Beschreibung: Mitochondrial dysfunction and synaptic damage are important features of Alzheimer's disease (AD) associated with amyloid β (Aβ) and tau. We reported previously that the scaffolding protein RanBP9, which is overall increased in brains of patients with AD and in mutant APP transgenic mice, simultaneously promotes Aβ generation and focal adhesion disruption by accelerating the endocytosis of APP and β1-integrin, respectively. Moreover, RanBP9 induces neurodegeneration in vitro and in vivo and mediates Aβ-induced neurotoxicity. Here we show in primary hippocampal neurons that RanBP9 potentiates Aβ-induced reactive oxygen species (ROS) overproduction, apoptosis, and calcium deregulation. Analyses of calcium-handling measures demonstrate that RanBP9 selectively delays the clearance of cytosolic Ca 2+ mediated by the mitochondrial calcium uniporter through a process involving the translocation of cofilin into mitochondria and oxidative mechanisms. Further, RanBP9 retards the anterograde axonal transport of mitochondria in primary neurons and decreases synaptic mitochondrial activity in brain. These data indicate that RanBP9, cofilin, and Aβ mimic and potentiate each other to produce mitochondrial dysfunction, ROS overproduction, and calcium deregulation, which leads to neurodegenerative changes reminiscent of those seen in AD.—Roh. S.-E., Woo, J. A., Lakshmana, M. K., Uhlar, C., Ankala, V., Boggess, T., Liu, T., Hong, Y.-H., Mook-Jung, I., Kim, S. J., Kang, D. E. Mitochondrial dysfunction and calcium deregulation by the RanBP9-cofilin pathway.

Beschreibung: Background The aim of this study was to construct a novel prediction model for the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) using immune-related gene expression data. Patients and methods DNA microarray data were used to perform a gene expression analysis of tumor samples obtained before NAC from 117 primary breast cancer patients. The samples were randomly divided into the training ( n = 58) and the internal validation ( n = 59) sets that were used to construct the prediction model for pCR. The model was further validated using an external validation set consisting of 901 patients treated with NAC from six public datasets. Results The training set was used to construct an immune-related 23-gene signature for NAC (IRSN-23) that is capable of classifying the patients as either genomically predicted responders (Gp-R) or non-responders (Gp-NR). IRSN-23 was first validated using an internal validation set, and the results showed that the pCR rate for Gp-R was significantly higher than that obtained for Gp-NR (38 versus 0%, P = 1.04E–04). The model was then tested using an external validation set, and this analysis showed that the pCR rate for Gp-R was also significantly higher (40 versus 11%, P = 4.98E–23). IRSN-23 predicted pCR regardless of the intrinsic subtypes (PAM50) and chemotherapeutic regimens, and a multivariate analysis showed that IRSN-23 was the most important predictor of pCR (odds ratio = 4.6; 95% confidence interval = 2.7–7.7; P = 8.25E–09). Conclusion The novel prediction model (IRSN-23) constructed with immune-related genes can predict pCR independently of the intrinsic subtypes and chemotherapeutic regimens.

Beschreibung: Background Oncogenic phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/AKT) pathway plays a critical role in cell proliferation and growth. Phosphorylated AKT (p-AKT) has been reported to be abnormally overexpressed and to have poor prognostic impact in solid tumors. Patients and methods To define the clinical implications of p-AKT expression in diffuse large B-cell lymphoma (DLBCL), we calculated arbitrary units (AUs) by multiplying the intensity and the proportion of p-AKT expression and investigated the impact of p-AKT expression on clinical outcomes. We assessed 262 patients with DLBCL. Based on a cutoff value of the upper limit of the third quartile of AUs, 56 patients were classified as high p-AKT and the remaining 206 patients were classified as low p-AKT. Results The high p-AKT group was closely associated with more advanced stage (stage III–IV, P = 0.02), two or more extranodal involvement ( P = 0.03), lactic dehydrogenase elevation ( P = 0.03), higher International Prognostic Index risk groups (high intermediate/high, P = 0.02), and the presence of B-symptoms ( P = 0.01). The high p-AKT group showed substantially worse overall survival (OS) (median OS, 115.0 months versus not reached, P = 0.004) and progression-free survival (PFS) (median PFS, 25.5 versus 105.8 months, P = 0.019) compared with the low p-AKT group. Multivariate analysis revealed that high p-AKT expression retained its significant poor prognostic impact for OS (hazard ratio 1.7; 95% confidence interval, 1.0–2.7; P = 0.031). The subgroup with high p-AKT expression and concurrent Epstein–Barr virus positivity showed worst prognosis with the median OS and PFS of 15.2 and 7.4 months. Conclusion DLBCL patients with high p-AKT expression showed distinct clinical features and followed a more rapidly deteriorating clinical course with worse OS and PFS. Thus, a more effective treatment option should be developed for this subset of DLBCL patients, and targeting PI3K/AKT pathway may be a promising therapeutic strategy. Trial registration This study is registered with ClinicalTrials.gov, number NCT01789060.

Beschreibung: Cystatin SN neutralizes the inhibitory effect of cystatin C on cathepsin B activity Cell Death and Disease 4, e974 (December 2013). doi:10.1038/cddis.2013.485 Authors: J-T Kim, S-J Lee, M A Kang, J E Park, B-Y Kim, D-Y Yoon, Y Yang, C-H Lee, Y I Yeom, Y-K Choe & H G Lee

Beschreibung: Claudin-1 induces epithelial–mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells Oncogene 32, 4873 (10 October 2013). doi:10.1038/onc.2012.505 Authors: Y Suh, C-H Yoon, R-K Kim, E-J Lim, Y S Oh, S-G Hwang, S An, G Yoon, M C Gye, J-M Yi, M-J Kim & S-J Lee

Beschreibung: Background Clinical features and outcomes of extranodal natural killer/T-cell lymphoma (ENKL) arising from extranasal sites are not fully understood. The purpose of this study was to study the prognosis and treatment outcome of skin/soft tissue primary ENKL. Patients and methods This multicenter retrospective study included 48 patients with skin/soft tissue primary ENKL diagnosed from 1993 to 2010. Results Patients with Ann Arbor stage I, T1–2N0M0 by International Society for Cutaneous Lymphomas–European Organization of Research and Treatment of Cancer TNM (tumour–node–metastasis) stage, International prognostic index score of 0–1, and a Korean prognostic index (KPI) score of 0–1 were associated with better survival. Four of five patients with T1–2N0M0 disease achieved complete response with radiation alone. In disseminated disease, only 6 of 13 patients responded to anthracycline-containing chemotherapy, and all the two patients receiving SMILE showed response. Conclusion In conclusion, we identified the prognostic value of KPI, and we suggest a treatment recommendation according to the TNM (tumour–node–metastasis) stage. Radiotherapy with/without chemotherapy seemed to be optimal in localized disease. In advanced stages, a more aggressive treatment regimen with newer agents should be sought.

Beschreibung: CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling Oncogene 31, 5123 (13 December 2012). doi:10.1038/onc.2012.18 Authors: J M Kang, S Park, S J Kim, H Y Hong, J Jeong, H-S Kim & S-J Kim

Beschreibung: Motivation: Structural characterization of protein interactions is necessary for understanding and modulating biological processes. On one hand, X-ray crystallography or NMR spectroscopy provide atomic resolution structures but the data collection process is typically long and the success rate is low. On the other hand, computational methods for modeling assembly structures from individual components frequently suffer from high false-positive rate, rarely resulting in a unique solution. Results: Here, we present a combined approach that computationally integrates data from a variety of fast and accessible experimental techniques for rapid and accurate structure determination of protein–protein complexes. The integrative method uses atomistic models of two interacting proteins and one or more datasets from five accessible experimental techniques: a small-angle X-ray scattering (SAXS) profile, 2D class average images from negative-stain electron microscopy micrographs (EM), a 3D density map from single-particle negative-stain EM, residue type content of the protein–protein interface from NMR spectroscopy and chemical cross-linking detected by mass spectrometry. The method is tested on a docking benchmark consisting of 176 known complex structures and simulated experimental data. The near-native model is the top scoring one for up to 61% of benchmark cases depending on the included experimental datasets; in comparison to 10% for standard computational docking. We also collected SAXS, 2D class average images and 3D density map from negative-stain EM to model the PCSK9 antigen–J16 Fab antibody complex, followed by validation of the model by a subsequently available X-ray crystallographic structure. Availability: http://salilab.org/idock Contact: dina@salilab.org or sali@salilab.org Supplementary information: Supplementary data are available at Bioinformatics online.

Beschreibung: Changes in cold hardiness, carbohydrate content and β-amylase gene expression were monitored in the shoots of the highbush blueberry ( Vaccinium corymbosum L.) cultivars ‘Sharpblue’ and ‘Jersey’ during cold acclimation (CA) and deacclimation (DA). The seasonal patterns were similar in both cultivars, but the levels of cold hardiness determined by electrolyte leakage analysis were significantly different; ‘Jersey’ was hardier than ‘Sharpblue’. Cold hardiness was closely related to total soluble sugar content ( r = –0.98** and –0.99** for ‘Sharpblue’ and ‘Jersey’, respectively). In ‘Jersey’, more soluble sugars accumulated during CA. Of the detected soluble sugars, glucose, fructose and raffinose contents were significantly associated with cold hardiness in both cultivars. Sucrose was abundant in both cultivars, and stachyose content changed significantly during CA and DA. However, they were not associated with cold hardiness. A sharp decrease in starch contents in the middle of CA coincided with β-amylase gene ( VcBMY ) expression, indicating the conversion of starch into soluble sugars. During CA, VcBMY was expressed up to twofold higher in ‘Jersey’ than in ‘Sharpblue’. These results suggest that intraspecies differences in the cold hardiness of highbush blueberries are associated with total soluble sugar content, which is driven partly by differential expression of VcBMY .

Beschreibung: Background The aim of this study was to investigate the clinicopathological characteristics of GATA binding protein 3 (GATA3)-positive breast cancers as well as the association of GATA3 expression with response to chemotherapy. Patients and methods Tumor specimens obtained before neoadjuvant chemotherapy [paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide)] from breast cancer patients ( n  = 130) were subjected to immunohistochemical and mutational analysis of GATA3 and DNA microarray gene expression analysis for intrinsic subtyping. Results Seventy-four tumors (57%) were immunohistochemically positive for GATA3. GATA3-positive tumors were significantly more likely to be lobular cancer, estrogen receptor (ER)-positive, progesterone receptor (PgR)-positive, Ki67-negative, and luminal A tumors. Somatic mutations were found in only three tumors. Pathological complete response (pCR) was observed in 8 (11%) GATA3-positive tumors and in 22 (39%) GATA3-negative tumors. Multivariate analysis showed that tumor size, human epidermal growth factor receptor 2 (HER2), and GATA3 were independent predictors of pCR. Conclusions GATA3-positive breast cancers showed luminal differentiation characterized by high ER expression and were mostly classified as luminal-type tumors following intrinsic subtyping. Interestingly, GATA3 was an independent predictor of response to chemotherapy, suggesting that GATA3 might be clinically useful as a predictor of a poor response to chemotherapy.