Genetic variants of the organic cation transporter 2 (protein, OCT2; gene, SLC22A2) were evaluated for their contribution to the variations in the pharmacokinetics of metformin, especially to its renal elimination. Genetic variants of SLC22A2 (c.596C>T, c.602C>T, and c.808G>T) showed significant differences in metformin pharmacokinetics when compared with the reference genotype, with higher peak plasma concentration (C(max)) and area under the curve (AUC) and lower renal clearance (Cl(renal)), thereby suggesting that a decrease in transport function associated with the SLC22A2 variants results in reduced Cl(renal) of metformin and consequently leads to increased plasma concentrations.

A number of genes involved in tumorigenesis have been known to be controlled by signal transducer and activator of transcription 3 (STAT3) and NF-jB, either synergistically or individually. In starved cancer cells, we found that NF-jB was activated through endoplasmic reticulum stress signals, which depend on reactive oxygen species, cytosolic calcium and preserved translation of NF-jB p65 subunit, but independent of IjBa serine phosphorylation, thereby resulting in IL6 induction. STAT3 was required for proper induction of IL6 by NF-jB. They existed as identical nuclear complexes in proximal IL6 promoters, and STAT3 had critical roles in binding to IL6 promoters as well as nuclear retention of NF-jB. The conditioned media from starved cancer cells contained various secretory factors, such as IL6, IL9, VWF (von Willebrand factor), FREM1 (FRAS1 related extracellular matrix 1), SAA1 (serum amyloid A1), SDK1 (sidekick homolog 1) and ADAM12 (ADAM metallopeptidase domain 12), induced by NF-jB and STAT3 and promoted clonogenic capacities of cancer cells, and proliferation and migration of human umbilical vein endothelial cells. These results suggest novel survival strategies of cancer cells by which two oncogenic transcriptional factors, NF-jB and STAT3, are activated simultaneously by an intrinsic mechanism during stressful conditions of cancer cells, and they cooperatively induce various survival factors.

Calbindin-D28k (CB), one of the major calcium-binding and buffering proteins, has a critical role in preventing a neuronal death as well as maintaining calcium homeostasis. Although marked reductions of CB expression have been observed in the brains of mice and humans with Alzheimer disease (AD), it is unknown whether these changes contribute to AD-related dysfunction. To determine the pathogenic importance of CB depletions in AD models, we crossed 5 familial AD mutations (5XFAD; Tg) mice with CB knock-out (CBKO) mice and generated a novel line CBKO·5XFAD (CBKOTg) mice. We first identified the change of signaling pathways and differentially expressed proteins globally by removing CB in Tg mice using mass spectrometry and antibody microarray. Immunohistochemistry showed that CBKOTg mice had significant neuronal loss in the subiculum area without changing the magnitude (number) of amyloid β-peptide (Aβ) plaques deposition and elicited significant apoptotic features and mitochondrial dysfunction compared with Tg mice. Moreover, CBKOTg mice reduced levels of phosphorylated mitogen-activated protein kinase (extracellular signal-regulated kinase) 1/2 and cAMP response element-binding protein at Ser-133 and synaptic molecules such as N-methyl-D-aspartate receptor 1 (NMDA receptor 1), NMDA receptor 2A, PSD-95 and synaptophysin in the subiculum compared with Tg mice. Importantly, this is the first experimental evidence that removal of CB from amyloid precursor protein/presenilin transgenic mice aggravates AD pathogenesis, suggesting that CB has a critical role in AD pathogenesis.

Objectives: The purpose of this study was to determine the relative accuracies of mammography, sonography, MRI and clinical examination in predicting residual tumour size and pathological response after neoadjuvant chemotherapy for locally advanced or inflammatory breast cancer. Each prediction method was compared with the gold standard of surgical pathology. Methods: 43 patients (age range, 25-62 years; mean age, 42.7 years) with locally advanced or inflammatory breast cancer who had been treated by neoadjuvant chemotherapy were enrolled prospectively. We compared the predicted residual tumour size and the predicted response on imaging and clinical examination with residual tumour size and response on pathology. Statistical analysis was performed using weighted kappa statistics and intraclass correlation coefficients (ICC). Conclusion:Predictions of response and residual tumour size made on MRI were better correlated with the assessments of response and residual tumour size made upon pathology than were predictions made on the basis of clinical examination, mammography or sonography. Thus, the evaluation of predicted response using MRI could provide a relatively sensitive early assessment of chemotherapy efficacy.

Resonant x-ray scattering experiments at the Gd L3 edge show interference between magnetic and anisotropic tensor susceptibility (ATS) reflections in GdB4. Energy profiles obtained from the magnetic and ATS resonances exhibited approximately 10 eV separation between the maximum resonance energies. The findings show that the Gd 5d band experienced hybridization giving rise to a significant split into isotropic lower energy band and distorted upper band states that account for the magnetic and ATS scattering, respectively.