bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natural Killer Cells Efficiently Reject Lymphoma Silenced for the Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing
Authors: Cifaldi Loredana , Lo Monaco Elisa , Forloni Matteo , Giorda Ezio , Lorenzi Silvia , Petrini Stefania , Tremante Elisa , Pende Daniela , Locatelli Franco , Giacomini Patrizio , Fruci Doriana 
Published: January 2011

AbstractThe endoplasmic reticulum aminopeptidase ERAAP is involved in the final trimming of peptides for presentation by MHC class I (MHC-I) molecules. Herein, we show that ERAAP silencing results in MHC-I peptide-loading defects eliciting rejection of the murine T-cell lymphoma RMA in syngeneic mice. Although CD4 and CD8 T cells are also involved, rejection is mainly due to an immediate natural killer (NK) cell response and depends on the MHC-I-peptide repertoire because replacement of endogenous peptides with correctly trimmed, high-affinity peptides is sufficient to restore an NK-protective effect of MHC-I molecules through the Ly49C/I NK inhibitory receptors. At the crossroad between innate and adaptive immunity, ERAAP is therefore unique in its two-tiered ability to control tumor immunogenicity. Because a large fraction of human tumors express high levels of the homologous ERAP1 and/or ERAP2, the present findings highlight a convenient, novel target for cancer immunotherapy. Cancer Res; 71(5); 1597–606. ©2011 AACR.
Synergistic Effects of Foretinib with HER-Targeted Agents in MET and HER1- or HER2-Coactivated Tumor Cells
Authors: Liu Li , Shi Hong , Liu Yuan , Anderson Amber , Peterson John , Greger James , Martin Anne-Marie , Gilmer Tona M. 
Published: January 2011

AbstractThe HER and MET receptor tyrosine kinases (RTK) are coactivated in a subset of human tumors. This study characterizes MET and HER expression and signaling in a panel of human tumor cell lines and the differential susceptibility of these cell lines to single agents or combinations of foretinib, a multikinase MET inhibitor, with HER-targeted agents, erlotinib or lapatinib. Most MET-amplified tumor lines without HER1 or HER2 amplification are sensitive to foretinib, whereas MET-amplified lines with HER1 or HER2 amplification are more sensitive to the combination of foretinib with lapatinib or erlotinib. Interestingly, MET-overexpressing tumor cell lines with HER1 or HER2 amplification also exhibited reduced sensitivity to lapatinib or erlotinib in the presence of hepatocyte growth factor (HGF), indicating MET activation can decrease the effectiveness of HER1/2 inhibitors in some cell lines. Consistent with this observation, the effect of HGF on lapatinib or erlotinib sensitivity in these cells was reversed by foretinib, other MET inhibitors, or siRNA to MET. Western blot analyses showed that combining foretinib with erlotinib or lapatinib effectively decreased the phosphorylation of MET, HER1, HER2, HER3, AKT, and ERK in these cells. Furthermore, HER2-positive advanced or metastatic breast cancer patients treated with lapatinib who had higher tumor MET expression showed shorter progression-free survival (19.29 weeks in MET-high patients vs. 28.14 weeks in MET-low patients, P &lt; 0.0225). These data suggest that combination therapy with foretinib and HER-targeted agents should be tested as a treatment option for HER1- or HER2-positive patients with MET-amplified or -overexpressing tumors. Mol Cancer Ther; 10(3); 518–30. ©2011 AACR.
Interactions of Tyrosine Kinase Inhibitors with Organic Cation Transporters and Multidrug and Toxic Compound Extrusion Proteins
Authors: Minematsu Tsuyoshi , Giacomini Kathleen M. 
Published: January 2011

AbstractThe drug–drug interaction (DDI) potential of tyrosine kinase inhibitors (TKI) as interacting drugs via transporter inhibition has not been fully assessed. Here, we estimated the half maximal inhibitory concentration (IC50) values for 8 small-molecule TKIs (imatinib, dasatinib, nilotinib, gefitinib, erlotinib, sunitinib, lapatinib, and sorafenib) on [14C]metformin transport by human organic cation transporters (OCT), OCT1, OCT2, and OCT3, and multidrug and toxic compound extrusion (MATE) proteins, MATE1 and MATE2-K, using human embryonic kidney cells stably expressing these transporters. We then compared the estimated IC50 values to the maximum clinical concentrations of unbound TKIs in plasma (unbound Cmax,sys,p). Results showed that imatinib, nilotinib, gefitinib, and erlotinib exerted selectively potent inhibitory effects, with unbound Cmax,sys,p/IC50 values ≥0.1, on MATE1, OCT3, MATE2-K, and OCT1, respectively. In comparison to the common form of OCT1, the OCT1 polymorphism, M420del, was more sensitive to drug inhibition by erlotinib. Major metabolites of several TKIs showed IC50 values similar to those for unchanged TKIs. Taken together, these findings suggest the potential of clinical transporter-mediated DDIs between specific TKIs and OCTs and MATEs, which may affect the disposition, efficacy, and toxicity of metformin and other drugs that are substrates of these transporters. The study provides the basis for further clinical DDI studies with TKIs. Mol Cancer Ther; 10(3); 531–9. ©2011 AACR.
Novel Role of Platelets in Mediating Inflammatory Responses and Ventricular Rupture or Remodeling Following Myocardial Infarction
Authors: Liu Yang , Gao Xiao-Ming , Fang Lu , Jennings Nicole L. , Su Yidan , Q Xu , Samson Andre L. , Kiriazis Helen , Wang Xin-Feng , Shan Leonard , Sturgeon Sharelle A. , Medcalf Robert L. , Jackson Shaun P. , Dart Anthony M. , Du Xiao-Jun 
Published: January 2011

Objective—
The goal of this study was to investigate the role of platelets in systemic and cardiac inflammatory responses and the development of postinfarct ventricular complications, as well as the efficacy of antiplatelet interventions.

Methods and Results—

Using a mouse myocardial infarction (MI) model, we determined platelet accumulation and severity of inflammation within the infarcted myocardium by immunohistochemistry and biochemical assays, analyzed peripheral blood platelet-leukocyte conjugation using flow cytometry, and tested antiplatelet interventions, including thienopyridines and platelet depletion. Platelets accumulated within the infarcted region early post-MI and colocalized with inflammatory cells. MI evoked early increase in circulating platelet-leukocyte conjugation mediated by P-selectin/P-selectin glycoprotein ligand-1. Antiplatelet interventions inhibited platelet-leukocyte conjugation in peripheral blood, inflammatory infiltration, content of matrix metalloproteinases or plasminogen activation, and expression of inflammatory mediators in the infarcted myocardium (all
P
<0.05) and lowered rupture incidence (
P
<0.01). Clopidogrel therapy alleviated the extent of chronic ventricular dilatation by serial echocardiography.

Conclusion—
Platelets play a pivotal role in promoting systemic and cardiac inflammatory responses post-MI. Platelets accumulate within the infarcted myocardium, contributing to regional inflammation, ventricular remodeling, and rupture. Antiplatelet therapy reduces the severity of inflammation and risk of post-MI complications, demonstrating a previously unrecognized protective action.
Physical Activity Modifies the Effect of
LPL, LIPC
, and
CETP
Polymorphisms on HDL-C Levels and the Risk of Myocardial Infarction in Women of European Ancestry
Authors: Ahmad Tariq , Chasman Daniel I. , Buring Julie E. , Lee I-Min , Ridker Paul M , Everett Brendan M. 
Published: January 2011

Background—
Recent genome-wide association studies have identified common variants associated with high-density lipoprotein cholesterol (HDL-C). Whether these associations are modified by physical activity, which increases HDL-C levels and reduces the risk of cardiovascular disease, is uncertain.

Methods and Results—

In a prospective cohort study of 22 939 apparently healthy US women of European ancestry, we selected 58 single nucleotide polymorphisms (SNPs) in 9 genes that demonstrated genome-wide association (
P
<5×10
−8
) with HDL-C levels and sought evidence of effect modification according to levels of physical activity. Physical activity modified the effects on HDL-C of 7 SNPs at 3 loci, and the strongest evidence of effect was observed for rs10096633 at lipoprotein lipase (
LPL
), rs1800588 at hepatic lipase (
LIPC
), and rs1532624 at cholesteryl ester transfer protein (
CETP
) (each
P
-interaction <0.05). The per-minor-allele increase in HDL-C for rs1800588 at
LIPC
and rs1532624 at
CETP
was greater in active than inactive women, whereas the reverse was observed for rs10096633 at
LPL
. Minor-allele carrier status at the
LPL
SNP was associated with a reduced risk of myocardial infarction in active (hazard ratio, 0.51; 95% confidence interval 0.30–0.86) but not among inactive women (hazard ratio 1.13; 95% confidence interval 0.79 to 1.61;
P
-interaction=0.007). By contrast, carrier status at the
CETP
SNP was associated with a reduced risk of myocardial infarction regardless of activity level (hazard ratio, 0.72; 95% confidence interval, 0.57 to 0.92;
P
-interaction=0.71). No association between
LIPC
SNP carrier status and myocardial infarction risk was noted.

Conclusions—

The effects of common variants in the
LPL, LIPC
, and
CETP
genes on HDL-C levels are modified by physical activity. For a common variant in
LPL
, the impact on myocardial infarction varied by activity level, whereas the effects of a common variant in
CETP
on myocardial infarction risk did not.
Neural Correlates of Encoding Within- and Across-domain Inter-item Associations
Authors: Park Heekyeong , Rugg Michael D. 
Published: January 2011

Abstract
The neural correlates of the encoding of associations between pairs of words, pairs of pictures, and word–picture pairs were compared. The aims were to determine, first, whether the neural correlates of associative encoding vary according to study material and, second, whether encoding of across- versus within-material item pairs is associated with dissociable patterns of hippocampal and perirhinal activity, as predicted by the “domain dichotomy” hypothesis of medial temporal lobe function. While undergoing fMRI scanning, subjects (n = 24) were presented with the three classes of study pairs, judging which of the denoted objects fit into the other. Outside of the scanner, subjects then undertook an associative recognition task, discriminating between intact study pairs, rearranged pairs comprising items that had been presented on different study trials, and unstudied item pairs. The neural correlates of successful associative encoding—subsequent associative memory effects—were operationalized as the difference in activity between study pairs correctly judged intact versus pairs incorrectly judged rearranged on the subsequent memory test. Pair type–independent subsequent memory effects were evident in the left inferior frontal gyrus (IFG) and the hippocampus. Picture–picture pairs elicited material-selective effects in regions of fusiform cortex that were also activated to a greater extent on picture trials than on word trials, whereas word–word pairs elicited material-selective subsequent memory effects in left lateral temporal cortex. Contrary to the domain-dichotomy hypothesis, neither hippocampal nor perirhinal subsequent memory effects differed depending on whether they were elicited by within- versus across-material study pairs. It is proposed that the left IFG plays a domain-general role in associative encoding, that associative encoding can also be facilitated by enhanced processing in material-selective cortical regions, and that the hippocampus and perirhinal cortex contribute equally to the formation of inter-item associations, regardless of whether the items belong to the same or to different processing domains.
Neuronal Signal Dynamics during Preparation and Execution for Behavioral Shifting in Macaque Posterior Parietal Cortex
Authors: Kamigaki Tsukasa , Fukushima Tetsuya , Miyashita Yasushi 
Published: January 2011

Abstract
Cognitive flexibility arises from our ability to shift behaviors depending on demand changes. Behavioral shifting recruits both a preparatory process for an upcoming behavior and an execution process for the actual behavior. Although neuroimaging studies have shown that several brain regions, including posterior parietal cortex (PPC) participated in each component process, it remains unresolved how such processes are implemented at the single-cell level or even whether these processes are distinctively carried out across microstructures in such regions. By recording single-unit activity from PPC of two monkeys performing an analog of the Wisconsin Card Sorting Test, we found that, in the execution process, two types of neurons exhibited activity modulation depending on whether shift was (shift trial) or was not required (nonshift trial): one type showing larger activity and the other showing smaller activity in the shift trial than in the nonshift trial. In the preparatory process, in contrast, the population activity of both types became larger in the shift trial than in the nonshift trial. The majority of both types exhibited shift-related activity modulation in both processes, whereas the remaining was specialized in the execution process. The former and the latter neurons were spatially intermingled within PPC. Significantly, when the animals performed set shifting spontaneously in prospect of a demand change, the shift-related activity modulation still emerged in both processes. We suggest that both execution and preparation signals are represented within PPC, and that these signals reflect behavioral shifting mechanisms that can be driven by either internal or external triggers.
Semantic Diversity Accounts for the “Missing” Word Frequency Effect in Stroke Aphasia: Insights Using a Novel Method to Quantify Contextual Variability in Meaning
Authors: Hoffman Paul , Rogers Timothy T. , Lambon Ralph Matthew A. 
Published: January 2011

AbstractWord frequency is a powerful predictor of language processing efficiency in healthy individuals and in computational models. Puzzlingly, frequency effects are often absent in stroke aphasia, challenging the assumption that word frequency influences the behavior of any computational system. To address this conundrum, we investigated divergent effects of frequency in two comprehension-impaired patient groups. Patients with semantic dementia have degraded conceptual knowledge as a consequence of anterior temporal lobe atrophy and show strong frequency effects. Patients with multimodal semantic impairments following stroke (semantic aphasia [SA]), in contrast, show little or no frequency effect. Their deficits arise from impaired control processes that bias activation toward task-relevant aspects of knowledge. We hypothesized that high-frequency words exert greater demands on cognitive control because they are more semantically diverse—they tend to appear in a broader range of linguistic contexts and have more variable meanings. Using latent semantic analysis, we developed a new measure of semantic diversity that reflected the variability of a word's meaning across different context. Frequency, but not diversity, was a significant predictor of comprehension in semantic dementia, whereas diversity was the best predictor of performance in SA. Most importantly, SA patients did show typical frequency effects but only when the influence of diversity was taken into account. These results are consistent with the view that higher-frequency words place higher demands on control processes, so that when control processes are damaged the intrinsic processing advantages associated with higher-frequency words are masked.
The Influence of Emotion Regulation on Decision-making under Risk
Authors: Martin Laura N. , Delgado Mauricio R. 
Published: January 2011

Abstract
Cognitive strategies typically involved in regulating negative emotions have recently been shown to also be effective with positive emotions associated with monetary rewards. However, it is less clear how these strategies influence behavior, such as preferences expressed during decision-making under risk, and the underlying neural circuitry. That is, can the effective use of emotion regulation strategies during presentation of a reward–conditioned stimulus influence decision-making under risk and neural structures involved in reward processing such as the striatum? To investigate this question, we asked participants to engage in imagery-focused regulation strategies during the presentation of a cue that preceded a financial decision-making phase. During the decision phase, participants then made a choice between a risky and a safe monetary lottery. Participants who successfully used cognitive regulation, as assessed by subjective ratings about perceived success and facility in implementation of strategies, made fewer risky choices in comparison with trials where decisions were made in the absence of cognitive regulation. Additionally, BOLD responses in the striatum were attenuated during decision-making as a function of successful emotion regulation. These findings suggest that exerting cognitive control over emotional responses can modulate neural responses associated with reward processing (e.g., striatum) and promote more goal-directed decision-making (e.g., less risky choices), illustrating the potential importance of cognitive strategies in curbing risk-seeking behaviors before they become maladaptive (e.g., substance abuse).
From Policy Research to Political Advocacy
Authors: Hasan Md Rahat 
Published: January 2011

Public policy research organisations or think tanks have played a critical role in the policymaking process and have served as catalyst of ideas, innovations and actions. They fill a void between the academic world, on the one hand, and the realm of government on the other. The ones that emerged in the first decades of the twentieth century were committed to bringing scientific expertise to bear on public policy issues. The advancement of knowledge for the purpose of improving governmental decision making was their main priority. However, new partisan think tanks have become more committed to influencing policy than to improving it. In fact, the intense competition between think tanks for influence in the marketplace of ideas had led some scholars to treat policy research institutions as another type of interest group committed to influencing public policy. Similarly, to provide greater expertise to decision makers, interest groups develop more resources to conducting research. While think tanks have many features in common with interest groups, they are different from each others. Accordingly, this article tries to outline a number of criteria to define characteristics of policy research institutes.
Activation peptides prolong the murine plasma half-life of human factor VII
Authors: Johansson Linda , Karpf Ditte M. , Hansen Lene , Pelzer Hermann , Persson Egon 
Published: January 2011

AbstractCoagulation factors VII (FVII), IX (FIX), X (FX), and protein C share the same domain organization but display very different plasma half-lives. It is plausible that the half-life is influenced by the activation peptide, differing in length and glycosylation and missing in FVII. To test this hypothesis, the influence of activation peptides on the plasma half-life of human FVII was studied by administering human FVII variants containing activation peptide motifs to mice. Insertion of the activation peptide from FX gave 4-fold longer terminal half-life (5.5 hours vs 1.4 hours for FVII), whereas the activation peptide from FIX and protein C resulted in half-lives of 4.3 and 1.7 hours, respectively. Using FX's activation peptide we identified the N-linked glycans as structural features important for the half-life. The peptide location within the FVII molecule appeared not to be critical because similar prolongation was obtained with the activation peptide inserted immediately before the normal site of activation and at the C-terminus. However, only the latter variant was activatable, yielding full amidolytic activity and reduced proteolytic activity with preserved long half-life. Our data support that activation peptides function as plasma retention signals and constitute a new manner to extend the half-life of FVII(a).
Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor–, granulocyte-macrophage colony-stimulating factor–, and interleukin-3–expressing NOD-SCID IL2Rγnull humanized mice
Authors: Billerbeck Eva , Barry Walter T. , Mu Kathy , Dorner Marcus , Rice Charles M. , Ploss Alexander 
Published: January 2011

Abstract
Human hematolymphoid mice have become valuable tools for the study of human hematopoiesis and uniquely human pathogens in vivo. Recent improvements in xenorecipient strains allow for long-term reconstitution with a human immune system. However, certain hematopoietic lineages, for example, the myeloid lineage, are underrepresented, possibly because of the limited cross-reactivity of murine and human cytokines. Therefore, we created a nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor-γ–null (NOD-SCID IL2Rγnull) mouse strain that expressed human stem cell factor, granulocyte-macrophage colony-stimulating factor, and interleukin-3, termed NSG-SGM3. Transplantation of CD34+ human hematopoietic stem cells into NSG-SGM3 mice led to robust human hematopoietic reconstitution in blood, spleen, bone marrow, and liver. Human myeloid cell frequencies, specifically, myeloid dendritic cells, were elevated in the bone marrow of humanized NSG-SGM3 mice compared with nontransgenic NSG recipients. Most significant, however, was the increase in the CD4+FoxP3+ regulatory T-cell population in all compartments analyzed. These CD4+FoxP3+ regulatory T cells were functional, as evidenced by their ability to suppress T-cell proliferation. In conclusion, humanized NSG-SGM3 mice might serve as a useful model to study human regulatory T-cell development in vivo, but this unexpected lineage skewing also highlights the importance of adequate spatiotemporal expression of human cytokines for future xenorecipient strain development.
Sézary syndrome cells overexpress syndecan-4 bearing distinct heparan sulfate moieties that suppress T-cell activation by binding DC-HIL and trapping TGF-β on the cell surface
Authors: Chung Jin-Sung , Shiue Lisa H. , Duvic Madeleine , Pandya Amit , Cruz Ponciano D. , Ariizumi Kiyoshi 
Published: January 2011

AbstractBecause syndecan-4 (SD-4) on effector and memory T cells inhibits T-cell activation by binding dendritic cell–associated heparan sulfate proteoglycan-integrin ligand (DC-HIL) on antigen presenting cells and because malignant cells of the cutaneous T-cell lymphoma (CTCL) subset, Sézary syndrome (SS), exhibit memory T-cell phenotype, we posited SS cells to express SD-4. Indeed, malignant T cells from patients with SS and from CTCL cell lines constitutively expressed SD-4 at high levels, in contrast to T cells from healthy volunteers and patients with other inflammatory skin diseases and to non-CTCL cell lines that did not. SS cells also bound to DC-HIL at a level higher than normal T cells activated in vitro, resulting in their inhibited proliferation to anti–CD3 antibody. SD-4 on SS cells also trapped transforming growth factor-β1 to their cell surface, enhancing their ability to inhibit activation of syngeneic and allogeneic normal T cells. All of these inhibitory properties were dependent on overexpression of distinct heparan sulfate (HS) moieties by SD-4 on SS cells. Finally, we showed toxin-conjugated DC-HIL to abrogate the ability of SS cells to proliferate in vitro. These findings indicate that SD-4 bearing distinct HS moieties plays a pathogenic role in SS and may be targeted for treatment.