Monogenic features of urolithiasis: A comprehensive review

Objective: Urolithiasis formation has been attributed to environmental and dietary factors. However, evidence is accumulating that genetic background can contribute to urolithiasis formation. Advancements in the identification of monogenic causes using high-throughput sequencing technologies have shown that urolithiasis has a strong heritable component.Methods: This review describes monogenic factors implicated in a genetic predisposition to urolithiasis. Peer-reviewed journals were evaluated by a PubMed search until July 2023 to summarize disorders associated with monogenic traits, and discuss clinical implications of identification of patients genetically susceptible to urolithiasis formation.Results: Given that more than 80% of urolithiases cases are associated with calcium accumulation, studies have focused mainly on monogenetic contributors to hypercalciuric urolithiases, leading to the identification of receptors, channels, and transporters involved in the regulation of calcium renal tubular reabsorption. Nevertheless, available candidate genes and linkage methods have a low resolution for evaluation of the effects of genetic components versus those of environmental, dietary, and hormonal factors, and genotypes remain undetermined in the majority of urolithiasis formers.Conclusion: The pathophysiology underlying urolithiasis formation is complex and multifactorial, but evidence strongly suggests the existence of numerous monogenic causes of urolithiasis in humans.

Prostate cancer with elevated free prostate-specific antigen density:A case report

BACKGROUND Prostate cancer is the second most common cancer among men worldwide,and prostate-specific antigen(PSA)is often used in clinical practice to screen for prostate cancer.Normal total PSA(tPSA)level initially excludes prostate cancer.Here,we report a case of prostate cancer with elevated free PSA density(fPSAD).CASE SUMMARY A patient diagnosed with benign prostatic hyperplasia underwent prostatectomy,and the postoperative pathological results showed acinar adenocarcinoma of the prostate.The patient is currently undergoing endocrine chemotherapy.CONCLUSION We provide a clinical reference for diagnosis and treatment of patients with normal tPSA but elevated fPSAD.

A preliminary study on rectal dose reduction associated with hyaluronic acid implantation in brachytherapy for prostate cancer

Objectives: Hydrogel spacer (HS) was developed to reduce rectal toxicities caused by radiotherapy, but has been reported to cause major adverse events. Our institute has attempted to introduce a hyaluronic acid (HA) as an alternative spacer. This study aimed to compare rectal doses and geometric distributions between the HS and HA implantation in prostate cancer.Methods: HS and HA were inserted in 20 and 18 patients undergoing high-dose brachytherapy, respectively. The rectum spacer volumes injected were 10 mL and 22 mL, respectively. In the treatment planning system, 13.5 Gy was administered with common catheter positions. The rectal dose indices were assessed between the spacer groups for dosimetry evaluation. Distances between the prostate and rectum and configurations of the spacers were compared.Results: The mean doses irradiated to 0.1 and 2 mL of the rectum were 10.45 Gy and 6.71 Gy for HS, and 6.73 Gy and 4.90 Gy for HA (p<0.001). The mean minimum distances between the prostate and rectum were 1.23 cm and 1.79 cm for HS and HA, respectively (p<0.05). Geometrical configuration comparisons revealed that HA has a higher ability to expand the space than HS.Conclusion: The rectal dose reduction ability of HA is significantly greater than that of HS, suggesting its potential as a new spacer.

Chinese expert consensus statement on clinical diagnosis and treatment of malignant tumor bone metastasis and bone related diseases

Clinical diagnosis and treatment of malignant tumor bone metastasesOverview Bone is the most common place of metastases in ad-vanced malignant diseases. Constant improvement in the treatment of malignant tumors has resulted in prolonged survival time, and so as an increased incidence of osseous metastases and skeletal complications.

Significant association between IL-18 and OCT4 gene polymorphisms in susceptibility and clinical characteristics of prostate cancer

Objective Recent studies have shown abnormal expression of octamer-binding transcription factor 4(OCT4) and interleukin-18(IL-18) to be related to cancer. However, the molecular mechanisms by which the IL-18 and OCT4 gene polymorphisms are associated with prostate cancer remain unclear. In this study, we aimed to determine whether the presence of IL-18 and OCT4 polymorphisms were associated with size, grade, tumor, nodes and metastasis(TNM) stage, or survival in patients with prostate cancer.Methods Polymorphisms in OCT4 and IL-18 genes were evaluated to determine susceptibility to prostate cancer in 120 patients. A control group consisted of 125 Chinese participants. Genotyping was performed using TaqMan allelic discrimination assays, and statistical analysis was performed using SPSS. Results No association was found between OCT4 and IL-18 gene polymorphisms and prostate cancer susceptibility. For OCT4 AA and IL-18-607 CC genotypes, there was a significant association with higher tumor grade(P = 0.03 and P = 0.025) and stage(P = 0.04 and P = 0.001). The OCT4 and IL-18-137 GG genotype was correlated with higher tumor grade(P = 0.028) and stage(P = 0.008). Furthermore, OCT4 AA was significantly more frequent in patients with lymph node metastasis(P = 0.02) and distant metastasis(P = 0.01). The Cox proportional hazard model showed that tumor grade and stage grouping were independent prognostic factors but IL-18 and OCT4 polymorphisms were not. Conclusion The OCT4 gene may have a profound effect on prostate cancer risk. Polymorphism variants in the IL-18(IL-18-607 and IL-18-137) and OCT4 genes may be associated with poor prognoses for individuals with prostate cancer.

Clinical study of IL-18 and NANOG gene polymorphisms in prostate cancer patients

Objective Recent studies have shown abnormal expression of NANOG and IL-18 to be related to cancer. However, the molecular mechanism by which IL-18 and NANOG gene polymorphisms are associated with prostate cancer is unclear. In this study, we examined whether IL-18 and NANOG gene polymorphisms and their interaction with prostate cancer-related risk factor are associated with the susceptibility to and clinicopathological development of prostate cancer among Chinese men.Methods Polymorphisms in the NANOG and IL-18 genes were evaluated for susceptibility in 120 patients with prostate cancer. The control group consisted of 125 samples from Chinese men. Genotyping was conducted using Taq Man allelic discrimination assays. Statistical analysis was performed using SPSS software. Results No association of NANOG and IL-18 gene polymorphisms and overall prostate cancer susceptibility was detected. The IL-18-607 CC genotype was significantly associated with a higher tumor grade(P = 0.025) and stage(P =0.001). The IL-18-137 GG genotype correlated with a higher tumor grade(P = 0.028) and stage(P = 0.008). The IL-18-137 G allele was significantly more frequent in patients with lymph node metastasis(P = 0.035). The IL-18-607 CC genotype was associated with distant metastasis(P = 0.025). However, no significant association was observed between NANOG polymorphisms and any clinicopathological feature. The Cox proportional hazard model showed that tumor grade and stage grouping were independent prognostic factors in IL-18, while IL-18 polymorphism was not. Polymorphism variants in the IL-18(IL-18-607 and IL-18-137) and NANOG(genotypes AC) genes might be associated with a worse prognosis of patients with prostate cancer.Conclusion NANOG may be associated with the early stages of prostate cancer carcinogenesis. IL-18 and NANOG gene polymorphisms may play a major role in the growth, invasion, and metastasis of prostate cancer.

Analysis of the Current Status and Influencing Factors of the Readiness for Discharge of Patients after Prostate Cancer Surgery Based on the Concept of Enhanced Recovery after Surgery (ERAS)

Objective To investigate the level of readiness for discharge of patients after prostate cancer surgery based on the concept of Enhanced Recovery After Surgery (ERAS), and to explore its influencing factors, so as to provide references for improving the readiness for discharge of patients after prostate cancer surgery. Methods The general information questionnaire, the discharge preparation scale, and the discharge guidance quality scale were used to investigate 119 patients discharged from the urological surgery department of a tertiary A-level hospital in Guangzhou after radical prostatectomy. Results The total score of discharge readiness of patients after radical prostatectomy was 147.74 ± 35.71 points, which was at a lower middle level and the total score of discharge guidance quality was 180.68 ± 38.91 points, which was at a medium level. Multiple linear regression analysis showed that education level, family monthly income, Gleason score, whether to perform lymphatic dissection, whether to discharge with a urinary catheter, and the quality of discharge guidance were the main factors influencing the readiness for discharge of patients after prostate cancer surgery. Conclusion In clinical nursing work, it is necessary to implement individualized health education according to the characteristics and needs of different patients to improve the level of preparation for discharge of patients after prostate cancer surgery.

Efficacy,safety,and dose comparison of degarelix for the treatment of prostate cancer:A systematic review and meta-analysis

AIM:To conduct a systematic review and meta-analysis into the efficacy,safety,and dosage regimens of degarelix for treating prostate cancer(PCa). METHODS:Pub Med,EMBASE,the Cochrane Library,and Web of Science was systematically searched to identify randomized controlled trials(RCTs) comparing degarelix(240/80 mg vs 240/160 mg) to the gonadotropin-releasing hormone agonists,goserelin and leuprolide,for the treatment of PCa. Two independent reviewers screened putative studies,assessed the risk of bias,and then extracted pertinent data. Analyses were performed using Review Manager 5.2. RESULTS:Seven papers from six RCTs,involving 1204 patients,were identified. The present meta-analysis showed that treatment with 240/160 mg degarelix is more effective and has fewer adverse events(AEs) relative to conventional 240/80 mg regimen. Degarelix significantly decreased International Prostate Symptom Scores [standardized mean differences(SMD) =-0.32,95%CI:-0.51 to-0.12,P = 0.02] and caused fewer AEs(SMD =-0.28,95%CI:-0.48 to-0.07,P = 0.008) than goserelin. Degarelix suppressed testosterone and prostate-specific antigen significantly faster than leuprolide. CONCLUSION:Degarelix is a useful option in the treatment of advanced PCa. Degarelix 240/160 mgregimen was superior to a 240/80 mg regimen. More rigorously designed RCTs are urgently needed to confirm the efficacy of degarelix.

Multimodality-imaging manifestations of primary renal-allograft synovial sarcoma:First case report and literature review

BACKGROUND Primary renal synovial sarcoma (PRSS) is an extremely rare tumor with a poor prognosis. Its imaging and immunohistochemical characteristics may overlap with other renal tumors, which renders its early diagnosis in a dilemma. The diagnosis of primary renal synovial sarcoma requires histopathology and the confirmation of SYT-SSX gene fusion using molecular techniques. Cases of primary renal synovial sarcoma have been previously reported in the literature. However, to our knowledge, primary renal allograft synovial sarcoma was never described. CASE SUMMARY A 43-year-old male patient who underwent kidney transplantation 9 months ago came to our hospital for regular follow-up. Traditional ultrasonography revealed multiple hypo-echo neoplasms in the renal allograft. Contrast-enhanced computed tomography (CECT) showed slightly hyper-density masses with slow homogeneous enhancement. Ultrasound-guided biopsy was conducted for accurate pathological diagnosis. The neoplasms were diagnosed as synovial sarcoma by pathological, immunohistochemical, and genetic analyses. Positron emission tomography/CT showed no evidence of metastasis. At approximately one week post biopsy, contrast-enhanced ultrasound was conducted to eliminate active hemorrhage. One month later, CECT showed that the biggest neoplasm grew from 3.3 cm to 5.7 cm in diameter. Parametric imaging was conducted with SonoLiver CAP to conduct further quantitative analysis, which showed that the enhancement pattern was heterogeneous hyper-vascular enhancement. Radical surgical resection of the whole renal allograft and ureter was conducted without additional adjuvant chemotherapy or external radiotherapy. Anlotinib was chosen for targeted therapy with a good response. CONCLUSION We propose multimodality imaging for accurate diagnosis of renal allograft synovial sarcoma especially when it is formed by spindle-shaped cells.

Effect of 935-MHz Phone-simulating Electromagnetic Radiation on Endometrial Glandular Cells during Mouse Embryo Implantation

This study examined the impact of 935MHz phone-simulating electromagnetic radiation on embryo implantation of pregnant mice.Each 7-week-old Kunming (KM) female white mouse was set up with a KM male mouse in a single cage for mating overnight after induction of ovulation.In the first three days of pregnancy,the pregnant mice was exposed to electromagnetic radiation at low-intensity (150 μW/cm2,ranging from 130 to 200 μW/cm2,for 2-or 4-h exposure every day),mid-intensity (570 μW/cm2,ranging from 400 to 700 μW/cm2,for 2-or 4-h exposure every day) or high-intensity (1400 μW/cm2,ranging from 1200 to 1500 μW/cm2,for 2-or 4-h exposure every day),respectively.On the day 4 after gestation (known as the window of murine embryo implantation),the endometrium was collected and the suspension of endometrial glandular cells was made.Laser scanning microscopy was employed to detect the mitochondrial membrane potential and intracellular calcium ion concentration.In high-intensity,2-and 4-h groups,mitochondrial membrane potential of endometrial glandular cells was significantly lower than that in the normal control group (P<0.05).The calcium ion concentration was increased in low-intensity 2-h group but decreased in high-intensity 4-h group as compared with the normal control group (P<0.05).However,no significant difference was found in mitochondrial membrane potential of endometrial glandular cells between low-or mid-intensity groups and the normal control group,indicating stronger intensity of the electromagnetic radiation and longer length of the radiation are required to inflict a remarkable functional and structural damage to mitochondrial membrane.Our data demonstrated that electromagnetic radiation with a 935-MHz phone for 4 h conspicuously decreased mitochondrial membrane potential and lowered the calcium ion concentration of endometrial glandular cells.It is suggested that high-intensity electromagnetic radiation is very likely to induce the death of embryonic cells and decrease the chance of their implantation,thereby posing a high risk to pregnancy.

Preoperative diagnosis of renal oncocytoma: case report and literature review

To differentiate renal oncocytoma from renal carcinoma, the clinical data of four patients with incidentally found renal oncocytomas were studied in this report. And additional Immunohistochemistry examinations were done to confirm diagnosis. Renal oncocytomas were found incidentally in four patients during medical examination. No characteristic changes were found in laboratory tests. Radiology examination provided the location and possibility of renal oncocytoma. History, laboratory test and radiology exanimation indicated the diagnosis of renal oncocytoma, but the final identify of renal oncocytoma need pathology examination.

Effect of interleukin-18 polymorphisms-607 and -137 on clinical characteristics of prostate cancer patients

Objective: The aim of this study was to determine whether the presence of IL-18 polymorphisms -137 G/C and -607 A/C was associated with grade, clinical stage, and survival in patients with prostate cancer. Methods: The study cohort included 126 patients with prostate cancer. Control group consisted of 125 samples from Chinese population. Genomic DNA was extracted from EDTA-anticoagulated peripheral blood leukocytes by the salting-out method. The genotyping of the two IL-18 polymorphisms was performed using predesigned TaqMan SNP Genotyping Assays. Results: The studied IL-18 gene polymorphisms did not influence susceptibility to prostate cancer in the analyzed group of patients (IL-18-607, P = 0.342; IL-18-137 P = 0.715) but may contribute to disease onset and aggressiveness. IL-18-607 CC genotype was significantly associated with higher tumor grade (P = 0.025) and stage (P = 0.001). IL-18-137 GG genotype was correlated with higher tumor grade (P = 0.018) and stage (P = 0.007). The Cox proportional hazard model showed that tuumor grade and stage grouping were independent prognostic factors but IL-18 polymorphism was not. Polymorphism variants in the IL-18 gene (IL-18-607 and IL-18-137) may be associated with a worse prognosis for prostate cancer. Conclusion: High levels of IL-18 production may play a major role in the growth, invasion and metastasis of prostate cancer.

Clinical value of serum interleukin-18 and nitric oxide activities in patients with prostate cancer

Objective:The aim of the study was to estimate the clinical value of serum interleukin-18(IL-18)and nitric oxide(NO)activities in patients with prostate cancer.Methods:The 50 patients with prostate cancer and 25 control subjects were measured in serum IL-18 by enzyme-linked immunosorbent assay(ELISA)and nitrate+nitrite level by an index of NO generation.Results:Serum IL-18 and nitrate+nitrite levels were significantly higher in patients with prostate cancer when compared to the control subjects(P<0.05).Serum IL-18 level was significantly higher in patients with stages B,C and D when compared to patients with stage A(P<0.05).Serum IL-18 level was significantly higher in the metastatic patients compared with the nonmetastatic patients(P<0.01).There was no difference in serum nitrate and nitrite level between metastatic and nonmetastatic patients(P>0.05).The serum IL-18 and nitrate and nitrite levels decreased after patients underwent surgical resection.Conclusion:Serum IL-18 level may be a useful marker to predict prognosis of patients with prostate cancer after surgery.Long-term follow-up is required to clarify this hypothesis.

Impact of IL-18 gene promoter polymorphisms on renal cell carcinoma occurrence and prognosis in Chinese Han population

Objective Genetic polymorphisms in various inflammatory cytokines have been associated with the risk and growth or invasiveness of renal cell carcinoma(RCC).However,the molecular basis of RCC pathogenesis is unclear.The aim of this study was to explore a possible association between two IL-18 gene promoter polymorphisms,-137G/C and -607 C/A,and RCC occurrence and prognosis in a Chinese Han population.Methods Chinese Han patients with RCC(n=175) and age-matched healthy controls(n=200) were analyzed by single nucleotide polymorphism genotyping during follow-up.Results IL-18-137G allele frequency was significantly higher in patients with lymph node metastasis(Odds ratio [OR],3.52;95% confidence interval [CI],0.97-16.17;P=0.045).The IL-18-607 CC genotype was associated with distant metastasis(OR,2.81;95% CI,1.35-6.24;P=0.025).The IL-18-137G allele was correlated with more advanced tumor stage(OR,1.83;95% CI,1.05-3.72;P=0.026) and higher tumor grade(OR,2.23;95% CI,0.78-4.12;P=0.041).The IL-18-607 CC genotype frequency was significantly higher in patients with more advanced cancer stage(OR,2.92;95% CI,1.80-6.87;P=0.001) and higher tumor grade(OR,2.21;95% CI,1.25-12.25;P=0.035).The IL-18-607 allele was associated with more advanced cancer stage(OR,2.47;95% CI,1.38-3.83;P=0.002).Carriers of the GG genotype with the -137G/C polymorphism had a 2.165-times higher risk of RCC progression than carriers of the GC genotype(Hazard ratio=2.15,95% CI,1.270-3.687).Conclusion The IL-18-137G allele was correlated with more advanced stage,higher tumor grade,and lymph node metastasis.IL-18 gene promoter polymorphism -137G/C may thus influence the prognosis of RCC patients.

Comparison of the postoperative trauma of the retroperitoneal laparoscopic intrasinusal pyelolithotomy and percutaneous nephrolithotomy

Objective: To study the postoperative trauma of the retroperitoneal laparoscopic intrasinusal pyelolithotomy (RLIP) and percutaneous nephrolithotomy (PCNL). Methods: A total of 118 patients who were diagnosed with single pelvis calculus in Shanghai Punan Hospital of Pudong New District between September 2013 and February 2017 were selected and randomly divided into RLIP group and PCNL group who received retroperitoneal laparoscopic intrasinusal pyelolithotomy and percutaneous nephrolithotomy respectively. The removal of the stones was observed 1 week and 4 weeks after surgery, and 3mL of cubital venous blood was collected 3 d and 7 d after operation to detect the renal function indicators, inflammatory markers and stress indicators. Results: The stone removal success rate of RLIP group 1 week and 4 weeks after operation were significantly higher than those of PCNL group, serum BUN, Scr and Cys-C contents as well as eGFR levels were not significantly different between RLIP group and PCNL group 3 d and 7 d after operation, and serum Cor, NE, HSP70, NO, IL-6, hs-CRP, TNF-α and PGE2 contents of RLIP group 3 d and 7 d after operation were significantly lower than those of PCNL group. Conclusion: RLIP is significantly better than PCNL in stone removal and causes significantly less postoperative trauma than PCNL.

Role and significance of SIRT1 in regulating the LPS-activated pyroptosis pathway in children with congenital hydronephrosis

Objective To explore the characteristics and mechanism of sirtuin 1(SIRT1)in lipopolysaccharide(LPS)-activated pyroptosis in the renal tissue of children with congenital hydronephrosis(CHn).Methods We detected the expression characteristics and clinical significance of SIRT1 and pyroptosis pathway proteins in CHn renal tissues by immunohistochemistry.The degree of renal fibrosis was detected by Masson staining.The human renal tubular epithelial cell line(HK-2)was cultured in vitro and treated with LPS(1µg/mL),the SIRT1-specific agonist SRT1720(2.5µmol/L)and small interfering RNA(siRNA)-SIRT1 for 48 hours.After 48 hours,Cell Counting Kit-8 was used to detect the changes in cell proliferation ability,and ELISA was used to detect the changes in the expression of interleukin(IL)-1β and IL-18 in the cell supernatant.Real-time PCR(quantitative RT-PCR)and western blot analysis were used to detect the expression of SIRT1,caspase-1,caspase-4,NOD-like receptor thermal protein domain associated protein 3(NLRP3),and cleaved gasdermin D(GSDMD)in each group.Results Serum inflammatory cytokines were significantly elevated in 13 children with CHn with urinary tract infection,mainly caused by Gram-negative bacteria.Severe renal fibrosis occurred in children with CHn.Compared with the control group,the expression of SIRT1 in CHn kidney tissues was decreased,and the expression of caspase-4 and GSDMD was increased.LPS inhibited the expression of SIRT1 in HK-2 cells,promoted the expression of caspase-1,caspase-4,NLRP3,cleaved GSDMD,promoted the expression of IL-1β and IL-18 in the supernatant,and promoted pyroptosis in HK-2 cells.SRT1720 can inhibit LPS-activated pyroptosis by promoting SIRT1 expression,while siRNA-SIRT1 can further aggravate LPS-activated pyroptosis after inhibiting SIRT1 expression.Conclusions LPS can promote the inflammatory response in children with CHn by activating non-canonical pyroptosis and inhibiting SIRT1 expression.Promoting SIRT1 expression can inhibit pyroptosis of renal tubular epithelial cells,reduce the release of IL-18 and IL-1β,and alleviate the progression of renal fibrosis in children with CHn.

Cold-preserved human spermatozoa in electrolyte-free solution retain their pene-tration capacity

Objective: To evaluate penetration capacity of human sperm preserved in electrolyte-free (EF) solution at 4 ℃.Methods: The motility, acrosomal status penetration rate and fertility index of human sperm were assessed before and after cold-preservation in EF solution, respectively.Results: The motility of human sperm cold-preserved in EF solution for 1 week was significantly higher than that of human sperm cold-preserved in modified human tubal fluid (mHTF) (43.4%±7.9% vs 9.5%±2.5%, P<0.01 ).Although acrosomal status of human sperm cold-preserved in the EF solution before reinitiation was not different from those of the fresh sperm (capacitated sperm: 7.6%±1.8% vs 6.4±1.8%; acrosome-reacted sperm: 3.0%±1.7% vs 2.4±1.1%, P>0.05), the percentage of capacitated and acrosome-reacted sperm in the EF solution significantly increased after reinitiation (capacitated sperm: 16.0%±2.3% vs 7.6±1.8%, acrosome-reacted sperm: 9.4%±2.1% vs 3.0%±1.7%, P<0.01).The penetration rate and fertility index of cool-preserved human sperm in the EF solution were comparable with those of fresh sperm (48.1% vs 50.9%; 1.38±0.16 vs 1.29±0.13, respectively, P>0.05).Conclusion: Cold-preservation did not induce capacitation and acrosome reaction of human sperm in the EF solution, but human sperm cold-preserved in the EF solution for 1 week possesses as much penetration capacity as fresh sperm.

Relationship between serum IL-18 and VEGF levels in patients with prostate cancer

Objective： The aim of our study was to analyze intedeukin-18 （IL-18） and vascular endothelial growth factor （VEGF） serum levels in patients with prostate cancer before and after operation and the possible correlation between IL-18 and VEGF serum levels. Methods： Serum IL-18 and VEGF levels were measured by enzyme-linked immunosorbent assay （ELISA） in 36 patients with prostate cancer before and after radical prostatectomy and in 25 healthy controls. Results： Serum IL-18 and VEGF levels were significantly higher in patients with prostate cancer before operation with respect to healthy controls （P 〈 0.05）, with a highly significant correlation between IL-18 and VEGF （R = 0.800, P = 0.017）. It was significantly reduced in IL-18 and VEGF after operation. IL-18 and VEGF serum concentrations were correlated with the clinicalopathologi- cal status of patients with prostate cancer. Conclusion： It is correlative with serum IL-18 and VEGF. Serum IL-18 and VEGF levels may be useful prognostic marker in patients with prostate cancer.

Evodiamine induces extrinsic and intrinsic apoptosis of ovarian cancer cells via the mitogen-activated protein kinase/phosphatidylinositol-3-kinase/protein kinase B signaling pathways

OBJECTIVE: To explore the effects of evodiamine on ovarian cancer cells and the mechanisms underlying such effects.METHODS: Human ovarian cancer cells HO-8910 PM were treated with evodiamine at 0, 1.25,2.5, and 5 μM for 1-4 d. 3-(4,5-Dimethiylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay was used to detect the growth inhibition rate of evodiamine-treated HO-8910 PM cells. The cell cycle was observed via propidium iodide(PI) staining. Apoptosis induction was assessed via Annexin V-fluorescein isothiocyanate/propidium iodide(Annexin V-FITC/PI) double staining assay. To verify the mechanism of apoptosis, caspase-dependent apoptotic pathway-related protein was detected by Western blot analysis. The expression levels of mitogen-activated protein kinase(MAPK)and/or phosphatidylinositol-3-kinase(PI3K)/pro-tein kinase B(Akt) pathway-related proteins were also investigated.RESULTS: Evodiamine significantly inhibited the proliferation of HO-8910 PM cells in a dose- and time-dependent manner. Evodiamine induced G2/M arrest with an increase of cyclin B1 level, and promoted cell apoptosis with a decrease of B cell lymphoma/lewkmia-2(Bcl-2) and an increase of Bcl-2-associated X protein(Bax) level. In addition,evodiamine treatment led to the activation of caspase-8, caspase-9, and caspase-3 and the cleavage of poly(ADP-ribose)-polymerase(PARP). Evodiamine targeted the MAPK and/or PI3K/Akt pathways by reducing the expression and activity of PI3 K, Akt, and extracellular signal-regulated kinase mitogen-activated protein kinase(ERK1/2 MAPK)and the activity of p38 MAPK.CONCLUSION: Evodiamine can inhibit the growth of ovarian cancer cells by G2/M arrest and intrinsic and extrinsic apoptosis. In addition, evodiamine-induced PI3K/Akt, ERK1/2 MAPK, and p38 MAPK signaling may be involved in cell death.

Current status and future perspectives of immunotherapy in bladder cancer treatment

The treatment strategy of bladder cancer has evolved not only through the traditional modalities of surgery and chemotherapy but also by immunotherapy over the past several decades.Immunotherapies such as intravesical Bacillus Calmette-Guérin(BCG)vaccines and immune checkpoint blockades(ICBs)are sometimes used for treating patients with bladder cancer,especially those who develop resistance to conventional first-line treatments such as surgery and chemotherapy.Unfortunately,it is a limited number of individuals that see clinical benefits from this approach,and complicating matters more is that many of these patients suffer severe immune-related adverse events(ir AEs).If current momentum continues to result in improved response rates and managed ir AEs,immunotherapy could be poised to revolutionize the landscape of urothelial carcinoma therapeutics.