bluuebunny/crossref_metadata_2025_split huggingface dataset:
Murid herpesvirus‐4 induces chronic inflammation of intrahepatic bile ducts in mice deficient in gamma‐interferon signalling
Authors: Gangadharan Babunilayam , Dutia Bernadette M , Rhind Susan M , Nash Anthony A 
Published: October 2008

Aim:  Infection of gamma interferon receptor defective mice with murid herpesvirus‐4 also known as murine gammaherpesvirus‐68 results in multi‐organ fibrosis. In this paper we characterise the pathological changes occurring in the liver in this model.Methods:  Standard immunohistochemistry and in situ hybridisation techniques were used to identify the cellular changes and the presence of virus at different times post infection.Results:  In liver sections from infected gamma interferon receptor defective mice sampled on day 16 to at least day 120, 79% showed proliferating intrahepatic bile ducts associated with a chronic mononuclear cell inflammation. Only 8% of wild type mice showed similar lesions. Coincident with the inflammatory response bile duct epithelial cells were positive for arginase 1. Around day 50 post infection onwards focal fibrotic lesions appeared in approximately 30% of gamma interferon receptor defective mice resulting in destruction of intrahepatic bile ducts. In contrast to the chronic persisting inflammatory response the presence of virus infected cells were only observed between day 12–20 post‐infection.Conclusion:  Infection of gamma interferon receptor defective mice with a murine gammaherpesvirus initiates a chronic persisting inflammatory response with a pathological profile similar to the human fibrotic liver disorder Primary Sclerosing Cholangitis.
EMPIRICAL MODE DECOMPOSITION: APPLICATIONS ON SIGNAL AND IMAGE PROCESSING
Authors: NUNES JEAN-CLAUDE , DELÉCHELLE ÉRIC 
Published: October 2008

In this paper, we propose some recent works on data analysis and synthesis based on Empirical Mode Decomposition (EMD). Firstly, a direct 2D extension of original Huang EMD algorithm with application to texture analysis, and fractional Brownian motion synthesis. Secondly, an analytical version of EMD based on PDE in 1D-space is presented.We proposed an extension in 2D-case of the so-called "sifting process" used in the original Huang's EMD. The 2D-sifting process is performed in two steps: extrema detection (by neighboring window or morphological operators) and surface interpolation by splines (thin plate splines or multigrid B-splines). We propose a multiscale segmentation approach by using the zero-crossings from each 2D-intrinsic mode function (IMF) obtained by 2D-EMD.We apply the Hilbert–Huang transform (which consists of two parts: (a) Empirical mode decomposition, and (b) the Hilbert spectral analysis) to texture analysis. We analyze each 2D-IMF obtained by 2D-EMD by studying local properties (amplitude, phase, isotropy, and orientation) extracted from the monogenic signal of each one of them. The monogenic signal proposed by Felsberg et al. is a 2D-generalization of the analytic signal, where the Riesz transform replaces the Hilbert transform. These local properties are obtained by the structure multivector such as proposed by Felsberg and Sommer.We present numerical simulations of fractional Brownian textures. Recent works published by Flandrin et al. relate that, in the case of fractional Gaussian noise (fGn), EMD acts essentially as a dyadic filter bank that can be compared to wavelet decompositions. Moreover, in the context of fGn identification, Flandrin et al. show that variance progression across IMFs is related to Hurst exponent H through a scaling law. Starting with these results, we proposed an algorithm to generate fGn, and fractional Brownian motion (fBm) of Hurst exponent H from IMFs obtained from EMD of a White noise, i.e., ordinary Gaussian noise (fGn with H = 1/2).Deléchelle et al. proposed an analytical approach (formulated as a partial differential equation (PDE)) for sifting process. This PDE-based approach is applied on signals. The analytical approach has a behavior similar to that of the EMD proposed by Huang.
Long-term progression and therapeutic response of visceral metastatic disease non-invasively monitored in mouse urine using β-human choriogonadotropin secreting tumor cell lines
Authors: Francia Giulio , Emmenegger Urban , Lee Christina R. , Shaked Yuval , Folkins Christopher , Mossoba Miriam , Medin Jeffrey A. , Man Shan , Zhu Zhenping , Witte Larry , Kerbel Robert S. 
Published: October 2008

Abstract
Historically, the use of mouse models of metastatic disease to evaluate anticancer therapies has been hampered because of difficulties in detection and quantification of such lesions without sacrificing the mice, which in turn may also be dictated by institutional or ethical guidelines. Advancements in imaging technologies have begun to change this situation. A new method to non-invasively measure tumor burden, as yet untested to monitor spontaneous metastases, is the use of transplanted tumors expressing secretable human β-chorionic gonadotropin (β-hCG) that can be measured in urine. We describe examples of β-hCG–transfected tumor cell lines for evaluating the effect of different therapies on metastatic disease, which in some cases involved monitoring tumor growth for &gt;100 days. We used β-hCG–tagged mouse B16 melanoma and erbB-2/Her-2–expressing human breast cancer MDA-MB-231 models, and drug treatments included metronomic low-dose cyclophosphamide chemotherapy with or without a vascular endothelial growth factor receptor 2–targeting antibody (DC101) or trastuzumab, the erbB-2/Her-2–targeting antibody. Both experimental and spontaneous metastasis models were studied; in the latter case, an increase in urine β-hCG always foreshadowed the development of lung, liver, brain, and kidney metastases. Metastatic disease was unresponsive to DC101 or trastuzumab monotherapy treatment, as assessed by β-hCG levels. Our results also suggest that β-hCG levels may be set as an end point for metastasis studies, circumventing guidelines, which have often hampered the use of advanced disease models. Collectively, our data indicates that β-hCG is an effective noninvasive preclinical marker for the long term monitoring of untreated or treated metastatic disease. [Mol Cancer Ther 2008;7(10):3452–9]
Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells
Authors: Gu Hongyan , Wang Xiaotang , Rao Shuyun , Wang Jia , Zhao Jie , Ren Fang Li , Mu Rong , Yang Yong , Qi Qi , Liu Wei , Lu Na , Ling Hua , You Qidong , Guo Qinglong 
Published: October 2008

Abstract
Gambogic acid (GA) is a natural product with potent apoptotic activity. Here, we showed that GA broadly inhibited the growth of cancer cells that expressed wild-type p53 as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol-iumbromide assay, 3H-thymidine incorporation analysis, and an in vivo mouse xenograft model. GA induced massive cell apoptosis as judged by Annexin V and propidium iodide dual-staining experiments. Furthermore, we found that GA partially induced cancer cell growth inhibition in a p53-dependent manner because cell survival could be restored after endogenous p53 was attenuated by p53 transcriptional repressor pifithrin-α or p53 small interfering RNA. Interestingly, GA had no influence on p53 mRNA synthesis but dramatically enhanced its protein expression. This unique observation could be accounted for by the down-regulation of mdm2 at both mRNA and protein levels. It is concluded that GA enhances p53 protein level through inhibition of mdm2 expression and thereby hampers p53 harboring tumor growth. [Mol Cancer Ther 2008;7(10):3298–305]
Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin
Authors: Peklak-Scott Christina , Smitherman Pamela K. , Townsend Alan J. , Morrow Charles S. 
Published: October 2008

Abstract
Cells expressing elevated levels of allelic variants of human glutathione S-transferase P1 (GSTP1) and/or efflux transporters, MRP1 or MRP2, were used to evaluate the role of GSTP1-1 in cisplatin resistance. These studies revealed that GSTP1-1 confers low-level resistance (1.4- to 1.7-fold) to cisplatin-induced cytotoxicity in MCF7 cells. However, expression of MRP1 (MCF7 cells) or MRP2 (HepG2 cells) failed to augment or potentiate GSTP1-1-mediated resistance in either cell line. To understand the mechanism by which variants of GSTP1-1 confer resistance to cisplatin, their relative abilities to catalyze conjugation of cisplatin with glutathione were examined. Enzymes encoded by all three alleles tested, GSTP1a (I104A113), GSTP1b (V104A113), and GSTP1c (V104V113), increased the formation rate of the mono-platinum/glutathione derivative of cisplatin with relative catalytic activities of 1.0 (GSTP1a-1a variant) and 1.8 to 1.9 (GSTP1b-1b and GSTP1c-1c variants). Although these data are consistent with the idea that very low level resistance to cisplatin may be conferred by GSTP1-1-mediated cisplatin/glutathione conjugation, two observations indicate that such catalysis plays a minor role in the protection from cisplatin toxicity. First, the rates of GSTP1-1-mediated conjugation are extremely slow (1.7-2.6 h−1 at 25°C). Second, despite an 80% to 90% increase in catalysis of cisplatin conjugation by GSTP1b-1b or GSTP1c-1c over GSTP1a-1a, we observed no discernable differences in relative resistances conferred by these alternative variants when expressed in MCF7 cells. We conclude that high-level cisplatin resistance attributed to GSTP1-1 in other studies is not likely due to catalysis of cisplatin conjugation but rather must be explained by other mechanisms, which may include GSTP1-mediated modulation of signaling pathways. [Mol Cancer Ther 2008;7(10):3247–55]
ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo
Authors: Ackler Scott , Xiao Yu , Mitten Michael J. , Foster Kelly , Oleksijew Anatol , Refici Marion , Schlessinger Sally , Wang Baole , Chemburkar Sanjay R. , Bauch Joy , Tse Christin , Frost David J. , Fesik Stephen W. , Rosenberg Saul H. , Elmore Steven W. , Shoemaker Alex R. 
Published: October 2008

Abstract
ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-xL, and Bcl-w, which is currently in phase I clinical trials. Previous work has shown that this compound has low nanomolar cell-killing activity in a variety of lymphoma and leukemia cell lines, many of which overexpress Bcl-2 through a variety of mechanisms. Rapamycin is a macrolide antibiotic that inhibits the mammalian target of rapamycin complex, leading to cell cycle arrest and inhibition of protein translation. Rapamycin (and its analogues) has shown activity in a variety of tumor cell lines primarily through induction of cell cycle arrest. Activity has also been shown clinically in mantle cell lymphoma and advanced renal cell carcinoma. Here, we show that treatment of the follicular lymphoma lines DoHH-2 and SuDHL-4 with 100 nmol/L rapamycin induces substantial G0-G1 arrest. Addition of as little as 39 nmol/L ABT-263 to the rapamycin regimen induced a 3-fold increase in sub-G0 cells. Combination of these agents also led to a significant increase in Annexin V staining over ABT-263 alone. In xenograft models of these tumors, rapamycin induced a largely cytostatic response in the DoHH-2 and SuDHL-4 models. Coadministration with ABT-263 induced significant tumor regression, with DoHH-2 and SuDHL-4 tumors showing 100% overall response rates. Apoptosis in these tumors was significantly enhanced by combination therapy as measured by staining with an antibody specific for cleaved caspase-3. These data suggest that combination of ABT-263 and rapamycin or its analogues represents a promising therapeutic strategy for the treatment of lymphoma. [Mol Cancer Ther 2008;7(10):3265–74]
Natural polyphenols facilitate elimination of HT-29 colorectal cancer xenografts by chemoradiotherapy: a Bcl-2- and superoxide dismutase 2-dependent mechanism
Authors: Priego Sonia , Feddi Fatima , Ferrer Paula , Mena Salvador , Benlloch María , Ortega Angel , Carretero Julian , Obrador Elena , Asensi Miguel , Estrela José M. 
Published: October 2008

AbstractColorectal cancer is one of the most common malignancies worldwide. The treatment of advanced colorectal cancer with chemotherapy and radiation has two major problems: development of tumor resistance to therapy and nonspecific toxicity towards normal tissues. Different plant-derived polyphenols show anticancer properties and are pharmacologically safe. In vitro growth of human HT-29 colorectal cancer cells is inhibited (∼56%) by bioavailable concentrations of trans-pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene; t-PTER) and quercetin (3,3′,4′,5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols. I.v. administration of t-PTER and QUER (20 mg/kg × day) inhibits growth of HT-29 xenografts (∼51%). Combined administration of t-PTER + QUER, FOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil; a first-line chemotherapy regimen), and radiotherapy (X-rays) eliminates HT-29 cells growing in vivo leading to long-term survival (&gt;120 days). Gene expression analysis of a Bcl-2 family of genes and antioxidant enzymes revealed that t-PTER + QUER treatment preferentially promotes, in HT-29 cells growing in vivo, (a) superoxide dismutase 2 overexpression (∼5.7-fold, via specificity protein 1-dependent transcription regulation) and (b) down-regulation of bcl-2 expression (∼3.3-fold, via inhibition of nuclear factor-κB activation). Antisense oligodeoxynucleotides to human superoxide dismutase 2 and/or ectopic bcl-2 overexpression avoided polyphenols and chemoradiotherapy-induced colorectal cancer elimination and showed that the mangano-type superoxide dismutase and Bcl-2 are key targets in the molecular mechanism activated by the combined application of t-PTER and QUER. [Mol Cancer Ther 2008;7(10):3330–42]
Oncogene AF1q enhances doxorubicin-induced apoptosis through BAD-mediated mitochondrial apoptotic pathway
Authors: Co Ngai Na , Tsang Wing Pui , Wong Timothy W.L. , Cheung Hoi Hung , Tsang Tsun Yee , Kong Siu Kai , Kwok Tim Tak 
Published: October 2008

Abstract
AF1q is an oncogenic factor involved in leukemia development, thyroid tumorigenesis, and breast cancer metastasis. In the present study, AF1q was found to be down-regulated in a doxorubicin-resistant subline of human squamous carcinoma A431 cells. Knockdown of AF1q decreased the apoptosis induced by doxorubicin, Taxol, γ-radiation, IFN-α, and IFN-γ in A431 cells. On the other hand, overexpression of AF1q increased the doxorubicin-induced apoptosis in A431 cells as well as in HepG2 and HL60 cells. Both exogenous and ectopic expression of AF1q in A431 cells increased the mRNA and protein levels of BAD, a proapoptotic BCL-2 family protein. Gene silencing of BAD by small interfering RNA suppressed the AF1q enhancement of apoptosis, suggesting that BAD is downstream of AF1q in regulation of apoptosis. Furthermore, AF1q enhanced the mitochondrial membrane depolarization, mitochondrial cytochrome c release, and activation of caspase-9 and caspase-3 on doxorubicin treatment. Collectively, AF1q increases doxorubicin-induced apoptosis in cells through activation of BAD-mediated apoptotic pathway. The study provides the first evidence that AF1q plays a critical role in the regulation of apoptosis and drug resistance. [Mol Cancer Ther 2008;7(10):3160–8]
Coronarin D, a labdane diterpene, inhibits both constitutive and inducible nuclear factor-κB pathway activation, leading to potentiation of apoptosis, inhibition of invasion, and suppression of osteoclastogenesis
Authors: Kunnumakkara Ajaikumar B. , Ichikawa Haruyo , Anand Preetha , Mohankumar Chiramel J. , Hema Padmanabhan S. , Nair Mangalam S. , Aggarwal Bharat B. 
Published: October 2008

Abstract
Compounds isolated from members of the Zingiberaceae family are traditionally used as a medicine against inflammatory diseases, but little is known about the mechanism. Here, we report the isolation and structural identification of coronarin D [E-labda-8(17),12-diene-15-ol], a labdane-type diterpene, from Hedychium coronarium and delineate its mechanism of action. Because the transcription factor nuclear factor-κB (NF-κB) is a key mediator of inflammation, apoptosis, invasion, and osteoclastogenesis, we investigated the effect of coronarin D on NF-κB activation pathway, NF-κB-regulated gene products, and NF-κB-regulated cellular responses. The coronarin D inhibited NF-κB activation induced by different inflammatory stimuli and carcinogens. This labdane also suppressed constitutive NF-κB activity in different cell lines and inhibited IκBα kinase activation, thus leading to the suppression of IκBα phosphorylation, degradation, p65 nuclear translocation, and reporter gene transcription. Coronarin D also inhibited the NF-κB-regulated gene products involved in cell survival (inhibitor of apoptosis protein 1, Bcl-2, survivin, and tumor necrosis factor receptor-associated factor-2), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of these gene products by the diterpene enhanced apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced cellular invasion, and abrogated receptor activator of NF-κB ligand-induced osteoclastogenesis. Coronarin D was found to be more potent than its analogue coronarin D acid. Overall, our results show that coronarin D inhibited NF-κB activation pathway, which leads to inhibition of inflammation, invasion, and osteoclastogenesis, as well as potentiation of apoptosis. [Mol Cancer Ther 2008;7(10):3306–17]
Structure-dependent activation of endoplasmic reticulum stress-mediated apoptosis in pancreatic cancer by 1,1-bis(3′-indoly)-1-(p-substituted phenyl)methanes
Authors: Lei Ping , Abdelrahim Maen , Cho Sung Dae , Liu Xingi , Safe Stephen 
Published: October 2008

Abstract1,1-Bis(3′-indoly)-1-(p-substituted phenyl)methanes (C-DIM) exhibit structure-dependent activation of peroxisome proliferator–activated receptor γ and nerve growth factor–induced Bα (Nur77) and induce receptor-dependent and receptor-independent apoptosis in cancer cells and tumors. In this study, we investigated the activation of apoptosis in pancreatic cancer cells by p-bromo (DIM-C-pPhBr) and p-fluoro (DIM-C-pPhF) and structurally related analogues that do not activate either peroxisome proliferator–activated receptor γ or Nur77. The ortho, meta, and para-bromo and -fluoro isomers all activated endoplasmic reticulum (ER) stress-dependent apoptosis in pancreatic cancer cells; however, methylation of the indole N group significantly decreased activity, suggesting that a free N was important for activation of ER stress. Both DIM-C-pPhBr and DIM-C-pPhF resembled the classic ER stress inducer thapsigargin in pancreatic cancer cells and activated ER stress markers, such as glucose-related protein 78 and the c-Jun NH2 kinase pathway, resulting in the induction of CCAAT/enhancer-binding protein homologous protein, death receptor 5, and the extrinsic apoptotic pathway. Moreover, DIM-C-pPhBr also inhibited tumor growth in an orthotopic model for pancreatic cancer, demonstrating the clinical potential for this C-DIM compound in pancreatic cancer chemotherapy. [Mol Cancer Ther 2008;7(10):3363–72]
Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition
Authors: Fischer Hendrik , Taylor Ninon , Allerstorfer Sigrid , Grusch Michael , Sonvilla Gudrun , Holzmann Klaus , Setinek Ulrike , Elbling Leonilla , Cantonati Heidelinde , Grasl-Kraupp Bettina , Gauglhofer Christine , Marian Brigitte , Micksche Michael , Berger Walter 
Published: October 2008

AbstractFibroblast growth factors (FGF) and their high-affinity receptors (FGFR) represent an extensive cellular growth and survival system. Aim of this study was to evaluate the contribution of FGF/FGFR-mediated signals to the malignant growth of non-small cell lung cancer (NSCLC) and to assess their potential as targets for therapeutic interventions. Multiple FGFR mRNA splice variants were coexpressed in NSCLC cells (n = 16) with predominance of FGFR1. Accordingly, both expression of a dominant-negative FGFR1 (dnFGFR1) IIIc-green fluorescent protein fusion protein and application of FGFR small-molecule inhibitors (SU5402 and PD166866) significantly reduced growth, survival, clonogenicity, and migratory potential of the majority of NSCLC cell lines. Moreover, dnFGFR1 expression completely blocked or at least significantly attenuated s.c. tumor formation of NSCLC cells in severe combined immunodeficient mice. Xenograft tumors expressing dnFGFR1 exhibited significantly reduced size and mitosis rate, enhanced cell death, and decreased tissue invasion. When FGFR inhibitors were combined with chemotherapy, antagonistic to synergistic in vitro anticancer activities were obtained depending on the application schedule. In contrast, simultaneous blockage of FGFR- and epidermal growth factor receptor-mediated signals exerted synergistic effects. In summary, FGFR-mediated signals in cooperation with those transmitted by epidermal growth factor receptor are involved in growth and survival of human NSCLC cells and should be considered as targets for combined therapeutic approaches. [Mol Cancer Ther 2008;7(10):3408–19]
Identification and characterization of small-molecule inhibitors of hepsin
Authors: Chevillet John R. , Park Gemma J. , Bedalov Antonio , Simon Julian A. , Vasioukhin Valeri I. 
Published: October 2008

AbstractHepsin is a type II transmembrane serine protease overexpressed in the majority of human prostate cancers. We recently demonstrated that hepsin promotes prostate cancer progression and metastasis and thus represents a potential therapeutic target. Here we report the identification of novel small-molecule inhibitors of hepsin catalytic activity. We utilized purified human hepsin for high-throughput screening of established drug and chemical diversity libraries and identified sixteen inhibitory compounds with IC50 values against hepsin ranging from 0.23-2.31 μM and relative selectivity of up to 86-fold or greater. Two compounds are orally administered drugs established for human use. Four compounds attenuated hepsin-dependent pericellular serine protease activity in a dose dependent manner with limited or no cytotoxicity to a range of cell types. These compounds may be used as leads to develop even more potent and specific inhibitors of hepsin to prevent prostate cancer progression and metastasis. [Mol Cancer Ther 2008;7(10):3343–51]