bluuebunny/crossref_metadata_2025 huggingface dataset:
Service provision and training for endoscopic ultrasound in the UK
Authors: Meenan J , Harris K , Oppong K , McKay C , Penman I , Carroll N , Norton S
Published: April 2011

Endoscopic ultrasound (EUS) is a standard procedure that plays an important role in the management of both malignant and benign disease. The development of EUS services in the UK has been haphazard and training inconsistent. The British Society of Gastroenterology has charged a working group with the task of laying down a national framework for how such services might be commissioned, structured and regulated; with particular attention to defining how endoscopist skills might be acquired, assessed and maintained. This report lays out a map for this process and its future revision.
Patients' perspectives of the substitute decision maker: who makes better decisions?
Authors: Mirzaei Komeil , Milanifar Alireza , Asghari Fariba
Published: April 2011

Introduction

Substitute decision making on behalf of incapable patients is based on the ethical principle of ‘respect for autonomy’. This study was conducted to assess patients' wishes and preferences in terms of a substitute decision maker and determinants of such preferences.

Methods

The authors conducted a cross-sectional study and selected samples randomly from patients presenting at Farabi Eye Hospital clinics who were 18 years of age or older. Questionnaires were completed through interviews.

Results

200 patients between the ages of 18 and 83 years were interviewed. About 52% (N=105) were men and 73% (N=77) were married. Among married patients, the spouse was chosen as the substitute decision maker in only 51% of cases. Single men preferred their father first in 36% (N=9) of cases, while single girls chose their father in 5.6% (N=1) of cases and their most prevalent choice was other unmentioned people (33.3%, N=6). Most patients (93.5%) wished to be asked about their substitute decision maker when hospitalised.

Conclusion

The results of this study show that the people we usually consult for decisions concerning patient treatment are significantly different from the patients' preferred substitute decision makers. The authors suggest patients be allowed to choose their substitute decision maker while conscious.
Double effect: a useful rule that alone cannot justify hastening death
Authors: Billings J Andrew
Published: April 2011

The rule of double effect is regularly invoked in ethical discussions about palliative sedation, terminal extubation and other clinical acts that may be viewed as hastening death for imminently dying patients. Unfortunately, the literature tends to employ this useful principle in a fashion suggesting that it offers the final word on the moral acceptability of such medical procedures. In fact, the rule cannot be applied appropriately without invoking moral theories that are not explicit in the rule itself. Four tenets of the rule each require their own ethical justification. A variety of moral theories are relevant to making judgements in a pluralistic society. Much of the rich moral conversation germane to the rule has been reflected in arguments about physician-asssisted suicide and voluntary active euthanasia, but the rule itself has limited relevance to these debates, and requires its own moral justifications when applied to other practices that might hasten death.
Combined endovascular and surgical resection of a giant lumbosacral arteriovenous malformation in a patient with Cobb syndrome
Authors: Spiotta Alejandro M , Hussain Muhammad Shazam , Masaryk Thomas J , Krishnaney Ajit A
Published: April 2011

Objective and importance

Cobb syndrome is a rare condition that includes a cutaneous nevus with an associated spinal vascular lesion at the same dermatome. We present a challenging case of a progressively symptomatic massive lumbosacral arteriovenous malformation (AVM) in a patient with Cobb's syndrome requiring a multimodality approach including staged preoperative transarterial and transvenous endovascular embolization followed by surgical excision and wound reconstruction.

Clinical presentation

The patient presented with a massive lumbosacral AVM with symptoms of congestive heart failure. Angiography demonstrated arterial feeders predominantly from internal iliac, median sacral and lumbar segmental arteries.

Intervention

The patient underwent staged transarterial and transvenous endovascular embolization resulting in 90% reduction in the AVM size, followed by surgical resection of the lesion. The patient made an excellent recovery with improvement in his symptoms of congestive heart failure.

Conclusion

The treatment algorithm for massive AVMs must be individualized. A combination of staged embolization and subsequent surgery may be required to obtain a good result. Through this carefully planned multidisciplinary approach a previously incurable lesion in this patient with Cobb syndrome was able to be treated successfully.
ABSOLUTE THERMOELECTRIC POWER OF Pb–Sn ALLOYS
Authors: KALDRE I. , FAUTRELLE Y. , ETAY J. , BOJAREVICS A. , BULIGINS L.
Published: April 2011

In this work, absolute thermoelectric power (ATP) of Pb , Sn , Pb -20 wt.% Sn , Pb -40 wt.% Sn , Pb -60 wt.% Sn , Pb -80 wt.% Sn are measured. Measurements are performed in a temperature gradient furnace from 20°C to 500°C, for both solid and liquid states. Temperatures are measured with T-type copper-constantan thermocouples, while voltage signal between copper electrodes of those thermocouples is recorded in order to calculate ATP of the sample metal.
EFFECTIVE MOBILITY MODEL OF GRAPHENE NANORIBBON IN PARABOLIC BAND ENERGY
Authors: AMIN N. A. , AHMADI M. T. , JOHARI Z. , MOUSAVI S. M. , ISMAIL R.
Published: April 2011

In this letter, we investigate the transport properties of one-dimensional semiconducting Graphene nanoribbons (GNRs) with parabolic band structure near the Dirac point. The analytical model of effective mobility is developed by using the conductance approach, which differs from the conventional method of extracting the effective mobility using the well-known Matthiessen rule. Graphene nanoribbons conductance model developed was applied in the Drude model to obtain the effective mobility, which then gives nearly close comparison with the experimental data.
GROWTH AND GLOBAL GENE EXPRESSION OF EUCARYOTIC CELLS
Authors: ZHDANOV VLADIMIR P.
Published: April 2011

We present a kinetic model describing the growth of eukaryotic cells or, more specifically, the dependence of the cell volume on time in terms of the global interplay of the mRNA and protein synthesis and degradation and lipid synthesis. Addressing two long-standing questions in this interdisciplinary field, we explain why the average protein concentration in growing cells is nearly constant and the growth can accurately be fitted by using a bilinear or exponential function.
Electrochemistry of Conductive Polymers 48. Electrochemical Polymerization of 3,4-Ethylenedioxythiophene in Ionic Liquids and Propylene Carbonate
Authors: Min Geun Gi , Kim Seung Bin , Park Su-Moon
Published: April 2011

Systematic studies on the electrochemical polymerization of 3,4-ethylenedioxythiophene (EDOT) were conducted at gold electrodes in two room temperature ionic liquids (RTILs) sharing the 1-butyl-3-methylimidazolium cation (BMIM+) for one of two anions, BF4−or TFSI−[bis(trifluoro-methylsulfonyl) imide], and in propylene carbonate (PC) containing BF4−or TFSI−for a common t-butylammonium cation. EDOT oxidation in RTILs was shown to undergo a change in charge-transfer mechanism during the potential sweep, which must have led to differences in polymerization reactions in the two media. Differences were noted between poly-EDOT (PEDOT) films prepared in RTILs and those in PC; PEDOT films were characterized using techniques including UV-visible absorption spectroscopic, scanning electron microscopic, and Fourier transform electrochemical impedance spectroscopic experiments. The films prepared in PC and with TFSI−displayed the better electrochemical properties. Differences in electron and mass transfer kinetics in different media led to differences observed for film growth kinetics, chain lengths, and redox characteristics for the PEDOT films. Also revealed was that different oxidation mechanisms are at work in RTILs in different potential regimes.
Ceiling culture-derived proliferative adipocytes retain high adipogenic potential suitable for use as a vehicle for gene transduction therapy
Authors: Asada Sakiyo , Kuroda Masayuki , Aoyagi Yasuyuki , Fukaya Yoshitaka , Tanaka Shigeaki , Konno Shunichi , Tanio Masami , Aso Masayuki , Satoh Kaneshige , Okamoto Yoshitaka , Nakayama Toshinori , Saito Yasushi , Bujo Hideaki
Published: April 2011

Adipose tissue is expected to provide a source of proliferative cells for regenerative medicine and cell-transplantation therapies using gene transfer manipulation. We have recently identified ceiling culture-derived proliferative adipocytes (ccdPAs) from the mature adipocyte fraction as cells suitable as a therapeutic gene vehicle because of their stable proliferative capacity. In this study, we examined the capability of adipogenic differentiation of the ccdPAs compared with stromal vascular fraction (SVF)-derived progenitor cells (adipose-derived stem cells, ASCs) with regard to their multipotential ability to be converted to another lineage and therefore their potential to be used for regenerative medicine research. After in vitro passaging, the surface antigen profile and the basal levels of adipogenic marker genes of the ccdPAs were not obviously different from those of the ASCs. However, the ccdPAs showed increased lipid-droplet accumulation accompanied with higher adipogenic marker gene expression after stimulation of differentiation compared with the ASCs. The higher adipogenic potential of the ccdPAs than the ASCs from the SVF was maintained for 42 days in culture. Furthermore, the difference in the adipogenic response was enhanced after partial stimulation without indomethacin. These results indicate that the ccdPAs retain a high adipogenic potential even after in vitro passaging, thus suggesting the commitment of ccdPAs to stable mature adipocytes after autotransplantation, indicating that they may have potential for use in regenerative and gene-manipulated medicine.
Glycolytic inhibition causes spontaneous ventricular fibrillation in aged hearts
Authors: Morita Norishige , Lee Jong-Hwan , Bapat Aneesh , Fishbein Michael C. , Mandel William J. , Chen Peng-Sheng , Weiss James N. , Karagueuzian Hrayr S.
Published: April 2011

Selective glycolytic inhibition (GI) promotes electromechanical alternans and triggered beats in isolated cardiac myocytes. We sought to determine whether GI promotes triggered activity by early afterdepolarization (EAD) or delayed afterdepolarizations in intact hearts isolated from adult and aged rats. Dual voltage and intracellular calcium ion (Cai2+) fluorescent optical maps and single cell glass microelectrode recordings were made from the left ventricular (LV) epicardium of isolated Langendorff-perfused adult (∼4 mo) and aged (∼24 mo) rat hearts. GI was induced by replacing glucose with 10 mM pyruvate in oxygenated Tyrode's. Within 20 min, GI slowed Cai2+transient decline rate and shortened action potential duration in both groups. These changes were associated with ventricular fibrillation (VF) in the aged hearts (64 out of 66) but not in adult hearts (0 out of 18; P < 0.001). VF was preceded by a transient period of focal ventricular tachycardia caused by EAD-mediated triggered activity leading to VF within seconds. The VF was suppressed by the ATP-sensitive K (KATP) channel blocker glibenclamide (1 μM) but not (0 out of 7) by mitochondrial KATPblock. The Ca-calmodulin-dependent protein kinase II (CaMKII) blocker KN-93 (1 μM) prevented GI-mediated VF ( P < 0.05). Block of Na-Ca exchanger (NCX) by SEA0400 (2 μM) prevented GI-mediated VF (3 out of 6), provided significant bradycardia did not occur. Aged hearts had significantly greater LV fibrosis and reduced connexin 43 than adult hearts ( P < 0.05). We conclude that in aged fibrotic unlike in adult rat hearts, GI promotes EADs, triggered activity, and VF by activation of KATPchannels CaMKII and NCX.
Photolysis of caged sphingosine-1-phosphate induces barrier enhancement and intracellular activation of lung endothelial cell signaling pathways
Authors: Usatyuk Peter V. , He Donghong , Bindokas Vytas , Gorshkova Irina A. , Berdyshev Evgeny V. , Garcia Joe G. N. , Natarajan Viswanathan
Published: April 2011

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates cellular functions by ligation via G protein-coupled S1P receptors. In addition to its extracellular action, S1P also has intracellular effects; however, the signaling pathways modulated by intracellular S1P remain poorly defined. We have previously demonstrated a novel pathway of intracellular S1P generation in human lung endothelial cells (ECs). In the present study, we examined the role of intracellular S1P generated by photolysis of caged S1P on EC barrier regulation and signal transduction. Intracellular S1P released from caged S1P caused mobilization of intracellular calcium, induced activation of MAPKs, redistributed cortactin, vascular endothelial cadherin, and β-catenin to cell periphery, and tightened endothelial barrier in human pulmonary artery ECs. Treatment of cells with pertussis toxin (PTx) had no effect on caged S1P-mediated effects on Ca2+mobilization, reorganization of cytoskeleton, cell adherens junction proteins, and barrier enhancement; however, extracellular S1P effects were significantly attenuated by PTx. Additionally, intracellular S1P also activated small GTPase Rac1 and its effector Ras GTPase-activating-like protein IQGAP1, suggesting involvement of these proteins in the S1P-mediated changes in cell-to-cell adhesion contacts. Downregulation of sphingosine kinase 1 (SphK1), but not SphK2, with siRNA or inhibition of SphK activity with an inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (CII) attenuated exogenously administrated S1P-induced EC permeability. Furthermore, S1P1 receptor inhibitor SB649164 abolished exogenous S1P-induced transendothelial resistance changes but had no effect on intracellular S1P generated by photolysis of caged S1P. These results provide evidence that intracellular S1P modulates signal transduction in lung ECs via signaling pathway(s) independent of S1P receptors.
Acute colonic inflammation triggers detrusor instability via activation of TRPV1 receptors in a rat model of pelvic organ cross-sensitization
Authors: Asfaw Tirsit S. , Hypolite Joseph , Northington Gina M. , Arya Lily A. , Wein Alan J. , Malykhina Anna P.
Published: April 2011

Chronic pelvic pain of unknown etiology is a common clinical condition and may develop as a result of cross-sensitization in the pelvis when pathological changes in one of the pelvic organs result in functional alterations in an adjacent structure. The aim of the current study was to compare transient receptor potential vanilloid 1 (TRPV1) activated pathways on detrusor contractility in vivo and in vitro using a rat model of pelvic organ cross-sensitization. Four groups of male Sprague-Dawley rats ( N = 56) were included in the study. Animals received intracolonic saline (control), resiniferatoxin (RTX, TRPV1 agonist, 10−7 M), 2,4,6-trinitrobenzene sulfonic acid (TNBS, colonic irritant), or double treatment (RTX followed by TNBS). Detrusor muscle contractility was assessed under in vitro and in vivo conditions. Intracolonic RTX increased the contractility of the isolated detrusor in response to electric field stimulation (EFS) by twofold ( P ≤ 0.001) and enhanced the contractile response of the bladder smooth muscle to carbachol (CCh). Acute colonic inflammation reduced detrusor contractility upon application of CCh in vitro, decreased bladder capacity by 28.1% ( P ≤ 0.001), and reduced micturition volume by 60% ( P ≤ 0.001). These changes were accompanied by an increased number of nonmicturition contractions from 3.7 ± 0.7 to 15 ± 2.7 ( N = 6 in both groups, P ≤ 0.001 vs. control). Desensitization of intracolonic TRPV1 receptors before the induction of acute colitis restored the response of isolated detrusor strips to CCh but not to EFS stimulation. Cystometric parameters were significantly improved in animals with double treatment and approximated the control values. Our data suggest that acute colonic inflammation triggers the occurrence of detrusor instability via activation of TRPV1-related pathways. Comparison of the results obtained under in vitro vs. in vivo conditions provides evidence that intact neural pathways are critical for the development of an overactive bladder resulting from pelvic organ cross talk.
Aortic stiffness is associated with vascular calcification and remodeling in a chronic kidney disease rat model
Authors: Ng Keith , Hildreth Cara M. , Phillips Jacqueline K. , Avolio Alberto P.
Published: April 2011

Increased aortic pulse-wave velocity (PWV) reflects increased arterial stiffness and is a strong predictor of cardiovascular risk in chronic kidney disease (CKD). We examined functional and structural correlations among PWV, aortic calcification, and vascular remodeling in a rodent model of CKD, the Lewis polycystic kidney (LPK) rat. Hemodynamic parameters and beat-to-beat aortic PWV were recorded in urethane-anesthetized animals [12-wk-old hypertensive female LPK rats ( n = 5)] before the onset of end-stage renal disease and their age- and sex-matched normotensive controls (Lewis, n = 6). Animals were euthanized, and the aorta was collected to measure calcium content by atomic absorption spectrophotometry. A separate cohort of animals ( n = 5/group) were anesthetized with pentobarbitone sodium and pressure perfused with formalin, and the aorta was collected for histomorphometry, which allowed calculation of aortic wall thickness, medial cross-sectional area (MCSA), elastic modulus (EM), and wall stress (WS), size and density of smooth muscle nuclei, and relative content of lamellae, interlamellae elastin, and collagen. Mean arterial pressure (MAP) and PWV were significantly greater in the LPK compared with Lewis (72 and 33%, respectively) animals. The LPK group had 6.8-fold greater aortic calcification, 38% greater aortic MCSA, 56% greater EM/WS, 13% greater aortic wall thickness, 21% smaller smooth muscle cell area, and 20% less elastin density with no difference in collagen fiber density. These findings demonstrate vascular remodeling and increased calcification with a functional increase in PWV and therefore aortic stiffness in hypertensive LPK rats.
Obesity and Type 2 Diabetes Prevalence in Adults from Two Remote First Nations Communities in Northwestern Ontario, Canada
Authors: Imbeault Pascal , Haman François , Blais Jules M. , Pal Shinjini , Seabert Tim , Krümmel Eva M. , Robidoux Michael A.
Published: April 2011

Objective. To assess the prevalence rates of obesity and type 2 diabetes in adults from two First Nations communities in northwestern Ontario, Canada.Methods. Body weight, height, and waist circumference as well as fasting and postprandial glucose levels following an oral glucose tolerance test were measured in 31 men and 41 women.Results. The mean age of the sample was 43 ± 13 y. The prevalence of obesity was 65.3% and was comparable between men and women. 90.3% of the individuals presented waist circumference levels greater than the thresholds associated with an increased risk of developing health problems. 26 of the 72 individuals (36.1%) were found to be type 2 diabetic. The prevalence of diabetes was not different between men and women.Conclusion. Using objective measurements, this study confirms that First Nations adults from remote communities of Canada continue to experience a disproportionately higher prevalence of obesity and type 2 diabetes than nonaboriginal Canadians.
Cardiac Conduction Safety during Coadministration of Artemether-Lumefantrine and Lopinavir/Ritonavir in HIV-Infected Ugandan Adults
Authors: Byakika-Kibwika Pauline , Lamorde Mohammed , Lwabi Peter , Nyakoojo Wilson B. , Okaba-Kayom Violet , Mayanja-Kizza Harriet , Boffito Marta , Katabira Elly , Back David , Khoo Saye , Merry Concepta
Published: April 2011

Background. We aimed to assess cardiac conduction safety of coadministration of the CYP3A4 inhibitor lopinavir/ritonavir (LPV/r) and the CYP3A4 substrate artemether-lumefantrine (AL) in HIV-positive Ugandans.
Methods. Open-label safety study of HIV-positive adults administered single-dose AL (80/400 mg) alone or with LPV/r (400/100 mg). Cardiac function was monitored using continuous electrocardiograph (ECG).
Results. Thirty-two patients were enrolled; 16 taking LPV/r -based ART and 16 ART naïve. All took single dose AL. No serious adverse events were observed. ECG parameters in milliseconds remained within normal limits. QTc measurements did not change significantly over 72 hours although were higher in LPV/r arm at 24 (424 versus 406; P=.02) and 72 hours (424 versus 408; P=.004) after AL intake.
Conclusion. Coadministration of single dose of AL with LPV/r was safe; however, safety of six-dose AL regimen with LPV/r should be investigated.
The Antiinfective Effects of Velvet Antler of Formosan Sambar Deer (Cervus unicolor swinhoei) on Staphylococcus aureus‐Infected Mice
Authors: Dai Ting-Yeu , Wang Chih-Hua , Chen Kun-Nan , Huang I-Nung , Hong Wei-Sheng , Wang Sheng-Yao , Chen Yen-Po , Kuo Ching-Yun , Chen Ming-Ju
Published: April 2011

We assayed the effects of velvet antler (VA) of Formosan sambar deer (Cervus unicolor swinhoei) and its extracts on the anti‐infective activity against pathogenic Staphylococcus aureus in vitro and in vivo in this study. In vitro data indicated that the VA extracts stimulated the proliferation of resting splenocytes and macrophages in a dose‐dependent manner up to the highest concentration used (150 μg mL−1). The production of proinflammatory cytokines (TNF‐α, IL‐6, IL‐12) by lipoteichoic acid was significantly suppressed after being cocultured with the VA extracts in a dose‐dependent manner. Animal test in S. aureus‐infected mice demonstrated that the numbers of bacteria determined in the kidneys and peritoneal lavage fluid of S. aureus‐infected mice were significantly higher than those found in the same organs of mice pretreated with the VA samples. Moreover, the highly enhanced phagocytic activity of macrophages was further verified after in vitro treatment with the VA samples. The protective mechanisms of the VA samples might include an immune enhancer and an inflammatory cytokine suppressor.
Assessment of Turbulence Models for Flow Simulation around a Wind Turbine Airfoil
Authors: Villalpando Fernando , Reggio Marcelo , Ilinca Adrian
Published: April 2011

This investigation focuses on the application of the computational
fluid dynamics tool FLUENT to the study of flows over the NACA
63–415 airfoil at various angles of attack. With the aim of selecting the
most suitable turbulence model to simulate flow around ice‐accreted
airfoils, this work concentrates on assessing the prediction capabilities
of various turbulence models on clean airfoils at the large angles
of attack that cause highly separated flows to occur. The study was
undertaken by conducting simulations with the one‐equation Spalart‐Allmaras (SA) model, the two‐equation RNG k‐ϵ and SST k‐ω models, and the Reynolds stress model (RSM). Domain discretization
was carried out using general quadrilateral grids generated with
GAMBIT, the FLUENT preprocessing tool. Comparisons were made
with available experimental data.
Health Promoting Schools Provide Community-Based Learning Opportunities Conducive to Careers in Rural Practice
Authors: Macnab Andrew , Kasangaki Arabat , Gagnon Faith
Published: April 2011

The World Health Organization conceived “health-promoting schools” as a means of providing the information and support systems necessary for the worldwide changes in behavior that are needed to improve health globally and decrease health care costs. We developed and evaluated a model of progressively implementing health-promoting schools with support from university medical school trainees in Canada and Uganda. The model uses oral health as a medium for establishing rapport and success around a topic with little stigma. The evaluation involved questionnaires of the Canadian trainees about practice intentions before and after involvement in the health-promoting schools to determine whether community-based learning in health-promoting schools resulted in more trainees planning to work in rural areas or underserved countries. We found that Canadian medical trainees cited their personal involvement and perceived ability to effect significant and identifiable positive change in both the school children and the community as reasons why they were more willing to practice in rural or under-served areas.
Development of Viral Vectors for Gene Therapy for Chronic Pain
Authors: Huang Yu , Liu Xin , Dong Lanlan , Liu Zhongchun , He Xiaohua , Liu Wanhong
Published: April 2011

Chronic pain is a major health concern that affects millions of people. There are no adequate long-term therapies for chronic pain sufferers, leading to significant cost for both society and the individual. The most commonly used therapy for chronic pain is the application of opioid analgesics and nonsteroidal anti-inflammatory drugs, but these drugs can lead to addiction and may cause side effects. Further studies of the mechanisms of chronic pain have opened the way for development of new treatment strategies, one of which is gene therapy. The key to gene therapy is selecting safe and highly efficient gene delivery systems that can deliver therapeutic genes to overexpress or suppress relevant targets in specific cell types. Here we review several promising viral vectors that could be applied in gene transfer for the treatment of chronic pain and further discuss the possible mechanisms of genes of interest that could be delivered with viral vectors for the treatment of chronic pain.
Expression of nm23-H1 Is Associated with Poor Prognosis in Peripheral T-Cell Lymphoma, Not Otherwise Specified
Authors: Niitsu Nozomi , Nakamine Hirokazu , Okamoto Masataka
Published: April 2011

Purpose: We examined whether nm23-H1 is a prognostic factor of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS).

Experimental Design: We studied 102 consecutive, untreated PTCL-NOS patients from 1998 to 2008. The expression of nm23-H1 and TIA-1 was studied by immunohistochemistry.

Results: nm23-H1 was positive in 44.1% and TIA-1 in 78.4% of the PTCL-NOS patients. nm23-H1 expression was not correlated with age, performance status (PS), lactate dehydrogenase (LDH) level, or stage but was significantly correlated with the prognostic index for T-cell lymphoma. The serum nm23-H1 level was 43.44 ng/mL in the cytoplasmic nm23-H1 strongly positive, 24.32 ng/mL in the cytoplasmic nm23-H1 moderately positive, and 13.64 ng/mL in the cytoplasmic nm23-H1–negative patients. The nm23-H1–positive group had significantly shorter overall survival (OS). TIA-1 had no prognostic impact on 5-year OS rates. OS was significantly shorter in patients with the following clinicopathologic features: age 60 or more years, PS of 2 to 4, LDH level greater than normal, bone marrow involvement, or nm23-H1–positive lymphoma. Multivariate analysis confirmed nm23-H1 expression to be an independent prognostic factor.

Conclusions: The nm23-H1 protein may be an important prognostic factor in PTCL-NOS. Because our results suggested that nm23-HI is produced by lymphoma cells, we expect to see the development of new treatments targeting nm23 overexpression. Clin Cancer Res; 17(9); 2893–9. ©2011 AACR.
The Multitargeted Receptor Tyrosine Kinase Inhibitor Linifanib (ABT-869) Induces Apoptosis through an Akt and Glycogen Synthase Kinase 3β–Dependent Pathway
Authors: Hernandez-Davies Jenny E. , Zape Joan P. , Landaw Elliot M. , Tan Xiaolin , Presnell Ajia , Griffith Diana , Heinrich Michael C. , Glaser Keith B. , Sakamoto Kathleen M.
Published: April 2011

The FMS-like receptor tyrosine kinase 3 (FLT3) plays an important role in controlling differentiation and proliferation of hematopoietic cells. Activating mutations in FLT3 occur in patients with acute myeloid leukemia (AML; 15%–35%), resulting in abnormal cell proliferation. Furthermore, both adult and pediatric patients with AML harboring the FLT3 internal tandem duplication (ITD) mutation have a poor prognosis. Several inhibitors have been developed to target mutant FLT3 for the treatment of AML, yet the molecular pathways affected by drug inhibition of the mutated FLT3 receptor alone have not been characterized as yet. Linifanib (ABT-869) is a multitargeted tyrosine kinase receptor inhibitor that suppresses FLT3 signaling. In this article, we show that treatment with linifanib inhibits proliferation and induces apoptosis in ITD mutant cells in vitro and in vivo. We show that treatment with linifanib reduces phosphorylation of Akt and glycogen synthase kinase 3β (GSK3β). In addition, we show that inhibition of GSK3β decreases linifanib-induced apoptosis. This study shows the importance of GSK3 as a potential target for AML therapy, particularly in patients with FLT3 ITD mutations. Mol Cancer Ther; 10(6); 949–59. ©2011 AACR.
Overexpression of Mitotic Centromere–Associated Kinesin Stimulates Microtubule Detachment and Confers Resistance to Paclitaxel
Authors: Ganguly Anutosh , Yang Hailing , Cabral Fernando
Published: April 2011

Numerous studies have implicated mutations in tubulin or the overexpression of specific tubulin genes in resistance to microtubule-targeted drugs. Much less is known about the role of accessory proteins that modulate microtubule behavior in the genesis of drug resistance. Here, we examine mitotic centromere–associated kinesin (MCAK), a member of the kinesin family of microtubule motor proteins that has the ability to stimulate microtubule depolymerization, and show that overexpressing the protein confers resistance to paclitaxel and epothilone A, but increases sensitivity to colcemid. Cells transfected with FLAG-tagged MCAK cDNA using a tet-off–regulated expression system had a disrupted microtubule cytoskeleton and were able to survive a toxic concentration of paclitaxel in the absence, but not in the presence of tetracycline, showing that drug resistance was caused by ectopic MCAK production. Moreover, a population that was heterogeneous with respect to FLAG-MCAK expression became enriched with cells that produced the ectopic protein when it was placed under paclitaxel selection. Similar to previously isolated mutants with altered tubulin, paclitaxel resistant cells resulting from MCAK overexpression were found to have decreased microtubule polymer and a seven-fold increase in the frequency of microtubule detachment from centrosomes. These data are consistent with a model for paclitaxel resistance that is based on stability of the attachment of microtubules to their nucleating centers, and they implicate MCAK in the mechanism of microtubule detachment. Mol Cancer Ther; 10(6); 929–37. ©2011 AACR.
A Coactivator Role of CARM1 in the Dysregulation of β-Catenin Activity in Colorectal Cancer Cell Growth and Gene Expression
Authors: Ou Chen-Yin , LaBonte Melissa J. , Manegold Philipp C. , So Alex Yick-Lun , Ianculescu Irina , Gerke Daniel S. , Yamamoto Keith R. , Ladner Robert D. , Kahn Michael , Kim Jeong Hoon , Stallcup Michael R.
Published: April 2011

Aberrant activation of Wnt/β-catenin signaling, resulting in the expression of Wnt-regulated oncogenes, is recognized as a critical factor in the etiology of colorectal cancer. Occupancy of β-catenin at promoters of Wnt target genes drives transcription, but the mechanism of β-catenin action remains poorly understood. Here, we show that CARM1 (coactivator-associated arginine methyltransferase 1) interacts with β-catenin and positively modulates β-catenin–mediated gene expression. In colorectal cancer cells with constitutively high Wnt/β-catenin activity, depletion of CARM1 inhibits expression of endogenous Wnt/β-catenin target genes and suppresses clonal survival and anchorage-independent growth. We also identified a colorectal cancer cell line (RKO) with a low basal level of β-catenin, which is dramatically elevated by treatment with Wnt3a. Wnt3a also increased the expression of a subset of endogenous Wnt target genes, and CARM1 was required for the Wnt-induced expression of these target genes and the accompanying dimethylation of arginine 17 of histone H3. Depletion of β-catenin from RKO cells diminished the Wnt-induced occupancy of CARM1 on a Wnt target gene, indicating that CARM1 is recruited to Wnt target genes through its interaction with β-catenin and contributes to transcriptional activation by mediating events (including histone H3 methylation) that are downstream from the actions of β-catenin. Therefore, CARM1 is an important positive modulator of Wnt/β-catenin transcription and neoplastic transformation, and may thereby represent a novel target for therapeutic intervention in cancers involving aberrantly activated Wnt/β-catenin signaling. Mol Cancer Res; 9(5); 660–70. ©2011 AACR.
FOXD3 Regulates Migration Properties and Rnd3 Expression in Melanoma Cells
Authors: Katiyar Pragati , Aplin Andrew E.
Published: April 2011

Forkhead transcription factor, Foxd3, plays a critical role during development by controlling the lineage specification of neural crest cells. Notably, Foxd3 is highly expressed during the wave of neural crest cell migration that forms peripheral neurons and glial cells but is downregulated prior to migration of cells that give rise to the melanocytic lineage. Melanoma is the deadliest form of skin cancer and is derived from melanocytes. Recently, we showed that FOXD3 expression is elevated following the targeted inhibition of the B-RAF–MEK (MAP/ERK kinase)–ERK (extracellular signal-regulated kinase)1/2 pathway in mutant B-RAF melanoma cells. Because melanoma cells are highly migratory and invasive in a B-RAF–dependent manner, we explored the role of FOXD3 in these processes. In this study, we show that ectopic FOXD3 expression inhibits the migration, invasion, and spheroid outgrowth of mutant B-RAF melanoma cells. Upregulation of FOXD3 expression following inhibition of B-RAF and MEK correlates with the downregulation of Rnd3, a Rho GTPase and inhibitor of RhoA–ROCK signaling. Indeed, expression of FOXD3 alone was sufficient to downregulate Rnd3 expression at the mRNA and protein levels. Mechanistically, FOXD3 was found to be recruited to the Rnd3 promoter. Inhibition of ROCK partially restored migration in FOXD3-expressing cells. These data show that FOXD3 expression downregulates migration and invasion in melanoma cells and Rnd3, a target known to be involved in these properties. Mol Cancer Res; 9(5); 545–52. ©2011 AACR.
Functional Inactivation of Endogenous MDM2 and CHIP by HSP90 Causes Aberrant Stabilization of Mutant p53 in Human Cancer Cells
Authors: Li Dun , Marchenko Natalia D. , Schulz Ramona , Fischer Victoria , Velasco-Hernandez Talia , Talos Flaminia , Moll Ute M.
Published: April 2011

The tight control of wild-type p53 by mainly MDM2 in normal cells is permanently lost in tumors harboring mutant p53, which exhibit dramatic constitutive p53 hyperstabilization that far exceeds that of wild-type p53 tumors. Importantly, mutant p53 hyperstabilization is critical for oncogenic gain of function of mutant p53 in vivo. Current insight into the mechanism of this dysregulation is fragmentary and largely derived from ectopically constructed cell systems. Importantly, mutant p53 knock-in mice established that normal mutant p53 tissues have sufficient enzymatic reserves in MDM2 and other E3 ligases to maintain full control of mutant p53. We find that in human cancer cells, endogenous mutant p53, despite its ability to interact with MDM2, suffers from a profound lack of ubiquitination as the root of its degradation defect. In contrast to wild-type p53, the many mutant p53 proteins which are conformationally aberrant are engaged in complexes with the HSP90 chaperone machinery to prevent its aggregation. In contrast to wild-type p53 cancer cells, we show that in mutant p53 cancer cells, this HSP90 interaction blocks the endogenous MDM2 and CHIP (carboxy-terminus of Hsp70-interacting protein) E3 ligase activity. Interference with HSP90 either by RNA interference against HSF1, the transcriptional regulator of the HSP90 pathway, or by direct knockdown of Hsp90 protein or by pharmacologic inhibition of Hsp90 activity with 17AAG (17-allylamino-17-demethoxygeldanamycin) destroys the complex, liberates mutant p53, and reactivates endogenous MDM2 and CHIP to degrade mutant p53. Of note, 17AAG induces a stronger viability loss in mutant p53 than in wild-type p53 cancer cells. Our data support the rationale that suppression of mutant p53 levels in vivo in established cancers might achieve clinically significant effects. Mol Cancer Res; 9(5); 577–88. ©2011 AACR.
Mesoscale Controls on the Mountainside Snow Line
Authors: Minder Justin R. , Durran Dale R. , Roe Gerard H.
Published: April 2011

Observations show that on a mountainside the boundary between snow and rain, the snow line, is often located at an elevation hundreds of meters below its elevation in the free air upwind. The processes responsible for this mesoscale lowering of the snow line are examined in semi-idealized simulations with a mesoscale numerical model and in simpler theoretical models. Spatial variations in latent cooling from melting precipitation, in adiabatic cooling from vertical motion, and in the melting distance of frozen hydrometeors are all shown to make important contributions. The magnitude of the snow line drop, and the relative importance of the responsible processes, depends on properties of the incoming flow and terrain geometry. Results suggest that the depression of the snow line increases with increasing temperature, a relationship that, if present in nature, could act to buffer mountain hydroclimates against the impacts of climate warming. The simulated melting distance, and hence the snow line, depends substantially on the choice of microphysical parameterization, pointing to an important source of uncertainty in simulations of mountain snowfall.
The Effect of Mesh Resolution on Convective Boundary Layer Statistics and Structures Generated by Large-Eddy Simulation
Authors: Sullivan Peter P. , Patton Edward G.
Published: April 2011

A massively parallel large-eddy simulation (LES) code for planetary boundary layers (PBLs) that utilizes pseudospectral differencing in horizontal planes and solves an elliptic pressure equation is described. As an application, this code is used to examine the numerical convergence of the three-dimensional time-dependent simulations of a weakly sheared daytime convective PBL on meshes varying from 323 to 10243 grid points. Based on the variation of the second-order statistics, energy spectra, and entrainment statistics, LES solutions converge provided there is adequate separation between the energy-containing eddies and those near the filter cutoff scale. For the convective PBL studied, the majority of the low-order moment statistics (means, variances, and fluxes) become grid independent when the ratio zi/(CsΔf) > 310, where zi is the boundary layer height, Δf is the filter cutoff scale, and Cs is the Smagorinsky constant. In this regime, the spectra show clear Kolmogorov inertial subrange scaling. The bulk entrainment rate determined from the time variation of the boundary layer height we = dzi/dt is a sensitive measure of the LES solution convergence; we becomes grid independent when the vertical grid resolution is able to capture both the mean structure of the overlying inversion and the turbulence. For all mesh resolutions used, the vertical temperature flux profile varies linearly over the interior of the boundary layer and the minimum temperature flux is approximately −0.2 of the surface heat flux. Thus, these metrics are inadequate measures of solution convergence. The variation of the vertical velocity skewness and third-order moments expose the LES’s sensitivity to grid resolution.
Impacts of Idealized Air–Sea Coupling on Madden–Julian Oscillation Structure in the Superparameterized CAM
Authors: Benedict James J. , Randall David A.
Published: April 2011

Air–sea interactions and their impact on intraseasonal convective organization are investigated by comparing two 5-yr simulations from the superparameterized Community Atmosphere Model version 3.0 (SP-CAM). The first is forced using prescribed sea surface temperatures (SSTs). The second is identical except that a simplified oceanic mixed-layer model is used to predict tropical SST anomalies that are coupled to the atmosphere. This partially coupled simulation allows SSTs to respond to anomalous surface fluxes.

Implementation of the idealized slab ocean model in the SP-CAM results in significant changes to intraseasonal convective variability and organization. The more realistic treatment of air–sea interactions in the coupled simulation improves many aspects of tropical convection on intraseasonal scales, from the relationships between precipitation and SSTs to the space–time structure and propagation of the Madden–Julian oscillation (MJO). This improvement is associated with a more realistic convergence structure and longitudinal gradient of SST relative to MJO deep convection. In the uncoupled SP-CAM, SST is roughly in phase with the MJO convective center and the development of the Kelvin wave response and boundary layer convergence east of the convective center is relatively weak. In the coupled SP-CAM, maxima in SST lead maxima in MJO convection by cycle. Coupling produces warmer SSTs, a stronger Kelvin wave response, enhanced low-level convergence, and increased convective heating ahead (east) of the MJO convective center. Convective development east of the MJO precipitation center is more favorable in the coupled versus the uncoupled version, resulting in more realistic organization and clearer eastward propagation of the MJO in the coupled SP-CAM.
Can Wind Lidars Measure Turbulence?
Authors: Sathe A. , Mann J. , Gottschall J. , Courtney M. S.
Published: April 2011

Modeling of the systematic errors in the second-order moments of wind speeds measured by continuous-wave (ZephIR) and pulsed (WindCube) lidars is presented. These lidars use the conical scanning technique to measure the velocity field. The model captures the effect of volume illumination and conical scanning. The predictions are compared with the measurements from the ZephIR, WindCube, and sonic anemometers at a flat terrain test site under different atmospheric stability conditions. The sonic measurements are used at several heights on a meteorological mast in combination with lidars that are placed on the ground. Results show that the systematic errors are up to 90% for the vertical velocity variance, whereas they are up to 70% for the horizontal velocity variance. For the ZephIR, the systematic errors increase with height, whereas for the WindCube, they decrease with height. The systematic errors also vary with atmospheric stability and are low for unstable conditions. In general, for both lidars, the model agrees well with the measurements at all heights and under different atmospheric stability conditions. For the ZephIR, the model results are improved when an additional low-pass filter for the 3-s scan is also modeled. It is concluded that with the current measurement configuration, these lidars cannot be used to measure turbulence precisely.
The Madden–Julian Oscillation’s Influence on African Easterly Waves and Downstream Tropical Cyclogenesis
Authors: Ventrice Michael J. , Thorncroft Chris D. , Roundy Paul E.
Published: April 2011

The influence of the Madden–Julian oscillation (MJO) over tropical Africa and Atlantic is explored during the Northern Hemisphere summer months. The MJO is assessed by using real-time multivariate MJO (RMM) indices. These indices divide the active convective signal of the MJO into 8 phases. Convection associated with the MJO is enhanced over tropical Africa during RMM phases 8, 1, and 2. Convection becomes suppressed over tropical Africa during the subsequent RMM phases (phases 3–7). African convective signals are associated with westward-propagating equatorial Rossby waves.

The MJO modulates African easterly wave (AEW) activity. AEW activity is locally enhanced during RMM phases 1–3 and suppressed during RMM phases 6–8. Enhanced AEW activity occurs during periods of enhanced convection over tropical Africa, consistent with stronger or more frequent triggering of AEWs as well as more growth associated with latent heat release. Enhanced AEW activity occurs during the low-level westerly wind phase of the MJO, which increases the cyclonic shear on the equatorward side of the AEJ, increasing its instability.

Atlantic tropical cyclogenesis frequency varies coherently with the MJO. RMM phases 1–3 show the greatest frequency of tropical cyclogenesis events whereas phases 7 and 8 show the least. RMM phase 2 is also the most likely phase to be associated with a train of three or more tropical cyclones over the tropical Atlantic. This observed evolution of tropical cyclogenesis frequency varies coherently with variations in AEW activity and the large-scale environment.
Cloud Modeling Tests of the ULTIMATE–MACHO Scalar Advection Scheme
Authors: Yamaguchi Takanobu , Randall David A. , Khairoutdinov Marat F.
Published: April 2011

Numerical diffusion can be minimized using fine grid spacing and/or higher-order numerical schemes. In this study, the authors focus on higher-order scalar advection schemes and their effects on simulated cloud fields. A monotonic multidimensional odd-order conservative advection scheme has been implemented, following the approach of Leonard. It has been tested in simulations of idealized scalar fields advected by simple prescribed motion, as well as turbulence fields; large-eddy simulations of turbulent stratocumulus clouds; and simulations of deep convective clouds. New third-, fifth-, and seventh-order schemes are compared with the second-order scheme originally used in the model. For the deep cumulus case, a high-resolution large-eddy simulation with the same domain size is used as a benchmark.

The fifth-order scheme shows much less numerical diffusion than the lower-order scheme. The additional improvement with the seventh-order scheme is minor. The higher-order scheme generally produces simulated cloud fields similar to those obtained with a lower-order scheme with a finer grid spacing. This effect is especially noticeable for the updraft-core statistics of the deep cumulus simulation, as compared with the benchmark simulation. The fifth-order scheme with coarse horizontal resolution produces results close to those of the benchmark simulation. Compared to a high-resolution simulation with the low-order scheme, the numerical cost of the fifth-order simulation is smaller than a factor of 10.
Extremal Dependence Indices: Improved Verification Measures for Deterministic Forecasts of Rare Binary Events
Authors: Ferro Christopher A. T. , Stephenson David B.
Published: April 2011

Verifying forecasts of rare events is challenging, in part because traditional performance measures degenerate to trivial values as events become rarer. The extreme dependency score was proposed recently as a nondegenerating measure for the quality of deterministic forecasts of rare binary events. This measure has some undesirable properties, including being both easy to hedge and dependent on the base rate. A symmetric extreme dependency score was also proposed recently, but this too is dependent on the base rate. These two scores and their properties are reviewed and the meanings of several properties, such as base-rate dependence and complement symmetry that have caused confusion are clarified. Two modified versions of the extreme dependency score, the extremal dependence index, and the symmetric extremal dependence index, are then proposed and are shown to overcome all of its shortcomings. The new measures are nondegenerating, base-rate independent, asymptotically equitable, harder to hedge, and have regular isopleths that correspond to symmetric and asymmetric relative operating characteristic curves.