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Inactivation of TP53 tumor suppressor gene is the most frequent molecular alteration in NSCLC, involving up to 60% of cases. Furthermore, TP53 mutational spectrum is related to the type of mutagen exposure, as well as racial and/or diet di erences. Nearly 95% of TP53 perturbations a ect codons included within exons 5 ± 8 which encode for almost the entire DNA-binding domain. In this study we addressed the possible prognostic value of the molecular alterations identi®ed in exons 5 ± 8 of the TP53 gene in DNAs from 151 para n-embedded NSCLC sections corresponding to 59 Spanish and 92 Polish stage I-IIIA resected patients. PCR/single-strand conformation polymorphism (SSCP) analysis revealed that the occurrence of TP53 exon 5 ± 8 mutations was 17/59 (29%) in the Spanish cohort and 17/92 (18%) in the Polish group. However, when DNA sequencing analysis was performed, these frequencies were reduced because of the presence of SSCP-false positive, intronic and silent mutations and polymorphisms. Fifteen of the 59 Spanish NSCLC tumors (25%) harbored TP53 mutations a ecting exons 5 ± 8 coding sequences, whereas only 12 of 92 Polish neoplasms (13%) contained alterations in the central hydrophobic region of p53. Our results indicate that the occurrence of TP53 mutations a ecting exon 5 ± 8 coding sequences in some European NSCLC populations may be lower than previously reported, and that the TP53 mutational patterns of these cohorts di er somewhat. The Spanish NSCLC patients contained missense mutations (9/59, 15%) and a relatively high percentage of null mutations (5/59, 8%) while the Polish patients mostly harbored missense mutations (9/92, 10%) and only one tumor contained a null type (1/92, 1%). Moreover, most TP53 missense mutations in the Spanish group were located outside the conserved regions, whereas the same mutations in the Polish group a ected conserved amino acids. Furthermore, the Polish patients harbored a high percentage of G?A transitions (most of them at non-CpG sites), while G?T transversions were predominant in the Spanish group. Our ®ndings suggest that there may be di erent racial or exogenous factors in these two populations which may help to explain both the distinct TP53 mutational pattern and the lower frequency obtained in the Polish group. The presence of missense mutations did not confer a worse clinical outcome in these subsets of NSCLC patients. However, patients whose tumors contained null TP53 gene mutations had a 5 month median disease-free survival time in contrast with 42 months in those patients without mutations (P=0.008). These ®ndings suggest that loss of p53 function may enhance tumor progression in NSCLC patients independently of whether dominant negative TP53 missense mutations are present.

Certain β-adrenergic blockers have proven useful in the regression of ventricular remodeling when administered as long-term treatment. However, early regression of left ventricular hypertrophy (LVH) has not been reported, following short-term administration of these drugs. We tested the hypothesis that short-term administration of the cardioselective β-blocker esmolol induces early regression of LVH in spontaneously hypertensive rats (SHR). Fourteen-month-old male SHRs were treated i.v. with vehicle (SHR) or esmolol (SHR-E) (300 μg kg(-1) min(-1)). Age-matched vehicle-treated male Wistar-Kyoto (WKY) rats served as controls. After 48 h, left ventricular morphology and function were assessed using M-mode echocardiograms (left ventricular mass index (LVMI), ejection fraction and transmitral Doppler (early-to-atrial filling velocity ratio (E/A), E-wave deceleration time (Edec time)). The standardized uptake value (SUV) was applied to evaluate FDG (2-deoxy-2[18F]fluoro-D-glucose) uptake by the heart using PET/CT. Left ventricular subendocardial and subepicardial biopsies were taken to analyze changes in cross-sectional area (CSA) of left ventricular cardiomyocytes and the fibrosis was expressed as collagen volume fraction (CVF). LVMI was lower in SHR-E with respect to SHR (P=0.009). There were no significant differences in EF, E/A ratio or Edec time in SHR-E compared with SHR (P=0.17, 0.55 and P=0.80, respectively). PET acquisitions in SHR-E showed lower (18)F-FDG uptake than SHR (P=0.003). Interestingly, there were no significant differences in SUV in either SHR-E or WKY (P=0.63). CSA in subendocardial and subepicardial regions was minor in SHR-E with respect to SHR (P<0.001), and there were no significant differences in CVF between both groups. Esmolol reverses early LVH in the SHR model of stable compensated ventricular hypertrophy. This is the first study to associate early regression of LVH with administration of a short-term β-blocker.