Glymphatic abnormality in systemic lupus erythematosus detected by diffusion tensor image analysis along the perivascular space.

OBJECTIVES: This study aimed to evaluate the activity of the glymphatic system in systemic lupus erythematosus (SLE) by a diffusion-based method termed "Diffusion Tensor Image Analysis aLong the Perivascular Space (DTI-ALPS)", and examined its correlations with morphological changes in the brain. METHODS: In this cross-sectional study, forty-five female patients with SLE and thirty healthy controls (HCs) were included. Voxel-based and surface-based morphometric analyses were performed to examine T1 weighted images, and diffusion tensor images were acquired to determine diffusivity along the x-, y-, and z-axes in the plane of the lateral ventricle body. The ALPS-index was calculated. The differences in values between SLE patients and HC group were compared using the independent samples t test or Mann-Whitney U test. For the correlations between the ALPS-index and brain morphological parameters, partial correlation analysis and Pearson's correlation analysis were conducted. RESULTS: SLE patients showed lower values for the ALPS-index in left (1.543 ± 0.141 vs 1.713 ± 0.175, p < 0.001), right (1.428 ± 0.142 vs 1.556 ± 0.139, p < 0.001) and whole (1.486 ± 0.121 vs 1.635 ± 0.139, p < 0.001) brain compared with the HC group. The reduced ALPS-index showed significant positive correlations with gray matter loss. CONCLUSION: The non-invasive ALPS-index could serve as a sensitive and effective neuroimaging biomarker for individually quantifying glymphatic activity in patients with SLE. Glymphatic system abnormality may be involved in the pathophysiologic mechanism underlying central nervous system damage in SLE patients.

MOICS, a novel classier deciphering immune heterogeneity and aid precise management of clear cell renal cell carcinoma at multiomics level.

Recent studies have indicated that the tumor immune microenvironment plays a pivotal role in the initiation and progression of clear cell renal cell carcinoma (ccRCC). However, the characteristics and heterogeneity of tumor immunity in ccRCC, particularly at the multiomics level, remain poorly understood. We analyzed immune multiomics datasets to perform a consensus cluster analysis and validate the clustering results across multiple internal and external ccRCC datasets; and identified two distinctive immune phenotypes of ccRCC, which we named multiomics immune-based cancer subtype 1 (MOICS1) and subtype 2 (MOICS2). The former, MOICS1, is characterized by an immune-hot phenotype with poor clinical outcomes, marked by significant proliferation of CD4+ and CD8+ T cells, fibroblasts, and high levels of immune inhibitory signatures; the latter, MOICS2, exhibits an immune-cold phenotype with favorable clinical characteristics, characterized by robust immune activity and high infiltration of endothelial cells and immune stimulatory signatures. Besides, a significant negative correlation between immune infiltration and angiogenesis were identified. We further explored the mechanisms underlying these differences, revealing that negatively regulated endopeptidase activity, activated cornification, and neutrophil degranulation may promote an immune-deficient phenotype, whereas enhanced monocyte recruitment could ameliorate this deficiency. Additionally, significant differences were observed in the genomic landscapes between the subtypes: MOICS1 exhibited mutations in TTN, BAP1, SETD2, MTOR, MUC16, CSMD3, and AKAP9, while MOICS2 was characterized by notable alterations in the TGF-ß pathway. Overall, our work demonstrates that multi-immune omics remodeling analysis enhances the understanding of the immune heterogeneity in ccRCC and supports precise patient management.

Robot-assisted single-port retroperitoneal partial nephrectomy with a novel purpose-built single-port robotic system with deformable surgical instruments.

OBJECTIVE: To investigate the safety and feasibility of using a novel purpose-built single-port robotic system (the SHURUI Robotic Surgical System) with deformable surgical instruments to perform retroperitoneal single-port partial nephrectomy. MATERIALS AND METHODS: A prospective study was conducted to recruit patients with a single renal tumor no more than 4 cm. Robot-assisted single-port partial nephrectomy was performed by using the novel purpose-built single-port robotic system with deformable surgical instruments. Patients' demographics, tumor characteristics, and perioperative parameters were recorded and analyzed. RESULTS: Sixteen patients were recruited to the study. The median tumor size was 2.0 cm (IQR: 1.2-2.4 cm). The median R.E.N.A.L score was 6 (IQR: 4-4.5). In 3 cases, pure single-port surgery was carried out, and all the assistance was through the robotic port. Median docking time was 15.5 min (IQR: 14.25-22.25 min). Median operating time was 148.5 min (IQR: 178-238.5 min). Median console time was 107 min (IQR: 92.75-149.75 min). Median warm ischemic time was 26.5 min (IQR: 24.5-30 min). Median blood loss was 17.5 ml (IQR: 10-50 ml). CONCLUSIONS: Retroperitoneal partial nephrectomy can be safely performed with this novel purpose-built single-port robotic system (SHURUI) with deformable surgical instruments. Further studies are needed to fully evaluate the role of this new platform.

Systemic lupus erythematosus-related brain abnormalities in the default mode network and the limbic system: A resting-state fMRI meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) is an immune-mediated and multi-systemic disease which may affect the nervous system, causing neuropsychiatric SLE (NPSLE). Recent neuroimaging studies have examined brain functional alterations in SLE. However, discrepant findings were reported. This meta-analysis aims to identify consistent resting-state functional abnormalities in SLE. METHODS: PubMed and Web of Science were searched to identify candidate resting-state functional MRI studies assessing SLE. A voxel-based meta-analysis was performed using the anisotropic effect-size version of the seed-based d mapping (AES-SDM). The abnormal intrinsic functional patterns extracted from SDM were mapped onto the brain functional network atlas to determine brain abnormalities at a network level. RESULTS: Twelve studies evaluating fifteen datasets were included in this meta-analysis, comprising 572 SLE patients and 436 healthy controls (HCs). Compared with HCs, SLE patients showed increased brain activity in the bilateral hippocampus and right superior temporal gyrus, and decreased brain activity in the left superior frontal gyrus, left middle temporal gyrus, bilateral thalamus, left inferior frontal gyrus and right cerebellum. Mapping the abnormal patterns to the network atlas revealed the default mode network and the limbic system as core neural systems commonly affected in SLE. LIMITATIONS: The number of included studies is relatively small, with heterogeneous analytic methods and a risk of publication bias. CONCLUSIONS: Brain functional alterations in SLE are predominantly found in the default mode network and the limbic system. These findings uncovered a consistent pattern of resting-state functional network abnormalities in SLE which may serve as a potential objective neuroimaging biomarker.

A Mendelian randomization study on causal effects of leisure sedentary behavior on the risk of erectile dysfunction.

BACKGROUND: Erectile dysfunction has been associated with leisure sedentary behavior in several epidemiological and observational studies. However, the interpretation of these findings is difficult due to residual confounding or reverse causality. OBJECTIVES: To explore the causal association between leisure sedentary behavior and erectile dysfunction, and to explore the underlying mechanism using Mendelian randomization. MATERIALS AND METHODS: In the present study, publicly available large-scale genome-wide association studies of leisure sedentary behaviors (television watching, computer use, and driving), erectile dysfunction, sex hormones (total testosterone, bioactive testosterone, estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, and sex hormone binding globulin), biomarkers of endothelial function (C reactive protein, E-selectin, and matrix metalloproteinase 7), and psychiatric symptoms (depression and anxiety) were used to perform two-sample Mendelian randomization analyses. The inverse variance weighting method was the main method used to estimate the association, and sensitivity analyses were also performed. RESULTS: A greater risk of erectile dysfunction was significantly associated with a higher genetic susceptibility to leisure computer usage (odds ratio = 3.57; 95% confidence interval = 1.78-7.16; p < 0.001). No evidence was obtained to suggest that watching television or driving for leisure increased the risk of erectile dysfunction. No association was found between computer use and depression, anxiety, C reactive protein, E-selectin, matrix metalloproteinase 7, or other sex hormones, with the exception of follicle-stimulating hormone levels (odds ratio = 0.29; 95% confidence interval = 0.12-0.69; p = 0.01). No indication of heterogeneity or pleiotropy was identified by sensitivity analysis. DISCUSSION: Extended computer usage for leisure raised the likelihood of developing erectile dysfunction, which may be associated to lower follicle-stimulating hormone levels; however, the role of endothelial dysfunction and psychological disorders in the development of erectile dysfunction should not be underestimated. Moderate physical activity may help to correct the dysfunction. CONCLUSION: The present study offered substantial evidence for a positive causal association between computer use and the risk of erectile dysfunction. However, a definitive causal association needs to be established by further research.

Neonatal stress disrupts the glymphatic system development and increases the susceptibility to Parkinson's disease in later life.

INTRODUCTION: Neonatal stress disrupts brain development and increases the risk of neurological disorders later in life. However, the impact of neonatal stress on the development of the glymphatic system and susceptibility to Parkinson's disease (PD) remains largely unknown. METHODS: Neonatal maternal deprivation (NMD) was performed on mice for 14 consecutive days to model chronic neonatal stress. Adeno-associated virus expressing A53T-α-synuclein (α-syn) was injected into the substantia nigra to establish PD model mice. Glymphatic activity was determined using in vivo magnetic resonance imaging, ex vivo fluorescence imaging and microplate assay. The transcription and expression of aquaporin-4 (AQP4) and other molecules were evaluated by qPCR, western blotting, and immunofluorescence. Animal's responses to NMD and α-syn overexpression were observed using behavioral tests. RESULTS: Glymphatic activity was impaired in adult NMD mice. AQP4 polarization and platelet-derived growth factor B (PDGF-B) signaling were reduced in the frontal cortex and hippocampus of both young and adult NMD mice. Furthermore, exogenous α-syn accumulation was increased and PD-like symptoms were aggravated in adult NMD mice. CONCLUSION: The results demonstrated that NMD could disrupt the development of the glymphatic system through PDGF-B signaling and increase the risk of PD later in life, indicating that alleviating neonatal stress could be beneficial in protecting the glymphatic system and reducing susceptibility to neurodegeneration.

SPCS, a Novel Classifier System Based on Senescence Axis Regulators Reveals Tumor Microenvironment Heterogeneity and Guides Frontline Therapy for Clear Cell Renal Carcinoma.

RATIONALE: The emerging evidence suggested that senescence regulator genes were involved in multi cancers, which may be utilized as new targets for cancers. However, the dysregulation and clinical impact of senescence regulator genes in clear cell renal cell cancer (ccRCC) were still in foggy. METHODS: Using multiomics data from TCGA-KIRC and other datasets, we comprehensively investigated the function of senescence regulator genes in ccRCC. ccRCC patients could be remodeled into 2 significant different groups basing on senescence regulators expression: senescence-pattern cancer subtype1 (SPCS1) and subtype2 (SPCS2). We further explored clinical characteristics, functional analysis, tumor immune microenvironment, immunotherapy response, genomic mutation and drug sensitivity between the 2 subtypes. Besides, senescence-pattern related risk model was established to determine the patient's prognosis of ccRCC. Finally, the overview of MECP2 function was investigated in multi cancers. RESULTS: ccRCC patients could be divided into SPCS1 (normal aging group) and SPCS2 (Aging disorder group). The 2 subtypes showed significant different clinical characteristics and biological process in ccRCC. SPCS2, an aggressive subtype, comprised higher clinical stage and worse prognosis of ccRCC patients. SPCS2 subtype indicated activated oncogenic signaling pathway and metabolic signatures to prompt cancer expansion. SPCS2 subgroup owned immunocompromised status, which induced immune dysfunction and low ICI therapy response. The genome-copy numbers of SPCS2, including arm-gain and arm-loss was significantly more frequent than SPCS1. In addition, the 2 subtypes argue contrasting drug sensitivity profiles in clinical specimens and matched cell lines. Finally, we constructed a prognostic risk model consisted of each subtype's leading biomarkers, which exerted a satisfied performance for ccRCC patients. CONCLUSION: Senescence regulator-related signature could modify functional pathways and tumor immune microenvironment by genome mutation and pathway interaction. Senescence regulator-related molecular subtype strengthen the understanding of ccRCC' characterization and guide clinical treatment. Targeting senescence regulators may be regard as a proper way in ccRCC.

Correlation of glymphatic system abnormalities with Parkinson's disease progression: a clinical study based on non-invasive fMRI.

BACKGROUND: The glymphatic system is reportedly involved in Parkinson's disease (PD). Based on previous studies, we aimed to confirm the correlation between the glymphatic system and PD progression by combining two imaging parameters, diffusion tensor image analysis along the perivascular space (DTI-ALPS), and enlarged perivascular spaces (EPVS). METHODS: Fifty-one PD patients and fifty healthy control (HC) were included. Based on the Hoehn-Yahr scale, the PD group was divided into early-stage and medium-to late-stage. All PD patients were scored using the Unified PD Rating Scale (UPDRS). We assessed the DTI-ALPS indices in the bilateral hemispheres and EPVS numbers in bilateral centrum semiovale (CSO), basal ganglia (BG), and midbrain. RESULTS: The DTI-ALPS indices were significantly lower bilaterally in PD patients than in the HC group, and EPVS numbers in any of the bilateral CSO, BG, and midbrain were significantly higher, especially for the medium- to late-stage group and the BG region. In PD patients, the DTI-ALPS index was significantly negatively correlated with age, while the BG-EPVS numbers were significantly positively correlated with age. Furthermore, the DTI-ALPS index was negatively correlated with UPDRS II and III scores, while the BG-EPVS numbers were positively correlated with UPDRS II and III scores. Similarly, the correlation was more pronounced in the medium- to late-stage group. CONCLUSION: The DTI-ALPS index and EPVS numbers (especially in the BG region) are closely related to age and PD progression and can serve as non-invasive assessments for glymphatic dysfunction and its interventions in clinical studies.

Tumor cell-intrinsic SETD2 inactivation sensitizes cancer cells to immune checkpoint blockade through the NR2F1-STAT1 pathway.

BACKGROUND: Cancer immunotherapies can induce durable tumor regression, but most patients do not respond. SETD2 mutation has been linked to the efficacy of immune checkpoint inhibitors (ICIs) immunotherapy. The functional importance of the SETD2 inactivation and how to modulate immunotherapy response remains unclear. METHODS: To explore the function of SETD2 in immunotherapy, knockout and subsequent functional experiments were conducted. Bulk RNA-seq, ATAC-seq, Chip-seq and single-cell RNA-seq were performed to dissect the mechanism and explore the immune microenvironment of mouse tumor. Flow cytometry was used to assess cell surface antigen and intratumoral T cell levels. RESULTS: We comprehensively determine the effect of SETD2 inactivation in ICIs therapy and elucidate the mechanistic impact on tumor immunity. Murine syngeneic tumors harboring Setd2 inactivation are sensitive to ICIs. By bulk and single-cell RNA-seq, we further reveal that SETD2 inactivation reprograms intratumoral immune cells and inflames the tumor microenvironment, which is characterized by high infiltration of T cells and enhanced antigen presentation to activate CD8+ T cell-mediated killing. Mechanistically, via an integrated multiomics analysis using ATAC-seq, ChIP-seq and RNA-seq, we demonstrate that SETD2 inactivation reduces NR2F1 transcription by impairing H3K36me3 deposition and chromatin accessibility, which activates the STAT1 signaling pathway to promote chemokines and programmed cell death protein-1 (PD-1) expression and enhance antigen presentation. All these regulatory mechanisms synergistically promote the effects of anti-programmed cell death ligand 1 immunotherapy in Setd2-knockout syngeneic mouse models. The SETD2-NR2F1-STAT1 regulatory axis is conserved in human and murine cancers. Finally, cancer patients harboring SETD2 mutations who received ICIs show increased durable clinical benefits and survival. CONCLUSIONS: These findings provide novel insights into the biology of SETD2 inactivation regulation and reveal a new potential therapeutic biomarker for ICIs immunotherapy in various refractory cancers.

Construction of the prognostic model in non-metastatic renal cancer patients with venous tumor thrombus.

Background: Venous system invasion is a prominent characteristic of local progression in renal cancer and treatment-naïve renal cancer patients with venous tumor thrombus (VTT) gained short natural course and poor prognosis. This study aimed to investigate the efficacy of the surgery and prognostic factors in non-metastatic renal cancer patients with VTT and to construct a nomogram prognostic model. Methods: Clinical data of 114 non-metastatic renal cancer patients with VTT who underwent surgical treatment from January 2011 to September 2022 were retrospectively analyzed. In order to find independent risk factors of prognosis, survival analysis was performed via univariate and multivariate Cox regression models and Kaplan-Meier method. Nomogram prognostic model was established to calculate patients' risk scores. Receiver operating characteristic curve and decision curve analysis were conducted to evaluate the efficacy of the prognostic model. Results: A total of 114 patients were included in this study and there were 48, 12, 25, 23, and 6 cases of grade 0-IV VTT. No perioperative death occurred. The 3-year probabilities of overall survival (OS) and 5-year probabilities of OS were 67% and 43.8%, respectively. Multivariate Cox regression analysis revealed that kidney tumor diameter, preoperative lactate dehydrogenase (LDH), and preoperative neutrophils were independent risk factors. Nomogram was constructed to predict prognosis in renal cancer patients with VTT based on above indicators and Mayo VTT grading. The area under the ROC curve of 1-, 2-, 3-, and 5-year OS of the patients were 0.82, 0.67, 0.57, and 0.55 respectively. Conclusions: Surgical treatment enables renal cancer patients with VTT to gain a better prognosis. Kidney tumor diameter, preoperative LDH, and preoperative neutrophils were independent risk factors. The nomogram perfects the Mayo grading, and provides a reliable reference for evaluation of prognosis of renal cancer patients with VTT.

Initial experience of laparoendoscopic single-site radical prostatectomy with a novel purpose-built robotic system.

Objective: This prospective single-arm clinical trial aimed to evaluated the feasibility and safety of the application of the SHURUI system (Beijing Surgerii Technology Co., Ltd., Beijing, China), a novel purpose-built robotic system, in single-port robotic radical prostatectomy. Methods: Sixteen patients diagnosed with prostate cancer were prospectively enrolled in and underwent robotic radical prostatectomy from October 2021 to August 2022 by the SHURUI single-port robotic surgical system. The demographic and baseline data, surgical, oncological, and functional outcomes as well as follow-up data were recorded. Results: The mean operative time was 226.3 (standard deviation [SD] 52.0) min, and the mean console time was 183.4 (SD 48.3) min, with the mean estimated blood loss of 116.3 (SD 90.0) mL. The mean length of postoperative hospital stay was 4.50 (SD 0.97) days. Two patients had postoperative complications (Clavien-Dindo Grade II), and both patients improved after conservative treatment. All patients' postoperative prostate-specific antigen levels decreased to below 0.2 ng/mL 1 month after discharge. The mean prostate-specific antigen level further decreased to a mean of 0.0219 (SD 0.0641) ng/mL 6 months after surgery. Thirty days postoperatively, 12 out of 16 patients reported using no more than one urinary pad per day, and all patients reported satisfactory urinary control without the need for pads 6 months after surgery. Conclusion: The SHURUI system is safe and feasible in performing radical prostatectomy via both transperitoneal and extraperitoneal approaches. Tumor control and urinary continence were satisfying for patients enrolled in. The next phase involves conducting a large-scale, multicenter randomized controlled trial to thoroughly assess the effectiveness and safety of the new technology in a broader population.

Intravesical Therapy for Upper Urinary Tract Urothelial Carcinoma: A Comprehensive Review.

Upper tract urothelial carcinoma (UTUC) poses unique challenges in diagnosis and treatment. This comprehensive review focuses on prophylactic intravesical therapy for UTUC, summarizing key aspects of intravesical therapy in various clinical scenarios, including concurrent with or following radical nephroureterectomy, kidney-sparing surgery, ureteroscopy-guided biopsy. The incidence of intravesical recurrence in UTUC after surgical treatment is significant, necessitating effective preventive measures. Intravesical therapy plays a vital role in reducing the risk of bladder recurrence following UTUC surgery. Tailoring timing, drug selection, dosage, and frequency is vital in optimizing treatment outcomes and reducing intravesical recurrence risk in UTUC. This review provides a comprehensive summary of the history, clinical trials, guideline recommendations, and clinical applications of intravesical therapy for UTUC. It also discusses the future directions based on current clinical needs and ongoing trials. Future directions entail optimizing dosage, treatment duration, and drug selection, as well as exploring novel agents and combination therapies. Intravesical therapy holds tremendous potential in improving outcomes for UTUC patients and reducing the risk of bladder recurrence. Although advancements have been made in UTUC treatment research, further refinements are necessary to enhance efficacy and safety.

18 F-PSMA-1007 PET/CT in a Case of Von Hippel-Lindau Syndrome.

ABSTRACT: We describe 18 F-PSMA-1007 PET/CT findings in case of von Hippel-Lindau syndrome with a cerebellar hemangioblastoma, 6 renal cell carcinomas in the bilateral kidneys, cystic lesions in the pancreas and left adrenal gland, and solid lesions in the bilateral epididymides. 18 F-PSMA-1007 PET/CT showed intense activity with SUV max of 111.3 of the cerebellar hemangioblastoma, variable activity with SUV max range of 6.4-37.6 of the renal cell carcinomas, and increased activity of the bilateral epididymal lesions (SUV max of 5.1 and 8.2 for the left and right epididymal lesions, respectively).