Electronic health records (EHRs) are expected to be a good source of data for pharmacovigilance. However, current quantitative methods are not applicable to EHR data. We propose a novel quantitative postmarketing surveillance algorithm, the Comparison of Laboratory Extreme Abnormality Ratio (CLEAR), for detecting adverse drug reaction (ADR) signals from EHR data. The methodology involves calculating the odds ratio of laboratory abnormalities between a specific drug-exposed group and a matched unexposed group. Using a 10-year EHR data set, we applied the algorithm to test 470 randomly selected drug-event pairs. It was found possible to analyze a single drug-event pair in just 109 ± 159 seconds. In total, 120 of the 150 detected signals corresponded with previously reported ADRs (positive predictive value (PPV) = 0.837 ± 0.113, negative predictive value (NPV) = 0.659 ± 0.180). By quickly and efficiently identifying ADR signals from EHR data, the CLEAR algorithm can significantly contribute to the utilization of EHR data for pharmacovigilance.

Metabolic enzymes have been shown to function as transcriptional regulators. p53, a tumor-suppressive transcription factor, was recently found to regulate energy metabolism. These combined facts raise the possibility that metabolic enzymes may directly regulate p53 function. Here, we discover that nucleocytoplasmic malate dehydrogenase-1 (MDH1) physically associates with p53. Upon glucose deprivation, MDH1 stabilizes and transactivates p53 by binding to p53-responsive elements in the promoter of downstream genes. Knockdown of MDH1 significantly reduces binding of acetylated-p53 and transcription-active histone codes to the promoter upon glucose depletion. MDH1 regulates p53-dependent cell-cycle arrest and apoptosis in response to glucose deprivation, suggesting that MDH1 functions as a transcriptional regulator for a p53-dependent metabolic checkpoint. Our findings provide insight into how metabolism is directly linked to gene expression for controlling cellular events in response to metabolic stress. Two fundamental processes-energy metabolism and gene regulation-in living organisms are considered indirectly linked to each other due to their different functional locations. Recent findings that some metabolic enzymes function as transcriptional regulators have implicated direct coupling of energy metabolism with gene regulation. [1][2][3] For instance, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serves as a co-activator to regulate the expression of histone H2B. 4 Nuclear GAPDH also activates p300/CBP and induces apoptotic genes. 5 In addition, Arg5/6, a yeast metabolic enzyme involved in arginine biosynthesis, regulates the transcription of nuclear and mitochondrial target genes, 6 and plant hexokinase 1 forms a nuclear glucose signaling complex core that directly modulates specific target gene transcription. 7 Glucose is the central molecule for energy metabolism in glycolysis and in the tricarboxylic acid (TCA) cycle and mitochondrial respiration. Interestingly, cancer cells have long been known to have altered glucose metabolism by preferentially acquiring energy from glycolysis rather than from mitochondrial respiration. 8 This metabolic shift to aerobic glycolysis in cancer cells is commonly referred to as the Warburg effect. 9,10 Recently, pyruvate kinase M2 isoform was found to be important for aerobic glycolysis and cancer metabolism. 11 But the molecular mechanism underlying the Warburg effect is still unclear. Because tumor formation is basically caused by dysregulation of gene expression by a genetic or epigenetic alteration, the Warburg effect may be caused by dysregulated transcription.p53 is the best-known transcription factor that controls cell-cycle arrest and cell death in response to a wide range of stresses. 12,13 However, the tumor-suppressive function of p53 has been mainly studied under conditions of DNA damage with g-irradiation, UV and free radicals. Intriguingly, recent findings that p53 regulates glucose metabolism have invoked vigorous interest in the direct linkage between metab...

Odontoblasts, with their strategic arrangement along the outermost compartment of the dentin-pulp complex, have been suggested to have sensory function. In addition to their primary role in dentin formation, growing evidence shows that odontoblasts are capable of sensing mechanical stimulation. Previously, we found that most odontoblasts express TRPM7, the nonselective mechanosensitive ion channel reported to be critical in Mg homeostasis and dentin mineralization. In line with this finding, we sought to elucidate the functional expression of TRPM7 in odontoblasts by pharmacological approaches and mechanical stimulation. Naltriben, a TRPM7-specific agonist, induced calcium transient in the majority of odontoblasts, which was blocked by TRPM7 blockers such as extracellular Mg and FTY720 in a dose-dependent manner. Mechanical stretch of the odontoblastic membrane with hypotonic solution also induced calcium transient, which was blocked by Gd, a nonselective mechanosensitive channel blocker. Calcium transient induced by hypotonic solution was also blocked by high extracellular Mg or FTY720. When TRPM7-mediated calcium transients in odontoblasts were analyzed on the subcellular level, remarkably larger transients were detected in the distal odontoblastic process compared with the soma, which was further verified with comparable immunocytochemical analysis. Our results demonstrate that TRPM7 in odontoblasts can serve as a mechanical sensor, with its distribution to facilitate intracellular Ca signaling in the odontoblastic process. These findings suggest TRPM7 as a mechanical transducer in odontoblasts to mediate intracellular calcium dynamics under diverse pathophysiological conditions of the dentin.

Mitochondria are essential organelles that are responsible for cellular energy production and cell death in response to various stimuli. Although C-terminal binding protein (CtBP) functions as a metabolic sensor in transcriptional corepressor complex, it is unclear whether CtBP controls gene transcription in response to metabolic stress. In this study, we found that CtBP represses Bcl-2-associated X protein (Bax) transcription in glucose-rich media by binding to the E-box region of the Bax promoter. Glucose withdrawal leads to the dissociation of CtBP from the Bax promoter and significant changes of the histone codes in the Bax promoter. CtBP knockout increases Bax transcription, ablates mitochondrial morphology and reduces mitochondrial activities. Ectopic expression of CtBP or knockdown of Bax in ctbp-knockout cells recovers mitochondrial morphology and function, suggesting that CtBP functions as a metabolic sensor that maintains mitochondrial activities. Our findings provide insights into how the intracellular energy level is reflected into gene transcription involved in mitochondrial morphology and function.

The performance of abdominal MDCT in patients with a high degree of clinical suspicion for acute appendicitis reduces the number of false positives and has the potential to reduce negative appendectomies.