Therapeutic potential of p53 restoration in spontaneous tumors

Over 80% of p53 mutations found in human cancers are p53 missense mutations. Recent studies have shown that p53 restoration leads to tumor regression in mice with p53 deletions, but the therapeutic efficacy of p53 restoration in tumors containing p53 missense mutations has not been evaluated. Since p53 mutant such as p53R172H has gain-of-function activities and dominant-negative effect that repress wild type p53, the activity of restored wild-type p53 might be compromised by the mutant p53 in tumors. We hypothesized that p53 restoration in tumors with the p53R172H mutation may be less therapeutically effective as p53 restoration in tumors null for p53. I tested this hypothesis by comparison of the therapeutic outcomes of p53 restoration in mice with spontaneous tumors that either lacked p53 or contained the p53R172H mutation. While p53 restoration causes tumor regression in mice lacking p53, the same p53 restoration halts tumor progression in mice with the p53R172H mutation. This phenotypic difference suggests a dominant-negative activity of the mutant p53. Moreover, I showed that the mutant p53 only inhibits part of the activity of the restored wild-type p53 and that the remaining wild-type activity still causes a delay in tumor progression. We conclude that p53 restoration has therapeutic potential in p53R172H tumors via suppression of tumor progression. This knowledge is of critical importance for p53 targeted cancer therapy because many patients with cancers harbor p53 missense mutations rather p53-null mutations. Since p53R172H mutation represents one of the most frequent and potent p53 missense mutations observed in human cancers, the current findings implicates that p53 restoration may be therapeutically important not only in human cancers characterized by loss of p53 alleles but also in those in which p53 missense mutations play an important pathogenetic role. ^

Impact of real time polymerase chain reaction technology on the therapeutic approach to treatment of staphylococcal infections

Can the early identification of the species of staphylococcus responsible for infection by the use of Real Time PCR technology influence the approach to the treatment of these infections? ^ This study was a retrospective cohort study in which two groups of patients were compared. The first group, ‘Physician Aware’ consisted of patients in whom physicians were informed of specific staphylococcal species and antibiotic sensitivity (using RT-PCR) at the time of notification of the gram stain. The second group, ‘Physician Unaware’ consisted of patients in whom treating physicians received the same information 24–72 hours later as a result of blood culture and antibiotic sensitivity determination. ^ The approach to treatment was compared between ‘Physician Aware’ and ‘Physician Unaware’ groups for three different microbiological diagnoses—namely MRSA, MSSA and no-SA (or coagulase negative Staphylococcus). ^ For a diagnosis of MRSA, the mean time interval to the initiation of Vancomycin therapy was 1.08 hours in the ‘Physician Aware’ group as compared to 5.84 hours in the ‘Physician Unaware’ group (p=0.34). ^ For a diagnosis of MSSA, the mean time interval to the initiation of specific anti-MSSA therapy with Nafcillin was 5.18 hours in the ‘Physician Aware’ group as compared to 49.8 hours in the ‘Physician Unaware’ group (p=0.007). Also, for the same diagnosis, the mean duration of empiric therapy in the ‘Physician Aware’ group was 19.68 hours as compared to 80.75 hours in the ‘Physician Unaware’ group (p=0.003) ^ For a diagnosis of no-SA or coagulase negative staphylococcus, the mean duration of empiric therapy was 35.65 hours in the ‘Physician Aware’ group as compared to 44.38 hours in the ‘Physician Unaware’ group (p=0.07). However, when treatment was considered a categorical variable and after exclusion of all cases where anti-MRS therapy was used for unrelated conditions, only 20 of 72 cases in the ‘Physician Aware’ group received treatment as compared to 48 of 106 cases in the ‘Physician Unaware’ group. ^ Conclusions. Earlier diagnosis of MRSA may not alter final treatment outcomes. However, earlier identification may lead to the earlier institution of measures to limit the spread of infection. The early diagnosis of MSSA infection, does lead to treatment with specific antibiotic therapy at an earlier stage of treatment. Also, the duration of empiric therapy is greatly reduced by early diagnosis. The early diagnosis of coagulase negative staphylococcal infection leads to a lower rate of unnecessary treatment for these infections as they are commonly considered contaminants. ^