ABSTRACT
The Bcl-2 family of proteins consists of both antiapoptotic and proapoptotic factors, which share sequence homology within conserved regions known as Bcl-2 homology domains. Interactions between Bcl-2 family members, as well as with other proteins, regulate apoptosis through control of mitochondrial membrane permeability and release of cytochrome c. Here we identify a novel regulator of apoptosis that lacks Bcl-2 homology domains but acts by binding Bcl-2 and modulating its antiapoptotic activity. To identify regulators of apoptosis, we performed expression profiling in human primary fibroblasts treated with tumor necrosis factor-alpha (TNF-alpha), a potent inflammatory cytokine that can regulate apoptosis and functions, at least in part, by inducing expression of specific genes through NF-kappaB. We found that the gene undergoing maximal transcriptional induction following TNF-alpha treatment was G(0)-G(1) switch gene 2 (G0S2), the activation of which also required NF-kappaB. We show that G0S2 encodes a mitochondrial protein that specifically interacts with Bcl-2 and promotes apoptosis by preventing the formation of protective Bcl-2/Bax heterodimers. We further show that ectopic expression of G0S2 induces apoptosis in diverse human cancer cell lines in which endogenous G0S2 is normally epigenetically silenced. Our results reveal a novel proapoptotic factor that is induced by TNF-alpha through NF-kappaB and that interacts with and antagonizes Bcl-2.
Subject(s)
Apoptosis/physiology , Cell Cycle Proteins/metabolism , Mitochondrial Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Tumor Necrosis Factor-alpha/metabolism , Apoptosis/drug effects , Cell Cycle Proteins/genetics , Cell Line, Tumor , Fibroblasts/metabolism , Fibroblasts/pathology , HeLa Cells , Humans , Mitochondrial Proteins/genetics , NF-kappa B/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Protein Binding , Protein Structure, Tertiary , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Transcriptional Activation/drug effects , Tumor Necrosis Factor-alpha/pharmacology , bcl-2-Associated X Protein/metabolismABSTRACT
PURPOSE: An analysis of the effect of stranded (125)I and loose (predominantly (103)Pd) sources on dosimetric outcomes of brachytherapy of the prostate. METHODS AND MATERIALS: Between September 1998 and December 2003, 473 patients were treated with brachytherapy for biopsy-proven carcinoma of the prostate. Of these, 337 (71%) procedures were performed using free seeds placed with a Mick applicator. Beginning in April 2002, a program of stranded (125)I sources (RAPIDStrand) was implemented; 136 (29%) patients were treated via this approach. Dosimetric variables were collected, as were events of urinary retention. RESULTS: Mean V100 values for the stranded (125)I approach were greater than those for free seeds (p < 0.0005), whether (125)I or (103)Pd (p < 0.005). Use of the strand was the most significant determinant of V100 of all variables examined. The stranded (125)I approach was also associated with higher mean D90 values and lower V150-urethral doses. CONCLUSIONS: Use of stranded (125)I was associated with superior dosimetric outcomes in this group of patients.
Subject(s)
Brachytherapy/methods , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/radiotherapy , Radiation Monitoring , Humans , Male , Perineum , Rectum , UltrasonographyABSTRACT
EC film has improved portal localization images with better contrast and improved distinction of bony structures and air-tissue interfaces. A cassette with slower speed screens was used with EC film to image the treatment portal during the entire course of treatment (verification) instead of taking separate films after treatment. Measurements of film density vs source to film distance (SFD) were made using 15 and 25 cm thick water phantoms with both 6 and 18 MV photons from I to 40 cm past the phantom. A characteristic (H & D) curve was measured in air to compare dose to film density. Results show the reduction in radiation between patient and cassette more closely follows an "inverse cube law" rather than an inverse square law. Formulas to calculate radiation exposure to the film, and the desired SFD were based on patient tumor dose, calculation of the exit dose, and the inverse cube relationship. A table of exposure techniques based on the SFD for a given tumor dose was evaluated and compared to conventional techniques. Although the film has a high contrast, there is enough latitude that excellent films can be achieved using a fixed SFD based simply on the tumor dose and beam energy. Patient diameter has a smaller effect. The benefits of imaging portal films during the entire treatment are more reliability in the accuracy of the portal image, ability to detect patient motion, and reduction in the time it takes to take portal images.
