bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I Clinical Study of Pertuzumab, a Novel HER Dimerization Inhibitor, in Patients With Advanced Cancer
Authors: Agus David B. , Gordon Michael S. , Taylor Charles , Natale Ronald B. , Karlan Beth , Mendelson David S. , Press Michael F. , Allison David E. , Sliwkowski Mark X. , Lieberman Gracie , Kelsey Stephen M. , Fyfe Gwen
Published: February 2005

Purpose

Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy.

Patients and Methods

Patients with incurable, locally advanced, recurrent or metastatic solid tumors that had progressed during or after standard therapy were recruited to a dose-escalation study of pertuzumab (0.5 to 15 mg/kg) given intravenously every 3 weeks.

Results

Twenty-one patients received pertuzumab and 19 completed at least two cycles. Pertuzumab was well tolerated. Overall, 365 adverse events were reported and 122 considered to be possibly drug related. Of these, 116 were of grade 1 to 2 intensity. The pharmacokinetics of pertuzumab were similar to other humanized immunoglobulin G antibodies, supporting a 3-week dosing regimen. Trough plasma concentrations were in excess of target concentrations at doses greater than 5 mg/kg. Two patients, one with ovarian cancer (5.0 mg/kg) and one with pancreatic islet cell carcinoma (15.0 mg/kg), achieved a partial response. Responses were documented by Response Evaluation Criteria in Solid Tumors after 1.5 and 6 months of pertuzumab therapy, and lasted for 11 and 10 months, respectively. Stable disease lasting for more than 2.5 months (range, 2.6 to 5.5 months) was observed in six patients.

Conclusion

These results demonstrate that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active, suggesting that inhibition of dimerization may be an effective anticancer strategy.
Bone Response to Intermittent Parathyroid Hormone Is Altered in Mice Null for β-Arrestin2
Authors: Ferrari S. L. , Pierroz D. D. , Glatt V. , Goddard D. S. , Bianchi E. N. , Lin F. T. , Manen D. , Bouxsein M. L.
Published: February 2005

Intermittent PTH administration increases bone turnover, resulting in net anabolic effects on bone. These effects are primarily mediated by intracellular cAMP signaling. However, the molecular mechanisms that regulate PTH activity in bone remain incompletely understood. β-Arrestin2, a G protein-coupled receptor regulatory protein, inhibits PTH-stimulated cAMP accumulation in vitro. Using β-arrestin2−/− (KO) and wild-type (WT) mice, we investigated the response to PTH in primary osteoblasts (POB) and the effects of intermittent PTH administration on bone mass and microarchitecture in vivo. Compared with that in WT mice, PTH-stimulated intracellular cAMP was increased and sustained in KO POB. Intermittent exposure of POB to PTH significantly decreased the ratio of osteoprotegerin (OPG) receptor activator of nuclear factor-κB ligand (RANKL) mRNA expression in KO POB, whereas it increased this ratio in WT POB. Total body bone mass and cortical and trabecular bone parameters were 5–10% lower in male KO mice compared with WT, and these differences were magnified upon in vivo administration of intermittent PTH (80 μg/kg·d) for 1 month. Thus, PTH significantly increased total body bone mineral content as well as vertebral trabecular bone volume and thickness in WT, but not KO mice. The anabolic response to PTH in cortical bone was also slightly more pronounced in WT than KO mice. Histomorphometry indicated that PTH prominently stimulated indexes of bone formation in both WT and KO mice, whereas it significantly increased indexes of bone resorption (i.e. osteoclast number and surface) in KO mice only. In conclusion, these results suggest that β-arrestins may specify the activity of intermittent PTH on the skeleton by limiting PTH-induced osteoclastogenesis.
Genetic Analysis of the Hypothalamic Corticotropin-Releasing Factor System
Authors: Garlow Steven J. , Boone Ericka , Li Wei , Owens Michael J. , Nemeroff Charles B.
Published: February 2005

The goal of this study was to use BxD recombinant inbred mice to search for genes that control the hypothalamic corticotrophin-releasing factor (CRF) system. The specific phenotype that was measured was abundance of transcripts that encode CRF, CRF receptor (Crf-R1), CRF binding protein, and arginine vasopressin (AVP) in total hypothalamic RNA. The strain distribution patterns for the transcript abundances for each target were continuously distributed, consistent with these being quantitative traits. Marker regression and interval mapping revealed associations with quantitative trait loci (QTL) for CRF transcript abundance on chromosome 1 (at 89.2 cM), chromosome 12 (between 54–58 cM), and chromosome 13 (between 26–30 cM); for Crf-R1 transcript abundance on chromosome 7 (at 1.5 cM), chromosome 12 (at 37 cM), and chromosome X (at 30 cM); for CRF binding protein transcript abundance on chromosome 7 (at 48.5 cM), chromosome 8 (at 65 cM), and chromosome 12 (at 19 cM); and for AVP transcript abundance on chromosome 7 (at 1 cM), chromosome 12 (at 13 cM), and chromosome 13 (at 45 cM). The transcript abundance QTL were not linked to their respective structural genes. Interval mapping on chromosome 7 reveals substantial overlap between QTL that control AVP and Crf-R1 transcript abundance and on chromosome 12 for QTL that control CRF and Crf-R1, which may indicate loci that coordinate regulation of the CRF system. There are QTL for all four targets on chromosome 12. There are a number of neurodevelopmental genes in very close proximity to the transcript abundance QTL that are potential candidate genes.
p66Shc Expression in Proliferating Thyroid Cells Is Regulated by Thyrotropin Receptor Signaling
Authors: Park Y. J. , Kim T. Y. , Lee S. H. , Kim H. , Kim S. W. , Shong M. , Yoon Y. K. , Cho B. Y. , Park D. J.
Published: February 2005

It is almost unanimously accepted that thyrocyte proliferation is synergistically activated by TSH and insulin/IGF-I. Moreover, it was recently suggested that p66Shc, which is an adaptor molecule of the IGF-I receptor, might play a critical role in this synergistic effect. In this study, we undertook to confirm the role and the mechanism underlying the regulation of p66Shc expression via TSH receptor in thyrocytes. We have found that p66Shc expression is elevated in proliferating human thyroid tissues, including adenomatous goiter, adenoma, Graves’ disease, and thyroid cancer, but not in normal thyroid. Among growth factors, TSH increased p66Shc expression both in vivo and in vitro; however, IGF-I, epidermal growth factor, or insulin did not. TSH and Graves’ Ig increased the p66Shc expression via the TSH receptor-Gs-cAMP pathway. However, interestingly, IGF-I or epidermal growth factor increased the tyrosine phosphorylations of p66Shc, and this was enhanced by TSH pretreatment. A similar synergism was observed during the DNA synthesis. When we measured the p66Shc levels induced by individual Igs from 130 patients with Graves’ disease, TSH receptor stimulating activity and goiter size showed a weak correlation. We conclude that the expression of p66Shc is regulated by signaling through the TSH receptor in proliferating thyroid cells and that p66Shc appears to be an important mediator of the synergistic effect between TSH and IGF-I with respect to thyrocyte proliferation. Moreover, we suggest that TSH potentiates the regulatory effect of IGF-I on thyrocyte growth, at least in part, by increasing the expression of p66Shc.
Molecular Screening and Association Analyses of the Interleukin 6 Receptor Gene Variants with Type 2 Diabetes, Diabetic Nephropathy, and Insulin Sensitivity
Authors: Wang Hua , Zhang Zhengxian , Chu Winston , Hale Terri , Cooper Judith J. , Elbein Steven C.
Published: February 2005

IL-6 levels and polymorphisms have been implicated in type 2 diabetes mellitus (T2DM) and insulin resistance. The IL-6 receptor (IL-6R) comprises two subunits, IL-6R and gp130, of which IL-6R confers specificity to IL-6 action and is located in a region of replicated linkage to T2DM on chromosome 1q21. We screened this gene for variation in Northern European Caucasian and African-American ethnic groups. We identified 11 variants with a minor allele frequency over 5%, including two amino acid changes (D358A and V385I) and four variants in the 3′ untranslated region. No variant was associated with obesity or measures of insulin sensitivity, but two single nucleotide polymorphisms in the 3′ untranslated region showed a trend to an association with T2DM in all Caucasians, and three single nucleotide polymorphisms, including D358A, showed a trend (P < 0.06) to an association with T2DM among the subset of Northern European Caucasians. Variant V385I was unique to African-Americans and was significantly associated with diabetes and diabetic nephropathy (P < 0.05). Among individuals heterozygous for the four variants in the transcribed sequence, one allele was significantly overrepresented, thus suggesting the existence of a regulatory variant controlling mRNA stability or expression. IL-6R is not likely to explain the linkage to diabetes in this region, but our work supports a minor role of variants in T2DM risk and suggests that sequence variants may alter IL-6R mRNA levels and possibly levels of soluble IL-6R.
Development of Self-Assembling Nucleators for Highly Transparent Semi-Crystalline Polypropylene
Authors: Kobayashi Toshiaki , Hashimoto Takeji
Published: February 2005

In 1,3:2,4-bis-O-(p-methylbenzylidene)-d-sorbitol (PDTS)/molten i-PP systems, the self-assembling ramified fibrils of PDTS are formed at Tfg,c higher than Tc during the cooling process. They function as the nucleators for the nucleation of molten i-PP. The ramified fibrils have the following characteristics: i) hexagonal crystal with the lattice cell a = b = 30.2, c = 4.4 Å, and γ = 120°, ii) mass fractal structure with large specific surface area, and iii) random orientation. Thus the following properties are induced for the i-PP: i) excellent transparency so that the lamellae build a sheaf-like crystalline superstructure with a small apex angle, ii) iso-directional and improved mechanical properties, and iii) shortened molding time.
The Potentiometric Effect of Hydrazine on a Belousov–Zhabotinskii Oscillating Chemical Reaction: Application to the Determination of Hydrazine
Authors: Raoof Jahan Bakhsh , Ojani Reza , Kiani Abolfazl , Khosravi Masomeh , Adnani Atena
Published: February 2005

A method for determination of hydrazine based on the Belousov–Zhabotinskii reaction is proposed. The addition of the hydrazine to the oscillating system increases the oscillating amplitude. This increase in oscillating amplitude was used as the analytical signal. To obtain a maximum value of analytical signal in determination of the hydrazine, the effects of different concentrations of malonic acid, potassium bromide, potassium bromate, cerium(IV) and sulfuric acid were investigated and the optimum concentration of each component was used for further experiments. The analytical signal is linearly proportional to the logarithm of the hydrazine concentration over the range of 1 × 10−6 M to 1 × 10−3 M (1 M = 1 mol dm−3) under optimum conditions. The obtained LOD (2σ) was 1 × 10−6 M and the relative standard deviation (RSD) for five measurements of 1.1 × 10−4 M hydrazine was 5%. The influences of some potential sources of interference were also investigated.
In Situ Deposition of Co9S8 Nanocrystallite on Its Single-Crystal Flakes at Low Temperatures
Authors: Zhang Yuanguang , Guo Fan , Wan Songming , Zheng Weiwei , Peng Yiya
Published: February 2005

Co9S8 hexagonal aggregations were synthesized in hydrazine hydrate (N2H4·H2O) solvent at 150 °C for 12 h using cobalt(II) sulfate hydrate (CoSO4·7H2O) and sodium sulfite (Na2SO3) as starting materials through a hydrothermal controlled-reduction method. The as-prepared samples were characterized by X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), and transmission electron microscopy (TEM), and their magnetic properties were evaluated on a vibrating sample magnetometer (VSM). The results showed the samples were mainly composed of Co9S8 hexagonal aggregations with an average diameter of 2.2 μm and a thickness of 200 nm. About 3 nm Co9S8 nanocrystallites deposited on its single-crystal flakes. The products exhibited ferromagnetism; the saturation magnetization (Ms) and coercivity (Hc) values of the samples were 80 emu/g and 320 Oe, respectively. The possible formation mechanism of Co9S8 hexagonal aggregations is discussed.
The Causes of Different Acid Strengths in Water: A Multivariate Statistical Approach
Authors: Aruga Roberto
Published: February 2005

Multivariate thermodynamic data of proton dissociation of 84 aromatic acids in aqueous medium have been processed with factor analysis. It is demonstrated that the concept of latent factor allows quantitative and rigorous determinations of the number and of the importance of the causes of different acid strengths.
Novel Through-Space Conjugated Polymers Consisting of Alternate [2.2]Paracyclophane and Fluorene
Authors: Morisaki Yasuhiro , Chujo Yoshiki
Published: February 2005

Novel through-space π-conjugated polymers having [2.2]paracyclophane and fluorene units were synthesized by the Suzuki coupling reaction. The polymers possessed good solubility in common organic solvents and good thermal stability. According to the UV–vis absorption spectra, the polymer showed an extension of π-delocalization via the through-space with π–π stacking compared with two kinds of model compounds. All of the polymers exhibited purplish-blue emission with high photoluminescence (PL) efficiencies of 73–81% in solution. The HOMO and LUMO energy levels of the polymer were estimated from the cyclic voltammogram.
Synthesis and Reactions of Cyclic Silylboranes
Authors: Suginome Michinori , Noguchi Hiroyoshi , Hasui Tomoaki , Murakami Masahiro
Published: February 2005

Five-membered cyclic silylboranes, 2-(diisopropylamino)-1,1-diorgano-1-sila-2-boracyclopentanes, were synthesized via intramolecular reductive B–Si bond formation with 3-[chloro(diisopropylamino)boryl]-1-(chlorodiorganosilyl)propane. The cyclic silylboranes were thermally stable and could be distilled under a vacuum. The reaction of the cyclic silylboranes with alcohols resulted in a cleavage of the Si–B bond, whereas a reaction with sec-amines led to an amino group exchange on the boron atom. The insertion of alkynes into the Si–B bond of the cyclic silylborane was effectively catalyzed by palladium catalysts, leading to a regioselective formation of seven-membered cyclic alkenes in high yields.
Novel Functional Groups with Fine-Controlled Metal Assembling Function
Authors: Yamamoto Kimihisa , Higuchi Masayoshi , Kimoto Atsushi , Imaoka Takane , Masachika Kiriko
Published: February 2005

Half-substituted dendritic phenylazomethine dendrimers with various substituents (Half-DPA-X Gn, where n is the generation number) were synthesized in order to elucidate the electron gradients in the dendrons by complexation with metal ions. Along with the change in the UV–vis spectra, the isosbestic point shifted about 11 nm from 371 to 360 nm. The number of added equivalents of SnCl2 required to induce a shift was in agreement with the number of the imine sites present in each layer of Half-DPA-H G4. The degree of the electron gradient in the phenylazomethine monodendrons, Half-DPAs, was estimated via titration with trifluoroacetic acid. We found drastic differences in the basicity of the imine sites; the basicity of the core imines is higher than that of the more peripheral imines. The stepwise complexation behavior is thermodynamically controlled from the core to terminal imines in Half-DPA-H. Furthermore, Half-DPA G4 with various substituents possesses the same electron gradients in the dendron, so the complexation behavior with metal ions is the same.
Selective Catalytic Reduction of NO by Methane over Pd Loaded on Heteropolyacids/SiO2 at Low Temperature
Authors: Okumura Kazu , Yoshimoto Ryosuke , Suzuki Katsuki , Niwa Miki
Published: February 2005

Pd was loaded on heteropolyacids/SiO2, and used for the selective reduction of NO with methane in the presence of oxygen and moisture. The catalyst exhibited activity in the selective reduction of NO in the temperature range between 473 and 573 K. The temperature was significantly lower than that in the conventional catalysts, such as Pd-loaded zeolites or monolayer-type oxides. Among tested heteropolyacids, H3PW12O40 gave rise to the highest activity in the reaction. The catalytic performance was improved by the addition of water vapor. The generation of highly dispersed PdO species was observed in the Pd K-edge EXAFS spectra, whose structure was similar to those found in the conventional Pd-loaded zeolites catalyst. The reason for the evolution of NO reduction activity over Pd/H3PW12O40/SiO2 was attributed to the formation of NOH+, as measured by IR, in addition to the generation of highly dispersed PdO species at low temperature on the Brønsted acid sites of heteropolyacid.
Perinuclear localization of slow troponin C m RNA in muscle cells is controlled by a cis-element located at its 3′ untranslated region
Authors: REDDY KISHORE K. , OITOMEN FERRY M. , PATEL GOPAL P. , BAG JNANANKUR
Published: February 2005

The process of mRNA localization within a specific cytoplasmic region is an integral aspect of the regulation of gene expression. Furthermore, colocalization of mRNAs and their respective translation products may facilitate the proper assembly of multi-subunit complexes like the thick and thin filaments of muscle. This postulate was tested by investigating the cytoplasmic localization of three mRNAs—the α-actin, slow troponin C (sTnC), and slow troponin I (sTnI), which encode different poly-peptide partners of the thin filament. Using in situ hybridization we showed that all three thin filament mRNAs are localized in the perinuclear cytoplasm of cultured C2C12 muscle cells. Their localization differs from that of the nonmuscle β-actin mRNA, which is localized in the peripheral region of both proliferating nondifferentiated myoblasts and the differentiated myocytes. Analysis of the localization signal of the sTnC mRNA showed that a 40-nucleotide-long region of the sTnC mRNA 3′ UTR is sufficient to confer the perinuclear localization on a heterologous reporter β-Gal mRNA. This localization signal showed tissue specificity and worked only in the differentiated myocytes, but not in the proliferating myoblasts or in HeLa cells. The predicted secondary structure of the localization signal suggests the presence of multiple stem and loop structures in this region of the 3′ UTR. Mutations within the stem region of the localization signal, which abolish the base pairing in this region, significantly reduced its perinuclear mRNA localization activity. Using UV-induced photo-cross-linking of RNA and proteins we found that a myotube-specific 42-kDa polypeptide binds to the localization signal.
Effects of Carburizing Treatment on First-Order Correlation between Steel Vickers Hardness and Thermal Diffusivity
Authors: Boubaker K
Published: February 2005

We have developed a theoretical and experimental model for imaging heat-treated steel hardness profiles. An analytical solution to the heat equation is presented as a guide to measurements, which are focused on prospecting both mechanical parameters and thermal local properties, indexed on the carbon-iron ratio along treatment depth. We tried to prove that the existence of a simple correlation between treated steel mechanical and thermal characteristics rises only beyond a critical carburizing depth. Comparison between several results allowed us to evaluate this critical depth and establish a simple correlation between treated steel HV microhardness and thermal diffusivity, in a particular case of surface hardening treatment.
Evaluation of Permeability of Tire Shreds Under Vertical Loading
Authors: Warith MA , Evgin E , Benson PAS , Rao SM
Published: February 2005

A concern in the use of tire shreds as drainage media in landfill leachate collection systems is the impact of compression strains on the permeability of the waste material, as earlier work has reported that these materials experience large (25 to 50 %) axial strains when subjected to vertical loading. This study examines the changes in permeability of a tire shred sample after being subjected to 30 to 50 % axial strain from average vertical stresses of 75 to 330 kPa. The maximum vertical stress of 330 kPa approximated 40 m of waste overburden. A constant-head permeability apparatus was fabricated to measure the permeability of the tire shred sample under different axial strains. Further, the fabricated assembly was capable of measuring permeability of the sample at various sample locations at a given strain level. Experimental results showed that despite experiencing large axial strains, the average permeability of the tire shred sample consistently remained two to three orders of magnitude higher than the design performance criterion of 0.01 cm/s for landfill drainage layers, suggesting that the compressible nature of tire shreds will not interfere in their use as a leachate collection drainage layer in municipal solid waste landfills.
An Investigation of Hydraulic Bulging as a Biaxial Straining Test for Sheet Metal
Authors: Atkinson M
Published: February 2005

The hydraulic bulging test was studied as a means to furnish accurate stress-strain relationships for constant straining rate through the large plastic strain range sustainable in biaxial tension. Careful attention to detail proved to be necessary.

Precise instrumentation was designed to monitor the progress of bulging with minimal interference in the process. Plastic behavior at the pole of the bulge was assessed by refined analysis taking into account curvature and thickness gradation near the pole. Effects of the initial dominance of bending and the later tendency to ‘secondary bulging’ on the derived stress-strain relationship were identified.

Tests of near-isotropic sheet iron showed good agreement with the flow stress level observed in uniaxial tension but revealed significant variation in the progress of strain hardening. The appearance of two-stage strain-hardening was found to be emphasized in biaxial tension.
Perovskite-related Ca(Nb,Ti)O3.33
Authors: Guevarra Jonathan , van Smaalen Sander , Daniels Peter , Rotiroti Nicola , Lichtenberg Frank
Published: February 2005

Crystals of nominal composition Ca(Nb0.8Ti0.2)O3.4, an n = 5 member of the homologous series A
n
B
n
O
3n+2, have been synthesized by floating-zone melting. The material was found to be multiphase consisting also of the n = 6 type. A good single crystal of this n = 6 type was found and the crystal structure at room temperature was determined by X-ray diffraction using synchrotron radiation. Structure refinements indicate a composition of Ca(Nb0.76Ti0.24)O3.33. The crystal structure is monoclinic P21 and consists of slabs of corner-sharing (Nb,Ti)O6 octahedra interrupted by layers of oxygen atoms. Ca atoms within the slabs are 12-fold coordinated whereas those at the borders show irregular coordination geometries. The octahedral distortion is greatest near the borders of the slabs and least near the middle of the slabs. Ti4+ preferentially occupy octahedral sites in the middle of slabs. The non-stoichiometry in the refined composition and the insulating character of the material may be explained in terms of extra oxygen, vacancies on the cation sites, or by localization of the electrons in the 4d orbitals of Nb at the borders of slabs.
Cancer Pharmacogenomics: Powerful Tools in Cancer Chemotherapy and Drug Development
Authors: Lee Wooin , Lockhart A. Craig , Kim Richard B. , Rothenberg Mace L.
Published: February 2005

Learning Objectives

After completing this course, the reader will be able to:

Explain how genetic factors contribute to variability in drug response. Apply this understanding to clinical outcomes in patients treated with specific chemotherapy agents. Describe approaches for improving clinical cancer therapy and cancer drug development.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Interindividual differences in tumor response and normal tissue toxicities are consistently observed with most chemotherapeutic agents or regimens. While many clinical variables have been associated with drug responses (e.g., age, gender, diet, drug-drug interactions), inherited variations in drug disposition (metabolism and transport) genes and drug target genes also likely contribute to the observed variability in cancer treatment outcome. Pharmacogenomic studies aim to elucidate the genetic bases for interindividual differences and to use such genetic information to predict the safety, toxicity, and/or efficacy of drugs. There exist several clinically relevant examples of the utility of pharmacogenomics that associate specific genetic polymorphisms in drug metabolizing enzymes (e.g., TPMT, UGT1A1, DPD), drug transporters (MDR1), and drug target enzymes (TS) with clinical outcomes in patients treated with commonly prescribed chemotherapy drugs, such as 5-fluorouracil and irinotecan (Camptosar®; Pfizer Pharmaceuticals; New York, NY http://www.pfizer.com). Techniques to discover and evaluate the functional significance of these polymorphisms have evolved in recent years and may soon be applied to clinical practice and clinical trials of currently prescribed anticancer drugs as well as new therapeutic agents. This review discusses the current and future applications of pharmacogenomics in clinical cancer therapy and cancer drug development.
Metastatic Carcinoid Tumors: A Clinical Review
Authors: Zuetenhorst Johanna M. , Taal Babs G.
Published: February 2005

Learning Objectives

After completing this course, the reader will be able to:

Describe the epidemiology of carcinoid tumors and the survival rates observed in patients with different stages of disease. Discuss the diagnostic modalities available for assessing carcinoid tumors and be able to use the results of these studies to choose a treatment option. Summarize the current therapeutic options for the treatment of carcinoid tumors. Identify the importance of carcinoid-related heart disease (CHD) on prognosis in patients with carcinoid tumors.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Carcinoid tumors are neuroendocrine tumors derived from enterochromaffin cells, which are widely distributed in the body. They can originate from any location in the body, but they are traditionally described as originating from the foregut, midgut, and hindgut. Although the overall incidence of carcinoid tumors appears to have increased in the past decades, the prognosis for patients with metastatic carcinoid tumors has improved during the last decade. Due to longer survival times, complications, such as carcinoid heart disease, and new metastatic patterns, like skin and bone metastases, may become more important features of carcinoid disease. Therapy focused on these complications should be part of the management. Combining new diagnostic and treatment modalities in metastatic carcinoid patients may result in better quality of life and longer survival times. The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach, with decisions made in multidisciplinary meetings focused on “tailor-made” therapy based on patients' specific conditions. Because carcinoid tumors are uncommon, effort should be made to treat these patients in specialized centers and for these centers to join together in multicenter studies.
Increasing Chemotherapy Dose Density and Intensity: Phase I Trials in Non-Small Cell Lung Cancer and Non-Hodgkin's Lymphoma
Authors: Blayney Douglas W. , McGuire Brian W. , Cruickshank Scott E. , Johnson David H.
Published: February 2005

Dose densification and dose escalation of cytotoxic chemotherapy may be important in improving the cure rates of chemotherapy-responsive cancers. We conducted two phase I studies, in non-small cell lung cancer (NSCLC) and in lymphoma, to explore the possibility of intensifying chemotherapy by compressing the delivery of and escalating the dose of standard combination chemotherapy. One study used etoposide and cisplatin chemotherapy in patients with unresectable stage III or IV NSCLC, intensifying chemotherapy by reducing the cycle length. The second study used cyclophosphamide, doxorubicin, vincristine, and prednisone, CHOP chemotherapy, in the treatment of stage II–IV intermediate or immunoblastic high-grade lymphoma, intensifying chemotherapy first by reducing the cycle length and then by escalating the dosages of cyclophosphamide and doxorubicin. Filgrastim support was used during dose intensification. Fifty-five patients with NSCLC and 49 with non-Hodgkin's lymphoma (NHL) were enrolled and treated in successive cohorts. At standard dosages and intervals of chemotherapy, filgrastim support resulted in incidences of grade 3 and 4 neutropenia that were between 62% and 77% lower than those in the no-filgrastim control; the mean duration of neutropenia was, likewise, more than 80% lower. Absolute neutrophil counts were ≥2 × 109/l at day 14 in virtually 100% of patients receiving filgrastim. In the NSCLC trial, etoposide and cisplatin were intensified by >50%, and in the lymphoma trial, cyclophosphamide was intensified by 270% and doxorubicin was intensified by 87%. Chemotherapy reductions or delays for neutropenia were rare in the groups receiving filgrastim; but at higher chemotherapy intensities, dose-limiting thrombocytopenia was encountered. We conclude that the delivery of myelosuppressive chemotherapy in both a dose-intense and a dose-dense manner is feasible with filgrastim support.
Syntheses Using Alkyne‐Derived Alkenyl‐ and Alkynylaluminum Compounds
Authors: Zweifel George , Miller Joseph A.
Published: February 2005

The stereoselective elaboration of alkynes into substituted alkenes via vinylic organometallics derived from hydrometalation and carbometalation of the triple bond comprises one of the most powerful tools for olefinic synthesis. The discovery that mono‐ and disubstituted alkenylaluminum compounds can be directly synthesized via
cis
hydroalumination of alkynes thus has played an important role in the development of stereoselective syntheses of functionally di‐ and tri‐substituted olefins. Also, the introduction of the zirconium‐catalyzed carboalumination has made available alkenylaluminum compounds that can be elaborated into stereodefined trisubstituted olefins, especially those of terpenoid origin. The fact that the hydroalumination of 1‐alkynes not only provides alkenylalanes, but also can be controlled through the choice of solvent to afford 1‐alkynylalanes and bis‐ and tris‐aluminoalkanes greatly enhances the versatility of alkyne‐derived organoaluminum derivatives. However, the chemistry of geminal aluminoalkanes remains to be delineated.

An important feature of alkenyl‐ and alkynylaluminum compounds is that they exhibit chemical properties that differ distinctly from those of the corresponding organolithium or organomagnesium compounds or of their organoboron congeners. For example, although unsaturated organoaluminum compounds undergo Grignard‐like reactions with a variety of organic and inorganic electrophiles, they show some significant differences in reactivity and substrate selectivity as compared to organolithium and Grignard reagents. This results because the trigonal aluminum in organoalanes possesses a rather low intrinsic nucleophilicity. However, conversion of the organoalanes into the corresponding filled‐octet aluminate species by treatment with bases markedly increases their carbanion character. Also, transmetalation of alkenylaluminum compounds with transition metals produces stereodefined organometallics with reaction characteristics different from those of their progenitors, thus providing an additional tool for modifying the reactivity of unsaturated organoaluminum compounds.

For simplicity and clarity, organoaluminum compounds are referred to in this chapter as monomers even though they actually may be associated. Except for the 1‐alkynylaluminum compounds, we have chosen to include in this chapter only those alkenylaluminum compounds whose preparations involve the direct formation of a carbon–aluminum bond. Those derived by exchange reactions are not covered.
TheBeckmann Reactions: Rearrangements, Elimination–Additions, Fragmentations, and Rearrangement–Cyclizations
Authors: Gawley Robert E.
Published: February 2005

The Beckmann rearrangement, the acid‐mediated isomerization of oximes to amides, was discovered by Beckmann in 1886. As one of the oldest and most familiar transformations in organic chemistry, it has been reviewed several times. What has become known as theBeckmannfragmentationwas in fact first observed by Wallach in 1889 but was not developed extensively until the 1960s. It has been referred to by several names over the years and has also been reviewed. The rearrangement cyclization is the intramolecular cyclization of a nitrilium ion generated by Beckmann rearrangement from an oxime. Within the context of an aromatic terminator, the process was first reported by Goldschmidt in 1895. Wallach reported the first case of an aliphatic terminator in 1901, although the reported structure was incorrect, and Perkin was apparently the first to observe a heteroatom terminator, but he also reported an incorrect structure. The process has been exploited only quite recently. This chapter is an update of these reactions, last reviewed in this series in 1960. Not covered are transformations that have been labeled Beckmann‐type reactions but are mechanistically unrelated. The most prominent of these is the so‐called photochemical Beckmann rearrangement, first observed by De Mayo in 1963 and discussed in a review several years ago. Worthy of mention, however, is the fact that many oximes that suffer fragmentation under acidic conditions undergo rearrangement when photolyzed.

Throughout this chapter, the (E) and (Z) nomenclature is used to describe oxime geometry.
The Persulfate Oxidation of Phenols and Arylamines (TheElbs and theBoyland–Sims Oxidations)
Authors: Behrman E. J.
Published: February 2005

A phenolate anion reacts with persulfate ion in alkaline solution to yield a product in which a sulfate group enters the ringparaororthoto the phenolic group.Parasubstitution predominates. Subsequent acid‐catalyzed hydrolysis yields the dihydric phenol.

The reaction was discovered by Karl Elbs in 1893 and named theElbs persulfate oxidation. The reaction is generally applicable toortho‐,meta‐, andpara‐substituted phenols with isomer distributions. The yields are not very high, particularly frompara‐substituted phenols, but the major contaminant is usually unchanged starting material that can be separated easily from the intermediate sulfate ester by solvent extraction. Other generally oxidizable groups such as an aldehyde or a double bond are usually not affected under the reaction conditions. The reaction was last thoroughly reviewed in 1951. T. R. Seshadri has made major contributions to the development of the Elbs oxidation. Nearly 30% of the references in this chapter are due to him and his colleagues.

By analogy with the Elbs persulfate oxidation of phenols, it might be expected that aromatic amines would react with persulfate to givep‐aminoaryl sulfates. Although the Elbs reaction had been known since 1893, it was not until 60 years later that Boyland et al. reported the extension of this reaction to aromatic amines. In accordance with expectations, aminoaryl sulfates were indeed the major products of the reaction, but, unexpectedly, the substitution took place exclusivelyorthoto the amino group rather than predominantly in theparaposition as in the phenol oxidation.Parasubstitution takes place only if theorthopositions are occupied by substituents other than hydrogen. Boyland and Sims explored the preparative aspects of this reaction in a series of papers. It seems appropriate to name the reaction the Boyland–Sims oxidation. Primary, secondary, and tertiary aromatic amines are all converted to the correspondingo‐aminoaryl sulfates under conditions similar to those used for the Elbs oxidation, that is, room temperature or below, aqueous alkali, and equimolar quantities of amine and persulfate.
Fluorination with Diethylaminosulfur Trifluoride and Related Aminofluorosulfuranes
Authors: Hudlický Miloš
Published: February 2005

Among the many organic fluorine compounds containing nitrogen and sulfur, dialkylaminotrifluorosulfuranes and bis(dialkylamino)difluorosulfuranes have become very useful fluorinating agents. The first representative of this group, dimethylaminosulfur trifluoride was prepared in 1964, followed in 1970 by diethylaminosulfur trifluoride, which became popular under the acronym DAST. Both compounds were synthesized by treatment of the appropriate dialkylaminotrimethylsilane with sulfur tetrafluoride.

Subsequently, bis(dialkylamino)sulfur difluorides were prepared by the reaction of dialkylaminosulfur trifluorides with dialkylaminotrimethylsilanes.

Both classes of compounds were found to convert alcohols into fluorides, and aldehydes and ketones into geminal difluorides:

Further uses include the preparation of acyl and sulfonyl fluorides from carboxylic and sulfonic acids and the conversion of sulfoxides into α‐fluoroalkyl sulfides.

Later, the reaction of bis(dialkylamino)difluorosulfuranes with dialkylaminotrimethylsilanes was shown to give tris(dialkylamino)sulfonium difluorotrimethylsilicates (TASF).

These salts no longer react with alcohols or carbonyl compounds, but they convert even relatively unreactive halides, such as primary chlorides, into fluorides under very mild conditions. Furthermore, they are readily soluble in organic solvents and are useful sources of “naked,” unsolvated fluoride ion.

This chapter deals with the preparation of all three classes of reagents and their use as fluorinating agents. The literature is covered exhaustively until the end of 1984; some papers beyond that date are included.
The [3 + 2] Nitrone–Olefin Cycloaddition Reaction
Authors: Confalone Pat N. , Huie Edward M.
Published: February 2005

Early researchers studying the condensation product of carbonyl compounds withN‐substituted hydroxylamines elected to coin the term “nitrone” as a combination of the words “nitrogen” and “ketone.” This was done to emphasize the parallel between this newly discovered functionality and the already rich chemistry of the carbonyl group.

For example, nitrones are capable of reacting with carbanions of various types, a consequence of the iminium species embedded in the nitrone that renders the functionality susceptible to nucleophilic attack. ThusC‐phenyl‐N‐methylnitrone undergoes a Reformatsky reaction with ethyl bromoacetate in complete analogy with benzaldehyde. The intermediate zinc alkoxide cyclizes to 2‐methyl‐3‐phenylisoxazolidin‐5‐one, a type of compound that can also be prepared by the related nucleophilic addition of dialkyl malonates to nitrones.

This chapter deals with a unique property of nitrones not shared by the corresponding carbonyl compounds, namely, a marked ability to undergo a [3 + 2] cycloaddition reaction in the presence of a dipolarophile. The reactions of nitrones with substituted olefins, both intermolecular and intramolecular are addressed. This process yields isoxazolidines directly, affording products related to those obtained in the Reformatsky reaction but arising by a different reaction mode.

The intent of the review presented in this chapter is to provide a thorough understanding of the nitrone–olefin [3 + 2] cycloaddition reaction and to illustrate its power by describing some significant applications to complex synthetic problems. Various aspects have been reviewed. This documentation of the nitrone–olefin cycloaddition reaction begins with the preparation and stability of the nitrone component and is followed by mechanistic considerations. A presentation of the dipolarophile syntheses is beyond the scope of this chapter; however, the tabular survey provides leading references to specific examples. The important concepts of regio‐ and stereo‐selectivities are introduced next. Since the general rules of regiochemistry that apply in the intermolecular version of the reaction are often reversed in the intramolecular version, the latter are dealt with separately. Finally, important applications to the total synthesis of natural products are presented. The versatile utility of the nitrone–olefin cycloaddition reaction in the synthesis of natural products has been the major driving force in the development of this long‐neglected chemistry. An in‐depth understanding of the key transformations of the isoxazolidines afforded by the reaction will place this chemistry firmly within the arsenal of organic reactions.
Reductions by Metal Alkoxyaluminum Hydrides. PartII. Carboxylic Acids and Derivatives, Nitrogen Compounds, and Sulfur Compounds
Authors: Málek Jaroslav
Published: February 2005

In continuation of the previous review on reductions by metal alkoxyaluminum hydrides, this chapter is devoted to reductions of carboxylic acids and their derivatives, open‐chain and heterocyclic nitrogen compounds, and open‐chain and heterocyclic sulfur compounds by alkoxyaluminum hydrides, metal alkoxyaluminum hydrides, and chiral metal alkoxyaluminohydride complexes. Emphasis is placed on the scope, limitations, and the synthetic utility of metal alkoxyaluminum hydrides. Accepted views on reaction mechanisms are mentioned briefly. Discussion of alternative methods of reduction, particularly those using other metal hydrides or complex metal hydrides, is limited to examples of the most important transformations of functional groups; reducing properties of these hydrides and hydride reagents such as borane–dimethyl sulfide, amine boranes, haloboranes, organoboranes, sodium borohydride–pyridine, sodium borohydride–triphenyl borate, sodium borohydride—transition‐metal complexes, potassium triisopropoxyborohydride, and sodium triacyloxyborohydrides have been reported in several papers and reviews. Monographs and reviews summarize reductions with metal alkoxyaluminum hydrides and asymmetric reductions with chiral lithium alkoxyaluminum hydrides and chiral boron reagents.
ThePeterson Olefination Reaction
Authors: Ager David J.
Published: February 2005

The Peterson olefination reaction provides a useful method for the preparation of alkenes from α‐silyl carbanions and carbonyl compounds. As alkenes hold a pivotal role in synthetic methodology for the introduction of vicinal functionality, particularly in a stereoselective manner, the Peterson reaction is increasing in importance in the reaction repertoire. This chapter discusses the reaction and its advantages over comparable methods such as the Wittig reaction.

Although elimination of β‐silylalkoxides, was noted in 1947, it was not until Peterson described the preparation of functionalized alkenes from α‐silyl carbanions in 1968 that the full potential of the reaction became apparent. Alkenes are usually only isolated directly from the condensation when an anion‐stabilizing group is present in the carbanion; if not, the β‐hydroxysilane is formed. Many examples of the formation of alkenes from β‐hydroxysilanes are cited in the literature. These eliminations are discussed in this chapter, although they strictly should not be called Peterson olefination reactions. However, the “common” organic reactions of β‐hydroxysilanes which follow the usual pathways—such as the thermolytic elimination of esters derived from those alcohols—are omitted.

The central nature of the Peterson reaction to organosilicon chemistry has led all reviews in this area to discuss the subject to some extent. In addition, the reaction itself has been reviewed previously.
TheNef Reaction
Authors: Pinnick Harold W.
Published: February 2005

The Nef reaction is usually defined as the conversion of a primary or secondary nitroalkane into the corresponding carbonyl compound. This reaction was reported by the Swiss chemist J. U. Nef in 1894. Hydrochloric and sulfuric acid give the same result. The conversion of a nitro group to a carbonyl group has become an important synthetic tool because of the ease of preparation of substituted nitro compounds by condensation of nitroalkanes with aldehydes (the Henry reaction), conjugate addition of nitroalkanes to electrophilic alkenes, or carbon alkylation of the dianion of primary nitroparaffins. The Nef reaction is one of the better examples of “umpolung” reactivity in which the original nitro compound anion functions as an acyl anion equivalent.

This chapter discusses the Nef reaction and modifications of the original process that extend the variety of compounds which are useful as substrates. Each modification is considered according to general mechanistic type and is organized in a “reagent” approach. The Tabular Survey lists all known examples of both the Nef reaction and these modifications so that specific comparison of methods can be made.
Infiltration and Coating of Rapid Prototyping Parts
Authors: Taha I. , Abdellatif M. H. , Dietz P.
Published: February 2005

EDM tools produced by Rapid Tooling (see Figure) were Cu coated and/or infiltrated with conducting particles to improve their EDM performance. Different machining procedures were tested to optimize the manufacturing process.
Improvement of the Adherence of Thermal Barrier Coatings for Rocket Combustion Chambers
Authors: Beyer S. , Klemm D. , Bobeth M. , Pompe W. , Trommer O. , Gawlitza P.
Published: February 2005

The improvement of the adherence of thermal barrier coatings on a copper material as used in rocket combustion chambers by introducing an additional Al or Ti reaction layer and by realizing an optimum surface roughness is presented. Boundary layer reactions of Al and Ti with the copper substrate have been investigated as well as the coating adherence as a function of the Cu surface roughness.
Twinning in Nanocrystalline fcc Metals
Authors: Frøseth A. G. , Derlet P. M. , Van Swygenhoven H.
Published: February 2005

Twinning has been observed in experimental deformation studies of nanocrystalline (nc) materials even for high stacking fault fcc metals. By using molecular dynamics and a knowledge of the general planar fault energy curves of the corresponding metal, we show how twinning can occur by means of partial dislocations nucleating at nc grain boundaries and how this process is influenced by the presence of grown‐in twins.
Energy of Compressed Aluminum Foam
Authors: Song Z. , Nutt S.
Published: February 2005

Compressed solid foams exhibit spatially heterogeneous distributions of local strain. In the present paper, we suggest a phenomenological explanation of compression behavior in solid foams. The analogy between the deformation of foam and a phase transformation is discussed.
Synthesis of Bulk Nanocrystalline Materials by Repeated Cold Rolling
Authors: Wilde G. , Dinda G.‐P. , Rösner H.
Published: February 2005

The article gives an overview on the preparation and characterization of bulk nanocrystalline or bulk amorphous metallic materials by repeated cold rolling with intermediate folding. The results that are highlighted for pure fcc and hcp metals and one binary glass‐forming alloy indicate that truly nanocrystalline materials with grain sizes below 10 nm can be obtained by this process that does not apply an additional hydrostatic pressure and that is compatible with continuous processing routes.