bluuebunny/crossref_metadata_2025 huggingface dataset:
Pravastatin normalizes ET-1-induced contraction in the aorta of type 2 diabetic OLETF rats by suppressing the KSR1/ERK complex
Authors: Nemoto Shingo , Taguchi Kumiko , Matsumoto Takayuki , Kamata Katsuo , Kobayashi Tsuneo
Published: August 2012

Endothelin (ET)-1 is a likely candidate for a key role in diabetic vascular complications. In the present study, we hypothesized that treatment with pravastatin (an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase) would normalize the ET-1-induced contraction in aortas isolated from type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Contractile responses were examined by measuring isometric force in endothelium-denuded aortic helical strips from four groups: Long-Evans Tokushima Otsuka (LETO; genetic control), OLETF (type 2 diabetic), pravastatin-treated LETO, and pravastatin-treated OLETF rats. Both immunoblot analysis and immunoprecipitation assays were used to examine Src, protein phosphatase (PP)2A, kinase suppressor of Ras (KSR)1, and ERK signaling pathway protein levels and activities. In endothelium-denuded aortas isolated from OLETF rats at the chronic stage of diabetes (56–60 wk) (vs. those from age-matched LETO rats), we found the following: 1) ET-1-induced contraction was enhanced, 2) ERK1/2 phosphorylation was increased, 3) phosphorylations of KSR1 and PP2A were reduced (i.e., enhancement of the kinase active state), 4) ERK1/2-KSR1 complexes were increased, and 5) Src tyrosine kinase activity was diminished. Endothelium-denuded aortas isolated from OLETF rats treated with pravastatin (10 mg/kg po, daily for 4 wk) exhibited normalized ET-1-induced contractions and suppressed ET-1-stimulated ERK phosphorylation, with the associated phosphorylated KSR1 and phosphorylated PP2A levels being increased toward normal levels. These results suggest that in type 2 diabetic rats, pravastatin normalizes ET-1-induced contraction in aortic smooth muscle via a suppression of PP2A/KSR1/ERK activities after an enhancement of Src kinase activity.
Pulmonary surfactant protein A and surfactant lipids upregulate IRAK-M, a negative regulator of TLR-mediated inflammation in human macrophages
Authors: Nguyen Huy A. , Rajaram Murugesan V. S. , Meyer Douglas A. , Schlesinger Larry S.
Published: August 2012

Alveolar macrophages (AMs) are exposed to frequent challenges from inhaled particulates and microbes and function as a first line of defense with a highly regulated immune response because of their unique biology as prototypic alternatively activated macrophages. Lung collectins, particularly surfactant protein A (SP-A), contribute to this activation state by fine-tuning the macrophage inflammatory response. During short-term (10 min–2 h) exposure, SP-A's regulation of human macrophage responses occurs through decreased activity of kinases required for proinflammatory cytokine production. However, AMs are continuously exposed to surfactant, and the biochemical pathways underlying long-term reduction of proinflammatory cytokine activity are not known. We investigated the molecular mechanism(s) underlying SP-A- and surfactant lipid-mediated suppression of proinflammatory cytokine production in response to Toll-like receptor (TLR) 4 (TLR4) activation over longer time periods. We found that exposure of human macrophages to SP-A for 6–24 h upregulates expression of IL-1 receptor-associated kinase M (IRAK-M), a negative regulator of TLR-mediated NF-κB activation. Exposure to Survanta, a natural bovine lung extract lacking SP-A, also enhances IRAK-M expression, but at lower magnitude and for a shorter duration than SP-A. Surfactant-mediated upregulation of IRAK-M in macrophages suppresses TLR4-mediated TNF-α and IL-6 production in response to LPS, and IRAK-M knockdown by small interfering RNA reverses this suppression. In contrast to TNF-α and IL-6, the surfactant components upregulate LPS-mediated immunoregulatory IL-10 production, an effect reversed by IRAK-M knockdown. In conclusion, these data identify an important signaling regulator in human macrophages that is used by surfactant to control the long-term alveolar inflammatory response, i.e., enhanced IRAK-M activity.
Computational and bioengineered lungs as alternatives to whole animal, isolated organ, and cell-based lung models
Authors: Patel Brijeshkumar , Gauvin Robert , Absar Shahriar , Gupta Vivek , Gupta Nilesh , Nahar Kamrun , Khademhosseini Ali , Ahsan Fakhrul
Published: August 2012

Development of lung models for testing a drug substance or delivery system has been an intensive area of research. However, a model that mimics physiological and anatomical features of human lungs is yet to be established. Although in vitro lung models, developed and fine-tuned over the past few decades, were instrumental for the development of many commercially available drugs, they are suboptimal in reproducing the physiological microenvironment and complex anatomy of human lungs. Similarly, intersubject variability and high costs have been major limitations of using animals in the development and discovery of drugs used in the treatment of respiratory disorders. To address the complexity and limitations associated with in vivo and in vitro models, attempts have been made to develop in silico and tissue-engineered lung models that allow incorporation of various mechanical and biological factors that are otherwise difficult to reproduce in conventional cell or organ-based systems. The in silico models utilize the information obtained from in vitro and in vivo models and apply computational algorithms to incorporate multiple physiological parameters that can affect drug deposition, distribution, and disposition upon administration via the lungs. Bioengineered lungs, on the other hand, exhibit significant promise due to recent advances in stem or progenitor cell technologies. However, bioengineered approaches have met with limited success in terms of development of various components of the human respiratory system. In this review, we summarize the approaches used and advancements made toward the development of in silico and tissue-engineered lung models and discuss potential challenges associated with the development and efficacy of these models.
miR-210 has an antiapoptotic effect in pulmonary artery smooth muscle cells during hypoxia
Authors: Gou Deming , Ramchandran Ramaswamy , Peng Xiao , Yao Lijun , Kang Kang , Sarkar Joy , Wang Zhixin , Zhou Goufei , Raj J. Usha
Published: August 2012

MicroRNAs (miRNAs) were recently reported to play an important role in the pathogenesis of pulmonary arterial hypertension (PAH), but it is not clear which miRNAs are important or what pathways are involved in the process. Because hypoxia is an important stimulus for human pulmonary artery smooth muscle cell (HPASMC) proliferation and PAH, we performed miRNA microarray assays in hypoxia-treated and control HPASMC. We found that miR-210 is the predominant miRNA induced by hypoxia in HPASMC. Induction of miR-210 was also observed in whole lungs of mice with chronic hypoxia-induced PAH. We found that transcriptional induction of miR-210 in HPASMC is hypoxia-inducible factor-1α dependent. Inhibition of miR-210 in HPASMC caused a significant decrease in cell number due to increased apoptosis. We found that miR-210 appears to mediate its antiapoptotic effects via the regulation of transcription factor E2F3, a direct target of miR-210. Our results have identified miR-210 as a hypoxia-inducible miRNA both in vitro and in vivo, which inhibits pulmonary vascular smooth muscle cell apoptosis in hypoxia by specifically repressing E2F3 expression.
Neuronal Wiskott-Aldrich syndrome protein (N-WASP) is critical for formation of α-smooth muscle actin filaments during myofibroblast differentiation
Authors: Cai Guo-Qiang , Chou Chu-Fang , Hu Meng , Zheng Anni , Reichardt Louis F. , Guan Jun-Lin , Fang Haotian , Luckhardt Tracy R. , Zhou Yong , Thannickal Victor J. , Ding Qiang
Published: August 2012

Myofibroblasts are implicated in pathological stromal responses associated with lung fibrosis. One prominent phenotypic marker of fully differentiated myofibroblasts is the polymerized, thick cytoplasmic filaments containing newly synthesized α-smooth muscle actin (α-SMA). These α-SMA-containing cytoplasmic filaments are important for myofibroblast contractility during tissue remodeling. However, the molecular mechanisms regulating the formation and maturation of α-SMA-containing filaments have not been defined. This study demonstrates a critical role for neuronal Wiskott-Aldrich syndrome protein (N-WASP) in regulating the formation of α-SMA-containing cytoplasmic filaments during myofibroblast differentiation and in myofibroblast contractility. Focal adhesion kinase (FAK) is activated by transforming growth factor-β1 (TGF-β1) and is required for phosphorylation of tyrosine residue 256 (Y256) of N-WASP. Phosphorylation of Y256 of N-WASP is essential for TGF-β1-induced formation of α-SMA-containing cytoplasmic filaments in primary human lung fibroblasts. In addition, we demonstrate that actin-related protein (Arp) 2/3 complex is downstream of N-WASP and mediates the maturation of α-SMA-containing cytoplasmic filaments. Together, this study supports a critical role of N-WASP in integrating FAK and Arp2/3 signaling to mediate formation of α-SMA-containing cytoplasmic filaments during myofibroblast differentiation and maturation.
Health-Related Quality of Life, Treatment Satisfaction, Adherence and Persistence inβ-Thalassemia and Myelodysplastic Syndrome Patients with Iron Overload Receiving Deferasirox: Results from the EPIC Clinical Trial
Authors: Porter John , Bowden Donald K. , Economou Marina , Troncy Jacques , Ganser Arnold , Habr Dany , Martin Nicolas , Gater Adam , Rofail Diana , Abetz-Webb Linda , Lau Helen , Cappellini Maria Domenica
Published: August 2012

Treatment of iron overload using deferoxamine (DFO) is associated with significant deficits in patients' health-related quality of life (HRQOL) and low treatment satisfaction. The current article presents patient-reported HRQOL, satisfaction, adherence, and persistence data fromβ-thalassemia (n=274) and myelodysplastic syndrome (MDS) patients (n=168) patients participating in the Evaluation of Patients' Iron Chelation with Exjade (EPIC) study (NCT00171821); a large-scale 1-year, phase IIIb study investigating the efficacy and safety of the once-daily oral iron chelator, deferasirox. HRQOL and satisfaction, adherence, and persistence to iron chelation therapy (ICT) data were collected at baseline and end of study using the Medical Outcomes Short-Form 36-item Health Survey (SF-36v2) and the Satisfaction with ICT Questionnaire (SICT). Compared to age-matched norms,β-thalassemia and MDS patients reported lower SF-36 domain scores at baseline. Low levels of treatment satisfaction, adherence, and persistence were also observed. HRQOL improved following treatment with deferasirox, particularly amongβ-thalassemia patients. Furthermore, patients reported high levels of satisfaction with deferasirox at end of study and greater ICT adherence, and persistence. Findings suggest deferasirox improves HRQOL, treatment satisfaction, adherence, and persistence with ICT inβ-thalassemia and MDS patients. Improving such outcomes is an important long-term goal for patients with iron overload.
Improved Metabolic Control in Diabetes, HSP60, and Proinflammatory Mediators
Authors: Blasi Claudio , Kim Eunjung , Knowlton Anne A.
Published: August 2012

The diabetes-atherosclerosis relationship remains to be fully defined. Repeated prolonged hyperglycemia, increased ROS production and endothelial dysfunction are important factors. One theory is that increased blood levels of heat shock protein (HSP)60 are proinflammatory, through activation of innate immunity, and contribute to the progression of vascular disease. It was hypothesized that improvement of diabetes control in patients presenting with metabolic syndrome would lower HSP60, and anti-HSP60 antibody levels and decrease inflammatory markers. Paired sera of 17 Italian patients, before and after intensive treatment, were assayed for cytokines, HSP60 and anti-HSP60 antibodies. As expected, intensive treatment was associated with a decrease in HgbA1C (P<0.001) and BMI (P<0.001). After treatment, there was a significant decrease in IL-6 (P<0.05). HSP60 levels were before treatment−6.9+1.9, after treatment−7.1+2.0 ng/mL (P=ns). Overall HSP60 concentrations were lower than published reports. Anti-HSP60 antibody titers were high and did not decrease with treatment. In conclusion, improvement of diabetic control did not alter HSP60 concentrations or antiHSP60 antibody titers, but led to a reduction of IL-6 levels.
Anti- and Protumorigenic Effects of PPARγin Lung Cancer Progression: A Double-Edged Sword
Authors: Li Howard , Weiser-Evans Mary C. M. , Nemenoff Raphael
Published: August 2012

Peroxisome proliferator-activated receptor-γ(PPARγ) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that plays an important role in the control of gene expression linked to a variety of physiological processes, including cancer. Ligands for PPARγinclude naturally occurring fatty acids and the thiazolidinedione class of antidiabetic drugs. Activation of PPARγin a variety of cancer cells leads to inhibition of growth, decreased invasiveness, reduced production of proinflammatory cytokines, and promotion of a more differentiated phenotype. However, systemic activation of PPARγhas been reported to be protumorigenic in somein vitrosystems andin vivomodels. Here, we review the available data that implicate PPARγin lung carcinogenesis and highlight the challenges of targeting PPARγin lung cancer treatments.
Medical Robots: Current Systems and Research Directions
Authors: Beasley Ryan A.
Published: August 2012

First used medically in 1985, robots now make an impact in laparoscopy, neurosurgery, orthopedic surgery, emergency response, and various other medical disciplines. This paper provides a review of medical robot history and surveys the capabilities of current medical robot systems, primarily focusing on commercially available systems while covering a few prominent research projects. By examining robotic systems across time and disciplines, trends are discernible that imply future capabilities of medical robots, for example, increased usage of intraoperative images, improved robot arm design, and haptic feedback to guide the surgeon.
A Note on Some Generalized Closed Sets in Bitopological Spaces Associated to Digraphs
Authors: Kannan K.
Published: August 2012

Many investigations are undergoing of the relationship between topological spaces and graph theory. The aim of this short communication is to study the nature and properties of some generalized closed sets in the bitopological spaces associated to the digraph. In particular, some relations between generalized closed sets in the bitopological spaces associated to the digraph are characterized.
Induction Chemotherapy in Locally Advanced Pharyngolaryngeal Cancers with Stridor: Is It Feasible and Safe?
Authors: Patil Vijay Maruti , Noronha Vanita , Joshi Amit , Muddu Vamshi , Poladia Bhavesh , Chauhan Bharat , Prabhash Kumar , Chaukar Devendra Arvind , Chatturvedi Pankaj , Pantvaidya Gouri , Juvekar Shashikant , D'cruz Anil
Published: August 2012

Background. The standard initial management of patients with locally advanced pharyngolaryngeal presenting with stridor is tracheostomy. Tracheostomy has been shown to negatively impact cancer-related outcomes. Methods. Retrospective analysis of prospectively collected data of 9 patients, who underwent induction chemotherapy with the aim of prevention of tracheostomy. Presenting features, time to resolution of stridor, and further management are reported. Results. Eight out of 9 patient received chemotherapy within 12 hours of presentation with stridor. There were 4 patients each with primary hypopharynx and larynx. The stage was IVA in 6 patients and IVB in 2 patients. In all patients receiving immediate chemotherapy, clinical stridor resolved within 48 hours. The radiological response rate was 62.5%. The median reduction in size of tumor was 37%.
Conclusion. Immediate neoadjuvant chemotherapy is a feasible and safe option for patients presenting with early stridor and helps in resolution of stridor and avoiding tracheostomy.
Significance of the Intraoperative Methylene Blue Test for Postoperative Evaluation of the Vesicourethral Anastomosis
Authors: Nyarangi-Dix J. N. , Pahernik S. , Bermejo J. L. , Prado L. , Hohenfellner M.
Published: August 2012

We prospectively investigated whether routine evaluation of the vesicourethral anastomosis (VUA) after radical prostatectomy can be waived. Primary integrity of the VUA was analysed by an intraoperative methylene-blue test (IMBT) and postoperatively by conventional cystography. Data on the IMBT, contrast extravasation and prostate volume as well as pad usage were collected prospectively. Significantly more patients with a primary watertight anastomosis demonstrated by the MBT had no leakage in the postoperative cystography (P<0.001). In a multivariate logistic regression with adjustment for prostate size and surgeon, the positive correlation between IMBT and postoperative cystography remained statistically significant (P=0.001). The IMBT is easy to perform, inexpensive, and timesaving. With it postoperative evaluation of VUA for integrity can be waived in a significant number of patients. Following our algorithm, the Foley can be removed without further testing of the VUA, whenever the IMBT detected no leakage.
Fixed Points and Generalized Hyers‐Ulam Stability
Authors: Cădariu L. , Găvruţa L. , Găvruţa P.
Published: August 2012

In this paper we prove a fixed‐point theorem for a class of operators with suitable properties, in very general conditions. Also, we show that some recent fixed‐points results in Brzdęk et al., (2011) and Brzdęk and Ciepliński (2011) can be obtained directly from our theorem. Moreover, an affirmative answer to the open problem of Brzdęk and Ciepliński (2011) is given. Several corollaries, obtained directly from our main result, show that this is a useful tool for proving properties of generalized Hyers‐Ulam stability for some functional equations in a single variable.
Subclass of Multivalent Harmonic Functions with Missing Coefficients
Authors: El-Ashwah R. M.
Published: August 2012

We have studied subclass of multivalent harmonic functions with missing coefficients in the open unit disc and obtained the basic properties such as coefficient characterization and distortion theorem, extreme points, and convolution.
Coupled Fixed Point Theorems for a Pair of Weakly Compatible Maps along with CLRg Property in Fuzzy Metric Spaces
Authors: Jain Manish , Tas Kenan , Kumar Sanjay , Gupta Neetu
Published: August 2012

The aim of this paper is to extend the notions of E.A. property and CLRg property for coupled mappings and use these notions to generalize the recent results of Xin‐Qi Hu (2011). The main result is supported by a suitable example.
Molecular Pathways: VCAM-1 as a Potential Therapeutic Target in Metastasis
Authors: Chen Qing , Massagué Joan
Published: August 2012

Interactions between disseminated tumor cells (DTC) and stromal cells in the microenvironment are critical for tumor colonization of distal organs. Recent studies have shown that vascular cell adhesion molecule-1 (VCAM-1) is aberrantly expressed in breast cancer cells and mediates prometastatic tumor-stromal interactions. Moreover, the usefulness of VCAM-1 to DTCs in 2 different organs—lung and bone—is based on distinct mechanisms. In the lungs, VCAM-1 on the surface of cancer cells binds to its counterreceptor, the α4β1 integrin (also known as very-late antigen, VLA-4), on metastasis-associated macrophages, triggering VCAM-1–mediated activation of the phosphoinositide 3-kinase growth and survival pathway in the cancer cells. In the bone marrow, cancer cell VCAM-1 attracts and tethers α4 integrin–expressing osteoclast progenitors to facilitate their maturation into multinucleated osteoclasts that mediate osteolytic metastasis. These findings highlight the importance of direct interactions between DTCs and stromal cells during tumor dissemination and draw attention to the possibility of targeting the α4 integrin–VCAM-1 interactions in metastatic breast cancer. Anti-α4 integrin inhibitors have been developed to treat various diseases driven by massive leukocyte infiltrates and have gained U.S. Food and Drug Administration approval or are undergoing clinical trials. Testing these drugs against tumor-stromal leukocyte interactions may provide a new strategy to suppress lung and bone relapse of breast cancer. Clin Cancer Res; 18(20); 5520–5. ©2012 AACR.
A Multicenter Phase II Study of Single-Agent Enzastaurin in Previously Treated Waldenström Macroglobulinemia
Authors: Ghobrial Irene M. , Moreau Philippe , Harris Brianna , Poon Tiffany , Jourdan Eric , Maisonneuve Hervé , Benhadji Karim A. , Hossain Anwar M. , Nguyen Tuan S. , Wooldridge James E. , Leblond Veronique
Published: August 2012

Purpose: Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. These findings provided the rationale for a multicenter phase II trial of oral enzastaurin in previously treated patients with WM.

Experimental design: Patients who were treated with 1 to 5 prior regimens and who had a baseline immunoglobulin M level 2 times or more the upper limit of normal received oral enzastaurin 250 mg twice daily (500 mg total) after a single loading dose (day 1, cycle 1) of 375 mg 3 times daily (1,125 mg total) for 8 cycles of 28 days each or until progressive disease. Six patients who progressed during treatment with enzastaurin had dexamethasone added per protocol.

Results: From July 2008 to December 2010, 42 patients were enrolled. The objective response rate (RR) was 38.1% (2 partial and 14 minor responses). One patient had grade 3 leukopenia and one patient died during the study from septic shock; both events were considered drug related. A statistically significant association between RR and interleukin 15 (IL-15) was observed, suggesting that higher concentration levels of IL-15 may be associated with better response.

Conclusion: Enzastaurin was active and well tolerated in previously treated patients with WM. Because of the small sample size of this uncontrolled study, further assessment of the relationship between IL-15 and response to enzastaurin in patients with WM is required. These results warrant further investigation of enzastaurin for the treatment of WM. Clin Cancer Res; 18(18); 5043–50. ©2012 AACR.
LAP+CD4+ T Cells Are Suppressors Accumulated in the Tumor Sites and Associated with the Progression of Colorectal Cancer
Authors: Mahalingam Jayashri , Lin Yung-Chang , Chiang Jy-Ming , Su Po-Jung , Fang Jian-He , Chu Yu-Yi , Huang Ching-Tai , Chiu Cheng-Tang , Lin Chun-Yen
Published: August 2012

Purpose: Suppressor T cells are one of the determinants of colorectal cancer (CRC) clinical outcome. LAP+CD4+ T cell is a recently identified subset of suppressor T cells. This study was designed to investigate their clinical relevance in patients with CRC.

Experimental Design: Sixty patients with CRC and 24 healthy donors (HD) were enrolled in this study. The percentages of LAP+CD4+ T cells in peripheral blood and tumor tissue were measured. The phenotype and functional relevance of LAP+CD4+ T cells were analyzed subsequently.

Results: The percentages of LAP+CD4+ T cells in peripheral blood of patients with CRC were significantly higher than HD (HD vs. CRC: 3.1% ± 0.78% vs. 8.8% ± 5.8%, P < 0.0001) and in tumor tissue when compared with nontumor tissue (nontumor vs. tumor: 3.2% ± 1.1% vs. 9.5% ± 5.5%, P = 0.0002). In addition, LAP+CD4+ T cells with effector memory (EM) phenotype were more likely to accumulate in the tumor sites than in peripheral blood. These LAP+CD4+ T cells produced significantly higher levels of IFN-γ, IL-17 and comparatively lower IL-2 and very few IL-10. LAP+CD4+ T cells could suppress the proliferation of LAP−CD4+ T cells that were partially mediated by TGF-β. Furthermore, these LAP+CD4+ T cells accumulated in tumor site and increased further in the peripheral blood in patients with metastasis.

Conclusions: LAP+CD4+ T cells as a suppressor subset could accumulate in the tumor microenvironment and circulated more in the peripheral blood with tumor progression in patients with CRC. Clin Cancer Res; 18(19); 5224–33. ©2012 AACR.
Counteracting Autophagy Overcomes Resistance to Everolimus in Mantle Cell Lymphoma
Authors: Rosich Laia , Xargay-Torrent Sílvia , López-Guerra Mónica , Campo Elías , Colomer Dolors , Roué Gaël
Published: August 2012

Purpose: Mantle cell lymphoma (MCL) is an aggressive B-lymphoid neoplasm with poor response to conventional chemotherapy and short survival. The phosphatidylinositol 3-kinase/Akt/mTOR survival pathway is constitutively activated in MCL cells, thereby making the mTOR inhibition an attractive therapeutic strategy. The first clinical studies of everolimus (RAD001), an mTOR inhibitor, in relapsed MCL patients have reported a significant response. Our aim was to analyze the mechanism related to everolimus resistance/sensitivity in MCL cells.

Experimental Design: Sensitivity to everolimus was analyzed in MCL cell lines and primary MCL cells. Everolimus mechanism of action was determined by flow cytometry and Western blot. Particularly, autophagy was studied by LC3BI/II expression, autophagolysosomes detection by flow cytometry and fluorescence microscopy, and siRNA-mediated gene silencing.

Results: Everolimus exerted antitumoral effect on MCL cells while sparing normal cells. In MCL cell lines, this phenomenon was associated to G1 cell-cycle arrest, dephosphorylation of the mTOR downstream targets, 4E-BP1 and S6RP, and rephosphorylation of Akt. A synergistic cytotoxic effect was observed between everolimus and an Akt inhibitor, which overcame the compensatory reactivation within the mTOR signaling pathway. Interestingly, MCL cells with low response to this combination showed high levels of autophagy. Accordingly, selective triple knockdown of the autophagy genes ATG7, ATG5 and ATG3, and pretreatment with the autophagy inhibitor hydroxychloroquine, efficiently overcame the resistance to Akt/mTOR inhibitors, leading to the activation of the mitochondrial apoptotic pathway.

Conclusions: These results suggest that autophagy induction protects MCL cells from Akt/mTOR targeting and counteracting autophagy may represent an attractive strategy for sensitizing MCL cells to everolimus-based therapy. Clin Cancer Res; 18(19); 5278–89. ©2012 AACR.
EWS-FLI-1-Targeted Cytotoxic T-cell Killing of Multiple Tumor Types Belonging to the Ewing Sarcoma Family of Tumors
Authors: Evans Christopher H. , Liu Fangjun , Porter Ryan M. , O'Sullivan Regina P. , Merghoub Taha , Lunsford Elaine P. , Robichaud Kyle , Van Valen Frans , Lessnick Stephen L. , Gebhardt Mark C. , Wells James W.
Published: August 2012

Purpose: The Ewing sarcoma family of tumors (ESFT) comprises a group of aggressive, malignant bone, and soft tissue tumors that predominantly affect children and young adults. These tumors frequently share expression of the EWS-FLI-1 translocation, which is central to tumor survival but not present in healthy cells. In this study, we examined EWS-FLI-1 antigens for their capacity to induce immunity against a range of ESFT types.

Design: Computer prediction analysis of peptide binding, HLA-A2.1 stabilization assays, and induction of cytotoxic T-lymphocytes (CTL) in immunized HLA-A2.1 transgenic mice were used to assess the immunogenicity of native and modified peptides derived from the fusion region of EWS-FLI-1 type 1. CTL-killing of multiple ESFT family members in vitro, and control of established xenografts in vivo, was assessed. We also examined whether these peptides could induce human CTLs in vitro.

Results: EWS-FLI-1 type 1 peptides were unable to stabilize cell surface HLA-A2.1 and induced weak CTL activity against Ewing sarcoma cells. In contrast, peptides with modified anchor residues induced potent CTL killing of Ewing sarcoma cells presenting endogenous (native) peptides. The adoptive transfer of CTL specific for the modified peptide YLNPSVDSV resulted in enhanced survival of mice with established Ewing sarcoma xenografts. YLNPSVDSV-specific CTL displayed potent killing of multiple ESFT types in vitro: Ewing sarcoma, pPNET, Askin's Tumor, and Biphenotypic sarcoma. Stimulation of human peripheral blood mononuclear cells with YLNPSVDSV peptide resulted in potent CTL-killing.

Conclusions: These data show that YLNPSVDSV peptide is a promising antigen for ESFT immunotherapy and warrants further clinical development. Clin Cancer Res; 18(19); 5341–51. ©2012 AACR.
Sex Differences in Clinical Characteristics and Outcomes in Elderly Patients With Heart Failure and Preserved Ejection Fraction
Authors: Lam Carolyn S.P. , Carson Peter E. , Anand Inder S. , Rector Thomas S. , Kuskowski Michael , Komajda Michel , McKelvie Robert S. , McMurray John J. , Zile Michael R. , Massie Barry M. , Kitzman Dalane W.
Published: August 2012

Background—

There are few sex-specific outcome data in heart failure with preserved ejection fraction.

Methods and Results—

We assessed sex differences in baseline characteristics and outcomes among 4128 patients with heart failure with preserved ejection fraction in the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial. Women (n=2491) with heart failure with preserved ejection fraction were ≈1 year older (72±7 years versus 71±7 years) and more likely to be obese (46% versus 35%) and have chronic kidney disease (34% versus 26%) and hypertension (91% versus 85%) than men but less likely to have an ischemic cause (19% versus 34%), atrial fibrillation (27% versus 33%), or chronic obstructive pulmonary disease (8% versus 13%) (all
P
<0.001). During a mean of 49.5 months, there were 881 deaths (447 in women, 434 in men; risk ratio, 0.64; 95% CI, 0.56–0.74) and 5776 hospitalizations (3239 in women, 2537 in men; risk ratio, 0.80; 95% CI, 0.76–0.84). Women had lower risk of all-cause events (deaths and hospitalizations), even after adjusting for baseline characteristics (adjusted hazards ratio, 0.81; 95% CI, 0.73–0.89). However, the sex-related difference in risk of all-cause events was modified in the presence or absence of atrial fibrillation, renal dysfunction, stable angina pectoris, or advanced New York Heart Association class symptoms.

Conclusions—

In patients with typical heart failure with preserved ejection fraction, there were prominent sex differences in baseline characteristics and outcomes. Women had better overall prognosis, although the presence of 4 common baseline characteristics seemed to moderate this finding.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT000095238.
Aligning Coronary Anatomy and Myocardial Perfusion Territories
Authors: Cerci Rodrigo J. , Arbab-Zadeh Armin , George Richard T. , Miller Julie M. , Vavere Andrea L. , Mehra Vishal , Yoneyama Kihei , Texter John , Foster Courtney , Guo Wei , Cox Christopher , Brinker Jeffrey , Di Carli Marcelo , Lima Joao A.C.
Published: August 2012

Background—

Appropriate clinical decisions concerning diagnosis and treatment of coronary artery disease rely on correct integration of data on coronary anatomy and myocardial perfusion. The purpose of this article is to introduce a new left ventricular segmentation model for improved alignment of coronary arterial segments and myocardial perfusion territories, designed for the CORE320 study.

Methods and Results—

CORE320 is a prospective, multicenter study with a primary objective to evaluate the diagnostic accuracy of 320-row detector computed tomography (CT) to detect coronary artery luminal stenosis and corresponding myocardial perfusion deficits in patients with suspected coronary artery disease compared with the gold standard of conventional coronary angiography and single-photon emission CT myocardial perfusion imaging. We describe a 19-coronary segment and 13-myocardial territory alignment model, its application in both standard and CT image data sets, and the adjudication process of the initial cohort of patients recruited for the CORE320 study. Adjudication committees reviewed the images of the first 101 gold standard and 107 CT data sets. On the basis of the presented model and rules, all cases for adjudication were correctly identified. During image review, 6 (5.9%) gold standard and 9 (8.4%) CT data sets needed further realignment not triggered by the algorithm.

Conclusions—

We present a vascular territory distribution model developed for the CORE320 multicenter study, which accounts for variability in coronary anatomy and potential myocardial perfusion territory overlap.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00934037.
3.0T Whole-Heart Coronary Magnetic Resonance Angiography Performed With 32-Channel Cardiac Coils
Authors: Yang Qi , Li Kuncheng , Liu Xin , Du Xiangying , Bi Xiaoming , Huang Feng , Jerecic Renate , Liu Zhi , An Jing , Xu Dong , Zheng Hairong , Fan Zhaoyang , Li Debiao
Published: August 2012

Background—

Whole-heart coronary magnetic resonance angiography (MRA) is a promising method for noninvasive, radiation-free detection and exclusion of obstructive coronary artery disease; however, the required imaging time and robustness of the technique are not yet satisfactory. We evaluated the value of whole-heart coronary MRA at 3.0T using a 32-channel cardiac coil, which reduces image-acquisition times and hence allows to increase the clinical throughput.

Methods and Results—

A total of 110 consecutive patients with suspected coronary artery disease referred for clinically indicated conventional coronary angiography were included in this prospective study. Acquisition of 3.0T coronary MRA data was done by using 32-channel receiver coils. An ECG-triggered, navigator-gated, inversion-recovery prepared, segmented gradient-echo sequence was used for image acquisition with an acceleration factor of 3 in the phase-encoding direction using generalized auto calibrating partially parallel acquisitions reconstruction. Acquisition of coronary MRA was successfully completed in 101 of 110 (92%) patients with average imaging time of 7.0±1.8 minutes. The sensitivity, specificity, positive and negative predictive value of coronary MRA on a patient-based analysis were 95.9% (47/49, 95% CI, 86.0%–99.4%), 86.5% (45/52, 95% CI, 74.2%–94.4%), 87.0% (47/54, 95% CI, 75.1%–94.6%) and 95.7% (45/47, 95% CI, 85.4%–99.4%), respectively.

Conclusions—

Whole-heart coronary MRA at 3.0T using a 32-channel cardiac coil allows high overall accuracy for detecting significant coronary artery disease with reduced imaging time. It has potential to be a robust and alternative technique for ruling out significant coronary artery disease.

Clinical Trial Registration—

URL:
http://www.chictr.org
. Unique identifier: ChiCTR-DDT-07000121.
Activation of Natural Killer T Cells Ameliorates Postinfarct Cardiac Remodeling and Failure in Mice
Authors: Sobirin Mochamad Ali , Kinugawa Shintaro , Takahashi Masashige , Fukushima Arata , Homma Tsuneaki , Ono Taisuke , Hirabayashi Kagami , Suga Tadashi , Azalia Putri , Takada Shingo , Taniguchi Masaru , Nakayama Toshinori , Ishimori Naoki , Iwabuchi Kazuya , Tsutsui Hiroyuki
Published: August 2012

Rationale:

Chronic inflammation in the myocardium is involved in the development of left ventricular (LV) remodeling and failure after myocardial infarction (MI). Invariant natural killer T (iNKT) cells have been shown to produce inflammatory cytokines and orchestrate tissue inflammation. However, no previous studies have determined the pathophysiological role of iNKT cells in post-MI LV remodeling.

Objective:

The purpose of this study was to examine whether the activation of iNKT cells might affect the development of LV remodeling and failure.

Methods and Results:

After creation of MI, mice received the injection of either α-galactosylceramide (αGC; n=27), the activator of iNKT cells, or phosphate-buffered saline (n=31) 1 and 4 days after surgery, and were followed during 28 days. Survival rate was significantly higher in MI+αGC than MI+PBS (59% versus 32%,
P
<0.05). LV cavity dilatation and dysfunction were significantly attenuated in MI+αGC, despite comparable infarct size, accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis. The infiltration of iNKT cells were increased during early phase in noninfarcted LV from MI and αGC further enhanced them. It also enhanced LV interleukin (IL)-10 gene expression at 7 days, which persisted until 28 days. AntienIL-10 receptor antibody abrogated these protective effects of αGC on MI remodeling. The administration of αGC into iNKT cell-deficient Jα18
−/−
mice had no such effects, suggesting that αGC was a specific activator of iNKT cells.

Conclusions:

iNKT cells play a protective role against post-MI LV remodeling and failure through the enhanced expression of cardioprotective cytokines such as IL-10.
A Pilot Study Examining the Severity and Outcome of the Post–Cardiac Arrest Syndrome
Authors: Donnino Michael W. , Miller Joseph C. , Bivens Matthew , Cocchi Michael N. , Salciccioli Justin D. , Farris Sarah , Gautam Shiva , Cutlip Donald , Howell Michael
Published: August 2012

Background—

Cardiac arrest occurs in >400 000 patients in the United States per year, and mortality rates vary across the country. Whether variations in cardiac arrest outcome are the result of differences in hospital or patient characteristics remains understudied. We tested whether hospital-independent factors would account for the difference in outcome between 2 geographically distinct hospitals.

Methods and Results—

Consecutive adult (age >18 years) out-of-hospital cardiac arrests were considered for analysis. The primary outcome was in-hospital mortality. Predictor variables were classified according to whether they were hospital-independent or whether they could be related to the hospital's quality of care. Only hospital-independent variables were considered for the analysis. Sequential logistic modeling was used to assess outcome. A propensity score was derived and was used in subsequent multivariate logistic regression to predict hospital outcome. A total of 208 subjects were included. Overall mortality in the Detroit cohort was 87% in comparison with 61% in the Boston cohort (odds ratio: 4.4; 95% confidence interval: 2.2–8.8). After sequential adjustments for baseline covariates, out-of-hospital cardiac arrest score and propensity score, city was not significantly associated with mortality (odds ratio: 1.16; 95% confidence interval: 0.45–2.97). After propensity matching there was no significant difference in the odds ratio for death between the 2 cities (odds ratio: 1.15; 95% confidence interval: 0.51–2.61).

Conclusions—

In this pilot study, we found that pre- and intra-arrest conditions contribute substantially to the severity of the postarrest syndrome and on outcomes. Postarrest quality-of-care evaluations should include inherent differences in the presenting syndrome rather than a crude mortality rate.
Incidence, Causes, and Survival Trends From Cardiovascular-Related Sudden Cardiac Arrest in Children and Young Adults 0 to 35 Years of Age
Authors: Meyer Lauren , Stubbs Benjamin , Fahrenbruch Carol , Maeda Chris , Harmon Kimberly , Eisenberg Mickey , Drezner Jonathan
Published: August 2012

Background—

Sudden cardiac arrest is a leading cause of death in children and young adults. This study determined the incidence, cause, and outcomes of cardiovascular-related out-of-hospital cardiac arrest (OHCA) in individuals <35 years of age.

Methods and Results—

A retrospective cohort of OHCA in children and young adults from 1980 through 2009 was identified from the King County (Washington) Division of Emergency Medical Services' Cardiac Arrest Database. Incidence was calculated from population census data and causes of arrest determined by review of autopsy reports and all available medical records. A total of 361 cases (26 cases 0–2 years of age, 30 cases 3–13 years of age, 60 cases 14–24 years of age, and 245 cases 25–35 years of age) of OHCA were treated by emergency medical services responders, for an overall incidence of 2.28 per 100 000 person-years (2.1 in those 0–2 years of age, 0.61 in those 3–13 years of age, 1.44 in those 14–24 years of age, and 4.40 in those 25–35 years of age). The most common causes of OHCA were congenital abnormalities in those 0 to 2 years of age (84.0%) and 3 to 13 years of age (21%), presumed primary arrhythmia in those 14 to 24 of age (23.5%), and coronary artery disease in those 25 to 35 years of age (42.9%). The overall survival rate was 26.9% (3.8% in those 0–2 years of age, 40.0% in those 3–13 years of age, 36.7% in those 14–24 years of age, and 27.8% in those 25–35 years of age). Survival increased throughout the study period from 13.0% in 1980 to 1989 to 40.2% in 2000 to 2009 (
P
<0.001).

Conclusions—

The incidence of OHCA in children and young adults is higher than previously reported, and a more specific understanding of the causes should guide future prevention programs. Survival trends support contemporary resuscitation protocols for OHCA in the young.
Aortic Regurgitation Quantification Using Cardiovascular Magnetic Resonance
Authors: Myerson Saul G. , d'Arcy Joanna , Mohiaddin Raad , Greenwood John P. , Karamitsos Theodoros D. , Francis Jane M. , Banning Adrian P. , Christiansen Jonathan P. , Neubauer Stefan
Published: August 2012

Background—

Current indications for surgery in patients with significant aortic regurgitation (AR) focus on symptoms and left ventricular dilation/dysfunction. However, prognosis is already reduced by this stage, and earlier identification of patients for surgery could be beneficial. Quantifying the regurgitation may help, but there are limited data on its link with outcome. Cardiovascular magnetic resonance (CMR) can accurately quantify AR, and we examined whether this was associated with the future need for surgery.

Methods and Results—

One hundred thirteen patients with echocardiographic moderate or severe AR were monitored for up to 9 years (mean 2.6±2.1 years) following a CMR scan, and the progression to symptoms or other indications for surgery was monitored. AR quantification identified outcome with high accuracy: 85% of the 39 subjects with regurgitant fraction >33% progressed to surgery (mostly within 3 years) in comparison with 8% of 74 subjects with regurgitant fraction ≤33% (
P
<0.0001); the area under the curve on receiver operating characteristic analysis was 0.93 (
P
<0.0001). This ability remained strong on time-dependent Kaplan–Meier survival curves. CMR-derived left ventricular end-diastolic volume >246 mL had good, although lower, discriminatory ability (area under the curve 0.88), but the combination of this measure with regurgitant fraction provided the best discriminatory power.

Conclusions—

High degrees of CMR-quantified AR were associated with the development of symptoms or other indications for surgery. Quantifying AR showed slightly better discriminatory ability than “gold standard” CMR ventricular volume assessment. This could provide a new paradigm for the timing of surgical intervention but requires confirmation in a clinical trial.
Targeting Mannose-Binding Lectin Confers Long-Lasting Protection With a Surprisingly Wide Therapeutic Window in Cerebral Ischemia
Authors: Orsini Franca , Villa Pia , Parrella Sara , Zangari Rosalia , Zanier Elisa R. , Gesuete Raffaella , Stravalaci Matteo , Fumagalli Stefano , Ottria Roberta , Reina José J. , Paladini Alessandra , Micotti Edoardo , Ribeiro-Viana Renato , Rojo Javier , Pavlov Vasile I. , Stahl Gregory L. , Bernardi Anna , Gobbi Marco , De Simoni Maria-Grazia
Published: August 2012

Background—

The involvement of the complement system in brain injury has been scarcely investigated. Here, we document the pivotal role of mannose-binding lectin (MBL), one of the recognition molecules of the lectin complement pathway, in brain ischemic injury.

Methods and Results—

Focal cerebral ischemia was induced in mice (by permanent or transient middle cerebral artery occlusion) and rats (by 3-vessel occlusion). We first observed that MBL is deposited on ischemic vessels up to 48 hours after injury and that functional MBL/MBL-associated serine protease 2 complexes are increased. Next, we demonstrated that (1) MBL
−/−
mice are protected from both transient and permanent ischemic injury; (2) Polyman2, the newly synthesized mannosylated molecule selected for its binding to MBL, improves neurological deficits and infarct volume when given up to 24 hours after ischemia in mice; (3) anti-MBL-A antibody improves neurological deficits and infarct volume when given up to 18 hours after ischemia, as assessed after 28 days in rats.

Conclusions—

Our data show an important role for MBL in the pathogenesis of brain ischemic injury and provide a strong support to the concept that MBL inhibition may be a relevant therapeutic target in humans, one with a wide therapeutic window of application.
Cardiovascular Risk of High- Versus Moderate-Intensity Aerobic Exercise in Coronary Heart Disease Patients
Authors: Rognmo Øivind , Moholdt Trine , Bakken Hilde , Hole Torstein , Mølstad Per , Myhr Nils Erling , Grimsmo Jostein , Wisløff Ulrik
Published: August 2012

Background—

Exercise performed at higher relative intensities has been found to elicit a greater increase in aerobic capacity and greater cardioprotective effects than exercise at moderate intensities. An inverse association has also been detected between the relative intensity of physical activity and the risk of developing coronary heart disease, independent of the total volume of physical activity. Despite that higher levels of physical activity are effective in reducing cardiovascular events, it is also advocated that vigorous exercise could acutely and transiently increase the risk of sudden cardiac death and myocardial infarction in susceptible persons. This issue may affect cardiac rehabilitation.

Methods and Results—

We examined the risk of cardiovascular events during organized high-intensity interval exercise training and moderate-intensity training among 4846 patients with coronary heart disease in 3 Norwegian cardiac rehabilitation centers. In a total of 175 820 exercise training hours during which all patients performed both types of training, we found 1 fatal cardiac arrest during moderate-intensity exercise (129 456 exercise hours) and 2 nonfatal cardiac arrests during high-intensity interval exercise (46 364 exercise hours). There were no myocardial infarctions in the data material. Because the number of high-intensity training hours was 36% of the number of moderate-intensity hours, the rates of complications to the number of patient-exercise hours were 1 per 129 456 hours of moderate-intensity exercise and 1 per 23 182 hours of high-intensity exercise.

Conclusions—

The results of the current study indicate that the risk of a cardiovascular event is low after both high-intensity exercise and moderate-intensity exercise in a cardiovascular rehabilitation setting. Considering the significant cardiovascular adaptations associated with high-intensity exercise, such exercise should be considered among patients with coronary heart disease.