Down-regulation of SLC14A1 in prostate cancer activates CDK1/CCNB1 and mTOR pathways and promotes tumor progression.

Prostate cancer (PCa) is the most common cancer among men in the United States and the leading cause of cancer-related death. The Solute Carrier Family 14 Member 1 (SLC14A1) is a member of urea transporters which are important for the regulation of urine concentration. However, the physiological significance of SLC14A1 in PCa still remains unclear. In the present study, via bioinformatics analysis and experiments, we found that expression of SLC14A1 is significantly decreased in PCa progression, which could be attributed to hypermethylation on SLC14A1 promoter region. Moreover, its low expression and hypermethylation on SLC14A1 promoter are closely related to the poor prognosis of PCa patients. On the other hand, overexpression of SLC14A1 inhibited cell proliferation and metastasis while its overexpression also suppressed CDK1/CCNB1 pathway and mTOR/MMP-9 signaling pathway. Additionally, SLC14A1 expression is enriched in prostate basal-type cells. In summary, our study indicates that its low expression level and promoter hypermethylation of SLC14A1 may represent novel indicators for PCa progression and prognosis, and SLC14A1 could inhibit the progression of PCa.

A Novel Photosensitizer Based 450-nm Blue Laser-Mediated Photodynamic Therapy Induces Apoptosis in Colorectal Cancer - in Vitro and in Vivo Study.

BACKGROUND: Due to its non-invasive and widely applicable features, photodynamic therapy (PDT) has been a prominent treatment approach against cancer in recent years. However, its widespread application in clinical practice is limited by the dark toxicity of photosensitizers and insufficient penetration of light sources. This study assessed the anticancer effects of a novel photosensitizer 5-(4-amino-phenyl)-10,15,20-triphenylporphyrin with diethylene-triaminopentaacetic acid (ATPP-DTPA)-mediated PDT (hereinafter referred to as ATPP-PDT) under the irradiation of a 450-nm blue laser on colorectal cancer (CRC) in vivo and in vitro. METHODS: After 450-nm blue laser-mediated ATPP-PDT and the traditional photosensitizer 5-aminolevulinic acid (5-ALA)-PDT treatment, cell viability was detected through Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. Reactive oxygen species (ROS) generation was quantified by flow cytometry and fluorescence microscopy. Western blotting and transcriptome RNA sequencing and functional experiments were used to evaluate cell apoptosis and its potential mechanism. Anti-tumor experiment in vivo was performed in nude mice with subcutaneous tumors. RESULTS: ATPP-DTPA had a marvelous absorption in the blue spectrum. Compared with 5-ALA, ATPP-DTPA could achieve significant killing effects at a lower dose. Owing to generating an excessive amount of ROS, 450-nm blue laser-mediated PDT based on ATPP-DTPA resulted in evident growth inhibition and apoptosis in CRC cells in vitro. After transcriptome RNA sequencing and functional experiments, p38 MAPK signaling pathway was confirmed to be involved in the regulation of apoptosis induced by 450-nm blue laser-mediated ATPP-PDT. Additionally, animal studies using xenograft model confirmed that ATPP-PDT had excellent anti-tumor effect and reasonable biosafety in vivo. CONCLUSIONS: PDT mediated by 450-nm blue laser combined with ATPP-DTPA may be a novel and effective method for the treatment of CRC.

Neoadjuvant chemohormonal therapy before radical prostatectomy in high-risk prostate cancer: a mini-review.

High-risk localized prostate cancer (PCa) has the potential of recurrence and progression to a lethal phenotype, and neoadjuvant therapy followed by radical prostatectomy (RP) may be an option for these patients. Docetaxel has been recently shown to be an effective chemotherapeutic agent for high-volume metastatic hormone-sensitive PCa and metastatic castration-resistant PCa, and these increased efficacy create the impetus to assess the potential role of preoperative docetaxel in high-risk localized PCa. In this mini-review, we found that neoadjuvant chemohormonal therapy (NCHT) may be an effective neoadjuvant regimen to improve oncological outcome of high-risk PCa. However, the addition of docetaxel in the neoadjuvant setting would unavoidably increase the rate of adverse events, impose additional economic burdens. Therefore, suitable patient selection is crucial and pathological response might be a surrogate endpoint. Furthermore, we also found that molecular imaging prostate-specific membrane antigen (PSMA) PET/CT was a promising tool to evaluation the effectiveness of NCHT, and the expression status of AR, AR-V7, Ki-67, PTEN and TP53 might be helpful for urologists to identify more suitable candidates for NCHT.

Curcumin Inhibits Vasculogenic Mimicry Via Regulating ETS-1 in Renal Cell Carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (RCC) poses a huge challenge once it has become resistant to targeted therapy. Vasculogenic mimicry (VM) is a novel blood supply system formed by tumor cells that can circumvent molecular targeted therapies. As one of the herbal remedies, curcumin has been demonstrated to play antineoplastic effects in many different types of human cancers; however, its function and mechanism of targeting VM in RCC remains unknown. OBJECTIVE: Here, in the work, we explored the role of curcumin and its molecular mechanism in the regulation of VM formation in RCC. METHODS: RNA-sequencing analysis, immunoblotting, and immunohistochemistry were used to detect E Twenty Six-1(ETS-1), vascular endothelial Cadherin (VE-Cadherin), and matrix metallopeptidase 9 (MMP9) expressions in RCC cells and tissues. RNA sequencing was used to screen the differential expressed genes. Plasmid transfections were used to transiently knock down or overexpress ETS-1. VM formation was determined by tube formation assay and animal experiments. CD31-PAS double staining was used to label the VM channels in patients and xenograft samples. RESULTS: Our results demonstrated that VM was positively correlated with RCC grades and stages using clinical patient samples. Curcumin inhibited VM formation in dose and time-dependent manner in vitro. Using RNA-sequencing analysis, we discovered ETS-1 as a potential transcriptional factor regulating VM formation. Knocking down or overexpression of ETS-1 decreased or increased the VM formation, respectively and regulated the expression of VE-Cadherin and MMP9. Curcumin could inhibit VM formation by suppressing ETS-1, VE-Cadherin, and MMP9 expression both in vitro and in vivo. CONCLUSION: Our finding might indicate that curcumin could inhibit VM by regulating ETS-1, VE-Cadherin, and MMP9 expression in RCC cell lines. Curcumin could be considered as a potential anti-cancer compound by inhibiting VM in RCC progression.

Gut Microbiota Disorders in Obesity-Associated Benign Prostatic Hyperplasia in Rats.

Benign prostatic hyperplasia (BPH), commonly seen in older men, can cause symptoms of discomfort, and may even need surgical intervention. Studies have shown the potential link between gut microbes and BPH, but the molecular association is not fully understood. METHODS: Four-week-old male Sprague-Dawley rats (n = 16) were randomly allocated to normal control diet (ND, 10% fat) and high-fat diet-induced BPH (HFD, 45% fat) groups. Metagenomic analysis was used to examine the abundance and discrepancies in gut microbiota within the two groups after 24 weeks of feeding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was conducted to assess the biological functions of the differentially expressed genes. RESULTS: Rats with HFD-induced obesity exhibited morphological abnormalities in their prostate tissues. Metagenomic analysis of the gut revealed that Firmicutes were the dominant phyla in the HFD group, whereas the ND group had a higher abundance of Spirochaetes. At the genus level, Ruminococcus spp exhibited greater abundance in the HFD group, whereas Treponema spp were more abundant in the ND group. KEGG analysis demonstrated that the differentially expressed genes were mainly enriched in the NOD-like receptor (NLR) signaling, PI3K-Akt signaling, estrogen-signaling, signalings associated with GABAergic synapses, pantothenate and CoA biosynthesis. CONCLUSION: The findings of our study indicated that there was a notable variation in the microbiota abundance within the intestinal tract of obese rats suffering from prostate hyperplasia. It is plausible that these differentially abundant bacteria played a role in the development of pathological alterations in the prostate through the facilitation of inflammatory responses; however, additional research is required to validate the findings.

Epidemiological investigation of fowl adenovirus (FAdV) infections in ducks and geese in Shandong Province, China.

RESEARCH HIGHLIGHTS: Samples of suspected FAdV-infected waterfowl from farms in Shandong Province were collected from 2019 to 2022.Single infections with FAdV were less frequent than mixed infections.477 out of 792 samples (60.23%) tested positive for FAdV nucleic acids.Detection rate of FAdV was 65.47% in fattening duck farms, 55.73% in breeder duck farms and 54.55% in fattening geese farms.

Wound healing process in beagles after vaporization of the prostate with a novel 200W 450-nm laser.

In comparison to other commercially used lasers, the coagulation layer of the novel 450-nm laser is thinner, and this coagulation layer's thickness is a key factor influencing wound healing. In this study, we investigated whether the novel 200W 450-nm laser system (BR6800, Blueray Medical Ltd., Shaanxi, China) is superior to classic transurethral resection of the prostate (TURP) for wound healing in beagles. Twenty-two 6-to 8-year-old male beagles were treated with TURP or blue laser vaporization of the prostate (BLVP). Prostate wounds were observed via cystoscopy at 3 h and at 1, 2, 3, and 5 weeks post-operation (two beagles per group). Additionally, two elderly beagles without surgery served as normal controls. After cystoscopy examination, prostate samples were collected and fixed for hematoxylin and eosin (H&E) and immunofluorescence staining to observe wound healing progression under microscopy. The urethras of prostates under cystoscopy in BLVP groups were healed three weeks after surgery, while in the TURP group, they were healed five weeks after surgery. H&E staining confirmed that the coagulation necrosis layer in the TURP group was thicker than that in the BLVP group and it took longer to remove coagulation necrosis after surgery. Macrophage polarity transformation was also earlier in the BLVP group. The new 200W 450-nm laser was superior to TURP for wound healing. The thinner coagulation layer of the 450-nm laser was the primary reason for this process.

Evidence of vertical transmission of fowl adenovirus 8b in ducks.

Fowl adenovirus mainly causes hydropericardium hepatitis syndrome (HHS), inclusion body hepatitis (IBH) and gizzard erosion (GE), etc. In 2015, the first outbreak of HHS was reported in broiler chickens in central China, followed by an outbreak in waterfowl. The first outbreak of HHS in broiler flocks in central China in 2015, followed by outbreaks in waterfowl, has severely restricted the healthy development of the poultry industry. During the investigation, fowl adenovirus was detected in ducklings from a total of seven hatcheries in Shandong, Inner Mongolia and Jiangsu provinces. In addition, the DNA of fowl adenovirus was detected in breeding ducks and their progeny. To test the hypothesis that FAdV can be transmitted vertically, sixty 250-day-old Cherry Valley breeder ducks were divided equally into three groups for experimental infection. FAdV-8b SDLY isolate (duck/Shandong/SDLY/2021, SDLY) preserved in our laboratory was injected intramuscularly into group A and inoculated orally into group B. FAdV-8b DNA was detected in the yolk membranes, embryos and allantoic fluid of duck embryos in the FAdV-infected group after inoculation. In addition, the FAdV-8b hexon gene isolated from yolk membranes, embryos, allantoic fluid and duck eggs was close to 100% nucleotide homology to the FAdV-8b hexon gene isolated from laying duck ovaries, indicating that fowl adenovirus can be transmitted vertically in ducks. These findings provide evidence for the possible vertical transmission of fowl adenovirus from breeder ducks to ducklings.

450-nm blue diode laser: a novel medical apparatus for upper tract urothelial lesions.

OBJECTIVE: To explore the feasibility, safety and effectiveness of the 450-nm blue diode laser (BL), novel blue laser in the treatment of upper tract urothelial carcinomas (UTUCs) and other lesions in a porcine model. MATERIAL AND METHODS: For in vitro experiment, the ureter tissue was vaporised and coagulated with BL, green-light laser (GL) and Ho:YAG laser (Ho). The efficiency, width and depth of vaporisation, and depth of coagulation were recorded and compared. For in vivo experiments, four swines weighing 70 kg were used. In the acute group, different modes of operations were performed to evaluate the thermal damage, perforation and bleeding. In the chronic group, the overall appearance of the ureter and laser wound healing were observed by the naked eyes and H&E staining 3 weeks after surgery. RESULTS: In in vitro study, the BL showed a higher efficiency of tissue vaporisation and less tissue coagulation for fresh ureter compared to GL and Ho. In the in vivo study, the power of BL set at 7 W was better, and the thickness of thermal damage varied with different surgery types in the range of 74-306 µm. After 3 weeks, the wound healed well static in vaporisation (SV), moving vaporisation (MV) and H&E staining indicated mucosal healing rather than scar healing. CONCLUSION: 5-10W blue diode laser achieved a higher efficiency of tissue vaporisation and less tissue coagulation in a porcine model, indicating its potential application in the endoscopic surgery of UTUC as an optional device with high performance and safety.

The isolation and characterizations of a duck adenovirus 1 causing Egg Drop Syndrome in ducks, China.

A fowl adenovirus variant designated as DAdV-JSXZ strain was isolated from the tissue specimen of fallopian tubes of a duck case, which was submitted from a 276-day-old Cherry valley breeding duck flock experienced egg-dropping syndromes in March 2022. Full-genome sequence of the DAdV-I JSXZ strain by next-generation sequencing revealed that the complete genome length of DAdV-JSXZ strain was 33,213 nucleotides and shared a high degree of nucleotide identity (97.0-99.4 %) with other DAdV-I reference strains. In pathogenicity studies, this isolated duck JSXZ strain reproduced similar egg-dropping symptoms in healthy breeding ducks, pathologic lesions of follicular hemorrhage, and the laid eggs in low fertilization and hatchability rates. Our research findings demonstrated that DAdV-I JSXZ strain was one of the causative agents of duck egg dropping syndrome in egg-laying ducks and could cause acute respiratory symptoms in ducklings.

Better prediction of clinical outcome in clear cell renal cell carcinoma based on a 6 metabolism-related gene signature.

It has been reported that metabolic disorders participate in the formation and progression of clear cell renal cell carcinoma (ccRCC). However, the predictive value of metabolism-related genes (MRGs) in clinical outcome of ccRCC is still largely unknown. Herein, a novel metabolism-related signature was generated to assess the effect of MRGs on the prognosis of ccRCC patients. Important module MRGs were selected by differentially expressed analysis and WGCNA. Subsequently, the hub MRGs were screened via univariate cox regression as well as LASSO regression. A new metabolism-related signature of 6 hub MRGs (PAFAH2, ACADSB, ACADM, HADH, PYCR1 and ITPKA) was constructed, with a good prognostic prediction ability in the TCGA cohort. The prediction accuracy of this signature was further confirmed in both GSE22541 and FAHWMU cohort. Interestingly, this MRG risk signature was highly correlated with tumor mutation burden and immune infiltration in ccRCC. Notably, lower PAFAH2, a member of 6 MRGs, was found in ccRCC. Knockdown of PAFAH2 contributed to renal cancer cell proliferation and migration. Collectively, a 6-MRG prognostic risk signature is generated to estimate the prognostic status of ccRCC patients, providing a novel insight in the prognosis prediction and treatment of ccRCC.

Impact of non-regional lymph node metastases accurately revealed on 18F-PSMA-1007 PET/CT in the clinical management of metastatic hormone-sensitive prostate cancer.

BACKGROUND: Non-regional lymph node (NRLN) metastases has shown increasing importance in the prognosis evaluation and clinical management of primary metastatic hormone-sensitive prostate cancer (mHSPC). Hence, this study aimed to investigate the concordance rates between 18F-PSMA-1007 PET/CT and conventional imaging (CI) in revealing NRLN metastases, and explore the impact of NRLN metastases on the management of primary mHSPC. METHODS: The medical records of 224 patients with primary mHSPC were retrospectively reviewed, including 101 patients (45.1%) only received CI for TNM classification, 24 patients (10.7%) only received 18F-PSMA-1007 PET/CT, and 99 patients (44.2%) received both 18F-PSMA-1007 PET/CT and CI. Among patients who received 18F-PSMA-1007 PET/CT and CI before initial treatment, the concordance rates between 18F-PSMA-1007 PET/CT and CI were analyzed. The high-volume disease was defined as the presence of visceral metastases and/or ≥ 4 bone metastases (≥ 1 beyond the vertebral bodies or the pelvis) based on the findings of 18F-PSMA-1007 PET/CT and/or CI. The primary endpoint was progression-free survival (PFS), and Cox regression analyses were performed to explore independent predictors of PFS. RESULTS: A total of 99 patients (44.2%) received both 18F-PSMA-1007 PET/CT and CI, the concordance rate in revealing NRLN metastases between 18F-PSMA-1007 PET/CT and CI was only 61.62%, and Cohen's kappa coefficient was as low as 0.092. Moreover, 18F-PSMA-1007 PET/CT detected an additional 37 of 94 (39.4%) patients with positive NRLNs who were negative on CI. Cox regression revealed that androgen deprivation therapy (ADT), N1, high-volume, NRLN and visceral metastases were associated with worse PFS (all P < 0.05) in 224 patients. Furthermore, in patients with low-volume disease, the median PFS of patients with NRLN metastases was significantly shorter than that of patients without NRLN metastases (19.5 vs. 27.5 months, P = 0.01), while the difference between patients with low-volume plus NRLN metastases and high-volume disease was not significant (19.5 vs. 16.9 months, P = 0.55). Moreover, early docetaxel chemotherapy significantly prolonged the PFS of these patients compared with ADT alone (20.7 vs. 12.3 months, P = 0.008). CONCLUSION: NRLN metastases could be accurately revealed by 18F-PSMA-1007 PET/CT, which should be considered a high-volume feature, especially concomitant with bone metastases. Furthermore, patients with low-volume plus NRLN metastases may be suitable for more intensive treatment, such as early docetaxel chemotherapy.

Apalutamide for metastatic castration-sensitive prostate cancer: final analysis of the Asian subpopulation in the TITAN trial.

The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg ( n = 111) or placebo ( n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.

Erratum: KLF5 downregulation desensitizes castration-resistant prostate cancer cells to docetaxel by increasing BECN1 expression and inducing cell autophagy: Erratum.

[This corrects the article DOI: 10.7150/thno.33282.].

Predictive factors associated with differential pathologic response to neoadjuvant chemohormonal therapy in high-risk localized prostate cancer.

PURPOSE: To explore the clinical parameters and molecular biomarkers that can predict differential pathologic response to neoadjuvant chemohormonal therapy (NCHT) in prostate cancer (CaP). METHODS: A total of 128 patients with primary high-risk localized CaP who had received NCHT followed by radical prostatectomy (RP) were included. Androgen receptor (AR), AR splice variant-7 (AR-V7) and Ki-67 staining were evaluated in prostate biopsy specimens by immunohistochemistry. The pathologic response to NCHT in whole mount RP specimens was measured based on the reduction degree of tumor volume and cellularity compared to the paired pretreatment needle biopsy, and divided into 5 tier grades (Grades 0-4). Patients with Grades 2 to 4 (the reduction degree more than 30%) were defined as having a favorable response. Logistic regression was performed to explore the predictive factors associated with a favorable pathologic response. The predictive accuracy was evaluated by receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). RESULTS: Ninety-seven patients (75.78%) had a favorable response to NCHT. Logistic regression showed that the preoperative PSA level, low AR expression and high Ki-67 expression in biopsy specimens were associated with a favorable pathologic response (P < 0.05). Furthermore, the AUC of the preoperative PSA level, AR and Ki-67 were 0.625, 0.624 and 0.723, respectively. Subgroup analysis revealed that the rate of favorable pathologic response to NCHT was 88.5% in patients with ARlowKi-67high, which was higher than patients with ARlowKi-67low, ARhighKi-67low, and ARhighKi-67high (88.5% vs. 73.9%, 72.9%, and 70.9%, all P < 0.05). CONCLUSIONS: A lower preoperative PSA level was an independent predictive factor for a favorable pathologic response. Moreover, the expression status of AR and Ki-67 in biopsy specimens were associated with differential pathologic response to NCHT, and AR low/Ki-67 high was also associated with favorable response but warrants further evaluation in this patient subgroup and future trial clinical trial design.

Efficacy and safety of LY01005 versus goserelin implant in Chinese patients with prostate cancer: A multicenter, randomized, open-label, phase III, non-inferiority trial.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04563936.

Proxalutamide in metastatic castration-resistant prostate cancer: Primary analysis of a multicenter, randomized, open-label, phase 2 trial.

We aim to assess the safety and efficacy of proxalutamide, a novel androgen receptor antagonist, for men with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter, randomized, open-label, phase 2 trial. In our study, the enrolled mCRPC patients were randomized to 100, 200 and 300 mg dose groups at 1:1:1. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and time to PSA and radiographic progression. Safety and pharmacokinetics were also assessed. Finally, there were 108 patients from 17 centers being enrolled. By week 16, there were 13 (35.1%), 12 (36.4%) and 15 (42.9%) patients with confirmed 50% or greater PSA decline in 100 mg (n = 37), 200 mg (n = 33) and 300 mg (n = 35) groups, respectively. Among the 19 patients with target lesions at study entry, three (15.8%) had a partial response and 12 (63.2%) had stable disease. The ORRs of 20.0%, 22.2%, 0% and DCRs of 80.0%, 88.9%, 60.0% were, respectively, achieved in 100, 200 and 300 mg groups. By the maximum follow-up time of 24 weeks, there were 42.6% and 10.2% of cases experiencing PSA progression and radiographic progression, respectively. Overall, adverse events (AEs) were experienced by 94.4% of patients, most of which were mild or moderate. There were 28 patients experiencing ≥grade 3 AEs. The most common AEs were fatigue (17.6%), anemia (14.8%), elevated AST (14.8%) and ALT (13.0%), decreased appetite (13.0%). These findings preliminarily showed the promising antitumor activity of proxalutamide in patients with mCRPC with a manageable safety profile. The proxalutamide dose of 200 mg daily is recommended for future phase 3 trial (Clinical trial registration no. CTR20170177).

Diagnostic accuracy of cystoscopic biopsy for tumour grade in outpatients with urothelial carcinoma of the bladder and the risk factors of upgrading.

Objective: To assess the concordance of tumour grade in specimens obtained from diagnostic cystoscopic biopsy and transurethral resection of bladder tumour (TURBT) and explore the risk factors of upgrading. Methods: The medical records of 205 outpatients who underwent diagnostic cystoscopic biopsy before initial TURBT were retrospectively reviewed. Comparative analysis of the tumour grade of biopsy and operation specimens was performed. Tumour grade changing from low-grade to high-grade with or without variant histology was defined as upgrading. Logistic regression analyses were performed to identify the risk factors of upgrading. Results: For the 205 patients, the concordance of tumour grade between specimens obtained from biopsy and operation was 0.639. The concordance for patients who were preoperatively diagnosed with low-grade and high-grade was 0.504 and 0.912, respectively. Univariate and multivariate logistic regression analyses showed that older age, tumour multifocality, high neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and low lymphocyte-to-monocyte ratio (LMR) were significantly associated with upgrading (odds ratio ranging from 0.412 to 4.364). The area under the curve of the different multivariate models was improved from 0.752 to 0.821, and decision curve analysis demonstrated a high net benefit when NLR, LMR, and PLR were added. Conclusion: Diagnostic cystoscopic biopsy may not accurately represent the true grade of primary bladder cancer, especially for outpatients with low-grade bladder cancer. Moreover, older age, tumour multifocality, high NLR, PLR, and low LMR are risk factors of upgrading, and systemic inflammatory markers improve the predictive ability.

A novel PDT: 5-aminolevulinic acid combined 450 nm blue laser photodynamic therapy significantly promotes cell death of HR-HPV infected cells.

Human papillomavirus (HPV) infection and related diseases are clinical challenges. The efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) using red laser (630 ± 5 nm) is remarkable and safe. In this study, we aim to investigate the efficacy of ALA-450 nm PDT comparing with ALA-635 nm PDT. We detected cell proliferation and cell apoptosis through MTT assay and flow cytometry assay respectively. Flow cytometry assay determined the intracellular reactive oxygen species (ROS) generation. Western blotting analysis investigated the protein expression. In vivo, immunohistochemical staining assay and TUNEL assay were performer to detect cell apoptosis. ALA-450 nm PDT inhibited the proliferation of End1 and HeLa cells, promoted cell apoptosis more effectively than ALA-635 nm PDT, and induced cell death probably through increasing the intracellular ROS generation and caspase-dependent apoptosis pathway. In vivo, ALA-450 nm PDT significantly inhibited tumour growth and activated cell apoptosis. The ALA-450 nm PDT had an advantage over ALA-635 nm PDT on inhibiting the proliferation of End1 and HeLa cells and inducing cell apoptosis. The ALA-450 nm PDT might be a promising therapeutic strategy for eradicating the HR-HPV infected cells and promoting the integration of diagnosis and treatment of HR-HPV related diseases.HighlightsWe combined 5-aminolevulinic acid with 450 nm blue laser using as a novel type of photodynamic therapy.The ALA-450 nm PDT had an advantage over ALA-635 nm PDT on inhibition of the proliferation of End1 and HeLa cells and inducing cell apoptosis in vitro and in vivo.The ALA-450 nm PDT may provide a novel alternative therapeutic option in patients with persistent HPV infection and promote the integration of diagnosis and treatment.

USP14-mediated deubiquitination of SIRT1 in macrophage promotes fatty acid oxidation amplification and M2 phenotype polarization.

There is a trend of increasing young cases with gastric cancer globally. Sensitive early diagnosis methods and new therapeutic approaches are still the focus of clinical diagnosis and therapy of gastric cancer. USP14 plays an extensive role in tumor malignancy and fat metabolism regulation. However, researchers still have gaps in their knowledge of its substrates, which makes it difficult for deubiquitinases to become clinical targets. TAMs were isolated from tumor or polarized from primary THP1 cells by tumors cell lines under the control of IU1 and FAO inhibitor therapy. Cytokines controlled macrophages were compared to evaluate the capability to induce USP14 expression. Fatty acid uptake assay and OCR measurement were used to analyze macrophage metabolism. USP14 is found the correlation with tumor poor prognosis and poor immunophenotype in gastric cancer patients and mouse tumor models. Activation of USP14 determines elevated protein stability of SIRT1 and is required for activation of macrophage fatty acid oxidation and immunosuppressive phenotype. Although overexpression of USP14 is not sufficient to polarize macrophages to the M2 phenotype, inhibition of USP14 by IU1 in tumor-bearing mice disrupts the suppressive activity of cancer-promoting macrophages and effectively reshapes immune microenvironment characteristics. Our study provides evidence that a novel therapeutic strategy that targets to lipid metabolism of macrophages in tumors could be a potential option for emerging treatments for gastric cancer.