bluuebunny/crossref_metadata_2025 huggingface dataset:
Mucopolysaccharidosis type IIIA: Clinical spectrum and genotype‐phenotype correlations
Authors: Valstar Marlies J. , Neijs Sanne , Bruggenwirth Hennie T. , Olmer Renske , Ruijter George J. G. , Wevers Ron A. , van Diggelen Otto P. , Poorthuis Ben J. , Halley Dicky J. , Wijburg Frits A.
Published: November 2010

Objective

Mucopolysaccharidosis (MPS) IIIA (Sanfilippo syndrome type A) is a lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. Information on the natural course of MPS IIIA is scarce, but is much needed in view of emerging therapies.

Methods

Clinical history and molecular defects of all 110 MPS IIIA patients identified by enzymatic studies in the Netherlands were collected and included in this study.

Results

First clinical signs, mainly consisting of delayed speech development and behavioral problems, were noted between the ages of 1 and 6 years. Other symptoms included sleeping and hearing problems, recurrent upper airway infections, diarrhea, and epilepsy. The clinical course varied remarkably and could be correlated with the molecular defects. The frequent pathogenic mutations p.R245H, p.Q380R, p.S66W, and c.1080delC were associated with the classical severe phenotype. Patients compound heterozygous for the p.S298P mutation in combination with 1 of the mutations associated with the classical severe phenotype had a significantly longer preservation of psychomotor functions and a longer survival. Two patients homozygous for the p.S298P mutation, and 4 patients from 3 families heterozygous for 3 missense variants not reported previously (p.T421R, p.P180L, and p.L12Q), showed a remarkably attenuated phenotype.

Interpretation

We report the natural history and mutational analysis in a large unbiased cohort of MPS IIIA patients. We demonstrate that the clinical spectrum of MPS IIIA is much broader than previously reported. A significant genotype‐phenotype correlation was established in this cohort. Ann Neurol 2010
Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis
Authors: Campbell Graham R. , Ziabreva Iryna , Reeve Amy K. , Krishnan Kim J. , Reynolds Richard , Howell Owen , Lassmann Hans , Turnbull Doug M. , Mahad Don J.
Published: November 2010

Objective

Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS). Mitochondria are now established to play a part in the pathogenesis of MS. Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system. We explored mitochondrial respiratory chain activity and mtDNA deletions in single neurons from secondary progressive MS (SPMS) cases.

Methods

Ninety‐eight snap‐frozen brain blocks from 13 SPMS cases together with complex IV/complex II histochemistry, immunohistochemistry, laser dissection microscopy, long‐range and real‐time PCR and sequencing were used to identify and analyze respiratory‐deficient neurons devoid of complex IV and with complex II activity.

Results

The density of respiratory‐deficient neurons in SPMS was strikingly in excess of aged controls. The majority of respiratory‐deficient neurons were located in layer VI and immediate subcortical white matter (WM) irrespective of lesions. Multiple deletions of mtDNA were apparent throughout the gray matter (GM) in MS. The respiratory‐deficient neurons harbored high levels of clonally expanded mtDNA deletions at a single‐cell level. Furthermore, there were neurons lacking mtDNA‐encoded catalytic subunits of complex IV. mtDNA deletions sufficiently explained the biochemical defect in the majority of respiratory‐deficient neurons.

Interpretation

These findings provide evidence that neurons in MS are respiratory‐deficient due to mtDNA deletions, which are extensive in GM and may be induced by inflammation. We propose induced multiple deletions of mtDNA as an important contributor to neurodegeneration in MS. Ann Neurol 2010
Predictors of neurologic outcome in hypothermia after cardiac arrest
Authors: Fugate Jennifer E. , Wijdicks Eelco F.M. , Mandrekar Jay , Claassen Daniel O. , Manno Edward M. , White Roger D. , Bell Malcolm R. , Rabinstein Alejandro A.
Published: November 2010

Objective

To evaluate the predictive value of neurologic prognostic indicators for patients treated with hypothermia after surviving cardiopulmonary arrest.

Methods

Patients who survived cardiopulmonary arrest were prospectively collected from June 2006 to October 2009. Detailed neurologic examinations were performed. Serum neuron specific enolase (NSE) measurements, brain imaging findings, somatosensory evoked potentials, and electroencephalogram (EEG) results were recorded. EEG patterns were blindly dichotomized with malignant patterns consisting of burst‐suppression, generalized suppression, status epilepticus, and nonreactivity. Outcome measure of in‐hospital mortality was assessed.

Results

A total of 192 patients (103 hypothermic, 89 nonhypothermic) were studied. The absence of pupillary light responses, corneal reflexes, and an extensor or absent motor response at Day 3 after cardiac arrest remained accurate predictors of poor outcome after therapeutic hypothermia (p < 0.0001 for all). Myoclonic status epilepticus was invariably associated with death (p = 0.0002). Malignant EEG patterns and global cerebral edema on head computed tomography (CT) were associated with death in both populations (p < 0.001). NSE > 33 ng/ml levels measured 1–3 days after cardiac arrest remained associated with poor outcome (p = 0.017), but had a false‐positive rate of 29.3% (95% confidence interval [CI] 0.164–0.361).

Interpretation

Clinical examination (brainstem reflexes, motor response, and presence of myoclonus) at Day 3 after cardiac arrest remains an accurate predictor of outcome after therapeutic hypothermia. Sedative medications in both hypothermic and nonhypothermic patients may confound the clinical exam. NSE > 33 ng/ml has a high false‐positive rate in patients treated with hypothermia and should be interpreted with caution. ANN NEUROL 2010
Activation of CXCR7 receptor promotes oligodendroglial cell maturation
Authors: Göttle Peter , Kremer David , Jander Sebastian , Ödemis Veysel , Engele Jürgen , Hartung Hans‐Peter , Küry Patrick
Published: November 2010

Objective:

Differentiation of oligodendroglial precursor cells is crucial for central nervous system (re)myelination and is influenced by multiple extrinsic and intrinsic factors. Chemokines, a group of small proteins, are highly conserved among mammals and have been implicated in a variety of biological processes during development, tissue homeostasis, and repair. We investigated whether the chemokine CXCL12 influences oligodendrocytes and what cellular differentiation/maturation processes are controlled by this molecule.

Methods:

Experimental autoimmune encephalomyelitis was induced using myelin oligodendrocyte glycoprotein. Immunostainings and quantitative gene expression analysis were used to study expression of the 2 currently known CXCL12 receptors on oligodendroglial cells. Stimulation of cultured primary oligodendroglial precursor cells was performed to determine the impact of the ligand/receptor interaction on morphological maturation and on myelin expression. Blocking and suppression experiments were conducted to reveal the identity of the transmitting receptor.

Results:

This analysis revealed the presence of CXCR4 as well as CXCR7 and that cellular maturation in vivo and in vitro is accompanied by upregulation of CXCR7 and downregulation of CXCR4. Of note, in the diseased demyelinating central nervous system, CXCR7 expression is maintained on oligodendroglial cells, whereas CXCR4 could not be detected. We then demonstrated that CXCL12 stimulation promotes morphological maturation of cultured primary oligodendrocyte precursor cells as well as their myelin expression. Pharmacological inhibition of the CXCR7 receptor was shown to block CXCL12‐dependent effects entirely.

Interpretation:

Our findings suggest that a specific activation of the CXCR7 receptor could provide a means to promote oligodendroglial differentiation in the diseased or injured central nervous system. Ann Neurol 2010
Preparation and characterization of poly(styrene‐co‐divinylbenzene)/fiberglass cation‐exchange composites
Authors: Huang Li , Liu Hao , Wang Chengzhong
Published: November 2010

Cation‐exchange composite materials were prepared by the sulfonation of the copolymer of styrene (St) and divinylbenzene (DVB) coated on glass fibers previously surface‐treated by a silane coupling agent. The results show that the surface treatment of the glass fibers by the coupling agent γ‐(methacryloyloxyethyl) trimethoxysilane led to a vinyl functionalized fiberglass surface, which served to covalently bond the copolymer to the fiberglass. Increasing the amount of the coupling agent increased the degree of coating of the copolymer on the fiberglass. A cation‐exchange composite with an exchange capacity of 4.08 mmol/g of resin was prepared by the copolymerization of St and DVB at a weight ratio of 95 : 5 for 30 min; this was followed by sulfonation of the copolymer at 100°C for 12 h. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Synergistic effect of a novel charring agent and ammonium polyphosphate on the flame retardancy of acrylonitrile butadiene styrene
Authors: Jun Wang , Yi Jiangsong , Cai Xu‐Fu
Published: November 2010

A novel charring agent, poly(p‐propane terephthalamide) (PPTA), was synthesized with terephthaloyl chloride and 1,2‐propanediamine through solution polycondensation at a low temperature. PPTA was used together with ammonium polyphosphate (APP) to prepare a novel intumescent flame retardant (IFR) for an acrylonitrile butadiene styrene (ABS) resin. The flammability and thermal stability of the IFR–ABS composites were investigated with limiting oxygen index, UL 94 vertical burning, and thermogravimetric analysis tests. The results showed that the IFR system had excellent flame retardancy and antidripping properties for ABS. The thermogravimetric curves suggested that there was a distinct synergistic effect of PPTA and APP, and this effect greatly promoted the char formation of the IFR–ABS composites and hence improved the flame retardancy. Additionally, the structure and morphology of char residues were studied with Fourier transform infrared and scanning electron microscopy. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Flexure and water sorption properties of wood thermoplastic composites made with polymer blends
Authors: Englund Karl , Villechevrolle Vivianne
Published: November 2010

Most WPC extrusion manufacturers utilize single polymer systems, where only one class of polymers is utilized. The concept of utilizing blended polymer systems can potentially provide lowered material costs, while maintaining or improving the composite properties. This cost savings can potentially be obtained in the ability to utilize mixed recycled plastics without the added costs of separation. Composites made of wood flour and binary blends of polypropylene (PP), high density polyethylene (HDPE), and polyvinyl‐chloride (PVC) were extruded and evaluated for their mechanical and physical performance. The WPCs were also exposed to repeated extrusion runs to determine the influence of enhanced melt‐blending of the composite properties. Torque rheometry, flexural, and water sorption tests revealed subtle differences between the blends and single polymer composites. With increasing extrusion runs, the WPCs water diffusion was decreased, whereas the strength and stiffness of the blends and single polymer systems increased or showed no change. These results indicate that polymer blends can be successfully utilized for commercial WPCs. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Morphology of crosslinked hyaluronic acid porous hydrogels
Authors: Collins Maurice N. , Birkinshaw Colin
Published: November 2010

Hydrogels, based on hyaluronic acid or hyaluronan (HA), are gaining attention as possible cell‐scaffolding materials for the regeneration of a variety of tissues. This article describes how HA, a naturally occurring polymer, has been crosslinked to reduce its degradation rate and freeze dried to produce porous materials suitable for tissue engineering. The resulting pore architecture has been assessed as a function of freezing temperature and freezing rate, type of crosslinkers, and methods used in the crosslinking process. On comparing the average densities of crosslinked and uncrosslinked scaffolds, it is apparent that the chemical modification increases sponge density and wall thickness of the pores while decreasing the pore size. The mechanical response of the modified materials has been investigated by equilibrium‐swelling measurements and compression tests. These materials have an average pore size ranging from 167 to 215 μm, which suggests that they would be a suitable temporary site for cell proliferation. The materials exhibit moderate mechanical integrity and are expected to be capable of withstanding physiological stresses in vivo. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Sustained release behavior of pH‐responsive poly(vinyl alcohol)/poly(acrylic acid) hydrogels containing activated carbon fibers
Authors: Yun Jumi , Im Ji Sun , Lee Young‐Seak , Yoo Sung Joon , Kim Hyung‐Il
Published: November 2010

The composites of pH‐responsive poly(vinyl alcohol)/poly(acrylic acid) hydrogel and activated carbon fibers (ACFs) were prepared as sustained drug release system with excellent mechanical properties. The mechanical properties of hydrogels were improved greatly by addition of ACFs. The thinner ACFs were more effective in increasing the mechanical properties of composite hydrogels. The cumulative amount of release and the release period were dependent on the surface area and the pore volume of ACFs. The drug release was maximized at basic condition due to the pH‐sensitive hydrogel matrices and the initial bust phenomenon was alleviated by incorporating ACFs in the hydrogels. The drug release was sustained about four times longer and the mechanical property was increased about 2.6 times higher because ACFs worked as drug reservoir and reinforcement. Cytotoxicity evaluation confirmed the biocompatible characteristics of the ACFs‐containing hydrogels. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
The structure and properties of a novel nanocomposite films from chitosan and layered zirconium phosphonate
Authors: Liu Changhua , Wu Haixia , Yang Yajuan , Zhu Lina , Teng Yingli
Published: November 2010

A new type of layered zirconium phosphonate (zirconium glycine‐N, N‐dimethylphosphonate, abbreviated as ZGDMP), with functional group of ‐COOH, has been successfully prepared and characterized by Fourier transform infrared (FTIR) spectroscopy, X‐ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). To confirm the effect of the functional group ‐COOH on the structure and properties of composites, a series of chitosan/zirconium phosphonate modified by n‐butylamine (BA‐ZGDMP) nanocomposite films were prepared by casting process. FTIR spectra suggested that strong interactions existed between BA‐ZGDMP and chitosan matrix. Compared to neat CS film, tensile strength (σb) and elongation at break (εb) of the nanocomposite film improved by 35.1% and 15.6%, respectively, with loading ratio of just 1.0 wt %. In addition, the BA‐ZGDMP also improved the water resistance of the nanocomposites. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Synovial inflammation in patients undergoing arthroscopic meniscectomy: Molecular characterization and relationship to symptoms
Authors: Scanzello Carla R. , McKeon Brian , Swaim Bryan H. , DiCarlo Edward , Asomugha Eva U. , Kanda Veero , Nair Anjali , Lee David M. , Richmond John C. , Katz Jeffrey N. , Crow Mary K. , Goldring Steven R.
Published: November 2010

Objective

Traumatic and degenerative meniscal tears have different anatomic features and different proposed etiologies, yet both are associated with the development or progression of osteoarthritis (OA). In established OA, synovitis is associated with pain and progression, but a relationship between synovitis and symptoms in isolated meniscal disease has not been reported. Accordingly, we sought to characterize synovial pathology in patients with traumatic meniscal injuries and determine the relationships between inflammation, meniscal and cartilage pathology, and symptoms.

Methods

Thirty‐three patients without evidence of OA who were undergoing arthroscopic meniscectomy for meniscal injuries were recruited. Pain and function were assessed preoperatively; meniscal and cartilage abnormalities were documented at the time of surgery. Inflammation in synovial biopsy specimens was scored, and associations between inflammation and clinical outcomes were determined. Microarray analysis of synovial tissue was performed, and gene expression patterns in patients with and those without inflammation were compared.

Results

Synovial inflammation was present in 43% of the patients and was associated with worse preoperative pain and function scores, independent of age, sex, or cartilage pathology. Microarray analysis and real‐time polymerase chain reaction revealed a chemokine signature in synovial biopsy specimens with increased inflammation scores.

Conclusion

Our findings indicate that in patients with traumatic meniscal injury undergoing arthroscopic meniscectomy without radiographic evidence of OA, synovial inflammation occurs frequently and is associated with increased pain and dysfunction. Synovia with increased inflammation scores exhibit a unique chemokine signature. Chemokines may contribute to the development of synovial inflammation in patients with meniscal pathology; they also represent potential therapeutic targets for reducing inflammatory symptoms.
DEK in the synovium of patients with juvenile idiopathic arthritis: Characterization of DEK antibodies and posttranslational modification of the DEK autoantigen
Authors: Mor‐Vaknin Nirit , Kappes Ferdinand , Dick Amalie E. , Legendre Maureen , Damoc Catalina , Teitz‐Tennenbaum Seagal , Kwok Roland , Ferrando‐May Elisa , Adams Barbara S. , Markovitz David M.
Published: November 2010

Objective

DEK is a nuclear phosphoprotein and autoantigen in a subset of children with juvenile idiopathic arthritis (JIA). Autoantibodies to DEK are also found in a broad spectrum of disorders associated with abnormal immune activation. We previously demonstrated that DEK is secreted by macrophages, is released by apoptotic T cells, and attracts leukocytes. Since DEK has been identified in the synovial fluid (SF) of patients with JIA, this study was undertaken to investigate how DEK protein and/or autoantibodies may contribute to the pathogenesis of JIA.

Methods

DEK autoantibodies, immune complexes (ICs), and synovial macrophages were purified from the SF of patients with JIA. DEK autoantibodies and ICs were purified by affinity‐column chromatography and analyzed by 2‐dimensional gel electrophoresis, immunoblotting, and enzyme‐linked immunosorbent assay. DEK in supernatants and exosomes was purified by serial centrifugation and immunoprecipitation with magnetic beads, and posttranslational modifications of DEK were identified by nano–liquid chromatography tandem mass spectrometry (nano–LC‐MS/MS).

Results

DEK autoantibodies and protein were found in the SF of patients with JIA. Secretion of DEK by synovial macrophages was observed both in a free form and via exosomes. DEK autoantibodies (IgG2) may activate the complement cascade, primarily recognize the C‐terminal portion of DEK protein, and exhibit higher affinity for acetylated DEK. Consistent with these observations, DEK underwent acetylation on an unprecedented number of lysine residues, as demonstrated by nano–LC‐MS/MS.

Conclusion

These results indicate that DEK can contribute directly to joint inflammation in JIA by generating ICs through high‐affinity interaction between DEK and DEK autoantibodies, a process enhanced by acetylation of DEK in the inflamed joint.
Overexpression of an exogenous phytoene synthase gene in the unicellular alga Chlamydomonas reinhardtii leads to an increase in the content of carotenoids
Authors: Couso I. , Vila M. , Rodriguez H. , Vargas M. A. , León R.
Published: November 2010

Phytoene synthase (PSY) catalyses the first step in the production of carotenoids, which has been described as a key regulatory step in the carotenoids biosynthetic pathway. PSY gene from Dunaliella salina was constitutively expressed in Chlamydomonas reinhardtii under the control of the RBCS2 and HSP70A promoters and targeted to the chloroplast by the RBCS2 transit peptide. DsPSY overexpression resulted in a stable increase in the corresponding PSY transcript level and in the content of carotenoids such as violaxanthin, lutein, and β‐carotene, reaching between 125 and 260% the levels in control untransformed cells. © 2011 American Institute of Chemical Engineers Biotechnol. Prog., 2011
Particle‐based realistic simulation of fluid–solid interaction
Authors: Sun Hongquan , Han Jiqing
Published: November 2010

In this paper a novel method for simulating incompressible viscous fluid and solid coupling is presented. In the coupling model, a rigid object is treated as a special fluid constrained to rigid body motion. To animate the coupling model, the Smoothed Particle Hydrodynamics method is used for solving the fluid motion equations. For keeping the rigidity of rigid objects, the total force and total torque exerted on solids is first worked out according to the impulse–momentum theorem, and then the movement of these rigid bodies is restricted to translations and rotations. Moreover, in order to prevent the fluids particles leaking into solids, a detection and correction procedure is presented, and the velocities of fluid particles will be tuned if the penetration is detected in this procedure. The proposed method can be implemented easily by extending the existing fluid solvers, the experimental results show that this method is capable of animating the realistic solid and fluid coupling. Copyright © 2010 John Wiley & Sons, Ltd.
Outcomes of patients with acute myocardial infarction rom a saphenous vein graft culprit undergoing percutaneous coronary intervention
Authors: Gaglia Michael A. , Torguson Rebecca , Xue Zhenyi , Gonzalez Manuel A. , Ben‐Dor Itsik , Suddath William O. , Kent Kenneth M. , Satler Lowell F. , Pichard Augusto D. , Waksman Ron
Published: November 2010

Objectives: We sought to describe characteristics of patients presenting with an acute MI from a SVG culprit, compared with a native culprit. Background: Percutaneous coronary intervention (PCI) of saphenous vein grafts (SVG) results in worse outcomes than native vessel PCI, but outcomes of such patients with acute myocardial infarction (MI) setting are not well‐described. Methods: Patients presenting with ST‐elevation or non‐ST‐elevation MI undergoing PCI from 2000 to 2010 were retrospectively analyzed to identify the culprit as a SVG vs. native vessel. Multiple linear regression was used to identify predictors of peak troponin‐I level. Cox proportional hazards regression was used to identify predictors of 30‐day mortality and 1‐year major adverse cardiac events (MACE). Results: 192 patients underwent PCI for a SVG culprit, compared with 4,001 with a native culprit. After multivariable adjustment, SVG culprit remained significantly associated with lower levels of the logarithm of the peak troponin (β = −0.17, SE = 0.07, P = 0.02). The likelihood of MACE was higher in SVG vs. native culprits in patients with small to modest troponin elevations. Patients with a SVG culprit also suffered higher unadjusted rates of mortality at 30 days (14.3% vs. 8.4%, P = 0.03) and MACE at 1 year (36.8% vs. 24.5%, P = 0.005); a modest effect upon mortality and MACE remained after multivariable adjustment. Conclusion: Even minimal elevations of troponin in patients with a SVG culprit may portend a poorer prognosis than in patients with a native culprit. The risk of PCI in this setting is driven by mortality and arises from both substantial comorbidities and the SVG itself. © 2011 Wiley‐Liss, Inc.
Aortic valve fibroelastoma presenting with myocardial infarction
Authors: Eftekhari Hossein , Islam Ashequl , Slawsky Mara
Published: November 2010

Fibroelastoma is a rare, benign cardiac tumor. It is the second most common primary cardiac tumor and the most common primary cardiac valvular tumor. Nonvalvular endocardial location is rare and may be difficult to differentiate from thrombus and myxoma. Fibroelastoma consists of a small, highly papillary, pedunculated, and avascular tumor which is covered by a single layer of endothelium. It contains fine elastic fibrils arranged in whorls in a hyaline stroma. Fibroelastoma is mostly found incidentally at the time of echocardiography, cardiac catheterization, surgery, or autopsy. Symptomatic patients present with various clinical presentations, mainly cardiovascular in nature. © 2011 Wiley‐Liss, Inc.
Patient satisfaction with postmastectomy breast reconstruction
Authors: McCarthy Colleen M. , Klassen Anne F. , Cano Stefan J. , Scott Amie , VanLaeken Nancy , Lennox Peter A. , Alderman Amy K. , Mehrara Babak J. , Disa Joseph J. , Cordeiro Peter G. , Pusic Andrea L.
Published: November 2010

BACKGROUND.

At a time when the safety and effectiveness of breast implants remains under close scrutiny, it is important to provide reliable and valid evidence regarding patient outcomes. In the setting of postmastectomy reconstruction, patient satisfaction and quality of life may be the most significant outcome variables when evaluating surgical success. The objective of the current study was to identify predictors of patient satisfaction with breast appearance, including implant type, in a large sample of women who underwent breast reconstruction surgery using implants.

METHODS.

A multicenter, cross‐sectional study design was used. A total of 672 women who had completed postmastectomy, implant‐based reconstruction at 1 of 3 centers in North America were asked to complete the BREAST‐Q (Reconstruction Module). Multivariate linear regression modeling was performed.

RESULTS.

Completed questionnaire data were available for 482 of the 672 patients. In 176 women, silicone implants were placed and in 306, saline implants were used. The multivariate model confirmed that patients' satisfaction with their breasts was significantly higher in patients with silicone implants (P = .016). The receipt of postmastectomy radiotherapy was found to have a significant, negative effect on breast satisfaction (P<.000) in both silicone and saline implant recipients. In addition, for women who received either silicone or saline implants, satisfaction diminished over time (P = .017).

CONCLUSIONS.

In the setting of postmastectomy reconstruction, patients who received silicone breast implants reported significantly higher satisfaction with the results of reconstruction than those who received saline implants. This information can be used to optimize shared medical decision‐making by providing patients with realistic postoperative expectations. Cancer 2010. © 2010 American Cancer Society.
Socioeconomic status and survival after an invasive breast cancer diagnosis
Authors: Sprague Brian L. , Trentham‐Dietz Amy , Gangnon Ronald E. , Ramchandani Ritesh , Hampton John M. , Robert Stephanie A. , Remington Patrick L. , Newcomb Polly A.
Published: November 2010

BACKGROUND:

Women who live in geographic areas with high poverty rates and low levels of education experience poorer survival after a breast cancer diagnosis than women who live in communities with indicators of high socioeconomic status (SES). However, very few studies have examined individual‐level SES in relation to breast cancer survival or have assessed the contextual role of community‐level SES independent of individual‐level SES.

METHODS:

The authors of this report examined both individual‐level and community‐level SES in relation to breast cancer survival in a population‐based cohort of women ages 20 to 69 years who were diagnosed with breast cancer in Wisconsin between 1995 and 2003 (N = 5820).

RESULTS:

Compared with college graduates, women who had no education beyond high school were 1.39 times more likely (95% confidence interval [CI], 1.10‐1.76) to die from breast cancer. Women who had household incomes <2.5 times the poverty level were 1.46 times more likely (95% CI, 1.10‐1.92) to die from breast cancer than women who had household incomes ≥5 times the poverty level. Adjusting the analysis for use of screening mammography, disease stage at diagnosis, and lifestyle factors eliminated the disparity by income, but the disparity by education persisted (hazard ratio [HR], 1.27; 95% CI, 0.99‐1.61). In multilevel analyses, low community‐level education was associated with increased breast cancer mortality even after adjusting for individual‐level SES (HR, 1.57; 95% CI, 1.09‐2.27 for ≥20% vs <10% of adults without a high school degree).

CONCLUSIONS:

The current results indicated that screening and early detection explain some of the disparity according to SES, but further research will be needed to understand the additional ways in which individual‐level and community‐level education are associated with survival. Cancer 2011. © 2010 American Cancer Society.
Chemoresistance of lung cancer stemlike cells depends on activation of Hsp27
Authors: Hsu Han‐Shui , Lin Jiun‐Han , Huang Wen‐Chien , Hsu Tien‐Wei , Su Kelly , Chiou Shih‐Hwa , Tsai Yo‐Ting , Hung Shih‐Chieh
Published: November 2010

BACKGROUND:

In the current study, the authors sought to identify the molecular mechanisms underlying the chemoresistance of lung cancer stem or initiation cells (cancer stem cells).

METHODS:

A549 lung cancer cells before and after selective enrichment of a subpopulation of cancer stem cells were treated with superoxide and traditional chemotherapeutics to determine their sensitivity or resistance to these cytotoxic agents. Apoptotic activity was measured using a variety of fluorescence‐based and biochemical techniques. Specific pathways involved in the chemoresistance of cancer stem cell‐enriched lung cancer cells were analyzed with Western blotting and pharmacologic targeting therapy in a xenograft model.

RESULTS:

Lung cancer stem cells exhibited significantly decreased apoptotic response to treatment with superoxide, cisplatin, gemcitabine, or a combination of cisplatin and gemcitabine compared with control A549 cells. Apoptotic resistance was mediated through the inactivation of caspase‐9 and caspase‐3. Increased activation of p38MAPK, MAPKAPK2, and Hsp27 was observed in lung cancer stem cells compared with control A549 cells both before and after exposure to superoxide and chemotoxic agents. In a mouse model of lung cancer, chemotherapy‐induced cells increased in the antiapoptosis pathway, and quercetin, an inhibitor of Hsp27, combined with traditional chemotherapy was effective in blocking the pathway and in the treatment of lung tumors in vivo.

CONCLUSIONS:

The authors' data demonstrate that lung cancer stem cells have elevated levels of activated Hsp27 upon treatment with superoxide and traditional chemotherapy. When combined with chemotoxic agents, blockage of Hsp27 decreased the survival of lung cancer stem cells, which otherwise were resistant to traditional chemotherapy. Cancer 2011. © 2010 American Cancer Society.
A prognostic model for soft tissue sarcoma of the extremities and trunk wall based on size, vascular invasion, necrosis, and growth pattern
Authors: Carneiro Ana , Bendahl Par‐Ola , Engellau Jacob , Domanski Henryk A. , Fletcher Christopher D. , Rissler Pehr , Rydholm Anders , Nilbert Mef
Published: November 2010

BACKGROUND:

In soft tissue sarcoma, better distinction of high‐risk and low‐risk patients is needed to individualize treatment and improve survival. Prognostic systems used in clinical practice identify high‐risk patients based on various factors, including age, tumor size and depth, histological type, necrosis, and grade.

METHODS:

Whole‐tumor sections from 239 soft tissue sarcomas of the extremities were reviewed for the following prognostic factors: size, vascular invasion, necrosis, and growth pattern. A new prognostic model, referred to as SING (Size, Invasion, Necrosis, Growth), was established and compared with other clinically applied systems.

RESULTS:

Size, vascular invasion, necrosis, and peripheral tumor growth pattern provided independent prognostic information with hazard ratios of 2.2‐2.6 for development of metastases in multivariate analysis. When these factors were combined into the prognostic model SING, high risk of metastasis was predicted with a sensitivity of 74% and a specificity of 85%. Moreover, the prognostic performance of SING compared favorably with other widely used systems.

CONCLUSIONS:

SING represents a promising prognostic model, and vascular invasion and tumor growth pattern should be considered in soft tissue sarcoma prognostication. Cancer 2011. © 2010 American Cancer Society.
Benefits of interferon‐β and temozolomide combination therapy for newly diagnosed primary glioblastoma with the unmethylated MGMT promoter
Authors: Motomura Kazuya , Natsume Atsushi , Kishida Yugo , Higashi Hiroyuki , Kondo Yutaka , Nakasu Yoko , Abe Tatsuya , Namba Hiroki , Wakai Kenji , Wakabayashi Toshihiko
Published: November 2010

BACKGROUND:

The aim of the current study was to catalog genomic and epigenomic abnormalities in newly diagnosed glioblastoma patients and determine the correlation among clinical, genetic, and epigenetic profiles and clinical outcome.

METHODS:

This study retrospectively included 68 consecutive patients who underwent surgical treatment and received standard radiotherapy with temozolomide (TMZ)‐based chemotherapy. Of a total of 68 patients, 39 patients (57.4%) received interferon (IFN)‐β in combination of TMZ.

RESULTS:

The genetic and epigenetic alterations frequently observed were EGFR amplification (51.5%), TP53 mutation (33.8%), CDKN2A loss (32.4%), TP53 loss (16.2%), methylation of the MGMT promoter (33.8%) and IDH1 mutation (5.9%). Multivariate analysis revealed that methylated MGMT promoter and the combination of TMZ and IFN‐β were independent prognostic factors associated with survival. The median survival time (MST) of the patients who received the combination of IFN‐β and TMZ was significantly greater with 19.9 months as compared to the TMZ alone group (12.7 months). Notably, in even patients whose tumors had unmethylated MGMT promoter, the MST prolonged to 17.2 months when receiving TMZ with IFN‐β, compared to 12.5 months in those receiving TMZ without IFN‐β.

CONCLUSIONS:

Taken together, addition of IFN‐β for newly diagnosed primary GBM achieved a favorable outcome, particularly in patients with unmethylated MGMT promoter. Cancer 2011. © 2010 American Cancer Society.
Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post‐brain metastases survival
Authors: Zakrzewski Jan , Geraghty Laurel N. , Rose Amy E. , Christos Paul J. , Mazumdar Madhu , Polsky David , Shapiro Richard , Berman Russell , Darvishian Farbod , Hernando Eva , Pavlick Anna , Osman Iman
Published: November 2010

BACKGROUND:

Melanoma patients who develop brain metastases (B‐Met) have limited survival and are excluded from most clinical trials. In the current study, the authors attempted to identify primary tumor characteristics and clinical features predictive of B‐Met development and post‐B–Met survival.

METHODS:

A prospectively accrued cohort of 900 melanoma patients was studied to identify clinicopathologic features of primary melanoma (eg, thickness, ulceration, mitotic index, and lymphovascular invasion) that are predictive of B‐Met development and survival after a diagnosis of B‐Met. Associations between clinical variables present at the time of B‐Met diagnosis (eg, extracranial metastases, B‐Met location, and the presence of neurological symptoms) and post‐B–Met survival were also assessed. Univariate associations were analyzed using Kaplan‐Meier survival analysis, and the effect of independent predictors was assessed using multivariate Cox proportional hazards regression analysis.

RESULTS:

Of the 900 melanoma patients studied, 89 (10%) developed B‐Met. Ulceration and site of the primary tumor on the head and neck were found to be independent predictors of B‐Met development on multivariate analysis (P = .001 and P = .003, respectively). Clinical variables found to be predictive of post‐B–Met survival on multivariate analysis included the presence of neurological symptoms (P = .008) and extracranial metastases (P = .04). Ulceration was the only primary tumor characteristic that remained a significant predictor of post‐B–Met survival on multivariate analysis (P = .04).

CONCLUSIONS:

Primary tumor ulceration was found to be the strongest predictor of B‐Met development and remained an independent predictor of decreased post‐B–Met survival in a multivariate analysis inclusive of primary tumor characteristics and clinical variables. The results of the current study suggest that patients with ulcerated primary tumors should be prospectively studied to determine whether heightened surveillance for B‐Met can improve clinical outcome. Cancer 2011. © 2010 American Cancer Society.
Identification and validation of Notch pathway activating compounds through a novel high‐throughput screening method
Authors: Pinchot Scott N. , Jaskula‐Sztul Renata , Ning Li , Peters Noel R. , Cook Mackenzie R. , Kunnimalaiyaan Muthusamy , Chen Herbert
Published: November 2010

BACKGROUND:

Carcinoids are neuroendocrine (NE) tumors with limited treatment options. Notch activation has been shown to suppress growth and hormone production in carcinoid cells.

METHODS:

The purpose of this study was to provide a process for identifying Notch activating compounds via high‐throughput screening (HTS) and to validate the effects of the strongest hit from the 7264 compounds analyzed: resveratrol (RESV).

RESULTS:

Treatment of carcinoid cells with RESV resulted in up‐regulation of the Notch signaling pathway as measured by suppression of its downstream target achaete‐scute complex‐like 1. Luciferase reporter assays incorporating the centromere‐binding factor 1 binding site also confirmed the functional activity of RESV‐induced Notch. Because activation of the Notch pathway has been shown to suppress carcinoid proliferation, RESV treatment of carcinoid cells led to a dose‐dependent inhibition of cellular growth. Immunoblotting revealed phosphorylation of cdc2 (Tyr15) and up‐regulation of p21Cip1/Waf, markers of cell cycle arrest, with RESV treatment. Flow cytometry confirmed the mechanism of RESV‐induced growth inhibition is S phase cell cycle arrest. Furthermore, because Notch has been shown to inhibit bioactive hormone production from NE tumors, RESV also suppressed expression of the NE peptides/hormones chromogranin A and serotonin. RNA interference assays demonstrated that the hormone suppressing capacity of RESV was due to up‐regulation of the Notch2 isoform.

CONCLUSIONS:

HTS can be used to identify novel Notch activating compounds, which may have the potential to suppress carcinoid tumor growth and the associated endocrinopathies. Cancer 2011. © 2010 American Cancer Society.
Racial disparities in the use of hospice services according to geographic residence and socioeconomic status in an elderly cohort with nonsmall cell lung cancer
Authors: Hardy Dale , Chan Wenyaw , Liu Chih‐Chin , Cormier Janice N. , Xia Rui , Bruera Eduardo , Du Xianglin L.
Published: November 2010

BACKGROUND:

The authors investigated whether there were racial disparities in the receipt of hospice services within geographic residence and socioeconomic status (SES) levels.

METHODS:

In total, 117,894 patients aged ≥66 years with nonsmall cell lung cancer (NSCLC) were identified from the Surveillance, Epidemiology, and End Results‐Medicare linked database who had received hospice services in the last 6 months before death and who died between January 1, 1991 and December 31, 2005. Multivariate odds ratios (ORs) with 95% confidence intervals (CIs) using mixed‐effects logistic regression models were used to describe relations.

RESULTS:

In urban areas, there were significant disparity trends in age/sex‐adjusted rates for blacks and Asians/Pacific Islanders compared with whites (P = .003 and P = .036, respectively). Blacks (OR, 0.79; 95% CI, 0.75‐0.82), Asians/Pacific Islanders (OR, 0.42; 95% CI, 0.39‐0.46), and Hispanics (OR, 0.81; 95% CI, 0.73‐0.91) were less likely to receive hospice services. In rural areas, blacks were 21% less likely to receive hospice services (OR, 0.79; 95% CI, 0.63‐0.98). Patients in the poorest socioeconomic status (SES) quartile were 7% less likely to receive hospice services (OR, 0.93; 95% CI, 0.86‐1.00). Moreover, within stratified SES quartiles, blacks and Asians/Pacific Islanders had lower receipt of hospice services, and Asians/Pacific Islanders were the least likely to receive hospice services, particularly those in the poorest SES quartile. In general, older patients and women were more likely to receive hospice services.

CONCLUSIONS:

There were substantial disparities in the receipt of hospice services among ethnic minorities within urban and rural areas and within SES levels. The results indicated that efforts are needed to identify barriers, enhance support, and educate patients on the benefits of hospice services. Cancer 2010. © 2010 American Cancer Society.
Considering temozolomide as a novel potential treatment for esophageal cancer
Authors: Bruyère Céline , Lonez Caroline , Duray Anaelle , Cludts Stéphanie , Ruysschaert Jean‐Marie , Saussez Sven , Yeaton Paul , Kiss Robert , Mijatovic Tatjana
Published: November 2010

BACKGROUND:

C‐X‐C ligand (CXCL) chemokines exert major roles in the biologic aggressiveness of esophageal cancer. In the current study, the authors investigated temozolomide (TMZ)‐induced effects on activity of the CXCL chemokine network in human esophageal cancer cells. To the authors' knowledge, TMZ has not been investigated previously in experimental or clinical esophageal cancers.

METHODS:

A complete mapping of CXCL chemokines and their receptor messenger RNA was performed in 2 established human esophageal cancer cell lines (OE21 and OE33) and in 4 surgical samples from patients with esophageal carcinoma. The analyses pointed out the potential importance of CXCL2, and monitoring CXCL2 with quantitative videomicroscopy indicated that its biologic activity was silenced in OE21 esophageal cancer cells. TMZ‐mediated antitumor activity was determined in vivo in an OE21 metastatic nude mice xenograft model.

RESULTS:

The messenger RNA levels of CXC chemokines and their receptors were similar in both cell lines and in the 4 surgical specimens. CXCL2 depletion by small interfering RNA (siRNA) displayed marked effects on the proliferation of transfected OE21 cells. Chronic in vitro TMZ treatment of OE21 and OE33 cells markedly decreased CXCL2 and CXCL3 secretion. In vivo, TMZ induced significant delays in OE21 xenograft tumor development and improved the survival of OE21 xenograft‐bearing mice, whereas cisplatin did not. Analyses performed on tissue samples from in vivo experiments revealed that TMZ also impaired tumor angiogenesis.

CONCLUSIONS:

The current study emphasized the role of proangiogenic chemokines in esophageal cancer biology and indicated the possibility of using TMZ as a clinically compatible drug to impair the actions of the CXCL chemokine network in esophageal cancers. Cancer 2011. © 2010 American Cancer Society.
Systemic administration of reovirus (Reolysin) inhibits growth of human sarcoma xenografts
Authors: Hingorani Pooja , Zhang Wendong , Lin Juan , Liu Laibin , Guha Chandan , Kolb E. Anders
Published: November 2010

BACKGROUND:

Despite advancement in therapies, overall survival rates for relapsed pediatric sarcomas are dismal. Newer therapies are needed to effectively salvage these patients. Oncolytic viruses (such as reovirus) and other genetically altered viruses (such as herpes simplex viruses and adenoviruses) have shown efficacy in a variety of solid tumors including sarcomas. Reolysin is an unmodified oncolytic reovirus that selectively replicates in Ras‐activated cancer cells while not causing any significant human illness in its wild form.

METHODS:

By using a panel of pediatric sarcoma cell lines in vitro and flank xenografts in vivo, Reolysin was evaluated as a single agent and in combination with cisplatin and radiation therapy. Electron microscopy and immunohistochemistry was used to demonstrated a cytopathic effect in treated tumors.

RESULTS:

Reolysin inhibited the proliferation and viability of sarcoma cell lines at a dose of 1 to 10 virus particles per cell. In vivo, 5 × 109 plaque‐forming units (PFU) administered via the tail vein every other day for 3 doses every 21 days inhibited the growth of tumor xenografts with improvement in event‐free survival. In the SKES1 Ewing sarcoma line, there was therapeutic enhancement when reovirus was administered in combination with radiation or cisplatin. In the RH30 line and the OS33 line, therapeutic enhancement was demonstrated with radiation and cisplatin, respectively.

CONCLUSIONS:

These results suggest that Reolysin alone or in combination with other cytotoxic agents may be effective therapy in pediatric sarcomas. Cancer 2011. © 2010 American Cancer Society.
On the decay and stability of global solutions to the 3‐D inhomogeneous Navier‐Stokes equations
Authors: Abidi Hammadi , Gui Guilong , Zhang Ping
Published: November 2010

In this paper, we investigate the large‐time decay and stability to any given global smooth solutions of the 3‐D incompressible inhomogeneous Navier‐Stokes equations. In particular, we prove that given any global smooth solution (a,u) of (1.2), the velocity fieldudecays to 0 with an explicit rate, which coincides with theL2norm decay for the weak solutions of the 3‐D classical Navier‐Stokes system [26,29] astgoes to ∞. Moreover, a small perturbation to the initial data of (a,u) still generates a unique global smooth solution to (1.2), and this solution keeps close to the reference solution (a,u) fort> 0. We should point out that the main results in this paper work for large solutions of (1.2). © 2010 Wiley Periodicals, Inc.
Separating early sensory neuron and blood vessel patterning
Authors: Miller Laura C. , Freter Sabine , Liu Feng , Taylor Jeremy S.H. , Patient Roger , Begbie Jo
Published: November 2010

The anatomical association between sensory nerves and blood vessels is well recognised in the adult, and interactions between the two are important during development. Here we have examined the relationship between developing blood vessels and sensory neuronal cell bodies, which is less well understood. We show in the chick that the nascent dorsal root ganglia (DRG) lie dorsal to the longitudinal anastomosis, adjacent to the developing neural tube at the level of the sulcus limitans. Furthermore, the blood vessel is present prior to the neurons suggesting that it may play a role in positioning the DRG. We use the zebrafish cloche mutation to analyse DRG formation in the absence of blood vessels and show that the DRG are positioned normally. Thus, despite their close anatomical relationship, the patterning of the blood vessel and DRG alongside the neural tube is separable rather than interdependent. Developmental Dynamics 239:3297–3302, 2010. © 2010 Wiley‐Liss, Inc.