bluuebunny/crossref_metadata_2025_split huggingface dataset:
Silencing of Elongation Factor-2 Kinase Potentiates the Effect of 2-Deoxy-d-Glucose against Human Glioma Cells through Blunting of Autophagy
Authors: Wu Hao , Zhu Hua , Liu David X. , Niu Ting-Kuang , Ren Xingcong , Patel Rajesh , Hait William N. , Yang Jin-Ming 
Published: February 2009

Abstract
2-Deoxy-d-glucose (2-DG), a synthetic glucose analogue that acts as a glycolytic inhibitor, is currently being evaluated in the clinic as an anticancer agent. In this study, we observed that treatment of human glioma cells with 2-DG activated autophagy, a highly conserved cellular response to metabolic stress and a catabolic process of self-digestion of intracellular organelles for energy use and survival in stressed cells. The induction of autophagy by 2-DG was associated with activation of elongation factor-2 kinase (eEF-2 kinase), a structurally and functionally unique enzyme that phosphorylates eEF-2, leading to loss of affinity of this elongation factor for the ribosome and to termination of protein elongation. We also showed that inhibition of eEF-2 kinase by RNA interference blunted the 2-DG–induced autophagic response, resulted in a greater reduction of cellular ATP contents, and increased the sensitivity of tumor cells to the cytotoxic effect of 2-DG. Furthermore, the blunted autophagy and enhanced 2-DG cytotoxicity were accompanied by augmentation of apoptosis in cells in which eEF-2 kinase expression was knocked down. The results of this study indicate that the energy stress and cytotoxicity caused by 2-DG can be accelerated by inhibition of eEF-2 kinase, and suggest that targeting eEF-2 kinase–regulated autophagic survival pathway may represent a novel approach to sensitizing cancer cells to glycolytic inhibitors. [Cancer Res 2009;69(6):2453–60]
TORC-Specific Phosphorylation of Mammalian Target of Rapamycin (mTOR): Phospho-Ser2481 Is a Marker for Intact mTOR Signaling Complex 2
Authors: Copp Jeremy , Manning Gerard , Hunter Tony 
Published: February 2009

Abstract
The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic component of two evolutionarily conserved signaling complexes. mTOR signaling complex 1 (mTORC1) is a key regulator of growth factor and nutrient signaling. S6 kinase is the best-characterized downstream effector of mTORC1. mTOR signaling complex 2 (mTORC2) has a role in regulating the actin cytoskeleton and activating Akt through S473 phosphorylation. Herein, we show that mTOR is phosphorylated differentially when associated with mTORC1 and mTORC2 and that intact complexes are required for these mTORC-specific mTOR phosphorylations. Specifically, we find that mTORC1 contains mTOR phosphorylated predominantly on S2448, whereas mTORC2 contains mTOR phosphorylated predominantly on S2481. Using S2481 phosphorylation as a marker for mTORC2 sensitivity to rapamycin, we find that mTORC2 formation is in fact rapamycin sensitive in several cancer cell lines in which it had been previously reported that mTORC2 assembly and function were rapamycin insensitive. Thus, phospho-S2481 on mTOR serves as a biomarker for intact mTORC2 and its sensitivity to rapamycin. [Cancer Res 2009;69(5):1821–7]
The Critical Role of the Class III Histone Deacetylase SIRT1 in Cancer
Authors: Liu Tao , Liu Pei Y. , Marshall Glenn M. 
Published: February 2009

Abstract
Gene expression and deacetylase activity of the class III histone deacetylase SIRT1 are up-regulated in cancer cells due to oncogene overexpression or loss of function of tumor suppressor genes. SIRT1 induces histone deacetylation and methylation, promoter CpG island methylation, transcriptional repression, and deacetylation of tumor suppressor proteins. SIRT1 may play a critical role in tumor initiation, progression, and drug resistance by blocking senescence and apoptosis, and promoting cell growth and angiogenesis. SIRT1 inhibitors have shown promising anticancer effects in animal models of cancer. Further screening for more potent SIRT1 inhibitors may lead to compounds suitable for clinical trials in patients. [Cancer Res 2009;69(5):1702–5]
RGS17, an Overexpressed Gene in Human Lung and Prostate Cancer, Induces Tumor Cell Proliferation Through the Cyclic AMP-PKA-CREB Pathway
Authors: James Michael A. , Lu Yan , Liu Yan , Vikis Haris G. , You Ming 
Published: February 2009

Abstract
We have identified RGS17 as a commonly induced gene in lung and prostate tumors. Through microarray and gene expression analysis, we show that expression of RGS17 is up-regulated in 80% of lung tumors, and also up-regulated in prostate tumors. Through knockdown and overexpression of RGS17 in tumor cells, we show that RGS17 confers a proliferative phenotype and is required for the maintenance of the proliferative potential of tumor cells. We show through exon microarray, transcript analysis, and functional assays that RGS17 promotes cyclic AMP (cAMP)-responsive element binding protein (CREB)-responsive gene expression, increases cAMP levels, and enhances forskolin-mediated cAMP production. Furthermore, inhibition of cAMP-dependent kinase prevents tumor cell proliferation, and proliferation is partially rescued by RGS17 overexpression. In the present study, we show a role for RGS17 in the maintenance of tumor cell proliferation through induction of cAMP signaling and CREB phosphorylation. The prevalence of the induction of RGS17 in tumor tissues of various types further implicates its importance in the maintenance of tumor growth. [Cancer Res 2009;69(5):2108–16]
The Tamoxifen Metabolite, Endoxifen, Is a Potent Antiestrogen that Targets Estrogen Receptor α for Degradation in Breast Cancer Cells
Authors: Wu Xianglin , Hawse John R. , Subramaniam Malayannan , Goetz Matthew P. , Ingle James N. , Spelsberg Thomas C. 
Published: February 2009

Abstract
Tamoxifen has been the most important therapeutic agent for the treatment of estrogen receptor (ER)-positive breast cancer for the past three decades. Tamoxifen is extensively metabolized by cytochrome P450 enzymes, and recent in vivo studies have shown that women with genetically impaired cytochrome P450 2D6 have reduced production of endoxifen and a higher risk of breast cancer recurrence. Despite these observations, the contribution of endoxifen to the overall drug effectiveness of tamoxifen remains uncertain. Here, we provide novel evidence that endoxifen is a potent antiestrogen that functions in part by targeting ERα for degradation by the proteasome in breast cancer cells. Additionally, we show that endoxifen blocks ERα transcriptional activity and inhibits estrogen-induced breast cancer cell proliferation even in the presence of tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxytamoxifen. All of the effects of endoxifen are concentration dependent and do not occur at concentrations observed in human CYP2D6 poor metabolizers. These results support the theory that endoxifen is the primary metabolite responsible for the overall effectiveness of tamoxifen in the treatment of ER-positive breast cancer. [Cancer Res 2009;69(5):1722–7]
The Interleukin-11 Receptor α as a Candidate Ligand-Directed Target in Osteosarcoma: Consistent Data from Cell Lines, Orthotopic Models, and Human Tumor Samples
Authors: Lewis Valerae O. , Ozawa Michael G. , Deavers Michael T. , Wang Guiying , Shintani Tomo , Arap Wadih , Pasqualini Renata 
Published: February 2009

Abstract
The interleukin-11 receptor α (IL-11Rα) is a functional target in bone metastasis. However, its role in primary bone tumors has not been established. As such, here, we evaluated IL-11Rα as a candidate target in primary and metastatic human osteosarcoma. First, in an orthotopic mouse model, we showed that IL-11Rα protein is markedly expressed in primary osseus and pulmonary metastatic osteosarcoma but absent from control normal tibia and lung. Moreover, systemic administration of an IL-11Rα–targeting phage displaying the cyclic nonapeptide CGRRAGGSC resulted in strong and selective accumulation of IL-11Rα–homing phage particles in the osteosarcoma but not in several control organs. Finally, IL-11Rα expression in a large panel of human primary and metastatic osteosarcoma samples was remarkably consistent with the observations in the orthotopic mouse model. These data establish IL-11Rα as a candidate target in human osteosarcoma and provide leads for the development of novel imaging and therapeutic agents for the management of this malignant tumor. [Cancer Res 2009;69(5):1995–9]
Expression of ABCC-Type Nucleotide Exporters in Blasts of Adult Acute Myeloid Leukemia: Relation to Long-term Survival
Authors: Guo Yanping , Köck Kathleen , Ritter Christoph A. , Chen Zhe-Sheng , Grube Markus , Jedlitschky Gabriele , Illmer Thomas , Ayres Mary , Beck James F. , Siegmund Werner , Ehninger Gerhard , Gandhi Varsha , Kroemer Heyo K. , Kruh Gary D. , Schaich Markus 
Published: February 2009

AbstractPurpose: Successful treatment of acute myeloid leukemia (AML) remains a therapeutic challenge, with a high percentage of patients suffering from persistent or relapsed disease. Resistance to drug therapy can develop from increased drug export and/or altered intracellular signaling. Both mechanisms are mediated by the efflux transporters ABCC4 (MRP4), ABCC5 (MRP5), and ABCC11 (MRP8), which are involved in cellular efflux of endogenous signaling molecules (e.g., cyclic adenosine 3′, 5′-monophosphate and cyclic guanosine 3′,5′-monophosphate) and nucleoside analogues. The nucleoside analogue cytosine arabinoside (AraC) is administered to all patients with AML.Experimental Design: Expression of ABCC transporters MRP4, MRP5, and MRP8 in blast samples from 50 AML patients was investigated by real-time reverse transcription-PCR analysis and correlated with clinical outcome measures. Accumulation of radiolabeled AraC, transport of AraC metabolites, and AraC cytotoxicity were analyzed in MRP8-transfected LLC-PK1 cells.Results: Regression analysis revealed that high expression of MRP8 is associated with a low probability of overall survival assessed over 4 years (P &lt; 0.03). MRP8-transfected LLC-PK1 cells accumulated reduced intracellular levels of AraC (63% of the parental vector-transfected LLC-PK1 control cells) as well as AraC metabolites. Furthermore, AraC monophosphate was transported by MRP8-enriched membrane vesicles (116 ± 6 versus 65 ± 13 pmol/mg/10 minutes by control vesicles), and MRP8-transfected cells were resistant to AraC.Conclusion: These data suggest that MRP8 is differentially expressed in AML blasts, that expression of MRP8 serves as a predictive marker for treatment outcome in AML, and that efflux of AraC metabolites by MRP8 is a mechanism that contributes to resistance of AML blasts.
Neuropilins in Tumor Biology
Authors: Bagri Anil , Tessier-Lavigne Marc , Watts Ryan J. 
Published: February 2009

Abstract
The neuropilin receptors were first discovered as regulators of nervous system development, acting as semaphorin coreceptors with plexins. Subsequently, the neuropilins were identified as receptors for vascular endothelial growth factor. Since those seminal discoveries, additional ligands that bind neuropilins have been described, and many studies have implicated neuropilins in playing key roles in tumor biology. Recent evidence has shown that manipulating neuropilin function can regulate tumor growth and metastasis through effects on vascular biology in the case of neuropilin-1 and lymphatic biology in the case of neuropilin-2. A direct role for neuropilins within in tumor cells has also been postulated. As data continue to accumulate pointing to a role for neuropilins in cancer, the promise for targeting this pathway is beginning to unfold.
Triptolide Inhibits Bcr-Abl Transcription and Induces Apoptosis in STI571-resistant Chronic Myelogenous Leukemia Cells Harboring T315I Mutation
Authors: Shi Xianping , Jin Yanli , Cheng Chao , Zhang Hui , Zou Waiyi , Zheng Qin , Lu Zhongzheng , Chen Qi , Lai Yingrong , Pan Jingxuan 
Published: February 2009

Abstract
Purpose: Resistance to STI571 is an emerging problem for patients with chronic myelogenous leukemia (CML). Mutation in the kinase domain of Bcr-Abl is the predominant mechanism of the acquired resistance to STI571. In the present study, we investigated the effect of triptolide on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl.
Experimental Design: CML cell lines (KBM5 versus KBM5-T315I, BaF3-Bcr-Abl versus BaF3-Bcr-Abl-T315I) and primary cells from CML patients with clinical resistance to STI571 were treated with triptolide, and analyzed in terms of growth, apoptosis, and signal transduction. Nude mouse xenograft model was also used to evaluate the antitumor activity.
Results: Triptolide potently down-regulated the mRNA and protein levels of Bcr-Abl independently of the caspase or proteosome activation in CML cells. It induced mitochondrial-dependent apoptosis in Bcr-Abl-T315I CML cells and primary cells from CML patients with clinical resistance to STI571. Additionally, triptolide inhibited the growth of STI571-sensitive KBM5 and STI571-resistant KBM5-T315I CML cells in nude mouse xenografts. Triptolide also down-regulated the expression of survivin, Mcl-1, and Akt in CML cells, which suggests that it may have multiple targets.
Conclusions: These findings suggest that triptolide is a promising agent to overcome STI571-resistant CML cells, and warrant a clinical trial of triptolide derivatives for CML with Bcr-Abl-T315I mutation.
Bcl-2 Blocks Cisplatin-Induced Apoptosis and Predicts Poor Outcome Following Chemoradiation Treatment in Advanced Oropharyngeal Squamous Cell Carcinoma
Authors: Michaud William A. , Nichols Anthony C. , Mroz Edmund A. , Faquin William C. , Clark John R. , Begum Shahnaz , Westra William H. , Wada Hiroshi , Busse Paul M. , Ellisen Leif W. , Rocco James W. 
Published: February 2009

Abstract
Purpose: This study aimed to test the hypothesis that elevated expression of antiapoptotic Bcl-2 family proteins predicts a poor therapeutic response of oropharyngeal squamous cell carcinoma (OPSCC) to concurrent platinum-based chemoradiation therapy.
Experimental Design: Levels of Bcl-2, Bcl-XL, and Bcl-w were determined and correlated with resistance to cisplatin in a large panel of cell lines derived from squamous cell carcinoma of the head and neck (HNSCC). Univariate and multivariate analyses were used to evaluate the relationship between Bcl-2 and Bcl-XL expression and disease-free survival following chemoradiation therapy in a uniformly treated cohort of patients with OPSCC.
Results: In HNSCC cell lines, high endogenous Bcl-2 expression was associated with increased cisplatin resistance, and experimental overexpression of Bcl-2 promoted cisplatin resistance. In patients, tumors positive for Bcl-2 before treatment had greater risk of treatment failure (hazard ratio, 5.99; 95% confidence interval, 1.73–20.8; P = 0.0014). In contrast, endogenous Bcl-XL showed no correlation either with cisplatin sensitivity in the cell line panel in vitro, or with risk of recurrence in vivo (hazard ratio, 1.28; 95% confidence interval, 0.39–4.19; P = 0.68). Associations between Bcl-2 expression and other clinical characteristics did not account for the predictive value of Bcl-2.
Conclusions: Immunohistochemical assessment of Bcl-2 in pretreatment biopsy specimens can predict response of advanced OPSCC to concurrent platinum-based chemoradiation. As treatments targeting Bcl-2 and its family members become available, this immunohistochemical assessment could help personalize therapy by identifying a subpopulation of patients with a poor prognosis who might benefit from such treatments.
Regulation of leukemic cell differentiation and retinoid-induced gene expression by statins
Authors: Sassano Antonella , Lo Iacono Marco , Antico Giovanni , Jordan Alison , Uddin Shahab , Calogero Raffaele A. , Platanias Leonidas C. 
Published: February 2009

AbstractThere is emerging evidence that, beyond their cholesterol-lowering properties, statins exhibit important antileukemic effects in vitro and in vivo, but the precise mechanisms by which they generate such responses remain to be determined. We have previously shown that statins promote differentiation of acute promyelocytic leukemia cells and enhance generation of all-trans retinoic acid (ATRA)–dependent antileukemic responses. We now provide evidence that statin-dependent leukemic cell differentiation requires engagement and activation of the c-Jun NH2-terminal kinase kinase pathway. In addition, in experiments, to define the molecular targets and mediators of statin-induced differentiation, we found a remarkable effect of statins on ATRA-dependent gene transcription, evidenced by the selective induction of over 400 genes by the combination of atorvastatin and ATRA. Altogether, our studies identify novel statin molecular targets linked to differentiation, establish that statins modulate ATRA-dependent transcription, and suggest that combined use of statins with retinoids may provide a novel approach to enhance antileukemic responses in acute promyelocytic leukemia and possibly other leukemias. [Mol Cancer Ther 2009;8(3):615–25]
Large-Scale Production and Characterization of Novel CD4+ Cytotoxic T Cells with Broad Tumor Specificity for Immunotherapy
Authors: Jursik Claudia , Prchal Michaela , Grillari-Voglauer Regina , Drbal Karel , Fuertbauer Elke , Jungfer Herbert , Albert Winfried H. , Steinhuber Eva , Hemetsberger Thomas , Grillari Johannes , Stockinger Hannes , Katinger Hermann 
Published: February 2009

AbstractImmune-cell–based approaches using cytotoxic and dendritic cells are under constant scrutiny to design novel therapies for the treatment of tumors. These strategies are hampered by the lack of efficient and economical large-scale production methods for effector cells. Here we describe the propagation of large amounts of a unique population of CD4+ cytotoxic T cells, which we termed tumor killer T cells (TKTC), because of their potent and broad antitumor cell activity. With this cultivation strategy, TKTCs from peripheral blood mononuclear cells are generated within a short period of time using a pulse with a stimulating cell line followed by continuous growth in serum-free medium supplemented with a mixture of interleukin-2 and cyclosporin A. Expression and functional profiling did not allow a classification of TKTCs to any thus far defined subtype of T cells. Cytotoxic assays showed that TKTCs kill a panel of tumor targets of diverse tissue origin while leaving normal cells unaffected. Blocking experiments revealed that TKTC killing was, to a significant extent, mediated by tumor necrosis factor-related apoptosis-inducing ligand and was independent of MHC restriction. These results suggest that TKTCs have a high potential as a novel tool in the adoptive immunotherapy of cancer. (Mol Cancer Res 2009;7(3):339–53)
Effects of Pressure on Collision, Coalescence, and Breakup of Raindrops. Part I: Experiments at 50 kPa
Authors: List Roland , Fung C. , Nissen R. 
Published: February 2009

Abstract
Previous breakup experiments have been carried out at laboratory pressures (∼100 kPa). However, raindrop interactions mainly take place higher up in the atmosphere, even in the supercooled part of a cloud where drops can be initiated by shedding from hailstones. Thus, 50 kPa, corresponding to a height of ∼5.5 km in the atmosphere at a temperature of ∼−20°C, was selected to bracket the region of interest for rain. Six drop pairs were studied at 50 kPa and laboratory temperature (∼20°C), one of them with reduced surface tension.
The apparatus consists of drop-producing nozzles, acceleration systems, deflectors, a timing and selection control, a pressure regulator, and a photographic unit, mostly set up in a low-pressure chamber. After acceleration to terminal speed, a smaller drop is blown into the path of the larger one while an electronic timing system selects suitable drop pairs that may collide, thereby triggering eight subsequent flashes with a frequency of up to 100 kHz. The results are displayed in terms of a normalized fragment probability per size bin, ready for parameterization in the Part II of this paper.
Five drop pairs were studied in 772 individual events. Overall, 51% resulted in filament breakup, 22% in sheet breakup, 7% in disk breakup, and 20% ended in coalescence. No bag breakups were observed. When compared to the 100-kPa results, the fragment numbers increased at large collision kinetic energies (CKEs) by factors of between 2.64 and 4.37 with pressure decreasing from 100 to 50 kPa, and they remained unchanged at low CKE. Detailed diagrams and tables show the results for the different drop pairs and collision categories. Increasing the sensitivity of the optical measurements from 0.05 to 0.01 cm increased the number of recognized fragments by factors up to 4.4, but only for the two higher-CKE cases. The higher resolution did not increase the fragment numbers detected in the lower-CKE range.
Characteristics of the Raindrop Size Distribution and Drop Shape Relation in Typhoon Systems in the Western Pacific from the 2D Video Disdrometer and NCU C-Band Polarimetric Radar
Authors: Chang Wei-Yu , Wang Tai-Chi Chen , Lin Pay-Liam 
Published: February 2009

Abstract
The drop size distribution (DSD) and drop shape relation (DSR) characteristics that were observed by a ground-based 2D video disdrometer and retrieved from a C-band polarimetric radar in the typhoon systems during landfall in the western Pacific, near northern Taiwan, were analyzed. The evolution of the DSD and its relation with the vertical development of the reflectivity of two rainband cases are fully illustrated. Three different types of precipitation systems were classified—weak stratiform, stratiform, and convective—according to characteristics of the mass-weighted diameter Dm, the maximum diameter, and the vertical structure of reflectivity. Further study of the relationship between the height H of the 15-dBZ contour of the vertical reflectivity profile, surface reflectivity Z, and the mass-weighted diameter Dm showed that Dm increased with a corresponding increase in the system depth H and reflectivity Z.
An analysis of DSDs retrieved from the National Central University (NCU) C-band polarimetric radar and disdrometer in typhoon cases indicates that the DSDs from the typhoon systems on the ocean were mainly a maritime convective type. However, the DSDs collected over land tended to uniquely locate in between the continental and maritime clusters. The average mass-weighted diameter Dm was about 2 mm and the average logarithmic normalized intercept Nw was about 3.8 log10 mm−1 m−3 in typhoon cases. The unique terrain-influenced deep convective systems embedded in typhoons in northern Taiwan might be the reason for these characteristics.
The “effective DSR” of typhoon systems had an axis ratio similar to that found by E. A. Brandes et al. when the raindrops were less than 1.5 mm. Nevertheless, the axis ratio tended to be more spherical with drops greater than 1.5 mm and under higher horizontal winds (maximum wind speed less than 8 m s−1). A fourth-order fitting DSR was derived for typhoon systems and the value was also very close to the estimated DSR from the polarimetric measurements in Typhoon Saomai (2006).