bluuebunny/crossref_metadata_2025_split huggingface dataset:
Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy
Authors: Ihle Nathan T. , Powis Garth 
Published: January 2009

AbstractThe phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is currently one of the most exciting drug targets in oncology. However, only a short time ago, the paradigm existed that drugs targeted to the four PI3K class I isoforms would be too toxic for use in cancer therapy due to effects on physiologic signaling. Since that time, studies have delineated the roles of these four isoforms in nonpathologic signaling as well as their roles in cancer. An extensive effort has gone into developing agents that inhibit one or more PI3K isoforms, as well as closely related proteins implicated in cancer. These agents have proved to be tolerable and therapeutically beneficial in animal studies, and a number are in clinical testing. The agents, their properties, and their molecular targets are discussed in this review. [Mol Cancer Ther 2009;8(1):1–9]
Platinum neurotoxicity pharmacogenetics
Authors: McWhinney Sarah R. , Goldberg Richard M. , McLeod Howard L. 
Published: January 2009

Abstract
Cisplatin, carboplatin, and oxaliplatin anticancer drugs are commonly used to treat lung, colorectal, ovarian, breast, head and neck, and genitourinary cancers. However, the efficacy of platinum-based drugs is often compromised because of the substantial risk for severe toxicities, including neurotoxicity. Neurotoxicity can result in both acute and chronic debilitation. Moreover, colorectal cancer patients treated with oxaliplatin discontinue therapy more often because of peripheral neuropathy than tumor progression, potentially compromising patient benefit. Numerous methods to prevent neurotoxicity have thus far proven unsuccessful. To circumvent this life-altering side effect while taking advantage of the antitumor activities of the platinum agents, efforts to identify mechanism-based biomarkers are under way. In this review, we detail findings from the current literature for genetic markers associated with neurotoxicity induced by single-agent and combination platinum chemotherapy. These data have the potential for broad clinical implications if mechanistic associations lead to the development of toxicity modulators to minimize the noxious sequelae of platinum chemotherapy. [Mol Cancer Ther 2009;8(1):10–6]
ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer
Authors: Greenaway James , Henkin Jack , Lawler Jack , Moorehead Roger , Petrik Jim 
Published: January 2009

Abstract
Epithelial ovarian cancer (EOC) is the fifth most common cancer in women and is characterized by a low 5-year survival rate. One strategy that can potentially improve the overall survival rate in ovarian cancer is the use of antitumor agents such as ABT-510. ABT-510 is a small mimetic peptide of the naturally occurring antiangiogenic compound thrombospondin-1 and has been shown to significantly reduce tumor growth and burden in preclinical mouse models and in naturally occurring tumors in dogs. This is the first evaluation of ABT-510 in a preclinical model of human EOC. Tumorigenic mouse surface epithelial cells were injected into the bursa of C57BL/6 mice that were treated with either 100 mg/kg ABT-510 or an equivalent amount of PBS. ABT-510 caused a significant reduction in tumor size, ascites fluid volume, and secondary lesion dissemination when compared with PBS controls. Analysis of the vasculature of ABT-510-treated mice revealed vascular remodeling with smaller diameter vessels and lower overall area, increased number of mature vessels, and decreased tissue hypoxia. Tumors of ABT-510-treated mice had a significantly higher proportion of apoptotic tumor cells compared with the PBS-treated controls. Immunoblot analysis of cell lysates revealed a reduction in vascular endothelial growth factor, vascular endothelial growth factor receptor-2, and proliferating cell nuclear antigen protein expression as well as expression of members of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase survival pathways. In vitro, ABT-510 induced tumor cell apoptosis in mouse and human ovarian cancer cells. This study shows ABT-510 as a promising candidate for inhibiting tumor growth and ascites formation in human EOC. [Mol Cancer Ther 2009;8(1):64–74]
Intensification therapy with anti-parathyroid hormone-related protein antibody plus zoledronic acid for bone metastases of small cell lung cancer cells in severe combined immunodeficient mice
Authors: Yamada Tadaaki , Muguruma Hiroaki , Yano Seiji , Ikuta Kenji , Ogino Hirokazu , Kakiuchi Soji , Hanibuchi Masaki , Uehara Hisanori , Nishioka Yasuhiko , Sone Saburo 
Published: January 2009

Abstract
Bone metastases occur in more than one-third of patients with advanced lung cancer and are difficult to treat. We showed previously the therapeutic effect of a third-generation bisphosphonate, minodronate, and anti-parathyroid hormone-related protein (PTHrP) neutralizing antibody on bone metastases induced by the human small cell lung cancer cell line, SBC-5, in natural killer cell-depleted severe combined immunodeficient mice. The purpose of our current study was to examine the effect of the combination of PTHrP antibody and zoledronic acid, which has been approved to treat bone metastases, against bone metastases produced by SBC-5 cells expressing PTHrP. Treatment with PTHrP antibody and/or zoledronic acid did not affect the proliferation of SBC-5 cells in vitro. Repeated treatments with either PTHrP antibody or zoledronic acid inhibited the formation of osteolytic bone metastases of SBC-5 cells but had no effect on metastases to visceral organs. Importantly, combined treatment with PTHrP antibody and zoledronic acid further inhibited the formation of bone metastases. Histologic assays showed that, compared with either PTHrP antibody or zoledronic acid alone, their combination decreased the number of tumor-associated osteoclasts and increased the number of apoptotic tumor cells. These findings suggest that this novel dual-targeting therapy may be useful for controlling bone metastases in a subpopulation of small cell lung cancer patients. [Mol Cancer Ther 2009;8(1):119–26]
Identification of phosphotyrosine mimetic inhibitors of human tyrosyl-DNA phosphodiesterase I by a novel AlphaScreen high-throughput assay
Authors: Marchand Christophe , Lea Wendy A. , Jadhav Ajit , Dexheimer Thomas S. , Austin Christopher P. , Inglese James , Pommier Yves , Simeonov Anton 
Published: January 2009

Abstract
Tyrosyl-DNA phosphodiesterase I (Tdp1) resolves topoisomerase I (Top1)-DNA adducts accumulated from natural DNA damage as well as from the action of certain anticancer drugs. Tdp1 catalyzes the hydrolysis of the phosphodiester bond between the catalytic tyrosine residue of topoisomerase I and the DNA 3′-phosphate. Only a limited number of weak inhibitors have been reported for Tdp1, and there is an unmet need to identify novel chemotypes through screening of chemical libraries. Herein, we present an easily configured, highly miniaturized, and robust Tdp1 assay using the AlphaScreen technology. Uninhibited enzyme reaction is associated with low signal, whereas inhibition leads to a gain of signal, making the present assay format especially attractive for automated large-collection high-throughput screening. We report the identification and initial characterization of four previously unreported inhibitors of Tdp1. Among them, suramin, NF449, and methyl-3,4-dephostatin are phosphotyrosine mimetics that may act as Tdp1 substrate decoys. We also report a novel biochemical assay using the SCAN1 Tdp1 mutant to study the mechanism of action of methyl-3,4-dephostatin. [Mol Cancer Ther 2009;8(1):240–8]
Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor
Authors: Sakurama Kazufumi , Noma Kazuhiro , Takaoka Munenori , Tomono Yasuko , Watanabe Nobuyuki , Hatakeyama Shinji , Ohmori Osamu , Hirota Seiichi , Motoki Takayuki , Shirakawa Yasuhiro , Yamatsuji Tomoki , Haisa Minoru , Matsuoka Junji , Tanaka Noriaki , Naomoto Yoshio 
Published: January 2009

Abstract
Focal adhesion kinase (FAK) is often up-regulated in a variety of malignancies, including gastrointestinal stromal tumor (GIST), and its overexpression seems to be associated with tumor progressiveness and poor prognosis. GIST is well known to have a mutation to c-KIT; thus, a specific c-KIT inhibitor (imatinib) is recognized as the first-line chemotherapy for GIST, although a certain type of c-KIT mutation reveals a resistance to imatinib due to as yet uncertain molecular mechanisms. To assess the c-KIT mutation-related variation of cellular responses to imatinib, murine lymphocyte-derived Ba/F3 cells, which are stably transduced with different types of c-KIT mutation, were treated with either imatinib or a FAK inhibitor (TAE226), and their antitumor effects were determined in vitro and in vivo. A mutation at exon 11 (KITdel559-560) displayed a high sensitivity to imatinib, whereas that at exon 17 (KIT820Tyr) showed a significant resistance to imatinib in vitro and in vivo. KIT820Tyr cells appeared to maintain the activities of FAK and AKT under the imatinib treatment, suggesting that FAK might play a role in cell survival in imatinib-resistant cells. When FAK activity in those cells was inhibited by TAE226, cell growth was equally suppressed and the cells underwent apoptosis regardless of the c-KIT mutation types. Oral administration of TAE226 significantly diminished tumor growth in nude mice bearing KIT820Tyr xenografts. In summary, c-KIT mutation at exon 17 displayed a resistance to imatinib with maintained activations of FAK and subsequent survival signals. Targeting FAK could be a potential therapeutic strategy for imatinib-resistant GISTs. [Mol Cancer Ther 2009;8(1):127–34]
Targeting homologous recombination using imatinib results in enhanced tumor cell chemosensitivity and radiosensitivity
Authors: Choudhury Ananya , Zhao Helen , Jalali Farid , AL Rashid Shahnaz , Ran Jane , Supiot Stephane , Kiltie Anne E. , Bristow Robert G. 
Published: January 2009

Abstract
RAD51 is a key protein in the homologous recombination (HR) pathway of DNA double-strand break repair, and HR represents a novel target for cancer therapy. Because imatinib (Gleevec) has been reported to reduce RAD51 protein levels, we tested the clonogenic survival for RT112, H1299, PANC1, and PC3 tumor cell lines of varying p53 status and normal GM05757 normal fibroblasts after exposure to single agent imatinib (0–20 μmol/L; 0–72 hours). We also combined imatinib with DNA damaging agents that are toxic to RAD51-deficient cells, including ionizing radiation, gemcitabine, and mitomycin C. We observed decreased nuclear expression and chromatin binding of RAD51 protein following imatinib treatment. Imatinib also resulted in decreased error-free HR as determined by a flow cytometry–based integrated direct repeat-green fusion protein reporter system; this correlated to reduced RAD51 expression. Clonogenic survival experiments revealed increased cell kill for imatinib-treated cells in combination with ionizing radiation, gemcitabine, and mitomycin C, due in part to mitotic catastrophe. In experiments using imatinib and gemcitabine, tumor cell lines were sensitized to a greater extent than normal fibroblasts. This preservation of the therapeutic ratio was confirmed in vivo using PC3 xenograft growth delay and intestinal crypt cell clonogenic assays. HR inhibition may be an additional mechanism of action for the chemosensitization and radiosensitization of solid tumors with imatinib with preservation of the therapeutic ratio. [Mol Cancer Ther 2009;8(1):203–13]
Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung
Authors: Qian Jun , Zou Yong , Rahman Jamshedur S.M. , Lu Bo , Massion Pierre P. 
Published: January 2009

Abstract
Adenocarcinomas of the lung commonly show an increase in the activity of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, yet many are resistant to apoptosis induced by the inhibition of PI3K. We hypothesized that Bcl-xL would have a synergistic effect on the apoptotic response induced by inhibition of the PI3K/Akt pathway in lung adenocarcinoma. To test this, we examined the effect of the PI3K inhibitor (LY294002) on lung adenocarcinoma cell lines expressing varying levels of Bcl-xL. We found that cells that overexpress Bcl-xL are resistant to LY294002-induced apoptosis, whereas cells that express little Bcl-xL readily are not. Restoring Bcl-xL expression in cells that express low level of Bcl-xL conferred resistance to apoptosis in response to LY294002. The simultaneous inhibition of the PI3K/Akt pathway by LY294002 or Akt1 small interfering RNA and Bcl-xL function by ABT-737 or Bcl-xL small interfering RNA greatly enhanced the apoptotic response. Moreover, this response was associated with the induction of proapoptotic BH3-only Bcl-2 family member Bim. Our data suggest that PI3K/Akt and Bcl-xL pathways control cell death in lung adenocarcinoma cells in a synergistic manner. Modulation of Bcl-xL expression may represent one important strategy to optimize the efficacy of therapeutic agents targeting the PI3K/Akt pathway in adenocarcinoma of the lung. [Mol Cancer Ther 2009;8(1):101–9]
Ixabepilone: targeting βIII-tubulin expression in taxane-resistant malignancies
Authors: Dumontet Charles , Jordan Mary Ann , Lee Francis F.Y. 
Published: January 2009

AbstractMicrotubule-targeting agents, such as taxanes and epothilones, block mitosis and cell proliferation by targeting the dynamics of the cytoskeleton. The taxanes are widely used for treatment of various malignancies, but primary and acquired resistance to chemotherapy remains a significant clinical concern. Class I, II, III, IV, and V β-tubulin isotypes are expressed in human tumors. Overexpression of the βIII-tubulin isotype is one mechanism that can render tumor cells resistant to taxanes. The relative expression of βIII-tubulin correlates with clinical outcomes in several tumor types, including breast cancer, non–small cell lung cancer, and ovarian cancer. A novel analogue of epothilone B, ixabepilone, has recently been approved in combination with capecitabine for the treatment of patients with anthracycline- and taxane-resistant locally advanced or metastatic breast cancer and as monotherapy in patients whose tumors are resistant or refractory to an anthracycline, a taxane, and capecitabine. The significant antitumor activity of ixabepilone in taxane-resistant tumors may be related to its preferential suppression of the dynamic instability of α/βIII-microtubules in cells expressing high levels of βIII-tubulin. [Mol Cancer Ther 2009;8(1):17–25]
Maximum Covariance Analysis of Typhoon Surface Wind and Rainfall Relationships in Taiwan
Authors: Tsai Hsiao-Chung , Lee Tim Hau 
Published: January 2009

Abstract
The multivariate relationships between hourly surface wind and rainfall observations during typhoons affecting Taiwan have been investigated with maximum covariance analysis (MCA). Historical surface observations from 1987 to 2004 are used when typhoon centers were located inside the domain of 19°–28°N, 117°–127°E. The three leading MCA modes explain 70%, 20.6%, and 7.6% of the squared covariance fraction, and the correlation coefficients are 0.59, 0.48, and 0.49, respectively. The wind directions of the three leading positive modes are 1) northwesterly flow perpendicular to the Snow Mountain Range (SMR), 2) southwesterly flow toward the river valleys of the southwestern Central Mountain Range (CMR) and the southern SMR, and 3) easterly flow toward the northeastern SMR and the northern CMR. The rainfall patterns of the three principal modes reveal the contrast between the windward and the leeward sides of the mountain ranges. Based on the MCA singular vectors, historical typhoon surface wind patterns are categorized into major types. The results show that the three major wind types consist of 53% of the data, with 25%, 9%, and 19%, respectively, for these wind types. Furthermore, the analyses of the corresponding surface air temperatures, relative humidities, and air pressures also reveal contrasting patterns between the windward and leeward sides.
On Robust Estimation of Low-Frequency Variability Trends in Discrete Markovian Sequences of Atmospheric Circulation Patterns
Authors: Horenko Illia 
Published: January 2009

AbstractIdentification and analysis of temporal trends and low-frequency variability in discrete time series is an important practical topic in the understanding and prediction of many atmospheric processes, for example, in analysis of climate change. Widely used numerical techniques of trend identification (like local Gaussian kernel smoothing) impose some strong mathematical assumptions on the analyzed data and are not robust to model sensitivity. The latter issue becomes crucial when analyzing historical observation data with a short record. Two global robust numerical methods for the trend estimation in discrete nonstationary Markovian data based on different sets of implicit mathematical assumptions are introduced and compared here. The methods are first compared on a simple model example; then the importance of mathematical assumptions on the data is explained and numerical problems of local Gaussian kernel smoothing are demonstrated. Presented methods are applied to analysis of the historical sequence of atmospheric circulation patterns over the United Kingdom between 1946 and 2007. It is demonstrated that the influence of the seasonal pattern variability on transition processes is dominated by the long-term effects revealed by the introduced methods. Despite the differences in the mathematical assumptions implied by both presented methods, almost identical symmetrical changes of the cyclonic and anticyclonic pattern probabilities are identified in the analyzed data, with the confidence intervals being smaller than in the case of the local Gaussian kernel smoothing algorithm. Analysis results are investigated with respect to model sensitivity and compared to a standard analysis technique based on a local Gaussian kernel smoothing. Finally, the implications of the discussed strategies on long-range predictability of the data-fitted Markovian models are discussed.
Analyzing the Climate Sensitivity of the HadSM3 Climate Model Using Ensembles from Different but Related Experiments
Authors: Rougier Jonathan , Sexton David M. H. , Murphy James M. , Stainforth David 
Published: January 2009

AbstractGlobal climate models (GCMs) contain imprecisely defined parameters that account, approximately, for subgrid-scale physical processes. The response of a GCM to perturbations in its parameters, which is crucial for quantifying uncertainties in simulations of climate change, can—in principle—be assessed by simulating the GCM many times. In practice, however, such “perturbed physics” ensembles are small because GCMs are so expensive to simulate. Statistical tools can help in two ways. First, they can be used to combine ensembles from different but related experiments, increasing the effective number of simulations. Second, they can be used to describe the GCM’s response in ways that cannot be extracted directly from the ensemble(s). The authors combine two experiments to learn about the response of the Hadley Centre Slab Climate Model version 3 (HadSM3) climate sensitivity to 31 model parameters. A Bayesian statistical framework is used in which expert judgments are required to quantify the relationship between the two experiments; these judgments are validated by detailed diagnostics. The authors identify the entrainment rate coefficient of the convection scheme as the most important single parameter and find that this interacts strongly with three of the large-scale-cloud parameters.
Effect of Volcanic Eruptions on the Vertical Temperature Profile in Radiosonde Data and Climate Models
Authors: Free Melissa , Lanzante John 
Published: January 2009

Abstract
Both observed and modeled upper-air temperature profiles show the tropospheric cooling and tropical stratospheric warming effects from the three major volcanic eruptions since 1960. Detailed comparisons of vertical profiles of Radiosonde Atmospheric Temperature Products for Assessing Climate (RATPAC) and Hadley Centre Atmospheric Temperatures, version 2 (HadAT2), radiosonde temperatures with output from six coupled GCMs show good overall agreement on the responses to the 1991 Mount Pinatubo and 1982 El Chichón eruptions in the troposphere and stratosphere, with a tendency of the models to underestimate the upper-tropospheric cooling and overestimate the stratospheric warming relative to observations. The cooling effect at the surface in the tropics is amplified with altitude in the troposphere in both observations and models, but this amplification is greater for the observations than for the models. Models and observations show a large disagreement around 100 mb for Mount Pinatubo in the tropics, where observations show essentially no change, while models show significant warming of ∼0.7 to ∼2.6 K. This difference occurs even in models that accurately simulate stratospheric warming at 50 mb. Overall, the Parallel Climate Model is an outlier in that it simulates more volcanic-induced stratospheric warming than both the other models and the observations in most cases.
From 1979 to 1999 in the tropics, RATPAC shows a trend of less than 0.1 K decade−1 at and above 300 mb before volcanic effects are removed, while the mean of the models used here has a trend of more than 0.3 K decade−1, giving a difference of ∼0.2 K decade−1. At 300 mb, from 0.02 to 0.10 K decade−1 of this difference may be due to the influence of volcanic eruptions, with the smaller estimate appearing more likely than the larger. No more than ∼0.03 K of the ∼0.1-K difference in trends between the surface and troposphere at 700 mb or below in the radiosonde data appears to be due to volcanic effects.
Examination of Relationships between Clear-Sky Longwave Radiation and Aspects of the Atmospheric Hydrological Cycle in Climate Models, Reanalyses, and Observations
Authors: Allan Richard P. 
Published: January 2009

Abstract
Relationships between clear-sky longwave radiation and aspects of the atmospheric hydrological cycle are quantified in models, reanalyses, and observations over the period 1980–2000. The robust sensitivity of clear-sky surface net longwave radiation (SNLc) to column-integrated water vapor (CWV) of 1–1.5 W m−2 mm−1 combined with the positive relationship between CWV and surface temperature (Ts) explains substantial increases in clear-sky longwave radiative cooling of the atmosphere (QLWc) to the surface over the period. Clear-sky outgoing longwave radiation (OLRc) is highly sensitive to changes in aerosol and greenhouse gas concentrations in addition to temperature and humidity. Over tropical ocean regions of mean descent, QLWc increases with Ts at ∼3.5–5.5 W m−2 K−1 for reanalyses, estimates derived from satellite data, and models without volcanic forcing included. Increased QLWc with warming across the tropical oceans helps to explain model ensemble mean increases in precipitation of 0.1–0.15 mm day−1 K−1, which are primarily determined by ascent regions where precipitation increases at the rate expected from the Clausius–Clapeyron equation. The implications for future projections in the atmospheric hydrological cycle are discussed.