bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of breaking up prolonged sitting on skeletal muscle gene expression
Authors: Latouche Celine , Jowett Jeremy B. M. , Carey Andrew L. , Bertovic David A. , Owen Neville , Dunstan David W. , Kingwell Bronwyn A.
Published: December 2012

Breaking up prolonged sitting has been beneficially associated with cardiometabolic risk markers in both observational and intervention studies. We aimed to define the acute transcriptional events induced in skeletal muscle by breaks in sedentary time. Overweight/obese adults participated in a randomized three-period, three-treatment crossover trial in an acute setting. The three 5-h interventions were performed in the postprandial state after a standardized test drink and included seated position with no activity and seated with 2-min bouts of light- or moderate-intensity treadmill walking every 20 min. Vastus lateralis biopsies were obtained in eight participants after each treatment, and gene expression was examined using microarrays validated with real-time quantitative PCR. There were 75 differentially expressed genes between the three conditions. Pathway analysis indicated the main biological functions affected were related to small-molecule biochemistry, cellular development, growth and proliferation, and carbohydrate metabolism. Interestingly, differentially expressed genes were also linked to cardiovascular disease. For example, relative to prolonged sitting, activity bouts increased expression of nicotamide N-methyltransferase, which modulates anti-inflammatory and anti-oxidative pathways and triglyceride metabolism. Activity bouts also altered expression of 10 genes involved in carbohydrate metabolism, including increased expression of dynein light chain, which may regulate translocation of the GLUT-4 glucose transporter. In addition, breaking up sedentary time reversed the effects of chronic inactivity on expression of some specific genes. This study provides insight into the muscle regulatory systems and molecular processes underlying the physiological benefits induced by interrupting prolonged sitting.
Chromothripsis and Focal Copy Number Alterations Determine Poor Outcome in Malignant Melanoma
Authors: Hirsch Daniela , Kemmerling Ralf , Davis Sean , Camps Jordi , Meltzer Paul S. , Ried Thomas , Gaiser Timo
Published: December 2012

Genetic changes during tumorigenesis are usually acquired sequentially. However, a recent study showed that in 2% to 3% of all cancers a single catastrophic event, termed chromothripsis, can lead to massive genomic rearrangements confined to one or a few chromosomes. To explore whether the degree of genomic instability and chromothripsis influences prognosis in cancer, we retrospectively applied array-comparative genomic hybridization (aCGH) to 20 malignant melanomas that showed, despite comparable conventional clinical and pathologic parameters, a profoundly different clinical course. We compared 10 patients who died of malignant melanoma 3.7 years (median, range 0.9–7.6 years) after diagnosis with 10 patients who survived malignant melanoma and had a median disease-free survival of 14.8 years (range 12.5–16.7 years; P = 0.00001). We observed a striking association between the degree of chromosomal instability, both numerical and structural, and outcome. Malignant melanomas associated with good prognosis showed only few chromosomal imbalances (mean 1.6 alterations per case), predominantly whole chromosome or chromosome arm gains and losses, whereas malignant melanomas with poor prognosis harbored significantly more chromosomal aberrations (13.9 per case; P = 0.008). Array-based CGH showed that these aberrations were mostly focal events, culminating in two cases in a pattern consistent with the phenomenon of chromothripsis, which was confirmed by paired-end sequencing. This is the first description of chromothripsis in primary malignant melanomas. Our study therefore links focal copy number alterations and chromothripsis with poor outcome in patients with malignant melanomas (P = 0.0002) and provides a genetic approach to predict outcome in malignant melanomas. Cancer Res; 73(5); 1454–60. ©2012 AACR.
p38α Inhibits Liver Fibrogenesis and Consequent Hepatocarcinogenesis by Curtailing Accumulation of Reactive Oxygen Species
Authors: Sakurai Toshiharu , Kudo Masatoshi , Umemura Atsushi , He Guobin , Elsharkawy Ahmed M. , Seki Ekihiro , Karin Michael
Published: December 2012

Most hepatocellular carcinomas (HCC) develop in the context of severe liver fibrosis and cirrhosis caused by chronic liver inflammation, which also results in accumulation of reactive oxygen species (ROS). In this study, we examined whether the stress-activated protein kinase p38α (Mapk14) controls ROS metabolism and development of fibrosis and cancer in mice given thioacetamide to induce chronic liver injury. Liver-specific p38α ablation was found to enhance ROS accumulation, which appears to be exerted through the reduced expression of antioxidant protein HSP25 (Hspb1), a mouse homolog of HSP27. Its reexpression in p38α-deficient liver prevents ROS accumulation and thioacetamide-induced fibrosis. p38α deficiency increased expression of SOX2, a marker for cancer stem cells and the liver oncoproteins c-Jun (Jun) and Gankyrin (Psmd10) and led to enhanced thioacetamide-induced hepatocarcinogenesis. The upregulation of SOX2 and c-Jun was prevented by administration of the antioxidant butylated hydroxyanisole. Intriguingly, the risk of human HCC recurrence is positively correlated with ROS accumulation in liver. Thus, p38α and its target HSP25/HSP27 appear to play a conserved and critical hepatoprotective function by curtailing ROS accumulation in liver parenchymal cells engaged in oxidative metabolism of exogenous chemicals. Augmented oxidative stress of liver parenchymal cells may explain the close relationship between liver fibrosis and hepatocarcinogenesis. Cancer Res; 73(1); 215–24. ©2012 AACR.
Interstitial Flow in a 3D Microenvironment Increases Glioma Invasion by a CXCR4-Dependent Mechanism
Authors: Munson Jennifer M. , Bellamkonda Ravi V. , Swartz Melody A.
Published: December 2012

Brain tumor invasion leads to recurrence and resistance to treatment. Glioma cells invade in distinct patterns, possibly determined by microenvironmental cues including chemokines, structural heterogeneity, and fluid flow. We hypothesized that flow originating from pressure differentials between the brain and tumor is active in glioma invasion. Using in vitro models, we show that interstitial flow promotes cell invasion in multiple glioma cell lines. Flow effects were CXCR4-dependent, because they were abrogated by CXCR4 inhibition. Furthermore, CXCR4 was activated in response to flow, which could be responsible for enhanced cell motility. Flow was seen to enhance cell polarization in the flow direction, and this flow-induced polarization could be blocked by CXCR4 inhibition or CXCL12 oversaturation in the matrix. Furthermore, using live imaging techniques in a three-dimensional flow chamber, there were more cells migrating and more cells migrating in the direction of flow. This study shows that interstitial flow is an active regulator of glioma invasion. The new mechanisms of glioma invasion that we identify here—namely, interstitial flow-enhanced motility, activation of CXCR4, and CXCL12-driven autologous chemotaxis—are significant in therapy to prevent or treat brain cancer invasion. Current treatment strategies can lead to edema and altered flow in the brain, and one popular experimental treatment in clinical trials, convection enhanced delivery, involves enhancement of flow in and around the tumor. A better understanding of how interstitial flow at the tumor margin can alter chemokine distributions, cell motility, and directed invasion offers a better understanding of treatment failure. Cancer Res; 73(5); 1536–46. ©2012 AACR.
Biologic Challenges in the Detection of Circulating Tumor Cells
Authors: Joosse Simon A. , Pantel Klaus
Published: December 2012

Carcinoma cells found in the blood of cancer patients are predictors of metastatic progression and may guide treatment decisions. Most of the current strategies for detecting circulating tumor cells (CTC) are based on the epithelial markers epithelial cell adhesion molecule and keratin; however, evidence is accumulating that in certain tumor types, these epithelial markers are downregulated during tumor cell dissemination, hampering the detection of CTCs. This short review discusses the implications of the cellular changes of tumor cells during the metastatic cascade on CTC diagnostics. Cancer Res; 73(1); 8–11. ©2012 AACR.
Molecular Pathways: Toll-like Receptors in the Tumor Microenvironment—Poor Prognosis or New Therapeutic Opportunity
Authors: Ridnour Lisa A. , Cheng Robert Y.S. , Switzer Christopher H. , Heinecke Julie L. , Ambs Stefan , Glynn Sharon , Young Howard A. , Trinchieri Giorgio , Wink David A.
Published: December 2012

Numerous reports have described Toll-like receptor (TLR) expression in the tumor microenvironment as it relates to cancer progression, as well as their involvement in inflammation. While TLRs mediate immune surveillance, clinical studies have associated TLR expression in the tumor with poor patient survival, indicating that TLR expression may affect cancer treatment and survival. This review will examine mechanisms in which TLR activation upregulates protumorigenic pathways, including the induction of inducible nitric oxide synthase (iNOS2) and COX2, which in turn increase TLR expression and promote a feed-forward loop leading to tumor progression and the development of more aggressive tumor phenotypes. These propagating loops involve cancer cell, stroma, and/or immune cell TLR expression. Because of abundant TLR expression in many human tumors, several TLR agonists are now in clinical and preclinical trials and some have shown enhanced efficacy when used as adjuvant with radiation, chemotherapy, or cancer vaccines. These findings suggest that TLR expression influences cancer biology and therapeutic response, which may involve specific interactions within the tumor microenvironment, including mediators of inflammation such as nitric oxide and the arachidonic acid signaling pathways. Clin Cancer Res; 19(6); 1340–6. ©2012 AACR.
VS-5584, a Novel and Highly Selective PI3K/mTOR Kinase Inhibitor for the Treatment of Cancer
Authors: Hart Stefan , Novotny-Diermayr Veronica , Goh Kee Chuan , Williams Meredith , Tan Yong Cheng , Ong Lai Chun , Cheong Albert , Ng Bee Kheng , Amalini Chithra , Madan Babita , Nagaraj Harish , Jayaraman Ramesh , Pasha Khalid M. , Ethirajulu Kantharaj , Chng Wee Joo , Mustafa Nurulhuda , Goh Boon Cher , Benes Cyril , McDermott Ultan , Garnett Mathew , Dymock Brian , Wood Jeanette M.
Published: December 2012

Dysregulation of the PI3K/mTOR pathway, either through amplifications, deletions, or as a direct result of mutations, has been closely linked to the development and progression of a wide range of cancers. Moreover, this pathway activation is a poor prognostic marker for many tumor types and confers resistance to various cancer therapies. Here, we describe VS-5584, a novel, low-molecular weight compound with equivalent potent activity against mTOR (IC50 = 37 nmol/L) and all class I phosphoinositide 3-kinase (PI3K) isoforms IC50: PI3Kα = 16 nmol/L; PI3Kβ = 68 nmol/L; PI3Kγ = 25 nmol/L; PI3Kδ = 42 nmol/L, without relevant activity on 400 lipid and protein kinases. VS-5584 shows robust modulation of cellular PI3K/mTOR pathways, inhibiting phosphorylation of substrates downstream of PI3K and mTORC1/2. A large human cancer cell line panel screen (436 lines) revealed broad antiproliferative sensitivity and that cells harboring mutations in PI3KCA are generally more sensitive toward VS-5584 treatment. VS-5584 exhibits favorable pharmacokinetic properties after oral dosing in mice and is well tolerated. VS-5584 induces long-lasting and dose-dependent inhibition of PI3K/mTOR signaling in tumor tissue, leading to tumor growth inhibition in various rapalog-sensitive and -resistant human xenograft models. Furthermore, VS-5584 is synergistic with an EGF receptor inhibitor in a gastric tumor model. The unique selectivity profile and favorable pharmacologic and pharmaceutical properties of VS-5584 and its efficacy in a wide range of human tumor models supports further investigations of VS-5584 in clinical trials. Mol Cancer Ther; 12(2); 151–61. ©2012 AACR.
WEE1 Kinase Inhibition Enhances the Radiation Response of Diffuse Intrinsic Pontine Gliomas
Authors: Caretti Viola , Hiddingh Lotte , Lagerweij Tonny , Schellen Pepijn , Koken Phil W. , Hulleman Esther , van Vuurden Dannis G. , Vandertop W. Peter , Kaspers Gertjan J.L. , Noske David P. , Wurdinger Thomas
Published: December 2012

Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric disease. Thus far, no therapeutic agent has proven beneficial in the treatment of this malignancy. Therefore, conventional DNA-damaging radiotherapy remains the standard treatment, providing transient neurologic improvement without improving the probability of overall survival. During radiotherapy, WEE1 kinase controls the G2 cell-cycle checkpoint, allowing for repair of irradiation (IR)-induced DNA damage. Here, we show that WEE1 kinase is one of the highest overexpressed kinases in primary DIPG tissues compared with matching non-neoplastic brain tissues. Inhibition of WEE1 by MK-1775 treatment of DIPG cells inhibited the IR-induced WEE1-mediated phosphorylation of CDC2, resulting in reduced G2–M arrest and decreased cell viability. Finally, we show that MK-1775 enhances the radiation response of E98-Fluc-mCherry DIPG mouse xenografts. Altogether, these results show that inhibition of WEE1 kinase in conjunction with radiotherapy holds potential as a therapeutic approach for the treatment of DIPG. Mol Cancer Ther; 12(2); 141–50. ©2012 AACR.
Selective Photodetection and Photodynamic Therapy for Prostate Cancer through Targeting of Proteolytic Activity
Authors: Zuluaga Maria-Fernanda , Sekkat Nawal , Gabriel Doris , van den Bergh Hubert , Lange Norbert
Published: December 2012

Frequent side effects of radical treatment modalities and the availability of novel diagnostics have raised the interest in focal therapies for localized prostate cancer. To improve the selectivity and therapeutic efficacy of such therapies, we developed a minimally invasive procedure based on a novel polymeric photosensitizer prodrug sensitive to urokinase-type plasminogen activator (uPA). The compound is inactive in its prodrug form and accumulates passively at the tumor site by the enhanced permeability and retention effect. There, the prodrug is selectively converted to its photoactive form by uPA, which is overexpressed by prostate cancer cells. Irradiation of the activated photosensitizer exerts a tumor-selective phototoxic effect. The prodrug alone (8 μmol/L) showed no toxic effect on PC-3 cells, but upon irradiation the cell viability was reduced by 90%. In vivo, after systemic administration of the prodrug, PC-3 xenografts became selectively fluorescent. This is indicative of the prodrug accumulation in the tumor and selective local enzymatic activation. Qualitative analysis of the activated compound confirmed that the enzymatic cleavage occurred selectively in the tumor, with only trace amounts in the neighboring skin or muscle. Subsequent photodynamic therapy studies showed complete tumor eradication of animals treated with light (150 J/cm2 at 665 nm) 16 hours after the injection of the prodrug (7.5 mg/kg). These promising results evidence the excellent selectivity of our prodrug with the potential to be used for both imaging and therapy for localized prostate cancer. Mol Cancer Ther; 12(3); 306–13. ©2012 AACR.
Neutralization of Prolactin Receptor Function by Monoclonal Antibody LFA102, a Novel Potential Therapeutic for the Treatment of Breast Cancer
Authors: Damiano Jason S. , Rendahl Katherine G. , Karim Christopher , Embry Millicent G. , Ghoddusi Majid , Holash Jocelyn , Fanidi Abdallah , Abrams Tinya J. , Abraham Judith A.
Published: December 2012

Numerous lines of evidence suggest that the polypeptide hormone prolactin (PRL) may contribute to breast and prostate tumorigenesis through its interactions with the prolactin receptor (PRLR). Here, we describe the biologic properties of LFA102, a humanized neutralizing monoclonal antibody directed against the extracellular domain of PRLR. This antibody was found to effectively antagonize PRL-induced signaling in breast cancer cells in vitro and in vivo and to block PRL-induced proliferation in numerous cell line models, including examples of autocrine/paracrine PRL activity. A single administration of LFA102 resulted in regression of PRL-dependent Nb2-11 tumor xenografts and significantly prolonged time to progression. Finally, LFA102 treatment significantly inhibited PRLR signaling as well as tumor growth in a carcinogen-induced, estrogen receptor-positive rat mammary cancer model as a monotherapy and enhanced the efficacy of the aromatase inhibitor letrozole when administered in combination. The biologic properties of LFA102, elucidated by the preclinical studies presented here, suggest that this antibody has the potential to be a first-in-class, effective therapeutic for the treatment of PRL-dependent cancers. Mol Cancer Ther; 12(3); 295–305. ©2012 AACR.
Emergence of an Unusual Genotype of Rotavirus in Andaman and Nicobar Islands, India
Authors: Reesu Rajesh , Bhattacharya Debdutta , Chaaithanya I.K. , Muruganandam N. , Bharadwaj A.P. , Singhania Munni , Sugunan A.P. , Vijayachari P.
Published: December 2012

Rotavirus is the most common cause of severe diarrhoea worldwide, affecting over 125 million young children every year in developing countries. The present study is a part of ongoing childhood diarrhoeal surveillance to determine the strain diversity of rotaviruses prevalent in Andaman and Nicobar Islands. From October 2010 to February 2012, 296 stool samples from children (age group 6–60 months) with gastroenteritis were obtained from different referral hospitals/primary health centres and community health centres in Andaman and Nicobar Islands. A total of 47 samples were found positive for GARV. Among these, 21 (44.7%) samples belong to G2P[4], 12 (25.5%) samples were G1P[8], 10 (21.2%) samples belong to G9P[4], 2 (4.3%) samples belong to G1P[4] and 2 (4.3%) samples had a mixed genotype. Rotavirus G2 genotype remains the most common genotype in these islands. The prevalence of G9 rotavirus reported in the present study is higher than that reported from mainland India. The results emphasize the role of the unusual serotype G9 as an epidemiologically important genotype and the need to include G9 specificity in a rotavirus vaccine.
Prevention of Chemotherapy-Induced Neutropenia with Pegfilgrastim: Pharmacokinetics and Patient Outcomes
Authors: Yang Bing-Bing , Savin Michael A. , Green Michael
Published: December 2012

Patients receiving cytotoxic chemotherapy are at risk for developing chemotherapy-induced neutropenia (CIN). Filgrastim, a recombinant granulocyte colony-stimulating factor (G-CSF) that stimulates the proliferation, differentiation and function of neutrophils, is approved for the prevention of CIN. To eliminate the burden of daily filgrastim injection, pegfilgrastim, a long-acting form of filgrastim, was developed by covalently attaching a 20-kDa polyethylene glycol molecule to filgrastim to increase molecular size and thus reduce renal elimination. Consequently, neutrophil-mediated clearance is the primary mechanism for pegfilgrastim elimination. Therefore, after a single pegfilgrastim injection following chemotherapy treatment, pegfilgrastim concentration is sustained during neutropenia and decreases with neutrophil recovery. Pegfilgrastim has received marketing authorization approval from many regions to reduce the incidence of CIN based on the similar efficacy and safety of a single injection of 6 mg of pegfilgrastim administered once per chemotherapy cycle and 10 to 11 daily injections of filgrastim at 5 µg/kg. The efficient self-regulating clearance of pegfilgrastim allows administration once per chemotherapy cycle, thereby providing a more convenient treatment regimen than filgrastim.
Stem Cells and Their Role in Renal Ischaemia Reperfusion Injury
Authors: Bagul Atul , Frost Jodie H. , Drage Martin
Published: December 2012

Background: Ischaemia-reperfusion injury (IRI) remains one of the leading causes of acute kidney injury (AKI). IRI is an underlying multifactorial pathophysiological process which affects the outcome in both native and transplanted patients. The high morbidity and mortality associated with IRI/AKI and disappointing results from current available clinical therapeutic approaches prompt further research. Stem cells (SC) are undifferentiated cells that can undergo both renewal and differentiation into one or more cell types which can possibly ameliorate IRI. Aim: To carry out a detailed literature analysis and construct a comprehensive literature review addressing the role of SC in AKI secondary to IRI. Methods: Evidence favouring the role of SC in renal IRI and evidence showing no benefits of SC in renal IRI are the two main aspects to be studied. The search strategy was based on an extensive search addressing MESH terms and free text terms. Results: The majority of studies in the field of renal IRI and stem cell therapy show substantial benefits. Conclusions: Studies were mostly conducted in small animal models, thus underscoring the need for further pre-clinical studies in larger animal models, and results should be taken with caution. SC therapy may be promising though controversy exists in the exact mechanism. Thorough scientific exploration is required to assess mechanism, safety profile, reproducibility and methods to monitor administered SC.
Mechanisms of Cyclosporine-Induced Renal Cell Apoptosis: A Systematic Review
Authors: Xiao Zheng , Shan Juan , Li Chengwen , Luo Lei , Lu Jun , Li Shengfu , Long Dan , Li Youping
Published: December 2012

Background/Aims: Chronic cyclosporine A (CsA) nephrotoxicity (CCN) is an important cause of chronic renal dysfunction with no effective clinical intervention. To further elucidate the mechanisms of renal cell apoptosis in CCN, all relevant in vivo studies on this subject were analyzed. Methods: We searched for in vivo studies on the mechanisms of CsA-induced renal cell apoptosis in Medline (1966–July 2010), Embase (1980–July 2010) and ISI (1986–July 2010). The studies were evaluated for their quality according to a set of in vivo standards, data extracted according to PICOS, and then synthesized. Results: Renal cell apoptosis was an important feature of CCN and an important factor of renal dysfunction. First, CsA could upregulate Fas/Fas ligand, downregulate Bcl-2/Bcl-XL, and increase caspase-1 and caspase-3. Second, it could induce oxidative stress and damage the antioxidant defense system. Third, it could increase endoplasmic reticulum stress protein in a dose- and time-dependent manner. Fourth, CsA could impair the urine concentration and decrease the expression of hypertonicity-induced genes. Fifth, CsA-induced renal cell apoptosis was significantly decreased by blocking the angiotensin II type 1 receptor using losartan. Conclusions: The in vivo mechanisms for CCN are more complex than those found in vitro. CsA can induce renal cell apoptosis using five pathways in vivo and activated caspases might be the ultimate intersection of these pathways and the common intracellular pathway mediating apoptosis. These data provide new potential points for intervention and need to be confirmed by further studies.
Low Serum Concentrations of Anti-Müllerian Hormone Are Common in 53 Female Childhood Cancer Survivors
Authors: Miyoshi Yoko , Ohta Hideaki , Namba Noriyuki , Tachibana Makiko , Miyamura Takako , Miyashita Emiko , Hashii Yoshiko , Oue Takaharu , Isobe Aki , Tsutsui Tateki , Kimura Tadashi , Ozono Keiichi
Published: December 2012

Background/Aims: Gonadal dysfunction is one of the major endocrinological late effects among childhood cancer survivors (CCSs). Periodic screening evaluation of gonadotropins and sex steroids has been recommended, although it remains difficult to predict gonadal function and reproductive capacity in childhood. We evaluated the effects of cancer treatments on the ovarian function of Japanese female CCSs by measuring serum levels of anti-Müllerian hormone (AMH) and gonadotropin. Methods: This was a retrospective, cross-sectional study at a single hospital. Results: Among 53 female CCSs, 28 (53%) had a decreased AMH level, while only 16 (30%) had an increased follicle-stimulating hormone (FSH) level. AMH was low in all patients with high FSH, while FSH was not elevated in 43% of patients with a low AMH level. AMH was low in 8 of 9 patients with no breast development, 11 of 14 patients with no spontaneous menstruation, and 3 of 22 patients with regular menstrual cycles. Conclusion: Measurement of AMH concentration is useful as a marker of ovarian reserve in female CCSs for detecting primary gonadal deficiency, particularly among patients without increased gonadotropin levels.
Cardiac-Specific Overexpression of Melanoma Differentiation–Associated Gene-5 Protects Mice From Lethal Viral Myocarditis
Authors: Philip Joseph , Xu Zhaohui , Bowles Neil E. , Vallejo Jesus G.
Published: December 2012

Background—

Viral myocarditis is among the most common causes of heart failure in children and young adults. The RNA helicase melanoma differentiation–associated gene-5 (MDA5) is critical for host antiviral responses against members of the
Picornaviridae
family, such as encephalomyocarditis virus (EMCV). MDA5-knockout mice are highly susceptible to EMCV infection and develop significant myocardial injury and left ventricular dysfunction. However, the mechanisms by which MDA5 signaling within cardiac myocytes contributes to the host response against viral infection have not been defined.

Methods and Results—

We generated cardiac-specific MDA5 transgenic (alpha-myosin heavy chain [αMHC]-MDA5) mice. These mice showed increased baseline cardiac expression of antiviral cytokines and increased cellular infiltration but no alterations in cardiac function and structure. αMHC-MDA5 mice were less susceptible to EMCV infection and had a significantly lower cardiac viral load compared with littermate control mice. The severity of myocarditis, prevalence of cardiac myocyte apoptosis, and cleavage of caspase 3 after EMCV infection were attenuated in αMHC-MDA5 mice. Furthermore, αMHC-MDA5 mice were protected against EMCV-induced myocardial dysfunction.

Conclusions—

Our data suggest that myocardial MDA5 may be a key molecule in protecting the heart from direct viral injury and myocardial dysfunction.
AAV9.I-1c Delivered via Direct Coronary Infusion in a Porcine Model of Heart Failure Improves Contractility and Mitigates Adverse Remodeling
Authors: Fish Kenneth M. , Ladage Dennis , Kawase Yoshiaki , Karakikes Ioannis , Jeong Dongtak , Ly Hung , Ishikawa Kiyotake , Hadri Lahouaria , Tilemann Lisa , Muller-Ehmsen Jochen , Samulski R. Jude , Kranias Evangelia G. , Hajjar Roger J.
Published: December 2012

Background—

Heart failure is characterized by impaired function and disturbed Ca
2+
homeostasis. Transgenic increases in inhibitor-1 activity have been shown to improve Ca
2
cycling and preserve cardiac performance in the failing heart. The aim of this study was to evaluate the effect of activating the inhibitor (I-1c) of protein phosphatase 1 (I-1) through gene transfer on cardiac function in a porcine model of heart failure induced by myocardial infarction.

Methods and Results—

Myocardial infarction was created by a percutaneous, permanent left anterior descending artery occlusion in Yorkshire Landrace swine (n=16). One month after myocardial infarction, pigs underwent intracoronary delivery of either recombinant adeno-associated virus type 9 carrying I-1c (n=8) or saline (n=6) as control. One month after myocardial infarction was created, animals exhibited severe heart failure demonstrated by decreased ejection fraction (46.4±7.0% versus sham 69.7±8.5%) and impaired (d
P
/d
t
)
max
and (d
P
/d
t
)
min
. Intracoronary injection of AAV9.I-1c prevented further deterioration of cardiac function and led to a decrease in scar size.

Conclusions—

In this preclinical model of heart failure, overexpression of I-1c by intracoronary in vivo gene transfer preserved cardiac function and reduced the scar size.
Predictors of New-Onset Heart Failure
Authors: Ho Jennifer E. , Lyass Asya , Lee Douglas S. , Vasan Ramachandran S. , Kannel William B. , Larson Martin G. , Levy Daniel
Published: December 2012

Background—

About one half of patients with heart failure (HF) have preserved ejection fraction (HFPEF) rather than reduced ejection fraction (HFREF). The differences in risk factors predisposing to the 2 subtypes of HF are poorly understood. We sought to identify clinical predictors of new-onset HF and to explore differences in HFPEF versus HFREF.

Methods and Results—

We studied new-onset HF cases between 1981 and 2008 in Framingham Heart Study participants, classified into HFPEF and HFREF (ejection fraction >45% versus ≤45%). We used Cox multivariable regression to examine predictors of 8-year risk of incident HF and competing-risks analysis to identify predictors that differed between HFPEF and HFREF. Among 6340 participants (60±12 years) with 97 808 person-years of follow-up, 512 developed incident HF. Of 457 participants with left ventricular ejection fraction evaluation at the time of HF diagnosis, 196 (43%) were classified as HFPEF and 261 (56%) as HFREF. Fourteen predictors of overall HF were identified. Older age, diabetes mellitus, and a history of valvular disease predicted both types of HF (
P
≤0.0025 for all). Higher body mass index, smoking, and atrial fibrillation predicted HFPEF only, whereas male sex, higher total cholesterol, higher heart rate, hypertension, cardiovascular disease, left ventricular hypertrophy, and left bundle-branch block predicted risk of HFREF.

Conclusions—

Although multiple risk factors preceded overall HF, distinct clusters of risk factors determine risk for new-onset HFPEF versus HFREF. This knowledge may enable the design of clinical trials of targeted prevention and the introduction of therapeutic strategies for prevention of HF and its 2 major subtypes.
Increased Oxidative Stress in the Nucleus Caused by Nox4 Mediates Oxidation of HDAC4 and Cardiac Hypertrophy
Authors: Matsushima Shouji , Kuroda Junya , Ago Tetsuro , Zhai Peiyong , Park Ji Yeon , Xie Lai-Hua , Tian Bin , Sadoshima Junichi
Published: December 2012

Rationale:

Oxidation of cysteine residues in class II histone deacetylases (HDACs), including HDAC4, causes nuclear exit, thereby inducing cardiac hypertrophy. The cellular source of reactive oxygen species responsible for oxidation of HDAC4 remains unknown.

Objective:

We investigated whether nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4), a major nicotinamide adenine dinucleotide phosphate oxidase, mediates cysteine oxidation of HDAC4.

Methods and Results:

Phenylephrine (100 μmol/L), an α1 adrenergic agonist, induced upregulation of Nox4 (1.5-fold;
P
<0.05) within 5 minutes, accompanied by increases in O
2
−
(3.5-fold;
P
<0.01) from the nuclear membrane and nuclear exit of HDAC4 in cardiomyocytes. Knockdown of Nox4, but not Nox2, attenuated O
2
−
production in the nucleus and prevented phenylephrine-induced oxidation and nuclear exit of HDAC4. After continuous infusion of phenylephrine (20 mg/kg per day) for 14 days, wild-type and cardiac-specific Nox4 knockout mice exhibited similar aortic pressures. Left ventricular weight/tibial length (5.7±0.2 versus 6.4±0.2 mg/mm;
P
<0.05) and cardiomyocytes cross-sectional area (223±13 versus 258±12 μm
2
;
P
<0.05) were significantly smaller in cardiac-specific Nox4 knockout than in wild-type mice. Nuclear O
2
−
production in the heart was significantly lower in cardiac-specific Nox4 knockout than in wild-type mice (4116±314 versus 7057±1710 relative light unit;
P
<0.05), and cysteine oxidation of HDAC4 was decreased. HDAC4 oxidation and cardiac hypertrophy were also attenuated in cardiac-specific Nox4 knockout mice 2 weeks after transverse aortic constriction.

Conclusions:

Nox4 plays an essential role in mediating cysteine oxidation and nuclear exit of HDAC4, thereby mediating cardiac hypertrophy in response to phenylephrine and pressure overload.
Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Trial
Authors: Dans Antonio L. , Connolly Stuart J. , Wallentin Lars , Yang Sean , Nakamya Juliet , Brueckmann Martina , Ezekowitz Michael , Oldgren Jonas , Eikelboom John W. , Reilly Paul A. , Yusuf Salim
Published: December 2012

Background—

The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial showed that dabigatran etexilate 150 mg BID was superior and dabigatran etexilate 110 mg BID was noninferior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation. In this subgroup analysis, we assess the efficacy and safety of dabigatran in patients who did and did not receive concomitant antiplatelets.

Methods and Results—

All comparisons used a Cox proportional hazards model with adjustments made for risk factors for bleeding. A time-dependent analysis was performed when comparing patients with concomitant antiplatelets with those without. Of 18 113 patients, 6952 (38.4%) received concomitant aspirin or clopidogrel at some time during the study. Dabigatran etexilate 110 mg BID was noninferior to warfarin in reducing stroke and systemic embolism, whether patients received antiplatelets (hazard ratio [HR], 0.93; 95% confidence interval [95% CI], 0.70–1.25) or not (HR, 0.87; 95% CI, 0.66–1.15; interaction
P
=0.738). There were fewer major bleeds than warfarin in both subgroups (HR, 0.82; 95% CI, 0.67–1.00 for patients who used antiplatelets; HR, 0.79; 95% CI, 0.64–0.96 for patients who did not; interaction
P
=0.794). Dabigatran etexilate 150 mg BID reduced the primary outcome of stroke and systemic embolism in comparison with warfarin. This effect seemed attenuated among patients who used antiplatelets (HR, 0.80; 95% CI, 0.59–1.08) in comparison with those who did not (HR, 0.52; 95% CI, 0.38–0.72;
P
for interaction=0.058). Major bleeding was similar to warfarin regardless of antiplatelet use (HR, 0.93; 95% CI, 0.76–1.12 for patients who used antiplatelets; HR, 0.94; 95% CI, 0.78–1.15 for patients who did not;
P
for interaction=0.875). In the time-dependent analysis, concomitant use of a single antiplatelet seemed to increase the risk of major bleeding (HR, 1.60; 95% CI, 1.42–1.82). Dual antiplatelet seemed to increased this even more (HR, 2.31; 95% CI, 1.79–2.98). The absolute risks were lowest on dabigatran etexilate 110 mg BID in comparison with dabigatran etexilate 150 mg BID or warfarin.

Conclusions—

Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE-LY without affecting the advantages of dabigatran over warfarin. Choosing between dabigatran etexilate 110 mg BID and dabigatran etexilate 150 mg BID requires a careful assessment of characteristics that influence the balance between benefit and harm.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
. Unique identifier: NCT00262600.
Online Learning with (Multiple) Kernels: A Review
Authors: Diethe Tom , Girolami Mark
Published: December 2012

This review examines kernel methods for online learning, in particular, multiclass classification. We examine margin-based approaches, stemming from Rosenblatt's original perceptron algorithm, as well as nonparametric probabilistic approaches that are based on the popular gaussian process framework. We also examine approaches to online learning that use combinations of kernels—online multiple kernel learning. We present empirical validation of a wide range of methods on a protein fold recognition data set, where different biological feature types are available, and two object recognition data sets, Caltech101 and Caltech256, where multiple feature spaces are available in terms of different image feature extraction methods.
Sufficient Dimension Reduction via Squared-Loss Mutual Information Estimation
Authors: Suzuki Taiji , Sugiyama Masashi
Published: December 2012

The goal of sufficient dimension reduction in supervised learning is to find the low-dimensional subspace of input features that contains all of the information about the output values that the input features possess. In this letter, we propose a novel sufficient dimension-reduction method using a squared-loss variant of mutual information as a dependency measure. We apply a density-ratio estimator for approximating squared-loss mutual information that is formulated as a minimum contrast estimator on parametric or nonparametric models. Since cross-validation is available for choosing an appropriate model, our method does not require any prespecified structure on the underlying distributions. We elucidate the asymptotic bias of our estimator on parametric models and the asymptotic convergence rate on nonparametric models. The convergence analysis utilizes the uniform tail-bound of a U-process, and the convergence rate is characterized by the bracketing entropy of the model. We then develop a natural gradient algorithm on the Grassmann manifold for sufficient subspace search. The analytic formula of our estimator allows us to compute the gradient efficiently. Numerical experiments show that the proposed method compares favorably with existing dimension-reduction approaches on artificial and benchmark data sets.
Movement Duration, Fitts's Law, and an Infinite-Horizon Optimal Feedback Control Model for Biological Motor Systems
Authors: Qian Ning , Jiang Yu , Jiang Zhong-Ping , Mazzoni Pietro
Published: December 2012

Optimization models explain many aspects of biological goal-directed movements. However, most such models use a finite-horizon formulation, which requires a prefixed movement duration to define a cost function and solve the optimization problem. To predict movement duration, these models have to be run multiple times with different prefixed durations until an appropriate duration is found by trial and error. The constrained minimum time model directly predicts movement duration; however, it does not consider sensory feedback and is thus applicable only to open-loop movements. To address these problems, we analyzed and simulated an infinite-horizon optimal feedback control model, with linear plants, that contains both control-dependent and control-independent noise and optimizes steady-state accuracy and energetic costs per unit time. The model applies the steady-state estimator and controller continuously to guide an effector to, and keep it at, target position. As such, it integrates movement control and posture maintenance without artificially dividing them with a precise, prefixed time boundary. Movement pace is determined by the model parameters, and the duration is an emergent property with trial-to-trial variability. By considering the mean duration, we derived both the log and power forms of Fitts's law as different approximations of the model. Moreover, the model reproduces typically observed velocity profiles and occasional transient overshoots. For unbiased sensory feedback, the effector reaches the target without bias, in contrast to finite-horizon models that systematically undershoot target when energetic cost is considered. Finally, the model does not involve backward and forward sweeps in time, its stability is easily checked, and the same solution applies to movements of different initial conditions and distances. We argue that biological systems could use steady-state solutions as default control mechanisms and might seek additional optimization of transient costs when justified or demanded by task or context.
The Deterrent Effect of the Castle Doctrine Law on Burglary in Texas
Authors: Ren Ling , Zhang Yan , Zhao Jihong Solomon
Published: December 2012

From 2005 through 2008, 23 states across the nation have enacted laws generally referred to as “castle doctrine” laws or “stand your ground” laws. A castle doctrine law gives a homeowner the legal right to use force (even deadly force) to defend himself or herself and the family against an intruder. No study, however, has been conducted to evaluate its deterrent effects. The State of Texas enacted its castle doctrine law on September 1, 2007, and the subsequent Joe Horn shooting incident in Houston in November, 2007, served to publicize the Texas law to a great extent. The purpose of this study is to evaluate the deterrent effect of the Texas castle doctrine law and the subsequent Horn shooting on burglary in the two largest cities in Texas, Houston and Dallas. Daily data of residential and business burglary, over the period from January 1, 2007, to August 31, 2008, were obtained from the Houston Police Department and the Dallas Police Department. Interrupted time-series designs were employed in the study to analyze the intervention effects. The findings reported suggest a place-conditioned deterrent effect of the law and the Horn shooting; both residential and business burglaries were reduced significantly after the shooting incident in Houston, but not in Dallas.
Pathways From Middle School to College
Authors: Ng Jennifer , Wolf-Wendel Lisa , Lombardi Karen
Published: December 2012

This study is based on a 2-year evaluation of the Pathways Partnership, a precollege preparation program involving one school district, multiple colleges and universities, and several major businesses in a Midwestern metropolitan area. The week-long summer program cultivates youth leadership and the exploration of higher education through various student activities. The program also involves parents in an orientation at the beginning of the week and a graduation ceremony at its culmination, and it sponsors workshops on college choice and access for teachers in the district throughout the academic year. Through quantitative and qualitative methods we conclude that a program like Pathways has a positive effect on the academic self-efficacy and college aspirations of urban youth. Factors useful in predicting the likelihood with which urban middle school students hold postsecondary aspirations include peer norms, parental involvement, and academic self-efficacy. Our study contributes to the need for systematically derived research on precollege preparation programs and their effectiveness, and it also provides data and insights to promote the development of such partnerships in other interested communities.
Gifted Education
Authors: Yeung Ryan
Published: December 2012

This article looks at the issue of gifted and talented education from the perspective of public policy. It asserts that the underachievement of gifted children is a national concern, as these children may someday benefit society in ways that are disproportionate to their share of the population. Perhaps more importantly, it concludes that gifted education need not be inequitable. In fact, in the current state of the affairs of the United States, I find tremendous variation in the resources districts receive from the state that go toward gifted education. The state is particularly important as it has the power to reduce inequalities between districts that are the result of wealth and other factors. Rather than exacerbating inequality, a larger distribution of the gifted and talented resources serves to ensure gifted children in both poor and rich districts have an opportunity to maximize their potential.
Additional Validity Evidence and Across-Group Equivalency of the HOPE Teacher Rating Scale
Authors: Peters Scott J. , Gentry Marcia
Published: December 2012

The HOPE Scale was developed to identify academic and social components of giftedness and talent in elementary-aged students with particular attention to students from low-income and/or culturally diverse families. Based on previous findings, additional research was conducted on revisions made to the HOPE Scale. Items were added, and 71 teachers completed the HOPE Scale on 1,700 diverse students. The HOPE Scale was evaluated for differential item and test functioning with regard to gender, ethnic/racial, and income groups. Differential item functioning was not found with ethnic/racial or income group membership, but it existed for gender. HOPE Scale scores were also compared with achievement test scores to contribute criterion-related validity information. Results indicate that HOPE Scale scores account for approximately 52% to 58% of achievement test scores.
Homeschooling the Gifted
Authors: Jolly Jennifer L. , Matthews Michael S. , Nester Jonathan
Published: December 2012

Homeschooling has witnessed a dramatic growth over the past decade. Included in this population are gifted and talented students, yet despite this growth there has been no appreciable increase in the research literature. To better understand the gifted homeschooling family, researchers interviewed 13 parents of homeschooled children their parents identified as being gifted. Four major themes emerged from the data: (a) parents know best, (b) isolation, (c) challenges, and (d) family roles. Findings reveal that these parents decided to homeschool only after numerous attempts to work in collaboration with the public school and that the mothers bore the primary burden of responsibility for homeschooling in these families. Though the move to homeschooling alleviated many of the issues experienced in public school, it brought a different set of challenges to these families. This exploratory study establishes a better understanding of why parents of gifted children ultimately decide to homeschool.
Eyes-On Training and Radiological Expertise
Authors: Beck Melissa R. , Martin Benjamin A. , Smitherman Emily , Gaschen Lorrie
Published: December 2012

Objective:

Our aim was to examine the specificity of the effects of acquiring expertise on visual working memory (VWM) and the degree to which higher levels of experience within the domain of expertise are associated with more efficient use of VWM.

Background:

Previous research is inconsistent on whether expertise effects are specific to the area of expertise or generalize to other tasks that also involve the same cognitive processes. It is also unclear whether more training and/or experience will lead to continued improvement on domain-relevant tasks or whether a plateau could be reached.

Method:

In Experiment 1, veterinary medicine students completed a one-shot visual change detection task. In Experiment 2, veterinarians completed a flicker change detection task. Both experiments involved stimuli specific to the domain of radiology and general stimuli.

Results:

In Experiment 1, veterinary medicine students who had completed an “eyes-on” radiological training demonstrated a domain-specific effect in which performance was better on the domain-specific stimuli than on the domain-general stimuli. In Experiment 2, veterinarians again showed a domain-specific effect, but performance was unrelated to the amount of experience veterinarians had accumulated.

Conclusion:

The effect of experience is domain specific and occurs during the first few years of training, after which a plateau is reached.

Application:

VWM training in one domain may not lead to improved performance on other VWM tasks. In acquiring expertise, eyes-on training is important initially, but continued experience may not be associated with further improvements in the efficiency of VWM.