Rapid killing of urothelial carcinoma-cells by wild-type p53

The effect of the tumor suppressor p53 on urothelial carcinoma cells was studied by transfecting six cell lines containing different mutations in the p53 gene with an expression construct for the wild-type protein. In all cell lines, the number of cell clones resistant to a neomycin analogue was strongly diminished when pCMVhup53 was cotransfected with the resistance plasmid pRSVneo as compared to cotransfection with either a plasmid vector, a p53 deletion and a mutant p53 expression vector. Cytochemical analysis showed that cells cotransfected with pCMVhup53 and an expression plasmid for beta-galactosidase disappeared during the second day after transfection. Thus, reexpression of wildtype p53 efficiently and rapidly kills urothelial carcinoma cells, independent of the different mutations in p53 they contain.     

Treatment of pains from bone metastases with 90Y (author's transl)

For palliation of pain caused by bone metastases beta radiation isotope therapy was successful. As shown in experimental work on animals bone uptake of 90Y with its shorter half-life is high when it is administered as a citrate complex. 90Y can be eluted with high purity from a 90Sr "cow". The retention in man was found by whole-body counting to be higher than 80%. In preliminary trials on 16 patients the analgetic effect was the same as that of 89Sr. The properties of 90Y therapy are discussed.     

The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective.

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.     

Improved long-term results with thymoglobuline induction therapy after cardiac transplantation: a comparison of two different rabbit-antithymocyte globulines

BACKGROUND: The aim of this retrospective single center analysis was to compare possible long-term benefits of two different rabbit-antithymocyte globuline (ATG) induction therapies after cardiac transplantation. PATIENTS AND METHODS: A total of 484 primary cardiac transplanted patients received induction therapy with two different rabbit-ATGs (thymoglobuline: n=342, ATG-fresenius: n=142). All patients received immunosuppressive maintenance therapy with cyclosporine, azathioprine, and prednisolone. Cardiac rejection was assessed by serial endomyocardial biopsies. Surveillance of graft arteriosclerosis was performed by angiograms 1, 3, and 5 years after transplantation. RESULTS: Five-year survival was significantly better in the thymoglobuline group (76 vs. 60%). Thymoglobuline patients had a lower rate of death from rejection (2.3 vs. 10%; P<0.01) and graft arteriosclerosis (0.88 vs. 5.6%; P<0.01). After 5 years, freedom from rejection was 72% in the thymoglobuline group compared to 42% in the ATG-fresenius group (P<0.01). Graft arteriosclerosis appeared in 14% of thymoglobuline patients and in 28% of ATG-fresenius patients (P<0.01). Viral infections occurred more often in thymoglobuline patients (53 vs. 39%, P<0.05) although there was no difference in appearance of cytomegalovirus disease (17 vs. 13%). Freedom from posttransplant malignant disease was comparable between the two groups. CONCLUSION: These results suggest that there are differences between rabbit ATG products. The superior prevention of rejection with thymoglobuline may be the reason for the lower rate of graft arteriosclerosis.     

Evidence against a pivotal role of preformed antibodies in delayed rejection of a guinea pig-to-rat heart xenograft

INTRODUCTION: Whereas the involvement of elicited xenoantibodies in delayed xenograft rejection is currently being substantiated, this study focuses on the role of the preformed fraction of xenoantibodies. METHODS: To check the influence of the latter, we combined pretransplant complement inactivation (cobra venom factor) and antibody reduction (plasmapheresis) in a guinea pig-to-rat heart transplant model. RESULTS: Antibody reduction on plasmapheresis before xenografting did not prolong delayed xenorejection in decomplemented rats, although the immunohistologic pattern lacked the immunoglobulin deposits along endothelial walls found in xenografts of merely decomplemented recipients. Astonishingly, plasmapheresis, if carried out 2 days before transplantation, almost tripled xenograft survival, although preformed antibody levels were completely restored and even rebounding at the time of grafting. The pattern and number of infiltrating cells did not differ in dependence of the timing of plasmapheresis nor did the proliferative response of lymphocytes in the mixed lymphocyte reaction differ. However, plasmapheresis led to a retarded decrease of the mononuclear cell tumor necrosis factor alpha secretory potential, which correlated well with a diminished immunohistologic staining of tumor necrosis factor alpha secreted by graft-infiltrating mononuclear cells. CONCLUSION: These findings argue against a pivotal role of preformed xenoantibodies in the pathomechanistic process of delayed xenograft rejection and challenge the therapeutic strategy to reduce preformed xenoantibody levels before xenotransplantation in complement-inactivated recipients.     

Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in caucasian women.

PURPOSE: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown. EXPERIMENTAL DESIGN: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [-889 C/T polymorphism of the IL1alpha gene (IL1A), -511 C/T polymorphism of the IL1beta promoter (IL1B promoter), a polymorphism of IL1beta exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the -174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. RESULTS: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. CONCLUSIONS: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the -174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.     

Comparative electrophysiological evaluation of hippocampal function following repeated inhalation exposures to JP-8, Jet A,JP-5, and the synthetic Fischer Tropsch fuel

Exposure to fuels continues to be a concern in both military and general populations. The aim of this study was to examine effects of in vivo rat repeated exposures to different types of jet fuel utilizing microelectrode arrays for comparative electrophysiological (EP) measurements in hippocampal slices. Animals were exposed to increasing concentrations of four jet fuels, Jet Propellant (JP)-8, Jet A, JP-5, or synthetic Fischer Tropsch (FT) fuel via whole-body inhalation for 20 d (6 hr/d, 5 d/week for 28 d) and synaptic transmission as well as behavioral performance were assessed. Our behavioral studies indicated no significant changes in behavioral performance in animals exposed to JP-8, Jet A, or JP-5. A significant deviation in learning pattern during the Morris water maze task was observed in rats exposed to the highest concentration of FT (2000 mg/m³). There were also significant differences in the EP profile of hippocampal neurons from animals exposed to JP-8, Jet A, JP-5, or FT compared to control air. However, these differences were not consistent across fuels or dose dependent. As expected, patterns of EP alterations in brain slices from JP-8 and Jet A exposures were more similar compared to those from JP-5 and FT. Further longitudinal investigations are needed to determine if these EP effects are transient or persistent. Such studies may dictate if and how one may use EP measurements to indicate potential susceptibility to neurological impairments, particularly those that result from inhalation exposure to chemicals or mixtures.