bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms involved in the inhibitory effect of chronic alcohol exposure on pancreatic acinar thiamin uptake
Authors: Srinivasan Padmanabhan , Subramanian Veedamali S. , Said Hamid M.
Published: February 2014

Pancreatic acinar cells (PAC) obtain thiamin from the circulation via a carrier-mediated process that involves thiamin transporters 1 and 2 (THTR-1 and THTR-2; products of SLC19A2 and SLC19A3, respectively). Chronic alcohol exposure of PAC inhibits thiamin uptake, and, on the basis of in vitro studies, this inhibition appears to be transcriptionally mediated. The aim of this study was to confirm the involvement of a transcriptional mechanism in mediating the chronic alcohol effect in in vivo settings and to delineate the molecular mechanisms involved. Using transgenic mice carrying full-length SLC19A2 and SLC19A3 promoters, we found that chronic alcohol feeding led to a significant reduction in the activity of SLC19A2 and SLC19A3 promoters (as well as in thiamin uptake and expression of THTR-1 and -2). Similar findings were seen in 266-6 cells chronically exposed to alcohol in vitro. In the latter studies, the alcohol inhibitory effect was found to be mediated via the minimal SLC19A2 and SLC19A3 promoters and involved the cis-regulatory elements stimulating protein 1 (SP1)/gut-enriched Kruppel-like factor and SP1-GG-box and SP1/GC, respectively. Chronic alcohol exposure of PAC also led to a significant reduction in the expression of the SP1 transcription factor, which upon correction (via expression) led to the prevention of alcohol inhibitory effects on not only the activity of SLC19A2 and SLC19A3 promoters but also on the expression of THTR-1 and -2 mRNA and thiamin uptake. These results demonstrate that the inhibitory effect of chronic alcohol exposure on physiological/molecular parameters of thiamin uptake by PAC is mediated via specific cis-regulatory elements in SLC19A2 and SLC19A3 minimal promoters.
High-frequency speckle tracking echocardiography in the assessment of left ventricular function and remodeling after murine myocardial infarction
Authors: Bhan Amit , Sirker Alexander , Zhang Juqian , Protti Andrea , Catibog Norman , Driver William , Botnar Rene , Monaghan Mark J. , Shah Ajay M.
Published: February 2014

The objectives of this study were to assess the feasibility and accuracy of high-frequency speckle tracking echocardiography (STE) in a murine model of myocardial infarction (MI). STE is used clinically to quantify global and regional cardiac function, but its application in mice is challenging because of the small cardiac size and rapid heart rates. A high-frequency microultrasound system with STE (Visualsonics Vevo 2100) was compared against magnetic resonance imaging (MRI) for the assessment of global left ventricular (LV) size and function after murine MI. Animals subjected to coronary ligation ( n = 46) or sham ligation ( n = 27) were studied 4 wk postoperatively. Regional and global deformation were also assessed. STE-derived LV ejection fraction (EF) and mass correlated well with MRI indexes ( r = 0.93, 0.77, respectively; P < 0.001), as did STE-derived mass with postmortem values ( r = 0.80, P < 0.001). Higher STE-derived volumes correlated positively with MRI-derived infarct size ( P < 0.01). Global strain parameters were significantly reduced after MI (all P < 0.001) and strongly correlated with LV mass and MRI-derived infarct size as promising surrogates for the extent of remodeling and infarction, respectively (both P < 0.05). Regional strain analyses showed that radial strain and strain rate were relatively preserved in anterior basal segments after MI compared with more apical segments ( P < 0.001); however, longitudinal strain and strain rate were significantly impaired both basally and distally ( P < 0.001). Strain-derived parameters of dyssynchrony were significantly increased in the MI group ( P < 0.01). Analysis time for STE was 210 ± 45 s with acceptable inter- and intraobserver variability. In conclusion, high-frequency STE enables quantitative assessment of regional and global function in the remodeling murine LV after MI.
Adrenergic α1 receptor activation is sufficient, but not necessary for phrenic long-term facilitation
Authors: Huxtable A. G. , MacFarlane P. M. , Vinit S. , Nichols N. L. , Dale E. A. , Mitchell G. S.
Published: February 2014

Acute intermittent hypoxia (AIH; three 5-min hypoxic episodes) causes a form of phrenic motor facilitation (pMF) known as phrenic long-term facilitation (pLTF); pLTF is initiated by spinal activation of Gq protein-coupled 5-HT2 receptors. Because α1 adrenergic receptors are expressed in the phrenic motor nucleus and are also Gq protein-coupled, we hypothesized that α1 receptors are sufficient, but not necessary for AIH-induced pLTF. In anesthetized, paralyzed, and ventilated rats, episodic spinal application of the α1 receptor agonist phenylephrine (PE) elicited dose-dependent pMF (10 and 100 μM, P < 0.05; but not 1 μM). PE-induced pMF was blocked by the α1 receptor antagonist prazosin (1 mM; −20 ± 20% at 60 min, −5 ± 21% at 90 min; n = 6). Although α1 receptor activation is sufficient to induce pMF, it was not necessary for AIH-induced pLTF because intrathecal prazosin (1 mM) did not alter AIH-induced pLTF (56 ± 9% at 60 min, 78 ± 12% at 90 min; n = 9). Intravenous (iv) prazosin (150 μg/kg) appeared to reduce pLTF (21 ± 9% at 60 min, 26 ± 8% at 90 min), but this effect was not significant. Hypoglossal long-term facilitation was unaffected by intrathecal prazosin, but was blocked by iv prazosin (−4 ± 14% at 60 min, −13 ± 18% at 90 min), suggesting different LTF mechanisms in different motor neuron pools. In conclusion, Gq protein-coupled α1 adrenergic receptors evoke pMF, but they are not necessary for AIH-induced pLTF.
Detection of Brain Tumor Cells in the Peripheral Blood by a Telomerase Promoter-Based Assay
Authors: MacArthur Kelly M. , Kao Gary D. , Chandrasekaran Sanjay , Alonso-Basanta Michelle , Chapman Christina , Lustig Robert A. , Wileyto E. Paul , Hahn Stephen M. , Dorsey Jay F.
Published: February 2014

Blood tests to detect circulating tumor cells (CTC) offer great potential to monitor disease status, gauge prognosis, and guide treatment decisions for patients with cancer. For patients with brain tumors, such as aggressive glioblastoma multiforme, CTC assays are needed that do not rely on expression of cancer cell surface biomarkers like epithelial cell adhesion molecules that brain tumors tend to lack. Here, we describe a strategy to detect CTC based on telomerase activity, which is elevated in nearly all tumor cells but not normal cells. This strategy uses an adenoviral detection system that is shown to successfully detect CTC in patients with brain tumors. Clinical data suggest that this assay might assist interpretation of treatment response in patients receiving radiotherapy, for example, to differentiate pseudoprogression from true tumor progression. These results support further development of this assay as a generalized method to detect CTC in patients with cancer. Cancer Res; 74(8); 2152–9. ©2014 AACR.
Bioluminescent Imaging of HPV-Positive Oral Tumor Growth and Its Response to Image-Guided Radiotherapy
Authors: Zhong Rong , Pytynia Matt , Pelizzari Charles , Spiotto Michael
Published: February 2014

The treatment paradigms for head and neck squamous cell cancer (HNSCC) are changing due to the emergence of human papillomavirus (HPV)-associated tumors possessing distinct molecular profiles and responses to therapy. Although patients with HNSCCs are often treated with radiotherapy, preclinical models are limited by the ability to deliver precise radiation to orthotopic tumors and to monitor treatment responses accordingly. To better model this clinical scenario, we developed a novel autochthonous HPV-positive oral tumor model to track responses to small molecules and image-guided radiation. We used a tamoxifen-regulated Cre recombinase system to conditionally express the HPV oncogenes E6 and E7 as well as a luciferase reporter (iHPV-Luc) in the epithelial cells of transgenic mice. In the presence of activated Cre recombinase, luciferase activity, and by proxy, HPV oncogenes were induced to 11-fold higher levels. In triple transgenic mice containing the iHPV-Luc, K14-CreERtam, and LSL-Kras transgenes, tamoxifen treatment resulted in oral tumor development with increased bioluminescent activity within 6 days that reached a maximum of 74.8-fold higher bioluminescence compared with uninduced mice. Oral tumors expressed p16 and MCM7, two biomarkers associated with HPV-positive tumors. After treatment with rapamycin or image-guided radiotherapy, tumors regressed and possessed decreased bioluminescence. Thus, this novel system enables us to rapidly visualize HPV-positive tumor growth to model existing and new interventions using clinically relevant drugs and radiotherapy techniques. Cancer Res; 74(7); 2073–81. ©2014 AACR.
Molecular Biomarkers in Advanced Renal Cell Carcinoma
Authors: Maroto Pablo , Rini Brian
Published: February 2014

The availability of agents directly targeting tumorigenic and angiogenic pathways has significantly improved the outcomes of patients with advanced renal cell carcinoma (RCC) in recent years. However, all patients eventually become resistant and a substantial percentage experience immediate disease progression with first-line targeted therapy. In addition, patients have variable clinical benefit and/or tolerance to different agents, including drugs within the same class. Thus, the choice of therapy for an individual patient remains empiric at present. Upon this landscape, several molecular biomarkers have been investigated with the purpose of guiding therapy. This review discusses prognostic biomarkers correlating with the outcome of patients independent of therapy, and predictive biomarkers of treatment response, including circulating biomarkers (such as VEGF and VEGF-related proteins, cytokine and angiogenic factors, and lactate dehydrogenase), and tissue-based biomarkers (such as single-nucleotide polymorphisms). Many potential prognostic and predictive molecular biomarkers have now been identified in RCC, although none has yet entered into clinical practice, and all require prospective validation in appropriately designed randomized studies. In the near future, however, validated biomarkers may become integral to management strategies in RCC, enabling tailored treatment for individual patients to improve clinical outcomes. Clin Cancer Res; 20(8); 2060–71. ©2014 AACR.
DNA Topoisomerase III Alpha Regulates p53-Mediated Tumor Suppression
Authors: Hsieh Mei-Yi , Fan Jia-Rong , Chang Han-Wen , Chen Hsiang-Chin , Shen Tang-Long , Teng Shu-Chun , Yeh Yen-Hsiu , Li Tsai-Kun
Published: February 2014

Purpose: Human DNA topoisomerase III alpha (hTOP3α) is involved in DNA repair surveillance and cell-cycle checkpoints possibly through formatting complex with tumor suppressors. However, its role in cancer development remained unsolved.

Experimental Design: Coimmunoprecipitation, sucrose gradient, chromatin immunoprecipitation (ChIP), real time PCR, and immunoblotting analyses were performed to determine interactions of hTOP3α with p53. Paired cell lines with different hTOP3α levels were generated via ectopic expression and short hairpin RNA (shRNA)-mediated knockdown approaches. Cellular tumorigenic properties were analyzed using cell counting, colony formation, senescence, soft agar assays, and mouse xenograft models.

Results: The hTOP3α isozyme binds to p53 and cofractionizes with p53 in gradients differing from fractions containing hTOP3α and BLM. Knockdown of hTOP3α expression (sh-hTOP3α) caused a higher anchorage-independent growth of nontumorigenic RHEK-1 cells. Similarly, sh-hTOP3α and ectopic expression of hTOP3α in cancer cell lines caused increased and reduced tumorigenic abilities, respectively. Genetic and mutation experiments revealed that functional hTOP3α, p53, and p21 are required for this tumor-suppressive activity. Mechanism-wise, ChIP data revealed that hTOP3α binds to the p53 and p21 promoters and positively regulates their expression. Two proteins affect promoter recruitments of each other and collaborate in p21 expression. Moreover, sh-hTOP3α and sh-p53 in AGS cells caused a similar reduction in senescence and hTOP3α mRNA levels were lower in gastric and renal tumor samples.

Conclusion: We concluded that hTOP3α interacts with p53, regulates p53 and p21 expression, and contributes to the p53-mediated tumor suppression. Clin Cancer Res; 20(6); 1489–501. ©2014 AACR.
Maximizing Return on Socioeconomic Investment in Phase II Proof-of-Concept Trials
Authors: Chen Cong , Beckman Robert A.
Published: February 2014

Phase II proof-of-concept (POC) trials play a key role in oncology drug development, determining which therapeutic hypotheses will undergo definitive phase III testing according to predefined Go-No Go (GNG) criteria. The number of possible POC hypotheses likely far exceeds available public or private resources. We propose a design strategy for maximizing return on socioeconomic investment in phase II trials that obtains the greatest knowledge with the minimum patient exposure. We compare efficiency using the benefit–cost ratio, defined to be the risk-adjusted number of truly active drugs correctly identified for phase III development divided by the risk-adjusted total sample size in phase II and III development, for different POC trial sizes, powering schemes, and associated GNG criteria. It is most cost-effective to conduct small POC trials and set the corresponding GNG bars high, so that more POC trials can be conducted under socioeconomic constraints. If δ is the minimum treatment effect size of clinical interest in phase II, the study design with the highest benefit–cost ratio has approximately 5% type I error rate and approximately 20% type II error rate (80% power) for detecting an effect size of approximately 1.5δ. A Go decision to phase III is made when the observed effect size is close to δ. With the phenomenal expansion of our knowledge in molecular biology leading to an unprecedented number of new oncology drug targets, conducting more small POC trials and setting high GNG bars maximize the return on socioeconomic investment in phase II POC trials. Clin Cancer Res; 20(7); 1730–4. ©2014 AACR.
A Short Treatment with Galactomannan GM-CT-01 Corrects the Functions of Freshly Isolated Human Tumor–Infiltrating Lymphocytes
Authors: Demotte Nathalie , Bigirimana René , Wieërs Grégoire , Stroobant Vincent , Squifflet Jean-Luc , Carrasco Javier , Thielemans Kris , Baurain Jean-François , Van Der Smissen Patrick , Courtoy Pierre J. , van der Bruggen Pierre
Published: February 2014

Purpose: Several galectins are released by tumor cells and macrophages and accumulate in the tumor microenvironment. Galectin-1 and -3 were found to bind to glycosylated receptors at the surface of tumor-infiltrating lymphocytes (TIL), forming glycoprotein–galectin lattices that could reduce the motility and therefore the functionality of surface molecules. In contrast to blood T cells, human TIL show defective IFN-γ secretion upon ex vivo stimulation. We have previously shown that extracellular galectin-3 participates in the impairment of TIL functions. Indeed, disruption of glycoprotein–galectin-3 lattices using anti-galectin-3 antibodies, or N-acetyllactosamine as a competing sugar, boosted cytokine secretion by TIL. Here we have tested a clinical grade galectin antagonist: GM-CT-01, a galactomannan obtained from guar gum reported to be safe in more than 50 patients with cancer.

Experimental Design: TIL were isolated from human tumor ascites, treated for 2 to 20 hours with galectin antagonists and tested for function.

Results: We found that GM-CT-01 boosts cytotoxicity of CD8+ TIL and their IFN-γ secretion in a dose-dependent manner. Treating TIL obtained from patients with various cancers, during a few hours, resulted in an increased IFN-γ secretion in up to 80% of the samples.

Conclusions: These observations pave the way for investigating the potential benefit of this galectin antagonist in patients with cancer, alone or combined with cancer vaccination, in order to correct in vivo impaired functions of TIL. Clin Cancer Res; 20(7); 1823–33. ©2014 AACR.
T-cell Responses to Oncogenic Merkel Cell Polyomavirus Proteins Distinguish Patients with Merkel Cell Carcinoma from Healthy Donors
Authors: Lyngaa Rikke , Pedersen Natasja Wulff , Schrama David , Thrue Charlotte Albæk , Ibrani Dafina , Met Özcan , thor Straten Per , Nghiem Paul , Becker Jürgen C. , Hadrup Sine Reker
Published: February 2014

Purpose: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with strong evidence of viral carcinogenesis. The association of MCC with the Merkel cell polyomavirus (MCPyV) may explain the explicit immunogenicity of MCC. Indeed, MCPyV-encoded proteins are likely targets for cytotoxic immune responses to MCC as they are both foreign to the host and necessary to maintain the oncogenic phenotype. However, to date only a single MCPyV-derived CD8 T-cell epitope has been described, thus impeding specific monitoring of T-cell responses to MCC.

Method: To overcome this limitation, we scanned the MCPyV oncoprotein large T and small T antigens and the virus capsid protein VP1 for potential T-cell epitopes, and tested for MHC class I affinity. We confirmed the relevance of these epitopes using a high-throughput platform for T-cell enrichment and combinatorial encoding of MHC class I multimers.

Results: In peripheral blood from 38 patients with MCC and 30 healthy donors, we identified 53 MCPyV-directed CD8 T-cell responses against 35 different peptide sequences. Strikingly, T-cell responses against oncoproteins were exclusively present in patients with MCC, but not in healthy donors. We further demonstrate both the processing and presentation of the oncoprotein-derived epitopes, as well as the lytic activity of oncoprotein-specific T cells toward MHC-matched MCC cells. Demonstrating the presence of oncoprotein-specific T cells among tumor-infiltrating lymphocytes further substantiated the relevance of the identified epitopes.

Conclusion: These T-cell epitopes represent ideal targets for antigen-specific immune therapy of MCC, and enable tracking and characterization of MCPyV-specific immune responses. Clin Cancer Res; 20(7); 1768–78. ©2014 AACR.
Interferon-β Induces Loss of Spherogenicity and Overcomes Therapy Resistance of Glioblastoma Stem Cells
Authors: Happold Caroline , Roth Patrick , Silginer Manuela , Florea Ana-Maria , Lamszus Katrin , Frei Karl , Deenen Rene , Reifenberger Guido , Weller Michael
Published: February 2014

Glioblastoma is the most common malignant brain tumor in adults and characterized by a poor prognosis. Glioma cells expressing O6-methylguanine DNA methyltransferase (MGMT) exhibit a higher level of resistance toward alkylating agents, including the standard of care chemotherapeutic agent temozolomide. Here, we demonstrate that long-term glioma cell lines (LTL) as well as glioma-initiating cell lines (GIC) express receptors for the immune modulatory cytokine IFN-β and respond to IFN-β with induction of STAT-3 phosphorylation. Exposure to IFN-β induces a minor loss of viability, but strongly interferes with sphere formation in GIC cultures. Furthermore, IFN-β sensitizes LTL and GIC to temozolomide and irradiation. RNA interference confirmed that both IFN-β receptors, R1 and R2, are required for IFN-β–mediated sensitization, but that sensitization is independent of MGMT or TP53. Most GIC lines are highly temozolomide-resistant, mediated by MGMT expression, but nevertheless susceptible to IFN-β sensitization. Gene expression profiling following IFN-β treatment revealed strong upregulation of IFN-β–associated genes, including a proapoptotic gene cluster, but did not alter stemness-associated expression signatures. Caspase activity and inhibition studies revealed the proapoptotic genes to mediate glioma cell sensitization to exogenous death ligands by IFN-β, but not to temozolomide or irradiation, indicating distinct pathways of death sensitization mediated by IFN-β. Thus, IFN-β is a potential adjunct to glioblastoma treatment that may target the GIC population. IFN-β operates independently of MGMT-mediated resistance, classical apoptosis-regulatory networks, and stemness-associated gene clusters. Mol Cancer Ther; 13(4); 948–61. ©2014 AACR.
Protein Biomarkers of New-Onset Cardiovascular Disease
Authors: Yin Xiaoyan , Subramanian Subha , Hwang Shih-Jen , O’Donnell Christopher J. , Fox Caroline S. , Courchesne Paul , Muntendam Pieter , Gordon Neal , Adourian Aram , Juhasz Peter , Larson Martin G. , Levy Daniel
Published: February 2014

Objective—

Incorporation of novel plasma protein biomarkers may improve current models for prediction of atherosclerotic cardiovascular disease (ASCVD) risk.

Approach and Results—

We used discovery mass spectrometry (MS) to determine plasma concentrations of 861 proteins in 135 myocardial infarction (MI) cases and 135 matched controls. Then, we measured 59 markers by targeted MS in 336 ASCVD case–control pairs. Associations with MI or ASCVD were tested in single-marker and multiple-marker analyses adjusted for established ASCVD risk factors. Twelve single markers from discovery MS were associated with MI incidence (at
P
<0.01), adjusting for clinical risk factors. Seven proteins in aggregate (cyclophilin A, cluster of differentiation 5 molecule [CD5] antigen-like, cell-surface glycoprotein mucin cell surface associated protein 18 [MUC-18], collagen-α 1 [XVIII] chain, salivary α-amylase 1, C-reactive protein, and multimerin-2) were highly associated with MI (
P
<0.0001) and significantly improved its prediction compared with a model with clinical risk factors alone (C-statistic of 0.71 versus 0.84). Through targeted MS, 12 single proteins were predictors of ASCVD (at
P
<0.05) after adjusting for established risk factors. In multiple-marker analyses, 4 proteins in combination (α-1–acid glycoprotein 1, paraoxonase 1, tetranectin, and CD5 antigen-like) predicted incident ASCVD (
P
<0.0001) and moderately improved the C-statistic from the model with clinical covariates alone (C-statistic of 0.69 versus 0.73).

Conclusions—

Proteomics profiling identified single- and multiple-marker protein panels that are associated with new-onset ASCVD and may lead to a better understanding of underlying disease mechanisms. Our findings include many novel protein biomarkers that, if externally validated, may improve risk assessment for MI and ASCVD.
Role of Endothelial Cell–Derived Angptl2 in Vascular Inflammation Leading to Endothelial Dysfunction and Atherosclerosis Progression
Authors: Horio Eiji , Kadomatsu Tsuyoshi , Miyata Keishi , Arai Yasumichi , Hosokawa Kentaro , Doi Yasufumi , Ninomiya Toshiharu , Horiguchi Haruki , Endo Motoyoshi , Tabata Mitsuhisa , Tazume Hirokazu , Tian Zhe , Takahashi Otowa , Terada Kazutoyo , Takeya Motohiro , Hao Hiroyuki , Hirose Nobuyoshi , Minami Takashi , Suda Toshio , Kiyohara Yutaka , Ogawa Hisao , Kaikita Koichi , Oike Yuichi
Published: February 2014

Objective—

Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression.

Approach and Results—

Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E–deficient mice (
ApoE
−/−
/
Angptl2
−/−
) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely,
ApoE
−/−
mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter (
ApoE
−/−
/Tie2-
Angptl2
Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2-
Angptl2
Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell–derived nitric oxide. Conversely,
Angptl2
−/−
mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis.

Conclusions—

Endothelial cell–derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.
Vascular Smooth Muscle Cell–Derived Transforming Growth Factor-β Promotes Maturation of Activated, Neointima Lesion–Like Macrophages
Authors: Ostriker Allison , Horita Henrick N. , Poczobutt Joanna , Weiser-Evans Mary C.M. , Nemenoff Raphael A.
Published: February 2014

Objective—

To define the contribution of vascular smooth muscle cell (SMC)–derived factors to macrophage phenotypic modulation in the setting of vascular injury.

Approach and Results—

By flow cytometry, macrophages (M4) were the predominant myeloid cell type recruited to wire-injured femoral arteries, in mouse, compared with neutrophils or eosinophils. Recruited macrophages from injured vessels exhibited a distinct expression profile relative to circulating mononuclear cells (peripheral blood monocytes; increased: interleukin-6, interleukin-10, interleukin-12b, CC chemokine receptor [CCR]3, CCR7, tumor necrosis factor-α, inducible nitric oxide synthase, arginase 1; decreased: interleukin-12a, matrix metalloproteinase [MMP]9). This phenotype was recapitulated in vitro by maturing rat bone marrow cells in the presence of macrophage-colony stimulating factor and 20% conditioned media from cultured rat SMC (sMφ) compared with maturation in macrophage-colony stimulating factor alone (M0). Recombinant transforming growth factor (TGF)-β1 recapitulated the effect of SMC conditioned media. Macrophage maturation studies performed in the presence of a pan-TGF-β neutralizing antibody, a TGF-β receptor inhibitor, or conditioned media from TGF-β–depleted SMCs confirmed that the SMC-derived factor responsible for macrophage activation was TGF-β. Finally, the effect of SMC-mediated macrophage activation on SMC biology was assessed. SMCs cocultured with sMφ exhibited increased rates of proliferation relative to SMCs cultured alone or with M0 macrophages.

Conclusions—

SMC-derived TGF-β modulates the phenotype of maturing macrophages in vitro, recapitulating the phenotype found in vascular lesions in vivo. SMC-modulated macrophages induce SMC activation to a greater extent than control macrophages.
Muscle-Specific RING Finger 1 Negatively Regulates Pathological Cardiac Hypertrophy Through Downregulation of Calcineurin A
Authors: Maejima Yasuhiro , Usui Soichiro , Zhai Peiyong , Takamura Masayuki , Kaneko Shuichi , Zablocki Daniela , Yokota Mitsuhiro , Isobe Mitsuaki , Sadoshima Junichi
Published: February 2014

Background—

Muscle-specific RING finger protein-1 (MuRF1) is an E3 ligase that inhibits cardiac hypertrophy. However, how MuRF1 regulates cardiac hypertrophy and function during pressure overload (PO) remains poorly understood. We investigated the role of endogenous MuRF1 in regulating cardiac hypertrophy in response to PO in vivo.

Methods and Results—

Transverse aortic constriction (TAC) for 4 weeks significantly reduced expression of MuRF1 in the mouse heart. After 2 and 4 weeks of TAC, MuRF1 knockout (
Murf1
−/−
) mice exhibited enhanced cardiac hypertrophy and left ventricular (LV) dysfunction compared with that of nontransgenic (NTg) mice. Histological analyses showed that
Murf1
−/−
mice exhibited more severe fibrosis and apoptosis than NTg mice after TAC. TAC-induced increases in the activity of a nuclear factor of activated T cells (NFAT) luciferase reporter were significantly greater in
Murf1
−/−
than in NTg mice. TAC-induced increases in calcineurin A (CnA) expression were also significantly enhanced in
Murf1
−/−
compared with that in NTg mice. Coimmunoprecipitation assays showed that endogenous MuRF1 and CnA interact with one another. Polyubiquitination of CnA was attenuated in
Murf1
−/−
mouse hearts at baseline and in response to TAC, and the protein stability of CnA was enhanced in cardiomyocytes, in which MuRF1 was downregulated in vitro. Furthermore, MuRF1 directly ubiquitinated CnA in vitro. Cardiac-specific overexpression of ZAKI-4β, an endogenous inhibitor of CnA, significantly suppressed the enhancement of TAC-induced cardiac hypertrophy and dysfunction, as well as increases in cardiac fibrosis and apoptosis, in
Murf1
−/−
mice.

Conclusions—

Endogenous MuRF1 negatively regulates cardiac hypertrophy and dysfunction in response to PO through inhibition of the calcineurin–NFAT pathway.
Fibroblast Growth Factor–23 and Cardiac Structure and Function
Authors: Agarwal Isha , Ide Noriko , Ix Joachim H. , Kestenbaum Bryan , Lanske Beate , Schiller Nelson B. , Whooley Mary A. , Mukamal Kenneth J.
Published: February 2014

Background

Fibroblast growth factor–23 (
FGF
‐23) is a phosphaturic factor previously associated with left ventricular hypertrophy and systolic dysfunction among individuals with chronic kidney disease. Whether
FGF
‐23 acts directly to induce left ventricular hypertrophy, potentially independent of its klotho coreceptor, remains uncertain. We investigated associations of
FGF
‐23 with cardiac structural abnormalities among individuals with a broad range of kidney function and explored potential biological mechanisms using cardiac magnetic resonance imaging and histology in
klotho
‐null mice, an established model of constitutively elevated
FGF
‐23.

Methods and Results

Among 887 participants with coronary artery disease in the
H
eart and
S
oul
S
tudy,
FGF
‐23 was modestly associated with worse left ventricular ejection fraction (−1.0% per standard deviation increase in ln
FGF
‐23; standard error, 0.4%), but was not associated with the overall prevalence of concentric hypertrophy (odds ratio, 1.5;
CI
, 0.9 to 2.4) or eccentric hypertrophy (odds ratio, 1.1;
CI
, 0.9 to 1.3).
FGF
‐23 was only associated with concentric hypertrophy among individuals with diminished kidney function (
eGFR
<60 mL/min per 1.73 m
2
; odds ratio, 2.3;
CI
, 1.0 to 5.3;
P
‐interaction=0.28). Comparing
klotho
‐null with wild‐type mice, null mice did not have greater left ventricular mass (
P
=0.37) or a lower ejection fraction (
P
=0.94).

Conclusions

Together, our results suggest that
FGF
‐23 is unlikely to have major effects on cardiovascular structure and function among patients free of substantial chronic kidney disease, and these effects may not be independent of the klotho coreceptor.
Upper Limb Recovery After Stroke Is Associated With Ipsilesional Primary Motor Cortical Activity
Authors: Favre Isabelle , Zeffiro Thomas A. , Detante Olivier , Krainik Alexandre , Hommel Marc , Jaillard Assia
Published: February 2014

Background and Purpose—

Although neuroimaging studies have revealed specific patterns of reorganization in the sensorimotor control network after stroke, their role in recovery remains unsettled. To review the existing evidence systematically, we performed activation likelihood estimation meta-analysis of functional neuroimaging studies investigating upper limb movement-related brain activity after stroke.

Methods—

Twenty-four studies using sensorimotor tasks in standardized coordinates were included, totaling 255 patients and 145 healthy controls. Across the entire brain, we compared task-related activity patterns in good and poor recovery and assessed the magnitude of spatial shifts in sensorimotor activity in cortical motor areas after stroke.

Results—

When compared with healthy controls, patients showed higher activation likelihood estimation values in contralesional primary motor soon after stroke that abated with time, but were not related to motor outcome. The observed activity changes were consistent with restoration of typical interhemispheric balance. In contrast, activation likelihood estimation values in ipsilesional medial-premotor and primary motor cortex were associated with good outcome, reorganization that may reflect vicarious processes associated with ventral activity shifts from BA4a to 4p. In the anterior cerebellum, a novel finding was the association of poor recovery with increased vermal activity, possibly reflecting behaviorally inadequate compensatory strategies engaging the fastigio-thalamo-cortical and corticoreticulospinal systems.

Conclusions—

Activity in ipsilesional primary motor and medial-premotor cortices in chronic stroke signals good motor recovery, whereas cerebellar vermis activity signals poor recovery. Functional MRI may be useful in identifying recovery biomarkers.
Urgent Carotid Surgery and Stenting May Be Safe After Systemic Thrombolysis for Stroke
Authors: Koraen-Smith Linn , Troëng Thomas , Björck Martin , Kragsterman Björn , Wahlgren Carl-Magnus ,   This work was supported by the Steering Committee of the Swedish Vascular Registry (Swedvasc):, Kragsterman Björn , Hager Jakob , Wellander Erik , Nordanstig Joakim , Sigvant Birgitta , Björses Katarina , Wigelius Ann ,   It was also supported by the Steering Committee of the Riks-Stroke Collaboration:, Asplund Kjell , Appelros Peter , Bjarne Daniela , Engberg Wania , von Euler Mia , Norrving Bo , Stegmayr Birgitta , Térent Andreas , Wallin Sari , Ytterberg Marianne
Published: February 2014

Background and Purpose—

Early carotid surgery or stenting after thrombolytic treatment for stroke has become more common during recent years. It is unclear whether this carries an increased risk of postoperative complications and death. The aim of this nationwide population-based study was, therefore, to investigate the safety of urgently performed carotid procedures in patients treated with thrombolysis for stroke.

Methods—

Using the national Vascular and Stroke registries, we identified 3998 patients who had undergone carotid endarterectomy or carotid artery stenting for symptomatic carotid stenosis between May 2008 and December 2012. Among these, 2% (79 of 3998) had undergone previous thrombolysis for stroke. We conducted a retrospective review of registry data and individual case records with regard to postoperative complications, including surgical-site bleeding, stroke, and death. The outcome was compared with the results for the remaining patient cohort (3919 of 3998) undergoing carotid surgery and stenting during the study period.

Results—

The median time between thrombolysis and the carotid procedure was 10 days. Seventy-one patients underwent carotid endarterectomy, and 6 patients underwent carotid artery stenting. The 30-day death and stroke rate for the thrombolysis cohort was 2.5% (2 of 79), and for the whole cohort, it was 3.8% (139 of 3626;
P
=0.55). The postoperative bleeding rates requiring reoperation were not significantly different between the groups (3.8% [3 of 79] in the thrombolysis group versus 3.3% [119 of 3626] in the whole cohort;
P
=0.79). There was no correlation between time from lysis to surgery or stenting and complications at 30 days postoperatively.

Conclusions—

Urgent carotid endarterectomy or carotid artery stenting after thrombolysis for stroke may be safe without increased risk of serious complications.
Serial Alberta Stroke Program Early CT Score From Baseline to 24 Hours in Solitaire Flow Restoration With the Intention for Thrombectomy Study
Authors: Liebeskind David S. , Jahan Reza , Nogueira Raul G. , Jovin Tudor G. , Lutsep Helmi L. , Saver Jeffrey L.
Published: February 2014

Background and Purpose—

The Alberta Stroke Program Early CT Score (ASPECTS) on baseline imaging is an established predictor of acute ischemic stroke outcomes. We analyzed change on serial ASPECTS at baseline and 24-hour imaging in the Solitaire Flow Restoration with the Intention for Thrombectomy (SWIFT) study to determine prognostic value and to identify subgroups with extensive injury after intervention.

Methods—

ASPECTS at baseline and 24 hours was independently scored in all anterior circulation SWIFT cases, blinded to all other trial data. ASPECTS at baseline, at 24 hours, and serial changes were analyzed with univariate and multivariate approaches.

Results—

One hundred thirty-nine patients (mean age, 67 [SD, 12] years; 52% women; median National Institutes of Health Stroke Scale, 18 [interquartile range, 8–28]) with complete data at both time points were studied. Multivariate analyses showed that higher 24-hour ASPECTS predicted good clinical outcome (day 90 modified Rankin Scale, 0–2; odds ratio, 1.67;
P
<0.001). Among patients with high baseline ASPECTS (8–10; n=109), dramatic infarct progression (decrease in ASPECTS ≥6 points at 24 hours) was noted in 31 of 109 (28%). Such serial ASPECTS change was predicted by higher baseline systolic blood pressure (
P
=0.019), higher baseline blood glucose (
P
=0.133), and failure to achieve Thrombolysis in Cerebral Infarction score of 2b/3 reperfusion (
P
<0.001), culminating in worse day 90 modified Rankin Scale outcomes (mean modified Rankin Scale, 4.4 versus 2.7;
P
<0.001).

Conclusions—

Twenty-four-hour ASPECTS provides better prognostic information compared with baseline ASPECTS. Predictors of dramatic infarct progression on ASPECTS are hyperglycemia, hypertension, and nonreperfusion. Serial ASPECTS change from baseline to 24 hours predicts clinical outcome, providing an early surrogate end point for thrombectomy trials.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01054560.
Do Standard Measures of Preschool Quality Used in Statewide Policy Predict School Readiness?
Authors: Sabol Terri J. , Pianta Robert C.
Published: February 2014

In the majority of states using Quality Rating and Improvement Systems (QRIS) to improve children's school readiness, the Early Childhood Environmental Rating Scale-Revised (ECERS-R) is a core assessment of preschool program quality and is central to QRIS metrics and incentive structures. The present study utilizes nationally representative data from the Early Childhood Longitudinal Study–Birth Cohort to examine relations between the ECERS-R and children's academic, language, and socioemotional functioning at age five years. After using a rich set of controls, we found little evidence that the ECERS-R related to children's development. Further, higher levels of quality failed to improve growth in academic, language, or socioemotional skills and behaviors for children with more exposure to sociodemographic risk. Implications of these findings are discussed with regard to recent policy initiatives and strengthening the measurement of quality in early childhood education settings.
Estimated Effect of the Teacher Advancement Program on Student Test Score Gains
Authors: Springer Matthew G. , Ballou Dale , Peng Art (Xiao)
Published: February 2014

This article presents findings from the first independent, third-party appraisal of the impact of the Teacher Advancement Program (TAP) on student test score gains in mathematics. TAP is a comprehensive school reform model designed to attract highly effective teachers, improve instructional effectiveness, and elevate student achievement. We use a panel data set to estimate a TAP treatment effect by comparing student test score gains in mathematics in schools that participated in TAP with student test score gains in non-TAP schools. Ordinary least squares estimation reveals a positive TAP treatment effect on student test score gains in the elementary grades, with weaker but still positive point estimates in the secondary grades. When estimation methods control for selection bias, the positive effect remains at the elementary level, but most estimates for grades 6 through 10 turn negative. Our findings are qualified by the lack of information on the fidelity of implementation across TAP schools and on variation in features of TAP programs at the school level.
Validating the Neuro VR-Based Virtual Version of the Multiple Errands Test: Preliminary Results
Authors: Raspelli Simona , Pallavicini Federica , Carelli Laura , Morganti Francesca , Pedroli Elisa , Cipresso Pietro , Poletti Barbara , Corra Barbara , Sangalli Davide , Silani Vincenzo , Riva Giuseppe
Published: February 2014

The purpose of this study was to establish ecological validity and initial construct validity of the virtual reality version of the Multiple Errands Test based on NeuroVR software as an assessment tool for executive functions. In particular, the Multiple Errands Test is an assessment of executive functions in daily life which consists of tasks that abide by certain rules and is performed in a shopping mall-like setting where there are items to be bought and information to be obtained. The study population included three groups: post-stroke participants (n = 9), healthy young participants (n = 10), and healthy older participants (n = 10). The general purpose of the study was investigated through the following specific objectives: (1) to examine the relationships between the performance of three groups of participants in the Virtual Multiple Errands Test (VMET) and in the traditional neuropsychological tests employed to assess executive functions; and (2) to compare the performance of post-stroke participants to those of healthy young and older controls in the Virtual Multiple Errands Test and in the traditional neuropsychological tests employed to assess executive functions. Correlations between Virtual Multiple Errands Test variables and some traditional executive functions measures provide preliminary support for the ecological and construct validity of the VMET; further performance obtained at the Virtual Multiple Errands Test provided a distinction between the clinical and healthy population, and between the two age control groups. These results suggest a possible future application of such an ecological approach for cognitive assessment and rehabilitation of stroke patients and elderly population with age-related cognitive decline.
Interactive Graphical Design of 3D Serious Neurorehabilitation Games
Authors: Moya Sergio , Tost Dani , Grau Sergi
Published: February 2014

We describe a graphical narrative editor that we have developed for the design of serious games for cognitive neurorehabilitation. The system is addressed to neuropsychologists. It is aimed at providing them an easy, user-friendly, and fast way of specifying the therapeutical contents of the rehabilitation tasks that constitute the serious games. The editor takes as input a description of the virtual task environment and the actions allowed inside. Therapists use it to describe the actions that they expect patients to do in order to fulfill the goals of the task and the behavior of the game if patients do not reach their goals. The output of the system is a complete description of the task logic. We have designed a 3D game platform that provides to the editor a description the 3D virtual environments, and that translates the task description created in the editor into the task logic. The main advantage of the system is that it is fully automatic, it allows therapists to interactively design the tasks and immediately validate them by realizing it virtually. We describe the design of the two applications and present the results of system testing.
Interactive Gait Rehabilitation System with a Locomotion Interface for Training Patients to Climb Stairs
Authors: Yano Hiroaki , Tamefusa Shintaro , Tanaka Naoki , Saito Hideyuki , Iwata Hiroo
Published: February 2014

This paper describes the development of a gait rehabilitation system with a locomotion interface (LI) for training patients to climb stairs. The LI consists of two 2-DOF manipulators equipped with footpads. These can move the patient's feet while his or her body remains stationary. The footpads follow the prerecorded motion of the feet of healthy individuals. For gait training, the patient progresses sequentially through successively more advanced modes. In this study, two modes, the enforced climbing of stairs and interactive climbing of stairs, were developed. In the interactive mode, foot pressure sensors are used to realize interactive walking. Comparisons were made between the modes for healthy individuals and a patient. The effectiveness of the system was examined using electromyography (EMG) and foot pressure data.
Adaptive Generation of Emotional Impact Using Enhanced Virtual Environments
Authors: Matthias Haringer , Beckhaus Steffi
Published: February 2014

In this paper we introduce novel methods of intensifying and varying the user experience in virtual environments (VE). VEs technically have numerous means for crafting the user experience. Little has yet been done to evaluate those means of expression (MoEs) for their emotional impact on people and to use their capability to create different experiences and subtly guide the user. One of the reasons is that this requires a system which is capable of easily and dynamically providing those MoEs in such a way that they can easily be composed, evaluated, and compared between applications and users. In the following, we first introduce our model of both informational and emotional impact of VEs on users, introduce our dynamic, expressive VR-system, and present our novel evaluation and rating method for MoEs. MoEs can be used to guide attention to specific objects or build up an emotion or mood over time. We then present a study in which users experience 30 selected MoEs and rate their qualitative emotional impact using this rating method. We found that different MoEs can be used to elicit many diverse emotions which were surprisingly consistent among the test persons. With these results, our work enables new ways to make VEs more interesting and emotionally engaging, especially over a longer period of time, opening new possibilities, for example, to increase the motivation for long, stressful, and tiresome training as in neurorehabilitation.
GREENSPACE: Virtual Reality Interface for Combine Operator Training
Authors: Luecke Greg R.
Published: February 2014

The complexity of operating a farm combine has increased dramatically in recent years with the introduction of features including automatic guidance, precision farming, and sophisticated implements with specialized controls. In this work, we describe the development of a virtual reality interface for use in operating a combine while harvesting virtual crops. Using the actual combine cab hardware for control input commands and operational displays, we provide a virtual farm that allows the operator to operate every aspect of the combine while using the true set of buttons, levers, and switches for a realistic driving experience. This simulator is designed primarily for operator training on the adjustment and operation of the machine controls, the use of automatic guidance systems, and interaction with the precision farming automation systems. However, the simulator is also applicable for engineering design development, where new control modes and hardware could be assessed in a virtual environment.