bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Akt/mTOR signaling in primary breast tumors and matched distant metastases
Authors: Akcakanat Argun , Sahin Aysegul , Shaye Alexandra N. , Velasco Marco A. , Meric‐Bernstam Funda
Published: April 2008

BACKGROUND.

The Akt/mammalian target of the rapamycin (mTOR) signaling pathway represents a promising target for cancer therapy. The phosphorylation status of Akt and of mTOR's phosphorylation target eukaryotic initiation factor 4E‐binding protein 1 (4E‐BP1) is often used to assess the activity of Akt and mTOR signaling. The purpose of this study was to determine whether primary tumors differ from their metastasis in their expression of pAkt and p4E‐BP1.

METHODS.

Primary breast tumors and their distant metastases surgically resected from the same patients were evaluated with immunohistochemical analysis (IHC) for pAkt (Ser473) and p4E‐BP1 (Ser65). The agreement between the IHC results for the primary tumor and metastases was evaluated with Cohen kappa (κ).

RESULTS.

Most primary breast tumors and metastatic tumors expressed pAkt (76% of each). Of the 23 matched evaluable pairs, however, 11 (47.8%) had discordant IHC results (κ −0.31; 95% confidence interval [CI], −0.49 to −0.13). Similarly, although most of the primary and metastatic tumors were positive for p4E‐BP1 (75% and 74%), of the 23 matched evaluable pairs, 8 (47.8%) were discordant (κ 0.10; 95% CI, −0.33–0.52).

CONCLUSIONS.

In this series, most primary breast tumors and metastases expressed pAkt and p4E‐BP1 by IHC. Concordance between IHC findings in primary tumors and metastases was poor, however. Further work is needed to determine whether this reflects true biological heterogeneity or poor reproducibility of IHC with phosphospecific antibodies, and to identify which biomarkers can be assessed most reproducibly in primary tumors to predict activity of Akt/mTOR signaling and sensitivity to pathway inhibitors. Cancer 2008. ©2008 American Cancer Society.
Effect of Surface Decoration of CNTs on the Interfacial Interaction and Microstructure of Epoxy/MWNT Nanocomposites
Authors: Zhou Wei , Wang Bo , Zheng Yaping , Zhu Yuchan , Wang Junjun , Qi Ning
Published: April 2008

Epoxy resin nanocomposites with different contents of multiwalled carbon nanotubes (MWNTs) are prepared. The interaction between MWNTs and the epoxy resin matrix and the microstructure and mechanical properties of the composites are systematically investigated by Fourier‐transform infrared (FTIR) spectroscopy, transmission electron microscopy, scanning electron microscopy, and positron annihilation technology. FTIR spectra reveal that two kinds of hydrogen bonds exist at the interface for the nanocomposites modified by amine, one between the epoxy group on the side chain and the NH group, and the other between the epoxy group on the alicycle and the NH group. Compared to unmodified MWNT composites, the modified MWNT composites possess better mechanical properties, which are attributed to stronger interfacial interaction resulting from an efficient load transfer from matrix to MWNTs. Positron annihilation lifetime spectroscopy is used to characterize the microstructure of the epoxy/MWNT composites. The subtransition and glass transition temperatures are determined by finite‐term positron lifetime analysis and the variation of the free‐volume size as a function of temperature. Shifts of structure transition temperatures of the composites are observed with increasing MWNT weight content. Interestingly, the continuous lifetime analysis reveals the existence of two long‐lived lifetime components above the glass transition temperature, which may be attributed to the formation of local ordered regions related to the packing density of chains.
Liquid Alkanes with Targeted Molecular Weights from Biomass‐Derived Carbohydrates
Authors: West Ryan M. , Liu Zhen Y. , Peter Maximilian , Dumesic James A.
Published: April 2008

Liquid transportation fuels must burn cleanly and have high energy densities, criteria that are currently fulfilled by petroleum, a non‐renewable resource, the combustion of which leads to increasing levels of atmospheric CO2. An attractive approach for the production of transportation fuels from renewable biomass resources is to convert carbohydrates into alkanes with targeted molecular weights, such as C8–C15 for jet‐fuel applications. Targeted n‐alkanes can be produced directly from fructose by an integrated process involving first the dehydration of this C6 sugar to form 5‐hydroxymethylfurfural, followed by controlled formation of CC bonds with acetone to form C9 and C15 compounds, and completed by hydrogenation and hydrodeoxygenation reactions to form the corresponding n‐alkanes. Analogous reactions are demonstrated starting with 5‐methylfurfural or 2‐furaldehyde, with the latter leading to C8 and C13 n‐alkanes.
The role of FGF signaling in the establishment and maintenance of mesodermal gene expression in Xenopus
Authors: Fletcher Russell B. , Harland Richard M.
Published: April 2008

FGF signaling is important for the formation of mesoderm in vertebrates, and when it is perturbed in Xenopus, most trunk and tail mesoderm fails to form. Here we have further dissected the activities of FGF in patterning the embryo by addressing its inductive and maintenance roles. We show that FGF signaling is necessary for the establishment of xbra expression in addition to its well‐characterized role in maintaining xbra expression. The role of FGF signaling in organizer formation is not clear in Xenopus. We find that FGF signaling is essential for the initial specification of paraxial mesoderm but not for activation of several pan‐mesodermal and most organizer genes; however, early FGF signaling is necessary for the maintenance of organizer gene expression into the neurula stage. Inhibition of FGF signaling prevents VegT activation of specific mesodermal transcripts. These findings illuminate how FGF signaling contributes to the establishment of distinct types of mesoderm. Developmental Dynamics 237:1243‐1254, 2008. © 2008 Wiley‐Liss, Inc.
Hsp60C is required in follicle as well as germline cells during oogenesis in Drosophila melanogaster
Authors: Sarkar Surajit , Lakhotia S.C.
Published: April 2008

Hsp60C gene of Drosophila melanogaster shows a dynamic spatiotemporal expression during oogenesis and seems to contribute bulk of the Hsp60 family proteins in ovarioles. Hsp60 distribution overlaps with that of F‐actin–rich membranes/structures in follicle, nurse, and egg cells throughout oogenesis. Skeletal muscle fibers associated with ovarioles and in other parts of the body show patterned location of Hsp60 in A‐bands. During stages 11–12, Hsp60 accumulates at junctions of nurse cells and oocyte, where a new microtubule organizing center is known to develop. A recessive hypomorph allele, Hsp60C1 causes complete sterility of the rare surviving homozygous adults. Their egg chambers show very little Hsp60C transcripts or Hsp60 protein. Beginning at stages 6–7, Hsp60C1 chambers show a disorganized follicle cell layer with poor cell adhesion in addition to abnormal organization of F‐actin and other cytoskeletal structures in follicle, nurse, and egg cells. Additionally, expression and localizations of Hrb98DE, Squid, and Gurken proteins in nurse cells and oocyte are also severely affected. Hsp60C1 homozygous follicle cell clones in Hsp60C1/+ ovarioles show disruptions in follicle epithelial and cytoskeleton arrangements. Likewise, egg chambers with Hsp60C1 homozygous germline clones in Hsp60C1/+ flies show abnormal oogenesis. Our results provide the first evidence for an essential role of Hsp60C in Drosophila oogenesis, especially in organization and maintenance of cytoskeletal and cell adhesion components. Developmental Dynamics 237:1334‐1347, 2008. © 2008 Wiley‐Liss, Inc.
Evolution of the thyroid: Anterior–posterior regionalization of theOikopleuraendostyle revealed byOtx,Pax2/5/8, andHox1expression
Authors: Cañestro Cristian , Bassham Susan , Postlethwait John H.
Published: April 2008

The thyroid in vertebrates and its homolog, the endostyle in nonvertebrate chordates, share a molecular code for dorsoventral patterning. Little is yet known, however, about mechanisms that pattern the endostyle's anterior–posterior (AP) axis. To extend our understanding of thyroid development and evolution, we studiedOikopleura dioica, a larvacean urochordate that retains a chordate body plan as adults. Transcription factor expression domains revealed AP regionalization of the endostyle, with expression ofOtxrostrally,Hox1caudally, and twoPax2/5/8paralogs centrally. Comparative analysis suggested that the endostyle of stem chordates expressed orthologs of these genes and that ancestral subfunctions partitioned differentially among lineages. Because the ordered expression ofOtx,Pax2/5/8, andHox1displays patterning in both the endodermally derived endostyle and the ectodermally derived central nervous system, we propose that this gene set belonged to the developmental genetic toolkit of stem bilaterians and repeatedly provided AP positional information in various developmental situations. Developmental Dynamics 237:1490‐1499, 2008. © 2008 Wiley‐Liss, Inc.
PAX6 dosage effects on corneal development, growth, and wound healing
Authors: Dorà Natalie , Ou Jingxing , Kucerova Romana , Parisi Ida , West John D. , Collinson J. Martin
Published: April 2008

The requirement for correct dosage of the transcription factor Pax6 during corneal growth and development was investigated using the Pax6‐overexpressing (PAX77) transgenic mouse. Transgenics had a microcornea phenotype due to failure of postnatal growth, associated with reduction in the number of cells layers in the corneal epithelium. Cell cycle progression was monitored using bromodeoxyuridine, p63, cyclin E, and phosphohistone‐3 labeling: proliferation rates were higher in PAX77+ than wild‐type, without a concomitant increase in apoptosis. Hence, failure of proliferation did not underlie microcornea. PAX77+ corneal epithelia had reduced levels of cytokeratin‐12, and exhibited severe wound healing delay that, in contrast to Pax6+/− mice, could not be modulated by exogenous growth factors. PAX77+ lenses showed partial failure of lens fiber differentiation. The data demonstrate that anterior eye development is very sensitive to Pax6 dosage. Although there are similarities between the eye phenotype of Pax6 heterozygotes and overexpressing mice, there are also striking differences. Developmental Dynamics 237:1295‐1306, 2008. © 2008 Wiley‐Liss, Inc.
Activation drives PD‐1 expression during vaccine‐specific proliferation and following lentiviral infection in macaques
Authors: Hokey David A. , Johnson F. Brad , Smith Jasmine , Weber Joshua L. , Yan Jian , Hirao Lauren , Boyer Jean D. , Lewis Mark G. , Makedonas George , Betts Michael R. , Weiner David B.
Published: April 2008

Recent data supports that increased expression of PD‐1, a negative regulator of immune function, is associated with T cell exhaustion during chronic viral infection. However, PD‐1 expression during acute infection and vaccination has not been studied in great detail in primates. Here, we examine PD‐1 expression on CD3+ T cells following DNA vaccination or lentiviral infection of macaques. Ex vivo peptide stimulation of PBMC from DNA‐vaccinated uninfected macaques revealed a temporal increase in PD‐1 expression in proliferating antigen‐specific CD8+ T cells. Following the initial increase, PD‐1 expression steadily declined as proliferation continued, with a concomitant increase in IFN‐γ secretion. Subsequent examination of PD‐1 expression on T cells from uninfected and lentivirus‐infected non‐vaccinated macaques revealed a significant increase in PD‐1 expression with lentiviral infection, consistent with previous reports. PD‐1 expression was highest on cells with activated memory and effector phenotypes. Despite their decreased telomere length, PD‐1hi T cell populations do not appear to have statistically significant uncapped telomeres, typically indicative of proliferative exhaustion, suggesting a different mechanistic regulation of proliferation by PD‐1. Our data indicate that PD‐1 expression is increased as a result of T cell activation during a primary immune response as well as during persistent immune activation in macaques.

Supporting Information for this article is available at www.wiley‐vch.de/contents/jc_2040/2008/37857_s.pdf
IL‐12, IL‐23, and IL‐27 enhance human β‐defensin‐2 production in human keratinocytes
Authors: Kanda Naoko , Watanabe Shinichi
Published: April 2008

IL‐12, IL‐23, and IL‐27, which are produced by APC, modulate innate and adaptive immunities. Human β‐defensin‐2 (hBD‐2) produced by epidermal keratinocytes promotes cutaneous antimicrobial defense and inflammation. We examined the in vitro effects of IL‐12, IL‐23, and IL‐27 on hBD‐2 production in human keratinocytes. IL‐12, IL‐23, and IL‐27 enhanced IL‐1β‐induced hBD‐2 secretion and mRNA expression in keratinocytes. The stimulatory effects of IL‐12, IL‐23, and IL‐27 were suppressed by antisense oligonucleotides against NF‐κB p50 and p65. In addition, the effects of IL‐12 and IL‐27 were suppressed by antisense STAT3 and STAT1, respectively. All the three IL enhanced the basal and IL‐1β‐induced transcriptional activities of NF‐κB, while IL‐12 and IL‐27 enhanced STAT3 and STAT1 activities, respectively. Further, IL‐12, IL‐23, and IL‐27 promoted basal and IL‐1β‐induced phosphorylation of IκBα. IL‐12 and IL‐23 tyrosine phosphorylated STAT3 and STAT1, respectively; IL‐12, IL‐23, and IL‐27 tyrosine phosphorylated JAK2 and tyrosine kinase‐2; and IL‐27 tyrosine phosphorylated JAK1. These results suggest that IL‐12, IL‐23, and IL‐27 may enhance IL‐1β‐induced hBD‐2 production in keratinocytes by activating NF‐κB. STAT3 and STAT1 are involved in the effects of IL‐12 and IL‐27, respectively. Thus, IL‐12, IL‐23, and IL‐27 may promote cutaneous antimicrobial defense and inflammation via hBD‐2.
Performance‐based optimum seismic design of reinforced concrete structures
Authors: Fragiadakis Michalis , Papadrakakis Manolis
Published: April 2008

A fully automated design methodology based on nonlinear response history analysis is proposed for the optimum seismic design of reinforced concrete (RC) structures. The conventional trial‐and‐error process is replaced by a structural optimization algorithm that serves as a search engine capable of locating the most efficient design in terms of cost and performance. Two variations of the proposed design methodology are introduced. The first approach treats the optimum design problem in a deterministic manner, while in the second variation the optimum design is sought in the framework of a reliability‐based optimization problem. The reliability‐based approach seems to be a more rational procedure since more meaningful design criteria that correlate better with the performance‐based design concept can be adopted. Thus, the practice of using the mean annual frequency of a limit‐state being exceeded to assess the candidate designs is compared with the use of deterministic criteria. Both formulations take into consideration the structural response for a number of limit‐states, from serviceability to collapse prevention. The proposed design procedure is specifically tailored to the design of RC structures, where a preliminary design step of generating tables of concrete sections is introduced. In order to handle the large size of the tables, the concept of multi‐database cascade optimization is implemented. The final design has to comply with the provisions of European design codes. The proposed methodology allows for a significant reduction of the direct construction cost combined with improved control of the seismic performance under earthquake loading. Copyright © 2008 John Wiley & Sons, Ltd.
Efficient synthesis of novel six‐member ring‐fused quinoline derivatives via the friedländer reaction
Authors: Yang Dingqiao , Guo Wei , Cai Yuepeng , Jiang Lasheng , Jiang Kailing , Wu Xiaobing
Published: April 2008

Novel quinolines fused with a six‐member ring 5a–j were prepared in high yields (75–95%) via the Friedländer reaction of dimethoxy‐substituted o‐aminobenzaldehydes of 3a or 3b with cyclic ketones 4, respectively. The structures of 5a–j were determined by IR, 1H NMR, MS, and elemental analysis. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:229–233, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20356
Synthetic and mechanistic aspects of preparation of phosphinito‐ and phosphito‐mercuries
Authors: Nycz Jacek E.
Published: April 2008

A >PO− (1) type of anion has been used as an efficient synthetic precursor of four‐coordinated compounds: R2P(O)Hg(O)PR2 (5) and R2P(O)HgBz (3) (R = alkoxy, alkyl, aryl). They were obtained in good yield. Bis(t‐butyl‐phenylphosphinito‐P)mercury (meso and rac) (5c,d) selectively decomposed into 1,2‐di‐t‐butyl‐1,2‐diphenyldiphosphane 1,2‐dioxide (meso and rac) (6c,d). Furthermore, some mechanistic aspects of the synthesis of mentioned compounds are elaborated.© 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:234–237, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20409
The preparation and characterization of guanylurea nitrate and perchlorate salts
Authors: Klapötke Thomas M. , Sabaté Carles Miró
Published: April 2008

Guanylurea nitrate (GUN) and guanylurea perchlorate (GUP) were prepared from cyanoguanidine (CG) and concentrated nitric or perchloric acid, respectively. Both compounds were fully characterized by analytical and spectroscopic methods. Crystals of GUP were grown from water, and its crystal structure was determined by single‐crystal X‐ray diffraction. GUP crystallizes in the monoclinic space group P21/c with four molecules in the unit cell; different unit cell parameters are a = 8.0115(2) Å, b = 9.7328(2) Å c = 9.5770(2) Å and β = 105.89(1)°. The heats of combustion of both compounds were determined using oxygen bomb calori‐metry. Finally, the EXPLO5 computer code was used to determine the detonation velocity (D = 5734 m s−1) and pressure (P = 10.6 GPa) of GUN as well as those of formulations with ammonium nitrate and dinitramide. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:301–306, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20419
Efficient synthesis of 2‐substituted thieno[2,3‐d]pyrimidin‐4(3H)‐ones via an iminophosphorane
Authors: Fang Zheng‐Dong , Hu Yang‐Gen , Ding Ming‐Wu
Published: April 2008

The carbodiimides 4, obtained from reactions of iminophosphorane 3 with aromatic isocyanates, were reacted with secondary amines to give 2‐dialkylamino‐5‐ethyl‐6‐methyl‐thieno[2,3‐d]pyrimidin‐4(3H)‐ones 6 in the presence of catalytic amount of EtONa. Reactions of 4 with phenols or ROH in the presence of the catalytic amount of K2CO3 or RONa gave 2‐aryloxy‐ or 2‐alkoxy‐5‐ethyl‐6‐methyl‐thieno[2,3‐d]pyrimidin‐4(3H)‐ones 6 in satisfactory yields. The effects of the nucleophiles on cyclization have been investigated. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:266–270, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20424
Biomimetic synthesis of esters of natural amino acids
Authors: Devedjiev Ivan T. , Bairyamov Stanislav G. , Videva Vladimira S.
Published: April 2008

A method for the synthesis of Gly, Ala, Phe, and Thr esters is proposed and considered as being a stage of possible biomimetic synthesis of peptides. The methyl esters of the said amino acids are obtained via intervention of 2‐hydroxypropyl phosphonate. The resulting aminoacyl phosphonates reacts with methanol to produce the amino acid methyl esters, with the release of phosphoric acid. The reaction is carried out at room temperature in water. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:252–255, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20427
A convenient synthesis of 2‐(1H‐1,2,4‐triazol‐1‐yl)‐2H‐1,4‐benzothiazine derivatives
Authors: Zhong Weihui , Sun Xiuling , Su Weike
Published: April 2008

A series of 2‐(1H‐1,2,4‐triazol‐1‐yl)‐2H‐1,4‐benzothiazines were designed and synthesized by condensation of 1,2,4‐triazole‐substituted ω‐bromoacetophenones and o‐aminothiophenols with the aid of K2CO3 under mild conditions with moderate to high yields. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:332–336, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20434
Crystal and molecular structures of atropisomeric N‐aryl‐1,2,3,4‐tetrahydro‐3,3‐dimethyl‐2,4‐quinolinediones
Authors: Cetina Mario , Košutić‐Hulita Nada , Nagl Ante , Mintas Mladen
Published: April 2008

The crystal structures of N‐aryl‐1,2,3,4‐tetrahydro‐3,3‐dimethyl‐2,4‐quinolinediones bearing methoxy‐ (1), methyl‐ (2), and chloro‐ (3) substituents in 2′‐position of the phenyl ring have been determined by X‐ray crystal structure analysis. The heterocyclic ring in 1–3 adopts an envelope conformation, with the smallest ring puckering in the ortho‐chloro derivative 3. The N‐aryl ring is almost perpendicular with respect to the quinoline‐2,4‐dione ring. The corresponding dihedral angle values are 83.2(1)°, 80.0(9)°, and 83.4(2)° in 1, 2 and 3, respectively. The hydrogen bond of CH⋅⋅⋅O type joins the molecules of the ortho‐methoxy derivative 1 into dimers. The supramolecular structure also contains two CH⋅⋅⋅π interactions that link the hydrogen‐bonded dimers into sheets. In ortho‐methyl derivative 2, one CH⋅⋅⋅π interaction generates infinite chains, whereas two CH⋅⋅⋅O hydrogen bonds and three CH⋅⋅⋅π interactions in the ortho‐chloro derivative 3 form three‐dimensional framework. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:325–331, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20436
Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma
Authors: Doecke James , Zhao Zhen Zhen , Pandeya Nirmala , Sadeghi Shahram , Stark Mitchell , Green Adèle C. , Hayward Nicholas K. , Webb Penelope M. , Whiteman David C. ,   for the Australian Cancer Study
Published: April 2008

Rates of adenocarcinoma of the esophagus (EAC) and esophago‐gastric junction (EGJAC) have increased rapidly in recent decades. The primary risk factors, gastro‐esophageal acid reflux and smoking, are potentially genotoxic through the generation of N‐nitroso compounds. The DNA repair protein O6‐methylguanine‐DNA methyltransferase (MGMT) is the major cellular defense against alkylating DNA damage. We compared patients with EAC (n = 263) or EGJAC (n = 303) with matched population controls (n = 1,337) for the frequency of 5 MGMT single nucleotide polymorphisms (SNPs) (rs12269324, rs12268840, L84F, I143V, K178R), as well as SNPs in DNA repair genes ERCC1 (N118N), XRCC1 (Q399R) and XPD (K751Q). Relative risks were estimated using multivariable logistic regression. Potential biological interaction was assessed through the synergy index S. Each MGMT SNP conferred increased risks of EAC but not EGJAC; strongest associations were found for the 2 variant MGMT alleles rs12268840 and I143V (p = 0.005 and p < 0.001, respectively). Homozygous carriers of MGMT rs12268840 with frequent acid reflux had significantly higher risks of EAC (OR 15.5, 95% CI 5.8–42) than expected under an additive model, consistent with biological interaction (S = 3.3, 95% CI 1.1–10). Modest, nonsignificant interactions with smoking were also observed. Homozygous variant ERCC1 genotype was associated with reduced risks of EAC (OR 0.6, 95% CI 0.4–1.1), while the homozygous variant XRCC1 genotype conferred higher risks of EGJAC (OR 1.6, 95% CI 1.1–2.4). No associations with EAC or EGJAC were observed with XPD (rs13181). In summary, MGMT SNPs are associated with increased risks of EAC. Exposure to acid reflux, and possibly smoking, confer markedly higher risks among homozygous variant genotype carriers. © 2008 Wiley‐Liss, Inc.
Curcumin induces cell‐arrest and apoptosis in association with the inhibition of constitutively active NF‐κB and STAT3 pathways in Hodgkin's lymphoma cells
Authors: Mackenzie Gerardo G. , Queisser Nina , Wolfson Manuel L. , Fraga Cesar G. , Adamo Ana M. , Oteiza Patricia I.
Published: April 2008

Although treatment of Hodgkin's lymphoma (HL) with a multi‐drug approach has been very successful, its toxicity becomes evident after several years as secondary malignancies and cardiovascular disease. Therefore, the current goal in HL treatment is to find new therapies that specifically target the deregulated signaling cascades, such as NF‐κB and STAT3, which cause Hodgkin and Reed‐Sternberg (H‐RS) cell proliferation and resistance of apoptosis. Based on the above information, we investigated the capacity of curcumin to inhibit NF‐κB and STAT3 in H‐RS cells, characterizing the functional consequences. Curcumin is incorporated into H‐RS cells and acts inhibiting both NF‐κB and STAT3 activation, leading to a decreased expression of proteins involved in cell proliferation and apoptosis, e.g. Bcl‐2, Bcl‐xL, cFLIP, XIAP, c‐IAP1, survivin, c‐myc and cyclin D1. Interestingly, curcumin caused cell cycle arrest in G2‐M and a significant reduction (80–97%) in H‐RS cell viability. Furthermore, curcumin triggered cell death by apoptosis, as evidenced by the activation of caspase‐3 and caspase‐9, changes in nuclear morphology and phosphatidylserine translocation. The above findings provide a mechanistic rationale for the potential use of curcumin as a therapeutic agent for patients with HL. © 2008 Wiley‐Liss, Inc.
DNA repair deficiency leads to susceptibility to develop arsenic‐induced premalignant skin lesions
Authors: Banerjee Mayukh , Sarma Nilendu , Biswas Rupanwita , Roy Jyoeeta , Mukherjee Anita , Giri Ashok K.
Published: April 2008

In West Bengal, India, although more than 6 million people are exposed to arsenic through drinking water, only 15–20% showed arsenic‐induced skin lesions, including premalignant hyperkeratosis. This indicates toward some factors that confer susceptibility to arsenic‐induced carcinogenicity. In this work, we wanted to explore whether differences in DNA repair capacity could impart arsenic‐induced carcinogenicity, through Comet assay, chromosomal aberration (CA) assay and challenge assay. Sixty arsenic exposed (30 individuals with arsenic‐induced premalignant hyperkeratosis and 30 without skin lesion, but drinking similar arsenic contaminated water) and 30 arsenic unexposed individuals were recruited as study participants. Alkaline comet assay, and challenge assay were carried out in whole blood and CA study in lymphocytes to find out the DNA damage and DNA repair capacity in both hyperkeratotic and without skin lesion individuals. DNA damage as well as CA were found to be significantly higher in the arsenic‐exposed individuals compared to unexposed individuals (p < 0.001). Within the exposed group, there was no significant difference as far as the level of DNA damage is concerned (p > 0.05), but CA was significantly higher in exposed individuals with hyperkeratosis than exposed individuals without hyperkeratosis (p < 0.01). Challenge assay showed that upon induction of DNA damage, the repair capacity in the exposed individuals with premalignant hyperkeratosis is significantly less (p < 0.001) than that of individuals without skin lesion, although the basal level of DNA damage was similar in both. Thus, the deficiency in DNA repair capacities in the hyperkeratotic individuals emerges as a prime contender for arsenic carcinogenicity. © 2008 Wiley‐Liss, Inc.
EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenografts
Authors: Geoerger Birgit , Gaspar Nathalie , Opolon Paule , Morizet Jackie , Devanz Pauline , Lecluse Yann , Valent Alexander , Lacroix Ludovic , Grill Jacques , Vassal Gilles
Published: April 2008

Malignant gliomas and childhood ependymomas have a high rate of treatment failure. Epidermal growth factor receptor (EGFR) activation has been implicated in the tumorigenesis and radioresistance of many cancers, including brain tumors. Therefore, combining EGFR targeting with irradiation is a potentially attractive therapeutic option. We evaluated the tyrosine kinase inhibitor gefitinib for its antitumor activity and potential to radio‐sensitize in vivo in two xenograft models: an EGFR amplified glioma and an EGFR expressing ependymoma, both derived from primary tumors. When administered at 100 mg/kg for 5 consecutive days, gefitinib‐induced partial tumor regression in all treated EGFR amplified IGRG88 glioma xenografts. The addition of 1 Gy of irradiation prior to gefitinib administration resulted in 5 complete and 4 partial regressions for the 9 treated tumors as well as a significant tumor growth delay of 33 days for the combined treatment compared to 19 days for each therapy alone, suggesting additive antitumor activity. Tumor regression was associated with inhibition of AKT and MAPK pathways by gefitinib. In contrast, the ependymoma IGREP83 was sensitive to irradiation, but remained resistant to gefitinib. Combined treatment was associated with inhibition of radiation‐induced MAPK phosphorylation and significant induction of apoptotic cell death though radiation‐induced AKT phosphorylation was maintained. Depending on the scheduling of both therapies, a trend towards superior antitumor activity was observed with combined treatment. Thus, EGFR targeting through tyrosine kinase inhibition appears to be a promising new approach in the treatment of EGFR‐driven glioma, particularly in combination with radiation therapy. © 2008 Wiley‐Liss, Inc.
Efficacy of titanium dioxide photocatalyst for inhibition of bacterial colonization on percutaneous implants
Authors: Oka Yoshinobu , Kim Wook‐Cheol , Yoshida Takashi , Hirashima Toshiko , Mouri Hisashi , Urade Hidenori , Itoh Yoshihisa , Kubo Toshikazu
Published: April 2008

The purpose of this study was to evaluate the efficacy of titanium dioxide photocatalyst in inhibition of bacterial colonization on percutaneous implants. Titanium dioxide photocatalyst was prepared by direct oxidization of pure titanium substrate, and a comparative study with pure titanium was performed. The bactericidal ability of the photocatalyst was examined using methicillin‐resistant Staphylococcus aureus (MRSA) suspensions in a colony‐forming assay according to the Japanese Industrial Standards committee standard. After exposing the MRSA suspension on sample plates to ultraviolet A (UVA) light, the number of surviving bacteria was estimated. Next, an animal model for inhibition of colonization was examined in vivo. Pins were inserted into the femurs of rabbits, were infected with 108 colony‐forming units of MRSA suspension, and were illuminated with UVA light for 60 min daily; the number of colonizing bacteria was estimated after 7 days. The bactericidal ability of the photocatalyst was apparent after 60 min, when the bacteria had almost disappeared. The number of colonizing bacteria on photocatalytic pins was decreased significantly in vivo. The photocatalyst was effective even against resistant bacterial colonization. Clinically, the incidence of percutaneous implant infection such as pin tract infection in external fixation could be reduced using the titanium photocatalyst. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2008
Electrospraying: A facile technique for synthesis of chitosan‐based micro/nanospheres for drug delivery applications
Authors: Arya Neha , Chakraborty Syandan , Dube Nikhil , Katti Dhirendra S.
Published: April 2008

Electrospraying is a novel technique for the generation of micro/nanospheres for biomedical applications. Apart from being a high yield technique; electrospraying has an added advantage of not making use of an external dispersion/emulsion phase which often involves ingredients that are undesirable for biomedical applications. In this study, we report the use of electrospraying for the synthesis of chitosan micro/nanospheres. The focus was to optimize the fabrication parameters involved in electrospraying for reproducible synthesis of chitosan based micro/nanospheres and to study their potential as delivery vehicles for bioactive agents. The influence of the following was studied (i) electrospraying voltage, (ii) needle gauge, (iii) concentration of chitosan solution, (iv) concentration of acetic acid solution, and (v) electrospraying distance. SEM analysis demonstrated that microspheres of less than 1 μm were obtained when chitosan concentration was 2% dissolved in 90% acetic acid. The working distance and needle gauge that yielded favorable results were 7 cm and 26 g, respectively. Average particle size of ampicillin loaded chitosan micro/nanospheres was 520 nm with zeta potential of +28.2 mV and encapsulation efficiency of 80.4%. The particles were characterized for drug release kinetics and results demonstrated an initial burst release followed by a sustained release over a period of 120 h. Further, antibacterial activity of drug loaded micro/nanospheres demonstrated that the encapsulated drug was in its active form postexposure to high voltage during electrospraying. This study indicates that electrospraying is a facile technique for the synthesis of chitosan micro/nanospheres for drug delivery applications. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009
A practical approach to boundaries in psychotherapy: making decisions, bypassing blunders, and mending fences
Authors: Pope Kenneth S. , Keith‐Spiegel Patricia
Published: April 2008

Nonsexual boundary crossings can enrich psychotherapy, serve the treatment plan, and strengthen the therapist–client working relationship. They also can undermine the therapy, disrupt the therapist–patient alliance, and cause harm to clients. Building on T. G. Gutheil and G. O. Gabbard's (1993) conceptualization of boundary crossings and boundary violations, this article discusses and illustrates grounding boundary decisions in a sound approach to ethics. We provides nine useful steps in deciding whether to cross a boundary, describe common cognitive errors in boundary decision making, and offer nine helpful steps to take when a boundary crossing has negative effects. © 2008 Wiley Periodicals, Inc. J Clin Psychol: In Session 64:1–15, 2008.
Secretion of mouse growth hormone by transduced primary human keratinocytes: prospects for an animal model of cutaneous gene therapy
Authors: Peroni Cibele Nunes , Cecchi Cláudia Regina , Rosauro Cristiane Wanderley , Nonogaki Suely , Boccardo Enrique , Bartolini Paolo
Published: April 2008

Background

Keratinocytes are a very attractive vehicle for ex vivo gene transfer and systemic delivery because proteins secreted by these cells may reach the circulation via a mechanism that mimics the natural process.

Methods

An efficient retroviral vector (LXSN) encoding the mouse growth hormone gene (mGH) was used to transduce primary human keratinocytes. Organotypic raft cultures were prepared with these genetically modified keratinocytes and were grafted onto immunodeficient dwarf mice (lit/scid).

Results

Transduced keratinocytes presented a high and stable in vitro secretion level of up to 11 µg mGH/106cells/day. Conventional epidermal sheets made with these genetically modified keratinocytes, however, showed a drop in secretion rates of > 80% due to detachment of the epithelium from its substratum. Substitution of conventional grafting methodologies with organotypic raft cultures completely overcame this problem. The stable long‐term grafting of such cultures onto lit/scid mice could be followed for more than 4 months, and a significant weight increase over the control group was observed in the first 40 days. Circulating mGH levels revealed a peak of 21 ng/ml just 1 h after grafting but, unfortunately, these levels rapidly fell to baseline values.

Conclusions

mGH‐secreting primary human keratinocytes presented the highest in vitro expression and peak circulatory levels reported to date for a form of GH with this type of cells. Together with previous data showing that excised implants can recover a remarkable fraction of their original in vitro mGH secretion efficiency in culture, the factors that might still hamper the success of this promising model of cutaneous gene therapy are discussed. Copyright © 2008 John Wiley & Sons, Ltd.
The diamond industry as a virtual organization: past success and challenging future
Authors: Mostovicz E. Isaac , Kakabadse Nada K. , Kakabadse Andrew P.
Published: April 2008

Having previously dominated diamond supply and exercised near total control over diamond distribution, the diamond industry market leader De Beers now accounts for just 40% of global diamond production and 45% of distribution. In the face of competitive and regulatory pressures, De Beers has recently sought to adapt its role from being the custodian of the industry to acting merely as a major player. However, its retreat from a position of industry dominance is creating tensions within De Beers and among industry participants.

This paper seeks to explain De Beers' behaviour and the reaction of the industry in terms of paradox management and identifies the requirement for a new form of leadership to replace the previous monopoly situation and guide the diamond industry into a better future.

Copyright © 2008 John Wiley & Sons, Ltd.
The successful management of organisational change in tourism SMEs: initial findings in UK visitor attractions
Authors: By Rune Todnem , Dale Crispin
Published: April 2008

Organisational change management theory for small and medium‐sized enterprises (SMEs) within the tourism industry is an under‐researched field. Changing political, economic, social and technological factors can leave unprepared SMEs exposed to external as well as internal pressures, which can lead to underperformance, or in worst case scenario, business failure. This paper, reporting on the findings of exploratory research of nine UK‐based visitor attractions, all qualifying as SMEs, suggests that the successful management of change is crucial for SMEs' survival and success. The findings argue that the current approach taken to organisational change management within the industry is bumpy incremental, bumpy continuous and planned. Hence, the paper provides a framework for managing organisational change based on eight critical success factors identified by the study: adaptability and flexibility, commitment and support, communication and co‐operation, continuous learning and improvement, formal strategies, motivation and reward, pragmatism, and the right people. Copyright © 2008 John Wiley & Sons, Ltd.
Parallel-type C+L band hybrid amplifier pumped by 1480 nm laser diodes
Authors: Liaw S-K , Huang C-K , Hsiao Y-L
Published: April 2008

A parallel-type, dispersion compensating C+L band erbium-doped fiber amplifier/Raman fiber amplifier is constructed by sharing a common 1480-nm pump source. The gain spectra of C+L band are flattened by optimally dividing the pump power ratio to 1:29 for EDFA and RFA, respectively. In a signal input power of –20 dBm, the average gain is 14 dB for the C-band EDFA and 13.6 dB for the L-band RFA when a pump reflector is used to recycle the residual pump power in L-band. The noise figure value ranges from 4.6 to 6.5 dB and the polarization dependent gain is less than 0.14 dB.
hp‐Mortar boundary element method for two‐body contact problems with friction
Authors: Chernov Alexey , Maischak Matthias , Stephan Ernst P.
Published: April 2008

We construct a novel hp‐mortar boundary element method for two‐body frictional contact problems for nonmatched discretizations. The contact constraints are imposed in the weak sense on the discrete set of Gauss–Lobatto points using the hp‐mortar projection operator. The problem is reformulated as a variational inequality with the Steklov–Poincaré operator over a convex cone of admissible solutions. We prove an a priori error estimate for the corresponding Galerkin solution in the energy norm. Due to the nonconformity of our approach, the Galerkin error is decomposed into the approximation error and the consistency error. Finally, we show that the Galerkin solution converges to the exact solution as 𝒪((h/p)1/4) in the energy norm for quasiuniform discretizations under mild regularity assumptions. We solve the Galerkin problem with a Dirichlet‐to‐Neumann algorithm. The original two‐body formulation is rewritten as a one‐body contact subproblem with friction and a one‐body Neumann subproblem. Then the original two‐body frictional contact problem is solved with a fixed point iteration. Copyright © 2008 John Wiley & Sons, Ltd.
Empirically predicted 13C NMR chemical shifts for 8‐hydroxyflavone starting from 7,8,4′‐trihydroxyflavone and from 7,8‐dihydroxyflavone
Authors: March Raymond E. , Burns Darcy C. , Ellis David A.
Published: April 2008

8‐Hydroxyflavone is not found in nature. While the 13C chemical shifts of 8‐hydroxyflavone have been reported previously, the observed 13C chemical shifts were not assigned. A previously reported empirical predictive tool has been applied in reverse in order to deconvolute the 13C chemical shifts for 8‐hydroxyflavone from each of those of 7,8,4′‐trihydroxyflavone and 7,8‐dihydroxyflavone together with those of 7‐hydroxyflavone, 4′‐hydroxyflavone, and flavone. The two sets of calculated 13C chemical shifts for 8‐hydroxyflavone are in good agreement with each other in that the average absolute difference is 0.4 ppm. The previously reported but unassigned 13C chemical shifts for 8‐hydroxyflavone have been assigned by matching them with the averages of the two sets of calculated 13C chemical shifts for 8‐hydroxyflavone such that the minimum average absolute difference is 0.63 ppm. The assigned 13C chemical shifts of 8‐hydroxyflavone may be used, along with the 13C chemical shifts of the remaining monohydroxyflavones, as part of a predictive tool to rapidly assess the 13C NMR spectra of C8‐hydroxylated flavonoids. Copyright © 2008 John Wiley & Sons, Ltd.
Mammary gland differentiation inversely correlates with GDF‐8 expression
Authors: Manickam Ravikumar , Pena Ramona N. , Whitelaw C. Bruce A.
Published: April 2008

GDF‐8 is recognised as an inhibitor of muscle cell growth and differentiation. Although initially thought to be restricted to muscle cells it is now accepted that GDF‐8 expression has a broader tissue distribution. We demonstrate GDF‐8 expression in the mouse mammary gland, which is predominantly associated with epithelial cells and displays an inverse correlation to the differentiated state of the gland. Specifically, the highest GDF‐8 mRNA levels correlate with periods of maximal ductal growth, diminish as pregnancy progressed and are down‐regulated to minimal levels by the onset of lactation as the epithelium differentiates. A similar profile is observed for both GDF‐8 protein processing and reflects Smad2/3 phosphorylation profile. However, in contrast to muscle cells, GDF‐8 neither reduces proliferation nor induces p21 expression levels in mammary epithelial cells. These data implicate a role for GDF‐8 in mammary epithelial cell differentiation and demonstrate that GDF‐8 has cell‐type specific activities. Mol. Reprod. Dev. 75: 1783–1788, 2008. © 2008 Wiley‐Liss, Inc.
Longitudinal study of the assessment by MRI and diffusion‐weighted imaging of tumor response in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy
Authors: Sharma Uma , Danishad Karikanni Kalathil A. , Seenu Vurthaluru , Jagannathan Naranamangalam R.
Published: April 2008

Measurements of tumor apparent diffusion coefficient (ADC), volume and diameter in assessing the response of patients with locally advanced breast cancer (LABC) (n = 56) undergoing neoadjuvant chemotherapy (NACT) at four time periods (before treatment and after three cycles of NACT) were carried out at 1.5 T using diffusion‐weighted imaging (DWI) and MRI. Ten benign tumors and 15 controls were also investigated. The MR tumor response was compared with the clinical response. Mean ADC before treatment of malignant breast tissue was significantly lower than that of controls, disease‐free contralateral tissue of the patients, and benign lesions, and gradually increased during the course of NACT. Analysis of the percentage change in ADC, volume and diameter after each cycle of NACT between clinical responders and non‐responders showed that the change in ADC after the first cycle was statistically significant compared with volume and diameter, indicating its potential in assessing early response. After the third cycle, the sensitivity for differentiating responders from non‐responders was 89% for volume and diameter and 68% for ADC, and the respective specificities were 50%, 70% and 100%. A sensitivity of 84% (specificity of 60% with an accuracy of 76%) was achieved when all three variables were taken together to predict the response. A cut‐off value of ADC was also calculated using receiver operator characteristics analysis to discriminate between normal, benign and malignant breast tissue. Similarly, a cut‐off value for ADC, volume and diameter was obtained after the second and third cycles of NACT to predict tumor response. The results show that ADC is more useful for predicting early tumor response to NACT than morphological variables, suggesting its potential in effective treatment management. Copyright © 2008 John Wiley & Sons, Ltd.
Clinical application of MRI in ophthalmology
Authors: Townsend Kelly A. , Wollstein Gadi , Schuman Joel S.
Published: April 2008

MRI has long been applied to clinical medical and neurological cases for the structural assessment of tissues as well as their physiological and functional needs and processes. These uses are at a variety of developmental stages in ophthalmology, from common use of clinical structural assessment for neuro‐ophthalmology and evaluation of space‐occupying lesions to the beginning stages of experimentally measuring functional activation of specific layers within the retina and measurement of physiological oxygen responses. New MRI methodologies, such as the use of orbital coils and Gd‐DTPA image enhancement, have been researched, developed, and validated in the eye, opening new possibilities for this technology to enter the clinic. This review aims to summarize the clinical ophthalmological uses of MRI, focusing on the current use of the technology and future applications. Copyright © 2008 John Wiley & Sons, Ltd.
Quantification of cerebral edema on diffusion tensor imaging in acute‐on‐chronic liver failure
Authors: Nath Kavindra , Saraswat Vivek A. , Krishna Yellapu R. , Thomas Michael A. , Rathore Ram K. S. , Pandey Chandra M. , Gupta Rakesh K.
Published: April 2008

Cerebral edema is a major complication of acute liver failure but may also be seen in other forms of liver failure such as acute‐on‐chronic liver failure (ACLF) and chronic liver failure (CLF). ACLF develops in patients with previously well‐compensated chronic liver disease following acute hepatitis A or E superimposed on underlying liver cirrhosis. The aim of this study was to detect the occurrence, and determine the nature, of cerebral edema in patients with the defined subset of ACLF using diffusion tensor imaging (DTI) metrics. Twenty‐three patients with ACLF were studied and compared with 15 healthy controls and 15 patients with CLF. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), linear anisotropy (CL), planar anisotropy (CP), and spherical isotropy (CS) were calculated by selecting regions of interest in the white matter and deep grey matter of the brain. Significantly decreased FA and increased CS were observed in the anterior limb (ALIC) and posterior limb (PLIC) of the internal capsule and frontal white matter (P < 0.05) in patients with different grades (1–4) of ACLF when compared with healthy controls. No significant changes in MD and CP were seen in any brain region. However, significantly decreased CL was observed in the PLIC, caudate nuclei and putamen. In patients with CLF, significantly decreased FA with increased CS in the ALIC and PLIC along with significantly increased MD in the ALIC and caudate nuclei were observed. The presence of significantly decreased FA and CL and increased CS along with no significant change in MD and CP suggests the presence of both intracellular and extracellular components of cerebral edema in patients with ACLF. Copyright © 2008 John Wiley & Sons, Ltd.