Genetic determinants of response to chemotherapy in transgenic mouse mammary and salivary tumors.

Several transgenic mouse tumor models were utilized to explore how specific genetic alterations affect the tumor cell response to chemotherapeutic agents in vivo. Specifically, MMTV-ras transgenic mice were interbred to p53 knock-out mice to create a model for assessing the role of p53 in chemotherapeutic responses. In addition, MMTV-ras tumors were compared to MMTV-myc and MMTV-ras/myc tumors. Mice of each genotype reproducibly develop mammary and/or salivary tumors, but tumor growth dynamics vary considerably between genotypes. MMTV-ras/p53-/- tumors exhibit higher S phase fractions than MMTV-ras/p53+/+ tumors, although both tumor types display very low apoptosis levels. In contrast, MMTV-myc tumors exhibit both high S phase fractions and spontaneous apoptosis levels. Tumor-bearing mice of each genotype were treated with either doxorubicin or paclitaxel, and effects on overall tumor growth, cell cycle distribution and apoptosis were evaluated. Surprisingly, neither agent efficiently induced apoptosis in any of the tumor models, including those with wildtype p53. Rather, tumor responses were mediated primarily by changes in cell cycle distribution. However, the spontaneous apoptosis levels did serve as a predictor of tumor growth response, in that only those tumors with high pretreatment apoptosis levels underwent significant regression following treatment with either agent.

Suppression of oncogenic viral interferon regulatory factor (vIRF) of Kaposi's sarcoma-associated herpesvirus by ribozyme-mediated cleavage.

Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV8) has been etiologically associated with several malignancies including Kaposi's sarcoma and primary effusion lymphoma. Oncogenic viral interferon regulatory factor (vIRF) encoded by KSHV ORF-K9 is a homologue of cellular interferon regulatory factor (IRF), and has been demonstrated to inhibit type I/II interferon signal transduction and transform NIH3T3 cells through the interactions with IRF-1, IRF-3, and CBP/p300 proteins. To counteract vIRF's pathogenic role, we have developed five ribozymes targeting ORF-K9 mRNA to suppress vIRF expression. The vIRF RNA substrates were cleaved up to 80% in a substrate-specific manner in transcript cleavage assays in vitro. In a transient transfection assay, two of the ribozymes efficiently suppressed the expression of vIRF protein measured by dual-color immunofluorescence assay that simultaneously detects the expression of both vIRF protein and ribozyme. Flow cytometry analysis showed that these ribozymes reduced vIRF expression up to 76%. A mutant ribozyme had no cleavage activity in vitro, but exhibited antisense effect in vivo. These results suggest that the ribozymes may provide a new approach for functional knockout of vIRF gene, and are potential candidates of antiviral therapy for KSHV-related malignancies.

Corticosteroids for Bell's palsy (idiopathic facial paralysis).

BACKGROUND: Inflammation and oedema of the facial nerve are implicated in causing Bell's palsy. Corticosteroids have a potent anti-inflammatory action which should minimise nerve damage and thereby improve the outcome of patients suffering from this condition. OBJECTIVES: The objective of this review was to assess the effect of steroid therapy in the recovery of patients with Bell's palsy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group register (searched December 2003) for randomised trials, as well as MEDLINE (January 1966 to April 2003), EMBASE (January 1980 to April 2003) and LILACS (January 1982 to April 2003). We contacted known experts in the field to identify additional published or unpublished trials. SELECTION CRITERIA: Randomised trials comparing different routes of administration and dosage schemes of corticosteroid or adrenocorticotrophic hormone therapy versus a control group where no therapy considered effective for this condition was administered, unless it was also given in a similar way to the experimental group. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed eligibility, trial quality, and extracted the data. MAIN RESULTS: Four trials with a total of 179 patients were included. One trial compared cortisone acetate with placebo; one compared prednisone plus vitamins, with vitamins alone; one compared high-dose prednisone administered intravenously against saline solution, and one, not-placebo controlled, tested the efficacy of methylprednisolone. Allocation concealment was appropriate in two trials, and the data reported allowed an intention-to-treat analysis. The data included in the meta-analyses were collected from three trials with a total of 117 patients. Overall 13/59 (22%) of the patients allocated to steroid therapy had incomplete recovery of facial motor function six months after randomisation, compared with 15/58 (26%) in the control group. This reduction was not significant (relative risk 0.86, 95% confidence interval 0.47 to 1.59). The reduction in the proportion of patients with cosmetically disabling sequelae six months after randomisation was also not significant (relative risk 0.86, 95% confidence interval 0.38 to 1.98). The trial not included in the meta-analysis showed a non-significant difference in outcomes between the arms. REVIEWERS' CONCLUSIONS: The available evidence from randomised controlled trials does not show significant benefit from treating Bell's palsy with corticosteroids. More randomised controlled trials with a greater number of patients are needed to determine reliably whether there is real benefit (or harm) from the use of corticosteroid therapy in patients with Bell's palsy.

Corticosteroids for Bell's palsy (idiopathic facial paralysis).

BACKGROUND: Inflammation and oedema of the facial nerve are implicated in causing Bell's palsy. Corticosteroids have a potent anti-inflammatory action which should minimise nerve damage and thereby improve the outcome of patients suffering from this condition. OBJECTIVES: The objective of this review was to assess the effect of steroid therapy in the recovery of patients with Bell's palsy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group register for randomised trials, as well as MEDLINE, EMBASE and LILACS (to December 2000). We contacted known experts in the field to identify additional published or unpublished trials. SELECTION CRITERIA: Randomised trials comparing different routes of administration and dosage schemes of corticosteroid or adrenocorticotrophic hormone therapy versus a control group where no therapy considered effective for this condition was administered, unless it was also given in a similar way to the experimental group. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed eligibility, trial quality, and extracted the data. MAIN RESULTS: Three trials with a total of 117 patients were included. One trial compared cortisone acetate with placebo; one compared prednisone plus vitamins, with vitamins alone; and one, not-placebo controlled, tested the efficacy of methylprednisolone. Allocation concealment was appropriate in two trials, and the data reported allowed an intention-to-treat analysis. Overall 13/59 (22%) of the patients allocated to steroid therapy had incomplete recovery of facial motor function six months after randomisation, compared with 15/58 (26%) in the control group. This reduction was not significant (relative risk 0.86, 95% confidence interval 0.47 to 1.59). The reduction in the proportion of patients with cosmetically disabling sequelae six months after randomisation was also not significant (relative risk 0.86, 95% confidence interval 0.38 to 1.98). REVIEWER'S CONCLUSIONS: The available evidence from randomised controlled trials does not show significant benefit from treating Bell's palsy with corticosteroids. More randomised controlled trials with a greater number of patients are needed to determine reliably whether there is real benefit (or harm) from the use of steroid therapy in patients with Bell's palsy.