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1.
Anticancer Res ; 41(4): 2183-2186, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813431

RESUMEN

BACKGROUND/AIM: The aim of this study was to identify simple and reliable factors to detect clinically insignificant prostate cancer (PC) for avoiding immediate prostate biopsies using biparametric magnetic resonance imaging (MRI), which consists of T2-weighted and diffusion-weighted imaging. PATIENTS AND METHODS: We retrospectively evaluated 427 men with suspected PC, who underwent biparametric MRI and standard 12-core transrectal prostate biopsy. MRI and prostate specific antigen density (PSAD) were analysed. To evaluate the combination of the two parameters, patients were divided into three groups (Group A: MRI negative and PSAD <0.23, Group B: MRI positive or PSAD ≥0.23, Group C: MRI positive and PSAD ≥0.23). A grade of ≥2 was defined as clinically significant PC. RESULTS: Clinically significant PC was detected in 46.5% of men with positive MRI findings, and 60.0% of men with PSAD ≥0.23. When combining MRI and PSAD, detection rates of clinically significant PC were 10.0%, 28.4% and 65.3% in group A, B and, C, respectively. CONCLUSION: Negative biparametric MRI findings with PSAD <0.23 might be a reliable evidence for avoiding immediate prostate biopsies.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Antígeno Prostático Específico/análisis , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja Gruesa/métodos , Imagen de Difusión por Resonancia Magnética , Humanos , Biopsia Guiada por Imagen , Pruebas Inmunológicas , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Cuidados Preoperatorios , Próstata/patología , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/metabolismo , Estudios Retrospectivos , Carga Tumoral , Ultrasonografía Intervencional
2.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799604

RESUMEN

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.


Asunto(s)
Proteína NEDD8/genética , Neoplasias de la Próstata/genética , Procesamiento Proteico-Postraduccional , Proteínas Quinasas Asociadas a Fase-S/genética , Factores de Transcripción de la Familia Snail/genética , Antígenos CD/genética , Antígenos CD/metabolismo , Antineoplásicos/farmacología , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Ciclopentanos/farmacología , Docetaxel/farmacología , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Masculino , Proteína NEDD8/metabolismo , Clasificación del Tumor , Células PC-3 , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Pirimidinas/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Proteínas Quinasas Asociadas a Fase-S/antagonistas & inhibidores , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo
3.
Br J Radiol ; 94(1121): 20210005, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33684304

RESUMEN

OBJECTIVES: To explore the potential value of multiparametric magnetic resonance imaging (mpMRI) texture analysis (TA) to predict new Gleason Grade Group (GGG). METHODS: Fifty-eight lesions of fifty patients who underwent mpMRI scanning, including T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) prior to trans-rectal ultrasound (TRUS)-guided core prostate biopsy, were retrospectively enrolled. TA parameters were obtained by the postprocessing software, and each lesion was assigned to its corresponding GGG. TA parameters derived from T2WI and DWI were statistically analyzed in detail. RESULTS: Energy, inertia, and correlation derived from apparent diffusion coefficient (ADC) maps and T2WI had a statistically significant difference among the five groups. Kurtosis, energy, inertia, correlation on ADC maps and Energy, inertia on T2WI were moderately related to the GGG trend. ADC-energy and T2-energy were significant independent predictors of the GGG trend. ADC-energy, T2WI-energy, and T2WI-correlation had a statistically significant difference between GGG1 and GGG2-5. ADC-energy were significant independent predictors of the GGG1. ADC-energy, T2WI-energy, and T2WI-correlation showed satisfactory diagnostic efficiency of GGG1 (area under the curve (AUC) 84.6, 74.3, and 83.5%, respectively), and ADC-energy showed excellent sensitivity and specificity (88.9 and 95.1%, respectively). CONCLUSION: TA parameters ADC-energy and T2-energy played an important role in predicting GGG trend. Both ADC-energy and T2-correlation produced a high diagnostic power of GGG1, and ADC-energy was perfect predictors of GGG1. ADVANCES IN KNOWLEDGE: TA parameters were innovatively used to predict new GGG trend, and the predictive factors of GGG1 were screen out.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Clasificación del Tumor/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Biopsia , Imagen de Difusión por Resonancia Magnética/métodos , Humanos , Masculino , Próstata/patología , Curva ROC , Estudios Retrospectivos , Programas Informáticos , Estadísticas no Paramétricas , Ultrasonografía Intervencional/métodos
4.
Artículo en Inglés | MEDLINE | ID: mdl-33787738

RESUMEN

We report a rare case of an infective endocarditis by Aerococcus spp in a bioprosthetic aortic valve following a prostate biopsy, in an asymptomatic adult with no additional risk factor for prostate cancer, excepting for age. The diagnosis was based on the presence of vegetations on the bioprosthesis seen on the echocardiogram, positive blood cultures and fever, and a favorable clinical outcome following the treatment with ceftriaxone and gentamicin.


Asunto(s)
Aerococcus/aislamiento & purificación , Ceftriaxona/uso terapéutico , Endocarditis/tratamiento farmacológico , Fiebre/etiología , Gentamicinas/uso terapéutico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Próstata/patología , Anciano , Biopsia , Ecocardiografía , Endocarditis/diagnóstico , Endocarditis/microbiología , Femenino , Infecciones por Bacterias Grampositivas/sangre , Infecciones por Bacterias Grampositivas/diagnóstico , Humanos , Masculino , ARN Ribosómico 16S , Resultado del Tratamiento
5.
Methods Mol Biol ; 2292: 105-113, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33651355

RESUMEN

Prostate cancer antigen 3 (PCA3) is a urinary biomarker for prostate cancer and has demonstrated a good specificity and sensitivity representing a minimally invasive test.PCA3 assay could be useful in combination with PSA to suggest an eventual rebiopsy in men who have had one or more previous negative prostate biopsies.Combination of multiple tumor biomarkers will be the trend in the near future to achieve the goal of evaluate the aggressiveness of cancer and at the same time reducing the number of unnecessary biopsies.


Asunto(s)
Antígenos de Neoplasias/análisis , Próstata/patología , Neoplasias de la Próstata/diagnóstico , Biomarcadores de Tumor/análisis , Biopsia/métodos , Humanos , Masculino
6.
Life Sci ; 271: 119198, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33577857

RESUMEN

The aim of this study was to evaluate whether high levels of exogenous testosterone (T) interfere in prostate morphogenesis. Pregnant females were exposed to subcutaneous injections of T cypionate (500 µg/animal) at gestational days 20 and 22. Male and female pups were euthanized at postnatal days 1 and 15. 15-day-old males had only fibroblast growth factor 10 (FGF10) immunostaining and nuclear form factor altered by the treatment, whereas treated females (T1 and T15) had almost all analyzed parameters changed. T1 females showed an increased anogenital distance (AGD), whereas T15 females had both AGD and ovary weight increased. T1 females had a higher number of epithelial buds emerging from the urethral and vaginal epithelium. We observed ectopic prostatic tissue surrounding the vagina in both T1 and T15 females. Moreover, the ectopic acini of T15 females showed delayed luminal formation, and there was a thickening of the periacinar smooth muscle layer (SML). Finally, FGF10 immunostaining intensity decreased in both T15 male and female prostates. Indeed, Sonic hedgehog (Shh) was upregulated in T15 female prostates, whereas no difference was observed between the male groups. These data showed that exogenous T changed the nuclear morphology of prostate epithelial cells in both males and females. Surprisingly, smooth muscle hyperplasia was also observed in the ectopic female prostate. Moreover, T downregulated FGF10 in both male and female prostates. Interestingly, the results suggest that FGF10 downregulation is mediated by the upregulation of Shh in females. In conclusion, exogenous T disrupts prostate development, particularly, affecting, the female.


Asunto(s)
Epitelio/metabolismo , Factor 10 de Crecimiento de Fibroblastos/biosíntesis , Proteínas Hedgehog/biosíntesis , Músculo Liso/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Próstata/metabolismo , Testosterona/toxicidad , Animales , Animales Recién Nacidos , Epitelio/efectos de los fármacos , Epitelio/patología , Femenino , Factor 10 de Crecimiento de Fibroblastos/genética , Regulación del Desarrollo de la Expresión Génica , Gerbillinae , Proteínas Hedgehog/genética , Masculino , Músculo Liso/citología , Músculo Liso/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Próstata/efectos de los fármacos , Próstata/patología
7.
Nat Commun ; 12(1): 935, 2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33568675

RESUMEN

Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness.


Asunto(s)
Células Plasmáticas/inmunología , Neoplasias de la Próstata/inmunología , Afroamericanos/genética , Anciano , Movimiento Celular , Estudios de Cohortes , Humanos , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Próstata/inmunología , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/fisiopatología
9.
AJR Am J Roentgenol ; 216(4): 952-959, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33566638

RESUMEN

OBJECTIVE. The purpose of this study was to report on the practice patterns and challenges of performing and interpreting prostate MRI. SUBJECTS AND METHODS. An electronic survey regarding prostate MRI practice patterns and challenges was sent to members of the Society of Abdominal Radiology. RESULTS. The response rate was 15% (212/1446). Most (65%) of the respondents were academic abdominal radiologists with 1-5 (52%), 6-10 (20%), 11-20 (15%), and more than 20 (5%) years of experience in reporting prostate MRI. The numbers of prostate MRI examinations reported per week were 0-5 (43%), 6-10 (38%), 11-20 (12%), 21-30 (5%), and more than 30 (2%). Imaging was performed at 3 T (58%), 1.5 T (20%), or either (21%), and most examinations (83%) were performed without an endorectal coil. Highest b values ranged from 800 to 5000 s/mm2; 1400 s/mm2 (26%) and 1500 s/mm2 (30%) were the most common. Most respondents (79%) acquired dynamic contrast-enhanced images with temporal resolution of less than 10 seconds. Most (71%) of the prostate MRI studies were used for fusion biopsy. PI-RADS version 2 was used by 92% of the respondents and template reporting by 80%. Challenges to performing and interpreting prostate MRI were scored on a 1-5 Likert scale (1, easy; 2, somewhat easy; 3, neutral; 4, somewhat difficult; 5, very difficult). The median scores were 2 or 3 for patient preparatory factors. Image acquisition and reporting factors were scored 1-2, except for performing spectroscopy or using an endorectal coil, both of which scored 4. Acquiring patient history scored 2 and quality factors scored 3. CONCLUSION. Most radiologists perform prostate MRI at 3 T without an endorectal coil and interpret the images using PI-RADS version 2. Challenges include obtaining quality images, acquiring feedback, and variability in the interpretation of PI-RADS scores.


Asunto(s)
Imagen por Resonancia Magnética , Pautas de la Práctica en Medicina , Próstata/diagnóstico por imagen , Neoplasias de la Próstata/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/normas , Imagen por Resonancia Magnética/estadística & datos numéricos , Masculino , Pautas de la Práctica en Medicina/estadística & datos numéricos , Próstata/patología , Neoplasias de la Próstata/diagnóstico , Sociedades Médicas , Encuestas y Cuestionarios
10.
Lancet Digit Health ; 3(3): e158-e165, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33549512

RESUMEN

BACKGROUND: Accurate prognostication is crucial in treatment decisions made for men diagnosed with non-metastatic prostate cancer. Current models rely on prespecified variables, which limits their performance. We aimed to investigate a novel machine learning approach to develop an improved prognostic model for predicting 10-year prostate cancer-specific mortality and compare its performance with existing validated models. METHODS: We derived and tested a machine learning-based model using Survival Quilts, an algorithm that automatically selects and tunes ensembles of survival models using clinicopathological variables. Our study involved a US population-based cohort of 171 942 men diagnosed with non-metastatic prostate cancer between Jan 1, 2000, and Dec 31, 2016, from the prospectively maintained Surveillance, Epidemiology, and End Results (SEER) Program. The primary outcome was prediction of 10-year prostate cancer-specific mortality. Model discrimination was assessed using the concordance index (c-index), and calibration was assessed using Brier scores. The Survival Quilts model was compared with nine other prognostic models in clinical use, and decision curve analysis was done. FINDINGS: 647 151 men with prostate cancer were enrolled into the SEER database, of whom 171 942 were included in this study. Discrimination improved with greater granularity, and multivariable models outperformed tier-based models. The Survival Quilts model showed good discrimination (c-index 0·829, 95% CI 0·820-0·838) for 10-year prostate cancer-specific mortality, which was similar to the top-ranked multivariable models: PREDICT Prostate (0·820, 0·811-0·829) and Memorial Sloan Kettering Cancer Center (MSKCC) nomogram (0·787, 0·776-0·798). All three multivariable models showed good calibration with low Brier scores (Survival Quilts 0·036, 95% CI 0·035-0·037; PREDICT Prostate 0·036, 0·035-0·037; MSKCC 0·037, 0·035-0·039). Of the tier-based systems, the Cancer of the Prostate Risk Assessment model (c-index 0·782, 95% CI 0·771-0·793) and Cambridge Prognostic Groups model (0·779, 0·767-0·791) showed higher discrimination for predicting 10-year prostate cancer-specific mortality. c-indices for models from the National Comprehensive Cancer Care Network, Genitourinary Radiation Oncologists of Canada, American Urological Association, European Association of Urology, and National Institute for Health and Care Excellence ranged from 0·711 (0·701-0·721) to 0·761 (0·750-0·772). Discrimination for the Survival Quilts model was maintained when stratified by age and ethnicity. Decision curve analysis showed an incremental net benefit from the Survival Quilts model compared with the MSKCC and PREDICT Prostate models currently used in practice. INTERPRETATION: A novel machine learning-based approach produced a prognostic model, Survival Quilts, with discrimination for 10-year prostate cancer-specific mortality similar to the top-ranked prognostic models, using only standard clinicopathological variables. Future integration of additional data will likely improve model performance and accuracy for personalised prognostics. FUNDING: None.


Asunto(s)
Algoritmos , Aprendizaje Automático , Próstata/patología , Neoplasias de la Próstata/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Humanos , Masculino , Persona de Mediana Edad , Nomogramas , Pronóstico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Medición de Riesgo , Análisis de Supervivencia , Estados Unidos/epidemiología
11.
Life Sci ; 271: 119180, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33571513

RESUMEN

AIMS: N6-Methyladenosine (m6A) is the most frequent posttranscriptional modification and plays important roles in tumorigenesis and metastasis. The roles of fat mass and obesity-associated (FTO) in metabolic diseases have been widely explored. However, the molecular mechanisms and physiological functions of FTO in prostate cancer remain largely unknown. This study aimed to explore the exact functions of FTO in the progression of prostate cancer metastasis. MAIN METHODS: Dot blot and m6A RNA methylation quantification assays were performed to determine m6A levels. The protein and mRNA expression levels were detected using immunoblot (IB) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses. Cell invasion and migration abilities were measured using transwell and wound healing assays. Bioinformatics was used to measure the expression level of FTO and possible correlation between FTO levels and advanced tumor stage. Immunofluorescence (IF) was performed to measure the cellular localization of FTO. KEY FINDINGS: FTO was downregulated in prostate cancer tissues and cell lines, and the m6A content was increased. Importantly, patients with lower FTO expression had advanced tumor stage and higher Gleason scores. Gain- and loss-of-function assays revealed that FTO inhibits prostate cancer cell invasion and migration in vitro. Moreover, we confirmed that FTO can decrease the total m6A level. SIGNIFICANCE: The present study revealed that the FTO m6A demethylase inhibits prostate cancer cell invasion and migration by regulating total m6A levels.


Asunto(s)
Adenosina/análogos & derivados , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/biosíntesis , Biomarcadores de Tumor/biosíntesis , Movimiento Celular/fisiología , Neoplasias de la Próstata/metabolismo , Adenosina/antagonistas & inhibidores , Adenosina/biosíntesis , Anciano , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/patología
12.
Med Sci Monit ; 27: e929913, 2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33556045

RESUMEN

BACKGROUND Two diagnostic models of prostate cancer (PCa) and clinically significant prostate cancer (CS-PCa) were established using clinical data of among patients whose prostate-specific antigen (PSA) levels are in the gray area (4.0-10.0 ng/ml). MATERIAL AND METHODS Data from 181 patients whose PSA levels were in the gray area were retrospectively analyzed, and the following data were collected: age, digital rectal examination, total PSA, PSA density (PSAD), free/total PSA (f/t PSA), transrectal ultrasound, multiparametric magnetic resonance imaging (mpMRI), and pathological reports. Patients were diagnosed with benign prostatic hyperplasia (BPH) and PCa by pathology reports, and PCa patients were separated into non-clinically significant PCa (NCS-PCa) and CS-PCa by Gleason score. Afterward, predictor models constructed by above parameters were researched to diagnose PCa and CS-PCa, respectively. RESULTS According to the analysis of included clinical data, there were 109 patients with BPH, 44 patients with NCS-PCa, and 28 patients with CS-PCa. Regression analysis showed PCa was correlated with f/t PSA, PSAD, and mpMRI (P<0.01), and CS-PCa was correlated with PSAD and mpMRI (P<0.01). The area under the receiver operating characteristic curves of 2 models for PCa (sensitivity=73.64%, specificity=64.23%) and for CS-PCa (sensitivity=71.41%, specificity=81.82%) were 0.79 and 0.87, respectively. CONCLUSIONS The prediction models had satisfactory diagnostic value for PCa and CS-PCa among patients with PSA in the gray area, and use of these models may help reduce overdiagnosis.


Asunto(s)
Calicreínas/sangre , Modelos Estadísticos , Antígeno Prostático Específico/sangre , Hiperplasia Prostática/diagnóstico , Neoplasias de la Próstata/diagnóstico , Factores de Edad , Anciano , Biopsia/estadística & datos numéricos , Diagnóstico Diferencial , Tacto Rectal/estadística & datos numéricos , Humanos , Masculino , Uso Excesivo de los Servicios de Salud/prevención & control , Imágenes de Resonancia Magnética Multiparamétrica/estadística & datos numéricos , Clasificación del Tumor , Próstata/diagnóstico por imagen , Próstata/patología , Hiperplasia Prostática/sangre , Hiperplasia Prostática/patología , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Curva ROC , Valores de Referencia , Estudios Retrospectivos , Medición de Riesgo/métodos , Ultrasonografía/estadística & datos numéricos
13.
PLoS Genet ; 17(1): e1008540, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33513133

RESUMEN

Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19-overexpressing LNCaP cells. We also examined genome-wide H3K27 acetylation. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 correspond to genes regulated by ELK1, a transcription factor that binds the AR N-terminus to induce select AR target gene expression and proliferation, and genomic sites occupied by MED19 and AR are enriched for motifs associated with ELK1. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.


Asunto(s)
Complejo Mediador/genética , Monoaminooxidasa/genética , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Acetilación , Antagonistas de Andrógenos/farmacología , Andrógenos/genética , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Regiones Promotoras Genéticas/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de los fármacos , Proteína Elk-1 con Dominio ets/genética
14.
Nat Commun ; 12(1): 401, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33452241

RESUMEN

Mechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required for homologous recombination. Collectively, these findings reveal that CRY1 is hormone-induced in tumors, is further stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation. These studies identify the circadian factor CRY1 as pro-tumorigenic and nominate CRY1 as a new therapeutic target.


Asunto(s)
Carcinogénesis/genética , Criptocromos/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata Resistentes a la Castración/genética , Reparación del ADN por Recombinación/genética , Anciano , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Andrógenos/metabolismo , Carcinogénesis/efectos de los fármacos , Línea Celular Tumoral , Secuenciación de Inmunoprecipitación de Cromatina , Criptocromos/genética , Roturas del ADN de Doble Cadena/efectos de los fármacos , Conjuntos de Datos como Asunto , Progresión de la Enfermedad , Estudios de Seguimiento , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Próstata/patología , Próstata/cirugía , Prostatectomía , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/terapia , RNA-Seq , Receptores Androgénicos/metabolismo , Reparación del ADN por Recombinación/efectos de los fármacos , Estudios Retrospectivos
15.
Medicina (Kaunas) ; 57(1)2021 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-33435132

RESUMEN

Background and objectives: Overdiagnosis, overtreatment, and the need for repeated procedures caused by transrectal ultrasound guided prostate biopsies and their related complications places a heavy burden on healthcare systems. This was a prospective cohort validating study to access the clinical accuracy of systematic and MRI-cognitive targeted transperineal prostate biopsies in detecting clinically significant prostate cancer after a previous negative biopsy and persistent suspicion of malignancy. The primary goal was to assess the ability of multiparametric magnetic resonance imaging (mpMRI) to detect clinically significant prostate cancer with an additional goal to assess the diagnostic value of systematic and MRI-cognitive transperineal biopsies. Materials and Methods: In total, 200 patients were enrolled who had rising serum prostate specific antigen (PSA) levels for at least 4 months after a previous negative transrectal ultrasound (TRUS) biopsy. All eligible men underwent 1.5T prostate mpMRI, reported using the Prostate Imaging Reporting and Data System version 2 (PI-RADS v2), followed by a 20-region transperineal prostate systematic biopsy and additional targeted biopsies. Results: Systematic 20-core transperineal prostate biopsies (TPBs) were performed for 38 (19%) patients. Systemic 20-core TPB with additional cognitive targeted biopsies were performed for 162 (81%) patients. Clinically significant prostate cancer (csPC) was detected for 31 (15.5%) patients, of which 20 (64.5%) cases of csPC were detected by systematic biopsy, eight (25.8%) cases were detected by targeted biopsy, and three (9.7%) both by systematic and targeted biopsies. Conclusions: Cognitive mpMRI guided transperineal target biopsies increase the detection rate of clinically significant prostate cancer after a previously negative biopsy. However, in a repeat prostate biopsy setting, we recommend applying a cognitive targeted biopsy with the addition of a systematic biopsy.


Asunto(s)
Adenocarcinoma/patología , Biopsia con Aguja Gruesa/métodos , Biopsia Guiada por Imagen/métodos , Imágenes de Resonancia Magnética Multiparamétrica , Próstata/patología , Neoplasias de la Próstata/patología , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Anciano , Estudios de Cohortes , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Perineo , Estudios Prospectivos , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo
19.
Urol Clin North Am ; 48(1): 25-33, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33218591

RESUMEN

"Approximately 1 million prostate biopsies are performed each year in the United States. This procedure has traditionally been performed using a transrectal approach, which is associated with a significant risk of infectious complications including sepsis. In recent years, transperineal prostate biopsy has been increasingly adopted due to its lower associated infectious risk. In this review, we explore the benefits of the transperineal approach for performing prostate biopsy and detail technical advancements that have allowed for this procedure to now be routinely performed in the outpatient settings under local anesthesia."


Asunto(s)
Biopsia/métodos , Biopsia Guiada por Imagen/métodos , Próstata/patología , Neoplasias de la Próstata/patología , Infecciones Bacterianas/etiología , Infecciones Bacterianas/prevención & control , Biopsia/efectos adversos , Biopsia/tendencias , Humanos , Biopsia Guiada por Imagen/efectos adversos , Biopsia Guiada por Imagen/tendencias , Imagen por Resonancia Magnética , Masculino , Perineo/cirugía , Próstata/cirugía , Neoplasias de la Próstata/cirugía , Recto/cirugía , Procedimientos Quirúrgicos Robotizados/métodos , Procedimientos Quirúrgicos Robotizados/tendencias , Ultrasonografía
20.
J Urol ; 205(1): 115-121, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32658588

RESUMEN

PURPOSE: Optimal treatment of intermediate risk prostate cancer remains unclear. National Comprehensive Cancer Network® guidelines recommend active surveillance, prostatectomy or radiotherapy. Recent trials demonstrated no difference in prostate cancer specific mortality for men undergoing active surveillance for low risk prostate cancer compared to prostatectomy or radiotherapy. The use of active surveillance for intermediate risk prostate cancer is less clear. In this study we characterize U.S. national trends for demographic, clinical and socioeconomic factors associated with active surveillance for men with intermediate risk prostate cancer. MATERIALS AND METHODS: This retrospective cohort study examined 176,122 men diagnosed with intermediate risk prostate cancer from 2010 to 2016 in the National Cancer Database. Temporal trends in demographic, clinical and socioeconomic factors among men with intermediate risk prostate cancer and association with the use of active surveillance were characterized. The analysis was performed in April 2020. RESULTS: In total, 176,122 men were identified with intermediate risk prostate cancer from 2010 to 2016. Of these men 57.3% underwent prostatectomy, 36.4% underwent radiotherapy and 3.2% underwent active surveillance. Active surveillance nearly tripled from 1.6% in 2010 to 4.6% in 2016 (p <0.001). On multivariate analysis use of active surveillance was associated with older age, diagnosis in recent years, lower Gleason score and tumor stage, type of insurance, treatment at an academic center and proximity to facility, and attaining higher education (p <0.05). Race and comorbidities were not associated with active surveillance. CONCLUSIONS: Our findings highlight increasing active surveillance use for men with intermediate risk prostate cancer demonstrating clinical and socioeconomic disparities. Prospective data and improved risk stratification are needed to guide optimal treatment for men with intermediate risk prostate cancer.


Asunto(s)
Disparidades en el Estado de Salud , Disparidades en Atención de Salud/estadística & datos numéricos , Neoplasias de la Próstata/terapia , Espera Vigilante/estadística & datos numéricos , Factores de Edad , Anciano , Anciano de 80 o más Años , Disparidades en Atención de Salud/economía , Humanos , Cobertura del Seguro/economía , Cobertura del Seguro/estadística & datos numéricos , Seguro de Salud/economía , Seguro de Salud/estadística & datos numéricos , Calicreínas/sangre , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Próstata/patología , Antígeno Prostático Específico/sangre , Prostatectomía/economía , Prostatectomía/estadística & datos numéricos , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Radioterapia/economía , Radioterapia/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Factores Socioeconómicos , Espera Vigilante/economía
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