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BACKGROUND Patients with major depressive disorder (MDD) frequently retain cognitive disturbances after recovery from mood symptoms. We investigated the relationship between early response of mood symptoms and/or remission, and residual cognitive disturbances after 6 months of antidepressant treatment. METHODS 518 patients with MDD were followed up for 6 months after antidepressant treatment initiation (first-line or switch from a previous drug). Subjective and objective cognitive disturbances were assessed by the Perceived Deficits Questionnaire - Depression (PDQ-D) and digit symbol substitution test (DSST), respectively. Depressive symptoms, as well as remission and early response to treatment, were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). Multivariable linear and logistic regression models were used to adjust for confounders. RESULTS Early response of depressive mood (≥50% reduction in MADRS score at month 1) was related with fewer residual subjective cognitive symptoms, as evaluated by the PDQ-D at month 6 (p

The effects of 7β-hydroxycholesterol (7βOH) and 25-hydroxycholesterol (25OH) on the phase behavior and the structural properties of the multilamellar vesicles of dipalmitoylphosphatidylcholine (DPPC) bilayers were investigated with comparing to the effects of cholesterol (Chol). Differential scanning calorimetry (DSC) measurements showed these three sterols have slightly but distinctly different effects on the thermal behavior of DPPC bilayers. X-ray diffraction data analysis on DPPC bilayers containing 30 mol% sterols with the aid of molecular volume data estimated by the neutral buoyancy method indicated that the order of apparent occupied surface area per molecule is DPPC/7βOH > DPPC/25OH > DPPC/Chol at both 25 ℃ and 50 ℃, suggesting that the strength of the condensation effect of these sterols follows inversely this order. Based on the findings in this study, we inferred the molecular orientations of Chol, 7βOH, and 25OH in DPPC bilayers.

The precise control for the micropatterning of nonparenchymal cells (endothelial cells; ECs and hepatic stellate cells; HSCs) is useful for regenerative medicine, artificial organs, and cell-based biodevice. The adhesion and alignment of nonparenchymal cells on a micro-patterned surface fabricated by two-step plasma polymerization process were investigated. The first functionalization step involves the deposition of a nitrogen-rich plasma-polymerized film to render the entire surface a cell-adherent region. Following this, a hydrophobic plasma-polymerized film is formed through a grid metal mask (hundred-micrometer-sized openings) to renders these areas cell repellent. Imaging ellipsometry showed that groove and ridge patterns 100 μm wide and steps with heights on the scale of tens of nanometers were obtained. EC and HSC culture experiments were conducted on the patterned surfaces. EC rapidly adhered and aligned along the cell-adherent groove of the patterned surface, while it did not adhere to the cell-repellent ridge. HSC patterning succeeded only when the height of the cell-repellent ridge was 20 nm, whereas the patterning failed when the ridge height was 10 nm. This indicates that EC patterning is possible with only a chemical effect, whereas HSC patterning required both a chemical effect and the topological constraints of the patterned surface.

Pancreatic cancer is one of the most difficult malignancies to treat owing to the rapid acquisition of resistance to chemotherapy. Gemcitabine, a first-line treatment for pancreatic cancer, prolongs patient survival by several months, and combination treatment with gemcitabine and other anti-cancer drugs in the clinic do not show any significant effects on overall survival. Thus, identification of a drug that resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine and a better understanding of the molecular mechanisms of gemcitabine resistance are critical to develop new therapeutic options for pancreatic cancer. Here, we report that zidovudine resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine as shown by screening a compound library, including clinical medicine, using gemcitabine-resistant cells. In analyzing the molecular mechanisms of zidovudine effects, we found that the epithelial-to-mesenchymal transition (EMT)-like phenotype and downregulation of human equilibrative nucleoside transporter 1 (hENT1) are essential for the acquisition of gemcitabine resistance, and zidovudine restored these changes. The chemical biology investigations also revealed that activation of the Akt-GSK3β-Snail1 pathway in resistant cells is a key signaling event for gemcitabine resistance, and zidovudine resensitized resistant cells to gemcitabine by inhibiting this activated pathway. Moreover, our in vivo study demonstrated that co-administration of zidovudine and gemcitabine strongly suppressed the formation of tumors by gemcitabine-resistant pancreatic cancer and prevented gemcitabine-sensitive pancreatic tumors from acquiring gemcitabine-resistant properties, inducing an EMT-like phenotype and downregulating hENT1 expression. These results suggested that co-treatment with zidovudine and gemcitabine may become a novel therapeutic strategy for pancreatic cancer by inhibiting chemoresistance-specific signaling.

Amyloid-β peptide (Aβ), especially its oligomeric form, is believed to play an important role in the pathogenesis of Alzheimer's disease (AD). To this end, the binding of Aβ oligomer to cellular prion protein (PrP(C)) plays an important role in synaptic dysfunction in a mouse model of AD. Here, we have screened for compounds that inhibit Aβ oligomer binding to PrP(C) from medicines already used clinically (Mizushima Approved Medicine Library 1), and identified dextran sulfate sodium (DSS) as a candidate. In a cell-free assay, DSS inhibited Aβ oligomer binding to PrP(C) but not to ephrin receptor B2, another endogenous receptor for Aβ oligomers, suggesting that the drug's action is specific to the binding of Aβ oligomer to PrP(C) . Dextran on the other hand did not affect this binding. DSS also suppressed Aβ oligomer binding to cells expressing PrP(C) but not to control cells. Furthermore, while incubation of mouse hippocampal slices with Aβ oligomers inhibited the induction of long-term potentiation, simultaneous treatment with DSS restored the long-term potentiation. As DSS has already been approved for use in patients with hypertriglyceridemia, and its safety in humans has been confirmed, we propose further analysis of this drug as a candidate for AD treatment. Amyloid-β peptide (Aβ) oligomer-binding to cellular prion protein (PrP(C) ) is important in synaptic dysfunction in Alzheimer's disease (AD). We found here that dextran sulfate sodium (DSS) inhibits Aβ oligomer binding to PrP(C) . Simultaneous treatment of hippocampal slices with DSS restored long-term potentiation (LTP) in the presence of Aβ oligomers. Since DSS has already been approved for clinical use, we propose this drug is a candidate drug for AD treatment.