Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas, and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine (5hmC) and higher 5-methylcytosine (5mC) levels, as well as increased dimethylation of histone H3K79. Mutations in IDH1 or IDH2 were associated with longer overall survival (p = 0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (p = 0.021). IDH1 and IDH2 mutations are significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2,309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.
(1976). Annals ofthe Rheumatic Diseases, 35,251-257. Auranofin. New oral gold compound for treatment of rheumatoid arthritis. Eight patients with rheumatoid arthritis were treated with SK&F D-39162 (auranofin), a new oral gold compound which was effective in suppressing adjuvant-induced arthritis in rats. Clinical and humoral parameters were studied during a 3-month period of drug administration followed by a 3-month period under placebo. The drug was absorbed, well tolerated, and its action was manifested by a drop in the mean IgG blood levels in the third week of treatment accompanied by clinical improvement after 5 weeks of oral gold intake. Together with IgG changes, an increase of the albumin ratio was observed, as well as a decrease of tx2-globulin and rheumatoid factor titres. From a total number of 60 swollen joints found initially in the 8 patients only 17 were swollen at week 12 and 9 at week 15. Although the number of patients treated was too small to allow definite conclusions, a follow-up study under placebo of clinical and laboratory changes in the same patients during another 3-month period showed that IgG serum levels rapidly reverted preceding a flare up of disease activity after withdrawal of the drug. This confirmed a direct role in cause-effect relation played by the new oral gold compound.
Summary
The VKORC1 Asp36Tyr single nucleotide polymorphism (SNP) is one of the most promising predictors of high warfarin dose, but data on its population prevalence is incomplete. We determined the frequency of this SNP in participants from seven countries on four continents and investigated its effect on warfarin dose requirement. 1000 samples were analyzed to define the population prevalence of this SNP. Those samples included individuals from Egypt, Ghana, Sudan, Kenya, Saudi Arabia, Peru and African Americans from the United States. 206 Egyptian samples were then used to investigate the effect of this SNP on warfarin dose requirements. This SNP was most frequent among Kenyans and Sudanese, with a minor allele frequency (MAF) of 6% followed by Saudi Arabians and Egyptians with a MAF of 3% and 2.5%, respectively. It was not detected in West Africans, based on our data from Ghana, and a large cohort of African Americans. Egyptian carriers of the VKORC1 Tyr36 showed higher warfarin dose requirement (57.1±29.4 mg/week) than those with the Asp36Asp genotype (35.8±16.6 mg/week; P<0.03). In linear regression analysis, this SNP had the greatest effect size among the genetic factors (16.6 mg/week increase in dose per allele), and improved the warfarin dose variability explained in Egyptians (model R2 from 31% to 36.5%). The warfarin resistant VKORC1 Asp36Tyr appears to be confined to north-eastern Africa and nearby Middle-Eastern populations, but in those populations where it is present, it has a significant influence on warfarin dose requirement and the percent of warfarin dose variability that can be explained.
Gold salts have been used in the treatment of rheumatoid arthritis for nearly 40 years. Their effectiveness, while not consistent, has been well established (Freyberg, 1966) and their use continues. Recently, conflicting results concerning the effectiveness of gold salts on adjuvant arthritis in rats have been reported (Newbould, 1963;Jessop and Currey, 1968). Adjuvant arthritis, a crippling deformity resulting from diffuse connective tissue involvement, is considered by some authorities to be the best available experimental model of rheumatoid arthritis because of its strong clinical and pathological siinilarities to the human disease (Pearson, 1963) HINDLEG VOLUME This was determined by a modified method of VanArman, Begany, Miller, and Pless (1965). On the day of assay (3 to 4 hours after drug administration), the hindlegs were immersed to the anatomical hairline into a mercury reservoir. The mercury column was connected to a Statham pressure transducer (Model P23BB, 0-5 cm. Hg.). The output from the transducer was led through an amplifier to a Hewlett-Packard digital voltmeter (Model HP-3440A), and a high gain/auto range unit (Model 3443A), and finally to a digital recorder (Model J74562A). The digital recordings were calibrated, and a linear relationship between MV and ML was obtained by placing cylinders of known volumes into the mercury reservoir.
ARTHRITIC SCOREThe severity of secondary lesions in the uninjected hindleg was graded 0 to 4, depending upon the area and magnitude of involvement.
DRUG ADMINISTRATIONGold sodium thiomalate (Myocrysine() was prepared at various concentrations in 0 5 per cent. benzyl alcohol and injected intramuscularly (right thigh) in a volume of 0 5 ml./kg. The drug was administered once daily (exclusive of weekend days indicated in the text) starti either on Day 0 or one week before adjuvant injection and continuing until the termination of the experiment (Day 16). Control animals were treated in an identical manner using 0 5 per cent. benzyl alcohol for the intramuscular injections. The benzyl alcohol solution was prepared with either 0 * 9 per cent. saline or water for injection.The level of significant difference between hindleg volumes, arthritic score, and body weight of drug-treated and control groups was determined by the Student's 't' test.
SERUM GOLD LEVELBlood samples were obtained after the decapitation of the adjuvant arthritic rats. 0 5 mJ. aliquot of serum was diluted to 3 0 ml. with distilled water and absorption measured in a Perkin-Elmer Model 303 atomic absorption spectrophotometer (wavelength 243 -3 mjt slit 4,
Recently approved medications for long-term management of obesity include lorcaserin, phentermine-topiramate, and naltrexone-bupropion. When these drugs are used to facilitate weight loss, pharmacists can play an important role in helping to ensure appropriate patient selection and monitoring.
MDA-produced wgaDNA provides accurate and reproducible genotypes with the DMET Plus array and is therefore a suitable template for this targeted pharmacogenetic genotyping array.
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