PC4 promotes bladder cancer progression and stemness by directly interacting with Sp1 to transcriptionally activate the Wnt5a/ß-catenin pathway.

Bladder cancer is a common malignancy with a poor prognosis worldwide. Positive cofactor 4 (PC4) is widely reported to promote malignant phenotypes in various tumors. Nonetheless, the biological function and mechanism of PC4 in bladder cancer remain unclear. Here, for the first time, we report that PC4 is elevated in bladder cancer and is associated with patient survival. Moreover, PC4 deficiency obviously inhibited bladder cancer cell proliferation and metastasis by reducing the expression of genes related to cancer stemness (CD44, CD47, KLF4 and c-Myc). Through RNA-seq and experimental verification, we found that activation of the Wnt5a/ß-catenin pathway is involved in the malignant function of PC4. Mechanistically, PC4 directly interacts with Sp1 to promote Wnt5a transcription. Thus, our study furthers our understanding of the role of PC4 in cancer stemness regulation and provides a promising strategy for bladder cancer therapy.

Association between kidney stones and poor sleep factors in U.S. adults.

The purpose of our study is to examine the correlation between sleep factors and the prevalence of kidney stones in US adults. A total of 34,679 participants from the National Health and Nutrition Examination Survey 2007 to 2018 were included in the analyses. Sleep data collection included: presleep factors (difficulty falling asleep, sleep onset latency), intra-sleep factors (risk index of obstructive sleep apnea, restless leg syndrome, difficulty maintaining sleep), post-sleep factors (daytime sleepiness, non-restorative sleep), sleep schedule and duration, and sleep quality. Logistic regression models were used to analyze the correlation between sleep factors and the prevalence of kidney stones. Among the 34,679 participants, the overall incidence of kidney stones was 9.3%. The presence of presleep factors (difficulty falling asleep [odds ratios [OR], 1.680; 95% CI, 1.310-2.150], prolonged sleep onset latency [OR, 1.320; 95% CI, 1.020-1.700]), intra-sleep factors (higher risk index of obstructive sleep apnea [OR, 1.750; 95% CI, 1.500-2.050], restless leg syndrome [OR, 1.520; 95% CI, 1.150-1.990], difficulty maintaining sleep [OR, 1.430; 95% CI, 1.130-1.810]), post-sleep factors (daytime sleepiness [OR, 1.430; 95% CI, 1.220-1.680], non-restorative sleep [OR, 1.400; 95% CI, 1.110-1.760]), short sleep duration (OR, 1.190; 95% CI, 1.080-1.310), mediate sleep quality (OR, 1.140; 95% CI, 1.020-1.290), and poor sleep quality (OR, 1.500; 95% CI, 1.310-1.720) are linked to the occurrence of kidney stones. However, short sleep onset latency, bedtime and wake-up time were not significantly associated with the prevalence of kidney stones. These findings showed positive associations between higher kidney stone prevalence and poor sleep factors.

A Molecular Dynamics Analysis of the Thickness and Adhesion Characteristics of the Quasi-Liquid Layer at the Asphalt-Ice Interface.

The quasi-liquid layer (QLL), a microstructure located between ice and an adhering substrate, is critical in generating capillary pressure, which in turn influences ice adhesion behavior. This study employed molecular dynamics (MD) methods to obtain QLL thickness and utilized these measurements to estimate the adhesive strength between ice and asphalt. The research involved constructing an ice-QLL-asphalt MD model, encompassing four asphalt types and five temperature ranges from 250 K to 270 K. The QLL thickness was determined for various asphalts and temperatures using the tetrahedral order parameter gradient. Additionally, capillary pressure was calculated based on the QLL thickness and other geometric parameters obtained from the MD analysis. These findings were then compared with ice adhesion strength data acquired from pull-off tests. The results indicate that QLL thickness varies with different asphalt types and increases with temperature. At a constant temperature, the QLL thickness decreases in the order of the basal plane, primary prism plane, and secondary prism plane. Furthermore, the adhesion strength of the QLL diminishes as the temperature rises, attributed to the disruption of hydrogen bonds at lower temperatures. The greater the polarity of the asphalt's interface molecules, the stronger the adhesion strength and binding free energy. The MD simulations of the asphalt-ice interface offer insights into the atomic-scale adhesive properties of this interface, contributing to the enhancement in QLL property prediction and calibration at larger scales.

Hyaluronic Acid-Conjugated Fluorescent Probe-Shielded Polydopamine Nanomedicines for Targeted Imaging and Chemotherapy of Bladder Cancer.

Bladder cancer is one of the most common malignancies in the urinary system, with high risk of recurrence and progression. However, the difficulty in detecting small tumor lesions and the lack of selectivity of intravesical treatment seriously affect the prognosis of patients with bladder cancer. In the present work, a nanoparticle-based delivery system with tumor targeting, high biocompatibility, simple preparation, and the ability to synergize imaging and therapy was fabricated. Specifically, this nanosystem consisted of the core of doxorubicin (DOX)-loaded polydopamine nanoparticles (PDD NPs) and the shell of hyaluronic acid (HA)-conjugated IR780 (HA-IR780). The HA-IR780-covered PDD NPs (HR-PDD NPs) demonstrated tumor targeting and visualization both in vitro and in vivo with properties of promoted cancer cell endocytosis and lysosomal escape, efficiently delivering drugs to the target site and exerting a killing effect on tumor cells. Encouragingly, intravesical instillation of HR-PDD NPs improved drug retention in the bladder and promoted its accumulation in tumor tissue, resulting in better tumor proliferation inhibition and apoptosis in an orthotopic bladder cancer model in rats. This study provides a promising strategy for the diagnosis and therapy of bladder cancer.

Intravesical IR-780 instillation prevents radiation cystitis by protecting urothelial integrity.

PURPOSE: To explore an efficient preventive strategy for radiation cystitis. METHODS: We instilled IR-780 into the bladders of rats 1 h before bladder irradiation, and its bio-distribution was observed at different times. Bladders were then examined for pathogenic alterations and inflammation levels by day 3 and week 12 postirradiation, and the functional characteristics of the bladder were tested via cystometry by week 12. Human uroepithelial sv-huc-1 cells were used to determine the effect of IR-780 on cell viability, regardless of irradiation. We measured the intracellular levels of oxidative stress, DNA damage, apoptosis proportion, and the expression of antioxidant proteases and apoptotic caspases in IR-780 pretreated cells after radiation. RESULTS: IR-780 is localized in the urothelium after intravesical instillation in vivo. Ionizing radiation could induce acute impairment of the bladder urothelium and inflammation in the bladder on day 3. Fibrosis of the irradiated bladder progressed and eventually affected voiding function at 12 weeks. Treatment with IR-780 before irradiation ameliorated these changes. In vitro, IR-780 protected against cell viability and apoptosis of sv-huc-1 cells after irradiation. Additionally, IR-780 may assist in eliminating reactive oxygen species and repairing irradiation-induced DNA damage. CONCLUSION: Our data indicate that IR-780 can be used before irradiation to prevent acute urinary mucosal injury and late bladder dysfunction. Moreover, early urothelial impairment plays a significant role in radiation cystitis development.

Sulfhydryl functionalized hyaluronic acid hydrogels attenuate cyclophosphamide-induced bladder injury.

Clinical management of cyclophosphamide (CYP) results in numerous side effects including hemorrhagic cystitis (HC), which is characterized by inflammation and oxidative stress damage. Intravesical hyaluronic acid (HA) supplementation, a therapeutic method to restore barrier function of bladder, avoid the stimulation of metabolic toxicants on bladder and reduce inflammatory response, has shown good results in acute or chronic bladder diseases. However, there are unmet medical needs for the treatment of HC to temporarily restore bladder barrier and reduce inflammation. Herein, sulfhydryl functionalized HA (HA-SH) and dimethyl sulfoxide (DMSO) were used to prepared a hydrogel system for optimizing the treatment of HC. We systematically evaluated the physicochemical of hydrogels and their roles in a rat model of CYP-induced HC. The prepared hydrogels exhibited outstanding gel forming properties, injectability, and biosafety. Swelling and retention studies showed that hydrogels were stable and could prolong the residence time of HA in the bladder. Histopathology and vascular permeability studies indicated that the hydrogels significantly attenuated bladder injury caused by CYP administration. Moreover, the hydrogels also showed excellent anti-inflammation and anti-oxidation properties. In conclusion, these data suggest that intravesical instillation of HA-SH/DMSO hydrogels reduces CYP-induced bladder toxicity and this work provides a new strategy for the prevention and early treatment of HC.

Synergistically Enhanced Mucoadhesive and Penetrable Polypeptide Nanogel for Efficient Drug Delivery to Orthotopic Bladder Cancer.

Intravesical chemotherapy has been recommended after the gold standard of transurethral resection of the bladder tumor to prevent bladder cancer (BC) from local recurrence in the clinic. However, due to rapid urine excretion and barrier protection of the bladder wall, the clinical performances of chemotherapeutic drugs are severely compromised. In the present work, a smart positively charged disulfide-crosslinked nanogel of oligoarginine-poly(ethylene glycol)-poly(L-phenylalanine-co-L-cystine) (R9-PEG-P(LP-co-LC)) was prepared to prolong the retention period and enhance the penetration capability of chemotherapeutic agent toward the bladder wall. PEG significantly improved the aqueous dispersibility of the 10-hydroxycamptothecin (HCPT)-loaded R9-PEG-P(LP-co-LC) (i.e., R9NG/HCPT) and enhanced the mucoadhesive capability by the nonspecific interaction between PEG chain and the bladder mucosa accompanied with the electrostatic interaction between the cationic R9 and negatively charged bladder mucosa. Besides, R9, as a cell-penetrating peptide, efficiently penetrated through the cell membrane and delivered carried cargo. The disulfide bond endowed the selective release behavior of HCPT triggered by the intracellular reductive microenvironment. As an advanced chemotherapeutic nanoformulation, the smart R9NG/HCPT demonstrated superior cytotoxicity against human BC 5637 cells in vitro and remarkably enhanced tumor suppression activity toward orthotopic BC models of mouse and rat in vivo, indicating its great potential in the clinical intravesical BC chemotherapy.

Preparation and Characterization of Chitosan Nanoparticles for Chemotherapy of Melanoma Through Enhancing Tumor Penetration.

The poor solubility and permeability of most chemotherapeutic drugs lead to unsatisfactory bioavailability combined with insufficient drug concentration. In this study, positively charged nanoparticles based on chitosan were developed and synthesized to enhance tumor penetration capability of 10-Hydroxycamptothecin (HCPT) in order to improve the chemotherapeutic effect of melanoma. The HCPT encapsulated nanoparticles were noted as NPs/HCPT. NPs/HCPT was characterized by dynamic light scattering and zeta potential measurements. In addition, cell uptake, in vitro cytotoxicity, apoptosis and in vivo antitumor activity of NPs/HCPT were further investigated. The average diameter of NPs/HCPT was approximately 114.6 ± 4.1 nm. The viability of murine melanoma cell lines (B16F10 and B16F1) was significantly decreased due to interaction with NPs/HCPT. Moreover, NPs/HCPT significantly inhibited the progression of tumors. These investigations implied that cationic NPs/HCPT could be potentially applied as a promising drug delivery nanosystem.

Intravesical Hydrogels as Drug Reservoirs.

The complex environment in the bladder weakens the efficacy of intravesical therapy. Hydrogel-based drug delivery systems are poised to revolutionize the delivery of therapeutic agents to bladder lesion sites. This forum article highlights the prospective applications of hydrogels as drug reservoirs in treating chronic bladder diseases.

Targeted multifunctional nanomaterials with MRI, chemotherapy and photothermal therapy for the diagnosis and treatment of bladder cancer.

Bladder cancer is a common urinary tract tumor in clinic, and its morbidity and mortality are always high. Surgical treatment is operator dependent, residual tumor cells often lead to tumor recurrence, and chemotherapy after surgery causes high side effects. So, it is urgent to develop new methods for the theranostics of bladder cancer. Among them, functional nanomaterials have shown good application in tumor theranostics, but they are rarely used in bladder cancer. In our work, we demonstrate the fabrication of folate-modified vincristine-loaded polydopamine-coated Fe3O4 superparticles (Fe3O4@PDA-VCR-FA SPs), and applied them in the theranostics of bladder cancer. The PDA shell not only improves the colloidal stability and biocompatibility, but also enhances the photothermal effect and prolongs the blood circulation half-life. The half-life of Fe3O4@PDA-VCR-FA SPs in blood is calculated as 2.83 h, and the tumor retention rate is 5.96 %ID g-1, these data are significantly higher than those before folic acid modification. The superparamagnetism of Fe3O4 and loading of vincristine endow Fe3O4@PDA-VCR-FA SPs with magnetic resonance imaging and chemotherapy capabilities. Further by employing NIR laser-triggered photothermal therapy, bladder tumors were ablated completely, and no recurrence was observed. Blood and histological tests of the major organs confirm that Fe3O4@PDA-VCR-FA SPs show good biosafety.

Ureteral inflammatory myofibroblastic tumor: A case report and literature review.

RATIONALE: Inflammatory myofibroblastic tumor (IMT) is a rare soft-tissue neoplasm which has been described in a variety of locations. In the urogenital system, IMT predominantly occurs in the bladder and the kidney. IMT arising from the ureter is exceedingly rare and has been sporadically reported before. PATIENT CONCERNS: We reported an extremely exceptional case of IMT arising from the ureteral submucosa in a 54-year-old man. The patient was hospitalized with the main complaint of intermittent and moderate left abdominal pain for 2 months. DIAGNOSES AND INTERVENTIONS: Computed tomography scan revealed a nearly circular mass in the left upper ureter. Ureteroscopy showed that the ureteral lumen mucosa was smooth. However, the upper ureter was compressed and narrow. Renal dynamic imaging was performed and the measured glomerular filtration rate was 46.98 mL/min (right renal) and 9.77 mL/min (left renal), respectively. A retroperitoneoscopic radical nephroureterectomy was performed. The histopathologic examination revealed that the soft-tissue neoplasm was mainly composed of myofibroblastic spindle cells proliferation with mixed inflammatory infiltrate, containing lymphocytes, neutrophils, and eosinophils. On immunohistochemical staining, the tumor was positive for smooth muscle actin and Ki-67 (<1%+), indicating a confirmed diagnosis of ureteral IMT. OUTCOMES: The patient recovered well with no occurrence of complications. At 3-year follow-up, there was no radiologic evidence of tumor recurrence or metastasis and the man was well. LESSONS: Ureteral IMT is extremely rare and often asymptomatic, resulting in delayed diagnosis. Radiologic evidences may be suggestive of the diagnosis of IMT. However, it is necessary to make an accurate diagnosis in terms of histopathologic assessment. Complete lesion excision is the best therapeutic approach with rare recurrences and excellent survival.

Polylactide-Cholesterol Stereocomplex Micelle Encapsulating Chemotherapeutic Agent for Improved Antitumor Efficacy and Safety.

For efficient therapy, optimized polymer micelle drug delivery systems require stability during circulation, appropriate diameters for targeting, and controlled drug release at the lesion site. To enhance the stability, adjust the sizes, and improve the selectivity of drug release of micelles from polylactides and polypeptides, stereocomplex interaction has been introduced. Herein, the cholesterol (CHOL)-enhanced doxorubicin (DOX)-loaded poly(D-lactide)-based micelle (CDM/DOX), poly(L-lactide)-based micelle (CLM/DOX), and stereocomplex micelle (SCM/DOX) from the equimolar mixture of the enantiomeric 4-armed poly(ethylene glycol)-polylactide copolymers were reported to enhance tumor cell uptake and control drug release for treatment of cervical carcinoma. The introduction of hydrophobic CHOL further upregulated the stability, drug-loading capability, and cell uptake of micelles. All these DOX-loaded micelles showed appropriate sizes of ∼100 nm for the enhanced permeability and retention (EPR) effect. Compared to CDM/DOX and CLM/DOX, SCM/DOX exhibited the highest cell uptake and the most efficient antitumor efficacy in vitro. For U14 cervical carcinoma mouse model, all of the DOX-loaded micelles, especially SCM/DOX, effectively inhibited the progression of cervical carcinoma, as demonstrated by nearly stagnant tumor growth and increased apoptosis and necrosis areas within tumor tissue. Furthermore, these DOX-loaded micelles effectively alleviated the systemic toxicity of DOX. All the above results suggest that the DOX-loaded micelles, especially SCM/DOX, are an ideal drug delivery system for combating cervical carcinoma.

Tropomyosin-1 promotes cancer cell apoptosis via the p53-mediated mitochondrial pathway in renal cell carcinoma.

Tropomyosin-1 (TPM1), a widely expressed actin-binding protein, is downregulated in many tumors and associated with cancer progression. A previous study from our group suggested that TPM1 could be involved in renal cell carcinoma (RCC) apoptosis, but the mechanisms and details remained unknown. The present study aimed to further examine the proapoptotic effects of TPM1 and investigate the underlying mechanisms in RCC cell lines. Results from cell viability, DAPI staining and apoptosis assays demonstrated that TPM1 upregulation inhibited cell proliferation and promoted cell apoptosis in both 786-O and ACHN RCC cell lines. However, TPM1 knockdown in the two RCC cell lines did not result in the opposite effects on cell proliferation or cell apoptosis. Comet assay and western blotting results demonstrated that TPM1 overexpression induced DNA damage and decreased the expression levels of the antiapoptotic factor BCL2 apoptosis regulator, while increasing the expression levels of the proapoptotic factors BCL2 associated X, Caspase-3 and p53 in 786-O and ACHN cells. The present findings suggest that TPM1 overexpression in RCC cell lines can induce tumor cell apoptosis via the p53-mediated mitochondrial pathway. Further studies are needed to fully elucidate the potential of TPM1 as a candidate for RCC targeted therapy in the future.

Urological complications after radical hysterectomy with postoperative radiotherapy and radiotherapy alone for cervical cancer.

Radiotherapy is a reliable method to cure cervical cancer patients, but it could cause serious urological complications after the treatment due to the anatomical location of the cervix. The main purpose of this retrospective analysis is to study the incidence, latency, and therapeutic efficacy of urological complications caused by radical hysterectomy with postoperative radiotherapy or radiotherapy alone in patients with cervical cancer.A retrospective analysis was conducted on patients with cervical cancer who received radical hysterectomy with postoperative radiotherapy or radiotherapy alone at the First Hospital of Jilin University between January 2010 and May 2016. The urological complications were confirmed by clinical manifestation, ultrasound, computed tomography (CT), nuclear scintigraphy, and assessment of renal function. All the patients with urological complications received conventional treatment, including conservative, electrosurgery, ureteral stents, nephrectomy, and neoplasty. The onset time of radiation injury symptoms was confirmed according to the medical history and follow-up. The surveillance for the therapeutic effects for these complications was accomplished by cystoscopy, imaging, and laboratory assessment.The overall rate of urological complications after treatment was 3.26%, comprising 2.12% ureteral obstruction, 0.98% radiocystitis, and 0.16% vesicovaginal fistula. The incidence of ureteral obstruction in patients treated with radical hysterectomy with postoperative radiotherapy and radiotherapy alone was not statistically significant (2.18% vs 1.59%, P > .05). The median onset time of radiocystitis and ureteral obstruction was 10 months (0-75 months) and 12 months (2-66.3 months), respectively. The onset time of vesicovaginal fistula was 3.5 months. After the appropriate treatment, the majority of the complications were under control.The incidence of urological complications is acceptable. There was no statistical difference in the risk between patients treated with radical hysterectomy with postoperative radiotherapy and radiotherapy alone. The latency period between radiotherapy and the manifestation of urological complications may be relatively long. So it is crucial to underline long-term follow-up after radiotherapy. The majority of urological complications were alleviated after symptomatic treatment and the patients with cervical cancer achieved long-term remissions or cures.