bluuebunny/crossref_metadata_2025 huggingface dataset:
Generativity as a Route to Active Ageing
Authors: Kruse Andreas , Schmitt Eric
Published: August 2012

We elucidate the significance of active ageing from an individual as well as from a societal perspective. Taking an individual perspective, maintaining activity in later years is linked to successful ageing because of empirical relationships to positive self-perception, satisfaction with life, and development of competences, whereas from a societal perspective, active ageing implies usage of older people’s life competences as a human capital of society—a societal imperative, particularly in times of demographic change but also more basically substantiated in an ethics of responsibility, intergenerational solidarity, and generation equity. We focus on the psychological construct of generativity which is interpreted as an aspect of the philosophical-anthropological category of joint responsibility. Our own research in Mexico and the Baltic States supports the notion that maintaining access to the public sphere and active engagement for others is a more basic individual concern than a life-stages specific developmental task. We report background and results of a Dialogue Forum Project Funding, a research cooperation between our institute and the Foundation Remembrance, Responsibility, and Future aimed to improve generativity in Belarus, Russia, and Ukraine by implementing and supporting local initiatives offering opportunities for intergenerational dialogue.
Patterns and Determinants of Complementary and Alternative Medicine Practitioner Use among Adults with Diabetes in Queensland, Australia
Authors: Lui Chi-Wai , Dower Jo , Donald Maria , Coll Joseph R.
Published: August 2012

There is evidence that complementary and alternative medicine (CAM) use is common among people with diabetes. The role of CAM in the treatment or management of diabetes is an emerging health issue given the potential side effects and benefits associated with the use of this kind of medicine. This paper examined patterns and determinants of CAM practitioner use in Queensland, Australia, using a large population-based sample of people with type 1 and type 2 diabetes. The study found that within a 12-month period, 7.7% of people with diabetes used the services of CAM practitioners alongside or as a complement to conventional health care service. Younger age, female gender, a higher education, having private health insurance, and engagement in preventive health behaviours are significant predictors of individuals who are more likely to visit a CAM practitioner. There was no significant difference in CAM practitioner use between people with type 1, type 2 insulin requiring, or type 2 noninsulin requiring diabetes. The findings highlight the need for further research on the role of CAM in the prevention and management of diabetes.
Menkes Kinky Hair Syndrome: A Rare Neurodegenerative Disease
Authors: Gandhi Rozil , Kakkar Ritu , Rajan Sajeev , Bhangale Rashmi , Desai Shrinivas
Published: August 2012

Menkes kinky hair disease is a rare X-linked recessive disease nearly exclusively affecting males who present at 2-3 months of age due to abnormal functioning of copper-dependent enzymes due to deficiency of copper. Here, we describe a completely worked-up case of a 4-month-old male infant with very typical history and radiological features confirmed by biochemical and trichoanalysis. The initially seen asymmetric cortical and subcortical T2 hyperintensities in cerebral and cerebellar hemispheres converted into symmetrical diffuse cerebral and predominantly cerebellar atrophy with uniform loss of both white and grey matter on follow-up MRI. Also, subdural hemorrhages of various sizes and different stages and tortuosity of larger proximal intracranial vessels with distal narrowing were identified. Ours is a completely worked-up proven case of Menkes kinky hair disease (MKHD) with history, electroencephalography, biochemical, trichoanalysis, and MRI findings. This is a good teaching case and shows importance of clinical examination and biochemistry as complimentary to MRI. Tortuous intracranial arteries with blocked major vessels are found only in this disease, thus stressing the value of MR Angiography in these patients.
Insulin Resistance in Patients with Chronic Kidney Disease
Authors: Liao Min-Tser , Sung Chih-Chien , Hung Kuo-Chin , Wu Chia-Chao , Lo Lan , Lu Kuo-Cheng
Published: August 2012

Metabolic syndrome and its components are associated with chronic kidney disease (CKD) development. Insulin resistance (IR) plays a central role in the metabolic syndrome and is associated with increased risk for CKD in nondiabetic patients. IR is common in patients with mild-to-moderate stage CKD, even when the glomerular filtration rate is within the normal range. IR, along with oxidative stress and inflammation, also promotes kidney disease. In patients with end stage renal disease, IR is an independent predictor of cardiovascular disease and is linked to protein energy wasting and malnutrition. Systemic inflammation, oxidative stress, elevated serum adipokines and fetuin-A, metabolic acidosis, vitamin D deficiency, depressed serum erythropoietin, endoplasmic reticulum stress, and suppressors of cytokine signaling all cause IR by suppressing insulin receptor-PI3K-Akt pathways in CKD. In addition to adequate renal replacement therapy and correction of uremia-associated factors, thiazolidinedione, ghrelin, protein restriction, and keto-acid supplementation are therapeutic options. Weight control, reduced daily prednisolone dosage, and the use of cyclosporin decrease the risk of developing new-onset diabetes after kidney transplantation. Improved understanding of the pathogenic mechanisms underlying IR in CKD may lead to more effective therapeutic strategies to reduce uremia-associated morbidity and mortality.
On the Formulation of the Exchange Field in the Landau-Lifshitz Equation for Spin-Wave Calculation in Magnonic Crystals
Authors: Krawczyk M. , Sokolovskyy M. L. , Klos J. W. , Mamica S.
Published: August 2012

The calculation of the magnonic spectra using the plane-wave method has limitations, the origin of which lies in the formulation of the effective magnetic field term in the equation of motion (the Landau-Lifshitz equation) for composite media. According to ideas of the plane-wave method the system dynamics is described in terms of plane waves (a superposition of a number of plane waves), which are continuous functions and propagate throughout the medium. Since in magnonic crystals the sought-for superposition of plane waves represents the dynamic magnetization, the magnetic boundary conditions on the interfaces between constituent materials should be inherent in the Landau-Lifshitz equations. In this paper we present the derivation of the two expressions for the exchange field known from the literature. We start from the Heisenberg model and use a linear approximation and take into account the spacial dependence of saturation magnetization and exchange constant present in magnetic composites. We discuss the magnetic boundary conditions included in the presented formulations of the exchange field and elucidate their effect on spin-wave modes and their spectra in one- and two-dimensional planar magnonic crystals from plane-wave calculations.
Hybrid Projective Synchronization for Two Identical Fractional‐Order Chaotic Systems
Authors: Zhou Ping , Ding Rui , Cao Yu-xia
Published: August 2012

A hybrid projective synchronization scheme for two identical fractional‐order chaotic systems is proposed in this paper. Based on the stability theory of fractional‐order systems, a controller for the synchronization of two identical fractional‐order chaotic systems is designed. This synchronization scheme needs not to absorb all the nonlinear terms of response system. Hybrid projective synchronization for the fractional‐order Chen chaotic system and hybrid projective synchronization for the fractional‐order hyperchaotic Lu system are used to demonstrate the validity and feasibility of the proposed scheme.
Electromyographical Comparison of Four Common Shoulder Exercises in Unstable and Stable Shoulders
Authors: Sciascia Aaron , Kuschinsky Nina , Nitz Arthur J. , Mair Scott D. , Uhl Tim L.
Published: August 2012

This study examines if electromyographic (EMG) amplitude differences exist between patients with shoulder instability and healthy controls performing scaption, prone horizontal abduction, prone external rotation, and push-up plus shoulder rehabilitation exercises. Thirty nine subjects were categorized by a single orthopedic surgeon as having multidirectional instability (n=10), anterior instability (n=9), generalized laxity (n=10), or a healthy shoulder (n=10). Indwelling and surface electrodes were utilized to measure EMG activity (reported as a % of maximum voluntary isometric contraction (MVIC)) in various shoulder muscles during 4 common shoulder exercises. The exercises studied effectively activated the primary musculature targeted in each exercise equally among all groups. The serratus anterior generated high activity (50–80% MVIC) during a push-up plus, while the infraspinatus and teres major generated moderate-to-high activity (30–80% MVIC) during both the prone horizontal and prone external rotation exercises. Scaption exercise generated moderate activity (20–50% MVIC) in both rotator cuff and scapular musculature. Clinicians should feel confident in prescribing these shoulder-strengthening exercises in patients with shoulder instability as the activation levels are comparable to previous findings regarding EMG amplitudes and should improve the dynamic stabilization capability of both rotator cuff and scapular muscles using exercises designed to address glenohumeral joint instability.
Potential Anticancer Properties of Grape Antioxidants
Authors: Zhou Kequan , Raffoul Julian J.
Published: August 2012

Dietary intake of foods rich in antioxidant properties is suggested to be cancer protective. Foods rich in antioxidant properties include grape (Vitis vinifera), one of the world’s largest fruit crops and most commonly consumed fruits in the world. The composition and cancer-protective effects of major phenolic antioxidants in grape skin and seed extracts are discussed in this review. Grape skin and seed extracts exert strong free radical scavenging and chelating activities and inhibit lipid oxidation in various food and cell modelsin vitro. The use of grape antioxidants are promising against a broad range of cancer cells by targeting epidermal growth factor receptor (EGFR) and its downstream pathways, inhibiting over-expression of COX-2 and prostaglandin E2 receptors, or modifying estrogen receptor pathways, resulting in cell cycle arrest and apoptosis. Interestingly, some of these activities were also demonstrated in animal models. However,in vivostudies have demonstrated inconsistent antioxidant efficacy. Nonetheless, a growing body of evidence from human clinical trials has demonstrated that consumption of grape, wine and grape juice exerts many health-promoting and possible anti-cancer effects. Thus, grape skin and seed extracts have great potential in cancer prevention and further investigation into this exciting field is warranted.
Mechanisms of Gene Duplication and Translocation and Progress towards Understanding Their Relative Contributions to Animal Genome Evolution
Authors: Mendivil Ramos Olivia , Ferrier David E. K.
Published: August 2012

Duplication of genetic material is clearly a major route to genetic change, with consequences for both evolution and disease. A variety of forms and mechanisms of duplication are recognised, operating across the scales of a few base pairs upto entire genomes. With the ever-increasing amounts of gene and genome sequence data that are becoming available, our understanding of the extent of duplication is greatly improving, both in terms of the scales of duplication events as well as their rates of occurrence. An accurate understanding of these processes is vital if we are to properly understand important events in evolution as well as mechanisms operating at the level of genome organisation. Here we will focus on duplication in animal genomes and how the duplicated sequences are distributed, with the aim of maintaining a focus on principles of evolution and organisation that are most directly applicable to the shaping of our own genome.
Cellular Cofactors of Lentiviral Integrase: From Target Validation to Drug Discovery
Authors: Taltynov Oliver , Desimmie Belete A. , Demeulemeester Jonas , Christ Frauke , Debyser Zeger
Published: August 2012

To accomplish their life cycle, lentiviruses make use of host proteins, the so-called cellular cofactors. Interactions between host cell and viral proteins during early stages of lentiviral infection provide attractive new antiviral targets. The insertion of lentiviral cDNA in a host cell chromosome is a step of no return in the replication cycle, after which the host cell becomes a permanent carrier of the viral genome and a producer of lentiviral progeny. Integration is carried out by integrase (IN), an enzyme playing also an important role during nuclear import. Plenty of cellular cofactors of HIV-1 IN have been proposed. To date, the lens epithelium-derived growth factor (LEDGF/p75) is the best studied cofactor of HIV-1 IN. Moreover, small molecules that block the LEDGF/p75-IN interaction have recently been developed for the treatment of HIV infection. The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus. Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets. Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs).
Alterations of theTP53Gene in Gastric and Esophageal Carcinogenesis
Authors: Bellini Marilanda Ferreira , Cadamuro Aline Cristina Targa , Succi Maysa , Proença Marcela Alcântara , Silva Ana Elizabete
Published: August 2012

TP53genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability. The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation. Thus, this study highlights the participation of the main genetic alterations of theTP53gene in esophageal and gastric carcinogenesis. Among these changes, high frequency ofTP53mutations, loss of heterozygosity (LOH), overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response. Furthermore, Single Nucleotide Polymorphisms (SNPs) ofTP53have been implicated in the development and prognosis of several cancers, mainlyTP53codon 72 polymorphism whose role has been extensively studied in relation to susceptibility for esophageal and gastric cancer development.
Functionalization of Mesoporous Silicon Nanoparticles for Targeting and Bioimaging Purposes
Authors: Rytkönen Jussi , Miettinen Riitta , Kaasalainen Martti , Lehto Vesa-Pekka , Salonen Jarno , Närvänen Ale
Published: August 2012

Carboxylic acid functionalized thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi‐NP) were synthesized, and their opsonization and targeting properties were studied in vitro alongside with in vivo biodistribution. The carboxyl groups on UnTHCPSi were utilized to further functionalize the nanoparticles. In order to reduce the opsonization of the UnTHCPSi‐NPs, different sized polyethylene glycol (PEG) were conjugated or adsorbed to the NPs surface. The latter approach, based on hydrophobic interaction, turned out to be more effective in reducing the opsonization and improving the stability of the nanoparticle suspension. The most abundant opsonins after plasma incubation were fibrinogen precursors and IgG. Furthermore, the targeting properties of UnTHCPSi‐NPs were studied in vitro with antibodies against glutathione S‐transferase (anti‐GST). PEGylated NPs conjugated with anti‐GST bound to GST‐agarose in human plasma nearly 35‐fold compared to control NPs, indicating that UnTHCPSi‐NPs are suitable for targeting in physiological environment. The in vivo biodistribution in mice revealed that PEGylated UnTHCPSi‐NPs, accumulate fast into the liver and the spleen, regardless of the reduced opsonization in vitro. However, autoradiography and transmission electron microscopy showed that majority of the NPs still remained in hepatic blood vessels and sinusoids suggesting a possibility to utilize them as a sustained release platform for payload molecules.
Synergistic Effect of Anemia and Red Blood Cells Transfusion on Inflammation and Lung Injury
Authors: Dong Anping , Sunkara Manjula , Panchatcharam Manikandan , Salous Abdel , Selim Samy , Morris Andrew J. , Smyth Susan S.
Published: August 2012

Anemia and resultant red blood cell transfusion may be associated with adverse long-term clinical outcomes. To investigate the mechanism(s) responsible, we profiled inflammatory biomarkers and circulating levels of the bioactive lysophospholipid mediator sphingosine-1-phosphate (S1P) in control and anemic mice with or without LPS-induced systemic inflammation. Acute anemia or lipopolysaccharide (LPS) challenge alone triggered an increase of circulating levels of the inflammatory markers IL-6 and keratinocyte-derived chemokine (CXCL1/KC). Moreover, administration of LPS to anemic mice reduced circulating S1P levels and augmented lung injury and pulmonary vascular permeability. Transfusion of aged, but not fresh, red blood cells (RBCs) worsened pulmonary vascular leak. S1P levels decline markedly during storage of mouse RBCs. Loading stored murine RBCs with S1P prior to transfusion partially attenuated anemia-associated acute pulmonary vascular leak. Taken together, our results indicate that anemia and systemic inflammation can alter the S1P buffering capacity of RBCs, suggesting possible strategies for alleviating transfusion-related lung injury in clinical practice.
Applying Neural Networks to Prices Prediction of Crude Oil Futures
Authors: Hu John Wei-Shan , Hu Yi-Chung , Lin Ricky Ray-Wen
Published: August 2012

The global economy experienced turbulent uneasiness for the past five years owing to large increases in oil prices and terrorist’s attacks. While accurate prediction of oil price is important but extremely difficult, this study attempts to accurately forecast prices of crude oil futures by adopting three popular neural networks methods including the multilayer perceptron, the Elman recurrent neural network (ERNN), and recurrent fuzzy neural network (RFNN). Experimental results indicate that the use of neural networks to forecast the crude oil futures prices is appropriate and consistent learning is achieved by employing different training times. Our results further demonstrate that, in most situations, learning performance can be improved by increasing the training time. Moreover, the RFNN has the best predictive power and the MLP has the worst one among the three underlying neural networks. This finding shows that, under ERNNs and RFNNs, the predictive power improves when increasing the training time. The exceptional case involved BPNs, suggesting that the predictive power improves when reducing the training time. To sum up, we conclude that the RFNN outperformed the other two neural networks in forecasting crude oil futures prices.
Frequent PVT1 Rearrangement and Novel Chimeric Genes PVT1-NBEA and PVT1-WWOX Occur in Multiple Myeloma with 8q24 Abnormality
Authors: Nagoshi Hisao , Taki Tomohiko , Hanamura Ichiro , Nitta Masakazu , Otsuki Takemi , Nishida Kazuhiro , Okuda Keiko , Sakamoto Natsumi , Kobayashi Satoru , Yamamoto-Sugitani Mio , Tsutsumi Yasuhiko , Kobayashi Tsutomu , Matsumoto Yosuke , Horiike Shigeo , Kuroda Junya , Taniwaki Masafumi
Published: August 2012

Chromosome 8q24 rearrangements are occasionally found in multiple myeloma and are associated with tumor progression. The 8q24 rearrangements were detected by FISH in 12 of 54 patients with multiple myeloma (22.2%) and in 8 of 11 multiple myeloma cell lines (72.7%). The breakpoints of 8q24 in 10 patients with multiple myeloma and in all multiple myeloma cell lines were assigned to a 360 kb segment, which was divided into 4 regions: approximately 120 kb centromeric to MYC (5′ side of MYC), the region centromerically adjacent to PVT1 (∼ 170 kb region, including MYC, of 5′ side of PVT1), the PVT1 region, and the telomeric region to PVT1. PVT1 rearrangements were most common and found in 7 of 12 patients (58.3%) and 5 of 8 cell lines (62.5%) with 8q24 abnormalities. A combination of spectral karyotyping (SKY), FISH, and oligonucleotide array identified several partner loci of PVT1 rearrangements, such as 4p16, 4q13, 13q13, 14q32, and 16q23-24. Two novel chimeric genes were identified: PVT1-NBEA in the AMU-MM1 cell line harboring t(8;13)(q24;q13) and PVT1-WWOX in RPMI8226 cell line harboring der(16)t(16;22)ins(16;8)(q23;q24). The PVT1-NBEA chimera in which PVT1 exon 1 was fused to NBEA exon 2 and the PVT1-WWOX in which PVT1 exon 1 was fused to WWOX exon 9 were associated with the expression of abnormal NBEA and WWOX lacking their N-terminus, respectively. These findings suggest that PVT1 rearrangements may represent a novel molecular paradigm underlying the pathology of 8q24 rearrangement–positive multiple myeloma. Cancer Res; 72(19); 4954–62. ©2012 AACR.
Intravesical Delivery of Small Activating RNA Formulated into Lipid Nanoparticles Inhibits Orthotopic Bladder Tumor Growth
Authors: Kang Moo Rim , Yang Glen , Place Robert F. , Charisse Klaus , Epstein-Barash Hila , Manoharan Muthiah , Li Long-Cheng
Published: August 2012

Practical methods for enhancing protein production in vivo remain a challenge. RNA activation (RNAa) is emerging as one potential solution by using double-stranded RNA (dsRNA) to increase endogenous gene expression. This approach, although related to RNA interference (RNAi), facilitates a response opposite to gene silencing. Duplex dsP21-322 and its chemically modified variants are examples of RNAa-based drugs that inhibit cancer cell growth by inducing expression of tumor suppressor p21WAF1/CIP1 (p21). In this study, we investigate the therapeutic potential of dsP21-322 in an orthotopic model of bladder cancer by formulating a 2′-fluoro-modified derivative (dsP21-322-2′F) into lipid nanoparticles (LNP) for intravesical delivery. LNP composition is based upon clinically relevant formulations used in RNAi-based therapies consisting of PEG-stabilized unilamellar liposomes built with lipid DLin-KC2-DMA. We confirm p21 induction, cell-cycle arrest, and apoptosis in vitro following treatment with LNP-formulated dsP21-322-2′F (LNP-dsP21-322-2′F) or one of its nonformulated variants. Both 2′-fluoro modification and LNP formulation also improve duplex stability in urine. Intravesical delivery of LNP-dsP21-322-2′F into mouse bladder results in urothelium uptake and extends survival of mice with established orthotopic human bladder cancer. LNP-dsP21-322-2′F treatment also facilitates p21 activation in vivo leading to regression/disappearance of tumors in 40% of the treated mice. Our results provide preclinical proof-of-concept for a novel method to treat bladder cancer by intravesical administration of LNP-formulated RNA duplexes. Cancer Res; 72(19); 5069–79. ©2012 AACR.
Effects of Selective Checkpoint Kinase 1 Inhibition on Cytarabine Cytotoxicity in Acute Myelogenous Leukemia Cells In Vitro
Authors: Schenk Erin L. , Koh Brian D. , Flatten Karen S. , Peterson Kevin L. , Parry David , Hess Allan D. , Smith B. Douglas , Karp Judith E. , Karnitz Larry M. , Kaufmann Scott H.
Published: August 2012

Purpose: Previous studies have shown that the replication checkpoint, which involves the kinases ataxia telangiectasia mutated and Rad3 related (ATR) and Chk1, contributes to cytarabine resistance in cell lines. In the present study, we examined whether this checkpoint is activated in clinical acute myelogenous leukemia (AML) during cytarabine infusion in vivo and then assessed the impact of combining cytarabine with the recently described Chk1 inhibitor SCH 900776 in vitro.

Experimental design: AML marrow aspirates harvested before and during cytarabine infusion were examined by immunoblotting. Human AML lines treated with cytarabine in the absence or presence of SCH 900776 were assayed for checkpoint activation by immunoblotting, nucleotide incorporation into DNA, and flow cytometry. Long-term effects in AML lines, clinical AML isolates, and normal myeloid progenitors were assayed using clonogenic assays.

Results: Immunoblotting revealed increased Chk1 phosphorylation, a marker of checkpoint activation, in more than half of Chk1-containing AMLs after 48 hours of cytarabine infusion. In human AML lines, SCH 900776 not only disrupted cytarabine-induced Chk1 activation and S-phase arrest but also markedly increased cytarabine-induced apoptosis. Clonogenic assays demonstrated that SCH 900776 enhanced the antiproliferative effects of cytarabine in AML cell lines and clinical AML samples at concentrations that had negligible impact on normal myeloid progenitors.

Conclusions: These results not only provide evidence for cytarabine-induced S-phase checkpoint activation in AML in the clinical setting, but also show that a selective Chk1 inhibitor can overcome the S-phase checkpoint and enhance the cytotoxicity of cytarabine. Accordingly, further investigation of the cytarabine/SCH 900776 combination in AML appears warranted. Clin Cancer Res; 18(19); 5364–73. ©2012 AACR.
A Locked, Dimeric CXCL12 Variant Effectively Inhibits Pulmonary Metastasis of CXCR4-Expressing Melanoma Cells Due to Enhanced Serum Stability
Authors: Takekoshi Tomonori , Ziarek Joshua J. , Volkman Brian F. , Hwang Sam T.
Published: August 2012

The CXC chemokine receptor-4 (CXCR4) plays a critical role in cancer by positively regulating cancer cell metastasis and survival. We previously showed that high concentrations of the CXCR4 ligand, wild-type CXCL12 (wtCXCL12), could inhibit colorectal cancer metastasis in vivo, and we have hypothesized that wtCXCL12 dimerizes at high concentration to become a potent antagonist of CXCR4. To address this hypothesis, we engineered a covalently locked, dimeric variant of CXCL12 (CXCL122). Herein, we show that CXCL122 can not only inhibit implantation of lung metastasis of CXCR4-B16-F10 melanoma cells more effectively than AMD3100, but that CXCL122 also blocks the growth of established pulmonary tumors. To identify a basis for the in vivo efficacy of CXCL122, we conducted Western blot analysis and ELISA analyses, which revealed that CXCL122 was stable for at least 12 hours in serum, whereas wtCXCL12 was quickly degraded. CXCL122 also maintained its antagonist properties in in vitro chemotaxis assays for up to 24 hours in serum, whereas wtCXCL12 was ineffective after 6 hours. Heat-inactivation of serum prolonged the stability and function of wtCXCL12 by more than 6 hours, suggesting enzymatic degradation as a possible mechanism for wtCXCL12 inactivation. In vitro analysis of amino-terminal cleavage by enzymes dipeptidylpeptidase IV (DPPIV/CD26) and matrix metalloproteinase-2 (MMP-2) resulted in 25-fold and 2-fold slower degradation rates, respectively, of CXCL122 compared with wtCXCL12. In summary, our results suggest CXCL122 possesses greater potential as an antimetastatic drug as compared with AMD3100 or wtCXCL12, potentially due to enhanced serum stability in the presence of N-terminal degrading enzymes. Mol Cancer Ther; 11(11); 2516–25. ©2012 AACR.
Cdk4/6 Inhibition Induces Epithelial–Mesenchymal Transition and Enhances Invasiveness in Pancreatic Cancer Cells
Authors: Liu Fang , Korc Murray
Published: August 2012

Aberrant activation of Cyclin D-Cdk4/6 signaling pathway is commonly found in pancreatic ductal adenocarcinoma (PDAC). Here, we show that PD-0332991, a highly specific inhibitor for Cdk4 and Cdk6, exerted growth inhibitory effects on three human PDAC cell lines. Microarray analysis revealed that PD-0332991 downregulated cell-cycle–related genes, but upregulated genes implicated in extracellular matrix (ECM) remodeling and pancreatic cancer cell invasion and metastasis. Moreover, PD-0332991 enhanced invasion in TGF-β–responsive PDAC cell lines that harbor a wild-type SMAD4 gene (COLO-357, PANC-1), but not in TGF-β–resistant AsPC-1 cells that harbor a mutated SMAD4. PD-0332991 also induced epithelial–mesenchymal transition (EMT) in COLO-357 and PANC-1, but not in AsPC-1 cells. Inhibition of CDK4/6 using shRNA mimicked the effects of PD-0332991 on EMT induction. Furthermore, PD-0332991 increased Smad transcriptional activity in luciferase readout assays and activated TGF-β signaling. SB-505124, an inhibitor of the type-I TGF-β receptor (TβRI) kinase, completely blocked EMT induction by PD-0332991. When combined with PD-0332991, SB-505124 inhibited the growth of COLO-357 and PANC-1 cells. Taken together, these data suggest that anti-Cdk4/6 therapy could induce EMT and enhance pancreatic cancer cell invasion by activating Smad-dependent TGF-β signaling, and that combining PD-0332991 and SB-505124 may represent a novel therapeutic strategy in PDAC. Mol Cancer Ther; 11(10); 2138–48. ©2012 AACR.
Evaluation of an Instrument for Screening Patients at Risk for Chronic Kidney Disease: Testing SCORED (Screening for Occult Renal Disease) in a Portuguese Population
Authors: de Almeida Edgar A.F. , Lavinas Carlota , Teixeira Catarina , Raimundo Mário , Nogueira Cristina , João Melo Maria , Ferreira Martina , Sampaio António , da Silva Henriques Inês , Teixeira Cecília , Almeida Sofia , Gomes da Costa António , Leal Miguel
Published: August 2012

Prevalence of chronic kidney disease (CKD) is increasing and CKD has a long asymptomatic phase suitable for screening. SCORED (Screening for Occult Renal Disease) is a prescreening test which has compared favorably with KEEP. We report the results of SCORED testing in subjects attending a World Kidney Day event. After SCORED, subjects were tested for creatinine, urinary albumin and creatinine, and renal ultrasound. Eighty-eight subjects participated (32 men; mean age 59.7 ± 14.8 years; 58% hypertensive and 15.9% diabetics) of which 60 had a high score for kidney disease. Thirty-eight of 47 (80.8%) subjects that were further evaluated had a high-risk score. All subjects with CKD had a high score (100% sensitivity). SCORED showed low specificity (24.3%), but a high negative predictive value (100%). Including albuminuria in the definition of CKD increased the positive predictive value to 43.6%. In conclusion, SCORED is good for prescreening subjects for CKD in a European population as it captures all patients with CKD. Moreover, in subjects with low risk, the probability of CKD is low. SCORED is useful in alerting the general population and the medical community about the risk factors of CKD.
Dermal Peptide Delivery Using Enhancer Molecules and Colloidal Carrier Systems – Part I: Carnosine
Authors: Goebel A.S.B. , Schmaus G. , Neubert R.H.H. , Wohlrab J.
Published: August 2012

Due to the lipophilic properties of the uppermost skin layer of the stratum corneum (SC), it is highly challenging to attain therapeutic concentrations of active substances; hydrophilic drugs, in particular, penetrate poorly. The purpose of this study was the improvement of the topical bioavailability of the hydrophilic dipeptides L-carnosine and its related compound N-acetyl-L-carnosine. Different strategies were investigated. On the one hand, an enhancer molecule, 1,2-pentylene glycol (PG), was added to a standard preparation, and on the other hand, a microemulsion (ME-PG) system was developed. Both were compared to the standard formulation without an enhancer molecule. For all 3 preparations, the penetration of the peptides in ex vivo human skin was investigated. This allows statements to be made regarding dermal penetration, localization and distribution of the active substances in each skin layer as well as the influence of vehicle variations, in this case, the addition of PG or the incorporation of N-acetyl-L-carnosine in an ME-PG system. For L-carnosine and N-acetyl-L-carnosine, the use of the standard preparation with PG resulted in a significant increase of the substance within the SC. Approximately 6-fold and higher dipeptide concentrations in the SC and in the viable skin layers were detected at all experimental periods compared to the formulation without the enhancer molecule and the ME-PG. High concentrations of the compounds were found after a short period of time in the viable skin layers after applying the enhancer molecule, even in concentrations of 5%. The application of the colloidal carrier system did not lead to a higher penetration rate of N-acetyl-L-carnosine in comparison to both standard preparations, although it must be said that the microstructure of the investigated ME-PG might not have been optimal for the hydrophilic properties of the dipeptide.
Expression of Stanniocalcin 1 as a Potential Biomarker of Gastric Cancer
Authors: Arigami Takaaki , Uenosono Yoshikazu , Ishigami Sumiya , Hagihara Takahiko , Haraguchi Naoto , Matsushita Daisuke , Yanagita Shigehiro , Nakajo Akihiro , Okumura Hiroshi , Hokita Shuichi , Natsugoe Shoji
Published: August 2012

Objective: We investigated stanniocalcin 1 (STC 1) expression to assess its clinical utility as a blood marker in patients with gastric cancer and evaluated its biological impact in terms of tumor aggressiveness. Methods: Blood specimens from 93 patients with gastric cancer and 21 normal healthy volunteers were assessed by quantitative reverse transcription-polymerase chain reaction for STC 1 mRNA expression. Results: The relative numbers of STC 1 mRNA copies were significantly higher in gastric cancer cell lines and in blood specimens from patients with gastric cancer than in blood specimens from healthy volunteers (p = 0.0001 and p = 0.003, respectively). The sensitivity and specificity of STC 1 mRNA expression for discriminating patients with gastric cancer from healthy volunteers were 69.9 and 71.4%, respectively. Furthermore, the sensitivity for STC 1 mRNA was higher than that for serum carcinoembryonic antigen and carbohydrate antigen 19-9. The presence of STC 1 expression was significantly correlated with depth of tumor invasion and tumor stage (p = 0.032 and p = 0.013, respectively). Conclusion: Our data strongly suggest that STC 1 is a potentially useful blood marker for predicting biological tumor aggressiveness in patients with gastric cancer.
Quantifying Pulmonary Regurgitation and Right Ventricular Function in Surgically Repaired Tetralogy of Fallot
Authors: Mercer-Rosa Laura , Yang Wei , Kutty Shelby , Rychik Jack , Fogel Mark , Goldmuntz Elizabeth
Published: August 2012

Background—

Patients with repaired tetralogy of Fallot are monitored for pulmonary regurgitation (PR) and right ventricular (RV) function. We sought to compare measures of PR and RV function on echocardiogram to those on cardiac magnetic resonance (CMR) and to develop a new tool for assessing PR by echocardiogram.

Methods and Results—

Patients with repaired tetralogy of Fallot (n=143; 12.5±3.2 years) had an echocardiogram and CMR within 3 months of each other. On echocardiogram, RV function was assessed by (1) Doppler tissue imaging of the RV free wall and (2) myocardial performance index. The ratio of diastolic and systolic time-velocity integrals measured by Doppler of the main pulmonary artery was calculated. CMR variables included RV ejection fraction, RV volumes, and pulmonary regurgitant fraction (RF). Pulmonary regurgitation was graded as mild (RF<20%), moderate (RF=20–40%), and severe (RF>40%). On CMR, RF was 34+17% and RV ejection fraction was 61+8%. Echocardiography had good sensitivity identifying cases with RF>20% (sensitivity 97%; 95% CI: 92–99%) but overestimated the amount of PR when RF<20% (false-positive rate 36%; 95% CI: 18–57%). The diastolic and systolic time-velocity integrals on echocardiogram showed moderate correlation with RF on CMR (
R
=0.60;
P
<0.0001). On CMR, RF of 20% and 40% corresponded with a diastolic and systolic time-velocity integral of 0.49 (95% CI: 0.44–0.56) and 0.72 (95% CI: 0.68–0.76), respectively. RV myocardial performance index correlated modestly with RV ejection fraction (
r
=−0.33;
P
<0.001).

Conclusions—

This study suggests that the diastolic and systolic time-velocity integrals ratio may make a modest contribution to the overall assessment of PR in patients with repaired tetralogy of Fallot and warrants further investigation. However, echocardiography continues to have a limited ability to quantify PR and RV function as compared with CMR.
Implantable Cardioverter-Defibrillators Have Reduced the Incidence of Resuscitation for Out-of-Hospital Cardiac Arrest Caused by Lethal Arrhythmias
Authors: Hulleman Michiel , Berdowski Jocelyn , de Groot Joris R. , van Dessel Pascal F.H.M. , Borleffs C. Jan Willem , Blom Marieke T. , Bardai Abdenasser , de Cock Carel C. , Tan Hanno L. , Tijssen Jan G.P. , Koster Rudolph W.
Published: August 2012

Background—

Over the last decades, a gradual decrease in ventricular fibrillation (VF) as initial recorded rhythm during resuscitation for out-of-hospital cardiac arrest (OHCA) has been noted. We sought to establish the contribution of implantable cardioverter-defibrillator (ICD) therapy to this decline.

Methods and Results—

Using a prospective database of all OHCA resuscitation in the province North Holland in the Netherlands (Amsterdam Resuscitation Studies [ARREST]), we collected data on all patients in whom resuscitation for OHCA was attempted in 2005–2008. VF OHCA incidence (per 100 000 inhabitants per year) was compared with VF OHCA incidence data during 1995–1997, collected in a similar way. We also collected ICD interrogations of all ICD patients from North Holland and identified all appropriate ICD shocks in 2005–2008; we calculated the number of prevented VF OHCA episodes, considering that only part of the appropriate shocks would result in avoided resuscitation. VF OHCA incidence decreased from 21.1/100 000 in 1995–1997 to 17.4/100 000 in 2005–2008 (
P
<0.001). Non-VF OHCA increased from 12.2/100 000 to 19.4/100 000 (
P
<0.001). VF as presenting rhythm declined from 63% to 47%. In 2005–2008, 1972 ICD patients received 977 shocks. Of these shocks, 339 were caused by a life-threatening arrhythmia. We estimate that these 339 shocks have prevented 81 (minimum, 39; maximum, 152) cases of VF OHCA, corresponding with 33% (minimum, 16%; maximum, 63%) of the observed decline in VF OHCA incidence.

Conclusions—

The incidence of VF OHCA decreased over the last 10 years in North Holland. ICD therapy explained a decrease of 1.2/100 000 inhabitants per year, corresponding with 33% of the observed decline in VF OHCA.
Autoantibody-Mediated Complement C3a Receptor Activation Contributes to the Pathogenesis of Preeclampsia
Authors: Wang Wei , Irani Roxanna A. , Zhang Yujin , Ramin Susan M. , Blackwell Sean C. , Tao Lijian , Kellems Rodney E. , Xia Yang
Published: August 2012

Preeclampsia (PE) is a prevalent life-threatening hypertensive disorder of pregnancy associated with increased complement activation. However, the causative factors and pathogenic role of increased complement activation in PE are largely unidentified. Here we report that a circulating maternal autoantibody, the angiotensin II type 1 receptor agonistic autoantibody, which emerged recently as a potential pathogenic contributor to PE, stimulates deposition of complement C3 in placentas and kidneys of pregnant mice via angiotensin II type 1 receptor activation. Next, we provide in vivo evidence that selectively interfering with C3a signaling by a complement C3a receptor–specific antagonist significantly reduces hypertension from 167±7 to 143±5 mm Hg and proteinuria from 223.5±7.5 to 78.8±14.0 μg of albumin per milligram creatinine (both
P
<0.05) in angiotensin II type 1 receptor agonistic autoantibody–injected pregnant mice. In addition, we demonstrated that complement C3a receptor antagonist significantly inhibited autoantibody-induced circulating soluble fms-like tyrosine kinase 1, a known antiangiogenic protein associated with PE, and reduced small placental size with impaired angiogenesis and intrauterine growth restriction. Similarly, in humans, we demonstrate that C3 deposition is significantly elevated in the placentas of preeclamptic patients compared with normotensive controls. Lastly, we show that complement C3a receptor activation is a key mechanism underlying autoantibody-induced soluble fms-like tyrosine kinase 1 secretion and decreased angiogenesis in cultured human villous explants. Overall, we provide mouse and human evidence that angiotensin II type 1 receptor agonistic autoantibody–mediated activation contributes to elevated C3 and that complement C3a receptor signaling is a key mechanism underlying the pathogenesis of the disease. These studies are the first to link angiotensin II type 1 receptor agonistic autoantibody with complement activation and to provide important new opportunities for therapeutic intervention in PE.
Implications of New Hypertension Guidelines in the United States
Authors: Bertoia Monica L. , Waring Molly E. , Gupta Priya S. , Roberts Mary B. , Eaton Charles B.
Published: August 2012

The American Heart Association released a scientific statement based on available clinical trials and expert opinion in 2007 for the treatment of hypertension to prevent coronary artery disease. These guidelines recommend more aggressive control of blood pressure (BP <130/80 mm Hg) among those at high risk for coronary artery disease, individuals with diabetes mellitus, chronic kidney disease, coronary artery disease or coronary artery disease risk equivalent, or a 10-year Framingham risk score ≥10%. Based on newer clinical trial data, the 2011 American College of Cardiology Foundation/American Heart Association (AHA) hypertension guidelines for the elderly recommend a less aggressive approach of <145/90 mm Hg in those over the age of 80 years. We estimated the burden of uncontrolled BP among those at an increased risk of coronary artery disease using the both the 2007 AHA and the 2011 American College of Cardiology Foundation/AHA hypertension guidelines. We used a cross-sectional analysis of National Health and Nutrition Examination Survey 2005–2008 participants. Participants were 10198 adults aged 18 to 85 years. Using the 2011 American College of Cardiology Foundation/AHA hypertension guidelines (≥140/90 mm Hg), 72 million Americans (35%) have hypertension. Using the 2007 AHA guidelines, an additional 7 million American adults (5%) have elevated BP requiring treatment, for a total of 79 million adults (40%). Although individuals at a higher risk for coronary artery disease are more likely to be aware of their hypertension and to be taking antihypertension medication, they are less likely to have their BP under control. Additional efforts are needed in the treatment of elevated BP, especially among individuals with an increased risk of coronary artery disease.
Lifestyle Factors and Antihypertensive Treatment on the Risks of Ischemic and Hemorrhagic Stroke
Authors: Zhang Yurong , Tuomilehto Jaakko , Jousilahti Pekka , Wang Yujie , Antikainen Riitta , Hu Gang
Published: August 2012

The joint relationship between healthy lifestyle and antihypertensive treatment with stroke risk is unclear. We prospectively investigated the individual and joint effects of healthy lifestyle factors and antihypertensive treatment on stroke risk among 36 686 Finnish participants aged 25 to 74 years and free of coronary heart disease and stroke at baseline. During a mean follow-up of 13.7 years, 1478 people developed stroke event (1167 ischemic and 311 hemorrhagic). The stroke risk was significantly decreased in people who adhered to ≥3 healthy lifestyle factors (never smoking, normal weight, moderate/high level of exercise, vegetable consumption ≥3 times per week, and light/moderate alcohol drinking) compared with those who adhered to <3 healthy lifestyle factors. The stroke risk was significantly increased in unaware untreated, aware untreated, aware treated and controlled, and aware treated and uncontrolled hypertensive people than in normotensive people. The risks of stroke were decreased in people who adhered to ≥3 healthy lifestyle factors compared with those who adhered to <3 healthy lifestyle factors within different hypertensive status. Compared with hypertensive people who did not use antihypertensive drugs and adhered to ≥3 healthy lifestyle factors, the multivariable-adjusted hazard ratios in hypertensive people who used antihypertensive drugs and adhered to <3 healthy lifestyle factors were associated with 37% to 42% increased risks of total, ischemic, and hemorrhagic stroke in men and 121% to 131% increased risks of stroke in women. The present study demonstrates that a healthy lifestyle significantly decreases stroke risk in both men and women in different strata of hypertension status and antihypertensive drug treatments.
Dipeptidyl Peptidase 4 Inhibitor Sitagliptin Protects Endothelial Function in Hypertension Through a Glucagon–Like Peptide 1–Dependent Mechanism
Authors: Liu Limei , Liu Jian , Wong Wing Tak , Tian Xiao Yu , Lau Chi Wai , Wang Yi-Xiang , Xu Gang , Pu Yunfei , Zhu Zhiming , Xu Aimin , Lam Karen S.L. , Chen Zhen Yu , Ng Chi Fai , Yao Xiaoqiang , Huang Yu
Published: August 2012

Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor, inhibits the inactivation and degradation of glucagon like peptide 1 (GLP-1), which is used for the treatment of type 2 diabetes mellitus. However, little is known about the role of GLP-1 in hypertension. This study investigated whether the activation of GLP-1 signaling protects endothelial function in hypertension. Two-week sitagliptin treatment (10 mg/kg per day, oral gavage) improved endothelium-dependent relaxation in renal arteries, restored renal blood flow, and reduced systolic blood pressure in spontaneously hypertensive rats. In vivo sitagliptin treatment elevated GLP-1 and GLP-1 receptor expressions, increased cAMP level, and subsequently activated protein kinase A, liver kinase B1, AMP-activated protein kinase-α and endothelial NO synthase in spontaneously hypertensive rat renal arteries. Inhibition of GLP-1 receptor, adenylyl cyclase, protein kinase A, AMP-activated protein kinase-α, or NO synthase reversed the protective effects of sitagliptin. We also demonstrate that GLP-1 receptor agonist exendin 4 in vitro treatment had similar vasoprotective effects in spontaneously hypertensive rat renal arteries and increased NO production in spontaneously hypertensive rat aortic endothelial cells. Studies using transient expressions of wild-type and dominant-negative AMP-activated protein kinase-α2 support the critical role of AMP-activated protein kinase-α in mediating the effect of GLP-1 in endothelial cells. Ex vivo exendin 4 treatment also improved endothelial function of renal arteries from hypertensive patients. Our results elucidate that upregulation of GLP-1 and related agents improve endothelial function in hypertension by restoring NO bioavailability, suggesting that GLP-1 signaling could be a therapeutic target in hypertension-related vascular events.