Prediction of T staging in PI-RADS 4-5 prostate cancer by combination of multiparametric MRI and 68Ga-PSMA-11 PET/CT.

BACKGROUND: In this study, we explored the diagnostic performances of multiparametric magnetic resonance imaging (mpMRI), 68 Ga-PSMA-11 PET/CT and combination of 68 Ga-PSMA-11 PET/CT and mpMRI (mpMRI + PET/CT) for extracapsular extension (ECE). Based on the analyses above, we tested the feasibility of using mpMRI + PET/CT results to predict T staging in prostate cancer patients. METHODS: By enrolling 75 patients of prostate cancer with mpMRI and 68 Ga-PSMA-11 PET/CT before radical prostatectomy, we analyzed the detection performances of ECE in mpMRI, 68 Ga-PSMA-11 PET/CT and mpMRI + PET/CT on their lesion images matched with their pathological sample images layer by layer through receiver operating characteristics (ROC) analysis. By inputting the lesion data into Prostate Imaging Reporting and Data System (PI-RADS), we divided the lesions into different PI-RADS scores. The improvement of detecting ECE was analyzed by net reclassification improvement (NRI). The predictors for T staging were evaluated by using univariate and multivariable analysis. The Kappa test was used to evaluate the prediction ability. RESULTS: One hundred three regions of lesion were identified from 75 patients. 50 of 103 regions were positive for ECE. The ECE diagnosis AUC of mpMRI + PET/CT is higher than that of mpMRI alone (ΔAUC = 0.101; 95% CI, 0.0148 to 0.1860; p < 0.05, respectively). Compared to mpMRI, mpMRI + PET/CT has a significant improvement in detecting ECE in PI-RADS 4-5 (NRI 36.1%, p < 0.01). The diagnosis power of mpMRI + PET/CT was an independent predictor for T staging (p < 0.001) in logistic regression analysis. In patients with PI-RADS 4-5 lesions, 40 of 46 (87.0%) patients have correct T staging prediction from mpMRI + PET/CT (κ 0.70, p < 0.01). CONCLUSION: The prediction of T staging in PI-RADS 4-5 prostate cancer patients by mpMRI + PET/CT had a quite good performance.

Mitochondrial-targeted brequinar liposome boosted mitochondrial-related ferroptosis for promoting checkpoint blockade immunotherapy in bladder cancer.

Checkpoint blockade immunotherapy (CBI) have exhibited remarkable benefits for cancer therapy. However, the low responsivity of CBI hinders its application in treatment of bladder cancer. Ferroptosis shows potential for increasing the responsivity of CBI by inducing immunogenic cell death (ICD) process. Herein, we developed a mitochondrial-targeted liposome loaded with brequinar (BQR) (BQR@MLipo) for enhancing the mitochondrial-related ferroptosis in bladder cancer in situ. It could be found that BQR@MLipo could selectively accumulate into mitochondria and inactivate dihydroorotate dehydrogenase (DHODH), which induced extensive mitochondrial lipid peroxidation and ROS, finally triggering ferroptosis of bladder cancer cells to boost the release of intracellular damage-associated molecular patterns (DAMPs) such as calreticulin (CRT), adenosine triphosphate (ATP), high mobility group box 1 (HMGB1). In addition, BQR@MLipo further promoted the release of mtDNA into the cytoplasm to activate the cGAS-STING pathway for the secretion of IFN-ß, which would increase the cross-presentation of antigens by dendritic cells and macrophage phagocytosis. Furthermore, the in vivo studies revealed that BQR@MLipo could remarkably accumulate into the bladder tumor and successfully initiate the infiltration of CD8+ T cells into tumor microenvironment for enabling efficient CBI to inhibit bladder tumor growth. Therefore, BQR@MLipo may represent a clinically promising modality for enhancing CBI in bladder tumor.

Mass cytometry reveals immune atlas of urothelial carcinoma.

Immunotherapy has emerged as a robust clinical strategy for cancer treatment. PD1/PD-L1 inhibitors have been used as second-line therapy for urothelial carcinoma due to the high tumor mutational burden. Despite the efficacy of the treatment is significant, the response rate is still poor. The tumor immune microenvironment plays a key role in the regulation of immunotherapeutic efficacy. However, a comprehensive understanding of the intricate microenvironment in clinical samples remains unclear. To obtain detailed systematic tumor immune profile, we performed an in-depth immunoassay on 12 human urothelial carcinoma tissue samples and 14 paratumor tissue samples using mass cytometry. Among the large number of cells assayed, we identified 71 T-cell phenotypes, 30 tumor-associated macrophage phenotypes. T cell marker expression profiles showed that almost all T cells in the tumor tissue were in a state of exhaustion. CD38 expression on tumor-associated macrophages (TAMs) was significantly higher than PDL1, and CD38+ TAMs were closely associated with immunosuppression. CD38 may be a more suitable target for immunotherapy in urothelial carcinoma compared to PD1/PDL1. This single-cell analysis of clinical samples expands our insights into the immune microenvironment of urothelial carcinoma and reveals potential biomarkers and targets for immunotherapy development.

Synergy of Tumor Microenvironment Remodeling and Autophagy Inhibition to Sensitize Radiation for Bladder Cancer Treatment.

Tumor hypoxia, acidosis, and excessive reactive oxygen species (ROS) were the main characteristics of the bladder tumor microenvironment (TME), and abnormal TME led to autophagy activation, which facilitated cancer cell proliferation. The therapeutic efficacy of autophagy inhibitors might also be impeded by abnormal TME. To address these issues, we proposed a new strategy that utilized manganese dioxide (MnO2) nanoparticles to optimize the abnormal TME and revitalize autophagy inhibitors, and both oxygenation and autophagy inhibition may sensitize the tumor cells to radiation therapy. Methods: By taking advantage of the strong affinity between negatively charged MnO2 and positively charged chloroquine (CQ), the nanoparticles were fabricated by integrating MnO2 and CQ in human serum albumin (HSA)-based nanoplatform (HSA-MnO2-CQ NPs). Results: HSA-MnO2-CQ NPs NPs efficiently generated O2 and increased pH in vitro after reaction with H+/H2O2 and then released the encapsulated CQ in a H+/H2O2 concentration-dependent manner. The NPs restored the autophagy-inhibiting activity of chloroquine in acidic conditions by increasing its intracellular uptake, and markedly blocked hypoxia-induced autophagic flux. In vivo studies showed the NPs improved pharmacokinetic behavior of chloroquine and effectively accumulated in tumor tissues. The NPs exhibited significantly decreased tumor hypoxia areas and increased tumor pH, and had remarkable autophagy inhibition efficacy on bladder tumors. Finally, a significant anti-tumor effect achieved by the enhanced autophagy inhibition and radiation sensitization. Conclusions: HSA-MnO2-CQ NPs synergistically regulated the abnormal TME and inhibited autophagic flux, and effectively sensitized radiation therapy to treat bladder cancers.

The mechanisms in the altered ontogenetic development and lung-related pathology in microcystin-leucine arginine (MC-LR)-paternal-exposed offspring mice.

A father's lifetime experience is a major risk factor for a range of diseases in an individual, and the consequences of the exposure can also be transmitted to his offspring. Our previous work has demonstrated that damage to testicular structures and decline in sperm quality in male mice can be caused by microcystin-leucine arginine (MC-LR), but the overall effects of the scope and extent of paternal exposure on health and disease in the offspring remain underexplored. Here, we report that MC-LR-paternal-exposed offspring mice showed reduced litter size and body weight accompanied by increased abnormalities in the lung. Analyses of the small noncoding RNAs (sncRNAs) in the sperm from MC-LR-exposed males demonstrated the downregulation of a wide range of piRNAs enriched for those target genes involved in the regulation of the embryo implantation pathways. Gene and protein expression analyses, as well as biochemical and functional studies, revealed suppressed expression of Hsp90α in testicular tissues from MC-LR-exposed males. Decreased Hsp90α in testicular tissues impaired the development of the offspring. In this study, we revealed that MC-LR alters the expression of Hsp90α in testicular tissues to cause changes in the expression profiles of sperm piRNAs produced by paternal mice. These changes lead to aberrant activation of the Wnt/ß-catenin signaling pathway in pulmonary tissues of offspring mice, causing lung tissue damage and abnormal development. We hereby confirmed that MC-LR-induced alterations in epigenetic inheritance are capable of contributing to intergenerational developmental defects in paternal-exposed offspring mice.

A transcriptomic regulatory network among miRNAs, piRNAs, circRNAs, lncRNAs and mRNAs regulates microcystin-leucine arginine (MC-LR)-induced male reproductive toxicity.

Microcystin-leucine arginine (MC-LR) which is produced by cyanobacteria is a potent toxin for the reproductive system. Our previous work has demonstrated that both acute and chronic reproductive toxicity engendered by MC-LR can result in the decline of sperm quality and damage of testicular structures in male mice. The present study was designed to investigate the impact of chronic low-dose exposure to MC-LR on the regulation of RNA networks including mRNA, microRNA (miRNA), piwi-associated RNA (piRNA), covalently closed circular RNA (circRNA) and long non-coding RNA (lncRNA) in testicular tissues. By high-throughput sequencing analysis, 1091 mRNAs, 21 miRNAs, 644 piRNAs, 278 circRNAs and 324 lncRNAs were identified to be significantly altered in testicular tissues treated with MC-LR. We performed gene ontology (GO) analysis to ascertain the biological functions of differentially expressed genes. Among the altered 21 miRNAs and 644 piRNAs, the miRNA chr13_8977, which is a newly discovered species, and the piRNA mmu_piR_027558 were dramatically down-regulated after exposure to MC-LR. Consistently, both mRNA levels and protein expression levels of their predicted targets were increased significantly when chr13_8977 and mmu_piR_027558 were each down-regulated. Testicular structures, germ cell apoptosis and sperm quality were also affected by the altered expression of chr13_8977 and mmu_piR_027558 severally. We further investigated the differential expression of circRNAs and lncRNAs and their biological functions in testicular tissues following treatment with chronic low-dose exposure to MC-LR. We also constructed a competing endogenous RNA (ceRNA) network to predict the functions of the altered expressed RNAs using MiRanda. Our study suggested a crucial role for the potential network regulation of miRNAs, piRNAs, circRNAs, lncRNAs and mRNAs impacting the cytotoxicity of MC-LR in testicular tissues, which provides new perspectives in the development of diagnosis and treatment strategies for MC-LR-induced male reproductive toxicity.

[The observation of the local anaesthesia effect of primacaine in the treatment of pulpitis].

PURPOSE: To explore the application and the anaesthetic effect of primacaine in anaesthetizing the pulp. METHODS: 162 teeth of pulpitis underwent submucous infiltration anaesthesia via the labial or buccal side (single side anaesthesia). There were 94 teeth of acute pulpitis and 68 teeth of chronic pulpitis among them. Anaesthesia effect were observed.Maxillary, mandibular molars and mandibular premolar were respectively divided into two groups, one underwent submucous infiltration anaesthesia via the labial or buccal and lingual sides (double sides anaesthesia), the other underwent single side anaesthesia. The data was analysed with X(2) test. RESULTS: The effective rate of single side anaesthesia was 72.8%, There was no significant difference between acute and chronic pulpitis(P>0.05). For mandibular molar,the effect of double side anaesthesia was better than the single side anaesthesia (P<0.05). CONCLUSIONS: Primacaine had a good anaesthesia effect when the teeth of pulpitis underwent pulpectomy. In order to get perfect anaesthetic effect, the double side anaesthesia for the mandibular molar was suggested.