Synergistic induction of tertiary lymphoid structures by chemoimmunotherapy in bladder cancer.

BACKGROUND: A substantial number of patients with bladder cancer fail to benefit from immune checkpoint inhibitors (ICIs). We aim to investigate whether the addition of other therapeutic modalities into immunotherapy may augment the immune reactivity, thereby improving the overall response rate. METHODS: We conducted a comprehensive assessment of the immunological changes following immunotherapy and chemotherapy, employing both single-cell RNA sequencing and bulk RNA sequencing analyses. RESULTS: The bladder cancer patient treated with ICIs exhibited a higher abundance of B cells and T follicular helper cells compared to the treatment-naïve patient. Analysis of public datasets and the in-house RJBLC-I2N003 cohort revealed the induction of tertiary lymphoid structure (TLS) neogenesis and maturation by immunotherapy. The IMvigor 210 study suggested that TLS could serve as a predictor of immunotherapy response and patient prognosis. In addition, genome-wide transcriptome data unveiled a shift towards the immune-enriched subtype over the desert subtype in patients receiving neoadjuvant chemotherapy. Notably, the proportions of CD20 + B cells, T follicular helper cells, and TLSs were significantly increased. In patients treated with a combination of neoadjuvant chemotherapy and ICIs, TLS positivity and maturity were improved compared to the baseline. Furthermore, neoadjuvant chemoimmunotherapy resulted in a higher rate of pathological complete response compared to monotherapies. CONCLUSIONS: This work pinpointed the individual effect of immunotherapy and chemotherapy in fostering TLS development, and underscored the superior effectiveness of combined modalities in enhancing TLS maturation and response rates.

Association between oxidative balance score and kidney stones: data from the national health and nutrition examination survey (NHANES).

PURPOSE: Some studies have found that the pathological formation of kidney stones is closely related to injury and inflammatory response. Behaviors such as dietary composition, physical activity, obesity and smoking can all affect the body's oxidative stress levels. In order to evaluate the effects of various diets and lifestyles on the body's oxidative and antioxidant systems, an oxidative balance score was developed. To investigate whether the OBS is associated with the development of kidney stones. METHODS: Data were taken from the National Health and Nutrition Examination Survey (NHANES) from 2007-2018, followed by retrospective observational studies. The association between kidney stones and OBS was analyzed using survey-weighted logistic regression by adjusting for demographics, laboratory tests, and medical comorbidity covariates. The oxidative balance score is calculated by screening 16 nutrients and 4 lifestyle factors, including 5 prooxidants and 15 antioxidants, based on prior information about the relationship between oxidation levels in the body and nutrients or lifestyle factors. RESULTS: A total of 26,786 adult participants were included in the study, of which 2,578, or 9.62%, had a history of nephrolithiasis. Weighted logistic regression analysis found an association between OBS and kidney stones. In the fully tuned model, i.e., model 3, the highest quartile array of OBS was associated with the lowest quartile array of OBS (OR = 0.73 (0.57, 0.92)) with the risk of kidney stone (p = 0.01), and was statistically significant and remained relatively stable in each model. At the same time, the trend test in the model is also statistically significant. With the increase of OBS, the OR value of kidney stones generally tends to decrease. CONCLUSIONS: There is an inverse correlation between OBS and kidney stone disease. At the same time, higher OBS suggests that antioxidant exposure is greater than pro-oxidative exposure in diet and lifestyle, and is associated with a lower risk of kidney stones.

Tenascin-C promotes bladder cancer progression and its action depends on syndecan-4 and involves NF-κB signaling activation.

BACKGROUND: Bladder Cancer (BCa) is a severe genitourinary tract disease with an uncertain pathology. Increasing evidence indicates that the tumor microenvironment plays a decisive role with respect to cancer progression, and that this is driven by tumor cell interactions with stromal components. Tenascin-C (TN-C) is an important extracellular matrix (ECM) component, which has been reported to be involved in other types of cancer, such as breast cancer. The expression of TN-C in BCa tissue has been reported to be positively associated with the BCa pathological grade, yet the presence of urine TN-C is considered as an independent risk factor for BCa. However, the role of TN-C in BCa progression is still unknow. Thus, the object of the present investigation is to determine the role of TN-C in BCa progression and the involved mechanism. METHODS: In this study, expression of TN-C in BCa tissue of Chinese local people was determined by IHC. Patients corresponding to tumor specimens were flowed up by telephone call to get their prognostic data and analyzed by using SPSS 19.0 statistic package. In vitro mechanistic investigation was demonstrated by QT-qPCR, Western Blot, Plasmid transfection to establishment of high/low TN-C-expression stable cell line, Boyden Chamber Assay, BrdU incorporation, Wound Healing, laser scanning confocal microscopy (LSCM) and ELISA. RESULTS: TN-C expression in BCa tissue increases with tumor grade and is an independent risk factor for BCa patient. The in vitro investigation suggested that TN-C enhances BCa cell migration, invasion, proliferation and contributes to the elevated expression of EMT-related markers by activating NF-κB signaling, the mechanism of which involving in syndecan-4. CONCLUSIONS: Expression of TN-C in BCa tissues of Chinese local people is increased according to tumor grade and is an independent risk factor. TN-C mediates BCa cell malignant behavior via syndecan-4 and NF-κB signaling. Although the mechanisms through which syndecan-4 is associated with the activation of NF-κB signaling are unclear, the data presented herein provide a foundation for future investigations into the role of TN-C in BCa progression.

Knockdown of CXCL5 inhibits the invasion, metastasis and stemness of bladder cancer lung metastatic cells by downregulating CD44.

In our previous studies, we found that T24 lung metastatic cancer cells showed high invasion and metastasis abilities and cancer stem cell characteristics compared with T24 primary cancer cells. By screening for the expression of CXC chemokines in both cell lines, we found that CXCL5 is highly expressed in T24-L cells. The aim of this study is to shed light on the relationship of CXCL5 with epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). RNAi technology was used to decrease CXCL5 expression in the T24-L cell line, and the EMT and CSCs of the shCXCL5 group and the control group were compared. The CXCR2 inhibitor SB225002 was used to inhibit the receptor of CXCL5 to determine the effect of the CXCL5/CXCR2 axis. The knockdown of CXCL5 expression in T24-L cells reduced their EMT and CSC characteristics. RT-PCR and Western blot analyses revealed the downregulation of N-cadherin, Vimentin and CD44. In addition, when CD44 expression was knocked down, the EMT ability of the cells was also inhibited. This phenomenon was most pronounced when both CXCL5 and CD44 were knocked down. CXCL5 and CD44 can affect the EMT and stem cell capacity of T24-L cells through some interaction.

Raman Spectrum-Based Diagnosis Strategy for Bladder Tumor.

Raman spectroscopy is an optical technique that can potentially serve as a molecular diagnosis method. This approach is excellent in many aspects for diagnosing bladder tumors, and over the last 20 years, there has been a rapid increase in the number of related studies. However, no review article has covered the wide use of Raman spectroscopy in bladder tumors. A total of 26 original studies have suggested that Raman spectroscopy shows good performance in diagnosing bladder tumors from 4 aspects, including tissue sections, endoscopic methods, cell screening, and biomarkers. However, Raman spectroscopy needs to be modified by combining it with other techniques, and studies based on a large population are still urgently needed to expand its clinical value.

Substratification of patients with highest-risk non-muscle invasive bladder cancer helps to identify the candidates for immediate radical cystectomy: A two-center study.

OBJECTIVES: Performing immediate radical cystectomy in all patients with the highest-risk non-muscle invasive bladder cancer results in overtreatment. We confirm whether the substratification of highest-risk patients can more effectively select suitable patients for radical cystectomy. METHODS: Patients with primary T1 high grade bladder cancer from two centers were included and roughly stratified into high-risk or highest-risk. The highest-risk patients were further substratified according to the number of risk factors. Endpoints were tumor recurrence and progression. The predictive accuracy was assessed with internal validation that consists of time-dependent receiver operating characteristic curve and calibration curves. RESULTS: A total of 262 patients were included. Although highest-risk patient had a poor prognosis, after further substratification, we found that those with only one factor showed the same prognosis with high-risk patients (recurrence: hazard ratio 1.79, P = 0.105; progression: hazard ratio 1.38, P = 0.532), while those with ≥2 factors had worst prognosis than high-risk patients. The 3-year area under the curve showed that the predictive accuracy of substratification in terms of recurrence and progression were superior to that of non-substratification (0.685 vs 0.622 and 0.666 vs 0.599, respectively). Additionally, calibration curves showed perfect agreement between the predicted and the actual recurrence and progression. CONCLUSIONS: Substratification of highest-risk enables us to further optimize the surgical decisions-making. Highest-risk patients with one factor show the similar outcomes as high-risk patients and deserve to try bladder-sparing treatment, whereas those with ≥2 risk factors were strongly recommended to undergo radical cystectomy.

Green-light laser en bloc resection versus conventional transurethral resection for initial non-muscle-invasive bladder cancer: A randomized controlled trial.

OBJECTIVE: To compare the safety and outcomes between green-light laser en bloc resection and transurethral resection of bladder tumor. METHODS: A single-center, randomized controlled trial was carried out from August 2014 to September 2018. Patients with initial non-muscle-invasive bladder cancer were randomized to green-light laser en bloc resection or transurethral resection of bladder tumor. The primary outcomes were pathological findings and perioperative events. The secondary outcome was tumor recurrence. RESULTS: A total of 233 patients were randomized to the transurethral resection of bladder tumor group (117 patients) and the green-light laser en bloc resection group (116 patients). The resection time was longer in the green-light laser en bloc resection group (P = 0.022); however, no differences were identified in overall operative time (P = 0.255). Nine patients (7.7%) had an obturator nerve reflex during transurethral resection of bladder tumor. The estimated volume of blood loss was significantly lower in the green-light laser en bloc resection group (P = 0.012). The green-light laser en bloc resection group had a higher rate of T1 bladder cancer (P = 0.031). A total of 104 patients (89.7%) treated with green-light laser en bloc resection had detrusor muscle presence in the specimen, whereas 37 (31.9%) patients had the presence of muscularis mucosae, which was significantly higher than the corresponding number of transurethral resection of bladder tumor patients (P = 0.005 and 0.002, respectively). After a median follow-up period of 48 months, just five patients had tumor recurrence (three in the transurethral resection of bladder tumor group and two in the green-light laser en bloc resection group), and there was no difference between these two groups. CONCLUSIONS: Compared with transurethral resection of bladder tumor, green-light laser en bloc resection is more effective due to less obturator nerve reflex and the same recurrence rate. Most importantly, green-light laser en bloc resection can provide better tumor specimens for pathological examinations.

Sub-Staging-Specific Differences in Recurrence-Free, Progression-Free, and Cancer-Specific Survival for Patients with T1 Bladder Cancer: A Systematic Review and Meta-Analysis.

INTRODUCTION: The efficiency of the T1 sub-staging system on categorizing bladder cancer (BC) patients into subgroups with different clinical outcomes was unclear. We summarized relevant evidences, including recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS), to analyze the prognostic significance of T1 sub-stage. METHODS: Systematic literature searches of MEDLINE, EMBASE, and the Cochrane Library were performed. We pooled data on recurrence, progression, and CSS from 35 studies. RESULTS: The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) indicated the difference in RFS between T1a sub-stage and T1b sub-stage (HR 1.28, 95% CI 1.14-1.43, p < 0.001). The significant difference was observed in PFS between the 2 arms (HR 2.18, 95% CI 1.95-2.44, p < 0.001). Worse CSS was found in T1b patients than in T1a patients (HR 1.36, 95% CI 1.21-1.54, p < 0.001). CONCLUSIONS: T1 sub-staging system based on the invasion depth into muscularis mucosae can be a significant prognostic factor for RFS, PFS, and CSS of patients with T1 BC. Urologists and pathologists are encouraged to work together to give a precise sub-stage classification of T1 BC, and T1 sub-staging system should be a routine part of any histopathological report when possible. Different treatment strategies need to be developed for both T1a BC and T1b BC.

Green-laser assisted laparoscopic partial cystectomy for selective muscle-invasive bladder cancer: technique and initial outcome.

PURPOSE: To describe a green-laser marking technique to assist partial cystectomy, which allows accurate identification of tumour margins, and provide our initial experience with ten patients. METHODS: Between January 2014 and February 2018, ten patients suspected with muscle-invasive bladder cancer and request of bladder-preserving treatment were selected. In each case, bilateral pelvic lymphadenectomy was performed before green-laser assisted laparoscopic partial cystectomy. Under the direct view of cystoscope, the front-firing green-laser incision was performed 0.5-1 cm away from the exterior margin of lesion with adequate depth into the fat tissue. Tumours were then en bloc removed via laparoscope under the tracing of laser beam. RESULTS: The location of 12 tumours in 10 patients was superior wall in 7 cases, lateral wall in 3 cases, anterior wall in 1 case, and posterior wall in 1 case. All procedures were completed without serious complications. The median operating time was 270 (210-360) min with a median haemoglobin decrease of 11 (3-38) g/L. Nine patients were high-grade transitional cell carcinoma and one patient was urachal carcinoma, and the clinical stage was pT1 in 1 case, pT2 in 4 cases, and pT3 in 5 cases. The pathological evaluation of tumour margins was negative in 10 patients. During the follow-up, no recurrence or metastasis were detected in 8 patients, but 2 patients presented regional recurrence. CONCLUSION: The use of green-laser marking technique during laparoscopic partial cystectomy is a feasible manoeuvre in assisting the accurate incision and minimizing injury to the remaining bladder.

En bloc resection improves the identification of muscularis mucosae in non-muscle invasive bladder cancer.

PURPOSE: The T1 substage, according to the relationship between muscularis mucosae (MM) and tumors, is a promising prognostic factor for T1 bladder cancer. However, the identification rate of MM is low in specimens, and it is, therefore, not widely used in clinical practice. In this study, we investigated whether en bloc resection of non-muscle invasive bladder cancer (NMIBC) could improve the identification of muscularis mucosae (MM), which may further accurate identification of the T1 substage. PATIENTS AND METHODS: Specimens from 158 patients with primary NMIBC were retrospectively reviewed by two independent pathologists to assess the presence of MM and stratify the T1 substage. Of 158 specimens, 70 specimens were obtained via TURBt with a plasma kinetic loop and 88 were obtained via front-firing potassium-titanyl-phosphate (KTP) green-light laser en bloc resection. Univariable and multivariable logistic regression models were used to analyze the relationship between the clinical characteristics and the presence of MM. RESULTS: The mean age was 58.22 years (range 18-85 years). Multivariable logistic regression analysis showed that the KTP laser resection method was associated with the presence of MM in specimens (P = 0.008). In addition, tumors with smaller sizes, which could also be en bloc resected with TURBt (e.g., ≤1 cm), had a higher presence of MM (P = 0.047). CONCLUSIONS: En bloc resection improves the identification rate of MM, which may enhance the accurate identification of the T1 substage.

Transurethral Enucleation of Bladder Leiomyoma: A Series of Six Cases and Review of the Literature.

OBJECTIVES: To investigate the feasibility and initial surgical outcomes of transurethral enucleation for 6 patients with bladder leiomyoma. MATERIALS: Six patients (mean age 50.2, range [34-67]) with bladder leiomyoma underwent transurethral enucleation. In each case, the resectoscope was inserted into the bladder. A resecting loop was used to incise the urothelium along the surgical margin of the bladder tumor, and a push was given through the resecting loop to further separate the tumor until it was shelled off the bladder wall. The intact mass was then cut into pieces and flushed out. After the operation, irrigation therapy was given. RESULTS: Surgery was performed successfully in all 6 patients. The mean size of the tumor was 3.9 cm (1.8-6.7 cm). The mean operation time was 60 min (30-100 min). The mean follow-up period was 14.8 months (2-30 months), and no evidence of recurrence was found in all cases. CONCLUSION: Transurethral enucleation is a safe, reliable, and effective surgical technique for selected patients with well-encapsulated tumors and is well suited for further pathological diagnosis and radical treatment.

A novel 450-nm blue laser system for surgical applications: efficacy of specific laser-tissue interactions in bladder soft tissue.

Low-power blue laser allows clean cutting with little bleeding and no undesired coagulations in adjacent tissues; however, studies on high-power blue laser soft tissue ablation properties, including vaporization and coagulation, have not been reported yet. The purpose of this study is to evaluate and analyze the ablation efficacy and coagulation properties of bladder epithelium tissues with a 30-W 450-nm wavelength blue laser. Well-designed ex vivo experiments compared blue laser and 532-nm LBO green laser, both with laser power up to 30 W, for porcine bladder tissue vaporization and coagulation at different experimental parameter settings. At working distance of 1 mm and sweeping speed of 1.5 mm/s, the vaporization efficiency of blue laser and green laser was 5.14mm3/s and 1.20mm3/s, while the depth of coagulation layer was 460 ± 70 µm and 470 ± 80 µm, respectively. We found both blue laser and green laser have excellent efficacy of tissue vaporization and similar tissue coagulation properties. Moreover, in a set of in vivo experiments simulated laser transurethral resection (TUR) surgery on dogs, we found both blue laser and green laser exhibited similar and satisfactory vaporization and coagulation outcomes. Taken together, our results demonstrate that a 450-nm wavelength high-power diode blue laser, like 532-nm wavelength green laser, is capable to produce high efficient tissue vaporization, low-laser tissue penetration, good tissue coagulation, and has low thermal damage to adjacent tissues. Therefore, a 30-W blue diode laser could be a new and safe alternative for surgeries of superficial bladder diseases.

Addition of intrarectal local analgesia to periprostatic nerve block improves pain control for transrectal ultrasonography-guided prostate biopsy: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the efficacy and safety of combined intrarectal local analgesia and periprostatic nerve block versus periprostatic nerve block alone for pain control during transrectal ultrasound-guided prostate biopsy. METHODS: We comprehensively searched PubMed, Embase and the Cochrane Library trials. Studies comparing the two techniques were identified and pooled for cumulative analysis. The outcome measurements included visual pain scales of three consecutive procedures of transrectal ultrasound-guided prostate biopsy, as well as short-term postoperative complication rates. RESULTS: There were 18 studies that were finally eligible for the quantitative analysis involving 2076 participants. Combined modalities significantly reduced the pain associated with probe manipulation (weighted mean difference -2.06, 95% confidence interval -2.77 to -1.35, P < 0.001), anesthesia infiltration (weighted mean difference -1.45, 95% confidence interval -2.20 to -0.70, P < 0.001) and needle biopsy (weighted mean difference -0.55, 95% confidence interval -0.76 to -0.34, P < 0.001). Subgroup analyses assessing different local analgesics showed that local anesthetics are generally more effective than myorelaxant and non-steroidal anti-inflammatory drugs. Lidocaine-prilocaine cream proved the most effective in pain control regardless of the origin of pain. No significant difference of short-term postoperative complications (fever, dysuria, acute urinary retention, hematuria, hematospermia and rectal bleeding) was found between the two techniques. The only side-effect associated with local analgesics was headache reported in studies using glyceryl trinitrate ointment. CONCLUSIONS: Combined modalities show better analgesic efficacy than periprostatic nerve block alone for transrectal ultrasound-guided prostate biopsy without increased morbidities. Among the various local analgesics, lidocaine-prilocaine cream seems to offer the best overall efficacy.

[Efficacy and tolerability of dapoxetine in the treatment of premature ejaculation].

OBJECTIVE: To investigate the efficacy and adverse effects of dapoxetine in the treatment of premature ejaculation. METHODS: We randomly assigned outpatients with premature ejaculation in the proportion of 2:1 to receive 30 mg dapoxetine on demand (n =78) or 50 mg sertraline qd for one month (n = 39). Follow-up was accomplished in 95 cases, 63 in the dapoxetine group and 32 in the sertraline group. We recorded the intravaginal ejaculatory latency time (IELT), clinical global impression of change (CGIC) score, and adverse reactions of the patients and compared them between the two groups. RESULTS: IELT was significantly increased in both the dapoxetine (from [0.87 ± 0.31] to [2.84 ± 0.68] min, P < 0.05) and the sertraline group (from [0.84 ± 0.28] to [2.71 ± 0.92] min, P < 0.05) after medication. Based on the CGIC scores in premature ejaculation, the rate of excellence or effectiveness was 36.5% in the dapoxetine and 37. 5% in the sertraline group, and the rate of improvement was 63.5% in the former and 71.9% in the latter. The incidence rates of dizziness, nausea, headache, and diarrhea were slightly higher (P > 0.05) while those of fatigue, somnolence, and dry mouth significantly higher (P < 0.05) in the sertraline than in the dapoxetine group. CONCLUSION: On-demand oral medication of dapoxetine is effective and well-tolerated for the treatment of premature ejaculation.

Evaluation of Raman spectroscopy for diagnosing EGFR mutation status in lung adenocarcinoma.

Somatic mutations in the epidermal growth factor receptor (EGFR) gene were associated with sensitivity to small molecule tyrosine kinase inhibitors for patients with lung adenocarcinomas. In this research, EGFR mutation status was analyzed by DNA sequencing in 153 lung adenocarcinoma tissues. Of these, 75 samples carried EGFR mutations, including 29 with E19del mutation, 33 with L858R mutation, 7 with T790M mutation, and 6 with multiple mutations. Then, 30 samples including 10 with wild type (wt)-EGFR, 10 with L858R and 10 with E19del mutations were selected for Raman and immunohistochemistry (IHC) analyses. After removing the spectra from normal and non-mutated regions, 441 spectra were found appropriate for Raman analysis: 149 from wt-EGFR, 135 from L858R and 157 from E19del mutations. The Raman peaks at 675, 1107, 1127 and 1582 cm(-1) were significantly increased in wt-EGFR tissues which can be attributed to specific amino acids and DNA. The Raman peaks at 1085, 1175 and 1632 cm(-1) assigned to arginine were slightly increased in L858R tissues. The overall intensity of E19del tissues was weaker than others due to exon 19 deletion that removes residues 746-750 of the expressed protein. Principal component analysis (PCA) and support vector machine (SVM) were applied for final prediction. The PCA/SVM algorithm yielded an overall accuracy of 87.8% for diagnosing L858R or E19del from wt-EGFR tissues. Finally, RS provides a simple, rapid and low-cost procedure based upon the molecular signatures for predicting EGFR mutation status.

[DAB2IP expression in bladder transitional cell carcinoma and its correlation with clinical outcome].

OBJECTIVE: To investigate the expression of DAB2IP in bladder transitional cell carcinoma (BTCC) and its correlation with clinical characteristics and prognosis of BTCC patients. METHODS: Immunohistochemical staining was applied to detect DAB2IP protein level in 79 cases of TCCB tissues and 11 cases of normal bladder tissues, and the relationships of the staining results with pathological grade, stage, lymph node metastasis, gender, age and the 3-year survival rate of the patients were analyzed. RESULTS: The expression of DAB2IP in BTCC tissues was significantly lower than that in normal bladder epithelium, and the expression score and rate of DAB2IP in the high-grade, invasive and metastatic BTCC were significantly lower than those in low-grade, superficial and non-metastatic BTCC (P < 0.05). The 3-year survival rate of the patients with high DAB2IP expression was significantly higher than that of the patients with low DAB2IP expression. CONCLUSION: DAB2IP may be one of the important inhibitory factors during the occurrence and progression of BTCC.

Global, regional, and national levels and trends in burden of urticaria: A systematic analysis for the Global Burden of Disease study 2019.

Background: Urticaria places a significant burden on individuals and society due to its widespread nature. The aim of this study was to evaluate the burden of urticaria in different regions and nations by analysing data from the Global Burden of Disease study 2019 (GBD 2019), with the goal of providing information to health care policymakers. Methods: By utilising data from the GBD 2019 database, this study analysed metrics such as incidence, prevalence, disability-adjusted life years (DALYs), age-standardised rate (ASR), and estimated annual percentage changes (EAPC) globally and across 204 countries and regions. The data was further stratified by age, sex, and sociodemographic index (SDI). Results: In 2019, global incidence cases, prevalence cases, and overall disease burden as measured by DALYs all increased. The distribution of the burden exhibited marked geographical heterogeneity. At the regional level, the burden is highest in Central and Eastern Europe and Central Asia, with the strongest growth in South Asia, compared with a decline in the high-income Asia Pacific. At the country level, Nepal reports the highest burden of urticaria, while Portugal has the lowest. Gender and age analyses showed that the burden of urticaria is higher in females than in males, with urticaria cases declining with age, especially in children, and picking up among the elderly. The study also finds a correlation between the burden of urticaria and the SDI, with the central part of the SDI showing a consistent increasing trend. Conclusion: This study found that the global burden of urticaria has risen from 1990 to 2019. Factors like geographic location, gender, and SDI influenced the urticaria burden. Overall, these results offer a resource to guide public health strategies seeking to reduce the burden of urticaria.

Prognosis and biological function of SGOL1 in clear cell renal cell carcinoma: a multiomics analysis.

BACKGROUND: Shugoshin-1 (SGOL1) is a mammalian ortholog of Shugoshin in yeast and is essential for precise chromosome segregation during mitosis and meiosis. Aberrant SGOL1 expression was reported to be closely correlated with the malignant progression of various tumors. However, the expression pattern and biological function of SGOL1 in clear cell renal cell carcinoma (ccRCC) are unclear. METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases provide mRNA expression data and outcome information for ccRCC patients. Immunohistochemistry (IHC) of ccRCC tissue chips verified SGOL1 protein expression in ccRCC patients. Data processing and visualization were performed with the UALCAN, TISIDB, TIMER, GSCA, LinkedOmics, and starBase databases. Gene Ontology (GO) annotation and gene set enrichment analysis (GSEA) were used to identify SGOL1-related biological functions and signaling pathways. Immune infiltration analysis was performed using the TISIDB database, ssGSEA algorithm, and TCGA-KIRC cohort. The biological role of SGOL1 in ccRCC was investigated using a series of in vitro cytological assays, including the MTT assay, EdU staining assay, flow cytometry analysis, Transwell assay, and wound healing assay. RESULTS: SGOL1 was highly expressed in ccRCC and linked to adverse clinicopathological parameters and unfavorable prognosis. Multivariate logistic regression and nomogram calibration suggested that SGOL1 might serve as an independent and reliable prognostic predictor of ccRCC. Functional enrichment analysis indicated that SGOL1 may be involved in the cell cycle, the p53 pathway, DNA replication, and T-cell activation. Furthermore, tumor microenvironment (TME) analysis suggested that SGOL1 was positively associated with Treg infiltration and immune checkpoint upregulation. In addition, we identified a potential SNHG17/PVT1/ZMIZ1-AS1-miR-23b-3p-SGOL1 axis correlated with ccRCC carcinogenesis and progression. Finally, we demonstrated that SGOL1 promoted ccRCC cell proliferation, migratory capacity, and invasion in vitro. CONCLUSIONS: SGOL1 potentially functions as an oncogene in ccRCC progression and might contribute to the immunosuppressive TME by increasing Treg infiltration and checkpoint expression, suggesting that targeting SGOL1 could be a novel therapeutic strategy for the treatment of ccRCC patients.

NEIL3 promotes cell proliferation of ccRCC via the cyclin D1-Rb-E2F1 feedback loop regulation.

Nei endonuclease VIII-like 3 (NEIL3), a novel tumor-related gene, is differentially expressed and involved in pathophysiological processes in multiple tumors. However, the potential biological functions and molecular mechanisms of NEIL3 in human clear cell renal cell carcinoma (ccRCC) have not been identified. In this research, we demonstrated that NEIL3, transcriptionally activated by E2F1, served as an oncogene to facilitate cell proliferation and cell cycle progression and contribute to tumorigenesis via the cyclin D1-Rb-E2F1 feedback loop in ccRCC. First, we found that NEIL3 expression was upregulated in ccRCC tissues and cell lines compared with matched adjacent nontumor tissues and renal tubular epithelial cells and was also positively correlated with adverse clinicopathological characteristics, such as advanced cancer stages and higher tumor grades, and acted as an independent prognostic marker in ccRCC. Mechanistically, we demonstrated that NEIL3 promoted cell proliferation, DNA replication and cell cycle progression in vitro and tumor growth in vivo. Furthermore, we found that NEIL3 overexpression activated the cyclin D1-Rb-E2F1 pathway, and the E2F1 upregulation transcriptionally activated NEIL3 expression, thus forming a feedback loop. In addition, there was a positive correlation between NEIL3 and E2F1 expression in clinical specimens of ccRCC. Taken together, our results suggest that NEIL3 serves as a proto-oncogene in ccRCC and presents as a novel candidate for ccRCC diagnosis and treatment.

Interaction of CCN1 with αvß3 integrin induces P-glycoprotein and confers vinblastine resistance in renal cell carcinoma cells.

Renal cell carcinoma (RCC) ranks among the most chemoresistant tumors, and P-glycoprotein (P-gp) predominates multidrug resistance mechanisms by reducing the accumulation of intracellular chemotherapy drugs such as vinblastine (VBL), which is considered the most effective chemotherapeutic agent for this neoplasia. Unfortunately, the mechanism by which the expression of P-gp is regulated and the ways to inhibit the function of P-gp are poorly understood. Our study was carried out to determine the possible role of CCN1 in P-pg-mediated drug resistance on the basis of the validated function of CCN1, an extracellular matrix protein, in promoting chemoresistance. As expected, CCN1 was overexpressed in VBL-resistant cell lines (ACHN/VBL, A498/VBL, Caki-1/VBL, and Caki-2/VBL) as measured by enzyme-linked immunosorbent assay. We then transfected non-VBL-resistant cell lines with Ad-CCN1 and observed that the IC50 of VBL increased by about 3-5 times. Furthermore, both CCN1 antibody neutralization and αvß3 integrin antibody blockade decreased the IC50 of VBL, which showed that CCN1 and αvß3 are associated with resistance to VBL in RCC. Simultaneously, the enhanced expression of CCN1 triggered the intracellular PI3K/Akt pathway by binding αvß3 integrin, as shown by western blot. P-gp expression was augmented in response to activation of the PI3K/Akt pathway, which could be modified by PI3K inhibitor LY294002 or multidrug resistance siRNA transfection. Therefore, targeted restraint of CCN1 or αvß3 integrin in combination with the administration of VBL may be beneficial in the treatment of primary and metastatic RCC.