bluuebunny/crossref_metadata_2025_split huggingface dataset:
Climate change: implications for engineering geology practice
Authors: Nathanail J. , Banks V. 
Published: December 2009

Abstract
The key questions addressed in this paper are: What is climate change? What are the impacts on engineering geology practice? Can engineering geologists contribute to mitigation of climate change? What research areas are engineering geologists involved with? Where should the focus for future research be? Following an overview of the papers presented for the ‘Legacy of the Past and Future Climate Change’ session of the 10th Congress of the International Association for Engineering Geology and the Environment, this paper reviews the sources of information and current models of climate change. An overview of some of the potential impacts of climate change on engineering geology practice follows. Attention has been given to areas of active research, the potential impacts on the more routine work of the engineering geologist, and the way in which the engineering geologist can contribute to climate change mitigation and adaptation. It is concluded that current planning guidance addresses climate change more fully than current engineering practice, and it is considered that there are considerable research areas open to engineering geologists with regard to potential impacts of climate change. More specifically, it has been noted that current engineering practice draws heavily on empirical approaches to design, and it is suggested that this approach should be reviewed in the context of climate change. Attention is given to a number of mitigating measures, such as ground source heat pumps, carbon sequestration, the ‘reduce, reuse and recycle’ approach to achieving sustainability and sustainable urban drainage systems (SUDSs).
Presence of high-grade rocks in NW Venezuela of possible Grenvillian affinity
Authors: Grande Sebastián , Urbani Franco 
Published: December 2009

AbstractHigh-grade metamorphic rocks – marble, charnockite, meta-anorthosite, metapelite, clinopyroxenite and garnet amphibolite – have been found in northwestern Venezuela. They occur as: (a) xenoliths in the Oligo-Miocene lavas of Cerro Atravesado, Central Falcón; (b) possibly olistoliths in Nuezalito Formation, NW Portuguesa; (c) in Cerro El Guayabo, an elongated east–west oriented hill in the Nirgua Complex, Yaracuy; (d) rounded clasts of marble in the basal conglomerate of Casupal Formation, Falcón; (e) rounded clasts of anorthosite and sillimanite gneiss in a conglomerate of Matatere Formation, Lara; and (f) basement cores extracted from La Vela Gulf, Falcón. These high-grade rocks probably suffered a retrograde metamorphism to amphibolite facies of Palaeozoic age, and an even more retrograde event to the greenschist facies during Early Cenozoic, together with strong shearing and hydrothermal alteration. They indicate the possible existence of an extensive high-grade basement, or a mosaic of such blocks, under northwestern Venezuela, especially below the Falcón petroleum basin. Similar rocks crop out extensively in northern and central Colombia, Mexico, Ecuador and Peru. This is the first time they are described from Venezuela. Their high-grade lithology, pre-Mesozoic positions, and the tectonic evolution of Northern South America allow interpretation of a possible Grenvillian affinity, related to the supercontinents of Rodinia and Pangaea.
In situorigin of the Caribbean: discussion of data
Authors: James Keith H. 
Published: December 2009

AbstractCompiled and synthesized geological data suggest that the Caribbean Plate consists of dispersed continental basement blocks, wedges of ?Triassic–Jurassic clastic rocks, Jurassic–Late Cretaceous carbonate rocks, volcanic arc rocks, widespread, probably subaerial basalts and serpentinized upper mantle. This points to anin situorigin of the Caribbean Plate as part of Middle America, continuing the geology of the eastern North America margin in a more extensional tectonic setting. Extension increases from the Gulf of Mexico through the Yucatán Basin to the Caribbean.
Elimination of Human Lung Cancer Stem Cells through Targeting of the Stem Cell Factor–c-kit Autocrine Signaling Loop
Authors: Levina Vera , Marrangoni Adele , Wang Tingting , Parikh Simul , Su Yunyun , Herberman Ronald , Lokshin Anna , Gorelik Elieser 
Published: December 2009

Abstract
Cancer stem cells (CSC) are thought to be responsible for tumor initiation and tumor regeneration after chemotherapy. Previously, we showed that chemotherapy of non–small cell lung cancer (NSCLC) cells lines can select for outgrowth of highly tumorigenic and metastatic CSCs. The high malignancy of lung CSCs was associated with an efficient cytokine network. In this study, we provide evidence that blocking stem cell factor (SCF)–c-kit signaling is sufficient to inhibit CSC proliferation and survival promoted by chemotherapy. CSCs were isolated from NSCLC cell lines as tumor spheres under CSC-selective conditions and their stem properties were confirmed. In contrast to other tumor cells, CSCs expressed c-kit receptors and produced SCF. Proliferation of CSCs was inhibited by SCF-neutralizing antibodies or by imatinib (Gleevec), an inhibitor of c-kit. Although cisplatin treatment eliminated the majority of tumor cells, it did not eliminate CSCs, whereas imatinib or anti-SCF antibody destroyed CSCs. Significantly, combining cisplatin with imatinib or anti-SCF antibody prevented the growth of both tumor cell subpopulations. Our findings reveal an important role for the SCF–c-kit signaling axis in self-renewal and proliferation of lung CSCs, and they suggest that SCF–c-kit signaling blockade could improve the antitumor efficacy of chemotherapy of human NSCLC. Cancer Res; 70(1); 338–46
AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP-Competitive Mammalian Target of Rapamycin Kinase Inhibitor with In vitro and In vivo Antitumor Activity
Authors: Chresta Christine M. , Davies Barry R. , Hickson Ian , Harding Tom , Cosulich Sabina , Critchlow Susan E. , Vincent John P. , Ellston Rebecca , Jones Darren , Sini Patrizia , James Dominic , Howard Zoe , Dudley Phillippa , Hughes Gareth , Smith Lisa , Maguire Sharon , Hummersone Marc , Malagu Karine , Menear Keith , Jenkins Richard , Jacobsen Matt , Smith Graeme C.M. , Guichard Sylvie , Pass Martin 
Published: December 2009

Abstract
The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, with an IC50 of 0.8 nmol/L. AZD8055 showed excellent selectivity (∼1,000-fold) against all class I phosphatidylinositol 3-kinase (PI3K) isoforms and other members of the PI3K-like kinase family. Furthermore, there was no significant activity against a panel of 260 kinases at concentrations up to 10 μmol/L. AZD8055 inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphorylation of the mTORC2 substrate AKT and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 were fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. In vitro, AZD8055 potently inhibits proliferation and induces autophagy in H838 and A549 cells. In vivo, AZD8055 induces a dose-dependent pharmacodynamic effect on phosphorylated S6 and phosphorylated AKT at plasma concentrations leading to tumor growth inhibition. Notably, AZD8055 results in significant growth inhibition and/or regression in xenografts, representing a broad range of human tumor types. AZD8055 is currently in phase I clinical trials. Cancer Res; 70(1); 288–98
Elevation of Receptor Tyrosine Kinase EphA2 Mediates Resistance to Trastuzumab Therapy
Authors: Zhuang Guanglei , Brantley-Sieders Dana M. , Vaught David , Yu Jian , Xie Lu , Wells Sam , Jackson Dowdy , Muraoka-Cook Rebecca , Arteaga Carlos , Chen Jin 
Published: December 2009

Abstract
One arising challenge in the treatment of breast cancer is the development of therapeutic resistance to trastuzumab, an antibody targeting the human epidermal growth factor receptor-2 (HER2), which is frequently amplified in breast cancers. In this study, we provide evidence that elevated level of the receptor tyrosine kinase Eph receptor A2 (EphA2) is an important contributor to trastuzumab resistance. In a screen of a large cohort of human breast cancers, we found that EphA2 overexpression correlated with a decrease in disease-free and overall survival of HER2-overexpressing patients. Trastuzumab-resistant cell lines overexpressed EphA2, whereas inhibiting EphA2 restored sensitivity to trastuzumab treatment in vivo. Notably, trastuzumab treatment could promote EphA2 phosphorylation by activating Src kinase, leading in turn to an amplification of phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase signaling in resistant cells. Our findings offer mechanistic insights into the basis for trastuzumab resistance and rationalize strategies to target EphA2 as a tactic to reverse trastuzumab resistance. Cancer Res; 70(1); 299–308.
Receptor Channel TRPC6 Is a Key Mediator of Notch-Driven Glioblastoma Growth and Invasiveness
Authors: Chigurupati Srinivasulu , Venkataraman Rajarajeswari , Barrera Daniel , Naganathan Anusha , Madan Meenu , Paul Leena , Pattisapu Jogi V. , Kyriazis George A. , Sugaya Kiminobu , Bushnev Sergey , Lathia Justin D. , Rich Jeremy N. , Chan Sic L. 
Published: December 2009

Abstract
Glioblastoma multiforme (GBM) is the most frequent and incurable type of brain tumor of adults. Hypoxia has been shown to direct GBM toward a more aggressive and malignant state. Here we show that hypoxia increases Notch1 activation, which in turn induces the expression of transient receptor potential 6 (TRPC6) in primary samples and cell lines derived from GBM. TRPC6 is required for the development of the aggressive phenotype because knockdown of TRPC6 expression inhibits glioma growth, invasion, and angiogenesis. Functionally, TRPC6 causes a sustained elevation of intracellular calcium that is coupled to the activation of the calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Pharmacologic inhibition of the calcineurin-NFAT pathway substantially reduces the development of the malignant GBM phenotypes under hypoxia. Clinically, expression of TRPC6 was elevated in GBM specimens in comparison with normal tissues. Collectively, our studies indicate that TRPC6 is a key mediator of tumor growth of GBM in vitro and in vivo and that TRPC6 may be a promising therapeutic target in the treatment of human GBM. Cancer Res; 70(1); 418–27
VentX, a Novel Lymphoid-Enhancing Factor/T-Cell Factor–Associated Transcription Repressor, Is a Putative Tumor Suppressor
Authors: Gao Hong , Le Yi , Wu Xiaoming , Silberstein Leslie E. , Giese Roger W. , Zhu Zhenglun 
Published: December 2009

Abstract
Lymphoid-enhancing factor/T-cell factors (LEF1/TCF) are a high-mobility group of transcriptional factors that play essential roles in cell fate determination during early embryogenesis and ontogenesis. Aberrant activations of LEF1/TCF-mediated transcription have been implicated in a variety of malignancies. Our recent studies on vertebrate embryogenesis identified Xom, a homeobox protein of the bone morphogenetic protein 4 pathway, as a novel LEF/TCF-associated transcriptional modulator. Here, we report that VentX, a human Xom homologue, is a LEF/TCF-associated inhibitor of canonical Wnt/β-catenin signaling and a negative regulator of cell proliferation. VentX is predominately expressed in hematopoietic cells, and its expression is significantly downregulated in chronic lymphocytic leukemia. Altered expression of VentX is associated with corresponding changes of LEF/TCF target oncogenes such as cyclin D1, suggesting a potential role of VentX in the clinical behavior of hematopoietic malignancies. Cancer Res; 70(1); 202–11
Alternative Splicing of the Cyclin D1 Proto-Oncogene Is Regulated by the RNA-Binding Protein Sam68
Authors: Paronetto Maria Paola , Cappellari Manuela , Busà Roberta , Pedrotti Simona , Vitali Roberta , Comstock Clay , Hyslop Terry , Knudsen Karen E. , Sette Claudio 
Published: December 2009

Abstract
Human cyclin D1 is expressed as two isoforms derived by alternate RNA splicing, termed D1a and D1b, which differ for the inclusion of intron 4 in the D1b mRNA. Both isoforms are frequently upregulated in human cancers, but cyclin D1b displays relatively higher oncogenic potential. The splicing factors that regulate alternative splicing of cyclin D1b remain unknown despite the likelihood that they contribute to cyclin D1 oncogenicity. In this study, we report that Sam68, an RNA-binding protein frequently overexpressed in prostate cancer cells, enhances splicing of cyclin D1b and supports its expression in prostate cancer cells. Chromatin immunoprecipitation and RNA coimmunoprecipitation experiments showed that Sam68 is recruited to the human CCND1 gene encoding cyclin D1 and that it binds to cyclin D1 mRNA. Transient overexpression and RNAi knockdown experiments indicated that Sam68 acts to enhance endogenous expression of cyclin D1b. Minigene reporter assays showed that Sam68 directly affected alternative splicing of CCND1 message, with a preference for the A870 allele that is known to favor cyclin D1b splicing. Sam68 interacted with the proximal region of intron 4, and its binding correlated inversely with recruitment of the spliceosomal component U1-70K. Sam68-mediated splicing was modulated by signal transduction pathways that elicit phosphorylation of Sam68 and regulate its affinity for CCND1 intron 4. Notably, Sam68 expression positively correlates with levels of cyclin D1b, but not D1a, in human prostate carcinomas. Our results identify Sam68 as the first splicing factor to affect CCND1 alternative splicing in prostate cancer cells, and suggest that increased levels of Sam68 may stimulate cyclin D1b expression in human prostate cancers. Cancer Res; 70(1); 229–39
Genetically Engineered Salmonella typhimurium as an Imageable Therapeutic Probe for Cancer
Authors: Nguyen Vu H. , Kim Hyung-Seok , Ha Jung-Min , Hong Yeongjin , Choy Hyon E. , Min Jung-Joon 
Published: December 2009

Abstract
Tumor-targeting bacteria have been studied in terms of their ability to visualize the infection pathway (through imaging probes) or to carry therapeutic molecules to tumors. To integrate these monitoring and therapeutic functions, we engineered attenuated Salmonella typhimurium defective in guanosine 5′-diphosphate-3′-diphosphate synthesis to carry cytotoxic proteins (cytolysin A) and express reporter genes. We successfully visualized the therapeutic process with these engineered bacteria in mice and found that they often mediated complete tumor (CT-26) eradication on cytotoxic gene induction. Furthermore, treatment with the engineered bacteria markedly suppressed metastatic tumor growth. Cancer Res; 70(1); 18–23
Inhibitor of Differentiation 1 Contributes to Head and Neck Squamous Cell Carcinoma Survival via the NF-κB/Survivin and Phosphoinositide 3-Kinase/Akt Signaling Pathways
Authors: Lin Jizhen , Guan Zhong , Wang Chuan , Feng Ling , Zheng Yiqing , Caicedo Emiro , Bearth Ellalane , Peng Jie-Ren , Gaffney Patrick , Ondrey Frank G. 
Published: December 2009

AbstractPurpose: A key issue in cancer is apoptosis resistance. However, little is known about the transcription factors that contribute to cellular survival of head and neck squamous cell carcinoma (HNSCC).Experimental Design: Three batches (54, 64, and 38) of HNSCC specimens were used for cellular and molecular analyses to determine the major molecular signaling pathways for cellular survival in HNSCC. Animal models (cell culture and xenografts) were used to verify the importance of apoptosis resistance in HNSCC.Results: Inhibitor of differentiation (Id) family member, Id1, was significantly upregulated in clinical HNSCC specimens and acted to protect keratinocytes from apoptosis. Transfection of HNSCC cells with Id1 in vitro induced the phosphorylation of Akt (p-Akt) via phosphoinositide 3-kinase and increased the expression of survivin via NF-κB. Blockage of both pathways by specific inhibitors (LY294002 and IκBαM, respectively) abrogated Id1-induced cell survival of keratinocytes. In vivo studies showed that increased expression of Id1 allowed nontumorigenic keratinocytes (Rhek-1A) to become tumorigenic in nude mice by increased expression of survival genes such as p-Akt and survivin. More importantly, short interfering RNA for Id1 significantly reduced HNSCC tumor volume of HNSCC in xenograft studies. Analysis of clinical data verified the importance of the Id1 downstream molecule, survivin, in the prognosis of HNSCC patients.Conclusions: The above data, taken together, suggest that Id1 and its downstream effectors are potential targets for treatment of HNSCC because of their contribution to apoptosis resistance. Clin Cancer Res; 16(1); 77–87
The Role of the Akt/mTOR Pathway in Tobacco Carcinogen–Induced Lung Tumorigenesis
Authors: Memmott Regan M. , Dennis Phillip A. 
Published: December 2009

AbstractLung cancer is the leading cause of cancer-related death in the United States, and 85 to 90% of lung cancer cases are associated with tobacco use. Tobacco components promote lung tumorigenesis through genotoxic effects, as well as through biochemical modulation of signaling pathways such as the Akt/mammalian target of rapamycin (mTOR) pathway that regulates cell proliferation and survival. This review will describe cell surface receptors and other upstream components required for tobacco carcinogen–induced activation of Akt and mTOR. Preclinical studies show that inhibitors of the Akt/mTOR pathway inhibit tumor formation in mouse models of carcinogen-induced lung tumorigenesis. Some of these inhibitors will be highlighted, and their clinical potential for the treatment and prevention of lung cancer will be discussed. Clin Cancer Res; 16(1); 4–10
Chromosome 8p Deletions and 8q Gains are Associated with Tumor Progression and Poor Prognosis in Prostate Cancer
Authors: El Gammal Alexander T. , Brüchmann Michael , Zustin Jozef , Isbarn Hendrik , Hellwinkel Olaf J.C. , Köllermann Jens , Sauter Guido , Simon Ronald , Wilczak Waldemar , Schwarz Jörg , Bokemeyer Carsten , Brümmendorf Tim H. , Izbicki Jakob R. , Yekebas Emre , Fisch Margit , Huland Hartwig , Graefen Markus , Schlomm Thorsten 
Published: December 2009

Abstract
Purpose: Deletions of 8p and gains of 8q belong to the most frequent cytogenetic alterations in prostate cancer. The target genes of these alterations and their biological significance are unknown.
Experimental Design: To determine the relationship between chromosome 8 changes, and prostate cancer phenotype and prognosis, a set of 1.954 fully annotated prostate cancers were analyzed in a tissue microarray format by fluorescence in situ hybridization.
Results: Both 8p deletions and 8q gains increased in number during different stages of prostate cancer progression. 8p deletions/8q gains were found in 26.1%/4.8% of 1,239 pT2 cancers, 38.5%/9.8% of 379 pT3a cancers, 43.5%/8.9% of 237 pT3b cancers, 40.7%/14.8% of 27 pT4 cancers, 39.1%/34.8% of 23 nodal metastases, 51.9%/33.3% of 27 bone metastases, and 45.5%/59.9% of 22 hormone refractory cancers (P &lt; 0.0001 each). Both 8p deletions and 8q gains were also significantly associated with high Gleason grade and with each other (P &lt; 0.0001 each). In primary tumors, 8p deletions were seen in only 27.3% of 1,882 cancers without 8q gain but in 57.4% of 122 tumors with 8q gain (P &lt; 0.0001). Among cancers treated with radical prostatectomy, 8p deletions (P = 0.003) and 8q gains (P = 0.02) were associated with biochemical tumor recurrence. However, multivariate analysis (including prostate-specific antigen, pT/pN stage, Gleason score, and surgical margin status) did not reveal any statistically independent effect of 8p or 8q alterations on biochemical tumor recurrence.
Conclusions: 8p deletions and 8q gains are relatively rare in early stage prostate cancer but often develop during tumor progression. The prognostic effect does not seem to be strong enough to warrant clinical application. Clin Cancer Res; 16(1); 56–64
Single Nucleotide Polymorphisms of Gemcitabine Metabolic Genes and Pancreatic Cancer Survival and Drug Toxicity
Authors: Okazaki Taro , Javle Milind , Tanaka Motofumi , Abbruzzese James L. , Li Donghui 
Published: December 2009

Abstract
Purpose: To show whether single nucleotide polymorphisms (SNP) of drug metabolic genes were associated with toxicity of 2′,2′-difluoro 2′-deoxycytidine (gemcitabine)–based chemoradiotherapy and overall survival (OS) of patients with pancreatic cancer.
Experimental Design: We evaluated 17 SNPs of the CDA, dCK, DCTD, RRM1, hCNT1, hCNT2, hCNT3, and hENT1 genes in 154 patients with potentially resectable pancreatic adenocarcinoma who were enrolled in clinical trials at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from February 1999 to January 2006, with follow-up until April 2009. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. The association of genotypes with toxicity or OS was tested, respectively, by logistic regression and Cox regression analysis.
Results: None of the 17 SNPs, individually, had a significant association with OS. A combined genotype effect of CDA A-76C, dCK C-1205T, DCTD T-47C, hCNT3 C-69T, hENT1 T-549C, and hENT1 C913T on OS was observed. Patients carrying 0 to 1 (n = 43), 2 to 3 (n = 77), or 4 to 6 (n = 30) variant alleles had median survival time of 31.5, 21.4, and 17.5 months, respectively. The hazard ratio of dying was 1.71 (95% confidence interval, 1.06-2.76) and 3.16 (95% confidence interval, 1.77-5.63) for patients carrying two to three or four to six at-risk genotypes (P = 0.028 and P &lt; 0.001), respectively, after adjusting for clinical predictors. CDA C111T, dCK C-1205T, dCK A9846G, and hCNT3 A25G, individually and jointly, had a significant association with neutropenia toxicity.
Conclusions: These observations suggest that polymorphic variations of drug metabolic genes were associated with toxicity of gemcitabine-based therapy and OS of patients with resectable pancreatic cancer. Clin Cancer Res; 16(1); 320–29