RESUMEN
AIMS: This multicentric retrospective study reports long-term clinical outcomes of non-metastatic grade group 5 prostate cancers treated with external beam radiotherapy (EBRT) alone with long-term androgen deprivation therapy (ADT). MATERIALS AND METHODS: Patients treated across 19 institutions were studied. The key endpoints that were evaluated were 5-year biochemical recurrence-free survival (bRFS), metastases-free survival (MFS), overall survival, together with EBRT-related acute and late toxicities. The impact of various prognostic factors on the studied endpoints was analysed using univariate and multivariate analyses. RESULTS: Among the 462 patients, 88% (405) had Gleason 9 disease and 31% (142) had primary Gleason pattern 5. A prostate-specific membrane antigen positron emission tomography-computed tomography scan was used for staging in 33% (153), 80% (371) were staged as T3/T4 and 30% (142) with pelvic nodal disease. The median ADT duration was 24 months; 66% received hypofractionated EBRT and 71.4% (330) received pelvic nodal irradiation. With a median follow-up of 56 months, the 5-year bRFS, MFS and overall survival were 73.1%, 77.4% and 90.5%, respectively. Primary Gleason pattern 5 was associated with worse bRFS, MFS and overall survival with hazard ratios of 0.51 (95% confidence interval 0.35 to 0.73, P < 0.001), 0.64 (95% confidence interval 0.43 to 0.96, P = 0.031) and 0.52 (95% confidence interval 0.28 to 0.97, P = 0.040), respectively, whereas pelvic nodal disease was associated with worse bRFS (hazard ratio 0.67, 95% confidence interval 0.46 to 0.98, P = 0.039) and MFS (hazard ratio 0.56, 95% confidence interval 0.37 to 0.85, P = 0.006). The acute and late radiation-related toxicities were low overall and pelvic nodal irradiation was associated with higher toxicities. CONCLUSION: Contemporary EBRT and long-term ADT led to excellent 5-year clinical outcomes and low rates of toxicity in this cohort of non-metastatic grade group 5 prostate cancers. Primary Gleason pattern 5 and pelvic node disease portends inferior clinical outcomes.
Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Antagonistas de Andrógenos/uso terapéutico , Andrógenos , Próstata/patología , Estudios Retrospectivos , Biopsia , Antígeno Prostático EspecíficoRESUMEN
AIMS: The safety and efficacy of stereotactic body radiotherapy (SBRT) in localised prostate cancer are now established through phase III randomised trials. Its utility in node-positive prostate cancer is restricted due to a lack of controlled studies specifically addressing this subgroup. Herein we report the safety and efficacy of SBRT in this subgroup. MATERIALS AND METHODS: In total, 60 patients treated with SBRT to prostate and pelvis were analysed. All patients received neoadjuvant androgen deprivation therapy for at least 6 months and long-term adjuvant hormonal therapy (70% medical and 30% surgical). All patients were treated with daily image-guided rotational intensity-modulated radiotherapy. The dose delivered to the prostate and gross node was 35-37.5 Gy and 25 Gy in five fractions to the elective pelvic nodal region on alternate days. Acute and late toxicities were graded as per Radiation Therapy Oncology Group common toxicity criteria. RESULTS: Forty-one (68%) patients had a Gleason score ≥8. The median prostate-specific antigen level at diagnosis was 39 ng/ml. Twenty (33%) patients had common iliac nodal uptake on initial prostate-specific membrane antigen positron emission tomography-computed tomography. After the median follow-up of 30 months, no acute or late Radiation Therapy Oncology Group grade ≥3 gastrointestinal toxicity was noted. Acute grade 2 genitourinary and gastrointestinal toxicities were 8.3% and 11.7%, respectively. Late grade 2 genitourinary and gastrointestinal toxicities were 3.3% and 8.3%, respectively. Late grade 3 genitourinary toxicity was seen in two (3.3%) patients. Three-year overall survival and biochemical failure-free survival was 89% and 77%, respectively. CONCLUSION: SBRT to the prostate and pelvis is safe and efficacious in node-positive prostate cancer even with common iliac nodal involvement (stage M1a).
Asunto(s)
Neoplasias de la Próstata , Radioterapia de Intensidad Modulada , Antagonistas de Andrógenos , Humanos , Masculino , Clasificación del Tumor , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Hipofraccionamiento de la Dosis de Radiación , Radiocirugia/efectos adversos , Radioterapia de Intensidad Modulada/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the hepatoprotective potential of Solanum xanthocarpum (Solanaceae) (S. xanthocarpum) in experimental rats to validate its traditional claim. METHODS: 50% ethanolic fruit extract of S. xanthocarpum (SXE, 100, 200 or 400 mg/kg body weight) was administered daily for 14 days in experimental animals. Liver injury was induced chemically, by CCl(4) administration (1 mL/kg i. p.). The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase (AST), alanine aminotransferase (ALT), Serum alkaline phosphatise (SALP) and total bilirubin. Meanwhile, in vivo antioxidant activities as lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were screened along with histopathological studies. RESULTS: Obtained results demonstrated that the treatment with SXE significantly (P<0.05-<0.001) and dose-dependently prevented chemically induced increase in serum levels of hepatic enzymes. Furthermore, SXE significantly (up to P<0.001) reduced the lipid peroxidation in the liver tissue and restored activities of defence antioxidant enzymes GSH, SOD and catalase towards normal levels. Histopathology of the liver tissue showed that SXE attenuated the hepatocellular necrosis and led to reduction of inflammatory cells inflltration. CONCLUSIONS: The results of this study strongly indicate the protective effect of SXE against acute liver injury which may be attributed to its hepatoprotective activity, and there by scientifically support its traditional use.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Frutas , Hígado/efectos de los fármacos , Fitoterapia , Extractos Vegetales/farmacología , Solanum , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Aspartato Aminotransferasas/sangre , Tetracloruro de Carbono , Catalasa/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Relación Dosis-Respuesta a Droga , Glutatión/sangre , Peroxidación de Lípido/efectos de los fármacos , Hígado/enzimología , Medicina Tradicional , Ratones , Ratas , Ratas Sprague-Dawley , Solanum/enzimología , Superóxido Dismutasa/sangre , Resultado del TratamientoRESUMEN
The FLP protein that is encoded by the 2-microns plasmid of yeast Saccharomyces cerevisiae is a 45-kDa site-specific recombinase that belongs to the Int family of recombination proteins. FLP catalyzes a recombination event within the plasmid by binding specifically to each of three 13-base pair (bp) symmetry elements of the FLP recognition target (FRT). We have shown previously that partial proteolysis of the FLP protein by proteinase K resulted in a COOH-terminal fragment of size 32 kDa (P32) and an NH2-terminal fragment of 13 kDa (P13). In this study we have used footprinting with dimethyl sulfate to show that P32 binds specifically to the outer 9 bp of the 13 bp symmetry element. Binding of P13 alone to the FRT site was not detectable in this assay. However, when P13 and P32 were incubated together with the FRT site, protection of the remaining 4-bp region of the symmetry element was observed. To confirm these results we used bromodeoxyuridine (BrdU)-dependent UV cross-linking. P32 became cross-linked to the substrate that contained BrdU substitutions in the outer 9 bp of a 13-bp symmetry element, but not to one with the BrdU substitutions in the inner 4 bp. Reciprocally P13 cross-linked to the latter substrate but not the former. Cross-linking was both BrdU and ultraviolet light-dependent. This study indicates that the COOH-terminal domain (P32) of FLP recognizes the outer 9 bp of the 13-bp symmetry element, whereas its NH2-terminal domain (P13) is needed for protection of the inner 4 bp of each symmetry element.
Asunto(s)
ADN Nucleotidiltransferasas/metabolismo , Proteínas Fúngicas/metabolismo , Adenina/metabolismo , Secuencia de Bases , Sitios de Unión , Bromodesoxiuridina , ADN Nucleotidiltransferasas/química , ADN Nucleotidiltransferasas/efectos de la radiación , ADN de Hongos/química , ADN de Hongos/metabolismo , Desoxirribonucleasa I , Proteínas Fúngicas/química , Proteínas Fúngicas/efectos de la radiación , Guanina/metabolismo , Metilación , Datos de Secuencia Molecular , Péptidos/química , Péptidos/efectos de la radiación , Saccharomyces cerevisiae/enzimología , Especificidad por Sustrato , Rayos UltravioletaRESUMEN
The FLP protein of the 2 microns plasmid of Saccharomyces cerevisiae promotes conservative site-specific recombination between DNA sequences that contain the FLP recognition target (FRT). FLP binds to each of the three 13 base pair symmetry elements in the FRT site in a site-specific manner. We have probed both major and minor groove contacts of FLP using dimethyl sulphate, monoacetyl-4-hydroxyaminoquinoline 1-oxide and potassium permanganate and find that the protein displays extensive interactions with residues of both the major and minor grooves of 10 base pairs of each symmetry element. We find no evidence that the FRT site assumes a single-stranded conformation upon FLP binding.
Asunto(s)
ADN Nucleotidiltransferasas/metabolismo , ADN de Hongos/metabolismo , Proteínas Fúngicas/metabolismo , 4-Hidroxiaminoquinolina-1-Óxido/farmacología , Secuencia de Bases , Sitios de Unión , ADN de Cadena Simple/metabolismo , Guanina/metabolismo , Metilación , Datos de Secuencia Molecular , Permanganato de Potasio/farmacología , Mapeo Restrictivo , Saccharomyces cerevisiae/metabolismo , Especificidad por Sustrato , Ésteres del Ácido Sulfúrico/farmacología , Timina/metabolismoRESUMEN
Monoacetyl-4-hydroxyaminoquinoline 1-oxide (Ac-HAQO) reacts with DNA to form adducts at the C8- and N2-positions of guanine and with the N6-position of adenine. Only the N2-guanine adduct blocks the 3'-5' exonuclease action of phage T4 DNA polymerase. Piperidine treatment cleaves the DNA at sites bearing C8-guanine adducts. The N2-position of guanine lies in the minor groove of DNA, whereas the C8-position of guanine occupies the major groove. We have taken advantage of these characteristics to employ Ac-HAQO in conjunction with either T4 DNA polymerase or piperidine in a footprinting technique to probe the interaction of the Escherichia coli integration host factor (IHF) with its binding site. We show that when IHF binds to its recognition site both the N2- and C8-positions of guanines are protected from modification by AcHAQO. In addition, the binding of IHF to DNA was prevented when either an N2- or a C8-AQO adduct was present in the binding site. When dimethylsulfate was used as the footprinting reagent, IHF protected against methylation of the N3 position of adenine in the minor groove but not the N7 position of guanine in the major groove. The difference in results obtained with the two reagents is ascribed to their relative sizes. Both DMS and AcHAQO are excluded by IHF from the minor groove, but only the larger AcHAQO molecule is excluded from the major groove.
Asunto(s)
Aminoquinolinas , Bacteriófago mu/genética , Proteínas Portadoras/genética , ADN Bacteriano/química , Elementos de Facilitación Genéticos , Guanina/química , Sondas Moleculares , Conformación de Ácido Nucleico , Regiones Promotoras Genéticas , Secuencia de Bases , Sitios de Unión , Factores de Integración del Huésped , Datos de Secuencia MolecularRESUMEN
Monoacetyl-hydroxyaminoquinoline 1-oxide (Ac-HAQO) is a model of the ultimate form of the carcinogen 4-nitroquinoline 1-oxide and so it is useful to characterize its reactions with DNA. We find that Ac-HAQO produces one single-strand break (SSB) for every 60 adducts formed in a reaction with supercoiled DNA. The SSBs do not appear to be formed by a free radical reaction and they are distributed throughout the DNA molecule without regard to nucleotide specificity. Unique DNA fragments were reacted with Ac-HAQO. These substrates could not be degraded by the 3'-5' exonuclease action of T4 DNA polymerase unless they were first cleaved by a restriction endonuclease. This indicated that the ends of all the DNA molecules were blocked by adduct formation in spite of the low overall frequency of adducts per DNA molecule.
Asunto(s)
Aminoquinolinas/metabolismo , Carcinógenos/metabolismo , Daño del ADN , ADN de Cadena Simple/metabolismo , Secuencia de Bases , ADN Polimerasa Dirigida por ADN/farmacología , Exonucleasas/farmacología , Datos de Secuencia MolecularRESUMEN
Nucleotide excision repair in Escherichia coli is initiated by (A)BC excinuclease, an enzyme which incises DNA on both sides of bulky adducts and removes the damaged nucleotide as a 12-13 base long oligomer. The incision pattern of the enzyme was examined using DNA modified by 4-nitroquinoline 1-oxide (4NQO) and UV light. Similar to the cleavage pattern of UV photoproducts and other bulky adducts, the enzyme incises the 8th phosphodiester bond 5' and 5th phosphodiester bond 3' to the 4NQO-modifed base, primarily guanine. The extent of DNA damage by these agents was determined using techniques which quantitatively cleave the DNA or stop at the site of the adduct. By comparison of the intensity of gel bands created by (A)BC excinuclease and the specific cleavage at the damaged site, the efficiency of (A)BC excinuclease incision at 13 different 4NQO-induced adducts and 13 different photoproducts was determined by densitometric scanning. In general, incisions made at 4NQO-induced adducts are proportional to the extent of damage, though the efficiency of cutting throughout the sequence tested varies from 25 to 75%. Incisions made at pyrimidine dimers are less efficient than at 4NQO-adducts, ranging from 13 to 65% incision relative to modification, though most are around 50%. The two (6-4) photoproducts within the region tested are incised more efficiently than any pyrimidine dimer.
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4-Nitroquinolina-1-Óxido/toxicidad , Daño del ADN , ADN Bacteriano/efectos de la radiación , Endodesoxirribonucleasas/genética , Proteínas de Escherichia coli , Secuencia de Bases , Reparación del ADN , Endodesoxirribonucleasas/efectos de la radiación , Escherichia coli/enzimología , Datos de Secuencia Molecular , Rayos UltravioletaRESUMEN
When O-acetyl-4-(hydroxyamino)quinoline 1-oxide (Ac-4HAQO) reacts with double-stranded DNA at 37 degrees C the major products, N2-guanine, C8-guanine, and N6-adenine adducts, are formed in the proportions of 5:3:2, respectively. When the reaction is carried out with single-stranded DNA at 0 degree C, the products are found in the ratio 1:7:2. Unique 174-bp DNA fragments were modified in these ways and used as substrates for the 3'-5' exonuclease activity of T4 DNA polymerase. The results obtained showed that the exonuclease is blocked by the N2-guanine adduct but not the other two adducts. Interpretation of the cleavage patterns suggested that the enzyme stopped 2 nucleotides before the N2-guanine adduct. The N2-guanine adduct lies in the minor groove of the DNA double helix, while the other two adducts are found in the major groove. Apparently, only the former hinders progression of the enzyme.
Asunto(s)
4-Nitroquinolina-1-Óxido , Adenina , Aminoquinolinas , ADN Polimerasa Dirigida por ADN , Exodesoxirribonucleasas , Guanina , Nitroquinolinas , Animales , Bovinos , ADN/efectos de los fármacos , Exodesoxirribonucleasa V , Hidrólisis , Fagos T/enzimología , Rayos UltravioletaRESUMEN
A substrate of DNA containing 4HAQO adducts, suitable for studies of excision repair, was prepared by reacting calf thymus DNA with [3H]monoacetyl-4HAQO. A crude HeLa cell extract was prepared by the method of Mortelmans et al (Proc. Natl. Acad. Sci. U.S.A. 73, 2757, 1976). The cell extract would specifically excise pyrimidine dimers from UV-irradiated DNA but would not release 4HAQO adducts in an acid soluble form. This result points to different initial steps in the excision repair process for these two forms of damage even though much of the repair mechanism is common to both.
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4-Hidroxiaminoquinolina-1-Óxido/metabolismo , Aminoquinolinas/metabolismo , Extractos Celulares/farmacología , Reparación del ADN/efectos de los fármacos , Dímeros de Pirimidina/metabolismo , Extractos de Tejidos/farmacología , Cromatografía Líquida de Alta Presión , Humanos , Hidrólisis , Células KB/metabolismo , SolubilidadRESUMEN
Frequencies of sister-chromatid exchanges (SCEs) were measured to study the genotoxicity of the total aqueous extract of betal nut and its tannin on mouse bone-marrow cells in vivo. Betal nut aqueous extract and tannin were injected i.p. into mice at doses of 12.5, 25 or 50 micrograms/g body weight and 50, 100 or 200 micrograms/g body weight respectively for 5, 10 or 15 days. Betal nut extract induced a dose-related increase in the frequency of SCEs after five daily doses of 12.5, 25 or 50 micrograms. Significant increases in SCEs were also observed in animals dosed for 10 days with 50 micrograms/g and for 15 days with 25 or 50 micrograms/g extract. After five daily doses of 50, 100 or 200 micrograms/g of betel nut tannin there was no significant induction of SCE. Mice dosed with 200 micrograms/g tannin for 10 days, or 100 or 200 micrograms/g for 15 days, showed significant increases in the frequency of SCEs.
Asunto(s)
Areca , Mutágenos , Extractos Vegetales/farmacología , Plantas Medicinales , Intercambio de Cromátides Hermanas/efectos de los fármacos , Taninos/farmacología , Animales , Médula Ósea/efectos de los fármacos , Células de la Médula Ósea , Ciclofosfamida/farmacología , Femenino , Masculino , RatonesRESUMEN
Pulmonary angiography is considered the definite method of diagnosing pulmonary emboli. It is hypothesized that pulmonary cineangiography is superior to conventional pulmonary angiography for quantitation of pulmonary emboli. The present study was undertaken to test the hypothesis. Six patients with an age range from 27 to 70 years with documented pulmonary emboli by pulmonary angiogram, had pulmonary cineangiograms. Pulmonary angiogram defined pulmonary emboli in nine major vessels in the six patients; while, pulmonary cineangiogram revealed another 10 major vessels with pulmonary emboli, which were either not detected or considered equivocal by the conventional pulmonary angiography. The pulmonary embolic score as an index of the extent of pulmonary emboli was 24 (mean 4 +/- 2.52 1SD) by the conventional pulmonary angiography, while the score was 60 (mean 10 +/- 3.22 1SD) by the pulmonary cineangiography, P less than 0.2. Thus, in cases with pulmonary emboli, pulmonary cineangiogram is superior to conventional pulmonary angiogram for the quantitation of pulmonary emboli.
Asunto(s)
Cineangiografía , Embolia Pulmonar/diagnóstico por imagen , Adulto , Anciano , Angiografía , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The genotoxicity of arecaidine, an alkaloid of betel nut, was studied on mouse bone marrow cells in vivo by sister chromatid exchange (SCE) method. Arecaidine was administered intraperitoneally to mice at the dose levels of 2.5 mg, 5 mg and 7.5 mg to each mouse weighing 25 +/- 1 g for 5, 10 and 15 days. Significant increase in the number of SCEs was observed in the treated groups, and this increase, although dose-dependent, was not dependent upon the duration of exposure.
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Areca , Arecolina/análogos & derivados , Médula Ósea/efectos de los fármacos , Intercambio Genético/efectos de los fármacos , Plantas Medicinales , Intercambio de Cromátides Hermanas/efectos de los fármacos , Animales , Areca/análisis , Arecolina/aislamiento & purificación , Arecolina/farmacología , Arecolina/toxicidad , Médula Ósea/ultraestructura , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos , Nueces/análisis , Factores de TiempoRESUMEN
The effect of exposure of mice for 5, 10 and 15 days to arecoline or/and caffeine on the frequency of sister-chromatid exchanges (SCEs) in bone-marrow cells was evaluated by using the fluorescence plus Giemsa technique. There was a significant increase in the frequency of SCEs after exposure to either arecoline or caffeine. When these two alkaloids were given in combination, the SCE frequency-enhancing effect was additive. The implications of coffee/tea drinking and betel chewing on oral cancer are discussed.
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Arecolina/toxicidad , Médula Ósea/fisiología , Cafeína/toxicidad , Intercambio Genético/efectos de los fármacos , Intercambio de Cromátides Hermanas/efectos de los fármacos , Animales , Médula Ósea/efectos de los fármacos , Cinética , Ratones , Ratones EndogámicosRESUMEN
Seventeen consecutive patients with stable coronary artery disease with a previous history of myocardial infarction were studied for evaluation of the effect of physical training on exercise hemodynamics. The patients were divided into two groups: Group A (n = 10), the control group and Group B (n = 7), the rehabilitated group. Patients in Group B had physical training for five months. The mean exercise time in Group B (trained group) was significantly greater than in Group A (17.0 +/- 3.3 vs 11.6 +/- 3.2, p less than 0.01). Cardiac output was measured by impedance cardiography. The resting hemodynamic parameters were not statistically different between the two groups. At sub-maximal levels of exercise, the blood pressure X heart rate product was the same in both groups. At maximal workload, the heart rate X blood pressure product was the same in both groups, while the cardiac output was significantly greater in Group B compared to Group A (16.0 +/- 5.7 vs 12.1 +/- 3.2 1/min, p less than 0.001). These results suggest that physical training may improve cardiac function during exercise.
Asunto(s)
Enfermedad Coronaria/terapia , Hemodinámica , Educación y Entrenamiento Físico , Presión Sanguínea , Gasto Cardíaco , Cardiografía de Impedancia , Enfermedad Coronaria/fisiopatología , Electrocardiografía , Humanos , Masculino , Persona de Mediana Edad , Esfuerzo Físico , Volumen SistólicoRESUMEN
Thirty-two consecutive patients with acute myocardial infarction (AMI) were studied during the first seven days following AMI. The stroke volume was measured by impedance cardiography. The patients were divided into two groups: Group A (n = 22), with clinically uncomplicated myocardial infarction and Group B (n = 10) with evidence of congestive failure, but not of pulmonary edema. Patients in Group B had predominantly anterior wall myocardial infarction compared to Group A (p less than 0.05). The heart rate was significantly greater in Group B compared to Group A (p = 0.0002). The systolic blood pressure, the mean blood pressure, stroke volume index, and left ventricular stroke work index were significantly lower (p less than 0.05) in Group B than Group A. Impedance cardiography can be easily applied to follow the course of the patients during the acute phase of myocardial infarction.
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Hemodinámica , Infarto del Miocardio/fisiopatología , Adulto , Anciano , Presión Sanguínea , Gasto Cardíaco , Cardiografía de Impedancia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Volumen Sistólico , Factores de Tiempo , Resistencia VascularRESUMEN
The chromosomal damaging properties of arecoline, a major betel-nut alkaloid were investigated in vivo after its administration to mice. Arecoline was injected in doses of 0.25, 0.5, 1 and 2 mg for 10, 20 and 30 days each. Significant numbers of aberrations were observed in the form of chromatid breaks, chromosome breaks, ring structure, multiple breaks and cells with pulverized chromosomal complements. The frequency of aberrations showed a dose-response relationship. So arecoline was concluded to have weak chromosome-damaging effects in vivo.