bluuebunny/crossref_metadata_2025 huggingface dataset:
Using Noncovalent Intra‐strand and Inter‐strand Interactions To Prescribe Helix Formation within a Metallo‐supramolecular System
Authors: Childs Laura J. , Pascu Mirela , Clarke Adam J. , Alcock Nathaniel W. , Hannon Michael J.
Published: July 2004

The effect of inter‐strand and intra‐strand interactions is explored in a metallo‐supramolecular system in which the metal–ligand coordination requirements may be satisfied by more than one different supramolecular architecture. This is achieved by introducing alkyl substituents onto the spacers of readily prepared bis(pyridylimine) ligands. The alkyl substituents induce twisting within the ligand strand and this intra‐strand effect favours formation of helical architectures. The alkyl substituents also introduce inter‐strand CH⋅⋅⋅π interactions into the system. For the smaller methyl group these are most effectively accommodated in a trinuclear circular helicate architecture. A solution mixture of dinuclear double‐helicate and trinuclear circular helicate results from which, for copper(I), the trinuclear circular helicate crystallises. The CH⋅⋅⋅π interactions endow the circular helicate with a bowl‐shaped conformation and the triangular unit aggregates into a tetrahedral ball‐shaped array. Low‐temperature NMR studies indicate that the CH⋅⋅⋅π interactions also confer a bowl‐shaped conformation on the triangle in solution. The larger ethyl groups can sustain intra‐strand CH⋅⋅⋅π interactions in the lower nuclearity double‐helical system and this is the unique architecture for that ligand system in both solution and the solid state. Crystal structures are described for both the copper(I) and silver(I) complexes. Thus we show that intra‐strand interactions may be used to induce helicity within this system, while the nuclearity of the array can be prescribed by the inter‐strand interactions.
A General and Versatile Approach to Thermally Generated N‐Heterocyclic Carbenes
Authors: Nyce Gregory W. , Csihony Szilard , Waymouth Robert M. , Hedrick James L.
Published: July 2004

The synthesis of N‐heterocyclic carbene (NHC) adducts by condensation of diamines with appropriately substituted benzaldehydes is described. This simplified approach provides the NHC adduct without first having to generate the carbene followed by its protection. These adducts undergo thermal deprotection to generate N‐heterocyclic carbene in situ. Adduct decomposition temperatures were investigated as a function of catalyst structure by using thermal analysis and spectroscopic techniques. Importantly, unlike adducts derived from chloroform, the new pentafluorobenzene‐based adducts are more readily prepared and are stable at room temperature. The utility of these adducts as organic catalyst precursors for living ring‐opening polymerization (ROP) of lactide, transesterification reactions, and the synthesis of N‐heterocyclic carbene ligated organometallic complexes is also described.
Cylindrical Micelles from the Aqueous Self‐Assembly of an Amphiphilic Poly(ethylene oxide)–b‐Poly(ferrocenylsilane) (PEO‐b‐PFS) Block Copolymer with a Metallo‐Supramolecular Linker at the Block Junction
Authors: Gohy Jean‐François , Lohmeijer Bas G. G. , Alexeev Alexander , Wang Xiao‐Song , Manners Ian , Winnik Mitchell A. , Schubert Ulrich S.
Published: July 2004

A supramolecular AB diblock copolymer has been prepared by the sequential self‐assembly of terpyridine end‐functionalized polymer blocks by using RuIII/RuIIchemistry. By this synthetic strategy a hydrophobic poly(ferrocenylsilane) (PFS) was attached to a hydrophilic poly(ethylene oxide) (PEO) block to give an amphiphilic metallo‐supramolecular diblock copolymer (PEO/PFS block ratio 6:1). This compound was used to form micelles in water that were characterized by a combination of dynamic and static light scattering, transmission electron microscopy, and atomic force microscopy. These complementary techniques showed that the copolymers investigated form rod‐like micelles in water; the micelles have a constant diameter but are rather polydisperse in length, and light scattering measurements indicate that they are flexible. Crystallization of the PFS in these micelles was observed by differential scanning calorimetry, and is thought to be the key behind the formation of rod‐like structures. The cylindrical micelles can be cleaved into smaller rods whenever the temperature of the solution is increased or they are exposed to ultrasound.
Self‐Assembled Metallocycles with Two Interactive Binding Domains
Authors: Chang Sung‐Youn , Jang Hye‐Young , Jeong Kyu‐Sung
Published: July 2004

Five metallocycles 1 a–e have been self‐assembled from S‐shaped bispyridyl ligands 2 a–e and a palladium complex, [Pd(dppp)(OTf)2] (dppp=1,3‐bis(diphenylphosphanyl)propane), and have been characterized by elemental analysis and various spectroscopic methods including 1H NMR spectroscopy and electrospray ionization (ESI) mass spectrometry. These metallocycles all are monocyclic compounds, but can fold to generate two binding domains bearing hydrogen‐bonding sites based on pyridine‐2,6‐dicarboxamide units. The binding properties of the metallocycles with N,N,N′,N′‐tetramethylterephthalamide (G) have been probed by means of ESI mass spectrometry and 1H NMR spectroscopy. The results both in the gas phase and in solution are consistent with the fact that the metallocycles accommodate two molecules of the guest G. Thus, the ESI mass spectra clearly show fragments corresponding to the 1:2 complexes in all cases. 1H NMR studies on 1 a and G support the formation of a 1:2 complex in solution; the titration curves are nicely fitted to a 1:2 binding isotherm, but not to a 1:1 binding isotherm. In addition, a Job plot also suggests a 1:2 binding mode between 1 a and G, showing maximum complexation at ∼0.33 mol fraction of the metallocycle 1 a in CDCl3. The binding constants K1 and K2 are calculated to be 1600 and 1400 M−1 (±10 %), respectively, at 25 °C in CDCl3, indicative of positively cooperative binding. This positive cooperativity was confirmed by the Hill equation, affording a Hill coefficient of n = 1.6. Owing to insufficient solubility in CDCl3, for comparison purposes the binding properties of the metallocycles 1 b–e were investigated in a more polar medium, 3 % CD3CN/CDCl3. 1H NMR titrations revealed that the metallocycles all bind two molecules of the guest G with Hill coefficients ranging from 1.4 to 1.8. This positive cooperativity may be attributed to a structural reorganization of the second binding cavity when the first guest binds to either one of the subcavities present in the metallocycles.
A New Phototransformation of Methoxycarbonyl‐Substituted (E,Z,E)‐1,3,5‐Hexatrienes: Easy Access to Ring‐Annelated 8‐Oxabicyclo[3.2.1]octa‐2,6‐diene Derivatives
Authors: von Essen Regina , von Zezschwitz Paultheo , Vidović Denis , de Meijere Armin
Published: July 2004

On attempting photochemically induced electrocyclizations of the previously reported 1,6‐bismethoxycarbonyl‐ or 1,6‐bistrimethylsilyl‐substituted ring‐attached (E,Z,E)‐1,3,5‐hexatrienes4 b,4 cand5 b,5 c, equilibrium mixtures of the starting materials and their diastereomers, the corresponding (E,Z,Z)‐hexatrienes4 b,4 cand5 b,5 cwere obtained. The desiredtrans‐disubstituted ring‐annelated cyclohexadienes9 band10 bwere formed by subsequent thermal 6π‐electrocyclization of the (E,Z,Z)‐hexatrienes4 band5 bin good yields (77–83 %). Upon treating the bissilyl‐substituted hexatrienes (E,Z,E)‐5 cor (E,Z,Z)‐5 cunder the same conditions, 6π‐electrocyclizations did occur, but the primary products immediately isomerized to a large extent, and mixtures of the cyclohexane‐annelated cyclohexadienes10 c–12 calong with the dehydrogenation products13,14 cwere formed. When the bismethoxycarbonyl‐substituted hexatriene (E,Z,E)‐5 bwas irradiated for an extended period of time (4.5 h), the gradual formation of the oxabicyclo[3.2.1]octa‐2,6‐diene17 bby a formal intramolecular hetero‐Diels–Alder reaction was observed and17 bcould be isolated in up to 69 % yield. To explore the scope of this new photochemical reaction, the new ring‐attached (E,Z,E)‐hexatrienes4 a,5 aand6 bwere synthesized by twofold Heck reactions from 1,2‐dibromocycloalkenes1–3(59–66 %). While irridiation of the cyclopentene‐attached 1,3,5‐hexatrienes only led to decomposition, the cyclohexene‐ and cycloheptene‐attached hexatrienes gave the hetero‐Diels–Alder products or other photoproducts depending on the size of the cycloalkene moiety and the nature of the alkoxycarbonyl substituents at the vinyl termini. The photoreaction products17 band18 bwhich are bicyclic acetals, underwent cleavage upon treatment with a Lewis acid such as Me3SiOTf to give the ring‐annelated methoxycarbonyl‐substituted troponecarboxylates21 band22 b.
A Novel Dimerization Mode of a Cyclic Ketene Imine
Authors: Langhals Elke , Huisgen Rolf , Polborn Kurt
Published: July 2004

The strained seven‐membered cyclic ketene imine 9, obtained by cycloaddition of thiocarbonyl ylide 6 with 2,3‐bis(trifluoromethyl)fumaronitrile (7), underwent base‐catalyzed dimerization at room temperature on treatment with KCN in acetonitrile or with proton sponge in acetonitrile or CDCl3. Two diastereoisomeric dimers, (6SR,3′RS)‐13 and (6SR,3′SR)‐13, were formed in 1:1 ratio in high yield. X‐ray analysis revealed a deep‐seated structural change which is unrelated to known dimerization pathways of ketene imines. In 13, one of the seven‐membered rings is opened, and attached to the second unit by a thioimidate group. An ionic chain reaction with a formal fluoride ion as transfer agent offers a rationalization.
Solid‐Phase Synthesis of Dihydrovirginiamycin S1, a Streptogramin B Antibiotic
Authors: Shaginian Alex , Rosen Marissa C. , Binkowski Brock F. , Belshaw Peter J.
Published: July 2004

We describe the first solid‐phase synthesis of dihydrovirginiamycin S1, a member of the streptogramin B family of antibiotics, which are nonribosomal‐peptide natural products produced by Streptomyces. These compounds, along with the synergistic group A components, are “last line of defense” antimicrobial agents for the treatment of life‐threatening infections such as vancomycin‐resistant enterococci. The synthesis features an on‐resin cyclization and is designed to allow production of streptogramin B analogues with diversification at positions 1′, 1, 2, 3, 4, and 6. Several synthetic challenges known to hinder the synthesis of this class of compounds were solved, including sensitivity to acids and bases, and epimerization and rearrangements, through the judicious choice of deprotection conditions, coupling conditions, and synthetic strategy. This work should enable a better understanding of structure–activity relationships in the streptogramin B compounds, possible identification of analogues that bypass known resistance mechanisms, and perhaps the identification of analogues with novel biological activities.
A New Color of the Synthetic Chameleon Methoxyallene: Synthesis of Trifluoromethyl‐Substituted Pyridinol Derivatives: An Unusual Reaction Mechanism, a Remarkable Crystal Packing, and First Palladium‐Catalyzed Coupling Reactions
Authors: Flögel Oliver , Dash Jyotirmayee , Brüdgam Irene , Hartl Hans , Reißig Hans‐Ulrich
Published: July 2004

Addition of lithiated methoxyallene to pivalonitrile afforded after aqueous workup the expected iminoallene 1 in excellent yield. Treatment of this intermediate with silver nitrate accomplished the desired cyclization to the electron‐rich pyrrole derivative 2 in moderate yield. Surprisingly, trifluoroacetic acid converted iminoallene 1 to a mixture of enamide 3 and trifluoromethyl‐substituted pyridinol 4 (together with its tautomer 5). A plausible mechanism proposed for this intriguing transformation involves addition of trifluoroacetate to the central allene carbon atom of an allenyl iminium intermediate as crucial step. Enamide 3 is converted to pyridinol 4 by an intramolecular aldol‐type process. A practical direct synthesis of trifluoromethyl‐substituted pyridinols 4, 10, 11, and 12 starting from typical nitriles and methoxyallene was established. Pyridinol 10 shows an interesting crystal packing with three molecules in the elementary cell and a remarkable helical supramolecular arrangement. Trifluoromethyl‐substituted pyridinol 4 was converted to the corresponding pyridyl nonaflate 13, which is an excellent precursor for palladium‐catalyzed reactions leading to pyridine derivatives 14–16 in good to excellent yields. The new synthesis of trifluoromethyl‐substituted pyridines disclosed here demonstrates a novel reactivity pattern of lithiated methoxyallene which is incorporated into the products as the unusual tripolar synthon B.
Generation of Cationic [Zr‐{tert‐Butyl Enolate}] Reactive Species: Methyl Abstraction versus Hydride Abstraction
Authors: Lian Bing , Toupet Loïc , Carpentier Jean‐François
Published: July 2004

Treatment of the neutral methyl–Zr–enolate [Cp2Zr(Me){O(tBuO)CCMe2}] (1) with one equivalent of B(C6F5)3 or [HNMe2Ph][B(C6F5)4] as a methyl abstractor in THF at 0 °C leads to the selective formation of the free ion pair complex [Cp2Zr(THF){O(tBuO)CCMe2}]+ [anion]− (2) (anion=MeB(C6F5)3−, B(C6F5)4−), which is relevant to the controlled polymerization of methacrylates. Cation 2 rapidly decomposes at 20 °C in THF with release of one equivalent of isobutene to form the cationic Zr–carboxylate species [Cp2Zr(THF)(O2CiPr)]+ (3), through a proposed intramolecular proton transfer process from the tert‐butoxy group to the enolate. The reaction of 1 with one equivalent of B(C6F5)3 or [HNMe2Ph][B(C6F5)4] in CH2Cl2 leads to the direct, rapid formation of the dimeric μ‐isobutyrato–Zr dicationic species [{Cp2Zr[μ‐(O2CiPr)]}2]2+ (4), which gives 3 upon dissolution in THF. Contrastingly, when [Ph3C][B(C6F5)4] is used to generate the cationic Zr–enolate species from 1 in CD2Cl2, a 15:85 mixture of dicationic complexes 4 and [{Cp2Zr[μ‐(O2CC(Me)CH2)]}2]2+[B(C6F5)4]${{{- \hfill \atop 2\hfill}}}$ (5‐[B(C6F5)4]2) is obtained quantitatively. The formation of 5 is proposed to arise from initial hydride abstraction from a methyl enolate group by Ph3C+, as supported by the parallel production of Ph3CH, and subsequent elimination of methane and isobutene. In addition to standard spectroscopic and analytical characterizations for the isolated complexes 2–5, complexes 4 and 5 have also been structurally characterized by X‐ray diffraction studies.
Enantioselective renal excretion of albendazole metabolites in patients with neurocysticercosis
Authors: Lanchote V.L. , Takayanagui O.M. , Mateus F.H.
Published: July 2004

The present study investigates the urinary excretion of the enantiomers of (+)‐ and (–)‐albendazole sulfoxide (ASOX) and albendazole sulfone (ASON) in 12 patients with neurocysticercosis treated with albendazole for 8 days (7.5 mg/kg/12 h). Serial blood samples (0–12 h) and urine (three periods of 8 h) were collected after administration of the last dose of albendazole. Plasma and urine (+)‐ASOX, (–)‐ASOX, and ASON metabolites were determined by HPLC using a chiral phase column (Chiralpak AD) with fluorescence detection. The pharmacokinetic parameters (P < 0.05) for (+)‐ASOX, (–)‐ASOX, and ASON metabolites are reported as means (95% CI); amount excreted (Ae) = 3.19 (1.53–4.85) vs. 0.72 (0.41–1.04) vs. 0.08 (0.03–0.13) mg; plasma concentration‐time area under the curve, AUC0–24 = 3.56 (0.93–6.18) vs. 0.60 (0.12–1.08) vs. 0.38 (0.20–0.55) μg.h/ml, and renal clearance ClR = 1.20 (0.66–1.73) vs. 2.72 (0.39–5.05) vs. 0.25 (0.13–0.37) l/h. Sulfone formation capacity, expressed as the Ae ratio ASON/ASOX + ASON, was 2.21 (1.43–2.99). These data point to enantioselectivity in the renal excretion of ASOX as a complementary mechanism to the metabolism responsible for the plasma accumulation of (+)‐ASOX. The results also suggest that the metabolite ASON is partially eliminated as a reaction product of the subsequent metabolism. Chirality 16:520–525, 2004. © 2004 Wiley‐Liss, Inc.
Ionen und Ionenbindung: Fehlvorstellungen hausgemacht! Ergebnisse empirischer Erhebungen und unterrichtliche Konsequenzen
Authors: Hilbing Claus , Barke Hans‐Dieter
Published: July 2004

KINDER UND JUGENDLICHE beobachten ihre Umgebung meist sehr genau und gelangen zu Erklärungen und Vorstellungen, die vom wissenschaftlichen Standpunkt aus gesehen zwar nicht angemessen sind, aber auf die Schüler bezogen als respektable Denkleistungen eingestuft werden müssen. Aus diesem Grund nennt man solche ursprünglichen Schülervorstellungen auch nicht falsch, sondern bezeichnet sie etwa als alternativ, vorläufig oder lebensweltlich. Solche Vorstellungen wurden vielfach empirisch erhoben und sind uns z. B. bezüglich der Stoffumwandlung, der Verbrennung, der Luft und anderer Gase oder erster Teilchenvorstellungen bekannt [1].
Computer und Multimedia im Chemieunterricht heute. Eine Einordnung aus didaktischer und lerntheoretischer Sicht
Authors: Eilks Ingo , Flintjer Bolko , Krilla Bodo , Möllencamp Hartwig , Wagner Walter
Published: July 2004

IM BEITRAG wird der Einsatz von Computer und Multimedia im Chemieunterricht aus didaktischer und lerntheoretischer Sicht diskutiert. Eine ausführliche Version des Textes mit einer umfassenden und weiter führenden Literatursicht ist auf der Seite der Fachgruppe Chemieunterricht verfügbar. Diese umfasst auch eine Betrachtung der lerntheoretischen Grundlagen, eine Übersicht über aktuelle Multimedia bezogene Forschung und Hinweise auf eine Vielzahl von unterrichtspraktischen Beiträgen.
Molekulares Sieben: Mit Einmachfolie ins Diskontinuum
Authors: Wilms Mareike , Fach Martin , Friedrich Jens , Oetken Marco
Published: July 2004

ES IST EINES der charakteristischen Kennzeichen der Chemie, experimentelle Beobachtungen nach einer zunächst phänomenologischen Betrachtung anschließend auf der submikroskopischen Ebene zu interpretieren. Schüler lernen deshalb bereits im Anfangsunterricht Chemie das Teilchenkonzept kennen. So wird ihnen das Verstehen vieler aus dem Alltag bekannter Phänomene wie der Wechsel der Aggregatzustände, das Lösen von Zucker in Tee, die Gewinnung von Salz aus Meerwasser oder das Riechen von Düften ermöglicht. Das Teilchenkonzept ist damit ein wichtiger Teil der naturwissenschaftlichen Allgemeinbildung.
Chemie fürs Leben — Sauerstoff aus Oxi‐Reinigern
Authors: Zucht Ulrike , Rossow Marco , Lange Gabriele , Flint Alfred
Published: July 2004

GRUNDSÄTZLICHES ANLIEGEN unseres Ansatzes „Chemie fürs Leben”︁ ist die Verbesserung der Akzeptanz und damit auch des Erfolgs von Chemieunterricht durch einen auch für die Schülerinnen und Schüler erkennbaren Beitrag des Faches zur Allgemeinbildung, einen verstärkten Alltagsbezug und möglichst viele Schülerexperimente, ohne dabei die notwendigen fachlichen Grundlagen zu vernachlässigen [1]. Dabei betrachten wir nicht die Alltagschemie als strukturierendes Element des Unterrichts, sondern Stoffe aus dem Alltag als Untersuchungs‐ und Anschauungsmaterial. Wann immer es möglich und sinnvoll ist, wollen wir so genannte „Laborchemikalien”︁ durch Stoffe aus dem Alltag ersetzen. Wie das in der Praxis geschehen kann, haben wir bereits im Rahmen einer von uns entwickelten neuen Unterrichtseinheit zum Thema Säuren, Laugen und Salze vorgestellt [1, 2].

Im folgenden Beitrag wollen wir zeigen, dass im Anfangsunterricht, ausgehend von der Untersuchung der bleichenden Wirkung so genannter Oxi‐Reiniger, sich aus diesen nicht nur in nennenswerten Mengen Sauerstoff freisetzen lässt (zur Freisetzung von Sauerstoff aus Fleckenmitteln siehe auch [3‐8]). Sie stellen damit eine interessante Alternative zur Erzeugung von Sauerstoff aus Kaliumpermanganat oder Wasserstoffperoxid dar. Weiterhin können sie auch problemlos in einer ganzen Reihe von Schülerexperimenten direkt eingesetzt werden, um die Oxidations‐ bzw. Redox‐Reaktionen zu erarbeiten.
Das Gesetz der Dynamik von links nach rechts bei chemischen Demonstrationen
Authors: Schmidkunz Heinz
Published: July 2004

DAS GESETZ DER DYNAMIK von links nach rechts gehört zu den Gesetzen des Sehens, die von Gestaltpsychologen empirisch gefunden wurden. Die richtige Anwendung der Gesetze führt zu einer prägnanten visuellen Wahrnehmung, die wiederum Voraussetzung für den gewünschten Ablauf von Denk‐ und Lernprozessen ist. Das hier betrachtete Gesetz wurde auf Experimente im Chemieunterricht übertragen und dessen Auswirkung untersucht. In einigen Fallstudien konnte die Wirksamkeit des Gesetzes anschaulich dokumentiert werden.
Association between laminin‐8 and glial tumor grade, recurrence, and patient survival
Authors: Ljubimova Julia Y. , Fugita Manabu , Khazenzon Natalya M. , Das Asha , Pikul Brian B. , Newman Daniel , Sekiguchi Kiyotoshi , Sorokin Lydia M. , Sasaki Takako , Black Keith L.
Published: July 2004

BACKGROUND

The authors previously sought to identify novel markers of glioma invasion and recurrence. Their research demonstrated that brain gliomas overexpressed a subset of vascular basement components, laminins, that contained the α4 chain. One of these laminins, laminin‐8, was found to be present in highly invasive and malignant glioblastoma multiforme (GBM) (Grade 4 astrocytoma); its expression was associated with a decreased time to tumor recurrence, and it was found in vitro to promote invasion of GBM cell lines.

METHODS

In the current study, the authors studied glial tumors of different grades in an attempt to correlate laminin‐8 expression with tumor recurrence and patient survival. Immunohistochemistry and Western blot analysis were used to detect laminin isoforms of interest.

RESULTS

Using immunohistochemistry and Western blot analysis, the authors confirmed high levels of laminin‐8 expression in approximately 75% of the GBM cases examined and in their adjacent tissues, whereas astrocytomas of lower grades expressed for the most part a different isoform, laminin‐9, which also was found in low amounts in normal brain tissue and benign meningiomas. Overexpression of laminin‐8 in GBM was found to be associated with a statistically significant shorter time to tumor recurrence (P < 0.0002) and a decreased patient survival time (P < 0.015).

CONCLUSIONS

The data suggest that laminin‐8, which may facilitate tumor invasion, contributes to tumor regrowth after therapy. Laminin‐8 may be used as a predictor of tumor recurrence and patient survival and as a potential molecular target for glioma therapy. Cancer 2004. © 2004 American Cancer Society.
Adenocarcinoma of the small bowel
Authors: Dabaja Bouthaina S. , Suki Dima , Pro Barbara , Bonnen Mark , Ajani Jaffer
Published: July 2004

BACKGROUND

Primary adenocarcinoma of the small bowel is a rare neoplasm, and to the authors' knowledge, few studies to date have addressed the topic.

METHODS

In the current study, the records of 217 patients with small bowel adenocarcinoma were reviewed retrospectively for the presentation, prognostic factors, treatment modalities, and outcome.

RESULTS

The median age of the patients was 55 years and there were 133 (61%) males. Tumors originated in the duodenum in 113 (52%) patients, the jejunum in 54 (25%) patients, the ileum in 28 (13%) patients, and in nonspecified sites in 22 (10%) patients. Patients with proximal tumors were diagnosed for the most part using endoscopy (i.e., 46 of 108 [43%]), whereas laparotomy enabled diagnosis in 16 of 28 (57%) patients with distal tumors. Based on TNM staging, 9 (4%) patients had Stage I disease, 43 (20%) patients had Stage II disease, 86 (39%) patients had Stage III disease, and 75 (35%) patients had Stage IV disease. The liver was the most common site of metastasis in 44 (59%) patients. Cancer‐directed surgery was performed in 146 (67 %) patients, including the Whipple procedure in 36 patients (17%). The median overall survival time was 20 months. The 5‐year overall survival rate was 26%. Cancer‐directed surgery, early‐stage disease, and lymph node involvement ratio were significantly associated with overall survival by univariate analysis. However, only cancer‐directed surgery and lymph node involvement ratio were independent predictors of overall survival in a multivariate analysis (adjusted rate ratio = 0.14; 95% confidence interval [95% CI], 0.04–0.46; P = 0.001 and adjusted rate ratio = 0.25; 95% CI, 0.12–0.53; P < 0.001, respectively).

CONCLUSIONS

Performing an oncologic surgery resulted in the best outcome in patients with nonmetastatic disease. Because cancer‐directed surgery is associated with high morbidity and mortality in primary centers, these patients should be referred to a tertiary center for adequate treatment. Cancer 2004. © 2004 American Cancer Society.
5‐HT5A receptor localization in the rat spinal cord suggests a role in nociception and control of pelvic floor musculature
Authors: Doly Stéphane , Fischer Jacqueline , Brisorgueil Marie‐Jeanne , Vergé Daniel , Conrath Marie
Published: July 2004

The 5‐HT5A receptor is a seven‐transmembrane receptor negatively coupled to adenylate cyclase, whose activation opens K+ channels. The 5‐HT5A receptor may thus exert an inhibitory effect on neuronal activity. However, the function of this receptor is still largely unknown, in particular at the spinal level, and this is partly due to lack of specific ligands. Immunocytochemistry using specific anti‐5‐HT5A antibodies reveals a particularly dense labeling in the two superficial layers of the dorsal horn, suggesting that the 5‐HT5A receptor may be involved in the spinal modulation of pain. In addition, a very intense staining in the lumbar dorsolateral nucleus (Onuf nucleus) in both males and females suggests that the 5‐HT5A receptor is also involved in micturition through the control of urethral sphincter muscles. Colchicine pretreatment allows the staining of numerous cell bodies in lamina II. Fewer labeled cell bodies are seen in laminae I and III–VI, in the lateral spinal nucleus, and in lamina X. Electron microscope examination of 5‐HT5A receptor immunoreactivity in spinal cords from untreated animals confirmed the postsynaptic labeling in all regions studied (dorsal horn, dorsolateral nucleus, and lamina X). The morphological heterogeneity of labeled dorsal horn cell bodies suggests that they belong to functionally distinct neurons (projection neurons and interneurons). In the lumbar dorsolateral nucleus, the labeling is preferentially localized on dendrites, suggesting that in this nucleus 5‐HT preferentially acts at the dendritic level. Finally, the dense labeling of postsynaptic specializations suggests that the receptor may be in stock before being addressed to the synaptic differentiation. J. Comp. Neurol. 476:316–329, 2004. © 2004 Wiley‐Liss, Inc.
Amygdaloid inputs define a caudal component of the ventral striatum in primates
Authors: Fudge Julie L. , Breitbart Michael A. , McClain Crystal
Published: July 2004

The ventral striatum mediates goal‐directed behavior through limbic afferents. One well‐established afferent to the ventral striatum is the amygdaloid complex, which projects throughout the shell and core of the nucleus accumbens, the rostral ventromedial caudate nucleus, and rostral ventromedial putamen. However, striatal regions caudal to the anterior commissure also receive inputs from the amygdala. These caudal areas contain histochemical and cytoarchitectural features that resemble the shell and core, based on our recent studies. Specifically, there is a calcium binding protein (CaBP)‐poor region in the lateral amygdalostriatal area that resembles the “shell.” To examine the idea that the caudal ventral striatum is part of the “classic” ventral striatum, we placed small injections of retrograde tracers throughout the caudal ventral striatum/amygdalostriatal area and charted the distribution of specific amygdaloid inputs. Amygdaloid inputs to the CaBP‐poor zone in the lateral amygdalostriatal area arise from the basal nucleus, the magnocellular subdivision of the accessory basal nucleus, the periamygdaloid cortex, and the medial subdivision of the central nucleus, resembling that of the shell of the ventral striatum found in our previous studies. There are also amygdaloid inputs to CaBP‐positive areas outside the shell, which originate mainly in the basal nucleus. Taken together, the “limbic‐related” striatum forms a continuum from the rostral ventral striatum through the caudal ventral striatum/lateral amygdalostriatal area based on histochemical and cellular similarities, as well as inputs from the amygdala. J. Comp. Neurol. 476:330–347, 2004. © 2004 Wiley‐Liss, Inc.
Mesostriatal and mesolimbic projections of midbrain neurons immunoreactive for estrogen receptor beta or androgen receptors in rats
Authors: Creutz Lela M. , Kritzer Mary F.
Published: July 2004

The dopamine (DA) inputs to the caudate putamen, the nucleus accumbens, and the amygdala in rats are sensitive to circulating estrogens and androgens. One mechanism for the hormone modulation of these systems may be via actions at cognate intracellular estrogen and androgen receptors. However, although it is known that specific subsets of midbrain DA neurons are immunopositive for estrogen receptor β (ERβ) or androgen receptors (ARs), it is not known where these receptor‐bearing cells project. To address this issue, we combined double‐label immunocytochemistry with retrograde tract tracing to identify the forebrain projections of ERβ‐ or AR‐immunoreactive (IR) midbrain neurons. Specifically, Fluoro‐Gold and/or cholera toxin were injected into discrete subregions of the caudate‐putamen, the nucleus accumbens, or the amygdala. Evaluations of the resultant midbrain labeling revealed that ERβ‐IR neurons sent collateral projections mainly to both the ventral caudate‐putamen and the amygdala, but not to the dorsal caudate or nucleus accumbens. In contrast, AR‐IR neurons projected either to the amygdala or the nucleus accumbens but not to the caudate‐putamen. The organization of these forebrain projections concurs with some of the known hormone sensitivities of mesostriatal and mesolimbic DA systems in rats and provides an anatomical model that predicts separate influences for androgens and estrogens over mesostriatal and mesolimbic DA systems. J. Comp. Neurol. 476:348–362, 2004. © 2004 Wiley‐Liss, Inc.
Distribution of vasoactive intestinal peptide and pituitary adenylate cyclase‐activating polypeptide receptors (VPAC1, VPAC2, and PAC1 receptor) in the rat brain
Authors: Joo Kyeung Min , Chung Yoon Hee , Kim Min Kyu , Nam Ryoung Hee , Lee Byung Lan , Lee Kyung Hoon , Cha Choong Ik
Published: July 2004

To examine the distributions of VIP/PACAP receptors (VPAC1, VPAC2, and PAC1 receptors) in the brain and to identify the cell types that express these receptors, we performed immunohistochemistry and double immunofluorescence in the rat brain with specific antibodies. The immunohistochemistry revealed that the receptors had distinctive, complementary, and overlapping distribution patterns. High levels of the VPAC1 receptor were expressed in the cerebral cortex, hippocampal formation, deep cerebellar nuclei, thalamus, hypothalamus, and brainstem. The VPAC2 receptors were concentrated in the cerebral cortex, hippocampal formation, amygdalar regions, cerebellar cortex, deep cerebellar nuclei, hypothalamus, and brainstem. On the other hand, the PAC1 receptors had a more restricted distribution pattern in the brain, and high levels of the PAC1 receptors were confined to the cerebellar cortex, deep cerebellar nuclei, epithalamus, hypothalamus, brainstem, and white matter of many brain regions. Also, many fibers expressing the PAC1 receptors were observed in various areas, i.e., the thalamus, hypothalamus, and brainstem. The double immunofluorescence showed that the VIP/PACAP receptors were confined to the neuroglia as well as the neurons. All three types of the VIP/PACAP receptors were expressed in the astrocytes, and the PAC1 receptors were also expressed in the oligodendrocytes. These findings indicate that VIP and PACAP exert their functions through their receptors in specific locations in different combinations. We hope that this first demonstration of the distributions of the VIP/PACAP receptors provides data useful in the investigation of the mechanisms of the many functions of VIP and PACAP in the brain, which require further elucidation. J. Comp. Neurol. 476:388–413, 2004. © 2004 Wiley‐Liss, Inc.
Projections from the amygdaloid complex to the piriform cortex: A PHA‐L study in the rat
Authors: Majak Katarzyna , Rönkkö Seppo , Kemppainen Samuli , Pitkänen Asla
Published: July 2004

Projections from the amygdala to the piriform cortex are proposed to provide a pathway via which the emotional system can modulate the processing of olfactory information as well as mediate the spread of seizure activity in epilepsy. To understand the details of the distribution and topography of these projections, we injected the anterograde tracerPhaseolus vulgaris‐leucoagglutinin into different nuclear divisions of the amygdaloid complex in 101 rats and analyzed the distribution and density of projections in immunohistochemically processed preparations. The heaviest projections from the amygdala to the piriform cortex originated in the medial division of the lateral nucleus, the periamygdaloid and sulcal subfields of the periamygdaloid cortex, and the posterior cortical nucleus. The heaviest terminal labeling was observed in layers Ib and III of the medial aspect of the posterior piriform cortex. Lighter projections to the posterior piriform cortex originated in the dorsolateral division of the lateral nucleus, the magnocellular and parvicellular divisions of the basal and accessory basal nuclei, and the anterior cortical nucleus. The projections to the anterior piriform cortex were light and originated in the dorsolateral and medial divisions of the lateral nucleus, the magnocellular division of the basal and accessory basal nuclei, the anterior and posterior cortical nuclei, and the periamygdaloid subfield of the periamygdaloid cortex. The results indicate that only selective amygdaloid nuclei or their subdivisions project to the piriform cortex. In addition, substantial projections from several amygdaloid nuclei converge in the medial aspect of the posterior piriform cortex. Via these projections, the amygdaloid complex can modulate the processing of olfactory information in the piriform cortex. In pathologic conditions such as epilepsy, these connections might provide pathways for the spread of seizure activity from the amygdala to extra‐amygdaloid regions. J. Comp. Neurol. 476:414–428, 2004. © 2004 Wiley‐Liss, Inc.
Tyrosine hydroxylase expression is affected by sexual vigor and social environment in male Cnemidophorus inornatus
Authors: Woolley S.C. , Sakata J.T. , Crews D.
Published: July 2004

Although the distribution of catecholamine‐synthesizing cells has been described for a variety of taxa, less is known about the functional significance of particular populations in nonmammalian species, especially reptiles. To understand the role of these populations in the display of social behaviors in lizards, we studied the interactive effects of sexual vigor (sexually vigorous vs. sluggish) and social condition (housing in isolation vs. with females) on the number and somal areas of cells expressing tyrosine hydroxylase (TH), a rate‐limiting enzyme in catecholamine synthesis, in male whiptail lizards, Cnemidophorus inornatus. We found that, regardless of social condition, sexually vigorous males had more TH‐immunoreactive (TH‐ir) cells in the dorsal hypothalamus (DH) relative to sluggish males. Sexually vigorous males also had more TH‐ir cells in the substantia nigra pars compacta (SNpc), but this difference was significant only among males housed with females. Sexually vigorous males that had been housed with females had smaller TH‐ir cells in the preoptic area (POA) than vigorous males housed in isolation. On the other hand, no significant differences were found in the anterior hypothalamus. These results highlight the regional heterogeneity in the plasticity of TH expression and suggest that, just as in other species, the DH, SNpc, and POA might be involved in the expression of social behaviors and in behavioral plasticity following social experiences in lizards. J. Comp. Neurol. 476:429–439, 2004. © 2004 Wiley‐Liss, Inc.
Anatomical and functional organization of somatosensory areas of the lateral fissure of the New World titi monkey (Callicebus moloch)
Authors: Coq Jacques‐Olivier , Qi Huixin , Collins Christine E. , Kaas Jon H.
Published: July 2004

The organization of anterior and lateral somatosensory cortex was investigated in titi monkeys (Callicebus moloch). Multiunit microelectrode recordings were used to identify multiple representations of the body, and anatomical tracer injections were used to reveal connections. (1) Representations of the face were identified in areas 3a, 3b, 1, S2, and the parietal ventral area (PV). In area 3b, the face was represented from chin/lower lip to upper lip and neck/upper face in a rostrocaudal sequence. The representation of the face in area 1 mirrored that of area 3b. Another face representation was located in area 3a. Adjoining face representations in S2 and PV exhibited mirror‐image patterns to those of areas 3b and 1. (2) Two representations of the body, the rostral and caudal ventral somatosensory areas (VSr and VSc), were found in the dorsal part of the insula. VSc was roughly a reversal image of the S2 body representation, and VSr was roughly a reversal of PV. (3) Neurons in the insula next to VSr and VSc responded to auditory stimuli or to both auditory and somatosensory stimuli. (4) Injections of tracers within the hand representations in areas 3b, 1, and S2 revealed reciprocal connections between these three areas. Injections in areas 3b and 1 labeled the ventroposterior nucleus, whereas injections in S2 labeled the inferior ventroposterior nucleus. The present study demonstrates features of somatosensory cortex of other monkeys in titi monkeys, while revealing additional features that likely apply to other primates. J. Comp. Neurol. 476:363–387, 2004. © 2004 Wiley‐Liss, Inc.
The role of functional genomics in selecting disease targets for antibody‐based therapy
Authors: Davis C. Geoffrey
Published: July 2004

Antibodies have clearly established themselves as comprising a significant segment of marketed drugs. The rapid evolution of technologies for generating antibodies and optimizing them for therapeutic applications has led to a succession of approvals over the last decade. The success of genomics in elucidating the contents of the human genome has provided a vast number of new potential targets for antibody therapy. Future development of antibody drugs will depend upon our ability to identify new targets from the tens of thousands of recently identified genes. This effort, too, will be technology‐driven. This review provides a general overview of the technologies available for enabling new target selection, technologies that are collectively referred to as “functional genomics.” For organizational purposes, the technologies are divided into the following broad categories: expression profiling, comparative genomics, loss of function strategies, proteomics, and computational biology. Through judicious application of combinations of these functional genomics technologies, we can anticipate a steady stream of novel well‐validated targets for antibody therapy for years to come. Drug Dev. Res. 61:155–171, 2004. © 2004 Wiley‐Liss, Inc.
Commercial manufacturing scale formulation and analytical characterization of therapeutic recombinant antibodies
Authors: Harris Reed J. , Shire Steven J. , Winter Charles
Published: July 2004

Stable therapeutic antibody dosage forms present production technology challenges, particularly when high‐concentration formulations are needed to meet the elevated dose requirements that are generally required for successful antibody therapy. Solid dosage forms, such as lyophilized powders, are generally more stable than liquid formulations. High‐concentration drug products can be achieved by reconstitution of the lyophilisate in a smaller volume than its initial (pre‐lyophilization) volume, but requires a significant vial overfill. High‐concentration liquid formulations are becoming feasible as new techniques and technologies become available. Analytical methods to detect subtle molecular variations have been developed to demonstrate manufacturing consistency. Some molecular heterogeneity is contributed by conserved sites, such as Asn297 glycosylation and the loss of heavy chain C‐terminal Lys residues. Characteristics that affect potency, stability, or immunogenicity must be elucidated for each therapeutic antibody. Drug Dev. Res. 61:137–154, 2004. © 2004 Wiley‐Liss, Inc.
Improving monoclonal antibodies for cancer therapy
Authors: Robinson M. K. , Weiner L. M. , Adams G. P.
Published: July 2004

Monoclonal antibodies have emerged as a promising class of pharmaceuticals for the treatment of many human diseases, including cancer. Historically, an inability to target monoclonal antibodies to solid tumors in sufficient quantities and with high enough specificity has hampered the effectiveness of antibodies as therapeutics. This review focuses on recent efforts in the field of antibody‐engineering directed at improving both the targeting of antibody‐based therapeutics as well as enhancing the efficacy of those therapeutics once they have been targeted to tumor. Drug Dev. Res. 61:172–187, 2004. © 2004 Wiley‐Liss, Inc.
The clinical pharmacology of therapeutic monoclonal antibodies
Authors: Roskos Lorin K. , Davis C. Geoffrey , Schwab Gisela M.
Published: July 2004

Seventeen monoclonal antibodies are currently approved in the United States for therapeutic use in organ transplantation, percutaneous coronary intervention, prophylaxis of respiratory syncytial virus disease, rheumatoid arthritis, Crohn's disease, asthma, chronic lymphocytic leukemia, acute myeloid leukemia, non‐Hodgkin's lymphoma, breast cancer, and colorectal cancer. All approved antibodies are of the IgG class. Thirteen are unconjugated intact antibodies, three are intact immunoconjugates, and one is a Fab fragment. Three of the antibodies are murine, five are chimeric, eight are humanized, and one is a fully human antibody generated by phage display technology. The antigen target and the structural and binding characteristics of the antibody determine the antibody's mechanism of action, pharmacokinetics, safety, and immunogenicity. Antibodies act through multiple mechanisms that include functional modulation of the antigen, recruitment of ADCC and CDC, and delivery of radionuclide or toxin payloads to target cells. Antibody half‐life is usually governed by interaction with the FcRn receptor. In some cases, the antigen may act as a sink for antibody elimination. Safety profiles are determined by the pharmacology and tissue distribution of the target antigen, antibody isotype, the antibody payload, cytokine release, hypersensitivity reactions to xenogeneic protein, and immunogenicity. Fully human antibody technology may allow development of antibodies that have reduced risks of hypersensitivity reactions and immunogenicity, thereby enhancing safety and efficacy. The exquisite target specificity of antibodies, improvements in antibody engineering technology, and the wide availability of novel and validated therapeutic targets provide many current and future opportunities for the clinical development of therapeutic antibodies. Drug Dev. Res. 61:108–120, 2004. © 2004 Wiley‐Liss, Inc.
Design and engineering human forms of monoclonal antibodies
Authors: Penichet Manuel L. , Morrison Sherie L.
Published: July 2004

The antibody molecule has multiple properties that make it a key component of the immune response. These include its ability to recognize a vast array of different foreign substrates and to interact with and activate the host effector systems. Antibodies with defined specificities may serve as “magic bullets” for the diagnosis and therapy of multiple diseases. With the development of the hybridoma technology, it was possible to produce rodent (mouse or rat) monoclonal antibodies that are the product of a single clone of antibody producing cells and have only one antigen binding specificity. However, the therapeutic use of rodent monoclonals antibodies in humans is limited by their immunogenicity, short circulating half‐life, and inability to efficiently trigger human effector mechanisms. However, it proved difficult to produce human monoclonal antibodies using the same methods. To address these problems genetic engineering and expression systems have instead been used to produce chimeric, humanized, and totally human antibodies as well as antibodies with novel structures and functional properties. In addition, the use of yeast and human artificial chromosome vectors for animal transgenesis has allowed the development of animal models that produce antigen specific antibodies that are totally human. As a consequence, recombinant antibody‐based therapies are now used to treat a variety of clinical conditions including infectious diseases, inflammatory disorders, and cancer. This article summarizes and compares different strategies for designing and engineering human antibodies and their derivatives. Drug Dev. Res. 61:121–136, 2004. © 2004 Wiley‐Liss, Inc.
Quantum‐information detection from optical memory using photonic crystals
Authors: Nihei Hiroyuki , Okamoto Atsushi
Published: July 2004

There is now great interest in optical memory using a three‐level atom embedded in photonic crystals, which can be used for quantum computing; however, quantum‐information detection from the optical memory has not been demonstrated. In this paper, first, considering the relative position of the photonic band gap (PBG) and two atomic levels split from the upper level of the atom used for the optical memory, we demonstrate that one of the split levels must be outside the PBG for quantum‐information detection. In this case, the quantum state of the atom can be changed by moving the other split level, where the quantum information is maintained or emitted for the cases in which the split level is inside or outside the PBG, respectively. The emitted quantum information can be measured as spontaneous emissions by a photon detector. Next, we propose two methods of moving the split level: one is realized by applying a direct current (DC) field to the atom and the other is realized by changing the intensity of the control laser field. Furthermore, by evaluating the intensities of the DC and the control laser fields, we find that the quantum information can be measured using the fields on the millielectronvolt order. © 2004 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 87(8): 10–19, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10205
A subgridding technique for the complex nonstandard FDTD method
Authors: Ohtani Tadao , Taguchi Kenji , Kashiwa Tatsuya
Published: July 2004

In this paper, a subgridding method is proposed for the two‐dimensional Complex Nonstandard FDTD (CNS‐FDTD) method. Taking into account the characteristics of the CNS‐FDTD method, new spatial interpolation, difference operator interpolation, and time interpolation are introduced. In order to demonstrate the usefulness of the proposed subgridding method, it is compared with the cases in which linear interpolation and quadratic interpolation of the conventional method are used for the main grids and local grids. It is found that the present subgridding method is superior to the conventional method in terms of stability and accuracy. Further, in the scattering analysis of a large rectangular cavity loaded with a lossy medium, the present subgridding method demonstrated substantial improvement in computation time and number of grids over CNS‐FDTD calculations with the local grid width over the entire space. As a subgridding method, a connection method is explained in a general case where the spatial division ratio of the main grids and local grids is 1:3. © 2004 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 87(8): 1–9, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.20078