Cross‐Imaging Platform Comparison of Ultrasonic Backscatter Coefficient Measurements of Live Rat Tumors

Objective. To translate quantitative ultrasound (QUS) from the laboratory into the clinic, it is necessary to demonstrate that the measurements are platform independent. Because the backscatter coefficient (BSC) is the fundamental estimate from which additional QUS estimates are calculated, agreement between BSC results using different systems must be demonstrated. This study was an intercomparison of BSCs from in vivo spontaneous rat mammary tumors acquired by different groups using 3 clinical array systems and a single‐element laboratory scanner system. Methods. Radio frequency data spanning the 1‐ to 14‐MHz frequency range were acquired in 3 dimensions from all animals using each system. Each group processed their radio frequency data independently, and the resulting BSCs were compared. The rat tumors were diagnosed as either carcinoma or fibroadenoma. Results. Carcinoma BSC results exhibited small variations between the multiple slices acquired with each transducer, with similar slopes of BSC versus frequency for all systems. Somewhat larger variations were observed in fibroadenomas, although BSC variations between slices of the same tumor were of comparable magnitude to variations between transducers and systems. The root mean squared (RMS) errors between different transducers and imaging platforms were highly variable. The lowest RMS errors were observed for the fibroadenomas between 4 and 5 MHz, with an average RMS error of 4 × 10^?5 cm^?1Sr^?1 and an average BSC value of 7.1 × 10^?4 cm^?1Sr^?1, or approximately 5% error. The highest errors were observed for the carcinoma between 7 and 8 MHz, with an RMS error of 1.1 × 10^?1 cm^?1Sr^?1 and an average BSC value of 3.5 × 10^?2 cm^?1Sr^?1, or approximately 300% error. Conclusions. This technical advance shows the potential for QUS technology to function with different imaging platforms.     

Targeting NFĸB mediated breast cancer chemoresistance through selective inhibition of sphingosine kinase-2

Resistance to chemotherapy remains a significant obstacle in the treatment of hormone-independent breast cancer. Recent evidence suggests that altered sphingolipid signaling through increased sphingosine kinase activity may be an important mediator of breast cancer drug resistance. Sphingosine kinase-1 (Sphk1) is a proposed key regulator of breast cancer tumorigenesis, proliferation and resistance. There is, however, conflicting data on the role of sphingosine kinase-2 (Sphk2) in cancer biology and resistance, with some suggesting that Sphk2 has an opposing role to that of Sphk1. Here, we studied the effects of the novel selective Sphk2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl) amide), on human breast cancer. ABC294640 blocked both viability and survival at low micromolar IC₅₀ concentrations in the endocrine therapy-resistant MDA-MB-231 and chemoresistant MCF-7TN-R cell systems. Treatment with the inhibitor significantly reduced proliferation, as seen in immunofluorescence staining of Ki-67 in vitro. Interestingly, pharmacological inhibition of Sphk2 induced apoptosis through the intrinsic programmed cell death pathway. Furthermore, ABC294640 also diminished NFκB survival signaling, through decreased activation of the Ser536 phosphorylation site on the p65 subunit. Xenografts of MCF-7TN-R cells growing in immunocompromised mice were utilized to validate the therapeutic efficacy of the sphingosine kinase-2 inhibitor. Treatment with 50 mg of ABC294640/kg completely blocked tumor volume in this model. These results indicate that pharmacological inhibition of Sphk2 with the orally bioavailable selective inhibitor, ABC294640, has therapeutic potential in the treatment of chemoand endocrine therapy-resistant breast cancer.Key words: sphingolipids, chemoresistance, sphingosine kinase, NFkappaB, breast cancer, ceramide, TNF, sphingosine-1-phosphate     

Inhibition of 2-nitropropane-induced rat liver DNA and RNA damage by benzyl selenocyanate

We observed that pretreatment of male F344 rats with benzyl selenocyanate, a versatile organoselenium chemopreventive agent in several animal model systems, decreases the levels of DNA and RNA modifications produced in the liver by the hepatocarcinogen 2- nitropropane. To clarify the mechanisms involved, we pretreated male F344 rats with either benzyl selenocyanate, its sulfur analog benzyl thiocyanate, phenobarbital or cobalt protoporphyrin IX; the latter is a depletor of P450. We then determined (1) the ability of liver microsomes to denitrify 2-nitropropane, (2) effects on 2-nitropropane- induced liver DNA and RNA modifications and (3) amount of nitrate excreted in rat urine following administration of the carcinogen. Pretreatment with benzyl selenocyanate or phenobarbital increased the denitrification activity of liver microsomes by 217 and 765%, respectively, increased liver P4502B1 by 31- and 435-fold, respectively, decreased the levels of 2-nitropropane-induced modifications in liver DNA (29-70% and 17-30%, respectively) and RNA (67-85% and 30-50%, respectively), and increased the 24-h urinary excretion of nitrate by 157 and 209%, respectively. Pretreatment with benzyl thiocyanate had no significant effect on any of these parameters. Pretreatment with cobalt protoporphyrin IX decreased liver P4502B 1 by 87%, decreased the denitrification activity of liver microsomes by 76%, decreased the 24 h urinary excretion of nitrate by 88.5%, but increased the extent of 2-nitropropane-induced liver nucleic acid modifications by 17-67%. These results indicate that the metabolic sequence from 2-nitropropane to the reactive species causing DNA and RNA modifications does not involve the removal of the nitro group. Moreover, they suggest that benzyl selenocyanate inhibits 2-NP-induced liver nucleic acid modifications in part by increasing its detoxication through induction of denitrification, although it is evident that other mechanisms must also be involved.      

Doppler assessment of brachial artery flow as a measure of endothelial dysfunction in pediatric chronic renal failure

Cardiovascular morbidity and mortality are highly prevalent among patients with chronic renal failure (CRF). Endothelial dysfunction is regarded as the initial reversible step in the development of atherosclerosis and has been demonstrated in all stages of renal failure. Non-invasive techniques to assess endothelial function have been recently developed and have been proven to predict future mortality in adults. We aimed to assess endothelial function in children with stage 4 chronic kidney disease (CKD 4) on conservative treatment, using a-non invasive, high-resolution, ultrasound Doppler study of the brachial artery flow, correlating it with other clinical and laboratory parameters. This study included 34 children with CKD 4 on conservative treatment who were compared with 30 healthy controls. Flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NTG-MD) and FMD/NTG-MD ratio were estimated. FMD was abnormal (< 5%) in 24 patients (71%). FMD and FMD/NTG-MD ratio were significantly lower in patients than in controls (P = 0.001 and P = 0.01, respectively). FMD correlated positively with serum calcium and negatively with alkaline phosphatase. We concluded that endothelial dysfunction is present in children with CKD 4 on conservative treatment and may reflect increased atherogenic and thrombogenic properties of the endothelium, contributing to subsequent adverse cardiovascular outcome.     

Acute bleomycin toxicity

A case of acute pulmonary toxicity due to bleomycin leading to death in 60 hours is described in an 11-year-old male with Hodgkin's disease. This acute presentation in an immunologically comprised host caused consideration of etiologies other than drugs. Previous reports in the literature have not documented such an acute fatal course as a result of bleomycin toxicity.     

Screening of the adult population in Iran for coeliac disease: comparison of the tissue-transglutaminase antibody and anti-endomysial antibody tests

BACKGROUND AND AIMS: Population-based studies for the prevalence of coeliac disease (CD) in west-Asian countries are scarce. We aimed to determine the prevalence of gluten-sensitive enteropathy (GSE) in the general population of northern and southern Iran, and evaluate the sensitivity and specificity of the anti-endomysial antibody (EMA) immunofluorescent test and the enzyme-linked immunosorbent assay-based test for determination of the IgA anti-tissue transglutaminase antibody (tTG-Ab) using the human recombinant transglutaminase antigen for the detection of CD in screening the asymptomatic adult population. MATERIAL AND METHODS: Using a stratified random sampling method we enrolled a total of 2799 individuals (1438 from Sari and 1361 from Kerman). The mean age was 33.7 years (range 18-66), with 1398 men. IgA anti-tissue transglutaminase (tTG) and IgA anti-EMA were determined in the serum of all subjects. Those participants with a positive serology for any of the two tests underwent small intestinal biopsy, and were classified according to revised Marsh criteria histologically. A diagnosis of GSE was based on positive serology and a compatible histopathological finding. The maximum likelihood latent class model was used to estimate the sensitivity and specificity of the two tests. RESULTS: Twenty-nine cases showed positive IgA tTG-Ab (15 men and 14 women, mean age 35.4 years, range 18-59), whereas only five were simultaneously positive for EMA. Except for two subjects with normal small bowel histology (Marsh 0), all other subjects were found to have biopsy findings compatible with GSE: 18 Marsh I, five Marsh II, three Marsh IIIa and one Marsh IIIc lesions. he prevalence of GSE was 0.96% or 1:104. The sensitivity and specificity of the human-recombinant IgA tTG-Ab assay were 100 and 99%, respectively, whereas the results for IgA EMA were 19 and 100%, respectively. The IgA EMA was positive in cases with advanced mucosal lesions of the small bowel. The mean serum value of IgA tTG-Ab was higher in patients with severe enteropathy compared with those showing slight mucosal changes (P<0.05). CONCLUSION: The minimum prevalence of gluten sensitivity among the general population of northern and southern Iran is 1:104. The best screening test for the detection of GSE in the general population is IgA tTG-Ab.     

MODERN LINES OF MANAGEMENT OF ECTOPIC PREGNANCY

The recent increase in the incidence of ectopic pregnancies was associated with rapid improvement in the diagnostic and therapeutic techniques. Quantitative serum B-HCG radioimmunoassay and high resolution vaginal ultrasonography have facilitated early diagnosis of ectopic pregnancy allowing a more conservative approach to patient management. Different conservative surgical and medical lines of management recently developed were associated with and increased chance of subsequent intrauterine pregnancy with no increase in the incidence of repeat ectopic pregnancy. Outpatient systemic medical treatment seems to be a preferred alternative to conservative surgery. In selected cases, it is associated with a lower complication rate and promising result for fertility. (Br J Clin Pract 1996; 50(7) : 376-380.)