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OBJECTIVE: This in vitro study aimed to evaluate the flexural strength (FS) and translucency parameter (TP) of resin nanoceramics (RNCs) with barium silicate for additive manufacturing. MATERIALS AND METHODS: An RNC slurry was prepared by mixing a barium silicate filler and resin monomer. For the FS tests, specimens with three filler contents (0, 50, and 63 wt%) were designed according to ISO6872 for dental ceramics and ISO10477 for dental polymers. These specimens were then formed into discs with thicknesses of 1 and 2 mm for TP measurement. RESULTS: In the specimens prepared according to ISO6872, the FS increased significantly depending on the filler content. However, in the case of ISO10477, there was no significant difference between the FSs of the specimens with 0 and 50 wt% filler contents. The increase in thickness affected translucency, and the lowest translucency was obtained at a filler content of 63 wt%. The filler distribution was dense in the specimen with 63 wt% filler and uniform but relatively sparse in the specimen with 50 wt% filler. More voids were observed in the specimen with 63 wt% filler. The thickness and filler content of the specimen affected its TP. The TP of the specimen with 63 wt% filler was similar to that of human enamel. CONCLUSION: The FS was significantly higher at a filler content of 63 wt%. The lowest translucency was obtained at a filler content of 63 wt% for all tested thicknesses. CLINICAL SIGNIFICANCE: Increasing the filler content was advantageous for the mechanical properties of the RNCs. A high filler content led to low translucency in the RNCs. Therefore, the esthetics of human teeth can be reproduced if layering according to the filler content is performed in areas where esthetic characteristics are required.
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Porcelana Dental , Resistencia Flexional , Humanos , Bario , Ensayo de Materiales , Silicatos , Propiedades de Superficie , CerámicaRESUMEN
Correction for 'Interfacial engineering of a Mo/Hf0.3Zr0.7O2/Si capacitor using the direct scavenging effect of a thin Ti layer' by Se Hyun Kim et al., Chem. Commun., 2021, 57, 12452-12455, https://doi.org/10.1039/D1CC04966F.
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Over the last few decades, the research on ferroelectric memories has been limited due to their dimensional scalability and incompatibility with complementary metal-oxide-semiconductor (CMOS) technology. The discovery of ferroelectricity in fluorite-structured oxides revived interest in the research on ferroelectric memories, by inducing nanoscale nonvolatility in state-of-the-art gate insulators by minute doping and thermal treatment. The potential of this approach has been demonstrated by the fabrication of sub-30 nm electronic devices. Nonetheless, to realize practical applications, various technical limitations, such as insufficient reliability including endurance, retention, and imprint, as well as large device-to-device-variation, require urgent solutions. Furthermore, such limitations should be considered based on targeting devices as well as applications. Various types of ferroelectric memories including ferroelectric random-access-memory, ferroelectric field-effect-transistor, and ferroelectric tunnel junction should be considered for classical nonvolatile memories as well as emerging neuromorphic computing and processing-in-memory. Therefore, from the viewpoint of materials science, this review covers the recent research focusing on ferroelectric memories from the history of conventional approaches to future prospects.
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An antiferroelectric Mo/Hf0.3Zr0.7O2/SIOx/Si capacitor was engineered using the direct scavenging effect of a sputtered Ti sacrificial layer. Charge trapping could be mitigated with the oxidized TiO2 layer, and the endurance could be enhanced beyond 109 cycles, which is higher than that of the gate stack of ferroelectric field-effect-transistors by 3-4 orders of magnitude.
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BACKGROUND: Prostate cancer in African American (AA) men has a poor prognosis. This study aimed to identify potential genetic risk factors for prostate cancer in AA men. METHODS: We used prostate cancer tissue from 61 patients who underwent radical prostatectomy. We compared somatic gene expression in Caucasian (CA) and AA men using RNA sequencing. RESULTS: By comparing the RNA-seq data obtained from prostate cancer tissue between AA and CA men, this study showed a significant difference in expression levels of 45 genes. Pathway analysis of 45 genes using Kyoto Encyclopedia of Genes and Genomesenrichment analysis revealed a neuroactive ligand-receptor interaction signal. In addition, the results of the Ingenuity Pathway Analysis showed pathways involved sphingosine-1-phosphate signaling. Furthermore, validating 45 genes in the The Cancer Genome Atlas (TCGA) Provisional cohort, cholinergic receptor muscarinic 3 expression level was significantly lower in AA than in CA men, and the results showed a significantly higher rate of biochemical recurrence in patients with low expression. CONCLUSIONS: We identified genetic differences of clinically localized prostate cancer in AAs and CAs by RNA sequencing.
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INTRODUCTION: Neuroendocrine differentiation is partly caused by antiandrogen therapy and exhibits an androgen receptor-independent growth mechanism. We hypothesized that the expression of transcription factor 4, an inducer of neuroendocrine differentiation, in circulating tumor cells is related to drug resistance in castration-resistant prostate cancer. CASE PRESENTATION: We evaluate the messenger ribonucleic acid expression of transcription factor 4 in circulating tumor cells from 17 patients with castration-resistant prostate cancer and compared these levels between patients receiving antiandrogen therapies and those who were resistant to antiandrogen therapies and receiving chemotherapies. The expression of transcription factor 4 in circulating tumor cells was significantly higher among patients receiving chemotherapies. CONCLUSION: This study shows that transcription factor 4 is higher in the group of patients who were judged by their physicians to need chemotherapy treatment.
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Although second-line antiandrogen therapy (SAT) is the standard of care in men with castration-resistant prostate cancer (CRPC), resistance inevitably occurs. One major proposed mechanism of resistance to SAT involves the emergence of androgen receptor (AR) splice variant-7, AR-V7. Recently, we developed MTX-23 using the principle of proteolysis targeting chimera (PROTAC) to target both AR-V7 and AR-full length (AR-FL). MTX-23 has been designed to simultaneously bind AR's DNA binding domain (DBD) and the Von Hippel-Lindau (VHL) E3 ubiquitin ligase. Immunoblots demonstrated that MTX-23's degradation concentration 50% (DC50) for AR-V7 and AR-FL was 0.37 and 2 µmol/L, respectively. Further studies revealed that MTX-23 inhibited prostate cancer cellular proliferation and increased apoptosis only in androgen-responsive prostate cancer cells. The antiproliferative effect of MTX-23 was partially reversed when either AR-V7 or AR-FL was overexpressed and was completely abrogated when both were overexpressed. To assess the potential therapeutic value of MTX-23, we next generated 12 human prostate cancer cell lines that are resistant to the four FDA-approved SAT agents-abiraterone, enzalutamide, apalutamide, and darolutamide. When resistant cells were treated with MTX-23, decreased cellular proliferation and reduced tumor growth were observed both in vitro and in mice. These results collectively suggest that MTX-23 is a novel PROTAC small molecule that may be effective against SAT-resistant CRPC by degrading both AR-V7 and AR-FL.
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Antagonistas de Andrógenos/uso terapéutico , Isoformas de Proteínas/metabolismo , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Animales , Apoptosis , Humanos , Masculino , Ratones , TransfecciónRESUMEN
In this study, the effects of the CXC chemokine/receptor axis on lymph node and distant metastases of prostate cancer (PC) were analyzed. Further, mRNA expression data of metastatic PC were extracted from the Stand Up To Cancer-Prostate Cancer Foundation Dream Team database and differences between metastatic sites were comprehensively analyzed. CXC chemokine/receptor mRNA expression data of primary PC included in the Cancer Genome Atlas were used to analyze the relationships of CXC chemokine/receptor expression with lymph node metastasis and cancer progression. In metastatic PC, significantly higher expression of ELR+ CXC chemokines/receptors and significantly lower expression of ELR- CXC chemokines/receptors were observed in bone metastases relative to lymph node metastases. In primary PC, significantly higher ELR- CXC chemokine/receptor expression and significantly lower ELR+ CXC chemokine/receptor expression were observed in patients with lymph node metastasis relative to those without. Multivariate logistic regression analysis identified CXCL10 expression as an independent predictor of lymph node metastasis. Furthermore, the log-rank test results revealed that co-expression of CXCL10/CXCR3 was associated with postoperative recurrence. These findings demonstrate heterogeneous expression of CXC chemokine/receptor genes in primary PC as well as differences in expression patterns according to the metastatic site.
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Denture adhesive is a material used to improve the retention and stability of the denture. And denture adhesive is divided into soluble and insoluble type. It improves the retention, stability of dentures, and masticatory functions of patients. Maintenance like cleansing and periodic follow up is essential. Almost of dental clinicians are only simply aware of the effects of denture adhesives and often rely on the manufacturer's instructions on precautions and maintenance. The purpose of this study is to examine the properties, effects, and precautions of denture adhesives, and to present clinical guidelines for patients and professionals.
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In treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies demonstrated that Transcription Factor-4 (TCF4), a transcription factor implicated in WNT signaling, mediated neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of metastatic CaP were examined, a positive correlation was found between the expression levels of TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide resistance via NED in CaP.
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Resistencia a Antineoplásicos/genética , Células Neuroendocrinas/metabolismo , Células Neuroendocrinas/patología , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteína 2 Similar al Factor de Transcripción 7/genética , Animales , Benzamidas , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Noqueados , Células Neuroendocrinas/efectos de los fármacos , Nitrilos , Feniltiohidantoína/farmacología , Unión Proteica , Transporte de Proteínas , Proteína 2 Similar al Factor de Transcripción 7/antagonistas & inhibidores , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismoRESUMEN
Although androgen deprivation therapy (ADT) and immunotherapy are potential treatment options in men with metastatic prostate cancer (CaP), androgen has conventionally been proposed to be a suppressor of the immune response. However, we herein report that DHT activates macrophages. When the murine macrophage cell line (RAW 264.7), human monocyte cell line (THP-1), and human peripheral blood monocytes were cultured with androgen-resistant CaP cell lines, DHT increased cytotoxicity of macrophages in a concentration-dependent manner. Further studies revealed that DHT induced M1 polarization and increased the expression levels of TNF-related apoptosis-inducing ligand (TRAIL) in macrophages and that this effect was abrogated when TRAIL was neutralized with a blocking antibody or small interfering RNA. Subsequent experiments demonstrated that induction of TRAIL expression was regulated by direct binding of androgen receptor to the TRAIL promoter region. Finally, an in vivo mouse study demonstrated that castration enhanced the growth of an androgen-resistant murine CaP tumor and that this protumorigenic effect of castration was blocked when macrophages were removed with clodronate liposomes. Collectively, these results demonstrate that DHT activates the cytotoxic activity of macrophages and suggest that immunotherapy may not be optimal when combined with ADT in CaP.
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Dihidrotestosterona/farmacología , Macrófagos/efectos de los fármacos , Neoplasias de la Próstata/terapia , Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Animales , Células Cultivadas , Citotoxicidad Inmunológica/efectos de los fármacos , Humanos , Inmunoterapia , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias de la Próstata/inmunología , Receptores Androgénicos/análisisRESUMEN
Prostate cancer (PCa) is the most common non-cutaneous cancer among men and the second leading cause of male cancer deaths in the United States. With no effective cure for advanced disease, the survival rates of castration-resistant disease and metastatic disease remains poor. Treatment via hormonal manipulation, immunotherapy, and chemotherapy remain marginally effective, indicating the need for novel treatment strategies. Cytoreductive prostatectomy (CRP) has grown as a treatment modality for metastatic castration resistant prostate cancer (mCRPC) and an emerging body of literature has demonstrated its survival benefits. In this review, we hope to further explore immunologic changes after CRP and the resultant effects on oncologic outcomes. Conclusively, the data and technical considerations of CRS evolve, CRS may continue to expand treat various type of metastatic cancer. Still, there are little reports about immunological changed after CRP. However, based on technical improvement, CRP and combinational immunotherapy are developing treatments of metastatic disease.
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Although garlic induces apoptosis in cancer cells, it is unclear whether the effects are similar to those of cisplatin against bladder cancer (BC). Therefore, this study investigated whether garlic extracts and cisplatin show similar activity when used to treat BC. The effect of garlic on T24 BC cell line was examined in a BALB/C-nude mouse xenograft model and compared with that of cisplatin. Tissue microarray analysis and gene network analysis were performed to identify differences in gene expression by control tumors and tumors exposed to garlic extract or cisplatin. Investigation of gene expression based on tissues from 165 BC patients and normal controls was then performed to identify common targets of garlic and cisplatin. Tumor volume and tumor weight in cisplatin (0.05[Formula: see text]mg/kg)- and garlic-treated mice were significantly smaller than those in negative control mice. However, cisplatin-treated mice also showed a significant reduction in body weight. Microarray analysis of tumor tissue identified 515 common anticancer genes in the garlic and cisplatin groups ([Formula: see text]). Gene network analysis of 252 of these genes using the Cytoscape and ClueGo software packages mapped 17 genes and 9 gene ontologies to gene networks. BC (NMIBC and MIBC) patients with low expression of centromere protein M (CENPM) showed significantly better progression-free survival than those with high expression. Garlic extract shows anticancer activity in vivo similar to that of cisplatin, with no evident of side effects. Both appear to act by targeting protein-DNA complex assembly; in particular, expression of CENPM.
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Antineoplásicos/administración & dosificación , Centrómero/metabolismo , Cisplatino/administración & dosificación , Ajo/química , Proteínas Nucleares/metabolismo , Fitoterapia , Extractos Vegetales/administración & dosificación , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular , ADN/metabolismo , Modelos Animales de Enfermedad , Supervivencia sin Enfermedad , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Terapia Molecular Dirigida , Proteínas de Neoplasias/metabolismo , Unión Proteica/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: There is growing interest in developing new non-invasive diagnostic tools for bladder cancer (BC) that have better sensitivity and specificity than cystoscopy and cytology. This study examined the value of urinary cell-free nucleic acid (NA) as a diagnostic marker for BC. MATERIAL AND METHODS: A total of 81 patients (74 BC and 7 normal controls) were used for a tissue set, and 212 patients (92 BC and 120 normal controls) were used as a urine set. Expression of tissue mRNA and urinary cell-free NAs was then examined. RESULTS: Four candidate genes were top-ranked in the tissue microarray. Expression levels of two of these (IQGAP3 and TOP2A) in BC tissue and urine samples from BC patients were significantly higher than those in samples from the control groups. Binary logistic regression analysis of cell-free NA levels in urine samples revealed that IQGAP3 was significantly associated with BC: PicoGreen-adjusted odds ratio (OR), 3.434; confidence interval (CI), 2.999-4.180; P<0.001; RiboGreen-adjusted OR, 2.242; CI, 1.793-2.840; P<0.001. Further analysis of IQGAP3 urinary cell-free NAs with respect to tumor invasiveness and grade also yielded a high AUC, suggesting that IQGAP3 can discriminate between BC patients and non-cancer patients with hematuria. CONCLUSIONS: Levels of IQGAP3 urinary cell-free NA in BC patients were significantly higher than those in normal controls or patients with hematuria. High levels of IQGAP3 urinary cell-free NA also reflected high expression in BC tissues. Therefore, IQGAP3 urinary cell-free NA may be a complementary diagnostic biomarker for BC.
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BACKGROUND: Although the standard treatment for the patients with recurrent and metastatic prostate cancer (CaP) is androgen deprivation therapy, castration-resistant prostate cancer (CRPC) eventually emerges. Our previous report indicated that bone morphogenetic protein 6 (BMP6) induced CRPC via tumour-infiltrating macrophages. In a separate line of study, we have observed that the WNT5A/BMP6 loop in CaP bone metastasis mediates resistance to androgen deprivation in tissue culture. Simultaneously, we have reported that BMP6 induced castration resistance in CaP cells via tumour-infiltrating macrophages. Therefore, our present study aims to investigate the mechanism of WNT5A and its interaction with macrophages on CRPC. METHODS: Doxycycline inducible WNT5A overexpression prostate cancer cell line was used for detailed mechanical study. RESULTS: WNT5A was associated with increased expression of chemokine ligand 2 (CCL2) in the human CaP cell line, LNCaP. Mechanistically, this induction of CCL2 by WNT5A is likely to be mediated via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signalling pathway. Our in vivo experiments demonstrated that the overexpression of WNT5A in LNCaP cells promoted castration resistance. Conversely, this resistance was inhibited with the removal of macrophages via clodronate liposomes. When patient-derived CaP LuCaP xenografts were analysed, high levels of WNT5A were correlated with increased levels of CCL2 and BMP6. In addition, higher levels of CCL2 and BMP6 were more commonly observed in intra-femoral transplanted tumours as compared to subcutaneous-transplanted tumours in the patient-derived PCSD1 bone-niche model. CONCLUSIONS: These findings collectively suggest that WNT5A may be a key gene that induces CRPC in the bone niche by recruiting and regulating macrophages through CCL2 and BMP6, respectively.
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Proteína Morfogenética Ósea 6/metabolismo , Quimiocina CCL2/metabolismo , Macrófagos/patología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Regulación hacia Arriba , Proteína Wnt-5a/metabolismo , Anciano , Animales , Línea Celular Tumoral , Ácido Clodrónico/farmacología , Regulación Neoplásica de la Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas , Macrófagos/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Trasplante de Neoplasias , Neoplasias de la Próstata Resistentes a la Castración/patología , Análisis de Matrices TisularesRESUMEN
As we learn more about the molecular biology of genitourinary malignancies, novel therapeutic strategies can be developed. This is especially crucial for prostate, renal, and bladder cancer, where mortality rates remain high especially in advanced disease states. The androgen signaling axis and the androgen receptor (AR) are areas that are actively being explored for their role in these diseases. Although long been associated with prostate cancer development and progression, the role of AR in renal cell carcinoma (RCC) and bladder cancer is becoming recognized as well. This review will highlight the current research into the role of the androgen signaling axis in genitourinary malignancies and how this pathway is being used to expand our therapeutic armamentarium.
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There is a growing interest in the use of naturally occurring agents in cancer prevention. This study investigated the garlic extract affects in bladder cancer (BC) prevention. The effect of garlic extract in cancer prevention was evaluated using the T24 BC BALB/C-nude mouse xenograft model. Microarray analysis of tissues was performed to identify differences in gene expression between garlic extract intake and control diet, and gene network analysis was performed to assess candidate mechanisms of action. Furthermore, we investigated the expression value of selected genes in the data of 165 BC patients. Compared to the control group, significant differences in tumor volume and tumor weight were observed in the groups fed 20 mg/kg (p<0.05), 200 mg/kg, and 1000 mg/kg of garlic extract (p<0.01). Genes (645) were identified as cancer prevention-related genes (fold change >2 and p<0.05) by tissue microarray analysis. A gene network analysis of 279 of these genes (p<0.01) was performed using Cytoscape/ClueGo software: 36 genes and 37 gene ontologies were mapped to gene networks. Protein kinase A (PKA) signaling pathway including AKAP12, RDX, and RAB13 genes were identified as potential mechanisms for the activity of garlic extract in cancer prevention. In BC patients, AKAP12 and RDX were decreased but, RAB13 was increased. Oral garlic extract has strong cancer prevention activity in vivo and an acceptable safety profile. PKA signaling process, especially increasing AKAP12 and RDX and decreasing RAB13, are candidate pathways that may mediate this prevention effect.
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Biomarcadores de Tumor/genética , Ajo/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Extractos Vegetales/farmacología , Neoplasias de la Vejiga Urinaria/prevención & control , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Análisis de Matrices Tisulares , Células Tumorales Cultivadas , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Renal cell carcinoma (RCC) is one of the most lethal genitourinary cancers. The presence of androgen receptor (AR) in RCC has recently been shown to be associated with higher tumour stage irrespective of gender. Because the clinical context of androgens in female RCC patients is similar to that of prostate cancer patients undergoing androgen-deprivation therapy, mechanisms underlying the emergence of castration-resistant prostate cancer (CRPC) may be at play in AR-positive RCC cells. Therefore, we hypothesized that AR-positive RCC has intratumoral steroidogenesis and that anti-androgen therapy may result in tumour suppression. METHODS: Mice were injected with an AR-positive RCC cell line. When tumours became palpable, surgical castration was performed and tumour volume was measured. Using ELISA, the levels of intracellular testosterone and dihydrotesterone were measured in AR-positive human RCC cell lines. Lastly, male mice containing xenografts were treated with enzalutamide or abiraterone acetate (AA) for 3 weeks to measure tumour volume. RESULTS: We first observed in vivo that castration retards the growth of AR-positive RCC tumour xenograft in mice. Next, AR-positive human RCC cell lines and tissues were found to have elevated levels of testosterone and dihydrotestosterone and express key enzymes required for intracellular androgen biosynthesis. A mouse xenograft study with AR-positive RCC cell line using the commonly used anti-androgen therapies showed significant tumour suppression (P<0.01). CONCLUSIONS: Intracrine androgen biosynthesis is a potential source of androgen in AR-positive RCC and that the androgen signaling axis is a potential target of intervention in RCC.
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Andrógenos/biosíntesis , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata/metabolismo , Acetato de Abiraterona/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzamidas , Western Blotting , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Proliferación Celular/efectos de los fármacos , Dihidrotestosterona/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Ratones , Ratones Desnudos , Nitrilos , Orquiectomía , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Pronóstico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Androgénicos/química , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Testosterona/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: There is no consensus on the best oral phosphodiesterase type 5 inhibitor (PDE5I) for patients undergoing penile rehabilitation after surgical nerve injury. AIM: To determine the mechanism of PDE5I on cultured neuronal cells and the effectiveness of local drug delivery using nanospheres (NSPs) to sites of nerve injury in a rat model of bilateral cavernous nerve injury (BCNI). METHODS: The effects of sildenafil, tadalafil, and vardenafil on cyclic adenosine monophosphate, cyclic guanosine monophosphate, and cell survival after exposure to hypoxia and H2O2 were measured in PC12, SH-SY5Y, and NTERA-2 (NT2) cell cultures. The effects of phosphodiesterase type 4 inhibitor (PDE4I) and PDE5I on neuronal cell survival were evaluated. Male rats underwent BCNI and were untreated (BCNI), immediately treated with application of empty NSPs (BCNI + NSP), NSPs containing sildenafil (Sild + NSP), or NSPs containing rolipram (Rol + NSP). MAIN OUTCOME MEASURES: Viability of neuronal cells was measured. Intracavernous pressure changes after cavernous nerve electrostimulation and expression of neurofilament, nitric oxide synthase, and actin in mid-shaft of penis were analyzed 14 days after injury. RESULTS: Sildenafil and rolipram significantly decreased cell death after exposure to H2O2 and hypoxia in PC12, SH-SY5Y, and NT2 cells. PC12 cells did not express PDE5 and knockdown of PDE4 significantly increased cell viability in PC12, SH-SY5Y, and NT2 cells exposed to hypoxia. The ratio of intracavernous pressure to mean arterial pressure and expression of penile neurofilament, nitric oxide synthase, and actin were significantly higher in the Sild + NSP and Rol + NSP groups than in the BCNI and BCNI + NSP groups. Limitations included analysis in only two PDE families using only a single dose. CONCLUSION: Sildenafil showed the most profound neuroprotective effect compared with tadalafil and vardenafil. Sildenafil- or rolipram-loaded NSP delivery to the site of nerve injury prevented erectile dysfunction and led to increased neurofilament, nitric oxide synthase, smooth muscle content in rat penile tissue after BCNI.
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Disfunción Eréctil/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Citrato de Sildenafil/administración & dosificación , Animales , GMP Cíclico/metabolismo , Humanos , Peróxido de Hidrógeno , Masculino , Músculo Liso/metabolismo , Óxido Nítrico Sintasa/metabolismo , Erección Peniana/efectos de los fármacos , Pene/cirugía , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Prostatectomía , Ratas , Ratas Sprague-Dawley , Traumatismos del Sistema NerviosoRESUMEN
PURPOSE: The role of androgen receptor in renal cell carcinoma is not well understood. In this study the correlation between androgen receptor mRNA expression and clinicopathological features in patients with localized renal cell carcinoma was investigated. Additionally, human renal cell carcinoma cell lines were examined for the presence and effect of androgen receptor. MATERIALS AND METHODS: Androgen receptor mRNA expression was evaluated by quantitative real-time polymerase chain reaction in 115 tumor samples from patients with primary pathological stage T1 or T2 (pT1/pT2) renal cell carcinoma and 57 specimens of corresponding normal kidney tissue. Reverse transcriptase-polymerase chain reaction and Western blot were done to examine the expression of androgen receptor in human renal cell carcinoma cell lines. Effects on cellular proliferation were investigated after activating and blocking androgen signaling in tissue culture. RESULTS: Androgen receptor mRNA expression levels were significantly higher in patients with pT2 tumors than in those with pT1 tumors (p = 0.011). Kaplan-Meier estimates revealed significant differences in time to progression and cancer specific survival between low and high androgen receptor mRNA expression groups regardless of gender. Multivariate Cox regression analysis demonstrated that the level of androgen receptor expression was an independent predictor of cancer specific survival (HR 15.546, 95% CI 1.320-183.131, p = 0.029). In tissue culture treatment with dihydrotestosterone caused proliferation in androgen receptor positive cell lines while enzalutamide resulted in reduced cell viability in a dose dependent manner. CONCLUSIONS: In patients with localized renal cell carcinoma the androgen receptor mRNA expression level is associated with prognosis. In addition, cell culture data suggest that enzalutamide may have an effect in limiting the growth of androgen receptor positive renal cell carcinoma.