bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association Study of 69 Genes in the Ret Pathway Identifies Low-penetrance Loci in Sporadic Medullary Thyroid Carcinoma
Authors: Ruiz-Llorente Sergio , Montero-Conde Cristina , Milne Roger L. , Moya Christian M. , Cebrián Arancha , Letón Rocío , Cascón Alberto , Mercadillo Fátima , Landa Iñigo , Borrego Salud , de Nanclares Guiomar Pérez , Álvarez-Escolá Cristina , Díaz-Pérez José Ángel , Carracedo Ángel , Urioste Miguel , González-Neira Anna , Benítez Javier , Santisteban Pilar , Dopazo Joaquín , Ponder Bruce A. , Robledo Mercedes ,   the Medullary Thyroid Carcinoma Clinical Group
Published: October 2007

Abstract
To date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium–based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases. [Cancer Res 2007;67(19):9561–7]
Enhancement of Antibody-Dependent Mechanisms of Tumor Cell Lysis by a Targeted Activator of Complement
Authors: Imai Masaki , Ohta Rieko , Varela Juan C. , Song Hongbin , Tomlinson Stephen 
Published: October 2007

AbstractComplement inhibitors expressed on tumor cells provide a hindrance to the therapeutic efficacy of some monoclonal antibodies (mAb). We investigated a novel strategy to overwhelm complement inhibitor activity and amplify complement activation on tumor cells. The C3-binding domain of human complement receptor 2 (CR2; CD21) was linked to the complement-activating Fc region of human IgG1 (CR2-Fc), and the ability of the construct to target and amplify complement deposition on tumor cells was investigated. CR2 binds C3 activation fragments, and CR2-Fc targeted tumor cells by binding to C3 initially deposited by a tumor-specific antibody. Complement deposition on Du145 cells (human prostate cancer cell line) and anti-MUC1 mAb-mediated complement-dependent lysis of Du145 cells were significantly enhanced by CR2-Fc. Anti-MUC1 antibody-dependent cell-mediated cytotoxicity of Du145 by human peripheral blood mononuclear cells was also significantly enhanced by CR2-Fc in both the presence and the absence of complement. Radiolabeled CR2-Fc targeted to s.c. Du145 tumors in nude mice treated with anti-MUC1 mAb, validating the targeting strategy in vivo. A metastatic model was used to investigate the effect of CR2-Fc in a therapeutic paradigm. Administration of CR2-Fc together with mAb therapy significantly improved long-term survival of nude mice challenged with an i.v. injection of EL4 cells. The data show that CR2-Fc enhances the therapeutic efficacy of antibody therapy, and the construct may provide particular benefits under conditions of limiting antibody concentration or low tumor antigen density. [Cancer Res 2007;67(19):9535–41]
Glucuronidation of Nicotine and Cotinine by UGT2B10: Loss of Function by the UGT2B10 Codon 67 (Asp&gt;Tyr) Polymorphism
Authors: Chen Gang , Blevins-Primeau Andrea S. , Dellinger Ryan W. , Muscat Joshua E. , Lazarus Philip 
Published: October 2007

Abstract
Nicotine, the major addicting agent in tobacco and tobacco smoke, undergoes a complex metabolic pathway, with ∼22% of nicotine urinary metabolites in the form of phase II N-glucuronidated compounds. Recent studies have shown that UGT2B10 is a major enzyme involved in the N-glucuronidation of several tobacco-specific nitrosamines. In the present study, microsomes of UGT2B10-overexpressing HEK293 cells exhibited high N-glucuronidation activity against both nicotine and cotinine with apparent KM's that were 37- and 3-fold lower than that observed for microsomes of UGT1A4-overexpressing cells against nicotine and cotinine, respectively. The KM of microsomes from wild-type (WT) UGT2B10-overexpressing cells for nicotine and cotinine was similar to that observed for human liver microsomes (HLM) against both substrates. The level of glucuronidated nicotine or cotinine in 112 HLM samples was correlated with UGT2B10 genotype; the levels of nicotine- and cotinine-glucuronide were 21% to 30% lower in specimens from subjects with the UGT2B10 (*1/*2) genotype compared with specimens from subjects with the WT UGT2B10 (*1/*1) genotype; a 5- and 16-fold lower level of nicotine- and cotinine-glucuronide formation, respectively, was observed in HLM from subjects with the UGT2B10 (*2/*2) genotype. In contrast to the relatively high activity observed for cells overexpressing WT UGT2B10 in vitro, little or no glucuronidation was observed for microsomes from cells overexpressing the UGT2B10*2 variant against either nicotine or cotinine. These data suggest that UGT2B10 is the major hepatic enzyme involved in nicotine/cotinine glucuronidation and that the UGT2B10*2 variant significantly reduces nicotine- and cotinine-N-glucuronidation formation and plays an important role in nicotine metabolism and elimination. [Cancer Res 2007;67(19):9024–9]
Molecular Analysis of Colorectal Cancer Tumors from Patients with Mismatch Repair–Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways
Authors: Sánchez-de-Abajo Ana , de la Hoya Miguel , van Puijenbroek Marjo , Tosar Alicia , López-Asenjo J.A. , Díaz-Rubio Eduardo , Morreau Hans , Caldes Trinidad 
Published: October 2007

Abstract
Purpose: A subset of colorectal cancers (CRC) arises in families that, despite fulfilling clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC), do not show evidence of a mismatch repair (MMR) deficiency. The main objective of this study was to characterize these tumors at the molecular level.
Experimental Design: After comprehensive germ line mutation scanning, microsatellite analysis, and MMR protein expressions, we selected a well-defined cohort of 57 colorectal tumors with no evidence of MMR defects. In this group of tumors, we analyzed KRAS, BRAF, and APC somatic mutations, as well as methylguanine methyltransferase (MGMT) and β-catenin expression. We correlated these alterations with clinicopathologic data and explored the relationship between KRAS G &gt; A transitions and lack of MGMT expression.
Results: The mutation profile at the RAS/RAF/MAPK pathway mimics sporadic microsatellite-stable CRCs. We found an average age of diagnosis 10 years older in KRAS-mutated patients (P = 0.001). In addition, we show that KRAS G &gt; A transitions are actively selected by tumors, regardless of MGMT status. Similarities with HNPCC high–microsatellite instability tumors are observed when APC data are analyzed. The APC mutation rate was low and small insertions/deletions accounted for 70% of the alterations. In addition, we found a low frequency of β-catenin nuclear staining. Finally, we did not find evidence of tumors arising in individuals from the same family sharing molecular features.
Conclusions: We show evidence that CRC tumors arising in HNPCC families without MMR alterations have distinctive molecular features. Overall, our work shows that systematic analysis of somatic alterations in a well-defined subset of CRCs is a good approach to provide new insights into the mechanisms of colorectal carcinogenesis.
Herpes Simplex Virus Us3(−) Mutant as Oncolytic Strategy and Synergizes with Phosphatidylinositol 3-Kinase-Akt–Targeting Molecular Therapeutics
Authors: Liu Ta-Chiang , Wakimoto Hiroaki , Martuza Robert L. , Rabkin Samuel D. 
Published: October 2007

Abstract
Purpose: Oncolytic herpes simplex virus (HSV) vectors have shown safety in clinical trials, but efficacy remains unsatisfactory. Novel HSV vectors that possess tumor selectivity with enhanced potency are therefore needed. The gene product of HSV Us3 protects virus-infected cells from apoptosis, a cellular pathway frequently dysfunctional in tumors. We hypothesized that Us3 mutants, whose replication would be inhibited by apoptosis in normal cells, would be selective for tumor cells.
Experimental Design: HSV mutants G207 (ribonucleotide reductase−/γ34.5−), R7041 (Us3−), and R7306 (Us3 revertant) were tested in normal and tumor cells for viral replication, antitumoral potency, apoptosis induction, and Akt activation. Safety and biodistribution after systemic administration and antitumoral efficacy after intratumoral (i.t.) or i.v. administration were examined.
Results: Us3 deletion results in up to 3-log replication inhibition in normal cells, which correlates with enhanced apoptosis induction. In contrast, R7041 replicates very well in tumor cells, showing 1 to 2 log greater yield than G207. In vivo, R7041 shows no signs of toxicity after systemic delivery in both immunocompetent and immunodeficient mice and shows preferential and prolonged replication in tumors compared with normal tissues. R7041 displays significant antitumoral efficacy after i.t. or i.v. administration. An additional feature of Us3 mutants is enhanced Akt activation compared with wild-type infection, which sensitizes cells to phosphatidylinositol 3-kinase-Akt inhibitors (LY294002, Akt inhibitor IV), shown by synergistic antitumoral activity in vitro and enhanced efficacy in vivo.
Conclusions: Us3 deletion confers enhanced tumor selectivity and antitumoral potency on herpes simplex virus-1 and provides for a novel mechanism of combination therapy with phosphatidylinositol 3-kinase-Akt–targeting molecular therapeutics.
Eotaxin-2 and Colorectal Cancer: A Potential Target for Immune Therapy
Authors: Cheadle Eleanor J. , Riyad Kallingal , Subar Daren , Rothwell Dominic G. , Ashton Garry , Batha Hayley , Sherlock David J. , Hawkins Robert E. , Gilham David E. 
Published: October 2007

AbstractPurpose: To study the production of chemokines by colorectal hepatic metastases.Experimental Design: Biopsies of resected colorectal hepatic metastases and nonneoplastic adjacent liver tissue were screened for chemokines using protein arrays and results were confirmed by ELISA and immunohistochemistry.Results: Two chemokines, eotaxin-2 and MCP-1, were found at elevated levels within the tumor biopsy compared with adjacent liver. The relative increase in expression from tumor was much higher for eotaxin-2 than MCP-1, with 10 of 25 donors having a &gt;100-fold increase in expression compared with 0 of 24 donors for MCP-1. In a parallel analysis, eotaxin-2 was also found at elevated levels in the tumor region of primary colorectal cancer biopsies. Immunohistochemical staining indicated that carcinoembryonic antigen–positive tumor cells stained strongly for eotaxin-2, implicating these cells as the predominant source of the chemokine. In vitro studies confirmed that several colorectal tumor lines produce eotaxin-2 and that secretion of this chemokine could be depressed by IFN-γ and enhanced by the Th2-type cytokines interleukin-4 and interleukin-13. Jurkat T cells were engineered to express the receptor for eotaxin-2 (CCR3). These cells effectively migrated in response to eotaxin-2 protein, suggesting that immune cells gene modified to express a chemokine receptor may have improved abilities to home to tumor.Conclusions: Taken together, these observations confirm eotaxin-2 as a chemokine strongly associated with primary and metastatic tumors of colorectal origin. Furthermore, the importance of this result may be a useful tool in the development of targeted therapeutic approaches to colorectal tumors.
Spatiotemporal Variations in Growing Season Exchanges of CO2, H2O, and Sensible Heat in Agricultural Fields of the Southern Great Plains
Authors: Fischer Marc L. , Billesbach David P. , Berry Joseph A. , Riley William J. , Torn Margaret S. 
Published: October 2007

Abstract
Climate, vegetation cover, and management create finescale heterogeneity in unirrigated agricultural regions, with important but not well-quantified consequences for spatial and temporal variations in surface CO2, water, and heat fluxes. Eddy covariance fluxes were measured in seven agricultural fields—comprising winter wheat, pasture, and sorghum—in the U.S. Southern Great Plains (SGP) during the 2001–03 growing seasons. Land cover was the dominant source of variation in surface fluxes, with 50%–100% differences between fields planted in winter–spring versus fields planted in summer. Interannual variation was driven mainly by precipitation, which varied more than twofold between years. Peak aboveground biomass and growing season net ecosystem exchange (NEE) of CO2 increased in rough proportion to precipitation. Based on a partitioning of gross fluxes with a regression model, ecosystem respiration increased linearly with gross primary production, but with an offset that increased near the time of seed production. Because the regression model was designed for well-watered periods, it successfully retrieved NEE and ecosystem parameters during the peak growing season and identified periods of moisture limitation during the summer. In summary, the effects of crop type, land management, and water limitation on carbon, water, and energy fluxes were large. Capturing the controlling factors in landscape-scale models will be necessary to estimate the ecological feedbacks to climate and other environmental impacts associated with changing human needs for agricultural production of food, fiber, and energy.
Precipitation and Circulation Covariability in the Extratropics
Authors: Garreaud RenéD. 
Published: October 2007

Abstract
Extratropical precipitation is primarily produced by cold and warm fronts associated with surface cyclones and upper-level troughs. The growth of these midlatitude storms is partially controlled by the dry baroclinicity of the troposphere, which in turn can be roughly quantified by the intensity of the upper-level zonal flow. Orographic rainfall, an important component of the precipitation in several midlatitude regions, is also partially determined by the intensity of the cross-mountain midlevel winds. Thus, at monthly and longer time scales, variations of precipitation and zonal flow aloft (as well as wind shear) at a given location should exhibit some degree of coherence. In this work the local covariability of these variables is documented over intermonthly and interannual time scales, using global precipitation products and atmospheric reanalysis from 1979 to 2004. The spatial correspondence between the precipitation and two indices of synoptic activity in the extratropics is also documented.
The local correlation (r0) between monthly anomalies of precipitation and upper-level (300 hPa) zonal flow varies in space, from moderately and even highly significant values (r0 ∼ 0.3 to 0.7) over the midlatitude oceans to near zero over the interior of continental areas. Broadly similar results are found when considering the monthly variance of the high-pass-filtered meridional wind (an index of eddy activity) or the midlevel Eady growth rate. The local correlation map between precipitation and low-level (850 hPa) zonal flow is similar to its upper-level counterpart, but the correlations over open ocean are somewhat weaker, while orographic effects show up more clearly. The correlations are positive and large upstream of the major north–south-oriented mountain ranges, as strong westerlies promote upslope rain in addition to storm-related precipitation. In contrast, the correlation tends to be negative downstream of the ranges, as strong westerlies enhance the rain shadow effects over the lee side.
Inclusion of Ice Microphysics in the NCAR Community Atmospheric Model Version 3 (CAM3)
Authors: Liu Xiaohong , Penner Joyce E. , Ghan Steven J. , Wang Minghuai 
Published: October 2007

AbstractA prognostic equation for ice crystal number concentration together with an ice nucleation scheme are implemented in the National Center for Atmospheric Research (NCAR) Community Atmospheric Model version 3 (CAM3) with the aim of studying the indirect effect of aerosols on cold clouds. The effective radius of ice crystals, which is used in the radiation and gravitational settlement calculations, is now calculated from model-predicted mass and number of ice crystals rather than diagnosed as a function of temperature. A water vapor deposition scheme is added to replace the condensation and evaporation (C–E) in the standard CAM3 for ice clouds. The repartitioning of total water into liquid and ice in mixed-phase clouds as a function of temperature is removed, and ice supersaturation is allowed. The predicted ice water content in the modified CAM3 is in better agreement with the Aura Microwave Limb Sounder (MLS) data than that in the standard CAM3. The cirrus cloud fraction near the tropical tropopause, which is underestimated in the standard CAM3 as revealed through comparison with the Stratospheric Aerosol and Gas Experiment II (SAGE II) data, is increased by 20%–30%, and the cold temperature bias there is reduced by 1–2 K. However, an increase in the cloud fraction in polar regions makes the underestimation (by ∼20 W m−2) of downwelling shortwave radiation in the standard CAM3 even worse. A sensitivity test reducing the threshold relative humidity with respect to ice (RHi) for heterogeneous ice nucleation from 120% to 105% (representing nearly perfect ice nuclei) increases the global cloud cover by 1.4%, temperature near the tropical tropopause by 4–5 K, and water vapor in the stratosphere by 50%–80%.
A Comparison of Forecast Errors in CAM2 and CAM3 at the ARM Southern Great Plains Site
Authors: Williamson David L. , Olson Jerry G. 
Published: October 2007

Abstract
The authors compare short forecast errors and the balance of terms in the moisture and temperature prediction equations that lead to those errors for the Community Atmosphere Model versions 2 and 3 (CAM2 and CAM3, respectively) at T42 truncation. The comparisons are made for an individual model column from global model forecasts at the Atmospheric Radiation Measurement Program (ARM) Southern Great Plains site for the April 1997 and June–July 1997 intensive observing periods. The goal is to provide insight into parameterization errors in the CAM, which ultimately should lead to improvements in the way processes are modeled. The atmospheric initial conditions are obtained from the 40-yr ECMWF Re-Analysis (ERA-40). The land initial conditions are spun up to be consistent with those analyses. The differences between the model formulations that are responsible for the major differences in the forecast errors and/or parameterization behaviors are identified. A sequence of experiments is performed, accumulating the changes from CAM3 back toward CAM2 to demonstrate the effect of the differences in formulations.
In June–July 1997 the CAM3 temperature and moisture forecast errors were larger than those of CAM2. The terms identified as being responsible for the differences are 1) the convective time scale assumed for the Zhang–McFarlane deep convection, 2) the energy associated with the conversion between water and ice of the rain associated with the Zhang–McFarlane convection parameterization, and 3) the dependence of the rainfall evaporation on cloud fraction. In April 1997 the CAM2 and CAM3 temperature and moisture forecast errors are very similar, but different tendencies arising from modifications to one parameterization component are compensated by responding changes in another component to yield the same total moisture tendency. The addition of detrainment of water in CAM3 by the Hack shallow convection to the prognostic cloud water scheme is balanced by a responding difference in the advective tendency. A halving of the time scale assumed for the Hack shallow convection was compensated by a responding change in the prognostic cloud water. Changes to the cloud fraction parameterization affect the radiative heating, which in turn modifies the stability of the atmospheric column and affects the convection. The resulting changes in convection tendency are balanced by responding changes in the prognostic cloud water parameterization tendency.
Roles of the Indian Ocean in the Australian Summer Monsoon–ENSO Relationship
Authors: Wu Renguang , Kirtman Ben P. 
Published: October 2007

Abstract
A negative correlation is observed between interannual variations of the Australian summer monsoon (ASM) and El Niño–Southern Oscillation (ENSO). This negative relationship is well simulated in the Center for Ocean–Land–Atmosphere (COLA) interactive ensemble coupled general circulation model (CGCM). The present study investigates roles of the Indian Ocean in the ASM–ENSO relationship through controlled numerical experiments with the COLA CGCM. It is found that air–sea coupling in the Indian Ocean plays an important role in maintaining the negative ASM–ENSO relationship. When the Indian Ocean is decoupled from the atmosphere, the ASM–ENSO relationship is significantly weakened or even masked by the internal atmospheric variability. This change in the ASM–ENSO relationship is related to complementary roles of Indian Ocean sea surface temperature (SST) anomalies in the ASM variability and feedbacks from the Indian Ocean on ENSO. Without a coupled Indian Ocean, the ENSO amplitude is reduced, leading to a decrease in the ENSO-induced ASM variability, and the constructive impacts of the Indian Ocean SST anomalies on the ASM variability are substantially reduced. This reduces the ASM variability related to ENSO. Consistent with the change in the ASM–ENSO relationship, the local air–sea relationship in the ASM region displays important differences with and without a coupled Indian Ocean.
The long-term change in the ASM–ENSO relationship is related to that in ENSO amplitude in the interactive ensemble coupled model. A relatively higher (lower) negative correlation occurs in periods of larger (smaller) ENSO amplitude. This relationship, however, is not clear in the anomaly coupled model with only one atmospheric realization. This difference is attributed to changes in the signal-to-noise ratio in the ASM variability. A comparison is made with observations and the long-term change in the Indian summer monsoon (ISM)–ENSO relationship in the model.