RESUMEN
OBJECTIVE: To examine whether infertile men with poor semen count subsequently developed testicular cancers and to describe their clinical presentation. DESIGN: We reviewed 460 male patients with abnormal semen counts between 1989 and 2004. SETTING: University hospital. PATIENT(S): Infertile men who developed testicular cancers after assisted reproductive technologies (ART). INTERVENTION(S): Description of patient characteristics: age at infertility, presentation, semen quality, and ART. MAIN OUTCOME MEASURE(S): The number of patients who subsequently developed testicular cancers and the period from ART to the development of clinical testicular cancers. RESULT(S): Of the 460 patients, 169 patients presented with mild oligozoospermia, 117 patients with severe oligozoospermia, and 174 patients with azoospermia. The follow-up periods were as follows: 1-192 months (median, 96.5 mo) for mild oligozoospermia, 1-156 months (median, 78.5 mo) for severe oligozoospermia, and 1-197 months (median, 99 mo) for azoospermia. We subsequently found three testicular cancers that had developed among severely oligozoospermic and azoospermic patients. The period from the claim of sterility to developing testicular cancers varied from 4 to 14 years (median, 9 y). CONCLUSION(S): These results indicate that severe semen abnormality may be a risk factor in developing testicular cancers. Self-examination of the testes could be used as an alternative or supplement to physical examination and testicular ultrasound as part of the infertility workup, even after ART.
Asunto(s)
Azoospermia/epidemiología , Oligospermia/epidemiología , Neoplasias Testiculares/epidemiología , Adulto , Azoospermia/complicaciones , Estudios de Seguimiento , Humanos , Masculino , Oligospermia/complicaciones , Estudios Retrospectivos , Neoplasias Testiculares/etiologíaRESUMEN
BACKGROUND: A retrospective study was conducted to examine the host factors of 240 testicular germ cell tumor patients. This study was performed to address a new theory proposed by Skakkebaek called testicular dysgenesis syndrome which claims that cryptorchism, hypospadias, poor semen quality and testicular germ cell tumors are symptoms of an underlying testicular dysgenesis in uterus. METHODS: The past health histories and familial episodes of 240 testicular germ cell tumor patients were examined. The past health histories included cryptorchism, hypospadias, infertility, atrophic testis and inguinal hernia. RESULTS: Of the 240 patients, 13 (5.4%) had a history of cryptorchism or orchidopexy. Two (0.8%) showed existence of hypospadias or had experienced urethroplasty. Among 129 married couples, 104 (80.6%) couples were fertile. Three (1.3%) patients developed testicular tumors after they were diagnosed as infertile or came to the hospital with the complaints of infertility. Four (1.7%) had contralateral atrophic testis. 19 (7.9%) had experienced inguinal herniorrhaphy before age 15. Three (1.3%) had testicular germ cell tumor patients among their family or relatives. CONCLUSIONS: The testicular germ cell tumor patients showed a considerable incidence of complications such as cryptorchism, hypospadias and incomplete closure of processus vaginalis. Cryptorchism, perinatal factors and familial factors could be risks for developing testicular germ cell tumors.
Asunto(s)
Germinoma/etiología , Neoplasias Testiculares/etiología , Adolescente , Adulto , Anciano , Atrofia/complicaciones , Niño , Preescolar , Criptorquidismo/complicaciones , Salud de la Familia , Germinoma/genética , Hernia Inguinal/complicaciones , Humanos , Hipospadias/complicaciones , Lactante , Infertilidad Masculina/complicaciones , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Testiculares/genética , Testículo/patologíaRESUMEN
PURPOSE: We performed contra-lateral testicular biopsies in 55 testicular tumor patients when high orchiectomy was performed. In these cases, two cases developed invasive testicular tumor later although the biopsies had not revealed testicular CIS. Then we re-examined the sensitivity of biopsies and judged if our results are contradictory against Skakkebaek's theory. PATIENTS AND METHODS: The paraffin blocks of two cases who later developed testicular tumor were sliced again and re-examined by H/E staining and immunostaining with PLAP antibody (clone No. 8A9). The other 53 H/E samples were re-examined and the result of the contra-lateral testis was re-searched in the case that CIS was detected in the specimen. RESULTS: CIS was detected in one of the two cases who later developed contra-lateral testicular tumor and another case among the other 53 cases. We could not reveal the result of the testis of case No. 3 because of the patient's disappearance. CIS existed 3.6% (2/55) and two cases were found to have been false negative. CONCLUSION: It is important for both urologists and pathologists to know well about testicular CIS and to perform biopsy according to Skakkebaek's guidance for raising the sensitivity to detect testicular CIS.
Asunto(s)
Carcinoma in Situ/patología , Germinoma/cirugía , Neoplasias Testiculares/patología , Neoplasias Testiculares/cirugía , Testículo/patología , Adolescente , Adulto , Biopsia , Carcinoma in Situ/etiología , Humanos , Masculino , Persona de Mediana Edad , Orquiectomía , Neoplasias Testiculares/etiologíaRESUMEN
Seminoma constitutes one subtype of human testicular germ cell tumors and is uniformly composed of cells that are morphologically similar to the primordial germ cells and/or the cells in the carcinoma in situ. We performed a genome-wide exploration of the genes that are specifically up-regulated in seminoma by oligonucleotide-based microarray analysis. This revealed 106 genes that are significantly and consistently up-regulated in the seminomas compared to the adjacent normal tissues of the testes. The microarray data were validated by semi-quantitative RT-PCR analysis. Of the 106 genes, 42 mapped to a small number of specific chromosomal regions, namely, 1q21, 2p23, 6p21-22, 7p14-15, 12pll, 12p13, 12q13-14 and 22q12-13. This list of up-regulated genes may be useful in identifying the causative oncogene(s) and/or the origin of seminoma. Furthermore, immunohistochemical analysis revealed that the seminoma cells specifically expressed the six gene products that were selected randomly from the list. These proteins include CCND2 and DNMT3A and may be useful as molecular pathological markers of seminoma.
Asunto(s)
Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos , Seminoma/genética , Neoplasias Testiculares/genética , Animales , Inmunohistoquímica , Masculino , Oncogenes , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
Obstructive nephropathy refers to the mechanical or functional changes in the urinary tract that interfere with normal urinary flow. Once obstruction is set, it leads to progressive renal damage that is mainly characterized with tubulointerstitial fibrosis. Here we reviewed the pathophysiology of urinary tract obstruction and indicated future therapeutic options. Following complete unilateral ureteral obstruction, there is a progressive fall in renal blood flow and glomerular filtration rate, and is a increase in intratubular pressure. These events activate the plasma and tissue renin-angiotensin systems (RAS). It has been proved that upregulated angiotensin II is one of the crucial factors those are responsible for the subsequent deleterious process. Angiotensin II induces transforming growth factor-beta, which causes overproduction of extracellular matrix (ECM) proteins like collagen, fibronectin, etc. The ECM proteins are dominantly accumulated in tubulointerstitium and result in deterioration of renal function. Along with the activation of the RAS, tissue ischemia and mononuclear leukocyte infiltration also modulate the fibrotic changes. The process from the RAS activation to renal fibrosis is observed not only in obstructive nephropathy but also in other renal diseases and is called the Final Common Pathway. Mechanical release of the obstruction is to perform in terms of the treatment, however, several promising pharmaceutical options are now under investigation.
Asunto(s)
Enfermedades Renales/fisiopatología , Obstrucción Ureteral/fisiopatología , Angiotensina II/fisiología , Animales , Fibrosis/etiología , Humanos , Hidronefrosis/etiología , Enfermedades Renales/patología , Túbulos Renales/patología , Ratones , Ratas , Receptores de Angiotensina/fisiología , Circulación Renal , Sistema Renina-Angiotensina/fisiologíaRESUMEN
The gene coding for microphthalmia-associated transcription factor (Mitf) contains many promoters that could generate multiple Mitf isoforms with distinct amino-termini, such as ubiquitously expressed Mitf-A and Mitf-H. To gain further insight into Mitf isoform multiplicity and the regulation of the promoter usage of the Mitf gene, we have analyzed the function of the amino-terminal domains of Mitf isoforms and the expression of Mitf mRNA in mouse postnatal testis, which is characterized by spermatogenesis and by a cool temperature because of its unique location. Here we show that the amino-terminal domain of Mitf-A possesses a transactivation activity, as judged by yeast expression analysis. We also show the expression of Mitf-A and Mitf-D mRNAs in testis by PCR-based methods. Moreover, in situ hybridization analysis revealed that an Mitf mRNA, probably representing Mitf-A and/or Mitf-D, is expressed in germ cells, including spermatogonia, spermatocytes that undergo meiosis, and round spermatids with the haploid genome, but is undetectable in elongated spermatids with remodeled and condensed chromatin. Notably, Mitf mRNA is undetectable in somatic Leydig cells and peritubular cells. Therefore, multiple promoters may direct differential expression of the Mitf gene in the testis and contribute to functional diversity of Mitf isoforms.
Asunto(s)
Proteínas de Unión al ADN/biosíntesis , ARN Mensajero/biosíntesis , Espermatozoides/metabolismo , Testículo/metabolismo , Factores de Transcripción/biosíntesis , Animales , Animales Recién Nacidos , Secuencia de Bases , Proteínas de Unión al ADN/genética , Exones/genética , Expresión Génica , Masculino , Ratones , Ratones Endogámicos C3H , Factor de Transcripción Asociado a Microftalmía , Regiones Promotoras Genéticas , Isoformas de Proteínas , Estructura Terciaria de Proteína , ARN Mensajero/genética , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Testículo/citología , Testículo/ultraestructura , Factores de Tiempo , Factores de Transcripción/genética , Transcripción Genética , Activación TranscripcionalRESUMEN
Tubulointerstitial fibrosis is a major cause of irreversible renal damage in the obstructed kidney. The effects of release of obstruction on the obstructed kidney are not clearly understood. We investigated the effects of the release of ureteral obstruction on renal fibrosis and the expression of fibrogenic factors. Rats underwent 5 day of unilateral ureteral obstruction (UUO). After release of obstruction by removing an encased rubber tube, changes in interstitial volume were morphologically evaluated and the mRNA expression of transforming growth factor-beta (TGF-beta), type IV collagen (collagen IV), and plasminogen activator inhibitor-1 (PAI-1) were examined by reverse transcription-polymerase chain reaction (RT-PCR) up to 28 days. Renal interstitial volume, collagen IV and PAI-1 mRNA gradually decreased from 7 days to 28 days after release of obstruction. However, increased expression of TGF-beta mRNA persisted up to 14 days, and then declined 28 days after release. In conclusion, obstruction-induced renal fibrosis was recovered with diminished expression of TGF-beta and collagen IV. Decreased PAI-1 expression in the post-obstructed kidney may contribute to the degradation of extracellular matrix proteins and recovery of tubulointerstitial fibrosis, at least partly, after release of ureteral obstruction.
Asunto(s)
Colágeno Tipo IV/metabolismo , Riñón/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Obstrucción Ureteral/terapia , Animales , Colágeno Tipo IV/genética , Femenino , Riñón/patología , Inhibidor 1 de Activador Plasminogénico/genética , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta/genética , Regulación hacia Arriba , Obstrucción Ureteral/metabolismoRESUMEN
Waardenburg syndrome type 2 (WS2) is associated with heterozygous mutations in the gene encoding microphthalmia-associated transcription factor (MITF) and characterized by deafness and hypopigmentation due to lack of melanocytes in the inner ear and skin. Melanocyte-specific MITF isoform (MITF-M) is essential for melanocyte differentiation and is transcriptionally induced by Wnt signaling that is mediated by beta-catenin and LEF-1. Here we show that MITF-M transactivates its own promoter (M promoter) by interacting with LEF-1, as judged by transient expression assays and in vitro protein-protein binding assays, whereas no transactivation of the M promoter was detected with MITF-M alone or with the combination of MITF-M and dominant-negative LEF1 that lacks the beta-catenin-binding domain. This synergy depends on the three LEF-1-binding sites that are clustered in the proximal M promoter. Importantly, MITF-M recruited on the M promoter could function as a non-DNA-binding cofactor for LEF-1. Thus, MITF-M may function as a self-regulator of its own expression to maintain a threshold level of MITF-M that is required for melanocyte development. We suggest that MITF-M haploinsufficiency may impair the dosage-sensitive role of MITF-M or the correct assembly of multiple transcription factors, involving MITF-M, on the M promoter, which could account for dominant inheritance of WS2.
Asunto(s)
Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Melanocitos/metabolismo , Regiones Promotoras Genéticas , Factores de Transcripción/metabolismo , Animales , Sitios de Unión , Células COS , Núcleo Celular/metabolismo , Proteínas de Unión al ADN/genética , Relación Dosis-Respuesta a Droga , Genes Dominantes , Células HeLa , Humanos , Luciferasas/metabolismo , Factor de Unión 1 al Potenciador Linfoide , Factor de Transcripción Asociado a Microftalmía , Modelos Genéticos , Mutación , Plásmidos/metabolismo , Unión Proteica , Isoformas de Proteínas , Estructura Terciaria de Proteína , Transducción de Señal , Activación Transcripcional , TransfecciónRESUMEN
PURPOSE: The plasminogen activator (PA)-plasmin system has been shown to influence turnover of the extracellular matrix in various tissues. We examined the alteration of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) in kidneys with unilateral ureteral obstruction in rats. MATERIALS AND METHODS: Female rats that underwent ligation of the left ureter were sacrificed 12 hours, 1, 5 or 10 days later. The expressions of PAI-1 and t-PA was determined by reverse transcription-polymerase chain reaction and immunohistochemical studies in the obstructed and contralateral kidneys in each group. RESULTS: Control kidneys showed no PAI-1 messenger (m)RNA expression. After days 1 through 10 of unilateral ureteral obstruction the amount of PAI-1 mRNA significantly increased in obstructed compared with contralateral kidneys (p <0.01). Meanwhile, slight polymerase chain reaction products of t-PA were observed in control kidneys. After 12 hours through 10 days of unilateral ureteral obstruction, t-PA mRNA in obstructed and contralateral kidneys was significantly elevated compared with in control kidneys (p <0.05). No significant difference in t-PA was observed in the obstructed and contralateral kidneys in each group. Immunoreactivity to PAI-1 and t-PA was identified in obstructed kidneys. CONCLUSIONS: PAI-1 and t-PA are up-regulated in obstructed rat kidneys. Our results indicate that the PA-plasmin system has a role in the process of matrix accumulation and degradation during rat obstructive nephropathy.
Asunto(s)
Regulación hacia Arriba , Obstrucción Ureteral/fisiopatología , Animales , Modelos Animales de Enfermedad , Matriz Extracelular , Femenino , Inmunohistoquímica , Inhibidor 1 de Activador Plasminogénico , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-Dawley , Activador de Tejido Plasminógeno , Obstrucción Ureteral/sangreRESUMEN
BACKGROUND: The present study provides data from clinical experience with gamma-knife radiosurgery (GK) in patients with brain metastasis from renal cell carcinoma (RCC) and shows the value of this less invasive treatment modality. METHODS: Forty-two patients received GK. Twenty of the 42 cases had multiple brain metastases. Extracranial metastases were observed in the lung (38 cases), bone (12 cases), liver (9 cases), lymph node (5 cases) and skin (6 cases). RESULTS: Neurological symptoms seen in 40 patients were rapidly improved after GK in 32 patients (80%). Magnetic resonance imaging (MRI) evaluation after GK in 32 patients showed the disappearance of brain tumor in 9 patients (28%). Complete response was obtained by GK in tumors up to 30 mm in diameter. Repeated GK for newly developed lesions was conducted in 11 patients. Extracranial tumor resection was conducted in 7 cases (lung: 3, skin: 2, liver: 1, adrenal: 1). Chemo-radiotherapy or immunotherapy was effective in 8 cases (lung: 5, liver: 2, bone: 1). The actual one-, two- and three-year survival rates were 44.9%, 16.8%, and 11.2%, respectively. The median survival time was 12.5 months. In univariate analysis, the patients with successfully treated extracranial metastases had significantly better prognosis. In multivariate analysis, the patients with Karnofsky performance scale (KPS) > or = 80%, who were treated by GK more than once and obtained complete response (CR) or partial response (PR) by GK, had significantly better prognosis. CONCLUSION: Gamma-knife radiosurgery for RCC is an effective non-invasive modality of treatment. It offers a high local control rate and an improved quality of life and survival rate.