bluuebunny/crossref_metadata_2025_split huggingface dataset:
PKC isoenzymes differentially modulate the effect of thrombin on MAPK-dependent RPE proliferation
Authors: Palma-Nicolas Jose P. , López Edith , López-Colomé Ana María 
Published: July 2008

Thrombin signalling through PAR (protease-activated receptor)-1 is involved in cellular processes, such as proliferation, differentiation and cell survival. Following traumatic injury to the eye, thrombin signalling may participate in disorders, such as PVR (proliferative vitreoretinopathy), a human eye disease characterized by the uncontrolled proliferation, transdifferentiation and migration of otherwise quiescent RPE (retinal pigment epithelium) cells. PARs activate the Ras/Raf/MEK/ERK MAPK pathway (where ERK is extracellular-signal-regulated kinase, MAPK is mitogen-activated protein kinase and MEK is MAPK/ERK kinase) through the activation of Gα and Gβγ heterotrimeric G-proteins, and the downstream stimulation of the PLC (phospholipase C)-β/PKC (protein kinase C) and PI3K (phosphoinositide 3-kinase) signalling axis. In the present study, we examined the molecular signalling involved in thrombin-induced RPE cell proliferation, using rat RPE cells in culture as a model system for PVR pathogenesis. Our results showed that thrombin activation of PAR-1 induces RPE cell proliferation through Ras-independent activation of the Raf/MEK/ERK1/2 MAPK signalling cascade. Pharmacological analysis revealed that the activation of ‘conventional’ PKC isoforms is essential for proliferation, although thrombin-induced phosphorylation of ERK1/2 requires the activation of atypical PKCζ by PI3K. Consistently, thrombin-induced ERK1/2 activation and RPE cell proliferation were prevented completely by PI3K or PKCζ inhibition. These results suggest that thrombin induces RPE cell proliferation by joint activation of PLC-dependent and atypical PKC isoforms and the Ras-independent downstream stimulation of the Raf/MEK/ERK1/2 MAPK cascade. The present study is the first report demonstrating directly thrombin-induced ERK phosphorylation in the RPE, and the involvement of atypical PKCζ in this process.
A probe-density-based analysis method for array CGH data: simulation, normalization and centralization
Authors: Chen Hung-I Harry , Hsu Fang-Han , Jiang Yuan , Tsai Mong-Hsun , Yang Pan-Chyr , Meltzer Paul S. , Chuang Eric Y. , Chen Yidong 
Published: July 2008

AbstractMotivation: Genomic instability is one of the fundamental factors in tumorigenesis and tumor progression. Many studies have shown that copy-number abnormalities at the DNA level are important in the pathogenesis of cancer. Array comparative genomic hybridization (aCGH), developed based on expression microarray technology, can reveal the chromosomal aberrations in segmental copies at a high resolution. However, due to the nature of aCGH, many standard expression data processing tools, such as data normalization, often fail to yield satisfactory results.Results: We demonstrated a novel aCGH normalization algorithm, which provides an accurate aCGH data normalization by utilizing the dependency of neighboring probe measurements in aCGH experiments. To facilitate the study, we have developed a hidden Markov model (HMM) to simulate a series of aCGH experiments with random DNA copy number alterations that are used to validate the performance of our normalization. In addition, we applied the proposed normalization algorithm to an aCGH study of lung cancer cell lines. By using the proposed algorithm, data quality and the reliability of experimental results are significantly improved, and the distinct patterns of DNA copy number alternations are observed among those lung cancer cell lines.Contact: chuangey@ntu.edu.twSupplementary information: Source codes and.gures may be found at http://ntumaps.cgm.ntu.edu.tw/aCGH_supplementary
TRITON: a graphical tool for ligand-binding protein engineering
Authors: Prokop Martin , Adam Jan , Kříž Zdeněk , Wimmerová Michaela , Koča Jaroslav 
Published: July 2008

Abstract
Summary: The new version of the TRITON program provides user-friendly graphical tools for modeling protein mutants using the external program MODELLER and for docking ligands into the mutants using the external program AutoDock. TRITON can now be used to design ligand-binding proteins, to study protein–ligand binding mechanisms or simply to dock any ligand to a protein.
Availability: Executable files of TRITON are available free of charge for academic users at http://ncbr.chemi.muni.cz/triton/
Contact: triton@chemi.muni.cz
Supplementary information: Supplementary data are available at Bioinformatics online.
A new modeling method in feature construction for the HSQC spectra screening problem
Authors: Arai Hiromi , Watanabe Satoru , Kigawa Takanori , Yamamura Masayuki 
Published: July 2008

Abstract
Motivation: Large-scale biological analyses produce huge amounts of data. As a consequence, automation in the data analysis process is needed. Sample screening problems in NMR high-throughput protein structure analysis are the typical examples. Especially, screening by protein 1H−15N heteronuclear single quantum coherence (HSQC) spectra must be done quantitatively by a human expert. One popular solution for this problem is data mining. Machine learning methods can automatically extract rules and achieve high accuracy in prediction when a good quality training dataset is prepared. However, they tend to be a black box and the learned machines suffer the risk of overfitting to the dataset.
Results: We propose a model which evaluates HSQC spectra for feature construction. The model calculates similarity between the measured chemical shifts and those of a random coil peak model. We applied our feature construction method for the machine learning discrimination of folded protein HSQC spectra from unfolded ones, and compared our model-based features with those of conventional sequence-based features and image recognition features. The results revealed that our method has sufficient discrimination power and less overfits on training data, as compared to the other methods. In addition, our method succeeded reduction of input data complexity towards further investigation.
Contact: arai@es.dis.titech.ac.jp
Supplementary information: Supplementary data are available at Bioinformatics online.
Bioimage informatics: a new area of engineering biology
Authors: Peng Hanchuan 
Published: July 2008

Abstract
In recent years, the deluge of complicated molecular and cellular microscopic images creates compelling challenges for the image computing community. There has been an increasing focus on developing novel image processing, data mining, database and visualization techniques to extract, compare, search and manage the biological knowledge in these data-intensive problems. This emerging new area of bioinformatics can be called ‘bioimage informatics’. This article reviews the advances of this field from several aspects, including applications, key techniques, available tools and resources. Application examples such as high-throughput/high-content phenotyping and atlas building for model organisms demonstrate the importance of bioimage informatics. The essential techniques to the success of these applications, such as bioimage feature identification, segmentation and tracking, registration, annotation, mining, image data management and visualization, are further summarized, along with a brief overview of the available bioimage databases, analysis tools and other resources.
Contact: pengh@janelia.hhmi.org
Supplementary information: Supplementary data are available at Bioinformatics online.
TUSC4/NPRL2, a novel PDK1‐interacting protein, inhibits PDK1 tyrosine phosphorylation and its downstream signaling
Authors: Kurata Atsuo , Katayama Ryohei , Watanabe Toshiki , Tsuruo Takashi , Fujita Naoya 
Published: July 2008

3‐Phosphoinositide–dependent protein kinase‐1 (PDK1) is a key regulator of cell proliferation and survival signal transduction. PDK1 is known to be constitutively active and is further activated by Src‐mediated phosphorylation at the tyrosine‐9, ‐373, and ‐376 residues. To identify novel regulators of PDK1, we performed E. coli‐based two‐hybrid screening and revealed that tumor suppressor candidate 4 (TUSC4), also known as nitrogen permease regulator‐like 2 (NPRL2), formed a complex with PDK1 and suppressed Src‐dependent tyrosine phosphorylation and activation of PDK1 in vitro and in cells. The NH2‐terminal 133 amino acid residues of TUSC4 were involved in binding to PDK1. The deletion mutant of TUSC4 that lacked the NH2‐terminal domain showed no inhibitory effects on PDK1 tyrosine phosphorylation or activation. Thus, complex formation is indispensable for TUSC4‐mediated PDK1 inactivation. The siRNA‐mediated down‐regulation of TUSC4 induced cell proliferation, while ectopic TUSC4 expression inactivated the PDK1 downstream signaling pathway, including Akt and p70 ribosomal protein S6 kinase, and increased cancer cell sensitivity to several anticancer drugs. Our results suggest that TUSC4/NPRL2, a novel PDK1‐interacting protein, plays a role in regulating the Src/PDK1 signaling pathway and cell sensitivity to multiple cancer chemotherapeutic drugs. (Cancer Sci 2008; 99: 1827–1834)
Targeted therapeutic approach for an anaplastic thyroid cancer in vitro and in vivo
Authors: Stenner Frank , Liewen Heike , Zweifel Martin , Weber Achim , Tchinda Joelle , Bode Beata , Samaras Panagiotis , Bauer Stefan , Knuth Alexander , Renner Christoph 
Published: July 2008

Anaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies, being responsible for the majority of thyroid cancer‐related deaths. Despite multimodal therapy including surgery, chemotherapy, and radiotherapy, the outcome of ATC is poor. The human ATC cell line MB1, derived from tumor tissue of a 57‐year‐old man with thyroid cancer and pronounced neutrophilia, was established from surgically excised tumor tissue. The karyotype of the cell line shows many chromosomal abnormalities. Preclinical investigations have shown antitumor activity and effectiveness of the BRAF kinase inhibitor Sorafenib and the proteasome inhibitor Bortezomib. After establishment of the MB1 cell line these agents were applied in vitro and, showing activity in a cell culture model, were also used for in vivo treatment. Sorafenib had some clinical effect, namely normalization of leucocytosis, but had no sustained impact on subsequent tumor growth and development of distant metastasis. Molecular diagnostics of the tumor demonstrated no BRAF mutations in exons 11 and 15 concordant with a rather modest effect of Sorafenib on MB1 cell growth. Clinical benefit was seen with subsequent bortezomib therapy inducing a temporary halt to lymph node growth and a progression‐free interval of 7 weeks. Our observations together with previous data from preclinical models could serve as a rationale for selecting those patients suffering from ATC most likely to benefit from targeted therapy. A prospective controlled randomized trial integrating kinase and proteasome inhibitors into a therapeutic regime for ATC is warranted. (Cancer Sci 2008; 99: 1847–1852)
Significance of CXCR3 expression in gastric low‐grade B‐cell lymphoma of mucosa‐associated lymphoid tissue type for predicting responsiveness to Helicobacter pylori eradication
Authors: Yamamoto Hideko , Nakamura Tsuneya , Matsuo Keitaro , Tajika Masahiro , Kawai Hiroki , Ohmiya Naoki , Niwa Yasumasa , Goto Hidemi , Nakamura Shigeo 
Published: July 2008

Gastric mucosa‐associated lymphoid tissue (MALT) lymphoma is a distinct low‐grade lymphoma that often regresses upon Helicobacter pylori eradication. It was reported that the chemokine receptor CXCR3 is expressed not only on activated T cells, but also on MALT lymphoma cells, and that CXCR3‐positive B lymphocytes migrate or home to the MALT of MALT lymphoma. In the present study, we aimed to elucidate the correlation between CXCR3 expression and the clinicopathological features of gastric MALT lymphoma, and to determine whether CXCR3 expression was predictive of responsiveness to H. pylori eradication. Sixty‐seven patients with gastric MALT lymphoma in a single‐center study were treated with H. pylori eradication therapy. We evaluated the correlation of CXCR3 expression with response to H. pylori eradication therapy by logistic regression stratified according to potential confounders. Immunohistochemical analysis revealed that 28 of 67 cases (42%) were positive for CXCR3 expression. CXCR3 expression was significantly more prevalent in those without H. pylori infection, advanced‐stage disease, and in those with API2–MALT1 fusion. In overall analysis, those with CXCR3 expression showed a significantly increased risk of non‐responsiveness to H. pylori eradication therapy (odds ratio = 28.6; 95% confidence interval 5.70–143.4) compared to those without CXCR3 expression. This higher risk was observed consistently regardless of sex, API2–MALT1 fusion, H. pylori infection, or clinical stage. We showed that CXCR3 expression was an independent predictive factor for non‐responsiveness to H. pylori eradication therapy in patients with gastric MALT lymphoma. (Cancer Sci 2008; 99: 1769–1773)
β‐catenin is strongly elevated in rat colonic epithelium following short‐term intermittent treatment with 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) and a high‐fat diet
Authors: Wang Rong , Dashwood W. Mohaiza , Löhr Christiane V. , Fischer Kay A. , Nakagama Hitoshi , Williams David E. , Dashwood Roderick H. 
Published: July 2008

Colon tumors expressing high levels of β‐catenin and c‐myc have been reported in male F344 rats given three short cycles of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) alternating with a high‐fat (HF) diet. Using the same experimental protocol, rats were euthanized 24 h after the last dose of PhIP so as to examine early changes in colonic crypt homeostasis and β‐catenin expression, before the onset of frank tumors. PhIP/HF dosing caused a significant increase in the bromodeoxyuridine labeling index throughout the entire colon, and within the colonic crypt column cleaved caspase‐3 was elevated in the basal and central zones, but reduced in the luminal region. In vehicle/HF controls, β‐catenin was immunolocalized primarily at the border between cells at the top of the crypt, whereas in rats given PhIP/HF diet there was strong cytoplasmic staining, which appeared as a gradient of increased β‐catenin extending from the base of the crypt column to the luminal region. Quantitative real‐time PCR and immunoblot analyses confirmed that β‐catenin and c‐myc were increased significantly in the colonic mucosa of rats given PhIP/HF diet. Collectively, these findings suggest that PhIP/HF cycling alters β‐catenin and c‐myc expression in the colonic mucosa, resulting in expansion of the proliferative zone and redistribution of apoptotic cells from the lumen to the central and basal regions of the colonic crypt. Thus, during the early stages of colon carcinogenesis, alternating exposure to heterocyclic amines and a high‐fat diet might facilitate molecular changes resulting in dysregulated β‐catenin and c‐myc expression. (Cancer Sci 2008; 99: 1754–1759)
Periodic analysis of urethane‐induced pulmonary tumors in living A/J mice by respiration‐gated X‐ray microcomputed tomography
Authors: Hori Yusaku , Takasuka Nobuo , Mutoh Michihiro , Kitahashi Tsukasa , Kojima Shuji , Imaida Katsumi , Suzuki Masahiro , Kohara Kazushi , Yamamoto Shuji , Moriyama Noriyuki , Sugimura Takashi , Wakabayashi Keiji 
Published: July 2008

X‐ray microcomputed tomography (micro‐CT) with a respiratory gating system is a useful non‐invasive approach to evaluate lung tumor development in living animal models. Here micro‐CT was applied for the detection of lung lesions induced by a single intraperitoneal injection (250 mg/kg) of urethane in male A/J mice, at 2‐week intervals from 10 to 30 weeks after carcinogen exposure. In micro‐CT cross sections, lung tumor images were easily distinguished from surrounding non‐tumorous tissues, the smallest detected tumor being approximately 0.5 mm in diameter. All of the urethane‐treated mice (n = 15) developed lung tumors and the number of tumors developed in each mouse was 8.6 ± 3.9. Six tumors, determined histopathologically to be adenocarcinomas, were detected, growing at different rates during the experimental period. The most aggressive carcinoma, increasing in diameter from 0.9 to 3.5 mm within 8 weeks, was a solid‐type nodule with a clear tumor margin on the micro‐CT imaging. Other tumors, histopathologically adenomas, grew slowly or moderately. The results provide evidence that micro‐CT is a useful non‐invasive imaging approach for evaluating the characteristics and growth of lung tumors in mice. (Cancer Sci 2008; 99: 1774–1777)
Phosphatidylinositol 3‐kinase inhibitors: promising drug candidates for cancer therapy
Authors: Kong Dexin , Yamori Takao 
Published: July 2008

Phosphatidylinositol 3‐kinases (PI3K) are a group of lipid kinases that phosphorylate phosphoinositides at the 3‐hydroxyl group of the inositol ring to generate phosphatidylinositol 3,4,5‐trisphosphate, a second messenger with key roles in fundamental cellular responses such as cell proliferation and metabolism. Frequent mutations found in or amplification of the PIK3CA gene and loss of phosphatase and tensin homolog deleted on chromosome 10 function in human tumors suggest that PI3K is a potential target for cancer therapy. During the last 5 years, several specific PI3K inhibitors were developed that were directed against various diseases. Some of them revealed potent anticancer efficacy and are now undergoing clinical trials. Some PI3K inhibitors showed antiangiogenic effects. Combined use of PI3K inhibitors with other chemotherapeutic agents or with radiotherapy produced synergistic therapeutic efficacies in treating cancer and showed reduced side effects. The rapid progress made in developing novel PI3K inhibitors in recent years promises bright prospects for finding a PI3K‐targeted anticancer drug in the near future. (Cancer Sci 2008; 99: 1734–1740)
Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome
Authors: Fujii Satoshi , Mitsunaga Shuichi , Yamazaki Manabu , Hasebe Takahiro , Ishii Genichiro , Kojima Motohiro , Kinoshita Taira , Ueno Takashi , Esumi Hiroyasu , Ochiai Atsushi 
Published: July 2008

Because autonomous proliferating cancer cells are often exposed to hypoxic conditions, there must be an alternative metabolic pathway, such as autophagy, that allows them to obtain energy when both oxygen and glucose are depleted. We previously reported finding that autophagy actually contributes to cancer cell survival in colorectal cancers both in vitro and in vivo. Pancreatic cancer remains a devastating and poorly understood malignancy, and hypoxia in pancreatic cancers is known to increase their malignant potential. In the present study archival pancreatic cancer tissue was retrieved from 71 cases treated by curative pancreaticoduodenectomy. Autophagy was evaluated by immunohistochemical staining with anti‐LC3 antibody, as LC3 is a key component of autophagy and has been used as a marker of autophagy. The results showed that strong LC3 expression in the peripheral area of pancreatic cancer tissue was correlated with a poor outcome (P = 0.0170) and short disease‐free period (P = 0.0118). Two of the most significant correlations among the clinicopathological factors tested were found between the peripheral intensity level of LC3 expression and tumor size (P = 0.0098) or tumor necrosis (P = 0.0127). Activated autophagy is associated with pancreatic cancer cells, and autophagy is thought to be a response to factors in the cancer microenvironment, such as hypoxia and poor nutrient supply. This is the first study to report the clinicopathological significance of autophagy in pancreatic cancer. (Cancer Sci 2008; 99: 1813–1819)
High mobility group box‐1‐inducible melanoma inhibitory activity is associated with nodal metastasis and lymphangiogenesis in oral squamous cell carcinoma
Authors: Sasahira Tomonori , Kirita Tadaaki , Oue Naohide , Bhawal Ujjal Kumar , Yamamoto Kazuhiko , Fujii Kiyomu , Ohmori Hitoshi , Luo Yi , Yasui Wataru , Bosserhoff Anja Katrin , Kuniyasu Hiroki 
Published: July 2008

Melanoma inhibitory activity (MIA) is an 11‐kDa secretory protein isolated from malignant melanoma cells that is correlated with invasion and metastasis in various human malignancies. We examined MIA expression in 62 oral squamous cell carcinomas (OSCC) by immunohistochemistry. MIA expression was significantly associated with nodal metastasis (P = 0.00018). MIA expression was also associated with expression of high mobility group box‐1 (HMGB1) (P < 0.0001) and lymph vessel density (P < 0.0001). Expression levels of MIA, HMGB1, nuclear factor kB (NFkB) p65 and HMGB1–NFkB p65 binding were significantly higher in a metastatic human OSCC cell line (HSC3) than those in a non‐metastatic OSCC cell line (HSC4). Treatment with receptor for advanced glycation end products (RAGE) antisense or small interfering RNA and human recombinant HMGB1 (hrHMGB1) did not affect MIA expression, whereas HMGB1 antisense or siRNA treatment decreased MIA expression in HSC3 cells. Then HMGB1 enhanced MIA expression as an NFkB cofactor but not as a RAGE ligand. MIA neutralization by MIA antibodies increased extracellular signal‐related kinase 1/2 phosphorylation, but decreased p38 phosphorylation and the expression of vascular epithelial growth factor (VEGF)‐C and ‐D. Treatment with p38 inihibitor decreased VEGF‐C and ‐D expression in HSC3 cells. These results suggest that MIA expression is enhanced by the interaction of intracellular HMGB1 and NFkBp65 and MIA is closely involved in tumor progression and nodal metastasis by the increments of VEGF‐C and VEGF‐D in OSCC. (Cancer Sci 2008; 99: 1806– 1812)
Evolutionary analysis of endopolygalacturonase‐encoding genes of Botrytis cinerea
Authors: CETTUL EMANUELE , REKAB DJAOUIDA , LOCCI ROMANO , FIRRAO GIUSEPPE 
Published: July 2008

SUMMARYSequence analysis of five of the six endopolygalacturonase‐encoding genes (Bcpg1, Bcpg2, Bcpg3, Bcpg4, Bcpg5) from 32 strains of Botrytis cinerea showed marked gene to gene differences in the amount of among‐strains diversity. Bcpg4 was almost invariable in all strains; Bcpg3 and Bcpg5 showed a moderate variability, similar to that of non‐pathogenicity‐associated genes examined in other studies. Conversely, Bcpg1 and Bcpg2 were highly variable and were shown to be under positive selection based on the McDonald–Kreitman test and likelihood ratio test. The evolution of the five endopolygalacturonase genes is explained by their different ecophysiological role. Diversification and balancing selection, as detected in Bcpg1 and Bcpg2, can be used by the pathogen to escape recognition by the host and delay plant reaction in the early phases of infection. The analysis of the polymorphisms and the location of the sites with high probability of being positively selected highlighted the relevance of variability of the BcPG1 and BcPG2 proteins at their C‐terminal end. By contrast, the absence of variability in Bcpg4 suggests that the efficiency of the product of this gene is critical for B. cinerea growth in late phases of infection or during intraspecific competition, thus markedly affecting strain fitness.