Epithelial cells derived exosomal miR-203a-3p facilitates stromal inflammation of type IIIA chronic prostatitis/chronic pelvic pain syndrome by targeting DUSP5 and increasing MCP-1 generation.

Increased proinflammatory cytokines and infiltration of inflammatory cells in the stroma are important pathological features of type IIIA chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS-A), and the interaction between stromal cells and other cells in the inflammatory microenvironment is closely related to the inflammatory process of CP/CPPS-A. However, the interaction between stromal and epithelial cells remains unclear. In this study, inflammatory prostate epithelial cells (PECs) released miR-203a-3p-rich exosomes and facilitated prostate stromal cells (PSCs) inflammation by upregulating MCP-1 expression. Mechanistically, DUSP5 was identified as a novel target gene of miR-203a-3p and regulated PSCs inflammation through the ERK1/2/MCP-1 signaling pathway. Meanwhile, the effect of exosomes derived from prostatic fluids of CP/CPPS-A patients was consistent with that of exosomes derived from inflammatory PECs. Importantly, we demonstrated that miR-203a-3p antagomirs-loaded exosomes derived from PECs targeted the prostate and alleviated prostatitis by inhibiting the DUSP5-ERK1/2 pathway. Collectively, our findings provide new insights into underlying the interaction between PECs and PSCs in CP/CPPS-A, providing a promising therapeutic strategy for CP/CPPS-A.

Clinicopathological Characteristics of Light and Heavy Chain Deposition Disease: A Case Series.

RATIONALE & OBJECTIVE: Light and heavy chain deposition disease (LHCDD) is a rare form of monoclonal immunoglobulin deposition disease (MIDD), and limited clinical data are available characterizing this condition. We described the clinicopathological characteristics and outcomes of LHCDD. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 13 patients with biopsy-proven LHCDD, diagnosed between January 2008 to December 2022, at two Chinese medical centers. FINDINGS: Among the 13 patients described, 6 were men and 7 were women, with a mean age of 52.6 ± 8.0 years. Patients presented with hypertension (76.9%), anemia (84.6%), elevated serum creatinine (84.6%, median serum creatinine 1.7 mg/dL), proteinuria (100%, average urine protein 3.0g/24h), nephrotic syndrome (30.8%) and microscopic hematuria (76.9%). Serum immunofixation electrophoresis showed monoclonal immunoglobulin for 11 (84.6%) patients. Serum free light chain (FLC) ratios were abnormal in 11 (84.6%) patients, and heavy/light chain (HLC) ratios were abnormal in 9 of 10 (90%) patients with available data. Five patients were diagnosed with multiple myeloma. A histological diagnosis of nodular mesangial sclerosis was made in 10 (76.9%) patients. Immunofluorescence demonstrated deposits of IgG subclass (γ-κ/γ-λ:4/3) in 7 patients, and IgA (α-κ/α-λ:2/3) in 5 patients. Six patients underwent IgG subclass staining (γ1/γ2/γ3:3/2/1). The deposits of IgD-κ were confirmed by mass spectrometry in 1 patient. Among 12 patients for whom data were available over a median of 26.5 months, 11 received chemotherapy, and 1 received conservative treatment. One patient died. Three (25%) patients progressed to kidney failure. Among the 9 patients evaluable for hematological and kidney disease progression, five (56%) had a hematologic response and one (11%) achieved improvement in kidney disease. LIMITATIONS: Retrospective descriptive study, limited number of patients, UPEP or UIFE missing for most patients. CONCLUSIONS: In this case series of LHCDD, light and heavy chain deposition in kidney tissues were most frequent with monoclonal IgG1-κ. Among patients with evaluable data, more than half had hematologic response but a kidney response was uncommon.

Clinicopathological characteristics and prognosis in patients with monoclonal gammopathy and renal damage in central China: a multicenter retrospective cohort study.

Renal involvement is common in monoclonal gammopathy (MG); however, the same patient may have both MG and non-paraprotein-associated renal damage. Accordingly, distinguishing the cause of renal damage is necessary because of the different clinical characteristics and associated treatments. In this multicenter retrospective cohort study, we described the clinicopathological characteristics and prognosis of 703 patients with MG and renal damage in central China. Patients were classified as having MG of renal significance (MGRS), MG of undetermined significance (MGUS), or hematological malignancy. 260 (36.98%), 259 (36.84%), and 184 (26.17%) had MGRS, MGUS, and hematological malignancies, respectively. Amyloidosis was the leading pattern of MGRS (74.23%), followed by thrombotic microangiopathy (8.85%) and monoclonal immunoglobulin deposition disease (8.46%). Membranous nephropathy was the leading diagnosis of MGUS (39.38%). Renal pathological findings of patients with hematological malignancies included paraprotein-associated lesions (84.78%) and non-paraprotein-associated lesions (15.22%). The presence of nephrotic syndrome and an abnormal free light chain (FLC) ratio were independently associated with MGRS. The overall survival was better in patients with MGUS than in those with MGRS or hematological malignancies.

Nanotherapeutics for prostate cancer treatment: A comprehensive review.

Prostate cancer (PCa) is the most prevalent solid organ malignancy and seriously affects male health. The adverse effects of prostate cancer therapeutics can cause secondary damage to patients. Nanotherapeutics, which have special targeting abilities and controlled therapeutic release profiles, may serve as alternative agents for PCa treatment. At present, many nanotherapeutics have been developed to treat PCa and have shown better treatment effects in animals than traditional therapeutics. Although PCa nanotherapeutics are highly attractive, few successful cases have been reported in clinical practice. To help researchers design valuable nanotherapeutics for PCa treatment and avoid useless efforts, herein, we first reviewed the strategies and challenges involved in prostate cancer treatment. Subsequently, we presented a comprehensive review of nanotherapeutics for PCa treatment, including their targeting methods, controlled release strategies, therapeutic approaches and mechanisms. Finally, we proposed the future prospects of nanotherapeutics for PCa treatment.

Beyond the individual: An improved telecom fraud detection approach based on latent synergy graph learning.

The development of telecom technology not only facilitates social interactions but also inevitably provides the breeding ground for telecom fraud crimes. However, telecom fraud detection is a challenging task as fraudsters tend to commit co-fraud and disguise themselves within the mass of benign ones. Previous approaches work by unearthing differences in calling sequential patterns between independent fraudsters, but they may ignore synergic fraud patterns and oversimplify fraudulent behaviors. Fortunately, graph-like data formed by traceable telecom interaction provides opportunities for graph neural network (GNN)-based telecom fraud detection methods. Therefore, we develop a latent synergy graph (LSG) learning-based telecom fraud detector, named LSG-FD, to model both sequential and interactive fraudulent behaviors. Specifically, LSG-FD introduces (1) a multi-view LSG extractor to reconstruct synergy relationship-oriented graphs from the meta-interaction graph based on second-order proximity assumption; (2) an LSTM-based calling behavior encoder to capture the sequential patterns from the perspective of local individuals; (3) a dual-channel based graph learning module to alleviate the disassortativity issue (caused by the camouflages of fraudsters) by incorporating the dual-channel frequency filters and the learnable controller to adaptively aggregate high- and low-frequency information from their neighbors; (4) an imbalance-resistant model trainer to remedy the graph imbalance issue by developing a label-aware sampler. Experiment results on the telecom fraud dataset and another two widely used fraud datasets have verified the effectiveness of our model.

Novel mutations in ATP7B in Chinese patients with Wilson's disease and identification of kidney disorder of thinning of the glomerular basement membrane.

Introduction: Wilson's disease is an autosomal recessive disorder caused by ATP7B pathogenic mutations. The hallmark of this disorder mainly consists of liver involvement, neurologic dysfunction and psychiatric features. In addition, the kidneys can also be affected by excessive copper deposition. Methods: A total of 34 patients clinically diagnosed with WD were recruited. They underwent ATP7B gene sequencing and clinical data of symptoms, examination, and treatment were collected. Moreover, renal pathology information was also investigated. Results: We identified 25 potentially pathogenic ATP7B variants (16 missense, 5 frameshift, 3 splicing variants and 1 large deletion mutation) in these 34 WD patients, 5 of which were novel. In our cases, the most frequent variant was c.2333G>T (R778L, 39.06%, exon 8), followed by c.2621C>T (A874V, 10.94%, exon 11) and c.3316G>A (V1106I, 7.81%, exon 11). Furthermore, we described the thinning of the glomerular basement membrane as a rare pathologically damaging feature of Wilson's disease for the first time. Additionally, two patients who received liver transplant were observed with good prognosis in present study. Discussion: Our work expanded the spectrum of ATP7B variants and presented rare renal pathological feature in WD patients, which may facilitate the development of early diagnosis, counseling, treatment regimens of WD.

CycMuNet+: Cycle-Projected Mutual Learning for Spatial-Temporal Video Super-Resolution.

Spatial-Temporal Video Super-Resolution (ST-VSR) aims to generate high-quality videos with higher resolution (HR) and higher frame rate (HFR). Quite intuitively, pioneering two-stage based methods complete ST-VSR by directly combining two sub-tasks: Spatial Video Super-Resolution (S-VSR) and Temporal Video Super-Resolution (T-VSR) but ignore the reciprocal relations among them. 1) T-VSR to S-VSR: temporal correlations help accurate spatial detail representation; 2) S-VSR to T-VSR: abundant spatial information contributes to the refinement of temporal prediction. To this end, we propose a one-stage based Cycle-projected Mutual learning network (CycMuNet) for ST-VSR, which makes full use of spatial-temporal correlations via the mutual learning between S-VSR and T-VSR. Specifically, we propose to exploit the mutual information among them via iterative up- and down projections, where spatial and temporal features are fully fused and distilled, helping high-quality video reconstruction. In addition, we also show interesting extensions for efficient network design (CycMuNet+), such as parameter sharing and dense connection on projection units and feedback mechanism in CycMuNet. Besides extensive experiments on benchmark datasets, we also compare our proposed CycMuNet (+) with S-VSR and T-VSR tasks, demonstrating that our method significantly outperforms the state-of-the-art methods.

Prognostic prediction by 18F-FDG-PET/CT parameters in patients with neuroblastoma: a systematic review and meta-analysis.

Purpose: Neuroblastoma is a solid malignant tumor with high malignancy and high risk for metastasis. The prognosis of neuroblastoma ranges from spontaneous regression to insensitivity to therapies and widespread metastasis. There is a non-invasive, panoramic imaging technique called 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT), which can provide both complete anatomical information via CT and extent of FDG uptake value in tumors via positron emission detection. PET/CT is a powerful approach to estimating tumoral metabolic activities, and PET/CT parameters have been demonstrated to be associated with the prognosis of various tumors. However, the predictive performance of PET/CT for the prognosis of neuroblastoma remains unclear. This meta-analysis aims to assess the predictive values of maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) in neuroblastoma patients. Methods: Literature in PubMed, Embase, Cochrane Library, and Web of Science from January 1985 to June 2023 was searched for studies evaluating predictive values of PET/CT parameters for the prognosis of neuroblastoma. Search items mainly included "Positron Emission Tomography Computed Tomography" and "Neuroblastoma". Hazard ratio (HR) was used as a pooled statistic to assess the association of SUVmax, MTV, and TLG with PFS, EFS, and OS in neuroblastoma patients. Heterogeneity test and sensitivity analysis were performed. Results: There were eight studies included, with 325 participants. Meta-analysis showed that higher SUVmax was associated with shorter OS [HR = 1.27, 95% CI (1.11, 1.45), p = 0.001], while no association with PFS [HR = 1.03, 95% CI (0.99, 1.07), p = 0.222] and EFS [HR = 2.58, 95% CI (0.37, 18.24), p = 0.341] was presented. MTV showed no association with OS [HR = 2.46, 95% CI (0.34, 18.06), p = 0.376] and PFS [HR = 2.60, 95% CI (0.68, 9.88), p = 0.161]. There was a statistically significant association between TLG and OS [HR = 1.00, 95% CI (1.00, 1.00), p = 0.00], while the HR was 1, so the association could not be concluded, and TLG showed no association with PFS [HR = 1.00, 95% CI (0.99, 1.00), p = 0.974]. Conclusion: High SUVmax indicates poor OS in patients with neuroblastoma. The MTV and TLG are potential prognostic predictors that need to be further validated by more well-designed studies. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier 340729.

Glucocorticoid nanoformulations relieve chronic pelvic pain syndrome and may alleviate depression in mice.

BACKGROUND: Chronic pelvic pain syndrome (CPPS) is a typical symptom of chronic prostatitis (CP) in males that may cause abnormal urination, sexual dysfunction, or depression and significantly affect the quality of life of the patient. Currently, there is no effective treatment for CPPS due to its recurrence and intractability. For synergistic CPPS therapy, we developed pH/reactive oxygen species (ROS) dual-responsive dexamethasone (Dex) nanoformulations using a ROS-responsive moiety and phytochemical modified α-cyclodextrin (α-CD) as the carrier. RESULTS: Dex release from the nanoformulations can be controlled in acidic and/or ROS-rich microenvironments. The fabricated Dex nanoformulations can also be efficiently internalized by lipopolysaccharide (LPS)-stimulated macrophages, prostatic epithelial cells, and stromal cells. Moreover, the levels of proinflammatory factors (e.g., TNF-α, IL-1ß, and IL-17 A) in these cells were significantly decreased by Dex nanoformulations treatment through the release of Dex, phytochemical and elimination of ROS. In vivo experiments demonstrated notable accumulation of the Dex nanoformulations in prostate tissue to alleviate the symptoms of CPPS through the downregulation of proinflammatory factors. Interestingly, depression in mice may be relieved due to alleviation of their pelvic pain. CONCLUSION: We fabricated Dex nanoformulations for the effective management of CPPS and alleviation of depression in mice.

Phytic acid-modified manganese dioxide nanoparticles oligomer for magnetic resonance imaging and targeting therapy of osteosarcoma.

Osteosarcoma is the most common malignant tumor in the skeletal system with high mortality. Phytic acid (PA) is a natural compound extracted from plant seeds, which shows certain antitumor activity and good bone targeting ability. To develop a novel theranostics for magnetic resonance imaging (MRI) and targeting therapy of osteosarcoma, we employed PA to modify manganese dioxide nanoparticles (MnO2@PA NPs) for osteosarcoma treatment. The MnO2 NPs oligomer was formed by PA modification with uniformed size distribution and negative zeta potential. Fourier-transform infrared spectroscopy, X-ray diffraction, energy dispersive spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis demonstrated that PA has been successfully modified on MnO2 NPs, and the structure of MnO2@PA NPs is amorphous. In vitro experiments demonstrated that MnO2@PA NPs oligomer can be efficiently internalized by tumor cell, and the internalized NPs can react with H2O2 under acid microenvironment to produce Mn2+ and O2. In vivo experiments demonstrated that MnO2@PA NPs oligomer can passively accumulate in tumor tissue, and the accumulated NPs can produce Mn2+ and O2 for MRI and targeting therapy of osteosarcoma. In conclusion, we prepared a novel bone-targeting nano theranostics for MRI and therapy of osteosarcoma.

Precise diagnosis and typing of early-stage renal immunoglobulin-derived amyloidosis by label-free quantification of parallel reaction monitoring-based targeted proteomics.

BACKGROUND: Early diagnosis and typing are crucial for improving the prognosis of patients with renal amyloidosis. Currently, Untargeted proteomics based precise diagnosis and typing of amyloid deposits are crucial for guiding patient management. Although untargeted proteomics achieve ultra-high-throughput by selecting the most abundant eluting cationic peptide precursors in series for tandem MS events, it lacks in sensitivity and reproducibility, which may not be suitable for early-stage renal amyloidosis with minor damages. Here, we aimed to develop parallel reaction monitoring (PRM)-based targeted proteomics to achieve high sensitivity and specificity by determining absolute abundances and codetecting all transitions of highly repeatable peptides of preselected amyloid signature and typing proteins in identifying early-stage renal immunoglobulin-derived amyloidosis. METHODS AND RESULTS: In 10 discovery cohort cases, Congo red-stained FFPE slices were micro-dissected and analyzed by data-dependent acquisition-based untargeted proteomics for preselection of typing specific proteins and peptides. Further, a list of proteolytic peptides from amyloidogenic proteins and internal standard proteins were quantified by PRM-based targeted proteomics to validate performance for diagnosis and typing in 26 validation cohort cases. The diagnosis and typing effectiveness of PRM-based targeted proteomics in 10 early-stage renal amyloid cases was assessed via a comparison with untargeted proteomics. A peptide panel of amyloid signature proteins, immunoglobulin light chain and heave chain in PRM-based targeted proteomics showed significantly distinguishing ability and amyloid typing performance in patients. The diagnostic algorithm of targeted proteomics with a low amount of amyloid deposits in early-stage renal immunoglobulin-derived amyloidosis showed better performance than untargeted proteomics in amyloidosis typing. CONCLUSIONS: This study demonstrates that the utility of these prioritized peptides in PRM-based targeted proteomics ensure high sensitivity and reliability for identifying early-stage renal amyloidosis. Owing to the development and clinical application of this method, rapid acceleration of the early diagnosis, and typing of renal amyloidosis is expected.

Established the first clinical prediction model regarding the risk of hyperuricemia in adult IgA nephropathy.

OBJECTIVE: To construct a novel nomogram model that predicts the risk of hyperuricemia incidence in IgA nephropathy (IgAN). METHODS: Demographic and clinicopathological characteristics of 1184 IgAN patients in the First Affiliated Hospital of Zhengzhou University Hospital were collected. Univariate analysis and multivariate logistic regression were used to screen out hyperuricemia risk factors. The risk factors were used to establish a predictive nomogram model. The performance of the nomogram model was evaluated using an area under the receiver-operating characteristic curve (AUC), calibration plots, and a decision curve analysis. RESULTS: Independent predictors for hyperuricemia incidence risk included sex, hypoalbuminemia, hypertriglyceridemia, blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), 24 h urinary protein (24 h TP), gross hematuria and tubular atrophy/interstitial fibrosis (T). The nomogram model exhibited moderate prediction ability with an AUC of 0.834 (95% CI 0.804-0.864). The AUC from validation reached 0.787 (95% CI 0.736-0.839). The decision curve analysis displayed that the hyperuricemia risk nomogram was clinically applicable. CONCLUSION: Our novel and simple nomogram containing 8 factors may be useful in predicting hyperuricemia incidence risk in IgAN.

In vivo targeting capacities of different nanoparticles to prostate tissues based on a mouse model of chronic bacterial prostatitis.

Chronic bacterial prostatitis usually occurs in men and seriously affects the quality of life of patients. The efficacy of chronic bacterial prostatitis treatment is limited by the difficulty for free drugs (e.g., antibiotics) to penetrate the prostate epithelium and target inflammatory tissues. The advent of nanotechnology offers the possibility to address this issue, such as the development of targeted nanoparticle delivery strategies that may overcome these important limitations. The physicochemical properties of nanoparticles, such as particle size, shape and surface modification ligands, determine their targeting effectiveness. In this study, nanoparticles with different physicochemical properties were prepared to explore and confirm their targeting capacities to inflammatory prostate tissues of chronic bacterial prostatitis, focusing on the effects of size and different modification ligands on the targeting performance. In vivo and ex vivo imaging results verified that folic acid-modified nanoparticles with a particle size of 180-190 nm via tail intravenous injection had the optimal targeting efficiency to prostate tissues. Our results provide an experimental basis and reference value for targeted therapy of prostate-related diseases with nanotechnology in the future.

Application of Artificial Neural Network Algorithm in Facial Biological Image Information Scanning and Recognition.

In order to solve the problem that the accuracy of face recognition is not good due to the influence of jitter and environmental factors in the mobile shooting environment, this paper proposes the application of an artificial neural network algorithm in the information scanning and recognition of face biological images. The spatial neighborhood information is integrated into the amplitude detection of multipose face images, and the dynamic corner features of multipose face images are extracted. The structural texture information of multipose face images is compared to a global moving RGB three-dimensional bit plane random field, and the multipose face images are detected and fused. At different scales, appropriate feature registration functions are selected to describe the feature points of multipose face images. The parallax analysis of target pixels and key feature detection of multipose face images are carried out. Image stabilization and automatic recognition are realized by combining artificial neural network learning and feature registration methods. The experimental results show that the experiment is designed with MATLAB, the frame frequency of dynamic face image acquisition is 1200 kHz, the number of collected samples of the multipose face image is 2000, the training sample set is 200, the noise coefficient = 0.24, the number of multipose face image blocks is 120, and the structural similarity is 0.12. It is found that the output signal-to-noise ratio of multipose face image recognition using the method in this paper is high. Conclusion. This method has good performance in feature point registration and high recognition accuracy for multipose face image recognition.

COVID-19 contact tracking by group activity trajectory recovery over camera networks.

Contact tracking plays an important role in the epidemiological investigation of COVID-19, which can effectively reduce the spread of the epidemic. As an excellent alternative method for contact tracking, mobile phone location-based methods are widely used for locating and tracking contacts. However, current inaccurate positioning algorithms that are widely used in contact tracking lead to the inaccurate follow-up of contacts. Aiming to achieve accurate contact tracking for the COVID-19 contact group, we extend the analysis of the GPS data to combine GPS data with video surveillance data and address a novel task named group activity trajectory recovery. Meanwhile, a new dataset called GATR-GPS is constructed to simulate a realistic scenario of COVID-19 contact tracking, and a coordinated optimization algorithm with a spatio-temporal constraint table is further proposed to realize efficient trajectory recovery of pedestrian trajectories. Extensive experiments on the novel collected dataset and commonly used two existing person re-identification datasets are performed, and the results evidently demonstrate that our method achieves competitive results compared to the state-of-the-art methods.

Antibiotic-loaded reactive oxygen species-responsive nanomedicine for effective management of chronic bacterial prostatitis.

Chronic bacterial prostatitis (CBP) occurs frequently in the male population and significantly influences quality of life. Antibiotics are the main strategy for managing chronic bacterial prostatitis; however, most antibiotics have low efficacy due to their poor penetration of prostate tissues. To overcome this challenge, we fabricated cefpodoxime proxetil (CPD)-loaded reactive oxygen species (ROS)-responsive nanoparticles (NPs) for targeted treatment of CBP. These NPs were modified with folic acid (FA) and could be effectively internalized by bacteria-infected macrophages and prostatic epithelial cells because of the high expression of folate receptors (FRs) in these cells. In vitro cellular assays demonstrated that the CPD-loaded nanomedicine can obviously reduce proinflammatory cytokine expression in cells since the nanomedicine can efficiently eradicate cellular bacteria. In vivo imaging results verified that FA-modified nanomedicines can penetrate the prostatic epithelium and accumulate in the glandular lumen because FRs overexpression was also observed in the prostate tissues of CBP mice. Animal experiments demonstrated that FA-modified nanomedicine can remarkably relieve pelvic pain in CBP mice and dramatically decrease proinflammatory cytokine expression in prostate tissues via eradication of bacteria and scavenging of ROS. Our results provide a new strategy to deliver antibiotics for targeted therapy of CBP. STATEMENT OF SIGNIFICANCE: To overcome poor penetration of antibiotics in prostatic tissues, we developed an antibiotics-loaded ROS-responsive NPs for targeted treatment of CBP. We demonstrated that both bacteria-infected macrophages and prostatic epithelial cells have FRs overexpression, thus FA-modified NPs can be efficiently internalized by these cells. FA-modified NPs can penetrate the prostatic epithelium and accumulate in the glandular lumen via FRs-mediated endocytosis, and the accumulated NPs can smartly release their payload under high ROS microenvironment. A distinguished therapy outcome was obtained in murine CBP model since CPD-loaded NPs can efficiently eradicate the resident bacteria in prostate tissues and downregulate proinflammatory cytokine expression. Our work provides a practicable strategy to expand the application of antibiotics for management of CBP.

Mechanisms of Senescence-Related NKG2D Ligands Release and Immune Escape Induced by Chemotherapy in Neuroblastoma Cells.

Chemotherapy-induced senescence promotes immunocyte aggregation in the tumor microenvironment by upregulating the surface expression of activating ligands in cancer cells. However, these senescent tumor cells cannot be completely cleared and can induce tumor recurrence. Previous studiesshowed that soluble natural killer (NK) group 2D (NKG2D) ligands impair the recognition of multiple immune cells. In this study, we established an in vitro senescence model using neuroblastoma cells subjected to low-dose Chemotherapeutic drug doxorubicin or the Aurora A inhibitor MLN8237. The results showed that different neuroblastoma cell lines showed increased secretion of the NKG2D ligand MHC class I polypeptide-related sequence A/B (MICA/B) following proteolysis after treatment, with MICA/B subsequently recruited to exosomes to downregulate NKG2D expression in NK cells. Interestingly, disintegrin and metalloproteinase domain-containing 10 (ADAM10) was upregulated in senescent tumor cells, and combined treatment with the ADAM10 inhibitor GI254023X and chemotherapeutic drugs inhibited MICA/B secretion and enhanced recognition and killing by NK cells. Additionally, we found that expression of the long noncoding RNA MALAT1 was significantly increased in senescent neuroblastoma cells, and that MALAT1 served as a sponge for microRNA (miR)-92a-3p to counteract miR-92a-3p-mediated repression of ADAM10 levels. Furthermore, administration of a MALAT1 inhibitor or an miR-92a-3p mimic reduced the MICA/B shedding and enhanced recognition and killing by NK cells. These results confirmed that low-dose chemotherapy induces senescence in neuroblastoma cells, and that senescent tumor cells promote the shedding of the NKG2D ligand MICA/B through the MALAT1/miR-92a/ADAM10 axis, thereby contributing to the formation of a suppressive immune microenvironment and promoting immune escape.

Hyperuricemia aggravates the progression of IgA nephropathy.

OBJECTIVE: The relationship between hyperuricemia and IgA nephropathy (IgAN) was evaluated systematically in this research. METHODS: The Preferred Reporting Items for Systematic Review and Meta-analysis statement was employed to design and report the study. RESULTS: Twenty-five studies were included in this meta-analysis with a total of 6048 IgAN patients. The clinical indicators indicated that blood urea nitrogen (BUN) (p < 0.00001, mean difference (MD) = 2.60, 95% confidence interval (CI) 1.74-3.46), serum creatinine (Scr) (p < 0.00001, MD = 44.56, 95% CI 31.15-57.98), diastolic blood pressure(DBP) (p < 0.00001, MD = 3.86, 95% CI 2.84-4.88), systolic blood pressure(SBP) (p < 0.00001, MD = 6.71, 95% CI 4.70-8.71), and 24-h urine protein(24 h TP) (p < 0.00001, MD = 0.76, 95% CI 0.58-0.94) were significantly increased in IgAN with hyperuricemia group than that in normouricemic IgAN group. The pathological analysis indicated that mesangial proliferation (p < 0.00001, MD = 0.12, 95% CI 0.07-0.17), vascular lesion (p < 0.00001, MD = 0.17, 95% CI 0.13-0.20), segmental lesion (p < 0.00001, MD = 0.15, 95% CI 0.03-0.26), tubulointerstitial damage (p < 0.00001, MD = 1.27, 95% CI 1.06-1.48), and glomerulosclerosis (p < 0.00001, MD = 0.56, 95% CI 0.40-0.72) were considerably climbed in IgAN patients with hyperuricemia compared without hyperuricemia group. Additionally, the estimated glomerular filtration rate (p < 0.00001, MD = - 29.03, 95% CI - 36.83 to - 21.23) was decreased in IgAN patients with hyperuricemia compared with normouricemic group. CONCLUSION: Hyperuricemia exacerbates IgAN prognosis through aggravating the clinical outcomes and pathological results of IgAN.

MicroRNA-137 targets EZH2 to exert suppressive functions in uveal melanoma via regulation of Wnt/ß-catenin signaling and epithelial-to-mesenchymal transition.

PURPOSE: Uveal melanoma (UM) is one of the primary intraocular malignancies. Emerging studies have confirmed dysregulation of microRNA (miRNA/miR) in UM. The present study focused on the biofunctions of miR-137 in UM. METHODS: MiR-137 expressions in tissue samples were analyzed by qRT-PCR. MTT and transwell assays were applied to investigate the impacts of miR-137 on UM cell proliferation, invasion and migration. Luciferase assay was carried out to explore the downstream target of miR-137. Western blot was used to analyze the roles of miR-137 in UM cells, Wnt/ß-catenin pathway and epithelial-mesenchymal transition (EMT). RESULTS: qRT-PCR showed that miR-137 expressions were lower in UM tissue samples than para-carcinoma tissues, whereas EZH2 was simultaneously upregulated. MiR-137 overexpression evidently suppressed UM cell proliferation, invasion and migration. The findings also indicated that miR-137 restoration could block Wnt/ß-catenin pathway and EMT in UM cells thus resulting in downregulation of malignant behaviors. EZH2 was a downstream target of miR-137 as demonstrated by luciferase assay. CONCLUSION: The present study indicated that EZH2 participated in the anti-UM functions of miR-137. Taken together, the data in our study established miR-137/EZH2 axis in regulating UM progression, suggesting that miR-137 may function as a novel therapeutic biomarker for UM patients.

Association between thrombotic microangiopathy and activated alternative complement pathway in malignant nephrosclerosis.

BACKGROUND: Malignant nephrosclerosis, defined as renal microangiopathy in the setting of severe hypertension, remains a critical renal emergency leading to end-stage renal disease despite aggressive anti-hypertensive treatment. Recently, activation of the complement alternative pathway (AP) has been reported to play a prominent role in the pathogenesis of malignant nephrosclerosis. However, subsequent study failed to recapitulate the findings of genetic complement abnormalities in the disease. This study aimed to determine the presence of AP activation and genetic complement defects and establish their correlations to renal microangiopathy lesions, clinical features and prognosis in patients with malignant nephrosclerosis. METHODS: Fifty patients with malignant hypertension and concomitant thrombotic microangiopathy (TMA) proven by renal biopsy were investigated; 25 cases of kidney donors who received zero-hour allograft biopsies were used as normal controls. Various renal TMA lesions in patients with malignant nephrosclerosis were reviewed and evaluated using a semi-quantitative scoring system. Deposition of C5b-9, C3a, C5a, C4d and mannose-binding lectin was assessed by immunohistochemistry. Co-localization of C5b-9 and CD34 was detected by confocal microscopy. Complement factor B (FB), factor P (FP; properdin), factor D (FD), factor H (FH), C3a and C5a levels were quantified by enzyme-linked immonosorbent assay in plasma and urine samples of patients with malignant nephrosclerosis and controls. Genetic abnormalities of complement components were analysed by whole-exome sequencing. RESULTS: Renal biopsies of malignant nephrosclerosis showed identical histopathological and ultrastructural features to atypical haemolytic uraemic syndrome. C5b-9, C3a and C5a deposits were found along the walls of arteries/arterioles and glomerular capillaries and localized in the endothelial cells. Elevated plasma and urinary levels of FB, FP, FD, C3a and C5a as well as decreased FH levels were observed in patients with malignant nephrosclerosis compared with normal controls. The urinary levels of complement AP components, but not the plasma levels, were correlated with renal functions, prognosis and active TMA lesions except for arteriolar thrombi. Finally, mutations of the MCP, CFB, CFH and CFHR5 genes were identified in 8 of 20 patients with malignant nephrosclerosis. CONCLUSIONS: Aberrant complement AP dysregulation was demonstrated and associated with the activity, severity and renal outcomes of malignant nephrosclerosis. This observation warrants screening for complement defects in patients with malignant nephrosclerosis for the potential use of complement regulators and also highlights the need for further investigation of the precise role of AP in the pathogenesis of the disease.