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.      

Patterns of spectrin expression in B-cell lymphomas: loss of spectrin isoforms is associated with nodule-forming and germinal center-related lymphomas.

Spectrins are a family of cytoskeletal proteins that organize and link membranes to subcellular motors and filaments. Although traditionally divided into erythroid and non-erythroid forms, the discovery of new spectrin isoforms in various tissues indicates that their distribution is not yet fully characterized. To our knowledge, there is no comprehensive analysis of spectrins in lymphoid malignancies. Using tumor microarrays of paraffin blocks, we immunohistochemically studied 10 lymph nodes with reactive lymphoid hyperplasia and 94 lymph nodes involved by B-cell malignant lymphoma. Expression of spectrins alphaI, alphaII, betaI, betaII, and betaIII was scored using a 20% cutoff for positive immunoperoxidase staining. All spectrin isoforms, except erythroid-specific alphaI spectrin, were detected in lymph nodes with reactive lymphoid hyperplasia. In contrast, various spectrins were lost in particular B-cell malignant lymphomas. Based on the absence of staining for one or more spectrin isoforms in at least 50% of cases, we identified three patterns: (1) loss of alphaII and betaII in follicular lymphoma, grades 2/3 and 3/3; nodular lymphocyte predominance Hodgkin's lymphoma; nodular sclerosis Hodgkin's lymphoma; (2) loss of betaI only in Burkitt lymphoma; and (3) loss of alphaII and betaI in mixed cellularity Hodgkin's lymphoma. In contrast, follicular lymphoma, grade 1/3 and diffuse large B-cell lymphoma retained spectrin in 67-100% of cases. The other lymphoma subtypes retained spectrin in greater than 50% of cases. We identified the loss of particular spectrin isoforms in B-cell malignant lymphomas that have a nodular growth pattern and/or are believed to arise from germinal center B-cells, that is follicular lymphoma, grades 2/3 and 3/3; Burkitt lymphoma; nodular sclerosis Hodgkin's lymphoma; mixed cellularity Hodgkin's lymphoma; and nodular lymphocyte predominance Hodgkin's lymphoma. The absence of particular spectrin isoforms may correlate with transformation or aggressive biologic behavior for some lymphoma subtypes.     

Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer

Purpose  

An open-label Phase 1 study of recombinant prime-boost poxviruses targeting CEA and MUC-1 in patients with advanced pancreatic cancer was conducted to determine safety, tolerability and obtain preliminary data on immune response and survival.     

Influence of handedness on calcaneal ultrasound: Implications for assessment of osteoporosis and study design

Calcaneal ultrasound has been increasingly studied for its potential in the assessment of osteoporotic fracture risk. The accuracy of such an assessment is, in part, dependent on the reproducibility of the measurement. This study examines the impact of handedness on ultrasound measurements [broadband ultrasound attenuation (BUA) and velocity of sound (VOS)] in the calcaneus. Two hundred and sixty-four subjects (57 men and 297 women) aged 51.1+13.6 years (mean ± SD) were studied. For each subject, calcaneal ultrasound measurements were performed on both heels with a McCue CUBA ultrasound densitometer. Right-handed dominance (94.7%) was determined by structured interview. In men, BUA measurements were significantly higher on the dominant side: mean difference 4.1±1.5 dB/MHz (mean ± SD;p=0.009), equivalent to 4.2+1.5% and more than 4 times the average rate of annual change in BUA. The difference between sides was greater in young (<50 years) than old men (>50 years). Among the women, the difference was not statistically significant (0.7±0.9 dB/MHz;p=0.4); however, it was significant in younger women (20–30 years) (99±4 vs 90±4 dB/MHz,p=0.01). By contrast VOS did not differ between sides in either men or women irrespective of age. Within-subject standard deviation of BUA was 9.8 dB/MHz for men and 8.6 dB/ MHz for women and the component due to right and left difference was 8.4 dB/MHz for men and 6.9 dB/MHz for women. This variability of BUA between right and left heels could increase the false-positive rate by up to 28% for a cut-off of 2 SD below the mean. These data indicate that variation between left and right heel measurements of BUA is higher than that of random error measurements, particularly in men and younger, presumably more physically active subjects. Although VOS measurements were not side dependent, in the smaller number of studies examining VOS and fracture risk, VOS appears to have a weaker predictive power than BUA. Clinical and epidemiological studies involving calcaneal BUA measurements should standardize the side measured to either the dominant or non-dominant heel, to reduce within-subject variation and increase their power.