Dual deficiency of melatonin and dihydrotestosterone promotes stromal cell damage and mediates prostatitis via the cGAS-STING pathway in sleep-deprived mice.

PURPOSE: Prostatitis is a highly prevalent condition that seriously affects men's physical and mental health. Although epidemiological investigations have provided evidence of a correlation between insufficient sleep and prostatitis, the pathogenesis of prostatitis remains unclear. We sought to identify the underlying mechanism involved and identify a promising therapeutic target. METHODS: Sleep deprivation (SD) was utilized to establish a mouse model of insufficient sleep in a special device. Prostatitis was observed at different time points post-SD. The degree of prostatitis was evaluated by pathological section and behavioural tests. Using immunofluorescence, western blot, and proteomic analyses, the underlying mechanism of SD-related prostatitis was investigated, and the development and therapeutic target of prostatitis were elucidated. RESULTS: SD, as an initial pathological trigger, resulted in a reduction in dihydrotestosterone and melatonin levels. Proteomic analysis revealed that the cGAS-STING pathway may play a significant role in inducing prostatitis. The subsequent results illustrated that the dual reduction in dihydrotestosterone and melatonin led to an accumulation of reactive oxygen species and the release of mitochondrial DNA (mt-DNA). The accumulation of mt-DNA activated the cGAS-STING pathway, which recruited inflammatory cells into the prostatic stroma through the secretion of interferon-ß. Consequently, an inflammatory microenvironment was formed, ultimately promoting the development of prostatitis. Notably, mice with SD-induced prostatitis gradually recovered to a normal state within 7 days of recovery sleep. However, after being subjected to SD again, these mice tended to have a more pronounced manifestation of prostatitis within a shorter timeframe, which suggested that prostatitis is prone to relapse. CONCLUSIONS: The cGAS-STING pathway activated by dual deficiency of dihydrotestosterone and melatonin plays a comprehensive inflammatory role in SD-related prostatitis. This research provides valuable insights into the pathogenesis, therapeutic targets, and prevention strategies of prostatitis.

PEGylated Manganese-Zinc Ferrite Nanocrystals Combined with Intratumoral Implantation of Micromagnets Enabled Synergetic Prostate Cancer Therapy via Ferroptotic and Immunogenic Cell Death.

Therapeutic efficacy for prostate cancer is highly restricted by insufficient drug accumulation and the resistance to apoptosis and immunogenic cell death (ICD). Although enhanced permeability and retention (EPR) effect of magnetic nanomaterials could benefit from external magnetic field, it falls off rapidly with increased distance from magnet surface. Considering the deep location of prostate in pelvis, the improvement of EPR effect by external magnetic field is limited. In addition, apoptosis resistance and cGAS-STING pathway inhibition-related immunotherapy resistance are major obstacles to conventional therapy. Herein, the magnetic PEGylated manganese-zinc ferrite nanocrystals (PMZFNs) are designed. Instead of providing external magnet, micromagnets into tumor tissues are intratumorally implanted to actively attract and retain intravenously-injected PMZFNs. As a result, PMZFNs accumulate in prostate cancer with high efficacy, depending on the established internal magnetic field, which subsequently elicit potent ferroptosis and the activation of cGAS-STING pathway. Ferroptosis not only directly suppresses prostate cancer but also triggers burst release of cancer-associated antigens and consequently initiates ICD against prostate cancer, where activated cGAS-STING pathway further amplifies the efficacy of ICD by generating interferon-ß. Collectively, the intratumorally implanted micromagnets confer a durable EPR effect of PMZFNs, which eventually achieve the synergetic tumoricidal efficacy with negligible systemic toxicity.

Segmental analysis of liver cirrhosis with different etiologies: a study based on iodine mixed imaging in port-venous phase.

BACKGROUND: Computed tomography (CT) in port-venous phase can display the intra-hepatic vessels, and may provide the possibility for segment function evaluation for cirrhosis. PURPOSE: To assess the value of iodine mixed imaging of dual-source dual-energy CT in port-venous phase in segmental evaluation of liver cirrhosis with different etiologies. MATERIAL AND METHODS: Patients diagnosed with liver cirrhosis were enrolled. Patients without cirrhosis were included as a control group. Each patient underwent iodine-contrast enhanced multi-phase dual-energy CT scanning. Parameters were analyzed by SPSS, version 22.0, and Medcalc. RESULTS: In total, 256 patients were investigated, including 114 Child-Pugh A, 51 Child-Pugh B, 41 Child-Pugh C and 50 control patients. Total iodine content (ICt)/body surface area (BSA) in the cirrhosis group was significantly lower than the control group (P < 0.05) and the standardized-iodine parameter (SI) of each segment decreased with cirrhosis progression. In Child-Pugh A and B, SI increased more significantly in the caudal and lateral segment in A (alcholism) than in the V (virus-related) and N (non-alcoholic steatohepatitis) groups (P < 0.001). ICt/BSA showed the best diagnosis power of cirrhosis with an area under the curve of 0.765, sensitivity of 76.0% and specificity of 71.8%. CONCLUSION: Blood flow compensated in the left lateral and caudal lobe in the early stage of liver cirrhosis. The compensation in alcoholism in the middle and early stages is significantly higher than that of V and N cirrhosis. Iodine mixed imaging in portal phase may provide the possibility of an incremental value in segmented blood flow perfusion and functional evaluation of liver cirrhosis on a morphological basis.

Mixed Imaging on Port-Venous Phase of Contrast-Enhanced Dual-Source Dual-Energy Computed Tomography: A Measurement Method Based on Couinaud Segments.

OBJECTIVE: The aim of this study was to evaluate the changes of the iodine value quantified on the Couinaud segments measured in port-venous phase using the iodine-mixed technique of contrast-enhanced dual-source dual-energy computed tomography (CT) scanning in different Child-Pugh stages of hepatitis B-induced liver cirrhosis. METHODS: Patients clinically diagnosed with hepatitis B-induced cirrhosis were prospectively engaged in our study. Each patient underwent multiphase iodine agent contrast-enhanced dual-source dual-energy CT scanning, and then the iodine-mixed imaging of port-venous phase was postprocessed. Iodine concentration was obtained for each segment based on the Couinaud segments. The volume of each segment and the total of the liver were measured and calculated using the postprocessing software of volume. All the cirrhosis patients were grouped into 3 subgroups based on the Child-Pugh stage method. Patients without cirrhosis were engaged for the control group. The iodine concentration, volume, and iodine storage among groups were analyzed by SPSS version 19.0. Single energy was used for the nonenhanced phase scanning, which was used for the radiation dosage comparison with dual-energy CT scanning. RESULTS: Two hundred three patients were ultimately enrolled in our study, including 148 patients with cirrhosis (Child A, 69; Child B, 51; Child C, 28) and 55 patients without cirrhosis as control subjects. The total volume and iodine storage of cirrhosis group were smaller than those of the control group (P < 0.001). Compared with the control group, the iodine concentration in each segment decreased with progression of cirrhosis. The volume, iodine concentration, and iodine storage of the right hepatic lobe and left medial segment decreased with cirrhosis severity (P < 0.001). There was no significant difference in the volume of right hepatic lobe between Child C group and Child B group, whereas the iodine storage of Child C group was lower than that of Child B group (P < 0.05). The volume and iodine storage of left lateral segment increased with the progression of liver cirrhosis in the Child A and Child B groups (P < 0.05), whereas there was no statistical difference between the Child B and Child C groups, and the iodine storage in the Child C group was lower than that of the Child B group (P < 0.05). The radiation dose of dual-energy scanning was lower than that of single-energy scanning (P < 0.001). The iodine concentration 1.512 mg/mL on the left medial segment reached the most optimal evaluation on cirrhosis, with a sensitivity of 100%, specificity of 0.722, and area under the curve of 0.914. CONCLUSIONS: Iodine concentration in portal phase measurement can evaluate and reflect the severity of cirrhosis. Iodine content segmental quantification can analyze the changes of the liver storage with a progression of cirrhosis. Dual-energy scanning reduced the radiation damage in patients and is valuable for a further study and clinical application.

The Application of Iodine Quantitative Information Obtained by Dual-Source Dual-Energy Computed Tomography on Chemoradiotherapy Effect Monitoring for Cervical Cancer: A Preliminary Study.

OBJECTIVE: The aim of the study is to investigate the potential contribution of the iodine quantitative parameters of dual-phase dual-energy computed tomography (DECT) scanning for chemoradiotherapy (CRT) response monitoring for cervical cancer. METHODS: Patients who were pathologically certified having cervical cancer and intended for concurrent radiotherapy and chemotherapy were prospectively included in our study. Contrast-enhanced DECT scanning was performed before CRT, which was repeated after 1 month of therapy, using a dual-source CT scanner onset. Changes in tumor size were assessed according to RECIST 1.0. Quantification of volume-normalized iodine uptake (mg/mL) was measured in dual phases and was standardized using the iodine uptake in the iliac artery. The decreased ratio of the standard iodine uptake was calculated and compared with the tumor size for the evaluation of the CRT effect. Data were analyzed using the statistics software SPSS version 19.0. Twenty women who performed normal pelvic contrast-enhanced CT scanning were randomly chosen as the control group for the radiation dose comparison with the dual-energy group. RESULTS: A total of 21 patients who completed therapeutic courses and performed the contrast-enhanced CT scanning were subsequently evaluated. According to RECIST 1.0, 15 cases were classified into the regression (R, including 5 completed regression cases and 10 partial regression cases) group. The remaining 6 cases were classified into the nonregression (NR, including 6 stable disease cases) group. The iodine value decreased ratio in the arterial phase (standardized iodine in arterial phase [SAI]) of the partial regression group was significantly higher than that of the stable disease group (P < 0.01), and there was no significant difference in the venous phase (P > 0.05). In a general quantitative comparison between the R group and the NR group before CRT, we controlled for the maximum diameter, age, iodine uptake in the arterial phase before CRT (pre-SAI), iodine uptake in the venous phase before CRT, and cell differentiated level, and we ultimately found no significant statistical differences except for the pre-SAI. In other words, the iodine value in the arterial phase of the R group before CRT was significantly higher than that of the NR group (P < 0.01). When the pre-SAI was 0.345, the area under the curve was 0.875 for therapeutic effect prediction. The mean effective dose was 5.63 ± 1.68 mSv for the DECT group and 5.37 ± 1.82 mSv for the control group (t = -1.137, P = 0.262), which showed no statistical difference in the radiation dose between the 2 scanning methods. CONCLUSIONS: The iodine mapping can be used to help evaluate the radiochemotherapy response effectively on the basis of tumor size change and can also be helpful in predicting the radiochemotherapy outcome for cervical cancer. The dual-phase DECT scanning did not increase the radiation dose and provided more valuable information, and thus, it was suitable for promotion in clinical application.

Comparison of PET with PET/CT in detecting peritoneal carcinomatosis: a meta-analysis.

PURPOSE: The study aims to perform a meta-analysis to compare the diagnostic value of FDG PET with PET/CT in detecting peritoneal carcinomatosis (PC) to identify the potentially most useful diagnostic modality. METHODS: A computer-aided search was performed in the Cochrane Library, PubMed, EMBASE, Web of Science, the China Biological Medicine Database, VIP, China National Knowledge Infrastructure database, and Wanfang databases for articles concerning diagnosis of peritoneal metastases with PET or PET/CT. QUADAS was used to evaluate the included articles' quality. RESULTS: On a per-patient basis, the pooled sensitivity of PET/CT (84%) was significantly higher than that of PET (60%), and the pooled specificity of PET (98%) was markedly higher than that for PET/CT (94%). On a per-lesion basis, the pooled sensitivity and specificity of PET/CT were 87 and 95%, respectively. Only 1 PET study on a per-lesion basis, its sensitivity is 65.8 and specificity is 94.1%. CONCLUSIONS: PET and PET/CT are powerful imaging techniques for detection and characterization of PC. PET/CT can be used as a screening tool and it may be acceptable to use PET as a diagnosis tool.

Significance of 4D US parameters for the clinical treatment of female patients with stress urinary incontinence.

Background: Stress urinary incontinence (SUI) that has been associated with abnormal pelvic floor muscle function or morphology is a common condition. This research aimed to study the impact of the four-dimensional (4D) pelvic floor ultrasound on the treatment of female patients with clinical diagnosis of SUI and to evaluate its clinical significance on SUI. Methods: We enrolled 51 women with SUI. Before transobturator suburethral tape procedures, the patients underwent 4D pelvic floor ultrasonography. The measurements include residual urine volume, bladder detrusor thickness in resting state, the vertical distance from the bladder neck to the posterior inferior edge of pubic symphysis at rest and Valsalva movement, posterior angle of bladder urethra, and urethral rotation angle. The degree of movement of the bladder neck (the difference between the vertical distance from the bladder neck to the posterior inferior edge of the pubic symphysis under the resting state and the maximum Valsalva movement) and the formation of a funnel at the internal orifice of the urethra were calculated. Results: The mean bladder detrusor thickness was 2.6 ± 0.9 mm, the vertical distance from the bladder neck to the posterior inferior edge of pubic symphysis was 27.7 ± 4.5 mm, the posterior angle of the bladder was 122.7 ± 18.9°, the vertical distance from the rectal ampulla to the posterior inferior edge of pubic symphysis was 18.5 ± 4.6 mm, and the mean area of hiatus of the levator ani muscle was 22.1 ± 6.0 cm2. The mean posterior angle of the bladder on Valsalva was 159.3 ± 23.1°, and the mean urethral rotation angle was 67.2 ± 21.4°. Conclusions: The 4D pelvic floor ultrasound is a reliable method in evaluating preoperational morphological characteristics of patients with SUI. With the help of the 4D pelvic floor ultrasound, the individualized treatment regimen can be developed and, more importantly, the inappropriate surgical decision can be avoided.

A novel immune-related RNA-binding proteins signature to predict survival and therapeutic responses in prostate cancer.

BACKGROUND: The present study aims to identify immune-related RBPs signature to predict prognosis and therapy response in prostate cancer. METHODS: Differentially expressed RBPs were compared and visualized using R packages. Immune-related RBPs were selected by Pearson correlation analysis. The prognostic immune-related RBPs were identified using the Kaplan-Meier method and LASSO regression. A multivariable Cox regression model was used to construct immune-related RBPs signature. RESULTS: We constructed a prognostic predictive risk model of prostate cancer containing ten immune-related RBP genes. We found that high-risk prostate cancer patients presented poorer prognosis, higher tumor immune cell infiltration, higher rates of genomic alterations, and were more sensitive to targeted and immunotherapy than the low-risk group. CONCLUSIONS: The immune-related RBPs' signature is an independent prognostic marker that could help screen patients with advanced prostate cancer who are better suited for targeted and immunotherapy.

The established chemokine-related prognostic gene signature in prostate cancer: Implications for anti-androgen and immunotherapies.

Background: Prostate cancer (PCa) was one of the most common malignancies among men, while the prognosis for PCa patients was poor, especially for patients with recurrent and advanced diseases. Materials and methods: Five PCa cohorts were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases, and the biochemical recurrence (BCR)-related chemokine genes were identified by LASSO-Cox regression. The chemokine-related prognostic gene signature (CRPGS) was established, and its association with PCa patients' clinical, pathological and immune characteristics was analyzed. The association between CRPGS and PCa patients' responses to androgen deprivation therapy (ADT) and immunotherapy was analyzed. The CRPGS was compared with other previously published molecular signatures, and the CRPGS was externally validated in our real-world AHMU-PC cohort. Results: Four recurrence-free survival (RFS)-related chemokine genes (CXCL14, CCL20, CCL24, and CCL26) were identified, and the CRPGS was established based on the four identified chemokine genes, and TCGA-PRAD patients with high riskscores exhibited poorer RFS, which was validated in the GSE70768 cohort. The CRPGS was associated with the clinical, pathological, and immune characteristics of PCa patients. Low-risk PCa patients were predicted to respond better to ADT and immunotherapy. By comparing with other molecular signatures, the CRPGS could classify PCa patients into two risk groups well, and the CRPGS was associated with the m6A level, as well as TP53 and SPOP mutation status of PCa patients. In the AHMU-PC cohort, the CRPGS was associated with the advanced pathology stage and Gleason score. Conclusions: The identified chemokine genes and CRPGS were associated with the prognosis of PCa, which could predict PCa patients' responses to anti-androgen and immunotherapies.

A novel immune-related RNA-binding proteins signature to predict survival and therapeutic responses in prostate cancer

BackgroundThe present study aims to identify immune-related RBPs signature to predict prognosis and therapy response in prostate cancer.MethodsDifferentially expressed RBPs were compared and visualized using R packages. Immune-related RBPs were selected by Pearson correlation analysis. The prognostic immune-related RBPs were identified using the Kaplan–Meier method and LASSO regression. A multivariable Cox regression model was used to construct immune-related RBPs signature.ResultsWe constructed a prognostic predictive risk model of prostate cancer containing ten immune-related RBP genes. We found that high-risk prostate cancer patients presented poorer prognosis, higher tumor immune cell infiltration, higher rates of genomic alterations, and were more sensitive to targeted and immunotherapy than the low-risk group.ConclusionsThe immune-related RBPs’ signature is an independent prognostic marker that could help screen patients with advanced prostate cancer who are better suited for targeted and immunotherapy.

GSK1838705A, an insulin-like growth factor-1 receptor/insulin receptor inhibitor, induces apoptosis and reduces viability of docetaxel-resistant prostate cancer cells both in vitro and in vivo.

Prostate cancer is the leading malignancy and the second most common cause of cancer-related death in men. Despite high cure rates with surgery and/or radiation, 30%-40% of patients eventually develop advanced cancer. Docetaxel is one of the most effective and well established chemotherapeutic agents for prostate cancer. However, docetaxel resistance often develops within months. Combination therapies have been proposed to improve the therapeutic efficacy of docetaxel in prostate cancer, and there is an urgent need to identify agents that are effective for treatment of the disease, especially docetaxel-resistant prostate cancer. In this work, we investigated the activity of GSK1838705A, a potent insulin-like growth factor-1 receptor (IGF1R)/insulin receptor (IR) inhibitor, in prostate cancer, especially docetaxel-resistant prostate cancer. We found that GSK1838705A could effectively reduce the viability of both docetaxel-sensitive and docetaxel-resistant prostate cancer cells. GSK1838705A induced marked apoptosis in docetaxel-resistant cells, and also dramatically inhibited migration of these cells. Further, GSK1838705A significantly inhibited phosphorylation of IGF1R/IR. Importantly, GSK1838705A significantly suppressed docetaxel-resistant PC-3R tumor growth in vivo. This is the first study of GSK1838705A in prostate cancer. Our results indicate that GSK1838705A is a promising compound for the treatment of prostate cancer, especially for those who develop resistance to docetaxel, and might shed new light on treatment for prostate cancer.

Risk factors for hypospadias in China.

This case-controlled study was designed to evaluate the association between various baseline parental factors and the risk of hypospadias in China. Patients were selected from tertiary referral hospitals in Anhui, a province in mid-eastern China. A questionnaire was given to the parents of each patient. The final database included 193 cases and 835 controls. The incidence of additional coexistent anomalies was 13.0%, primarily cryptorchidism (9.8%). Ten patients (5.1%) were from families with genital anomaly, including five families (2.6%) with hypospadias. The risks of hypospadias was higher for children of mothers > 35 (odds ratio [OR] =1.47) and < 18 (OR = 2.95) years of age, and in mothers who had consumed alcohol (OR = 2.67), used drugs (OR = 1.53) and had an infection (OR = 1.87) during pregnancy. The risk of hypospadias was also higher when mothers (OR = 1.68) and fathers (OR = 1.74) were engaged in agriculture. Other factors assessed were not associated with the risk of hypospadias.