Pyridine nucleotide metabolism in imaginal discs of Drosophila melanogaster

The pyridine nucleotide metabolism of imaginal discs of Drosophila melanogaster has been studied in vitro by incubating discs with labeled nicotinic acid in the presence and absence of ecdysterone. The major labeled compounds found within the discs are NAD, NADP, and nicotinic acid. There is preferential uptake of nicotinamide over nicotinic acid, although the Priess-Handler pathway is used exclusively. The presence of ecdysterone produces a small increase in the NADP/NAD ratio, and an increase in NAD synthesis, probably to compensate for increased NAD turnover.Supported by Grant GB 43569 from the National Science Foundation.     

Hepatic organelle interaction. IV. Mechanism of succinate enhancement of formaldehyde accumulation from endoplasmic reticulum N-dealkylations

Further evidence for organelle interaction during drug metabolism by the liver is presented. The apparent stimulation by succinate of formaldehyde accumulation in the medium, which was reported to occur with liver slices and homogenates as well as with mitochondria plus microsomes, has been shown to be the result of succinate inhibition of mitochondrial aldehyde dehydrogenase. The mechanism of succinate inhibition is shown to be by reverse electron transport, and an increase in the NADH to NAD+ ratio in the mitochondria; the aldehyde dehydrogenase requires the oxidized form of the pyridine nucleotide as its cofactor. Studies on in vitro N-demethylation by liver microsomes and endoplasmic reticulum segments which cosediment with the mitochondria indicate that formaldehyde produced by the mixed function oxidase is handled differently from formaldehyde added to the medium. The latter is mainly retained in the medium containing 5 mM semicarbazide, while the generated formaldehyde is more than 50% consumed by the mitochondria. Electron microscopy has indicated that the microsomes and the endoplasmic reticulum fragments have a tendency to align themselves close to the mitochondria when present in the same medium. Consequently, it is possible that formaldehyde released to the medium adjacent to the mitochondria, as by N-demethylation, would be exposed to semicarbazide for shorter periods than that added directly to the medium. In agreement with this suggestion, complexing of formaldehyde with semicarbazide was observed spectroscopically not to be an extremely rapid reaction even at 37 degrees C. This is believed to be the reason for the greater extent of consumption of formaldehyde generated by the endoplasmic reticulum.     

Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer

Genetic and epigenetic alterations are essential for the initiation and progression of human cancer. We previously reported that primary human medulloblastomas showed extensive cancer-specific CpG island DNA hypermethylation in critical developmental pathways. To determine whether genetically engineered mouse models (GEMMs) of medulloblastoma have comparable epigenetic changes, we assessed genome-wide DNA methylation in three mouse models of medulloblastoma. In contrast to human samples, very few loci with cancer-specific DNA hypermethylation were detected, and in almost all cases the degree of methylation was relatively modest compared with the dense hypermethylation in the human cancers. To determine if this finding was common to other GEMMs, we examined a Burkitt lymphoma and breast cancer model and did not detect promoter CpG island DNA hypermethylation, suggesting that human cancers and at least some GEMMs are fundamentally different with respect to this epigenetic modification. These findings provide an opportunity to both better understand the mechanism of aberrant DNA methylation in human cancer and construct better GEMMs to serve as preclinical platforms for therapy development.     

The Effect of Ag Nanoparticles on Surface-Enhanced Luminescence from Au Nanovoid Arrays

Studies comparing the effect of adding two different nanoparticle compositions on the plasmonic properties of Au nanovoid arrays were undertaken. Surface-enhanced resonance luminescence and surface-enhanced resonance Raman studies comparing dispersed Ag nanoparticles and Ag nanoparticle aggregates on gold nanovoid arrays were undertaken. These studies showed that using Ag nanoparticle aggregates increased both luminescence and Raman efficiency relative to when dispersed nanoparticles were used; in addition, these studies also showed that adding dispersed Ag nanoparticles supported a more reproducible enhancement in luminescence and Raman across the substrate compared to using Ag nanoparticle aggregates. Finite element analysis simulations indicated that surface plasmon polariton distribution in the sample was affected by the presence of the Ag nanoparticles on the Au nanovoid array.     

A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma

BACKGROUND: Fractionated plasma metanephrine measurements are commonly used in biochemical testing in search of pheochromocytoma. METHODS: We aimed to critically appraise the diagnostic efficacy of fractionated plasma free metanephrine measurements in detecting pheochromocytoma. Nine electronic databases, meeting abstracts, and the Science Citation Index were searched and supplemented with previously unpublished data. Methodologic and reporting quality was independently assessed by two endocrinologists using a checklist developed by the Standards for Reporting of Diagnostic Studies Accuracy Group and data were independently abstracted. RESULTS: Limitations in methodologic quality were noted in all studies. In all subjects (including those with genetic predisposition): the sensitivities for detection of pheochromocytoma were 96%-100% (95% CI ranged from 82% to 100%), whereas the specificities were 85%-100% (95% CI ranged from 78% to 100%). Statistical heterogeneity was noted upon pooling positive likelihood ratios when those with predisposition to disease were included (p < 0.001). However, upon pooling the positive or negative likelihood ratios for patients with sporadic pheochromocytoma (n = 191) or those at risk for sporadic pheochromocytoma (n = 718), no statistical heterogeneity was noted (p = 0.4). For sporadic subjects, the pooled positive likelihood ratio was 5.77 (95% CI = 4.90, 6.81) and the pooled negative likelihood ratio was 0.02 (95% CI = 0.01, 0.07). CONCLUSION: Negative plasma fractionated free metanephrine measurements are effective in ruling out pheochromocytoma. However, a positive test result only moderately increases suspicion of disease, particularly when screening for sporadic pheochromocytoma.     

Site-dependent angiogenic cytokine production in human tumor xenografts

Tumor microenvironment plays a critical role in tumor growth, angiogenesis, and metastasis. Differences in site of tumor implantation result in differences in tumor growth, metastasis, as well as response to chemotherapy. We hypothesized that tumor-induced angiogenic growth factor production into the plasma will also be influenced by site of tumor implantation. We evaluated the site-dependent production of angiogenic growth factors in the plasma of tumor bearing animals at two different sites of implantation. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) were evaluated in nude mice bearing A2780, SKOV-3, or OVCAR-3 human ovarian tumors, as well as Panc-1, AsPC-1, or BxPC-3 human pancreatic tumors grown as subcutaneous (SC) xenografts or in the intraperitoneal (IP) cavity. Plasma VEGF and bFGF levels produced by two ovarian tumor lines and two pancreatic tumor lines were substantially higher when the tumors were implanted in the IP cavity than in the SC space. These studies indicated that the site of tumor implantation was an important determinant in the production of plasma VEGF and bFGF levels. As more and more anti-angiogenic agents are developed, the need for appropriate animal models becomes apparent. These results suggest the demand for an appropriate model for the in vivo evaluation of anti-angiogenesis.     

Tourism, Ethnicity and the State in Asian and Pacific Societies

Tourism, Ethnicity and the State in Asian and Pacific Societies. Michel Picard and Robert E. Wood .eds.Honolulu: University of Hawaii Press, 1997.260 pp.