bluuebunny/crossref_metadata_2025 huggingface dataset:
The Kronecker Summation Method for Robust Stabilization Applied to a Chemical Reactor
Authors: Matušů Radek , Závacká Jana , Prokop Roman , Bakošová Monika
Published: June 2011

The paper focuses on robust stabilization where the suitable parameters of a simple continuous‐time PI controller are determined through a combination of the Kronecker summation method, sixteen plant theorem, and an algebraic approach to control design in the ring of proper and stable rational functions. The initial theoretical background is followed by an illustrative experiment which includes computation of the controller and verification of control results for a continuous stirred tank reactor with exothermic reaction modelled as a fourth‐order interval system.
TP53 Status and Response to Treatment in Breast Cancers
Authors: Varna Mariana , Bousquet Guilhem , Plassa Louis-François , Bertheau Philippe , Janin Anne
Published: June 2011

The p53 wild‐type protein plays an important role in cells as is shown by its fine regulation at different levels. Since its discovery, numerous mutations have been described. In breast cancers, p53 is mutated in almost 30% of cases, with a higher frequency in some tumor subtypes. TP53 mutation is reported to be a factor for good prognosis in some studies, while in others it is a factor for poor prognosis. The explanation for these different results could be linked to the fact that the studies were performed on different tumor types and with different therapy regimens.
Impact of Short-Term Systemic Hypoxia on Phagocytosis, Cytokine Production, and Transcription Factor Activation in Peripheral Blood Cells
Authors: Fritzenwanger Michael , Jung Christian , Goebel Bjoern , Lauten Alexander , Figulla Hans R.
Published: June 2011

Hypoxia frequently associated with certain physiologic and pathologic conditions influences numerous cellular functions. Because the effects of short-term hypoxia are incompletely understood, we examined phagocytosis and cytokine production as well as the activation of the transcription factors HIF-1 and NFκB in peripheral blood cells of healthy volunteers exposed to an oxygen concentration equivalent to that found at a height of 5500 m. Furthermore, we analysed plasma HIF-1 and serum concentrations of various HIF-1-dependent genes. Results showed that short-term hypoxia increased phagocytosis in neutrophils without affecting monocyte phagocytosis. Hypoxia decreased basal TNFα concentration in monocytes and basal interferon γ concentration in CD4+T lymphocytes. In contrast, plasma HIF and serum VEGF concentrations were not affected by hypoxia, although serum EPO concentration was raised. In PBMC, hypoxia increased cytosolic HIF-1 concentration without affecting nuclear HIF-1 concentration and led to a rise in the nuclear NFκB in PBMC. Our results show that short-term hypoxia affects immune functions in healthy individuals. Furthermore, we speculate that the effects of hypoxia are not due to HIF-1, but are caused by the activation of NFκB .
Rayleigh Waves in Generalized Magneto‐Thermo‐Viscoelastic Granular Medium under the Influence of Rotation, Gravity Field, and Initial Stress
Authors: Abd-Alla A. M. , Abo-Dahab S. M. , Bayones F. S.
Published: June 2011

The surface waves
propagation in generalized
magneto‐thermo‐viscoelastic granular medium
subjected to continuous boundary conditions has
been investigated. In addition, it is also
subjected to thermal boundary conditions. The
solution of the more general equations are
obtained for thermoelastic coupling. The
frequency equation of Rayleigh waves is obtained
in the form of a determinant containing a term
involving the coefficient of friction of a
granular media which determines Rayleigh waves
velocity as a real part and the attenuation
coefficient as an imaginary part, and the effects
of rotation, magnetic field, initial stress, viscosity, and
gravity field on Rayleigh waves velocity and
attenuation coefficient of surface waves have
been studied in detail. Dispersion curves are
computed numerically for a specific model and
presented graphically. Some special cases have
also been deduced. The results indicate that the
effect of rotation, magnetic field, initial
stress, and gravity field is very
pronounced.
Near UV-Blue Excitable Green-Emitting Nanocrystalline Oxide
Authors: Rodríguez-García C. E. , Perea-López N. , Hirata G. A.
Published: June 2011

Green-emitting Eu-activated powders were produced by a two-stage method consisting of pressure-assisted combustion synthesis and postannealing in ammonia. The as-synthesized powders exhibited a red photoluminescence (PL) peak located at  nm when excited with  nm UV. This emission peak corresponds to the5D0→7F2transition in Eu3+. After annealing in ammonia, the PL emission changed to an intense broad-band peak centered at  nm, most likely produced by 4f65d1→4f7electronic transitions in Eu2+. This green-emitting phosphor has excitation band in the near UV-blue region (–450 nm). X-ray diffraction analysis reveals mainly the orthorhombic EuAlO3and Al2O3phases. Transmission electron microscopy observations showed that the grains are formed by faceted nanocrystals (~4 nm) of polygonal shape. The excellent excitation and emission properties make these powders very promising to be used as phosphors in UV solid-state diodes coupled to activate white-emitting lamps.
Pulmonary Arteriovenous Malformation (AVM) Causing Tension Hemothorax in a Pregnant Woman Requiring Emergent Cesarean Delivery
Authors: Sood Nidhi , Sood Nikhil , Dhawan Vibhu
Published: June 2011

Pulmonary arteriovenous malformations (PAVMs), although most commonly congenital, are usually detected later in life. We present a case of a 25-year-old woman with no previous history of AVM or telangiectasia, who presented with life-threatening hypoxia, hypotension, and pleuritic chest pain in 36th week of gestation. Chest tube placement revealed 4 liters of blood. Patient was subsequently found to have bleeding pulmonary AVM as the source of hemothorax. Successful embolisation of the bleeding vessel followed by thoracoscopic evacuation of the organized clot relieved the hypoxia. Further screening for AVM revealed large splenic AVM for which patient underwent splenectomy in the coming months.
Killing of Chronic Lymphocytic Leukemia by the Combination of Fludarabine and Oxaliplatin Is Dependent on the Activity of XPF Endonuclease
Authors: Zecevic Alma , Sampath Deepa , Ewald Brett , Chen Rong , Wierda William , Plunkett William
Published: June 2011

Purpose: Chronic lymphocytic leukemia (CLL) resistant to fludarabine-containing treatments responds to oxaliplatin-based therapy that contains fludarabine. We postulated that a mechanism for this activity is the incorporation of fludarabine into DNA during nucleotide excision repair (NER) stimulated by oxaliplatin adducts.

Experimental Design: We analyzed CLL cell viability, DNA damage, and signaling pathways in response to treatment by fludarabine, oxaliplatin, or the combination. The dependency of the combination on oxaliplatin-induced DNA repair was investigated using siRNA in CLL cells or cell line models of NER deficiency.

Results: Synergistic apoptotic killing was observed in CLL cells after exposure to the combination in vitro. Oxaliplatin induced DNA synthesis in CLL cells, which was inhibited by fludarabine and was eliminated by knockdown of XPF, the NER 5′-endonuclease. Wild-type Chinese hamster ovarian cells showed synergistic killing after combination treatment, whereas only additive killing was observed in cells lacking XPF. Inhibition of repair by fludarabine in CLL cells was accompanied by DNA single-strand break formation. CLL cells initiated both intrinsic and extrinsic apoptotic pathways as evidenced by the loss of mitochondrial outer membrane potential and partial inhibition of cell death upon incubation with FasL antibody.

Conclusions: The synergistic cell killing is caused by a mechanistic interaction that requires the initiation of XPF-dependent excision repair in response to oxaliplatin adducts, and the inhibition of that process by fludarabine incorporation into the repair patch. This combination strategy may be useful against other malignancies. Clin Cancer Res; 17(14); 4731–41. ©2011 AACR.
Myeloid Biomarkers Associated with Glioblastoma Response to Anti-VEGF Therapy with Aflibercept
Authors: de Groot John F. , Piao Yuji , Tran Hai , Gilbert Mark , Wu Hua-Kang , Liu Jun , Bekele B. Nebiyou , Cloughesy Tim , Mehta Minesh , Robins H. Ian , Lassman Andrew , DeAngelis Lisa , Camphausen Kevin , Chen Alice , Yung WKA , Prados Michael , Wen Patrick Y. , Heymach John V.
Published: June 2011

Purpose: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma.

Experimental Design: In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients.

Results: Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1+ monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9.

Conclusions: These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis. Clin Cancer Res; 17(14); 4872–81. ©2011 AACR.
Phase I Study Utilizing a Novel Antigen-Presenting Cell–Targeted Vaccine with Toll-like Receptor Stimulation to Induce Immunity to Self-antigens in Cancer Patients
Authors: Morse Michael A. , Chapman Robert , Powderly John , Blackwell Kimberly , Keler Tibor , Green Jennifer , Riggs Renee , He Li-Zhen , Ramakrishna Venky , Vitale Laura , Zhao Biwei , Butler Stephen A. , Hobeika Amy , Osada Takuya , Davis Thomas , Clay Timothy , Lyerly H. Kim
Published: June 2011

Purpose: The use of tumor-derived proteins as cancer vaccines is complicated by tolerance to these self-antigens. Tolerance may be broken by immunization with activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting cells (APC); however, targeting tumor antigen directly to APC in vivo would be a less complicated strategy. We wished to test whether targeted delivery of an otherwise poorly immunogenic, soluble antigen to APC through their mannose receptors (MR) would induce clinically relevant immunity.

Experimental Design: Two phase I studies were conducted with CDX-1307, a vaccine composed of human chorionic gonadotropin beta-chain (hCG-β) fused to an MR-specific monoclonal antibody, administered either locally (intradermally) or systemically (intravenously) in patients with advanced epithelial malignancies. An initial dose escalation of single-agent CDX-1307 was followed by additional cohorts of CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC.

Results: CDX-1307 induced consistent humoral and T-cell responses to hCG-β when coadministered with TLR agonists. Greater immune responses and clinical benefit, including the longest duration of stable disease, were observed with immunization combined with local TLR agonists. Immune responses were induced equally efficiently in patients with elevated and nonelevated levels of serum hCG-β. Antibodies within the serum of vaccinated participants had tumor suppressive function in vitro. Toxicity consisted chiefly of mild injection site reactions.

Conclusions: APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer immunotherapy. Clin Cancer Res; 17(14); 4844–53. ©2011 AACR.
Molecular and Cellular Pharmacology of the Novel Noncamptothecin Topoisomerase I Inhibitor Genz-644282
Authors: Sooryakumar Dhriti , Dexheimer Thomas S. , Teicher Beverly A. , Pommier Yves
Published: June 2011

Camptothecin derivatives are powerful anticancer drugs because of their ability to trap topoisomerase I (Top1)–DNA cleavage complexes. However, they exhibit clinical limitations due to the instability of their α-hydroxylactone six-membered E-ring structure. In addition, they exhibit bone marrow and intestinal toxicity, especially in adults, and are drug efflux substrates. Here, we report a novel Top1 inhibitor, Genz-644282. We show that Genz-644282 and its metabolites induce Top1 cleavage at similar, as well as unique genomic positions, compared with camptothecin. The compound also induces protein-linked DNA breaks and Top1–DNA cleavage complexes that persist longer after compound removal than camptothecin. Concentration-dependent and persistent γH2AX formation was readily observed in cells treated with Genz-644282, and was present in greater than 50% of the cell population following 24 hours compound exposure. The compound shows partial cross-resistance in cell lines resistant to camptothecin. These cell lines include the human prostate DU145RC0.1 and the leukemic CEM/C2 cells. Limited cross-resistance to Genz-644282 was also found in the Top1 knockdown colon cancer (HCT116) and breast cancer (MCF7) cell lines and in human adenocarcinoma cells (KB31/KBV1) that overexpress (P-glycoprotein, ABCB1), a member of the ATP-binding cassette family of cell surface transport proteins known to confer MDR. Together, our results provide the first molecular and cellular characterization of Genz-644282 and its clinically relevant metabolites. Mol Cancer Ther; 10(8); 1490–9. ©2011 AACR.
Phenotypic Reversion of Invasive Neurofibromin-Deficient Schwannoma by FTS: Ras Inhibition Reduces BMP4/Erk/Smad Signaling
Authors: Barkan Batya , Kloog Yoel , Ehrlich Marcelo
Published: June 2011

Neurofibromin-deficient (Nf1−/−) malignant peripheral nerve sheath tumors (MPNST) are highly invasive, refractory to chemotherapy, and characterized by overactivated Ras. Ras activates mitogenic pathways and regulates morphogenic programs—such as those induced by bone morphogenetic proteins (BMP) and TGF-β. The role of such a cross-talk in determining the phenotype and transformation potential of MPNSTs is unknown. Here, we used MPNST cell lines and selective Ras inhibition with S-trans,trans-farnesylthiosalicylic-acid (FTS; salirasib) in conjunction with specific inhibitors of TGF-β and BMP signaling. FTS perturbed signaling of BMP4 and TGF-β1 to Smad-dependent and Erk-dependent pathways. Furthermore, FTS inhibited motility and spreading, reduced the gelatinase secretion, eliminated the expression and activation of regulators of cell–matrix interaction, and altered gene expression. These phenomena are indicative of a phenotypic reversion of NF1-defficient cells by FTS. Inhibition of BMP4 and TGF-β by noggin and SB-431542, respectively, mimicked the FTS-mediated effects on adhesion, spreading, and cell morphology. This strongly suggests that a cross-talk among TGF-β superfamily ligands and Ras plays a significant role in the transformation of NF1−/− MPNSTs. Our results support the therapeutic potential of FTS, in conjuncture with BMP and TGF-β pathway inhibitors, toward the inhibition of mitogenic and morphogenic signaling pathways and the alleviation of NF1 symptoms. Mol Cancer Ther; 10(8); 1317–26. ©2011 AACR.
Evaluation of Difluoromethylornithine for the Chemoprevention of Barrett's Esophagus and Mucosal Dysplasia
Authors: Sinicrope Frank A. , Broaddus Russell , Joshi Nina , Gerner Eugene , Half Elizabeth , Kirsch Ilan , Lewin Jan , Morlan Bruce , Hong Waun Ki
Published: June 2011

Patients with Barrett's esophagus (BE) and dysplasia are candidates for chemopreventive strategies to reduce cancer risk. We determined the effects of difluoromethylornithine (DMFO) on mucosal polyamines, gene expression, and histopathology in BE. Ten patients with BE and low-grade dysplasia participated in a single-arm study of DFMO (0.5 g/m2/d) given continuously for 6 months. Esophagoscopy with biopsies was conducted at baseline, 3, 6, and 12 months. Dysplasia was graded by a gastrointestinal pathologist. Audiology was assessed (at baseline and at 6 months). Mucosal polyamines were measured by high-performance liquid chromatography. Microarray-based gene expression was analyzed using a cDNA two-color chip. DFMO suppressed levels of the polyamines putrescine (P = 0.02) and spermidine (P = 0.02) and the spermidine/spermine ratio (P < 0.01) in dysplastic BE (6 months vs. baseline) that persisted at 6 months following drug cessation. Among the top 25 modulated genes, we found those regulating p53-mediated cell signaling (RPL11), cell-cycle regulation (cyclin E2), and cell adhesion and invasion (Plexin1). DFMO downregulated Krüppel-like factor 5 (KLF5), a transcription factor promoting cell proliferation, and suppressed RFC5 whose protein interacts with proliferating cell nuclear antigen. Histopathology showed regression of dysplasia (n = 1), stable disease (n = 8), and progression to high-grade dysplasia (n = 1). Polyamines were suppressed in the responder to a greater extent than in stable cases. DFMO was well tolerated, and one patient had subclinical, unilateral ototoxicity. DFMO suppressed mucosal polyamines and modulated genes that may be mechanistically related to its chemopreventive effect. Further study of DFMO for the chemoprevention of esophageal cancer in BE patients is warranted. Cancer Prev Res; 4(6); 829–39. ©2011 AACR.
Bexarotene Plus Erlotinib Suppress Lung Carcinogenesis Independent of KRAS Mutations in Two Clinical Trials and Transgenic Models
Authors: Dragnev Konstantin H. , Ma Tian , Cyrus Jobin , Galimberti Fabrizio , Memoli Vincent , Busch Alexander M. , Tsongalis Gregory J. , Seltzer Marc , Johnstone David , Erkmen Cherie P. , Nugent William , Rigas James R. , Liu Xi , Freemantle Sarah J. , Kurie Jonathan M. , Waxman Samuel , Dmitrovsky Ethan
Published: June 2011

The rexinoid bexarotene represses cyclin D1 by causing its proteasomal degradation. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib represses cyclin D1 via different mechanisms. We conducted a preclinical study and 2 clinical/translational trials (a window-of-opportunity and phase II) of bexarotene plus erlotinib. The combination repressed growth and cyclin D1 expression in cyclin-E- and KRAS/p53-driven transgenic lung cancer cells. The window-of-opportunity trial in early-stage non–small-cell lung cancer (NSCLC) patients (10 evaluable), including cases with KRAS mutations, repressed cyclin D1 (in tumor biopsies and buccal swabs) and induced necrosis and inflammatory responses. The phase II trial in heavily pretreated, advanced NSCLC patients (40 evaluable; a median of two prior relapses per patient (range, 0–5); 21% with prior EGFR-inhibitor therapy) produced three major clinical responses in patients with prolonged progression-free survival (583-, 665-, and 1,460-plus days). Median overall survival was 22 weeks. Hypertriglyceridemia was associated with an increased median overall survival (P = 0.001). Early PET (positron emission tomographic) response did not reliably predict clinical response. The combination was generally well tolerated, with toxicities similar to those of the single agents. In conclusion, bexarotene plus erlotinib was active in KRAS-driven lung cancer cells, was biologically active in early-stage mutant KRAS NSCLC, and was clinically active in advanced, chemotherapy-refractory mutant KRAS tumors in this study and previous trials. Additional lung cancer therapy or prevention trials with this oral regimen are warranted. Cancer Prev Res; 4(6); 818–28. ©2011 AACR.
Oral Iloprost Improves Endobronchial Dysplasia in Former Smokers
Authors: Keith Robert L. , Blatchford Patrick J. , Kittelson John , Minna John D. , Kelly Karen , Massion Pierre P. , Franklin Wilbur A. , Mao Jenny , Wilson David O. , Merrick Daniel T. , Hirsch Fred R. , Kennedy Timothy C. , Bunn Paul A. , Geraci Mark W. , Miller York E.
Published: June 2011

There are no established chemopreventive agents for lung cancer, the leading cause of cancer death in the United States. Prostacyclin levels are low in lung cancer and supplementation prevents lung cancer in preclinical models. We carried out a multicenter double-blind, randomized, phase II placebo-controlled trial of oral iloprost in current or former smokers with sputum cytologic atypia or endobronchial dysplasia. Bronchoscopy was performed at study entry and after completion of six months of therapy. Within each subject, the results were calculated by using the average score of all biopsies (Avg), the worst biopsy score (Max), and the dysplasia index (DI). Change in Avg was the primary end point, evaluated in all subjects, as well as in current and former smokers. The accrual goal of 152 subjects was reached and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure, and baseline histology. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). When compared with placebo, former smokers receiving oral iloprost exhibited a significantly greater improvement in Avg (0.41 units better, P = 0.010), in Max (1.10 units better, P = 0.002), and in DI (12.45%, P = 0.006). No histologic improvement occurred in current smokers. Oral iloprost significantly improves endobronchial histology in former smokers and deserves further study to determine if it can prevent the development of lung cancer. Cancer Prev Res; 4(6); 793–802. ©2011 AACR.
Biomarkers in Exploring the Frontiers of Diagnosis, Prognosis, and Therapy of Barrett's Esophagus
Authors: Yachimski Patrick , Peek Richard M.
Published: June 2011

Barrett's esophagus (BE) is the principal risk factor for esophageal adenocarcinoma. BE patients currently undergo periodic endoscopic surveillance with tissue sampling and histopathologic assessment for dysplasia. They frequently are prescribed proton pump inhibitors to pharmacologically suppress gastric acid that is the cause of BE. These standard endoscopic and pharmacologic approaches for managing BE are crude at best. Identification of novel tissue biomarkers within BE may allow for more accurate endoscopic risk stratification and provide potential targets for chemoprevention. Cancer Prev Res; 4(6); 783–6. ©2011 AACR.
Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic Apolipoprotein E−/− Mice
Authors: Vedantham Srinivasan , Noh HyeLim , Ananthakrishnan Radha , Son Ni , Hallam Kellie , Hu Yunying , Yu Shuiquing , Shen Xiaoping , Rosario Rosa , Lu Yan , Ravindranath Thyyar , Drosatos Konstantinos , Huggins Lesley Ann , Schmidt Ann Marie , Goldberg Ira J. , Ramasamy Ravichandran
Published: June 2011

Objective—

There are several pathways that mediate the aberrant metabolism of glucose and that might induce greater vascular damage in the setting of diabetes. The polyol pathway mediated by aldose reductase (AR) has been postulated to be one such pathway. However, it has been reported that AR reduces toxic lipid aldehydes and, under some circumstances, might be antiatherogenic.

Methods and Results—

Atherosclerosis development was quantified in 2 lines of transgenic mice expressing human AR (hAR) crossed on the apolipoprotein E knockout background. The transgenes were used to increase the normally low levels of this enzyme in wild-type mice. Both generalized hAR overexpression and hAR expression via the Tie 2 promoter increased lesion size in streptozotocin diabetic mice. In addition, pharmacological inhibition of AR reduced lesion size.

Conclusion—

Although in some settings AR expression might reduce levels of toxic aldehydes, transgenic expression of this enzyme within the artery wall leads to greater atherosclerosis.
Overexpression of VEGF
165
b, an Inhibitory Splice Variant of Vascular Endothelial Growth Factor, Leads to Insufficient Angiogenesis in Patients With Systemic Sclerosis
Authors: Manetti Mirko , Guiducci Serena , Romano Eloisa , Ceccarelli Claudia , Bellando-Randone Silvia , Conforti Maria Letizia , Ibba-Manneschi Lidia , Matucci-Cerinic Marco
Published: June 2011

Rationale:

Systemic sclerosis (SSc) is characterized by widespread microangiopathy, fibrosis, and autoimmunity. Despite the lack of angiogenesis, the expression of vascular endothelial growth factor A (VEGF) was shown to be upregulated in SSc skin and circulation; however, previous studies did not distinguish between proangiogenic VEGF
165
and antiangiogenic VEGF
165
b isoforms, which are generated by alternative splicing in the terminal exon of VEGF pre-RNA.

Objective:

We investigated whether VEGF isoform expression could be altered in skin and circulation of patients with SSc.

Methods and Results:

Here, we show that the endogenous antiangiogenic VEGF
165
b splice variant is selectively overexpressed at both the mRNA and protein levels in SSc skin. Elevated VEGF
165
b expression correlated with increased expression of profibrotic transforming growth factor-β1 and serine/arginine protein 55 splicing factor in keratinocytes, fibroblasts, endothelial cells, and perivascular inflammatory cells. Circulating levels of VEGF
165
b were significantly higher in patients with SSc than in control subjects. Microvascular endothelial cells (MVECs) isolated from SSc skin expressed and released higher levels of VEGF
165
b than healthy MVECs. Transforming growth factor-β1 upregulated the expression of VEGF
165
b and serine/arginine protein 55 in both SSc and healthy MVECs. In SSc MVECs, VEGF receptor-2 was overexpressed, but its phosphorylation was impaired. Recombinant VEGF
165
b and SSc-MVEC–conditioned medium inhibited VEGF
165
-mediated VEGF receptor-2 phosphorylation and capillary morphogenesis in healthy MVECs. The addition of anti-VEGF
165
b blocking antibodies abrogated the antiangiogenic effect of SSc-MVEC–conditioned medium. Capillary morphogenesis was severely impaired in SSc MVECs and could be ameliorated by treatment with recombinant VEGF
165
and anti-VEGF
165
b blocking antibodies.

Conclusions:

In SSc, a switch from proangiogenic to antiangiogenic VEGF isoforms may have a crucial role in the insufficient angiogenic response to chronic ischemia.
White Matter Hyperintensity Penumbra
Authors: Maillard Pauline , Fletcher Evan , Harvey Danielle , Carmichael Owen , Reed Bruce , Mungas Dan , DeCarli Charles
Published: June 2011

Background and Purpose—

White matter hyperintensities (WMHs) are associated with progressive age-related cognitive decline and cardiovascular risk factors, but their biological relevance as indicators of generalized white matter injury is unclear. Diffusion tensor imaging provides more sensitive indications of subtle white matter disruption and can therefore clarify whether WMHs represent foci of generalized white matter damage that extends over a broader neighborhood.

Methods—

Two hundred eight participants from the University of California, Davis Alzheimer's Disease Center received a comprehensive clinical evaluation and brain MRI including fluid-attenuated inversion recovery and diffusion tensor imaging sequences. Voxelwise maps of WMHs were produced from fluid-attenuated inversion recovery using a standardized WMH detection protocol. Fractional anisotropy maps were calculated from diffusion tensor imaging. All WMH and fractional anisotropy maps were coregistered to a standardized space. For each normal-appearing white matter voxel in each subject fluid-attenuated inversion recovery scan, a neighborhood white matter injury score was calculated that increased with increasing number and proximity of WMH in the vicinity of the normal-appearing white matter voxel. Fractional anisotropy was related to neighborhood white matter injury using a nonlinear mixed effect model controlling for relevant confounding factors.

Results—

Fractional anisotropy was found to decrease as neighborhood white matter injury increased (β=−0.0017/%,
P
<0.0001) with an accelerated rate (
P
<0.0001) for neighborhood white matter injury >0.4. An increase of 1% in neighborhood white matter injury score was associated with a decrease in mean fractional anisotropy of 0.012 (
P
<0.001).

Conclusions—

WMH may represent foci of more widespread and subtle white matter changes rather than distinct, sharply delineated anatomic abnormalities. We use the term white matter hyperintensities penumbra to explain this phenomenon.
Biases and Model Agreement in Projections of Climate Extremes over the Tropical Pacific
Authors: Perkins Sarah E.
Published: June 2011

Using the Coupled Model Intercomparison Project phase 3 (CMIP3) general circulation models (GCMs), projections of a range of climate extremes are explored for the western Pacific. These projections include the 1-in-20-yr return levels and a selection of climate indices for minimum temperature, maximum temperature, and precipitation, and they are compared to corresponding mean projections for the Special Report on Emission Scenarios (SRES) A2 scenario during 2081–2100. Models are evaluated per variable based on their ability to simulate current extremes, as well as the overall daily distribution. Using the standardized evaluation scores for each variable, models are divided into four subsets where ensemble variability is calculated to measure model uncertainty and biases are calculated in respect to the multimodel ensemble (MME). Results show that higher uncertainty in projections of climate extremes exists when compared to the mean, even in those subsets consisting of higher-skilled models. Higher uncertainty exists for precipitation projections than for temperature, and biases and uncertainties in the 1-in-20-yr precipitation events are an order of magnitude higher than the corresponding mean. Poorer performing models exhibit a cooler bias in the mean and 1-in-20-yr return levels for maximum and minimum temperature, and ensemble variability is low among all subsets of mean minimum temperature, especially the lower-skilled subsets. Higher-skilled models project 1-in-20-yr precipitation return levels that are more intense than in the MME. The frequency of temperature extremes increase dramatically; however, this is explained by the underpinning small temperature range of the region. Although some systematic biases occur in the higher- and lower-skilled models and omitting the poorer performers is recommended, great care should be exercised when interpreting the reduction of uncertainty because the ensemble variability among the remaining models is comparable and in some cases greater than the MME. Such results should be treated on a case-by-case basis.
Impact of Upstream Urbanization on the Urban Heat Island Effects along the Washington–Baltimore Corridor
Authors: Zhang Da-Lin , Shou Yi-Xuan , Dickerson Russell R. , Chen Fei
Published: June 2011

Although there has been considerable research on urban heat island (UHI) effects, most of the previous studies have attributed UHI effects to localized, surface processes. In this study, the impact of upstream urbanization on enhanced UHI effects is examined using surface observations and numerical simulations of an extreme UHI event that occurred on 9 July 2007 over Baltimore, Maryland. Under southwesterly wind, Baltimore experienced higher peak surface temperatures and higher pollution concentrations than did the larger urban area of Washington, D.C. Results from a coupled ultrahigh-resolution mesoscale–urban canopy model with 2001 National Land Cover Data show an advective contribution from upstream urbanization to the UHI event. This dynamical process is demonstrated by replacing Baltimore or its upstream urban areas by natural vegetation (in the model), indicating that the UHI effects could be reduced by as much as 25%. An analysis of the urban–bay interaction reveals the importance of horizontal wind direction in determining the intensity of bay breezes and the urban boundary layer structures. In addition, the vertical growth and structures of UHI effects are shown as layered “hot plumes” in the mixed layer with pronounced rising motions, and these plumes can be advected many kilometers downstream. These findings suggest that judicious land use and urban planning, especially in rapidly developing countries, could help to alleviate UHI consequences, including heat stress and smog. They also have important implications for improving the prediction of urban weather, including the initiation of moist convection, air quality, and other environment-related problems.
Boundary Layer Turbulence and Orographic Precipitation Growth in Cold Clouds: Evidence from Profiling Airborne Radar Data
Authors: Geerts Bart , Miao Qun , Yang Yang
Published: June 2011

Airborne vertically pointing Doppler radar data collected in 10 winter storms over the Medicine Bow Range in Wyoming are used to examine the importance of boundary layer (BL) turbulence for orographic precipitation growth. In all 10 cases, the cloud-base temperature was below 0°C and the bulk Froude number was more than 1.0, implying little or no blocking of the flow by the mountain barrier. Seven of the 10 storms sampled were postfrontal, with weak static stability and relatively shallow cloud tops.

Doppler vertical velocity transects depict an approximately 1-km-deep turbulent layer draped over the terrain, sometimes clearly distinct from the stratified flow in the free troposphere aloft, where vertical motion is largely controlled by gravity wave dynamics. Spectral analysis of near-surface Doppler vertical velocity data in terrain-following coordinates reveals an inertial subrange with decreasing power with height toward the BL top. The composite of radar data profiles from the 10 flights is analyzed in frequency-by-altitude diagrams, with altitude expressed above ground level. These diagrams indicate a wide range of vertical velocities in the BL, and rapid snow growth within the BL as air rises through the cloud base, especially when BL turbulence is more intense. This snow growth is concentrated on the windward side of mountains, above the terrain–cloud base intersection. The dominant snow growth mechanism in the BL (i.e., by accretion or vapor deposition) cannot be established because of restrictions in aircraft flight level over complex terrain. Snow aggregation may have contributed to the observed rapid increase in reflectivity in the BL along the windward slope.
Nocturnal Aerosol Optical Depth Measurements with a Small-Aperture Automated Photometer Using the Moon as a Light Source
Authors: Berkoff Timothy A. , Sorokin Mikail , Stone Tom , Eck Thomas F. , Hoff Raymond , Welton Ellsworth , Holben Brent
Published: June 2011

A method is described that enables the use of lunar irradiance to obtain nighttime aerosol optical depth (AOD) measurements using a small-aperture photometer. In this approach, the U.S. Geological Survey lunar calibration system was utilized to provide high-precision lunar exoatmospheric spectral irradiance predictions for a ground-based sensor location, and when combined with ground measurement viewing geometry, provided the column optical transmittance for retrievals of AOD. Automated multiwavelength lunar measurements were obtained using an unmodified Cimel-318 sunphotometer sensor to assess existing capabilities and enhancements needed for day/night operation in NASA’s Aerosol Robotic Network (AERONET). Results show that even existing photometers can provide the ability for retrievals of aerosol optical depths at night near full moon. With an additional photodetector signal-to-noise improvement of 10–100, routine use over the bright half of the lunar phase and a much wider range of wavelengths and conditions can be achieved. Although the lunar cycle is expected to limit the frequency of observations to 30%–40% compared to solar measurements, nevertheless this is an attractive extension of AERONET capabilities.
XSBR/NR Rubber Blends Filled with Polystyrene-Encapsulated Nanosilica Prepared by in situ Differential Microemulsion Polymerization
Authors: Chuayjuljit Saowaroj , Luecha Wasuthep
Published: June 2011

Rubber blends of caboxylated styrene butadiene rubber (XSBR) and natural rubber (NR) filled with polystyrene-encapsulated nanosilica (PS-nSiO 2) were prepared by latex compounding. The PS-nSiO2 synthesized by in situ differential microemulsion polymerization was used at 3 phr as the filler in three different XSBR/NR blend ratios (70/30, 50/50, and 30/70). The nanocomposite latex was cast into sheets on glass molds and cured in an oven. The specimens were examined for their tensile properties, dynamic mechanical properties, and thermal stability. The tensile strength and elongation at break were found to increase with increasing levels of NR in the rubber blends, but the modulus decreased. Moreover, the tensile properties, dynamic mechanical properties, and thermal stability were all improved by the addition of PS-nSiO2 within the blend systems.
Self-reported handling of bullying among junior high school teachers in Finland
Authors: Sairanen Leena , Pfeffer Karen
Published: June 2011

Teachers play an important role in bullying prevention. This study examines teachers' views on the extent and ways in which they would intervene in bullying situations. The sample comprised 136 teachers from junior high schools in Finland (107 females and 29 males). Years of service ranged from newly qualified to over 20 years of experience. Seventy teachers reported they had previously received training for school bullying situations. Participants completed the Handling Bullying Questionnaire which measures teachers' responses to five key aspects of intervention: working with bullies, working with victims, disciplining the bully, enlisting other adults and the extent of ignoring the incident. Results indicated that, overall, teachers were most inclined to discipline the bullies, followed by enlisting other adults, working with bullies, working with victims, and finally ignoring the incident. Anti-bullying training was found to be a significant factor in explaining teachers' handling of bullying. Teachers with over 20 years of experience were more likely to report that they would work with the bully than teachers with less than ten years service. Implications of the findings were discussed with regards to the provision of anti-bullying training.
Addressing cases of bullying through the Method of Shared Concern
Authors: Rigby Ken , Griffiths Coosje
Published: June 2011

Reports from schoolchildren in a variety of countries suggest that school-based interventions tackling cases of bullying are often unsuccessful. Closer attention is needed to the adequacy and appropriateness of specific forms of intervention. This article examines the contribution that can be made through the use of a non-punitive approach known as the Method of Shared Concern. Its use was explored in depth in 17 cases of moderately severe peer victimization in which the Method was applied in schools by trained practitioners. Detailed reports of the meetings with students suspected of bullying and the target were obtained from the practitioners. The practitioners and each of the students were subsequently interviewed to ascertain the effectiveness of the Method. Despite some variations in the way the Method was implemented, positive outcomes were achieved in a large majority of cases for a range of age groups and educational settings. Appropriate and inappropriate applications of the Method in resolving bully/victim problems are examined and discussed.
Modeling the Measurements of Cochlear Microcirculation and Hearing Function after Loud Noise
Authors: Arpornchayanon Warangkana , Canis Martin , Suckfuell Markus , Ihler Fritz , Olzowy Bernhard , Strieth Sebastian
Published: June 2011

Objective

Recent findings support the crucial role of microcirculatory disturbance and ischemia for hearing impairment especially after noise‐induced hearing loss (NIHL). The aim of this study was to establish an animal model for in vivo analysis of cochlear microcirculation and hearing function after a loud noise to allow precise measurements of both parameters in vivo.

Study Design

Randomized controlled trial.

Setting

Animal study.

Subjects and Methods

After assessment of normacusis (0 minutes) using evoked auditory brainstem responses (ABRs), noise (106‐dB sound pressure level [SPL]) was applied to both ears in 6 guinea pigs for 30 minutes while unexposed animals served as controls. In vivo fluorescence microscopy of the stria vascularis capillaries was performed after surgical exposure of 1 cochlea. ABR measurements were derived from the contralateral ear.

Results

After noise exposure, red blood cell velocity was reduced significantly by 24.3% (120 minutes) and further decreased to 44.5% at the end of the observation (210 minutes) in contrast to stable control measurements. Vessel diameters were not affected in both groups. A gradual decrease of segmental blood flow became significant (38.1%) after 150 minutes compared with controls. Hearing thresholds shifted significantly from 20.0 ± 5.5 dB SPL (0 minutes) to 32.5 ± 4.2 dB SPL (60 minutes) only in animals exposed to loud noise.

Conclusion

With regard to novel treatments targeting the stria vascularis in NIHL, this standardized model allows us to analyze in detail cochlear microcirculation and hearing function in vivo.
Effects of virtual reality training on functional reaching movements in people with Parkinson’s disease: a randomized controlled pilot trial
Authors: Ma Hui-Ing , Hwang Wen-Juh , Fang Jing-Jing , Kuo Jui-Kun , Wang Ching-Yi , Leong Iat-Fai , Wang Tsui-Ying
Published: June 2011

Objective: To investigate whether practising reaching for virtual moving targets would improve motor performance in people with Parkinson’s disease.

Design: Randomized pretest–posttest control group design.

Setting: A virtual reality laboratory in a university setting.

Participants: Thirty-three adults with Parkinson’s disease.

Interventions: The virtual reality training required 60 trials of reaching for fast-moving virtual balls with the dominant hand. The control group had 60 practice trials turning pegs with their non-dominant hand.

Main outcome measures: Pretest and posttest required reaching with the dominant hand to grasp real stationary balls and balls moving at different speeds down a ramp. Success rates and kinematic data (movement time, peak velocity and percentage of movement time for acceleration phase) from pretest and posttest were recorded to determine the immediate transfer effects.

Results: Compared with the control group, the virtual reality training group became faster ( F = 9.08, P = 0.005) and more forceful ( F = 9.36, P = 0.005) when reaching for real stationary balls. However, there was no significant difference in success rate or movement kinematics between the two groups when reaching for real moving balls.

Conclusion: A short virtual reality training programme improved the movement speed of discrete aiming tasks when participants reached for real stationary objects. However, the transfer effect was minimal when reaching for real moving objects.
Effects of vitamin E on reproductive hormones and testis structure in chronic dioxin-treated mice
Authors: Yin Hai-Ping , Xu Jian-Ping , Zhou Xian-Qing , Wang Ying
Published: June 2011

The purpose of this study was to investigate the effects of vitamin E on reproductive hormones and testis structure in mice treated with 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). Five experimental groups of a combination of TCDD and vitamin E were designed as follows: 0 ng/kg/d and 0 mg/kg/d (control group), 100 ng/kg/d and 0 mg/kg/d (Group I), 100 ng/kg/d and 20 mg/kg/d (Group II), 100 ng/kg/d and 100 mg/kg/d (Group III), and 100 ng/kg/d and 500 mg/kg/d (Group IV) respectively. Vitamin E and TCDD were given by oral gavage for 7 weeks. The results demonstrated that TCDD decreased the levels of brain gonadotropin releasing hormone (GnRH), testis luteinizing hormone (LH) and follicle stimulating hormone (FSH), serum testosterone and testis spermatozoa number, and damaged testis structure. Vitamin E at 20 mg/kg alleviated the decrease of GnRH; vitamin E at 20, 100, and 500 mg/kg antagonized the decline of LH and FSH; vitamin E at 20 and 100 mg/kg reversed the decrease of testosterone and spermatozoa number; and vitamin E at 100 mg/kg decreased the damage of the testis structure caused by TCDD. The results indicate that vitamin E antagonizes the reproductive endocrine toxicity and alleviates the changes in testicular structure caused by TCDD.
Reducing the emissions and fuel consumption of a spark ignition engine by utilizing heat exchangers in the exhaust gas stream
Authors: Eftekhar M , Keshavarz A
Published: June 2011

In this study, an analytical technique has been used to design four types of heat exchanger in a spark ignition engine in an attempt to reduce both the warm-up period and the exhaust gas temperature under high-load conditions. The heat exchangers are installed in two different positions. One is installed after the outlet of the close-coupled catalytic converter to reduce the warm-up period, using the exhaust gas energy, and the other is installed between the exhaust manifold and the inlet of the close-coupled catalytic converter to avoid thermal ageing. To increase the heat transfer between the exhaust gas and the engine coolant, internally finned tubes have been selected. The first and second laws of thermodynamics are applied to optimize the number of fins and their geometry (i.e. the height and the thickness). Finally, the impact of heat exchangers on the warm-up period and the catalyst inlet temperature at high loads are presented. The results indicate that both the warm-up period and the exhaust gas temperature are decreased when the heat exchangers are installed along the exhaust gas stream. The results also show that a heat exchanger in the exhaust gas stream has the potential to reduce the requirement for high-load component-protection fuelling which, in turn, results in reduced fuel consumption and emissions.