bluuebunny/crossref_metadata_2025_split huggingface dataset:
Less Yin, More Yang: Confronting the Barriers to Cancer Immunotherapy
Authors: Lizée Gregory , Cantu Mayra A. , Hwu Patrick 
Published: September 2007

AbstractClinical trials involving T cell–based immunotherapy for the treatment of human cancer have shown limited degrees of success. In cancer vaccine trials conducted at multiple centers worldwide, immunization has often resulted in the robust elicitation of T cells that specifically recognize antigens expressed on the surface of tumor cells. However, to date, objective clinical responses resulting from these approaches have remained relatively rare. By contrast, adoptive transfer of laboratory-expanded T cells into patients has had more success, producing impressive clinical regressions in a subset of advanced metastatic melanoma patients. The failure of activated T cells to consistently induce clinical responses in many other patients has pushed us toward a deeper understanding of natural immunoregulatory mechanisms that are directly responsible for diminishing tumor-specific T-cell activation, migration, and effector function in vivo. Such immunosuppressive factors likely evolved to prevent autoimmunity, but are frequently co-opted by tumors to evade tumor-specific immune responses. With this knowledge, it now becomes imperative to develop specific clinical interventions capable of eliminating tumor-specific immunosuppression, with the goal of shifting the balance to favor effector T-cell function and tumor cell killing.
The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progressionin vitroandin vivo
Authors: Martin Lesley-Ann , Head Julia E. , Pancholi Sunil , Salter Janine , Quinn Emma , Detre Simone , Kaye Stan , Howes Angela , Dowsett Mitch , Johnston Stephen R.D. 
Published: September 2007

AbstractCross-talk between receptor tyrosine kinases and estrogen receptor is at least partly responsible for the development of acquired resistance to endocrine therapies. Hence, targeting receptor tyrosine kinases and their downstream partners with inhibitors/antagonists may reverse this resistance. Although ras mutations are rare in breast cancer (2%), aberrant function of Ras signal transduction pathways is common. We therefore investigated the efficacy of the farnesyltransferase inhibitor (FTI) R115777 (tipifarnib) in combination with tamoxifen in MCF-7 human breast cancer models both in vitro and in vivo. There was a synergistic antiproliferative interaction between R115777 and 4-hydroxy-tamoxifen in vitro as calculated by median effect analysis. The combination resulted in a significantly greater G1 arrest than either drug alone and this was associated with marked inhibition of cyclin D1 and induction of the cell cycle inhibitor p27kip1. Combining R115777 with either tamoxifen or estrogen withdrawal in vivo produced a significantly greater inhibition of tumor growth and lower xenograft cell proliferation than either therapy alone. These results suggest that the combination of this FTI with endocrine therapy may be of therapeutic benefit in the treatment of breast cancer. Enhanced G1 arrest due to modulation of cell cycle regulatory proteins may be the underlying mechanism for the positive interaction between FTIs and tamoxifen. [Mol Cancer Ther 2007;6(9):2458–67]
Effect of the histone deacetylase inhibitor LBH589 against epidermal growth factor receptor–dependent human lung cancer cells
Authors: Edwards Arthur , Li Jiannong , Atadja Peter , Bhalla Kapil , Haura Eric B. 
Published: September 2007

AbstractActivating mutations in the epidermal growth factor receptor (EGFR) selectively activate signal transducers and activators of transcription (STAT) and Akt survival signaling pathways important in lung cancer cell growth and survival. Many kinases, such as EGFR, rely on heat shock protein 90 (Hsp90) chaperone function for conformational maturation and proper function. Histone deacetylase inhibitors (HDACi) have been suggested to regulate signaling protein interactions via modulation of protein chaperone function through Hsp90. For these reasons, we evaluated the effect of a HDACi in lung cancer cells with defined EGFR status. Cell lines with defined EGFR status and sensitivity to EGFR tyrosine kinase inhibitors were exposed to the HDACi LBH589, and the effects on cell survival, proliferation, and downstream signaling were evaluated. LBH589 resulted in increased acetylation of Hsp90 and reduced association of Hsp90 with EGFR, Akt, and STAT3. LBH589 selectively depleted proteins important in signaling cascades in cell lines harboring EGFR kinase mutations, such as EGFR, STAT3, and Akt, and these cells underwent apoptosis following exposure to LBH589. In addition, we found depletion of STAT3-dependent survival proteins, including Bcl-xL, Mcl-1, and Bcl-2. Conversely, LBH589 had little effect on apoptosis in cells not dependent on EGFR for survival, no changes were identified in the expression of EGFR or other survival proteins, and the predominant effect was cell cycle arrest rather than apoptosis. A 10-fold increase in LBH589 was necessary to observe durable depletion of EGFR and Akt in cells not harboring EGFR mutation. Treatment of cells with erlotinib and LBH589 resulted in synergistic effects on lung cancer cells dependent on EGFR for growth and/or survival. Based on these results, LBH589 can acetylate Hsp90, deplete EGFR and other key survival signaling proteins, and trigger apoptosis only in lung cancer cells harboring EGFR mutations. Therefore, EGFR mutation status may be predictive of outcome with LBH589 and possibly other HDACi. [Mol Cancer Ther 2007;6(9):2515–24]
Improved low molecular weight Myc-Max inhibitors
Authors: Wang Huabo , Hammoudeh Dalia I. , Follis Ariele Viacava , Reese Brian E. , Lazo John S. , Metallo Steven J. , Prochownik Edward V. 
Published: September 2007

Abstract
Compounds that selectively prevent or disrupt the association between the c-Myc oncoprotein and its obligate heterodimeric partner Max (Myc-Max compounds) have been identified previously by high-throughput screening of chemical libraries. Although these agents specifically inhibit the growth of c-Myc–expressing cells, their clinical applicability is limited by their low potency. We describe here several chemical modifications of one of these original compounds, 10058-F4, which result in significant improvements in efficacy. Compared with the parent structure, these analogues show enhanced growth inhibition of c-Myc–expressing cells in a manner that generally correlates with their ability to disrupt c-Myc-Max association and DNA binding. Furthermore, we show by use of a sensitive fluorescence polarization assay that both 10058-F4 and its active analogues bind specifically to monomeric c-Myc. These studies show that improved Myc-Max compounds can be generated by a directed approach involving deliberate modification of an index compound. They further show that the compounds specifically target c-Myc, which exists in a dynamic and relatively unstructured state with only partial and transient α-helical content. [Mol Cancer Ther 2007;6(9):2399–408]
AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma
Authors: Huynh Hung , Chow Pierce K.H. , Soo Khee-Chee 
Published: September 2007

AbstractHepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with no effective treatment for most individuals who succumb to this neoplasm. We report that treatment of primary HCC cells with the mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor AZD6244 (ARRY-142886) plus doxorubicin led to synergistic growth inhibition and apoptosis. In vivo administration of AZD6244, doxorubicin, or the combination of AZD6244 and doxorubicin in mice bearing 5-1318 HCC xenografts resulted in approximately 52% ± 15%, 12% ± 9%, and 76% ± 7% growth inhibition, respectively. AZD6244-inhibited tumor growth was associated with increased apoptosis, inactivation of ERK1/2, inhibition of cell proliferation, and down-regulation of cell cycle regulators, including cyclin D1, cdc-2, cyclin-dependent kinases 2 and 4, cyclin B1, and c-Myc. The AZD6244-doxorubicin combined protocol not only promoted apoptosis but also induced a synergistic effect not seen in single-agent–treated tumors, including increased expression of the p130 RB tumor suppressor gene. Our study provides a strong rationale for clinical investigation of combination therapy with the mitogen-activated protein/ERK kinase 1/2 inhibitor AZD6244 and doxorubicin in patients with HCC. [Mol Cancer Ther 2007;6(9):2468–76]
Selenium inhibition of survivin expression by preventing Sp1 binding to its promoter
Authors: Chun Jae Yeon , Hu Yan , Pinder Elaine , Wu Jianguo , Li Fengzhi , Gao Allen C. 
Published: September 2007

AbstractSurvivin, an antiapoptotic protein highly expressed in cancer, regulates multiple cellular network associated with cancer cell viability and drug resistance. Inhibition of survivin expression has been pursued as a valid cancer therapeutic target. In this study, we showed that selenium, an effective chemopreventive agent for many types of cancers, down-regulated survivin expression. Selenium inhibited survivin expression in both mRNA and protein levels in a dose- and time-dependent manner. Using a series of survivin promoter–luciferase constructs, a 37-bp DNA element in the survivin core promoter region that mediates the ability of selenium to inhibit survivin transcription was identified. Gel mobility shift assays and chromatin immunoprecipitation analyses revealed that selenium prevents the binding of Sp1 or Sp1-like proteins to the 37-bp cis-acting DNA element in the survivin promoter. Furthermore, inhibition of survivin expression by small interfering RNA enhanced selenium's inhibitory effects on cell growth, whereas overexpression of survivin in LNCaP human prostate cancer cells desensitized cancer cells to selenium effect, suggesting that the expression of survivin plays an important role in determining the response of cancer cells to selenium. Taken together, these results suggest that selenium down-regulated survivin expression by preventing the binding of Sp1 or Sp1-like proteins to the promoter of survivin, which contributes at least in part to the inhibitory effect of selenium on survivin gene transcription. In addition, down-regulation of survivin expression may account for one of the molecular mechanisms of the anticancer effects of selenium. [Mol Cancer Ther 2007;6(9):2572–80]
The radiosensitization effect of parthenolide in prostate cancer cells is mediated by nuclear factor-κB inhibition and enhanced by the presence of PTEN
Authors: Sun Yulan , St. Clair Daret K. , Fang Fang , Warren Graham W. , Rangnekar Vivek M. , Crooks Peter A. , St. Clair William H. 
Published: September 2007

AbstractParthenolide has been shown to have anti-inflammatory and antitumor properties. However, whether and how parthenolide enhances tumor sensitivity to radiation therapy are unknown. In this study, we show that inhibition of the nuclear factor-κB (NF-κB) pathway is a common mechanism for the radiosensitization effect of parthenolide in prostate cancer cells LNCaP, DU145, and PC3. Parthenolide inhibits radiation-induced NF-κB DNA-binding activity and the expression of its downstream target sod2, the gene coding for an important antiapoptotic and antioxidant enzyme (manganese superoxide dismutase) in the three prostate cancer cells. Different susceptibilities to parthenolide's effect are observed in two radioresistant cancer cells, DU145 and PC3, with DU145 cells showing higher sensitivity. This differential susceptibility to parthenolide is due, in part, to the fact that in addition to NF-κB inhibition, parthenolide activates the phosphatidylinositol-3-kinase/Akt prosurvival pathway in both cell lines. However, the activated Akt in DU145 cells is kept at a relatively low level compared with that in PC3 cells due to the presence of functional PTEN. Transfection of wild-type PTEN into PTEN-null cells, PC3, confers the enhanced radiosensitization effect of parthenolide in PTEN-expressing cells. When PTEN expression is knocked down in DU145 cells, the cells become more resistant to parthenolide's effect. Taken together, these results suggest that parthenolide inhibits the NF-κB pathway and activates the phosphatidylinositol-3-kinase/Akt pathway in prostate cancer cells. The radiosensitization effect of parthenolide is due, in part, to the inhibition of the NF-κB pathway. The presence of PTEN enhances the radiosensitization effect of parthenolide, in part, by suppressing the absolute amount of activated p-Akt. [Mol Cancer Ther 2007;6(9):2477–86]
Histone deacetylase inhibitors selectively suppress expression of HDAC7
Authors: Dokmanovic Milos , Perez Gisela , Xu Weisheng , Ngo Lang , Clarke Cathy , Parmigiani Raphael B. , Marks Paul A. 
Published: September 2007

Abstract
There are 18 histone deacetylases (HDAC) generally divided into four classes based on homology to yeast HDACs. HDACs have many protein substrates in addition to histones that are involved in regulation of gene expression, cell proliferation, and cell death. Inhibition of HDACs can cause accumulation of acetylated forms of these proteins, thus altering their function. HDAC inhibitors (HDACi), such as the hydroxamic acid–based vorinostat (suberoylanilide hydroxamic acid), inhibit the zinc-containing classes I, II, and IV, but not the NAD+-dependent class III, enzymes. HDACis are a group of novel anticancer agents. Vorinostat is the first HDACi approved for clinical use in the treatment of the cancer cutaneous T-cell lymphoma. Factors affecting expression of HDACs are not well understood. This study focuses on the effect of the HDACi vorinostat on the expression of class I and class II HDACs. We found that vorinostat selectively down-regulates HDAC7 with little or no effect on the expression of other class I or class II HDACs. Fourteen cell lines were examined, including normal, immortalized, genetically transformed, and human cancer-derived cell lines. Down-regulation of HDAC7 by vorinostat is more pronounced in transformed cells sensitive to inhibitor-induced cell death than in normal cells or cancer cells resistant to induced cell death. Modulation of HDAC7 levels by small interfering RNA–mediated knockdown or by HDAC7 overexpression is associated with growth arrest but without detectable changes in acetylation of histones or p21 gene expression. Selective down-regulation of HDAC7 protein may serve as a marker of response of tumors to HDACi. [Mol Cancer Ther 2007;6(9):2525–34]
Hypoxia modulation and radiosensitization by the novel dual EGFR and VEGFR inhibitor AEE788 in spontaneous and related allograft tumor models
Authors: Oehler-Jänne Christoph , Jochum Wolfram , Riesterer Oliver , Broggini-Tenzer Angela , Caravatti Giorgio , Vuong Van , Pruschy Martin 
Published: September 2007

Abstract
Concomitant inhibition of ErbB1/2- and VEGF receptor-signaling synergizes when used in combination with DNA-damaging agents. Here, we investigated for the first time the combined treatment modality of the novel dual specific receptor tyrosine kinase inhibitor AEE788 with ionizing radiation and analyzed treatment-induced end points in situ as indicators for a potential sensitizing mechanism. Furthermore, we assessed tumor hypoxia in response to different antiangiogenic and antiproliferative treatment modalities. The combined treatment effect was investigated in a spontaneously growing mammary carcinoma model and against Her-2/neu-overexpressing mammary carcinoma allografts. In tumor allografts derived from murine mammary carcinoma cells of mouse mammary tumor virus/c-neu transgenic mice, a minimal treatment regimen with AEE788 and fractionated irradiation resulted in an at least additive tumor response. Treatment response in the corresponding spontaneous tumor model strongly exceeded the response induced in the isogenic allografts. Treatment-induced changes of tumor proliferation, apoptosis, and microvessel density were similar in the two tumor models. Treatment with AEE788 alone or in combination with IR strongly improved tumor oxygenation in both tumor models as determined by the detection of endogenous and exogenous markers of tumor hypoxia. Specific inhibition of the VEGF-receptor tyrosine kinase versus Erb1/2-receptor tyrosine kinase indicated that it is the antiproliferative and not the antiangiogenic potency of AEE788 that mediates the hypoxia-reducing effect of this dual kinase-specific inhibitor. Overall, we show that concomitant inhibition of ErbB- and VEGF-receptor signaling by AEE788, in combination with ionizing radiation, is a promising treatment approach, especially in hypoxic, oncogenic ErbB-driven tumors. [Mol Cancer Ther 2007;6(9):2496–504]
Empirical Master Equations. Part II: Application to Stratospheric QBO, Solar Cycle, and Northern Annular Mode
Authors: Dall’Amico Mauro , Egger Joseph 
Published: September 2007

AbstractTime series of stratospheric climate variables are used to derive master equations in the discretized phase space spanned by three variables. The empirical master equation (EME) predicts the probability density function (PDF) in this phase space. The numerical properties of EMEs have been investigated in the first part of this paper using synthetic time series. In this part of the paper, the time series consist of normalized and deseasonalized daily and zonally averaged meteorologically relevant quantities obtained from the 40-yr ECMWF Re-Analysis (ERA-40) and observations. One EME reproduces the climatological features of the quasi-biennial oscillation (QBO) of stratospheric equatorial zonal wind including the probabilistic character of transitions between phases. Also, the Arctic stratosphere at 10 hPa is about 2 K warmer during the easterly phase of the QBO than during the westerly phase. Another EME including a time series of the solar radio flux at 10.7 cm hints that the relationship between the QBO and the temperature in the Arctic stratosphere is shifted toward warmer (colder) states by about 1 K during periods of high (low) solar activity. Finally, an EME is derived from time series of variables highly correlated with the northern annular mode (NAM). The EME shows that NAM anomalies in the middle stratosphere propagate into the lower stratosphere and then into the lower troposphere with a time scale of about two and four weeks, respectively. The influence of strong tropospheric NAM anomalies is confined to the lower stratosphere.
The Very Stable Boundary Layer on Nights with Weak Low-Level Jets
Authors: Banta Robert M. , Mahrt Larry , Vickers Dean , Sun Jielun , Balsley Ben B. , Pichugina Yelena L. , Williams Eric J. 
Published: September 2007

Abstract
The light-wind, clear-sky, very stable boundary layer (vSBL) is characterized by large values of bulk Richardson number. The light winds produce weak shear, turbulence, and mixing, and resulting strong temperature gradients near the surface. Here five nights with weak-wind, very stable boundary layers during the Cooperative Atmosphere–Surface Exchange Study (CASES-99) are investigated. Although the winds were light and variable near the surface, Doppler lidar profiles of wind speed often indicated persistent profile shapes and magnitudes for periods of an hour or more, sometimes exhibiting jetlike maxima. The near-surface structure of the boundary layer (BL) on the five nights all showed characteristics typical of the vSBL. These characteristics included a shallow traditional BL only 10–30 m deep with weak intermittent turbulence within the strong surface-based radiation inversion. Above this shallow BL sat a layer of very weak turbulence and negligible turbulent mixing. The focus of this paper is on the effects of this quiescent layer just above the shallow BL, and the impacts of this quiescent layer on turbulent transport and numerical modeling. High-frequency time series of temperature T on a 60-m tower showed that 1) the amplitudes of the T fluctuations were dramatically suppressed at levels above 30 m in contrast to the relatively larger intermittent T fluctuations in the shallow BL below, and 2) the temperature at 40- to 60-m height was nearly constant for several hours, indicating that the very cold air near the surface was not being mixed upward to those levels. The presence of this quiescent layer indicates that the atmosphere above the shallow BL was isolated and detached both from the surface and from the shallow BL.
Although some of the nights studied had modestly stronger winds and traveling disturbances (density currents, gravity waves, shear instabilities), these disturbances seemed to pass through the region without having much effect on either the SBL structure or on the atmosphere–surface decoupling. The decoupling suggests that under very stable conditions, the surface-layer lower boundary condition for numerical weather prediction models should act to decouple and isolate the surface from the atmosphere, for example, as a free-slip, thermally insulated layer.
A multiday time series of ozone from an air quality campaign in Tennessee, which exhibited nocturnal behavior typical of polluted air, showed the disappearance of ozone on weak low-level jets (LLJ) nights. This behavior is consistent with the two-stratum structure of the vSBL, and with the nearly complete isolation of the surface and the shallow BL from the rest of the atmosphere above, in contrast to cases with stronger LLJs, where such coupling was stronger.
Numerical Simulations of Forced Shallow-Water Turbulence: Effects of Moist Convection on the Large-Scale Circulation of Jupiter and Saturn
Authors: Showman Adam P. 
Published: September 2007

AbstractTo test the hypothesis that the zonal jets on Jupiter and Saturn result from energy injected by thunderstorms into the cloud layer, forced-dissipative numerical simulations of the shallow-water equations in spherical geometry are presented. The forcing consists of sporadic, isolated circular mass pulses intended to represent thunderstorms; the damping, representing radiation, removes mass evenly from the layer. These results show that the deformation radius provides strong control over the behavior. At deformation radii &lt;2000 km (0.03 Jupiter radii), the simulations produce broad jets near the equator, but regions poleward of 15°–30° latitude instead become dominated by vortices. However, simulations at deformation radii &gt;4000 km (0.06 Jupiter radii) become dominated by barotropically stable zonal jets with only weak vortices. The lack of midlatitude jets at a small deformation radii results from the suppression of the beta effect by column stretching; this effect has been previously documented in the quasigeostrophic system but never before in the full shallow-water system. In agreement with decaying shallow-water turbulence simulations, but in disagreement with Jupiter and Saturn, the equatorial flows in these forced simulations are always westward. In analogy with purely two-dimensional turbulence, the size of the coherent structures (jets and vortices) depends on the relative strengths of forcing and damping; stronger damping removes energy faster as it cascades upscale, leading to smaller vortices and more closely spaced jets in the equilibrated state. Forcing and damping parameters relevant to Jupiter produce flows with speeds up to 50–200 m s−1 and a predominance of anticyclones over cyclones, both in agreement with observations. However, the dominance of vortices over jets at deformation radii thought to be relevant to Jupiter (1000–3000 km) suggests that either the actual deformation radius is larger than previously believed or that three-dimensional effects, not included in the shallow-water equations, alter the dynamics in a fundamental manner.