bluuebunny/crossref_metadata_2025 huggingface dataset:
The Importance of the Active Site Histidine for the Activity of Epoxide‐ or Aziridine‐Based Inhibitors of Cysteine Proteases
Authors: Mladenovic Milena , Schirmeister Tanja , Thiel Stefan , Thiel Walter , Engels Bernd
Published: October 2006

In the present study the importance of the active site histidine residue (His) for the activity of epoxide‐ or aziridine‐based cysteine protease inhibitors is examined theoretically. To account for all important effects, QM/MM hybrid approaches are employed which combine quantum mechanical (QM) methods that are necessary to describe bond‐breaking and formation processes, with molecular mechanics (MM) methods that incorporate the influence of the protein environment. Using various model systems, the computations exclude a direct proton shift from the active site His residue to the inhibitor, but show that one water molecule is sufficient to establish a very efficient relay system. This relay system allows an easy proton transfer from the active site His residue to the inhibitor and is thus essential for the activity of both types of inhibitors. Differences between the epoxides and the aziridines are discussed, along with some implications for the rational design of optimized inhibitors. The work presented herein represents the first QM/MM study into the mode of action of these important inhibitor classes.
FDG‐PET after 1 cycle of therapy predicts outcome in diffuse large cell lymphoma and classic Hodgkin disease
Authors: Kostakoglu Lale , Goldsmith Stanley J. , Leonard John P. , Christos Paul , Furman Richard R. , Atasever Tamer , Chandramouly Angely , Verma Sumeet , Kothari Pratichi , Coleman Morton
Published: October 2006

BACKGROUND.

Early prediction of response to therapy may offer the potential to identify patients who will benefit from standard conventional therapy. The objective of this study was to determine the predictive value of FDG‐PET as an early response indicator after 1 cycle of chemotherapy for progression‐free survival (PFS) in diffuse large cell lymphoma (DLCL) and classic Hodgkin disease (HD).

METHODS.

FDG‐PET was performed before, after 1 cycle, and after completion of chemotherapy in 47 patients. The patients were followed with a median follow‐up of 21 months (range, 3–47 months). PFS was compared between PET‐positive and PET‐negative patients after 1 cycle and after completion of therapy.

RESULTS.

All PET‐negative patients after 1 cycle (n = 31) had sustained complete remission with a median follow‐up of 28 months. Fourteen of 16 PET‐positive patients after 1 cycle had refractory disease or relapsed (median PFS, 5.5 months). There were 2 false‐positive results, 1 with an active infection at the biopsy site and the other in a patient who had been in remission after radiation therapy. There was good agreement between the results obtained after 1 cycle and at completion of therapy (kappa, 0.80); however, the negative predictive value was higher for FDG‐PET after 1 cycle than after completion of chemotherapy (100% vs 91.4%), although not statistically different (P = .40).

CONCLUSIONS.

FDG‐PET had a high prognostic value after 1 cycle of chemotherapy, thus it can be a valid alternative for posttreatment evaluation of DLCL and HD and may offer the potential for change in treatment paradigms. Cancer 2006. © 2006 American Cancer Society.
Radiosurgery for the treatment of spinal lung metastases
Authors: Gerszten Peter C. , Burton Steven A. , Belani Chandra P. , Ramalingam Suresh , Friedland David M. , Ozhasoglu Cihat , Quinn Annette E. , McCue Kevin J. , Welch William C.
Published: October 2006

BACKGROUND.

Spinal metastases are a common source of pain as well as neurologic deficit in patients with lung cancer. Metastases from lung cancer traditionally have been believed to be relatively responsive to radiation therapy. However, conventional external beam radiotherapy lacks the precision to allow delivery of large single‐fraction doses of radiation and simultaneously limit the dose to radiosensitive structures such as the spinal cord. The current study evaluated the efficacy of single‐fraction radiosurgery for the treatment of spinal lung cancer metastases.

METHODS.

In the current prospective cohort evaluation, 87 lung cancer metastases to the spine in 77 patients were treated with a single‐fraction radiosurgery technique with a follow‐up period of 6 to 40 months (median, 12 months). The indication for radiosurgery treatment was pain in 73 cases, as a primary treatment modality in 7 cases, for radiographic tumor progression in 4 cases, and for progressive neurologic deficit in 3 cases.

RESULTS.

Tumor volume ranged from 0.2 to 264 cm3 (mean, 25.7 cm3). The maximum tumor dose was maintained at 15 to 25 grays (Gy) (mean, 20 Gy; median, 20 Gy). No radiation‐induced toxicity occurred during the follow‐up period. Long‐term axial and radicular pain improvement occurred in 65 of 73 patients (89%) who were treated primarily for pain. Long‐term radiographic tumor control was observed in all patients who underwent radiosurgery as their primary treatment modality or for radiographic tumor progression.

CONCLUSIONS.

Spinal radiosurgery was found to be feasible, safe, and clinically effective for the treatment of spinal metastases from lung cancer. The results of the current study indicate the potential of radiosurgery in the treatment of patients with spinal lung metastases, especially those with solitary sites of spine involvement, to improve long‐term palliation. Cancer 2006. © 2006 American Cancer Society.
Parameter identification of framed structures using an improved finite element model‐updating method—Part I: formulation and verification
Authors: Yu Eunjong , Taciroglu Ertugrul , Wallace John W.
Published: October 2006

In this study, we formulate an improved finite element model‐updating method to address the numerical difficulties associated with ill conditioning and rank deficiency. These complications are frequently encountered model‐updating problems, and occur when the identification of a larger number of physical parameters is attempted than that warranted by the information content of the experimental data. Based on the standard bounded variables least‐squares (BVLS) method, which incorporates the usual upper/lower‐bound constraints, the proposed method (henceforth referred to as BVLSrc) is equipped with novel sensitivity‐based relative constraints. The relative constraints are automatically constructed using the correlation coefficients between the sensitivity vectors of updating parameters. The veracity and effectiveness of BVLSrc is investigated through the simulated, yet realistic, forced‐vibration testing of a simple framed structure using its frequency response function as input data. By comparing the results of BVLSrc with those obtained via (the competing) pure BVLS and regularization methods, we show that BVLSrc and regularization methods yield approximate solutions with similar and sufficiently high accuracy, while pure BVLS method yields physically inadmissible solutions. We further demonstrate that BVLSrc is computationally more efficient, because, unlike regularization methods, it does not require the laborious a priori calculations to determine an optimal penalty parameter, and its results are far less sensitive to the initial estimates of the updating parameters. Copyright © 2006 John Wiley & Sons, Ltd.
Cyclic tests on steel and concrete‐filled tube frames with Slit Walls
Authors: Hitaka Toko , Matsui Chiaki , Sakai Jun'ichi
Published: October 2006

Cyclic loading tests were performed on three one‐storey steel frames and four three‐storey concrete‐filled tube (CFT) moment frames reinforced with a new type of earthquake‐resisting element consisting of a steel plate shear wall with vertical slits. In this shear wall system, the steel plate segments between the slits behave as a series of flexural links, which provide fairly ductile response without the need for heavy stiffening of the wall. The steel shear walls and the moment frames behaved in a ductile manner up to more than 4% drift without abrupt strength degradation or loss of axial resistance. Results of these tests and complementary analysis provide a basis for an equivalent brace model to be employed in commercially available frame analysis programs. Test and analytical results suggest that the horizontal force is carried by the bolts in the middle portion of the wall–frame connection, while the vertical forces coupled with the moment in the connection are resisted by the bolts in the edge portion of the connection, for which the friction bolts in the connection should be designed. When sufficient transverse stiffening is provided, full plastic strength and non‐degrading hysteretic behaviour can be achieved for this new type of shear wall. Copyright © 2006 John Wiley & Sons, Ltd.
Neandertals and moderns mixed, and it matters
Authors: Zilhão João
Published: October 2006

Twenty‐five years ago, the Middle‐to‐Upper Paleolithic transition in Europe could be represented as a straightforward process subsuming both the emergence of symbolic behavior and the replacement of Neandertals by modern humans. The Aurignacian was a proxy for the latter, during which enhanced cognitive capabilities explained ornaments and art. The few instances of Neandertal symbolism were deemed to long postdate contact and dismissed as “imitation without understanding,” if not geological contamination. Such views were strengthened by the recent finding that, in southern Africa, several features of the European Upper Paleolithic, including bone tools, ornaments, and microliths, emerged much earlier. Coupled with genetic suggestions of a recent African origin for extant humans, fossil discoveries bridging the transition between “archaics” and “moderns” in the realm of anatomy (Omo‐Kibish, Herto) seemingly closed the case. Over the last decade, however, taphonomic critiques of the archeology of the transition have made it clear that, in Europe, fully symbolic sapiens behavior predates both the Aurignacian and moderns. And, in line with evidence from the nuclear genome rejecting strict replacement models based on mtDNA alone, the small number of early modern specimens that passed the test of direct dating present archaic features unknown in the African lineage, suggesting admixture at the time of contact.

In the realm of culture, the archeological evidence also supports a Neandertal contribution to Europe's earliest modern human societies, which feature personal ornaments completely unknown before immigration and are characteristic of such Neandertal‐associated archeological entities as the Châtelperronian and the Uluzzian. The chronometric data suggest that, north of the Ebro divide, the entire interaction process may have been resolved within the millennium centered around 42,000 calendar years ago. Such a rapid absorption of the Neandertals is consistent with the size imbalance between the two gene reservoirs and further supports significant levels of admixture.
Improvement of mass source/sink for an immersed boundary method
Authors: Huang Wei‐Xi , Sung Hyung Jin
Published: October 2006

An improved immersed boundary method using a mass source/sink as well as momentum forcing is developed for simulating flows over or inside complex geometries. The present method is based on the Navier–Stokes solver adopting the fractional step method and a staggered Cartesian grid system. A more accurate formulation of the mass source/sink is derived by considering mass conservation of the virtual cells in the fluid crossed by the immersed boundary. Two flow problems (the decaying vortex problem and uniform flow past a circular cylinder) are used to validate the proposed formulation. The results indicate that the accuracy near the immersed boundary is improved by introducing the accurate mass source/sink. Copyright © 2006 John Wiley & Sons, Ltd.
A numerical method for flows in porous and homogenous fluid domains coupled at the interface by stress jump
Authors: Yu P. , Lee T. S. , Zeng Y. , Low H. T.
Published: October 2006

A numerical method was developed for flows involving an interface between a homogenous fluid and a porous medium. The numerical method is based on the finite volume method with body‐fitted and multi‐block grids. A generalized model, which includes Brinkman term, Forcheimmer term and non‐linear convective term, was used to govern the flow in the porous medium region. At its interface, a shear stress jump that includes the inertial effect was imposed, together with a continuity of normal stress. Furthermore, the effect of the jump condition on the diffusive flux was considered, additional to that on the convective part which has been usually considered. Numerical results of three flow configurations are presented. The method is suitable for coupled problems with regions of homogeneous fluid and porous medium, which have complex geometries. Copyright © 2006 John Wiley & Sons, Ltd.
Hanns Fischer: Radical Pioneer
Authors: Beckwith Athelstan L. J. , Ingold Keith U.
Published: October 2006

For four decades, Hanns Fischer played a major and highly innovative role in the development of free radical chemistry. The present article describes the science in several of Fischer's papers. These papers were chosen for analysis because they nicely illustrate Fischer's originality, passion for exactitude, and impact on chemistry, and because they are well‐read favorites of the present authors.
Intramolecular Hydrogen Bonding: The Case of β‐Phosphorylated Nitroxide (= Aminoxyl) Radical
Authors: Acerbis Sébastien , Bertin Denis , Boutevin Bernard , Gigmes Didier , Lacroix‐Desmazes Patrick , Le Mercier Christophe , Lutz Jean‐François , Marque Sylvain R. A. , Siri Didier , Tordo Paul
Published: October 2006

Alkoxyamines and persistent nitroxide (= aminoxyl) radicals are important regulators of nitroxide‐mediated radical polymerization. Since polymerization times decrease with the increasing homolysis rate constant of the CON bond homolysis between the polymer chain and the aminooxy moiety, the factors influencing the cleavage rate constant are of considerable interest. It has already been shown that the value of the homolysis rate constant kd is very sensitive to the stabilization of both released radical species. X‐Ray, EPR, and kinetic data showed that the intramolecular H‐bonding radical in the 1‐(diethoxyphosphoryl)‐2,2‐dimethylpropyl 2‐hydroxy‐1,1‐dimethylethyl nitroxide (3a) (homologue of 2‐hydroxy‐1,1‐dimethylethyl 1‐phenyl‐2‐methylpropyl nitroxide (2a)) did not occur with the nitroxide moiety as expected but with the phosphoryl group. However, the polymerization rate of styrene (= ethenylbenzene) was significantly enhanced.
15N Chemically Induced Dynamic Nuclear Polarization (15N‐CIDNP) Investigations of the Peroxynitrite Decay and Nitration of N‐Acetyl‐L‐tyrosine
Authors: Lehnig Manfred , Kirsch Michael
Published: October 2006

During the decay of (15N)peroxynitrite (O15NOO−) in the presence of N‐acetyl‐L‐tyrosine (Tyrac) in neutral solution and at 268 K, the 15N‐NMR signals of 15NO$\rm{_2^ - }$ and 15NO$\rm{_3^ - }$ show emission (E) and enhanced absorption (A) as it has already been observed by Butler and co‐workers in the presence of L‐tyrosine (Tyr). The effects are built up in radical pairs [CO$\rm{_3^{\bullet - } }$, 15NO$\rm{_2^\bullet }$]S formed by OO bond scission of the (15N)peroxynitriteCO2 adduct (O15NOOCO$\rm{_2^ - }$). In the absence of Tyrac and Tyr, the peroxynitrite decay rate is enhanced, and 15N‐CIDNP does not occur. This is explained by a chain reaction during the peroxynitrite decay involving N2O3 and radicals NO. and NO$\rm{_2^\bullet }$. The interpretation is supported by 15N‐CIDNP observed with (15N)peroxynitrite generated in situ during reaction of H2O2 with N‐acetyl‐N‐(15N)nitroso‐dl‐tryptophan ((15N)NANT) at 298 K and pH 7.5. In the presence of Na15NO2 at pH 7.5 and in acidic solution, 15N‐CIDNP appears in the nitration products of Tyrac, 1‐(15N)nitro‐N‐acetyl‐L‐tyrosine (1‐15NO2‐Tyrac) and 3‐(15N)nitro‐N‐acetyl‐L‐tyrosine (3‐15NO2‐Tyrac). The effects are built up in radical pairs [Tyrac., 15NO$\rm{_2^\bullet }$]F formed by encounters of independently generated radicals Tyrac. and 15NO$\rm{_2^\bullet }$. Quantitative 15N‐CIDNP studies show that nitrogen dioxide dependent reactions are the main if not the only pathways for yielding both nitrate and nitrated products.
Homolytic Substitution at the Sulfur Atom as a Tool for Organic Synthesis
Authors: Crich David
Published: October 2006

The use of intramolecular homolytic substitution at the sulfur atom by aryl and vinyl radicals, as an alternative to the use of alkyl halides, and chalcogenides as radical precursors in organic synthesis is reviewed.
Olefin Isomerization via Radical‐Ion Pairs in Triplet States Studied by Chemically Induced Dynamic Nuclear Polarization (CIDNP)
Authors: Goez Martin , Eckert Gerd
Published: October 2006

Geometric isomerizations of olefins following photoinduced electron transfer (PET) are classified according to the relative energetic positions of the radical‐ion pairs and the reactant triplets. Each class exhibits characteristic CIDNP (chemically induced dynamic nuclear polarization) effects, for which typical examples are presented. Time‐resolved CIDNP experiments on the system triphenylamine/fumarodinitrile (= (2E)‐but‐2‐enedinitrile), where formation of the olefin triplet is impossible, show that there is also no isomerization of the olefin radical anion. With triisopropylamine or fumarodinitrile as the reaction partner for 4,4′‐dimethoxystilbene (= 1,1′‐[(1E)‐ethane‐1,2‐diyl]bis[4‐methoxybenzene]), both oxidative and reductive quenching give almost mirror‐image CIDNP spectra because of the pairing theorem; reverse electron transfer of the triplet radical‐ion pairs populates the stilbene triplet only, which then isomerizes. With anethole (= 1‐methoxy‐4‐(prop‐1‐enyl)benzene; M), the competition between electron return of triplet pairs $\rm{{}^{{3}}\overline {{{M}}^{ \bullet + } {{X}}^{ \bullet - } } }$ to give either M + 3X or 3M + X was studied by using a second isomerizable olefin (diethyl fumarate (= diethyl (2E)‐but‐2‐enedioate) or cinnamonitrile (= (2E)‐3‐phenylprop‐2‐enenitrile)) as the reaction partner X. Classes can be changed by employing PET sensitization. With ACN (anthracene‐9‐carbonitrile) as the sensitizer, anethole does not produce any directly observable polarizations, but a substitution of ACN.− by the radical anion of 1,4‐benzoquinone (= cyclohexa‐2,5‐diene‐1,4‐dione) or fumarodinitrile within the lifetime of the spin‐correlated radical‐ion pairs leads to very strong CIDNP signals that reflect the effects of both pairs.
A New Sterically Highly Hindered 7‐Membered Cyclic Nitroxide for the Controlled Living Radical Polymerization
Authors: Chang Che‐Chien , Siegenthaler Kai Oliver , Studer Armido
Published: October 2006

The synthesis of a new sterically highly hindered 7‐membered alkoxyamine, 2,2,7,7‐tetraethyl‐1‐(1‐phenylethoxy)‐1,4‐diazepan‐5‐one (4), starting from known 2,2,6,6‐tetraethyl‐1‐(1‐phenylethoxy)piperidin‐4‐one (3) via a Beckmann‐type rearrangement is presented. It is shown that ring‐enlargement by insertion of an NH moiety in going from 3 to 4 leads to a more efficient regulator for nitroxide‐mediated controlled living radical styrene (= ethenylbenzene) and butyl acrylate (= butyl prop‐2‐enoate) polymerization. In addition to the polymerization experiments, kinetic data on the reversible CO bond homolysis of alkoxyamines 3 and 4 are presented.
Alkoxyamines of Stable Aromatic Nitroxides: NO vs. CO Bond Homolysis
Authors: Gigmes Didier , Gaudel‐Siri Anouk , Marque Sylvain R. A. , Bertin Denis , Tordo Paul , Astolfi Paola , Greci Lucedio , Rizzoli Corrado
Published: October 2006

A series of stable 2,2‐disubstituted 3‐(phenylimino)indol‐1‐oxyls, the alkoxyamines 3, were prepared, characterized, and tested as possible candidates in controlled radical polymerization (CRP). The sturctures of 3d and 10 were additionally solved by X‐ray diffraction. The lability of the NO(C) and (N)OC bonds of compounds 3 were compared, and the possibility of NO vs. OC bond cleavage was evaluated by thermal degradation, ESR spin trapping, MS experiments, and DFT calculations. Alkoxyamines with a primary‐ or secondary‐alkyl group bound to the O‐atom of the nitroxide function (hexyl and i‐Pr) mainly underwent (undesired) NO bond homolysis. When the O‐alkyl radical was a tertiary or a benzyl group (crotonyl or styryl), OC bond cleavage occurred as the main process, thus suggesting a possible use of these compounds in CRP processes.
Absolute Rate Constants for the Addition of the 1‐(tert‐Butoxy)carbonylethyl Radical onto Cyclic Alkenes in Solution
Authors: Fischer Hanns , Knühl Bernhard , Marque Sylvain R. A.
Published: October 2006

Absolute rate constants are reported for the addition of the 1‐[(tert‐butoxy)carbonyl]ethyl (= 2‐(1,1‐dimethylethoxy)‐1‐methyl‐2‐oxoethyl) radical .CHMeCO2(t‐Bu) to several cyclic and monosubstituted alkenes in MeCN as obtained by time‐resolved electron paramagnetic resonance (EPR). The activation energies for the addition of this alkyl radical are mainly governed by the addition enthalpy but are also substantially lowered by the ambiphilic effect and by relief of cyclic strain.
Oxidative and Photochemical Stability of Ionomers for Fuel‐Cell Membranes
Authors: Mitov Svetlin , Delmer Olga , Kerres Jochen , Roduner Emil
Published: October 2006

To predict hydroxyl‐radical‐initiated degradation of new proton‐conducting polymer membranes based on sulfonated polyetherketones (PEK) and polysulfones (PSU), three nonfluorinated aromatics are chosen as model compounds for EPR experiments, aiming at the identification of products of HO.‐radical reactions with these monomers. Photolysis of H2O2 was chosen as the source of HO. radicals. To distinguish HO.‐radical attack from direct photolysis of the monomers, experiments were carried out in the presence and absence of H2O2. A detailed investigation of the pH dependence was performed for 4,4′‐sulfonylbis[phenol] (SBP), bisphenol A (= 4,4′‐isopropylidenebis[phenol]; BPA), and [1,1′‐biphenyl]‐4,4′‐diol (BPD). At pH ≥ pKA of HO. and H2O2, reactions between the model compounds and O2.− or 1O2 are the most probable ways to the phenoxy and ‘semiquinone’ radicals observed in this pH range in our EPR spectra. A large number of new radicals give evidence of multiple hydroxylation of the aromatic rings. Investigations at low pH are particularly relevant for understanding degradation in polymer‐electrolyte fuel cells (PEFCs). However, the chemistry depends strongly on pH, a fact that is highly significant in view of possible pH inhomogeneities in fuel cells at high currents. It is shown that also direct photolysis of the monomers leads to ‘semiquinone’‐type radicals. For SBP and BPA, this involves cleavage of a CC bond.
Antioxidant and Antiradical Activity of Hydroxy‐Substituted 4‐Thiaflavanes
Authors: Amorati Riccardo , Fumo Maria Grazia , Pedulli Gian Franco , Menichetti Stefano , Pagliuca Chiara , Viglianisi Caterina
Published: October 2006

The antioxidant activities of several hydroxy‐substituted 4‐thiaflavanes, compounds 1–3, were determined by measuring their ability of inhibiting the autoxidation of styrene or cumene. On this basis, the role played by the number and position of OH groups and by the oxidation state of the S‐atom was quantified and rationalized. With these data, it should be possible to optimize the structural features of these ‘double‐faced’ antioxidants for structureactivity‐relationship studies. A comparison between the kinetic data (kinh) reported in this paper and the previously reported values of the antiradical activities (SC50), measured by the DPPH. bleaching method, for 1–3 is made (Table).
Pulse EPR Methods for Studying Chemical and Biological Samples Containing Transition Metals
Authors: Calle Carlos , Sreekanth Anandaram , Fedin Matvey V. , Forrer Jörg , Garcia‐Rubio Inés , Gromov Igor A. , Hinderberger Dariush , Kasumaj Besnik , Léger Patrick , Mancosu Bruno , Mitrikas George , Santangelo Maria Grazia , Stoll Stefan , Schweiger Arthur , Tschaggelar René , Harmer Jeffrey
Published: October 2006

This review discusses the application of pulse EPR to the characterization of disordered systems, with an emphasis on samples containing transition metals. Electron nuclear double‐resonance (ENDOR), electron‐spin‐echo envelope‐modulation (ESEEM), and double electron–electron resonance (DEER) methodologies are outlined. The theory of field modulation is outlined, and its application is illustrated with DEER experiments. The simulation of powder spectra in EPR is discussed, and strategies for optimization are given. The implementation of this armory of techniques is demonstrated on a rich variety of chemical systems: several porphyrin derivatives that are found in proteins and used as model systems, otherwise highly reactive aminyl radicals stabilized with electron‐rich transition metals, and nitroxide–copper–nitroxide clusters. These examples show that multi‐frequency continuous‐wave (CW) and pulse EPR provides detailed information about disordered systems.
Photochemical Reactions and Photoinduced Electron‐Transfer Processes in Liquids, Frozen Solutions, and Proteins as Studied by Multifrequency Time‐Resolved EPR Spectroscopy
Authors: Savitsky Anton , Möbius Klaus
Published: October 2006

In this overview, modern multifrequency EPR spectroscopy, in particular at high magnetic fields, is shown to provide detailed information about structure, motional dynamics, and spin chemistry of transient radicals and radical pairs occurring in photochemical reactions. Examples discussed comprise photochemical reactions in liquid solution and light‐initiated electron transfer processes both in biomimetic donor–acceptor model systems in frozen solution or liquid crystals and in natural photosynthetic‐reaction‐center protein complexes. The transient paramagnetic states exhibit characteristic electron polarization (CIDEP) effects. They contain valuable information about structure and dynamics of the transient reaction intermediates. Moreover, they are exploited for signal enhancement. Continuous‐wave (cw) and pulsed versions of time‐resolved high‐field EPR spectroscopy, such as cw‐transient‐EPR (TREPR) and pulsed‐electron‐spin‐echo (ESE) experiments, are compared with respect to their advantages and limitations for the specific system under study. For example, W‐band (95‐GHz) TREPR spectroscopy in conjunction with a continuous‐flow system for light‐generated short‐lived transient spin‐polarized radicals of organic photoinitiators in solution was performed with a time resolution of 10 ns. The increased Boltzmann polarization at high fields even allows detection of transient radicals without CIDEP effects. This enables one to determine initial radical polarization contributions as well as radical‐addition reaction constants. Another example of the power of combined X‐band and W‐band TREPR spectroscopy is given for the complex electron‐transfer and spin dynamics of covalently linked porphyrin–quinone as well as Watson–Crick base‐paired porphyrin–dinitrobenzene donor–acceptor biomimetic model systems. Furthermore, W‐band ESE experiments on the spin‐correlated coupled radical pair $\rm{{{P}}_{865}^{\bullet + } }$$\rm{{{Q}}_{{A}}^{\bullet - } }$ in reaction centers of the purple photosynthetic bacterium Rb. sphaeroides reveal details of distance and orientation of the pair partners in their charge‐separated transient state. The results are compared with those of the ground‐state P865QA. The high orientation selectivity of high‐field EPR provides single‐crystal‐like information even from disordered frozen‐solution samples. The examples given demonstrate that high‐field EPR adds substantially to the capability of ‘classical’ spectroscopic and diffraction techniques for determining structure–dynamics–function relations of biochemical systems, since transient intermediates can be observed in real time in their working states on biologically relevant time scales.
Reactivation of Kaposi's sarcoma‐associated herpesvirus by natural products from Kaposi's sarcoma endemic regions
Authors: Whitby Denise , Marshall Vickie A. , Bagni Rachel K. , Miley Wendell J. , McCloud Thomas G. , Hines‐Boykin Rebecca , Goedert James J. , A.Conde Betty , Nagashima Kunio , Mikovits Judy , Dittmer Dirk P. , Newman David J.
Published: October 2006

Kaposi's sarcoma (KS) and its causative agent, Kaposi's sarcoma associated herpesvirus (KSHV/HHV‐8), a gamma2 herpesvirus, have distinctive geographical distributions that are largely unexplained. We propose the “oncoweed” hypothesis to explain these differences, namely that environmental cofactors present in KS endemic regions cause frequent reactivation of KSHV in infected subjects, leading to increased viral shedding and transmission leading to increased prevalence of KSHV infection as well as high viral load levels and antibody titers. Reactivation also plays a role in the pathogenesis of KSHV‐associated malignancies. To test this hypothesis, we employed an in vitro KSHV reactivation assay that measured increases in KSHV viral load in KSHV infected primary effusion lymphoma (PEL) cells and screened aqueous natural product extracts from KS endemic regions. Of 4,842 extracts from 38 countries, 184 (5%) caused KSHV reactivation. Extracts that caused reactivation came from a wide variety of plant families, and extracts from Africa, where KSHV is highly prevalent, caused the greatest level of reactivation. Time course experiments were performed using 28 extracts that caused the highest levels of reactivation. The specificity of the effects on viral replication was examined using transcriptional profiling of all viral mRNAs. The array data indicated that the natural extracts caused an ordered cascade of lytic replication similar to that seen after induction with synthetic activators. These in vitro data provide support for the “oncoweed” hypothesis by demonstrating basic biological plausibility. © 2006 Wiley‐Liss, Inc.
Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice
Authors: Suzuki Rikako , Kohno Hiroyuki , Yasui Yumiko , Hata Kazuya , Sugie Shigeyuki , Miyamoto Shingo , Sugawara Kuniaki , Sumida Takashi , Hirose Yoshinobu , Tanaka Takuji
Published: October 2006

The modulatory effects of dietary citrus unshiu segment membrane (CUSM) on the occurrence of aberrant crypt foci (ACF) and β‐catenin accumulated crypts (BCACs) were determined in male C57BL/KsJ‐db/db (db/db) mice initiated with azoxymethane (AOM). Male db/db, db/+ and +/+ mice were given 5 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then they were fed the diet containing 0.02%, 0.1% or 0.5% CUSM for 7 weeks. At Week 12, a significant increase in the numbers of ACF and BCAC was noted in the db/db mice in comparison with the db/+ and +/+ mice. Feeding with CUSM caused reduction in the frequency of ACF in all genotypes of mice and the potency was high in order of the db/db mice, db/+ mice and +/+ mice. The number of BCACs was also reduced by feeding with CUSM, thus resulting in a 28–61% reduction in the db/db mice, possibly due to suppression of cell proliferation activity in the lesions by feeding with CUSM‐containing diet. Clinical chemistry revealed a low serum level of triglyceride in mice fed CUSM. In addition, CUSM feeding inhibited fatty metamorphosis and fibrosis in the liver of db/db mice. Our findings show that CUSM in the diet has a chemopreventive ability against the early phase of AOM‐induced colon carcinogenesis in the db/db as well as db/+ and +/+ mice, indicating potential use of CUSM in cancer chemoprevention in obese people. © 2006 Wiley‐Liss, Inc.
Inhibition of heme oxygenase‐1 by zinc protoporphyrin IX reduces tumor growth of LL/2 lung cancer in C57BL mice
Authors: Hirai Kaeko , Sasahira Tomonori , Ohmori Hitoshi , Fujii Kiyomu , Kuniyasu Hiroki
Published: October 2006

Heme oxygenase (HO)‐1 is a key player reducing cytotoxicity and enhancing protumoral effects of nitric oxide (NO). We examined zinc protoporphyrin (ZnPP) IX, an HO‐1 inhibitor, to affect tumor growth of LL/2 mouse lung cancer cells. ZnPPIX reduced HO‐1 expression and HO activity in LL/2 cells, whereas cobalt PPIX (CoPPIX), an HO‐1 activator, increased both. LL/2 cells treated with sodium nitropurusside, an NO donor, showed growth inhibition dose‐dependently, which was enhanced by ZnPPIX cotreatment, but was reduced by CoPPIX. In mice tumors, ZnPPIX decreased HO‐1 expression. LL/2‐tumors were found in 88% (7/8) vehicle‐treated mice, whereas tumors were found in 38% (3/8) and 25% (2/8) mice treated with 5 and 20 μg/mouse ZnPPIX, respectively (p = 0.0302). Tumor growth was inhibited dose‐dependently by ZnPPIX. Vascular endothealial growth factor concentration in tumors was reduced by ZnPPIX (p = 0.0341). Microvessel density (MVD) in ZnPPIX‐treated tumors was lower than that in vehicle‐treated tumors (p = 0.0362). Apoptotic cell count in ZnPPIX‐treated tumors was higher than that in vehicle‐treated tumors (p = 0.0003). In contrast, CoPPIX treatment increased HO‐1 expression, enhanced tumorigenicity and MVD and reduced apoptosis. From these findings, inhibition of HO‐1 by ZnPPIX provides relevant antitumoral effects. © 2006 Wiley‐Liss, Inc.
Expression of activation‐induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis
Authors: Kou Tadayuki , Marusawa Hiroyuki , Kinoshita Kazuo , Endo Yoko , Okazaki Il‐mi , Ueda Yoshihide , Kodama Yuzo , Haga Hironori , Ikai Iwao , Chiba Tsutomu
Published: October 2006

Activation‐induced cytidine deaminase (AID) plays a role as a genome mutator in activated B cells, and inappropriate expression of AID has been implicated in the immunopathological phenotype of human B‐cell malignancies. Notably, we found that the transgenic mice overexpressing AID developed lung adenocarcinoma and hepatocellular carcinoma (HCC), suggesting that ectopic expression of AID can lead to tumorigenesis in epithelial tissues as well. To examine the involvement of AID in the development of human HCC, we analyzed the AID expression and its correlation with mutation frequencies of the p53 gene in liver tissues from 51 patients who underwent resection of primary HCCs. The specific expression, inducibility by cytokine stimulation and mutagenic activity of AID were investigated in cultured human hepatocytes. Only trace amounts of AID transcripts were detected in the normal liver; however, endogenous AID was significantly upregulated in both HCC and surrounding noncancerous liver tissues with underlying chronic hepatitis or liver cirrhosis (p < 0.05). Most liver tissues with underlying chronic inflammation with endogenous AID upregulation already contained multiple genetic changes in the p53 gene. In both hepatoma cell lines and cultured human primary hepatocytes, the expression of AID was substantially induced by TGF‐β stimulation. Aberrant activation of AID in hepatocytes resulted in accumulation of multiple genetic alterations in the p53 gene. Our findings suggest that the aberrant expression of AID is observed in human hepatocytes with several pathological settings, including chronic liver disease and HCC, which might enhance the genetic susceptibility to mutagenesis leading to hepatocarcinogenesis. © 2006 Wiley‐Liss, Inc.
The involvement of hypoxia‐inducible factor‐1α in the susceptibility to γ‐rays and chemotherapeutic drugs of oral squamous cell carcinoma cells
Authors: Sasabe Eri , Zhou Xuan , Li Dechao , Oku Naohisa , Yamamoto Tetsuya , Osaki Tokio
Published: October 2006

The transcription factor hypoxia‐inducible factor‐1α (HIF‐1α) is the key regulator that controls the hypoxic response of mammalian cells. The overexpression of HIF‐1α has been demonstrated in many human tumors. However, the role of HIF‐1α in the therapeutic efficacy of chemotherapy and radiotherapy in cancer cells is poorly understood. In this study, we investigated the influence of HIF‐1α expression on the susceptibility of oral squamous cell carcinoma (OSCC) cells to chemotherapeutic drugs (cis‐diamminedichloroplatinum and 5‐fluorouracil) and γ‐rays. Treatment with chemotherapeutic drugs and γ‐rays enhanced the expression and nuclear translocation of HIF‐1α, and the susceptibility of OSCC cells to the drugs and γ‐rays was negatively correlated with the expression level of HIF‐1α protein. The overexpression of HIF‐1α induced OSCC cells to become more resistant to the anticancer agents, and down‐regulation of HIF‐1α expression by small interfering RNA enhanced the susceptibility of OSCC cells to them. In the HIF‐1α‐knockdown OSCC cells, the expression of P‐glycoprotein, heme oxygenase‐1, manganese‐superoxide dismutase and ceruloplasmin were downregulated and the intracellular levels of chemotherapeutic drugs and reactive oxygen species were sustained at higher levels after the treatment with the anticancer agents. These results suggest that enhanced HIF‐1α expression is related to the resistance of tumor cells to chemo‐ and radio‐therapy and that HIF‐1α is an effective therapeutic target for cancer treatment. © 2006 Wiley‐Liss, Inc.
Downregulation of the upstream binding factor1 by glycogen synthase kinase3β in myeloid cells induced to differentiate
Authors: Liu Mingli , Tu Xiao , Ferrari‐Amorotti Giovanna , Calabretta Bruno , Baserga Renato
Published: October 2006

The upstream binding factor 1 (UBF1), one of the
proteins that regulate the activity of RNA polymerase I, is downregulated in 32D myeloid cells induced to differentiate into granulocytes, either by the type 1 insulin‐like growth factor (IGF‐1) or the granulocytic colony stimulating factor (G‐CSF). Downregulation of UBF1 is largely due to protein degradation, while mRNA levels are not affected. Inhibition of UBF1 degradation by lithium chloride (LiCl)and lactacystin suggest a role of glycogen synthase kinase β (GSK3β) in a proteasome‐dependent degradation of UBF. GSK3β phosphorylates in vitro and in vivo the UBF protein, which has five putative motifs for phosphorylation by GSK3β. Elimination and/or mutations of these motifs stabilize the UBF1 protein even in cells induced to differentiate. Conversely, a stably transfected, constitutively active GSK3β accelerates the downregulation of UBF1. We show further that activation of the differentiating protein C/EPBα in 32D cells transformed by the oncogenic BCR/ABL protein causes downregulation of UBF1. Finally, inhibition of differentiation of myeloid cells by a dominant negative mutant of Stat3 stabilizes the UBF1 protein, while rapamycin‐induced differentiation of myeloid cells downregulates UBF1 levels. Taken together, our results indicate that the induction of granulocytic differentiation in 32D murine myeloid cells causes the degradation of UBF1, via GSK3β and the proteasome pathway. J. Cell. Biochem. 100: 1154–1169, 2007. © 2006 Wiley‐Liss, Inc.
Valence and extra‐valence orbitals in main group and transition metal bonding
Authors: Landis C. R. , Weinhold F.
Published: October 2006

We address the issue first raised by Maseras and Morokuma with regard to the questionable treatment of empty p‐orbitals in the algorithm for natural atomic/bond orbitals (NAOs, NBOs) and associated natural population analysis. We quantify this issue in terms of the numerical error (root‐mean‐square density deviation) resulting from the two alternative treatments of empty p‐sets, leading to distinct NAOs, atomic charges, and idealized Lewis structural representations. Computational application of this criterion to a broad spectrum of main group and transition group species (employing both single‐ and multi‐structure resonance models) reveals the interesting general pattern of (i) relatively insignificant differences for normal‐valent species, where a single resonance structure is usually adequate, but (ii) clear superiority of the standard NAO algorithm for hypervalent species, where multi‐resonance character is pronounced. These comparisons show how the divisive issue of “valence shell expansion” in transition metal bonding is deeply linked to competing conceptual models of hypervalency (viz., “p‐orbital participation” in skeletal hybridization vs. 3c/4e resonance character). The results provide a quantitative measure of superiority both for the standard NAO evaluation of atomic charges as well as the general 3c/4e (A: B‐C ↔ A‐B :C resonance) picture of main‐ and transition‐group hypervalency. © 2006 Wiley Periodicals, Inc. J Comput Chem, 2007
Partial hepatectomy as first‐line treatment for patients with hepatocellular carcinoma
Authors: Cillo Umberto , Vitale Alessandro , Brolese Alberto , Zanus Giacomo , Neri Daniele , Valmasoni Michele , Bonsignore Pasquale , Grigoletto Francesco , Burra Patrizia , Farinati Fabio , D'Amico Davide Francesco
Published: October 2006

Background

Partial hepatectomy (PH) and liver transplantation (LT) compete as first‐line treatment for hepatocellular carcinoma (HCC). A prospectively collected database was retrospectively reviewed to establish when PH can compete with LT.

Methods

Between 1991 and 2002, PH was performed in 131 cases of HCC (Child‐Pugh A–B, technically resectable tumor without metastases). To ascertain patient survival after PH, we compared this series with a group of 40 HCC patients (G1–G2 HCC with no gross vascular invasion or metastasis) enlisted for liver transplantation during the same period.

Results

The 1‐, 3‐, and 5‐year intention‐to‐treat survival rates were 75%, 52%, and 31% for resection and 89%, 71%, and 63% for transplantation. Two tumor‐related variables (gross vascular invasion and histological grade) and three liver function parameters (Child‐Pugh score, bilirubin, Okuda stage) proved to be independent predictors of survival after resection, whereas nodule size and number, and Milan criteria did not. The 5‐year survival of the best candidates for resection (favorable tumor biology with very well preserved liver function, n = 52) was 58%. On a descriptive basis alone, this result did not differ significantly from the outcome in LT patients. PH patients with a poorly differentiated tumor and/or gross vascular invasion (n = 28) had the worst outcome, irrespective of their liver function parameters.

Conclusions

For technically resectable tumors without aggressive features (G3 or macroscopic vascular invasion), PH can only compete with LT, in terms of long‐term survival, when patients with a well‐preserved liver function are selected. J. Surg. Oncol. 2007;95:213–220. © 2006 Wiley‐Liss, Inc.
Regioselective separation of isomeric triacylglycerols by reversed‐phase high‐performance liquid chromatography: Stationary phase and mobile phase effects
Authors: Momchilova Svetlana , Itabashi Yutaka , Nikolova‐Damyanova Boryana , Kuksis Arnis
Published: October 2006

Complete regioselective separation of five pairs of isomeric dipalmitoyl polyalkenoyl glycerols with two to six double bonds in the unsaturated acyl residues has been achieved by RP‐HPLC on a single ODS column. Four ODS columns with stationary phases containing different percentages of free silanol groups have been tested. Binary mobile phases of ACN admixed with dichloromethane, tetrahydrofuran, 1‐propanol, 2‐propanol, ethanol, or acetone have been examined. The choice of modifier depended on the nature of the stationary phase. The more polar solvents were better suited for stationary phases with higher percentage of free silanol groups. Isomeric species were eluted according to chain length, number of double bonds, and the position of the unsaturated acyl chain in the glycerol molecule. Retention increases in the order 20:5 < 22:6 < 18:3 < 20:4 << 18:2. Within each isomeric pair, the species with unsaturated acyl chain occupying either the sn‐1‐ or the 3‐position were retained preferentially. Complete simultaneous regioselective separation of 10 isomeric triacylglycerols in a single isocratic run on a single ODS column was demonstrated.
In vitro and in vivo tissue repair with laser‐activated chitosan adhesive
Authors: Lauto A. , Stoodley M. , Marcel H. , Avolio A. , Sarris M. , McKenzie G. , Sampson D.D. , Foster L.J.R.
Published: October 2006

Background and Objectives

Sutures are currently the gold standard for wound closure but they are still unable to seal tissue and may induce scarring or inflammation. Biocompatible glues, based on polysaccharides such as chitosan, are a possible alternative to conventional wound closure. In this study, the adhesion of laser‐activated chitosan films is investigated in vitro and in vivo. In particular we examine the effect of varying the laser power, as well as adding a natural cross‐linker (genipin) to the adhesive composition.

Study Design/Materials and Methods

Flexible and insoluble strips of chitosan films (surface area ∼34 mm2, thickness ∼20 µm) were bonded to sheep intestine using several laser powers (0, 80, 120, and 160 mW) at 808‐nm wavelength. The strength of repaired tissue was tested by a calibrated tensiometer to select the best power. A natural cross‐linker (genipin) was also added to the film and the tissue repair strength compared with the strength of plain films. The adhesive was also bonded in vivo to the sciatic nerve of rats and the thermal damage induced by the laser assessed 4 days post‐operatively.

Results

Chitosan adhesives successfully repaired intestine tissue, attaining a maximum repair strength of 14.7±4.3 kPa (n = 30) at the laser power of 120 mW. The chitosan‐genipin films achieved lower repair strength (9.1±2.9 kPa). The laser caused partial demyelination of axons at the site of operation, but the myelinated axons retained a normal morphology proximally and distally.

Conclusions

The chitosan adhesive effectively bonded to tissue causing only localized thermal damage in vivo, when the appropriate laser parameters were selected. Lasers Surg. Med. © 2006 Wiley‐Liss, Inc.
A prospective study of admissions for febrile neutropenia in secondary paediatric units in South East England
Authors: Duncan C. , Chisholm J.C. , Freeman S. , Riley U. , Sharland M. , Pritchard‐Jones K.
Published: October 2006

Background

The Paediatric Oncology Centres (POCs) treating childhood cancer in South East England produce unified supportive care guidelines for use in the secondary pediatric (shared care) units. This study evaluated the adherence to current guidelines for febrile neutropenia (FN) and documented outcome in terms of bacterial isolates, antibiotic resistance patterns, length of hospital stay, and mortality.

Procedure

Prospective study of pediatric FN admissions between July 2001 and December 2002.

Results

Data were received on 433 eligible FN episodes in 212 patients. The recommended empirical antibiotics (piptazobactam + gentamicin) were used in 354 (82%) admissions. Blood cultures were positive in 129 episodes (30%). Gram‐positive organisms predominated (120/149 organisms isolated) and the majority were coagulase‐negative Staphylococci (95/120). There were 27 Gram‐negative isolates and 1 fungal isolate. No Gram‐negative isolate was resistant to both first‐line antibiotics. Only one death was recorded in the study group. The median length of hospital stay was 5 days.

Conclusions

We obtained data on a large number of shared care episodes of FN. The antibiotic guidelines were followed in most episodes. Bacteremia was common, but little resistance to first‐line antibiotics was documented among Gram‐negative isolates, confirming the safety of the strategy in our population. Pediatr Blood Cancer 2007;49:678–681. © 2006 Wiley‐Liss, Inc.