Risk factors for SARS-CoV-2 pneumonia among renal transplant recipients in Beijing Omicron wave.

The novel coronavirus disease-19 had become an unprecedented global health emergency, quickly expanding worldwide. Omicron (B.1.1.529), as a novel variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was initially identified in South Africa and Botswana. Renal transplant recipients (RTRs) are a special group and are more vulnerable to viral pneumonia. Thus, this study aimed to assess the incidence and risk factors of SARS-CoV-2 pneumonia that occurred in RTRs with Omicron infection. This single-center case-control study enrolled the RTRs who were diagnosed with SARS-CoV-2 infection by the SARS-CoV-2 nucleic acid test, which were divided into two groups according to the imaging features of SARS-CoV-2 pneumonia. The parameters were collected by questionnaires and analyzed using Statistical Product and Service Solutions. A total of 313 RTRs completed the questionnaires, and 131 were enrolled in this study with a mean age of 42.66 years. The incidence of SARS-CoV-2 pneumonia among the enrolled participants was 76.3%. The first symptoms included fever (89.3%), cough (93.1%), and expectoration (81.7%). From the comparison, the parameters such as age, gender, body mass index, lymphocyte count, and the percent of neutrophils and the basic serum creatinine before SARS-CoV-2 infection were significantly different between the two groups (P < 0.05). In multivariate analysis, age and the basic serum creatinine were independent risk factors for developing SARS-CoV-2 pneumonia (P < 0.05). Older RTRs with a high level of serum creatinine before SARS-CoV-2 infection were more at risk of developing SARS-CoV-2 pneumonia. More randomized controlled studies are needed.IMPORTANCEThis study aimed to assess the incidence and the risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia that occurred in renal transplant recipients (RTRs) with Omicron infection. In conclusion, older RTRs with a high level of serum creatinine before SARS-CoV-2 infection were more at risk of developing SARS-CoV-2 pneumonia and should be timely treated, in case of severe pneumonia.

Specific subsets of urothelial bladder carcinoma infiltrating T cells associated with poor prognosis.

Comprehensive investigation of tumor-infiltrating lymphocytes in cancer is crucial to explore the effective immunotherapies, but the composition of infiltrating T cells in urothelial bladder carcinoma (UBC) remains elusive. Here, single-cell RNA sequencing (scRNA-seq) were performed on total 30,905 T cells derived from peripheral blood, adjacent normal and tumor tissues from two UBC patients. We identified 18 distinct T cell subsets based on molecular profiles and functional properties. Specifically, exhausted T (TEx) cells, exhausted NKT (NKTEx) cells, Ki67+ T cells and B cell-like T (B-T) cells were exclusively enriched in UBC. Additionally, the gene signatures of TEx, NKTEx, Ki67+ T and B-T cells were significantly associated with poor survival in patients with BC and various tumor types. Finally, IKZF3 and TRGC2 are the potential biomarkers of TEx cells. Overall, our study demonstrated an exhausted context of T cells in UBC, which layed a theoretical foundation for the development of effective tumor immunotherapies.

Immune escape mechanisms and immunotherapy of urothelial bladder cancer.

BACKGROUND AND AIM: Urothelial bladder cancer (UBC) is a common malignant tumor of the urogenital system with a high rate of recurrence. Due to the sophisticated and largely unexplored mechanisms of tumorigenesis of UBC, the classical therapeutic approaches including transurethral resection and radical cystectomy combined with chemotherapy have remained unchanged for decades. However, with increasingly in-depth understanding of the microenvironment and the composition of tumor-infiltrating lymphocytes of UBC, novel immunotherapeutic strategies have been developed. Bacillus Calmette-Guerin (BCG) therapy, immune checkpoint blockades, adoptive T cell immunotherapy, dendritic cell (DC) vaccines, etc., have all been intensively investigated as immunotherapies for UBC. This review will discuss the recent progress in immune escape mechanisms and immunotherapy of UBC. METHODS: Based on a comprehensive search of the PubMed and ClinicalTrials.gov database, this review included the literature reporting the immune escape mechanisms of UBC and clinical trials assessing the effect of immunotherapeutic strategies on tumor or immune cells in UBC patients published in English between 1999 and 2020. RESULTS: Immune surveillance, immune balance, and immune escape are the three major processes that occur during UBC tumorigenesis. First, the role of immunosuppressive cells, immunosuppressive molecules, immunosuppressive signaling molecules, and DCs in tumor microenvironment is introduced elaborately in the immune escape mechanisms of UBC section. In addition, recent progress of immunotherapies including BCG, checkpoint inhibitors, cytokines, adoptive T cell immunotherapy, DCs, and macrophages on UBC patients are summarized in detail. Finally, the need to explore the mechanisms, molecular characteristics and immune landscape during UBC tumorigenesis and development of novel and robust immunotherapies for UBC are also proposed and discussed. CONCLUSION: At present, BCG and immune checkpoint blockades have been approved by the US Food and Drug Administration for the treatment of UBC patients and have achieved encouraging therapeutic results, expanding the traditional chemotherapy and surgery-based treatment for UBC. RELEVANCE FOR PATIENTS: Immunotherapy has achieved desirable results in the treatment of UBC, which not only improve the overall survival but also reduce the recurrence rate and the occurrence of treatment-related adverse events of UBC patients. In addition, the indicators to predict the effectiveness and novel therapy strategies, such as combination regimen of checkpoint inhibitor with checkpoint inhibitor or chemotherapy, should be further studied.

Botulinum toxin A improves neurogenic bladder fibrosis by suppressing transforming growth factor ß1 expression in rats.

BACKGROUND: Intradetrusor botulinum toxin A injection is recommended for the treatment of refractory detrusor overactivity (DO) in patients with neurogenic bladder, however, whether it could inhibit neurogenic bladder fibrosis is uncertain. This study aimed to investigate the effect of botulinum toxin A on neurogenic bladder fibrosis and the underlying mechanism. METHODS: Forty eight Female Wistar rats were evenly randomized into 4 groups: Sham, T10 transection, Early and Late groups. The last three groups were subjected to T10 spinal cord transection, while the Sham group was treated with sham surgery. 0.9% saline was injected into the detrusor in the Sham and T10 transection groups simultaneously with the surgery, while 2 U/rat botulinum toxin A was injected into the detrusor simultaneously with the surgery in the Early group and 4 weeks following the surgery in the Late group. Body/bladder weight, cystometric parameters, bladder Hematoxylin-eosin staining were used to evaluate the bladder fibrosis. Western blot and quantitative Real-time PCR were used to evaluate the expression of bladder transforming growth factor ß1. RESULTS: Compared with the T10 transection group, the bladder/body weight was decreased significantly in the Early and Late groups (P<0.05), along with the significant inhibition of non-voiding contraction (NVC) frequency and amplitude (P<0.05), and the significant increase of bladder volume (P<0.05). The detrusor connective tissue percentage (P<0.05) and the expression of transforming growth factor ß1 (P<0.05) also decreased significantly in the Early and Late groups. Those changes were more obviously in the Early group than in the Late group. CONCLUSIONS: Intradetrusor botulinum toxin A injection reduced bladder fibrosis in rats with spinal cord injury (SCI), which was more obviously in the Early group than in the Late group. The mechanisms might be mediated by suppression of transforming growth factor ß1 (TGF-ß1) expression.

The Resonance and the Allium ureteral stents in the treatment of non-malignant refractory ureterostenosis.

BACKGROUND: Refractory non-malignant ureterostenosis is challenging to treat. The experience to treat the stenosis primarily cause by retroperitoneal fibrosis with the Resonance and Allium metallic stent is still limited. We aim to evaluate the efficacy and safety of these two stents and provide alternative treatment options. METHODS: A retrospective study was conducted for patients with non-malignant ureterostenosis and treated with the Resonance and Allium stents from March 2011 to September 2020 in our department. The efficacy was evaluated by the change of serum creatinine, glomerular filtration rate (GFR), the proportion of GFR of the affected side and hydronephrosis grade. The safety was evaluated by postoperative presence of moderate or severe overactive bladder (OAB), recurrent urinary infection, pain, stent displacement, encrustation and re-obstruction. RESULTS: 33 patients were eligible for the study, including 18 cases treated by the Resonance stents and 15 patients treated by the Allium stents. The patients of two groups had similar age and gender proportion. The cause of ureterostenosis was mainly retroperitoneal fibrosis in both groups but the Resonance group had more idiopathic cases. Follow-up time was significantly longer in the Resonance group than the Allium group (36.2 ± 24.0 vs 9.4 ± 5.0 months, p < 0.001). Both groups showed improvement or maintenance of serum creatinine level, GFR, the GFR proportion of the affected side and hydronephrosis grade after treatment. The Resonance group presented significant higher incidence of moderate or severe OAB, recurrent urinary infection and pain, while the Allium group showed significant more cases of re-obstruction. CONCLUSION: Both the Resonance and Allium stent can relieve the non-malignant refractory ureterostenosis effectively. The Resonance stent may cause more irritable symptoms while the Allium stent may have a higher rate of re-obstruction. The long term efficacy and safety of the Allium stent in treating non-malignant refractory ureterostenosis requires further study.

Evaluation of neurogenic bladder outlet obstruction mimicking sphincter bradykinesia in male patients with Parkinson's disease.

BACKGROUND: Lower urinary tract symptoms are one of the most common groups of non-movement symptoms in patients with Parkinson's disease (PD). Storage symptoms are well-acknowledged, but neurogenic voiding dysfunction caused by PD remains a knowledge gap. This study aimed to evaluate the neurogenic bladder outlet obstruction in male patients with PD and its clinical significance. METHODS: Male patients who were diagnosed with PD and underwent urodynamic studies were retrospectively reviewed. The patients with prostate size < 30 ml and bladder outlet obstruction index ≥40 were included in the study. Lower urinary tract symptoms were evaluated by International Prostate Symptom Score (IPSS). Free flowmetry was performed and post void residual (PVR) volume was measured by ultrasound at follow-up. RESULTS: Six patients were included in the final analysis. The mean age was 68.2 and the mean movement symptom duration was 70.7 months. The patients had a mean IPSS of 12.5 and mean PVR volume of 70.8 ml. All patients had slow stream but none of them reported significant voiding difficulty. Urodynamic studies showed the delayed urinary sphincter relaxation and the special trace pattern. After a mean follow-up of 20 months, they had a mean IPSS of 12.5 and mean PVR volume of 73.3 ml. None of them complained of significant voiding difficulty at follow-up. CONCLUSION: The delayed urinary sphincter relaxation is a rare but repeatable phenomenon in male patients with PD. It is unlikely to cause disturbing voiding dysfunction, as reported by the patients, and does not progress prominently during the course of PD. Further studies are needed to investigate the nature of this special type of neurogenic BOO and whether it is peculiar to PD in a larger patient cohort.

Proteomic analysis reveals distinctive protein expression patterns of thrombus in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a type of malignant tumor of the urinary system. The renal vein or vena cava thrombus can be found in a subset of ccRCC patients in whom it leads to worse prognosis. However, the protein expression profile and molecular features of ccRCC thrombus remain largely unclear. Here, a comparative proteomic analysis was performed using the 2D-LC-MS strategy for the thrombus-tumor-normal tissue triples of 15 ccRCC patients. Statistical analysis, GO enrichment analysis, protein-protein interaction network construction, and mRNA-based survival analysis were used to interpret the proteomic data. Three dysregulated proteins, GGT5 (gamma-glutamyl transferase 5), KRT7 (keratin 7) and CFHR1 (complement factor H related 1), were analyzed using western blot (WB) and immunohistochemistry (IHC) to validate the reliability of the proteomic analysis. The result of this analysis revealed 251 dysregulated proteins, which could be divided into 11 clusters depending on the changing trends, among the thrombus, tumor, and normal tissues. Several pathways and regulation networks were found to be associated with the thrombus, and some dysregulated proteins showed potential values for prognosis prediction. WB and IHC results were in accordance with the proteomic results, further validating the reliability of this study. In conclusion, our findings provide an overview of the thrombus at the molecular level as well as valuable information for further pathological studies or research on biomarkers and therapeutic targets.

Chaetocin Abrogates the Self-Renewal of Bladder Cancer Stem Cells via the Suppression of the KMT1A-GATA3-STAT3 Circuit.

Bladder cancer stem cells (BCSCs) have the abilities of self-renewal, differentiation, and metastasis; confer drug resistance; and exhibit high tumorigenicity. We previously identified that the KMT1A-GATA3-STAT3 axis drives the self-renewal of BCSCs. However, the therapeutic effect of targeting KMT1A in BCSCs remains unknown. In this study, we confirmed that the expression of KMT1A was remarkably higher in BCSCs (3-5-fold) than those in bladder cancer non-stem cells or normal bladder epithelial cells. Among the six KMT1A inhibitors, chaetocin significantly suppressed the cell propagation (inhibition ratio: 65%-88%, IC50 = 24.4-32.5 nM), induced apoptosis (2-5-fold), and caused G1 phase cell cycle arrest (68.9 vs 55.5%) of bladder cancer (BC) cells, without influencing normal bladder epithelial cells. More importantly, chaetocin abrogated the self-renewal of BCSCs (inhibition ratio: 80.1%) via the suppression of the KMT1A-GATA3-STAT3 circuit and other stemness-related pathways. Finally, intravesical instillation of chaetocin remarkably inhibited the growth of xenograft tumors (inhibition ratio: 71-82%) and prolonged the survival of tumor-bearing mice (70 vs 53 days). In sum, chaetocin abrogated the stemness maintenance and tumor growth of BCSCs via the suppression of the KMT1A-GATA3-STAT3 circuit. Chaetocin is an effective inhibitor targeting KMT1A in BCSCs and could be a promising therapeutic strategy for BC.

Neurogenic lower urinary tract dysfunction predicts prognosis in patients with multiple system atrophy.

PURPOSE: To evaluate whether neurogenic lower urinary tract dysfunction and urodynamic parameters predict the outcomes of patients with multiple system atrophy (MSA). METHODS: A retrospective study was performed in patients who were diagnosed with MSA and underwent urodynamic studies simultaneously from September 2014 to July 2018. The urodynamic traces were reviewed by urologists. Detrusor contractility was evaluated by the bladder contractility index (BCI) and Schäfer nomogram. Telephone follow-up was conducted in July 2019 to acquire survival data. Clinical and urodynamic parameters were analyzed for survival using Cox regression analysis. RESULTS: Overall, 70 MSA patients were eligible for analysis, and 61 of them underwent urodynamic study within 3 years of initial symptom onset. The parkinsonian subtype of MSA (MSA-P) had a smaller proportion of men as well as longer motor and lower urinary tract symptom durations than the cerebellar subtype (MSA-C). MSA-P also had a lower mean BCI than MSA-C (32.0 ± 27.0 versus 53.6 ± 33.4, p = 0.025). The mean MSA survival time was 5.4 [95% confidence interval (CI) 4.8-6.3] years. Cox regression analysis showed that survival from baseline was correlated only with BCI [hazard ratio (HR) 0.983, 95% CI 0.969-0.997, p = 0.020]. Overall survival was correlated with BCI (HR 0.982, 95% CI 0.966-0.999, p = 0.039) and the presence of urinary incontinence (HR 3.007, 95% CI 0.993-9.220, p = 0.052). CONCLUSION: Detrusor contractility can be a prognostic marker in MSA patients. A high BCI value is a protective factor for survival from baseline and overall survival. The presence of urinary incontinence predicts shortened overall survival.

Candle soot-templated silica nanobiointerface chip for detecting circulating tumour cells from patients with urologic malignancies.

Liquid biopsy, known as fluid biopsy or fluid phase biopsy, is of great clinical significance in cancer diagnosis and treatment monitoring. However, traditional techniques still meet restrictions when aiming for the detection of circulating tumour cells (CTCs) with high efficiency and low cost. Herein, we applied an easily prepared silica nanobiointerface chip for detecting CTCs in prostate cancer (PCa) and clear cell renal cell carcinoma (ccRCC) patients with high efficiency. The silica nanobiointerface chip was fabricated by depositing candle soot on a glass slide, followed by chemical vapour deposition, and then by modifying anti-epithelial cell adhesion molecule (EpCAM) antibody. The silica nanobiointerface chips exhibited excellent abilities to capture PC3 PCa cell lines, with average efficiency of 81.2 ± 1.4%. We demonstrate that the strong topographic interaction between targeted cells and nanostructured surface is critical to enhancing the capture efficiency of CTCs. We further tested peripheral blood samples from 10 preoperative PCa and 7 ccRCC patients. The results show that CTCs from 7 PCa cases and 4 ccRCC cases were successfully detected. We believe that the nanobiointerface chip will provide great potential for the clinical application of CTC.

Data-Independent Acquisition-Based Quantitative Proteomic Analysis Reveals Potential Biomarkers of Kidney Cancer.

PURPOSE: Renal cell carcinoma (RCC) is a malignant and metastatic cancer with 95% mortality, and clear cell RCC (ccRCC) is the most observed among the five major subtypes of RCC. Specific biomarkers that can distinguish cancer tissues from adjacent normal tissues should be developed to diagnose this disease in early stages and conduct a reliable prognostic evaluation. EXPERIMENTAL DESIGN: Data-independent acquisition (DIA) strategy has been widely employed in proteomic analysis because of various advantages, including enhanced protein coverage and reliable data acquisition. In this study, a DIA workflow is constructed on a quadrupole-Orbitrap LC-MS platform to reveal dysregulated proteins between ccRCC and adjacent normal tissues. RESULTS: More than 4000 proteins are identified, 436 of these proteins are dysregulated in ccRCC tissues. Bioinformatic analysis reveals that multiple pathways and Gene Ontology items are strongly associated with ccRCC. The expression levels of L-lactate dehydrogenase A chain, annexin A4, nicotinamide N-methyltransferase, and perilipin-2 examined through RT-qPCR, Western blot, and immunohistochemistry confirm the validity of the proteomic analysis results. CONCLUSIONS AND CLINICAL RELEVANCE: The proposed DIA workflow yields optimum time efficiency and data reliability and provides a good choice for proteomic analysis in biological and clinical studies, and these dysregulated proteins might be potential biomarkers for ccRCC diagnosis.

Epigenomics of clear cell renal cell carcinoma: mechanisms and potential use in molecular pathology.

Clear cell renal cell carcinoma (ccRCC) is one frequent form of urologic malignancy with numerous genetic and epigenetic alterations. This review summarizes the recent major findings of epigenetic alterations including DNA methylation, histone modifications, microRNAs and recently identified long noncoding RNAs in the development and progression of ccRCC. These epigenetic profilings can provide a promising means of prognostication and early diagnosis for patients with ccRCCs. With the developed high-throughput technologies nowadays, the epigenetic analyses will have possible clinical applications in the molecular pathology of ccRCC.