bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancing Work-Focused Supports for People with Severe Mental Illnesses in Australia
Authors: Contreras Natalia , Rossell Susan L. , Castle David J. , Fossey Ellie , Morgan Dea , Crosse Caroline , Harvey Carol
Published: July 2012

Persons with severe mental illness (SMI) have reduced workforce participation, which leads to significant economic and social disadvantage. This theoretical review introduces the strategies that have been implemented to address this issue. These include Individual Placement and Support (IPS) services, the most widely researched form of supported employment, to which cognitive remediation has more recently been recognised in the USA, as an intervention to improve employment outcomes by addressing the cognitive impairments often experienced by people with SMI. The authors review the international literature and discuss specifically the Australian context. They suggest that Australia is in a prime position to engage clients in such a dual intervention, having had recent success with increasing access to supported employment programs and workforce reentry, through implementation of the Health Optimisation Program for Employment (HOPE). Such programs assist withgainingandmaintainingemployment. However, they do not address the cognitive issues that oftenpreventpersons with SMI from effectively participating in work. Thus, optimising current interventions, with work-focused cognitive skills development is critical to enhancing employment rates that remain low for persons with SMI.
Unsteady Unidirectional MHD Flow of Voigt Fluids Moving between Two Parallel Surfaces for Variable Volume Flow Rates
Authors: Chen Wei-Fan , Lai Hsin-Yi , Chen Cha′o-Kuang
Published: July 2012

The velocity profile and pressure gradient of an unsteady state unidirectional MHD flow of Voigt fluids moving between two parallel surfaces under magnetic field effects are solved by the Laplace transform method. The flow motion between parallel surfaces is induced by a prescribed inlet volume flow rate that varies with time. Four cases of different inlet volume flow rates are considered in this study including (1) constant acceleration piston motion, (2) suddenly started flow, (3) linear acceleration piston motion, and (4) oscillatory piston motion. The solution for each case is elaborately derived, and the results of associated velocity profile and pressure gradients are presented in analytical forms.
Strategies to Identify Recognition Signals and Targets of SUMOylation
Authors: Da Silva-Ferrada Elisa , Lopitz-Otsoa Fernando , Lang Valérie , Rodríguez Manuel S. , Matthiesen Rune
Published: July 2012

SUMOylation contributes to the regulation of many essential cellular factors. Diverse techniques have been used to explore the functional consequences of protein SUMOylation. Most approaches consider the identification of sequences on substrates, adaptors, or receptors regulating the SUMO conjugation, recognition, or deconjugation. The large majority of the studied SUMOylated proteins contain the sequence [IVL]KxE. SUMOylated proteins are recognized by at least 3 types of hydrophobic SUMO-interacting motifs (SIMs) that contribute to coordinate SUMO-dependent functions. Typically, SIMs are constituted by a hydrophobic core flanked by one or two clusters of negatively charged amino acid residues. Multiple SIMs can integrate SUMO binding domains (SBDs), optimizing binding, and control over SUMO-dependent processes. Here, we present a survey of the methodologies used to study SUMO-regulated functions and provide guidelines for the identification ofcisandtranssequences controlling SUMOylation. Furthermore, an integrative analysis of known and putative SUMO substrates illustrates an updated landscape of several SUMO-regulated events. The strategies and analysis presented here should contribute to the understanding of SUMO-controlled functions and provide rational approach to identify biomarkers or choose possible targets for intervention in processes where SUMOylation plays a critical role.
The Genetics ofPTPN1and Obesity: Insights from Mouse Models of Tissue-Specific PTP1B Deficiency
Authors: Tsou Ryan C. , Bence Kendra K.
Published: July 2012

The protein tyrosine phosphatase PTP1B is a negative regulator of both insulin and leptin signaling and is involved in the control of glucose homeostasis and energy expenditure. Due to its prominent role in regulating metabolism, PTP1B is a promising therapeutic target for the treatment of human obesity and type 2 diabetes. The PTP1B protein is encoded by thePTPN1gene on human chromosome 20q13, a region that shows linkage with insulin resistance, type 2 diabetes, and obesity in human populations. In this paper, we summarize the genetics of thePTPN1locus and associations with metabolic disease. In addition, we discuss the tissue-specific functions of PTP1B as gleaned from genetic mouse models.
Assessing Vulnerability to Chronic Undernutrition among Under-Five Children in Egypt: Contextual Determinants of an Individual Consequence
Authors: Mazumdar Sumit
Published: July 2012

Nutritional outcomes remain an important development indicator and reflect a household's vulnerability to improved quality of life. Drawing upon recent household survey data from Egypt, this paper applies hierarchical models to test the effect of contextual factors on chronic undernutrition among under-five children and identifies the demographic and socioeconomic characteristics that underscore such vulnerability. Results indicate considerable neighborhood effects influencing a household’s nutritional choices. However, no significant effect could be identified for mother’s education and women’s decision-making power, but a clear positive association is evident between nutritional status and better health service utilization as well as child care and feeding practices. Focused intervention strategies need to augment household level behavioral change for these identified factors and supplement such individual efforts with targeted strategies aimed at vulnerable Egyptian communities to reduce child undernutrition.
Putting the Evidence into Preceptor Preparation
Authors: Myrick Florence , Luhanga Florence , Billay Diane , Foley Vicki , Yonge Olive
Published: July 2012

The term evidence-based practice refers to the utilization of knowledge derived from research. Nursing practice, however, is not limited to clinical practice but also encompasses nursing education. It is, therefore, equally important that teaching preparation is derived from evidence also. The purpose of this study was to examine whether an evidence-based approach to preceptor preparation influenced preceptors in a assuming that role. A qualitative method using semistructured interviews was used to collect data. A total of 29 preceptors were interviewed. Constant comparative analysis facilitated examination of the data. Findings indicate that preceptors were afforded an opportunity to participate in a preparatory process that was engaging, enriching, and critically reflective/reflexive. This study has generated empirical evidence that can (a) contribute substantively to effective preceptor preparation, (b) promote best teaching practices in the clinical setting, and (c) enhance the preceptorship experience for nursing students.
Some New Classes of Extended General Mixed Quasi‐Variational Inequalities
Authors: Noor Muhammad Aslam , Noor Khalida Inayat
Published: July 2012

We consider and study a new class of variational inequality, which is called the extended general mixed quas‐variational inequality. We use the auxiliary principle technique to study the existence of a solution of the extended general mixed quasi‐variational inequality. Several special cases are also discussed. Results proved in this paper may stimulate further research in this area.
Mental Health Services Required after Disasters: Learning from the Lasting Effects of Disasters
Authors: McFarlane A. C. , Williams Richard
Published: July 2012

Disasters test civil administrations’ and health services’ capacity to act in a flexible but well-coordinated manner because each disaster is unique and poses unusual challenges. The health services required differ markedly according to the nature of the disaster and the geographical spread of those affected. Epidemiology has shown that services need to be equipped to deal with major depressive disorder and grief, not just posttraumatic stress disorder, and not only for victims of the disaster itself but also the emergency service workers. The challenge is for specialist advisers to respect and understand the existing health care and support networks of those affected while also recognizing their limitations. In the initial aftermath of these events, a great deal of effort goes into the development of early support systems but the longer term needs of these populations are often underestimated. These services need to be structured, taking into account the pre-existing psychiatric morbidity within the community. Disasters are an opportunity for improving services for patients with posttraumatic psychopathology in general but can later be utilized for improving services for victims of more common traumas in modern society, such as accidents and interpersonal violence.
Parameter Identification Problem for the Kirchhoff‐Type Equation with Viscosity
Authors: Hwang Jinsoo
Published: July 2012

The constant parameter identification problem in the Kirchhoff‐type equation with viscosity is studied. The problem is formulated by a minimization of quadratic cost functionals by distributive measurements. The existence of optimal parameters and necessary optimality conditions for the parameters are proved.
Optimal Portfolio Estimation for Dependent Financial Returns with Generalized Empirical Likelihood
Authors: Ogata Hiroaki
Published: July 2012

This paper proposes to use the method of generalized empirical likelihood to find the optimal portfolio weights. The log-returns of assets are modeled by multivariate stationary processes rather than i.i.d. sequences. The variance of the portfolio is written by the spectral density matrix, and we seek the portfolio weights which minimize it.
Reactive Oxygen Species in the Signaling and Adaptation of Multicellular Microbial Communities
Authors: Čáp Michal , Váchová Libuše , Palková Zdena
Published: July 2012

One of the universal traits of microorganisms is their ability to form multicellular structures, the cells of which differentiate and communicate via various signaling molecules. Reactive oxygen species (ROS), and hydrogen peroxide in particular, have recently become well-established signaling molecules in higher eukaryotes, but still little is known about the regulatory functions of ROS in microbial structures. Here we summarize current knowledge on the possible roles of ROS during the development of colonies and biofilms, representatives of microbial multicellularity. InSaccharomyces cerevisiaecolonies, ROS are predicted to participate in regulatory events involved in the induction of ammonia signaling and later on in programmed cell death in the colony center. While the latter process seems to be induced by the total ROS, the former event is likely to be regulated by ROS-homeostasis, possibly H2O2-homeostasis between the cytosol and mitochondria. InCandida albicansbiofilms, the predicted signaling role of ROS is linked with quorum sensing molecule farnesol that significantly affects biofilm formation. In bacterial biofilms, ROS induce genetic variability, promote cell death in specific biofilm regions, and possibly regulate biofilm development. Thus, the number of examples suggesting ROS as signaling molecules and effectors in the development of microbial multicellularity is rapidly increasing.
Periostin as a Biomarker of the Amniotic Membrane
Authors: Dobreva Mariya P. , Lhoest Larissa , Pereira Paulo N. G. , Umans Lieve , Chuva de Sousa Lopes Susana M. , Zwijsen An
Published: July 2012

Tracing the precise developmental origin of amnion and amnion-derived stem cells is still challenging and depends chiefly on analyzing powerful genetic model amniotes like mouse. Profound understanding of the fundamental differences in amnion development in both the disc-shaped primate and human embryo and the cup-shaped mouse embryo is pivotal in particular when sampling amniotic membrane from nonprimate species for isolating candidate amniotic stem cells. The availability of molecular marker genes that are specifically expressed in the amniotic membrane and not in other extraembryonic membranes would be instrumental to validate unequivocally the starting material under investigation. So far such amniotic markers have not been reported. We postulated that bone morphogenetic protein (BMP) target genes are putative amniotic membrane markers mainly because deficiency in one of several components of the BMP signaling cascade in mice has been documented to result in defective development of the early amnion. Comparative gene expression analysis of acknowledged target genes for BMP in different extraembryonic tissues, combined within situhybridization, identifiedPeriostin (Postn)mRNA enrichment in amnion throughout gestation. In addition, we identify and propose a combination of markers as transcriptional signature for the different extraembryonic tissues in mouse.
Synthesis of Novel S‐Glucosides Containing 5‐Methylisoxazole Substituted 1,2,4‐Triazole
Authors: Chao Shujun , Wang Yingling
Published: July 2012

Nine new S‐β‐D‐glucosides containing 4‐aryl‐5‐(5‐methylisoxazol‐3‐yl)‐1,2,4‐triazol‐3‐thiols have been synthesized by the direct glycosylation of 4‐aryl‐5‐(5‐methylisoxazol‐3‐yl)‐1,2,4‐triazol‐3‐thiols with 2,3,4,6‐tetra‐O‐acetyl‐α‐D‐glucopyranosyl bromide in ethanol in the presence of potassium hydroxide followed by deacetylation using dry ammonia in dry methanol. All the compounds synthesized have been characterized by their elemental analyses and spectral data.
Tin(IV) Complexes of Schiff Base Derived from Amino Acid: Synthesis and Characteristic Spectral Studies
Authors: Aman Robina , Matela Garima
Published: July 2012

A new series of tin(IV) complexes of general formula [Sn(L‐1)(Opri)2] (1), [Sn(HL‐1)2(Opri)2] (2), [Sn(L‐2)(Opri)2] (3), [Sn(HL‐2)2(Opri)2] (4), (L is dianion of Schiff bases derived from the condensation of 2‐hydroxy‐1‐naphthaldehyde with glycine (L‐1) and Lβ‐alanine (L‐2)) was synthesized by reaction of tin(IV) tetraisopropoxide with the ligands, in appropriate stoichiometric ratios (1 : 1 and 1 : 2). This would result in the replacement of the isopropoxide group from the tin(IV) tetraisopropoxide and hydrogen(s) from ligand with the azeotropical removal of isopropanol. An attempt has been made to prove the structure of the resulting complexes on the basis of elemental analysis, IR, 1H nuclear magnetic resonance. The binding site of the ligand was identified by IR spectroscopic measurement. In these complexes, the tin(IV) centre is bonded to oxygen atom of the hydroxyl or carboxylate group. The spectra data suggest that the carboxylate group is coordinated to tin(IV) centre in monodentate manner.
Electrochemical Study of Esculetin Nitration by Digital Simulation of Cyclic Voltammograms
Authors: Khalafi Lida , Yari Mohammad , Yadaei Farzaneh , Majidzade Shabnam
Published: July 2012

The reaction of electrochemically generated o‐quinones from oxidation of esculetin as Michael acceptor with nitrite ion as nucleophile has been studied using cyclic voltammetry. The reaction mechanism is believed to be EC, including oxidation of catechol moiety of esculetin followed by Michael addition of nitrite ion. The observed homogeneous rate constants (kobs) for reactions were estimated by comparing the experimental voltammetric responses with the digitally simulated results based on the proposed mechanism. Also the effects of pH and nucleophile concentration on voltammetric behavior and the rate constants of chemical reactions were described.
Tyrosinase Inhibitory Activity, 3D QSAR, and Molecular Docking Study of 2,5‐Disubstituted‐1,3,4‐Oxadiazoles
Authors: Sawant Ramesh L. , Lanke Prashant D. , Wadekar Jyoti B.
Published: July 2012

In continuation with our research program, in search of potent enzyme tyrosinase inhibitor, a series of synthesized 2,5‐disubstituted 1,3,4‐oxadiazoles have been evaluated for enzyme tyrosinase inhibitory activity. Subsequently, 3D QSAR and docking studies were performed to find optimum structural requirements for potent enzyme tyrosinase inhibitor from this series. The synthesized 20 compounds of 2,5‐disubstituted‐1,3,4‐oxadiazole series were screened for mushroom tyrosinase inhibitory activity at various concentrations by enzyme inhibition assay. The percentage enzyme inhibition was calculated by recording absorbance at 492 nm with microplate reader. 3D QSAR and docking studies were performed using VLife MDS 3.5 software. In the series 2,5‐disubstituted‐1,3,4‐oxadiazoles enzyme tyrosinase inhibitory activity was found to be dose dependent with maximum activity for compounds 4c, 4h, 4m, and 4r. 3D QSAR and docking studies revealed that more electropositive and less bulky substituents if placed on 1,3,4‐oxadiazole nucleus may result in better tyrosinase inhibitory activity in the series.
HSP90 Inhibitor 17-AAG Selectively Eradicates Lymphoma Stem Cells
Authors: Newman Bryan , Liu Yan , Lee Hsiu-Fang , Sun Duxin , Wang Yin
Published: July 2012

Cancer stem cells (CSC; also called tumor-initiating cells) comprise tumor cell subpopulations that preserve the properties of quiescence, self-renewal, and differentiation of normal stem cells. In addition, CSCs are therapeutically important because of their key contributions toward drug resistance. The hypoxia-inducible transcription factor HIF1α is critical for CSC maintenance in mouse lymphoma. In this study, we showed that low concentrations of the HSP90 inhibitor 17-AAG eliminate lymphoma CSCs in vitro and in vivo by disrupting the transcriptional function of HIF1α, a client protein of HSP90. 17-AAG preferentially induced apoptosis and eliminated the colony formation capacity of mouse lymphoma CSCs and human acute myeloid leukemia (AML) CSCs. However, low concentrations of 17-AAG failed to eliminate highly proliferative lymphoma and AML cells (non-CSCs), in which the AKT-GSK3 signaling pathway is constitutively active. The heat shock transcription factor HSF1 is highly expressed in non-CSCs, but it was weakly expressed in lymphoma CSCs. However, siRNA-mediated attenuation of HSF1 abrogated the colony formation ability of both lymphoma and AML CSCs. This study supports the use of 17-AAG as a CSC targeting agent and, in addition, shows that HSF1 is an important target for elimination of both CSCs and non-CSCs in cancer. Cancer Res; 72(17); 4551–61. ©2012 AACR.
Strain-Specific Variation in Murine Natural Killer Gene Complex Contributes to Differences in Immunosurveillance for Urethane-Induced Lung Cancer
Authors: Kreisel Daniel , Gelman Andrew E. , Higashikubo Ryuji , Lin Xue , Vikis Haris G. , White J. Michael , Toth Kelsey A. , Deshpande Charuhas , Carreno Beatriz M. , You Ming , Taffner Samantha M. , Yokoyama Wayne M. , Bui Jack D. , Schreiber Robert D. , Krupnick Alexander S.
Published: July 2012

Non–small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide and results from a complex interaction between carcinogen exposure and inherent susceptibility. Despite its prevalence, genetic factors that predispose to the development of lung cancer remain elusive. Inbred mouse models offer a unique and clinically relevant tool to study genetic factors that contribute to lung carcinogenesis due to the development of tumors that resemble human adenocarcinoma and broad strain-specific variation in cancer incidence after carcinogen administration. Here, we set out to investigate whether strain-specific variability in tumor immunosurveillance contributes to differences in lung cancer. Using bone marrow transplantation, we determined that hematopoietic cells from lung cancer–resistant mice could significantly impede the development of cancer in a susceptible strain. Furthermore, we show that this is not due to differences in tumor-promoting inflammatory changes or variability in immunosurveillance by the adaptive immune system but results from strain-specific differences in natural killer (NK) cell cytotoxicity. Using a newly discovered congenic strain of mice, we show a previously unrecognized role for strain-specific polymorphisms in the natural killer gene complex (NKC) in immunosurveillance for carcinogen-induced lung cancer. Because polymorphisms in the NKC are highly prevalent in man, our data may explain why certain individuals without obvious risk factors develop lung cancer whereas others remain resistant to the disease despite heavy environmental carcinogen exposure. Cancer Res; 72(17); 4311–7. ©2012 AACR.
Copper Chelation Enhances Antitumor Efficacy and Systemic Delivery of Oncolytic HSV
Authors: Yoo Ji Young , Pradarelli Jason , Haseley Amy , Wojton Jeffrey , Kaka Azeem , Bratasz Anna , Alvarez-Breckenridge Christopher A. , Yu Jun-Ge , Powell Kimerly , Mazar Andrew P. , Teknos Theodoros N. , Chiocca E. Antonio , Glorioso Joseph C. , Old Matthew , Kaur Balveen
Published: July 2012

Purpose: Copper in serum supports angiogenesis and inhibits replication of wild-type HSV-1. Copper chelation is currently being investigated as an antiangiogenic and antineoplastic agent in patients diagnosed with cancer. Herpes simplex virus–derived oncolytic viruses (oHSV) are being evaluated for safety and efficacy in patients, but several host barriers limit their efficacy. Here, we tested whether copper inhibits oHSV infection and replication and whether copper chelation would augment therapeutic efficacy of oHSV.

Experimental Design: Subcutaneous and intracranial tumor-bearing mice were treated with oHSV ± ATN-224 to evaluate tumor burden and survival. Virus replication and cell killing was measured in the presence or absence of the copper chelating agent ATN-224 and in the presence or absence of copper in vitro. Microvessel density and changes in perfusion were evaluated by immunohistochemistry and dynamic contrast enhanced MRI (DCE-MRI). Serum stability of oHSV was measured in mice fed with ATN-224. Tumor-bearing mice were injected intravenously with oHSV; tumor burden and amount of virus in tumor tissue were evaluated.

Results: Combination of systemic ATN-224 and oHSV significantly reduced tumor growth and prolonged animal survival. Immunohistochemistry and DCE-MRI imaging confirmed that ATN-224 reduced oHSV-induced blood vessel density and vascular leakage. Copper at physiologically relevant concentrations inhibited oHSV replication and glioma cell killing, and this effect was rescued by ATN-224. ATN-224 increased serum stability of oHSV and enhanced the efficacy of systemic delivery.

Conclusion: This study shows that combining ATN-224 with oHSV significantly increased serum stability of oHSV and greatly enhanced its replication and antitumor efficacy. Clin Cancer Res; 18(18); 4931–41. ©2012 AACR.
BRCA2 Deep Intronic Mutation Causing Activation of a Cryptic Exon: Opening toward a New Preventive Therapeutic Strategy
Authors: Anczuków Olga , Buisson Monique , Léoné Mélanie , Coutanson Christine , Lasset Christine , Calender Alain , Sinilnikova Olga M. , Mazoyer Sylvie
Published: July 2012

Purpose: Diagnostic screening of the BRCA1/2 genes in breast cancer families is mostly done on genomic DNA. For families with a very strong family history and no mutation identified in the coding sequences or the exon–intron boundaries, BRCA1/2 transcripts' analysis is an efficient approach to uncover gene inversion and pre-mRNA splicing defaults missed by conventional DNA-based protocols.

Experimental Design: We analyzed RNA from patients of negative BRCA families by reverse transcriptase PCR and identified an insertion in one family that we characterized by sequencing and by using a minigene splicing assay. More than 2,000 additional BRCA1/2 negative families were subsequently screened for this mutation using a dedicated PCR approach.

Results: Nine families were found to harbor a BRCA2 mutant transcript containing a 95-nucleotide cryptic exon between exons 12 and 13. This cryptic exon results from a new mutation located deep into intron 12, c.6937+594T > G, which reinforces the strength of a preexisting 5′ splice site, turning it into a perfect consensus sequence. It is systematically included in transcripts produced by the mutant allele in cells from mutation carriers or produced by a mutant splicing reporter minigene. The inclusion of the cryptic exon was prevented when we cotransfected the minigene with antisense oligonucleotides complementary to the 3′ or mutated 5′ splice sites.

Conclusion: This first deep intronic BRCA mutation emphasizes the importance of analyzing RNA to provide comprehensive BRCA1/2 diagnostic tests and opens the possibility of using antisense therapy in the future as an alternative strategy for cancer prevention. Clin Cancer Res; 18(18); 4903–9. ©2012 AACR.
Killing of Kras-Mutant Colon Cancer Cells via Rac-Independent Actin Remodeling by the βGBP Cytokine, a Physiological PI3K Inhibitor Therapeutically Effective In Vivo
Authors: Mallucci Livio , Shi Dong-yun , Davies Derek , Jordan Peter , Nicol Alastair , Lotti Lavinia , Mariani-Costantini Renato , Verginelli Fabio , Wells Valerie , Zicha Daniel
Published: July 2012

Activating mutations in Kras are the most frequent mutations in human cancer. They define a subset of patients who do not respond to current therapies and for whom prognosis is poor. Oncogenic Kras has been shown to deregulate numerous signaling pathways of which the most intensively studied are the Ras/extracellular signal–regulated kinase cascade and the phosphoinositide 3-kinase (PI3K)/Akt cascade. However, to date, there are no effective targeted therapies in the clinic against Kras-mutant cancers. Here, we report that the β-galactoside–binding protein (βGBP) cytokine, a physiologic inhibitor of class I PI3Ks, is a potent activator of apoptosis in Kras-mutant colorectal cancer cells, even when coharboring mutant-activated PIK3CA. Our study unveils an elective route to intrinsic and extrinsic apoptosis, which involves the cytoskeleton. Early events are inhibition of PI3K activity and Rac-independent actin rearrangement assignable to phosphoinositide changes at the plasma membrane. Cyclin E deregulation, arrest of DNA synthesis, and checkpoint kinase 2 activation underscore events critical to the activation of an intrinsic apoptotic program. Clustering of CD95/Fas death receptors underscore events critical to the activation of extrinsic apoptosis. In nude mice, we present the first evidence that xenograft tumor development is strongly inhibited by Hu-r-βGBP. Taken together, our results open a new therapeutic opportunity to a subset of patients refractive to current treatments. This first demonstration of therapeutic efficacy against Kras-mutant colon cancer suggests that Hu-r-βGBP may also be therapeutically effective against other cancers harboring activating Ras mutations as well as PIK3CA mutations. Mol Cancer Ther; 11(9); 1884–93. ©2012 AACR.
Induction of the Transcriptional Repressor ZBTB4 in Prostate Cancer Cells by Drug-Induced Targeting of MicroRNA-17-92/106b-25 Clusters
Authors: Kim KyoungHyun , Chadalapaka Gayathri , Pathi Satya S. , Jin Un-Ho , Lee Ju-Seog , Park Yun-Yong , Cho Sung-Gook , Chintharlapalli Sudhakar , Safe Stephen
Published: July 2012

Androgen-insensitive DU145 and PC3 human prostate cancer cells express high levels of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4, and treatment of cells with methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) inhibited cell growth and downregulated Sp1, Sp3, and Sp4 expression. CDODA-Me (15 mg/kg/d) was a potent inhibitor of tumor growth in a mouse xenograft model (PC3 cells) and also decreased expression of Sp transcription factors in tumors. CDODA-Me–mediated downregulation of Sp1, Sp3, and Sp4 was due to induction of the transcriptional repressor ZBTB4, which competitively binds and displaces Sp transcription factors from GC-rich sites in Sp1-, Sp3-, Sp4-, and Sp-regulated gene promoters. ZBTB4 levels are relatively low in DU145 and PC3 cells due to suppression by miR paralogs that are members of the miR-17-92 (miR-20a/17-5p) and miR-106b-25 (miR-106b/93) clusters. Examination of publically available prostate cancer patient array data showed an inverse relationship between ZBTB4 and miRs-20a/17-5p/106b/93 expression, and increased ZBTB4 in patients with prostate cancer was a prognostic factor for increased survival. CDODA-Me induces ZBTB4 in prostate cancer cells through disruption of miR–ZBTB4 interactions, and this results in downregulation of pro-oncogenic Sp transcription factors and Sp-regulated genes. Mol Cancer Ther; 11(9); 1852–62. ©2012 AACR.
Genetic Variation That Predicts Platinum Sensitivity Reveals the Role of miR-193b* in Chemotherapeutic Susceptibility
Authors: Ziliak Dana , Gamazon Eric R. , LaCroix Bonnie , Kyung Im Hae , Wen Yujia , Huang Rong Stephanie
Published: July 2012

Platinum agents are the backbone of cancer chemotherapy. Recently, we identified and replicated the role of a single nucleotide polymorphism (SNP, rs1649942) in predicting platinum sensitivity both in vitro and in vivo. Using the CEU samples from the International HapMap Project, we found the same SNP to be a master regulator of multiple gene expression phenotypes, prompting us to investigate whether rs1649942-mediated regulation of miRNAs may in part contribute to variation in platinum sensitivity. To these ends, 60 unrelated HapMap CEU I/II samples were used for our discovery-phase study using high-throughput genome-wide miRNA and gene expression profiling. Examining the relationships among rs1649942, its gene expression targets, genome-wide miRNA expression, and cellular sensitivity to carboplatin and cisplatin, we identified 2 platinum-associated miRNAs (miR-193b* and miR-320) that inhibit the expression of 5 platinum-associated genes (CRIM1, IFIT2, OAS1, KCNMA1, and GRAMD1B). We further replicated the relationship between the expression of miR-193b*, CRIM1, IFIT2, KCNMA1, and GRAMD1B, and platinum sensitivity in a separate HapMap CEU III dataset. We then showed that overexpression of miR-193b* in a randomly selected HapMap cell line results in resistance to both carboplatin and cisplatin. This relationship was also found in 7 ovarian cancer cell lines from NCI60 dataset and confirmed in an OVCAR-3 that overexpression of miR-193b* leads to increased resistance to carboplatin. Our findings highlight a potential mechanism of action for a previously observed genotype-survival outcome association. Further examination of miR-193b* in platinum sensitivity in ovarian cancer is warranted. Mol Cancer Ther; 11(9); 2054–61. ©2012 AACR.
The Hedgehog Receptor Patched Functions in Multidrug Transport and Chemotherapy Resistance
Authors: Bidet Michel , Tomico Amandine , Martin Patrick , Guizouarn Hélène , Mollat Patrick , Mus-Veteau Isabelle
Published: July 2012

Most anticancer drugs fail to eradicate tumors, leading to the development of drug resistance and disease recurrence. The Hedgehog signaling plays a crucial role during embryonic development, but is also involved in cancer development, progression, and metastasis. The Hedgehog receptor Patched (Ptc) is a Hedgehog signaling target gene that is overexpressed in many cancer cells. Here, we show a link between Ptc and resistance to chemotherapy, and provide new insight into Ptc function. Ptc is cleared from the plasma membrane upon interaction with its ligand Hedgehog, or upon treatment of cells with the Hedgehog signaling antagonist cyclopamine. In both cases, after incubation of cells with doxorubicin, a chemotherapeutic agent that is used for the clinical management of recurrent cancers, we observed an inhibition of the efflux of doxorubicin from Hedgehog-responding fibroblasts, and an increase of doxorubicin accumulation in two different cancer cell lines that are known to express aberrant levels of Hedgehog signaling components. Using heterologous expression system, we stringently showed that the expression of human Ptc conferred resistance to growth inhibition by several drugs from which chemotherapeutic agents such as doxorubicin, methotrexate, temozolomide, and 5-fluorouracil. Resistance to doxorubicin correlated with Ptc function, as shown using mutations from Gorlin's syndrome patients in which the Ptc-mediated effect on Hedgehog signaling is lost. Our results show that Ptc is involved in drug efflux and multidrug resistance, and suggest that Ptc contributes to chemotherapy resistance of cancer cells. Mol Cancer Res; 10(11); 1496–508. ©2012 AACR.
Reasons for Quitting Smoking in Patients with First-Ever Ischemic Stroke
Authors: Sienkiewicz-Jarosz Halina , Zatorski Pawel , Ryglewicz Danuta , Bienkowski Przemyslaw
Published: July 2012

Ninety-eight cigarette smokers with ischemic stroke were recruited between December 2006 and December 2008 in an urban hospital. Smoking status and reasons for quit attempts after stroke were assessed at 3-month follow-up. 73% of patients (72/98) made at least one quit attempt between stroke onset and the follow-up visit. 47% of quit attempters (34/72) declared that stroke was the major reason for quitting. The patients reporting stroke as the major reason for quitting were more likely to be abstinent at the follow-up as compared to the patients who did not (61.8 vs. 36.8%). The study suggests that some motives for quitting smoking are associated with a higher chance for short-term abstinence in stroke patients.
Opium Could Be Considered an Independent Risk Factor for Lung Cancer: A Case-Control Study
Authors: Masjedi Mohammad Reza , Naghan Parisa Adimi , Taslimi Shervin , Yousefifard Mahmoud , Ebrahimi Seyyed Meisam , Khosravi Adnan , Karimi Shirin , Hosseini Mostafa , Mortaz Esmaeil
Published: July 2012

Background: Lung cancer is the leading cause of cancer-related death worldwide, and half of all incident lung cancers are believed to occur in the developing countries, including Iran. Objective: We investigated the association of opium with the risk of lung cancer in a case-control study. Methods: We enrolled 242 cases and 484 matched controls in this study. A questionnaire was developed, containing questions on basic demographic characteristics, as well as lifelong history of smoking cigarettes, exposure to passive smoking, opium use and alcohol consumption. For smoking cigarettes and opium and also oral opium intake frequency, duration and cumulative use were categorized into three groups: no use, low use and high use. Conditional logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). Results: Multivariate analysis in men showed that after adjusting for the effect of ethnicity, education and pack years of smoking cigarettes, smoking opium remained as a significant independent risk factor with an OR of 3.1 (95% CI 1.2–8.1). In addition, concomitant heavy smoking of cigarettes and opium dramatically increased the risk of lung cancer to an OR of 35.0 (95% CI 11.4–107.9). Conclusion: This study demonstrated that smoking opium is associated with a high risk of lung cancer as an independent risk factor.
Perception of the Postural Vertical and Falls in Older People
Authors: Menant Jasmine C. , St George Rebecca J. , Fitzpatrick Richard C. , Lord Stephen R.
Published: July 2012

Background: Research on the relationship between vestibular function and falls in older people is sparse. The perception of the postural vertical (PPV) provides an indicator measure of vestibular (otolith) function in the absence of visual input and diminished somatosensory feedback. Objective: This study examined whether impaired PPV is associated with falls in this group. Methods: One hundred and ninety-five people aged 70 plus years stood blindfolded on a motorised platform that could be tilted in the roll plane and attempted to adjust it so that their bodies were aligned to the vertical. Somatosensory feedback was minimised as the base and vertical support surfaces on the tilting platform were covered in thick soft foam rubber. PPV error from true vertical and PPV variability (°) were calculated. Participants also underwent an assessment of distal tactile sensitivity and the physiological profile assessment (PPA); fallers were defined as those who had one or more falls during a prospective 12-month follow-up period. Results: Eighty-eight participants (45%) reported falling in the follow-up year. Increased PPV error and variability were correlated with increased lateral sway in a condition of absent visual input and reduced foot somatosensory feedback (eyes closed/foam; r range = 0.16–0.20, p < 0.05) and with composite PPA fall risk scores (r range = 0.22–0.26, p < 0.05). PPV variability was a significant and independent predictor of falls after adjusting for the composite PPA scores, age and gender [adjusted RR = 1.42 (1.01–1.98)]. Conclusions: Older people with increased PPV variability are at increased risk of falls. These findings indicate that assessment of PPV may augment fall risk assessments in older people.
Quantitative Analysis of Isolation Area and Rhythm Outcome in Patients With Paroxysmal Atrial Fibrillation After Circumferential Pulmonary Vein Antrum Isolation Using the Pace-and-Ablate Technique
Authors: Kiuchi Kunihiko , Kircher Simon , Watanabe Norikazu , Gaspar Thomas , Rolf Sascha , Arya Arash , Piorkowski Christopher , Hindricks Gerhard , Sommer Philipp
Published: July 2012

Background—

We sought to determine the relationship between the size of the left atrial isolated surface area (ISA) after pulmonary vein antrum isolation for paroxysmal atrial fibrillation (AF) and rhythm outcome during a 12-month follow-up.

Methods and Results—

One hundred one consecutive patients with paroxysmal AF (mean age, 59±11 years; median [range] AF history, 36 [24–96] months; mean left atrial size, 42±6 mm) were enrolled. The ISA was defined as the ratio of the total isolated antral surface area excluding the pulmonary veins to the sum of the total isolated antral surface area and the left atrial posterior wall surface area, while considering the individual characteristics of antral anatomy. All surface areas were assessed using the NavX system. Patients were divided into 4 groups according to ISA (group I: <50%; group II: 50 to <60%; group III: 60 to <70%; group IV: ≥70%). The average ISA for all patients was 59.2±11.6%. Subgroup analysis showed that ISA was 42.8±4.2% in group I (n=23), 54.2±3.0% in group II (n=23), 64.3±3.0% in group III (n=33), and 73.9±3.6% in group IV (n=22). After a 12-month follow-up period, 70% of patients in group I, 78% in group II, 97% in group III, and 100% in group IV were free from AF and atrial macroreentrant tachycardia. There was a significant difference between groups I and III, I and IV, II and III, and II and IV but not groups I and II and groups III and IV (log-rank test
P
=0.024, 0.016, 0.037, 0.044, 0.584, and 0.500, respectively). Receiver operating characteristic curve analysis yielded an optimal cutoff value of 55% for ISA.

Conclusions—

After 12 months, a larger ISA was associated with a significantly lower AF and macroreentrant tachycardia recurrence rate. ISA≥55% may thus serve as a predictor for long-term success after pulmonary vein antrum isolation.
Direct and Indirect Involvement of MicroRNA-499 in Clinical and Experimental Cardiomyopathy
Authors: Matkovich Scot J. , Hu Yuanxin , Eschenbacher William H. , Dorn Lisa E. , Dorn Gerald W.
Published: July 2012

Rationale:

MicroRNA-499 and other members of the myomiR family regulate myosin isoforms in pressure-overload hypertrophy. miR-499 expression varies in human disease, but results of mouse cardiac miR-499 overexpression are inconsistent, either protecting against ischemic damage or aggravating cardiomyopathy after pressure overload. Likewise, there is disagreement over direct and indirect cardiac mRNAs targeted in vivo by miR-499.

Objective:

To define the associations between regulated miR-499 level in clinical and experimental heart disease and modulation of its predicted mRNA targets and to determine the consequences of increased cardiac miR-499 on direct mRNA targeting, indirect mRNA modulation, and on myocardial protein content and posttranslational modification.

Methods and Results:

miR-499 levels were increased in failing and hypertrophied human hearts and associated with decreased levels of predicted target mRNAs. Likewise, miR-499 is increased in Gq-mediated murine cardiomyopathy. Forced cardiomyocyte expression of miR-499 at levels comparable to human cardiomyopathy induced progressive murine heart failure and exacerbated cardiac remodeling after pressure overloading. Genome-wide RNA-induced silencing complex and RNA sequencing identified 67 direct, and numerous indirect, cardiac mRNA targets, including Akt and MAPKs. Myocardial proteomics identified alterations in protein phosphorylation linked to the miR-499 cardiomyopathy phenotype, including of heat shock protein 90 and protein serine/threonine phosphatase 1-α.

Conclusions:

miR-499 is increased in human and murine cardiac hypertrophy and cardiomyopathy, is sufficient to cause murine heart failure, and accelerates maladaptation to pressure overloading. The deleterious effects of miR-499 reflect the cumulative consequences of direct and indirect mRNA regulation, modulation of cardiac kinase and phosphatase pathways, and higher-order effects on posttranslational modification of myocardial proteins.
Role of Copper Transport Protein Antioxidant 1 in Angiotensin II–Induced Hypertension
Authors: Ozumi Kiyoshi , Sudhahar Varadarajan , Kim Ha Won , Chen Gin-Fu , Kohno Takashi , Finney Lydia , Vogt Stefan , McKinney Ronald D. , Ushio-Fukai Masuko , Fukai Tohru
Published: July 2012

Extracellular superoxide dismutase (SOD3) is a secretory copper enzyme involved in protecting angiotensin II (Ang II)–induced hypertension. We found previously that Ang II upregulates SOD3 expression and activity as a counterregulatory mechanism; however, underlying mechanisms are unclear. Antioxidant 1 (Atox1) is shown to act as a copper-dependent transcription factor, as well as a copper chaperone, for SOD3 in vitro, but its role in Ang II–induced hypertension in vivo is unknown. Here we show that Ang II infusion increases Atox1 expression, as well as SOD3 expression and activity, in aortas of wild-type mice, which are inhibited in mice lacking Atox1. Accordingly, Ang II increases vascular superoxide production, reduces endothelium-dependent vasodilation, and increases vasoconstriction in mesenteric arteries to a greater extent in Atox1
−/−
than in wild-type mice. This contributes to augmented hypertensive response to Ang II in Atox1
−/−
mice. In cultured vascular smooth muscle cells, Ang II promotes translocation of Atox1 to the nucleus, thereby increasing SOD3 transcription by binding to Atox1-responsive element in the SOD3 promoter. Furthermore, Ang II increases Atox1 binding to the copper exporter ATP7A, which obtains copper from Atox1, as well as translocation of ATP7A to plasma membranes, where it colocalizes with SOD3. As its consequence, Ang II decreases vascular copper levels, which is inhibited in Atox1
−/−
mice. In summary, Atox1 functions to prevent Ang II–induced endothelial dysfunction and hypercontraction in resistant vessels, as well as hypertension, in vivo by reducing extracellular superoxide levels via increasing vascular SOD3 expression and activity.
Arterial Stiffness and Wave Reflection
Authors: Russo Cesare , Jin Zhezhen , Palmieri Vittorio , Homma Shunichi , Rundek Tatjana , Elkind Mitchell S.V. , Sacco Ralph L. , Di Tullio Marco R.
Published: July 2012

Increased arterial stiffness and wave reflection have been reported in heart failure with normal ejection fraction (HFNEF) and in asymptomatic left ventricular (LV) diastolic dysfunction, a precursor of HFNEF. It is unclear whether women, who have higher frequency of HFNEF, are more vulnerable than men to the deleterious effects of arterial stiffness on LV diastolic function. We investigated, in a large community-based cohort, whether sex differences exist in the relationship among arterial stiffness, wave reflection, and LV diastolic function. Arterial stiffness and wave reflection were assessed in 983 participants from the Cardiovascular Abnormalities and Brain Lesions study using applanation tonometry. The central pulse pressure/stroke volume index, total arterial compliance, pulse pressure amplification, and augmentation index were used as parameters of arterial stiffness and wave reflection. LV diastolic function was evaluated by 2-dimensional echocardiography and tissue-Doppler imaging. Arterial stiffness and wave reflection were greater in women compared with men, independent of body size and heart rate (all
P
<0.01), and showed inverse relationships with parameters of diastolic function in both sexes. Further adjustment for cardiovascular risk factors attenuated these relationships; however, a higher central pulse pressure/stroke volume index predicted LV diastolic dysfunction in women (odds ratio, 1.54; 95% confidence intervals, 1.03 to 2.30) and men (odds ratio, 2.09; 95% confidence interval, 1.30 to 3.39), independent of other risk factors. In conclusion, in our community-based cohort study, higher arterial stiffness was associated with worse LV diastolic function in men and women. Women's higher arterial stiffness, independent of body size, may contribute to their greater susceptibility to develop HFNEF.
Renal Responses to Chronic Suppression of Central Sympathetic Outflow
Authors: Iliescu Radu , Irwin Eric D. , Georgakopoulos Dimitrios , Lohmeier Thomas E.
Published: July 2012

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as hypertension therapy for patients with resistant hypertension. However, the chronic changes in renal function associated with natural suppression of sympathetic activity are largely unknown. In normotensive dogs, we investigated the integrative cardiovascular effects of chronic baroreflex activation (2 weeks) alone and in combination with the calcium channel blocker amlodipine, which is commonly used in the treatment of resistant hypertension. During baroreflex activation alone, there were sustained decreases in mean arterial pressure (17±1 mmHg) and plasma (norepinephrine; ≈35%), with no change in plasma renin activity. Despite low pressure, sodium balance was achieved because of decreased tubular reabsorption, because glomerular filtration rate and renal blood flow decreased 10% to 20%. After 2 weeks of amlodipine, arterial pressure was also reduced 17 mmHg, but with substantial increases in norepinephrine and plasma renin activity and no change in glomerular filtration rate. In the presence of amlodipine, baroreflex activation greatly attenuated neurohormonal activation, and pressure decreased even further (by 11±2 mmHg). Moreover, during amlodipine administration, the fall in glomerular filtration rate with baroreflex activation was abolished. These findings suggest that the chronic blood pressure–lowering effects of baroreflex activation are attributed, at least in part, to sustained inhibition of renal sympathetic nerve activity and attendant decreases in sodium reabsorption before the macula densa. Tubuloglomerular feedback constriction of the afferent arterioles may account for reduced glomerular filtration rate, a response abolished by amlodipine, which dilates the preglomerular vasculature.