bluuebunny/crossref_metadata_2025 huggingface dataset:
Robust Adaptive Generalized Projective Synchronization of Chaotic Systems with Uncertain Disturbances
Authors: Jia Zhen , Deng Guangming
Published: October 2012

The generalized projective synchronization (GPS) of chaotic systems with uncertain parameter noise and external disturbance is discussed. Based on the adaptive technique, a response system is constructed, and a novel adaptive controller is designed to guarantee the GPS between the drive‐response systems, and to eliminate the effect of external disturbance and parameters noise on GPS. The conclusion is proved theoretically, and corresponding numerical simulations are provided to verify the effectiveness of the proposed method.
Trends in Prevalence and Mortality of Dementia in Elderly Hong Kong Population: Projections, Disease Burden, and Implications for Long-Term Care
Authors: Yu Ruby , Chau Pui Hing , McGhee Sarah M. , Cheung Wai Ling , Chan Kam Che , Cheung Sai Hei , Woo Jean
Published: October 2012

Background. We describe the trends in prevalence and mortality of dementia among older people in Hong Kong over time. Projections of the number of older people with dementia through 2039 and estimation of the disease burden are also included.Methods. Prevalence data were extracted from previous studies in Hong Kong. Mortality data were obtained from the Department of Health of Hong Kong. Projections of the number of people with dementia were calculated by applying the prevalence rates of dementia obtained from previous studies to Hong Kong population projections. The burden of dementia was measured by Disability-Adjusted Life Years (DALYs).Results. The number of people aged 60 and above with dementia is projected to increase by 222%, from 103,433 in 2009 to 332,688 in 2039, with a large proportion of those living in institutions. The number of deaths due to dementia among people aged 60 and above has more than doubled between 2001 and 2009. Mortality rates for dementia have also risen. In 2006, about 286,313 DALYS were lost due to dementia.Conclusions. The information presented may be used to formulate a long-term care strategy for dementia of the ageing population in Hong Kong.
The Role of Nephritis-Associated Plasmin Receptor (NAPlr) in Glomerulonephritis Associated with Streptococcal Infection
Authors: Oda Takashi , Yoshizawa Nobuyuki , Yamakami Kazuo , Sakurai Yutaka , Takechi Hanako , Yamamoto Kojiro , Oshima Naoki , Kumagai Hiroo
Published: October 2012

It is well known that glomerulonephritis can occur after streptococcal infection, which is classically referred to as acute poststreptococcal glomerulonephritis (APSGN). The pathogenic mechanism of APSGN has been described by so-called immune complex theory, which involves glomerular deposition of nephritogenic streptococcal antigen and subsequent formation of immune complexesin situand/or the deposition of circulating antigen-antibody complexes. However, the exact entity of the causative antigen has remained a matter of debate. We isolated a nephritogenic antigen for APSGN from the cytoplasmic fractions of group A streptococcus (GAS) depending on the affinity for IgG of APSGN patients. The amino acid and the nucleotide sequences of the isolated protein revealed to be highly identical to those of reported plasmin(ogen) receptor of GAS. Thus, we termed this antigen nephritis-associated plasmin receptor (NAPlr). Immunofluorescence staining of the renal biopsy tissues with anti-NAPlr antibody revealed glomerular NAPlr deposition in essentially all patients with early-phase APSGN. Furthermore, glomerular plasmin activity was detected byin situzymography in the distribution almost identical to NAPlr deposition in renal biopsy tissues of APSGN patients. These data suggest that NAPlr has a direct, nonimmunologic function as a plasmin receptor and may contribute to the pathogenesis of APSGN by maintaining plasmin activity.
Comparison of the Subgross Distribution of the Lesions in Invasive Ductal and Lobular Carcinomas of the Breast: A Large-Format Histology Study
Authors: Hofmeyer Syster , Pekár Gyula , Gere Mária , Tarján Miklós , Hellberg Dan , Tot Tibor
Published: October 2012

To compare the lesion distribution and the extent of the disease in ductal and lobular carcinomas of the breast, we studied 586 ductal and 133 lobular consecutive cancers. All cases were documented on large-format histology slides. The invasive component of ductal carcinomas was unifocal in 63.3% (371/586), multifocal in 35.5% (208/586), and diffuse in 1.2% (7/586) of the cases. The corresponding figures in the lobular group were 27.8% (37/133), 45.9% (61/586), and 26.3% (35/133), respectively. When the distribution of the in situ and invasive component in the same tumors was combined to give an aggregate pattern, the ductal carcinomas were unifocal in 41.6% (244/586), multifocal in 31.6% (185/586), and diffuse in 26.8% (157/586) of the cases. The corresponding figures in the lobular category were 15.0% (20/133), 54.2% (72/133), and 30.8% (41/133), respectively. Ductal cancers were extensive in 45.7% (268/586), lobular in 65.4% (87/133) of the cases. All these differences were statistically highly significant (). While the histological tumor type itself (ductal versus lobular) did not influence the lymph node status, multifocal and diffuse distribution of the lesions were associated with significantly increased risk of lymph node metastases in both ductal and lobular cancers.
An Optimal Approach to Study the Nonlinear Behaviour of a Rotating Electrical Machine
Authors: Herişanu Nicolae , Marinca Vasile
Published: October 2012

We introduce a novel analytical approximate technique, called Optimal Variational Method (OVM), to investigate the nonlinear behaviour of a rotating electrical machine modelled as an oscillator with cubic elastic restoring force and time variable coefficients. The proposed procedure involves the presence of some initially unknown convergence‐control parameters whose values are later optimally determined. Comparisons between the obtained results and exact ones reveal that OVM is very effective and convenient providing highly accurate results.
PHA Productivity and Yield ofRalstonia eutrophaWhen Intermittently or Continuously Fed a Mixture of Short Chain Fatty Acids
Authors: Chakraborty Panchali , Muthukumarappan Kasiviswanathan , Gibbons William R.
Published: October 2012

The research described in this present study was part of a larger effort focused on developing a dual substrate, dual fermentation process to produce Polyhydroxyalkanoate (PHA). The focus of this study was developing and optimizing a strategy for feeding a mixture of SCFAs (simulated ARF) and maximizing PHA production in a cost-effective way. Three different feeding strategies were examined in this study. The substrate evaluated in this study for the growth phase ofR. eutrophawas condensed corn solubles, a low-value byproduct of the dry-mill, corn ethanol industry. The culture was grown to high cell densities in nitrogen-supplemented condensed corn solubles media in 5 L bioreactors. The overall growth rate ofR. eutrophawas 0.2 h−1. The 20 mL ARF feeding every 3 h from 48 to 109 h strategy gave the best results in terms of PHA production. PHA productivity (0.0697 g L−1 h−1), PHA concentration (8.37 g L−1), and PHA content (39.52%) were the highest when ARF was fed every 3 h for 61 h. This study proved that condensed corn solubles can be potentially used as a growth medium to boost PHA production byR. eutrophathus reducing the overall cost of biopolymer production.
Cell Surface Remodeling by Plasmin: A New Function for an Old Enzyme
Authors: Deryugina Elena I. , Quigley James P.
Published: October 2012

Plasmin, one of the most potent and reactive serine proteases, is involved in various physiological processes, including embryo development, thrombolysis, wound healing and cancer progression. The proteolytic activity of plasmin is tightly regulated through activation of its precursor, plasminogen, only at specific times and in defined locales as well as through inhibition of active plasmin by its abundant natural inhibitors. By exploiting the plasminogen activating system and overexpressing distinct components of the plasminogen activation cascade, such as pro-uPA, uPAR and plasminogen receptors, malignant cells can enhance the generation of plasmin which in turn, modifies the tumor microenvironment to sustain cancer progression. While plasmin-mediated degradation and modification of extracellular matrix proteins, release of growth factors and cytokines from the stroma as well as activation of several matrix metalloproteinase zymogens, all have been a focus of cancer research studies for decades, the ability of plasmin to cleave transmembrane molecules and thereby to generate functionally important cleaved products which induce outside-in signal transduction, has just begun to receive sufficient attention. Herein, we highlight this relatively understudied, but important function of the plasmin enzyme as it is generatedde novoat the interface between cross-talking cancer and host cells.
Existence of Global Attractors for the Nonlinear Plate Equation with Memory Term
Authors: Niu Lifang , Zhang Jianwen
Published: October 2012

A two‐dimensional nonlinear plate equation is revisited, which arises from the model of the viscoelastic thin rectangular plate with four edges supported. We establish that the system is exponentially decayed if the memory kernel satisfies the condition of the exponential decay. Furthermore, we show the existence of the global attractor by verifying the condition (C).
Virilisation during Pregnancy in a Patient with Metastatic Colorectal Cancer
Authors: Conway F. , Jarvis S. , Thornton M.
Published: October 2012

This paper describes the case of a 25-year-old woman with virilisation occurring during pregnancy in the presence of metastatic colorectal cancer. Virilisation during pregnancy is rare. The potential causes include adrenal, foetal, or ovarian pathologies. The most common causes during pregnancy are pregnancy luteoma and hyperreactio luteinalis. The incidence of cancer during pregnancy is rare and the incidence of colorectal cancer (CRC) in pregnancy is even rarer. The presenting signs and symptoms of CRC can be confused with symptoms commonly encountered during pregnancy, thereby delaying diagnosis and commencement of treatment. Diagnosis and staging also proves more problematic in the pregnant patient as the usual modalities of colonoscopy with biopsy and imaging with CT are relatively contraindicated. Treatment is dependent on gestational age of the foetus. There is currently no agreed best practice as to the role of prophylactic oophorectomy in the prevention of metachronous ovarian metastases. Surgical and adjuvant treatments have implications for females of child-bearing age.
Genetically Encoded Libraries of Nonstandard Peptides
Authors: Kawakami Takashi , Murakami Hiroshi
Published: October 2012

The presence of a nonproteinogenic moiety in a nonstandard peptide often improves the biological properties of the peptide. Non-standard peptide libraries are therefore used to obtain valuable molecules for biological, therapeutic, and diagnostic applications. Highly diverse non-standard peptide libraries can be generated by chemically or enzymatically modifying standard peptide libraries synthesized by the ribosomal machinery, using posttranslational modifications. Alternatively, strategies for encoding non-proteinogenic amino acids into the genetic code have been developed for the direct ribosomal synthesis of non-standard peptide libraries. In the strategies for genetic code expansion, non-proteinogenic amino acids are assigned to the nonsense codons or 4-base codons in order to add these amino acids to the universal genetic code. In contrast, in the strategies for genetic code reprogramming, some proteinogenic amino acids are erased from the genetic code and non-proteinogenic amino acids are reassigned to the blank codons. Here, we discuss the generation of genetically encoded non-standard peptide libraries using these strategies and also review recent applications of these libraries to the selection of functional non-standard peptides.
Computation of the Added Masses of an Unconventional Airship
Authors: Azouz Naoufel , Chaabani Said , Lerbet Jean , Abichou Azgal
Published: October 2012

This paper presents a modelling of an unmanned airship. We are studying a quadrotor flying wing. The modelling of this airship includes an aerodynamic study. A special focus is done on the computation of the added masses. Considering that the velocity potential of the air surrounding the airship obeys the Laplace′s equation, the added masses matrix will be determined by means of the velocity potential flow theory. Typically, when the shape of the careen is quite different from that of an ellipsoid, designers in preprocessing prefer to avoid complications arising from mathematical analysis of the velocity potential. They use either complete numerical studies, or geometric approximation methods, although these methods can give relatively large differences compared to experimental measurements performed on the airship at the time of its completion. We tried to develop here as far as possible the mathematical analysis of the velocity potential flow of this unconventional shape using certain assumptions. The shape of the careen is assumed to be an elliptic cone. To retrieve the velocity potential shapes, we use the spheroconal coordinates. This leads to the Lamé′s equations. The whole system of equations governing the interaction air‐structure, including the boundary conditions, is solved in an analytical setting.
New Phase Fitted and Amplification Fitted Numerov‐Type Methods for Periodic IVPs with Two Frequencies
Authors: Fang Yonglei , You Xiong , Chen Zhaoxia
Published: October 2012

Phase fitted and amplification fitted Numerov‐type methods for periodic initial value problems with two frequencies are investigated. A one‐frequency method and a two‐frequency method are constructed. The two new methods both have algebraic order five and are dispersive of order six and dissipative of order five. The two‐dimensional absolute stability region for the one‐frequency method and the three‐dimensional absolute stability region for the two‐frequency method are plotted. Numerical experiments are reported to show the efficiency and competence of the two new methods.
Mitigation of Voltage Dip and Voltage Flickering by Multilevel D-STATCOM
Authors: Ballal M. S. , Suryawanshi H. M. , Venkateswara Reddy T.
Published: October 2012

The basic power quality problems in the distribution network are voltage sag (dip), voltage flickering, and the service interruptions. STATCOM is a Flexible AC Transmission Systems (FACTS) technology device which can independently control the flow of reactive power. This paper presents the simulation and analysis of a STATCOM for voltage dip and voltage flickering mitigation. Simulations are carried out in MATLAB/Simulink to validate the performance of the STATCOM. A comparison between the six-pulse inverter and the five-level diode-clamped inverter is carried out for the performance of 66/11 KV distribution system.
Bilateral and Simultaneous Rupture of the Triceps Tendon in a Patient without Predisposing Factors
Authors: Desai Bobby , Slish John , Allen Brandon
Published: October 2012

Tendon rupture is typically associated with predisposing features including renal failure, hyperparathyroidism, and connective tissue elastosis. We present a case in which none of these risk factors is present and in a completely healthy patient. To our knowledge, this has never been reported in the literature.
Global Fluoroquinolone Resistance Epidemiology and Implictions for Clinical Use
Authors: Dalhoff Axel
Published: October 2012

This paper on the fluoroquinolone resistance epidemiology stratifies the data according to the different prescription patterns by either primary or tertiary caregivers and by indication. Global surveillance studies demonstrate that fluoroquinolone resistance rates increased in the past years in almost all bacterial species exceptS. pneumoniaeandH. influenzae, causing community-acquired respiratory tract infections. However, 10 to 30% of these isolates harbored first-step mutations conferring low level fluoroquinolone resistance. Fluoroquinolone resistance increased in Enterobacteriaceae causing community acquired or healthcare associated urinary tract infections and intraabdominal infections, exceeding 50% in some parts of the world, particularly in Asia. One to two-thirds of Enterobacteriaceae producing extended spectrum -lactamases were fluoroquinolone resistant too. Furthermore, fluoroquinolones select for methicillin resistance inStaphylococci.Neisseria gonorrhoeaeacquired fluoroquinolone resistance rapidly; actual resistance rates are highly variable and can be as high as almost 100%, particularly in Asia, whereas resistance rates in Europe and North America range from <10% in rural areas to >30% in established sexual networks. In general, the continued increase in fluoroquinolone resistance affects patient management and necessitates changes in some guidelines, for example, treatment of urinary tract, intra-abdominal, skin and skin structure infections, and traveller’s diarrhea, or even precludes the use in indications like sexually transmitted diseases and enteric fever.
Stromal Progenitor Cells from Endogenous Adipose Tissue Contribute to Pericytes and Adipocytes That Populate the Tumor Microenvironment
Authors: Zhang Yan , Daquinag Alexes C. , Amaya-Manzanares Felipe , Sirin Olga , Tseng Chieh , Kolonin Mikhail G.
Published: October 2012

Epidemiologic studies associate cancer with obesity, but the pathophysiologic connections remain obscure. In this study, we show that obesity facilitates tumor growth in mice irrespective of concurrent diet, suggesting a direct effect of excess white adipose tissue (WAT). When transplanted into mice, adipose stromal cells (ASC) can serve as perivascular adipocyte progenitors that promote tumor growth, perhaps helping explain the obesity–cancer link. In developing this hypothesis, we showed that ASCs are expanded in obesity and that they traffic from endogenous WAT to tumors in several mouse models of cancer. Strikingly, a comparison of circulating and tumor-infiltrating cell populations in lean, and obese mice revealed that cancer induces a six-fold increase of ASC frequency in the systemic circulation. We obtained evidence that ASCs mobilized in this way can be recruited into tumors, where they can be incorporated into blood vessels as pericytes and they can differentiate into adipocytes in an obesity-dependent manner. Extending this evidence, we found that increased tumor vascularization (reflected by changes in tumor vascular morphology and a two-fold increase in vascular density) was associated with intratumoral adipocytes and elevated proliferation of neighboring malignant cells. Taken together, our results suggest that ASCs recruited from endogenous adipose tissue can be recruited by tumors to potentiate the supportive properties of the tumor microenvironment. Cancer Res; 72(20); 5198–208. ©2012 AACR.
The CRTC1-NEDD9 Signaling Axis Mediates Lung Cancer Progression Caused by LKB1 Loss
Authors: Feng Yan , Wang Ye , Wang Zuoyun , Fang Zhaoyuan , Li Fei , Gao Yijun , Liu Hongyan , Xiao Tian , Li Fuming , Zhou Yang , Zhai Qiwei , Liu Xiaolong , Sun Yihua , Bardeesy Nabeel , Wong Kwok-kin , Chen Haiquan , Xiong Zhi-qi , Ji Hongbin
Published: October 2012

Somatic mutation of the tumor suppressor gene LKB1 occurs frequently in lung cancer where it causes tumor progression and metastasis, but the underlying mechanisms remain mainly unknown. Here, we show that the oncogene NEDD9 is an important downstream mediator of lung cancer progression evoked by LKB1 loss. In de novo mouse models, RNAi-mediated silencing of Nedd9 inhibited lung tumor progression, whereas ectopic NEDD9 expression accelerated this process. Mechanistically, LKB1 negatively regulated NEDD9 transcription by promoting cytosolic translocation of CRTC1 from the nucleus. Notably, ectopic expression of either NEDD9 or CRTC1 partially reversed the inhibitory function of LKB1 on metastasis of lung cancer cells. In clinical specimens, elevated expression of NEDD9 was associated with malignant progression and metastasis. Collectively, our results decipher the mechanism through which LKB1 deficiency promotes lung cancer progression and metastasis, and provide a mechanistic rationale for therapeutic attack of these processes. Cancer Res; 72(24); 6502–11. ©2012 AACR.
EGFR/JIP-4/JNK2 Signaling Attenuates Cetuximab-Mediated Radiosensitization of Squamous Cell Carcinoma Cells
Authors: Eke Iris , Schneider Lydia , Förster Claudia , Zips Daniel , Kunz-Schughart Leoni A. , Cordes Nils
Published: October 2012

EGF receptor (EGFR) promotes tumor growth as well as radio- and chemoresistance in various human malignancies including squamous cell carcinomas (SCC). In addition to deactivation of prosurvival signaling, cetuximab-mediated EGFR targeting might concomitantly induce self-attenuating signaling bypasses. Identification of such bypass mechanisms is key to improve the efficacy of targeted approaches. Here, we show great similarity of EGFR signaling and radiation survival in cetuximab-treated SCC cells grown in a more physiologic three-dimensional extracellular matrix and as tumor xenografts in contrast to conventional monolayer cell cultures. Using phosphoproteome arrays, we observed strong induction of JNK2 phosphorylation potentially resulting from cetuximab-inhibited EGFR through c-jun-NH2-kinase (JNK)-interacting protein-4 (JIP-4), which was identified using an immunoprecipitation-mass spectrometric approach. Inhibition of this signaling bypass by JIP-4 or JNK2 knockdown or pharmacologic JNK2 inhibition enhanced cetuximab efficacy and tumor cell radiosensitivity. Our findings add new facets to EGFR signaling and indicate signaling bypass possibilities of cancer cells to improve their survival on cetuximab treatment. By deactivation of cetuximab–self-attenuating JNK2-dependent signaling, the cytotoxicity, and radiosensitizing potential of cetuximab can be augmented. Cancer Res; 73(1); 297–306. ©2012 AACR.
miR-23b Represses Proto-oncogene Src Kinase and Functions as Methylation-Silenced Tumor Suppressor with Diagnostic and Prognostic Significance in Prostate Cancer
Authors: Majid Shahana , Dar Altaf A. , Saini Sharanjot , Arora Sumit , Shahryari Varahram , Zaman Mohd Saif , Chang Inik , Yamamura Soichiro , Tanaka Yuichiro , Deng Guoren , Dahiya Rajvir
Published: October 2012

The miRNAs have great potential as biomarkers and therapeutic agents owing to their ability to control multiple genes and potential to influence cellular behavior. Here, we identified that miR-23b is a methylation-silenced tumor suppressor in prostate cancer. We showed that miR-23b expression is controlled by promoter methylation and has great promise as a diagnostic and prognostic biomarker in prostate cancer. High levels of miR-23b expression are positively correlated with higher overall and recurrence-free survival in patients with prostate cancer. Furthermore, we elucidated the tumor suppressor role of miR-23b using in vitro and in vivo models. We showed that proto-oncogene Src kinase and Akt are direct targets of miR-23b. Increased expression of miR-23b inhibited proliferation, colony formation, migration/invasion, and triggered G0–G1 cell-cycle arrest and apoptosis in prostate cancer. Overexpression of miR-23b inhibited epithelial-to-mesenchymal transition (EMT) causing a decline in mesenchymal markers Vimentin and Snail and increasing the epithelial marker, E-cadherin. Depletion of Src by RNA interference conferred similar functional effects as that of miR-23b reconstitution. miR-23b expression caused a dramatic decrease in tumor growth in nude mice and attenuated Src expression in excised tumors compared with a control miR. These findings suggest that miR-23b is a methylation-silenced tumor suppressor that may be a useful biomarker in prostate cancer. Loss of miR-23b may confer proliferative advantage and promote prostate cancer migration and invasion, and reexpression of miR-23b may contribute to the epigenetic therapy for prostate cancer. Cancer Res; 72(24); 6435–46. ©2012 AACR.
Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells
Authors: Tamada Mayumi , Suematsu Makoto , Saya Hideyuki
Published: October 2012

The M2 splice isoform of pyruvate kinase (PKM2), an enzyme that catalyzes the later step of glycolysis, is a key regulator of aerobic glycolysis (known as the Warburg effect) in cancer cells. Expression and low enzymatic activity of PKM2 confer on cancer cells the glycolytic phenotype, which promotes rapid energy production and flow of glycolytic intermediates into collateral pathways to synthesize nucleic acids, amino acids, and lipids without the accumulation of reactive oxygen species. PKM2 enzymatic activity has also been shown to be negatively regulated by the interaction with CD44 adhesion molecule, which is a cell surface marker for cancer stem cells. In addition to the glycolytic functions, nonglycolytic functions of PKM2 in cancer cells are of particular interest. PKM2 is induced translocation into the nucleus, where it activates transcription of various genes by interacting with and phosphorylating specific nuclear proteins, endowing cancer cells with a survival and growth advantage. Therefore, inhibitors and activators of PKM2 are well underway to evaluate their anticancer effects and suitability for use as novel therapeutic strategies. Clin Cancer Res; 18(20); 5554–61. ©2012 AACR.
c-Myc and Cancer Metabolism
Authors: Miller Donald M. , Thomas Shelia D. , Islam Ashraful , Muench David , Sedoris Kara
Published: October 2012

The processes of cellular growth regulation and cellular metabolism are closely interrelated. The c-Myc oncogene is a “master regulator” which controls many aspects of both of these processes. The metabolic changes which occur in transformed cells, many of which are driven by c-Myc overexpression, are necessary to support the increased need for nucleic acids, proteins, and lipids necessary for rapid cellular proliferation. At the same time, c-Myc overexpression results in coordinated changes in level of expression of gene families which result in increased cellular proliferation. This interesting duality of c-Myc effects places it in the mainstream of transformational changes and gives it a very important role in regulating the “transformed phenotype.” The effects induced by c-Myc can occur either as a “primary oncogene” which is activated by amplification or translocation or as a downstream effect of other activated oncogenes. In either case, it appears that c-Myc plays a central role in sustaining the changes which occur with transformation. Although efforts to use c-Myc as a therapeutic target have been quite frustrating, it appears that this may change in the next few years. Clin Cancer Res; 18(20); 5546–53. ©2012 AACR.
IDH1andIDH2Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives
Authors: Yang Hui , Ye Dan , Guan Kun-Liang , Xiong Yue
Published: October 2012

Genes encoding for isocitrate dehydrogenases 1 and 2, IDH1 and IDH2, are frequently mutated in multiple types of human cancer. Mutations targeting IDH1 and IDH2 result in simultaneous loss of their normal catalytic activity, the production of α-ketoglutarate (α-KG), and gain of a new function, the production of 2-hydroxyglutarate (2-HG). 2-HG is structurally similar to α-KG, and acts as an α-KG antagonist to competitively inhibit multiple α-KG–dependent dioxygenases, including both lysine histone demethylases and the ten-eleven translocation family of DNA hydroxylases. Abnormal histone and DNA methylation are emerging as a common feature of tumors with IDH1 and IDH2 mutations and may cause altered stem cell differentiation and eventual tumorigenesis. Therapeutically, unique features of IDH1 and IDH2 mutations make them good biomarkers and potential drug targets. Clin Cancer Res; 18(20); 5562–71. ©2012 AACR.
Combretastatin A-4 Phosphate Affects Tumor Vessel Volume and Size Distribution as Assessed Using MRI-Based Vessel Size Imaging
Authors: Nielsen Thomas , Bentzen Lise , Pedersen Michael , Tramm Trine , Rijken Paul F.J.W. , Bussink Johan , Horsman Michael R. , Østergaard Leif
Published: October 2012

Purpose: Combretastatin A-4 disodium phosphate (CA4P) is a promising vascular disrupting agent (VDA) in clinical trials. As CA4P acts on dividing endothelial cells, we hypothesize that CA4P affects vessels of certain sizes. The aim of this study was to evaluate the effect of CA4P by the MRI-based vessel size imaging (VSI).

Experimental Design: C3H mammary carcinomas were grown to 200 mm3 in the right rear foot of female CDF1 mice. A control group of mice received no treatment, and a treatment group had CA4P administered intraperitoneally at a dose of 250 mg/kg. VSI was conducted on a 3 Tesla MR scanner to estimate the tumor blood volume (ζ0) and mean vessel radius (R). Vascularization was also estimated histologically by endothelial and Hoechst 33342 staining.

Results: ζ 0 and R showed different spatial heterogeneity. Tumor median and quartile values of ζ0 were all significantly reduced by about 35% in the CA4P-treated group as compared with the control group, and the median and upper quartile of R were significantly increased. Histograms of ζ0 and R showed a general decrease in ζ0 following treatment, and values of R in a certain range (≈20–30 μm) were decreased in the treatment group. The drug-induced change in ζ0 was in agreement with histology and our previous dynamic contrast enhanced MRI (DCE-MRI) data.

Conclusions: Tumor blood volume and mean vessel radius showed a clear response following treatment with CA4P. VSI may prove valuable in estimation of tumor angiogenesis and prediction of response to VDAs. Clin Cancer Res; 18(23); 6469–77. ©2012 AACR.
SuperTAG Methylation-specific Digital Karyotyping Reveals Uremia-induced Epigenetic Dysregulation of Atherosclerosis-Related Genes
Authors: Zawada Adam M. , Rogacev Kyrill S. , Hummel Björn , Grün Oliver S. , Friedrich Annika , Rotter Björn , Winter Peter , Geisel Jürgen , Fliser Danilo , Heine Gunnar H.
Published: October 2012

Background—

Accelerated atherosclerosis is a hallmark of chronic kidney disease (CKD). Although the role of epigenetic dysregulation in atherosclerosis is increasingly appreciated, only a few studies focused on epigenetics in CKD-associated cardiovascular disease, virtually all of which assessed epigenetic dysregulation globally. We hypothesized that gene-specific epigenetic dysregulation in CKD exists, affecting genes pertinent to inflammation and atherosclerosis.

Methods and Results—

Ten clinically stable patients undergoing hemodialysis therapy and 10 healthy age- and sex-matched controls were recruited. Genome-wide analysis of DNA methylation was performed by SuperTAG methylation-specific digital karyotyping, in order to identify genes differentially methylated in CKD. Analysis of 27 043 436 tags revealed 4288 genomic loci with differential DNA methylation (
P
<10
–10
) between hemodialysis patients and control subjects. Annotation of UniTags to promoter databases allowed us to identify 52 candidate genes associated with cardiovascular disease and 97 candidate genes associated with immune/infection diseases. These candidate genes could be classified to distinct proatherogenic processes, including lipid metabolism and transport (eg,
HMGCR
,
SREBF1
,
LRP5
,
EPHX2
, and
FDPS
), cell proliferation and cell-cycle regulation (eg,
MIK67
,
TP53
, and
ALOX12
), angiogenesis (eg,
ANGPT2
,
ADAMTS10
, and
FLT4
), and inflammation (eg,
TNFSF10
,
LY96
,
IFNGR1
,
HSPA1A
, and
IL12RB1
).

Conclusions—

We provide a comprehensive analysis of genome-wide epigenetic alterations in CKD, identifying candidate genes associated with proatherogenic and inflammatory processes. These results may spur further research in the field of epigenetics in kidney disease and point to new therapeutic strategies in CKD-associated atherosclerotic disease.
Cardiac Structural and Sarcomere Genes Associated With Cardiomyopathy Exhibit Marked Intolerance of Genetic Variation
Authors: Pan Stephen , Caleshu Colleen A. , Dunn Kyla E. , Foti Marcia J. , Moran Maura K. , Soyinka Oretunlewa , Ashley Euan A.
Published: October 2012

Background—

The clinical significance of variants in genes associated with inherited cardiomyopathies can be difficult to determine because of uncertainty regarding population genetic variation and a surprising amount of tolerance of the genome even to loss-of-function variants. We hypothesized that genes associated with cardiomyopathy might be particularly resistant to the accumulation of genetic variation.

Methods and Results—

We analyzed the rates of single nucleotide genetic variation in all known genes from the exomes of >5000 individuals from the National Heart, Lung, and Blood Institute’s Exome Sequencing Project, as well as the rates of structural variation from the Database of Genomic Variants. Most variants were rare, with over half unique to 1 individual. Cardiomyopathy-associated genes exhibited a rate of nonsense variants, about 96.1% lower than other Mendelian disease genes. We tested the ability of
in silico
algorithms to distinguish between a set of variants in
MYBPC3
,
MYH7
, and
TNNT2
with strong evidence for pathogenicity and variants from the Exome Sequencing Project data. Algorithms based on conservation at the nucleotide level (genomic evolutionary rate profiling, PhastCons) did not perform as well as amino acid-level prediction algorithms (Polyphen-2, SIFT). Variants with strong evidence for disease causality were found in the Exome Sequencing Project data at prevalence higher than expected.

Conclusions—

Genes associated with cardiomyopathy carry very low rates of population variation. The existence in population data of variants with strong evidence for pathogenicity suggests that even for Mendelian disease genetics, a probabilistic weighting of multiple variants may be preferred over the single gene causality model.
Myocardial Tissue Characterization Using Magnetic Resonance Noncontrast T1 Mapping in Hypertrophic and Dilated Cardiomyopathy
Authors: Dass Sairia , Suttie Joseph J. , Piechnik Stefan K. , Ferreira Vanessa M. , Holloway Cameron J. , Banerjee Rajarshi , Mahmod Masliza , Cochlin Lowri , Karamitsos Theodoros D. , Robson Matthew D. , Watkins Hugh , Neubauer Stefan
Published: October 2012

Background—

Noncontrast magnetic resonance T1 mapping reflects a composite of both intra- and extracellular signal. We hypothesized that noncontrast T1 mapping can characterize the myocardium beyond that achieved by the well-established late gadolinium enhancement (LGE) technique (which detects focal fibrosis) in both hypertrophic (HCM) and dilated (DCM) cardiomyopathy, by detecting both diffuse and focal fibrosis.

Methods and Results—

Subjects underwent Cardiovascular Magnetic Resonance imaging at 3T (28 HCM, 18 DCM, and 12 normals). Matching short-axis slices were acquired for cine, T1 mapping, and LGE imaging (0.1 mmol/kg). Circumferential strain was measured in the midventricular slice, and
31
P magnetic resonance spectroscopy was acquired for the septum of the midventricular slice. Mean T1 relaxation time was increased in HCM and DCM (HCM 1209±28 ms, DCM 1225±42 ms, normal 1178±13 ms,
P
<0.05). There was a weak correlation between mean T1 and LGE (
r
=0.32,
P
<0.001). T1 values were higher in segments with LGE than in those without (HCM with LGE 1228±41 ms versus no LGE 1192±79 ms,
P
<0.01; DCM with LGE 1254±73 ms versus no LGE 1217±52 ms,
P
<0.01). However, in both HCM and DCM, even in segments unaffected by LGE, T1 values were significantly higher than normal (
P
<0.01). T1 values correlated with disease severity, being increased as wall thickness increased in HCM; conversely, in DCM, T1 values were highest in the thinnest myocardial segments. T1 values also correlated significantly with circumferential strain (
r
=0.42,
P
<0.01). Interestingly, this correlation remained statistically significant even for the slices without LGE (
r
=0.56,
P
=0.04). Finally, there was also a statistically significant negative correlation between T1 values and phosphocreatine/adenosine triphosphate ratios (
r
=−0.59,
P
<0.0001).

Conclusions—

In HCM and DCM, noncontrast T1 mapping detects underlying disease processes beyond those assessed by LGE in relatively low-risk individuals.
The Neural Correlates of Cognitive Control: Successful Remembering and Intentional Forgetting
Authors: Rizio Avery A. , Dennis Nancy A.
Published: October 2012

The ability to control how we process information by remembering that which is important and forgetting that which is irrelevant is essential to maintain accurate, up-to-date memories. As such, memory success is predicated on both successful intentional encoding and successful intentional forgetting. The current study used an item-method directed forgetting paradigm to elucidate the cognitive and neural processes that underlie both processes while also examining the relationship between them to understand how the two may work together. Results indicated that encoding-related processes in the left inferior PFC and medial-temporal lobe (MTL) contribute to subsequent memory success, whereas inhibitory processes in the right superior frontal gyrus and right inferior parietal lobe contribute to subsequent forgetting success. Furthermore, connectivity analyses found a negative correlation between activity in the right superior frontal cortex and activity in the left MTL during successful intentional forgetting but not during successful encoding, incidental forgetting, or incidental encoding. Results support the theory that intentional forgetting is mediated by inhibition-related activity in the right frontal cortex and the interaction of this activity with that of encoding-related activity in the MTL. Further support for this inhibitory-related account was found through a clear dissociation between intentional and incidental forgetting, such that intentional forgetting was associated with regions shown to support inhibition, whereas incidental forgetting was associated with regions supporting encoding.
Prediction of September–December Fire in New Caledonia (Southwestern Pacific) Using July Niño-4 Sea Surface Temperature Index
Authors: Moron Vincent , Barbero Renaud , Mangeas Morgan , Borgniet Laurent , Curt Thomas , Berti-Equille Laure
Published: October 2012

An empirical statistical scheme for predicting September–December fires in New Caledonia in the southwestern Pacific Ocean region using a cross-validated generalized linear model has been developed for the 2000–10 period. The predictor employs July sea surface temperatures (SST) recorded over the Niño-4 box (5°S–5°N, 160°–210°E), which are closely related to austral spring (September–November) rainfall anomalies across New Caledonia. The correlation between the logarithm of observed and simulated total burned areas across New Caledonia is 0.87. A decrease in the local-scale skill (median correlation between the log of observed and simulated total burned areas in a 20-km radius around a rain gauge = 0.46) around the main town (Nouméa) and its suburbs in the southwest of Grande Terre, and also in northern New Caledonia, could be associated either with a weaker climatic forcing from the Niño-4 SST index or a small-scale climatic forcing not linearly related to the El Niño–Southern Oscillation (ENSO) phenomenon. It is more likely that the decrease is tied to the influence of human-driven factors that blur the regional-scale climatic signal mostly associated with central Pacific ENSO events.
A Comparison of Tidal Conversion Parameterizations for Tidal Models
Authors: Green J. A. Mattias , Nycander Jonas
Published: October 2012

The conversion of barotropic to baroclinic tidal energy in the global abyssal ocean is calculated using three different formulations. The calculations are done both “offline,” that is, using externally given tidal currents to estimate the energy conversion, and “online,” that is, by using the formulations to parameterize linear wave drag in a prognostic tidal model. All three schemes produce globally integrated offline dissipation rates beneath 500-m depth of ~0.6–0.8 TW for the M2 constituent, but the spatial structures vary significantly between the parameterizations. Detailed investigations of the energy transfer in local areas confirm the global results: there are large differences between the schemes, although the horizontally integrated conversion rates are similar. The online simulations are evaluated by comparing the sea surface elevation with data from the TOPEX/Poseidon database, and the error is then significantly lower when using the parameterization provided by Nycander than with the other two parameterizations examined.
The Operational Generation of Continuous Winds in the Australian Region and Their Assimilation with 4DVAR
Authors: Le Marshall John , Seecamp Rolf , Xiao Yi , Gregory Paul , Jung Jim , Stienle Peter , Skinner Terry , Tingwell Chris , Le Tan
Published: October 2012

Atmospheric motion vectors (AMVs) have been generated continuously from Multifunctional Transport Satellite 1 Replacement (MTSAT-1R) radiance data (imagery) since 2005, and more recently from MTSAT-2, which are operated by the Japan Meteorological Agency (JMA). These are the primary geostationary meteorological satellites observing the western Pacific, Asia, and the Australian region. The vectors are used operationally, for analysis in the Darwin Regional Forecast Office. The near-continuous AMVs have been stringently error characterized and used in near-real-time trials to gauge their impact on operational regional numerical weather prediction (NWP), using four-dimensional variational data assimilation (4DVAR). The use of these locally generated hourly vectors (the only hourly AMV source in the region at the time) and 4DVAR has resulted in both improved temporal and spatial data coverage in the operational regional forecast domain. The beneficial impact of these data on the Bureau of Meteorology’s (Bureau’s) current operational system is described. After these trials, the hourly MTSAT AMVs were introduced into the Bureau’s National Meteorological and Oceanographic Centre’s (NMOC) operational NWP suite for use by the operational Australian Community Climate Earth System Simulator (ACCESS) regional and global models, ACCESS-R and ACCESS-G, respectively. Examples of their positive impact on both midlatitude and tropical cyclone forecasts are presented.
Effects of leaders and social power on opinion formation in complex networks
Authors: Jalili Mahdi
Published: October 2012

Social networks are inevitable parts of daily life and there has been an increasing interest in analyzing social phenomena on networked structures. Evolution of opinion formation is one of the topics that has attracted many scholars in the field. In this work we consider the influence of leaders and social power in the evolution of opinion formation. A number of central nodes with specific properties (e.g. nodes with highest degree, betweenness or vulnerability values) are taken as leaders whose opinions are kept unchanged, that is, not influenced by other agents. The leaders try to coordinate the opinions of other agents where the connection structure is considered to be preferential attachment scale-free, Watts–Strogatz small-world or Erdős–Rényi random networks. Numerical simulations show that scale-free networks provide faster consensus compared with other networks. We also study the effects of social power on the consensus time. The social power of a node is considered to be a function of its centrality. Having leaders in the network, we show that the consensus time could be significantly decreased by introducing social power. For scale-free networks, there is an optimal degree of social power in which the consensus time is minimal. These results show the appropriateness of scale-free topology in hierarchal organizations where leaders posit influence on peripheral agents.
Facet-Based Analysis of Vacation Planning Processes
Authors: Grigolon Anna , Kemperman Astrid , Timmermans Harry
Published: October 2012

This article documents the design and results of a study on vacation planning processes with a particular focus on aggregate relationships between the probability that a certain facet of the vacation decision has been decided at a particular point in time, as a function of lead time to the actual trip, life cycle characteristics, income, travel experience, and any other facet already being decided. A binary mixed logit panel model was formulated and estimated to examine the assumed relationships. The Dutch Continuous Vacation panel was used to collect the data. Results indicate that the closer to the actual date of the trip, the higher the probability of a facet being planned. Moreover, vacation facets are planned at different points in time. We also found differences in the level of planning for different life cycle groups, levels of income, and travel experience. A discussion of the limitations of the study and possible future research directions completes the article.
Composite Severity Indices Reflect Sleep Apnea Disease Burden More Comprehensively Than the Apnea‐Hypopnea Index
Authors: Balakrishnan Karthik , James Kathryn T. , Weaver Edward M.
Published: October 2012

Objective

To compare 2 composite indices of sleep apnea disease burden with the commonly used apnea‐hypopnea index with regard to baseline measurement of subjective and objective disease burden.

Study Design

Cross‐sectional study.

Setting

Tertiary academic medical center sleep laboratory.

Subjects and Methods

Patients with suspected diagnosis of sleep apnea undergoing first diagnostic polysomnography. Subjective data were collected via validated questionnaires; objective data were obtained by standardized physical examination, chart extraction, and polysomnography. Four subjective (patient‐reported) disease burden measures and 3 objective (anatomic and physiologic) disease burden measures were used for validation. Associations between composite indices or apnea‐hypopnea index and these 7 construct validation measures were compared using bootstrapped correlation coefficients.

Results

Two hundred sixteen subjects were included in the final analysis. Both composite disease burden indices showed clinically important or nearly important associations with 3 of 4 subjective validation measures and all 3 objective validation measures, whereas the apnea‐hypopnea index was associated only with the objective validation measures.

Conclusion

Composite indices of sleep apnea disease burden may capture the breadth of baseline sleep apnea disease burden, particularly subjective disease burden, better than the apnea‐hypopnea index.
The Role of Transcendence in a Holistic View of Successful Aging
Authors: McCarthy Valerie Lander , Bockweg Amanda
Published: October 2012

Background: Although successful aging is most often defined by the absence of disease and disability, older adults consistently report aging successfully even in the presence of chronic illness and functional limitations. A more holistic way of looking at old age suggests transcendence may be an important missing criterion for successful aging. Aim: Transcendence, a late life developmental process, appears to have a profound effect within the spiritual domain but is an abstract, complex, and unfamiliar concept. A clear understanding of the meaning of transcendence is necessary to explore the concept’s usefulness as a potential basis for future interventions to increase successful aging. Method: Walker and Avant’s method of concept analysis was adapted to analyze literature from philosophy, theology, developmental psychology, sociology, psychiatry, and nursing in order to gain a thorough understanding of transcendence. Results: Antecedents, attributes, referents, and consequences of transcendence were identified and then displayed in a conceptual model. A definition of transcendence in relation to successful aging was synthesized from the analysis. Conclusion: The concept analysis suggested transcendence may provide a theoretical foundation for development of potentially cost-effective, efficacious interventions to foster a sense of meaning in life, well-being, and life satisfaction. The model under development may prove useful in planning potential interventions.