bluuebunny/crossref_metadata_2025 huggingface dataset:
Fabrication of a Novel Micro-Nano-Hybrid Porous Silicon Array for Photonic Crystal Application
Authors: Ge Daohan , Wang Minchang , Liu Wenjun , Jiao Jiwei
Published: October 2013

In this study, we present a novel technique for the fabrication of 2D hybrid photonic crystal structures based on ordered porous silicon array. Each unit of the array consists of a centric micro-sized macropore and six surrounding nano- pores. The fabrication process is based on photoelectrochemical etching, combined with steps of oxidation, CMP and TMAH etching. We investigate the absolute photonic band gap in such made 2D hybrid photonic crystal composed of triangular and honeycomb lattices. Our results indicate strongly that the photonic band gap is very sensitive to the structure parameters (especially to the diameter of nano-pores), and it can be an effective way to enlarge the absolute photonic band gap by modifying the pore diameters.
Formation of Natural Polyelectrolyte Layer by Layer (LBL) Coating on Magnesium Alloy
Authors: Mahapatro Anil , Elson Laura , Asmatulu Ramazan
Published: October 2013

Magnesium (Mg) and its alloys are being investigated for its use as a biodegradable metallic scaffold for bone tissue engineering applications. In this manuscript we report the formation of natural polyelectrolyte layer by layer (LBL) coating on magnesium alloy which could serve as a matrix to support the growth and differentiation of cells. Chitosan and pectin polyelectrolyte LBL coatings were formed on magnesium alloy. The coatings formed were characterized using scanning electron microscope (SEM), contact angle measurements and electrochemical tests. SEM images confirmed formation of the LBL coatings. The LBL coatings did not affect surface property and biodegradation behavior of the underlying magnesium alloy as indicated by contact angle measurement and electrochemical corrosion tests respectively.
Characteristiscs of Nanocrystalline Silicon Films Deposited by Cat-CVD below 100 °C
Authors: Song Tae-Ho , Hong Wan-Shick
Published: October 2013

Nanocrystalline Silicon (nc-Si) films were deposited by catalytic chemical vapor deposition (Cat-CVD) at a low substrate temperature (100 °C) for use as an active layer in bottom-gate thin-film transistors (TFTs). Hydrogen dilution technique was attempted to increase the crystalline volume fraction (Xc). The hydrogen dilution ratio, RH
= [H2]/[SiH4], was varied from 44 to 74. In order to obtain nc-Si film with a high XC, a thin incubation layer and a fast deposition rate simultaneously, we varied RH and pressure as the deposition proceeded. When the pressure was set to 50 mTorr during the initial stage and changed to 60 mTorr for the rest of the deposition, the incubation layer thickness was suppressed to 4 nm.
The Effect of Bimetallic Surface Composition for Methanol Oxidation
Authors: Garrick Taylor R. , Diao Weijian , Tengco John Meynard , Monnier John , Weidner John W.
Published: October 2013

A methodology for the electroless deposition (ED) of ruthenium (Ru) on a commercial carbon-supported Pt catalyst has been developed for electrochemical and fuel cell applications. This procedure has been used to produce several different bimetallic catalysts composed of Pt and Ru. These bimetallic catalysts have shown higher activities compared to either monometallic Pt or Ru catalysts or the commercially-available Ru-Pt/C catalyst.
New Routes towards Formation of Tin Oxide Inverted Opals for Charge Storage Applications
Authors: Osiak Michal , Armstrong Eileen , O'Dwyer Colm
Published: October 2013

New routes to formation of tin oxide inverted opals with unique morphologies are presented. Inverted opals with walls formed from assemblies of tin oxide nanocrystals are formed from tin acetate precursor, while mesoporous walls are formed when tin alkoxide precursors are used. The inverted opals are investigated by a variety of techniques in order to determine their structure and the dependence of electrochemical properties on the type of precursor used. We found that the initial discharge capacity of the inverted opal based batteries reaches 1200 mAhg-1 but quickly fades afterwards, as it is typical for tin oxide based anodes. Careful investigation of processes occurring in the tin oxide inverted opal anodes may lead to improvement of their performance improvement, and further development of self-supported tin oxide based anodes.
Strain-specific suppression of microRNA-320 by carcinogenic Helicobacter pylori promotes expression of the antiapoptotic protein Mcl-1
Authors: Noto Jennifer M. , Piazuelo M. Blanca , Chaturvedi Rupesh , Bartel Courtney A. , Thatcher Elizabeth J. , Delgado Alberto , Romero-Gallo Judith , Wilson Keith T. , Correa Pelayo , Patton James G. , Peek Richard M.
Published: October 2013

Helicobacter pylori is the strongest risk factor for gastric cancer, and strains harboring the cag pathogenicity island, which translocates the oncoprotein CagA into host cells, further augment cancer risk. We previously reported that in vivo adaptation of a noncarcinogenic H. pylori strain (B128) generated a derivative strain (7.13) with the ability to induce adenocarcinoma, providing a unique opportunity to define mechanisms that mediate gastric carcinogenesis. MicroRNAs (miRNAs) are small noncoding RNAs that regulate expression of oncogenes or tumor suppressors and are frequently dysregulated in carcinogenesis. To identify miRNAs and their targets involved in H. pylori-mediated carcinogenesis, miRNA microarrays were performed on RNA isolated from gastric epithelial cells cocultured with H. pylori strains B128, 7.13, or a 7.13 cagA − isogenic mutant. Among 61 miRNAs differentially expressed in a cagA-dependent manner, the tumor suppressor miR-320 was significantly downregulated by strain 7.13. Since miR-320 negatively regulates the antiapoptotic protein Mcl-1, we demonstrated that H. pylori significantly induced Mcl-1 expression in a cagA-dependent manner and that suppression of Mcl-1 results in increased apoptosis. To extend these results, mice were challenged with H. pylori strain 7.13 or its cagA − mutant; consistent with cell culture data, H. pylori induced Mcl-1 expression in a cagA-dependent manner. In human subjects, cag + strains induced significantly higher levels of Mcl-1 than cag − strains, and Mcl-1 expression levels paralleled the severity of neoplastic lesions. Collectively, these results indicate that H. pylori suppresses miR-320, upregulates Mcl-1, and decreases apoptosis in a cagA-dependent manner, which likely confers an increased risk for gastric carcinogenesis.
Effects of aging on mineralocorticoid-induced salt appetite in rats
Authors: Thunhorst Robert L. , Beltz Terry G. , Johnson Alan Kim
Published: October 2013

This work examined the effects of age on salt appetite measured in the form of daily saline (i.e., 0.3 M NaCl) drinking in response to administration of deoxycorticosterone acetate (DOCA; 5 mg/kg body wt) using young (4 mo), “middle-aged” adult (12 mo), and old (30 mo) male Brown Norway rats. Water and sodium intakes, excretions, and balances were determined daily. The salt appetite response was age dependent with “middle-aged” rats ingesting the most saline solution followed in order by young and then old rats. While old rats drank the least saline solution, the amounts of saline ingested still were copious and comprise an unambiguous demonstration of salt appetite in old rats. Middle-aged rats had the highest saline preference ratios of the groups under baseline conditions and throughout testing consistent with an increased avidity for sodium taste. There were age differences in renal handling of water and sodium that were consistent with a renal contribution to the greater saline intakes by middle-aged rats. There was evidence of impaired renal function in old rats, but this did not account for the reduced saline intakes of the oldest rats.
Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway
Authors: Yang Ju-Rong , Yao Feng-Hua , Zhang Jian-Guo , Ji Zhi-Yong , Li Kai-Long , Zhan Jun , Tong Yu-Na , Lin Li-Rong , He Ya-Ni
Published: October 2013

The apoptotic or necrotic death of renal tubule epithelial cells is the main pathogenesis of renal ischemia-reperfusion-induced acute kidney injury (AKI). Pyroptosis is a programmed cell death pathway that depends on the activation of the caspase cascade and IL-1 cytokine family members. However, the role of pyroptosis in AKI induced by ischemia-reperfusion remains unclear. In this study, we found that the levels of the pyroptosis-related proteins, including caspase-1, caspase-11, and IL-1β, were significantly increased after 6 h of renal ischemia-reperfusion injury (IRI) and peaked at 12 h after IRI. Enhanced pyroptosis was accompanied by elevated renal structural and functional injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in renal tubule epithelial NRK-52E cells, which was characterized by increased pore formation and elevated lactate dehydrogenase release. In addition, obvious upregulation of the endoplasmic reticulum (ER) stress biomarkers glucose-regulated protein 78 and C/EBP homologous protein (CHOP) preceded the incidence of pyroptosis in cells treated with IRI or HRI. Pretreatment with a low dose of tunicamycin, an inducer of ER stress, relieved IRI-induced pyroptosis and renal tissue injury. Silencing of CHOP by small interfering RNA significantly decreased HRI-induced pyroptosis of NRK-52E cells, as evidenced by reduced caspase-11 activity and IL-1β generation. Therefore, we conclude that pyroptosis of renal tubule epithelial cells is a key event during IRI and that CHOP-caspase-11 triggered by overactivated ER stress may be an essential pathway involved in pyroptosis.
Vasopressin induces apical expression of caveolin in rat kidney collecting duct principal cells
Authors: Păunescu Teodor G. , Lu Hua A. J. , Russo Leileata M. , Pastor-Soler Núria M. , McKee Mary , McLaughlin Margaret M. , Bartlett Bianca E. , Breton Sylvie , Brown Dennis
Published: October 2013

Caveolin (Cav)1 is expressed in the basolateral membrane domain of renal collecting duct (CD) principal cells (PCs), where it is associated with caveolae. To reveal any potential involvement of Cav1 in vasopressin signaling, we used specific monoclonal and polyclonal antibodies to examine its localization in CD PCs of Brattleboro (BB) rats treated with vasopressin (DDAVP). Compared with controls, immunofluorescence revealed a time-dependent increase in Cav1 expression in the apical membrane domain of PCs, where it overlapped with aquaporin-2 (AQP2). After 24 h of DDAVP treatment, Cav1 was visible as an increased number of small apical spots. The staining gradually became more extensive, and, after 2 wk of DDAVP, it occupied the majority of the apical membrane domain of many PCs. Cav1 also assumed an apical localization in PCs of DDAVP-treated Sprague-Dawley and Long-Evans rats. Similarly, Cav2 appeared at the apical pole of PCs after DDAVP treatment of BB, Sprague-Dawley, and Long-Evans rats. Immunogold electron microscopy confirmed bipolar Cav1 membrane expression in DDAVP-treated BB rats, whereas caveolae were only detected on the basolateral membrane. Immunoblot analysis of BB rat whole kidney homogenates revealed no significant increase in Cav1 levels in DDAVP-treated rats, suggesting that DDAVP induces Cav1 relocalization or modifies its targeting. We conclude that Cav1 and Cav2 trafficking and membrane localization are dramatically altered by the action of DDAVP. Importantly, the absence of apical caveolae indicates that while Cavs may have an as yet undetermined role in vasopressin-regulated signaling processes, this is probably unrelated to AQP2 internalization by caveolae.
Long-term in vivo time-lapse imaging of synapse development and plasticity in the cerebellum
Authors: Nishiyama Naoko , Colonna Jeremy , Shen Elise , Carrillo Jennifer , Nishiyama Hiroshi
Published: October 2013

Synapses are continuously formed and eliminated throughout life in the mammalian brain, and emerging evidence suggests that this structural plasticity underlies experience-dependent changes of brain functions such as learning and long-term memory formation. However, it is generally difficult to understand how the rewiring of synaptic circuitry observed in vivo eventually relates to changes in animal's behavior. This is because afferent/efferent connections and local synaptic circuitries are very complicated in most brain regions, hence it is largely unclear how sensorimotor information is conveyed, integrated, and processed through a brain region that is imaged. The cerebellar cortex provides a particularly useful model to challenge this problem because of its simple and well-defined synaptic circuitry. However, owing to the technical difficulty of chronic in vivo imaging in the cerebellum, it remains unclear how cerebellar neurons dynamically change their structures over a long period of time. Here, we showed that the commonly used method for neocortical in vivo imaging was not ideal for long-term imaging of cerebellar neurons, but simple optimization of the procedure significantly improved the success rate and the maximum time window of chronic imaging. The optimized method can be used in both neonatal and adult mice and allows time-lapse imaging of cerebellar neurons for more than 5 mo in ∼80% of animals. This method allows vital observation of dynamic cellular processes such as developmental refinement of synaptic circuitry as well as long-term changes of neuronal structures in adult cerebellum under longitudinal behavioral manipulations.
Cerebrospinal Fluid Secretion by the Choroid Plexus
Authors: Damkier Helle H. , Brown Peter D. , Praetorius Jeppe
Published: October 2013

The choroid plexus epithelium is a cuboidal cell monolayer, which produces the majority of the cerebrospinal fluid. The concerted action of a variety of integral membrane proteins mediates the transepithelial movement of solutes and water across the epithelium. Secretion by the choroid plexus is characterized by an extremely high rate and by the unusual cellular polarization of well-known epithelial transport proteins. This review focuses on the specific ion and water transport by the choroid plexus cells, and then attempts to integrate the action of specific transport proteins to formulate a model of cerebrospinal fluid secretion. Significant emphasis is placed on the concept of isotonic fluid transport across epithelia, as there is still surprisingly little consensus on the basic biophysics of this phenomenon. The role of the choroid plexus in the regulation of fluid and electrolyte balance in the central nervous system is discussed, and choroid plexus dysfunctions are described in a very diverse set of clinical conditions such as aging, Alzheimer's disease, brain edema, neoplasms, and hydrocephalus. Although the choroid plexus may only have an indirect influence on the pathogenesis of these conditions, the ability to modify epithelial function may be an important component of future therapies.
Postischemic Revascularization: From Cellular and Molecular Mechanisms to Clinical Applications
Authors: Silvestre Jean-Sébastien , Smadja David M. , Lévy Bernard I.
Published: October 2013

After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.
Physiology and Pathophysiology of Carnosine
Authors: Boldyrev Alexander A. , Aldini Giancarlo , Derave Wim
Published: October 2013

Carnosine (β-alanyl-l-histidine) was discovered in 1900 as an abundant non-protein nitrogen-containing compound of meat. The dipeptide is not only found in skeletal muscle, but also in other excitable tissues. Most animals, except humans, also possess a methylated variant of carnosine, either anserine or ophidine/balenine, collectively called the histidine-containing dipeptides. This review aims to decipher the physiological roles of carnosine, based on its biochemical properties. The latter include pH-buffering, metal-ion chelation, and antioxidant capacity as well as the capacity to protect against formation of advanced glycation and lipoxidation end-products. For these reasons, the therapeutic potential of carnosine supplementation has been tested in numerous diseases in which ischemic or oxidative stress are involved. For several pathologies, such as diabetes and its complications, ocular disease, aging, and neurological disorders, promising preclinical and clinical results have been obtained. Also the pathophysiological relevance of serum carnosinase, the enzyme actively degrading carnosine into l-histidine and β-alanine, is discussed. The carnosine system has evolved as a pluripotent solution to a number of homeostatic challenges. l-Histidine, and more specifically its imidazole moiety, appears to be the prime bioactive component, whereas β-alanine is mainly regulating the synthesis of the dipeptide. This paper summarizes a century of scientific exploration on the (patho)physiological role of carnosine and related compounds. However, far more experiments in the fields of physiology and related disciplines (biology, pharmacology, genetics, molecular biology, etc.) are required to gain a full understanding of the function and applications of this intriguing molecule.
A Dose-Escalation Study of SAR3419, an Anti-CD19 Antibody Maytansinoid Conjugate, Administered by Intravenous Infusion Once Weekly in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma
Authors: Ribrag Vincent , Dupuis Jehan , Tilly Herve , Morschhauser Franck , Laine Fabrice , Houot Roch , Haioun Corinne , Copie Christiane , Varga Andrea , Lambert John , Hatteville Laurence , Ziti-Ljajic Samira , Caron Anne , Payrard Sandrine , Coiffier Bertrand
Published: October 2013

Purpose: To determine recommended dose, dose-limiting toxicity, safety profile, pharmacokinetics, preliminary antitumor activity, and exploratory pharmacodynamics of SAR3419, an antibody–drug conjugate targeting CD19, administered alone by intravenous infusion weekly (qw), in a dose-escalation phase I study in patients with refractory/relapsed (R/R) non-Hodgkin lymphoma (NHL).

Experimental Design: Patients with R/R CD19+ B-NHL were treated with escalating doses of SAR3419 repeated qw for eight to 12 doses. On the basis of clinical evidence of late or cumulative toxicities, the study protocol was amended to test an “optimized” administration schedule consisting of four qw doses followed by four biweekly (q2w) doses (qw/q2w) at the recommended dose with the intent of reducing drug accumulation.

Results: Forty-four patients were treated on seven dose levels ranging from 5 to 70 mg/m2. SAR3419 recommended dose was determined as 55 mg/m2 qw. Twenty-five patients received the qw/q2w schedule at 55 mg/m2, which showed an improved safety profile compared with the qw schedule. Antilymphoma activity was observed with both schedules in around 30% of patients with either indolent or aggressive diseases. SAR3419 displayed a long terminal half-life (approximately 7 days) and a low clearance (approximately 0.6 L/d), with no dose effect. The qw/q2w schedule allowed limiting accumulation with a decrease in SAR3419 plasma trough and average concentrations by around 1.4-fold compared with the qw schedule.

Conclusion: While administered weekly, SAR3419 is well tolerated and active. The qw/q2w schedule that shows an improved safety profile and preserves antilymphoma activity is selected for clinical phase II studies. Clin Cancer Res; 20(1); 213–20. ©2013 AACR.
Loss of PTEN Expression Is Associated with Poor Prognosis in Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: Garcia-Carracedo Dario , Turk Andrew T. , Fine Stuart A. , Akhavan Nathan , Tweel Benjamin C. , Parsons Ramon , Chabot John A. , Allendorf John D. , Genkinger Jeanine M. , Remotti Helen E. , Su Gloria H.
Published: October 2013

Purpose: Previously, we reported PIK3CA gene mutations in high-grade intraductal papillary mucinous neoplasms (IPMN). However, the contribution of phosphatidylinositol-3 kinase pathway (PI3K) dysregulation to pancreatic carcinogenesis is not fully understood and its prognostic value unknown. We investigated the dysregulation of the PI3K signaling pathway in IPMN and its clinical implication.

Experimental Design: Thirty-six IPMN specimens were examined by novel mutant-enriched sequencing methods for hot-spot mutations in the PIK3CA and AKT1 genes. PIK3CA and AKT1 gene amplifications and loss of heterozygosity at the PTEN locus were also evaluated. In addition, the expression levels of PDPK1/PDK1, PTEN, and Ki67 were analyzed by immunohistochemistry.

Results: Three cases carrying the E17K mutation in the AKT1 gene and one case harboring the H1047R mutation in the PIK3CA gene were detected among the 36 cases. PDK1 was significantly overexpressed in the high-grade IPMN versus low-grade IPMN (P = 0.034) and in pancreatic and intestinal-type of IPMN versus gastric-type of IPMN (P = 0.020). Loss of PTEN expression was strongly associated with presence of invasive carcinoma and poor survival in these IPMN patients (P = 0.014).

Conclusion: This is the first report of AKT1 mutations in IPMN. Our data indicate that oncogenic activation of the PI3K pathway can contribute to the progression of IPMN, in particular loss of PTEN expression. This finding suggests the potential employment of PI3K pathway-targeted therapies for IPMN patients. The incorporation of PTEN expression status in making surgical decisions may also benefit IPMN patients and should warrant further investigation. Clin Cancer Res; 19(24); 6830–41. ©2013 AACR.
Development, Characterization, and Reversal of Acquired Resistance to the MEK1 Inhibitor Selumetinib (AZD6244) in an In Vivo Model of Childhood Astrocytoma
Authors: Bid Hemant K. , Kibler Aaron , Phelps Doris A. , Manap Sagymbek , Xiao Linlin , Lin Jiayuh , Capper David , Oswald Duane , Geier Brian , DeWire Mariko , Smith Paul D. , Kurmasheva Raushan T. , Mo Xiaokui , Fernandez Soledad , Houghton Peter J.
Published: October 2013

Purpose: The BT-40 low-grade childhood astrocytoma xenograft model expresses mutated BRAFV600E and is highly sensitive to the MEK inhibitor selumetinib (AZD6244). In this study, we developed and characterized selumetinib resistance and explored approaches to circumventing the mechanisms of acquired resistance.

Experimental Design: BT-40 xenografts were selected in vivo for selumetinib resistance. Resistant tumors were obtained and characterized, as were tumors that reverted to sensitivity. Characterization included expression profiling, assessment of MEK signature and compensatory pathways, MEK inhibition, BRAF expression, and cytokine levels. Combination treatment of BT-40/AZD–resistant tumors with the MEK inhibitor and a STAT3 inhibitor (LLL12) was assessed.

Results: Resistance was unstable, tumors reverting to selumetinib sensitivity when passaged in untreated mice, and MEK was equally inhibited in sensitive and resistant tumors by selumetinib. Drug resistance was associated with an enhanced MEK signature and increased interleukin (IL)-6 and IL-8 expression. Selumetinib treatment induced phosphorylation of STAT3 (Y705) only in resistant xenografts, and similar results were observed in BRAFV600E astrocytic cell lines intrinsically resistant to selumetinib. Treatment of BT-40–resistant tumors with selumetinib or LLL12 had no significant effect, whereas combined treatment induced complete regressions of BT-40/AZD–resistant xenografts.

Conclusions: Resistance to selumetinib selected in vivo in BT-40 tumor xenografts was unstable. In resistant tumors, selumetinib activated STAT3, and combined treatment with selumetinib and LLL12 induced complete responses in resistant BT-40 tumors. These results suggest dual targeting BRAF (V600E) signaling and STAT3 signaling may be effective in selumetinib-resistant tumors or may retard or prevent onset of resistance. Clin Cancer Res; 19(24); 6716–29. ©2013 AACR.
αB-Crystallin: A Novel Regulator of Breast Cancer Metastasis to the Brain
Authors: Malin Dmitry , Strekalova Elena , Petrovic Vladimir , Deal Allison M. , Al Ahmad Abraham , Adamo Barbara , Miller C. Ryan , Ugolkov Andrey , Livasy Chad , Fritchie Karen , Hamilton Erika , Blackwell Kimberly , Geradts Joseph , Ewend Matt , Carey Lisa , Shusta Eric V. , Anders Carey K. , Cryns Vincent L.
Published: October 2013

Purpose: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs.

Experimental Design: αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood–brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models.

Results: In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin–dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models.

Conclusion: αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease. Clin Cancer Res; 20(1); 56–67. ©2013 AACR.
Skin Color Is Relevant to Vitamin D Synthesis
Authors: Libon F. , Cavalier E. , Nikkels A.F.
Published: October 2013

Background: Whether dark skin produces less vitamin D after UVB radiation than fair skin remains controversial. Objective: To compare 25-hydroxyvitamin D [25-(OH)-D] levels after a single UVB exposure in fair (phototype II-III) and black-skinned (phototype VI) volunteers. Methods: Fair-skinned volunteers (n = 20, 4 males/16 females, mean age: 23.2 years) and black-skinned (n = 11, 6 males/5 females, mean age: 23.8 years) received a single total body UVB exposure (0.022 J/cm2). The 25-(OH)-D levels were measured on days 0, 2 and 6. Results: On day 0, all volunteers were severely vitamin D deficient. On day 2, 25-(OH)-D levels of fair-skinned volunteers increased significantly (median: 11.9-13.3 ng/ml, p < 0.0001), but not in black-skinned people (median: 8.60-8.55 ng/ml, p = 0.843). Again, on day 6, 25-(OH)-D levels of fair-skinned volunteers increased significantly (median: 11.9-14.3 ng/ml, p < 0.0001), but not in black-skinned people (median: 8.60-9.57 ng/ml, p = 0.375). Conclusion: This study suggests that skin pigmentation negatively influences vitamin D synthesis.
Fibroblast Growth Factor Receptor 1 as a Putative Therapy Target in Colorectal Cancer
Authors: Göke Friederike , Göke Antonia , von Mässenhausen Anne , Franzen Alina , Sharma Rakesh , Kirsten Robert , Böhm Diana , Kristiansen Glen , Stenzinger Albrecht , Wynes Murry , Hirsch Fred R. , Weichert Wilko , Heasley Lynn , Buettner Reinhard , Perner Sven
Published: October 2013

Background/Aims: Resembling a potential therapeutic drug target, fibroblast growth factor receptor 1 (FGFR1) amplification and expression was assessed in 515 human colorectal cancer (CRC) tissue samples, lymph node metastases and CRC cell lines. Methods: FGFR1 amplification status was determined using fluorescence in situ hybridization. Additionally, we assessed protein levels employing Western blots and immunohistochemistry. The FGFR1 mRNA localization was analyzed using mRNA in situ hybridization. Functional studies employed the FGFR inhibitor NVP-BGJ398. Results: Of 454 primary CRCs, 24 displayed FGFR1 amplification. 92/94 lymph node metastases presented the same amplification status as the primary tumor. Of 99 investigated tumors, 18 revealed membranous activated pFGFR1 protein. FGFR1 mRNA levels were independent of the amplification status or pFGFR1 protein occurrence. In vitro, a strong antiproliferative effect of NVP-BGJ398 could be detected in cell lines exhibiting high FGFR1 protein. Conclusion: FGFR1 is a potential therapeutic target in a subset of CRC. FGFR1 protein is likely to represent a central factor limiting the efficacy of FGFR inhibitors. The lack of correlation between its evaluation at genetic/mRNA level and its protein occurrence indicates that the assessment of the receptor at an immunohistochemical level most likely represents a suitable way to assess FGFR1 as a predictive biomarker for patient selection in future clinical trials.
Effects of Different Trehalose Concentrations in a Warming Medium on Embryo Survival and Clinical Outcomes in Vitrified Human Embryos
Authors: Matsuo Koki , Takahashi Toshifumi , Igarashi Hideki , Hara Shuichiro , Amita Mitsuyoshi , Kurachi Hirohisa
Published: October 2013

Background/Aims: In the present study, we examined the effects of different concentrations of trehalose in a warming medium on both embryo survival and clinical outcomes in vitrified-warmed embryo transfer cycles. Methods: We retrospectively analyzed a total of 209 vitrified-warmed cycles from 177 patients who underwent in vitro fertilization or intracytoplasmic sperm injection and embryo transfer. Embryos were cryopreserved by the vitrification method and warmed in solutions containing either 0.5 or 1.0 M trehalose. We compared the 0.5 and 1.0 M trehalose warming solution groups with respect to the embryo survival rate after warming and clinical outcomes. Results: The embryo survival rate in the 1.0 M trehalose group (96.5%) was significantly higher than that in the 0.5 M trehalose group (57.0%). The percentage of embryo transfers after warming in the 1.0 M trehalose group (94.3%) was significantly higher than that in the 0.5 M trehalose group (83.7%). The clinical pregnancy rate in the 1.0 M trehalose group (25.0%) was significantly higher than that in the 0.5 M trehalose group (11.1%). Conclusion: Embryo survival and clinical pregnancy rates were higher when a 1.0 M trehalose solution was used than when a 0.5 M trehalose solution was used during the embryo warming process.
Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin
Authors: Mason Christopher , Lynch Stephen , Benjamin James , Ashak Dani , Prakash Jamunabai M. , Moore Andrew , Bagsiyao Pamela , Albert Trevine , Mathew Lynn M. , Jost Monika , Soslau Gerald
Published: October 2013

Matrix metalloproteinase (MMP) activity is generally associated with normal or pathological extracellular processes such as tissue remodeling in growth and development or in tumor metastasis and angiogenesis. Platelets contain at least three MMPs, 1, 2 and 9 that have been reported to stimulate or inhibit agonist-induced platelet aggregation via extracellular signals. The non-selective Zn+2 chelating MMP inhibitor, 1,10-phenanthroline, and the serine protease inhibitor, AEBSF, were found to inhibit all tested agonist-induced platelet aggregation reactions. In vitro analysis demonstrated that 1,10-phenanthroline completely inhibited MMP-1,2,and 9 but had little to no effect on calpain activity while the converse was true with AEBSF. We now demonstrate that MMP-2 functions intracellularly to regulate agonistinduced platelet aggregations via the hydrolytic activation of talin, the presumed final activating factor of glycoprotein (GP)IIb/IIIa integrin (the inside-out signal). Once activated GPIIb/IIIa binds the dimeric fibrinogen molecule required for platelet aggregation. The active intracellular MMP-2 molecule is complexed with JAK 2/STAT 3, as demonstrated by the fact that all three proteins are co-immunoprecipitated with either anti-JAK 2, or anti-STAT 3 antibodies and by immunofluorescence studies. The MMP-2 platelet activation pathway can be synergistically inhibited with the non-selective MMP inhibitor, 1,10-phenanthroline, plus a JAK 2 inhibitor. This activation pathway is distinct from the previously reported calpain-talin activating pathway. The identification of a new central pathway for platelet aggregation presents new potential targets for drug regulation and furthers our understanding of the complexity of platelet activation mechanisms.
Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?
Authors: Hoffman Maureane , Dickneite Gerhard
Published: October 2013

Newer oral anticoagulants offer several advantages over traditional agents (e.g. warfarin), but they are still associated with a bleeding risk and currently there is no validated reversal treatment for them. While there is little support for the use of fresh frozen plasma, and limited data available on the effects of activated recombinant factor VII, preclinical data suggest that prothrombin complex concentrates (PCCs) may have potential in this setting. PCCs are currently used to successfully reverse warfarin-induced anticoagulation; however, clinical evidence for their use with new oral anticoagulants is lacking, with most of the available data coming from preclinical animal studies. Furthermore, there appears to be variation in the ability of different PCCs to reverse the coagulopathy induced by the new anticoagulants, and a lack of correlation between the reversal of laboratory test results and the reversal of anticoagulant-induced bleeding. Although there have been encouraging results, care must be taken in generalising findings from animal models and nonbleeding human subjects to the situation in bleeding patients. Ultimately, more evidence supporting anticoagulation reversal for new anticoagulants is needed, particularly regarding the treatment of bleeding in human patients in a clinical setting. According to the current evidence, use of PCCs may be considered a reasonable approach in dire clinical situations; however, a consensus has not yet been reached regarding PCC use or dosing, due to lack of clinical data.
Factor IX-Padua enhances the fibrinolytic resistance of plasma clots
Authors: Ammollo Concetta T. , Semeraro Fabrizio , Colucci Mario , Simioni Paolo
Published: October 2013

Hypercoagulable conditions may determine a hypofibrinolytic state by increasing the activation of thrombin-activatable fibrinolysis inhibitor (TAFI). Factor (F)IX-Padua is a mutated FIX with an eight-fold increased clotting activity and associates with a higher venous thrombotic risk. We evaluated the influence of FIX-Padua on TAFI-mediated regulation of fibrinolysis. A subject hemizygous for FIX-Padua, two family members (heterozygous and normal) and six healthy controls were studied. Clot lysis, TAFI activation and thrombin generation were evaluated in contact-inhibited plasma challenged with low concentrations of tissue factor. Fibrinolysis times were significantly longer in FIX-Padua carriers than controls. The difference disappeared when activated TAFI (TAFIa) was inhibited, when TAFI activation was avoided or when clotting was made independent of FIX. TAFIa generation was markedly enhanced in FIX-Padua carriers as compared to controls, and this could be explained by a greater thrombin generation in the former. Hyperactive FIX, but not wild-type FIX, enhanced fibrinolytic resistance also when the FXI-dependent positive feedback was blocked by a neutralising anti-FXI antibody. This thrombin-mediated, TAFI-dependent down-regulation of fibrinolysis provides new clues for explaining the heightened thrombotic risk in subjects carrying the FIXPadua mutation.
A new species of Cyathura (Isopoda, Anthuridae) from fresh water in Shanghai, P.R. China
Authors: Liu Wenliang , Poore Gary C. B. , Chen Xiaohua
Published: October 2013

Anthurid isopods collected from the river courses in Shanghai, China, are described as a new species,Cyathura shanghaiensis, representing the first record of the genus in fresh waters of China.
“The Redeemer to Arise from the House of Dan”: Samson, Apocalypticism, and Messianic Hopes in Late Antique Galilee
Authors: Grey Matthew J.
Published: October 2013

Abstract

In the last five years, two mosaics depicting Samson’s biblical exploits have been discovered in Lower Eastern Galilee. Both mosaics were found in synagogues that date to the Late Roman/Byzantine period and are located in close proximity to Tiberias. Because of the rarity of Samson in ancient Jewish art and Samson’s lack of historical ties to the region, the significance of these mosaics requires explanation. This article explores this significance by considering the socio-religious context of the region in which the mosaics were discovered. Sources indicate that apocalyptic thought and messianic expectations flourished in Jewish Galilee throughout late antiquity, particularly in the vicinity of Tiberias. In addition, liturgical texts show that some Jews in this period viewed Samson as a biblical type of the future messiah—a redeemer of the past who foreshadowed Israel’s eschatological redemption. This confluence of evidence suggests that the Samson mosaics can be viewed as apocalyptic images reflecting messianic hopes that were popular in late antique Galilee.
Re-establishment of Pithecellobium subglobosum in Colombia and Venezuela (Leguminosae, Mimosoideae, tribe Ingeae)
Authors: DE STEFANO RODRIGO DUNO , ARCE MARÍA DE LOURDES RICO , CONTRERAS JOSÉ ENRIQUE LÓPEZ , CAN LILIA LORENA , RUIZ SAMUEL CAMPOS
Published: October 2013

Pithecellobium subglobosum is re-established as a species and P. concinnum and P. larense are referred to its synonymy. A critical analysis of type specimens of Pithecellobium section Pithecellobium from the Neotropic as well as many other herbarium collections shows that P. subglobosum is a morphologically distinct species related to P. roseum. Pithecellobium subglobosum is found in northeastern Colombia and northwestern Venezuela. An amended description, including information on pollen, foliar anatomy, ecology, distribution and conservation assessment are included.
Dual-Wavelength Polarimetric Radar Analyses of Tornadic Debris Signatures
Authors: Bodine David J. , Palmer Robert D. , Zhang Guifu
Published: October 2013

Statistical properties of tornado debris signatures (TDSs) are investigated using S- and C-band polarimetric radar data with comparisons to damage surveys and satellite imagery. Close proximity of the radars to the 10 May 2010 Moore–Oklahoma City, Oklahoma, tornado that was rated as a 4 on the enhanced Fujita scale (EF4) provides a large number of resolution volumes, and good temporal and spatial matching for dual-wavelength comparisons. These comparisons reveal that S-band TDSs exhibit a higher radar reflectivity factor (ZHH) and copolar cross-correlation coefficient (ρhv) than do C-band TDSs. Higher S-bandρhvmay result from a smaller ratio of non-Rayleigh scatterers to total scatterers due to the smaller electrical sizes of debris and, consequently, reduced resonance effects. A negativeZDRsignature is observed at 350 m AGL at both the S and C bands as the tornado passes over a vegetated area near a large body of water. Another interesting signature is a positive (negative) shift in propagation differential phase (ΦDP) at S band (C band), which could result from increased phase folding at C band. With increasing height above 350 m AGL, the S- and C-bandZHHdecreases andρhvincreases, indicating a decrease in debris size. To investigate relationships between polarimetric variables and tornado wind fields, range profiles of radial and tangential wind speeds are obtained using two radars. Velocity profiles reveal radial divergence within vortex core flow through 700 m AGL collocated with the TDS. Formation of a weak-echo hole and higherρhvin the vortex center aloft suggests debris centrifuging, outward motion of scatterers due to radial divergence (i.e., two-cell vortex flow), or both.
Hypothesis Testing for Autocorrelated Short Climate Time Series
Authors: Guemas Virginie , Auger Ludovic , Doblas-Reyes Francisco J.
Published: October 2013

Commonly used statistical tests of hypothesis, also termed inferential tests, that are available to meteorologists and climatologists all require independent data in the time series to which they are applied. However, most of the time series that are usually handled are actually serially dependent. A common approach to handle such a serial dependence is to replace in those statistical tests the actual number of data by an estimated effective number of independent data that is computed from a classical and widely used formula that relies on the autocorrelation function. Despite being perfectly demonstrable under some hypotheses, this formula provides unreliable results on practical cases, for two different reasons. First, the formula has to be applied using the estimated autocorrelation function, which bears a large uncertainty because of the usual shortness of the available time series. After the impact of this uncertainty is illustrated, some recommendations of preliminary treatment of the time series prior to any application of this formula are made. Second, the derivation of this formula is done under the hypothesis of identically distributed data, which is often not valid in real climate or meteorological problems. It is shown how this issue is due to real physical processes that induce temporal coherence, and an illustration is given of how not respecting the hypotheses affects the results provided by the formula.
An Orthodontic Retainer Preventing Remission in Celiac Disease
Authors: Memon Zebunnissa , Baker Susan S. , Khan Abdur , Hashmi Humaira , Gelfond Daniel
Published: October 2013

Celiac disease is a gluten enteropathy that is treated with dietary elimination of gluten. Exposure to nondietary sources of gluten, which are used in the manufacture of products such as plastics, dental equipment, and cosmetics, can also trigger or exacerbate disease. We report the case of a 9-year-old child who presented with nonspecific abdominal discomfort with abnormal serology for celiac disease. She underwent duodenal biopsies that revealed Marsh 3B histopathology. Despite strict dietary elimination of gluten, she continued to be symptomatic and demonstrate positive serum markers for active disease. It was then discovered that the child was exposed to gluten from her orthodontic retainer that contained a plasticized methacrylate polymer. Gluten is a common additive in plastics. She discontinued its use and demonstrated symptom resolution and complete normalization of serology. All possible sources of gluten, including nondietary, must be considered when managing a child with celiac disease.
When is the Use of Race/Ethnicity Appropriate in Risk Assessment Tools for Preconceptual or Antenatal Genetic Screening and How Should it be Used?
Authors: Aspinall Peter J
Published: October 2013

In the UK a ‘Family Origin Questionnaire’ (FOQ) has been introduced as a decision-making tool primarily to identify partners of high risk status in ‘low prevalence’ areas in antenatal screening for haemoglobin variants. A ‘family origins’ laboratory form for Down’s syndrome antenatal screening has followed, with active consideration of Tay Sachs Disease antenatal/ pre-conception carrier screening for Ashkenazi Jewish women. Similar screening developments for the haemoglobinopathies and cystic fibrosis are occurring in other countries. It is timely to ask when and how categories based on family origin concepts should be operationalised and used to assess genetic risk, given the methodological uncertainties and potential risk of offence, essentialisation, discrimination and/or stigmatisation. The potential limitations of these tools are examined, including generic concepts, social sensitivities of language, issues of testing, implementation, and training, and time-limitedness of the categories, to assess where the balance lies between the benefits and disadvantages of such usage.
‘The NDNAD Has No Ability in Itself to be Discriminatory’: Ethnicity and the Governance of the UK National DNA Database
Authors: Skinner David
Published: October 2013

This article explores the place of ‘ethnicity’ in the operation, management and contestation of the UK National DNA Database (NDNAD). In doing so, it examines the limitations of bioethics as a response to political questions raised by the new genetics. The UK police forensic database has been racialised in a number of distinct ways: in the over-representation of black people in the database population; in the classification of all DNA profiles according to ‘ethnic appearance’; in the use of data for experiments to determine the ethnicity of crime scene DNA; and in the focus on ethnicity in public debate about the database. This racialisation presented potential problems of legitimacy for the NDNAD but, as the article shows, these have been partly neutralised through systems of ethico-political governance. In these systems of governance discussion of institutional racism has been postponed or displaced by other ways of talking about ethnicity and identity.