bluuebunny/crossref_metadata_2025 huggingface dataset:
CK20 expression, CDX2 expression, K‐ras mutation, and goblet cell morphology in a subset of lung adenocarcinomas
Authors: Yatabe Yasushi , Koga Takaomi , Mitsudomi Tetsuya , Takahashi Takashi
Published: May 2004

There are data in the literature that suggest a close relationship between the expression of CK20 and CDX2, K‐ras mutations, and goblet cell morphology. The present study has examined these factors in a cohort of 264 non‐small cell lung cancers. Thirteen of 212 adenocarcinomas expressed CK20; 29 expressed CDX2; K‐ras mutation was identified in 28; and goblet cell features were present in 19. These four factors correlated with each other in a complex way and therefore a logistic regression model was constructed. Significant correlations were found between CK20 and CDX2 expression, and between K‐ras mutation and goblet cell morphology, and there was a marginal correlation between CDX2 immunoreactivity and goblet cell morphology. These four features have also been commonly detected in colorectal, pancreato‐biliary, and ovarian mucinous carcinomas, suggesting that these adenocarcinomas may be prototypical, independent of the organ of origin. Furthermore, as high and uniform expression of CDX2 was characteristic of metastatic colorectal cancer, weak and/or focal CDX2 expression should alert surgical pathologists to the possibility of primary lung adenocarcinoma, especially in the presence of goblet cell morphology. However, some lung adenocarcinomas may express CDX2 strongly: in this case, CK20 also tends to be positive. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Up‐regulation of MDA‐BF‐1, a secreted isoform of ErbB3, in metastatic prostate cancer cells and activated osteoblasts in bone marrow
Authors: Vakar‐Lopez Funda , Cheng Chien‐Jui , Kim Jeri , Shi Gary G , Troncoso Patricia , Tu Shi‐Ming , Yu‐Lee Li‐yuan , Lin Sue‐Hwa
Published: May 2004

Prostate cancer (PCa) has a propensity to metastasize to bone. The identification of molecules that mediate the biological interactions between PCa cells and the bone environment is crucial to the understanding of PCa bone metastasis. The present study has used protein purification to identify bone metastasis‐related factors present in bone marrow aspirates from PCa patients with bone metastasis. MDA‐BF‐1 was the first bone metastasis factor to be identified and is a secreted isoform of the ErbB3 growth factor receptor. To determine which cell types in PCa bone metastases express MDA‐BF‐1, MDA‐BF‐1 expression was studied in both primary and metastatic PCa cells, using an antibody to the extracellular domain (Ab10) and another to the cytoplasmic domain (RTJ.2) of ErbB3 to distinguish MDA‐BF‐1 from p180‐ErbB3. It was found that epithelial cells in primary PCa did not express MDA‐BF‐1. In contrast, epithelial cells in 41 of 45 PCa metastases (18 of 19 lymph node metastases and 23 of 26 bone metastases), and activated osteoblasts in bone metastases, expressed MDA‐BF‐1. In addition, newly formed bone matrices adjacent to activated osteoblasts were also immunopositive for MDA‐BF‐1, suggesting that activated osteoblasts secrete MDA‐BF‐1. These observations indicate that MDA‐BF‐1 is up‐regulated in metastatic PCa and raise the interesting possibility that MDA‐BF‐1 may play a role in the metastasis and progression of PCa, particularly in bone. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Expression of the Epstein–Barr virus (EBV)‐encoded latent membrane protein 2A (LMP2A) in EBV‐associated nasopharyngeal carcinoma
Authors: Heussinger Nicole , Büttner Maike , Ott German , Brachtel Elena , Pilch Ben Z , Kremmer Elisabeth , Niedobitek Gerald
Published: May 2004

The Epstein–Barr virus (EBV) is associated with virtually all cases of undifferentiated nasopharyngeal carcinoma (NPC) and has been classified as a group I carcinogen. In addition to its potential role in the pathogenesis of NPC, EBV also provides a possible target for immunotherapy of NPC, since a limited number of viral genes are expressed in the neoplastic cells. The EBV‐encoded latent membrane protein 2A (LMP2A) is considered a promising target since it provides epitopes recognized by EBV‐specific T‐cells. Using immunohistochemistry, the present study shows that LMP2A is expressed at the protein level in the neoplastic cells of 16 of 35 (45.7%) NPC biopsies. This finding provides further evidence suggesting that NPC tumour cells may be susceptible to lysis by cytotoxic T‐cells directed against LMP2A and should encourage efforts to develop immunotherapeutic approaches for the treatment of NPC. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis
Authors: Hamming I , Timens W , Bulthuis MLC , Lely AT , Navis GJ , van Goor H
Published: May 2004

Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS‐CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin‐converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS‐CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS‐CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Haemangiomas are formed by cells expressing high levels of αvβ3 integrin and lacking acetylated LDL uptake
Authors: Aurrand‐Lions Michel , Johnson‐Leger Caroline , Pepper Michael S , Imhof Beat A
Published: May 2004

Haemangiomas are benign tumours occurring in up to 12% of Caucasians, particularly in infancy and childhood. In the present study, two variant cell lines were isolated from murine endothelioma cells. One variant, named t.End.1Vhigh, represented 16.9% of the parental cell population and was selected by virtue of high expression levels of integrin αvβ3 and reduced capacity to endocytose acetylated low‐density lipoproteins (Ac‐LDLs). A second variant, named t.End.1Vlow, represented 38.8% of the parental endothelioma cell line, expressed low levels of αvβ3 integrin, and was able to endocytose Ac‐LDL. These phenotypic modifications were stable and correlated with specific morphological and functional properties of the two variant cell lines. While the t.End.1Vhigh cells induced the formation of large haemangiomas when injected subcutaneously into mice, the t.End.1Vlow cells formed haemangiocytomas. When compared with t.End.1Vlow cells, the t.End.1Vhigh cells showed increased migratory capacity, lacked an inflammatory response, and formed cord‐like structures in fibrin gels. In contrast, the t.End.1Vlow cells organized into cysts with a lumen in fibrin gels. They rarely formed blood‐filled haemangiomas in vivo and recruited host smooth muscle cells, a phenomenon typical for vessel wall maturation of resting cells. These data suggest that Ac‐LDL uptake and the level of αvβ3 integrin expression are linked to the ability of endothelial cells to form large haemangiomas in vivo. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Basic fibroblast growth factor promotes apoptosis and suppresses granulation tissue formation in acute incisional wounds
Authors: Akasaka Yoshikiyo , Ono Ichiro , Yamashita Toshiharu , Jimbow Kowichi , Ishii Toshiharu
Published: May 2004

Cytokines are thought to play an important role in cellular loss and apoptosis during the repair of granulation tissue. In order to investigate the role of apoptosis following the administration of basic fibroblast growth factor (bFGF) to a wound, the present study examined the relationship between the degree of granulation tissue formation and the level of apoptosis in rat skin incisional wounds, following treatment with an intradermal injection of bFGF (0.1 µg and 1 µg per cm of wound). Histological assessment of the width of the wound tissue showed that the degree of granulation tissue in the 1 µg‐bFGF‐treated group had increased by day 7, but then subsequently diminished by days 14 and 28. The TUNEL index increased rapidly from day 1, peaking on day 7, with the index being higher in the 1 µg‐bFGF‐treated group on days 4, 7, and 14, when compared with a control group. In parallel with a marked increase in the TUNEL index over the first 14 days, the number of cells positive for vimentin and CD3 in the 1 µg‐bFGF‐treated wounds had decreased by day 14. The number of PCNA‐positive cells, an indicator of cell proliferation, peaked on day 4 in the bFGF‐treated wounds and then declined rapidly. On the basis of these results, it is suggested that the suppression of granulation tissue formation in bFGF‐treated wounds is mainly due to an early and persistent increase in apoptosis in the granulation tissue cells. The expression of both transforming growth factor (TGF)‐β1 and bFGF was also elevated in the bFGF‐treated wounds on days 4 and 7, suggesting that fibroblast apoptosis was induced by bFGF treatment. Unexpectedly, on day 28, the wound breaking strength was not reduced in the bFGF‐treated wounds. These results indicate that apoptosis regulation following bFGF administration to an incisional wound may lead effectively to granulation tissue formation and promote a scar‐less repair process. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Matrix proteoglycans and remodelling of interstitial lung tissue in lymphangioleiomyomatosis
Authors: Merrilees Mervyn J , Hankin Elyshia J , Black Judith L , Beaumont Brent
Published: May 2004

The interstitial lung disease lymphangioleiomyomatosis (LAM) is characterized by diffuse proliferation of smooth muscle cells (SMCs), which in many patients show TSC2 (tuberin) gene mutations, in addition to thickening of interstitial tissues, loss of alveoli, and the development of cystic spaces. While SMC proliferation is the defining feature of LAM, a significant proportion of LAM lung tissue consists of expanded interstitial connective tissue that is negative for smooth muscle actin and TSC2 mutations. The importance of this actin‐negative interstitial tissue to the pathophysiology of LAM is not clear. The present study has determined the contribution of this interstitial tissue to LAM lung volume by morphometric analysis and has examined its cell and matrix proteoglycan composition by immunohistochemistry. Lung tissue from nine LAM patients and four control subjects was examined. LAM lung contained twice as much interstitial tissue as control lung (27% versus 13% of total lung volume), with SMCs accounting for less than 25% of the interstitial volume. Areas of interstitial tissue stained strongly for the matrix proteoglycans versican and biglycan. Decorin was prominent in association with collagen bundles. SMCs did not stain, or stained lightly, for proteoglycans. Versican and biglycan deposits were closely associated with actin‐negative interstitial fibroblasts identified by prolyl 4‐hydroxylase immuno‐staining. Comparatively normal alveolar walls in LAM lung also stained strongly for versican and had a reduced elastin content. Thickened interstitial regions contained significant amounts of elastin (∼13% of interstitial volume) but with fibres in disorganized patterns. Elastic fibres were absent from areas that stained strongly for versican and biglycan. These areas also showed weak staining for elastin binding protein (EBP), consistent with proteoglycan‐induced shedding of EBP and inhibition of elastic fibre formation. These findings point to a significant contribution from matrix proteoglycans to the expanded and remodelled interstitial lung tissue of LAM patients. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Pathophysiologie venöser Thromboembolien: Hämostase — Ein fein regulierter Schutzmechanismus!
Authors: Riess Hanno
Published: May 2004

Das zunehmende Verständnis der Pathophysiologie thromboembolischer Erkrankungen mit ihrer unterschiedlichen Gewichtung der zugrundeliegenden verschiedenen Störungen begründet die dann auf klinischen Studienergebnissen beruhenden differenten Therapieempfehlungen für arterielle, kardiale und venöse Thromboembolien. Die Aufklärung vielfältiger Störungen im Bereich plasmatischer Hämostasekomponenten insbesondere bei venösen thromboembolischen Erkrankungen erlaubt nun die relative Risikoquantifizierung der wesentlichen hereditären und erworbenen Thrombophiliefaktoren und ihrer Interaktionen. Diese Kenntnis ist nicht nur Voraussetzung für die sachgerechte Therapie mit den verschiedenen Antikoagulanzien, sondern sie schafft auch die Voraussetzung für eine zunehmend differenzierte, optimierte und evidenzbasierte Patientenführung.
Vom Naturstoff zum selektiven Faktor‐Xa‐Inhibitor: Paradigmenwechsel in der Antikoagulation
Authors: Alban Susanne
Published: May 2004

Die Einführung der NMH Mitte der 80er Jahre brachte einen großen Fortschritt gegenüber UFH. Als polydisperse Produkte tierischen Ursprungs und auch hinsichtlich ihrer Wirksamkeit und Unbedenklichkeit gelten jedoch auch sie nicht als ideale Antikoagulanzien. Mit den Methoden des Rationalen Drug Design werden heute verschiedene Strategien verfolgt. Mit dem synthetisch hergestellten, strukturell definierten Oligosaccharid Oligosaccharid Fondaparinux steht nun der erste selektiv wirkende FXa‐Inhibitor zur Verfügung. Angesichts etlicher weiterer Kandidaten in der Entwicklung kündigt sich ein Paradigmenwechsel im Bereich der Antikoagulanzien an und man wird künftig nicht mehr auf Produkte tierischen Ursprungs angewiesen sein.
Rationales Design von Thrombinhemmstoffen: Von Fibrinogen und Hirudin zu synthetischen Antikoagulanzien
Authors: Steinmetzer Torsten , Stürzebecher Jörg
Published: May 2004

Thrombin ist eines der am intensivsten bearbeiteten Targets in der Wirkstoffentwicklung der vergangenen drei Jahrzehnte. Das Ziel, mit einem selektiven und oral wirksamen Thrombinhemmstoff das ideale Antikoagulans zu entwickeln, ist bisher noch nicht vollständig gelungen. Keiner der in den letzten Jahren zugelassenen direkten Thrombininhibitoren (rekombinant hergestellte Hirudine, Bivalirudin und Argatroban) ist oral applizierbar und für die Langzeitprophylaxe thromboembolischer Erkrankungen geeignet. Darüber hinaus gibt es mittlerweile vielversprechende Entwicklungen, wie beispielsweise die Inhibitoren 15, 21, 22 und 27, die direkt oral applizierbar sind und nicht erst wie im Falle des Ximelagatrans in ein Prodrug überführt werden müssen. Jedoch muss deren antithrombotische Wirksamkeit in klinischen Studien erst noch nachgewiesen werden.
Neue Daten aus klinischen Studien: Niedermolekulare Heparine, Fondaparinux und Melagatran
Authors: Bauersachs Rupert M.
Published: May 2004

Ximelagatran (in der perioperativen Phase in Kombination mit der parenteralen applizierbaren Form Melagatran) hat sich in der Hochrisikoprophylaxe — je nach Anwendungsregime — als sehr sichere bzw. sehr wirksame antithrombotische Substanz bewiesen. In der Therapie der VTE kann Ximelagatran sowohl für die Initial‐ und Langzeittherapie eingesetzt werden, ohne dass ein Substanzwechsel oder ein Gerinnungsmonitoring erforderlich ist. Durch die bessere Steuerbarkeit und das niedrige Blutungsrisiko ergibt sich die Möglichkeit, die Sekundärprophylaxe über einen längeren Zeitraum auszudehnen. Diese Vorteile haben sich auch für die Indikation des chronischen Vorhofflimmern bewährt.
Auswahlkriterien zu Antikoagulanzien: Klinische und pharmakoökonomische Aspekte
Authors: Lipp Hans‐Peter
Published: May 2004

Wie bei vielen anderen Arzneimittelgruppen stellt sich auch bei den Antikoagulanzien immer wieder die Frage, welche Auswahlkriterien bei der Entscheidung für ein bestimmtes Präparat unter mehreren verfügbaren zu berücksichtigen sind. Unter mediko‐legalen Aspekten ist es wichtig, den nationalen und internationalen Zulassungsstatus des Präparats zu kennen, da eine Anwendung im off‐label‐use grundsätzlich eine weitergehende Beratungspflicht gegenüber dem Patienten erforderlich werden lässt. Bei speziellen Indikationen, wie z.B. Anwendung in der Schwangerschaft, ist es ratsam, auf Präparate zurückzugreifen, bei denen möglichst viele dokumentierte Fälle vorliegen. Ergeben sich diesbezüglich keine Unterschiede, so entscheiden häufig Praktikabilitätsgründe (z.B. Möglichkeit der Einmalgabe pro Tag, Möglichkeit der Fixdosierung, Verfügbarkeit von Multidose, Pen oder Fertigspritzen) vor Ort die Auswahl. Während in den letzten 15 Jahren die niedermolekularen Heparine (NMH) aufgrund der Fülle der Studienergebnisse das unfraktionierte Heparin (UFH) zunehmend aus verschiedenen Indikationen verdrängten, ist bereits jetzt absehbar, dass mit dem selektiven Faktor‐Xa‐Inhibitor Fondaparinux und dem oralen direkten Thrombininhibitor (ODTI) Ximelagatran neue Diskussionen in Gang kommen, wie z.B. die ausschließliche Fixdosierung in der Thromboseprophylaxe und ‐therapie, der Verzicht auf Thrombozytenbestimmungen, die erleichterte Anwendung in Verbindung mit einer rückenmarksnahen Punktion oder Anbringen eines Katheters und — im Fall des ODTI — die Möglichkeit der oralen Thromboseprophylaxe ohne das Risiko von Cytochrom‐P450‐abhängigen Arzneimittelinteraktionen oder die Notwendigkeit eines INR—Monitorings [25]. Die Arbeitsgruppe um R. Janknegt hat in den 90er Jahren mit der SOJA‐Methode ein System vorgeschlagen, das über ein definiertes Punktesystem eine ständig aktualisierbare, transparente und objektive Beurteilung von Arzneimitteln unter Berücksichtigung verschiedener, klinisch relevanter Parameter (Tab. 1) erlaubt [1]. Ein entsprechendes System ist derzeit in Deutschland nicht etabliert, wäre aber aus klinischpharmakologischen, pharmakoökonomischen und medikolegalen Aspekten wünschenswert, insbesondere auch unter dem Aspekt, dass neue Entwicklungen zeitnah diesem Rating unterzogen werden könnten.
Anwendung der Vitamin‐K‐Antagonisten: Aus der Praxis
Authors: Heidinger Kathrin
Published: May 2004

Orale Antikoagulanzien vom Cumarintyp haben seit über 50 Jahren einen großen Stellenwert in der Therapie und Prävention von venösen und arteriellen Thromboembolien. Aufgrund des engen therapeutischen Bereichs ist eine regelmäßige und engmaschige Überwachung der antikoagulatorischen Aktivität durch Messung der Thromboplastinzeit notwendig, um thromboembolische oder hämorrhagische Komplikationen zu vermeiden. Fachgesellschaften empfehlen die Verwendung des INR‐Wertes, als objektives Maß für die Intensität der Antikoagulation. Immer mehr Patienten kontrollieren im Rahmen des Selbstmanagement der oralen Antikoagulation selbstständig die Gerinnungswerte. Leitlinien formulieren Anforderungen an Patient, Gerät und Schulungen. Das Selbstmanagement ermöglicht es dem Patienten, selbstständig und unabhängig seine Gerinnungswerte zu messen — zu Hause oder unterwegs. Diese laborunabhängige Kontrolle steigert die Lebensqualität des Patienten und erhöht die Sicherheit der Therapie mit Vitamin‐K‐Antagonisten.
HIV‐Therapie: und noch ein neuer Therapieansatz — PA‐457
Authors: Holzgrabe Ulrike
Published: May 2004

Zur Behandlung HIV‐infizierter Patienten werden heute fast ausschließlich nukleosidische und nicht‐nukleosidische Reverse‐Transkriptase‐ Hemmstoffe sowie Inhibitoren der HIV‐Protease eingesetzt. Da aber bereits 40—45 % der HIV‐Infizierten resistente Viren in sich tragen und die Zahl der Resistenzen wächst [1], wird die Suche nach neuen Virustatika mit neuem Wirkmechanismus immer wichtiger.
Missing Link im Vitamin‐K‐Metabolismus entdeckt
Authors: Dingermann Theo , Zündorf Ilse
Published: May 2004

Die Nature‐Ausgabe 427 (5), Februar 2004, widmete ihre Titelseite einer Entdeckung aus dem Vitamin‐K‐Metabolismus. Zwei Arbeitsgruppen war es unabhängig voneinander gelungen, das Gen für das Warfarin‐Zielprotein zu identifizieren.
Wichtige Maßnahme bei Tumorpatienten
Authors: Kakkar Ajay K.
Published: May 2004

In der Thromboseprophylaxe bei Tumorpatienten hat Dalteparin längst einen festen Platz. Es könnte aber auch noch einen Zusatznutzen geben, wie jüngste Daten zeigen. So lassen die Ergebnisse der FAMOUS‐Studie hoffen, dass Dalteparin positiven Einfluss auf die Überlebenszeit von Tumorpatienten hat. Grund genug, sich für Dalteparin zu entscheiden? Im Rahmen der 48. Jahrestagung der Gesellschaft für Thrombose‐ und Hämostaseforschung e.V., die vom 25. — 28. Februar 2004 in Hamburg stattfand, erläuterte Dr. Ajay Kakkar vom Thrombosis Research Institute in London, warum der Einsatz von Dalteparin bei Tumorpatienten besondere Vorteile hat.
Protease‐Inhibitor gegen Hepatitis C
Authors: Holzgrabe Ulrike
Published: May 2004

Mehr als 170 Millionen Menschen sind weltweit mit dem Hepatitis‐C‐Virus (HCV) infiziert und leiden an einer chronischen Lebererkrankung, die zum Tod führen kann.
Synthesis and characterization of alt‐bipyridinylene‐phenylene copolymers containing ruthenium(II) complexes
Authors: Pautzsch Thomas , Klemm Elisabeth
Published: May 2004

Poly{bis(4,4′‐tert‐butyl‐2,2′‐bipyridine)–(2,2′‐bipyridine‐5,5′‐diyl‐[1,4‐phenylene])–ruthenium(II)bishexafluorophosphate} (3a), poly{bis(4,4′‐tert‐butyl‐2,2′‐bipyridine)–(2,2′‐bipyridine‐4,4′‐diyl‐[1,4‐phenylene])–ruthenium(II)bishexafluorophosphate} (3b), and poly{bis(2,2′‐bipyridine)–(2,2′‐bipyridine‐5,5′‐diyl‐[1,4‐phenylene])–ruthenium(II)bishexafluorophosphate} (3c) were synthesized by the Suzuki coupling reaction. The alternating structure of the copolymers was confirmed by 1H and 13C NMR and elemental analysis. The polymers showed, by ultraviolet–visible, the π–π* absorption of the polymer backbone (320–380 nm) and at a lower energy attributed to the d–π* metal‐to‐ligand charge‐transfer absorption (450 nm for linear 3a and 480 nm for angular 3b). The polymers were characterized by a monomodal molecular weight distribution. The degree of polymerization was approximately 8 for polymer 3b and 28 for polymer 3d. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2911–2919, 2004
Synthesis of polybutadiene‐graft‐poly(dimethylsiloxane) and polyethylene‐graft‐poly(dimethylsiloxane) copolymers with hydrosilylation reactions
Authors: Ciolino A. E. , Pieroni O. I. , Vuano B. M. , Villar M. A. , Vallés E. M.
Published: May 2004

We report preliminary results for the synthesis of polyethylene‐graft‐poly(dimethylsiloxane) copolymers obtained by catalytic hydrogenation of polybutadiene‐graft‐poly(dimethylsiloxane) copolymers (PB‐g‐PDMS). These last copolymers were synthesized by hydrosilylation reactions between commercial polybutadiene and ω‐silane poly(dimethylsiloxane). The reaction was carried in solution catalyzed by cis‐dichloro bis(diethylsufide) platinum(II) salt. The PB‐g‐PDMS copolymers were analyzed by 1H and 13C NMR spectroscopies, and the relative weight percentages of the grafted poly(dimethylsiloxane) macromonomer were determined from the integrated peak areas of the spectra. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2920–2930, 2004
New class of cationic ring‐opening polymerizations of 2,2‐diphenyl‐1,3‐oxathiolanes accompanying quantitative elimination of benzophenone
Authors: Haba Osamu , Sasaki Nobuaki , Sasaki Yusuke , Endo Takeshi
Published: May 2004

Cationic polymerizations of three 2‐substituted 1,3‐oxathiolanes, 2,2‐diphenyl‐1,3‐oxathiolane (1a), 5‐methyl‐2,2‐diphenyl‐1,3‐oxathiolane (1b), and 4‐methyl‐2,2‐diphenyl‐1,3‐oxathiolane (1c), were carried out with boron trifluoride etherate (BF3 · OEt2) in dichloromethane at 30 °C to obtain poly(alkylene sulfide)s accompanying the elimination of benzophenone. In the cationic polymerization of 1b and 1c, the consumption of the monomers and formation of benzophenone proceeded simultaneously. The obtained poly(propylene sulfide)s from 1b and 1c contain 41% head–head units, which is in good agreement with that of the polymer from methylthiirane with BF3 · OEt2. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2943–2949, 2004
Atom‐transfer radical grafting polymerization of 2‐methacryloyloxyethyl phosphorylcholine from silicon wafer surfaces
Authors: Feng Wei , Brash John , Zhu Shiping
Published: May 2004

2‐Methacryloyloxyethyl phosphorylcholine (MPC), a biomimetic monomer, was grafted from silicon wafer surfaces at room temperature by combining self‐assembly of initiator and surface‐initiated atom transfer radical polymerization. Two methods were used to control the grafting process. One was to add free initiator to the reaction system; the other was to add excess deactivator. The grafting densities up to 0.3 chains/nm2 were obtained. The surface thickness increased linearly with MPC conversion. The thickness depended on catalyst and monomer concentrations, as well as activator/deactivator ratio. Poly(MPC) layers of >100 nm thick were obtained by optimizing the polymerization conditions. A second block of either poly(MPC) or poly[2‐(dimethylamino)ethyl methacrylate] was also grown from the grafted poly(MPC), demonstrating the system livingness. X‐ray photoelectron spectroscopy was used to examine the surface chemical compositions showed good agreement with the theoretical values. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2931–2942, 2004
Vibration‐induced change of crystal structure in isotactic polypropylene and its improved mechanical properties
Authors: Zhang Jie , Shen Kaizhi , Na Shun , Fu Qiang
Published: May 2004

In order to understand the formation of different crystal structures and improve the mechanical properties of isotactic polypropylene (iPP), melt vibration technology, which generally includes shear vibration and hydrostatic pressure vibration, was used to induce the change of crystal structure of iPP. iPP forms α crystal structure in traditional injection molding. Through melt vibration, crystal orientated and its size became smaller, and a change of crystal structure of iPP from α form to β form and γ form was achieved. Therefore, the mechanical properties of iPP were improved. At high melting temperature (230 °C), only β form can be induced. At low melting temperature (190 °C), either β form or γ form can be induced, depending on the combination of frequency and vibration pressure. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 2385–2390, 2004
Characterization of epoxy resin (SU‐8) film using thickness‐shear mode (TSM) resonator under various conditions
Authors: Hossenlopp Jeanne , Jiang Lizhong , Cernosek Richard , Josse Fabien
Published: May 2004

Characterization of an epoxy resin film, commonly known as SU‐8, is presented using thickness shear mode (TSM) quartz resonator. The impedance‐admittance characteristics of the equivalent circuit models of the unperturbed and coated resonators are analyzed to extract the storage modulus and loss modulus (G′ andG″). Those parameters are needed to establish SU‐8 film as an effective wave‐guiding layer in the implementation of guided shear‐horizontal surface acoustic wave (SH‐SAW) sensor platforms. Both cured and uncured polymer films are studied at the fundamental and third harmonic frequencies of the TSM resonators. The storage modulus (G′) and loss modulus (G″) of the SU‐8 film approach constant values of 1.66 × 1010dyne/cm2and 6.0 × 108dyne/cm2, respectively, for relatively thicker films (>20 μm) at a relatively low frequency of 9 MHz. The most accurate values for the extracted shear moduliG(G=G′+jG″) are obtained at high thickness where the viscoelastic contribution to the TSM response is substantial. The effect of temperature on the storage and loss moduli is determined for the range of −75 to 40 °C. It is found that the polymer approaches a totally glassy state below −60 °C. Exposure to water appears to follow Fickian diffusion behavior at short times and this exposure also results in changes to bothG′ andG″. However, stability is rapidly reached with exposure to water, indicating relatively lower water absorption, consistent with the extracted diffusion coefficient. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 2373–2384, 2004
Job stress and job satisfaction of cancer care workers
Authors: Grunfeld Eva , Zitzelsberger Louise , Coristine Marjorie , Whelan Timothy J. , Aspelund Faye , Evans William K.
Published: May 2004

Background: There is an increasing demand for oncology care as a result of a number of trends. In combination with ongoing changes to the health‐care system, these trends have an impact on the workplace environment of systemic therapy personnel.

Methods: A postal survey was sent to major providers of tertiary systemic therapy services in Ontario. Included in the survey were measures of job satisfaction and stress. In order to capture in‐depth data related to survey themes, focus groups were held with personnel at six major cancer treatment facilities. Content analysis identified major themes.

Results: Analysis of focus group and survey studies showed that the greatest source of job satisfaction stemmed from patient care and contact. Manifestations of increasing workload emerged as major sources of job stress. Personnel were concerned as to what they saw as negative consequences of heavy workload—a perceived decrease in the quality of patient care and staff morale.

Conclusions: The findings of this research suggest that the current workplace environment is having a negative impact on the well‐being of systemic therapy staff, and may have consequences in terms of quality of patient care. Personnel identified system changes that they felt would help alleviate workload and resulting stress. Copyright © 2004 John Wiley & Sons, Ltd.
The structural genomics experimental pipeline: Insights from global target lists
Authors: O'Toole Nicholas , Grabowski Marek , Otwinowski Zbyszek , Minor Wladek , Cygler Miroslaw
Published: May 2004

Structural genomics (SG) initiatives are currently attempting to achieve the high‐throughput determination of protein structures on a genome‐wide scale. Here we analyze the SG target data that have been publicly released over a period of 16 months to assess the potential of the SG initiatives. We use statistical techniques most commonly applied in epidemiology to describe the dynamics of targets through the experimental SG pipeline. There is no clear bottleneck among the key stages of cloning, expression, purification and crystallization. An SG target will progress through each of these steps with a probability of approximately 45%. Around 80% of targets with diffraction data will yield a crystal structure, and 20% of targets with HSQC spectra will yield an NMR structure. We also find the overlaps among SG targets: 61% of SG protein sequences share at least 30% sequence identity with one or more other SG targets. There is no significant difference in average structure quality among SG structures and other structures in the PDB determined by “traditional” methods, but on average SG structures are deposited to the PDB twice as quickly after X‐ray data collection. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Prediction of transmembrane regions of β‐barrel proteins using ANN‐ and SVM‐based methods
Authors: Natt Navjyot K. , Kaur Harpreet , Raghava G. P. S.
Published: May 2004

This article describes a method developed for predicting transmembrane β‐barrel regions in membrane proteins using machine learning techniques: artificial neural network (ANN) and support vector machine (SVM). The ANN used in this study is a feed‐forward neural network with a standard back‐propagation training algorithm. The accuracy of the ANN‐based method improved significantly, from 70.4% to 80.5%, when evolutionary information was added to a single sequence as a multiple sequence alignment obtained from PSI‐BLAST. We have also developed an SVM‐based method using a primary sequence as input and achieved an accuracy of 77.4%. The SVM model was modified by adding 36 physicochemical parameters to the amino acid sequence information. Finally, ANN‐ and SVM‐based methods were combined to utilize the full potential of both techniques. The accuracy and Matthews correlation coefficient (MCC) value of SVM, ANN, and combined method are 78.5%, 80.5%, and 81.8%, and 0.55, 0.63, and 0.64, respectively. These methods were trained and tested on a nonredundant data set of 16 proteins, and performance was evaluated using “leave one out cross‐validation” (LOOCV). Based on this study, we have developed a Web server, TBBPred, for predicting transmembrane β‐barrel regions in proteins (available at http://www.imtech.res.in/raghava/tbbpred). Proteins 2004. © 2004 Wiley‐Liss, Inc.
Predictive reconstruction of the mitochondrial iron–sulfur cluster assembly metabolism: I. The role of the protein pair ferredoxin–ferredoxin reductase (Yah1–Arh1)
Authors: Alves Rui , Herrero Enrique , Sorribas Albert
Published: May 2004

Adrenodoxin reductase homologue (Arh1) and yeast adrenodoxin homologue (Yah1) are essential Saccharomyces cerevisiae mitochondrial proteins involved in heme A biosynthesis and in iron–sulfur cluster (FeSC) assembly. Although the role of Arh1 and Yah1 in heme A biosynthesis is fairly well established, their systemic role on FeSC synthesis is not well understood. Also, while it is thought that the reductase Arh1 provides electrons for the ferredoxin Yah1, two hybrid experiments do not show interaction between the two proteins. In the first part of this article, we use structural bioinformatics methods to evaluate the possibility of interaction between Arh1 and Yah1. Using protein model building and docking algorithms, we predict a complex between Arh1 and Yah1 that is similar to that of their bovine homologues (adrenodoxin reductase–adrenodoxin reductase), suggesting that Arh1 can indeed reduce Yah1. The predicted complex allows us to suggest point mutations to either molecule that could hinder Arh1–Yah1 interaction and test the role of Arh1 as the reductase for Yah1. In the second part of this article, we investigate the physiological role of Arh1–Yah1 on FeSC assembly by deriving alternative mathematical models of the process, based on published information. Comparing the dynamical behavior of each model with that observed in reported experiments emphasizes the importance of Arh1–Yah1 providing electrons for in situ FeSC repair. Only when this mode of action of either of the two proteins in FeSC synthesis is considered can previously reported results be reproduced. Proteins 2004; © 2004 Wiley‐Liss, Inc.
The structure of murine neuroglobin: Novel pathways for ligand migration and binding
Authors: Vallone Beatrice , Nienhaus Karin , Brunori Maurizio , Nienhaus G. Ulrich
Published: May 2004

Neuroglobin, a recently discovered globin predominantly expressed in neuronal tissue of vertebrates, binds small, gaseous ligands at the sixth coordination position of the heme iron. In the absence of an exogenous ligand, the distal histidine (His64) binds to the heme iron in the ferrous and ferric states. The crystal structure of murine ferric (met) neuroglobin at 1.5 Å reveals interesting features relevant to the ligand binding mechanism. Only weak selectivity is observed for the two possible heme orientations, the occupancy ratio being 70:30. Two small internal cavities are present on the heme distal side, which enable the His64(E7) side chain to move out of the way upon exogenous ligand binding. Moreover, a third, huge cavity (volume approximately 290 Å3) connecting both sides of the heme, is open towards the exterior and provides a potential passageway for ligands. The CD and EF corners exhibit substantial flexibility, which may assist ligands in entering the protein and accessing the active site. Based on this high‐resolution structure, further structure‐function studies can be planned to elucidate the role of neuroglobin in physiological responses to hypoxia. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Strategy for supplementing structure calculations using limited data with hydrophobic distance restraints
Authors: Alexandrescu Andrei T.
Published: May 2004

Introductory biochemistry texts often note that the fold of a protein is completely defined when the dihedral angles ϕ and ψ are known for each amino acid. This assertion was examined with torsion angle dynamics and simulated annealing (TAD/SA) calculations of protein G using only dihedral angle restraints. When all dihedral angles were restrained to within 1° of the values of the X‐ray structure, the TAD/SA structures gave a backbone root mean square deviation to the target of 4 Å. Factors that contributed to divergence from the correct solution include deviations of peptide bonds from planarity, internal conflicts resulting from the nonuniform energies of different ϕ, ψ combinations, and relaxation to extended conformations in the absence of long‐range constraints. Simulations including hydrogen‐bond restraints showed that even a few long‐range contacts constrain the fold better than a complete set of accurate dihedral restraints. A procedure is described for TAD/SA calculations using hydrogen‐bond restraints, idealized dihedral restraints for residues in regular secondary structures, and “hydrophobic distance restraints” derived from the positions of hydrophobic residues in the amino acid sequence. The hydrogen‐bond restraints are treated as inviolable, whereas violated hydrophobic restraints are removed following reduction of restraint upper bounds from 2 to 1 times the predicted radius of gyration. The strategy was tested with simulated restraints from X‐ray structures of proteins from different fold classes and NMR data for cold shock protein A that included only backbone chemical shifts and hydrogen bonds obtained from a long‐range HNCO experiment. Proteins 2004. © 2004 Wiley‐Liss, Inc.
The SHS2 module is a common structural theme in functionally diverse protein groups, like Rpb7p, FtsA, GyrI, and MTH1598/TM1083 superfamilies
Authors: Anantharaman V. , Aravind L.
Published: May 2004

Using structural comparisons, we identified a novel domain with a simple fold in the bacterial cell division ATPase FtsA, the archaeo‐eukaryotic RNA polymerase subunit Rpb7p, the GyrI superfamily, and the uncharacterized MTH1598/Tm1083‐like proteins. The fold contains a core of 3 strands, forming a curved sheet, and a single helix in a strand–helix–strand–strand (SHS2) configuration. The SHS2 domain may exist either in single or duplicate copies within the same polypeptide. The single‐copy versions of the domain in FtsA and Rbp7p are most closely related, and appear to mediate protein–protein interactions by means of strand 1, and the loop between strand 2 and strand 3 of the domain. We predict that the interactions between FtsA and its functional partners in bacterial cell division are likely to be similar to the interactions of Rbp7p in the archaeo‐eukaryotic RNA polymerase complex. The dimeric versions typified by the GyrI superfamily appear to have been adapted for small‐molecule binding. Sequence profiles searches helped us to identify several new versions of the GyrI superfamily, including a family of secreted forms that is found only in animals and the bacterial pathogen Leptospira. Through sequence–structure comparisons, we predict the positions that are likely to be important for ligand specificity in the GyrI superfamily. In the MTH1598/Tm1083‐like proteins, a SHS2 domain is inserted into the loop between strand 1 and helix 1 of another SHS2 domain. This has resulted in a structure that has convergent similarities with the Hsp33 and green fluorescent protein folds. The sequence conservation pattern and its phyletic profile suggest that it might function as an enzyme in some conserved aspect of nucleic acid metabolism. Thus, the SHS2 domain is an example of a simple module that has been adapted to perform an entire spectrum of functions ranging from protein–protein interactions to small‐molecule recognition and catalysis. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Designing proteins from the inside out
Authors: Ventura Salvador , Serrano Luis
Published: May 2004

Globular proteins are characterized by the specific and tight packing of hydrophobic side‐chains in the so‐called “hydrophobic core.” Formation of the core is key in folding, stabilization, and conformational specificity. The critical role of hydrophobic cores in maintaining the highly ordered structures present in natural proteins justifies the tremendous efforts devoted to their redesign. Both experimental and computational combinatorial‐based approaches have been reported in the last years as powerful protein design tools. These manage to explore large regions of the sequence/conformational space, allowing the search for alternative protein core arrangements displaying native‐like properties. The overall results obtained from core design projects have contributed significantly to our present knowledge of protein folding and function. In addition, core design has worked as a benchmark for the development of ambitious protein design projects that nowadays are allowing the de novo design of novel protein structures and functions. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Hydrophobic complementarity in protein–protein docking
Authors: Berchanski Alexander , Shapira Boaz , Eisenstein Miriam
Published: May 2004

Formation of hydrophobic contacts across a newly formed interface is energetically favorable. Based on this observation we developed a geometric–hydrophobic docking algorithm that estimates quantitatively the hydrophobic complementarity at protein–protein interfaces. Each molecule to be docked is represented as a grid of complex numbers, storing information regarding the shape of the molecule in the real part and information regarding the hydropathy of the surface in the imaginary part. The grid representations are correlated using fast Fourier transformations. The algorithm is used to compare the extent of hydrophobic complementarity in oligomers (represented by D2tetramers) and in hetero‐dimers of soluble proteins (complexes). We also test the implication of hydrophobic complementarity in distinguishing correct from false docking solutions. We find that hydrophobic complementarity at the interface exists in oligomers and in complexes, and in both groups the extent of such complementarity depends on the size of the interface. Thus, the non‐polar portions of large interfaces are more often juxtaposed than non‐polar portions of small interfaces. Next we find that hydrophobic complementarity helps to point out correct docking solutions. In oligomers it significantly improves the ranks of nearly correct reassembled and modeled tetramers. Combining geometric, electrostatic and hydrophobic complementarity for complexes gives excellent results, ranking a nearly correct solution < 10 for 5 of 23 tested systems, < 100 for 8 systems and < 1000 for 19 systems. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Towards a MIP‐based alignment and docking in computer‐aided drug design
Authors: Barbany Montserrat , Terán Hugo Gutiérrez‐de‐ , Sanz Ferran , Villà‐Freixa Jordi
Published: May 2004

Structural alignment of ligands in their biological conformation is a crucial step in the building of pharmacophoric models in structure‐based drug design. In addition, docking algorithms are limited in some cases by the quality of the scoring functions and the limited flexibility of the environment that the different programs allow. On the other hand, GRID molecular interaction potentials (MIPs) have been used for a long time in 3D‐QSAR studies. However, in most of these studies the alignment of the molecules is performed on the basis of geometrical or physico‐chemical criteria that differ from the MIPs used in the partial least squares statistical analysis. We have previously developed a method to use the same scoring function for the molecular alignment and for 3D‐QSAR studies. This methodology, based on the use of GRID potentials, consists in the weighted averaging of similarities of the relevant MIPs of the molecules to be aligned. Here we present a method to obtain the weights for the different GRID probes in the average based on the structural information on protein‐ligand complexes for relevant systems. The method, implemented in MIPSIM, is shown to yield good accuracy in the prediction of the alignments for two systems: a set of three inhibitors of dihydrofolate reductase and a set of fifteen non‐nucleoside HIV‐1 reverse transcriptase inhibitors (NNRTIs). The smooth GRID potentials are shown to capture the flexible character of the active site, as opposed to traditional docking scoring energy functions. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Folding thermodynamics of three β‐sheet peptides: A model study
Authors: Irbäck Anders , Sjunnesson Fredrik
Published: May 2004

We study the folding thermodynamics of a β‐hairpin and two three‐stranded β‐sheet peptides using a simplified sequence‐based all‐atom model, in which folding is driven mainly by backbone hydrogen bonding and effective hydrophobic attraction. The native populations obtained for these three sequences are in good agreement with experimental data. We also show that the apparent native population depends on which observable is studied; the hydrophobicity energy and the number of native hydrogen bonds give different results. The magnitude of this dependence matches well with the results obtained in two different experiments on the β‐hairpin. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Study of local lattice relaxation of substitutional impurities in silicon and germanium
Authors: Sasireka D. , Palaniyandi E. , Iyakutti K.
Published: May 2004

Local lattice relaxation of substitutional donors in silicon investigated using self‐consistent multiple scattering Xα (MSXα) method within the framework of the standard muffin‐tin potential approximation is extended to substitutional donors in germanium and substitutional acceptors in both silicon and germanium. Incorporating the effect of lattice relaxation surrounding the impurity makes the model suitable for both shallow and deep levels. Chemical trends of some aspects of impurity states, such as local lattice relaxation and charge transfer, of the impurities both in silicon and germanium are inferred. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2004