RESUMEN
Components of transcriptional machinery are selectively partitioned into specific condensates, often mediated by protein disorder, yet we know little about how this specificity is achieved. Here, we show that condensates composed of the intrinsically disordered region (IDR) of MED1 selectively partition RNA polymerase II together with its positive allosteric regulators while excluding negative regulators. This selective compartmentalization is sufficient to activate transcription and is required for gene activation during a cell-state transition. The IDRs of partitioned proteins are necessary and sufficient for selective compartmentalization and require alternating blocks of charged amino acids. Disrupting this charge pattern prevents partitioning, whereas adding the pattern to proteins promotes partitioning with functional consequences for gene activation. IDRs with similar patterned charge blocks show similar partitioning and function. These findings demonstrate that disorder-mediated interactions can selectively compartmentalize specific functionally related proteins from a complex mixture of biomolecules, leading to regulation of a biochemical pathway.
Asunto(s)
Proteínas Intrínsecamente Desordenadas , ARN Polimerasa II , Transcripción Genética , Proteínas Intrínsecamente Desordenadas/metabolismo , ARN Polimerasa II/metabolismo , Activación Transcripcional , Animales , RatonesRESUMEN
The MED1 subunit has been shown to mediate ligand-dependent binding of the Mediator coactivator complex to multiple nuclear receptors, including the adipogenic PPARγ, and to play an essential role in ectopic PPARγ-induced adipogenesis of mouse embryonic fibroblasts. However, the precise roles of MED1, and its various domains, at various stages of adipogenesis and in adipose tissue have been unclear. Here, after establishing requirements for MED1, including specific domains, for differentiation of 3T3L1 cells and both primary white and brown preadipocytes, we used multiple genetic approaches to assess requirements for MED1 in adipocyte formation, maintenance, and function in mice. We show that MED1 is indeed essential for the differentiation and/or function of both brown and white adipocytes, as its absence in these cells leads to, respectively, defective brown fat function and lipodystrophy. This work establishes MED1 as an essential transcriptional coactivator that ensures homeostatic functions of adipocytes.
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Adipocitos/citología , Diferenciación Celular/genética , Regulación del Desarrollo de la Expresión Génica/genética , Subunidad 1 del Complejo Mediador/genética , Subunidad 1 del Complejo Mediador/metabolismo , Células 3T3-L1 , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Células Cultivadas , Células Madre Embrionarias/citología , Complejo Mediador/genética , Ratones , Unión Proteica/genética , Dominios ProteicosRESUMEN
Increasing evidence suggests that tRNA levels are dynamically and specifically regulated in response to internal and external cues to modulate the cellular translational program. However, the molecular players and the mechanisms regulating the gene-specific expression of tRNAs are still unknown. Using an inducible auxin-degron system to rapidly deplete RPB1 (the largest subunit of RNA Pol II) in living cells, we identified Pol II as a direct gene-specific regulator of tRNA transcription. Our data suggest that Pol II transcription robustly interferes with Pol III function at specific tRNA genes. This activity was further found to be essential for MAF1-mediated repression of a large set of tRNA genes during serum starvation, indicating that repression of tRNA genes by Pol II is dynamically regulated. Hence, Pol II plays a direct and central role in the gene-specific regulation of tRNA expression.
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Regulación de la Expresión Génica , ARN Polimerasa III/metabolismo , ARN Polimerasa II/metabolismo , ARN de Transferencia/metabolismo , Proteínas Represoras/metabolismo , Proteínas Celulares de Unión al Retinol/metabolismo , Transcripción Genética , Células HeLa , Humanos , Procesamiento Proteico-Postraduccional , ARN Polimerasa II/genética , ARN Polimerasa III/genética , ARN de Transferencia/genética , Proteínas Represoras/genética , Proteínas Celulares de Unión al Retinol/genéticaRESUMEN
Liver regeneration and metabolism are highly interconnected. Here, we show that hepatocyte-specific ablation of RNA polymerase II (Pol II)-associated Gdown1 leads to down-regulation of highly expressed genes involved in plasma protein synthesis and metabolism, a concomitant cell cycle re-entry associated with induction of cell cycle-related genes (including cyclin D1), and up-regulation of p21 through activation of p53 signaling. In the absence of p53, Gdown1-deficient hepatocytes show a severe dysregulation of cell cycle progression, with incomplete mitoses, and a premalignant-like transformation. Mechanistically, Gdown1 is associated with elongating Pol II on the highly expressed genes and its ablation leads to reduced Pol II recruitment to these genes, suggesting that Pol II redistribution may facilitate hepatocyte re-entry into the cell cycle. These results establish an important physiological function for a Pol II regulatory factor (Gdown1) in the maintenance of normal liver cell transcription through constraints on cell cycle re-entry of quiescent hepatocytes.
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Ciclo Celular/genética , Regulación hacia Abajo/genética , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Animales , Proliferación Celular/genética , Regulación del Desarrollo de la Expresión Génica/genética , Técnicas de Inactivación de Genes , Genes p53/genética , Hepatocitos , Hígado/citología , Hígado/metabolismo , Transducción de Señal/genéticaRESUMEN
Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC.
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Carcinoma de Células Renales , Genotipo , Antígenos HLA , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/inmunología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/inmunología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Antígenos HLA/genética , Antígenos HLA/inmunología , Nivolumab/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/genética , Adulto , Anciano de 80 o más AñosRESUMEN
PURPOSE: To determine the prevalence of concomitant squamous metaplasia (SM), the initial histological change from normal urethra to urethral stricture, in bulbar urethral strictures and to investigate the associated clinical factors. METHODS: A retrospective review was conducted on 165 male patients with bulbar urethral strictures who underwent excision and primary anastomosis (EPA) between 2010 and 2020, for whom complete clinical data and excised urethral specimens were available. An experienced pathologist histologically evaluated concomitant SM in paraffin sections of the proximal end of the excised urethra blinded to the clinical data. Disease duration was calculated as the period from the initial diagnosis of urethral stricture to the date of EPA. The association between concomitant SM and clinical background was investigated. RESULTS: SM was identified in 86 (52.1%) patients. The median disease duration in patients with SM (38 months) was significantly longer than that in patients without SM (9 months, p < 0.0001). In multivariate analysis, the longer disease duration, non-traumatic stricture etiology, and failure to maintain urethral rest with urinary diversion via a suprapubic tube for more than 90 days were independent factors predicting concomitant SM. No significant difference was observed in success rates of EPA between patients with SM (93.2%) and those without SM (97.5%, p = 0.18). CONCLUSIONS: Reconstructive urologists need to be aware that concomitant SM is frequent in patients with bulbar urethral stricture, especially in those with long disease duration and those who were voiding volitionally during the period of urethral rest.
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Metaplasia , Uretra , Estrechez Uretral , Procedimientos Quirúrgicos Urológicos Masculinos , Humanos , Estrechez Uretral/epidemiología , Estrechez Uretral/patología , Estrechez Uretral/cirugía , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Uretra/patología , Adulto , Procedimientos Quirúrgicos Urológicos Masculinos/métodos , Tiempo de TratamientoRESUMEN
The chimeric transcription factor E2A-PBX1, containing the N-terminal activation domains of E2A fused to the C-terminal DNA-binding domain of PBX1, results in 5% of pediatric acute lymphoblastic leukemias (ALL). We recently have reported a mechanism for RUNX1-dependent recruitment of E2A-PBX1 to chromatin in pre-B leukemic cells; but the subsequent E2A-PBX1 functions through various coactivators and the general transcriptional machinery remain unclear. The Mediator complex plays a critical role in cell-specific gene activation by serving as a key coactivator for gene-specific transcription factors that facilitates their function through the RNA polymerase II transcriptional machinery, but whether Mediator contributes to aberrant expression of E2A-PBX1 target genes remains largely unexplored. Here we show that Mediator interacts directly with E2A-PBX1 through an interaction of the MED1 subunit with an E2A activation domain. Results of MED1 depletion by CRISPR/Cas9 further indicate that MED1 is specifically required for E2A-PBX1-dependent gene activation and leukemic cell growth. Integrated transcriptome and cistrome analyses identify pre-B cell receptor and cell cycle regulatory genes as direct cotargets of MED1 and E2A-PBX1. Notably, complementary biochemical analyses also demonstrate that recruitment of E2A-PBX1 to a target DNA template involves a direct interaction with DNA-bound RUNX1 that can be further stabilized by EBF1. These findings suggest that E2A-PBX1 interactions with RUNX1 and MED1/Mediator are of functional importance for both gene-specific transcriptional activation and maintenance of E2A-PBX1-driven leukemia. The MED1 dependency for E2A-PBX1-mediated gene activation and leukemogenesis may provide a potential therapeutic opportunity by targeting MED1 in E2A-PBX1+ pre-B leukemia.
Asunto(s)
Carcinogénesis/genética , Proteínas de Homeodominio/metabolismo , Leucemia/genética , Leucemia/patología , Subunidad 1 del Complejo Mediador/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Transcripción Genética , Linfocitos B/patología , Carcinogénesis/patología , Puntos de Control del Ciclo Celular , Proliferación Celular/genética , Supervivencia Celular , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , ADN de Neoplasias/metabolismo , Regulación hacia Abajo/genética , Regulación Leucémica de la Expresión Génica , Genes Relacionados con las Neoplasias , Humanos , Unión Proteica , Estabilidad ProteicaRESUMEN
OBJECTIVE: To investigate the clinicopathological factors affecting discrepancies between multi-parametric magnetic resonance imaging (mpMRI) and histopathological evaluation for diagnosis of extraprostatic extension (EPE) of prostate cancer. METHODS: One hundred-and-three lesions from 96 cases with suspected EPE on preoperative mpMRI, of which 60 and 43 showed bulging and frank capsular breach, respectively, were grouped according to pathological (p)EPE in radical prostatectomy specimens. Additionally, clinicopathological/immunohistochemical findings for periostin reflecting a desmoplastic stromal reaction were compared between these groups. RESULTS: pEPE was detected in 49 (48%) of the 103 lesions. Of these, 25 (42%) showed bulging and 24 (56%) showed frank capsular breach on MRI. In the total cohort, the absence of pEPE was significantly associated with a lower Gleason Grade Group (GG) (p < 0.0001), anterior location (p = 0.003), absence of intraductal carcinoma of the prostate (IDC-P) (p = 0.026), and high stromal periostin expression (p < 0.0001). These trends were preserved in subgroups defined by MRI findings, except for anterior location/IDC-P in the bulging subgroup. CONCLUSIONS: GG, anterior location, and periostin expression may cause mpMRI-pathological discrepancies regarding EPE. Periostin expression was a significant pEPE-negative factor in all subgroup analyses. Our results indicate that patients with suspected EPE on MRI, regardless of their pEPE results, should be followed as carefully as those with definite pEPE.
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Imágenes de Resonancia Magnética Multiparamétrica , Prostatectomía , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/cirugía , Anciano , Persona de Mediana Edad , Próstata/patología , Próstata/diagnóstico por imagen , Moléculas de Adhesión Celular/análisis , Moléculas de Adhesión Celular/metabolismo , Clasificación del Tumor , Estudios Retrospectivos , Imagen por Resonancia MagnéticaRESUMEN
α-Actinin4 (ACTN4), an isoform of non-muscular α-actinin, is involved in enhancing cell motility and promoting cancer infiltration and metastasis in various cancers. However, information remains limited regarding the pathological significance of ACTN4 expression in upper urinary tract urothelial carcinomas (UUTUCs). We obtained tumor samples from 168 consecutive patients with newly diagnosed UUTUCs (92 with renal pelvic cancers and 76 with ureteral cancers), who were treated with nephroureterectomy or partial ureterectomy, and analyzed the expression of the ACTN4 protein and the amplification of ACTN4 using immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. The median follow-up duration was 65 months. Among 168 cases, 49 (29%) showed ACTN4 protein overexpression and 25 (15%) showed copy number gain (≥4 copies per cell) of ACTN4. The copy number gain of ACTN4 detected using FISH significantly correlated with ACTN4 protein overexpression and several adverse clinicopathological factors, including higher pathological T stage, lymphovascular invasion, lymph node metastasis, positive surgical margin, concomitant subtype histology, and non-papillary gross finding. Cox univariate regression analyses revealed that both copy number gain of ACTN4 and ACTN4 protein overexpression were significant risk factors for extraurothelial recurrence and death (each p < 0.0001), but multivariate analysis revealed that only copy number gain of ACTN4 was an independent risk factor for extraurothelial recurrence and death (p = 0.038 and 0.027, hazard ratio = 2.16 and 2.17, respectively). This is the first study demonstrating the aberrant expression status of ACTN4 in UUTUC and indicating its putative usefulness as a prognostic indicator in patients with UUTUC.
Asunto(s)
Carcinoma de Células Transicionales , Neoplasias Renales , Neoplasias Ureterales , Neoplasias de la Vejiga Urinaria , Sistema Urinario , Humanos , Neoplasias Ureterales/genética , Neoplasias Ureterales/cirugía , Variaciones en el Número de Copia de ADN/genética , Hibridación Fluorescente in Situ , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Pronóstico , Sistema Urinario/química , Estudios Retrospectivos , Actinina/genéticaRESUMEN
BACKGROUND: Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. METHODS: This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. RESULTS: A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. CONCLUSION: This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Nivolumab/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Estudio de Asociación del Genoma Completo , Supervivencia sin Progresión , Polimorfismo de Nucleótido Simple , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genéticaRESUMEN
BACKGROUND: This study is part of the SNPs in Nivolumab PD-1 inhibitor for RCC (SNiP-RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients. METHODS: We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression-free survival (PFS), overall survival (OS), and treatment-related grade ≥ 3 (serious adverse events [SAEs]). RESULTS: We included 222 patients. The median age was 69 years (interquartile range 62-74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS. CONCLUSION: The SNiP-RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Carcinoma de Células Renales/patología , Nivolumab/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Renales/patología , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVES: Large mucosal defects following gastric endoscopic submucosal dissection (ESD) cause postoperative bleeding. To address this limitation and ensure closure of large mucosal defects, we developed the reopenable clip-over-the-line method (ROLM) using a reopenable clip and nylon line. The purpose of this study was to evaluate the feasibility of the ROLM for closure of large mucosal defects following gastric ESD in a prospective, consecutive series of cases. METHODS: We performed the ROLM on 50 consecutive patients with gastric mucosal defects at the Ise Red Cross Hospital and Mie Prefectural Shima Hospital. The time to complete the ROLM, numbers of clips and lines required, size of defect, and closure success rate were measured, and postoperative adverse events were recorded. RESULTS: In all, 50 lesions were included in this study period between July 2021 and March 2022. The success rates of defect closure and defect closure without submucosal dead space of the ROLM were both 100% (50/50), with a median ROLM time of 30 (range, 14-35) min and a median resected specimen major axis of 45 (range, 31-73) mm. The median number of reopenable clips used was 31 (range, 10-93). Following gastric ESD, two cases of post-ESD bleeding were observed during the follow-up periods. CONCLUSION: Our results suggest that ROLM is a feasible strategy for complete closure of mucosal defects post-ESD without submucosal dead space. Future comparative studies with post-ESD bleeding rate as the main outcome are desirable to evaluate the efficacy of ROLM.
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Resección Endoscópica de la Mucosa , Humanos , Resección Endoscópica de la Mucosa/efectos adversos , Resección Endoscópica de la Mucosa/métodos , Estudios de Factibilidad , Estudios Prospectivos , Mucosa Gástrica/cirugía , Instrumentos Quirúrgicos , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
PURPOSE: We investigated inpatient convalescent rehabilitation outcomes of Branch atheromatous disease (BAD). SUBJECTS AND METHODS: The subjects were 116 patients with lenticulostriate artery territory - BAD (LSA-BAD) and 29 with paramedian pontine artery territory - BAD (PPA-BAD). For all patients, the National Institutes of Health Stroke Scale (NIHSS), Functional Independence Measure (FIM) scores, and Brunnstrom recovery stages (BRS) of the upper limb, fingers, and lower limb were measured on admission and at discharge. RESULTS: There were no significant differences in clinical characteristics on admission between the LSA-BAD and PPA-BAD groups. The neurological severity of PPA-BAD, as measured by the NIHSS, was significantly milder compared with that of LSA-BAD upon admission (p = 0.015) and at discharge (p = 0.001). Patients with LSA-BAD had significantly less improvement in the BRS of the upper limb (p = 0.001), fingers (p < 0.001), and lower limb (p = 0.007) at discharge. Furthermore, they had significantly smaller changes in BRS between admission and discharge for the upper limb (p = 0.033) and fingers (p = 0.014) compared with patients with PPA-BAD. The improvement in BRS for patients with LSA-BAD tended to be limited to two stages; however, both patients with LSA-BAD and PPA-BAD saw sufficient gains in FIM at discharge. CONCLUSION: Rehabilitation outcomes following BAD in the convalescent period should be assessed in terms of improvements in pure-motor hemiparesis and activities of daily living. Furthermore, the disturbance patterns in the corticospinal tract by ischemic stroke lesions may be different between LSA-BAD and PPA-BAD.
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Placa Aterosclerótica , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Humanos , Pacientes Internos , Actividades Cotidianas , Resultado del Tratamiento , Arterias , Recuperación de la Función , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapiaRESUMEN
BACKGROUND: Histopathological characteristics affecting the detectability of clinically significant prostate cancer (csPCa) on magnetic resonance imaging (MRI) remain unclear. This study aimed to compare the histopathology between MRI-detectable and MRI-undetectable cancers, emphasizing intraductal carcinoma of the prostate (IDC-P) and predominant Gleason pattern 4 subtype. METHODS: This single-center retrospective study enrolled 153 consecutive patients with 191 lesions who underwent preoperative multiparametric MRI and subsequent radical prostatectomy. MRI/histopathological findings and area fractions of histological components (cancer cells, stroma, and luminal spaces) of MRI-detectable and MRI-undetectable cancers were compared. Data were analyzed using Fisher's exact, independent t, or Mann-Whitney U tests. RESULTS: Overall, 148 (77%) and 43 (23%) cancers were MRI-detectable and MRI-undetectable, respectively. MRI-detectable cancers were significantly larger than MRI-undetectable cancers (p = 0.03). The percentage of lesions in Grade Group 3 or higher was significantly higher among MRI-detectable cancers than among MRI-undetectable cancers (p = 0.02). MRI detectability of csPCa was associated with increases in relative area fractions of cancer cells (p < 0.001) and decreases in those of stroma (p < 0.001) and luminal spaces (p < 0.001) in prostate cancer (PCa) than the percentage of Gleason pattern 4 (p = 0.09). The percentage of lesions containing IDC-P was similar for MRI-detectable and MRI-undetectable cancers (40% vs. 33%; p = 0.48). The distribution of cribriform gland subtypes was not significantly different between MRI-detectable and MRI-undetectable Gleason pattern 4 subtype cancers (p > 0.99). Contrarily, the ratio of fused gland subtype was significantly higher in MRI-detectable than in MRI-undetectable cancers (p = 0.03). Furthermore, the ratio of poorly-formed gland subtype was significantly higher in MRI-undetectable than in MRI-detectable cancers (p = 0.01). CONCLUSIONS: MRI detectability of csPCa is strongly associated with the relative area fractions of cancer cells, stroma, and luminal spaces in PCa rather than conventional histopathological parameters. Neither the presence nor the percentage of IDC-P affected MRI detectability.
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Carcinoma Intraductal no Infiltrante/patología , Imágenes de Resonancia Magnética Multiparamétrica , Neoplasias de la Próstata/patología , Anciano , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Oportunidad Relativa , Periodo Preoperatorio , Prostatectomía , Neoplasias de la Próstata/cirugía , Estudios RetrospectivosRESUMEN
OBJECTIVES: Up to 0.3% of Japanese have hypouricaemia. Most cases appear to result from a hereditary disease, renal hypouricaemia (RHUC), which causes exercise-induced acute kidney injury and urolithiasis. However, to what extent RHUC accounts for hypouricaemia is not known. We therefore investigated its frequency and evaluated its risks by genotyping a general Japanese population. METHODS: A cohort of 4993 Japanese was examined by genotyping the non-functional variants R90H (rs121907896) and W258X (rs121907892) of URAT1/SLC22A12, the two most common causative variants of RHUC in Japanese. RESULTS: Participants' fractional excretion of uric acid and risk allele frequencies markedly increased at lower serum uric acid (SUA) levels. Ten participants (0.200%) had an SUA level ≤2.0 mg/dl and nine had R90H or W258X and were likely to have RHUC. Logistic regression analysis revealed these URAT1 variants to be significantly and independently associated with the risk of hypouricaemia and mild hypouricaemia (SUA ≤3.0 mg/dl) as well as sex, age and BMI, but these URAT1 variants were the only risks in the hypouricaemia population (SUA ≤2.0 mg/dl). W258X was only a risk in males with SUA ≤3.0 mg/dl. CONCLUSION: Our study accurately reveals the prevalence of RHUC and provides genetic evidence for its definition (SUA ≤2.0 mg/dl). We also show that individuals with SUA ≤3.0 mg/dl, especially males, are prone to RHUC. Our findings will help to promote a better epidemiological understanding of RHUC as well as more accurate diagnosis, especially in males with mild hypouricaemia.
Asunto(s)
Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Cálculos Urinarios/genética , Femenino , Variación Genética , Genotipo , Humanos , Japón/epidemiología , Masculino , Defectos Congénitos del Transporte Tubular Renal/epidemiología , Cálculos Urinarios/epidemiologíaRESUMEN
BACKGROUND: Periostin is an extracellular matrix protein that has been known to be implicated in fibrillogenesis and cell migration, including cancer metastasis. Periostin overexpression in cancer cells and/or intervening stroma is usually related to tumor progression and poor patient outcomes in various human cancers; however, its role in urothelial carcinoma, especially upper urinary tract urothelial carcinomas (UTUCs), remains inconclusive. METHODS: Samples from 126 consecutive cases of invasive UTUC (69 renal pelvic cancers and 57 ureteral cancers) were histologically reviewed and analyzed for periostin expression using immunohistochemistry. The intensities of immunoreactivity and the fraction of positive cancer cells and stroma (i.e., epithelial and stromal expression, respectively) were classified into four categories each (intensity, 0-3; fraction, 0-25% = 1; 26-50% = 2; 51-75% = 3; and > 75% = 4). The overall score was determined by multiplying both scores, and overall scores ≥ 6 were considered to indicate high periostin expression. RESULTS: Among 126 UTUCs, 55 (44%; 27 renal pelvic and 28 ureteral cancers) showed high stromal periostin expression. None of the cases were considered to have high epithelial periostin expression. High stromal periostin expression was associated with non-papillary gross findings, higher pathological T category, lymphovascular invasion, concomitant carcinoma in situ, subtype histology, lymph node metastasis, positive surgical margins, high tumor budding, and high tumor-associated immune cell status. Multivariate analysis revealed that high stromal periostin expression was an independent predictor of overall survival (p = 0.00072, hazard ratio = 3.62), and lymphovascular invasion and high stromal periostin expression were independent predictors of cancer-specific survival (p = 0.032 and 0.020, hazard ratio = 2.61 and 3.07, respectively). CONCLUSIONS: Stromal periostin expression was often observed in invasive UTUCs with adverse clinicopathological factors and may be a useful predictor of patient outcomes.
Asunto(s)
Carcinoma de Células Transicionales , Neoplasias Renales , Neoplasias Ureterales , Neoplasias de la Vejiga Urinaria , Sistema Urinario , Carcinoma de Células Transicionales/patología , Humanos , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Pronóstico , Neoplasias Ureterales/patología , Neoplasias Ureterales/cirugía , Neoplasias de la Vejiga Urinaria/patología , Sistema Urinario/patologíaRESUMEN
PURPOSE: We studied the impact of membranous urethral length (MUL) on magnetic resonance imaging (MRI) on post-urethroplasty continence in male patients with pelvic fracture urethral injury (PFUI). METHODS: Of 169 male patients with PFUI who underwent delayed anastomotic urethroplasty between 2008 and 2020, 85 who underwent preoperative MRI, had no recurrent stenosis on cystoscopy, and underwent a 1-h pad test 1 year after surgery were included. MUL was defined as the distance from the distal end of the disrupted proximal urethra to the apex of the prostate, as measured using T2-weighted MRI. Urinary incontinence (UI) was defined as a 1-h pad test weight > 2.0 g. RESULTS: None of the patients had UI before a pelvic fracture. Eighty-two patients (96.5%) had a measurable MUL, and the median length was 8.1 (interquartile range [IQR], 5.2-10.8) mm. The median weight of the 1-h pad test was 1.0 (IQR, 0.0-4.0) g, and 26 (30.6%) patients had UI. An open bladder neck (odds ratio [OR], 4.6; 95% confidence interval [CI], 1.0-22.0; p = 0.04) and a short measurable membranous urethra (for every extra mm: OR, 1.2; 95% CI, 1.0-1.3; p = 0.04) were significant UI predictors on multivariate analysis. CONCLUSIONS: A long MUL is significantly positively associated with urinary continence in male patients with PFUI. This could be of potential value to reconstructive urologists when counseling patients regarding post-urethroplasty continence before urethroplasty.
Asunto(s)
Fracturas Óseas/complicaciones , Imagen por Resonancia Magnética , Huesos Pélvicos/lesiones , Complicaciones Posoperatorias/epidemiología , Uretra/diagnóstico por imagen , Uretra/lesiones , Incontinencia Urinaria/epidemiología , Adulto , Anastomosis Quirúrgica , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Tiempo de Tratamiento , Uretra/anatomía & histología , Procedimientos Quirúrgicos Urológicos Masculinos/métodosRESUMEN
The management of male pelvic fracture urethral injury remains a urological challenge. Pelvic fracture urethral injury can be associated with sequelae, such as urethral gap, erectile dysfunction and urinary incontinence. Delayed anastomotic urethroplasty, the gold standard treatment for urethral gaps caused by pelvic fracture urethral injuries, is technically demanding, and reconstructive urologists should preoperatively obtain as much detailed anatomical information as possible. A combination of antegrade and retrograde urethrography is the fundamental preoperative evaluation, but it cannot accurately assess the urethral gap length, the degree of lateral prostatic displacement, the anatomical relationship of the urethra with its surrounding structures (such as the rectum and dorsal venous complex) or periurethral problems (such as minor fistulae or cavitation). To make up for these limitations of urethrography, magnetic resonance imaging has emerged as a non-invasive, multiplanar and high-resolution modality for the evaluation of pelvic fracture urethral injury. Magnetic resonance imaging has excellent soft-tissue contrast, and can clearly show the urethra and periurethral tissues without the effects of radiation, thus enabling clinicians to anticipate the required ancillary techniques for delayed anastomotic urethroplasty and to predict functional outcomes, such as erectile function and urinary continence, after delayed anastomotic urethroplasty. This review discusses the role of magnetic resonance imaging in the evaluation of pelvic fracture urethral injury and its impact on patient management.
Asunto(s)
Fracturas Óseas , Huesos Pélvicos , Enfermedades Uretrales , Fracturas Óseas/complicaciones , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Huesos Pélvicos/diagnóstico por imagen , Huesos Pélvicos/lesiones , Uretra/diagnóstico por imagen , Uretra/lesiones , Uretra/cirugía , Enfermedades Uretrales/diagnóstico por imagen , Enfermedades Uretrales/etiología , Enfermedades Uretrales/cirugíaRESUMEN
OBJECTIVES: We report our surgical experience of transperineal bulbovesical anastomosis (BVA) for extensive posterior urethral stenosis (PUS). METHODS: Six male patients who had extensive PUS extending from the bulbomembranous urethra to the bladder neck due to prostatic disease treatment and underwent transperineal BVA between 2014 and 2020 were retrospectively reviewed. BVA was performed according to the elaborate perineal approach for pelvic fracture urethral repair with minor modifications. After confirming the absence of recurrent stenosis 6 months postoperatively, the patients were offered artificial urinary sphincter (AUS) placement for subsequent urinary incontinence (UI). RESULTS: Median patient age was 68, and the etiology of PUS was radical prostatectomy for prostate cancer in four patients, brachytherapy for prostate cancer in one, and transurethral resection of the prostate for benign prostatic hyperplasia in one. All patients had been previously treated with multiple transurethral procedures such as urethrotomy and dilation. Median operative time and blood loss were 211 min and 154 ml, respectively. Five cases (83.3%) had no recurrent stenosis with a median follow-up of 45 months, but a single direct vision internal urethrotomy was performed in one (16.7%) due to restenosis. Four (66.7%) patients underwent AUS placement via transcorporal approach for subsequent UI, but two had it removed due to urethral erosion. CONCLUSION: Transperineal BVA could effectively manage extensive PUS after prostatic disease treatment. Staged AUS placement could be a viable option for subsequent UI, but the risk of urethral erosion seemed high.
Asunto(s)
Neoplasias de la Próstata , Resección Transuretral de la Próstata , Estrechez Uretral , Incontinencia Urinaria , Esfínter Urinario Artificial , Humanos , Masculino , Estrechez Uretral/etiología , Estrechez Uretral/cirugía , Estudios Retrospectivos , Resección Transuretral de la Próstata/efectos adversos , Constricción Patológica/etiología , Constricción Patológica/cirugía , Esfínter Urinario Artificial/efectos adversos , Prostatectomía/efectos adversos , Prostatectomía/métodos , Uretra/cirugía , Incontinencia Urinaria/etiología , Anastomosis Quirúrgica/efectos adversos , Neoplasias de la Próstata/complicacionesRESUMEN
OBJECTIVES: We investigated the efficacy of urethral reconstruction in male patients with iatrogenic urethral stricture after transurethral prostate surgery. METHODS: We retrospectively reviewed the cases of 82 patients who underwent urethral reconstruction for iatrogenic urethral stricture caused by transurethral prostate surgery between August 2011 and July 2021. Patients were followed up postoperatively with uroflowmetry, postvoid residual urine measurement, and questionnaires using Peeling's picture score, International Prostate Symptom Score, International Consultation on Incontinence Questionnaire Short Form, Sexual Health Inventory for Men, EuroQol-5 dimensions, and EuroQol-5 dimensions visual analog scores. Successful urethral reconstruction was defined as the absence of a postoperative decrease in urinary force and any additional treatment. RESULTS: The median patient age was 72 years, and the stricture site was the urethral meatus in eight (9.8%) patients, penoscrotal junction in 42 (51.2%), and proximal bulbar urethra in 26 (31.7%). Six patients (7.3%) had synchronous urethral strictures. Urethral reconstruction was successful in 78 patients (95.1%), with a median follow-up of 43 months. The mean maximum flow rate (P < 0.0001), postvoid residual urine (P = 0.004), Peeling's picture score (P < 0.0001), the score for each question and total International Prostate Symptom Score and International Prostate Symptom Score-quality of life scores (P < 0.0001 for all comparisons), and EuroQol-5 dimensions and EuroQol-5 dimensions visual analog scores (P < 0.0001 for both) significantly improved postoperatively. However, the Sexual Health Inventory for Men and International Consultation on Incontinence Questionnaire Short Form scores remained unchanged (P = 0.09 and 0.70, respectively). CONCLUSIONS: Urethral reconstruction was effective for urethral stricture due to transurethral prostate surgery in both subjective and objective aspects.