bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Toll-Like Receptor 9 Agonist Cooperates with Trastuzumab in Trastuzumab-Resistant Breast Tumors through Multiple Mechanisms of Action
Authors: Damiano Vincenzo , Garofalo Sonia , Rosa Roberta , Bianco Roberto , Caputo Rosa , Gelardi Teresa , Merola Gerardina , Racioppi Luigi , Garbi Corrado , Kandimalla Ekambar R. , Agrawal Sudhir , Tortora Giampaolo 
Published: November 2009

AbstractPurpose: Resistance to anti-HER2 monoclonal antibody trastuzumab is a relevant issue in breast cancer patients. Among the mechanisms implicated in trastuzumab resistance, increasing evidence supports a role of tumor microenvironment. We previously found that a novel toll-like receptor 9 agonist, referred to as immune modulatory oligonucleotide (IMO) and currently under clinical investigation, acts through epidermal growth factor receptor (EGFR) and shows direct antiangiogenic effects by cooperating with anti-EGFR or anti-VEGF drugs, thus interfering with cancer cells and microenvironment.Experimental Design: In this study, we used KPL-4 and JIMT-1 trastuzumab-resistant breast cancer cells to evaluate the combination IMO plus trastuzumab as a therapeutic option for trastuzumab-resistant breast cancers.Results: IMO inhibits KPL-4 and JIMT-1 xenografts growth and potentiates trastuzumab antitumor effect, with complete suppression of tumor growth, potent enhancement of trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity, and strong inhibition of EGFR/HER2-related signaling. In KPL-4 xenografts, IMO alone interferes with HER signal transduction, whereas trastuzumab is ineffective. IMO induces an HER-dependent signal inhibition also in vitro by modulating a functional interaction between toll-like receptor 9 and HER receptors occurring at membrane level. Finally, IMO plus trastuzumab produces a cooperative antiangiogenic effect related to suppression of endothelial HER-related signaling.Conclusions: We showed a cooperative effect of IMO plus trastuzumab in trastuzumab-resistant breast cancers due to IMO direct antitumor and antiangiogenic activity and antibody-dependent cell-mediated cytotoxicity enhancement. Moreover, we provided first evidence of a toll-like receptor 9/HER interaction at membrane level as novel mechanism of action. Altogether, we propose IMO plus trastuzumab as an effective strategy in trastuzumab-resistant breast cancers. (Clin Cancer Res 2009;15(22):692130)
Epidermal Growth Factor Receptor Is Required for Colonic Tumor Promotion by Dietary Fat in the Azoxymethane/Dextran Sulfate Sodium Model: Roles of Transforming Growth Factor- and PTGS2
Authors: Dougherty Urszula , Cerasi Dario , Taylor Ieva , Kocherginsky Masha , Tekin Ummuhan , Badal Shamiram , Aluri Lata , Sehdev Amikar , Cerda Sonia , Mustafi Reba , Delgado Jorge , Joseph Loren , Zhu Hongyan , Hart John , Threadgill David , Fichera Alessandro , Bissonnette Marc 
Published: November 2009

AbstractPurpose: Colon cancer is a major cause of cancer deaths. Dietary factors contribute substantially to the risk of this malignancy. Western-style diets promote development of azoxymethane-induced colon cancer. Although we showed that epidermal growth factor receptors (EGFR) controlled azoxymethane tumorigenesis in standard fat conditions, the role of EGFR in tumor promotion by high dietary fat has not been examined.Experimental Design: A/J C57BL6/J mice with wild-type Egfr (Egfrwt) or loss-of-function waved-2 Egfr (Egfrwa2) received azoxymethane followed by standard (5 fat) or western-style (20 fat) diet. As F1 mice were resistant to azoxymethane, we treated mice with azoxymethane followed by one cycle of inflammation-inducing dextran sulfate sodium to induce tumorigenesis. Mice were sacrificed 12 weeks after dextran sulfate sodium. Tumors were graded for histology and assessed for EGFR ligands and proto-oncogenes by immunostaining, Western blotting, and real-time PCR.Results: Egfrwt mice gained significantly more weight and had exaggerated insulin resistance compared with Egfrwa2 mice on high-fat diet. Dietary fat promoted tumor incidence (71.2 versus 36.7; P &lt; 0.05) and cancer incidence (43.9 versus 16.7; P &lt; 0.05) only in Egfrwt mice. The lipid-rich diet also significantly increased tumor and cancer multiplicity only in Egfrwt mice. In tumors, dietary fat and Egfrwt upregulated transforming growth factor-, amphiregulin, CTNNB1, MYC, and CCND1, whereas PTGS2 was only increased in Egfrwt mice and further upregulated by dietary fat. Notably, dietary fat increased transforming growth factor- in normal colon.Conclusions: EGFR is required for dietary fat-induced weight gain and tumor promotion. EGFR-dependent increases in receptor ligands and PTGS2 likely drive diet-related tumor promotion. (Clin Cancer Res 2009;15(22):67809)
Getting Knit-PI3Ky: PIK3CA Mutation Status to Direct Multimodality Therapy?
Authors: Myers Andrea P. , Meyerhardt Jeffrey A. , Cantley Lewis C. 
Published: November 2009

Abstract
There is high morbidity associated with local recurrence of rectal cancer. However, the adjuvant therapies given to prevent such recurrences also have significant side effects and associated risks. The ability to select patients with the highest risk of recurrence and greatest therapeutic response will improve rectal cancer care. (Clin Cancer Res 2009;15(22):674850)
Immunostimulation Versus Immunosuppression after Multiple Vaccinations: the Woes of Therapeutic Vaccine Development
Authors: Eggermont Alexander M.M. 
Published: November 2009

Abstract
Three articles in this issue of Clinical Cancer Research show how multiple vaccinations can lead to immunosuppression. Moreover, two studies in patients show that granulocyte macrophage colony-stimulating factor (GM-CSF) as an adjuvant immunostimulant to different kind of vaccines can lead to adverse outcome in terms of relapse-free and overall survival. Modulation of regulatory T-cell activity may be required to overcome this outcome and may be crucial for the successful development of therapeutic vaccines. (Clin Cancer Res 2009;15(22):67457)
Critical Role of Endogenous Heme Oxygenase 1 as a Tuner of the Invasive Potential of Prostate Cancer Cells
Authors: Gueron Geraldine , De Siervi Adriana , Ferrando Mercedes , Salierno Marcelo , De Luca Paola , Elguero Belen , Meiss Roberto , Navone Nora , Vazquez Elba S. 
Published: November 2009

Abstract
Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Inflammation has been recognized as a risk factor for this disease. Heme oxygenase 1 (HO-1), the inducible isoform of the rate-limiting enzyme in heme degradation, counteracts oxidative and inflammatory damage. Here, we investigated the regulated expression of HO-1 and its functional consequences in PCa. We studied the effect of genetic and pharmacologic disruption of HO-1 in the growth, invasion, and migration in androgen-sensitive (MDA PCa2b and LNCaP) and androgen-insensitive (PC3) PCa cell lines. Our results show that HO-1 levels are markedly decreased in PC3 compared with MDA PCa2b and LNCaP. Hemin treatment increased HO-1 at both protein and mRNA levels in all cell lines and decreased cell proliferation and invasion. Furthermore, overexpression of HO-1 in PC3 resulted in markedly reduced cell proliferation and migration. Accordingly, small interfering RNA–mediated silencing of HO-1 expression in MDA PCa2b cells resulted in increased proliferation and invasion. Using reverse transcription-quantitative PCR–generated gene array, a set of inflammatory and angiogenic genes were upregulated or downregulated in response to HO-1 overexpression identifying matrix metalloprotease 9 (MMP9) as a novel downstream target of HO-1. MMP9 production and activity was downregulated by HO-1 overexpression. Furthermore, PC3 cells stably transfected with HO-1 (PC3HO-1) and controls were injected into nu/nu mice for analysis of in vivo tumor xenograft phenotype. Tumor growth and MMP9 expression was significantly reduced in PC3HO-1 tumors compared with control xenografts. Taken together, these results implicate HO-1 in PCa cell migration and proliferation suggesting its potential role as a therapeutic target in clinical settings. (Mol Cancer Res 2009;7(11):1745–55)
Upregulation of MMP-2 by HMGA1 Promotes Transformation in Undifferentiated, Large-Cell Lung Cancer
Authors: Hillion Joelle , Wood Lisa J. , Mukherjee Mita , Bhattacharya Raka , Di Cello Francescopaolo , Kowalski Jeanne , Elbahloul Ossama , Segal Jodi , Poirier John , Rudin Charles M. , Dhara Surajit , Belton Amy , Joseph Biju , Zucker Stanley , Resar Linda M.S. 
Published: November 2009

Abstract
Although lung cancer is the leading cause of cancer death worldwide, the precise molecular mechanisms that give rise to lung cancer are incompletely understood. Here, we show that HMGA1 is an important oncogene that drives transformation in undifferentiated, large-cell carcinoma. First, we show that the HMGA1 gene is overexpressed in lung cancer cell lines and primary human lung tumors. Forced overexpression of HMGA1 induces a transformed phenotype with anchorage-independent cell growth in cultured lung cells derived from normal tissue. Conversely, inhibiting HMGA1 expression blocks anchorage-independent cell growth in the H1299 metastatic, undifferentiated, large-cell human lung carcinoma cells. We also show that the matrix metalloproteinase-2 (MMP-2) gene is a downstream target upregulated by HMGA1 in large-cell carcinoma cells. In chromatin immunoprecipitation experiments, HMGA1 binds directly to the MMP-2 promoter in vivo in large-cell lung cancer cells, but not in squamous cell carcinoma cells. In large-cell carcinoma cell lines, there is a significant, positive correlation between HMGA1 and MMP-2 mRNA. Moreover, interfering with MMP-2 expression blocks anchorage-independent cell growth in H1299 large-cell carcinoma cells, indicating that the HMGA1–MMP-2 pathway is required for this transformation phenotype in these cells. Blocking MMP-2 expression also inhibits migration and invasion in the H1299 large-cell carcinoma cells. Our findings suggest an important role for MMP-2 in transformation mediated by HMGA1 in large-cell, undifferentiated lung carcinoma and support the development of strategies to target this pathway in selected tumors. (Mol Cancer Res 2009;7(11):1803–12)
p34SEI-1 Inhibits Doxorubicin-Induced Senescence through a Pathway Mediated by Protein Kinase C-δ and c-Jun-NH2-Kinase 1 Activation in Human Breast Cancer MCF7 Cells
Authors: Lee Sae Lo Oom , Hong Seung-Woo , Shin Jae-Sik , Kim Jin Sun , Ko Seong-Gyu , Hong Nam-Joo , Kim Dae Jin , Lee Wang-Jae , Jin Dong-Hoon , Lee Myeong-Sok 
Published: November 2009

Abstract
In this study, we describe a novel function of the p34SEI-1 protein, which is both an oncogenic protein and a positive regulator of the cell cycle. The p34SEI-1 protein was found to inhibit doxorubicin-induced senescence. We investigated the molecular mechanisms of the inhibitory effect of p34SEI-1 on senescence. First, we found that the activation of protein kinase C-δ (PKC-δ), which is cleaved into a 38 kDa active form from a 78 kDa pro-form, induced after doxorubicin treatment, was inhibited by p34SEI-1. Furthermore, p34SEI-1 induced the ubiquitination of PKC-δ. Yet, there is no interaction between p34SEI-1 and PKC-δ. We also found that the phosphorylation of c-Jun-NH2-kinase 1 (JNK1) induced after doxorubicin treatment was suppressed by p34SEI-1, but not in JNK2. Consistently, pharmacologic or genetic inactivation of either PKC-δ or JNK1 was found to inhibit doxorubicin-induced senescence. In addition, the genetic inactivation of PKC-δ by PKC-δ small interfering RNA resulted in an inhibition of JNK1 activation, but PKC-δ expression was not inactivated by JNK1 small interfering RNA, implying that the activation of JNK1 could be dependently induced by PKC-δ. Therefore, p34SEI-1 inhibits senescence by inducing PKC-δ ubiquitination and preventing PKC-δ–dependent phosphorylation of JNK1. [Mol Cancer Res 2009;7(11):1845–53]
Activated Platelets Provide a Functional Microenvironment for the Antiangiogenic Fragment of Histidine-Rich Glycoprotein
Authors: Thulin Åsa , Ringvall Maria , Dimberg Anna , Kårehed Karin , Väisänen Timo , Väisänen Marja-Riitta , Hamad Osama , Wang Jian , Bjerkvig Rolf , Nilsson Bo , Pihlajaniemi Taina , Åkerud Helena , Pietras Kristian , Jahnen-Dechent Wilhelm , Siegbahn Agneta , Olsson Anna-Karin 
Published: November 2009

Abstract
The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine- and proline-rich (His/Pro-rich) domain. Using a combination of immunohistochemistry and mass spectrometry, we here provide biochemical evidence for the presence of a proteolytic peptide, corresponding to the antiangiogenic domain of HRG, in vivo in human tissue. This finding supports a role for HRG as an endogenous regulator of angiogenesis. Interestingly, the His/Pro-rich peptide bound to the vessel wall in tissue from cancer patients but not to the vasculature in tissue from healthy persons. Moreover, the His/Pro-rich peptide was found in close association with platelets. Relesate from in vitro–activated platelets promoted binding of the His/Pro-rich domain of HRG to endothelial cells, an effect mediated by Zn2+. Previous studies have shown that zinc-dependent binding of the His/Pro-rich domain of HRG to heparan sulfate on endothelial cells is required for inhibition of angiogenesis. We describe a novel mechanism to increase the local concentration and activity of an angiogenesis inhibitor, which may reflect a host response to counteract angiogenesis during pathologic conditions. Our finding that tumor angiogenesis is elevated in HRG-deficient mice supports this conclusion. (Mol Cancer Res 2009;7(11):1792–802)
Caveolin-1 Promotes Autoregulatory, Akt-Mediated Induction of Cancer-Promoting Growth Factors in Prostate Cancer Cells
Authors: Li Likun , Ren Chengzhen , Yang Guang , Goltsov Alexei A. , Tabata Ken-ichi , Thompson Timothy C. 
Published: November 2009

Abstract
Caveolin-1 (cav-1) and the cancer-promoting growth factors vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGF-β1), and fibroblast growth factor 2 (FGF2) are often found to be upregulated in advanced prostate cancer and other malignancies. However, the relationship between cav-1 overexpression and growth factor upregulation remains unclear. This report presents, to our knowledge, the first evidence that in prostate cancer cells, a positive autoregulatory feedback loop is established in which VEGF, TGF-β1, and FGF2 upregulate cav-1, and cav-1 expression, in turn, leads to increased levels of VEGF, TGF-β1, and FGF2 mRNA and protein, resulting in enhanced invasive activities of prostate cancer cells, i.e., migration and motility. Our results further show that cav-1–enhanced mRNA stability is a major mechanism underlying the upregulation of these cancer-promoting growth factors, and that PI3-K-Akt signaling is required for forming this positive autoregulatory feedback loop.(Mol Cancer Res 2009;7(11):1781–91)
Structure of the Atmospheric Boundary Layer in the Vicinity of a Developing Upslope Flow System: A Numerical Model Study
Authors: Serafin Stefano , Zardi Dino 
Published: November 2009

AbstractThe development of a morning upslope flow is studied by means of idealized numerical simulations. In particular, two cases are examined: a plane slope connecting a lower plain and an elevated plateau and a symmetric mountain in the middle of a uniform plain. The analysis examines various steepness cases and aims at understanding the processes occurring in the area of transition between the upslope flow region and the convective boundary layers (CBLs) growing nearby. A characteristic sequence of events is recognized in the simulations, and their relationship with the along-slope variability of the thermal energy and turbulent kinetic energy budgets is studied. Features occurring after the onset of the upslope wind include a transient depression in the boundary layer depth at the base of the slope and the formation of elevated turbulent layers above the CBL, caused by the divergence of turbulent flow from a thermal plume at the slope top. Numerical evidence agrees well with the results of previous experiments, including both field campaigns and water tank models. It is observed that the occurrence of streamwise inhomogeneities in the upslope flow field favors the occurrence of a multilayered vertical structure of the CBL near heated slopes. Multiple layering appears to be a transient feature, only persisting until sufficient heating causes the merging of the CBL with the overlying elevated turbulent layers. The analysis suggests that the slope steepness is an important factor in determining the speed at which the boundary layer structure near a slope evolves in time: in particular, the development of the wind system appears to occur faster in the vicinity of a steeper slope.
Validation of a High-Resolution Regional Climate Model for the Alpine Region and Effects of a Subgrid-Scale Topography and Land Use Representation
Authors: Im E-S. , Coppola E. , Giorgi F. , Bi X. 
Published: November 2009

Abstract
A mosaic-type parameterization of subgrid-scale topography and land use (SubBATS) is applied for a high-resolution regional climate simulation over the Alpine region with a regional climate model (RegCM3). The model coarse-gridcell size in the control simulation is 15 km while the subgridcell size is 3 km. The parameterization requires disaggregation of atmospheric variables from the coarse grid to the subgrid and aggregation of surface fluxes from the subgrid to the coarse grid. Two 10-yr simulations (1983–92) are intercompared, one without (CONT) and one with (SUB) the subgrid scheme. The authors first validate the CONT simulation, showing that it produces good quality temperature and precipitation statistics, showing in particular a good performance compared to previous runs of this region. The subgrid scheme produces much finer detail of temperature and snow distribution following the topographic disaggregation. It also tends to form and melt snow more accurately in response to the heterogeneous characteristics of topography. In particular, validation against station observations shows that the SUB simulation improves the model simulation of the surface hydrologic cycle, in particular snow and runoff, especially at high-elevation sites. Finally, two experiments explore the model sensitivity to different subgrid disaggregation assumptions, namely, the temperature lapse rate and an empirical elevation-based disaggregation of precipitation.
Relating Convective and Stratiform Rain to Latent Heating
Authors: Tao Wei-Kuo , Lang Stephen , Zeng Xiping , Shige Shoichi , Takayabu Yukari 
Published: November 2009

Abstract
The relationship among surface rainfall, its intensity, and its associated stratiform amount is established by examining observed precipitation data from the Tropical Rainfall Measuring Mission (TRMM) Precipitation Radar (PR). The results show that for moderate–high stratiform fractions, rain probabilities are strongly skewed toward light rain intensities. For convective-type rain, the peak probability of occurrence shifts to higher intensities but is still significantly skewed toward weaker rain rates. The main differences between the distributions for oceanic and continental rain are for heavily convective rain. The peak occurrence, as well as the tail of the distribution containing the extreme events, is shifted to higher intensities for continental rain. For rainy areas sampled at 0.5° horizontal resolution, the occurrence of conditional rain rates over 100 mm day−1 is significantly higher over land. Distributions of rain intensity versus stratiform fraction for simulated precipitation data obtained from cloud-resolving model (CRM) simulations are quite similar to those from the satellite, providing a basis for mapping simulated cloud quantities to the satellite observations.
An improved convective–stratiform heating (CSH) algorithm is developed based on two sources of information: gridded rainfall quantities (i.e., the conditional intensity and the stratiform fraction) observed from the TRMM PR and synthetic cloud process data (i.e., latent heating, eddy heat flux convergence, and radiative heating/cooling) obtained from CRM simulations of convective cloud systems. The new CSH algorithm-derived heating has a noticeably different heating structure over both ocean and land regions compared to the previous CSH algorithm. Major differences between the new and old algorithms include a significant increase in the amount of low- and midlevel heating, a downward emphasis in the level of maximum cloud heating by about 1 km, and a larger variance between land and ocean in the new CSH algorithm.
Reduction of Middle-Atmospheric Forecast Bias through Improvement in Satellite Radiance Quality Control
Authors: Kim Young-Joon , Campbell William F. , Swadley Steven D. 
Published: November 2009

Abstract
This article discusses a practical problem faced in operational atmospheric forecasting and data assimilation, and efforts to improve forecast quality through the choice of quality control parameters. The need to utilize as much data as possible must be carefully balanced against the need to reject observations deemed erroneous because they are far from the background value. Alleviation of forecast bias in the middle atmosphere for a global atmospheric prediction system is attempted via improvement of the quality control and bias correction of the satellite radiance data; in particular, the sensitivity of the analysis to the satellite radiance outlier check parameters for the Naval Research Laboratory’s three-dimensional variational data assimilation system [Naval Research Laboratory Atmospheric Variational Data Assimilation System (NAVDAS)] is investigated. A series of forecast experiments are performed with an extended-top (0.04 hPa or ∼65 km) version of the U.S. Navy’s Operational Global Atmospheric Prediction System (NOGAPS) for the month of January 2007. The experiments vary the prescribed radiance observation error variance for the Advanced Microwave Sounding Unit-A (AMSU-A) and the tolerance factors for the AMSU-A and NAVDAS quality control processes. The biases of geopotential height, temperature, and wind in the middle atmosphere are significantly reduced when the observation error limit for the highest-altitude AMSU-A channel (i.e., 14) is relaxed from 0.95 to 3 K and the tolerance factors for the AMSU-A and NAVDAS quality control processes are relaxed from 3 to 4. The improvement is due to assimilation of more high quality AMSU-A radiance data from the highest-peaking channel.
Post Hoc Evaluation of Hazardous Weather: Snowstorms in the Montréal, Québec, Area in March 2008
Authors: Descurieux Jacques 
Published: November 2009

AbstractThe post hoc evaluation of meteorological events that have severe consequences for individuals, property, economic activities, and the environment is a powerful analytical tool. The paper provides a factual and evidence-based analytical framework for the study of hazardous weather events that have major social, economic, and environmental effects. It is a process that seeks to improve and to determine the relevance of services. The analysis of the winter storms that hit the Montréal area in early March 2008 examines the relationship between the storms, the collapse of 18 roofs, the death of 3 persons, and the closure of more than 200 schools. It highlights the limited perception of the risks associated with unusual and severe winter weather. It reveals the lack of attention given in meteorology to the important paradigmatic relationship that exists between the weather elements, the associated risk factors, and the ensuing impacts. This study reveals the need for improvements in meteorological services related to risk communication and knowledge management.