More than half of non‐muscle‐invasive bladder cancer (NMIBC) patients eventually relapse even if treated with surgery and BCG without optional bladder‐preserving therapy. This study aims to investigate the antitumor activity and safety of a HER2‐targeted antibody‐drug conjugate, RC48‐ADC, intravesical instillation for NMIBC treatment. In this preclinical study, it is revealed that human epidermal growth factor receptor 2 (HER2) expression scores of 1+, 2+, and 3+ are recorded for 16.7%, 56.2%, and 14.6% of NMIBC cases. The antitumor effect of RC48‐ADC is positively correlated with HER2 expression in bladder cancer (BCa) cell lines and organoid models. Furthermore, RC48‐ADC is revealed to exert its antitumor effect by inducing G2/M arrest and caspase‐dependent apoptosis. In an orthotopic BCa model, tumor growth is significantly inhibited by intravesical instillation of RC48‐ADC versus disitamab, monomethyl auristatin E, epirubicin, or phosphate‐buffered saline control. The potential toxicity of intravesical RC48‐ADC is also assessed by dose escalation in normal nude mice and revealed that administration of RC48‐ADC by intravesical instillation is safe within the range of effective therapeutic doses. Taken together, RC48‐ADC demonstrates promising antitumor effects and safety with intravesical administration in multiple preclinical models. These findings provide a rational for clinical trials of intravesical RC48‐ADC in NMIBC patients.

Ubiquitination plays an essential role in protein stability, subcellular localization, and interactions. Crosstalk between different types of ubiquitination results in distinct biological outcomes for proteins. However, the role of ubiquitination-related crosstalk in lymph node (LN) metastasis and the key regulatory factors controlling this process have not been determined. Using high-throughput sequencing, we found that ubiquitin-conjugating enzyme E2 C ( UBE2C ) was overexpressed in bladder cancer (BCa) and was strongly associated with an unfavorable prognosis. Overexpression of UBE2C increased BCa lymphangiogenesis and promoted LN metastasis both in vitro and in vivo. Mechanistically, UBE2C mediated sodium-coupled neutral amino acid transporter 2 (SNAT2) monoubiquitination at lysine 59 to inhibit K63-linked polyubiquitination at lysine 33 of SNAT2. Crosstalk between monoubiquitination and K63-linked polyubiquitination increased SNAT2 membrane protein levels by suppressing epsin 1–mediated (EPN1-mediated) endocytosis. SNAT2 facilitated glutamine uptake and metabolism to promote VEGFC secretion, ultimately leading to lymphangiogenesis and LN metastasis in patients with BCa. Importantly, inhibition of UBE2C significantly attenuated BCa lymphangiogenesis in a patient-derived xenograft model. Our results reveal the mechanism by which UBE2C mediates crosstalk between the monoubiquitination and K63-linked polyubiquitination of SNAT2 to promote BCa metastasis and identify UBE2C as a promising target for treating LN-metastatic BCa.

To construct a predicting model for urosepsis risk for patients with upper urinary tract calculi based on ultrasound and urinalysis.

Objective: The aim of the study was to analyze the characteristics of renal function in patients diagnosed with COVID-19. Methods: In this retrospective, single-center study, we included all confirmed cases of COVID-19 in a tertiary hospital in Guangdong, China from January 20, 2020 to March 20, 2020. Blood and urine laboratory findings related to renal function were summarized, and the estimated glomerular filtration rate (eGFR) and endogenous creatinine clearance (Ccr) were also calculated to assess the renal function. Results: A total of 12 admitted hospital patients were diagnosed with COVID-19, included 3 severe cases, and 9 common cases. Serum creatinine (Scr) was not abnormally elevated in all of the patients, and blood urea nitrogen (BUN) was abnormally elevated in only 25.0% of the patients. However, compared with the recovery period, the patient's Scr and BUN increased significantly in peak of disease (p-scr = 0.002 & p-bun < 0.001). By observing the fluctuations in Scr and BUN from admission to recovery, it was found that the peak of Scr and BUN appeared within the first 14 day of the course of the disease. Urinary microprotein detection indicated that the abnormally elevated rates of urine microalbumin (UMA), α1-microglobulin (A1M), urine immunoglobulin-G (IGU), and urine transferring (TRU) standardized by urinary creatinine in peak of disease were 41.7, 41.7, 50.0, and 16.7%, respectively. The abnormal rates of the calculated eGFR and Ccr were 66.7 and 41.7%. Conclusion: Scr and BUN were generally increased during the course of COVID-19. Detection of urinary microproteins and application of multiple indicators assessment could be helpful for discovering abnormal renal function in patients with COVID-19. However, the evidence is limited due to the small sample size and observational nature. Additional studies, especially large prospective cohort studies, are required to confirm these findings.

Purpose: The extracellular matrix in the tumor microenvironment are closely related to the development of tumors. This study’s primary aim is to study the association between prolyl 3-hydroxylase 1 (P3H1) which mainly expresses collagen in extracellular matrix and the progression and prognosis of bladder cancer (BC). Methods: The clinical and transcriptome data were acquired from the cancer genome atlas database. BLCAsubtyping is used to evaluate tissue subtypes of BC. The COX proportional hazards can be used to evaluate the survival process’s influencing factors. Immunohistochemistry was used to identify differences in the expression of P3H1 in cancer and paired adjacent tissues. GSEA was used to investigate the underlying biological processes. Finally, ssGSEA, TIMER and pRRophetic were used to study the relationship between P3H1 and immune cell infiltration and drug sensitivity. Results: The expression of P3H1 was substantially higher in highly invasive BC samples than in low invasive BC. P3H1 was an independent predictor of overall survival (HR = 1.12, p = 0.03). P3H1 expression was significantly higher in tumor tissues than adjacent normal tissues in clinical tissue samples, and was significantly higher in highly stage cancer than low stage cancer samples. Samples with high P3H1 expression had a higher level of immune cell infiltration and immune function, as well as a significant correlation with macrophage and dendritic cell infiltration and TGF-beta, Th1 cells, and macrophage regulation (cor > 0.3, p < 0.05). P3H1 high expression samples were substantially more sensitive to docetaxel, cisplatin, vinblastine, camptothecin, paclitaxel, and other medicines than P3H1 low expression samples. Discussion: P3H1 is a possible oncogene and an independent predictor of poor prognosis in BC; it also has enhanced sensitivity to docetaxel, cisplatin, vinblastine, camptothecin, paclitaxel, and other medications.

Objectives: The aim of the study was to analyze the incidence of COVID-19 with early renal injury, and to explore the value of multi-index combined detection in diagnosis of early renal injury in COVID-19.Design: The study was an observational, descriptive study.Setting: This study was carried out in a tertiary hospital in Guangdong, China.Participants: 12 patients diagnosed with COVID-19 from January 20, 2020 to February 20, 2020.Primary and secondary outcome measures: The primary outcome was to evaluate the incidence of early renal injury in COVID-19. In this study, the estimated glomerular filtration rate (eGFR), endogenous creatinine clearance (Ccr) and urine microalbumin / urinary creatinine ratio (UACR) were calculated to assess the incidence of early renal injury. Secondary outcomes were the diagnostic value of urine microalbumin (UMA), α1-microglobulin (A1M), urine immunoglobulin-G (IGU), urine transferring (TRU) alone and in combination in diagnosis of COVID-19 with early renal injury.Results: While all patients had no significant abnormalities in serum creatinine (Scr) and blood urea nitrogen (BUN), the abnormal rates of eGFR, Ccr, and UACR were 66.7%, 41.7%, and 41.7%, respectively. Urinary microprotein detection indicated that the area under curve (AUC) of multi-index combined to diagnose early renal injury in COVID-19 was 0.875, which was higher than UMA (0,813), A1M (0.813), IGU (0.750) and TRU (0.750) alone. Spearman analysis showed that the degree of early renal injury was significantly related to C-reactive protein (CRP) and neutrophil ratio (NER), suggesting that the more severe the infection, the more obvious the early renal injury. Hypokalemia and hyponatremia were common in patients with COVID-19, and there was a correlation with the degree of renal injury.Conclusions: Early renal injury was common in patients with COVID-19. Combined detection of UMA, A1M, IGU, and TRU was helpful for the diagnosis of early renal injury in COVID-19.