bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of Systemic Lupus Erythematosus in NZM 2328 Mice in the Absence of any Single BAFF Receptor
Authors: Jacob Chaim O. , Yu Ning , Guo Shunhua , Jacob Noam , Quinn William J. , Sindhava Vishal , Cancro Michael P. , Goilav Beatrice , Putterman Chaim , Migone Thi‐Sau , Stohl William
Published: January 2013

Objective

To determine the necessity for any individual BAFF receptor in the development of systemic lupus erythematosus (SLE).

Methods

Bcma‐, Taci‐, and Br3‐null mutations were introgressed into NZM 2328 mice. NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice were evaluated for lymphocyte phenotype and BAFF receptor expression by flow cytometry; for B cell responsiveness to BAFF by in vitro culture; for serum levels of BAFF and total IgG and IgG anti–double‐stranded DNA (anti‐dsDNA) by enzyme‐linked immunosorbent assay; for renal immunopathology by immunofluorescence and histopathology; and for clinical disease.

Results

BCMA, TACI, and B lymphocyte stimulator receptor 3 (BR3) were not surface‐expressed in NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice, respectively. Transitional and follicular B cells from NZM.Br3−/− mice were much less responsive to BAFF than were the corresponding cells from wild‐type, NZM.Bcma−/−, or NZM.Taci−/− mice. In comparison with wild‐type mice, NZM.Bcma−/− and NZM.Taci−/− mice harbored an increased number of spleen B cells, T cells, and plasma cells, whereas serum levels of total IgG and IgG anti‐dsDNA were similar to those in wild‐type mice. Despite their paucity of B cells, NZM.Br3−/− mice had an increased number of T cells, and the numbers of plasma cells and levels of IgG anti‐dsDNA were similar to those in wild‐type mice. Serum levels of BAFF were increased in NZM.Taci−/− and NZM.Br3−/− mice but were decreased in NZM.Bcma−/− mice. Despite their phenotypic differences, NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice had renal immunopathology and clinical disease that were at least as severe as that in wild‐type mice.

Conclusion

Any single BAFF receptor, including BR3, is dispensable for the development of SLE in NZM mice. Development of disease in NZM.Br3−/− mice demonstrates that BAFF–BCMA and/or BAFF–TACI interactions contribute to SLE, and that a profound, life‐long reduction in the numbers of B cells does not guarantee protection against SLE.
Interleukin‐22 Reduces the Severity of Collagen‐Induced Arthritis in Association With Increased Levels of Interleukin‐10
Authors: Sarkar Sujata , Zhou Xiaoqun , Justa Shivali , Bommireddy Swaroopa Rani
Published: January 2013

Objective

The mechanism of action of interleukin‐ 22 (IL‐22) in inflammatory arthritis remains unknown. IL‐22–deficient mice exhibit an intact humoral and cellular immune response to collagen and yet have a reduced incidence of collagen‐induced arthritis (CIA). Further, administration of anti–IL‐22 does not reduce the severity of clinical arthritis but rather improves only certain aspects of joint inflammation as assessed histologically. This study was undertaken to investigate the mechanism of action and role of systemic IL‐22 in modulating target organ inflammation.

Methods

CIA was induced in DBA mice by immunization with collagen and Freund's complete adjuvant. Expression of IL‐22 and its receptor (IL‐22R) in lymphoid organ and target tissues was determined during various phases of arthritis. The effector functions of IL‐22 on induction/regulation of various cytokines in in vitro restimulation cultures were analyzed by enzyme‐linked immunosorbent assay (ELISA). Recombinant IL‐22 with or without anti–IL‐10 antibody was administered to mice following immunization with collagen and prior to the onset of arthritis, and the severity of arthritis was evaluated by clinical scoring and histopathologic assessment. Anticollagen antibodies in mouse sera were analyzed by ELISA.

Results

IL‐22 and IL‐22R were up‐regulated in lymphoid organs and joints during the course of arthritis. IL‐22 augmented IL‐10, IL‐17, and IL‐6 in lymphoid tissues in vitro. Administration of recombinant IL‐22 was associated with an increase in IL‐10 levels in vivo and a significant reduction in the progression of arthritis severity. Anti–IL‐10 antibody treatment was associated with the abrogation of this protective effect of IL‐22.

Conclusion

Our data demonstrate, for the first time, that IL‐22 has a protective role in inflammatory arthritis.
Suppression of Hyaluronan Synthesis Alleviates Inflammatory Responses in Murine Arthritis and in Human Rheumatoid Synovial Fibroblasts
Authors: Yoshioka Yutaka , Kozawa Eiji , Urakawa Hiroshi , Arai Eisuke , Futamura Naohisa , Zhuo Lisheng , Kimata Koji , Ishiguro Naoki , Nishida Yoshihiro
Published: January 2013

Objective

To clarify the roles of hyaluronan (HA) in joint inflammation and the process of joint destruction, using 4‐methylumbelliferone (4‐MU), an inhibitor of HA synthesis, in a mouse model of collagen‐induced arthritis (CIA) and in a monolayer culture of fibroblast‐like synoviocytes (FLS) derived from patients with rheumatoid arthritis.

Methods

DAB/1J mice were immunized with type II collagen. The effects of 4‐MU were evaluated by the physiologic arthritis score, paw swelling, the histologic arthritis score, and expression of matrix metalloproteinase 3 (MMP‐3) and MMP‐13 in chondrocytes and synovial tissue. In vitro, the effect of 4‐MU on messenger RNA and protein expression of MMP‐1 and MMP‐3 was determined. The effects of 4‐MU on HA deposition and on serum/medium concentrations of HA were analyzed using biotinylated HA binding protein staining and an HA binding assay, respectively.

Results

Treatment with 4‐MU in mice with CIA dramatically decreased the severity of arthritis (based on the arthritis score), paw thickness, and histopathologic changes. MMP‐3 and MMP‐13 expression in chondrocytes and synovial cells was significantly inhibited by 4‐MU in vivo. Treatment with 4‐MU also inhibited MMP‐1 and MMP‐3 expression in tumor necrosis factor α–stimulated FLS, in a dose‐dependent manner. The 4‐MU–induced decreases in the serum HA concentration in mice with CIA and in “medium” and “pericellular” HA concentrations in cultured FLS support the contention that the inhibitory mechanism of 4‐MU is mediated by HA suppression.

Conclusion

Reduced disease activity induced by 4‐MU in mice with CIA revealed HA to be a crucial regulator in the course of arthritis. Therefore, 4‐MU is a potential therapeutic agent in arthritis, and its inhibitory mechanism is possibly mediated by suppression of HA synthesis.
Environmental tradeoffs of stover removal and erosion in Indiana
Authors: English Alicia , Tyner Wallace E. , Sesmero Juan , Owens Phillip , Muth David J.
Published: January 2013

Abstract: When considering the market for biomass from corn stover resources, the consequences of soil erosion and soil quality issues are important considerations. Removal of stover can be beneficial in some areas, especially when coordinated with other conservation practices, such as vegetative barrier strips and cover crops. However, benefits are highly dependent on several factors, namely if farmers see costs and benefits associated with erosion and the tradeoffs with the removal of biomass. Although typically considered an internal cost, the implication is important to policy and contracting for biomass. This paper uses results from an integrated RUSLE2/WEPS model to incorporate six different regime choices, covering management, harvest, and conservation, into a simple profit maximization model to show these tradeoffs explicitly. The results of this work show how different costs for erosion, biomass, and conservation management will affect behavior. If the private costs of erosion are low and no conservation requirement exists, biomass removal will significantly increase erosion, but only in some areas. Alternatively, when erosion prices are high, farmers will parallel socially optimal levels of erosion, and conservation management practices can be incentivized through access to a market for stover. © 2013 Society of Chemical Industry and John Wiley & Sons, Ltd
Myelin‐specific proteins: A structurally diverse group of membrane‐interacting molecules
Authors: Han Huijong , Myllykoski Matti , Ruskamo Salla , Wang Chaozhan , Kursula Petri
Published: January 2013

The myelin sheath is a multilayered membrane in the nervous system, which has unique biochemical properties. Myelin carries a set of specific high‐abundance proteins, the structure and function of which are still poorly understood. The proteins of the myelin sheath are involved in a number of neurological diseases, including autoimmune diseases and inherited neuropathies. In this review, we briefly discuss the structural properties and functions of selected myelin‐specific proteins (P0, myelin oligodendrocyte glycoprotein, myelin‐associated glycoprotein, myelin basic protein, myelin‐associated oligodendrocytic basic protein, P2, proteolipid protein, peripheral myelin protein of 22 kDa, 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase, and periaxin); such properties include, for example, interactions with lipid bilayers and the presence of large intrinsically disordered regions in some myelin proteins. A detailed understanding of myelin protein structure and function at the molecular level will be required to fully grasp their physiological roles in the myelin sheath. © 2013 BioFactors, 2013
Multi‐cycle recovery of lactoferrin and lactoperoxidase from crude whey using fimbriated high‐capacity magnetic cation exchangers and a novel “rotor–stator” high‐gradient magnetic separator
Authors: Brown Geoffrey N. , Müller Christine , Theodosiou Eirini , Franzreb Matthias , Thomas Owen R.T.
Published: January 2013

Cerium (IV) initiated “graft‐from” polymerization reactions were employed to convert M‐PVA magnetic particles into polyacrylic acid‐fimbriated magnetic cation exchange supports displaying ultra‐high binding capacity for basic target proteins. The modifications, which were performed at 25 mg and 2.5 g scales, delivered maximum binding capacities (Qmax) for hen egg white lysozyme in excess of 320 mg g−1, combined with sub‐micromolar dissociation constants (0.45–0.69 µm) and “tightness of binding” values greater than 49 L g−1. Two batches of polyacrylic acid‐fimbriated magnetic cation exchangers were combined to form a 5 g pooled batch exhibiting Qmax values for lysozyme, lactoferrin, and lactoperoxidase of 404, 585, and 685 mg g−1, respectively. These magnetic cation exchangers were subsequently employed together with a newly designed “rotor–stator” type HGMF rig, in five sequential cycles of recovery of lactoferrin and lactoperoxidase from 2 L batches of a crude sweet bovine whey feedstock. Lactoferrin purification performance was observed to remain relatively constant from one HGMF cycle to the next over the five operating cycles, with yields between 40% and 49% combined with purification and concentration factors of 37‐ to 46‐fold and 1.3‐ to 1.6‐fold, respectively. The far superior multi‐cycle HGMF performance seen here compared to that observed in our earlier studies can be directly attributed to the combined use of improved high capacity adsorbents and superior particle resuspension afforded by the new “rotor–stator” HGMS design. Biotechnol. Bioeng. 2013; 110: 1714–1725. © 2013 Wiley Periodicals, Inc.
Catalytic Asymmetric Alkylation Reactions for the Construction of Protected Ethylene‐Amino and Propylene‐Amino Motifs Attached to Quaternary Stereocentres
Authors: Moss Thomas A. , Barber David M. , Kyle Andrew F. , Dixon Darren J.
Published: January 2013

An efficient catalytic and stereoselective method for the direct construction of protected ethylene‐amino and propylene‐amino scaffolds attached to quaternary stereocentres is reported. Preliminary investigations revealed a mild base catalysed nucleophilic ring opening of N‐sulfonyl aziridines using the commercially available phosphazene base 2‐tert‐butylimino‐2‐diethylamino‐1,3‐dimethyl‐perhydro‐1,3,2‐diazaphosphorine (BEMP) was possible and resulted in highly efficient alkylation reactions with a range of methine carbon acids. This reaction could be rendered highly asymmetric (up to 97 % ee) by employing phase‐transfer catalysis to control stereoinduction. Incorporation of alkyl substituents onto the aziridine electrophile, resulted in a highly diastereoselective (up to 30:1 d.r.) variant of this methodology. A further extension using N‐protected cyclic sulfamidates as the electrophilic component was successful with a range of pro‐nucleophiles (up to 96 % ee and 45:1 d.r.) and allowed a range of nitrogen protecting groups (carbamate, sulfonyl, phosphonyl, benzyl) to be incorporated into the alkylation adducts. Finally, the utility of the products have been demonstrated in the synthesis of useful heterocycles and compounds bearing structural components of natural products.
Traveling Waves with Multiple and Nonconvex Fronts for a Bistable Semilinear Parabolic Equation
Authors: del Pino Manuel , Kowalczyk Michał , Wei Juncheng
Published: January 2013

We construct new examples of traveling wave solutions to the bistable and balanced semilinear parabolic equation in
\input amssym ${\Bbb R}^N+1$, $N\geq 2$. Our first example is that of a traveling wave solution with two non planar fronts that move with the same speed. Our second example is a traveling wave solution with a nonconvex moving front. To our knowledge no existence results of traveling fronts with these type of geometric characteristics have been previously known. Our approach explores a connection between solutions of the semilinear parabolic PDE and eternal solutions to the mean curvature flow in \input amssym ${\Bbb R}^N+1$.
Performance analysis of cooperative network over Nakagami and Rician fading channels
Authors: Khan I. , Rajatheva N. , Tanoli S. A. , Jan S.
Published: January 2013

This paper presents an analysis on the performance of single‐relay and multiple fixed‐relay cooperative network. The relay nodes operate in amplify‐and‐forward (AF) mode and transmit the signal through orthogonal channels. We consider maximal‐ratio combining at the destination to get the spatial diversity by adding the received signals coherently. The closed‐form moment‐generating function (MGF) for the total equivalent signal‐to‐noise ratio (SNR) is derived. The exact expressions of symbol‐error rate, outage capacity, and outage probability are obtained using the closed‐form MGF for single‐relay and multiple‐relay cooperative network with M‐ary phase shift keying (M‐PSK) and M‐ary quadrature amplitude modulation (M‐QAM) over independent and non‐identical Nakagami‐m channels and Rician fading channels. The approximated closed‐form expression of ergodic capacity is derived for both Nakagami‐m and Rician fading channels. The performance of the system is analyzed at various relay locations. The theoretical results are then compared with the simulation results obtained for binary PSK, quadrature PSK, and 16‐QAM modulation schemes to verify the analysis. Here, the expressions derived can be easily and more efficiently used to compute the performance parameters than doing Monte Carlo simulations. It is shown that cooperation is significant only for low K values for Rician by plotting cooperation gain versus K. The results show that the cooperative network performs best when the relay is located in the middle of source to destination link, at lower SNR values, and the performance of the system is worst if the relay is located closer to the source than to the destination. Copyright © 2013 John Wiley & Sons, Ltd.
Epigenetic regulation of adaptive responses of forest tree species to the environment
Authors: Bräutigam Katharina , Vining Kelly J. , Lafon‐Placette Clément , Fossdal Carl G. , Mirouze Marie , Marcos José Gutiérrez , Fluch Silvia , Fraga Mario Fernández , Guevara M. Ángeles , Abarca Dolores , Johnsen Øystein , Maury Stéphane , Strauss Steven H. , Campbell Malcolm M. , Rohde Antje , Díaz‐Sala Carmen , Cervera María‐Teresa
Published: January 2013

Epigenetic variation is likely to contribute to the phenotypic plasticity and adaptative capacity of plant species, and may be especially important for long‐lived organisms with complex life cycles, including forest trees. Diverse environmental stresses and hybridization/polyploidization events can create reversible heritable epigenetic marks that can be transmitted to subsequent generations as a form of molecular “memory”. Epigenetic changes might also contribute to the ability of plants to colonize or persist in variable environments. In this review, we provide an overview of recent data on epigenetic mechanisms involved in developmental processes and responses to environmental cues in plant, with a focus on forest tree species. We consider the possible role of forest tree epigenetics as a new source of adaptive traits in plant breeding, biotechnology, and ecosystem conservation under rapid climate change.
A Modified Synthetic Pathway for the Synthesis of so far Inaccessible N1‐Functionalized Tetrazole Ligands – Synthesis and Characterization of the 1D Chain‐Type Spin Crossover Compound [Fe(3ditz)3](BF4)2
Authors: Müller Danny , Knoll Christian , Stöger Berthold , Artner Werner , Reissner Michael , Weinberger Peter
Published: January 2013

A modified phase‐transfer‐catalyst‐assisted synthetic pathway was developed that widens the pool of accessible 1‐substituted tetrazoles, which are possible ligands for iron(II) spin‐crossover compounds. Within the family of α,ω‐bis(tetrazol‐1‐yl)alkanes, a series of ligands and their respective iron(II) spin‐crossover compounds were synthesized and structurally and spectroscopically characterized in the past. The classical route to prepare these ligands is based on the respective amino‐precursors. Hence the pool of accessible compounds is limited by the commercial or synthetical availability of α,ω‐diaminoalkanes. Furthermore, the concomitant transformation to the tetrazole moieties turns out to be easier for diamino‐alkanes with an even number of carbon atoms than for those with an odd number. In line with this observation, the shortest odd‐numbered homologues such as 1,1‐bis(tetrazol‐1‐yl)methane (1ditz) and 1,3‐bis(tetrazol‐1‐yl)propane (3ditz) were inaccessible so far. In this paper, we report the successful preparation and characterisation of the classically inaccessible 1,3‐bis(tetrazol‐1‐yl)propane (3ditz) and of its spin‐crossover complex [Fe(3ditz)3](BF4)2, which features an abrupt and almost complete spin transition at T${1 \over 2}$ = 159 K. The single‐crystal X‐ray structure of the low‐spin and the high‐spin species is presented. The magnetic data are supported by variable‐temperature IR, UV/Vis/NIR, and 57Fe Mössbauer spectra.
A Bivariate Mann‐Whitney Approach for Unraveling Genetic Variants and Interactions Contributing to Comorbidity
Authors: Wen Yalu , Schaid Daniel J. , Lu Qing
Published: January 2013

Although comorbidity among complex diseases (e.g., drug dependence syndromes) is well documented, genetic variants contributing to the comorbidity are still largely unknown. The discovery of genetic variants and their interactions contributing to comorbidity will likely shed light on underlying pathophysiological and etiological processes, and promote effective treatments for comorbid conditions. For this reason, studies to discover genetic variants that foster the development of comorbidity represent high‐priority research projects, as manifested in the behavioral genetics studies now underway. The yield from these studies can be enhanced by adopting novel statistical approaches, with the capacity of considering multiple genetic variants and possible interactions. For this purpose, we propose a bivariate Mann‐Whitney (BMW) approach to unravel genetic variants and interactions contributing to comorbidity, as well as those unique to each comorbid condition. Through simulations, we found BMW outperformed two commonly adopted approaches in a variety of underlying disease and comorbidity models. We further applied BMW to datasets from the Study of Addiction: Genetics and Environment, investigating the contribution of 184 known nicotine dependence (ND) and alcohol dependence (AD) single nucleotide polymorphisms (SNPs) to the comorbidity of ND and AD. The analysis revealed a candidate SNP from CHRNA5, rs16969968, associated with both ND and AD, and replicated the findings in an independent dataset with a P‐value of 1.06 × 10–03.
Cytokine secretion from human peripheral blood mononuclear cells cultured in vitro with metal particles
Authors: Cachinho Sandra C. P. , Pu Fanrong , Hunt John A.
Published: January 2013

The failure of implanted medical devices can be associated with changes in the production of cytokines by cells of the immune system. Cytokines released by peripheral blood mononuclear cells upon contact with metal particles were quantified to understand their role in implantation intergration and their importance as messengers in the recruitment of T‐lymphocytes at the implantation site. Opsonization was utilised to understand the influence of serum proteins on particle‐induced cytokine production and release. Different metal compositions were used in the particulate format, Titanium (Ti), Titanium alloy (Ti6Al4V), and Stainless Steel 316L (SS), and were cultured in vitro with a mixed population of monocytes/macrophages and lymphocytes. The cells were also exposed to an exogenous stimulant mixture of phytohemagglutinin‐P and interferon‐gamma (IFN‐γ) and opsonized particles with human serum. Interleukins, IL‐1α, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IFN‐γ, and tumor necrosis factor‐alpha (TNF‐α) were investigated using enzyme‐linked immunosorbent assay as they are an indicator of the inflammation evoked by particulate metals. It has been experimentally evidenced that metal particles induced higher amounts of IL‐6 and IL‐1 but very low amounts of TNF‐α. T‐lymphocyte activation was evaluated by the quantification of IL‐2 and IFN‐γ levels. The results showed that nonopsonized and opsonized metal particles did not induce the release of increased levels of IL‐2 and IFN‐γ. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
Study on the Attractive Electroanalytical Performance of Carbon‐Ionic Liquid Paste Electrode
Authors: Zhang Xuzhi , Li Meng , Zhao Jun , Chen Bijuan , Qu Keming
Published: January 2013

Carbon paste electrode made of graphite and ionic liquid n‐octylpyridinum hexafluorophosphate (OPFP) displays many attractive electroanalytical abilities towards lots of species, allowing sensitive, low‐potential, simple, low‐cost, and stable performances. Herein a new hypothesis is proposed to explain the formation of these performances based on the results of electrochemical, scanning electron microscopic and transmission electron microscopic investigations. The mechanical force produces mono‐ or multi‐layered graphene during the grinding process. And the OPFP molecules are prone to combine with the graphene, which cause the avoidance of the agglomeration of the exfoliated flakes. The presence of graphene, which is edge plane characteristic, provides high density of electrochemical reactive sites on the surface of the electrode.
Cardiac capillary hemangioma: A case report and brief review of the literature
Authors: Han Yuna , Chen Xin , Wang Xiaobing , Yang Liang , Zeng Yanling , Yang Jun
Published: January 2013

Among primary cardiac tumors, hemangiomas are relatively rare, with a reported incidence of 2.8%. To date, less than 100 cases have been reported in literature. We report the case of a 61‐year‐old woman who complained from chest discomfort since 3 years and in whom transthoracic echocardiography revealed a pedunculated tumor in the left ventricle. The tumor was successfully resected and its histopathological examination revealed a capillary hemangioma. The patient had an uneventful recovery without any complication. © 2012 Wiley Periodicals, Inc. J Clin Ultrasound 42:53–56, 2014
Large‐scale preparation of 13C‐labeled 2‐(phenylthio)acetic acid and the corresponding labeled sulfoxides and sulfones
Authors: Martinez Rodolfo A. , Glass David R. , Ortiz Erick G. , Alvarez Marc A. , Juarez Ernesto , Lodwig Siegfried N. , Unkefer Clifford J.
Published: January 2013

We have developed large‐scale efficient procedures for the conversion of commercially available [13C]‐ or [2H3,13C]methanol and 13CO2 or 13C‐labeled bromoacetic acid to 2‐(phenylthio)[1,2‐13C2]‐, [1‐13C]‐, and [2‐13C]acetic acid. The resulting derivatives are versatile, chemically stable, and nonvolatile two‐carbon labeling precursors. We have used the 13C‐isotopomers of 2‐(phenylthio)acetic acid in the synthesis of 13C‐labeled acrylic acid, methacrylic acid, and trans‐crotonic acid.
Mouse brain fixation to preserve In vivo manganese enhancement for ex vivo manganese‐enhanced MRI
Authors: Liu Yutong , Sajja Balasrinivasa R. , Gendelman Howard E. , Boska Michael D.
Published: January 2013

Purpose

To develop a tissue fixation method that preserves in vivo manganese enhancement for ex vivo magnetic resonance imaging (MRI). The needs are clear, as conventional in vivo manganese‐enhanced MRI (MEMRI) applied to live animals is time‐limited, hence limited in spatial resolution and signal‐to‐noise ratio (SNR). Ex vivo applications can achieve superior spatial resolution and SNR through increased signal averaging and optimized radiofrequency coil designs. A tissue fixation method that preserves in vivo Mn2+ enhancement postmortem is necessary for ex vivo MEMRI.

Materials and Methods

T1 measurements and T1‐weighted MRI were performed on MnCl2‐administered mice. The mice were then euthanized and the brains were fixed using one of two brain tissue fixation methods: aldehyde solution or focused beam microwave irradiation (FBMI). MRI was then performed on the fixed brains.

Results

T1 values and T1‐weighted signal contrasts were comparable between in vivo and ex vivo scans on aldehyde‐fixed brains. FBMI resulted in the loss of Mn2+ enhancement.

Conclusion

Aldehyde fixation, not FBMI, maintained in vivo manganese enhancement for ex vivo MEMRI. J. Magn. Reson. Imaging 2013;38:482–487. © 2013 Wiley Periodicals, Inc.
Segmental copy number loss in the region of Semaphorin 4D gene in patients with acetabular dysplasia
Authors: Sekimoto Tomohisa , Ishii Miho , Emi Mitsuru , Kurogi Syuji , Funamoto Taro , Hamada Hiroaki , Chosa Etsuo
Published: January 2013

Acetabular dysplasia (AD) appears to be a multi‐factorial disease, which may involve both genetic and environmental factors and whose pathogenesis remains obscure. The present study aims to identify a genetic variation that might confer risk of AD. We performed whole‐genome screening of a copy number variation (CNV) using a deCODE‐Illumina CNV beadchip with 20 female AD patients and 131 control subjects. Subsequently, Agilent's region‐targeted high‐density oligonucleotide tiling microarray was used to analyze 64 female AD patients and 32 female control subjects. By sequential analyses, we found a copy number loss in 18 of 64 AD patients, but none in the 32 controls. The loss occurred within a 472 kb region on 9q22.2, which harbors the gene for Semaphorin 4D (Sema4D; 18/64 vs. 0/32, p = 4.81 × 10−4, OR = 25.86). We suggest that a copy number loss of the Sema4D gene region may play a role in the etiology of AD. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 957–961, 2013
Cartilage‐on‐cartilage versus metal‐on‐cartilage impact characteristics and responses
Authors: Heiner Anneliese D. , Smith Abigail D. , Goetz Jessica E. , Goreham‐Voss Curtis M. , Judd Kyle T. , McKinley Todd O. , Martin James A.
Published: January 2013

A common in vitro model for studying acute mechanical damage in cartilage is to impact an isolated osteochondral or cartilage specimen with a metallic impactor. The mechanics of a cartilage‐on‐cartilage (COC) impact, as encountered in vivo, are likely different than those of a metal‐on‐cartilage (MOC) impact. The hypothesis of this study was that impacted in vitro COC and MOC specimens would differ in their impact behavior, mechanical properties, chondrocyte viability, cell metabolism, and histologic structural damage. Osteochondral specimens were impacted with either an osteochondral plug or a metallic cylinder at the same delivered impact energy per unit area, and processed after 14 days in culture. The COC impacts resulted in about half of the impact maximum stress and a quarter of the impact maximum stress rate of change, as compared to the MOC impacts. The impacted COC specimens had smaller changes in mechanical properties, smaller decreases in chondrocyte viability, higher total proteoglycan content, and less histologic structural damage, as compared to the impacted MOC specimens. If MOC impact conditions are to be used for modeling of articular injuries and post‐traumatic osteoarthritis, the differences between COC and MOC impacts must be kept in mind. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 887–893, 2013
Biaxial mechanics and inter‐lamellar shearing of stem‐cell seeded electrospun angle‐ply laminates for annulus fibrosus tissue engineering
Authors: Driscoll Tristan P. , Nakasone Ryan H. , Szczesny Spencer E. , Elliott Dawn M. , Mauck Robert L.
Published: January 2013

The annulus fibrosus (AF) of the intervertebral disk plays a critical role in vertebral load transmission that is heavily dependent on the microscale structure and composition of the tissue. With degeneration, both structure and composition are compromised, resulting in a loss of AF mechanical function. Numerous tissue engineering strategies have addressed the issue of AF degeneration, but few have focused on recapitulation of AF microstructure and function. One approach that allows for generation of engineered AF with appropriate (+/−)30° lamellar microstructure is the use of aligned electrospun scaffolds seeded with mesenchymal stem cells (MSCs) and assembled into angle‐ply laminates (APL). Previous work indicates that opposing lamellar orientation is necessary for development of near native uniaxial tensile properties. However, most native AF tensile loads are applied biaxially, as the disk is subjected to multi‐axial loads and is constrained by its attachments to the vertebral bodies. Thus, the objective of this study was to evaluate the biaxial mechanical response of engineered AF bilayers, and to determine the importance of opposing lamellar structure under this loading regime. Opposing bilayers, which replicate native AF structure, showed a significantly higher modulus in both testing directions compared to parallel bilayers, and reached ∼60% of native AF biaxial properties. Associated with this increase in biaxial properties, significantly less shear, and significantly higher stretch in the fiber direction, was observed. These results provide additional insight into native tissue structure–function relationships, as well as new benchmarks for engineering functional AF tissue constructs. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 864–870, 2013
Is Illinois heeding the call to regionalize pancreatic surgery?
Authors: Hayman Amanda V. , Fisher Matthew J. , Kluz Thomas , Merkow Ryan P. , Wang Edward C. , Bentrem David J.
Published: January 2013

Background and Objectives

Recommendations to refer pancreatic procedures to high‐volume centers have been in place for a decade. We sought to determine whether regionalization of pancreatic procedures to high‐volume centers is occurring in Illinois.

Methods

We compared pancreatic procedures performed in Illinois hospitals from 2000 to 2004 [time period (TP) 1] versus 2005–2009 (TP2) for changes in inpatient mortality and hospital volume. Hospitals were categorized into low‐ (LVH), intermediate‐ (IVH), or high‐volume (HVH).

Results

From TP1 to TP2, there was a 23% increase in absolute case volume (2,232–2,737), despite fewer hospitals performing pancreatic procedures (114–95). In hospital mortality decreased (5.5–3.3%, P < 0.01) and was lowest at HVHs. LVHs and IVHs were associated with a 4.7 and 3.0 higher odds of mortality, respectively (both P < 0.001). Overall, HVHs performed 659 (+73%) more procedures, whereas cumulative procedure volume dropped by 154 cases at LVHs (+1%) and IVHs (−18%).

Conclusions

We observed limited evidence of regionalization of pancreatic procedures in Illinois. The increase in HVH case volume cannot be solely attributed to regionalization, given the corresponding modest decrease seen at non‐HVHs. There is opportunity for Illinois hospitals to implement strategies such as selective referral to improve mortality after pancreatic resection. J. Surg. Oncol. 2013;107:685–691. © 2013 Wiley Periodicals, Inc.
Determination of the Ideal Surfactant Concentration in Miniemulsion Polymerization
Authors: Hecht Lena Lore , Schoth Alexander , Muñoz‐Espí Rafael , Javadi Aliyar , Köhler Karsten , Miller Reinhard , Landfester Katharina , Schuchmann Heike Petra
Published: January 2013

In a miniemulsion polymerization, droplets are transformed to polymer particles keeping the particle size and composition during polymerization. To avoid changes due to coalescence or secondary nucleation, the surfactant concentration has to be adjusted according to the materials used and to the droplet size that is resulting from the emulsification process. To calculate the ideal surfactant concentration, it is important to know how many molecules are solved in the continuous phase. Therefore, a new method to calculate the ratio between adsorbed and dissolved surfactant molecules is presented and used to calculate the ideal surfactant concentration for polymerization of MMA miniemulsion droplets. The adsorption behavior of the surfactant is observed to influence the nucleation mechanism in miniemulsion polymerization significantly. This knowledge can be used to facilitate the design of the miniemulsion polymerization process.

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Predicting future popularity trend of events in microblogging platforms
Authors: Gupta Manish , Gao Jing , Zhai ChengXiang , Han Jiawei
Published: January 2013

The fast information sharing on Twitter from millions of users all over the world leads to almost real‐time reporting of events. It is extremely important for business and administrative decision makers to learn events' popularity as quickly as possible, as it can buy extra precious time for them to make informed decisions. Therefore, we introduce the problem of predicting future popularity trend of events on microblogging platforms. Traditionally, trend prediction has been performed by using time series analysis of past popularity to forecast the future popularity changes. As we can encode the rich Twitter dynamics using a rich variety of features from microblogging data, we explore regression, classification and hybrid approaches, using a large set of popularity, social and event features, to predict event popularity. Experimental results on two real datasets of 18382 events extracted from ∼133 million tweets show the effectiveness of the extracted features and learning approaches. The predicted popularity trend of events can be directly used for a variety of applications including recommendation systems, ad keywords bidding price decisions, stock trading decisions, dynamic ticket pricing for sports events, etc.
Identification of eight candidate target genes of the recurrent 3p12–p14 loss in cervical cancer by integrative genomic profiling
Authors: Lando Malin , Wilting Saskia M , Snipstad Kristin , Clancy Trevor , Bierkens Mariska , Aarnes Eva‐Katrine , Holden Marit , Stokke Trond , Sundfør Kolbein , Holm Ruth , Kristensen Gunnar B , Steenbergen Renske DM , Lyng Heidi
Published: January 2013

The pathogenetic role, including its target genes, of the recurrent 3p12–p14 loss in cervical cancer has remained unclear. To determine the onset of the event during carcinogenesis, we used microarray techniques and found that the loss was the most frequent 3p event, occurring in 61% of 92 invasive carcinomas, in only 2% of 43 high‐grade intraepithelial lesions (CIN2/3), and in 33% of 6 CIN3 lesions adjacent to invasive carcinomas, suggesting a role in acquisition of invasiveness or early during the invasive phase. We performed an integrative DNA copy number and expression analysis of 77 invasive carcinomas, where all genes within the recurrent region were included. We selected eight genes, THOC7, PSMD6, SLC25A26, TMF1, RYBP, SHQ1, EBLN2, and GBE1, which were highly down‐regulated in cases with loss, as confirmed at the protein level for RYBP and TMF1 by immunohistochemistry. The eight genes were subjected to network analysis based on the expression profiles, revealing interaction partners of proteins encoded by the genes that were coordinately regulated in tumours with loss. Several partners were shared among the eight genes, indicating crosstalk in their signalling. Gene ontology analysis showed enrichment of biological processes such as apoptosis, proliferation, and stress response in the network and suggested a relationship between down‐regulation of the eight genes and activation of tumourigenic pathways. Survival analysis showed prognostic impact of the eight‐gene signature that was confirmed in a validation cohort of 74 patients and was independent of clinical parameters. These results support the role of the eight candidate genes as targets of the 3p12–p14 loss in cervical cancer and suggest that the strong selection advantage of the loss during carcinogenesis might be caused by a synergetic effect of several tumourigenic processes controlled by these targets. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Does body mass index at diagnosis or weight change during therapy predict toxicity or survival in intermediate risk rhabdomyosarcoma? A report from the Children's Oncology Group soft tissue sarcoma committee
Authors: Burke Megan E. , Lyden Elizabeth R. , Meza Jane L. , Ladas Elena J. , Dasgupta Roshni , Wiegner Ellen A. , Arndt Carola A.S.
Published: January 2013

Background

Weight loss prevalence and its impact on toxicities and survival in intermediate risk rhabdomyosarcoma (IRMS) patients are unknown. We evaluated the association between weight change during therapy and number of toxicities, hospital days, infections, and overall survival and between baseline body mass index (BMI) and survival in patients treated on Children's Oncology Group trial D9803.

Procedure

Four hundred sixty‐eight IRMS patients age ≥2 and <21 years treated on D9803 had required data. Regression models evaluated association between weight loss from baseline and toxicities, hospital days, infections, and survival. Kaplan–Meier curves and regression models evaluated baseline BMI percentile's association with survival.

Results

Thirty‐five percent and 37% of patients had >5% weight loss at 12 and 24 weeks, respectively, with 16% and 19% losing >10% weight respectively. Greater than 10% weight loss at 24 weeks was associated with more toxicities and hospital days during subsequent therapy but not infection rate or survival. Baseline underweight patients (<5th percentile BMI) had borderline inferior survival compared with baseline average weight patients while there was no difference in survival seen between average weight and overweight or obese patients.

Conclusions

Nearly one in five IRMS patients experienced >10% weight loss on therapy. This was associated with increased toxicity but not decreased survival compared with patients who had less weight loss. Baseline BMI percentile trended toward a significant association with survival. Future studies might investigate nutritional impact on quality of life and if weight loss is preventable by early nutritional intervention. Pediatr Blood Cancer 2013; 60: 748–753. © 2013 Wiley Periodicals, Inc.
The impact of the written request process on drug development in childhood cancer
Authors: Snyder Kristen M. , Reaman Gregory , Avant Debbie , Pazdur Richard
Published: January 2013

Purpose

The Food and Drug Administration (FDA) Modernization Act, enacted in 1997, created a pediatric exclusivity incentive allowing sponsors to qualify for an additional 6 months of marketing exclusivity after satisfying the requirements outlined in the Written Request (WR). This review evaluates the impact of the WR mechanism on the development of oncology drugs in children.

Methods

A search of the FDA document archiving, reporting, and regulatory tracking system was performed for January 1, 2000 to December 31, 2010. Drugs were identified and pediatric‐specific labeling information was obtained from Drugs@fda.gov and FDA Pediatric Labeling Changes Table.

Results

Fifty WRs have been issued for oncology drugs. Pediatric studies have been submitted for 14 drugs. Thirteen received pediatric exclusivity. As of December 31, 2010, labeling changes have been made for 11 drugs. Three drugs were approved for pediatric use.

Conclusion

WRs have provided a mechanism to promote the study of drugs in pediatric malignancies. Information from studies resulting from the WRs regarding safety, pharmacokinetics, and tolerability of oncology drugs has been incorporated into pediatric labeling for 11/14 of the drugs. Earlier communication and collaboration between the FDA, National Cancer Institute, clinical investigators, and commercial sponsors are envisioned to facilitate the identification and prioritization of emerging new drugs of interest for WR consideration. Since this is the only regulatory mechanism, resulting from specific legislative initiatives relevant to cancer drug development for children, efforts to enhance its impact on increasing drug approval for pediatric cancer indications are warranted. Pediatr Blood Cancer 2013; 60: 531–537. © 2013 Wiley Periodicals, Inc.
Factors associated with poor quality of life in survivors of childhood acute lymphoblastic leukemia and lymphoma
Authors: Kanellopoulos Adriani , Hamre Hanne Mari , Dahl Alv A. , Fosså Sophie D. , Ruud Ellen
Published: January 2013

Background

Previous studies of health‐related quality of life (QoL) in childhood cancer survivors have hardly focused on factors associated with poor QoL. The aims of our study were: (1) to assess QoL in long‐term survivors (LTSs) of childhood acute lymphoblastic leukemia (ALL) and lymphomas compared to age‐matched controls from the general population (NORMs). (2) To investigate factors associated with poor QoL in LTSs.

Procedure

This population‐based cross‐sectional study enrolled 285 LTSs of ALL and lymphomas diagnosed between 1970 and 2002 at age <18 years. The LTSs completed an extensive mailed questionnaire including the Short Form 36 (SF‐36) as QoL‐measure. NORMs consisted of five age‐matched controls for each LTS (N = 1,425). Poor QoL was defined as SF‐36 physical or mental component summary score <40.

Results

The median age of LTSs' at survey was 30 years (range: 18–54), median follow‐up time 21 years (range: 7–39). Compared to NORMs, LTSs scored significantly lower on 7 of 8 SF‐36 subscales. Among LTSs 32% reported poor QoL versus 19% among NORMs (P < 0.001). Among LTSs, psychosocial, lifestyle‐ and health‐related variables, but not type of malignancy, treatment factors or socio‐demographic factors were clinically significantly associated with poor QoL in bivariate regression analyses. In multivariate analysis, levels of fatigue, anxiety and depression, as well as obesity and insomnia remained significantly associated with poor QoL.

Conclusion

Significantly more LTSs than age‐matched NORMs experienced poor QoL. Clinically significant associations with fatigue, anxiety, depression, obesity and insomnia were observed, which may be amenable for interventions, and thereby improvement of QoL in LTSs. Pediatr Blood Cancer 2013; 60: 849–855. © 2013 Wiley Periodicals, Inc.
Phase I/II trial of clofarabine and cytarabine in children with relapsed/refractory acute lymphoblastic leukemia (AAML0523): A report from the Children's Oncology Group
Authors: Cooper Todd M. , Razzouk Bassem I. , Gerbing Robert , Alonzo Todd A. , Adlard Kathleen , Raetz Elizabeth , Gamis Alan S. , Perentesis John , Whitlock James A.
Published: January 2013

Background

The discovery of effective re‐induction regimens for children with more than one relapse of acute lymphoblastic leukemia (ALL) remains elusive. The novel nucleoside analog clofarabine exhibits modest single agent efficacy in relapsed ALL, though optimal combinations of this agent with other active chemotherapy drugs have not yet been defined. Herein we report the response rates of relapsed ALL patients treated on Children's Oncology Group study AAML0523, a Phase I/II study of the combination of clofarabine and cytarabine.

Procedure

AAML0523 enrolled 21 children with ALL in second or third relapse, or those refractory to re‐induction therapy. The study consisted of two phases: a dose finding phase and an efficacy phase. The dose finding portion consisted of a single dose escalation/de‐escalation of clofarabine for 5 days in combination with a fixed dose of cytarabine (1 g/m2/day for 5 days). Eight patients received clofarabine at 40 mg/m2/day and 13 patients at 52 mg/m2/day.

Results

Toxicities observed at all doses of clofarabine were typical of intensive chemotherapy regimens for leukemia, with infection being the most common. We did not observe significant hepatotoxicity as reported in other clofarabine combination regimens. The recommended pediatric Phase II dose of clofarabine in combination with cytarabine for the efficacy portion of AAML0523 was 52 mg/m2. Of 21 patients with ALL, 3 (14%) achieved a complete response (CR). Based on the two‐stage design definition of first‐stage inactivity, the therapy was deemed ineffective.

Conclusion

The combination of clofarabine and cytarabine in relapsed/refractory childhood ALL does not warrant further clinical investigation. Pediatr Blood Cancer 2013; 60: 1141–1147. © 2013 Wiley Periodicals, Inc.
Utility of platelet function analyzer as a screening tool for the diagnosis of Von Willebrand disease in adolescents with menorrhagia
Authors: Naik Swati , Teruya Jun , Dietrich Jennifer E. , Jariwala Purvi , Soundar Esther , Venkateswaran Lakshmi
Published: January 2013

Background

Von Willebrand disease (VWD), and in particular, VWD type 1 and low VW factor (defined as Von Willebrand Ristocetin cofactor activity (RCoF) <30 and <50 IU/dl, respectively with normal multimers) are frequently detected in adolescents with menorrhagia and both groups benefit from similar management. Platelet function analyzer (PFA‐100®) is often used as a screening test to detect VWD. We analyzed the utility of PFA‐100® as a screening tool in the detection of VWD type 1 and low VW factor (VWF) in an exclusive adolescent population with menorrhagia.

Methods

The study population consisted of adolescents with menorrhagia who had simultaneously drawn blood samples for VWD and PFA‐100®. Abnormal PFA‐100® was defined as values >183 seconds for collagen/epinephrine and/or >126 seconds for collagen/ADP.

Results

Of a total of 235 patients tested, 23 patients had RCoF <50 IU/dl and normal multimer patterns. Statistical analysis of the utility of PFA‐100® in detecting RCoF <50 IU/dl with normal multimers yielded sensitivity, specificity, positive predictive, and negative predictive values of 52%, 89%, 34%, and 95%, respectively.

Conclusions

Based on our results, PFA‐100® was not sufficiently sensitive to detect RCoF values <50 IU/dl with normal multimer patterns in teen‐aged women with menorrhagia. We conclude that in the setting of adolescent menorrhagia, PFA‐100® does not have utility as an initial screening test for the diagnosis of VWD and in particular, low VWF and that clinicians need to be aware of this limitation of PFA‐100® while evaluating adolescents with menorrhagia. Pediatr Blood Cancer 2013; 60: 1184–1187. © 2013 Wiley Periodicals, Inc.