Endoscopic Cryoablation Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma.

BACKGROUND AND OBJECTIVE: Cryoablation is a traditional antitumor therapy with good prospects for development. The efficacy of endoscopic management as a kidney-sparing surgery for high-risk upper tract urothelial carcinoma (UTUC) remains controversial. Our aim was to evaluate the impact of endoscopic cryoablation (ECA) versus radical nephroureterectomy (RNU) on survival outcomes, renal function, and complications. METHODS: We retrospectively analyzed data for 116 patients with newly diagnosed high-risk UTUC who underwent either ECA (n = 13) or RNU (n = 103) from March 25, 2019 to December 8, 2021. Propensity score matching (1:4) using the nearest neighbor method was performed before analysis. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), intravesical recurrence-free survival (RFS), the change in renal function, and treatment-emergent adverse events (TEAEs). KEY FINDINGS AND LIMITATIONS: At median follow-up of 28.2 mo for the ECA group and 27.6 mo for the RNU group, 2-yr OS (82% vs 84%), PFS (73% vs 71%), and intravesical RFS (81% vs 83%) rates after matching did not significantly differ. A decline in renal function was observed after RNU, but not after ECA. Five (41.7%) patients in the ECA group reported six TEAEs, and 17 patients (35.4%) in the RNU group reported 20 TEAEs. CONCLUSIONS AND CLINICAL IMPLICATIONS: In comparison to RNU, ECA for UTUC resulted in noninferior oncological outcomes and superior preservation of renal function. PATIENT SUMMARY: Our study suggests that a treatment called endoscopic cryoablation for high-risk cancer in the upper urinary tract can help in preserving kidney function, with similar survival outcomes to those after more extensive surgery. This option can be considered for selected patients with a strong preference for kidney preservation.

Toward morphologically relevant extracellular matrix: nanofiber-hydrogel composites for tumor cell culture.

The natural extracellular matrix (ECM) consists of a continuous integrated fibrin network and a negatively charged proteoglycan-based matrix. In this work, we report a novel three-dimensional nanofiber hydrogel composite that mimics the natural ECM structure, exhibiting both degradability and mechanical characteristics comparable to that of tumor tissue. The embedded nanofiber improves the hydrogel mechanical properties, and varying the fiber density can match the elastic modulus of different tumor tissues (1.51-10.77 kPa). The degradability of the scaffold gives sufficient space for tumor cells to secrete and remodel the ECM. The expression levels of cancer stem cell markers confirmed the development of aggressive and metastatic phenotypes of prostate cancer cells in the 3D scaffold. Similar results were obtained in terms of anticancer resistance of prostate cancer cells in 3D scaffolds showing stem cell-like properties, suggesting that the current bionic 3D scaffold tumor model has broad potential in the development of effective targeted agents.

Unbalanced regularized optimal mass transport with applications to fluid flows in the brain.

As a generalization of the optimal mass transport (OMT) approach of Benamou and Brenier's, the regularized optimal mass transport (rOMT) formulates a transport problem from an initial mass configuration to another with the optimality defined by the total kinetic energy, but subject to an advection-diffusion constraint equation. Both rOMT and the Benamou and Brenier's formulation require the total initial and final masses to be equal; mass is preserved during the entire transport process. However, for many applications, e.g., in dynamic image tracking, this constraint is rarely if ever satisfied. Therefore, we propose to employ an unbalanced version of rOMT to remove this constraint together with a detailed numerical solution procedure and applications to analyzing fluid flows in the brain.

Pathogen inhibition and indication by gelatin nonwoven mats with incorporation of polyphenol derivatives.

There is a need for non-pharmaceutical intervention methods that can prevent and indicate the risk of airborne disease spread. In this study, we developed a nonwoven mat based on the polyphenol gallic acid, which can inhibit pathogens growth and also indicate pathogen levels in the surrounding environment. Using nuclear magnetic resonance, Fourier-transform infrared spectroscopy, and high-performance liquid chromatography, we characterized this novel gelatin-based nonwoven mat and investigated the mechanism governing its ability to indicate pathogen levels. We demonstrated that the incorporation of gallic acid serves a vital role in indicating the presence of bacteria, causing the nonwoven mat to change in color from white to brown. We have proposed a plausible mechanism for this color change behavior based on a reaction of gallic acid with components excreted by bacteria, including glutamate, valine, and leucine. The concentrations of these components reflect the bacterial counts, enabling a real-time indication of pathogen levels in the surrounding air. In summary, the nonwoven mat presented herein can serve as an excellent antibacterial agent and as an indicator of nearby bacteria for fabricating personal protection equipment like filtration mask.

Methionine orchestrates the metabolism vulnerability in cisplatin resistant bladder cancer microenvironment.

Metabolism vulnerability of cisplatin resistance in BCa cells remains to be discovered, which we applied integrated multi-omics analysis to elucidate the metabolism related regulation mechanism in bladder cancer (BCa) microenvironment. Integrated multi-omics analysis of metabolomics and proteomics revealed that MAT2A regulated methionine metabolism contributes to cisplatin resistance in BCa cells. We further validated MAT2A and cancer stem cell markers were up-regulated and circARHGAP10 was down-regulated through the regulation of MAT2A protein stability in cisplatin resistant BCa cells. circARHGAP10 formed a complex with MAT2A and TRIM25 to accelerate the degradation of MAT2A through ubiquitin-proteasome pathway. Knockdown of MAT2A through overexpression of circARHGAP10 and restriction of methionine up-take was sufficient to overcome cisplatin resistance in vivo in immuno-deficiency model but not in immuno-competent model. Tumor-infiltrating CD8+ T cells characterized an exhausted phenotype in tumors with low methionine. High expression of SLC7A6 in BCa negatively correlated with expression of CD8. Synergistic inhibition of MAT2A and SLC7A6 could overcome cisplatin resistance in immuno-competent model in vivo. Cisplatin resistant BCa cells rely on methionine for survival and stem cell renewal. circARHGAP10/TRIM25/MAT2A regulation pathway plays an important role in cisplatin resistant BCa cells while circARHGAP10 and SLC7A6 should be evaluated as one of the therapeutic target of cisplatin resistant BCa.

Carbon nitride nanotubes anchored with Cu(I) triggers peracetic acid activation with visible light for removal of antibiotic contaminants: Probing mechanisms of non-radical pathways and identifying active sites.

The peracetic acid (PAA)-activation process has attracted much attention in wastewater treatment. However, the low electron efficiency at the interface between heterogeneous catalysts and PAA has affected its practical application. For this study, we developed a carbon nitride hollow-nanotube catalysts with dispersed Cu(I) sites (Cu(I)-TCN) for the photocatalytic activation of PAA for antibiotics degradation. The obtained Cu(I)-TCN catalyst demonstrated an enhanced capacity for visible light harvesting along with increased charge transfer rates. Specifically, the developed Cu(I)-TCN/visible light/PAA system was able to completely remove antibiotics within 20 min, with a kinetic constant that was 25 times higher than a Cu(I)-TCN/visible light system, and 83 times higher than Cu(I)-TCN/PAA systems. Scavenging experiment and electron paramagnetic resonance (EPR) indicated that singlet oxygen was dominant reactive specie for sulfisoxazole (SIZ) removal. Besides, electrochemical tests and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy verified that the electron transfer efficiency of PAA activation was promoted due to the formation of inner-sphere interactions between PAA and Cu(I)-TCN, resulting in the quick removal of antibiotics. Further, after exposure to visible light, the Cu(I)-TCN excited photogenerated electrons which supplemented the electrons consumed in the reaction and drove the valence cycle of Cu ions. Overall, this research offered novel insights into the non-radical pathway for heterogeneous visible light-driven advanced oxidation processes and their potential for practical wastewater remediation.

The rs9402373 polymorphism of CTGF gene may not be related to inflammatory bowel disease susceptibility in Chinese population based on ARMS-PCR genotyping.

Background: It has been confirmed that the connective tissue growth factor (CTGF) gene rs9402373 polymorphism is associated with fibrotic and inflammatory diseases. However, studies on the relationship between polymorphisms in CTGF rs9402373 and inflammatory bowel disease (IBD) remain rare. Therefore, the aim of this study was to assess the association between the CTGF rs9402373 polymorphism and IBD susceptibility in a Chinese population. Materials and methods: To establish an amplification refractory mutation system (ARMS) PCR technology for genotyping CTGF gene rs9402373 polymorphism, we designed two specific forward primers for the wild and mutant types by placing the allele-specific nucleotide at the penultimate position of the '3' end of the primer. Then, 10 samples were randomly selected and rechecked by DNA sequencing to verify the accuracy of this method. We further used the established method to detect specimens collected from 191 patients with inflammatory bowel disease, including 120 Crohn's disease (CD) and 71 ulcerative colitis (UC), and 110 healthy Han Chinese individuals. Results: We successfully established the ARMS-PCR method for genotyping, and the results of 10 randomly selected samples were completely consistent with DNA sequencing. The rs9402373 G allele frequencies in UC and CD cases were 38.03% and 43.75%, respectively, and in controls, they were 41.82%. No significant difference was found in minor allele frequencies between the UC or CD and control groups (P = 0.473, P = 0.676). Genotype analysis demonstrated that there was no relationship between CTGF rs9402373 polymorphism and the risk of IBD regardless of the inheritance mode (P > 0.05). Conclusions: In this preliminary study, we successfully developed a simple, efficient and cost-effective method for genotyping CTGF rs9402373 polymorphism. The polymorphism may not be related to IBD susceptibility in the Chinese Han population.

Cryoablation inhibits the recurrence and progression of bladder cancer by enhancing tumour-specific immunity.

BACKGROUND: Recurrence and metastasis of bladder cancer are major factors affecting patient prognosis. Endoscopic cryoablation achieved a better clinical outcome among clinical patients and could be synergistic with ICIs. Thus, this study aimed to evaluate the immunological mechanism of cryoablation for bladder cancer to reveal the therapeutic mechanism. METHODS: We systematically reviewed the clinical prognosis of patients underwent cryoablation at Huashan Hospital in these first-in-human studies (ChiCTR-INR-17013060). Murine models were constructed to explore cryoablation-induced tumour-specific immunity, which was further confirmed by primary bladder tumour organoids and autologous lymphocytes cocultured system. RESULTS: Cryoablation improved progression-free survival and recurrence-free survival respectively. Assessment of murine models after cryoablation confirmed microenvironment remodelling and tumour-specific T cells expansion. Enhanced antitumour effects were found after coculture of organoids with autologous lymphocytes collected from post-cryoablation. We also demonstrated cryoablation-induced tumour elimination required IFNGR expression on tumour cells. In addition, a long-lasting antitumour memory response is achieved by cryoablation and could be enhanced after combination with ICIs. CONCLUSIONS: This study revealed endoscopic cryoablation is an efficient and safe therapy for bladder tumour treatment. The tumour-specific immune responses induced by cryoablation could reduce tumour recurrence and metastasis.

Continuous positive airway pressure increases CSF flow and glymphatic transport.

Respiration can positively influence cerebrospinal fluid (CSF) flow in the brain, yet its effects on central nervous system (CNS) fluid homeostasis, including waste clearance function via glymphatic and meningeal lymphatic systems, remain unclear. Here, we investigated the effect of supporting respiratory function via continuous positive airway pressure (CPAP) on glymphatic-lymphatic function in spontaneously breathing anesthetized rodents. To do this, we used a systems approach combining engineering, MRI, computational fluid dynamics analysis, and physiological testing. We first designed a nasal CPAP device for use in the rat and demonstrated that it functioned similarly to clinical devices, as evidenced by its ability to open the upper airway, augment end-expiratory lung volume, and improve arterial oxygenation. We further showed that CPAP increased CSF flow speed at the skull base and augmented glymphatic transport regionally. The CPAP-induced augmented CSF flow speed was associated with an increase in intracranial pressure (ICP), including the ICP waveform pulse amplitude. We suggest that the augmented pulse amplitude with CPAP underlies the increase in CSF bulk flow and glymphatic transport. Our results provide insights into the functional crosstalk at the pulmonary-CSF interface and suggest that CPAP might have therapeutic benefit for sustaining glymphatic-lymphatic function.

Discovery of novel glucosinolates inhibiting advanced glycation end products: Virtual screening and molecular dynamic simulation.

Protein glycation can result in the formation of advanced glycation end products (AGEs), which pose a potential health risk due to their association with diabetic complications. Natural products are a source of drugs discovery and the search for potential natural inhibitors of AGEs is of great significance. Glucosinolates (GSLs) mainly from cruciferous plants have potential antioxidant, anti-inflammatory, and anti-glycation activities. In this study, the inhibitory activity of GSLs on bovine serum albumin (BSA) along with its mechanism was investigated by virtual screening and various computational simulation techniques. Virtual screening revealed that 174 GSLs were screened using Maestro based on the glide score and 89% of the compounds were found to have potential anti-glycation ability with the docking scores less than -5 kcal/mol. Molecular docking showed that the top 10 GSLs were bound to the IIA structural domain of BSA. Among them, glucohesperin (1) and 2-hydroxyethyl glucosinolate (2) had the lowest docking scores of -9.428 and -9.333 kcal/mol, respectively, reflecting their good binding affinity. Molecular dynamics simulations of 1 (ΔG = -43.46 kcal/mol) and 2 (ΔG = -43.71 kcal/mol) revealed that the complexes of these two compounds with proteins had good stability. Further binding site analysis suggested that the mechanism of inhibition of protein glycation by these two active ingredients might be through competitive hydrogen bonding to maintain the structural integrity of the protein, thus inhibiting glycation reaction. Moreover, the ADMET values and CYP450 metabolism prediction data were within the recommended values. Therefore, it can be concluded that 1 and 2 may act as potential anti-glycation agents.

Prevalence of tumour-infiltrating CD103+ cells identifies therapeutic-sensitive prostate cancer with poor clinical outcome.

BACKGROUND: The clinical significance and immune correlation of CD103+ cells in prostate cancer (PCa) remain explored. METHODS: In total, 1080 patients with PCa underwent radical prostatectomy from three cohorts were enrolled for retrospective analysis. Tumour microarrays were constructed and fresh tumour samples were analysed by flow cytometry. RESULTS: High CD103+ cell infiltration correlated with reduced biochemical recurrence (BCR)-free survival in PCa. Adjuvant hormone therapy (HT) prolonged the BCR-free survival for high-risk node-negative diseases with CD103+ cell abundance. CD103+ cell infiltration correlated with less cytotoxic expression and increased infiltration of CD8+ and CD4+ T cells, M1 macrophages and mast cells in PCa. Intratumoral CD8+ T cell was the predominant source of CD103, and the CD103+ subset of CD8+ T cells was featured with high IL-10, PD-1 and CTLA-4 expression. Tumour-infiltrating CD103+ CD8+ T cells exerted anti-tumour function when treated with HT ex vivo. DISCUSSION: CD103+ cell infiltration predicted BCR-free survival and response to adjuvant HT in PCa. CD103+ cell infiltration correlated with an enriched but immune-evasive immune landscape. The study supported a model that CD103 expression conferred negative prognostic impact and immunosuppressive function to tumour-infiltrating CD8+ T cells, while the CD103+ CD8+ T cells exhibited a powerful anti-tumour immunity with response to HT.

Design, synthesis and antibacterial evaluation of a novel class of tetrahydrobenzothiophene derivatives.

In this study, a new series of tetrahydrobenzothiophene derivatives have been designed. Newly designed molecules have been synthesized through a medicinal chemistry route, and their characterization was done by using NMR and HR-MS techniques. Biological evaluation of the synthesized compounds has been done on Gram-negative and Gram-positive bacteria. The marketed antibiotics such as ciprofloxacin and gentamicin were used as controls. The in vitro evaluation results have shown that most of the targeted compounds exhibit good potency in inhibiting the growth of bacteria, including E. coli (MIC: 0.64-19.92 µM), P. aeruginosa (MIC: 0.72-45.30 µM), Salmonella (MIC: 0.54-90.58 µM) and S. aureus (MIC: 1.11-99.92 µM). In particular, compound 3b showed excellent activity with an MIC value of 1.11 µM against E. coli, 1.00 µM against P. aeruginosa, 0.54 µM against Salmonella, and 1.11 µM against S. aureus. From the results, a promising lead compound was identified for future development.

The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus.

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.

CircDHRS3 inhibits prostate cancer cell proliferation and metastasis through the circDHRS3/miR-421/MEIS2 axis.

Prostate cancer is the most prevalent type of cancer among men worldwide. The importance of circular RNA (circRNA) in prostate cancer and its connection to malignancy has been steadily recognized. circRNA expression was obtained by circRNA sequencing of prostate cancer. circRNA and its function were further analysed. The results were verified by qRT-PCR, RIP assay, FISH, RNA pulldown, WB, CCK-8, colony formation assay and wound-healing assay. BALB/c Nude mice were used for xenograft hosts. Low expression of circDHRS3 was assessed in prostate cancer. Overexpression of circDHRS3 inhibited prostate cancer growth and migration in vitro. Additionally, miR-421 was shown to be the downstream target of circDHRS3, as shown by fluorescence in situ hybridization and dual-luciferase experiments. The rescue assay results for the PC3 and Du145 cell lines demonstrated that circDHRS3 inhibits prostate cancer cell lines' ability to proliferate and metastasize by modulating MEIS2 expression through the circDHRS3/miR-421/MEIS2 axis. In vivo investigations confirmed that the overexpression of circDHRS3 could inhibit both the lung and bone metastasis of prostate cancer cells. circDHRS3 has the potential to become a biomarker and a targeted therapeutic site for prostate cancer, particularly in the malignant stage. Our study indicates that circDHRS3 inhibits prostate cancer cell proliferation and metastasis through the circDHRS3/miR-421/MEIS2 axis.

KNTC1 as a putative tumor oncogene in pancreatic cancer.

PURPOSE: Recent studies have demonstrated that kinetochore-associated protein 1 (KNTC1) plays a significant role in the carcinogenesis of numerous types of cancer. This study aimed to explore the role and possible mechanisms of KNTC1 in the development of pancreatic cancer. METHODS AND RESULTS: We analyzed differentially expressed genes by RNA sequencing in three paired pancreatic cancer and para-cancerous tissue samples and found that the expression of KNTC1 was significantly upregulated in pancreatic cancer. A Cancer and Tumor Gene Map pan-analysis showed that high expression of KNTC1 was related to poor prognosis in 9499 tumor samples. With immunohistochemical staining, we found that the high expression of KNTC1 in pancreatic cancer was related to pathological grade and clinical prognosis. Similarly, RT-PCR results indicated that the expression of KNTC1 was higher in three groups of pancreatic cancer cell lines (BxPC-3, PANC-1, and SW1990) than in normal pancreatic ductal cells. We introduced lentivirus-mediated shRNA targeting KNTC1 into PANC-1 and SW1990 cells and found that KNTC1 knockdown significantly decreased cell growth and increased cell apoptosis compared to the control group cells. Bioinformatic analysis of the cell expression profile revealed that differential genes were mainly enriched in the cell cycle, mitosis, and STAT3 signaling pathways, and co-immunoprecipitation confirmed an interaction between KNTC1 and cell division cycle associated 8. CONCLUSIONS: KNTC1 could be linked to the pathophysiology of pancreatic cancer and may be an early diagnostic marker of cervical precancerous lesions.

Blood lipids, lipid-regulatory medications, and risk of bladder cancer: a Mendelian randomization study.

Background: The influences of blood lipids and lipid-regulatory medications on the risk of bladder cancer have long been suspected, and previous findings remain controversial. We aimed to assess the causality between blood lipids or lipid-regulatory medications and bladder cancer susceptibility by means of a comprehensive Mendelian Randomization (MR) study. Methods: Genetic proxies from genome-wide association studies (GWAS) of four blood lipid traits and lipid-lowering variants in genes encoding the targets of lipid-regulatory medications were employed. The largest ever GWAS data of blood lipids and bladder cancer involving up to 440,546 and 205,771 individuals of European ancestry were extracted from UK Biobank and FinnGen Project Round 6, respectively. A two-sample bidirectional MR study was performed using the inverse variance weighted as the main method. The heterogeneity, horizontal pleiotropy, MR Steiger, and leave-one-out analyses were also conducted as sensitivity tests. Results: There was indicative evidence that genetically predicted low-density lipoprotein cholesterol (LDL-C) affected bladder cancer susceptibility based on 146 single nucleotide polymorphisms (SNPs) with an odds ratio (OR) of 0.776 (95% confidence interval [CI] = 0.625-0.965, p = 0.022). However, this result became non-significant after two SNPs that possibly drove the effect were removed as demonstrated by leave-one-out analysis. The reversed MR analysis suggested that bladder cancer could not affect serum lipid levels. No causal relationship was found between the lipid-lowering effect of lipid-regulatory medications (fibrates, probucol, statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, and evinacumab) and the risk of bladder cancer. No heterogeneity or pleiotropy was found (all p > 0.05). Conclusion: This MR study revealed for the first time, using the most recent and comprehensive GWAS data to date, that genetically predicted total cholesterol (TC) and the lipid-lowering effect of lipid-regulatory medications had no causal association with bladder cancer susceptibility. We also verified claims from early studies that low-density lipoprotein cholesterol (HDL-C), LDL-C, and triglyceride (TG) are not related to bladder cancer susceptibility either. The current study indicated that lipid metabolism may not be as important in the tumorigenesis of bladder cancer as previously believed.