Citations

Metabolic memory (MM) is the phenomenon whereby diabetes complications persist and progress after glycemic recovery is achieved. Here, we present data showing that MM is heritable and that the transmission correlates with hyperglycemia-induced DNA hypomethylation and aberrant gene expression. Streptozocin was used to induce hyperglycemia in adult zebrafish, and then, following streptozocin withdrawal, a recovery phase was allowed to reestablish a euglycemic state. Blood glucose and serum insulin returned to physiological levels during the first 2 weeks of the recovery phase as a result of pancreatic β-cell regeneration. In contrast, caudal fin regeneration and skin wound healing remained impaired to the same extent as in diabetic fish, and this impairment was transmissible to daughter cell tissue. Daughter tissue that was never exposed to hyperglycemia, but was derived from tissue that was, did not accumulate AGEs or exhibit increased levels of oxidative stress. However, CpG island methylation and genome-wide microarray expression analyses revealed the persistence of hyperglycemia-induced global DNA hypomethylation that correlated with aberrant gene expression for a subset of loci in this daughter tissue. Collectively, the data presented here implicate the epigenetic mechanism of DNA methylation as a potential contributor to the MM phenomenon.

AbstractGene‐set analyses have been widely used in gene expression studies, and some of the developed methods have been extended to genome wide association studies (GWAS). Yet, complications due to linkage disequilibrium (LD) among single nucleotide polymorphisms (SNPs), and variable numbers of SNPs per gene and genes per gene‐set, have plagued current approaches, often leading to ad hoc “fixes.” To overcome some of the current limitations, we developed a general approach to scan GWAS SNP data for both gene‐level and gene‐set analyses, building on score statistics for generalized linear models, and taking advantage of the directed acyclic graph structure of the gene ontology when creating gene‐sets. However, other types of gene‐set structures can be used, such as the popular Kyoto Encyclopedia of Genes and Genomes (KEGG). Our approach combines SNPs into genes, and genes into gene‐sets, but assures that positive and negative effects of genes on a trait do not cancel. To control for multiple testing of many gene‐sets, we use an efficient computational strategy that accounts for LD and provides accurate step‐down adjustedP‐values for each gene‐set. Application of our methods to two different GWAS provide guidance on the potential strengths and weaknesses of our proposed gene‐set analyses.

Erythromelalgia is a rare clinical syndrome characterized by intermittent heat, redness, swelling and pain more commonly affecting the lower extremities. Symptoms are mostly aggravated by warmth and are eased by a cold temperature. In some cases, symptoms can be very severe and disabling. Erythromelalgia can be classified as either familial or sporadic, with the familial form inherited in an autosomal dominant manner. Recently, there has been a lot of progress in studying Na(v)1.7 sodium channels (expressed mostly in the sympathetic and nociceptive small-diameter sensory neurons of the dorsal root ganglion) and different mutations affecting the encoding SCN9A gene that leads to channelopathies responsible for some disorders, including primary erythromelalgia. We present a severe case of progressive primary erythromelalgia caused by a new de novo heterozygous missense mutation (c.2623C>G) of the SCN9A gene which substitutes glutamine 875 by glutamic acid (p.Q875E). To our knowledge, this mutation has not been previously reported in the literature. We also provided a short literature review about erythromelalgia and Na(v) sodium channelopathies.

Abstract Purpose: To investigate the associations between baseline and posttreatment circulating tumor cell (CTC) gene expression and outcome of patients enrolled in four North Central Cancer Treatment Group metastatic breast cancer (MBC) trials in which specimens were shipped (at 4°C) from community-based sites to a reference laboratory (Mayo Clinic, Rochester, MN). Experimental Design: Blood was collected at treating sites from MBC patients before (baseline), during, and at the end of treatment with erlotinib + gemcitabine (N0234), sorafenib (N0336), irinotecan + cetuximab (N0436), or paclitaxel-poliglumex + capecitabine (N0437). CTCs from 10 mL of EDTA blood were enriched with CD45 depletion, 24 to 30 hours postblood collection. Reverse transcription/quantitative PCR was used to determine cytokeratin-19 (CK19) and mammaglobin (MGB1) mRNA levels in CTCs from up to 13 (N0234), 16 (N0336), 18 (N0436), and 39 (N0437) patients. The gene expressions were normalized to β2-microglobulin and calibrated to healthy blood using the 2–ΔΔCq algorithm; positivity was defined as 2 or more. Results: CK19+mRNA cells were detected in 56% to 75% and MGB1+mRNA cells in 23% to 38% of 86 patients at baseline. CK19+mRNA cells were detected in 30% to 67% and MGB1+mRNA cells in 14% to 64% of 110 postbaseline serial samples. The presence of baseline CK19+mRNA cells (P = 0.01) but not MGB1+mRNA cells (P = 0.14) was significantly associated with shorter overall survival. A decrease in MGB1+mRNA levels (baseline-week 8) seemed to be associated with clinical response (P = 0.05). Conclusions: CTC gene expression analysis conducted by a reference laboratory is feasible when blood is collected from treating sites and processed 24 to 30 hours postcollection. The presence of baseline CK19+mRNA CTCs was associated with poor prognosis; a decrease in MGB1+mRNA CTCs may help predict response to therapy of MBC patients. Clin Cancer Res; 17(22); 7183–93. ©2011 AACR.

Abstract Background. Half of all breast cancers are early stage, lymph node negative, and hormone receptor positive. A 21-gene (Oncotype DX®; Genomic Health, Inc., Redwood City, CA) recurrence score (RS) is prognostic for recurrence and predictive of chemotherapy benefit. We explored the ability of oncologists to predict the RS using standard prognostic criteria. Methods. Standard demographic and tumor prognostic criteria were obtained from patients with an available RS. Two academic pathologists provided tumor grade, histologic type, and hormone receptor status. Six academic oncologists predicted the RS category (low, intermediate, or high) and provided a recommendation for therapy. The oncologists were then given the actual RS and provided recommendations for therapy. Analysis for agreement was performed. Results. Thirty-one cases, including nine additional cases with variant pathology reads, were presented. There was substantial agreement in oncologists' ability to discriminate between true low or true intermediate and true high (κ = 0.75; p < .0001). Predictions between low and intermediate were not consistent. The most common discrepancies were predictions of a low RS risk when cases were true intermediate and predictions of an intermediate RS risk when cases were true low. The actual RS resulted in a change in the treatment recommendations in 19% of cases. Of the 186 scenarios and six oncologists in aggregate, five fewer chemotherapy recommendations resulted with the actual RS. Conclusions. Oncologists are able to differentiate between a low or intermediate RS and a high RS using standard prognostic criteria. However, provision of the actual RS changed the treatment recommendations in nearly 20% of cases, suggesting that the RS may reduce chemotherapy use. This effect was observed in particular in intermediate-risk cases. Prospective clinical trials are necessary to determine whether decisions based on the RS change outcomes.