Alkylglycerols are natural etherlipids abundant in shark liver oil (SLO) in a diacylated form. SLO is known to have antitumor properties and was recently described as an inhibitor of tumor neovascularization. However, most studies did not discriminate between the respective activities of alkylglycerols and of fatty acids, which both have potent biological properties. In this work, a mouse model was used to investigate the antitumor effects of SLO and of alkylglycerols purified from the same source, both administered orally. We demonstrated that either pure alkylglycerols or SLO reduced the tumor growth in a similar manner, suggesting that alkylglycerols were involved in this effect. In alkylglycerol-treated mice, metastasis dissemination was reduced by 64 +/- 8%, whereas SLO effect was 30 +/- 9% below control. Purified alkylglycerols also decreased significantly plasmalogen content in tumors, whereas SLO had no such effect. Finally, we demonstrated that a 5-day treatment with alkylglycerols curtailed the presence in tumors of von Willebrand factor, a marker of endothelial cells. This result suggested an anti-angiogenic effect of alkylglycerols. In summary, alkylglycerols were shown to decrease the growth, vascularization, and dissemination of Lewis lung carcinoma tumors in mice. These findings suggest that the antitumor activity of SLO is likely mediated by the presence of alkylglycerols.
We studied the inhibition of peroxidation by local anesthetics in an inflammatory animal model. Inflammatory lipid peroxidation was assessed by the thiobarbituric assay in plasma from rats injected or not injected with carrageenan (Carra) and killed 1, 2, 4, 6, 12, and 24 h thereafter. Thiobarbituric acid reactive substances (TBARS) values in inflammatory animals were maximal 6 h after Carra administration. This result, in accordance with the evolution of paw edema width during time, supports that TBARS reflect the intensity of inflammation. Local anesthetics (bupivacaine, lidocaine, ropivacaine, or bupivacaine-loaded microspheres) or amitriptyline were injected in clinically relevant concentrations as a sciatic nerve block or intraperitoneally in inflamed animals. Ropivacaine did not exhibit any protective effect on Carra-induced lipid peroxidation in rats. With all the other drugs administered as a sciatic nerve block, the maximal TBARS increase was not observed at 6 h. Our conclusion is that bupivacaine (plain or encapsulated), lidocaine, and amitriptyline in clinically relevant concentrations administered via the sciatic nerve showed antioxidant properties toward lipid peroxidation induced by Carra inflammation. Intraperitoneal injection of those drugs gave the same effect as nerve block; this result suggests that their mechanism of action is not strictly limited to the nerve. IMPLICATIONS. We investigated the antioxidant effects of local anesthetics and amitriptyline in an inflammatory rat model. Amitriptyline exhibits antioxidant properties per se, whereas lidocaine and bupivacaine (plain or encapsulated) seem to inhibit the peroxidation process. This may have future application in limiting toxic oxygen metabolite production during the inflammatory process.
Because of the differential effect observed on the contralateral side, the mechanism underlying the prolongation of ipsilateral block with amitriptyline may not result only from a prolonged Na(+) channel blockade but might be explained by a local toxic effect or lack of systemic actions.
Polyamines are thought to be involved in the regulation of numerous metabolic and electrophysiological processes in the nervous system. In this study we evaluated the effect of a synthetic polyamine-deficient diet on pain in a carrageenan (Car)-induced inflammatory rat model. Inflammation was induced with a unilateral subcutaneous injection of Car in a plantar hindpaw in rats fed without (control group) or with (deficiency group) a polyamine-deficient diet. Ipsilateral and contralateral hyperalgesia was evaluated using the Randall-Sellito pressure test. Heart rate changes were also recorded under general anesthesia. Then, the effects of a bupivacaine sciatic nerve block and subcutaneous injection of naloxone or ketamine were evaluated for Car-induced hyperalgesia. Data were analyzed using analysis of variance followed by unpaired Student's t-test (significance P < 0.05). Before Car injection, no significant difference was observed in response to mechanical stimuli between the control and the deficiency groups (n = 114 in pooled data). Car injection induced significant ipsilateral and contralateral hyperalgesia in the control groups, whereas a significant analgesic effect appeared in the deficient groups on both the ipsilateral and contralateral hindpaws. This analgesic effect was confirmed by the electrocardiogram recording that showed a significant increase in heart rate in the control group after Car injection compared with the deficiency group that showed a decrease in heart rate under general anesthesia. Bupivacaine sciatic nerve block had no significant effect on hypoalgesia phenomena induced by polyamine deficiency. Naloxone administration had no effect in the control group but reversed the analgesic effect in the deficiency group. Ketamine administration induced a significant analgesic effect in the control group and partly reversed the analgesic effect in the deficiency group. In conclusion, a synthetic polyamine-deficient diet had a significant general analgesic effect on Car-induced mechanical hyperalgesia. The mechanism of analgesic action remains to be elucidated.
INTRODUCTION: Despite the demonstrated effectiveness of average-risk screening, colorectal cancer (CRC) remains the 2nd leading cause of cancer death in the US. For optimal prevention, CRC screening tools should be highly accurate, user-friendly, and broadly accessible. Patient and provider adoption of the FDA-approved, guideline-endorsed multi-target stool DNA (mt-sDNA) test has grown exponentially since its launch in 2014. Toward ongoing improvement in CRC screening effectiveness, we conducted a blinded case-control study to assess the detection accuracy of a mt-sDNA panel of novel, highly discriminant methylated DNA markers (MDMs). METHODS: We selected 12 candidate MDMs from prior whole methylome discovery and validation in tissue. Stool was obtained as part of previous large, multicenter studies and collected prior to or 7 days post-colonoscopy (prior to any clinically-indicated treatment). CRC, advanced adenoma (AA; size ≥1 cm, high-grade dysplasia, or ≥25% villous morphology), non-AA, or control (no neoplasia) status was defined by colonoscopy and histopathology. Samples were blinded to operators and randomized by characterization to balance the test sets prior to assessment. MDMs were quantified by target-specific DNA capture and Long-probe Quantitative Amplified Signal assay on bisulfite-converted DNA; fecal hemoglobin was quantified by immunoassay. Bootstrapping methods were used to select a panel of 3 MDMs, which was then 10-fold cross-validated; hemoglobin was also included, as was a colon epithelium-specific MDM to normalize stool MDM levels. RESULTS: Participant samples included 117 CRC, 120 AA, 161 non-AA, and 327 controls. Median age was 67 (IQR 61, 75) years; 51% were men. The AUC with best-fit was 0.97 for CRC and 0.84 for AA, and these high AUCs held up tightly on cross-validation (Figure 1). At 92% (95% CI 88-94%) specificity, sensitivity of the panel was 92% (95% CI 86-96%) for CRC. Neither CRC stage (Figure 2) nor CRC site significantly affected performance. At the same 92% specificity, sensitivity was 65% (95% CI 56-73%) for AAs overall, 67% (38-88%) for sessile serrated polyps ≥1 cm, and 71% (57-82%) for adenomas with villous features (Figure 3). CONCLUSION: These data support highly accurate performance of a novel panel of mt-sDNA markers for detecting both CRC (including early stage lesions) and AAs at greatest risk of progression. Prospective comparative studies are warranted to further establish the clinical potential of this novel screening tool.
Background: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States, yet it is potentially the most treatable and preventable cancer with effective screening. Exact Sciences has developed a multi-biomarker CRC screening test that targets DNA methylation, DNA mutations, and hemoglobin in stool. The aim of this study was to evaluate the analytical accuracy of a novel assay for the detection of KRAS mutation sequences at Codons 12 and 13 in well-characterized colorectal tissues. Methodology: A multiplexed KRAS assay was designed utilizing QuARTS (Quantitative Allele-specific Real-time Target and Signal amplification), a highly sensitive technology that combines allele-specific DNA amplification with invasive cleavage chemistry to generate signal during each amplification cycle similar to real-time PCR. The assay, which detects seven KRAS mutations and the reference gene β-actin, was used to assess 87 colorectal tissue samples (52 CRCs, 16 adenomas ≥ 1cm, and 19 normal epithelia) as determined by Mayo Clinic Pathology. Samples were obtained by microdissection of fresh frozen tissue biopsies. DNA was extracted by Mayo Clinic using a standardized chloroform/phenol methodology. The genotypes of each sample were established using dye terminator dideoxy sequencing in both the forward and reverse orientations. Copy numbers of KRAS mutations and β-actin were determined by conventional comparison against standard curves. KRAS data are reported as percent mutation and calculated by dividing mutant copies by β-actin copies and multiplying by 100. Results: Based on sequencing data: the 52 CRC samples contained 22 KRAS mutations and 30 wild-type genotypes, the 16 adenomas ≥ 1cm contained 8 mutations and 8 wild-type genotypes, and the 19 normal tissues contained all wild-type genotypes. The QuARTS assay detected 100% of the KRAS mutations in the CRC and adenomas and provided excellent differentiation between wild-type and mutation, with the highest percent KRAS mutation of normal wild-type samples at 0.55% and the lowest percent mutation of KRAS positive samples at 8.34%. Based on this data, this assay has the potential to be more sensitive analytically than standard sequencing. Conclusion: The QuARTS assay detects KRAS mutations in tissue with high sensitivity and specificity. This assay method could provide an accurate and high throughput approach to detection of KRAS mutations in biospecimens for multiple clinical applications. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A22.
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