A Selective-Tumor-Penetrating Strategy via Unidirectional Direct Transfer for Intravesical Therapy of Bladder Cancer.

A selective tumor-penetrating strategy generally exploits tumor-targeted ligands to modify drugs so that the conjugate preferentially enters tumors and subsequently undergoes transcellular transport to penetrate tumors. However, this process shields ligands from their corresponding targets on the cell surface, possibly inducing an off-target effect during drug penetration at the tumor-normal interface. Herein, we first describe a selective tumor-penetrating drug (R11-phalloidin conjugates) for intravesical therapy of bladder cancer. The intravesical conjugates rapidly translocated across the mucus layer, specifically bound to tumors, and infiltrated throughout the tumor via direct intercellular transfer. Notably, direct transfer from normal cells to tumor cells was unidirectional because the pathways required for direct transfer, termed F-actin-rich tunneling nanotubes, were more unidirectionally extended from normal cells to tumor cells. Moreover, the intravesical conjugates displayed strong anticancer activity and well-tolerated biosafety in murine orthotopic bladder tumor models. Our study demonstrated the potential of a selective tumor-penetrating conjugate for effective intravesical anticancer therapy.

Divergent synthesis of carbamates and N-methyl carbamates from dimethyl carbonate and nitroarenes with Mo(CO)6 as a multiple promoter.

Dialkyl carbonates are green and versatile reagents that can be used in alkylation and alkoxycarbonylation reactions. Herein, we disclosed a reductive methoxycarbonylation of aromatic nitro compounds with dimethyl carbonate for the construction of diverse carbamates and N-methyl carbamates. Using Mo(CO)6 as a multiple promoter, different nitroarenes were smoothly transformed into the corresponding carbamates in yields between 27 and 94% using DMC as both solvent and reagent. It is worth noting that the choice of different bases allowed the desired products to be controlled: K3PO4 favoured the formation of carbamates as the primary product, whereas DBU facilitated the formation of N-methyl carbamates as the main product.

Comparison of acupuncture and moxibustion related non-surgical therapies for women with stress urinary incontinence: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Stress urinary incontinence (SUI) significantly impacts women's health and imposes substantial mental and socio-economic burdens. Acupuncture and moxibustion, either alone or in combination with other non-surgical therapies, are recognized as effective treatments for SUI. This study aimed to assess the efficacy of various treatments for women with SUI using network meta-analysis (NMA). METHOD: We systematically searched databases up until June 30, 2022, to identify relevant randomized controlled trials (RCTs) focusing on SUI in women. Subsequently, the quality of the included studies was assessed. NMA was performed using STATA 14.0 software. RESULTS: A total of 31 RCTs involving 2922 participants were included in the analysis. A total of 18 treatment plans were identified. The treatment plan consisting of Moxibustion + PFMT + EB demonstrated the most significant reduction in ICIQ-UI-SF. Due to lack of consistency across studies, a NMA was not performed for the outcomes of effectiveness and the 1 h pad test. CONCLUSIONS: The combined intervention of Moxibustion + PFMT + EB appears to be the most effective in reducing patients' reported symptoms and improving their quality of life. However, due to the limitations of the included studies, further high-quality RCTs are necessary to reinforce the current evidence.

The value of ATAD3A as a potential biomarker for bladder cancer.

BACKGROUND: Bladder cancer (BCa) is a highly malignant tumor, and if left untreated, it can develop severe hematuria and tumor metastasis, thereby endangering the patient's life. The purpose of this paper was to detect the expression of ATAD3A in BCa and research the relationship between ATAD3A and pathological features of bladder cancer and the prognosis of patients. METHODS: First, the expression of ATAD3A in BCa and normal bladder tissues was analyzed based on the UALCAN and Oncomine public databases. Second, 491 cases of surgically resected bladder cancer specimens and 110 cases of normal adjacent tissues were immunohistochemically stained. The expression of ATAD3A was quantified, and the value and prognosis of ATAD3A as a biomarker of BCa were evaluated. RESULTS: The expression of ATAD3A in bladder cancer tissues was higher than that in normal bladder mucosa. High expression of ATAD3A was correlated with patient age, tumor size, number of tumors, distant metastasis, lymph node metastasis, lymphovascular invasion, and TNM stage (p < 0.05). Overexpression of ATAD3A is closely related to cancer patient survival. The mean survival time of bladder cancer patients with high ATAD3A expression was shorter than those with low ATAD3A levels. According to the relative comparing result, the high ATAD3A expression herald reduced overall survival in BCa patients. CONCLUSIONS: The abnormal overexpression of ATAD3A may be related to the initiation and progress of bladder cancer. The upregulation of ATAD3A can be used as an effective indicator to diagnose bladder cancer and predict tumor progression. Furthermore, the combination of information from public databases and the results of clinical sample analysis can help us better understand the mechanism of action of molecular oncogenes in bladder cancer.

Advances in Enzyme-responsive Supramolecular In situ Self-assembled Peptide for Drug Delivery.

Because of low immunogenicity, ease of modification, and inherent biosafety, peptides have been well recognized as vehicles to deliver therapeutic agents to targeted regions with improved pharmacokinetic characteristics. Enzyme-responsive self-assembled peptides (ERSAPs) show superiority over their naive forms due to their enhanced targeting efficacy and long-retention property. In this review, we have summarized recent advances in the therapeutic application of ERSAPs, mainly focusing on their self-therapeutic properties and potential as vehicles to deliver different drugs.

Application Process of Coating Agent and the Coating Effect Evaluation Based on Molecular Dynamics.

In the field of energy-containing materials, the modification of nanoaluminum powders has been widely studied. However, in modified experimental design, the lack of theoretical prediction usually leads to long experimental cycles and high resource consumption. To this end, this study evaluated the process and effect of dopamine (PDA)- and polytetrafluoroethylene (PTFE)-modified nanoaluminum powders based on molecular dynamics (MD). Through the calculation of the coating stability, compatibility, and oxygen barrier performance of the modified material, the modification process and effect were explored from a microscopic point of view. The results showed that the adsorption of PDA on the nanoaluminum was the most stable, and the binding energy was 463.03 kcal·mol-1. PDA and PTFE with different ratios are compatible systems at 350 K, and the best compatibility ratio is 10 wt % PTFE/90 wt % PDA. The 90 wt % PTFE/10 wt % PDA bilayer model has the best barrier performance for oxygen molecules in a wide temperature range. The calculated results of the coating stability agree with the experiments, and it is pointed out that it is feasible to evaluate the modification effect in advance by MD simulation. In addition, the simulation results concluded that the double-layered PDA and PTFE have better oxygen barrier properties. Compatibility can be used only to determine whether phase separation occurs between mixtures and is not directly related to the dense mixing of polymers and the barrier properties of small gas molecules. The simulation provided in this article can predict the experimental results and provide theoretical guidance for coating modification experiments in order to reduce unnecessary experiments, shorten the experimental cycle, and reduce costs.

The cause analysis of benign uretero-ileal anastomotic stricture after radical cystectomy and urinary diversion.

Background: Benign uretero-ileal anastomotic stricture (UIAS) is a major complication following radical cystectomy (RC) and ileal orthotopic bladder substitution, and it can occur in combination with other complications. But risk factors for patients with UIAS have not been well described. Material and methods: We retrospectively reviewed 198 patients treated with RC for bladder cancer from 2014 to 2019 at the Zhejiang Provincial People's Hospital. Patient demographic and clinical variables were examined to determine the risk factors associated with UIAS by univariate and multivariate logistic regression analysis. Results: A total of 180 patients into the group standards and in all 360 uretero-ileal anastomoses. Among the above cases, 22 patients developed UIAS, including 10 cases of left UIAS, nine cases of right UIAS, and three cases of bilateral UIAS. There was no difference in demographic, operative, or perioperative variables between patients with and without UIAS. In a multivariate analysis, after adjusting for gender, age, surgical methods, and underlying diseases, intraoperative or postoperative blood transfusion (HR = 0.144, P <0.01), postoperative urinary tract infection (HR = 3.624, P <0.01), and extracorporeal bladder anastomosis (HR = 3.395, P = 0.02) significantly increased the risk of UIAS. Conclusions: In our experience, intraoperative or postoperative blood transfusion, postoperative urinary tract infection, and extracorporeal neobladder anastomoses increased the risk of UIAS after radical cystectomy and ileal orthotopic bladder substitution surgery. Further studies with larger samples are necessary to validate this result.

R11 modified tumor cell membrane nanovesicle-camouflaged nanoparticles with enhanced targeting and mucus-penetrating efficiency for intravesical chemotherapy for bladder cancer.

Intravesical chemotherapy is generally used in the clinic for treating bladder cancer (BCa), but its efficacy is limited due to the permeation barrier and side effects caused by the off-targeting of normal urothelial cells. In this study, BCa cell-derived membrane nanovesicles were used as drug carriers, and their homologous tumor-targeting capacity was utilized. A BCa-targeting hendeca-arginine peptide was functionalized onto the nanovesicles to impart a mucus-penetrating ability and thus overcome the permeation barrier. The tumor-targeting and mucus-penetrating nanovesicles were stable in urine, were highly permeable to the glycosaminoglycan layer, and specifically targeted BCa. The vesicles were internalized through caveolin-mediated endocytosis, were transported to nonlysosome-localized intracellular regions, and efficiently infiltrated bladder tumor spheroids. In in vivo intravesical chemotherapy, the nanovesicles achieved chemo-resection in murine orthotopic BCa models. This BCa-targeting and mucus-penetrating drug delivery system may be promising for the intravesical chemotherapy of BCa.

Combined Self-Assembled Hendeca-Arginine Nanocarriers for Effective Targeted Gene Delivery to Bladder Cancer.

Introduction: Bladder cancer (BCa) is among the most prevalent cancers worldwide. However, the effectiveness of intravesical therapy for BCa is limited due to the short dwell time and the presence of the permeation barrier. Methods: Nanocomplexes were self-assembled between DNA and hendeca-arginine peptide (R11). Stepwise intravesical instillation of R11 and the generated nanocomplexes significantly enhanced the targeting capacity and penetration efficiency in BCa therapy. The involved mechanism of cellular uptake and penetration of the nanocomplexes was determined. The therapeutic effect of the nanocomplexes was verified preclinically in murine orthotopic BCa models. Results: Nanocomplexes exhibited the best BCa targeting efficiency at a nitrogen-to-phosphate (NP) ratio of 5 but showed a lack of stability during cellular uptake. The method of stepwise intravesical instillation not only increased the stability and target specificity of the DNA component but also caused the delivered DNA to more effectively penetrate into the glycosaminoglycan layer and plasma membrane. The method promotes the accumulation of the delivered DNA in the clathrin-independent endocytosis pathway, directs the intracellular trafficking of the delivered DNA to nonlysosome-localized regions, and enables the intercellular transport of the delivered DNA via a direct transfer mechanism. In preclinical trials, our stepwise method was shown to remarkably enhance the targeting and penetration efficiency of DNA in murine orthotopic BCa models. Conclusion: With this method, a stepwise intravesical instillation of self-assembled nanocomplexes, which are generated from hendeca-arginine peptides, was achieved; thus, this method offers an effective strategy to deliver DNA to target and penetrate BCa cells during gene therapy and warrants further development for future intravesical gene therapy in the clinical context.

Microalgal-bacterial consortia for efficient wastewater treatment: Optimization using response surface methodology.

The performance of microalgal-bacterial consortia in wastewater treatment and biomass production needs to be further optimized to meet increasingly stringent effluent standards and operating costs. Besides, due to uncontrollability of ambient conditions, it is generally believed that operating conditions (e.g., aeration) respond to ambient conditions (e.g., illumination). Therefore, response surface methodology (RSM) based on Box-Behnken design was used in this study to analyze the removal of chemical oxygen demand (COD), NH3 -N and TP, and algal biomass of the microalgal-bacterial consortia within 48 h. The results showed that under medium illumination intensity (5000 lx), photoperiod (12:12) and aeration rate (0.55 L min -1 ), the removal efficiency of COD, NH3 -N and TP was the highest, and the maximal biomass growth rates were 95.43%, 95.49%, 89.42% and 99.63%, respectively. However, as the limited critical removal requirements of TP, the effluent standards can only be achieved within the small illumination intensity and photoperiod available range, even under medium aeration conditions, which means that under fixed operating conditions, the effective operation range will be very limited. In addition, based on RSM and differential equation analysis, the further study indicated that the effective treatment range can be greatly expanded within aeration responding, which meets the discharge standard of pollutants in China. PRACTITIONER POINTS: Illumination was responded by aeration for optimizing performance of microalgal-bacterial consortium for wastewater treatment and biomass productivity. The strategy of optimization was based on response surface methodology. The maximum effect on wastewater treatment and biomass productivity was based on partial differential equations and quadratic inhomogeneous equations. Limited to critical TP-removal requirements, effluent standards can meet only in the small-usable range of illumination, under medium aeration.

Boosting the capacitive property of nickel cobalt aluminum layered double hydroxide in neutral electrolyte.

Layered double hydroxide (LDH) has shown great potential for energy storage due to their high theoretical specific capacitance, relatively low cost and eco-friendliness. LDH, however, always works in alkali aqueous electrolyte for supercapacitors, which brings serious environmental pollution. In this work, a reduced graphite oxide/Fe(CN)63-- nickel cobalt aluminum LDH (RGO/Fe(CN)63--LDH) composite has been prepared via ion-exchange reaction using RGO/LDH as precursor. RGO/Fe(CN)63--LDH electrode provides a specific capacitance of 221 F g-1 in a wide potential window of -1 ~ 0.8 V vs. SCE in Na2SO4 aqueous electrolyte, and which is much higher than that of LDH electrode (3.56 F g-1). Owing to the wide potential window of RGO/Fe(CN)63--LDH electrode, a symmetrical solid supercapacitor device (RGO/Fe(CN)63--LDH//RGO/Fe(CN)63--LDH) with a high voltage of 2.0 V can deliver a high specific energy of 25.2 Wh kg-1 at a specific power of 250 W kg-1, and a capacitance retention of 75% after galvanostatic charging/discharging at 5 A g-1 for 5000 times. This work supplies enlightenment for boosting the capacitive performance of LDHs in neutral electrolyte.