Citations

Abstract Defective microRNA (miRNA) biogenesis contributes to the development and progression of epithelial ovarian cancer (EOC). In this study, we examined the hypothesis that single nucleotide polymorphisms (SNP) in miRNA biogenesis genes may influence EOC risk. In an initial investigation, 318 SNPs in 18 genes were evaluated among 1,815 EOC cases and 1,900 controls, followed up by a replicative joint meta-analysis of data from an additional 2,172 cases and 3,052 controls. Of 23 SNPs from 9 genes associated with risk (empirical P < 0.05) in the initial investigation, the meta-analysis replicated 6 SNPs from the DROSHA, FMR1, LIN28, and LIN28B genes, including rs12194974 (G>A), an SNP in a putative transcription factor binding site in the LIN28B promoter region (summary OR = 0.90, 95% CI: 0.82–0.98; P = 0.015) which has been recently implicated in age of menarche and other phenotypes. Consistent with reports that LIN28B overexpression in EOC contributes to tumorigenesis by repressing tumor suppressor let-7 expression, we provide data from luciferase reporter assays and quantitative RT-PCR to suggest that the inverse association among rs12194974 A allele carriers may be because of reduced LIN28B expression. Our findings suggest that variants in LIN28B and possibly other miRNA biogenesis genes may influence EOC susceptibility. Cancer Res; 71(11); 3896–903. ©2011 AACR.

Os linfomas primários do SNC são raros, mas sua incidência tem aumentado nos últimos anos, Estes tumores frequentemente se localizam nos gânglios da base e tálamo ou se apresentam de forma multifocal. O tratamento atual para eles é a radioterapia, associada ou não a quimioterapia. Devido à sua extremamente baixa morbidade, a biópsia estereo-táxica é o método ideal para determinar o diagnóstico histológico em pacientes com suspeita de linfomas do SNC. Os autores apresentam estudo de 49 casos de linfomas primários do SNC, diagnosticado por biópsia estereotáxica.

Streptozotocin (STZ)-induced diabetes mellitus (DM) offers a very cost-effective and expeditious technique that can be used in most strains of rodents, opening the field of DM research to an array of genotypic and phenotypic options that would otherwise be inaccessible. Despite widespread use of STZ in small animal models, the data available concerning drug preparation, dosing and administration, time to onset and severity of DM, and any resulting moribundity and mortality are often limited and inconsistent. Because of this, investigators inexperienced with STZ-induced diabetes may find it difficult to precisely design new studies with this potentially toxic chemical and account for the severity of DM it is capable of inducing. Until a better option becomes available, attempts need to be made to address shortcomings with current STZ-induced DM models. In this paper we review the literature and provide data from our pancreatic islet transplantation experiments using single high-dose STZ-induced DM in NCr athymic nude mice with hopes of providing clarification for study design, suggesting refinements to the process, and developing a more humane process of chemical diabetes induction.

The time-dependent release of prostaglandin E 2 (PGE 2 ), prostaglandin F 2α (PGF 2α ), thromboxane (Tx) B 2 , and 6-keto-PGF 1α (6-keto) from brain was measured before, during, and after a 15-min interval of total ischemia (four-vessel occlusion) in halothane-anesthetized cats using the technique of cerebroventricular perfusion. Resting levels of PGE 2 , PGF 2α , 6-keto, and Tx were: 253 ± 75, 953 ± 300, 650 ± 200, and 550 ± 170 pg/ml, respectively. During the 15-min ischemia, all prostanoids rose significantly, yet the highest levels were not observed until the first 15–60 min of the reflow at which time levels of PGE 2 , PGF 2α , 6-keto, and Tx, as compared with the preischemic baseline, rose ∼8, 3.4, 3, and 55-fold, respectively. Significantly, although all prostanoids showed increases relative to baseline, the ratios of PGF 2α /6-keto and PGE 2 /6-keto remained stable throughout the experiment in both groups of animals. In contrast, the Tx/6-keto ratio rose from ∼1 to ∼ 30 during the 60 min after reflow in untreated cats. Treatment with zomepirac sodium (5 mg/kg, i.v.), a cyclooxygenase inhibitor, resulted in highly significant reductions in the levels of all prostanoids during the preischemic period. In zomepirac sodium-treated animals, there were also highly significant reductions in the prostanoid response to ischemia. Of particular interest was that the degree of inhibition of Tx as compared with 6-keto, during the post-ischemic period of peak secretion was such that the Tx/6-keto ratio fell from 30 in the control ischemic animal to 0.3 in the zomepirac sodium-treated animal, suggesting a selective blockade of the formation of Tx as compared with prostacyclin.

We report that regional CBF determined by the initial slope technique using 133 Xe and 85 Kr in cats and rabbits can be significantly influenced by the size of the field of measurement. The clearance curves of umbelliferone, a lipid-soluble intracellular pH fluorescent indicator, from a visually avascular 80-fm field were used to cross-correlate rCBF with focal cortical perfusion. Our findings indicate that in the cat, as the gamma or beta detector's field of volume was reduced, regional CBF (rCBF) measured by intraarterially injected 133 Xe or 85 Kr decreased in value by 33% and 28%, respectively, and the slope of the rCBF-P a co 2 response curve became less steep by 56% and 45%, respectively. Umbelliferone, measuring a much smaller volume of tissue, showed a lower normocapnic flow and a more oblique P a co 2 response curve. In the rabbits studied, the normocarbic rCBFs and the rCBF-P a co 2 response curves measured with the three techniques corresponded to those measured in the cat. These results suggest that large field/volume measurements assess a measure of flow that is a weighted average of several distinct flow compartments and that these compartments differ in their response to changes in P a co 2 .

Nimodipine, a calcium entry blocker, was administered in increasing doses of 0.1–3.0 μg kg −1 min −1 to six dogs after they had recovered consciousness from a surgical preparation that was conducted under general anesthesia and while they were under the influence of total spinal anesthesia. CBF was measured with a sagittal sinus outflow technique and CMRO 2 was calculated as the product of CBF and the arteriovenous O 2 difference. Nimodipine did not influence either CBF or CMRO 2 . There was a decrease in the cortical pyruvate level at the end of the study, but no significant change in phosphocreatine, ATP, lactate, or energy charge when compared with six control dogs. It has previously been reported that nimodipine increases the CBF in global ischemia with a potentially beneficial effect on the neurological outcome. With no effect on normal CBF or metabolism, this suggests that nimodipine may be useful in a variety of ischemic situations without fear of either a steal phenomenon or untoward effects on intracranial pressure.

Zomepirac sodium (ZS) (5 mg/kg i.v.) was used to evaluate the effects of preischemia cyclooxygenase inhibition on CBF (as assessed by 133 Xe clearance), CBF–P a CO 2 responsiveness, and electrophysiologic (EEG) parameters before and after a 15-min period of complete global ischemia produced by four-vessel occlusion and mild hypotension. During the 15-min period of ischemia, CBF was essentially zero. Following reflow all groups displayed an initial hyperemia as compared with control (92 ± 11 vs. 141–146 ml/100 g/min). Saline-treated animals during reflow displayed a delayed hypoperfusion (26 ± 3 ml/100 g/min), which showed no improvement during the 2-h reflow period prior to death. In contrast, ZS-treated animals during reflow displayed significantly higher flows during the hypoperfusion phase (72 ± 9 ml/100 g/min). The CBF–P a CO 2 response displayed an approximately sevenfold reduction in slope at 2 h after reflow in saline-treated animals. This decrease in P a CO 2 reactivity was not observed in the ZS-pretreated animals. With regard to EEG, all animals showed a total flattening during the 15 min of ischemia. In saline-treated animals only one of seven showed any sign of even marginal recovery. In ZS-treated animals EEG activity showed prominent recovery in seven of seven. Brainstem auditory evoked potentials were monitored and showed prominent recovery of amplitude and latency in ZS but not saline-treated animals during reflow.

Ten minutes of complete ischemia was produced in 11 dogs by temporary ligation of the aorta. Immediately before the ischemic episode, the dogs received nimodipine, a new calcium entry blocker, 10 μg kg −1 , i.v., followed by an infusion of 1 μg kg −1 min −1 for 2 h. Post-ischemic cerebral blood flow and metabolism were measured for 120 min in six dogs. Neurologic recovery was evaluated 48 h post-ischemia in five dogs. The results were compared to previously determined controls. Nimodipine nearly doubled cerebral blood flow in the delayed post-ischemic hypoperfusion period, compared to untreated dogs (approximately 45% versus 25% of pre-ischemic control values), but had no significant effect on metabolism. Nimodipine also improved neurologic recovery. Four of five treated dogs were normal and one was moderately damaged, whereas six of seven controls were either severely damaged or dead. This suggests that the delayed hypoperfusion state occurring after complete cerebral ischemia probably does contribute to the ultimate neurologic damage, and that nimodipine offers a potential protective effect.