Dual-Ligand-Functionalized Liposomes Based on Glycyrrhetinic Acid and cRGD for Hepatocellular Carcinoma Targeting and Therapy.

Hepatocellular carcinoma (HCC) is one of the most common cancers, with high mortality. Chemotherapy is one of the main treatment options for HCC. However, the high toxicity and poor specificity of chemotherapeutic drugs have limited their clinical application. In this study, dual-ligand liposomes modified with glycyrrhetinic acid (GA) and cyclic arginine-glycine-aspartic acid (cRGD) (GA/cRGD-LP) were designed to target the GA receptor and αvß3 integrin, respectively. The aim was to develop a highly selective targeted drug delivery system and further enhance the antitumor efficiency of drugs by targeting both hepatic tumor cells and vasculature. A novel lipid conjugate (mGA-DOPE) by coupling dioleoylphosphatidyl ethanolamine (DOPE) with methyl glycyrrhetinic acid (mGA) was synthesized, and its structure was confirmed. The targeting efficiency of GA/cRGD-LP by in vitro cellular uptake and ex vivo imaging was assessed. GA- and cRGD-modified doxorubicin-loaded liposomes (GA/cRGD-LP-DOX) were prepared, and their cytotoxicity in HepG2 and antitumor activity were evaluated. The results showed that the average particle size of the GA/cRGD-LP-DOX was 114 ± 4.3 nm, and the zeta potential was -32.9 ± 2.0 mV. The transmission electron microscopy images showed that the shapes of our liposomes were spherical. cGA/cRGD-LP-DOX displayed an excellent cellular uptake in both HepG2 and human umbilical vein endothelial cells. In the in vivo study, pharmacokinetic parameters indicated that cGA/cRGD-LP can prolong the circulation time of DOX in the blood. GA/cRGD-LP-DOX showed greater inhibition of tumor growth for HepG2-bearing mice than either the single-ligand-modified liposomes or nontargeted liposomes. GA/cRGD-LP-DOX displayed higher liver tumor localization than that of single-ligand-modified liposomes or free DOX. GA/cRGD-LP is a promising drug delivery system for liver cancer targeting and therapy and is worthy of further study.

[Correlation of Mycoplasma genitalium infection with semen parameters and sperm DNA integrity in male infertility patients].

OBJECTIVE: To analyze the relationship of Mycoplasma genitalium (MG) infection with routine semen parameters and sperm DNA integrity in male infertility patients. METHODS: Totally, 114 semen samples, 34 MG-positive and 80 MG-negative, were collected from male infertility patients and subjected to routine semen analysis with the computer-assisted sperm analysis system, Papanicolaou staining for observation of sperm morphology, and sperm chromatin diffusion (SCD) test for detection of sperm DNA integrity. Semen parameters and DNA integrity were compared between the MG-positive and MG-negative groups with SPSS 21.0 statistical software and the relationship between the semen parameters and DNA integrity analyzed by Pearson correlation analysis. RESULTS: The MG-positive samples, compared with the MG-negative ones, showed significantly decreased semen volume (ï¼»2.87 ± 0.37ï¼½ vs ï¼»3.86 ± 0.43ï¼½ ml, P < 0.01), sperm concentration (ï¼»29.05 ± 6.17ï¼½ vs ï¼»32.56 ± 5.97ï¼½ ×106/ml, P < 0.01), and percentages of progressively motile sperm (PMS) (ï¼»15.86 ± 2.79ï¼½% vs ï¼»23.65 ± 3.47ï¼½%, P < 0.01) and morphologically normal sperm (MNS) (ï¼»6.35 ± 2.06ï¼½% vs ï¼»7.14 ± 1.89ï¼½%, P < 0.05), increased proportions of non-halo sperm (ï¼»15.02 ± 3.52ï¼½% vs ï¼»9.72 ± 2.94ï¼½%, P <0.01) and small-halo sperm (ï¼»16.37 ± 5.26ï¼½% vs ï¼»11.07 ± 1.65ï¼½%, P < 0.01) and sperm DNA fragmentation index (DFI) (ï¼»31.39 ± 3.16ï¼½% vs ï¼»20.79 ± 3.59ï¼½%, P < 0.01), and reduced proportion of large-halo sperm (ï¼»54.75 ± 8.74ï¼½% vs ï¼»64.15 ± 9.76ï¼½%, P < 0.01). DFI was negatively correlated with the percentages of PMS (r = －0.516, P < 0.05) and MNS (r = －0.429, P < 0.05) in the MG-positive group, but not correlated with any of the routine semen parameters in the MG-negative patients (P > 0.05). CONCLUSIONS: MG infection may be an important factor affecting sperm quality in male infertility patients. Active prevention and treatment of MG infection can help prevent male infertility.

miR-7-5p acts as a tumor suppressor in bladder cancer by regulating the hedgehog pathway factor Gli3.

Although important progresses have been made in the diagnosis and treatment of bladder cancer (BCa), the overall survival for patients with advanced BCa remains poor. It is necessary to uncover the molecular mechanism underlying the initiation and progression of bladder cancer. According to previous reports, mircoRNAs (miRNAs) can regulate tumorigenesis by targeting their downstream mRNAs. This study aims to explore and analyze a novel miRNA-mRNA axis which can regulate the progression of bladder cancer. Based on the microarray analysis, 182 mRNAs were found to be upregulated in BCa tissues. Gene oncology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that these upregulated mRNAs are related with hedgehog pathway. Gli3, an important factor of hedgehog pathway, belongs to these 182 upregulated mRNAs. Therefore, Gli3 was chosen to do further study. Kaplan-Meier analysis revealed that highly expressed Gli3 predicted unfavorable prognosis for patients with BCa. Results of functional experiments indicated the inhibitory effects of silenced Gli3 on cell proliferation, migration and EMT progress. Mechanically, Gli3 was the target mRNA of miR-7-5p in BCa cells. Finally, rescue assays were performed to validate the specific function of miR-7-5p/Gli3 axis in BCa progression. According to all data, we concluded that miR-7-5p acts as a tumor suppressor in BCa by downregulating Gli3.

Long non-coding RNA CCAT2 promotes cell proliferation and invasion through regulating Wnt/ß-catenin signaling pathway in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common urologic malignancy. Long non-coding RNA colon cancer-associated transcript 2 (CCAT2) has been suggested as serving pivotal roles in tumorigenesis. However, the clinical significance and biological role of CCAT2 in ccRCC remains elusive. The purpose of this study is to identify the function of CCAT2 in ccRCC and its possible molecular mechanism. Expression of CCAT2 was analyzed in 61 ccRCC tissues and two ccRCC cell lines (786-O and ACHN) by quantitative reverse transcription polymerase chain reaction. The functional roles of CCAT2 in ccRCC were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, Transwell assay, and flow cytometric analysis. The influence of CCAT2 on tumorigenesis was monitored by in vivo mice xenograft model. The activation of Wnt/ß-catenin signaling pathway was evaluated by the TOP/FOP Wnt luciferase reporter assay and western blot assay. CCAT2 expression was markedly higher in ccRCC cell lines and tissues, being positively associated with tumor size and tumor stage in ccRCC patients. Patients with higher CCAT2 expression had a markedly poorer overall survival than did patients with low CCAT2 expression. Knocking down CCAT2 expression led to reduced cell proliferation and increased apoptosis of ccRCC cells in vitro as well as the activation of Wnt/ß-catenin signaling pathway, and CCAT2 overexpression remarkably enhanced these oncogenic properties. In vivo mice xenograft model also showed that knocking CCAT2 expression inhibited the growth of ccRCC xenografts. In conclusion, these results indicated that CCAT2 may play a critical role in ccRCC progression and will be further considered as a biomarker for predicting the survival of ccRCC patients and a potential therapeutic target for ccRCC intervention.

miR-143 Induces the Apoptosis of Prostate Cancer LNCap Cells by Suppressing Bcl-2 Expression.

BACKGROUND Prostate cancer has become a serious threat to the life of patients. microRNAs are small non-coding RNA molecules that regulate the growth and apoptosis of cells. We aimed to investigate the regulation and mechanism of microRNA (miR-143) in the proliferation and apoptosis of prostate cancer LNCap cells. MATERIAL AND METHODS miR-143 and control scramble miRNA were synthesized and respectively transfected into LNCap cells. The proliferation and apoptosis were detected by MTT assay, flow cytometry, and caspase-3 activity assay. The intracellular expression of Bcl-2 was determined by Western blot. Further, LNCap cells were transfected with small interfering RNA (siRNA) targeting Bcl-2 (siBcl-2) or plasmid expressing Bcl-2, followed by transfection of miR-143 or control miRNA. Bcl-2 expression was detected by Western blot, and cell apoptosis was measured by caspase-3 activity assay. RESULTS Transfection of miR-143 significantly inhibited the proliferation of LNCap cells (P=0.0073), increased the percentage of externalized phosphatidylserine (P=0.0042), activated the caspase-3 (P=0.0012), and decreased the expression of Bcl-2 (P=0.012) when compared with the control miRNA group. The expression of Bcl-2 was significantly reduced after siBcl-2 transfection. The apoptosis in the siBcl-2+miR-143 group was significantly increased compared with that in the miR-143 group (P=0.036), whereas there was no significant difference in the apoptosis between the siBcl-2+miRNA and miRNA groups. The expression of Bcl-2 was obviously higher after the transfection of Bcl-2-expressing plasmid. The apoptosis in Bcl-2+miR-143 group was significantly reduced compared with the miR-143 group (P=0.031), whereas no significant difference in the apoptosis was detected between the miRNA and Bcl-2+miRNA groups. CONCLUSIONS Transfection of miR-143 induces the apoptosis of prostate cancer LNCap cells by down-regulating Bcl-2 expression, suggesting that Bcl-2 might be a potential therapeutic target for prostate cancer.

[Microscopic spermatic vein ligation for the treatment of varicocele].

OBJECTIVE: To explore the effect of spermatic vein ligation under the microscope in the treatment of varicocele (VC). METHODS: A total of 120 VC patients received in our department from September 2011 to February 2015 were randomly divided into an experimental and a control group of equal number, the former treated by microscopic spermatic vein ligation and the latter by conventional open high ligation. Comparisons were made between the two groups of patients in the internal diameters of the spermatic vein during eupnea and Valsalva maneuver, the reflux time of the spermatic vein, blood flow parameters of the testicular artery, and semen quality before and at 3 months after surgery. RESULTS: At 3 months after surgery, the experimental group, as compared with the control, showed significantly decreased reflux time of the spermatic vein (ï¼»0.41 ± 0.10ï¼½ vs ï¼»1.08 ± 0.10ï¼½ s, P <0.05) and peak systolic velocity (9.26 ± 1.35 vs 10.64 ± 1.28, P <0.05) and resistance index (0.52 ± 0.03 vs 0.61 ± 0.03, P <0.05) of the testicular artery but markedly increased internal diameters of the spermatic vein during eupnea (ï¼»1.63 ± 0.07ï¼½ vs ï¼»1.59 ± 0.06ï¼½ mm, P <0.05) and Valsalva maneuver (ï¼»1.72 ± 0.05ï¼½ vs ï¼»1.68 ± 0.07ï¼½ mm, P <0.05), sperm concentration (ï¼»46.84 ± 5.24ï¼½ vs ï¼»35.35 ± 4.26ï¼½ ×106/ml, P <0.05), sperm motility (ï¼»63.75 ± 7.73ï¼½ vs ï¼»53.87 ± 6.46ï¼½ %, P <0.05), and total sperm count (ï¼»89.54 ± 7.95ï¼½ vs ï¼»75.24 ± 8.43ï¼½ ×106/ml, P <0.05). CONCLUSIONS: Microscopic spermatic vein ligation has a definite effect in the treatment of varicocele, which can significantly improve the testicular blood flow and semen quality of the patient.

[Effect of RUNX3 on the Expression of Smad4 in T24 Bladder Cancer Cell Line].

OBJECTIVES: To examine the effects of RUNX3 on cell proliferation and apoptosis and the expression level of Smad4 mRNA in the bladder cancer cell line of T24 by transfection with recombinant plasmid of pIRES-EGFP-RUNX3. METHODS: The recombinant plasmid of pIRES-EGFP-RUNX3 was constructed successfully. Cultured T24 cells were divided into three groups, including control group, empty vector group,and recombinant plasmid group. The cells in empty vector group and recombinant plasmid group were respectively transfected by pIRES-EGFP and pIRES-EGFP-RUNX3 The cells were harvested at 24 h after the transfection, the variation of cell morphology was examined by fluorescence microscopy. The cell apoptosis was detected by flow cytometry. The expression level of RUNX3 and Smad4 mRNA was measured by RT-PCR. RESULTS: Cell death was observed in two transfection groups. At 24 h after transfection,the apoptosis rate was (3.23±0.45)% in control group, (8.98±1.62)% in empty vector group and (43.61±2.69)% in recombinant plasmid group. The expression level of RUNX3 mRNA was 2.79±0.36,detected only in recombinant plasmid group, which was significantly up-regulated compared with the other two groups (P<0.05). CONCLUSIONS: The expression level of Smad4 mRNA was up-regulated by transfection with pIRES-EGFP-RUNX3,which also inhibited cell proliferation and promoted cell apoptosis.The tumor suppressor gene of RUNX3 could regulate the bladder cancer cell proliferation and apoptosis by TGF-ß/Smad signaling pathway.

Impact of serum vitamin D level on risk of bladder cancer: a systemic review and meta-analysis.

Vitamin D has important biological functions including modulation of the immune system and anti-cancer effects. There was no conclusive finding of the impact of serum vitamin D level on bladder cancer risk. A systemic review and meta-analysis was performed to assess the impact of serum 25-hydroxyvitamin D level on bladder cancer risk. The pooled relative risk (RR) with 95% confidence interval (95%CI) was used to assess the impact of serum 25-hydroxyvitamin D level on bladder cancer risk. A total of 89,610 participants and 2238 bladder cancer cases were finally included into the meta-analysis. There was no obvious heterogeneity among those included studies (I(2) = 0%). Meta-analysis total included studies which showed that a high serum 25-hydroxyvitamin D level could obviously decrease risk of bladder cancer (RR = 0.75, 95%CI 0.65-0.87, P < 0.001). In addition, the pooled RRs were not significantly changed by excluding any single study. The findings from the meta-analysis suggest an obvious protective effect of vitamin D against bladder cancer. Individuals with higher serum 25-hydroxyvitamin D levels suffer from less risk of subsequent bladder cancer.

Pure endoscopic removal of epidermoid tumors of the cerebellopontine angle.

PURPOSE: Epidermoid tumors located in the cerebellopontine angle (CPA) are challenging lesions because they tend to grow slowly in the subarachnoid cisterns around delicate neurovascular structures and often extend into surgical anatomic corners. The aim of this paper is to demonstrate the advantages and limitations of purely endoscopic removal of the CPA epidermoids. METHODS: Six patients harboring an epidermoid tumor located in the CPA were treated using an endoscope-controlled microsurgical technique. A retrosigmoid suboccipital approach was used in all patients. The cerebellomedullary cistern and the cisterna magna were opened to allow cerebrospinal fluid drainage and cerebellar drop, thus yielding a wide and straight working channel to the CPA. Then, the tumor and its capsule were removed by the modified microsurgical instruments. RESULT: The symptoms caused by mass effect of the lesion resolved after surgery. There were no deaths, but permanent deficits occurred in one patient whose cranial nerves VII/VIII complex was accidentally lesioned. Tumors and their capsules were totally removed in five cases. All patients were discharged 3-5 days after surgery. To date, no recurrences have been observed (follow-up range 14-50 months). CONCLUSION: The endoscope-controlled microsurgical technique enables a safe tumor removal even when parts of the lesion are not visible in a straight line in CPA epidermoids. By angled endoscopic lenses, tumor extending into adjacent cranial compartments or surgical anatomic corners can be removed through a single small craniotomy without retracting neurovascular structures.

[Effects of transforming growth factor-ß1 gene silencing on the expression of vascular endothelial growth factor in human bladder cancer cell lines].

OBJECTIVE: To employ RNA interference technology to silence transforming growth factor-ß1 (TGF-ß1) gene to examine the gene silencing effects of RNAi on the expression of vascular endothelial growth factor (VEGF) in human bladder cancer cell lines (EJ). METHODS: The TGF-ß1 gene-specific siRNA expression vector was constructed. And the most efficiently suppressed target sequences were screened through reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The samples were divided into 3 groups of EJ, control (TGF-ß1) and recombinant plasmid (TGF-ß1 siRNA expression vector). And the expression level of VEGF protein was detected by Western blot. RESULTS: TGF-ß1 gene-specific siRNA expression vector was constructed successfully. TGF-ß1 relative mRNA expression was 0.92 ± 0.19 and the protein expression level (50 ± 6) pg/ml. The protein expression level of EJ group after transfection was (0.86 ± 0.18) pg/ml, control group (1.15 ± 0.29) pg/ml and recombinant plasmid group (0.45 ± 0.16) pg/ml(both P < 0.05). CONCLUSIONS: An inhibition of TGF-ß1 gene down-regulates the expression of VEGF. And TGF-ß1 may regulate angiogenesis of bladder tumor through an induction of VEGF gene expression.

[Down-regulation effect of TGF-beta1 on expression of VEGF in bladder cancer cell line].

OBJECTIVE: To explore the down-regulation effect of transforming growth factor-beta1 (TGF-beta1) on the expression of vascular endothelial growth factor (VEGF) in bladder cancer cell line EJ cell strain. METHODS: The siRNA expression vectors of TGF-beta1, gene were constructed, the highest inhibition target sequence was screened and selected by real time-PCR and ELISA, and then the vectors were transfected into EJ cells, the expression level of VEGF mRNA was detected by Real time-PCR. RESULTS: TGF-beta1 targeting expression vectors were successfully constructed, Real time-PCR and ELISA screened the highest inhibition target sequence (the lowest expression level of TGF-beta1 mRNA was 0.92 +/- 0.19; ELISA result was 50.08 +/- 5.85). The relative expression level of VEGF mRNA in TGF-beta1 siRNA group was the lowest, indicating that the expression of VEGF was decreased by silencing TGF-beta1, gene. CONCLUSION: Inhibition of TGF-beta1 gene expression could down regulate the expression of VEGF in bladder neoplasm.

Independent association between prostate-specific antigen nadir and PSA progression-free survival in first-line abiraterone acetate treatment in castration-resistant prostate cancer patients: a pilot study.

Background: There is limited evidence regarding the correlation between prostate-specific antigen (PSA) kinetics and clinical outcomes. Therefore, after regulating other covariates, we studied patients with castration-resistant prostate cancer who received abiraterone acetate as the first-line treatment. In this study, we investigated whether time to PSA nadir was independently associated with PSA progression-free survival (PFS). Methods: As a retrospective cohort study, this study contained a total of 77 castration-resistant prostate cancer patients who received abiraterone acetate from October 2015 to April 2021 in a Chinese hospital. The dependent variable was PSA-PFS. The objective independent variable was time to PSA nadir (TTPN). Covariates involved in this study included age, duration of androgen deprivation therapy (ADT), PSA level at baseline, time of 50% PSA decline, time of PSA decline to nadir, Gleason score, bone metastasis, previous treatment, PSA decline <50% in 3 months, PSA to nadir in 3 months, PSA decline <90%, PSA decline <0.2 ng/mL, and PSA flare. Results: For the 77 subjects, their mean age was 72.70 ± 8.08 years. Fully calibrated linear regression findings indicated that PSA decline and kinetics were positively associated with PFS (months) after adjusting confounders (ß = 0.77, 95% CI: 0.11-1.44). A non-linear relationship was not detected between PSA decline or PSA kinetics and progression-free survival. Conclusion: According to the data of this study, there was a correlation between early PSA changes and patients treated with abiraterone acetate.

Real-world effectiveness and safety of goserelin 10.8-mg depot in Chinese patients with localized or locally advanced prostate cancer.

OBJECTIVE: Real-word data on long-acting luteinizing hormone-releasing hormone (LHRH) agonists in Chinese patients with prostate cancer are limited. This study aimed to determine the real-world effectiveness and safety of the LHRH agonist, goserelin, particularly the long-acting 10.8-mg depot formulation, and the follow-up patterns among Chinese prostate cancer patients. METHODS: This was a multicenter, prospective, observational study in hormone treatment-naïve patients with localized or locally advanced prostate cancer who were prescribed goserelin 10.8-mg depot every 12 weeks or 3.6-mg depot every 4 weeks with or without an anti-androgen. The patients had follow-up evaluations for 26 weeks. The primary outcome was the effectiveness of goserelin in reducing serum testosterone and prostate-specific antigen (PSA) levels. The secondary outcomes included testosterone and PSA levels, attainment of chemical castration (serum testosterone <50 ng/dL), and goserelin safety. The exploratory outcome was the monitoring pattern for serum testosterone and PSA. All analyses were descriptive. RESULTS: Between September 2017 and December 2019, a total of 294 eligible patients received ≥ 1 dose of goserelin; 287 patients (97.6%) were treated with goserelin 10.8-mg depot. At week 24 ± 2, the changes from baseline [standard deviation (95% confidence interval)] in serum testosterone (n = 99) and PSA (n = 131) were -401.0 ng/dL [308.4 ng/dL (-462.5, -339.5 ng/dL)] and -35.4 ng/mL [104.4 ng/mL (-53.5, -17.4 ng/mL)], respectively. Of 112 evaluable patients, 100 (90.2%) achieved a serum testosterone level < 50 ng/dL. Treatment-emergent adverse events (TEAEs) and severe TEAEs occurred in 37.1% and 10.2% of patients, respectively. The mean testing frequency (standard deviation) was 1.6 (1.5) for testosterone and 2.2 (1.6) for PSA. CONCLUSIONS: Goserelin 10.8-mg depot effectively achieved and maintained castration and was well-tolerated in Chinese patients with localized and locally advanced prostate cancer.

A randomized, single-blind, multi-center clinical observational study of a new super lubricath coating catheter latex catheters using in urethral catheterization.

Polymer polyvinylpyrrolidone (PVP) can be described as the main coating. After heating and curing, it is able to build a strong adhesion to the latex catheter for creating a durable and effective hydrophilic coating. In this study, we aim to explore the advantages and disadvantages of the new super lubricath latex catheter PVP coating compared with the common latex catheter. 148 patients who participated in the study were completely randomly divided into two groups, the observation group and the control group. When the urinary catheter was incubated, indwelling in subjects' body, and removed from the subjects, the researchers accordingly recorded the subjects' comfort feedback, device safety evaluation and the patient's vital signs, relevant blood and urine examination index, electrocardiogram (ECG) changes and recorded various adverse events. PVP super lubricath coating latex catheter offered better comfort, less damage to the urethra, and no significant disadvantage in safety compared to regular latex catheters, improving quality of care and patient satisfaction compared to regular latex urinary catheters.

DOK7, a target of miR-299-5p, suppresses the progression of bladder cancer.

OBJECTIVE: Bladder cancer (BLCA) is the 6th most common malignancy in males. microRNA (miRNAs) can function as tumor suppressors or oncogenic factors, which are of significance in the progression of BLCA. This study explored the mechanisms by which miR-299-5p modulates DOK7 (Docking Protein 7) expression and the functional role of DOK7 in the progression of BLCA. METHODS: The expression of the DOK7 in BLCA patient samples was examined by RT-qPCR (Real-time quantitative polymerase chain reaction), Western blotting and Immunohistochemical (IHC) staining. The malignant phenotype of BLCA cells upon DOK7 overexpression or silencing was assessed by functional assays including cell count kit-9 (CCK8), colony formation and 5-ethynyl-2'-deoxyuridine (Edu) staining assays, as well as Transwell migration and invasion assays. The miRNA regulators of DOK7 were identified through bioinformatics prediction, and the biological role of miR-299-5p/DOK7 axis was validated by functional assays. The impact of miR-299-5p/DOK7 axis on Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway was further examined by Western blotting. RESULTS: DOX7 was significantly downregulated in BLCA tumor tissues compared with normal tissues. Ectopic DOK7 expression suppressed the proliferation, migration and invasion of BLCA cells. DOK7 overexpression also attenuated the tumorigenesis of BLCA cells in nude mice. miR-299-5p was a negative regulator of DOK7 expression in BLCA cells. miR-299-5p/DOK7 axis impaired the malignancy of BLCA cells through regulating the JAK signaling pathway. CONCLUSION: Our data indicate that miR-299-5p/DOK7 axis suppresses BLCA progression possibly by regulating the JAK signaling pathway.

Feasibility of apalutamide combined with androgen deprivation therapy and short-course low-dose prednisone in treating metastatic hormone-sensitive prostate cancer: a pilot randomized controlled trial.

Introduction: The role of prednisone in the prevention of androgen receptor antagonist-related rash and treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is unclear. This pilot trial (ChiCTR2200060388) aimed to investigate the feasibility of apalutamide combined with androgen deprivation therapy (ADT) and short-course low-dose prednisone in the treatment of mHSPC. Methods: All patients received apalutamide and ADT and were randomly divided into two groups based on the administration of oral prednisone or not (control group). The primary endpoint was the incidence of rash. The secondary endpoint included the proportions of patients with a decline in PSA ≥50% from baseline, PSA ≥90% from baseline, and decreased to PSA ≤0.2 ng/mL. Results: Between June 2021 and March 2022, a total of 83 patients were enrolled (41 in the prednisone group and 42 in the control group). During the 6-month follow-up, the incidence of rash was significantly lower in the prednisone group compared with the control group (17.1% vs. 38.1%, P=0.049). There were no significant differences in the incidence of other adverse events, the number of patients who required dose adjustment (reduction, interruption, or discontinuation) of apalutamide due to rash, the number of patients with prostate-specific antigen (PSA) decreased by ≥50%, the number of patients with PSA decrease ≥90%, and the number of patients with PSA ≤0.2 ng/mL between the two groups. All patients with diabetes had stable glycemic control with no glucose-related adverse events. Discussion: In patients with mHSPC, the addition of short-course low-dose prednisolone to apalutamide plus ADT can reduce the incidence of rash without risk of other adverse events.

Comprehensive characterization of tumor microenvironment in colorectal cancer via molecular analysis.

Colorectal cancer (CRC) remains a challenging and deadly disease with high tumor microenvironment (TME) heterogeneity. Using an integrative multi-omics analysis and artificial intelligence-enabled spatial analysis of whole-slide images, we performed a comprehensive characterization of TME in colorectal cancer (CCCRC). CRC samples were classified into four CCCRC subtypes with distinct TME features, namely, C1 as the proliferative subtype with low immunogenicity; C2 as the immunosuppressed subtype with the terminally exhausted immune characteristics; C3 as the immune-excluded subtype with the distinct upregulation of stromal components and a lack of T cell infiltration in the tumor core; and C4 as the immunomodulatory subtype with the remarkable upregulation of anti-tumor immune components. The four CCCRC subtypes had distinct histopathologic and molecular characteristics, therapeutic efficacy, and prognosis. We found that the C1 subtype may be suitable for chemotherapy and cetuximab, the C2 subtype may benefit from a combination of chemotherapy and bevacizumab, the C3 subtype has increased sensitivity to the WNT pathway inhibitor WIKI4, and the C4 subtype is a potential candidate for immune checkpoint blockade treatment. Importantly, we established a simple gene classifier for accurate identification of each CCCRC subtype. Collectively our integrative analysis ultimately established a holistic framework to thoroughly dissect the TME of CRC, and the CCCRC classification system with high biological interpretability may contribute to biomarker discovery and future clinical trial design.

Polydatin protects against calcium oxalate crystal-induced renal injury through the cytoplasmic/mitochondrial reactive oxygen species-NLRP3 inflammasome pathway.

BACKGROUND: Oxidative stress and inflammatory responses are critical factors in calcium oxalate (CaOx) crystal-induced renal injury. Reactive oxygen species (ROS) are usually produced in the cytoplasm and mitochondria and trigger the priming and activation of the NLRP3 inflammasome, thereby regulating cytokines and inflammation. Polydatin is a plant rhizome extract with anti-inflammatory, antioxidant, and antitumor effects. However, it remains not clear whether and how these pathophysiological processes exists in CaOx crystal-induced renal inflammatory injury. METHODS: Here, we measured the expression of the NLRP3 inflammasome, IL-18, IL-1ß, intracellular and mitochondrial ROS (mtROS) levels and relevant morphological changes in treated renal tubular epithelial cells (TECs) and stone-forming rats. The study further explored the action of intracellular ROS and mtROS on these inflammatory damage, and the beneficial effects and pathway of polydatin. RESULTS: We verified that CaOx crystal-induced cytoplasmic ROS and mtROS upregulation promoted the priming and activation of the NLRP3 inflammasome, thereby stimulating IL-18/1ß maturation and activation. Polydatin can relieve oxidative stress and inflammatory damage by decreasing ROS. We further demonstrated that mtROS is the main target for polydatin to exert the NLRP3 inflammasome-regulating function. The inhibition of mtROS can effectively relieve the inflammatory damage to TECs and kidney caused by CaOx crystal. CONCLUSION: These findings provide new insight into the relationship between mitochondrial damage and inflammation in nephrolithiasis and show that polydatin-mediated anti-inflammatory and antioxidative protection is a therapeutic strategy for, but not limited to, crystalline nephropathy.

Systematic review and meta-analysis of ureteral stent for risk factors of restenosis after laparoscopic pyeloplasty.

BACKGROUND: Laparoscopic pyeloplasty (LP) has been widely used to treat ureteropelvic junction obstruction (UPJO); however, no previous series of reports has focused on analyzing the factors that influence the complications and outcomes of LP. In this study, we analyzed the risk factors related to complications of LP, especially that of restenosis. The aim of this study is to perform meta-analysis of relevant comparative studies to analyze the risk factors of restenosis after LP treatment with ureteral stent as of 30 April 2021. METHODS: A systematic search was conducted in April 2021. The evaluation results included operation time (OT), intraoperative blood loss (IBL), anastomotic tension (AT), postoperative drainage (PD), and ectopic blood vessels (EBV). Relative risk (RR) and standardized mean difference (SMD) were extrapolated with a 95% confidence interval (CI). Subgroup analysis was performed based on research design and technology. RESULTS: After screening, 7 studies were included, incorporating a total of 979 patients with PUJO treated by LP. Analysis revealed the likelihood of risk factors as follows: OT [mean difference (MD) -3.16, 95% CI: -7.18 to 0.85; P=0.12], IBL (MD -3.16, 95% CI: -7.18 to 0.85; P=0.12), AT (RR 3.86, 95% CI: 2.96 to 5.02; P<0.00001), PD (MD 303.97, 95% CI: 219.49 to 388.44; P<0.00001), and EBV (RR 1.15, 95% CI: 0.78 to 1.68; P=0.49). The results indicated that high AT and increased PD are risk factors for postoperative ureteral restenosis. DISCUSSION: The results of the meta-analysis showed that among the factors related to the efficacy of LP in the treatment of ureteral stenosis, OT, IBL, AT, and EBV were not significantly correlated with postoperative restenosis. However, AT and PD are independent risk factors for postoperative restenosis of the ureter. Therefore, during the operation, the AT should be reduced, and the local injury is reduced to reduce the PD, thereby reducing the risk of restenosis.

Systematic review and meta-analysis of the efficacy of tension-free vaginal tape on pelvic organ prolapse complicated by stress urinary incontinence.

BACKGROUND: Patients with pelvic organ prolapse combined with stress urinary incontinence (SUI) require pelvic floor repair and surgical treatment; however, there is currently no systematic evaluation of the treatment effect. METHODS: PubMed, Medline, Embase, Elsevier, The Cochrane Library, Web of science, and other databases were searched for randomized controlled trials (RCTs) published between January 2000 and December 2020 regarding tension-free vaginal tape (TVT) treatment of pelvic organ prolapse combined with SUI. Quality evaluation of the articles included in this study was conducted in accordance with the Cochrane Work Manual (5.3), and RevMan 5.3 software was used to conduct meta-analysis of the data extracted from literature meeting the requirements. RESULTS: A total of 10 articles were included, involving a total of 1,361 subjects, including 553 in the control group (a different surgical treatment) and 808 in the observation group (single TVT or TVT combined with pelvic floor repair). The bias evaluation results showed that all of the included literature was rated as level B, so there was no need for sensitivity analysis. The meta-analysis showed that the combined effect size of the clinical cure rate was {odds ratio (OR) [95% confidence interval (CI)]: 3.82 (1.39, 10.52); Z=2.59, P=0.010}, and the combined effect size of the clinical complication rate was [risk difference (RD) (95% CI): -0.09 (-0.16, -0.02); Z=2.38; P=0.02]. The results showed that the clinical cure rate of the observation group was significantly higher than that of the control group, while the clinical complication rate was significantly lower than that of the control group (P<0.05). DISCUSSION: TVT surgery or TVT combined with pelvic floor repair surgery can significantly improve the cure rate of patients with pelvic organ prolapse combined with SUI, and reduce the incidence of postoperative complications. Therefore, TVT is a suitable surgical method for the treatment of patients with pelvic organ prolapse combined with SUI.