RESUMEN
Data on the age of the preferred partner of same-sex attracted men show that the abuse of minors by priests and deacons is primarily a question of "ordinary" homosexuality, and secondarily of homosexual pedophilia (not just unspecified "pedophilia"). This points to the substantial over-representation of homosexually inclined men among seminarians and priests, which in turn is related to a process of "homosexualization" (and feminization) in the Church. The general dissent from the moral doctrine on sexuality and marriage (as set forth in the encyclical Humanae vitae) has paved the way for this process. A few suggestions are discussed for the prevention of the abuses of the past decades: (a) improved screening of candidates for the priesthood as well as for the office of bishop on masculine personality maturity, which includes normal heterosexuality and fatherhood qualities; (b) a spiritual regime for seminary students and priests that is demanding on the self and directs the battle for holiness;
RESUMEN
The best-established facts in relation to homosexuality point to developmental-psychological, not genetic or physiological, causation. The efforts of the last few decades to find evidence to support a biological theory have made it more doubtful than ever that such evidence will be found. In contrast, many studies have shown that the most significant factor which correlates with homosexuality is "gender nonconformity" or same-sex peer isolation. Another factor closely associated with homosexuality is an imbalance in parent-child interaction, notably forms of over-influence of the opposite-sex parent in combination with a deficient relationship with the same-sex parent. The third well-established correlation is with inherent, rather than discrimination-produced, "neuroticism" or emotional instability/immaturity. Structured around this pivotal evidence from statistical as well as clinical research, homosexuality is explained here as a character neurosis. Characteristics of this neurotic character syndrome include personality immaturity, self-victimization, and self-centeredness. This syndrome affects not only the emotional but also the moral and spiritual dimensions of the psyche and if indulged leads to generalized personality deterioration. Therapeutically, a holistic approach, simultaneously addressing the emotional, moral, and spiritual components of the psyche, offers the best opportunity for overcoming homosexuality. De-egocentrization and personality maturity, including the development of mature manhood/womanhood, are the goals of therapy.
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Mutations in the CSB gene cause Cockayne syndrome (CS), a DNA repair disorder characterized by UV sensitivity and severe physical and neurological impairment. CSB functions in the transcription-coupled repair subpathway of nucleotide excision repair. This function may explain the UV sensitivity but hardly clarifies the other CS symptoms. Many of these, including retinopathy, are associated with premature aging. We studied eye pathology in a mouse model for CS. Csb(m/m) mice were hypersensitive to UV light and developed epithelial hyperplasia and squamous cell carcinomas in the cornea, which underscores the importance of transcription-coupled repair of photolesions in the mouse. In addition, we observed a spontaneous loss of retinal photoreceptor cells with age in the Csb(m/m) retina, resulting in a 60% decrease in the number of rods by the age of 18 months. Importantly, when Csb(m/m) mice (as well as Csa(-/-) mice) were exposed to 10 Gy of ionizing radiation, we noticed an increase in apoptotic photoreceptor cells, which was not observed in wild-type animals. This finding, together with our observation that the expression of established oxidative stress marker genes is upregulated in the Csb(m/m) retina, suggests that (endogenous) oxidative DNA lesions play a role in this CS-specific premature-aging feature and supports the oxidative DNA damage theory of aging.
Asunto(s)
Síndrome de Cockayne/patología , Tolerancia a Radiación , Degeneración Retiniana/patología , Animales , Antioxidantes/metabolismo , Córnea/citología , Córnea/patología , Córnea/efectos de la radiación , Enzimas Reparadoras del ADN/deficiencia , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/genética , Estrés Oxidativo/efectos de la radiación , Células Fotorreceptoras de Vertebrados/citología , Células Fotorreceptoras de Vertebrados/patología , Células Fotorreceptoras de Vertebrados/efectos de la radiación , Proteínas de Unión a Poli-ADP-Ribosa , Proteínas/metabolismo , Radiación Ionizante , Rayos Ultravioleta , Regulación hacia Arriba/genética , Regulación hacia Arriba/efectos de la radiaciónRESUMEN
Cellular activity of the tumor suppressor protein p53 is primarily regulated by posttranslational modifications. Phosphorylation of the COOH terminus, including Ser389, is thought to result in a conformational change of the p53 protein, enhancing DNA binding and transcriptional activity. In vitro studies presented here show that, in addition to UV radiation, Ser389 is phosphorylated upon exposure to 2-acetylaminofluorene (2-AAF). Both agents induce bulky DNA adducts repaired by nucleotide excision repair (NER). In contrast, ionizing radiation, known to induce DNA damage not repaired by NER, does not result in Ser389 phosphorylation. Previously, we have shown that p53.S389A mutant mice, lacking the Ser389 phosphorylation site, are sensitive to developing UV-induced skin tumors. Here, we show that p53.S389A mice are also prone to developing 2-AAF-induced urinary bladder tumors, whereas no increased tumor response was found upon ionizing irradiation. These results provide evidence for our hypothesis that phosphorylation of Ser389 is important for activation of p53 to exert its function as a tumor suppressor not exclusively upon the presence of UV-induced DNA damage, but also upon exposure to other bulky adduct-inducing agents. Analysis of 2-AAF- and UV-induced tumors from p53.S389A mice revealed the presence of additional p53 mutations, indicating that lack of Ser389 phosphorylation by itself is not sufficient to abrogate p53 function in tumor suppression. In addition, analyses of skin tumors of p53.S389A mice revealed an interesting hotspot mutation previously found exclusively in NER-deficient mice and patients.
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2-Acetilaminofluoreno/toxicidad , Carcinógenos/toxicidad , Linfoma/metabolismo , Neoplasias Inducidas por Radiación/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Animales , Daño del ADN , Femenino , Genes p53/efectos de la radiación , Linfoma/etiología , Linfoma/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación , Neoplasias Inducidas por Radiación/genética , Fosforilación , Serina/metabolismo , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Proteína p53 Supresora de Tumor/genética , Rayos Ultravioleta/efectos adversos , Neoplasias de la Vejiga Urinaria/inducido químicamente , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
Phosphorylation is important for p53 protein stabilization and activation after DNA damage. Serine 389 of p53 is specifically phosphorylated after UV irradiation, whereas gamma radiation activates p53 through a different pathway. To study the in vivo significance of p53 phosphorylation at serine 389, we generated a physiological mouse model in which p53 phosphorylation at serine 389 is abolished by alanine substitution. Homozygous mutant p53.S389A mice are viable and have an apparently normal phenotype. However, cells isolated from these mice are partly compromised in transcriptional activation of p53 target genes and apoptosis after UV irradiation, whereas gamma radiation-induced responses are not affected. Moreover, p53.S389A mice show increased sensitivity to UV-induced skin tumor development, signifying the importance of serine 389 phosphorylation for the tumor-suppressive function of p53.
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Mutación Puntual , Serina/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Rayos Ultravioleta , Animales , Antibióticos Antineoplásicos/farmacología , Apoptosis/fisiología , Carcinoma/patología , Ciclo Celular/fisiología , Células Cultivadas , Doxorrubicina/farmacología , Fibroblastos/citología , Fibroblastos/fisiología , Rayos gamma , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Ratones , Neoplasias de Células Escamosas/patología , Papiloma/patología , Fenotipo , Fosforilación , Piel/efectos de la radiación , Células Madre/fisiología , Tasa de Supervivencia , Timo/citología , Timo/efectos de los fármacos , Activación TranscripcionalRESUMEN
AIM: The rat pancreatic CA20948 tumor cell line is widely used in receptor-targeted preclinical studies because many different peptide receptors are expressed on the cell membrane. The response of the tumor cells to peptide radionuclide therapy, however, is dependent on the cell line's radiosensitivity. Therefore, we measured the radiosensitivity of the CA20948 tumor cells by using clonogenic survival assays after high-energy external-beam radiotherapy (XRT) in vitro. It can, however, be expected that results of high-dose-rate XRT are not representative for those after low-dose-rate radionuclide therapy (RT), such as peptide-receptor radionuclide therapy. Therefore, we compared clonogenic survival in vitro in CA20948 tumor cells after increasing doses of XRT or RT, the latter using (131)I. METHODS: Survival of CA20948 cells was investigated using a clonogenic survival assay after RT by incubation with increasing amounts of (131)I, leading to doses of 1-10 Gy after 12 days of incubation (maximum dose rate, 0.92 mGy/min), or with doses of 1-10 Gy using an X-ray machine (dose rate, 0.66 Gy/min). Colonies were scored after a 12-day-incubation period. Also, the doubling time of this cell line was calculated. RESULTS: We observed a dose-dependent reduction in tumor-cell survival, which, at low doses, was similar for XRT and RT. For high-dose-rate XRT, the quadratic over linear component ratio (alpha/beta) for CA20948 was 8.3 Gy, whereas that ratio for low-dose-rate RT was calculated to be 86.5 Gy. The calculated doubling time of CA20948 cells was 22 hours. CONCLUSIONS: Despite the huge differences in dose rate, RT tumor cell-killing effects were approximately as effective as those of XRT at doses of 1 and 2 Gy, the latter being the common daily dose given in fractionated external-beam therapies. At higher doses, RT was less effective than XRT.
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Supervivencia Celular/efectos de la radiación , Radioisótopos de Yodo/uso terapéutico , Neoplasias Pancreáticas/radioterapia , Animales , Línea Celular Tumoral , Radioisótopos de Yodo/metabolismo , Método de Montecarlo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Dosificación Radioterapéutica , RatasRESUMEN
PURPOSE: To investigate the effects of split-dose irradiation on primary and metastatic uveal melanoma cell lines, with a clonogenic survival assay. METHODS: Appropriate cell concentrations of four primary and four metastatic human uveal melanoma cell lines were cultured for irradiation with single doses and with two equal fractions separated by 5 hours. After irradiation, colony formation was allowed for 7 to 21 days. Two cutaneous melanomas were also tested for comparison. All survival curves were analyzed using the linear quadratic (LQ) model. Specific parameters for the intrinsic radiosensitivity (alpha-component, SF2), for the capacity of repair of DNA damage (beta-component), as well as the alpha/beta ratio were calculated. RESULTS: After single-dose irradiation a wide range in the values of the alpha- and beta-component was obtained for both primary and metastatic uveal melanomas, which resulted in a wide range of alpha/beta ratios. In contrast, calculations based on split-dose data, with which the beta-component could be estimated independent of the alpha-component, indicated that estimates for the capacity of sublethal DNA damage repair was very similar in all cell lines. This indicated that intrinsic factors dominated the radiosensitivity of these cell lines. Split-dose irradiation had little influence on the intrinsic radiosensitivity (alpha-component), but cell survival increased for all cell lines. For the two cutaneous melanomas comparable split-dose results were obtained. CONCLUSIONS: For both primary and metastatic uveal melanoma cell lines, data from single and fractionated doses indicate large variations in radiosensitivity, which are mainly dominated by the intrinsic radiosensitivities. Doses of approximately 8 Gy in five fractions would be sufficient to eradicate 10(9) cells (approximately 1 cm3) of the most radioresistant tumor cell lines, but this schedule is an overkill for the radiosensitive tumor cell lines. Based on specific morphologic and histologic tumor markers, more individualized dose fractionation schedules could improve the therapeutic ratio for uveal melanomas.
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Melanoma/radioterapia , Neoplasias de la Úvea/radioterapia , Supervivencia Celular/efectos de la radiación , Daño del ADN/efectos de la radiación , Reparación del ADN , ADN de Neoplasias/efectos de la radiación , Fraccionamiento de la Dosis de Radiación , Colorantes Fluorescentes , Humanos , Melanoma/patología , Metástasis de la Neoplasia/radioterapia , Dosis de Radiación , Tolerancia a Radiación , Rodaminas , Neoplasias Cutáneas/radioterapia , Células Tumorales Cultivadas/efectos de la radiación , Ensayo de Tumor de Célula Madre , Neoplasias de la Úvea/patología , Rayos XRESUMEN
Radiation-induced complications of the rectum are an important dose-limiting factor in radiotherapy of pelvic malignancies. In general, animal studies demonstrated no differences in acute and late normal tissue toxicity with age, but little is known about rectal complications in relation to age. For this purpose, an extensive histological and dose fractionation study was carried out on the rectum of young (12 weeks) and older (77-80 weeks) rats. In this paper, the results of dose fractionation are presented in relation to age at the time of irradiation. Young and older animals were irradiated with single and fractionated doses. After irradiation, rectal complications could lead to occlusion and stenosis, eventually resulting in the clinical symptoms of a megacolon and a possible fistula. For each dose group, cumulative survival rates were obtained with Kaplan-Meier analysis, from which dose-effect curves and the associated LD(50) values for a megacolon/fistula were calculated. The majority of responders died between 8 and 24 weeks after irradiation, irrespective of age. For both age groups, only the fractionation data showed a reduction in the mean latency with increasing dose. In the older age group, 39% of the responders developed a fistula compared to 26% for the younger animals. The LD(50) values increased from around 30 Gy after single doses to nearly 65 Gy after 10 fractions. The increases in LD(50) values with the number of fractions were independent of the age of the rats. For each of the dose fractionation schedules, log-rank testing indicated no significant differences in cumulative survival rates between younger and older animals (P > 0.10). The high alpha/beta ratios obtained for both the young and older animals strongly suggested that the late rectal complications were a consequence of early epithelial injury. Associated histological findings indicated that blood vessel damage, which was already evident at a high incidence at 4 weeks after irradiation, could also play a significant role in the occurrence of consequential late injuries. In conclusion, data obtained for the latent period of rectal occlusion, for the dose-effect curves, for the log-rank testing of cumulative survival rates, and for the alpha/beta ratios strongly support the hypothesis that the incidence of radiation-induced rectal complications is independent of age. Late rectal complications could be a consequence of radiation-induced acute injury.
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Fraccionamiento de la Dosis de Radiación , Recto/efectos de la radiación , Factores de Edad , Animales , Relación Dosis-Respuesta en la Radiación , Femenino , Dosificación Letal Mediana , Tolerancia a Radiación , Ratas , Ratas WistarRESUMEN
Mutations in the CSB gene cause Cockayne syndrome (CS), a rare inherited disorder, characterized by UV-sensitivity, severe neurodevelopmental and progeroid symptoms. CSB functions in the transcription-coupled repair (TCR) sub-pathway of nucleotide excision repair (NER), responsible for the removal of UV-induced and other helix-distorting lesions from the transcribed strand of active genes. Several lines of evidence support the notion that the CSB TCR defect extends to other non-NER type transcription-blocking lesions, notably various kinds of oxidative damage, which may provide an explanation for part of the severe CS phenotype. We used genetically defined mouse models to examine the relationship between the CSB defect and sensitivity to oxidative damage in different cell types and at the level of the intact organism. The main conclusions are: (1) CSB(-/-) mouse embryo fibroblasts (MEFs) exhibit a clear hypersensitivity to ionizing radiation, extending the findings in genetically heterogeneous human CSB fibroblasts to another species. (2) CSB(-/-) MEFs are highly sensitive to paraquat, strongly indicating that the increased cytotoxicity is due to oxidative damage. (3) The hypersenstivity is independent of genetic background and directly related to the CSB defect and is not observed in totally NER-deficient XPA MEFs. (4) Wild type embryonic stem (ES) cells display an increased sensitivity to ionizing radiation compared to fibroblasts. Surprisingly, the CSB deficiency has only a very minor additional effect on ES cell sensitivity to oxidative damage and is comparable to that of an XPA defect, indicating cell type-specific differences in the contribution of TCR and NER to cellular survival. (5) Similar to ES cells, CSB and XPA mice both display a minor sensitivity to whole-body X-ray exposure. This suggests that the response of an intact organism to radiation is largely determined by the sensitivity of stem cells, rather than differentiated cells. These findings establish the role of transcription-coupled repair in resistance to oxidative damage and reveal a cell- and organ-specific impact of this repair pathway to the clinical phenotype of CS and XP.
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Síndrome de Cockayne/metabolismo , Daño del ADN/fisiología , Reparación del ADN/fisiología , Xerodermia Pigmentosa/metabolismo , Animales , Síndrome de Cockayne/genética , Modelos Animales de Enfermedad , Rayos gamma , Ratones , Estrés Oxidativo/fisiología , Paraquat/metabolismo , Rayos X , Xerodermia Pigmentosa/genéticaRESUMEN
PURPOSE: To investigate the radiosensitivity of uveal melanoma cell lines by a clonogenic survival assay, to improve the efficiency of the radiation regimen. METHODS: Four primary and four metastatic human uveal melanoma cell lines were cultured in the presence of conditioned medium. After single-dose irradiation (0-12 Gy), colonies were allowed to form for 6 to 14 days. Two cutaneous melanomas cell lines were also tested for comparison. The survival curves were analyzed by the linear quadratic (LQ) model, and the surviving fraction at a dose of 2 Gy (SF(2)), the SF at 10 Gy (SF(10)), the ratio of initial irreparably damaged DNA (alpha-coefficient) to the capacity to repair sublethally damaged DNA (beta-coefficient), and the plating efficiency were calculated. RESULTS: The melanomas displayed a wide range of initial irreparable DNA damage (alpha-component), as well as a capacity for repair of sublethal DNA damage (beta-component), which ultimately resulted in a wide range of alpha/beta ratios. These findings were similar in both primary and metastatic melanomas and were comparable with data obtained from two cutaneous melanomas. CONCLUSIONS: Cell lines obtained from primary and metastatic human uveal melanomas displayed a wide range of radiosensitivity, similar to that published for cutaneous melanomas. Translating these data to the clinical setting indicates that a fractionated dose of 8 to 10 Gy administered in three to four fractions, as currently delivered in many centers, should be sufficient to eradicate tumors of approximately 1 cm(3).