Description: Motivation: Identification of altered pathways that are clinically relevant across human cancers is a key challenge in cancer genomics. Precise identification and understanding of these altered pathways may provide novel insights into patient stratification, therapeutic strategies and the development of new drugs. However, a challenge remains in accurately identifying pathways altered by somatic mutations across human cancers, due to the diverse mutation spectrum. We developed an innovative approach to integrate somatic mutation data with gene networks and pathways, in order to identify pathways altered by somatic mutations across cancers. Results: We applied our approach to The Cancer Genome Atlas (TCGA) dataset of somatic mutations in 4790 cancer patients with 19 different types of tumors. Our analysis identified cancer-type-specific altered pathways enriched with known cancer-relevant genes and targets of currently available drugs. To investigate the clinical significance of these altered pathways, we performed consensus clustering for patient stratification using member genes in the altered pathways coupled with gene expression datasets from 4870 patients from TCGA, and multiple independent cohorts confirmed that the altered pathways could be used to stratify patients into subgroups with significantly different clinical outcomes. Of particular significance, certain patient subpopulations with poor prognosis were identified because they had specific altered pathways for which there are available targeted therapies. These findings could be used to tailor and intensify therapy in these patients, for whom current therapy is suboptimal. Availability and implementation: The code is available at: http://www.taehyunlab.org . Contact: jhcheong@yuhs.ac or taehyun.hwang@utsouthwestern.edu or taehyun.cs@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Plant endomembranes are required for the biosynthesis and secretion of complex cell wall matrix polysaccharides, glycoproteins and proteoglycans. To define the biochemical roadmap that guides the synthesis and deposition of these cell wall components it is first necessary to outline the localization of the biosynthetic and modifying enzymes involved, as well as the distribution of the intermediate and final constituents of the cell wall. Thus far, a comprehensive understanding of cell wall matrix components has been hampered by the multiplicity of trafficking routes in the secretory pathway, and the diverse biosynthetic roles of the endomembrane organelles, which may exhibit tissue and development specific features. However, the recent identification of protein complexes producing matrix polysaccharides, and those supporting the synthesis and distribution of a grass-specific hemicellulose are advancing our understanding of the functional contribution of the plant secretory pathway in cell wall biosynthesis. In this review, we provide an overview of the plant membrane trafficking routes and report on recent exciting accomplishments in the understanding of the mechanisms underlying secretion with focus on cell wall synthesis in plants.

Description: 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 .

Description: 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.

Description: Background In this study, the prognostic impact of the presence of the multifocal or multicentric tumor (MMT) and its association with molecular subtypes were investigated. Patients and methods We investigated the breast cancer metastasis and survival in patients with multifocal or multicentric invasive foci in the same breast. The study population includes 2882 patients in the Seoul National University Hospital Breast Care Center (SNUHBCC) dataset and 41 179 patients in Korean Breast Cancer Registry (KBCR) dataset. Results From SNUHBCC dataset, we observed a significant role of MMT in developing distant metastasis and death when the tumors were triple-negative subtype. This subtype-specific prognostic importance of MMT in overall survival was also seen in KBCR dataset (HR, 1.32; 95% CI, 1.02–1.69). In tumors 〈2 cm, the hazard ratios (HRs) for node metastasis and death were similar along the tumor size change in triple-negative subtype, while other subtypes showed a stepwise increment, suggesting the biologic importance of small invasive foci in this subtype. Conclusions Our results demonstrate the prognostic importance of MMT in patients with triple-negative breast cancers. Small additional invasive foci in triple-negative breast cancer patients should be considered as clinically relevant tumor deposits.

Description: Electron microscopy is used to determine the form and size of samples from images. Consequently, distortion or error in the images produces incorrect data. This study developed an algorithm to enhance the scanner signal in order to improve the orthogonality of the image. The results of images with poor orthogonality, when observed from the central axis standard, are analogous to those of rotationally transformed images. Therefore, we believe that transmitting enhanced signals with rotationally transformed images will improve the quality of the data.

Description: We present numerical studies of the imaging and caustic properties of the singular isothermal sphere (SIS) under a wide range of external shear (from 0.0 to 2.0). Using a direct inverse-mapping formula for this lensing system,we investigate various lensing properties for both low-shear (i.e.  〈 1.0) and high-shear (i.e.  〉 1.0) cases: the image separations, the total or individual magnifications, the flux ratios of two images, the maximum number of images and the lensing cross-sections. We systematically analyse the effective lensing cross-sections of double-lensing and quadruple-lensing systems, based on the radio luminosity function obtained by the Jodrell–VLA Astrometric Survey (JVAS) and the Cosmic Lens All-Sky Survey (CLASS). We find that the limit of a survey selection bias (i.e. between brighter and fainter images) preferentially reduces the effective lensing cross-sections of two-image lensing systems. By considering the effects of survey selection bias, we demonstrate that the long-standing anomaly over the high quads-to-doubles ratios (i.e. 50–70 per cent for JVAS and CLASS) can be explained by the moderate effective shear of 0.16–0.18, which is half that of previous estimates. The derived inverse-mapping formula could make the SIS + shear lensing model useful for galaxy-lensing simulations.

Description: 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.

Description: 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.

Description: Background Everolimus, an oral mTOR inhibitor, has single-agent activity against relapsed lymphomas. Thus, we carried out a phase II study of everolimus in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) as a first-line treatment for patients with peripheral T-cell lymphoma (PTCL) based on our phase I study results. Patients and methods Participants ( n = 30) received CHOP with 5 mg everolimus per day from day 1 to 14 every 21 days for a total of six cycles. The primary end point was the overall response rate (ORR), which included complete response (CR) and partial response (PR) to this regimen. Immunohistochemistry was used to evaluate the expression of phosphatase and tensin homology (PTEN) and phosphorylated S6 kinase (pS6K) as a response. Results The objective response rate was 90% with CR ( n = 17) and PR ( n = 10). The CR rate was different among subtypes; angioimmunoblastic T-cell lymphoma (AITL, n = 3) had a CR whereas PTCL–not-otherwise specified and ALK-negative anaplastic large-cell lymphoma (ALCL) patients showed 63% (12/19) and 29% (2/7) of CR rate, respectively. This difference in CR rate among subtypes was associated with PTEN loss because PTEN loss was not seen in AITL but 33% of ALCL patients. The most common toxicity was hematological, with 80% of patients experiencing at least one event of grade 3/4 neutropenia, and 60% of patients had grade 3/4 thrombocytopenia. Conclusion The everolimus plus CHOP was effective for PTCL patients, and its efficacy might be related with the preservation of PTEN.