RESUMO
BACKGROUND: Partner of SLD5 1 (PSF1) is an evolutionarily conserved DNA replication factor. Previous studies have suggested that transcriptional activity of the PSF1 gene correlated with malignancy of cancer cells. The objective of the current study was to evaluate the relationship between PSF1 expression and the clinical features of prostate cancer. METHODS: We determined the expression of PSF1 in 120 needle biopsy samples of prostate cancer by immunohistochemistry. We divided patients into PSF1-positive or -negative groups and analyzed the relationships between the expression of PSF1, the Gleason score, PSA level, TNM classification and prognosis. RESULTS: Our results showed that the PSF1 expression correlated significantly with PSA values at diagnosis (P=0.0028), with tumor grade (P<0.0001), and with clinical stage (P=0.0005). Moreover, the PSF1 expression correlated significantly with overall survival (hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.17-15.8; P=0.003) and progression-free survival in 99 consecutive patients with prostate cancer. Noteworthy, the prognosis of PSF1-positive cases was also worse in patients with a Gleason score of 8-10 (HR 3.7; 95% CI 1.28-13.43; P=0.0143). Limitations include that this study had a retrospective design, that patients in the study were heterogeneous and included those with early and advanced cancer, and that small tumor fragments may not be representative of the entire carcinoma. CONCLUSIONS: PSF1 is expressed in high-grade prostate cancer and may be a useful biomarker to identify patients with a poor prognosis at the time of diagnosis.
Assuntos
Transportadores de Cassetes de Ligação de ATP/biossíntese , Biomarcadores Tumorais/biossíntese , Neoplasias da Próstata/genética , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We describe a 40-month-old male infant with renal failure, treated with peritoneal dialysis, who developed massive calcification of soft tissues including the heart and lungs with subsequent cardiopulmonary insufficiency. A diagnosis of Jeune syndrome was made. After starting peritoneal dialysis, the patient exhibited an intractable metabolic acidosis of unknown etiology necessitating treatment with intravenous or oral sodium bicarbonate. Myocardial calcification was first detected by 2-dimensional echocardiography performed 3 months after starting dialysis. The patient was not suitable for renal transplantation because of his cardiac dysfunction and died of cardiac and respiratory failure at the age of 6 years. Although the patient exhibited a variety of risk factors for ectopic calcification including hyperphosphatemia, hyperparathyroidism, high calcium-phosphate product and treatment with vitamin D, the early and massive soft tissue calcification may have been accelerated by correction of the metabolic acidosis. Therefore, the use of sodium bicarbonate may be involved in the etiology of the myocardial calcification.
Assuntos
Acidose/tratamento farmacológico , Calcinose/etiologia , Cardiomiopatias/etiologia , Pneumopatias/etiologia , Diálise Peritoneal/efeitos adversos , Bicarbonato de Sódio/efeitos adversos , Acidose/sangue , Acidose/complicações , Calcinose/sangue , Calcinose/diagnóstico , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico , Ecocardiografia , Evolução Fatal , Seguimentos , Humanos , Lactente , Pneumopatias/sangue , Pneumopatias/diagnóstico , Masculino , Insuficiência Renal/terapia , Bicarbonato de Sódio/farmacocinética , Bicarbonato de Sódio/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
We have used fluorescence anisotropy to measure in situ the thermodynamics of binding of alanine-rich mutants of the GCN4 basic region/leucine zipper (bZIP) to short DNA duplexes, in which thymines were replaced with uracils, in order to quantify the contributions of the C5 methyl group on thymines with alanine methyl side chains. We simplified the alpha-helical GCN4 bZIP by alanine substitution: 4A, 11A, and 18A contain four, 11, and 18 alanine mutations in their DNA-binding basic regions, respectively. Titration of fluorescein-labeled duplexes with increasing amounts of protein yielded dissociation constants in the low-to-mid nanomolar range for all bZIP mutants in complex with the AP-1 target site (5'-TGACTCA-3'); binding to the nonspecific control duplex was >1000-fold weaker. Small changes of <1 kcal/mol in binding free energies were observed for wild-type bZIP and 4A mutant to uracil-containing AP-1, whereas 11A and 18A bound almost equally well to native AP-1 and uracil-containing AP-1. These modest changes in binding affinities may reflect the multivalent nature of protein-DNA interactions, as our highly mutated proteins still exhibit native-like behavior. These protein mutations may compensate for changes in enthalpic and entropic contributions toward DNA-binding in order to maintain binding free energies similar to that of the native protein-DNA complex.
Assuntos
Alanina/química , Proteínas de Ligação a DNA/química , Mutação , Timina/química , Fatores de Transcrição/química , Motivos de Aminoácidos , Substituição de Aminoácidos , Fatores de Transcrição de Zíper de Leucina Básica , Sítios de Ligação , DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Polarização de Fluorescência , Fatores de Ligação G-Box , Ligação Proteica , Termodinâmica , Titulometria , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Uracila/química , Leveduras/químicaRESUMO
The excised rat crystalline lens opacified when incubated aerobically with phenazine methosulfate, but no opacification was observed under anaerobic conditions. Morphological studies revealed development of opacification in the cortex. The opacification resembled that often seen in the early period of senile cataract as well as in naphthalene-induced and UV cataract. Both an increase in hydration and in electrolyte imbalance accompanied this opacification. Na,K-ATPase activity of the opacified lens was found to decrease. In order to investigate if activated oxygen is involved in these processes, we conducted an electron spin resonance study by means of a spin trapping technique. When the lens homogate was incubated with phenazine methosulfate, OH radicals were generated under aerobic but not under anaerobic conditions. Reduced pyridine nucleotides must be involved in the process, because the mixture of nicotinamide adenine dinucleotide phosphate [NAD(P)] and phenazine methosulfate did not generate OH radicals, but the mixture of NAD(P)H and phenazine methosulfate generates OH radicals, indicating that reduced phenazine methosulfate was involved in the OH radical generation. Probably, the generated OH radicals inactivated Na,K-ATPase residing in the epithelium of the lens, which eventually caused opacification of the lens. The present experiment system may be used for the elucidation of lens opacification (cataract) involved with reactive oxygen species.