bluuebunny/crossref_metadata_2025 huggingface dataset:
Corroles programmed for regioselective cycloaddition chemistry — synthesis of a bisadduct with C60-fullerene
Authors: Li Chengjie , Fechtel Martin , Feng Yaqing , Kräutler Bernhard
Published: May 2012

A symmetrical β,β′-tetrasulfoleno-corrole is described here as an excellent and selective precursor to highly reactive corrole-β,β′-dienes, opening a selective route to specific β,β′-functionalized corroles via cycloaddition chemistry. The β,β′-tetrasulfoleno-corrole was prepared by acid catalyzed condensation of tolylaldehyde and a β,β′-disulfoleno-dipyrromethane, which was obtained by standard procedures. Crystalline deep green β,β′-tetrasulfoleno-corrole was isolated in 8–10% yield. Thermolysis of the corrole at 140 °C and in presence of an excess of C60 -fullerene gave a difullereno-corrole selectively (> 80% yield). The spectroscopic data indicated attachment of the two fullerene units at the "western," directly connected pyrrole rings. The tetrasulfoleno-corrole thus showed a remarkable preference for loss of sulphur dioxide and subsequent cycloaddition at the two "western" rings. In the difullereno-adduct, two sulfolene groups in the remaining "eastern" β,β″-disulfoleno-pyrroles still are available as "caged dienes" for further thermal diene formation, and attachment of additional groups via [4 + 2]-cycloaddition reactions.
Conduction and refractory disorders in the diabetic atrium
Authors: Watanabe Masaya , Yokoshiki Hisashi , Mitsuyama Hirofumi , Mizukami Kazuya , Ono Taisuke , Tsutsui Hiroyuki
Published: May 2012

Diabetes mellitus (DM) is an independent risk of atrial fibrillation. However, its arrhythmogenic substrates remain unclear. This study sought to examine the precise propagation and the spatiotemporal dispersion of the action potential (AP) in the diabetic atrium. DM was induced by streptozotocin (65 mg/kg) in 8-wk-old male Wister rats. Optical mapping and histological analysis were performed in the right atrium (RA) from control ( n = 26) and DM ( n = 27) rats after 16 wk. Rate-dependent alterations of conduction velocity (CV) and its heterogeneity and the spatial distribution of AP were measured in RA using optical mapping. The duration of atrial tachyarrhythmia (AT) induced by rapid atrial stimulation was longer in DM (2.4 ± 0.6 vs. 0.9 ± 0.3 s, P < 0.05). CV was decreased, and its heterogeneity was greater in DM than control. Average action potential duration of 80% repolarization (APD80) at pacing cycle length (PCL) of 200 ms from four areas within the RA was prolonged (53 ± 2 vs. 40 ± 3 ms, P < 0.01), and the coefficient of variation of APD80 was greater in DM than control (0.20 ± 0.02 vs. 0.15 ± 0.01%, P < 0.05). The ratio of APD80 at PCL shorter than 200 ms to that at 200 ms was smaller ( P < 0.001), and the incidence of APD alternans was higher in DM than control (100 vs. 0%, P < 0.001). Interstitial fibrosis was greater and connexin 40 expression was lower in DM than control. The remodeling of the diabetic atrium was characterized as follows: greater vulnerability to AT, increased conduction slowing and its heterogeneity, the prolongation of APD, the increase in spatial dispersion and frequency-dependent shortening of APD, and increased incidence of APD alternans.
Cardiac mTOR protects the heart against ischemia-reperfusion injury
Authors: Aoyagi Toshinori , Kusakari Yoichiro , Xiao Chun-Yang , Inouye Brendan T. , Takahashi Masaya , Scherrer-Crosbie Marielle , Rosenzweig Anthony , Hara Kenta , Matsui Takashi
Published: May 2012

Cardiac mammalian target of rapamycin (mTOR) is necessary and sufficient to prevent cardiac dysfunction in pathological hypertrophy. However, the role of cardiac mTOR in heart failure after ischemic injury remains undefined. To address this question, we used transgenic (Tg) mice with cardiac-specific overexpression of mTOR (mTOR-Tg mice) to study ischemia-reperfusion (I/R) injury in two animal models: 1) in vivo I/R injury with transient coronary artery ligation and 2) ex vivo I/R injury in Langendorff-perfused hearts with transient global ischemia. At 28 days after I/R, mortality was lower in mTOR-Tg mice than littermate control mice [wild-type (WT) mice]. Echocardiography and MRI demonstrated that global cardiac function in mTOR-Tg mice was preserved, whereas WT mice exhibited significant cardiac dysfunction. Masson's trichrome staining showed that 28 days after I/R, the area of interstitial fibrosis was smaller in mTOR-Tg mice compared with WT mice, suggesting that adverse left ventricular remodeling is inhibited in mTOR-Tg mice. In the ex vivo I/R model, mTOR-Tg hearts demonstrated improved functional recovery compared with WT hearts. Perfusion with Evans blue after ex vivo I/R yielded less staining in mTOR-Tg hearts than WT hearts, indicating that mTOR overexpression inhibited necrosis during I/R injury. Expression of proinflammatory cytokines, including IL-6 and TNF-α, in mTOR-Tg hearts was lower than in WT hearts. Consistent with this, IL-6 in the effluent post-I/R injury was lower in mTOR-Tg hearts than in WT hearts. These findings suggest that cardiac mTOR overexpression in the heart is sufficient to provide substantial cardioprotection against I/R injury and suppress the inflammatory response.
Left ventricular endocardial or triventricular pacing to optimize cardiac resynchronization therapy in a chronic canine model of ischemic heart failure
Authors: Bordachar Pierre , Grenz Nathan , Jais Pierre , Ritter Philippe , Leclercq Christophe , Morgan John M. , Gras Daniel , Yang Ping
Published: May 2012

Cardiac resynchronization therapy (CRT) is a proven treatment for heart failure but ∼30% of patients appear to not benefit from the therapy. Left ventricular (LV) endocardial and multisite epicardial [triventricular (TriV)] pacing have been proposed as alternatives to traditional LV transvenous epicardial pacing, but no study has directly compared the hemodynamic effects of these approaches. Left bundle branch block ablation and repeated microembolizations were performed in dogs to induce electrical dysynchrony and to reduce LV ejection fraction to <35%. LVdP/d tmax and other hemodynamic indexes were measured with a conductance catheter during LV epicardial, LV endocardial, biventricular (BiV) epicardial, BiV endocardial, and TriV pacing performed at three atrioventricular delays. LV endocardial pacing was obtained with a clinically available pacing system. The optimal site was defined as the site that increased dP/d tmax by the largest percentage. Implantation of the endocardial lead was feasible in all canines ( n = 8) without increased mitral regurgitation seen with transesophageal echocardiography and with full access to the different LV endocardial pacing sites. BiV endocardial pacing increased dP/d tmax more than BiV epicardial and TriV pacing on average ( P < 0.01) and at the optimal site ( P < 0.01). There were no significant differences between BiV epicardial and TriV pacing. BiV endocardial pacing was superior to BiV epicardial and to TriV pacing in terms of acute hemodynamic response. Further investigation is needed to confirm the chronic benefit of this approach in humans.
Differential modulation of surfactant protein D under acute and persistent hypoxia in acute lung injury
Authors: Sakamoto Koji , Hashimoto Naozumi , Kondoh Yasuhiro , Imaizumi Kazuyoshi , Aoyama Daisuke , Kohnoh Takashi , Kusunose Masaaki , Kimura Motohiro , Kawabe Tsutomu , Taniguchi Hiroyuki , Hasegawa Yoshinori
Published: May 2012

Hypoxia contributes to the development of fibrosis with epithelial-mesenchymal transition (EMT) via stimulation of hypoxia-inducible factor 1α (HIF-1α) and de novo twist expression. Although hypoxemia is associated with increasing levels of surfactant protein D (SP-D) in acute lung injury (ALI), the longitudinal effects of hypoxia on SP-D expression in lung tissue injury/fibrosis have not been fully evaluated. Here, the involvement of hypoxia and SP-D modulation was evaluated in a model of bleomycin-induced lung injury. We also investigated the molecular mechanisms by which hypoxia might modulate SP-D expression in alveolar cells, by using a doxycycline (Dox)-dependent HIF-1α expression system. Tissue hypoxia and altered SP-D levels were present in bleomycin-induced fibrotic lesions. Acute hypoxia induced SP-D expression, supported by the finding that Dox-induced expression of HIF-1α increased SP-D expression. In contrast, persistent hypoxia repressed SP-D expression coupled with an EMT phenotype and twist expression. Long-term expression of HIF-1α caused SP-D repression with twist expression. Ectopic twist expression repressed SP-D expression. The longitudinal observation of hypoxia and SP-D levels in ALI in vivo was supported by the finding that HIF-1α expression stabilized by acute hypoxia induced increasing SP-D expression in alveolar cells, whereas persistent hypoxia induced de novo twist expression in these cells, causing repression of SP-D and acquisition of an EMT phenotype. Thus this is the first study to demonstrate the molecular mechanisms, in which SP-D expression under acute and persistent hypoxia in acute lung injury might be differentially modulated by stabilized HIF-1α expression and de novo twist expression.
Endothelial connexin43 mediates acid-induced increases in pulmonary microvascular permeability
Authors: Parthasarathi Kaushik
Published: May 2012

Acid aspiration, a common cause of acute lung injury, leads to alveolar edema. Increase in lung vascular permeability underlies this pathology. To define mechanisms, isolated rat lungs were perfused with autologous blood. Hydrochloric acid and rhodamine-dextran 70 kDa (RDx70) were coinstilled into an alveolus by micropuncture. RDx70 fluorescence was used to establish the spatial distribution of acid. Subsequently, FITC-dextran 20 kDa (FDx20) was infused into microvessels for 60 min followed by a 10-min HEPES-buffered saline wash. During the infusion, FITC fluorescence changes were recorded to quantify the ratio of peak to postwash fluorescence. The ratio, termed normalized fluorescence, was low for acid compared with buffer instillation both in microvessels abutting acid-treated alveoli and those located more than 700 μm away. In contrast, the normalized fluorescence was similar to buffer controls when a higher molecular weight tracer (FITC-dextran 70 kDa) was infused instead of FDx20, suggesting that normalized FDx20 fluorescence faithfully represented microvascular permeability. Inhibiting endothelial connexin43 (Cx43) gap junction communication with Gap27 blunted the acid-induced reduction in normalized fluorescence, although scrambled Gap27 did not have any effect. The blunting was evident not only in microvessels away from the site of injury, but also in those abutting directly injured alveoli. Thus the new fluorescence-based method reveals that acid increases microvascular permeability both at acid-instilled and away sites. Inhibiting endothelial Cx43 blocked the permeability increase even at the direct injury sites. These data indicate for the first time that Cx43-dependent mechanisms mediate acid-induced increases in microvascular permeability. Cx43 may be a therapeutic target in acid injury.
Response of Paroxysmal Nocturnal Hemoglobinuria Clone with Aplastic Anemia to Rituximab
Authors: Raghupathy Radha , Derman Olga
Published: May 2012

Paroxysmal nocturnal hemoglobinuria is caused by expansion of a hematopoietic stem cell clone with an acquired somatic mutation in the PIG-A gene. This mutation aborts the synthesis and expression of the glycosylphosphatidylinositol anchor proteins CD55 and CD59 on the surface of blood cells, thereby making them more susceptible to complement-mediated damage. A spectrum of disorders occurs in PNH ranging from hemolytic anemia and thrombosis to myelodysplasia, aplastic anemia and, myeloid leukemias. Aplastic anemia is one of the most serious and life-threatening complications of PNH, and a PNH clone is found in almost a third of the cases of aplastic anemia. While allogeneic bone marrow transplantation and T cell immune suppression are effective treatments for aplastic anemia in PNH, these therapies have significant limitations. We report here the first case, to our knowledge, of PNH associated with aplastic anemia treated with the anti-CD20 monoclonal antibody rituximab, which was associated with a significant reduction in the size of the PNH clone and recovery of hematopoiesis. We suggest that this less toxic therapy may have a significant role to play in treatment of PNH associated with aplastic anemia.
Abdominoperineal Resection for Rectal Cancer: Is the Pelvic Drain Externalization Site an Independent Risk Factor for Perineal Wound Healing?
Authors: Pramateftakis M. G. , Raptis D. , Kanellos D. , Christoforidis E. , Tsoulfas G. , Kanellos I. , Lazaridis Ch.
Published: May 2012

Aim. The aim of this paper is to investigate if the insertion of the pelvic drainage tubeviathe perineal wound could be considered as an independent risk factor for perineal healing disorders, after abdominoperineal resection for rectal malignancy.Patients and Methods. The last two decades, 75 patients underwent elective abdominoperineal resection for malignancy. In 42 patients (56%), the pelvic drain catheter was inserted through the perineal wound (PW group), while in the remaining 33 (44%) through a puncture skin wound of the perineum (SW group). Patients’ data with respect to age (P=0.136), stage (P>0.05), sex (P=0.188) and comorbidity (P=0.128) were similar in both groups. 25 patients (PWversusSW: 8 versus 17,P=0.0026) underwent neoadjuvant radio/chemotherapy.Results. The overall morbidity rate was 36%, but a significant increase was revealed inPWgroup (52.4% versus 9%,P=0.0007). In 33.3% of the patients in thePWgroup, perineal healing was delayed, while in theSWgroup, no delay was noted. Perineal healing disorders were revealed as the main source of increased morbidity in this group.Conclusion. The insertion of the pelvic drain tube through the perineal wound should be considered as an independent risk factor predisposing to perineal healing disorders.
Free Radical Shadow Cure Initiated Using Two-Component and Three-Component Initiator Systems
Authors: Kitano Hajime , Ramachandran Karthik , Scranton Alec B.
Published: May 2012

In photopolymerization systems, “shadow cure” may be defined as polymerization which extends into regions which are not illuminated by the incident initiating light source. The objective of this study is to evaluate the use of fluorescent additives for polymerization in masked regions that are unilluminated by the incident initiating light. Two different fluorescent dyes are investigated: fluorescein (FL) and eosin Y spirit soluble (EYss). A systematic series of studies was performed to characterize the effects of fluorescence intensity, the incident light intensity, and the presence of a diphenyl iodonium salt on the observed degree of shadow cure. It was concluded that shadow cure may be enhanced if one or more fluorescent compounds emit fluorescent light at wavelengths absorbed by the dye in a two- or three-component photoinitiator system. The addition of DPI to the two-component systems containing MDEA and FL or EYss led to a significant enhancement in the observed shadow cure. This result was attributed to the fact that DPI will increase both the number of active centers and the mobility of the active centers as a result of the electron transfer reactions in which it participates.
Asymptotic Formulae via a Korovkin‐Type Result
Authors: Cárdenas-Morales Daniel , Garrancho Pedro , Raşa Ioan
Published: May 2012

We present a sort of Korovkin‐type result that provides a tool to obtain asymptotic formulae for sequences of linear positive operators.
Mathematical Fundamentals of Modern Linear Optics
Authors: Gitin Andrey V.
Published: May 2012

All known quantum-mechanical approaches to wave and statistical optics are united into a single theory, using Feynman's path integral as a fundamental principle. In short-wave approximations, this principle, the Fourier transformations, and concepts of the theory reproduce Fermat's principle, the Legendre transformations, and concepts of Hamilton's optics and radiometry in a one-to-one fashion.
rAAV Vectors as Safe and Efficient Tools for the Stable Delivery of Genes to Primary Human Chondrosarcoma CellsIn VitroandIn Situ
Authors: Madry Henning , Venkatesan Jagadeesh K. , Schmitt Gertrud , Schetting Sarah , Ekici Myriam , Kohn Dieter , Cucchiarini Magali
Published: May 2012

Treatment of chondrosarcoma remains a major challenge in orthopaedic oncology. Gene transfer strategies based on recombinant adenoassociated viral (rAAV) vectors may provide powerful tools to develop new, efficient therapeutic options against these tumors. In the present study, we tested the hypothesis that rAAV is adapted for a stable and safe delivery of foreign sequences in human chondrosarcoma tissue by transducing primary human chondrosarcoma cellsin vitroandin situwith different reporter genes (E. coli lacZ, fireflyluc, Discosoma sp.RFP). The effects of rAAV administration upon cell survival and metabolic activities were also evaluated to monitor possibly detrimental effects of the gene transfer method. Remarkably, we provide evidence that efficient and prolonged expression of transgene sequences via rAAV can be safely achieved in all the systems investigated, demonstrating the potential of the approach of direct application of therapeutic gene vectors as a means to treat chondrosarcoma.
Objective Assessment of the Core Laparoscopic Skills Course
Authors: Mansour Sami , Din Nizar , Ratnasingham Kumaran , Irukulla Shashidhar , Vasilikostas George , Reddy Marcus , Wan Andrew
Published: May 2012

Objective.The demand for laparoscopic surgery has led to the core laparoscopic skills course (CLSC) becoming mandatory for trainees in UK. Virtual reality simulation (VR) has a great potential as a training and assessment tool of laparoscopic skills. The aim of this study was to determine the role of the CLSC in developing laparoscopic skills using the VR.Design.Prospective study. Doctors were given teaching to explain how to perform PEG transfer and clipping skills using the VR. They carried out these skills before and after the course. During the course they were trained using the Box Trainer (BT). Certain parameters assessed.Setting.Between 2008 and 2010, doctors attending the CLSC at St Georges Hospital.Participants.All doctors with minimal laparoscopic experience attending the CLSC.Results. Forty eight doctors were included. The time taken for the PEG skill improved by 52%, total left hand and right hand length by 41% and 48%. The total time in the clipping skill improved by 57%. Improvement in clips applied in the marked area was 38% and 45% in maximum vessel stretch.Conclusions.This study demonstrated that CLSC improved some aspects of the laparoscopic surgical skills. It addresses Practice-based Learning and patient care.
Adaptive Hybrid Function Projective Synchronization of Chaotic Systems with Time‐Varying Parameters
Authors: Xing Jinsheng
Published: May 2012

The adaptive hybrid function projective synchronization (AHFPS) of different chaotic systems with unknown time‐varying parameters is investigated. Based on the Lyapunov stability theory and adaptive bounding technique, the robust adaptive control law and the parameters update law are derived to make the states of two different chaotic systems asymptotically synchronized. In the control strategy, the parameters need not be known throughly if the time‐varying parameters are bounded by the product of a known function of t and an unknown constant. In order to avoid the switching in the control signal, a modified robust adaptive synchronization approach with the leakage‐like adaptation law is also proposed to guarantee the ultimately uni‐formly boundedness (UUB) of synchronization errors. The schemes are successfully applied to the hybrid function projective synchronization between the Chen system and the Lorenz system and between hyperchaotic Chen system and generalized Lorenz system. Moreover, numerical simulation results are presented to verify the effectiveness of the proposed scheme.
Bank Liquidity and the Global Financial Crisis
Authors: Gideon Frednard , Petersen Mark A. , Mukuddem-Petersen Janine , De Waal Bernadine
Published: May 2012

We investigate the stochastic dynamics of bank liquidity parameters such as
liquid assets and nett cash outflow in relation to the global financial crisis. These parameters
enable us to determine the liquidity coverage ratio that is one of the metrics used in ratio
analysis to measure bank liquidity. In this regard, numerical results show that bank behavior related to liquidity was highly procyclical during the financial crisis. We also consider a
theoretical‐quantitative approach to bank liquidity provisioning. In this case, we provide an
explicit expression for the aggregate liquidity risk when a locally risk‐minimizing strategy is
utilized.
Pyrazinamide Effects on Cartilage Type II Collagen Amino Acid Composition
Authors: Bondarenko Larysa B. , Kovalenko Valentina M.
Published: May 2012

Introduction. Current therapeutic regimens with first-line antitubercular agents are associated to a high rate of adverse effects which could cause pronounced changes in collagen's contents and structure. Investigation of these changes is very important for optimization of antitubercular therapy and minimization of treatment-caused harm. The aim of present paper was to investigate potential effect of pyrazinamide on male rats' cartilage type II collagen amino acid composition.Materials and Methods. Wistar albino male rats (160–200 g b.w.) were divided into three groups: I—received pyrazinamideper osat a dose of 1000 mg/kg b.w./day; II—at a dose of 2000 mg/kg b.w./day, in both groups it was given for 60 days; III—control. After 60 days of the experiment, rats of the experimental (groups I and II) and control groups were sacrificed and the amino acids contents of male rat cartilage type II collagens were determined using amino acid analyzer.Results and Discussion. The study of pyrazinamide effects (administered in different doses) on rat cartilage type II collagen amino acid contents demonstrated presence of dose-dependent pyrazinamide-mediated quantitative and qualitative changes in these rat extracellular matrix proteins in comparison with control.
Dynamical Behavior of a Stochastic Ratio‐Dependent Predator‐Prey System
Authors: Wu Zheng , Huang Hao , Wang Lianglong
Published: May 2012

This paper is concerned with a stochastic ratio‐dependent predator‐prey model with varible coefficients. By the comparison theorem of stochastic equations and the Itô formula, the global existence of a unique positive solution of the ratio‐dependent model is obtained. Besides, some results are established such as the stochastically ultimate boundedness and stochastic permanence for this model.
The Nedd8-Activating Enzyme Inhibitor MLN4924 Induces Autophagy and Apoptosis to Suppress Liver Cancer Cell Growth
Authors: Luo Zhongguang , Yu Guangyang , Lee Hyuk Woo , Li Lihui , Wang Lingyan , Yang Dongqin , Pan Yongfu , Ding Chan , Qian Jing , Wu Lijun , Chu Yiwei , Yi Jing , Wang Xiangdong , Sun Yi , Jeong Lak Shin , Liu Jie , Jia Lijun
Published: May 2012

Posttranslational neddylation of cullins in the Cullin-Ring E3 ligase (CRL) complexes is needed for proteolytic degradation of CRL substrates, whose accumulation induces cell-cycle arrest, apoptosis, and senescence. The Nedd8-activating enzyme (NAE) is critical for neddylation of CRL complexes and their growth-promoting function. Recently, the anticancer small molecule MLN4924 currently in phase I trials was determined to be an inhibitor of NAE that blocks cullin neddylation and inactivates CRL, triggering an accumulation of CRL substrates that trigger cell-cycle arrest, apoptosis, and senescence in cancer cells. Here, we report that MLN4924 also triggers autophagy in response to CRL inactivation and that this effect is important for the ability of MLN4924 to suppress the outgrowth of liver cancer cells in vitro and in vivo. MLN4924-induced autophagy was attributed partially to inhibition of mTOR activity, due to accumulation of the mTOR inhibitory protein Deptor, as well as to induction of reactive oxygen species stress. Inhibiting autophagy enhanced MLN4924-induced apoptosis, suggesting that autophagy is a survival signal triggered in response to CRL inactivation. In a xenograft model of human liver cancer, MLN4924 was well-tolerated and displayed a significant antitumor effect characterized by CRL inactivation and induction of autophagy and apoptosis in liver cancer cells. Together, our findings support the clinical investigation of MLN4924 for liver cancer treatment and provide a preclinical proof-of-concept for combination therapy with an autophagy inhibitor to enhance therapeutic efficacy. Cancer Res; 72(13); 3360–71. ©2012 AACR.
FRMD4A Upregulation in Human Squamous Cell Carcinoma Promotes Tumor Growth and Metastasis and Is Associated with Poor Prognosis
Authors: Goldie Stephen J. , Mulder Klaas W. , Tan David Wei-Min , Lyons Scott K. , Sims Andrew H. , Watt Fiona M.
Published: May 2012

New therapeutic strategies are needed to improve treatment of head and neck squamous cell carcinoma (HNSCC), an aggressive tumor with poor survival rates. FRMD4A is a human epidermal stem cell marker implicated previously in epithelial polarity that is upregulated in SCC cells. Here, we report that FRMD4A upregulation occurs in primary human HNSCCs where high expression levels correlate with increased risks of relapse. FRMD4A silencing decreased growth and metastasis of human SCC xenografts in skin and tongue, reduced SCC proliferation and intercellular adhesion, and stimulated caspase-3 activity and expression of terminal differentiation markers. Notably, FRMD4A attenuation caused nuclear accumulation of YAP, suggesting a potential role for FRMD4A in Hippo signaling. Treatment with the HSP90 inhibitor 17-DMAG or ligation of CD44 with hyaluronan caused nuclear depletion of FRMD4A, nuclear accumulation of YAP and reduced SCC growth and metastasis. Together, our findings suggest FRMD4A as a novel candidate therapeutic target in HNSCC based on the key role in metastatic growth we have identified. Cancer Res; 72(13); 3424–36. ©2012 AACR.
CXCL10 Promotes Osteolytic Bone Metastasis by Enhancing Cancer Outgrowth and Osteoclastogenesis
Authors: Lee Jong-Ho , Kim Ha-Neui , Kim Kyung-Ok , Jin Won Jong , Lee Seungbok , Kim Hong-Hee , Ha Hyunil , Lee Zang Hee
Published: May 2012

Amplification of the chemokines CXCL10 and RANKL has been suggested to promote osteoclast differentiation and osteolytic bone metastasis, but a function for endogenous CXCL10 in these processes is not well established. In this study, we show that endogenous CXCL10 is critical to recruit cancer cells to bone, support osteoclast differentiation and promote for the formation of osteolytic bone metastases. Neutralizing CXCL10 antibody reduced migration of cancer cells expressing the CXCL10 receptor CXCR3, and loss of CXCR3 or CXCL10 decreased bone tumor burden in vivo. Bone colonization augmented host production of CXCL10, which was required for cancer growth and subsequent osteolysis. Direct interactions between cancer cells and macrophages further stimulated CXCL10 production from macrophages. Growth of bone metastases required CXCL10-stimulated adhesion of cancer cells to type I collagen as well as RANKL-mediated osteoclast formation. Together, our findings show that CXCL10 facilitates trafficking of CXCR3-expressing cancer cells to bone, which augments its own production and promotes osteoclastic differentiation. CXCL10 therefore may represent a therapeutic target for osteolytic bone metastasis. Cancer Res; 72(13); 3175–86. ©2012 AACR.
Engineering and Therapeutic Application of Single-Chain Bivalent TGF-β Family Traps
Authors: Zwaagstra John C. , Sulea Traian , Baardsnes Jason , Lenferink Anne E.G. , Collins Cathy , Cantin Christiane , Paul-Roc Béatrice , Grothe Suzanne , Hossain Sazzad , Richer Louis-Philippe , L'Abbé Denis , Tom Roseanne , Cass Brian , Durocher Yves , O'Connor-McCourt Maureen D.
Published: May 2012

Deregulation of TGF-β superfamily signaling is a causative factor in many diseases. Here we describe a protein engineering strategy for the generation of single-chain bivalent receptor traps for TGF-β superfamily ligands. Traps were assembled using the intrinsically disordered regions flanking the structured binding domain of each receptor as "native linkers" between two binding domains. This yields traps that are approximately threefold smaller than antibodies and consists entirely of native receptor sequences. Two TGF-β type II receptor-based, single-chain traps were designed, termed (TβRII)2 and (TβRIIb)2, that have native linker lengths of 35 and 60 amino acids, respectively. Both single-chain traps exhibit a 100 to 1,000 fold higher in vitro ligand binding and neutralization activity compared with the monovalent ectodomain (TβRII-ED), and a similar or slightly better potency than pan–TGF-β–neutralizing antibody 1D11 or an Fc-fused receptor trap (TβRII-Fc). Despite its short in vivo half-life (<1 hour), which is primarily due to kidney clearance, daily injections of the (TβRII)2 trap reduced the growth of 4T1 tumors in BALB/c mice by 50%, an efficacy that is comparable with 1D11 (dosed thrice weekly). In addition, (TβRII)2 treatment of mice with established 4T1 tumors (100 mm3) significantly inhibited further tumor growth, whereas the 1D11 antibody did not. Overall, our results indicate that our rationally designed bivalent, single-chain traps have promising therapeutic potential. Mol Cancer Ther; 11(7); 1477–87. ©2012 AACR.
Bilateral Oophorectomy, Body Mass Index, and Mortality in U.S. Women Aged 40 Years and Older
Authors: McCarthy Anne Marie , Menke Andy , Ouyang Pamela , Visvanathan Kala
Published: May 2012

Bilateral oophorectomy is used as a risk reduction strategy in BRCA1/2 mutation carriers, although data on long-term side effects are not yet available. In the general population, oophorectomy, particularly at a young age, has been associated with increased overall and cardiovascular disease (CVD) mortality. The mechanisms for this association are not well understood. We examined the association between prior bilateral oophorectomy, obesity, and all-cause, cancer, and CVD mortality. Our study population included women ages 40 and above from the Third National Health and Nutrition Examination Survey (NHANES III), a nationally representative survey with enrollment from 1988 to 1994 and prospective mortality follow-up through December 31, 2006. We excluded women with a history of reproductive cancer or missing oophorectomy status, yielding a study population of 4,040. Cox proportional hazards modeling was used to estimate HR for all-cause and cause-specific mortality. In multivariate analyses, body mass index (BMI) significantly modified the association between oophorectomy and mortality (Pinteraction = 0.04). Women who were obese at the time of interview and who had an oophorectomy at less than 40 years were more than twice as likely to die [HR, 2.23; 95% confidence interval (CI), 1.25–3.98], particularly of CVD (HR, 2.77; 95% CI, 0.91–8.41), than nonobese women with intact ovaries. These associations persisted after excluding women who used estrogen therapy and women who had oophorectomy before 35 years of age. The joint effect of obesity and early oophorectomy on mortality was significantly greater than expected, given the independent effects of both exposures. Our results suggest that minimizing weight gain after oophorectomy and addressing cardiovascular risk factors could beneficially impact mortality. Cancer Prev Res; 5(6); 847–54. ©2012 AACR.
A Novel Sulindac Derivative that Potently Suppresses Colon Tumor Cell Growth by Inhibiting cGMP Phosphodiesterase and β-Catenin Transcriptional Activity
Authors: Whitt Jason D. , Li Nan , Tinsley Heather N. , Chen Xi , Zhang Wei , Li Yonghe , Gary Bernard D. , Keeton Adam B. , Xi Yaguang , Abadi Ashraf H. , Grizzle William E. , Piazza Gary A.
Published: May 2012

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to inhibit tumor growth by a COX-independent mechanism, although alternative targets have not been well defined or used to develop improved drugs for cancer chemoprevention. Here, we characterize a novel sulindac derivative referred to as sulindac benzylamine (SBA) that does not inhibit COX-1 or COX-2, yet potently inhibits the growth and induces the apoptosis of human colon tumor cells. The basis for this activity appears to involve cyclic guanosine 3′,5′,-monophosphate phosphodiesterase (cGMP PDE) inhibition as evident by its ability to inhibit cGMP hydrolysis in colon tumor cell lysates and purified cGMP-specific PDE5, increase intracellular cGMP levels, and activate cGMP-dependent protein kinase G at concentrations that suppress tumor cell growth. PDE5 was found to be essential for colon tumor cell growth as determined by siRNA knockdown studies, elevated in colon tumor cells as compared with normal colonocytes, and associated with the tumor selectivity of SBA. SBA activation of PKG may suppress the oncogenic activity of β-catenin as evident by its ability to reduce β-catenin nuclear levels, Tcf (T-cell factor) transcriptional activity, and survivin levels. These events preceded apoptosis induction and appear to result from a rapid elevation of intracellular cGMP levels following cGMP PDE inhibition. We conclude that PDE5 and possibly other cGMP degrading isozymes can be targeted to develop safer and more efficacious NSAID derivatives for colorectal cancer chemoprevention. Cancer Prev Res; 5(6); 822–33. ©2012 AACR.
Development of Hyperactivity and Anxiety Responses in Dopamine Transporter-Deficient Mice
Authors: Carpenter Alex C. , Saborido Tommy P. , Stanwood Gregg D.
Published: May 2012

Dopamine (DA) is a catecholamine neurotransmitter that regulates many aspects of motivated behavior in animals. Extracellular DA is highly regulated by the presynaptic high-affinity dopamine transporter (DAT), and drug- or genetically induced deficiencies in DAT function result in loss of DA reuptake. Mice in which DAT expression has been ablated have been previously proposed to be a relevant model of attention deficit hyperactivity disorder and have led to mechanistic insights regarding psychostimulant drug actions. However, very little previous work has emphasized the biobehavioral development of DAT-deficient mice. We therefore examined motoric, emotional and cognitive phenotypes in preadolescent (P22–26) DAT mutant mice. Consistent with previous reports in adult DAT–/– mice, we observed a hyperlocomotive phenotype in preadolescent mice across multiple assays. Somewhat surprisingly, spatial working memory in a Y-maze appeared intact, suggesting that cognitive phenotypes may emerge relatively late in development following hyperdopaminergia. Anxiety levels appeared to be reduced in DAT–/– mice, as defined by elevated plus maze and light-dark preference assays. No significant differences were observed between wild-type and heterozygous mice, suggesting a minimal impact of DAT haploinsufficiency on neurobehavioral status. Taken together, these data for the first time establish behavioral phenotypes of DAT mutant mice during development and suggest complex developmental stage-dependent effects of DA signaling on cognitive and emotional behaviors.
Early Stage Soliton Observations in the Sulu Sea*
Authors: Tessler Zachary D. , Gordon Arnold L. , Jackson Christopher R.
Published: May 2012

Observations of early stage, large-amplitude, nonlinear internal waves in the Sulu Sea are presented. Water column displacement and velocity profile time series show the passage of two solitary-like waves close to their generation site. Additional observations of the same waves are made as they propagate through the Sulu Sea basin. These waves of depression have an estimated maximum amplitude of 44 m. Observed wave amplitude and background stratification are used to estimate parameters for both a Korteweg–de Vries (K-dV) and a Joseph wave solution. These analytic model solutions are compared with a fully nonlinear model as well. Model wave half-widths bracket the observed wave, with the Joseph model narrower than the K-dV model. The modal structure of the waves change as they transit northward though the Sulu Sea, with higher mode features present in the southern Sulu Sea, which dissipate by the time the waves reach the north. Observed and modeled energies are roughly comparable, with observed potential energy estimated at 6.5 × 107 J m−1, whereas observed kinetic energy is between 4.6 × 107 J m−1 and 1.5 × 108 J m−1, depending on the integration limits. If this energy remains in the Sulu Sea, an average dissipation rate of 10−9 W kg−1 is required over its volume, helping to maintain elevated mixing rates.
The Built Environment and Childhood Obesity in Durham, North Carolina
Authors: Miranda Marie Lynn , Edwards Sharon E. , Anthopolos Rebecca , Dolinsky Diana H. , Kemper Alex R.
Published: May 2012

The relationship between childhood obesity and aspects of the built environment characterizing neighborhood social context is understudied. This study evaluates the association between 7 built environment domains and childhood obesity in Durham, North Carolina. Measures of housing damage, property disorder, vacancy, nuisances, and territoriality were constructed using data from a 2008 community assessment. Renter-occupied housing and crime measures were developed from public databases. The authors linked these measures to 2008-2009 Duke University Medical Center pediatric preventive care visits. Age- and sex-specific body mass index percentiles were used to classify children as normal weight (>5th and ≤85th percentile), overweight (>85th and ≤95th percentile), or obese (>95th percentile). Ordinal logistic regression models with cluster-corrected standard errors evaluated the association between weight status and the built environment. Adjusting for child-level socioeconomic characteristics, nuisances and crime were associated with childhood overweight/obesity ( P < .05). Built environment characteristics appear important to childhood weight status in Durham, North Carolina.
Beyond a Test Score
Authors: Milner H. Richard
Published: May 2012

The author shares an opportunity gap explanatory framework to assist educational researchers and theorists in analyzing, explaining, and naming educational practice, especially in highly diverse and urban social contexts. The author argues that too much attention is placed on achievement gaps and challenges researchers and theorists to expand their analyses to opportunity gaps. Focusing on opportunity allows researchers to examine the causes of disparities that exist between and among students in schools. Emerging from the author’s own research and from an established body of theory and research, the framework encompasses five interrelated tenets essential to understanding and explaining educational practice related to opportunity: color blindness, cultural conflicts, meritocracy, deficit mindsets and low expectations, and context-neutral mindsets and practices. Implications of the framework point to potential synergy in language and research emphases that can shed light in the educational literature on deeply inequitable systems, processes, structures, policies, and practices that can prevent some students from reaching their full capacity.
A study of the fiber distribution in yarn cross section for vortex-spun yarn
Authors: Zheng ShaoMing , Zou ZhuanYong , Shen Wei , Cheng LongDi
Published: May 2012

The image-processing method, based on Photoshop software, was used to analyze the fiber distribution pattern in yarn cross section for vortex-spun yarn. Fiber packing density and fiber effective packing density, as well as the fiber migration index, were investigated to provide a better understanding of the internal structures of vortex-spun yarn. The research results indicate that the vortex-spun yarn has a lower fiber packing density value than the conventional ring-spun yarn at the yarn center and surface. For the bamboo pulp fiber/white cotton blend vortex-spun yarn, the bamboo pulp fibers are more easily distributed in the yarn core. In addition, the coarser the vortex-spun yarn, the higher the migration level of the bamboo pulp fiber tending to migrate towards the inner layer of the blend yarn.
Identification of the most significant comfort factors for textiles from processing mechanical, handfeel, fabric construction, and perceived tactile comfort data
Authors: Sztandera Les M , Cardello Armand V , Winterhalter Carole , Schutz Howard
Published: May 2012

Engineered fabrics are desired for military protective clothing applications. Such fabrics, exhibiting high tactile comfort, can be computationally designed. Through the use of an extensive database that contains handfeel, mechanical, construction, and tactile comfort data for fabrics, desired comfort can be predicted by measuring a limited number of properties. Output systems can be optimized to exhibit the highest level of comfort by engineering a fabric with specific properties.

Using an extensive fabric database, we identify the most significant handfeel, mechanical, and construction properties influencing tactile fabric comfort. This is done through the use of regression analysis of handfeel, mechanical, construction fabric properties, and perceived tactile comfort, using B un-standardized coefficients and Beta standardized coefficients.
Testing and Extending the Escalator Hypothesis: Does the Pattern of Post-migration Income Gains in Toronto Suggest Productivity and/or Learning Effects?
Authors: Newbold K. Bruce , Brown W. Mark
Published: May 2012

Workers earn incomes that are significantly higher in large metropolitan areas as compared with other locations in the urban hierarchy, reflecting both agglomeration economies and variation in the composition of skills and abilities across space. What benefits accrue to in-migrants to large urban areas? Fielding’s concept of the escalator region provides one way to evaluate the role of large metropolitan areas vis-à-vis the labour market, occupational mobility and migration. The purpose of this paper is to evaluate whether young adult migrants to Toronto aged 20–29 receive income benefits that are higher than those associated with other migrants or stayers. Results indicate that Toronto in-migrants receive an income benefit consistent with a productivity effect that is greater than the income benefit received by migrants elsewhere in the system or those who did not migrate. However, it does not appear that migration leads to an acceleration in income gains.
The Role of the Public Institution in Iconic Architectural Development
Authors: Patterson Matt
Published: May 2012

Research on iconic architecture has typically explained its popularity with reference to global political-economic trends like neo-liberalism and urban entrepreneurialism, but the role of the immediate clients has often been overlooked. Quantitative analysis demonstrates that the majority of these clients are public cultural institutions. In order to explain the affinity between this organisational form and iconic architecture, this paper develops a model of the public institution based on its need to establish public legitimacy and attract outside support. To develop this model further, the paper presents a comparative case study of two museum expansion projects in Toronto: Daniel Libeskind’s Royal Ontario Museum and Frank Gehry’s Art Gallery of Ontario. The study addresses the underlying motivations behind the projects, the role of global political-economic trends and how the unique logic of the public institution structured the development process itself.
The Moderating Influence of Property Legislation on Planning Policy and Urban Form
Authors: Davies Amanda , Atkinson Mark
Published: May 2012

This paper investigates the role that property titling legislation has had on the form of high-density residential development. A conceptual framework is developed for theorising the role of property legislation in moderating the impact of urban land use policy. It is argued that the impact of legislation on urban form is much more significant and direct than is often implied or suggested in reviews of planning policy. It is argued that property legislation has a greater role than simply supporting the implementation of urban planning policy. Property legislation has a moderating influence on policy and provides a barrier to the implementation of urban policy. To support this argument, the paper considers the development and implications of Western Australia’s strata titling legislation for the form of high-density development in that state’s capital city.
What Really Matters for Increasing Transit Ridership: Understanding the Determinants of Transit Ridership Demand in Broward County, Florida
Authors: Thompson Gregory , Brown Jeffrey , Bhattacharya Torsha
Published: May 2012

In 2004, Broward County Transit, located in Broward County, Florida, had among the highest ridership per capita and lowest cost per passenger kilometre of all-bus systems in US metropolitan areas with between 1 million and 5 million people. Broward County has few land use attributes thought necessary for transit success. This (2000) study seeks to understand its performance despite its transit-unfriendly urban environment by estimating a transit ridership demand model that differs from most by including generalised price of transit travel from origin to destination. The hypothesis, which the study confirms, is that price (time to reach employment) is more important than land use variables for explaining transit patronage, at least for a bus-only transit system with a large number of transit-dependent riders. The results of this study give further empirical support to recent transit system initiatives to focus more service on decentralised employment centres using multidestination transit network structures.
The Point of Diminishing Returns: An Examination of Expanding Vancouver’s Insite
Authors: Andresen Martin A. , Jozaghi Ehsan
Published: May 2012

North America’s only government-sanctioned supervised injection facility, Insite, has been subjected to substantial research. This research has found evidence for numerous public health benefits: decreased risky injection behaviour, decreased fatal overdoses, increased probability of initiating and maintaining addiction treatment, and cost-effectiveness. To date, a small number of costing studies have emerged with none of them investigating Insite expansions. Such an analysis is reported in this paper and it is found that, based on benefit–cost ratios, Insite should be expanded. However, this expansion is dependent on altering injection drug user behaviour outside Insite.
Effective Strategies for the Inclusion of Children With Autism in General Education Classrooms
Authors: Crosland Kimberly , Dunlap Glen
Published: May 2012

Successful inclusion of students with autism spectrum disorder (ASD) in general education classrooms can be challenging and may require additional supports. This article provides information on recent trends in autism intervention research and a review of research that has addressed individualized and systemic interventions for promoting inclusion. Response to intervention and schoolwide positive behavior support are reviewed as organizational/ systems strategies relevant to preventing problems and improving social and academic outcomes for students with ASD. Additional individualized strategies that can be implemented within these models are described. A discussion of future research directions is provided.