Drug resistance is a major obstacle to the successful chemotherapy. Several ATP-binding cassette (ABC) transporters including ABCB1, ABCC1 and ABCG2 have been known to be important mediators of chemoresistance. Using oligonucleotide microarrays (HG-U133 Plus 2.0; Affymetrix), we analyzed the ABC transporter gene expression profiles in breast cancer patients who underwent sequential weekly paclitaxel/FEC (5-fluorouracil, epirubicin and cyclophosphamide) neoadjuvant chemotherapy. We compared the ABC transporter expression profile between two classes of pretreatment tumor samples divided by the patients' pathological response to neoadjuvant chemotherapy (residual disease [RD] versus pathologic complete response [pCR]) ABCB3, ABCC7 and ABCF2 showed significantly high expression in the pCR. Several ABC transporters including ABCC5, ABCA12, ABCA1 ABCC13, ABCB6 and ABCC11 showed significantly increased expression in the RD (p<0.05). We evaluated the feasibility of developing a multigene predictor model of pathologic response to neoadjuvant chemotherapy using gene expression profiles of ABC transporters. The prediction error was evaluated by leave-one-out cross-validation (LOOCV). A multigene predictor model with the ABC transporters differentially expressed between the two classes (p

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Caffeine is thought to increase the antitumor effect of cisplatin or DNA-damaging agents because it is known that caffeine inhibits DNA repair. Caffeine-assisted chemotherapy has been used in the treatment of osteosarcomas. In addition, there are several reports about combination chemotherapy with caffeine for certain malignancies other than osteosarcomas. However, there are no reports that show the utility of combination chemotherapy with caffeine for hepatocellular carcinoma (HCC). We examined the combined effects of caffeine and cisplatin in human HCC cell lines, and screened for a more effective administration method of caffeine in vitro. Human HCC cell lines (HepG2, HLF, HuH-7, and Li-7) were exposed to caffeine (0-0.5 mM) and cisplatin (0-1.2 μg/mL) for 72 h, either alone or in combination. Cell numbers were measured by WST-8 assay, and cell apoptosis was determined by annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) binding assay. As a result, caffeine increased the antitumor effect of cisplatin on cell proliferation and cell apoptosis in the HCC cell lines. Moreover, this effect was dependent on the amount of exposure to caffeine. These results suggest that caffeine-assisted chemotherapy is useful for HCC treatment.

Borna disease virus (BDV), a negative nonsegmented single-stranded RNA virus, has not been fully characterized morphologically. Here we present what is to our knowledge the first data on the fine ultrastructure and morphogenesis of BDV. The supernatant of MDCK cells persistently infected with BDV treated with n-butyrate contained many virus-like particles and more BDV-specific RNA than that of untreated samples. The particles were spherical, enveloped, and approximately 130 nm in diameter; had spikes 7 nm in length; and reacted with BDV p40 antibody. A thin nucleocapsid, 4 nm in width, was present peripherally in contrast to the thick nucleocapsid of hemagglutinating virus of Japan. The BDV particles reproduced by budding on the cell surface.

The aim of this study was to identify glycobiological biomarkers that indicate sensitivity to trastuzumab, a humanized monoclonal antibody against HER2 in plasma samples from breast cancer patients. Plasma samples were obtained from 24 breast cancer patients treated with trastuzumab monotherapy. The catalytic activities of plasma alpha1-6, fucosyltransferase (FUT8) and alpha-L fucosidase (FUCA) were analyzed using high-performance liquid chromatography (HPLC) and spectrophotometer, respectively. The plasma N-glycan profiles were investigated using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Plasma FUT8 activity was not significantly correlated with either the clinical response or progression-free survival (PFS). On the other hand, plasma FUCA activity was significantly correlated with PFS (p < 0.05). The MALDI-TOF-MS analysis of the plasma N-glycan profile revealed that the expression of 2534 m/z N-glycan was lower in patients with progressive disease (PD) and was correlated with PFS. Low expression of 2534 m/z N-glycan discriminated between PD and non-PD with 75% sensitivity and 82% specificity. We demonstrated that the plasma FUCA activity and 2534 m/z N-glycan may be predictive biomarkers of sensitivity to trastuzumab. Our results suggest that glycosylation analysis may provide useful information for determining clinical cancer therapy and provide novel insight into biomarker studies using glycobiological tools in the field of breast cancer.

Helicobacter pylori CagA modifies the signalling of host cells and causes gastric diseases. Although CagA is injected into gastric epithelial cells through the type IV secretion machinery, it remains unclear how CagA is transported towards the machinery in the bacterial cytoplasm. In this study, it was determined that the proton-dependent intracytoplasmic transport system correlates with the priming of CagA secretion from H. pylori. The cytotoxicity of neutral-pH-and acidic-pH-treated H. pylori was examined in the AGS cell line. The amount of phosphorylated CagA in AGS cells incubated with acidic-pH-and neutral-pH-treated H. pylori was determined by enzyme immunoassay and Western blot. The production of CagA and adherence of the treated bacteria were examined by enzyme immunoassay and light microscopy, respectively. To clarify how CagA is transported towards the inner membrane of the treated bacteria, the localization of CagA was analysed by immunoelectron microscopy. The proportion of hummingbird cells in the AGS cell line rapidly increased following the inoculation of acidic-pH-treated H. pylori but increased more slowly with neutral-pH-treated H. pylori, and the phenomenon correlated with the amount of phosphorylated CagA in AGS cells. CagA was densely localized near the inner membrane in the acidic-pH-treated bacterial cytoplasm, but this localization was not observed in the neutral-pHtreated bacterial cytoplasm, suggesting that CagA shifts from the centre to the peripheral portion of the cytoplasm as a result of an extracellular decrease in pH. This phenomenon depended on the presence of UreI, a proton-dependent urea channel, but not on the presence of urea. The pH treatments did not enhance CagA production or the adherence of the bacterium to AGS cells. The authors propose that H. pylori possesses a proton-dependent intracytoplasmic transport system that probably accelerates priming for CagA injection.