bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial inflammation correlates with subject triglycerides and waist size after a high-fat meal
Authors: Wang Ying I. , Schulze John , Raymond Nadine , Tomita Tyler , Tam Kayan , Simon Scott I. , Passerini Anthony G.
Published: December 2010

A rise in postprandial serum triglycerides (PP-sTG) can potentiate inflammatory responses in vascular endothelial cells (ECs) and thus serves as an independent risk factor for predicting increased cardiovascular morbidity. We examined postprandial triglyceride-rich lipoproteins (PP-TGRLs) in subjects ranging from normal to hypertriglyceridemic for their capacity to alter EC acute inflammatory responses. Cultured human aortic ECs (HAECs) were conditioned with PP-TGRLs isolated from human serum at the peak after a moderately high-fat meal. VLDL particle size increased postprandially and varied directly with the subject's PP-sTG level and waist circumference. PP-TGRL particles bound to HAECs and were internalized via LDL receptor-mediated endocytosis. PP-TGRL alone did not induce an inflammatory response over the range of individuals studied. However, combined with low-dose TNF-α stimulation (0.3 ng/ml), it elicited a net 10–15% increase above cytokine alone in the membrane expression of VCAM-1, ICAM-1, and E-selectin, which was not observed with fasting TGRLs. In contrast to upregulation of ICAM-1 and E-selectin, VCAM-1 transcription and expression varied in direct proportion with individual PP-sTG and waist circumference. The extent of monocyte arrest on inflamed HAECs under shear stress also correlated closely with VCAM-1 expression induced by conditioning with PP-TGRL and TNF-α stimulation. This ex vivo approach provides a quantitative means to assess an individual's inflammatory potential, revealing a greater propensity for endothelial inflammation in hypertriglyceridemic individuals with abdominal obesity.
Inhibition of histone deacetylase causes emphysema
Authors: Mizuno Shiro , Yasuo Masanori , Bogaard Herman J. , Kraskauskas Donatas , Natarajan Ramesh , Voelkel Norbert F.
Published: December 2010

In patients with chronic obstructive pulmonary disease (COPD), histone deacetylase (HDAC) expression and activity are reduced in the lung tissue. However, whether HDAC activity controls the maintenance of the lung alveolar septal structures has not been investigated. To explore the consequences of HDAC inhibition and address the question of whether HDAC inhibition causes lung cell apoptosis and emphysema, male Sprague-Dawley rats and human pulmonary microvascular endothelial cells (HPMVEC) were treated with trichostatin A (TSA), a specific inhibitor of HDACs. Chronic TSA treatment increased the alveolar air space area, mean linear intercept, and the number of caspase-3-positive cells in rat lungs. TSA suppressed hypoxia-inducible factor-1α (HIF-1α), VEGF, and lysyl oxidase (LOX) and increased microtubule-associated protein-1 light chain 3 (LC3), p53, and miR34a microRNA expression in both rat lungs and cultured HPMVEC. Gene silencing of HDAC2 using small interfering RNA (siRNA) in cultured HPMVEC resulted in the suppression of HIF-1α, VEGF, and LOX and an increase of p53 expression. These data indicate that HDAC inhibition causes emphysema and that HDAC-dependent mechanisms contribute to the maintenance of the adult lung structure. Our results also suggest that the increase in apoptosis, as a consequence of HDAC inhibition, is associated with decreased VEGF and HIF-1α expression.
Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats
Authors: Takagi Ryo , Fujita Naoto , Arakawa Takamitsu , Kawada Shigeo , Ishii Naokata , Miki Akinori
Published: December 2010

The influence of icing on muscle regeneration after crush injury was examined in the rat extensor digitorum longus. After the injury, animals were randomly divided into nonicing and icing groups. In the latter, ice packs were applied for 20 min. Due to the icing, degeneration of the necrotic muscle fibers and differentiation of satellite cells at early stages of regeneration were retarded by ∼1 day. In the icing group, the ratio of regenerating fibers showing central nucleus at 14 days after the injury was higher, and cross-sectional area of the muscle fibers at 28 days was evidently smaller than in the nonicing group. Besides, the ratio of collagen fibers area at 14 and 28 days after the injury in the icing group was higher than in the nonicing group. These findings suggest that icing applied soon after the injury not only considerably retarded muscle regeneration but also induced impairment of muscle regeneration along with excessive collagen deposition. Macrophages were immunohistochemically demonstrated at the injury site during degeneration and early stages of regeneration. Due to icing, chronological changes in the number of macrophages and immunohistochemical expression of transforming growth factor (TGF)-β1 and IGF-I were also retarded by 1 to 2 days. Since it has been said that macrophages play important roles not only for degeneration, but also for muscle regeneration, the influence of icing on macrophage activities might be closely related to a delay in muscle regeneration, impairment of muscle regeneration, and redundant collagen synthesis.
Nm23-H1 Indirectly Promotes the Survival of Acute Myeloid Leukemia Blast Cells by Binding to More Mature Components of the Leukemic Clone
Authors: Lilly Andrew J. , Khanim Farhat L. , Hayden Rachel E. , Luong Quang T. , Drayson Mark T. , Bunce Christopher M.
Published: December 2010

Nm23-H1 plays complex roles in the development of diverse cancers including breast carcinoma, high-grade lymphomas, and acute myeloid leukemia (AML). In the case of AML and lymphomas, serum Nm23-H1 protein is elevated with the highest levels correlating with poorest prognosis. A recent study identified that this association is most likely causal in AML and that Nm23-H1 acts as an AML cell survival factor. In this study, we report heterogeneity in the ability of AML samples to bind and respond to Nm23-H1, and we offer evidence that binding is essential for improved survival. Further, we show that the subset of AMLs that bind Nm23-H1 do not do so through the putative Nm23-H1 receptor MUC1*. Although rNm23-H1 promoted the survival of the most primitive blasts within responding AMLs, it was not these cells that actually bound the protein. Instead, rNm23-H1 bound to more mature CD34lo/CD34− and CD11b+ cells, revealing an indirect survival benefit of Nm23-H1 on primitive blasts. In support of this finding, the survival of purified blast cells was enhanced by medium conditioned by more mature cells from the clone that had been stimulated by rNm23-H1. Levels of interleukin 1β (IL1β) and IL6 in rNm23-H1 conditioned medium mirrored the potency of the conditioned media to promote blast cell survival. Furthermore, Nm23-H1 expression was significantly associated with IL1β and IL6 expression in primary uncultured AML samples. These findings have implications for the role of Nm23-H1 in AML and its use as a prognostic marker. Additionally, they offer the first evidence of novel cross-talk between cell populations within the tumor clone. Cancer Res; 71(3); 1177–86. ©2010 AACR.
Using a Stem Cell–Based Signature to Guide Therapeutic Selection in Cancer
Authors: Shats Igor , Gatza Michael L. , Chang Jeffrey T. , Mori Seiichi , Wang Jialiang , Rich Jeremy , Nevins Joseph R.
Published: December 2010

Given the very substantial heterogeneity of most human cancers, it is likely that most cancer therapeutics will be active in only a small fraction of any population of patients. As such, the development of new therapeutics, coupled with methods to match a therapy with the individual patient, will be critical to achieving significant gains in disease outcome. One such opportunity is the use of expression signatures to identify key oncogenic phenotypes that can serve not only as biomarkers but also as a means of identifying therapeutic compounds that might specifically target these phenotypes. Given the potential importance of targeting tumors exhibiting a stem-like phenotype, we have developed an expression signature that reflects common biological aspects of various stem-like characteristics. The consensus stemness ranking (CSR) signature is upregulated in cancer stem cell–enriched samples at advanced tumor stages and is associated with poor prognosis in multiple cancer types. Using two independent computational approaches we utilized the CSR signature to identify clinically useful compounds that could target the CSR phenotype. In vitro assays confirmed selectivity of several predicted compounds including topoisomerase inhibitors and resveratrol towards breast cancer cell lines that exhibit a high-CSR phenotype. Importantly, the CSR signature could predict clinical response of breast cancer patients to a neoadjuvant regimen that included a CSR-specific agent. Collectively, these results suggest therapeutic opportunities to target the CSR phenotype in a relevant cohort of cancer patients. Cancer Res; 71(5); 1772–80. ©2010 AACR.
Activation of NF-κB by TMPRSS2/ERG Fusion Isoforms through Toll-Like Receptor-4
Authors: Wang Jianghua , Cai Yi , Shao Long-jiang , Siddiqui Javed , Palanisamy Nallasivam , Li Rile , Ren Chengxi , Ayala Gustavo , Ittmann Michael
Published: December 2010

The TMPRSS2/ERG (T/E) fusion gene is present and thought to be an oncogenic driver of approximately half of all prostate cancers. Fusion of the androgen-regulated TMPRSS2 promoter to the ERG oncogene results in constitutive high level expression of ERG which promotes prostate cancer invasion and proliferation. Here, we report the characterization of multiple alternatively spliced T/E fusion gene isoforms which have differential effects on invasion and proliferation. We found that T/E fusion gene isoforms differentially increase NF-κB–mediated transcription, which may explain in part the differences in biological activities of the T/E fusion isoforms. This increased activity is due to phosphorylation of NF-κB p65 on Ser536. Tissue microarray immunochemistry revealed that p65 phospho-Ser536 is present in the majority of prostate cancers where it is associated with ERG protein expression. The T/E fusion gene isoforms differentially increase expression of a number of NF-κB associated genes including PAR1, CCL2, FOS, TLR3, and TLR4 (Toll-like receptor). TLR4 activation is known to promote p65 Ser536 phosphorylation and knockdown of TLR4 with shRNA decreases Ser536 phosphorylation in T/E fusion gene expressing cells. TLR4 can be activated by proteins in the tumor microenvironment and lipopolysacharide from Gram (−) bacteria. Our findings suggest that bacterial infection of the prostate and/or endogenous microenvironment proteins may promote progression of high-grade prostatic intraepithelial neoplasia and/or prostate cancers that express the T/E fusion gene, where the NF-κB pathway might be targeted as a rational therapeutic approach. Cancer Res; 71(4); 1325–33. ©2010 AACR.
The Epithelial-Mesenchymal Transition Mediator S100A4 Maintains Cancer-Initiating Cells in Head and Neck Cancers
Authors: Lo Jeng-Fan , Yu Cheng-Chia , Chiou Shih-Hwa , Huang Chih-Yang , Jan Chia-Ing , Lin Shu-Chun , Liu Chung-Ji , Hu Wen-Yuan , Yu Yau-Hua
Published: December 2010

Cancer-initiating cells (CIC) comprise a rare subpopulation of cells in tumors that are proposed to be responsible for tumor growth. Starting from CICs identified in head and neck squamous cell carcinomas (HNSCC), termed head and neck cancer-initiating cells (HN-CIC), we determined as a candidate stemness-maintaining molecule for HN-CICs the proinflammatory mediator S100A4, which is also known to be an inducer of epithelial-mesenchymal transition. S100A4 knockdown in HN-CICs reduced their self-renewal capability and their stemness and tumorigenic properties, both in vitro and in vivo. Conversely, S100A4 overexpression in HNSCC cells enhanced their stem cell properties. Mechanistic investigations indicated that attenuation of endogenous S100A4 levels in HNSCC cells caused downregulation of Notch2 and PI3K (phosphoinositide 3-kinase)/pAKT along with upregulation of PTEN, consistent with biological findings. Immunohistochemical analysis of HNSCC clinical specimens showed that S100A4 expression was positively correlated with clinical grading, stemness markers, and poorer patient survival. Together, our findings reveal a crucial role for S100A4 signaling pathways in maintaining the stemness properties and tumorigenicity of HN-CICs. Furthermore, our findings suggest that targeting S100A4 signaling may offer a new targeted strategy for HNSCC treatment by eliminating HN-CICs. Cancer Res; 71(5); 1912–23. ©2010 AACR.
A Mammaglobin-A Targeting Agent for Noninvasive Detection of Breast Cancer Metastasis in Lymph Nodes
Authors: Tafreshi Narges K. , Enkemann Steven A. , Bui Marilyn M. , Lloyd Mark C. , Abrahams Dominique , Huynh Amanda S. , Kim Jongphil , Grobmyer Stephen R. , Carter W. Bradford , Vagner Josef , Gillies Robert J. , Morse David L.
Published: December 2010

Pathologic axillary lymph node (ALN) status is an important prognostic factor for staging breast cancer. Currently, status is determined by histopathology following surgical excision of sentinel lymph node(s), which is an invasive, time consuming, and costly procedure with potential morbidity to the patient. Here, we describe an imaging platform for noninvasive assessment of ALN status, eliminating the need for surgical examination of patients to rule out nodal involvement. A targeted imaging probe (MamAb-680) was developed by conjugation of a mammaglobin-A–specific monoclonal antibody to a near-infrared fluorescent dye. Using DNA and tissue microarray, mammaglobin-A was validated as a cell-surface target that is expressed in ALN-positive patient samples but is not expressed in normal lymph nodes. In vivo selectivity was determined by i.v. injection of MamAb-680 into mice with mammaglobin-A–positive and -negative mammary fat pad (MFP) tumors; and by peritumoral MFP injection of the targeted imaging probe in mice with spontaneous ALN metastases. Fluorescence imaging showed that probe was only retained in positive tumors and metastases. As few as 1,000 cells that endogenously express mammaglobin-A were detected in ALN, indicating high sensitivity of this method. Translation of this approach offers considerable potential as a noninvasive clinical strategy to stage breast cancer. Cancer Res; 71(3); 1050–9. ©2010 AACR.
The Molecular Basis of Synergism between Carboplatin and ABT-737 Therapy Targeting Ovarian Carcinomas
Authors: Jain Harsh Vardhan , Meyer-Hermann Michael
Published: December 2010

Resistance to standard chemotherapy (carboplatin + paclitaxel) is one of the leading causes of therapeutic failure in ovarian carcinomas. Emergence of chemoresistance has been shown to be mediated in part by members of the Bcl family of proteins including the antiapoptotic protein Bcl-xL, whose expression is correlated with shorter disease-free intervals in recurrent disease. ABT-737 is an example of one of the first small-molecule inhibitors of Bcl-2/Bcl-xL that has been shown to increase the sensitivity of ovarian cancer cells to carboplatin. To exploit the therapeutic potential of these two drugs and predict optimal doses and dose scheduling, it is essential to understand the molecular basis of their synergistic action. Here, we build and calibrate a mathematical model of ABT-737 and carboplatin action on an ovarian cancer cell line (IGROV-1). The model suggests that carboplatin treatment primes cells for ABT-737 therapy because of an increased dependence of cells with DNA damage on Bcl-xL for survival. Numerical simulations predict the existence of a threshold of Bcl-xL below which these cells are unable to recover. Furthermore, co- plus posttreatment of ABT-737 with carboplatin is predicted to be the best strategy to maximize synergism between these two drugs. A critical challenge in chemotherapy is to strike a balance between maximizing cell-kill while minimizing patient drug load. We show that the model can be used to compute minimal doses required for any desired fraction of cell kill. These results underscore the potential of the modeling work presented here as a valuable quantitative tool to aid in the translation of novel drugs such as ABT-737 from the experimental to clinical setting and highlight the need for close collaboration between modelers and experimental scientists. Cancer Res; 71(3); 705–15. ©2010 AACR.
Explaining Marginal Benefits to Patients, When “Marginal” Means Additional but Not Necessarily Small
Authors: Smith Thomas J. , Hillner Bruce E.
Published: December 2010

Patients and their families want us to be realistic, honest, and caring about their prognosis and their options, even when the news is bad. Most oncologists will tell a patient if he is not curable, but not give specific survival information unless prompted. As an example, chemotherapy for pancreas cancer improves survival and does not worsen quality of life, but the impact on lifespan is small. Patients with advanced pancreas cancer have options that increase their average survival by about 16/100 at 1 year, and by about 9 weeks compared with best supportive care, but almost all patients are dead by 24 months. As an example of “marginal benefit” (“marginal” is defined here as more than that offered by the alternative care, not necessarily small or worthless), erlotinib added to gemcitabine compared with gemcitabine alone improves survival by six additional people at 1 year, and an average of 2 weeks, with no survival tail. In addition, the additional drug cost alone can be more than $12,000 a month. We use this clinical practice as a way to describe marginal benefit to patients. Telling patients that they have incurable disease and that treatment is ineffective is hard. Partly as a result, only about a third of cancer patients are told they are going to die, and those who are not told live no longer but have worse medical outcomes, such as dying on a ventilator and less time with hospice. These difficult conversations can be done if the oncologist has the right medical information, the right script, and some decision aids. Clin Cancer Res; 16(24); 5981–6. ©2010 AACR.
CYP24A1Is an Independent Prognostic Marker of Survival in Patients with Lung Adenocarcinoma
Authors: Chen Guoan , Kim So Hee , King Amanda N. , Zhao Lili , Simpson Robert U. , Christensen Paul J. , Wang Zhuwen , Thomas Dafydd G. , Giordano Thomas J. , Lin Lin , Brenner Dean E. , Beer David G. , Ramnath Nithya
Published: December 2010

Purpose: The active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25-D3), exerts antiproliferative effects in cancers, including lung adenocarcinoma (AC). CYP24A1 is overexpressed in many cancers and encodes the enzyme that catabolizes 1,25-D3. The purpose of our study was to assess CYP24A1 as a prognostic marker and to study its relevance to antiproliferative activity of 1,25-D3 in lung AC cells.

Experimental Design: Tumors and corresponding normal specimens from 86 patients with lung AC (stages I–III) were available. Affymetrix array data and subsequent confirmation by quantitative real time-PCR were used to determine CYP24A1 mRNA expression. A subsequent validation set of 101 lung AC was used to confirm CYP24A1 mRNA expression and its associations with clinical variables. The antiproliferative effects of 1,25-D3 were examined using lung cancer cell lines with high as well as low expression of CYP24A1 mRNA.

Results: CYP24A1 mRNA was elevated 8- to 50-fold in lung AC (compared to normal nonneoplastic lung) and significantly higher in poorly differentiated cancers. At 5 years of follow-up, the probability of survival was 42% (high CYP24A1, n = 29) versus 81% (low CYP24A1, n = 57) (P = 0.007). The validation set of 101 tumors showed that CYP24A1 was independently prognostic of survival (multivariate Cox model adjusted for age, gender, and stage, P = 0.001). A549 cells (high CYP24A1) were more resistant to antiproliferative effects of 1,25-D3 compared with SKLU-1 cells (low CYP24A1).

Conclusions: CYP24A1 overexpression is associated with poorer survival in lung AC. This may relate to abrogation of antiproliferative effects of 1,25-D3 in high CYP24A1 expressing lung AC. Clin Cancer Res; 17(4); 817–26. ©2010 AACR.
EfficientIn vivoPriming by Vaccination with Recombinant NY-ESO-1 Protein and CpG in Antigen Naïve Prostate Cancer Patients
Authors: Karbach Julia , Neumann Antje , Atmaca Akin , Wahle Claudia , Brand Kathrin , von Boehmer Lotta , Knuth Alexander , Bender Armin , Ritter Gerd , Old Lloyd J. , Jäger Elke
Published: December 2010

Purpose: NY-ESO-1, one of the most immunogenic tumor antigens, is expressed in 15% to 25% of metastatic prostate cancers. The immunological and clinical effects of vaccination with recombinant NY-ESO-1 protein combined with CpG as adjuvant were evaluated.

Experimental Design: In a phase I clinical study, patients with advanced prostate cancer were vaccinated with recombinant NY-ESO-1 protein (100 μg) mixed with CpG 7909 (2.5 mg) every 3 weeks intradermally for 4 doses. Objectives of the study were the safety of the vaccine and changes of specific humoral and cellular immunological responses to NY-ESO-1 in relation to detectable NY-ESO-1 expression in the individual tumor.

Results: All 12 baseline sero-negative patients developed high-titer NY-ESO-1 antibody responses. B-cell epitope mapping identified NY-ESO-1 p91–110 to be recognized most frequently by vaccine-induced antibodies. Two patients developed significant antibody titers against the adjuvant CpG. NY-ESO-1-specific CD4+ and/or CD8+ T-cell responses were induced in 9 patients (69%). Five of these 9 patients did not express NY-ESO-1 in the autologous tumor. Postvaccine CD8+ T-cell clones recognized and lyzed HLA-matched tumor cell lines in an antigen-specific manner.

Conclusion: Our data provide clear evidence for the capacity of NY-ESO-1 protein/CpG vaccine to induce integrated antigen-specific immune responses in vivo and to efficiently prime CD8+ T-cell responses in NY-ESO-1 antigen-negative patients. Our results may also support further clinical vaccination protocols with NY-ESO-1 protein not only focused on the treatment of existing cancer, but also to prevent further development of NY-ESO-1 positive cancers in vivo. Clin Cancer Res; 17(4); 1–10. ©2010 AACR.
Functional Genomics Reveals Diverse Cellular Processes That Modulate Tumor Cell Response to Oxaliplatin
Authors: Harradine Kelly A. , Kassner Michelle , Chow Donald , Aziz Meraj , Von Hoff Daniel D. , Baker Joffre B. , Yin Hongwei , Pelham Robert J.
Published: December 2010

Oxaliplatin is widely used to treat colorectal cancer, as both adjuvant therapy for resected disease and palliative treatment of metastatic disease. However, a significant number of patients experience serious side effects, including prolonged neurotoxicity, from oxaliplatin treatment creating an urgent need for biomarkers of oxaliplatin response or resistance to direct therapy to those most likely to benefit. As a first step to improve selection of patients for oxaliplatin-based chemotherapy, we have conducted an in vitro cell-based small interfering RNA (siRNA) screen of 500 genes aimed at identifying genes whose loss of expression alters tumor cell response to oxaliplatin. The siRNA screen identified twenty-seven genes, which when silenced, significantly altered colon tumor cell line sensitivity to oxaliplatin. Silencing of a group of putative resistance genes increased the extent of oxaliplatin-mediated DNA damage and inhibited cell-cycle progression in oxaliplatin-treated cells. The activity of several signaling nodes, including AKT1 and MEK1, was also altered. We used cDNA transfection to overexpress two genes (LTBR and TMEM30A) that were identified in the siRNA screen as mediators of oxaliplatin sensitivity. In both instances, overexpression conferred resistance to oxaliplatin. In summary, this study identified numerous putative predictive biomarkers of response to oxaliplatin that should be studied further in patient specimens for potential clinical application. Diverse gene networks seem to influence tumor survival in response to DNA damage by oxaliplatin. Finally, those genes whose loss of expression (or function) is related to oxaliplatin sensitivity may be promising therapeutic targets to increase patient response to oxaliplatin. Mol Cancer Res; 9(2); 173–82. ©2010 AACR.
Castration Has Antihypertensive and Organoprotective Effects in Male but Not in Female Heterozygous Ren-2 Rats
Authors: Vaněčková Ivana , Husková Zuzana , Vaňourková Zdeňka , Červenka Luděk
Published: December 2010

Gender differences in the regulation of blood pressure (BP) and the contributions of the renin-angiotensin system remain controversial. We assessed the effect of castration on BP and organ damage, as well as angiotensin II (ANG II), estradiol and testosterone levels in heterozygous Ren-2 transgenic (TGR) rats and transgene-negative Hannover Sprague-Dawley control rats. Male TGR had severe hypertension throughout the experiment, while the BP of female TGR declined after 5 months to normotensive levels. Ovariectomy had no effect on BP, cardiac hypertrophy or proteinuria in female Ren-2 TGR. On the contrary, BP and cardiac hypertrophy were significantly reduced in castrated male TGR as compared to sham-operated TGR. Moreover, proteinuria in these animals was normalized to the levels of control rats. ANG II levels did not differ between male and female TGR, and no effect of castration on plasma and tissue ANG II levels was found either in male or female TGR at the end of the experiment. In conclusion, the contribution of the renin-angiotensin system to the gender difference in BP homeostasis seems to be negligible in aging heterozygous Ren-2 transgenic rats.
High Glucose Enhances Thrombin Responses via Protease-Activated Receptor-4 in Human Vascular Smooth Muscle Cells
Authors: Dangwal Seema , Rauch Bernhard H. , Gensch Thomas , Dai Luru , Bretschneider Ellen , Vogelaar Christina Francisca , Schrör Karsten , Rosenkranz Anke C.
Published: December 2010

Objective—

Diabetes is associated with vascular remodeling and increased thrombin generation. Thrombin promotes vascular smooth muscle cell (SMC) mitogenesis and migration via protease-activated receptors (PAR)-1, PAR-3, and PAR-4. We investigated the effect of high glucose on expression and function of vascular thrombin receptors.

Methods and Results—

In human vascular SMCs, high glucose (25 versus 5.5 mmol/L) induced a rapid and sustained increase in PAR-4 mRNA, protein, and cell surface expression. PAR-1 and PAR-3 expression were not changed. High glucose pretreatment (48 hours) enhanced thrombin or PAR-4–activating peptide but not PAR-1–activating peptide evoked intracellular calcium mobilization, migration, and tumor necrosis factor α gene expression. This enhancement of thrombin-stimulated migration and gene expression by high glucose was abolished by endogenous PAR-4 knockdown.

PAR-4 regulation was prevented by inhibition of protein kinase (PK)C-β and -δ isoforms or nuclear factor (NF)κB. Nuclear translocation of NFκB in high glucose–stimulated SMCs led to PKC-dependent NFκB binding to the PAR-4 promoter in a chromatin immunoprecipitation assay. Furthermore, in situ hybridization and immunohistochemistry confirmed high abundance of PAR-4 in human diabetic vessels as compared with nondiabetic vessels.

Conclusion—

High glucose enhances SMC responsiveness to thrombin through transcriptional upregulation of PAR-4, mediated via PKC-β, -δ, and NFκB. This may play an important role in the vascular complications of diabetes.
Familial Thoracic Aortic Aneurysms and Dissections
Authors: Guo Dong-Chuan , Regalado Ellen S. , Minn Charles , Tran-Fadulu Van , Coney Joshua , Cao Jiumei , Wang Min , Yu Robert K. , Estrera Anthony L. , Safi Hazim J. , Shete Sanjay S. , Milewicz Dianna M.
Published: December 2010

Background—

Thoracic aortic aneurysms leading to acute aortic dissections are the major diseases that affect the thoracic aorta. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of TAAD, and these patients present younger with more rapidly enlarging aneurysms than patients without a family history of aortic disease.

Methods and Results—

A large family with multiple members with TAAD inherited in an autosomal-dominant manner was identified. The ascending aortic aneurysms were associated with slow enlargement, a low risk of dissection, and decreased penetrance in women. Genome-wide linkage analysis was performed, and a novel locus on chromosome 12 was identified for the mutant gene causing disease in this family. Of the 12 male members who carry the disease-linked microsatellite haplotype, 9 had ascending aortic aneurysms with an average diameter of 4.7 cm at an average age of 52.4 years (range, 32 to 76 years) at the time of diagnosis; only 1 individual had progressed to acute aortic dissection, and no other members with aortic dissections were identified. Women harboring the disease-linked haplotype did not have thoracic aortic disease, including 1 aged 84 years. Sequencing of 9 genes within the critical interval at the chromosome 12 locus did not identify the mutant gene.

Conclusions—

Mapping a locus for ascending thoracic aortic aneurysms associated with a low risk of aortic dissection supports our hypothesis that genes leading to familial disease can be associated with less-aggressive thoracic aortic disease.
Sphingosine-1-Phosphate Receptor 3 Promotes Recruitment of Monocyte/Macrophages in Inflammation and Atherosclerosis
Authors: Keul Petra , Lucke Susann , von Wnuck Lipinski Karin , Bode Constantin , Gräler Markus , Heusch Gerd , Levkau Bodo
Published: December 2010

Rationale:

The role of sphingosine-1-phosphate (S1P) and its receptors in the pathogenesis of atherosclerosis has not been investigated.

Objective:

We hypothesized that the S1P receptor 3 (S1P
3
) plays a causal role in the pathogenesis of atherosclerosis.

Methods and Results:

We examined atherosclerotic lesion development in mice deficient for S1P
3
and apolipoprotein (Apo)E. Although S1P
3
deficiency did not affect lesion size after 25 or 45 weeks of normal chow diet, it resulted in a dramatic reduction of the monocyte/macrophage content in lesions of S1P
3
−/−
/ApoE
−/−
double knockout mice. To search for putative defects in monocyte/macrophage recruitment, we examined macrophage-driven inflammation during thioglycollate-induced peritonitis. Elicited peritoneal macrophages were reduced in S1P
3
-deficient mice and expressed lower levels of tumor necrosis factor-α and monocyte chemoattractant protein-1. Bone marrow–derived S1P
3
-deficient macrophages produced less MCP-1 in response to lipopolysaccharide stimulation. In vitro, S1P was chemotactic for wild-type but not S1P
3
-deficient peritoneal macrophages. In vivo, S1P concentration increased rapidly in the peritoneal cavity after initiation of peritonitis. Treatment with the S1P analog FTY720 attenuated macrophage recruitment to the peritoneum. Studies in bone marrow chimeras showed that S1P
3
in both hematopoietic and nonhematopoietic cells contributed to monocyte/macrophage accumulation in atherosclerotic lesions. Finally, S1P
3
deficiency increased the smooth muscle cell content of atherosclerotic lesions and enhanced neointima formation after carotid ligation arguing for an antiproliferative/antimigratory role of S1P
3
in the arterial injury response.

Conclusions:

Our data suggest that S1P
3
mediates the chemotactic effect of S1P in macrophages in vitro and in vivo and plays a causal role in atherosclerosis by promoting inflammatory monocyte/macrophage recruitment and altering smooth muscle cell behavior.
Tissue Kallikrein Is Essential for Invasive Capacity of Circulating Proangiogenic Cells
Authors: Spinetti Gaia , Fortunato Orazio , Cordella Daniela , Portararo Paola , Kränkel Nicolle , Katare Rajesh , Sala-Newby Graciela B. , Richer Christine , Vincent Marie-Pascale , Alhenc-Gelas Francois , Tonolo Giancarlo , Cherchi Sara , Emanueli Costanza , Madeddu Paolo
Published: December 2010

Rationale:

Homing of proangiogenic cells (PACs) is guided by chemoattractants and requires proteases to disrupt the extracellular matrix. The possibility that PAC recruitment involves an interaction between proteases and chemotactic factor receptors remains largely unexplored.

Objective:

To determine the role of human tissue kallikrein (hK1) in PAC invasion and its dependency on kinin receptor signaling.

Methods and Results:

Human mononuclear cells (MNCs) and culture-selected PACs express and release mature hK1 protein. HK1 gene (KLK1) silencing reduced PACs migratory, invasive, and proangiogenic activities.KLK1-knockout mouse bone marrow–derived MNCs showed similar impairments and were unable to support reparative angiogenesis in a mouse model of peripheral ischemia. Conversely, adenovirus-mediatedKLK1(Ad.KLK1) gene transfer enhanced PAC-associated functions, whereas the catalytically inactive variantR53H-KLK1was ineffective. HK1-induced effects are mediated by a kinin B2receptor (B2R)-dependent mechanism involving inducible nitric oxide synthase and metalloproteinase-2 (MMP2). Lower hK1 protein levels were observed in PACs from type 2 diabetic (T2D) patients, whereasKLK1mRNA levels were similar to those of healthy subjects, suggesting a post-transcriptional defect. Furthermore, B2R is normally expressed on T2D-PACs but remains uncoupled from downstream signaling. Importantly, whereasAd.KLK1alone could not restore T2D-PAC invasion capacity, combinedKLK1andB2Rexpression rescued the diabetic phenotype.

Conclusions:

This study reveals new interactive components of the PACs invasive machinery, acting via protease- and kinin receptor–dependent mechanisms.
Targeting the Ischemic Penumbra
Authors: Ramos-Cabrer Pedro , Campos Francisco , Sobrino Tomás , Castillo José
Published: December 2010

Background—

In the last 3 decades, and from a therapeutic point of view, the classical concept of ischemic penumbra based on hemodynamic and electrophysiological parameters has loosened up the rigidity of therapeutic windows in acute stroke management. Thirty years later, the ischemic penumbra is an evolved concept that presents more applications. Thus, the ischemic penumbra is a diagnostic target, allowing the extension of therapeutic windows; it is also a biochemical target, in which an intermittent bioenergetic compromise takes place, and it is a target for brain plasticity, neuroprotection, and neurorepair.

Summary of Review—

In this work, we review how the concept of ischemic penumbra has been evolving from its purely electrophysiological/ hemodynamic based definition to the wider metabolic–cellular–therapeutic concept that is managed today by neuroscientists.
Imaging of Microglia Activation in Stroke
Authors: Thiel Alexander , Heiss Wolf-Dieter
Published: December 2010

Activated microglia is one of the most important cellular components of poststroke neuroinflammation, which occurs early in the area of the infarct but also in remote regions with fiber tract connections to the site of the primary lesion. The development of different radioligands for the translocator protein, a mitochondrial membrane protein expressed in microglial cells when they transform from the resting to the activated state, allows to study the temporal dynamics of this cellular neuroinflammatory component in vivo in animal models and human stroke using positron emission tomography. In this article, we review the advantage and limitations of current and future methods for microglia imaging as well as new results of multimodal imaging approaches in clinical stroke, which try to combine microglia imaging with diffusion tensor imaging to investigate the clinical relevance of remote microglia activation along fiber tracts for poststroke recovery.
The Ecclesial Body's Grace: Obedience and Faithfulness in Rowan Williams' Ecclesiology
Authors: Higton Mike
Published: December 2010

In his 1989 lecture, 'The Body's Grace', Rowan Williams describes sexual relationships as capable of playing a role in the communication and learning of the gospel. I argue that the lecture gives the church a threefold task in relation to such relationships: to call them to loving mutuality, to faithfulness, and to faith. The same pattern characterises Williams' ecclesiology, and helps make sense of many of his public statements about recent Anglican controversies: as Archbishop of Canterbury he sees himself as tasked with issuing the same threefold call to the participants in ecclesial arguments about obedience.
An Ecclesiological Journey: The Way of the Methodist – Roman Catholic International Dialogue
Authors: Wainwright Geoffrey
Published: December 2010

Ecclesiology eventually imposed itself as the main theme of the international Methodist / Catholic dialogue by virtue of what have been from the beginning the differences in the respective self-understanding and ecclesial claims of the partners. Confessing that no ecclesiology shaped in a time of division is likely to be entirely satisfactory, the Joint Commission in its Nairobi Report of 1986 ('Towards a Statement on the Church') began exploring 'ways of being one Church' that might obtain in the case of reunion, and the goal of the Methodist / Catholic dialogue was formulated as 'full communion in faith, mission and sacramental life'; and so it has remained, although 'governance' should probably be added as a fourth element in communion. By the time of the Seoul Report of 2006 ('The Grace Given You in Christ: Catholics and Methodists Reflect Further on the Church'), the Commission decided to face head-on the need for 'a mutual reassessment' in the 'new context' set by the ecumenical movement: each partner would look at the other with the eye of faith for what could be discerned there as 'truly of Christ and of the Gospel and thereby of the Church'. The way was thus opened for an 'exchange of gifts' on the road to 'full communion'. The dialogue continues to confront long-standing questions on what may be called 'the instrumentality of grace' as the Joint Commission prepares a Report for Durban 2011 on 'Encountering Christ the Saviour: Church and Sacraments'. The classic Faith and Order themes of baptism, eucharist and ministry remain in need of full settlement, and an ecumenical confession of 'the faith of the Church' would be welcome. Meanwhile, the Joint Commission has produced – under the title 'Together to Holiness'- a thematic synthesis of the first eight rounds of dialogue (1967-2006).
ПЕРЕПИСКА А. С. ЛАППО-ДАНИЛЕВСКОГО И П. Н. МИЛЮКОВА
Authors:   Трибунский
Published: December 2010

Переписка двух известных русских историков рубежа XIX–XX вв. А.С. ЛаппоДанилевского (1863–1919) и П.Н. Милюкова (1859–1943) охватывает 1889–1914 гг., с преимущественным вниманием к периоду 1889–1891 гг. Переписка велась в период становления их как историков, вхождения в ученую корпорацию, времени появления их первых серьезных трудов. Основные темы переписки: диссертация ЛаппоДанилевского о финансовой истории Московской Руси и возражения на нее Милюкова, продвижение коллег по службе, новости и сплетни об историках. Переписка позволяет восстановить существенные детали развития исторической науки в России, университетской жизни конца XIX в., биографии ряда историков. Публикация сопровождается достаточно полным комментарием по содержанию и вводит в научный оборот ценный исторический источник из трех архивных хранилищ России и США.
Changes in Spring Snowpack for Selected Basins in the United States for Different Climate-Change Scenarios
Authors: Mastin Mark C. , Chase Katherine J. , Dudley R. W.
Published: December 2010

Spring snowpack is an important water resource in many river basins in the United States in areas where snowmelt comprises a large part of the annual runoff. Increasing temperatures will likely reduce snowpacks in the future, resulting in more winter runoff and less available water during the summer low-flow season. As part of the National Climate Change Modeling Project by the U.S. Geological Survey, distributed watershed-model output was analyzed to characterize areal extent and water-equivalent volumes of spring snowpack for a warming climate. The output from seven selected watershed models from the mountainous western United States and one model from coastal Maine in the northeastern United States shows a future of declining spring snowpack. Snow-cover area (SCA) and snow-water equivalent (SWE) were used to compare the spring snowpack for current conditions (2006) with three time periods in the future (2030, 2060, and 2090) using three Intergovernmental Panel on Climate Change (IPCC) emission scenarios published in the 2007 Special Report on Emission Scenarios (SRES): A2, B1, and A1B. Distributed SWE and SCA values were sorted into elevation zones in each basin. The change in spring snowpack over time was greater than the change among different emission scenarios, suggesting that, even for a globally reduced carbon emission scenario, large decreases in SWE are likely to occur. The SRES A2 scenario resulted in the greatest decrease in SWE for six of the basins, and the SRES B1 and A1B scenarios resulted in the greatest decrease in one basin each.
Watershed-Scale Response to Climate Change through the Twenty-First Century for Selected Basins across the United States
Authors: Hay Lauren E. , Markstrom Steven L. , Ward-Garrison Christian
Published: December 2010

The hydrologic response of different climate-change emission scenarios for the twenty-first century were evaluated in 14 basins from different hydroclimatic regions across the United States using the Precipitation-Runoff Modeling System (PRMS), a process-based, distributed-parameter watershed model. This study involves four major steps: 1) setup and calibration of the PRMS model in 14 basins across the United States by local U.S. Geological Survey personnel; 2) statistical downscaling of the World Climate Research Programme’s Coupled Model Intercomparison Project phase 3 climate-change emission scenarios to create PRMS input files that reflect these emission scenarios; 3) run PRMS for the climate-change emission scenarios for the 14 basins; and 4) evaluation of the PRMS output.

This paper presents an overview of this project, details of the methodology, results from the 14 basin simulations, and interpretation of these results. A key finding is that the hydrological response of the different geographical regions of the United States to potential climate change may be very different, depending on the dominant physical processes of that particular region. Also considered is the tremendous amount of uncertainty present in the climate emission scenarios and how this uncertainty propagates through the hydrologic simulations. This paper concludes with a discussion of the lessons learned and potential for future work.
Attributes of Child Care Centers and Outdoor Play Areas Associated With Preschoolers’ Physical Activity and Sedentary Behavior
Authors: Sugiyama Takemi , Okely Anthony D. , Masters Jane M. , Moore Gary T.
Published: December 2010

This study examined characteristics of child care centers associated with preschoolers’ moderate-to-vigorous physical activity and sedentary behavior while in child care (MVPA-C, SB-C), and attributes of outdoor play areas associated with the same behaviors during outdoor time (MVPA-O, SB-O). Participants were 89 children (3 -5 years) recruited from 10 child care centers in Brisbane, Australia. Children’s activity was measured by accelerometer over a 3-day period. Center characteristics and outdoor play area attributes were identified through survey and observation. We found that children were mostly sedentary while in child care. Lower child-staff ratios and using indoor play areas for motor activity were associated with more MVPA-C and less SB-C. Fixed play equipment in outdoor areas was conducive to more MVPA-O and less SB-O. This study suggests the possibility of enhancing preschoolers’ activity levels through changing these attributes. Further research with more centers from diverse settings is needed to test these findings.
Nonresponse of Secondary Respondents in Multi-Actor Surveys: Determinants, Consequences, and Possible Remedies
Authors: Kalmijn Matthijs , Liefbroer Aart C.
Published: December 2010

Multi-actor survey data are highly valuable for answering questions about family relations, but the collection of such data is complicated by nonresponse among secondary (nonresident) respondents. Little is known, however, about the degree to which nonresponse of secondary respondents is selective and about the degree to which selective nonresponse biases substantive findings. Using a large representative survey, we analyze nonresponse of nonresident adult children of primary respondents. Nonresponse appears strongly related to characteristics of the parent—child relationship and to characteristics of both parents and children. Consequences are examined for three dependent variables: children’s attitudes, children’s support giving to parents, and children’s well-being. Heckman models, which correct for sample selection bias, show that selective response hardly biases the substantive estimates.
Evaluating a Policing Strategy Intended to Disrupt an Illicit Street-Level Drug Market
Authors: Corsaro Nicholas , Brunson Rod K. , McGarrell Edmund F.
Published: December 2010

The authors examined a strategic policing initiative that was implemented in a high crime Nashville, Tennessee neighborhood by utilizing a mixed-methodological evaluation approach in order to provide (a) a descriptive process assessment of program fidelity; (b) an interrupted time-series analysis relying upon generalized linear models; (c) in-depth resident interviews. Results revealed that the initiative corresponded with a statistically significant reduction in drug and narcotics incidents as well as perceived changes in neighborhood disorder within the target community. There was less-clear evidence, however, of a significant impact on other outcomes examined. The implications that an intensive crime prevention strategy corresponded with a reduction in specific forms of neighborhood crime illustrates the complex considerations that law enforcement officials face when deciding to implement this type of crime prevention initiative.
Effects of dieting status and cigarette deprivation on progressive ratio responding for cigarette puffs by young women smokers
Authors: Jenks Rebecca A , Higgs Suzanne
Published: December 2010

There is evidence from self-report measures which suggests that young women dieters find cigarette smoking less rewarding than non-dieters. We aimed to further elucidate differences between dieters and non-dieters in their evaluation of smoking using a behavioural measure of drug reward . Thirty female undergraduates attended two sessions (cigarette deprived and non-deprived). A computer-based progressive ratio operant procedure was employed to assess the amount of effort that participants were willing to expend to gain a puff on a cigarette. The point at which responding ceased was taken as a measure of drug reward (breakpoint). Self-report measures of sensory/hedonic aspects of smoking were also completed. The breakpoints of both dieters and non-dieters were greater under deprived than non-deprived conditions but the breakpoints of dieters were significantly lower than those of the non-dieting smokers under both conditions. Self-reported enjoyment of smoking was lower for dieters than non-dieters and reports for non-dieters but not dieters were affected by deprivation level. Both behavioural and self-report measures of rewarding aspects of smoking suggest that young women dieters find smoking less rewarding than non-dieters, but self-report measures are more resistant to deprivation effects for dieters. This is consistent with the suggestion that subjective and behavioural measures assess different dimensions of the rewarding effects of smoking.