0.635, respectively. Incorporating them significantly improved the accuracy of the model predicting efficacy (0.892 vs. 0.738, p = 0.001), suggesting that modulating these specific metabolites may be a novel strategy for PE treatment. Moreover, differential metabolic ions between the two groups were mostly enriched in the arachidonic acid metabolism pathway, indicating that this pathway may represent an additional route associated with dapoxetine response. CONCLUSIONS:This study revealed serum metabolites correlated with dapoxetine efficacy, paving the way for future research into novel therapeutic targets and personalized treatment strategies.

Tacrolimus (TAC) is essential in post-kidney transplantation immunosuppressive therapy but is hindered by its narrow therapeutic window and patient long-term adherence challenges, leading to severe side effects in recipients. To address this, we developed an injectable self-assembling peptide hydrogel that encapsulates TAC within a microcrystalline phase via a novel multiphase assembly strategy. This hydrogel enables sustained TAC release, maintaining therapeutic blood concentrations (5-15 ng/mL) for seven days post-injection. In a vascularized composite allotransplant model, TAC-loaded hydrogel preserves skin integrity on day 7 with vessel sutures, highlighting its potential for tissue preservation. In a life-sustaining kidney transplantation model, rats receiving a single injection of TAC-loaded hydrogel exhibited significantly improved survival (∼68 days) compared to the oral administration group (∼21 days). Histopathological and blood analysis confirmed minimal inflammation and intact tissue architecture in hydrogel-treated grafts, alongside no systemic toxicity in major organs. These findings highlight multiphase assembly as a novel, effective strategy for controlled TAC release, offering a promising approach to improve patient outcomes in organ transplantation.

BACKGROUND:Despite being the only approved oral therapy for premature ejaculation (PE), dapoxetine faces high discontinuation rates because of its suboptimal efficacy. Given that the role of gut microbiota in PE treatment has remained unexplored, we aim to investigate gut microbiota that may reflect the efficacy of dapoxetine. METHODS:Clinical data and fecal samples were collected from patients with lifelong PE before treatment. Gut microbiota was profiled via 16S rDNA sequencing, and differential microbiota between effective and ineffective groups were identified with the LEfSe method. To explore potential links between gut dysbiosis and efficacy, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional predictions were performed with the PICRUSt2 method. Efficacy was assessed using the Clinical Global Impression of Change (CGIC) scale, with scores ≥1 defined as the effective group. RESULTS:In the effective group, Erysipelotrichaceae_UCG_003, Parabacteroides_distasonis, and Prevotella_7_unclassified were significantly more prevalent, while Collinsella aerofaciens was less abundant. Their abundance was significantly correlated with CGIC scores, with correlation coefficients of 0.331, 0.250, 0.288, and ‒0.345, respectively. The discriminatory abilities of the four differential microbiota were 0.654, 0.669, 0.701, and 0.615, respectively. Incorporating them significantly improved the accuracy of the model predicting efficacy (0.796 vs. 0.738), which further suggests that modulating microbiota could be a novel strategy for PE treatment. The predicted gene abundance in the arachidonic acid metabolism pathway was significantly elevated in the effective group, indicating that dapoxetine's mechanism may also involve modulating this pathway. CONCLUSIONS:This study identified gut microbiota associated with the efficacy of dapoxetine for the first time. Targeted modulation of specific gut microbiota may provide a novel strategy for PE treatment.

BACKGROUND:Although a nomogram for predicting the efficacy of dapoxetine (DapE-Nomo) has already been developed, its reliability is limited due to only 4 weeks of follow-up and a lack of external validation. Several patients with premature ejaculation (PE) achieve satisfactory therapeutic effects after longer periods of treatment clinically, we therefore aimed to develop and validate an 8-week DapE-Nomo. METHODS:The training cohort included 243 patients with lifelong PE from Xijing Hospital and Northwest Women's and Children's Hospital (Jan 2019-Jul 2020), while the validation cohort comprised 397 patients from Xijing Hospital and Xi'an Daxing Hospital (Aug 2020-Jan 2022). Efficacy was measured using the Clinical Global Impression of Change (CGIC) scale, with a CGIC score ≥ 1 indicating an improvement (iCGI). LASSO regression was utilized to identify the most valuable predictors (MVPs) of iCGI. The DapE-Nomo was developed utilizing logistic regression coefficients of MVPs and validated across both cohorts. RESULTS:After 8 weeks of medication, 47.7% of patients in the training cohort and 47.6% in the validation cohort achieved iCGI. MVPs of iCGI included intravaginal ejaculation latency time, difficulty delaying ejaculation, and education level. The DapE-Nomo showed discriminatory abilities of 0.722 and 0.709 in internal and external validations, respectively, with satisfactory calibration and clinical utility in both. The optimal cutoff value of the DapE-Nomo was identified as 153.4 in both cohorts. Individuals with scores ≥153.4 exhibited a 3.833-fold and 4.137-fold chance of achieving iCGI, respectively, compared with those with scores < 153.4. CONCLUSION:We constructed and validated the inaugural 8-week DapE-Nomo. In outpatient settings, it will enable andrologists to more accurately evaluate the efficacy and promptly adjust treatment plans for patients with scores below 153.4. Moreover, It will help patients who've taken dapoxetine for 4 weeks with poor results decide whether to stop.

Ovarian cancer poses a severe threat to women's health, with drug resistance representing a major obstacle in antitumor therapy. Inducing ferroptosis in tumor cells has emerged as a promising novel strategy for overcoming drug resistance in cancer treatment. Importantly, ferrous iron (Fe2+) in mitochondria serves as a vital indicator of ferroptosis and influences its progression. Thus, it is imperative to monitor the levels of mitochondrial Fe2+. Here, a near-infrared (NIR) mitochondrial-targeted fluorescent probe, DHX-Fe, for selectively detecting Fe2+ via nitroxide radical reduction was developed, achieving fast response (< 5 min) and low limit of detection (115 nM). Most importantly, DHX-Fe was further employed to evaluate and image Fe2+ dynamics in A2780 cisplatin-resistant (A2780/DPP) cells with ferroptosis inducers. We identified Brusatol as a promising anti-tumor candidate in both living cells and tumor-bearing mice. Notably, Brusatol-induced ferroptosis promotes the accumulation of Fe2+ levels, elevates ROS levels, and induces LPO, suggesting its potential as a promising therapeutic agent for ovarian cancer. Our research hinted that DHX-Fe provides a valuable visual tool for assessing ferroptosis inducers to combat chemoresistance in cancer therapy.

With the increasing exposure to electromagnetic radiation (EMR) and its detrimental effects on male reproductive health, there is an urgent demand for advanced protective materials. This study presents a multifunctional hydrogen-bond-cross-linked PDMS/MXene/Fe3O4-NH2/cotton fabric (PMFC) designed for male reproductive electromagnetic protection. The composite fabric integrates MXene nanosheets and Fe3O4-NH2 nanoparticles via layer-by-layer assembly, enhanced by hydrogen bonding and hydrophobic PDMS coating. Remarkably, PMFC achieves an exceptional electromagnetic interference shielding efficiency of 56.4 dB at 0.35 mm thickness, outperforming existing materials. Its ultralow infrared emissivity (0.33) enables effective thermal stealth, while programmable Joule heating (up to 109.9 degrees C at 4.5 V) ensures adaptability to diverse environments. Furthermore, PMFC retains cotton's inherent breathability, moisture permeability, and softness, coupled with superhydrophobicity (water contact angle: 147.7 degrees) and mechanical durability. This work not only addresses the critical challenge of electromagnetic protection for male reproductive health but also pioneers a versatile textile platform for multifunctional wearable applications

The increasing prevalence of high-frequency electromagnetic interference (EMI) and bacterial contamination in medical environments demands multifunctional shielding materials that integrate EMI shielding, thermal management, and antimicrobial properties. Herein, an asymmetric trilayer composite film is fabricated via in situ growth of CuS nanoparticles on bacterial cellulose (CuS@BC) and vacuum-assisted assembly with Ti3C2Tx MXene and BC/Fe3O4 layers. The resulting structure exhibits an exceptional EMI shielding effectiveness of 67.5 dB in the X-band, enabled by a synergistic "reflection-absorption-reabsorption" mechanism. The film also demonstrates dual-mode thermal management, achieving 72.6 °C under Joule heating (at 2.0 V) and 126.6 °C under NIR irradiation (808 nm, 1.0 W/cm2). Furthermore, it shows broad-spectrum antibacterial efficacy exceeding 99.9% against both Staphylococcus aureus and Escherichia coli, without compromising shielding performance. This work provides a new paradigm for flexible multifunctional materials suited to advanced medical electronic applications.

Urinary tumors pose a significant health threat because of their high prevalence and recurrence rates. Despite the availability of various treatment options, many patients poorly respond to traditional therapies, highlighting the urgent need for alternative approaches. Oncolytic viruses are promising therapeutic agents. These viruses exploit the unique characteristics of cancer cells to specifically target and destroy them, thereby triggering potent antitumor immune responses. This review delves into recent advancements and future prospects of oncolytic viruses, focusing on their application in renal, bladder, and prostate cancers. By discussing practical implications and the potential of different viruses, including the cowpox virus, adenovirus, measles virus, coxsackievirus, and reovirus, we pave the way for further exploration and refinement of this exciting field.

Bladder cancer (BC) is the tenth most common malignancy globally. Urothelial carcinoma (UC) is a major type of BC, and advanced UC (aUC) is associated with poor clinical outcomes and limited survival rates. Current options for aUC treatment mainly include chemotherapy and immunotherapy. These options have moderate efficacy and modest impact on overall survival and thus highlight the need for novel therapeutic approaches. aUC patients harbor a high tumor mutation burden and abundant molecular alterations, which are the basis for targeted therapies. Erdafitinib is currently the only Food and Drug Administration (FDA)-approved targeted therapy for aUC. Many potential targeted therapeutics aiming at other molecular alterations are under investigation. This review summarizes the current understanding of molecular alterations associated with aUC targeted therapy. It also comprehensively discusses the related interventions for treatment in clinical research and the potential of using novel targeted drugs in combination therapy.

Abstract Background Urothelial carcinoma (UC) is the second most common urological malignancy. Despite numerous molecular markers have been evaluated during the past decades, no urothelial markers for diagnosis and recurrence monitoring have shown consistent clinical utility. Methods The methylation level of tissue samples from public database and clinical collected were analyzed. Patients with UC and benign diseases of the urinary system (BUD) were enrolled to establish TAGMe (TAG of Methylation) assessment in a training cohort (n = 567) using restriction enzyme-based bisulfite-free qPCR. The performance of TAGMe assessment was further verified in the validation cohort (n = 198). Urine samples from 57 UC patients undergoing postoperative surveillance were collected monthly for six months after surgery to assess the TAGMe methylation. Results We identified TAGMe as a potentially novel Universal-Cancer-Only Methylation (UCOM) marker was hypermethylated in multi-type cancers and investigated its application in UC. Restriction enzyme-based bisulfite-free qPCR was used for detection, and the results of which were consistent with gold standard pyrosequencing. Importantly, hypermethylated TAGMe showed excellent sensitivity of 88.9% (95% CI: 81.4–94.1%) and specificity of 90.0% (95% CI: 81.9–95.3%) in efficiently distinguishing UC from BUD patients in urine and also performed well in different clinical scenarios of UC. Moreover, the abnormality of TAGMe as an indicator of recurrence might precede clinical recurrence by three months to one year, which provided an invaluable time window for timely and effective intervention to prevent UC upstaging. Conclusion TAGMe assessment based on a novel single target in urine is effective and easy to perform in UC diagnosis and recurrence monitoring, which may reduce the burden of cystoscopy. Trial registration ChiCTR2100052507. Registered on 30 October 2021

Journal of Medical VirologyVolume 96, Issue 3 e29537 LETTER TO THE EDITOR Omicron breakthrough infected individuals show enhanced nasal antibody responses and preserved T cell responses against the EG.5.1 and BA.2.86 Zheng Zhu, Zheng Zhu orcid.org/0000-0002-4112-5294 Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaSearch for more papers by this authorShixiong Li, Shixiong Li Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China College of Life Sciences, Nankai University, Tianjin, ChinaSearch for more papers by this authorJunhao Fan, Junhao Fan Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, ChinaSearch for more papers by this authorShihao Shang, Shihao Shang Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaSearch for more papers by this authorYao Zhang, Yao Zhang Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, ChinaSearch for more papers by this authorQiong Zi, Qiong Zi Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, ChinaSearch for more papers by this authorJihao Zheng, Jihao Zheng Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, ChinaSearch for more papers by this authorDongfang Wang, Dongfang Wang Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, ChinaSearch for more papers by this authorXiaoli Mou, Xiaoli Mou Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, ChinaSearch for more papers by this authorKepu Liu, Kepu Liu Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaSearch for more papers by this authorMaoxin Lv, Maoxin Lv Department of Urology, The First Affiliated Hospital of Kunming Medical University, Kunming, ChinaSearch for more papers by this authorJianlin Yuan, Corresponding Author Jianlin Yuan [email protected] Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China Correspondence Jianlin Yuan, Department of Urology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Rd, Xi'an, Shaanxi, China. Email: [email protected] Zhongfang Wang, and Jingyou Yu, Guangzhou National Laboratory, Guangzhou International Bio Island, No. 9 XingDaoHuanBei Rd, Guangzhou 510005, Guangdong Province, China. Email: [email protected] and [email protected]Search for more papers by this authorZhongfang Wang, Corresponding Author Zhongfang Wang [email protected] Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China Correspondence Jianlin Yuan, Department of Urology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Rd, Xi'an, Shaanxi, China. Email: [email protected] Zhongfang Wang, and Jingyou Yu, Guangzhou National Laboratory, Guangzhou International Bio Island, No. 9 XingDaoHuanBei Rd, Guangzhou 510005, Guangdong Province, China. Email: [email protected] and [email protected]Search for more papers by this authorJingyou Yu, Corresponding Author Jingyou Yu [email protected] orcid.org/0000-0002-0775-6623 Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China Correspondence Jianlin Yuan, Department of Urology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Rd, Xi'an, Shaanxi, China. Email: [email protected] Zhongfang Wang, and Jingyou Yu, Guangzhou National Laboratory, Guangzhou International Bio Island, No. 9 XingDaoHuanBei Rd, Guangzhou 510005, Guangdong Province, China. Email: [email protected] and [email protected]Search for more papers by this author Zheng Zhu, Zheng Zhu orcid.org/0000-0002-4112-5294 Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaSearch for more papers by this authorShixiong Li, Shixiong Li Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China College of Life Sciences, Nankai University, Tianjin, ChinaSearch for more papers by this authorJunhao Fan, Junhao Fan Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, ChinaSearch for more papers by this authorShihao Shang, Shihao Shang Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaSearch for more papers by this authorYao Zhang, Yao Zhang Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, ChinaSearch for more papers by this authorQiong Zi, Qiong Zi Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, ChinaSearch for more papers by this authorJihao Zheng, Jihao Zheng Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, ChinaSearch for more papers by this authorDongfang Wang, Dongfang Wang Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, ChinaSearch for more papers by this authorXiaoli Mou, Xiaoli Mou Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, ChinaSearch for more papers by this authorKepu Liu, Kepu Liu Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaSearch for more papers by this authorMaoxin Lv, Maoxin Lv Department of Urology, The First Affiliated Hospital of Kunming Medical University, Kunming, ChinaSearch for more papers by this authorJianlin Yuan, Corresponding Author Jianlin Yuan [email protected] Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China Correspondence Jianlin Yuan, Department of Urology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Rd, Xi'an, Shaanxi, China. Email: [email protected] Zhongfang Wang, and Jingyou Yu, Guangzhou National Laboratory, Guangzhou International Bio Island, No. 9 XingDaoHuanBei Rd, Guangzhou 510005, Guangdong Province, China. Email: [email protected] and [email protected]Search for more papers by this authorZhongfang Wang, Corresponding Author Zhongfang Wang [email protected] Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China Correspondence Jianlin Yuan, Department of Urology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Rd, Xi'an, Shaanxi, China. Email: [email protected] Zhongfang Wang, and Jingyou Yu, Guangzhou National Laboratory, Guangzhou International Bio Island, No. 9 XingDaoHuanBei Rd, Guangzhou 510005, Guangdong Province, China. Email: [email protected] and [email protected]Search for more papers by this authorJingyou Yu, Corresponding Author Jingyou Yu [email protected] orcid.org/0000-0002-0775-6623 Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China Correspondence Jianlin Yuan, Department of Urology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Rd, Xi'an, Shaanxi, China. Email: [email protected] Zhongfang Wang, and Jingyou Yu, Guangzhou National Laboratory, Guangzhou International Bio Island, No. 9 XingDaoHuanBei Rd, Guangzhou 510005, Guangdong Province, China. Email: [email protected] and [email protected]Search for more papers by this author First published: 18 March 2024 https://doi.org/10.1002/jmv.29537 Zheng Zhu, Shixiong Li, Junhao Fan, Shihao Shang, Yao Zhang, and Qiong Zi are contributed equally to this study. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Supporting Information Filename Description jmv29537-sup-0001-Supplementary_Materials_Word_template-clean.docx1.5 MB Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Leung K, Lau EHY, Wong CKH, Leung GM, Wu JT. Estimating the transmission dynamics of SARS-CoV-2 Omicron BF.7 in Beijing after adjustment of the zero-COVID policy in November−December 2022. Nature Med. 2023; 29: 579-582. doi:10.1038/s41591-023-02212-y 10.1038/s41591-023-02212-y CASPubMedWeb of Science®Google Scholar 2Zhu A, Wei P, Man M, et al. Antigenic characterization of SARS-CoV-2 Omicron subvariants XBB.1.5, BQ.1, BQ.1.1, BF.7 and BA.2.75.2. Signal Transduct Target Ther. 2023; 8: 125. doi:10.1038/s41392-023-01391-x 10.1038/s41392-023-01391-x CASPubMedWeb of Science®Google Scholar 3Wang Q, Guo Y, Liu L, et al. Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike. 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e14623 Background: In patients afflicted with advanced urothelial carcinoma (aUC), the durable response rate to immune checkpoint inhibitor (ICI) is approximately 20%. Recent study showed the pivotal role of N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) in immune escape and the progression of aUC. This study aimed to develop a novel METTL3 peptide degrader RKL and investigate its synergistic effects and underlying mechanisms in combination with ICI for aUC. Methods: Methyltransferase expression profiles were scrutinized using The Cancer Genome Atlas database; while the prognostic implications of METTL3 expression in response to ICI were analyzed in the IMvigor210 cohort study. Single-cell RNA sequencing (scRNA-seq) was employed to elucidate the mechanistic insights. The METTL3 peptide degrader RKL was synthesized using Fmoc solid-phase peptide synthesis and purified with high-performance liquid chromatography. In vivo and in vitro experiments were conducted to assess the impact of RKL, ICI, and their combination on aUC inhibition. Results: In aUC, METTL3 exhibited the most significant up-regulation among m6A methyltransferases, while METTL14 and WTAP showed down-regulated expression. In the IMvigor210 cohort study, aUC patients with elevated METTL3 expression and treated with ICI demonstrated a poorer prognosis. scRNA-seq revealed that METTL3 upregulation promoted the expression of genes regulating cancer-associated fibroblast proliferation, contributing to enhanced tumor resistance to immunotherapy. RKL demonstrated high toxicity to urothelial carcinoma cell lines, inhibiting their proliferative, migratory, and invasive capacities in vitro. The combined treatment of RKL and ICI significantly reduced tumor volume (P<0.001), with a complete response achieved in 87.5% (7/8) of mice in the combination group, 12.5% (1/8) in the RKL group, and 25.0% (2/8) in the ICI group. Conclusions: METTL3 overexpression in aUC is associated with immune escape and resistance to ICI therapy. The METTL3 peptide degrader RKL, when combined with ICI, demonstrates synergistic antitumor effects in aUC, warranting further exploration in clinical research.

Supplementary Figure Legends

Blood counts, Hemoglobin and Platelets determination and biochemistry panel

Premature ejaculation (PE), despite its wide prevalence, is largely underdiagnosed and undertreated. Being a multifactorial dysfunction with strong cultural characteristics, PE requires skillful attitudes in the psychosexological support, necessary to manage the patient's and the couple's expectations, as well as in the medical treatment. Dapoxetine is a short-acting selective serotonin reuptake inhibitor approved for use in lifelong and acquired PE in a number of countries. Opinions, not always generated by the evidence-based medicine, impacted the attitudes of Western andrologists, as a nocebo effect which produced a drug's Waterloo, characterized by low prescription rates much more built on the patients' and doctors' expectations than on costs, side effects, and efficacy. In the present study, we retrospectively reviewed real-life data from eight Andrology and Sexual Medicine Public Centers in China to assess the prevalence of PE among attending patients, its association with erectile dysfunction, its subtype, and the proposed treatments. In 2019, among 156,486 patients coming to the centers, 32,667 visits having PE as the chief complaint were performed (20.9%). Almost all patients received treatment prescriptions (32,641 patients, 99.92%); 23,273 patients came back for a follow-up visit in the subsequent 12 months (71.2% of those who initially received treatment). Dapoxetine, either alone or in combination with another therapy, was the most prevalent treatment, prescribed to 22,767 patients (69.7% of treated patients), followed by traditional Chinese medicine (TCM) (39.4%). At follow-up, 8174 patients were unsatisfied with treatment, and a new treatment was proposed (35.12%). Dapoxetine was the best treatment, with an overall 27.1% switching rate when used either alone or in combination: Although the switching rate for Dapoxetine alone was 44.2%, the association of the same drug with psychotherapy resulted in much lower rates (19.5%) and reached a minimum of 12% when also combined with TCM demonstrating how cultural aspects and medical attitudes may dramatically impact on the therapy of a multifaceted, complex, and culture-grounded sexual symptom such as PE. In conclusion, taking switching rates as surrogate markers of treatment failure, this real-life study-the largest in the field-shows that in a more patient-oriented (as in Chinese medical culture), and less symptom-oriented (as in Western medical attitudes), Dapoxetine is a successful treatment for PE patients, with higher reliability when used alone or as part of combined and integrated therapies.

Body weight change during PDX bladder cancer mice experiment

RATIONALE:Wounds caused by firearms are intractable problems in treating war traumas and clinical management. Conventional open surgery inflicts large injury and leads to slow recovery. At the same time, most patients suffer from compound injuries with the critical condition and poor operation tolerance. Thus, it is crucial to probe into the minimally invasive surgical removal of residual kidney bullets.PATIENT CONCERNS:We report a case where a bullet remained in the right renal parenchyma on the patient, with penetrating injury in his liver.DIAGNOSIS:Obviously the patient has suffered gunshot wound with a bullet stuck in his kidney, while his liver function was impacted.INTERVENTIONS:Six months after the injury, we performed the minimally-invasive procedures on the patient with percutaneous nephroscope technology and laser technology under the guidance of ultrasound localization. The bullet and ammunition granulation and scar surrounding tissue were fully removed. Intraoperative bleeding was little, while the incision was small. The patient could leave the bed and walk on the 1st postoperative day. The drainage tube was removed on the 3rd postoperative day, after which the patient was discharged on the 4th postoperative day.OUTCOMES:The patient recovered well after surgery and was followed up for 5 years. The latest examination of his liver and kidney function was as follows: alanine aminotransferase 61IU/L, aspartate aminotransferase 33 IU/L, albumin/globulin 46.6/26.0, total bilirubin 19.1μmol/L, direct bilirubin 4.9μmol/L, indirect bilirubin 14.2μmol/L, alkaline phosphatase 111 IU/L, creatinine 57μmol/L, urea 5.16mmol/L, cystatin 0.73mg/L. The plain computed tomography scan showed a few calcifications in the liver and a patchy low-density shadow in the right kidney. It was proved that the liver and kidney function of the patient recovered well, and his living qualify has come back to the track, with no postoperative complications.LESSONS:Innovative integration of percutaneous nephroscopy technology and laser was used to remove kidney foreign bodies and developed the optimal surgical plan, small trauma, fast recovery, and the treatment of kidney foreign bodies was newly explored.

PURPOSE:Although several reviews have evaluated the use of PDE5 inhibitors (PDE5i) for treating erectile dysfunction (ED), their specific use in middle-aged and old patients has not been fully evaluated. Given that elderly patients with ED often have a complex combination of systemic and sexual health risk factors, the safety and efficacy of PDE5i in such a context are hereby reviewed.MATERIALS AND METHODS:A thorough examination of existing literature has been conducted on PubMed.RESULTS:PDE5i has good safety and efficacy, but the situation is more complex for patients with hypogonadism than those with normal testosterone levels, with reduced responsiveness to PDE5i. In this case, combination therapy with testosterone is recommended, safe and effective.CONCLUSIONS:Eliminating or reducing reversible risk factors and controlling or slowing the development of irreversible factors is an important foundation for using PDE5i to treat ED in all patients, especially middle-aged and elderly ones.

Background Prostate cancer (PCa), one of the common malignant tumors, is the second leading cause of cancer-related deaths in men. The circadian rhythm plays a critical role in disease. Circadian disturbances are often found in patients with tumors and enable to promote tumor development and accelerate its progression. Accumulating evidence suggests that the core clock gene NPAS2 (neuronal PAS domain-containing protein 2) has been implicated in tumors initiation and progression. However, there are few studies on the association between NPAS2 and prostate cancer. The purpose of this paper is to investigate the impact of NPAS2 on cell growth and glucose metabolism in prostate cancer. Methods Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) staining, western blot, GEO (Gene Expression Omnibus) and CCLE (Cancer Cell Line Encyclopedia) databases were used to analyze the expression of NPAS2 in human PCa tissues and various PCa cell lines. Cell proliferation was assessed using MTS, clonogenic assays, apoptotic analyses, and subcutaneous tumor formation experiments in nude mice. Glucose uptake, lactate production, cellular oxygen consumption rate and medium pH were measured to examine the effect of NPAS2 on glucose metabolism. The relation of NPAS2 and glycolytic genes was analyzed based on TCGA (The Cancer Genome Atlas) database. Results Our data showed that NPAS2 expression in prostate cancer patient tissue was elevated compared with that in normal prostate tissue. NPAS2 knockdown inhibited cell proliferation and promoted cell apoptosis in vitro and suppressed tumor growth in a nude mouse model in vivo. NPAS2 knockdown led to glucose uptake and lactate production diminished, oxygen consumption rate and pH elevated. NPAS2 increased HIF-1A (hypoxia-inducible factor-1A) expression, leading to enhanced glycolytic metabolism. There was a positive correlation with the expression of NPAS2 and glycolytic genes, these genes were upregulated with overexpression of NPAS2 while knockdown of NPAS2 led to a lower level. Conclusion NPAS2 is upregulated in prostate cancer and promotes cell survival by promoting glycolysis and inhibiting oxidative phosphorylation in PCa cells.

IHC staining of bladder PDX tumor tissues (BL0293)