bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ‘dirty dozen’: socio‐economic factors amplify the invasion potential of 12 high‐risk aquatic invasive species in Great Britain and Ireland
Authors: Gallardo Belinda , Aldridge David C. 
Published: May 2013

Summary

Aquatic invasive species are a growing concern to environmental managers because of their diverse impacts on aquatic biodiversity and high eradication costs, necessitating effective management policies. In this study, we evaluate the ability of environmental and socio‐economic factors to predict the risk of invasion in Great Britain and Ireland of 12 potential aquatic invaders covering all major aquatic groups. Despite their potential to inform risk assessments, this is the first time socio‐economic factors related to propagule pressure have been specifically integrated in distribution modelling.

Species distribution models (SDM, MaxEnt algorithm) were calibrated with a set of environmental factors (e.g. bioclimatic, geographical and geological) and integrated with socio‐economic (e.g. human influence index, population density, closeness to ports) predictors.

The inclusion of socio‐economic factors in SDM did not affect accuracy scores (AUC already >0·90), but their effects were more pronounced in spatial predictions, resulting in up to a sixfold amplification of the area predicted suitable for each species. Despite the inclusion of potential surrogates of water chemistry (e.g. geology) and propagule pressure (e.g. population density), temperature‐related variables were most important predictors of aquatic species' distributions.

According to SDM, the environmental suitability for a suite of invaders belonging to different taxonomic groups and regions of origin is greatest in east and south‐east England and decreases towards the north and west. Multiple invasions in this region are of special concern, as species are known to modify their habitat facilitating subsequent invasions, thereby potentially exacerbating their impacts.

Major management regions to be prioritized in monitoring programmes include the Humber, Thames and Anglian River Basin Districts. Species of special concern include a mysid (Hemimysis anomala), a gammarid (Dikerogammarus villosus), a plant (Ludwigia grandiflora) and two crayfishes (Procambarus clarkii and P. fallax).

Synthesis and Applications. The inclusion of socio‐economic factors in species distribution models has the potential to improve predictions of areas under a highest risk of multiple invasions and to help disentangle the complex interplay between biological invasions and global environmental and socio‐economic processes. Such understanding is pivotal to prioritize limited resources for the optimum prevention and control of biological invasions.
Clostridium difficile Binary Toxin CDT Induces Clustering of the Lipolysis-Stimulated Lipoprotein Receptor into Lipid Rafts
Authors: Papatheodorou Panagiotis , Hornuss Daniel , Nölke Thilo , Hemmasi Sarah , Castonguay Jan , Picchianti Monica , Aktories Klaus 
Published: May 2013

ABSTRACT

Clostridium difficile
is the leading cause of antibiotics-associated diarrhea and pseudomembranous colitis. Hypervirulent
C. difficile
strains produce the binary actin-ADP-ribosylating toxin CDT (
C. difficile
transferase), in addition to the Rho-glucosylating toxins A and B. We recently identified the lipolysis-stimulated lipoprotein receptor (LSR) as the host receptor that mediates uptake of CDT into target cells. Here we investigated in H1-HeLa cells, which ectopically express LSR, the influence of CDT on the plasma membrane distribution of the receptor. We found by fluorescence microscopy that the binding component of CDT (CDTb) induces clustering of LSR into subcompartments of the plasma membrane. Detergent extraction of cells treated with CDTb, followed by sucrose gradient fractionation, uncovered accumulation of LSR in detergent-resistant membranes (DRMs) that contained typical marker proteins of lipid rafts. Membrane cholesterol depletion with methyl-β-cyclodextrin inhibited the association of LSR with DRMs upon addition of CDTb. The receptor-binding domain of CDTb also triggered LSR clustering into DRMs. CDTb-triggered clustering of LSR into DRMs could be confirmed in Caco-2 cells. Our data suggest that CDT forces its receptor to cluster into lipid rafts and that oligomerization of the B component might enhance but is not essential for this process.

IMPORTANCE
C. difficile
binary toxin CDT is a member of the iota-like, actin ADP-ribosylating toxin family. The mechanism that mediates endocytic uptake of these toxins still remains elusive. Previous studies highlighted the importance of lipid rafts for oligomerization of the binding component of these toxins and for cell entry. Recently, the host cell receptor for this toxin family, namely, the lipolysis-stimulated lipoprotein receptor (LSR), has been identified. Our study now demonstrates that the binding component of CDT (CDTb) induces clustering of LSR into lipid rafts. Importantly, LSR clustering is efficiently induced also by the receptor-binding domain of CDTb, suggesting that oligomerization of the B component of CDT is not the main trigger of this process. The current work extends our knowledge on the cooperative play between iota-like toxins and their receptor.
Simultaneous Targeting of Tumor Antigens and the Tumor Vasculature Using T Lymphocyte Transfer Synergize to Induce Regression of Established Tumors in Mice
Authors: Chinnasamy Dhanalakshmi , Tran Eric , Yu Zhiya , Morgan Richard A. , Restifo Nicholas P. , Rosenberg Steven A. 
Published: May 2013

Abstract
Most systemic cancer therapies target tumor cells directly, although there is increasing interest in targeting the tumor stroma that can comprise a substantial portion of the tumor mass. We report here a synergy between two T-cell therapies, one directed against the stromal tumor vasculature and the other directed against antigens expressed on the tumor cell. Simultaneous transfer of genetically engineered syngeneic T cells expressing a chimeric antigen receptor targeting the VEGF receptor-2 (VEGFR2; KDR) that is overexpressed on tumor vasculature and T-cells specific for the tumor antigens gp100 (PMEL), TRP-1 (TYRP1), or TRP-2 (DCT) synergistically eradicated established B16 melanoma tumors in mice and dramatically increased the tumor-free survival of mice compared with treatment with either cell type alone or T cells coexpressing these two targeting molecules. Host lymphodepletion before cell transfer was required to mediate the antitumor effect. The synergistic antitumor response was accompanied by a significant increase in the infiltration and expansion and/or persistence of the adoptively transferred tumor antigen–specific T cells in the tumor microenvironment and thus enhanced their antitumor potency. The data presented here emphasize the possible beneficial effects of combining antiangiogenic with tumor-specific immunotherapeutic approaches for the treatment of patients with cancer. Cancer Res; 73(11); 3371–80. ©2013 AACR.
Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T-Cell Rejection Function in Tumors
Authors: Duraiswamy Jaikumar , Kaluza Karen M. , Freeman Gordon J. , Coukos George 
Published: May 2013

AbstractTumor progression is facilitated by regulatory T cells (Treg) and restricted by effector T cells. In this study, we document parallel regulation of CD8+ T cells and Foxp3+ Tregs by programmed death-1 (PD-1, PDCD1). In addition, we identify an additional role of CTL antigen-4 (CTLA-4) inhibitory receptor in further promoting dysfunction of CD8+ T effector cells in tumor models (CT26 colon carcinoma and ID8-VEGF ovarian carcinoma). Two thirds of CD8+ tumor-infiltrating lymphocytes (TIL) expressed PD-1, whereas one third to half of CD8+ TIL coexpressed PD-1 and CTLA-4. Double-positive (PD-1+CTLA-4+) CD8+ TIL had characteristics of more severe dysfunction than single-positive (PD-1+ or CTLA-4+) TIL, including an inability to proliferate and secrete effector cytokines. Blockade of both PD-1 and CTLA-4 resulted in reversal of CD8+ TIL dysfunction and led to tumor rejection in two thirds of mice. Double blockade was associated with increased proliferation of antigen-specific effector CD8+ and CD4+ T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs, and upregulation of key signaling molecules critical for T-cell function. When used in combination with GVAX vaccination (consisting of granulocyte macrophage colony-stimulating factor–expressing irradiated tumor cells), inhibitory pathway blockade induced rejection of CT26 tumors in 100% of mice and ID8-VEGF tumors in 75% of mice. Our study indicates that PD-1 signaling in tumors is required for both suppressing effector T cells and maintaining tumor Tregs, and that PD-1/PD-L1 pathway (CD274) blockade augments tumor inhibition by increasing effector T-cell activity, thereby attenuating Treg suppression. Cancer Res; 73(12); 3591–603. ©2013 AACR.
Regulation of FANCD2 by the mTOR Pathway Contributes to the Resistance of Cancer Cells to DNA Double-Strand Breaks
Authors: Shen Changxian , Oswald Duane , Phelps Doris , Cam Hakan , Pelloski Christopher E. , Pang Qishen , Houghton Peter J. 
Published: May 2013

Abstract
Deregulation of the mTOR pathway is closely associated with tumorigenesis. Accordingly, mTOR inhibitors such as rapamycin and mTOR-selective kinase inhibitors have been tested as cancer therapeutic agents. Inhibition of mTOR results in sensitization to DNA-damaging agents; however, the molecular mechanism is not well understood. We found that an mTOR-selective kinase inhibitor, AZD8055, significantly enhanced sensitivity of a pediatric rhabdomyosarcoma xenograft to radiotherapy and sensitized rhabdomyosarcoma cells to the DNA interstrand cross-linker (ICL) melphalan. Sensitization correlated with drug-induced downregulation of a key component of the Fanconi anemia pathway, FANCD2 through mTOR regulation of FANCD2 gene transcripts via mTORC1-S6K1. Importantly, we show that FANCD2 is required for the proper activation of ATM-Chk2 checkpoint in response to ICL and that mTOR signaling promotes ICL-induced ATM-Chk2 checkpoint activation by sustaining FANCD2. In FANCD2-deficient lymphoblasts, FANCD2 is essential to suppress endogenous and induced DNA damage, and FANCD2-deficient cells showed impaired ATM-Chk2 and ATR-Chk1 activation, which was rescued by reintroduction of wild-type FANCD2. Pharmacologic inhibition of PI3K–mTOR–AKT pathway in Rh30 rhabdomyosarcoma cells attenuated ICL-induced activation of ATM, accompanied with the decrease of FANCD2. These data suggest that the mTOR pathway may promote the repair of DNA double-strand breaks by sustaining FANCD2 and provide a novel mechanism of how the Fanconi anemia pathway modulates DNA damage response and repair. Cancer Res; 73(11); 3393–401. ©2013 AACR.
SENP1 deSUMOylates and Regulates Pin1 Protein Activity and Cellular Function
Authors: Chen Chun-Hau , Chang Che-Chang , Lee Tae Ho , Luo ManLi , Huang Pengyu , Liao Pei-Hsin , Wei Shuo , Li Fu-An , Chen Ruey-Hwa , Zhou Xiao Zhen , Shih Hsiu-Ming , Lu Kun Ping 
Published: May 2013

Abstract
The Pin1 prolyl isomerase regulates phosphorylation signaling by controlling protein conformation after phosphorylation, and its upregulation promotes oncogenesis via acting on numerous oncogenic molecules. SUMOylation and deSUMOylation are dynamic mechanisms regulating a spectrum of protein activities. The SUMO proteases (SENP) remove SUMO conjugate from proteins, and their expression is deregulated in cancers. However, nothing is known about the role of SUMOylation in regulating Pin1 function. Here, we show that Pin1 is SUMOylated on Lys6 in the WW domain and on Lys63 in the PPIase domain. Pin1 SUMOylation inhibits its protein activity and oncogenic function. We further identify that SENP1 binds to and deSUMOylates Pin1. Importantly, either overexpression of SENP1 or disruption of Pin1 SUMOylation promotes the ability of Pin1 to induce centrosome amplification and cell transformation. Moreover, SENP1 also increases Pin1 protein stability in cell cultures, and Pin1 levels are positively correlated with SENP1 levels in human breast cancer specimens. These results not only uncover Pin1 SUMOylation on Lys6/63 as a novel mechanism to inhibit its activity and function but also identify a critical role for SENP1-mediated deSUMOylation in promoting Pin1 function during tumorigenesis. Cancer Res; 73(13); 3951–62. ©2013 AACR.
Dynamic Mast Cell–Stromal Cell Interactions Promote Growth of Pancreatic Cancer
Authors: Ma Ying , Hwang Rosa F. , Logsdon Craig D. , Ullrich Stephen E. 
Published: May 2013

Abstract
Pancreatic ductal adenocarcinoma (PDAC) exists in a complex desmoplastic microenvironment, which includes cancer-associated fibroblasts [also known as pancreatic stellate cells (PSC)] and immune cells that provide a fibrotic niche that impedes successful cancer therapy. We have found that mast cells are essential for PDAC tumorigenesis. Whether mast cells contribute to the growth of PDAC and/or PSCs is unknown. Here, we tested the hypothesis that mast cells contribute to the growth of PSCs and tumor cells, thus contributing to PDAC development. Tumor cells promoted mast cell migration. Both tumor cells and PSCs stimulated mast cell activation. Conversely, mast cell–derived interleukin (IL)-13 and tryptase stimulated PSC proliferation. Treating tumor-bearing mice with agents that block mast cell migration and function depressed PDAC growth. Our findings suggest that mast cells exacerbate the cellular and extracellular dynamics of the tumor microenvironment found in PDAC. Therefore, targeting mast cells may inhibit stromal formation and improve therapy. Cancer Res; 73(13); 3927–37. ©2013 AACR.
Cap-Translation Inhibitor, 4EGI-1, Restores Sensitivity to ABT-737 Apoptosis through Cap-Dependent and -Independent Mechanisms in Chronic Lymphocytic Leukemia
Authors: Willimott Shaun , Beck Daniel , Ahearne Matthew J. , Adams Victoria C. , Wagner Simon D. 
Published: May 2013

Abstract
Purpose: The lymph node microenvironment promotes resistance to chemotherapy in chronic lymphocytic leukemia (CLL), partly through induction of BCL2 family prosurvival proteins. Currently available inhibitors do not target all BCL2 family prosurvival proteins and their effectiveness is also modified by proapoptotic BCL2 homology domain 3 (BH3) only protein expression. The goal of this study was to evaluate synergy between the eIF4E/eIF4G interaction inhibitor, 4EGI-1, and the BH3 mimetic, ABT-737.
Experimental Design: CLL cells were cultured in conditions to mimic the lymph node microenvironment. Protein synthesis and cap-complex formation were determined. Polysome association of mRNAs from BCL2 family survival genes was analyzed by translational profiling. The effects of 4EGI-1 and the BCL2/BCL2L1 antagonist, ABT-737, on CLL cell apoptosis were determined.
Results: Protein synthesis was increased approximately 6-fold by stromal cell/CD154 culture in a phosphoinositide 3-kinase α (PI3Kα)–specific manner and was reduced by 4EGI-1. PI3K inhibitors and 4EGI-1 also reduced cap-complex formation but only 4EGI-1 consistently reduced BCL2L1 and BCL2A1 protein levels. 4EGI-1, but not PI3K inhibitors or rapamycin, induced an endoplasmic reticulum stress response including proapoptotic NOXA and the translation inhibitor phosphorylated eIF2α. 4EGI-1 and ABT-737 synergized to cause apoptosis, independent of levels of prosurvival protein expression in individual patients.
Conclusions: Overall protein synthesis and cap-complex formation are induced by microenvironment stimuli in CLL. Inhibition of the cap-complex was not sufficient to repress BCL2 family prosurvival expression, but 4EGI-1 inhibited BCL2A1 and BCL2L1 while inducing NOXA through cap-dependent and -independent mechanisms. 4EGI-1 and ABT-737 synergized to produce apoptosis, and these agents may be the basis for a therapeutically useful combination. Clin Cancer Res; 19(12); 3212–23. ©2013 AACR.
PIK3CA and PTEN Gene and Exon Mutation-Specific Clinicopathologic and Molecular Associations in Colorectal Cancer
Authors: Day Fiona L. , Jorissen Robert N. , Lipton Lara , Mouradov Dmitri , Sakthianandeswaren Anuratha , Christie Michael , Li Shan , Tsui Cary , Tie Jeannie , Desai Jayesh , Xu Zheng-Zhou , Molloy Peter , Whitehall Vicki , Leggett Barbara A. , Jones Ian T. , McLaughlin Stephen , Ward Robyn L. , Hawkins Nicholas J. , Ruszkiewicz Andrew R. , Moore James , Busam Dana , Zhao Qi , Strausberg Robert L. , Gibbs Peter , Sieber Oliver M. 
Published: May 2013

Abstract
Purpose: PIK3CA and PTEN mutations are prevalent in colorectal cancer and potential markers of response to mitogen-activated protein/extracellular signal–regulated kinase inhibitors and anti-EGF receptor antibody therapy. Relationships between phosphoinositide 3-kinase (PI3K) pathway mutation, clinicopathologic characteristics, molecular features, and prognosis remain controversial.
Experimental Design: A total of 1,093 stage I–IV colorectal cancers were screened for PIK3CA (exons 9 and 20), KRAS (codons 12–13), BRAF (codon 600) mutations, and microsatellite instability (MSI). PTEN (exons 3–8) and CpG island methylator phenotype (CIMP) status were determined in 744 and 489 cases. PIK3CA data were integrated with 17 previous reports (n = 5,594).
Results: PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of colorectal cancers. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high (MSI-H), CIMP-high (CIMP-H), and BRAF mutation (P &lt; 0.02). PIK3CA mutation was related to older age, proximal tumors, mucinous histology, and KRAS mutation (P &lt; 0.04). In integrated cohort analysis, PIK3CA exon 9 and 20 mutations were overrepresented in proximal, CIMP-low (CIMP-L), and KRAS-mutated cancers (P ≤ 0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-H, CIMP-H, and BRAF mutation, and exon 9 mutation was associated with KRAS mutation (P ≤ 0.027). Disease-free survival for stage II/III colorectal cancers did not differ by PI3K pathway status.
Conclusion: PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-H/CIMP-H/BRAFmut), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/KRASmut) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct colorectal cancer subtypes. Clin Cancer Res; 19(12); 3285–96. ©2013 AACR.
Molecular Pathways: Fumarate Hydratase-Deficient Kidney Cancer—Targeting the Warburg Effect in Cancer
Authors: Linehan W. Marston , Rouault Tracey A. 
Published: May 2013

Abstract
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for development of cutaneous and uterine leiomyomas and an aggressive form of type II papillary kidney cancer. HLRCC is characterized by germline mutation of the tricarboxylic acid (TCA) cycle enzyme, fumarate hydratase (FH). FH-deficient kidney cancer is characterized by impaired oxidative phosphorylation and a metabolic shift to aerobic glycolysis, a form of metabolic reprogramming referred to as the Warburg effect. Increased glycolysis generates ATP needed for increased cell proliferation. In FH-deficient kidney cancer, levels of AMP-activated protein kinase (AMPK), a cellular energy sensor, are decreased resulting in diminished p53 levels, decreased expression of the iron importer, DMT1, leading to low cellular iron levels, and to enhanced fatty acid synthesis by diminishing phosphorylation of acetyl CoA carboxylase, a rate-limiting step for fatty acid synthesis. Increased fumarate and decreased iron levels in FH-deficient kidney cancer cells inactivate prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor (HIF)-1α and increased expression of genes such as VEGF and glucose transporter 1 (GLUT1) to provide fuel needed for rapid growth demands. Several therapeutic approaches for targeting the metabolic basis of FH-deficient kidney cancer are under development or are being evaluated in clinical trials, including the use of agents such as metformin, which would reverse the inactivation of AMPK, approaches to inhibit glucose transport, lactate dehydrogenase A (LDHA), the antioxidant response pathway, the heme oxygenase pathway, and approaches to target the tumor vasculature and glucose transport with agents such as bevacizumab and erlotinib. These same types of metabolic shifts, to aerobic glycolysis with decreased oxidative phosphorylation, have been found in a wide variety of other cancer types. Targeting the metabolic basis of a rare cancer such as FH-deficient kidney cancer will hopefully provide insights into the development of effective forms of therapies for other, more common forms of cancer. Clin Cancer Res; 19(13); 3345–52. ©2013 AACR.
Patterns of Emergency Medical Services Use and Its Association With Timely Stroke Treatment
Authors: Ekundayo Olaniyi James , Saver Jeffrey L. , Fonarow Gregg C. , Schwamm Lee H. , Xian Ying , Zhao Xin , Hernandez Adrian F. , Peterson Eric D. , Cheng Eric M. 
Published: May 2013

Background—
Prior studies found that only about half of stroke patients arrived at hospitals via emergency medical services (EMSs), yet since then, there have been efforts to increase public awareness that time is brain. Using contemporary Get With the Guidelines-Stroke data, we assessed nationwide EMS use by stroke patients.

Methods and Results—
We analyzed data from 204 591 patients with ischemic and hemorrhagic stroke admitted to 1563 Get With the Guidelines-Stroke participating hospitals with data on National Institute of Health Stroke Score and insurance status. Hospital arrival by EMSs was observed in 63.7% of patients. Older patients, those with Medicaid and Medicare insurance, and those with severe stroke were more likely to activate EMSs. In contrast, minority race and ethnicity and living in rural communities were associated with decreased odds of EMS use. EMS transport was independently associated with earlier arrival (onset-to-door time, ≤3 hours; adjusted odds ratio, 2.00; 95% confidence interval, 1.93–2.08), prompter evaluation (more patients with door-to-imaging time, ≤25 minutes; odds ratio, 1.89; 95% confidence interval, 1.78–2.00), more rapid treatment (more patients with door-to-needle time, ≤60 minutes; odds ratio, 1.44; 95% confidence interval, 1.28–1.63), and more eligible patients to be treated with tissue-type plasminogen activator if onset is ≤2 hours (67% versus 44%; odds ratio, 1.47; 95% confidence interval, 1.33–1.64).

Conclusions—
Although EMS use is independently associated with more rapid evaluation and treatment of stroke, more than one third of stroke patients fail to use EMSs. Interventions aimed at increasing EMS activation should target populations at risk, particularly younger patients and those of minority race and ethnicity.