bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plk1 Inhibition Enhances the Efficacy of Androgen Signaling Blockade in Castration-Resistant Prostate Cancer
Authors: Zhang Zhe , Hou Xianzeng , Shao Chen , Li Junjie , Cheng Ji-Xin , Kuang Shihuan , Ahmad Nihal , Ratliff Timothy , Liu Xiaoqi 
Published: September 2014

Abstract
Prostate cancer is thought to be driven by oxidative stress, lipid metabolism, androgen receptor (AR) signaling, and activation of the PI3K–AKT–mTOR pathway, but it is uncertain how they may become coordinated during progression to castration-resistant disease that remains incurable. The mitotic kinase polo-like kinase 1 (Plk1) is elevated in prostate cancer, where its expression is linked to tumor grade. Notably, Plk1 signaling and lipid metabolism were identified recently as two of the top five most upregulated pathways in a mouse xenograft model of human prostate cancer. Herein, we show that oxidative stress activates both the PI3K–AKT–mTOR pathway and AR signaling in a Plk1-dependent manner in prostate cells. Inhibition of the PI3K–AKT–mTOR pathway prevented oxidative stress-induced activation of AR signaling. Plk1 modulation also affected cholesteryl ester accumulation in prostate cancer via the SREBP pathway. Finally, Plk1 inhibition enhanced cellular responses to androgen signaling inhibitors (ASI) and overcame ASI resistance in both cultured prostate cancer cells and patient-derived tumor xenografts. Given that activation of AR signaling and the PI3K–AKT–mTOR pathway is sufficient to elevate SREBP-dependent expression of key lipid biosynthesis enzymes in castration-resistant prostate cancer (CRPC), our findings argued that Plk1 activation was responsible for coordinating and driving these processes to promote and sustain the development of this advanced stage of disease. Overall, our results offer a strong mechanistic rationale to evaluate Plk1 inhibitors in combination drug trials to enhance the efficacy of ASIs in CRPC. Cancer Res; 74(22); 6635–47. ©2014 AACR.
Clinical Relevance of KRAS-Mutated Subclones Detected with Picodroplet Digital PCR in Advanced Colorectal Cancer Treated with Anti-EGFR Therapy
Authors: Laurent-Puig Pierre , Pekin Deniz , Normand Corinne , Kotsopoulos Steve K. , Nizard Philippe , Perez-Toralla Karla , Rowell Rachel , Olson Jeff , Srinivasan Preethi , Le Corre Delphine , Hor Thevy , El Harrak Zakaria , Li Xinyu , Link Darren R. , Bouché Olivier , Emile Jean-François , Landi Bruno , Boige Valérie , Hutchison J. Brian , Taly Valerie 
Published: September 2014

Abstract
Purpose: KRAS mutations are predictive of nonresponse to anti-EGFR therapies in metastatic colorectal cancer (mCRC). However, only 50% of nonmutated patients benefit from them. KRAS-mutated subclonal populations nondetectable by conventional methods have been suggested as the cause of early progression. Molecular analysis technology with high sensitivity and precision is required to test this hypothesis.
Experimental Design: From two cohorts of patients with mCRC, 136 KRAS, NRAS, and BRAF wild-type tumors with sufficient tumor material to perform highly sensitive picodroplet digital PCR (dPCR) and 41 KRAS-mutated tumors were selected. All these patients were treated by anti-EGFR therapy. dPCR was used for KRAS or BRAF mutation screening and compared with qPCR. Progression-free survival (PFS) and overall survival (OS) were analyzed according to the KRAS-mutated allele fraction.
Results: In addition to the confirmation of the 41 patients with KRAS-mutated tumors, dPCR also identified KRAS mutations in 22 samples considered as KRAS wild-type by qPCR. The fraction of KRAS-mutated allele quantified by dPCR was inversely correlated with anti-EGFR therapy response rate (P &lt; 0.001). In a Cox model, the fraction of KRAS-mutated allele was associated with worse PFS and OS. Patients with less than 1% of mutant KRAS allele have similar PFS and OS than those with wild-type KRAS tumors.
Conclusions: This study suggests that patients with mCRC with KRAS-mutated subclones (at least those with a KRAS-mutated subclones fraction lower or equal to 1%) had a benefit from anti-EGFR therapies. Clin Cancer Res; 21(5); 1087–97. ©2014 AACR.
Combination Therapy for KIT-Mutant Mast Cells: Targeting Constitutive NFAT and KIT Activity
Authors: Macleod Alison C. , Klug Lillian R. , Patterson Janice , Griffith Diana J. , Beadling Carol , Town Ajia , Heinrich Michael C. 
Published: September 2014

Abstract
Resistant KIT mutations have hindered the development of KIT kinase inhibitors for treatment of patients with systemic mastocytosis. The goal of this research was to characterize the synergistic effects of a novel combination therapy involving inhibition of KIT and calcineurin phosphatase, a nuclear factor of activated T cells (NFAT) regulator, using a panel of KIT-mutant mast cell lines. The effects of monotherapy or combination therapy on the cellular viability/survival of KIT-mutant mast cells were evaluated. In addition, NFAT-dependent transcriptional activity was monitored in a representative cell line to evaluate the mechanisms responsible for the efficacy of combination therapy. Finally, shRNA was used to stably knockdown calcineurin expression to confirm the role of calcineurin in the observed synergy. The combination of a KIT inhibitor and a calcineurin phosphatase inhibitor (CNPI) synergized to reduce cell viability and induce apoptosis in six distinct KIT-mutant mast cell lines. Both KIT inhibitors and CNPIs were found to decrease NFAT-dependent transcriptional activity. NFAT-specific inhibitors induced similar synergistic apoptosis induction as CNPIs when combined with a KIT inhibitor. Notably, NFAT was constitutively active in each KIT-mutant cell line tested. Knockdown of calcineurin subunit PPP3R1 sensitized cells to KIT inhibition and increased NFAT phosphorylation and cytoplasmic localization. Constitutive activation of NFAT appears to represent a novel and targetable characteristic of KIT-mutant mast cell disease. Our studies suggest that combining KIT inhibition with NFAT inhibition might represent a new treatment strategy for mast cell disease. Mol Cancer Ther; 13(12); 2840–51. ©2014 AACR.
SNAI2 Modulates Colorectal Cancer 5-Fluorouracil Sensitivity through miR145 Repression
Authors: Findlay Victoria J. , Wang Cindy , Nogueira Lourdes M. , Hurst Katie , Quirk Daniel , Ethier Stephen P. , Staveley O'Carroll Kevin F. , Watson Dennis K. , Camp E. Ramsay 
Published: September 2014

Abstract
Epithelial-to-mesenchymal transition (EMT) has been associated with poor treatment outcomes in various malignancies and is inversely associated with miRNA145 expression. Therefore, we hypothesized that SNAI2 (Slug) may mediate 5-fluorouracil (5FU) chemotherapy resistance through inhibition of miR145 in colorectal cancer and thus represents a novel therapeutic target to enhance current colorectal cancer treatment strategies. Compared with parental DLD1 colon cancer cells, 5FU-resistant (5FUr) DLD1 cells demonstrated features of EMT, including &gt;2-fold enhanced invasion (P &lt; 0.001) and migration, suppressed E-cadherin expression, and 2-fold increased SNAI2 expression. DLD1 and HCT116 cells with stable expression of SNAI2 (DLD1/SNAI2; HCT116/SNAI2) also demonstrated EMT features such as the decreased E-cadherin as well as significantly decreased miR145 expression, as compared with control empty vector cells. On the basis of an miR145 luciferase promoter assay, we demonstrated that SNAI2 repressed activity of the miR145 promoter in the DLD1 and HCT116 cells. In addition, the ectopic expressing SNAI2 cell lines demonstrated decreased 5FU sensitivity, and, conversely, miR145 replacement significantly enhanced 5FU sensitivity. In the parental SW620 colon cancer cell line with high SNAI2 and low miR145 levels, inhibition of SNAI2 directly with short hairpin sequence for SNAI2 and miR145 replacement therapy both decreased vimentin expression and increased in vitro 5FU sensitivity. In pretreatment rectal cancer patient biopsy samples, low miR145 expression levels correlated with poor response to neoadjuvant 5FU-based chemoradiation. These results suggested that the SNAI2:miR145 pathway may represent a novel clinical therapeutic target in colorectal cancer and may serve as a response predictor to chemoradiation therapy. Mol Cancer Ther; 13(11); 2713–26. ©2014 AACR.
An Antimesothelin-Monomethyl Auristatin E Conjugate with Potent Antitumor Activity in Ovarian, Pancreatic, and Mesothelioma Models
Authors: Scales Suzie J. , Gupta Nidhi , Pacheco Glenn , Firestein Ron , French Dorothy M. , Koeppen Hartmut , Rangell Linda , Barry-Hamilton Vivian , Luis Elizabeth , Chuh Josefa , Zhang Yin , Ingle Gladys S. , Fourie-O'Donohue Aimee , Kozak Katherine R. , Ross Sarajane , Dennis Mark S. , Spencer Susan D. 
Published: September 2014

Abstract
Mesothelin (MSLN) is an attractive target for antibody–drug conjugate therapy because it is highly expressed in various epithelial cancers, with normal expression limited to nondividing mesothelia. We generated novel antimesothelin antibodies and conjugated an internalizing one (7D9) to the microtubule-disrupting drugs monomethyl auristatin E (MMAE) and MMAF, finding the most effective to be MMAE with a lysosomal protease-cleavable valine–citrulline linker. The humanized (h7D9.v3) version, αMSLN-MMAE, specifically targeted mesothelin-expressing cells and inhibited their proliferation with an IC50 of 0.3 nmol/L. Because the antitumor activity of an antimesothelin immunotoxin (SS1P) in transfected mesothelin models did not translate to the clinic, we carefully selected in vivo efficacy models endogenously expressing clinically relevant levels of mesothelin, after scoring mesothelin levels in ovarian, pancreatic, and mesothelioma tumors by immunohistochemistry. We found that endogenous mesothelin in cancer cells is upregulated in vivo and identified two suitable xenograft models for each of these three indications. A single dose of αMSLN-MMAE profoundly inhibited or regressed tumor growth in a dose-dependent manner in all six models, including two patient-derived tumor xenografts. The robust and durable efficacy of αMSLN-MMAE in preclinical models of ovarian, mesothelioma, and pancreatic cancers justifies the ongoing phase I clinical trial. Mol Cancer Ther; 13(11); 2630–40. ©2014 AACR.
lincRNA-RoR and miR-145 Regulate Invasion in Triple-Negative Breast Cancer via Targeting ARF6
Authors: Eades Gabriel , Wolfson Benjamin , Zhang Yongshu , Li Qinglin , Yao Yuan , Zhou Qun 
Published: September 2014

Abstract
Triple-negative (ER−, HER2−, PR−) breast cancer (TNBC) is an aggressive disease with a poor prognosis with no available molecularly targeted therapy. Silencing of microRNA-145 (miR-145) may be a defining marker of TNBC based on molecular profiling and deep sequencing. Therefore, the molecular mechanism behind miR-145 downregulation in TNBC was examined. Overexpression of the long intergenic noncoding RNA regulator of reprogramming, lincRNA-RoR, functions as a competitive endogenous RNA sponge in TNBC. Interestingly, lincRNA-RoR is dramatically upregulated in TNBC and in metastatic disease and knockdown restores miR-145 expression. Previous reports suggest that miR-145 has growth-suppressive activity in some breast cancers; however, these data in TNBC indicate that miR-145 does not affect proliferation or apoptosis but instead, miR-145 regulates tumor cell invasion. Investigation of miR-145-regulated pathways involved in tumor invasion revealed a novel target, the small GTPase ADP-ribosylation factor 6 (Arf6). Subsequent analysis demonstrated that ARF6, a known regulator of breast tumor cell invasion, is dramatically upregulated in TNBC and in breast tumor metastasis. Mechanistically, ARF6 regulates E-cadherin localization and affects cell–cell adhesion. These results reveal a lincRNA-RoR/miR-145/ARF6 pathway that regulates invasion in TNBCs.
Implications: The lincRNA-RoR/miR-145/ARF6 pathway is critical to TNBC metastasis and could serve as biomarkers or therapeutic targets for improving survival. Mol Cancer Res; 13(2); 330–8. ©2014 AACR.
Candidate Pathway-Based Genome-Wide Association Studies Identify Novel Associations of Genomic Variants in the Complement System Associated With Coronary Artery Disease
Authors: Xu Chengqi , Yang Qin , Xiong Hongbo , Wang Longfei , Cai Jianping , Wang Fan , Li Sisi , Chen Jing , Wang Chuchu , Wang Dan , Xiong Xin , Wang Pengyun , Zhao Yuanyuan , Wang Xiaojing , Huang Yufeng , Chen Shanshan , Yin Dan , Li Xiuchun , Liu Ying , Liu Jinqiu , Wang Jingjing , Li Hui , Ke Tie , Ren Xiang , Wu Yanxia , Wu Gang , Wan Jing , Zhang Rongfeng , Wu Tangchun , Wang Junhan , Xia Yunlong , Yang Yanzong , Cheng Xiang , Liao Yuhua , Chen Qiuyun , Zhou Yanhong , He Qing , Tu Xin , Wang Qing K. 
Published: September 2014

Background—
Genomic variants identified by genome-wide association studies (GWAS) explain <20% of heritability of coronary artery disease (CAD), thus many risk variants remain missing for CAD. Identification of new variants may unravel new biological pathways and genetic mechanisms for CAD. To identify new variants associated with CAD, we developed a candidate pathway-based GWAS by integrating expression quantitative loci analysis and mining of GWAS data with variants in a candidate pathway.

Methods and Results—

Mining of GWAS data was performed to analyze variants in 32 complement system genes for positive association with CAD. Functional variants in genes showing positive association were then identified by searching existing expression quantitative loci databases and validated by real-time reverse transcription polymerase chain reaction. A follow-up case–control design was then used to determine whether the functional variants are associated with CAD in 2 independent GeneID Chinese populations. Candidate pathway-based GWAS identified positive association between variants in
C3AR1
and
C6
and CAD. Two functional variants, rs7842 in
C3AR1
and rs4400166 in
C6
, were found to be associated with expression levels of
C3AR1
and
C6
, respectively. Significant association was identified between rs7842 and CAD (
P
=3.99×10
−6
; odds ratio, 1.47) and between rs4400166 and CAD (
P
=9.30×10
−3
; odds ratio, 1.24) in the validation cohort. The significant findings were confirmed in the replication cohort (
P
=1.53×10
−5
; odds ratio, 1.37 for rs7842;
P
=8.41×10
−3
; odds ratio, 1.21 for rs4400166).

Conclusions—

Integration of GWAS with biological pathways and expression quantitative loci is effective in identifying new risk variants for CAD. Functional variants increasing
C3AR1
and
C6
expression were shown to confer significant risk of CAD for the first time.
Comparison of the Seattle Angina Questionnaire With Daily Angina Diary in the TERISA Clinical Trial
Authors: Arnold Suzanne V. , Kosiborod Mikhail , Li Yan , Jones Philip G. , Yue Patrick , Belardinelli Luiz , Spertus John A. 
Published: September 2014

Background—
As new techniques emerge to quantify patients’ health status, new opportunities are created to validate patient-reported outcome questionnaires. The Seattle Angina Questionnaire (SAQ), a widely used coronary artery disease–specific health status tool, has not been validated against daily records of angina frequency and sublingual nitroglycerin (SL NTG) use. Additional evidence supporting the validity of the SAQ could justify its broader use as an outcome for clinical studies designed to evaluate treatments that may improve patients’ symptoms, function, and quality of life.

Methods and Results—
We used data from 917 patients with type 2 diabetes mellitus, coronary artery disease, and stable angina from the multinational Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) trial. The number of angina episodes and SL NTG used were recorded and transmitted daily using an electronic diary. In cross-sectional analyses, there was a strong relationship between the 2 SAQ angina frequency questions (ie, frequency of angina and SL NTG use) and the corresponding diary responses, with correlation coefficients of −0.64 for angina frequency (95% confidence interval,−0.68 to −0.60) and −0.69 for SL NTG use (95% confidence interval, −0.73 to −0.66). Longitudinally, changes in SAQ angina frequency scores from day 1 to week 8 also correlated with changes in angina frequency (−0.42; 95% confidence interval, −0.48 to −0.30) and SL NTG use by diary (−0.38; 95% confidence interval, −0.43 to −0.32) over the corresponding time period. Correlations were similar when stratified by age, sex, or geography.

Conclusions—
In a multinational cohort of patients with stable angina, the SAQ angina frequency domain was significantly correlated, both cross sectionally and longitudinally, with daily diary entries of angina frequency and SL NTG use. These data further support the validity of the SAQ angina frequency domain across a broad spectrum of patients with stable angina.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01425359.
New synonymies and new records of Afrotropical and Madagascan Pentatominae (Hemiptera: Heteroptera: Pentatomidae)
Authors: KMENT PETR , JINDRA ZDENĚK , RIDER DAVID A. 
Published: September 2014

The following new synonymies within the family Pentatomidae, subfamily Pentatominae, are established: Aesula Stål, 1876 = Pseudacrosternum Day, 1965, syn. nov. (Nezarini), Aesula viridissima (Signoret, 1861) = Aesula signoretiana Kirkaldy, 1909, syn. nov. = Pseudacrosternum cachani Day, 1965, syn. nov. = Pseudacrosternum cachani var. scutellatum Day, 1965, syn. nov., and Andocides vittaticeps (Stål, 1858) = Andocides vittaticeps var. viridescens Schumacher, 1913, syn. nov. Afrania brachyptera (Schaum, 1853), stat. restit., is restored as the oldest available name for that species, with Afrania wahlbergi Stål, 1854, syn. restit., being its junior synonym. Lectotype of Pentatoma viridissima Signoret, 1861 is designated, and lectotype designation of Pseudolerida incerta (Schouteden, 1909) is commented. The following new or confirmed state records are provided: Cappaeini: Leridella kenyensis Jeannel, 1913 (Cameroon), Paralerida bolivari (Schouteden, 1904) (Republic of the Congo, Uganda), P. niokana Linnavuori, 1982 (Uganda), Tripanda (Tripanda) dispar Schouteden, 1964 (Cameroon, Ghana, Liberia), T. (T.) horacekorum Kment & Jindra, 2009 (Cameroon, Guinea), T. (T.) jurickorum Kment & Jindra, 2009 (Gabon, Ivory Coast), T. (T.) longiceps (Villiers, 1967) (Democratic Republic of the Congo, Gabon), T. (T.) signitenens (Distant, 1898) (Democratic Republic of the Congo, Mozambique), T. (Tenerva) decorata (Jensen-Haarup, 1937) (Kenya, Oman, Tanzania); Carpocorini: Andocides vittaticeps (Angola); Diploxyini: Acoloba lanceolata (Fabricius, 1803) (Angola, Central African Republic, Zambia, Zimbabwe); Eysarcorini: Pseudolerida bitalensis Schouteden, 1958 (Cameroon), Pseudolerida incerta (Equatorial Guinea: Bioko Island, Tanzania, Uganda); Myrocheini: Humria bimaculicollis Linnavuori, 1975 (Botswana, Democratic Republic of the Congo, Guinea, Kenya, Mozambique, Namibia, South Africa, Zambia, Zimbabwe); Strachiini: Afrania brachyptera (Schaum, 1853) (Botswana, Democratic Republic of the Congo; Tanzania: Tanganyika, Zanzibar; Uganda). Variability of Tripanda jurickorum, Pseudolerida incerta and Humria bimaculicollis is discussed.
Large-Scale Atmospheric and Oceanic Conditions for Extensive and Persistent Icing Events in China
Authors: Wang Zunya , Yang Song , Ke Zongjian , Jiang Xingwen 
Published: September 2014

AbstractBased on the observational datasets of rime and glaze from 743 stations in China and the atmospheric circulation data from the NCEP–NCAR reanalysis during 1954–2009, large-scale atmospheric and oceanic conditions for extensive and persistent rime and glaze events were examined with a composite analysis. Results show that rime events mostly occur in northern China while glaze events are mainly observed in southern China. The icing events are accompanied by low temperature and high humidity but not necessarily by above-normal precipitation. The Asian low, blocking highs, strong moisture transport, and an inversion layer related to major abnormal circulation systems contribute to the occurrence and persistence of icing events in China. The Ural blocking high plays a major role in the glaze events, and the Okhotsk blocking high is closely related to the rime events. For glaze events, extratropical circulation anomalies and the southward outbreak of cold air play a dominant role. In contrast, the strong northward transport of warm and moist airflows plays a leading role and the blocking high and the southward outbreak of extratropical cold air take a supporting role for rime events. There is nearly an equal chance for occurrences of rime events under La Niña and El Niño backgrounds. However, glaze events more likely occur under the background of La Niña. Additionally, the sea surface temperatures from the tropical Indian Ocean to the tropical northwestern Pacific Ocean also contribute to the occurrence and maintenance of icing events in China.
The Transient Circulation Response to Radiative Forcings and Sea Surface Warming*
Authors: Staten Paul W. , Reichler Thomas , Lu Jian 
Published: September 2014

Abstract
Tropospheric circulation shifts have strong potential to impact surface climate. However, the magnitude of these shifts in a changing climate and the attending regional hydrological changes are difficult to project. Part of this difficulty arises from the lack of understanding of the physical mechanisms behind the circulation shifts themselves. To better delineate circulation shifts and their respective causes the circulation response is decomposed into 1) the “direct” response to radiative forcings themselves and 2) the “indirect” response to changing sea surface temperatures. Using ensembles of 90-day climate model simulations with immediate switch-on forcings, including perturbed greenhouse gas concentrations, stratospheric ozone concentrations, and sea surface temperatures, this paper documents the direct and indirect transient responses of the zonal-mean general circulation, and investigates the roles of previously proposed mechanisms in shifting the midlatitude jet. It is found that both the direct and indirect wind responses often begin in the lower stratosphere. Changes in midlatitude eddies are ubiquitous and synchronous with the midlatitude zonal wind response. Shifts in the critical latitude of wave absorption on either flank of the jet are not indicted as primary factors for the poleward-shifting jet, although some evidence for increasing equatorward wave reflection over the Southern Hemisphere in response to sea surface warming is seen. Mechanisms for the Northern Hemisphere jet shift are less clear.
An Improved Second-Moment Closure Model of Langmuir Turbulence
Authors: Harcourt Ramsey R. 
Published: September 2014

AbstractA prior second-moment closure (SMC) model of Langmuir turbulence in the upper ocean is modified by introduction of inhomogeneous pressure–strain rate and pressure–scalar gradient closures that are similar to the high Reynolds number, near-wall treatments for solid wall boundaries. This repairs several near-surface defects in the algebraic Reynolds stress model (ARSM) of the prior SMC by redirecting Craik–Leibovich (CL) vortex force production of turbulent kinetic energy out of the surface-normal vertical component and into a horizontal one, with an associated reduction in near-surface CL production of vertical momentum flux. A surface-proximity function introduces a new closure parameter that is tuned to previous results from large-eddy simulations (LES), and a numerical SMC model based on stability functions from the new ARSM produces improved comparisons with mean profiles of momentum and TKE components from steady-state LES results forced by aligned wind and waves. An examination of higher-order quasi-homogeneous closures and a numerical simulation of Langmuir turbulence away from the boundaries both show the near-surface inhomogeneous closure to be both necessary for consistency and preferable for simplicity.