bluuebunny/crossref_metadata_2025 huggingface dataset:
Proliferation of Immature Tumor Vessels Is a Novel Marker of Clinical Progression in Prostate Cancer
Authors: Gravdal Karsten , Halvorsen Ole J. , Haukaas Svein A. , Akslen Lars A.
Published: June 2009

Nestin (neuroepithelial stem cell protein) is expressed in immature endothelial cells, and we here introduce coexpression of Nestin and Ki-67 as a novel angiogenesis marker on tissue sections. Including vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor-1α (HIF-1α) expression, we studied relation to disease progression in prostate cancer. Different patient series were included. Sections from 104 radical prostatectomies with long follow-up, 33 castration-resistant prostate cancers, 28 nonskeletal metastases, 13 skeletal metastases, and 41 benign prostatic hyperplasias were immunostained for Nestin/Ki-67, VEGF-A, and HIF-1α. Vascular proliferation by Nestin/Ki-67–positive vessels was counted within “hotspot” areas. Median vascular proliferation counts were 4- to 5-fold higher in castration-resistant prostate cancers and metastases versus localized cancers and prostatic hyperplasias (P < 0.0005). Among localized cancers, high vascular proliferation was significantly related to adverse clinicopathologic features and was a strong and independent predictor of biochemical failure (P < 0.005), clinical recurrence (P = 0.005), and skeletal metastasis (P = 0.025) in multivariate analysis. Castration-resistant cancers were characterized by reduced VEGF-A and increased HIF-1α expression, and vascular proliferation was associated with reduced patient survival in this group. Thus, vascular proliferation was of independent prognostic importance among prostate cancers. When compared with localized cancers, vascular proliferation was significantly increased in castration-resistant cases and metastatic lesions. The castration-resistant tumors exhibited weak VEGF-A but strong HIF-1α expression. These novel data might have an effect on clinical evaluation and treatment of prostate cancer patients. [Cancer Res 2009;69(11):4708–15]
Transcript Level Modulates the Inherent Oncogenicity of RET/PTC Oncoproteins
Authors: Richardson Douglas S. , Gujral Taranjit S. , Peng Susan , Asa Sylvia L. , Mulligan Lois M.
Published: June 2009

Mutations to the RET proto-oncogene occur in as many as one in three cases of thyroid cancer and have been detected in both the medullary (MTC) and the papillary (PTC) forms of the disease. Of the nearly 400 chromosomal rearrangements resulting in oncogenic fusion proteins that have been identified to date, the rearrangements that give rise to RET fusion oncogenes in PTC remain the paradigm for chimeric oncoprotein involvement in solid tumors. RET-associated PTC tumors are phenotypically indolent and relatively less aggressive than RET-related MTCs. The mechanism(s) contributing to the differences in oncogenicity of RET-related MTC and PTC remains unexplained. Here, through cellular and molecular characterization of the two most common RET/PTC rearrangements (PTC1 and PTC3), we show that RET/PTC oncoproteins are highly oncogenic when overexpressed, with the ability to increase cell proliferation and transformation. Further, RET/PTCs activate similar downstream signaling cascades to wild-type RET, although at different levels, and are relatively more stable as they avoid lysosomal degradation. Absolute quantitation of transcript levels of RET, CCDC6, and NCOA4 (the 5′ fusion genes involved in PTC1 and PTC3, respectively) suggest that these rearrangements result in lower RET expression in PTCs relative to MTCs. Together, our findings suggest PTC1 and PTC3 are highly oncogenic proteins when overexpressed, but result in indolent disease compared with RET-related MTCs due to their relatively low expression from the NCOA4 and CCDC6 promoters in vivo. [Cancer Res 2009;69(11):4861–9]
Estrogen Receptor-β Affects the Prognosis of Human Malignant Mesothelioma
Authors: Pinton Giulia , Brunelli Elisa , Murer Bruno , Puntoni Riccardo , Puntoni Matteo , Fennell Dean A. , Gaudino Giovanni , Mutti Luciano , Moro Laura
Published: June 2009

Malignant pleural mesothelioma is an asbestos-related neoplasm with poor prognosis, refractory to current therapies, the incidence of which is expected to increase in the next decades. Female gender was identified as a positive prognostic factor among other clinical and biological prognostic markers for malignant mesothelioma, yet a role of estrogen receptors (ERs) has not been studied. Our goal was to investigate ERs expression in malignant mesothelioma and to assess whether their expression correlates with prognosis. Immunohistochemical analysis revealed intense nuclear ERβ staining in normal pleura that was reduced in tumor tissues. Conversely, neither tumors nor normal pleura stained positive for ERα. Multivariate analysis of 78 malignant mesothelioma patients with pathologic stage, histologic type, therapy, sex, and age at diagnosis indicated that ERβ expression is an independent prognostic factor of better survival. Moreover, studies in vitro confirmed that treatment with 17β-estradiol led to an ERβ-mediated inhibition of malignant mesothelioma cell proliferation as well as p21CIP1 and p27KIP1 up-regulation. Consistently cell growth was suppressed by ERβ overexpression, causing a G2-M-phase cell cycle arrest, paralleled by cyclin B1 and survivin down-regulation. Our data support the notion that ERβ acting as a tumor suppressor is of high potential relevance to prediction of disease progression and to therapeutic response of malignant mesothelioma patients. [Cancer Res 2009;69(11):4598–604]
AKR1C Isoforms Represent a Novel Cellular Target for Jasmonates alongside Their Mitochondrial-Mediated Effects
Authors: Davies Nicholas J. , Hayden Rachel E. , Simpson Paul J. , Birtwistle Jane , Mayer Katarina , Ride Jonathan P. , Bunce Chris M.
Published: June 2009

Members of the aldo-keto reductase (AKR) superfamily, particularly the AKR1C subfamily, are emerging as important mediators of the pathology of cancer. Agents that inhibit these enzymes may provide novel agents for either the chemoprevention or treatment of diverse malignancies. Recently, jasmonates, a family of plant stress hormones that bear a structural resemblance to prostaglandins, have been shown to elicit anticancer activities both in vitro and in vivo. In this study, we show that jasmonic acid (JA) and methyl jasmonate (MeJ) are capable of inhibiting all four human AKR1C isoforms. Although JA is the more potent inhibitor of recombinant AKR1C proteins, including the in vitro prostaglandin F synthase activity of AKR1C3, MeJ displayed greater potency in cellular systems that was, at least in part, due to increased cellular uptake of MeJ. Moreover, using the acute myelogenous leukemia cell lines HL-60 and KG1a, we found that although both jasmonates were able to induce high levels of reactive oxygen species in a dose-dependent fashion, only MeJ was able to induce high levels of mitochondrial superoxide (MSO), possibly as an epiphenomenon of mitochondrial damage. There was a strong correlation observed between MSO formation at 24 hours and reduced cellularity at day 5. In conclusion, we have identified AKR1C isoforms as a novel target of jasmonates in cancer cells and provide further evidence of the promise of these compounds, or derivatives thereof, as adjunctive therapies in the treatment of cancer. [Cancer Res 2009;69(11):4769–75]
Selective Killing of Cancer Cells by Suppression of Geminin Activity
Authors: Zhu Wenge , DePamphilis Melvin L.
Published: June 2009

Eukaryotic cells normally restrict genome duplication to once per cell division. In metazoa, re-replication of DNA during a single S phase seems to be prevented solely by suppressing CDT1 activity, a protein required for loading the replicative MCM DNA helicase. However, siRNA suppression of geminin (a specific inhibitor of CDT1) arrested proliferation only of cells derived from cancers by inducing DNA re-replication and DNA damage that spontaneously triggered apoptosis. None of these effects were detected either in cells derived from normal human tissues or in cells immortalized by a viral oncogene. To induce these effects in noncancer cells required suppression of both geminin and cyclin A, another cell cycle regulator. Therefore, initiating DNA replication in some cancer cells is limited solely by regulating the level of CDT1 activity with geminin, whereas noncancer cells contain additional safeguards that prevent DNA re-replication. These results show that inhibition of geminin activity could be used to selectively kill cancer cells without harming other cells. [Cancer Res 2009;69(11):4870–7]
Industasis, a Promotion of Tumor Formation by Nontumorigenic Stray Cells
Authors: Pajer Petr , Karafiát Vít , Pec̆enka Vladimír , Pru̇ková Dana , Dudlová Jana , Plachý Jiří , Kašparová Petra , Dvořák Michal
Published: June 2009

A tumor cell is formed when a critical amount of endogenous and/or exogenous tumorigenic stimuli is exceeded. We have shown that the transient presence of nontumorigenic stray cells in tissues of experimental animals that contain cells with a subcritical set of genetic mutations can act as a tumor-promoting stimulus. To induce somatic mutations in all chicken tissues, we have used the MAV-2 retroviral insertion system that almost exclusively generates nephroblastomas. MAV-2 mutagenized animals i.v. inoculated with nonmalignant cells developed early clonal lung tumors before nephroblastomas. Importantly, the injected cells did not become a component of resultant tumors. Lung tumors displayed specific mutational signature characterized by an insertion of MAV-2 provirus into the fyn-related kinase (frk) promoter that results in the overexpression of the frk gene. In contrast, plag1, foxP, and twist genes were most often mutagenized in nephroblastomas. Based on such observations, we propose the mechanism termed industasis, a promotion of fully malignant phenotype of incipient tumor cell by stray cells, and hypothesize that it might be the underlying cause of human multiple primary tumors. [Cancer Res 2009;69(11):4605–12]
Angiopoietin-1 Overexpression Modulates Vascular Endothelium to Facilitate Tumor Cell Dissemination and Metastasis Establishment
Authors: Holopainen Tanja , Huang Huilian , Chen Caiping , Kim Kyung Eun , Zhang Luqing , Zhou Fei , Han Wencan , Li Chaojun , Yu Jun , Wu Jun , Koh Gou Young , Alitalo Kari , He Yulong
Published: June 2009

The angiopoietin-1 (Ang1)/Tie2 signaling pathway is known to play an important role in the regulation of vascular maturation and maintenance of vessel integrity. In this study, we have investigated the effect of systemic Tie2 activation or inhibition on tumor growth and metastasis. We found that treatment with Ang1 delivered via an adenoviral vector promoted s.c. implanted tumor metastasis to the lungs. Ang1 treatment did not significantly increase vascular density in the tumors but induced enlargement of blood vessels in both the tumor and normal tissues, which increased tumor cell dissemination into the blood circulation. Ang1 also enhanced the formation of metastatic foci in the lungs when tumor cells were injected into the circulation via the tail vein. The effect of Ang1 on metastasis was validated by a simultaneous treatment with a soluble form of Tie2 (sTie2), which led to the suppression of Ang1-induced increase of tumor metastasis. Furthermore, using a highly metastatic tumor model, we confirmed that systemic treatment with sTie2 suppressed tumor metastasis to the lungs and lymph nodes, whereas tumor-associated angiogenesis and lymphangiogenesis were not significantly affected. This suggests that the Ang1/Tie2 signals contribute to tumor progression by increasing vascular entry and exit of tumor cells to facilitate tumor dissemination and establishment of metastases. [Cancer Res 2009;69(11):4656–64]
Nitric Oxide Induces Early Viral Transcription Coincident with Increased DNA Damage and Mutation Rates in Human Papillomavirus–Infected Cells
Authors: Wei Lanlan , Gravitt Patti E. , Song Hebin , Maldonado Anastacia M. , Ozbun Michelle A.
Published: June 2009

High-risk human papillomavirus (HPV) infections are necessary but insufficient causes of cervical cancers. Other risk factors for cervical cancer (e.g., pregnancy, smoking, infections causing inflammation) can lead to high and sustained nitric oxide (NO) concentrations in the cervix, and high NO levels are related to carcinogenesis through DNA damage and mutation. However, the effects of NO exposure in HPV-infected cells have not been investigated. In this study, we used the NO donor DETA-NO to model NO exposure to cervical epithelium. In cell culture media, 24-hour exposure to 0.25 to 0.5 mmol/L DETA-NO yielded a pathologically relevant NO concentration. Exposure of cells maintaining episomal high-risk HPV genomes to NO increased HPV early transcript levels 2- to 4-fold but did not increase viral DNA replication. Accompanying increased E6 and E7 mRNA levels were significant decreases in p53 and pRb protein levels, lower apoptotic indices, increased DNA double-strand breaks, and higher mutation frequencies when compared with HPV-negative cells. We propose that NO is a molecular cofactor with HPV infection in cervical carcinogenesis, and that modifying local NO cervical concentrations may constitute a strategy whereby HPV-related cancer can be reduced.[Cancer Res 2009;69(11):4878–84]
Src Stimulates Fibroblast Growth Factor Receptor-2 Shedding by an ADAM15 Splice Variant Linked to Breast Cancer
Authors: Maretzky Thorsten , Le Gall Sylvain M. , Worpenberg-Pietruk Susanne , Eder Jörg , Overall Christopher M. , Huang Xin-Yun , Poghosyan Zaruhi , Edwards Dylan R. , Blobel Carl P.
Published: June 2009

ADAMs (a disintegrin and metalloproteinase) have important roles in development and diseases such as cancer. Previously, an ADAM15 splice variant (ADAM15B), which contains an inserted cytoplasmic Src-binding site, was linked to clinical aggressiveness in breast cancer, yet little was known about how this splice variant affects the function of ADAM15. Here, we show that ADAM15B has enhanced catalytic activity in cell-based assays compared with ADAM15A, which lacks a Src-binding site, using shedding of fibroblast growth factor receptor 2iiib variant as an assay for catalytic activity. Moreover, the enhanced activity of ADAM15B compared with ADAM15A depends on Src because it is abolished by Src-kinase inhibitors and in Src−/− cells, but not in Src−/− cells rescued with Src. These findings provide insights into the mechanism of how a splice variant linked to clinical agressiveness in breast cancer causes increased activity of ADAM15B, and suggest that inhibitors of the ADAM15 protease activity or of the interaction of ADAM15B with Src could be useful to treat breast cancer in patients with dysregulated ADAM15B. [Cancer Res 2009;69(11):4573–6]
Targeting LMO2 with a Peptide Aptamer Establishes a Necessary Function in Overt T-Cell Neoplasia
Authors: Appert Alex , Nam Chang-Hoon , Lobato Natividad , Priego Eva , Miguel Ricardo Nunez , Blundell Tom , Drynan Lesley , Sewell Helen , Tanaka Tomoyuki , Rabbitts Terence
Published: June 2009

LMO2 is a transcription regulator involved in human T-cell leukemia, including some occurring in X-SCID gene therapy trials, and in B-cell lymphomas and prostate cancer. LMO2 functions in transcription complexes via protein-protein interactions involving two LIM domains and causes a preleukemic T-cell development blockade followed by clonal tumors. Therefore, LMO2 is necessary but not sufficient for overt neoplasias, which must undergo additional mutations before frank malignancy. An open question is the importance of LMO2 in tumor development as opposed to sustaining cancer. We have addressed this using a peptide aptamer that binds to the second LIM domain of the LMO2 protein and disrupts its function. This specificity is mediated by a conserved Cys-Cys motif, which is similar to the zinc-binding LIM domains. The peptide inhibits Lmo2 function in a mouse T-cell tumor transplantation assay by preventing Lmo2-dependent T-cell neoplasia. Lmo2 is, therefore, required for sustained T-cell tumor growth, in addition to its preleukemic effect. Interference with LMO2 complexes is a strategy for controlling LMO2-mediated cancers, and the finger structure of LMO2 is an explicit focus for drug development. [Cancer Res 2009;69(11):4784–90]
ERG Is a Megakaryocytic Oncogene
Authors: Salek-Ardakani Samira , Smooha Gil , de Boer Jasper , Sebire Neil J. , Morrow Michelle , Rainis Liat , Lee Sandy , Williams Owen , Izraeli Shai , Brady Hugh J.M.
Published: June 2009

Ets-related gene (ERG) is a member of the ETS transcription factor gene family located on Hsa21. ERG is known to have a crucial role in establishing definitive hematopoiesis and is required for normal megakaryopoiesis. Truncated forms of ERG are associated with multiple cancers such as Ewing's sarcoma, prostate cancer, and leukemia as part of oncogenic fusion translocations. Increased expression of ERG is highly indicative of poor prognosis in acute myeloid leukemia and ERG is expressed in acute megakaryoblastic leukemia (AMKL); however, it is unclear if expression of ERG per se has a leukemogenic activity. We show that ectopic expression of ERG in fetal hematopoietic progenitors promotes megakaryopoiesis and that ERG alone acts as a potent oncogene in vivo leading to rapid onset of leukemia in mice. We observe that the endogenous ERG is required for the proliferation and maintenance of AMKL cell lines. ERG also strongly cooperates with the GATA1s mutated protein, found in Down syndrome AMKL, to immortalize megakaryocyte progenitors, suggesting that the additional copy of ERG in trisomy 21 may have a role in Down syndrome AMKL. These data suggest that ERG is a hematopoietic oncogene that may play a direct role in myeloid leukemia pathogenesis. [Cancer Res 2009;69(11):4665–73]
Up-regulation of C-Terminal Tensin-like Molecule Promotes the Tumorigenicity of Colon Cancer through β-Catenin
Authors: Liao Yi-Chun , Chen Nien-Tsu , Shih Yi-Ping , Dong Ying , Lo Su Hao
Published: June 2009

C-terminal tensin-like (cten) is a focal adhesion molecule belonging to the tensin family. Previous studies have suggested that cten may function as a prostate-specific tumor suppressor. Here, we show that although cten is expressed at a very low level in normal colon, its expression is significantly up-regulated in colon cancer. Furthermore, a high population of cten is found in the nucleus, where it interacts with β-catenin, a critical player in the canonical Wnt pathway. This interaction may contribute to the role of cten in enhancing the colony formation, anchorage-independent growth, and invasiveness of colon cancer cells. Our studies have identified cten as a novel nuclear partner of β-catenin, showed an oncogenic activity of cten in colon cancers, and revealed cten as a potential biomarker and target for colon cancers. [Cancer Res 2009;69(11):4563–6]
Aurora-A and hBora Join the Game of Polo
Authors: Macurek Libor , Lindqvist Arne , Medema René H.
Published: June 2009

Overactivation of both Polo-like kinase-1 (Plk1) and Aurora-A is linked to cancer development, and small-molecule inhibitors that target these kinases are currently tested as anticancer drugs. Here, we discuss recent advances in the understanding of the functional crosstalk between Plk1 and Aurora-A before and during mitosis. Several recent findings have led to a better appreciation of how the activities of these distinct mitotic kinases are intertwined. Such insight is important for the expected utility of small-molecule inhibitors targeting Plk1 or Aurora-A, and it might help us to improve their application. [Cancer Res 2009;69(11):4555–8]
Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma
Authors: Ward Ryan J. , Lee Lilian , Graham Kevin , Satkunendran Thevagi , Yoshikawa Koichi , Ling Erick , Harper Lauren , Austin Ryan , Nieuwenhuis Erica , Clarke Ian D. , Hui Chi-chung , Dirks Peter B.
Published: June 2009

Subpopulations of tumorigenic cells have been identified in many human tumors, although these cells may not be very rare in some types of cancer. Here, we report that medulloblastomas arising from Patched-1–deficient mice contain a subpopulation of cells that show a neural precursor phenotype, clonogenic and multilineage differentiation capacity, activated Hedgehog signaling, wild-type Patched-1 expression, and the ability to initiate tumors following allogeneic orthotopic transplantation. The normal neural stem cell surface antigen CD15 enriches for the in vitro proliferative and in vivo tumorigenic potential from uncultured medulloblastomas, supporting the existence of a cancer stem cell hierarchy in this clinically relevant mouse model of cancer. [Cancer Res 2009;69(11):4682–90]
The Role of HuR in Gemcitabine Efficacy in Pancreatic Cancer: HuR Up-regulates the Expression of the Gemcitabine Metabolizing Enzyme Deoxycytidine Kinase
Authors: Costantino Christina L. , Witkiewicz Agnieszka K. , Kuwano Yuki , Cozzitorto Joseph A. , Kennedy Eugene P. , Dasgupta Abhijit , Keen Judith C. , Yeo Charles J. , Gorospe Myriam , Brody Jonathan R.
Published: June 2009

RNA-binding protein HuR binds U- or AU-rich sequences in the 3′-untranslated regions of target mRNAs, stabilizing them and/or modulating their translation. Given the links of HuR with cancer, we studied the consequences of modulating HuR levels in pancreatic cancer cells. HuR-overexpressing cancer cells, in some instances, are roughly up to 30-fold more sensitive to treatment with gemcitabine, the main chemotherapeutic component of treatment regimens for pancreatic ductal adenocarcinoma (PDA), compared with control cells. In pancreatic cancer cells, HuR associates with deoxycytidine kinase (dCK) mRNA, which encodes the enzyme that metabolizes and thereby activates gemcitabine. Gemcitabine exposure to pancreatic cancer cells enriches the association between HuR and dCK mRNA and increases cytoplasmic HuR levels. Accordingly, HuR overexpression elevates, whereas HuR silencing reduces, dCK protein expression in pancreatic cancer cells. In a clinical correlate study of gemcitabine treatment, we found a 7-fold increase in risk of mortality in PDA patients with low cytoplasmic HuR levels compared with patients with high HuR levels, after adjusting for other treatments and demographic variables. These data support the notion that HuR is a key mediator of gemcitabine efficacy in cancer cells, at least in part through its ability to regulate dCK levels posttranscriptionally. We propose that HuR levels in PDA modulate the therapeutic efficacy of gemcitabine, thus serving as a marker of the clinical utility of this common chemotherapeutic agent and a potential target for intervention in pancreatic cancer. [Cancer Res 2009;69(11):4567–72]
CAR Mechanics: Driving T Cells into the MUC of Cancer
Authors: Maher John , Wilkie Scott
Published: June 2009

Several monoclonal antibodies bind in a highly selective manner to tumor-associated glycoforms of MUC1. We set out to exploit this by developing a MUC1-specific chimeric antigen receptor. Difficulties were encountered in this endeavor, owing to MUC1-imposed steric hindrance and antigenic heterogeneity. These issues were addressed by the iterative engineering of all components of the fusion receptor. Our experience underlines the need for careful individual optimization of immunotherapeutic reagents as dictated by the molecular vagaries of the target under study. [Cancer Res 2009;69(11):4559–62]
Bacterial Cytosine Deaminase Mutants Created by Molecular Engineering Show Improved 5-Fluorocytosine–Mediated Cell KillingIn vitroandIn vivo
Authors: Fuchita Michi , Ardiani Andressa , Zhao Lei , Serve Kinta , Stoddard Barry L. , Black Margaret E.
Published: June 2009

Cytosine deaminase is used in combination with 5-fluorocytosine as an enzyme-prodrug combination for targeted genetic cancer treatment. This approach is limited by inefficient gene delivery and poor prodrug conversion activities. Previously, we reported individual point mutations within the substrate binding pocket of bacterial cytosine deaminase (bCD) that result in marginal improvements in the ability to sensitize cells to 5-fluorocytosine (5FC). Here, we describe an expanded random mutagenesis and selection experiment that yielded enzyme variants, which provide significant improvement in prodrug sensitization. Three of these mutants were evaluated using enzyme kinetic analyses and then assayed in three cancer cell lines for 5FC sensitization, bystander effects, and formation of 5-fluorouracil metabolites. All variants displayed 18- to 19-fold shifts in substrate preference toward 5FC, a significant reduction in IC50 values and improved bystander effect compared with wild-type bCD. In a xenograft tumor model, the best enzyme mutant was shown to prevent tumor growth at much lower doses of 5FC than is observed when tumor cells express wild-type bCD. Crystallographic analyses of this construct show the basis for improved activity toward 5FC, and also how two different mutagenesis strategies yield closely related but mutually exclusive mutations that each result in a significant alteration of enzyme specificity. [Cancer Res 2009;69(11):4791–9]
Mutational Profile of Advanced Primary and Metastatic Radioactive Iodine-Refractory Thyroid Cancers Reveals Distinct Pathogenetic Roles forBRAF, PIK3CA, andAKT1
Authors: Ricarte-Filho Julio C. , Ryder Mabel , Chitale Dhananjay A. , Rivera Michael , Heguy Adriana , Ladanyi Marc , Janakiraman Manickam , Solit David , Knauf Jeffrey A. , Tuttle R. Michael , Ghossein Ronald A. , Fagin James A.
Published: June 2009

Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET–positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors. [Cancer Res 2009;69(11):4885–93]
Cortex and Memory: Emergence of a New Paradigm
Authors: Fuster Joaquín M.
Published: June 2009

Converging evidence from humans and nonhuman primates is obliging us to abandon conventional models in favor of a radically different, distributed-network paradigm of cortical memory. Central to the new paradigm is the concept of memory network or cognit—that is, a memory or an item of knowledge defined by a pattern of connections between neuron populations associated by experience. Cognits are hierarchically organized in terms of semantic abstraction and complexity. Complex cognits link neurons in noncontiguous cortical areas of prefrontal and posterior association cortex. Cognits overlap and interconnect profusely, even across hierarchical levels (heterarchically), whereby a neuron can be part of many memory networks and thus many memories or items of knowledge.
Impact of Airborne Doppler Radar Data Assimilation on the Numerical Simulation of Intensity Changes of Hurricane Dennis near a Landfall
Authors: Pu Zhaoxia , Li Xuanli , Sun Juanzhen
Published: June 2009

Accurate forecasting of a hurricane’s intensity changes near its landfall is of great importance in making an effective hurricane warning. This study uses airborne Doppler radar data collected during the NASA Tropical Cloud Systems and Processes (TCSP) field experiment in July 2005 to examine the impact of airborne radar observations on the short-range numerical simulation of hurricane track and intensity changes. A series of numerical experiments is conducted for Hurricane Dennis (2005) to study its intensity changes near a landfall. Both radar reflectivity and radial velocity–derived wind fields are assimilated into the Weather Research and Forecasting (WRF) model with its three-dimensional variational data assimilation (3DVAR) system. Numerical results indicate that the radar data assimilation has greatly improved the simulated structure and intensity changes of Hurricane Dennis. Specifically, the assimilation of radar reflectivity data shows a notable influence on the thermal and hydrometeor structures of the initial vortex and the precipitation structure in the subsequent forecasts, although its impact on the intensity and track forecasts is relatively small. In contrast, assimilation of radar wind data results in moderate improvement in the storm-track forecast and significant improvement in the intensity and precipitation forecasts of Hurricane Dennis. The hurricane landfall, intensification, and weakening during the simulation period are well captured by assimilating both radar reflectivity and wind data.
The Global Hydrological Cycle and Atmospheric Shortwave Absorption in Climate Models under CO2 Forcing
Authors: Takahashi Ken
Published: June 2009

The spread among the predictions by climate models for the strengthening of the global hydrological cycle [i.e., the global mean surface latent heat flux (LH), or, equivalently, precipitation] at a given level of CO2-induced global warming is of the same magnitude as the intermodel mean. By comparing several climate models from the World Climate Research Programme (WCRP) Coupled Model Intercomparison Project phase 3 (CMIP3) database under idealized CO2 forcings, it is shown that differences in the increase in global atmospheric shortwave heating (SWabs) induced by clear-sky absorption, presumably by water vapor, partly explains this spread. The increases in SWabs and LH present similar spreads across models but are anticorrelated, so the sum SWabs + LH increases more robustly than either alone. This is consistent with a recently proposed theory (Takahashi) that predicts that this sum (or, equivalently, the net longwave divergence minus the surface sensible heat flux) is constrained by energy conservation and robust longwave physics.

The intermodel scatter in SWabs changes is explained neither by differences in the radiative transfer models nor in intermodel differences in global water vapor content change, but perhaps by more subtle aspects of the changes in the water vapor distribution. Nevertheless, the fact that the radiative transfer models generally underestimate the increase in SWabs relative to the corresponding line-by-line calculation for a given change in water vapor content suggests that the climate models might be overestimating the rate of increase in the global hydrological cycle with global warming.
Drought in the Southeastern United States: Causes, Variability over the Last Millennium, and the Potential for Future Hydroclimate Change*
Authors: Seager Richard , Tzanova Alexandrina , Nakamura Jennifer
Published: June 2009

An assessment of the nature and causes of drought in the southeastern United States is conducted as well as an assessment of model projections of anthropogenically forced hydroclimate change in this region. The study uses observations of precipitation, model simulations forced by historical SSTs from 1856 to 2007, tree-ring records of moisture availability over the last millennium, and climate change projections conducted for the Fourth Assessment Report of the Intergovernmental Panel on Climate Change. From the perspective of the historical record, the recent drought that began in winter 2005/06 was a typical event in terms of amplitude and duration. Observations and model simulations are used to show that dry winter half-years in the Southeast are weakly associated with La Niñas in the tropical Pacific but that this link varies over time and was possibly of opposite sign from about 1922 to 1950. Summer-season precipitation variability in the Southeast appears governed by purely internal atmospheric variability. As such, model simulations forced by historical SSTs have very limited skill in reproducing the instrumental record of Southeast precipitation variability and actual predictive skill is also presumably low. Tree-ring records show that the twentieth century has been moist from the perspective of the last millennium and free of long and severe droughts that were abundant in previous centuries. The tree-ring records show a 21-yr-long uninterrupted drought in the mid-sixteenth century, a long period of dry conditions in the early to mid-nineteenth century, and that the Southeast was also affected by some of the medieval megadroughts centered in western North America. Climate model projections predict that in the near term, future precipitation in the Southeast will increase but that evaporation will also increase. The median of the projections predicts a modest reduction in the atmospheric supply of water vapor to the region; however, the multimodel ensemble exhibits considerable variation, with a quarter to a third of the models projecting an increase in precipitation minus evaporation. The recent drought, forced by reduced precipitation and with reduced evaporation, has no signature of model-projected anthropogenic climate change.
Pentad Evolution of the 1988 Drought and 1993 Flood over the Great Plains: An NARR Perspective on the Atmospheric and Terrestrial Water Balance
Authors: Weaver Scott J. , Ruiz-Barradas Alfredo , Nigam Sumant
Published: June 2009

The evolution of the atmospheric and land surface states during extreme hydroclimate episodes over North America is investigated using the North American Regional Reanalysis (NARR), which additionally, and successfully, assimilates precipitation. The pentad-resolution portrayals of the atmospheric and terrestrial water balance over the U.S. Great Plains during the 1988 summer drought and the July 1993 floods are analyzed to provide insight into the operative mechanisms including regional circulation (e.g., the Great Plains low-level jet, or GPLLJ) and hydroclimate (e.g., precipitation, evaporation, soil moisture recharge, runoff).

The submonthly (but supersynoptic time scale) fluctuations of the GPLLJ are found to be very influential, through related moisture transport and kinematic convergence (e.g., ∂υ/∂y), with the jet anomalies in the southern plains leading the northern precipitation and related moisture flux convergence, accounting for two-thirds of the dry and wet episode precipitation amplitude. The soil moisture influence on hydroclimate evolution is assessed to be marginal as evaporation anomalies are found to lag precipitation ones, a lead–lag not discernible at monthly resolution. The pentad analysis thus corroborates the authors’ earlier findings on the importance of transported moisture over local evaporation in Great Plains’ summer hydroclimate variability.

The regional water budgets—atmospheric and terrestrial—are found to be substantially unbalanced, with the terrestrial imbalance being unacceptably large. Pentad analysis shows the atmospheric imbalance to arise from the sluggishness of the NARR evaporation, including its overestimation in wet periods. The larger terrestrial imbalance, on the other hand, has its origins in the striking unresponsiveness of the NARR’s runoff, which is underestimated in wet episodes.

Finally, the influence of ENSO and North Atlantic Oscillation (NAO) variability on the GPLLJ is quantified during the wet episode, in view of the importance of moisture transports. It is shown that a significant portion (∼25%) of the GPLLJ anomaly (and downstream precipitation) is attributable to NAO and ENSO’s influence, and that this combined influence prolongs the wet episode beyond the period of the instigating GPLLJ.
Submonthly Polar Vortex Variability and Stratosphere–Troposphere Coupling in the Arctic
Authors: Black Robert X. , McDaniel Brent A.
Published: June 2009

A principal component analysis is performed to characterize intraseasonal variability in the boreal stratospheric polar vortex. In contrast to previous studies, the current analysis examines daily zonal-mean variability within a limited spatial domain encompassing the stratospheric polar vortex. The leading EOFs are vertically coherent north–south dipoles in the zonal-mean zonal wind extending through the lower stratosphere. The first mode represents variability in polar vortex strength and is highly correlated with the stratospheric northern annular mode (SNAM). The second mode, the polar annular mode (PAM), represents variability in the latitudinal position of the polar vortex and possesses a poleward-retracted dipole anomaly structure. Composite analyses indicate that large-amplitude PAM events are relatively short lived (1–2 weeks) compared to SNAM events (1 month or longer). Trend analyses further reveal that recent decadal trends in the boreal polar vortex project more strongly onto PAM than SNAM.

Composite analyses illustrate that the time evolution of sudden stratospheric warming events is dominated by SNAM, whereas SNAM and PAM play approximately equal roles in final warming events. Linear regression analyses reveal that SNAM and PAM result in circumpolar circulation and temperature anomalies of similar magnitudes within the high-latitude troposphere. It is concluded that PAM represents a previously unrecognized annular mode that strongly couples the stratosphere and troposphere on submonthly time scales at mid- to high latitudes. It is further suggested that the SNAM/PAM framework provides a means for isolating the proximate tropospheric response to respective variations in the strength and position of the stratospheric polar vortex.
Amazon Deforestation and Climate Change in a Coupled Model Simulation
Authors: Nobre Paulo , Malagutti Marta , Urbano Domingos F. , de Almeida Roberto A. F. , Giarolla Emanuel
Published: June 2009

The effects of Amazon deforestation on climate change are investigated using twin numerical experiments of an atmospheric general circulation model (AGCM) with prescribed global sea surface temperature and the same AGCM coupled to an ocean GCM (CGCM) over the global tropics. An ensemble approach is adopted, with 10-member ensemble averages of a control simulation compared with perturbed simulations for three scenarios of Amazon deforestation. The latest 20 yr of simulation from each experiment are analyzed. Local surface warming and rainfall reduction are simulated by both models over the Amazon basin. The coupled model presented a rainfall reduction that is nearly 60% larger compared to its control run than those obtained by the AGCM. The results also indicated that both the fraction of the deforested area and the spatial continuity of the vegetated area might be important for modulating global climate variability and change. Additionally, significant remote atmospheric responses to Amazon deforestation scenarios are detected for the coupled simulations, which revealed global ocean and atmosphere circulation changes conducive to enhanced ocean–atmosphere variability over the Pacific Ocean. This, in turn, is interpreted as a manifestation of enhanced El Niño–Southern Oscillation (ENSO) activity over the Pacific and a positive feedback contributing to the extra rainfall reduction over the Amazon on the coupled simulations.
Historical SAM Variability. Part I: Century-Length Seasonal Reconstructions*
Authors: Jones Julie M. , Fogt Ryan L. , Widmann Martin , Marshall Gareth J. , Jones Phil D. , Visbeck Martin
Published: June 2009

Seasonal reconstructions of the Southern Hemisphere annular mode (SAM) index are derived to extend the record before the reanalysis period, using station sea level pressure (SLP) data as predictors. Two reconstructions using different predictands are obtained: one [Jones and Widmann (JW)] based on the first principal component (PC) of extratropical SLP and the other (Fogt) on the index of Marshall. A regional-based SAM index (Visbeck) is also considered.

These predictands agree well post-1979; correlations decline in all seasons except austral summer for the full series starting in 1958. Predictand agreement is strongest in spring and summer; hence agreement between the reconstructions is highest in these seasons. The less zonally symmetric SAM structure in winter and spring influences the strength of the SAM signal over land areas, hence the number of stations included in the reconstructions. Reconstructions from 1865 were, therefore, derived in summer and autumn and from 1905 in winter and spring.

This paper examines the skill of each reconstruction by comparison with observations and reanalysis data. Some of the individual peaks in the reconstructions, such as the most recent in austral summer, represent a full hemispheric SAM pattern, while others are caused by regional SLP anomalies over the locations of the predictors. The JW and Fogt reconstructions are of similar quality in summer and autumn, while in winter and spring the Marshall index is better reconstructed by Fogt than the PC index is by JW. In spring and autumn the SAM shows considerable variability prior to recent decades.
Seasonal Variations of Yellow Sea Fog: Observations and Mechanisms*
Authors: Zhang Su-Ping , Xie Shang-Ping , Liu Qin-Yu , Yang Yu-Qiang , Wang Xin-Gong , Ren Zhao-Peng
Published: June 2009

Sea fog is frequently observed over the Yellow Sea, with an average of 50 fog days on the Chinese coast during April–July. The Yellow Sea fog season is characterized by an abrupt onset in April in the southern coast of Shandong Peninsula and an abrupt, basin-wide termination in August. This study investigates the mechanisms for such steplike evolution that is inexplicable from the gradual change in solar radiation. From March to April over the northwestern Yellow Sea, a temperature inversion forms in a layer 100–350 m above the sea surface, and the prevailing surface winds switch from northwesterly to southerly, both changes that are favorable for advection fog. The land–sea contrast is the key to these changes. In April, the land warms up much faster than the ocean. The prevailing west-southwesterlies at 925 hPa advect warm continental air to form an inversion over the western Yellow Sea. The land–sea differential warming also leads to the formation of a shallow anticyclone over the cool Yellow and northern East China Seas in April. The southerlies on the west flank of this anticyclone advect warm and humid air from the south, causing the abrupt fog onset on the Chinese coast. The lack of such warm/moist advection on the east flank of the anticyclone leads to a gradual increase in fog occurrence on the Korean coast. The retreat of Yellow Sea fog is associated with a shift in the prevailing winds from southerly to easterly from July to August. The August wind shift over the Yellow Sea is part of a large-scale change in the East Asian–western Pacific monsoons, characterized by enhanced convection over the subtropical northwest Pacific and the resultant teleconnection into the midlatitudes, the latter known as the western Pacific–Japan pattern. Back trajectories for foggy and fog-free air masses support the results from the climatological analysis.
Physical Mechanisms Linking the Winter Pacific–North American Teleconnection Pattern to Spring North American Snow Depth
Authors: Ge Yan , Gong Gavin , Frei Allan
Published: June 2009

The wintertime Pacific–North American (PNA) teleconnection pattern has previously been shown to influence springtime snow conditions over portions of North America. This paper develops a more complete physical understanding of this linkage across the continent, using a recently released long-term, continental-scale gridded North American snow depth dataset and the 40-yr European Centre for Medium-Range Weather Forecasts Re-Analysis data. An empirical orthogonal function–based filtering process is used to identify and isolate the interannual snow depth variations associated with PNA. Then linear and partial correlations are employed to investigate the physical mechanisms that link winter PNA with spring snow depth. In the positive phase of PNA, the enhanced PNA pressure centers lead to warmer temperatures over northwestern North America and less precipitation at midlatitudes. The temperature and precipitation pathways act independently and in distinct geographical regions, and together they serve to reduce winter snow depth across much of North America. Winter anomalies in the snow depth field then tend to persist into spring. Dynamic mechanisms responsible for the PNA-influenced North American precipitation and temperature anomalies, involving moisture transport and cold air intrusions, are confirmed in this study and also extended to continental snow depth anomalies.
Maintenance of Lower Tropospheric Temperature Inversion in the Saharan Air Layer by Dust and Dry Anomaly
Authors: Wong Sun , Dessler Andrew E. , Mahowald Natalie M. , Yang Ping , Feng Qian
Published: June 2009

The role of Saharan dust and dry anomaly in maintaining the temperature inversion in the Saharan air layer (SAL) is investigated. The dust aerosol optical thickness (AOT) in the SAL is inferred from the measurements taken by Aqua Moderate Resolution Imaging Spectroradiometer (MODIS), and the corresponding temperature and specific humidity anomalies are identified using the National Centers for Environmental Prediction (NCEP) data in August–September over the North Atlantic tropical cyclone (TC) main development region (MDR; 10°–20°N, 40°–60°W). The authors also study the SAL simulated in the National Center of Atmospheric Research (NCAR) Community Atmosphere Model, version 3 (CAM3), coupled with dust radiative effect. It is found that higher AOT is associated with warmer and dryer anomalies below 700 hPa, which increases the atmospheric stability. The calculated instantaneous radiative heating anomalies from a radiative transfer model indicate that both the dust and low humidity are essential to maintaining the temperature structure in the SAL against thermal relaxation. At 850 hPa, heating anomalies caused by both the dust and dry anomalies (for AOT > 0.8) are 0.2–0.4 K day−1. The dust heats the atmosphere below 600 hPa, while the dry anomaly cools the atmosphere below 925 hPa, resulting in a peak of heating rate anomaly located at 700–850 hPa. In the eastern Atlantic, dust contributes about 50% of the heating rate anomaly. Westward of 40°W, when the dust content becomes small (AOT < 0.6), the heating rates are more sensitive to the water vapor profile used in the radiative transfer calculation. Retrieving or simulating correct water vapor profiles is essential to the assessment of the SAL heating budgets in regions where the dust content in the SAL is small.