Effects of acute systemic endothelin receptor blockade on cardiac electrophysiology in vivo

BQ-123, a selective endothelin-A receptor antagonist, has been demonstrated to suppress arrhythmias. However, the role of physiologic levels of endogenous endothelin-1 (ET-1) with respect to electrophysiologic properties of the heart is unknown. BQ-123 (0.45, 0.9, 1.8, 3.6, 7.2, and 14.4 microg/kg/min; n = 10) or saline (control, n = 5) was administered IV for 15 minutes of continuous-rate infusion at incremental doses to anesthetized normal pigs. BQ-123 had no effect on PR and QT interval, QRS duration, intraatrial and AV nodal conduction time as well as the atrial, AV nodal, and ventricular effective refractory periods. As compared with baseline, BQ-123 at 7.2 and 14.4 microg/kg/min caused an increase in heart rate (99 +/- 17 versus 110 +/- 14 and 118 +/- 14 bpm, respectively; P < 0.05), shortened sinus node recovery time (818 +/- 165 versus 641 +/- 69 and 609 +/- 74 milliseconds, respectively; P < 0.05) and decreased mean arterial pressure at 14.4 microg/kg/min (95 +/- 18 versus 80 +/- 11 mm Hg; P < 0.05). We conclude that in the normal pig, physiologic levels of ET-1 have no effect on conduction properties of atrial, AV nodal, or Purkinje fibers. However, antagonism of ET-1 by BQ-123 unmasks the effect of ET-1 on maintenance of vasomotor tone, which in turn may affect heart rate and sinus node automaticity in the intact pig.     

Mapping drug resistance genes in Plasmodium falciparum by genome-wide association

When alleles conferring drug resistance spread through a population of malaria parasites, they leave characteristic "scars" in the parasite genome. Flanking neutral polymorphisms "hitchhike" to high frequency with the resistance mutation, generating deep valleys of reduced variation and broad swathes of elevated linkage disequilibrium around the resistance locus. We can systematically search the genome for these scars by genotyping polymorphic marker loci at intervals throughout the genome of P. falciparum, and use them as signposts for locating drug resistance genes. In this review I outline the rational behind this approach to genetic mapping. I describe key features of P. falciparum population biology, such as recombination rate, inbreeding, and selection intensity that influence the size of genomic regions affected by selection and the choice of study population. I discuss suitable genetic markers, study designs, and statistical approaches to data analysis. Finally, to demonstrate the utility of the approach I describe two proof-of-principle studies documenting patterns of genetic variability around known drug resistance genes.     

Ser392 phosphorylation regulates the oncogenic function of mutant p53

Despite the wealth of information on the regulation of wild-type p53 function by phosphorylation, nothing is known about the biological effect of phosphorylation on mutant p53. Here we show that p53H175 is phosphorylated like wild-type p53 in cells of the same background. Ser(392) nonphosphorylatable p53 mutants p53H175A392 and p53W248A392 more potently transformed rat embryo fibroblasts in cooperation with the ras oncogene than p53H175S392 and p53W248S392. p53H175A392 also had an enhanced ability to confer cellular resistance to the cytotoxic effect of cisplatin and UV radiation. This correlated with p53H175A392 being a more potent dominant negative mutant than p53H175 in inhibiting the apoptotic functions of wild-type p53. Moreover, p53H175E392, which mimics the phosphorylated form of p53H175, was less able to confer cellular resistance to DNA-damaging agents. p53H175 and p53W248 are phosphorylated like wild-type p53 in cells of the same background. Ser(392) nonphosphorylated p53 was present in human breast tumors expressing mutant p53 including p53H175. Together, these results demonstrated a novel function of Ser(392) phosphorylation in regulating the oncogenic function of mutant p53.     

Decreased expression of cytochrome P450 2E1 is associated with poor prognosis of hepatocellular carcinoma

Cytochrome P450-2E1 (CYP2E1) is one of the major hepatic enzymes involved in the metabolism of procarcinogen. Our study aimed to investigate the differential expression level of CYP2E1 and its clinicopathological significance in hepatocellular carcinoma (HCC). CYP2E1 revealed low level of expression in 70% of the tumor tissues, when compared to the adjacent nontumor tissues, at both mRNA and protein levels. The low expression of CYP2E1 was significantly correlated with the aggressive tumor phenotype, including poor differentiation status (by the Edmondson grading system) (p=0.038), absence of tumor capsule (p=0.030) and younger age of the patients (p=0.002). Multivariate analysis indicated that CYP2E1 expression level and pTNM stage were independent prognostic factors for disease-free survival. CYP2E1 was also shown to have a differential expression level in different liver tissues. The level of CYP2E1 was significantly higher in nontumor tissues from HCC patients compared to the intermediate level in cirrhosis livers from noncancer patients and normal livers from healthy persons. Tumor tissues were shown to have the lowest expression level. In conclusion, our results have shown that CYP2E1 is upregulated in the nontumor tissue and downregulated in tumor tissue, which is associated with aggressive tumor type and poor prognosis of the patients. It suggested that the differential expression of CYP2E1 may play an important role in HCC tumorigenesis.     

Screen-detected prostate cancer and the insulin-like growth factor axis: results of a population-based case-control study

Higher circulating levels of IGF-I have been associated with increased risk of prostate and some other cancers. Most research on prostate cancer has been based on men with symptoms or identified following treatment of benign disease. However, increasing numbers of cancer cases are now detected in asymptomatic men following prostate-specific antigen (PSA) tests. We therefore used a population-based case-finding exercise using the PSA test to examine whether associations between the IGF axis and cancer risk were apparent in this population. A matched case-control study was conducted among 7,383 men (50-70 years) receiving a PSA test as part of a case-finding exercise. Assays of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were performed on cases and 2 controls matched on age, recruitment center and calendar time. Analyses were based on 176 cases and 324 matched controls. The risk of prostate cancer increased across quartiles of IGF-I (highest vs. lowest quartile, OR = 2.34; 95% CI = 1.26-4.34; p(trend) = 0.02) and IGF-II (OR = 1.78; 95% CI = 0.94-3.15; p(trend) = 0.09). Controlling for smoking history and IGFBP-3 strengthened associations with cancer for both IGF-I (OR = 3.00; 95% CI = 1.50-6.01; p(trend) 0.005) and IGF-II (OR = 2.02; 95% CI = 1.07-3.84; p(trend) = 0.04) Associations between the IGFs and cancer risk were stronger for advanced cases. Our findings suggest that both IGF-I and IGF-II are associated with an increased risk of screen-detected prostate cancer.     

The Early Effects of Radiotherapy on Intellectual and Cognitive Functioning in Patients with Frontal Brain Tumours: The Use of a New Neuropsychological Methodology

Investigations of the effects of radiation on neuropsychological functions have revealed variable outcomes, ranging from no effect to severe cognitive impairment. However, many of the previous studies have relied on retrospective data or have been limited by methodological problems. In this study, prospective neuropsychological assessments were compared at baseline (after surgery and before radiotherapy) and within 4 months of completion of radiotherapy (except one case), to examine early-delayed effects of radiation on intellectual and cognitive functioning. Sixteen adult patients with either low- or high-grade brain tumours, 15 of whom were treated with radiotherapy, were compared with 8 control participants with nonmalignant brain tumours whom did not undergo radiotherapy. All participants had lesions situated mainly in the frontal lobes. All groups of patients had evidence of intellectual and cognitive impairment at baseline. The low- and high-grade brain tumour groups showed a differential pattern of performance following radiotherapy, with the low-grade tumour group's performance being more competent on all of the five main neuropsychological measures. Their pattern of improvement was very similar to that of the nonmalignant brain tumour group who had not undergone radiotherapy. The present study provides some preliminary information about the neuropsychological deficits associated with primary brain tumours, their severity, and the relationship between neuropsychological functioning and brain tumours and radiotherapy.