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Neurotrophic receptor tyrosine kinase 3 (NTRK3) has pleiotropic functions: it acts not only as an oncogene in breast and gastric cancers but also as a dependence receptor in tumor suppressor genes in colon cancer and neuroblastomas. However, the role of NTRK3 in upper tract urothelial carcinoma (UTUC) is not well documented. This study investigated the association between NTRK3 expression and outcomes in UTUC patients and validated the results in tests on UTUC cell lines. A total of 118 UTUC cancer tissue samples were examined to evaluate the expression of NTRK3. Survival curves were generated using Kaplan–Meier estimates, and Cox regression models were used for investigating survival outcomes. Higher NTRK3 expression was correlated with worse progression‐free survival, cancer‐specific survival, and overall survival. Moreover, the results of an Ingenuity Pathway Analysis suggested that NTRK3 may interact with the PI3K‐AKT‐mTOR signaling pathway to promote cancer. NTRK3 downregulation in BFTC909 cells through shRNA reduced cellular migration, invasion, and activity in the AKT‐mTOR pathway. Furthermore, the overexpression of NTRK3 in UM‐UC‐14 cells promoted AKT‐mTOR pathway activity, cellular migration, and cell invasion. From these observations, we concluded that NTRK3 may contribute to aggressive behaviors in UTUC by facilitating cell migration and invasion through its interaction with the AKT‐mTOR pathway and the expression of NTRK3 is a potential predictor of clinical outcomes in cases of UTUC. [ABSTRACT FROM AUTHOR]

Background: Upper tract urothelial carcinoma (UTUC) is a rare tumor with extraordinarily different features between Eastern and Western countries. Vascular endothelial growth factor‐A (VEGFA) was originally identified as a secreted signaling protein and regulator of vascular development and cancer progression. In this study, we aimed to elucidate the molecular mechanisms underlying the regulation of VEGFA by microRNA in UTUC. Methods: VEGFA expression was evaluated by immunohistochemistry in 140 human UTUC tissue samples. Next, we assessed the regulatory relationship between VEGFA and miR‐299‐3p by real‐time PCR, western blotting, ELISA and dual‐luciferase reporter assays using two UTUC cell lines. The role of miR‐299‐3p/VEGFA in cell proliferation, motility, invasion, and tube formation was analyzed in vitro. Results: High VEGFA expression was significantly associated with tumor stage, grade, distant metastasis and cancer‐related death and correlated with poor progression‐free and cancer‐specific survival. VEGFA knockdown repressed proliferation, migration, invasion and angiogenesis in UTUC cell lines. miR‐299‐3p significantly reduced VEGFA protein expression and miR‐299‐3p overexpression inhibited VEGFA mRNA and protein expression by directly targeting its 3′‐UTR. Functional studies indicated that VEGFA overexpression reversed the miR‐299‐3p‐mediated suppression of tumor cell proliferation, migration, invasion and angiogenesis. In addition, miR‐299‐3p/VEGFA suppressed cellular functions in UTUC by modulating the expression of P18 and cyclin E2. Conclusions: Our findings suggest that miR‐299‐3p possibly suppresses UTUC cell proliferation, motility, invasion and angiogenesis via VEGFA. VEGFA may act as a prognostic predictor, and both VEGFA and miR‐299‐3p could be potential therapeutic targets for UTUC. [ABSTRACT FROM AUTHOR]

We present a novel idea to construct a solar concentrator with a circular prism array. FRED ray tracing software is used to evaluate our proposed structure in which the incident light rays are deflected by total internal reflection and the optical energy is concentrated and collected at the center. The light rays to be collected travel within the disk once they enter the module, saving the space that is reserved for ray propagation in other concentrators. Simulations for both single-wavelength and broadband light are performed. Our device can be used alone or serve as a secondary concentrator when combined with another solar-energy focusing module. For the proposed concentrator, an optical efficiency of 90% (single wavelength, 0.87 [micro]m) is achieved under normal incidence and with antireflection coating, and a high geometric concentration ratio of 93 is reached. When combined with a Fresnel lens, which is used as a primary concentrator, the overall efficiency and concentration ratio can reach 92% (single wavelength, 0.87 [micro]m) and 837, respectively. OCIS codes: 350.6050, 080.0080.

Upper tract urothelial carcinoma (UTUC) is a rare tumor with an incidence that varies greatly between Eastern and Western countries. Transaldolase 1 (TALDO1) is a rate‐limiting enzyme of the pentose phosphate pathway. In humans, aberrant TALDO1 activity has been implicated in various autoimmune diseases and malignancies; however, the function of TALDO1 in UTUC has not been previously investigated. Here we evaluated the clinical significance of TALDO1 expression in 115 paraffin‐embedded tumor samples from patients with UTUC using immunohistochemistry. Our results demonstrated that there was an association between high TALDO1 expression and advanced stage (P = 0.011), tumor size (P = 0.005), tumor location (P = 0.047), distant metastases (P = 0.023), local recurrence (P = 0.002), and cancer death (P = 0.003). Using univariate and multivariate analyses, we found that chemotherapy was an independent factor for bladder recurrence‐free survival. Late stage (III/IV) and high TALDO1 expression were independent prognostic factors for progression‐free and cancer‐specific survival. In summary, increased TALDO1 expression in UTUC was significantly correlated with late stage, tumor size, tumor location, distant metastases, local recurrence, and cancer death. Therefore, high TALDO1 expression could be a predictor of poor survival in patients with UTUC. Further studies are necessary to investigate the role of TALDO1 in UTUC development. [ABSTRACT FROM AUTHOR]

ADP‐ribosylation factor 6 (ARF6) is a well‐studied protein that is involved in multiple biological functions including cell migration and invasion. The mechanism by which ARF6 regulates the migration and invasion of upper tract urothelial carcinoma (UTUC) is still unknown. MiR‐145‐5p is a tumor suppressor microRNA, which is downregulated in several cancer types. We aimed to elucidate the molecular mechanism underlying the regulation of ARF6 by miR‐145‐5p in UTUC. ARF6 expression was observed to be higher in UTUC tissues than paired adjacent normal tissues. A reverse correlation between ARF6 and miR‐145‐5p was found in UTUC tissues. MiR‐145‐5p inhibited ARF6 expression by directly targeting its 3′‐UTR. The functional studies indicated that ARF6 expression reversed the miR‐145‐5p‐reduced tumor cell migration and invasion. Notably, miR‐145‐5p reduced MMP2, N‐cadherin, FAK and MMP7, and elevated E‐cadherin protein levels in vitro; however, the above effects were reversed by ARF6. Further, the expression of epithelial‐to‐mesenchymal transition (EMT) markers and cell invasion was suppressed by knocking down MMP7 in UTUC cells. These findings suggest that miR‐145‐5p may suppress UTUC cell motility and invasion by targeting ARF6/MMP7 through EMT. [ABSTRACT FROM AUTHOR]

CSN6 is a subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN). CSN is involved in cellular and developmental processes such as signal transduction, transcriptional activation, cell cycle control, and tumorigenesis. CSN6 is highly expressed in several human cancers, including colorectal cancer, and breast cancer. However, no previous research has elaborated on the relationship between CSN6 expression and survival in patients with upper tract urothelial carcinoma (UTUC). Therefore, the purpose of this study is to evaluate the clinical significance of CSN6 in UTUC. CSN6 expression in 89 patients with UTUC enrolled in this study was examined using immunohistochemistry. The associations between CSN6 expression and clinicopathological variables were analyzed. CSN6 expression was significantly correlated with patients with high pathological stage (P =.006), male gender (P =.025), and high serum creatinine levels (P =.014). In univariate and multivariable analysis, high CSN6 expression was associated with a higher bladder recurrence (P =.005) and poor cancer‐specific survival (P =.001) for UTUC. In conclusion, CSN6 expression is a potential biomarker for predicting cancer recurrence and clinical survival in UTUC. Further research is necessary to investigate its role in the progression of UTUC. [ABSTRACT FROM AUTHOR]

Background. Colony-stimulating factor-1 (CSF-1) is a homodimeric glycoprotein. The main role of CSF-1 is as a hematopoietic growth factor that modulates proliferation, differentiation, and survival of macrophages. Moreover, CSF-1 has also been reported to be aberrantly expressed in several human cancers. However, the precise role of CSF-1 in upper tract urothelial carcinomas (UTUC) has not been studied. In this research, we examined the clinical significance of CSF-1 expression in UTUC. Materials and Methods. One hundred twelve cancer tissue samples of UTUC from patients were included in this study, and the other cohort of 35 UTUC were paired cancer-adjacent normal samples. CSF-1 expression was evaluated by immunohistochemistry, and the association of CSF-1 expression with different clinicopathological variables was analyzed. Results. CSF-1 expression was higher in UTUC than in the normal urothelium (P=0.005). The CSF-1 expression was primarily localized in the nucleus and was significantly correlated with tumor size (P=0.04) and patients who had a high stage (P<0.001), distant metastasis (P=0.006), recurrence (P=0.003), and cancer death (P=0.005). High CSF-1 expression was correlated with poor disease-free survival (P=0.008) and cancer-specific survival (P=0.001). Our results also used univariate and multivariable analyses, which found that high CSF-1 expression was an independent predictor of poor disease-free survival (hazard ratio=2.56; P=0.007) and cancer-specific survival (hazard ratio=5.14; P=0.022). Conclusions. Our findings indicate that the expression of CSF-1 is a potential prognostic marker for predicting patient survival and recurrence in UTUC. [ABSTRACT FROM AUTHOR]

Simple Summary: The Derlin-1 protein, encoded by DERL1, is located in the endoplasmic reticulum membrane and is responsible for the unfolded protein response. Derlin-1 has recently drawn lots of attention with regard to cancer pathogenesis. The purpose of this study is to examine its role and molecular mechanism in upper tract urothelial carcinoma (UTUC). The protein levels of Derlin-1 in human UTUC specimens are observed by immunohistochemistry. Derlin-1 overexpression is evidently associated with cancer stage, distant metastasis, recurrence, and poor prognosis in patients with UTUC. In an in vitro study, the knockdown of Derlin-1 represses, while over-expression of Derlin-1 increases migration and invasion of UTUC cells significantly. We identify the microRNA-375-3p (miR-375-3p) as one of the potential candidate microRNAs and then examine the relationship between Derlin-1 and miR-375-3p. The dual-luciferase reporter assay confirms that miR-375-3p directly targets Derlin-1. Furthermore, we reveal that miR-375-3p modulate Derlin-1 and epithelial–mesenchymal transition (EMT) marker protein levels. However, the above effects are reversed by the restoration of Derlin-1. Our study clarifies that miR-375-3p represses invasion and migration by directly targeting Derlin-1 and regulating the expression of EMT-associated proteins in UTUC cells, suggesting Derlin-1 may act as a useful predictor of prognosis and that both Derlin-1 and miR-375-3p could be potential therapeutic targets in UTUC. Little is known regarding the molecular characterization of upper tract urothelial carcinoma (UTUC). Novel therapeutic targets and prognostic predictors are imminent. In the present study, we aim to examine the oncogenic function and molecular mechanism of Derlin-1 in UTUC. Derlin-1 overexpression is significantly associated with poor prognosis in patients with UTUC. In vitro, knockdown or over-expression of Derlin-1 markedly regulated UTUC cell invasion and migration. We further discovered miR-375-3p suppresses cell invasion and migration by inversely regulating Derlin-1 and blocking EMT in UTUC cells. Taking this together, miR-375-3p functions as a tumor suppressive microRNA by directly targeting Derlin-1 and blocking epithelial–mesenchymal transition (EMT) in UTUC. [ABSTRACT FROM AUTHOR]

Upper tract urothelial carcinoma (UTUC) is an aggressive malignancy with characteristics of high metastasis and poor prognosis. There are some particularly different features of UTUC between the Asian and Western countries. Double-strand break repair protein MRE11 is a component of the MRN complex that is involved in the DNA repair pathway. Emerging studies have focused on the role of MRE11 in human malignancies with conflicting results. We aimed to establish the relationship between MRE11 expression and the oncological outcome of UTUC. This study retrospectively reviewed 150 patients who underwent radical nephroureterectomy with pathologically confirmed UTUC. Pathologic slides were reviewed, and clinical parameters were collected. An immunohistochemical study was performed, and the cytoplasmic and nuclear-staining results of UTUC were recorded. The expression of MRE11 was analyzed to identify correlations with various clinicopathological parameters, metastasis-free survival, and cancer-specific survival (CSS). MRE11 expression was significantly correlated with patients with a high pathologic stage ( P =0.001), perineural invasion ( P =0.015), and tumor necrosis ( P =0.034). Upon univariate analysis, a high MRE11 expression was associated with poor metastasis-free survival ( P =0.014, 95% CI 1.18, 4.38) and poor CSS ( P =0.001, 95% CI 2.45, 27.75). Upon multivariable analysis, a high MRE11 expression was associated with poor CSS ( P =0.019, 95% CI 1.28, 15.65). In summary, MRE11 expression could serve as a potential predictor of prognosis in patients with UTUC., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ubiquitin-mediated protein degradation has been reported to be involved in regulating the activity of oncoproteins and tumor suppressors. Dysfunction or dysregulation of the ubiquitin-proteasome system may induce tumorigenesis. Deubiquitinase ubiquitin-specific protease 2a (USP2a) has been reported to regulate cell growth or death and is involved in the pathogenesis of various diseases, including cancers. However, the role of USP2a in upper tract urothelial carcinoma (UTUC) has not been investigated yet. The goal of this study was to evaluate the clinical significance of USP2a expression in UTUC., Materials and Methods: A total of 110 UTUC cases were included in this study. USP2a expression level was evaluated through immunohistochemistry staining, and the correlation of USP2a expression level with both clinical and pathologic variables was analyzed., Results: High USP2a expression level was observed in 48 (43.6%) cancer specimens. USP2a expression level was significantly correlated with tumor stage (P=0.001), grade (P=0.033), and tumor recurrence (P=0.008). High USP2a expression level was correlated with poor disease-free survival (P=0.005) and cancer-specific survival (P<0.001). In addition, high USP2a expression level was an independent predictor of poor disease-free survival (hazard ratio=2.31; P=0.007) and cancer-specific survival (hazard ratio=5.49; P=0.009)., Conclusions: This study indicated that USP2a protein expression level may be a potential biomarker for predicting UTUC patient survival. Further prospective studies are needed to investigate the role of USP2a in UTUC progression., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Signal transducer and activator of transcription proteins (STATs) play important roles in gene regulation, cell proliferation, and cell differentiation. We aimed to establish the relationship between phosphorylated STAT3 (p-Ser-STAT3) expression and the prognosis of upper tract urothelial carcinoma (UTUC). Methods: This study retrospectively reviewed 100 patients with pathologically confirmed UTUC at Kaohsiung Medical University Hospital. We quantified the expression of p-Ser-STAT3 in cancer cells by immunohistochemistry, and determined the clinicopathological significance of p-Ser-STAT3 expression and prognostic outcomes in patients with UTUC. Results: High p-Ser-STAT3 expression was detected in 52% of UTUC patients. High p-Ser-STAT3 expression was associated with poor recurrence-free survival ( p = 0.018) and overall survival ( p = 0.026). In advanced cancer samples (stage T3/T4), p-Ser-STAT3 expression is the only independent prognostic factor for recurrence-free survival (hazard ratio = 5.91, p = 0.01) and cancer-specific survival (hazard ratio = 8.83, p = 0.039). Conclusions: The expression of p-Ser-STAT3 can be a potential prognostic marker for cancer recurrence and survival in UTUC, especially in advanced stage cases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: Hypoxia has been shown to facilitate tumor progression. Hypoxia-regulated microRNA-210 (miR-210) may play an important role in carcinogenesis and tumor progression. In this study, we evaluated the clinical significance of miR-210 expression in upper tract urothelial carcinoma (UTUC)., Methods: Eighty-three UTUC patients participated in this study. All of them provided cancer tissue samples and 50 of them provided non-cancerous urothelium samples. Clinicopathologic data were collected by reviewing medical records. The expression of miR-210 and hypoxia-inducible factor-1α (HIF-1α) was determined by quantitative real-time polymerase chain reaction. The relationship between clinicopathologic variables and the expression of miR-210 and HIF-1α was analyzed statistically., Results: MiR-210 is overexpressed in UTUC compared to non-cancerous urothelium ( p < 0.001); it is also upregulated in high-stage and high-grade tumors ( p = 0.020 and 0.049, respectively). HIF-1α is overexpressed in UTUC and correlates positively with miR-210 expression ( r = 0.442, p = 0.001)., Conclusion: Both miR-210 and HIF-1α are involved in promoting UTUC carcinogenesis. MiR-210 is also correlated with tumor progression. Further studies are needed to clarify the underlying mechanism., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Resistance to chemotherapeutic drugs is one of the major challenges in the treatment of cancer. A better understanding of how resistance arises and what molecular alterations correlate with resistance is the key to developing novel effective therapeutic strategies. To investigate the underlying mechanisms of gemcitabine (Gem) resistance and provide possible therapeutic options, three Gem-resistant urothelial carcinoma sublines were established (NG0.6, NG0.8, and NG1.0). These cells were cross-resistant to arabinofuranosyl cytidine and cisplatin, but sensitive to 5-fluorouracil. The resistant cells expressed lower values of [hENT1 × dCK/RRM1 × RRM2] mRNA ratio. Two adenosine triphosphate-binding cassette proteins ABCD1 as well as multidrug resistance protein 1 were elevated. Moreover, cyclin D1, cyclin-dependent kinases 2 and 4 were upregulated, whereas extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase (MAPK) activity were repressed significantly. Administration of p38 MAPK inhibitor significantly reduced the Gem sensitivity in NTUB1 cells, whereas that of an extracellular signal-regulated kinase MAPK inhibitor did not. Furthermore, the Gem-resistant sublines also exhibited higher migration ability. Forced expression of p38 MAPK impaired the cell migration activity and augmented Gem sensitivity in NG1.0 cells. Taken together, these results demonstrate that complex mechanisms were merged in acquiring Gem resistance and provide information that can be important for developing therapeutic targets for treating Gem-resistant tumors., (Copyright © 2014. Published by Elsevier B.V.)