bluuebunny/crossref_metadata_2025 huggingface dataset:
Age‐related efficacy of parathyroid hormone on osseointegration in the rat
Authors: Mair Birgit , Tangl Stefan , Feierfeil Johannes , Skiba Daniela , Watzek Georg , Gruber Reinhard
Published: March 2009

Objective: Aging is a physiological determinant that can distinguish the outcome of a pharmaceutical therapy to improve osseointegration of titanium implants. Here we examined the possible interaction of intermittent parathyroid hormone (PTH) and the age of the recipient on the parameters of osseointegration in a rat tibia implantation model.

Material and methods: Twenty female Wistar rats aged 8 months and 20 female rats aged 2 months received PTH at 60 μg/kg body weight or a vehicle by a subcutaneous injection three times a week. After 4 weeks, histomorphometric analysis of the peri‐implant area was performed. The possible interaction of the two factors on ‘bone volume per tissue volume’ (BV/TV) and ‘bone‐to‐implant contact’ (BIC) was tested by two‐way analysis of variance.

Results: Based on data from the medullary compartment, two‐way analysis of variance revealed that the effect of ‘intermittent PTH’ depends on the ‘age of the recipient’ when BV/TV is considered the dependent variable (P=0.04). Post hoc tests indicated that PTH leads to an increase of BV/TV of adult and young rats. However, when BIC was considered the dependent variable, no interaction was observed (P=0.14). PTH but not aging has a significant impact on BIC. In the cortical compartment, no effects of PTH on osseointegration were observed.

Conclusions: The findings indicate that treatment with PTH is more effective on the peri‐implant bone regeneration in adult than in young animals, supporting the importance to consider the influences of age on the development of pharmaceutical therapies to increase the process of osseointegration.
Double‐blind randomized controlled trial study on post‐extraction immediately restored implants using the switching platform concept: soft tissue response. Preliminary report
Authors: Canullo Luigi , Iurlaro Giorgia , Iannello Giuliano
Published: March 2009

Aim: To evaluate the soft tissue response to immediately placed implants using the platform switching concept.

Material and methods: In 22 patients, 22 implants of 5.5 mm platform diameter were placed immediately into fresh extraction sockets in maxillae without compromised bone tissue. Eventual post‐extraction bone defects were filled using bovine bone matrix mixed with collagen. Immediately after insertion, implants were randomly divided: 11 implants were connected with a 3.8 mm diameter abutment (test group) and 11 with a 5.5 mm diameter abutment (control group). A provisional crown was adapted and adjusted for non‐functional immediate positioning. Two months later, definitive prosthetic rehabilitation was performed. Periodontal parameter, buccal peri‐implant mucosal changes (REC), mesial and distal papilla height (PH) and vertical height of jumping distance (VHG) were measured at the time of implant placement, of definitive prosthesis insertion and every 6 months thereafter.

Results: The mean follow‐up was 25 months. All implants were clinically osseointegrated.

The test group showed a +0.18 mm REC gain. PH gain was +0.045 mm on average. The mean values were statistically significant (P≤0.005) compared with the control group (PH=−0.88 mm; REC=−0.45 mm). No difference between the two groups in periodontal parameters was found. The mean value of bone filling was 7.51 mm in the test group (97.4% of VHG) and 8.57 mm in the control group (95.2% of VHG). No statistically significant difference was found between the two groups.

Conclusions: This study suggests that, in a limited time period of 2 years, immediately placed implants with subsequent platform switching can provide peri‐implant tissue stability.
Successful outcome of splinted implants supporting a ‘planned’ maxillary overdenture: a retrospective evaluation and comparison with fixed full dental prostheses
Authors: Sanna A. , Nuytens P. , Naert I. , Quirynen M.
Published: March 2009

Objective: Whereas an overdenture concept is generally accepted for the mandible, the outcome of this therapy for the maxilla remains less documented. This retrospective analysis evaluated the peri‐implant parameters of implants supporting a ‘planned’ overdenture in the maxilla, and compared these data with those of an age‐matched control group, with a fixed full dental prosthesis.

Material and methods: All patients with an implant‐supported overdenture in the maxilla from the Leuven University Hospital (at least 12 months in function) were recalled for a thorough examination. Forty‐four patients (162 implants, Brånemark type) could be enrolled.

Results: The mean loading time was 9 years (range: >1 to >20 years). The cumulative survival rate after 10 years of function was 99.3% if four to six interconnected implants supported the overdenture, but only 85.7% in case two non‐connected implants were used as support. The marginal bone level in the former group remained stable, with changes comparable with those observed for implants supporting fixed full dental prostheses.

Conclusions: These results fully support the overdenture treatment concept for the maxilla, at least when ≥4 splinted implants are used.
Vertical bone augmentation with fluvastatin in an injectable delivery system: a rat study
Authors: Jinno Yohei , Ayukawa Yasunori , Ogino Yoichiro , Atsuta Ikiru , Tsukiyama Yoshihiro , Koyano Kiyoshi
Published: March 2009

Objectives: HMG‐CoA reductase inhibitors (statins) are widely used for hyperlipidemia. Previous studies demonstrate that statins stimulate bone morphogenetic protein‐2 (BMP‐2) expression and lead to bone formation. The aim of this study was to evaluate whether percutaneously injected statin with a novel statin delivery system achieved vertical bone augmentation.

Material and methods: As experimental groups, atelocollagen‐α‐tricalcium phosphate (αTCP) composites containing 3.3 mg (low dose) or 6.7 mg (high dose) of fluvastatin were injected (one shot) subcutaneously over the calvarial periosteum of rats. The animals were then sacrificed 1, 2, and 4 weeks after injection. Vertically augmented bone was assessed by histomorphometric procedures, i.e., by measuring new bone thickness (NBT) and bone density (BD).

Results: In control groups, no newly formed bone could be seen over the calvarial bone. In the experimental groups, in contrast, a large amount of newly formed bone could be seen over the preexisting calvarial bone. The newly formed bone was seen to be in direct contact with the preexisting bone. During the entire observation, significant NBT was observed in the experimental groups (P<0.05). At the final stage of observation (4 weeks), NBT was 66.7% (low‐dose group) and 59.7% (high‐dose group), while they were from 1% to 16.3% in the control groups. In the experimental groups, BD significantly increased in a time‐dependent manner.

Conclusion: Percutaneously applied fluvastatin (one shot) with a composite of αTCP and collagen has great potential to augment the height of the bone.
Cadmium‐induced Cytosolic Ca2+ Elevation and Subsequent Apoptosis in Renal Tubular Cells
Authors: Yeh Jeng‐Hsien , Huang Chorng‐Chih , Yeh Mei‐Yin , Wang Jyh‐Seng , Lee Jenn‐Kuen , Jan Chung‐Ren
Published: March 2009

Abstract: Cadmium (Cd2+) is an industrial and environmental metal. The effect of Cd2+ on intracellular free‐Ca2+ levels ([Ca2+]i) and viability in Madin Darby canine kidney cells was explored. Cd2+increased [Ca2+]i in a concentration‐dependent manner with an EC50 of 85 µM. Cd2+‐induced Mn2+ entry demonstrated Ca2+ influx. Removal of extracellular Ca2+ decreased the [Ca2+]i signal by 60%. The [Ca2+]i signal was inhibited by La3+ but not by L‐type Ca2+ channel blockers. In Ca2+‐free medium, Cd2+‐induced [Ca2+]i signal was abolished by pre‐treatment with 1 µM thapsigargin (an endoplasmic reticulum Ca2+pump inhibitor) and 2 µM carbonylcyanide m‐chlorophenylhydrazone (CCCP; a mitochondrial uncoupler). Cd2+‐induced Ca2+ release was not altered by inhibition of phospholipase C. At concentrations between 10 and 100 µM, Cd2+killed cells in a concentration‐dependent manner. The cytotoxic effect of 100 µM Cd2+was reversed by pre‐chelating cytosolic Ca2+with BAPTA. Cd2+‐induced apoptosis was demonstrated by propidium iodide. Collectively, this study shows that Cd2+ induced a [Ca2+]i increase in Madin Darby canine kidney cells via evoking Ca2+ entry through non‐selective Ca2+ channels, and releasing stored Ca2+ from endoplasmic reticulum and mitochondria in a phospholipase C‐independent manner.
POROSITY DEVELOPMENT AND ITS EFFECT ON OIL UPTAKE DURING FRYING PROCESS
Authors: ZIAIIFAR AMAN MOHAMMAD , COURTOIS FRANCIS , TRYSTRAM GILLES
Published: March 2009

The objective of this work was to study certain physical properties of French fries, such as density and porosity, and their relationship with oil absorption during the frying process. The effects of oil temperature and frying time on moisture loss, oil content and crust thickness were first studied. Changes in apparent density, absolute density as well as porosity during two successive periods of frying process (frying and cooling) were then investigated, and possible reasons for these changes were discussed. Finally, the porosity changes were related to oil uptake. Potatoes were cut into rectangular shapes and were fried at different oil temperatures (140, 155, 170 and 185C) for periods ranging from 60 to 240 s. Results showed that during frying, the porosity of the product increases, reaching a maximum at the end of frying, whereas during the cooling period, it decreases because of oil absorption and collapse phenomena.

PRACTICAL APPLICATIONS

This study shows some physical changes that can be related to oil absorption during the frying process of French fries. Many food research projects attempt to understand oil uptake during the frying process in order to control and reduce the fat content of fried products. The results of this work may lead to finding the way(s) to produce less greasy fried products.
Public and User Participation in Public Service Delivery: Tensions in Policy and Practice
Authors: Martin Graham P.
Published: March 2009

Social‐scientific analysis of public‐participation initiatives has proliferated in recent years. This review article discusses some key aspects of recent work. First, it analyses some of the justifications put forward for public participation, drawing attention to differences and overlaps between rationales premised on democratic representation/representativeness and those based on more technocratic ideas about the knowledge that the public can offer. Second, it considers certain tensions in policy discourses on participation, focusing in particular on policy relating to the National Health Service and other British public services. Third, it examines the challenges of putting a coherent vision for public participation into practice, noting the impediments that derive from the often‐competing ideas about the remit of participation held by different groups of stakeholders. Finally, it analyses the gap between policy and practice, and the consequences of this for the prospects for the enactment of active citizenship through participation initiatives.
Role of epidermal growth factor receptor (EGFR) in corneal remodelling in diabetes
Authors: Akhtar Saeed , Almubrad Turki , Bron Anthony J. , Yousif Mariam H. M. , Benter Ibrahim F. , Akhtar Saghir
Published: March 2009

Purpose:  This study examined the role of epidermal growth factor receptor (EGFR) signalling on the organization and remodelling of collagen fibrils (CFs) and proteoglycans (PGs) in the stroma of diabetic rat cornea.

Methods:  Diabetes was induced in female Wistar rats (n = 5) by streptozotocin (STZ) injection (55 mg/kg). Treatment with a selective inhibitor of EGFR tyrosine kinase, AG1478, was started on the same day as the induction of diabetes and administered every other day for 4 weeks. Corneas were fixed in 4% paraformaldehyde at 4 ° to allow for analysis of CF diameters and in 2.5% glutaraldehyde in sodium acetate buffer containing cuprolinic blue to enable the study of PG distribution. AnalySIS soft imaging software was used to analyse CFs and PGs.

Results:  Epithelial thickness, and median diameter and area fraction of CF in corneal stroma were decreased in diabetic rat cornea compared with normal cornea (p < 0.001), whereas the median PG area and area fractions were significantly increased (p < 0.001). Treatment with AG1478, although it had no action on normal cornea, prevented these diameter and area fraction changes in CFs and PGs. The cornea of AG1478‐treated diabetic rats showed a slight increase in CF diameter and area fraction and a decreased number density.

Conclusions:  These data show that the distribution of corneal stroma CFs and PGs was altered after 4 weeks of diabetes and that, furthermore, treatment with an EGFR signalling inhibitor normalized these abnormalities. The data suggest that EGFR plays an important role in the development of diabetes‐induced corneal remodelling.
MAGNONS TRANSMISSION THROUGH AN ATOMIC WIRE CONNECTING TWO ULTRATHIN HEISENBERG FERROMAGNETS
Authors: BELHADI M. , KHATER A.
Published: March 2009

The magnons transport properties of molecular wires connecting two Heisenberg ferromagnets are studied within the framework of the matching method and with use of a realistic atomic structure. The model system consists of two nanostructured ferromagnetic films on either side of the junction and the atomic wire consists of a linear molecule connecting two ultrathin solid ferromagnetic films. A theoretical model is presented for the study of the transmission and the reflection of spin waves at the atomic wire junction. The calculation was made at the atomic scale for two identical waveguides with ordered spins and coupled by Heisenberg exchange interaction between first neighbors. Our analysis yields a detailed understanding of the spin-wave coherent scattering at the linear molecular junction. We calculate, in particular, the coherent reflection R and transmission T coefficients, which constitute the elements of the scattering matrix in accordance with the Landauer–Büttiker scattering formalism, as well as the magnon transmittance of the atomic wire for spin-waves incident from the interior of the film on the junction. The most representative numerical results obtained for the system of two slabs made up of three Fe ferromagnetic atomic layers connected with an Fe or Gd atomic wire are presented as function of the dimensionless frequency Ω in the magnons energy band. The coherent reflection and transmission scattering cross sections show characteristic spectral features, depending on the length of the wire, on the cut-off frequencies for the propagating magnons, as well as on the magnons incidence angle. The results illustrate the occurrence of Fano resonances in the transmitted spectra due to the interaction of localized spin states on the atomic wire with the propagating spin waves of the waveguide. An interesting physical effect is observed for this magnetic atomic junction, namely the frequency selective conductance of the spin waves via Fano resonances, by an appropriate choice of the spin-wave incident angle.
COMPARISON OF FERROELECTRIC PROPERTIES OF COSUBSTITUTED BISMUTH TITANATE FILMS BETWEEN Bi3.15Nd0.85Ti2.97Mg0.03O12 AND Bi3.15Nd0.85Ti2.95Mn0.05O12
Authors: HU Z. S. , ZHONG X. L. , WANG J. B. , LIAO M. , ZHENG X. J. , ZHOU Y. C.
Published: March 2009

Aiming at the influence of substitution on ferroelectric behaviors, Nd and Mg / Mn cosubstituted bismuth titanate films, Bi 3.15 Nd 0.85 Ti 2.97 Mg 0.03 O 12 (BNTMg) and Bi 3.15 Nd 0.85 Ti 2.95 Mn 0.05 O 12 (BNTMn), have been prepared on Pt / Ti / SiO 2/ Si (100) substrates at 700°C by a chemical solution deposition technique, respectively. A series of comparisons including structures, surface morphologies, and ferroelectric properties of the as-prepared films were carried out by X-ray diffraction, scanning electron microscope, and a Radiant Technologies Precision Workstation for ferroelectric test system. It was found that the films possess preferred the (117) and (00l)-oriented polycrystalline structures, and the remnant polarization of BNTMg film is larger than that of BNTMn film and the coercive field of BNTMn film is lower than that of BNTMg film. The values of 2Pr and 2Ec of BNTMg and BNTMn are 28 μC/cm2 and 212 kV/cm, and 15 μC/cm2 and 175 kV/cm, respectively. The relevant physical mechanisms were pursued.
Organisational Learning Capability of Malaysia SMEs: Examining the Effects of Entrepreneurial Orientation and Human-Capital Development Practices
Authors: Ngui Kwang Sing , Songan Peter , Hong Kian Sam
Published: March 2009

The current study built and empirically tested a model of the relationships between selected organisational variables, Organisational Learning (OL) capability and performance in the context of small- and medium-sized enterprises (SMEs) in Malaysia. Theoretical advances in the OL domain have been based on the experiences of large organisations in the western hemisphere. In response, the study focuses on analysing the OL capability of SMEs in a transitional economy, namely Malaysia. Structural equation modeling was applied to analyse the datasets from 256 manufacturing and services SMEs. Statistical results showed that entrepreneurial orientation and human-capital development practices have direct positive effects on SMEs' OL capability. It was further found that human-capital development practices mediated the relationship between entrepreneurial orientation and OL capability. This implied that while entrepreneurial orientation fosters the need for a strong OL capability, human-capital development practices serve as the mechanisms for developing such capability. Lastly, empirical evidence was provided to support the notion that OL capability enhances the performance of SMEs.
A Numerical Solution Using an Adaptively Preconditioned Lanczos Method for a Class of Linear Systems Related with the Fractional Poisson Equation
Authors: Ilić M. , Turner I. W. , Anh V.
Published: March 2009

This study considers the solution of a class of linear systems related with the fractional
Poisson equation (FPE) with nonhomogeneous boundary conditions on a
bounded domain. A numerical approximation to FPE is derived using a matrix representation of the
Laplacian to generate a linear system of equations with its matrix A raised to the fractional power α/2. The solution of the linear system then requires the action of the matrix function
f(A) = A−α/2 on a vector b. For large, sparse, and symmetric positive definite matrices, the Lanczos approximation
generates f(A)b ≈ β0Vmf(Tm)e1. This method works well when both the analytic grade of A with respect
to b and the residual for the linear system are sufficiently small. Memory constraints often
require restarting the Lanczos decomposition; however this is not straightforward in the context of
matrix function approximation. In this paper, we use the idea of thick‐restart and adaptive preconditioning
for solving linear systems to improve convergence of the Lanczos approximation. We
give an error bound for the new method and illustrate its role in solving FPE. Numerical results are
provided to gauge the performance of the proposed method relative to exact analytic solutions.
DDB1 Targets Chk1 to the Cul4 E3 Ligase Complex in Normal Cycling Cells and in Cells Experiencing Replication Stress
Authors: Leung-Pineda Van , Huh Jiwon , Piwnica-Worms Helen
Published: March 2009

The Chk1 protein kinase preserves genome integrity in normal proliferating cells and in cells experiencing replicative and genotoxic stress. Chk1 is currently being targeted in anticancer regimens. Here, we identify damaged DNA-binding protein 1 (DDB1) as a novel Chk1-interacting protein. DDB1 is part of an E3 ligase complex that includes the cullin proteins Cul4A and Cul4B. We report that Cul4A/DDB1 negatively regulates Chk1 stability in vivo. Chk1 associates with Cul4A/DDB1 during an unperturbed cell division cycle and both Chk1 phosphorylation and replication stress enhanced these interactions. Cul4A/DDB1 regulates Chk1 ubiquitination in vivo and Chk1 is directly ubiquitinated in vitro in a Cul4A/DDB1–dependent manner. Furthermore, Chk1 is stabilized in cells deficient for Cul4A/DDB1. This study shows that Chk1 abundance is regulated by the Cul4A/DDB1 ubiquitin ligase during an unperturbed cell division cycle, in response to replicative stress and on heat shock protein 90 inhibition, and that deregulation of the Chk1/Cul4A/DDB1 pathway perturbs the ionizing radiation–induced G2 checkpoint. [Cancer Res 2009;69(6):2630–7]
Magnetovaccination as a Novel Method to Assess and Quantify Dendritic Cell Tumor Antigen Capture and Delivery to Lymph Nodes
Authors: Long Christopher M. , van Laarhoven Hanneke W.M. , Bulte Jeff W.M. , Levitsky Hyam I.
Published: March 2009

A major parameter limiting immune responses to vaccination is the number of activated antigen-presenting cells (APC) that capture antigen and migrate to draining lymph nodes (LN). Currently, a quantitative noninvasive technique for monitoring in vivo antigen capture and delivery is lacking. The use of cellular magnetic resonance (MR) imaging (MRI) is a promising approach for this purpose; however, cellular imaging currently requires ex vivo prelabeling of cells with contrast agents followed by reintroduction of cells into the subject being monitored. Here, we describe an in vivo labeling method, which relies upon cell-to-cell transfer of superparamagnetic iron oxide (SPIO) from tumor cells to endogenous APCs, in situ, to quantify APC delivery to LNs in a tumor vaccine model. Mice were immunized with a tumor cell–based vaccine that was irradiated and labeled with SPIO. APCs that had captured SPIO were imaged over time as they accumulated in LNs. We show here that MRI is capable of monitoring, in vivo, the trafficking of magnetically labeled APCs inducing a tumor-specific immune response, and that these cells can be magnetically recovered ex vivo. Excellent correlation was observed between in vivo and ex vivo quantification of APCs, with resolution sufficient to detect increased APC trafficking elicited by an adjuvant. This study shows the potential of magnetovaccination and MRI cell tracking to systematically evaluate a key parameter relevant to the optimization of vaccine therapies through noninvasive MRI-based quantification of APC numbers. [Cancer Res 2009;69(7):3180–7]
E2F1 Induces Tumor Cell Survival via Nuclear Factor-κB–Dependent Induction of EGR1 Transcription in Prostate Cancer Cells
Authors: Zheng Chaogu , Ren Zijia , Wang Hetian , Zhang Weici , Kalvakolanu Dhananjaya V. , Tian Zhigang , Xiao Weihua
Published: March 2009

Transcription factor E2F1 has been implicated in both apoptosis-promoting and apoptosis-suppressing effects. However, factors that mediate its antiapoptotic effects are still not identified. Using prostate tumor–derived cell lines, we showed here that E2F1 activated the expression of transcription factor EGR1 for promoting cell survival. E2F1 up-regulated the production of EGR1-induced growth factors, epidermal growth factor, platelet-derived growth factor, and insulin-like growth factor II, which in turn activated the phosphoinositide-3-kinase/Akt pathway to resist drug-induced apoptosis. Moreover, E2F1 directly induced the transcription of the Egr1 gene using the κB site located in its proximal promoter. E2F1 physically interacted with the RelA subunit of nuclear factor-κB and modulated its transactivity to fully activate EGR1 transcription. Together, these studies uncovered a novel mechanism for E2F1-induced suppression of apoptosis in prostate cancer. [Cancer Res 2009;69(6):2324–31]
Dose-Response Relationships forN7-(2-Hydroxyethyl)Guanine Induced by Low-Dose [14C]Ethylene Oxide: Evidence for a Novel Mechanism of Endogenous Adduct Formation
Authors: Marsden Debbie A. , Jones Donald J.L. , Britton Robert G. , Ognibene Ted , Ubick Esther , Johnson George E. , Farmer Peter B. , Brown Karen
Published: March 2009

Ethylene oxide (EO) is widely used in the chemical industry and is also formed in humans through the metabolic oxidation of ethylene, generated during physiologic processes. EO is classified as a human carcinogen and is a direct acting alkylating agent, primarily forming N7-(2-hydroxyethyl)guanine (N7-HEG). To conduct accurate human risk assessments, it is vital to ascertain the relative contribution of endogenously versus exogenously derived DNA damage and identify the sources of background lesions. We have therefore defined in vivo dose-response relationships over a concentration range relevant to human EO exposures using a dual-isotope approach. By combining liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography-accelerator mass spectrometry analysis, both the endogenous and exogenous N7-HEG adducts were quantified in tissues of [14C]EO-treated rats. Levels of [14C]N7-HEG induced in spleen, liver, and stomach DNA increased in a linear manner from 0.002 to 4 adducts/108 nucleotides. More importantly, the extent of damage arising through this route was insignificant compared with the background abundance of N7-HEG naturally present. However, at the two highest doses, [14C]EO exposure caused a significant increase in endogenous N7-HEG formation in liver and spleen, suggesting that EO can induce physiologic pathways responsible for ethylene generation in vivo and thereby indirectly promote N7-HEG production. We present evidence for a novel mechanism of adduct formation to explain this phenomenon, involving oxidative stress and 1-aminocyclopropane-1-carboxylic acid as a potential biosynthetic precursor to ethylene in mammalian cells. Based on the proposed pathway, N7-HEG may have potential as a biomarker of cellular oxidative stress. [Cancer Res 2009;69(7):3052–9]
Effective Incorporation of Biomarkers into Phase II Trials
Authors: McShane Lisa M. , Hunsberger Sally , Adjei Alex A.
Published: March 2009

The incorporation of biomarkers into the drug development process will improve understanding of how new therapeutics work and allow for more accurate identification of patients who will benefit from those therapies. Strategically planned biomarker evaluations in phase II studies may allow for the design of more efficient phase III trials and better screening of therapeutics for entry into phase III development, hopefully leading to increased chances of positive phase III trial results. Some examples of roles that a biomarker can play in a phase II trial include predictor of response or resistance to specific therapies, patient enrichment, correlative endpoint, or surrogate endpoint. Considerations for using biomarkers most effectively in these roles are discussed in the context of several examples. The substantial technical, logistic, and ethical challenges that can be faced when trying to incorporate biomarkers into phase II trials are also addressed. A rational and coordinated approach to the inclusion of biomarker studies throughout the drug development process will be the key to attaining the goal of personalized medicine.
Genomic Analysis Using High-Density Single Nucleotide Polymorphism-Based Oligonucleotide Arrays and Multiplex Ligation-Dependent Probe Amplification Provides a Comprehensive Analysis of INI1/SMARCB1 in Malignant Rhabdoid Tumors
Authors: Jackson Eric M. , Sievert Angela J. , Gai Xiaowu , Hakonarson Hakon , Judkins Alexander R. , Tooke Laura , Perin Juan Carlos , Xie Hongbo , Shaikh Tamim H. , Biegel Jaclyn A.
Published: March 2009

Purpose: A high-resolution genomic profiling and comprehensive targeted analysis of INI1/SMARCB1 of a large series of pediatric rhabdoid tumors was done. The aim was to identify regions of copy number change and loss of heterozygosity (LOH) that might pinpoint additional loci involved in the development or progression of rhabdoid tumors and define the spectrum of genomic alterations of INI1 in this malignancy.

Experimental Design: A multiplatform approach using Illumina single nucleotide polymorphism-based oligonucleotide arrays, multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, and coding sequence analysis was used to characterize genome-wide copy number changes, LOH, and genomic alterations of INI1/SMARCB1 in a series of pediatric rhabdoid tumors.

Results: The biallelic alterations of INI1 that led to inactivation were elucidated in 50 of 51 tumors. INI1 inactivation was shown by a variety of mechanisms, including deletions, mutations, and LOH. The results from the array studies highlighted the complexity of rearrangements of chromosome 22 compared with the low frequency of alterations involving the other chromosomes.

Conclusions: The results from the genome-wide single nucleotide polymorphism array analysis suggest that INI1 is the primary tumor suppressor gene involved in the development of rhabdoid tumors with no second locus identified. In addition, we did not identify hotspots for the breakpoints in sporadic tumors with deletions of chromosome 22q11.2. By employing a multimodality approach, the wide spectrum of alterations of INI1 can be identified in the majority of patients, which increases the clinical utility of molecular diagnostic testing.
Regulatory T-Cell–Mediated Attenuation of T-Cell Responses to the NY-ESO-1 ISCOMATRIX Vaccine in Patients with Advanced Malignant Melanoma
Authors: Nicholaou Theo , Ebert Lisa M. , Davis Ian D. , McArthur Grant A. , Jackson Heather , Dimopoulos Nektaria , Tan Bee , Maraskovsky Eugene , Miloradovic Lena , Hopkins Wendie , Pan Linda , Venhaus Ralph , Hoffman Eric W. , Chen Weisan , Cebon Jonathan
Published: March 2009

Purpose: NY-ESO-1 is a highly immunogenic antigen expressed in a variety of malignancies, making it an excellent target for cancer vaccination. We recently developed a vaccine consisting of full-length recombinant NY-ESO-1 protein formulated with ISCOMATRIX adjuvant, which generated strong humoral and T-cell–mediated immune responses and seemed to reduce the risk of disease relapse in patients with fully resected melanoma. This study examines the clinical and immunologic efficacy of the same vaccine in patients with advanced metastatic melanoma.

Experimental Design: Delayed-type hypersensitivity responses, circulating NY-ESO-1–specific CD4+ and CD8+ T cells, and proportions of regulatory T cells (Treg) were assessed in patients.

Results: In contrast to patients with minimal residual disease, advanced melanoma patients showed no clinical responses to vaccination. Although strong antibody responses were mounted, the generation of delayed-type hypersensitivity responses was significantly impaired. The proportion of patients with circulating NY-ESO-1–specific CD4+ T cells was also reduced, and although many patients had CD8+ T cells specific to a broad range of NY-ESO-1 epitopes, the majority of these responses were preexisting. Tregs were enumerated in the blood by flow cytometric detection of cells with a CD4+CD25+FoxP3+ and CD4+CD25+CD127− phenotype. Patients with advanced melanoma had a significantly higher proportion of circulating Treg compared with those with minimal residual disease.

Conclusions: Our results point to a tumor-induced systemic immune suppression, showing a clear association between the stage of melanoma progression, the number of Treg in the blood, and the clinical and immunologic efficacy of the NY-ESO-1 ISCOMATRIX cancer vaccine.
Neamine Inhibits Prostate Cancer Growth by Suppressing Angiogenin-Mediated rRNA Transcription
Authors: Ibaragi Soichiro , Yoshioka Norie , Li Shuping , Hu Miaofen G. , Hirukawa Saori , Sadow Peter M. , Hu Guo-fu
Published: March 2009

Purpose: Angiogenin (ANG) undergoes nuclear translocation and stimulates rRNA transcription in both prostate cancer cells and endothelial cells. The purpose of this study is to assess the antitumor activity of neamine, a nontoxic degradation product of neomycin that blocks nuclear translocation of ANG.

Experimental Design: The anti-prostate cancer activity of neamine was first evaluated in a xenograft animal model. It was then examined in the murine prostate-restricted AKT transgenic mice that develop prostate intraepithelial neoplasia (PIN) owing to AKT transgene overexpression.

Results: Neamine inhibits xenograft growth of PC-3 human prostate cancer cells in athymic mice. It blocks nuclear translocation of ANG and inhibits rRNA transcription, cell proliferation, and angiogenesis. Neamine also prevents AKT-induced PIN formation as well as reverses fully developed PIN in murine prostate-restricted AKT mice, accompanied by a decrease in rRNA synthesis, cell proliferation, and angiogenesis and an increase in prostate epithelial cell apoptosis.

Conclusion: We confirmed that ANG is a molecular target for cancer drug development and that blocking nuclear translocation of ANG is an effective means to inhibit its activity. Our results also suggested that neamine is a lead compound for further preclinical evaluation.
A Negative Feedback Regulatory Loop Associates the Tyrosine Kinase Receptor ERBB2 and the Transcription Factor GATA4 in Breast Cancer Cells
Authors: Hua Guoqiang , Zhu Bing , Rosa Fréderic , Deblon Nicolas , Adélaïde José , Kahn-Perlès Brigitte , Birnbaum Daniel , Imbert Jean
Published: March 2009

Overexpression of the ERBB2 gene, linked to genomic and transcriptional amplifications, is a poor prognosis indicator in 25% to 30% of breast cancers. In contrast to some well-documented genomic amplifications, molecular mechanisms leading to ERBB2 transcriptional overexpression remain poorly characterized. Gene expression analyses of breast cancer have characterized distinct transcriptional signatures allowing a molecular classification of breast carcinoma. Coexpression of the ERBB2 and GATA4 genes was originally observed in tumors. Both genes are essential for cardiovascular development and GATA4 has been proposed to control the transcription of critical genes for the differentiation and the function of myocardium. We determined that ERBB2-targeted small interfering RNA repressed both ERBB2 and GATA4 genes, whereas GATA4-targeted small interfering RNA repressed GATA4 and activated ERBB2 transcription. Transfected GATA4-expressing construct repressed ERBB2 promoter. Phylogenetic foot printing revealed multiple putative GATA4 binding sites conserved in mammals within the ERBB2 promoter region. Chromatin immunoprecipitation showed that GATA4 binds specifically to several ERBB2 gene noncoding regions. Electrophoretic mobility shift assay revealed GATA4 binding to a well-conserved consensus motif. Site-directed mutagenesis confirmed the role of this new regulatory element for the activity of the ERBB2 gene enhancer. In agreement with a repressor role of GATA4 on ERBB2 gene expression balanced by ERBB2 activation of the GATA4 gene, a negative correlation between the relative levels of ERBB2 and GATA4 mRNA was observed in breast cancer cell lines and breast tumor samples. We propose that the negative feedback loop linking ERBB2 and GATA4 plays a role in the transcriptional dysregulation of ERBB2 gene expression in breast cancer. (Mol Cancer Res 2009;7(3):402–14)
Galectin-1-Mediated Tumor Invasion and Metastasis, Up-Regulated Matrix Metalloproteinase Expression, and Reorganized Actin Cytoskeletons
Authors: Wu Ming-Heng , Hong Tse-Ming , Cheng Hui-Wen , Pan Szu-Hua , Liang Yu-Ray , Hong Hsiao-Chin , Chiang Wei-Fan , Wong Tung-Yiu , Shieh Dar-Bin , Shiau Ai-Li , Jin Ying-Tai , Chen Yuh-Ling
Published: March 2009

Galectin-1 (Gal-1) is a β-galactose-binding lectin; its expression level has been reported to correlate with tumor progression. Gal-1 is highly expressed in the invasive front of primary tumors and in the cancer cells of metastatic lesions in the lymph nodes of patients with oral squamous cell carcinoma. However, the molecular mechanism of Gal-1 in tumor metastasis is not completely clear. We found that increased Gal-1 expression is closely associated with its high levels of invasion in lung adenocarcinoma and oral squamous cell carcinoma cell lines. Knocking down Gal-1 with small interfering RNA in highly invasive cancer cells reduced their invasion levels. Moreover, the invasion ability of poorly invasive cancer cells was significantly increased after Gal-1 overexpression of Gal-1. Mechanism studies revealed that Gal-1 promoted tumor invasion mainly by up-regulating matrix metalloproteinase (MMP)-9 and MMP-2 and by reorganizing actin cytoskeleton. Gal-1 enhanced the activation of Cdc42, a small GTPase and member of the Rho family, thus increasing the number and length of filopodia on tumor cells. Furthermore, Gal-1-overexpressing cells had higher metastatic abilities in tail vein metastasis assays in vivo. We conclude that Gal-1 is involved in tumor invasion and metastasis by increasing MMP expression and reorganizing cytoskeletons in oral cancers and lung adenocarcinoma. (Mol Cancer Res 2009;7(3):311–8)
Ultrastructural Evaluation of Gingival Glycosaminoglycans in Ovariectomized Rats: Effects of Steroid Hormone Therapy
Authors: Calió Pedro Luiz , Santos Simões Ricardo , Oliveira-Filho Ricardo Martins , Rosa Maciel Gustavo Arantes , de Jesus Simões Manuel , Baracat Edmund C. , Soares, Jr. José Maria
Published: March 2009

Background/Aims: To evaluate the behavior of glycosaminoglycans (GAGs) in rat gingiva and the effects of lack of sexual steroids and the hormonal therapy with estrogen and dexamethasone (DEX). Methods: 40 female rats were divided into four groups: GI: animals in permanent estrus; GII: ovariectomized (OVX) animals + vehicle; GIII: OVX animals treated with 17β-estradiol benzoate (10 µg/kg), and GIV: OVX animals treated with 17β-estradiol benzoate (10 µg/kg) + DEX (3 mg/kg). After treatment, the gingiva was removed and its GAGs content was evaluated by electronic microscopy after stained by cuprolinic blue technique. Results: The electron-microscopic data showed that low values of chondroitin sulfate were found in castrated animals (35.05 ± 3.58%) compared to other groups (GI: 41.17 ± 1.13; GIII: 48.04 ± 2.60; GIV: 49.09 ± 2.68%). In contrast, the amount of dermatan sulfate in GII (57.70 ± 2.50%) was higher than in the other groups (GI: 46.12 ± 1.30; GIII: 42.65 ± 2.98; GIV: 42.68 ± 5.43%). Conclusions: GAGs may be influenced by estradiol, and DEX did not seem to antagonize the role of estradiol in the GAGs of gingiva. The histotypical structure of gingiva is related to the amount of chondroitin sulfate. Consequently, the estrogen therapy may be important for gingival health.
Mutation Analysis of FOXF2 in Patients with Disorders of Sex Development (DSD) in Combination with Cleft Palate
Authors: Jochumsen U. , Werner R. , Miura N. , Richter-Unruh A. , Hiort O. , Holterhus P.M.
Published: March 2009

In contrast to disorders of sexual differentiation caused by lack of androgen production or inhibited androgen action, defects affecting development of the bipotent genital anlagen have rarely been investigated in humans. We have previously documented that the transcription factor FOXF2 is highly expressed in human foreskin. Moreover, Foxf2 knockout mice present with cleft palate in combination with hypoplasia of the genital tubercle. We hypothesized that humans with disorders of sex development (DSD) in combination with cleft palate could have mutations in the FOXF2 gene. Eighteen children with DSD and cleft palate were identified in the Lübeck DSD database (about 1,500 entries). Genomic DNA sequence analysis of the FOXF2 gene was performed and compared with 10 normal female and 10 normal male controls, respectively. Two heterozygous DNA sequence variations were solely present in one single patient each but in none of the 20 normal controls: a duplication of GCC (c.97GCC[9]+[10]) resulting in an extra alanine within exon 1 and a 25*G>A substitution in the 3′-untranslated region. Two patients carried a c.262G>A sequence variation predicting for an Ala88Thr exchange which was also detected in 2 normal controls. Two silent mutations, c.1272C>T (Ser424Ser) and c.1284T>C (Tyr428Tyr), respectively, occurred in the coding region of exon 2, again in both patients and normal controls. In conclusion, the majority of the detected sequence alterations were polymorphisms without obvious functional relevance. However, it cannot be excluded that the 2 unique DNA sequence alterations could have affected FOXF2 on the mRNA or protein level thus contributing to the observed disturbances in genital and palate development.
A Short Cycle of Narrow-Band UVB Phototherapy in the Early Phase of Long-Term Efalizumab Can Provide a Quicker Remission of Moderate and Severe Psoriasis: A Pilot Study
Authors: Zane Cristina , Capezzera Rossana , Venturini Marina , Sala Raffaella , Facchinetti Elena , Pedretti Alessandra , Calzavara-Pinton Piergiacomo
Published: March 2009

Background: Efalizumab, albeit highly efficient in psoriasis treatment, displays a slower rate of clearance when compared to anti-tumor-necrosis-factor-α drugs. It has been suggested that a combination of treatments might accelerate efalizumab response. Objective: To determine whether the combination of narrow-band ultraviolet B (NB-UVB) phototherapy and efalizumab could improve the therapeutic efficacy of efalizumab alone in moderate to severe psoriasis. Methods: Ten patients underwent a treatment cycle with a whole-body NB-UVB phototherapy (3 sessions a week) during the first 4 weeks of a 6-month treatment with efalizumab at 1 mg/kg body weight/week. In addition, one of two similar plaques, selected for each patient, was shielded during phototherapy. Results: A statistically significant reduction of the psoriasis severity index score was observed at 4 weeks in the irradiated plaque. A Psoriasis Area and Severity Index 75 was achieved by 70% of patients by week 12 as compared to 22–39% reported in the literature. Conclusion: This pilot study indicates that the combination with NB-UVB improves the efficacy of efalizumab monotherapy in the treatment of moderate to severe psoriasis.
Adjustment Disorder with Depressed Mood
Authors: Baumeister Harald , Maercker Andreas , Casey Patricia
Published: March 2009

Background: The volume of research involving adjustment disorder (AD) is limited. The scientific neglect of AD seems to result from the inadequate operationalisation of AD in DSM-IV and ICD-10. The aims of the present proposal are to discuss the shortcomings of AD conceptualisations and to present recommendations for the future. Sampling and Methods: This conceptual paper is based on an iterative process of debate between the authors. Results: The current operational definition of AD is characterised by 3 main limitations: (1) the inadequately defined clinical significance criterion, (2) the relegation of AD behind other diagnoses and (3) the missed recognition of the importance of contextual factors, such that normal human adaptive processes might be pathologised. Furthermore, subtypes of AD lack operational clarity. Based on a discussion of the limitations, recommendations for DSM-V are presented, including the addition of new subtypes. Conclusions: The revision of AD criteria will reduce the likelihood of false-positive and false-negative diagnoses. These changes will enable the scientific exploration of this common and relevant disorder, and will make epidemiological studies, and ultimately service planning based on these, more reliable than at present.
Muscovite Reverses Gastric Gland Atrophy and Intestinal Metaplasia by Promoting Cell Proliferation in Rats with Atrophic Gastritis
Authors: Wang Liang-jing , Zhou Qun-yan , Chen Yan , Chen Shu-jie , Xu Miao , Du Qin , Zhu Fang-shi , Si Jian-min
Published: March 2009

Objective: To detect whether muscovite exerts its protective role in the progression of atrophic gastritis (AG) and evaluate the possible mechanism. Methods: AG rats were established and then randomly divided into groups administrated with different doses of muscovite for 8 weeks. Histological changes in gastric antrum and the number of parietal cells, chief cells, and G/D cells were observed. Serum gastrin and prostaglandin E2 (PGE2) were evaluated by enzyme-linked immunosorbent assay (ELISA). The expression of proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor (EGFR), C-erbB-2, p21, p53, p16 and bcl-2 in gastric tissue were detected by immunohistochemistry. The concentrations of TNF-α and IL-1β secreted by THP-1 cells were detected when incubated with different doses of muscovite. Results: The grade of inflammation in muscovite groups was lower (p < 0.05), while the thickness and number of gastric glands were significantly elevated in muscovite groups (p < 0.01). The expression height of PCNA in the muscovite group was higher than in the AG group (p < 0.01). Immunohistochemistry results showed a positive expression rate of EGFR; p16 in muscovite-treated AG rats was increased (p < 0.05), while C-erbB-2 and p21 were decreased (p < 0.05). Serum gastrin and PGE2 were significantly elevated in the high-dose muscovite-treated rats (p < 0.05). In vitro studies showed that muscovite had a dose-dependent adsorption of TNF-α and IL-1β. Conclusion: Muscovite could reverse gastric gland atrophy and intestinal metaplasia by promoting cell proliferation and revitalization in gastric mucosa in AG rats.
Equatorial Zonal Jet Formation through the Barotropic Instability of Low-Frequency Mixed Rossby–Gravity Waves, Equilibration by Inertial Instability, and Transition to Superrotation
Authors: Fruman Mark D. , Hua Bach Lien , Schopp Richard
Published: March 2009

Depth-dependent barotropic instability of short mixed Rossby–gravity (MRG) waves is proposed as a mechanism for the formation of equatorial zonal jets. High-resolution primitive equation simulations show that a single MRG wave of very short zonal wavelength and small to moderate amplitude is unstable and leads to the development of a largely barotropic, zonally symmetric flow, featuring a westward jet at the equator and extra-equatorial jets alternating in direction with latitude. At higher but still moderate amplitude, westward flow still prevails at the equator at depths of maximum horizontal velocity amplitude in the initial wave, but the long-term equilibrated state can also feature eastward “superrotating” jets at the equator near the depths of zero horizontal velocity in the initial wave. The formation of the superrotating jets in the simulations is found to be sensitive to the inclusion of the nontraditional Coriolis force in the equations of motion. A linear theory is used to demonstrate the existence of exponentially growing horizontally nondivergent perturbations with a dominant zonally symmetric zonal velocity component. An argument for the sense and positioning of the jets relative to the equator is given in terms of inertial instability and the meridional mixing of planetary vorticity by the small zonal-scale components of the linearly unstable modes. In the long time evolution of the flow, if the amplitude of the westward equatorial jet becomes too great, zonally symmetric inertial instability limits the growth of the jets, and inertial adjustment leads to the homogenization of potential vorticity in latitude and depth around the equator.
Modified Exit-ply Delamination Model for Drilling FRPs
Authors: Gururaja S. , Ramulu M.
Published: March 2009

Delamination has been identified as one of the most deleterious damage processes associated with drilling fiber reinforced plastics (FRPs) due to the resulting drastic reduction of structural strength and stiffness. In recent years, several experimental, numerical, and analytical studies have been conducted aimed at understanding delamination initiation and progression during drilling. In this study, a comprehensive review of existing analytical studies has been presented comparing and contrasting their respective advantages and disadvantages. Special emphasis has been laid upon presenting all assumptions made and the underlying implications thereby. Suggestions at improving the existing models so as to facilitate a more realistic description of the drill process using composite lamination theories have also been included.