bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epilepsy following cortical injury: Cellular and molecular mechanisms as targets for potential prophylaxis
Authors: Prince David A. , Parada Isabel , Scalise Karina , Graber Kevin , Jin Xiaoming , Shen Fran 
Published: January 2009

SummaryThe sequelae of traumatic brain injury, including posttraumatic epilepsy, represent a major societal problem. Significant resources are required to develop a better understanding of the underlying pathophysiologic mechanisms as targets for potential prophylactic therapies. Posttraumatic epilepsy undoubtedly involves numerous pathogenic factors that develop more or less in parallel. We have highlighted two potential “prime movers”: disinhibition and development of new functional excitatory connectivity, which occur in a number of animal models and some forms of epilepsy in humans. Previous experiments have shown that tetrodotoxin (TTX) applied to injured cortex during a critical period early after lesion placement can prevent epileptogenesis in the partial cortical (“undercut”) model of posttraumatic epilepsy. Here we show that such treatment markedly attenuates histologic indices of axonal and terminal sprouting and presumably associated aberrant excitatory connectivity. A second finding in the undercut model is a decrease in spontaneous inhibitory events. Current experiments show that this is accompanied by regressive alterations in fast‐spiking γ‐aminobutyric acid (GABA)ergic interneurons, including shrinkage of dendrites, marked decreases in axonal length, structural changes in inhibitory boutons, and loss of inhibitory synapses on pyramidal cells. Other data support the hypothesis that these anatomic abnormalities may result from loss of trophic support normally provided to interneurons by brain‐derived neurotrophic factor (BDNF).Approaches that prevent these two pathophysiologic mechanisms may offer avenues for prophylaxis for posttraumatic epilepsy. However, major issues such as the role of these processes in functional recovery from injury and the timing of the critical period(s) for application of potential therapies in humans need to be resolved.
Grp94 acts as a mediator of curcumin‐induced antioxidant defence in myogenic cells
Authors: Pizzo Paola , Scapin Cristina , Vitadello Maurizio , Florean Cristina , Gorza Luisa 
Published: January 2009

AbstractCurcumin is a non‐toxic polyphenol with pleiotropic activities and limited bioavailability. We investigated whether a brief exposure to low doses of curcumin would induce in the myogenic C2C12 cell line an endoplasmic reticulum (ER) stress response and protect against oxidative stress. A 3‐hr curcumin administration (5–10 μM) increased protein levels of the ER chaperone Grp94, without affecting those of Grp78, calreticulin and haeme‐oxygenase‐1 (HO‐1). Exposure of cells to hydrogen peroxide 24 hrs after the curcumin treatment decreased caspase‐12 activation, total protein oxidation and translocation of NF‐κB to the nucleus, compared with untreated cells. Grp94 overexpression, achieved by means of either stable or transient trasfection, induced comparable cytoprotective effects to hydrogen peroxide. The delayed cytoprotection induced by curcumin acted through Grp94, because the curcumin‐induced increase in Grp94 expression was hampered by either stable or transient transfection with antisense cDNA; in these latter cells, the extent of total protein oxidation, as well as the translocation of NF‐κB to the nucleus, and the percentage of apoptotic cells were comparable to those observed in both curcumin‐untreated wild‐type and empty vector transfected cells. Defining the mechanism(s) by which Grp94 exerts its antioxidant defence, the determination of cytosolic calcium levels in C2C12 cells by fura‐2 showed a significantly reduced amount of releasable calcium from intracellular stores, both in conditions of Grp94 overexpression and after curcumin pre‐treatment. Therefore, a brief exposure to curcumin induces a delayed cytoprotection against oxidative stress in myogenic cells by increasing Grp94 protein level, which acts as a regulator of calcium homeostasis.
Impact of oral disease on quality of life in the US and Australian populations
Authors: Sanders Anne E. , Slade Gary D. , Lim Sungwoo , Reisine Susan T 
Published: January 2009

Abstract –  The US National Health and Nutrition Examination Survey (NHANES 2003–2004) evaluated oral health quality of life for the first time using a previously untested subset of seven Oral Health Impact Profile (OHIP) questions, i.e. the NHANES‐OHIP.Objectives:  (i) To describe the impact of dental conditions on quality of life in the US adult population; (ii) to evaluate construct validity and adequacy of the NHANES‐OHIP in NHANES 2003–2004 and a comparable Australian survey.Methods:  In the cross‐sectional NHANES 2003–2004 survey of a nationally representative sample of US adults (n = 4907), prevalence was quantified as the proportion of adults who reported experiencing one or more impacts fairly often or very often within the past year. Construct validity was tested by comparing prevalence estimates across categories of sociodemographic, dental health and utilization characteristics known to vary in oral health. In 2002, Australian cross‐sectional survey of a nationally representative sample of adults (n = 2644), adequacy of the NHANES‐OHIP questions were tested with reference to a slightly modified version of the OHIP‐14 questions.Results:  NHANES‐OHIP prevalence estimates were markedly similar in the United States (15.3%) and Australia (15.7%). In the US construct, validity was evidenced by higher NHANES‐OHIP scores among groups with greater levels of tooth loss, perceived treatment need and problem‐oriented visiting and with lack of private dental insurance and low income. In Australia, prevalence for the NHANES‐OHIP closely resembled prevalence estimates of the modified OHIP‐14. Both varied to a similar degree across levels of tooth loss, perceived treatment need, problem‐oriented visiting, and private dental insurance and income, demonstrating adequacy of the NHANES‐OHIP as a brief independent instrument.Conclusions:  There was acceptable construct validity and adequacy of the NHANES‐OHIP questionnaire. In the United States, the impact of oral disease disproportionately affected disadvantaged groups, a finding that supports application of the US Healthy People 2010 major goals of improved quality of life and reduced health disparities.
Proposed New Fatigue Design Curves for Carbon and Low-Alloy Steels in
High Temperature Water
Authors: O’Donnell William J. , O’Donnell William John , O’Donnell Thomas P. 
Published: January 2009

Abstract
High temperature (&gt;300°F, 149°C) water has been found to greatly accelerate fatigue crack growth rates in carbon and low-alloy steels. Current ASME Code fatigue design curves are based entirely on data obtained in air. While a factor of 2 on life was applied to the air data to account for environmental effects, the actual effects have been found to be an order of magnitude greater in the low-cycle regime. A great deal of work has been carried out on these environmental effects by talented investigators worldwide. The ASME Code Subgroup on Fatigue Strength has been working for 20years on the development of new fatigue design methods and curves to account for high temperature water environmental effects. This paper presents an overview of the data and analyses used to formulate proposed new environmental fatigue design curves, which maintain the same safety margins as existing Code fatigue design curves for air environments, and a historical summary of ASME Code Work in this field.
Selective Spectrophotometric and Spectrofluorometric Methods for the Determination of Amantadine Hydrochloride in Capsules and Plasma via Derivatization with 1,2‐Naphthoquinone‐4‐sulphonate
Authors: Mahmoud Ashraf M. , Khalil Nasr Y. , Darwish Ibrahim A. , Aboul-Fadl Tarek 
Published: January 2009

New selective and sensitive spectrophotometric and spectrofluorometric methods have been developed and validated for the determination of amantadine hydrochloride (AMD) in capsules and plasma. The methods were based on the condensation of AMD with 1,2‐naphthoquinone‐4‐sulphonate (NQS) in an alkaline medium to form an orange‐colored product. The spectrophotometric method involved the measurement of the colored product at 460  nm. The spectrofluorometric method involved the reduction of the product with potassium borohydride, and the subsequent measurement of the formed fluorescent reduced AMD‐NQS product at 382  nm after excitation at 293  nm. The variables that affected the reaction were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9972–0.9974) and low LOD (1.39 and 0.013 μg mL−1) were obtained in the ranges of 5–80 and 0.05–10
μg mL−1 for the spectrophotometric and spectrofluorometric methods, respectively. The precisions of the methods were satisfactory; RSD
≤2.04%. Both methods were successfully applied to the determination of AMD in capsules. As its higher sensitivity, the spectrofluorometric method was applied to the determination of AMD in plasma; the recovery was 96.3–101.2 ± 0.57–4.2%. The results obtained by the proposed methods were comparable with those obtained by the official method
Signal Transducers and Activators of Transcription Mediate Fibroblast Growth Factor–Induced Vascular Endothelial Morphogenesis
Authors: Yang Xinhai , Qiao Dianhua , Meyer Kristy , Friedl Andreas 
Published: January 2009

AbstractThe fibroblast growth factors (FGF) play diverse roles in development, wound healing, and angiogenesis. The intracellular signal transduction pathways, which mediate these pleiotropic activities, remain incompletely understood. We show here that the proangiogenic factors FGF2 and FGF8b can activate signal transducers and activators of transcription (STAT) in mouse microvascular endothelial cells (EC). Both FGF2 and FGF8b activate STAT5 and to a lesser extent STAT1, but not STAT3. The FGF2-dependent activation of endothelial STAT5 was confirmed in vivo with the Matrigel plug angiogenesis assay. In tissue samples of human gliomas, a tumor type wherein FGF-induced angiogenesis is important, STAT5 is detected in tumor vessel EC nuclei, consistent with STAT5 activation. By forced expression of constitutively active or dominant-negative mutant STAT5A in mouse brain ECs, we further show that STAT5 activation is both necessary and sufficient for FGF-induced cell migration, invasion, and tube formation, which are key events in vascular endothelial morphogenesis and angiogenesis. In contrast, STAT5 is not required for brain EC mitogenesis. The cytoplasmic tyrosine kinases Src and Janus kinase 2 (Jak2) both seem to be involved in the activation of STAT5, as their inhibition reduces FGF2- and FGF8b-induced STAT5 phosphorylation and EC tube formation. Constitutively active STAT5A partially restores tube formation in the presence of Src or Jak2 inhibitors. These observations show that FGFs use distinct signaling pathways to induce angiogenic phenotypes. Together, our findings implicate the FGF-Jak2/Src-STAT5 cascade as a critical angiogenic FGF signaling pathway. [Cancer Res 2009;69(4):1668–77]
p34SEI-1 Inhibits Apoptosis through the Stabilization of the X-Linked Inhibitor of Apoptosis Protein: p34SEI-1 as a Novel Target for Anti–Breast Cancer Strategies
Authors: Hong Seung-Woo , Kim Chang-Jae , Park Won-Sang , Shin Jae-Sik , Lee Soon-Duck , Ko Seong-Gyu , Jung Sam-Il , Park In-Chul , An Sung-Kwan , Lee Won-Keun , Lee Wang-Jae , Jin Dong-Hoon , Lee Myeong-Sok 
Published: January 2009

Abstract
The p34SEI-1 protein exerts oncogenic effects via regulation of the cell cycle, which occurs through a direct interaction with cyclin-dependent kinase 4. Such regulation can increase the survival of various types of tumor cells. Here, we show that the antiapoptotic function of p34SEI-1 increases tumor cell survival by protecting the X-linked inhibitor of apoptosis protein (XIAP) from degradation. Our findings show that p34SEI-1 inhibits apoptosis. This antiapoptotic effect was eliminated by the suppression of p34SEI-1 expression. We also determined that direct binding of p34SEI-1 to the BIR2 domain prevents ubiquitination of XIAP. Interestingly, p34SEI-1 expression is absent or weak in normal tissues but is strongly expressed in tissues obtained from patients with breast cancer. Furthermore, the expression levels of p34SEI-1 and XIAP seem to be coordinated in human breast cancer cell lines and tumor tissues. Thus, our findings reveal that p34SEI-1 uses a novel apoptosis-inhibiting mechanism to stabilize XIAP. [Cancer Res 2009;69(3):741–6]
The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase IIα in Breast Cancer Cells
Authors: Rao V. Ashutosh , Klein Sarah R. , Agama Keli K. , Toyoda Eriko , Adachi Noritaka , Pommier Yves , Shacter Emily B. 
Published: January 2009

Abstract
Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) is being developed as an iron chelator with selective anticancer activity. We investigated the mechanism whereby Dp44mT kills breast cancer cells, both as a single agent and in combination with doxorubicin. Dp44mT alone induced selective cell killing in the breast cancer cell line MDA-MB-231 when compared with healthy mammary epithelial cells (MCF-12A). It induces G1 cell cycle arrest and reduces cancer cell clonogenic growth at nanomolar concentrations. Dp44mT, but not the iron chelator desferal, induces DNA double-strand breaks quantified as S139 phosphorylated histone foci (γ-H2AX) and Comet tails induced in MDA-MB-231 cells. Doxorubicin-induced cytotoxicity and DNA damage were both enhanced significantly in the presence of low concentrations of Dp44mT. The chelator caused selective poisoning of DNA topoisomerase IIα (top2α) as measured by an in vitro DNA cleavage assay and cellular topoisomerase-DNA complex formation. Heterozygous Nalm-6 top2α knockout cells (top2α+/−) were partially resistant to Dp44mT-induced cytotoxicity compared with isogenic top2α+/+ or top2β−/− cells. Specificity for top2α was confirmed using top2α and top2β small interfering RNA knockdown in HeLa cells. The results show that Dp44mT is cytotoxic to breast cancer cells, at least in part, due to selective inhibition of top2α. Thus, Dp44mT may serve as a mechanistically unique treatment for cancer due to its dual ability to chelate iron and inhibit top2α activity. [Cancer Res 2009;69(3):948–57]
Translymphatic Chemotherapy by Intrapleural Placement of Gelatin Sponge Containing Biodegradable Paclitaxel Colloids Controls Lymphatic Metastasis in Lung Cancer
Authors: Liu Jiang , Meisner Dale , Kwong Elizabeth , Wu Xiao Y. , Johnston Michael R. 
Published: January 2009

Abstract
As a means of treating lymphatic metastasis from lung cancer, the pharmacokinetics and therapeutic effects of an intrapleural (ipl) implantable drug delivery system consisting of a gelatin sponge impregnated with polylactide-co-glycolide paclitaxel (PLGA-PTX) microspheres were studied. PLGA-PTX with 7% (w/w) drug loading were incorporated into gelatin matrix. The pharmacokinetics were studied in rats with one of the following regimens: (a) Taxol 8 mg/kg by i.v. injection; (b) Taxol 8 mg/kg ipl; (c) PLGA-PTX (100 mg/kg) ipl; (d) sponge containing PLGA-PTX (100 mg/kg) ipl. PTX concentrations in lymph node and plasma were determined by liquid chromatography mass spectrometry, and the area under the curve (AUC) was calculated. Therapeutic efficacy was assessed in an orthotopic lung cancer model with tumor resection 14 days following tumor implantation. Animals were randomized to ipl placement of PLGA-PTX sponge, placebo sponge, or no treatment. Lymph node metastases were examined at 32 d. The results show that the mediastinal lymph node AUC was significantly higher with ipl. placement of PLGA-PTX sponge compared with i.v. and ipl administration of Taxol. This represents 100- to 400-fold increase of lymphatic drug exposure compared with i.v. dosing. Peak plasma concentration was significantly reduced in the PLGA-PTX sponge group compared with i.v. dosing. PLGA-PTX particles were microscopically identified in lymphatic tissue and resulted in an 80% reduction of lymphatic metastasis compared with controls. Translymphatic-targeted drug delivery significantly decreases lymphatic metastasis in an orthotopic lung cancer model. This effect may be attributable to the improved distribution of PTX to the lymphatic system. [Cancer Res 2009;69(3):1174–81]
In vivo Molecular Imaging of Cancer with a Quenching Near-Infrared Fluorescent Probe Using Conjugates of Monoclonal Antibodies and Indocyanine Green
Authors: Ogawa Mikako , Kosaka Nobuyuki , Choyke Peter L. , Kobayashi Hisataka 
Published: January 2009

Abstract
Near-infrared (NIR) fluorophores have several advantages over visible fluorophores, including improved tissue penetration and lower autofluorescence; however, only indocyanine green (ICG) is clinically approved. Its use in molecular imaging probes is limited because it loses its fluorescence after protein binding. This property can be harnessed to create an activatable NIR probe. After cell binding and internalization, ICG dissociates from the targeting antibody, thus activating fluorescence. ICG was conjugated to the antibodies daclizumab (Dac), trastuzumab (Tra), or panitumumab (Pan). The conjugates had almost no fluorescence in PBS but became fluorescent after SDS and 2-mercaptoethanol, with a quenching capacity of 10-fold for 1:1 conjugates and 40- to 50-fold for 1:5 conjugates. In vitro microscopy showed activation within the endolysosomes in target cells. In vivo imaging in mice showed that CD25-expressing tumors were specifically visualized with Dac-ICG. Furthermore, tumors overexpressing HER1 and HER2 were successfully characterized in vivo by using Pan-ICG(1:5) and Tra-ICG(1:5), respectively. Thus, we have developed an activatable NIR optical probe that “switches on” only in target cells. Because both the antibody and the fluorophore are Food and Drug Administration approved, the likelihood of clinical translation is improved. [Cancer Res 2009;69(4):1268–72]
Low-Density Lipoprotein Receptor-Related Protein 1 Promotes Cancer Cell Migration and Invasion by Inducing the Expression of Matrix Metalloproteinases 2 and 9
Authors: Song Heesang , Li Yonghe , Lee Jiyeon , Schwartz Alan L. , Bu Guojun 
Published: January 2009

Abstract
The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor involved in the metabolism of various extracellular ligands, including proteinases, that play critical roles in tumor invasion. Although several studies have shown an increased expression of LRP1 in cancer cells, its function in tumor development and progression remains largely unclear. Here, we reveal a novel mechanism by which LRP1 induces the expression of matrix metalloproteinase 2 (MMP2) and MMP9 and thereby promotes the migration and invasion of human glioblastoma U87 cells. Knockdown of LRP1 expression greatly decreased U87 cell migration and invasion, which was rescued by the forced expression of a functional LRP1 minireceptor. Inhibition of ligand binding to LRP1 by a specific antagonist, receptor-associated protein, also led to reduced cancer cell migration and invasion. Because MMPs play critical roles in cancer cell migration and invasion, we examined the expression of several MMPs and found that the expression of functional MMP2 and MMP9 was selectively decreased in LRP1 knockdown cells. More importantly, decreased cell migration and invasion of LRP1 knockdown cells were completely rescued by exogenous expression of MMP2 or MMP9, suggesting that these MMPs are likely downstream targets of LRP1-mediated signaling. We further show that the level of phosphorylated extracellular signal-regulated kinase (ERK) was significantly decreased in LRP1-silenced cells, suggesting that ERK is a potential mediator of LRP1-regulated MMP2 and MMP9 expression in U87 cells. Together, our data strongly suggest that LRP1 promotes glioblastoma cell migration and invasion by regulating the expression and function of MMP2 and MMP9 perhaps via an ERK-dependent signaling pathway. [Cancer Res 2009;69(3):879–86]
Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells
Authors: Baumann Philipp , Mandl-Weber Sonja , Völkl Andreas , Adam Christian , Bumeder Irmgard , Oduncu Fuat , Schmidmaier Ralf 
Published: January 2009

AbstractMultiple myeloma is still an incurable disease; therefore, new therapeutics are urgently needed. A771726 is the active metabolite of the immunosuppressive drug leflunomide, which is currently applied in the treatment of rheumatoid arthritis, BK virus nephropathy, and cytomegaly viremia. Here, we show that dihydroorotate dehydrogenase (DHODH) is commonly expressed in multiple myeloma cell lines and primary multiple myeloma cells. The DHODH inhibitor A771726 inhibits cell growth in common myeloma cell lines at clinically achievable concentrations in a time- and dose-dependent manner. Annexin V-FITC/propidium iodide staining revealed induction of apoptosis of multiple myeloma cell lines and primary multiple myeloma cells. The 5-bromo-2′-deoxyuridine cell proliferation assay showed that inhibition of cell growth was partly due to inhibition of multiple myeloma cell proliferation. A771726 induced G1 cell cycle arrest via modulation of cyclin D2 and pRb expression. A771726 decreased phosphorylation of protein kinase B (Akt), p70S6K, and eukaryotic translation initiation factor 4E-binding protein-1 as shown by Western blotting experiments. Furthermore, we show that the stimulatory effect of conditioned medium of HS-5 bone marrow stromal cells on multiple myeloma cell growth is completely abrogated by A771726. In addition, synergism studies revealed synergistic and additive activity of A771726 together with the genotoxic agents melphalan, treosulfan, and doxorubicin as well as with dexamethasone and bortezomib. Taken together, we show that inhibition of DHODH by A771726/leflunomide is effective in multiple myeloma. Considering the favorable toxicity profile and the great clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in multiple myeloma. [Mol Cancer Ther 2009;8(2):366–75