bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction of Titanasiloxanes by Incorporation of Silanols to the Metal Oxide Model [{Ti(η5‐C5Me5)(μ‐O)}3(μ3‐CR)]: DFT Elucidation of the Reaction Mechanism
Authors: Carbó Jorge J. , González‐del Moral Octavio , Martín Avelino , Mena Miguel , Poblet Josep‐M. , Santamaría Cristina
Published: July 2008

A family of novel titanasiloxanes containing the structural unit {[Ti(η5‐C5Me5)O]3} were synthesized by hydron‐transfer processes involving reactions with equimolecular amounts of μ3‐alkylidyne derivatives [{Ti(η5‐C5Me5)(μ‐O)}3(μ3‐CR)] (R=H (1), Me (2)) and monosilanols, R3′Si(OH), silanediols, R2′Si(OH)2, and the silanetriol tBuSi(OH)3. Treatment of 1 and 2 with triorganosilanols (R′=Ph, iPr) in hexane affords the new metallasiloxane derivatives [{Ti(η5‐C5Me5)(μ‐O)}3(μ‐CHR)(OSiR3′)] (R=H, R′=Ph (3), iPr (4); R=Me, R′=Ph (5), iPr (6)). Analogous reactions with silanediols, (R′=Ph, iPr), give the cyclic titanasiloxanes [{Ti(η5‐C5Me5)(μ‐O)}3(μ‐O2SiR′2)(R)] (R=Me, R′=Ph (7), iPr (8); R=Et, R′=Ph (9), iPr (10)). Utilization of tBuSi(OH)3 with 1 or 2 at room temperature produces the intermediate complexes [{Ti(η5‐C5Me5) (μ‐O)}3(μ‐O2Si(OH)tBu)(R)] (R=Me (11), Et(12)). Further heating of solutions of 11 or 12 affords the same compound with an adamantanoid structure, [{Ti(η5‐C5Me5)(μ‐O)}3(μ‐O3SitBu)] (13) and methane or ethane elimination, respectively. The X‐ray crystal structures of 3, 4, 6, 8, 10, 12, and 13 have been determined. To gain an insight into the mechanism of these reactions, DFT calculations have been performed on the incorporation of monosilanols to the model complex [{Ti(η5‐C5H5)(μ‐O)}3(μ3‐CMe)] (2 H). The proposed mechanism consists of three steps: 1) hydron transfer from the silanol to one of the oxygen atoms of the Ti3O3 ring, forming a titanasiloxane; 2) intramolecular hydron migration to the alkylidyne moiety; and 3) a μ‐alkylidene ligand rotation to give the final product.
Synthesis of functional poly(phenyl isocyanide)s with macromolecular helicity memory and their use as asymmetric organocatalysts
Authors: Miyabe Toshitaka , Hase Yoko , Iida Hiroki , Maeda Katsuhiro , Yashima Eiji
Published: July 2008

To develop a novel polymer‐based asymmetric organocatalyst, a series of helical poly(phenyl isocyanide)s with functional pendant groups were prepared by modifying the side groups of the optically active helical poly(4‐carboxyphenyl isocyanide) with a macromolecular helicity memory. Helical polyisocyanides partially modified with achiral amines, such as piperazine, maintained their chiral memory and enantioselectively catalyzed a direct aldol reaction. Although the enantioselectivity was low, the original helical poly(4‐carboxyphenyl isocyanide) showed no catalytic activity. These results indicated that the macromolecular helicity of the modified polyisocyanides together with bifunctional amino and carboxy acid pendant residues arranged in a helical array along the polymer backbones plays an important role in the enantioselectivity. Chirality, 2009. © 2008 Wiley‐Liss, Inc.
Back Trajectory Analysis of Precipitation Chemistry in the Urban and Forest Areas of Istanbul, Turkey
Authors: Saylan Levent , Toros Hüseyin , Sen Orhan
Published: July 2008

There are many influences on precipitation chemistry and its variation. The transport paths of air masses before rainfall provide useful knowledge for evaluating and understanding the results of the analysis of the chemical compositions of precipitation. As a consequence, it is important to determine the variation of the chemical composition of rainwater by back trajectory analysis for estimating the source of the emissions. In this study, the rainwater samples were collected using specially designed collectors between November 1997 and June 1998 in the urban and forest areas of Istanbul. The rainwater samples were analyzed for major ion concentrations and pH. The volume‐weighed mean pH values were 5.8. The rainwater samples were classified to determine the source region of pollutants in rainwater using synoptic maps. In general, the results of the analysis on the chemical concentrations of precipitation during the measurement period showed that most of ions reached Istanbul from the directions of W‐SW, NW‐W, and NE‐N, respectively.
CaMK‐II promotes focal adhesion turnover and cell motility by inducing tyrosine dephosphorylation of FAK and paxillin
Authors: Easley Charles A. , Brown Claire M. , Horwitz Alan F. , Tombes Robert M.
Published: July 2008

Transient elevations in Ca2+ have previously been shown to promote focal adhesion disassembly and cell motility through an unknown mechanism. In this study, evidence is provided to show that CaMK‐II, a Ca2+/calmodulin dependent protein kinase, influences fibroblast adhesion and motility. TIRF microscopy reveals a dynamic population of CaMK‐II at the cell surface in migrating cells. Inhibition of CaMK‐II with two mechanistically distinct, membrane permeant inhibitors (KN‐93 and myr‐AIP) freezes lamellipodial dynamics, accelerates spreading on fibronectin, enlarges paxillin‐containing focal adhesions and blocks cell motility. In contrast, constitutively active CaMK‐II is not found at the cell surface, reduces cell attachment, eliminates paxillin from focal adhesions and decreases the phospho‐tyrosine levels of both FAK and paxillin; all of these events can be reversed with myr‐AIP. Thus, both CaMK‐II inhibition and constitutive activation block cell motility through over‐stabilization or destabilization of focal adhesions, respectively. Coupled with the existence of transient Ca2+ elevations and a dynamic CaMK‐II population, these findings provide the first direct evidence that CaMK‐II enables cell motility by transiently and locally stimulating tyrosine dephosphorylation of focal adhesion proteins to promote focal adhesion turnover. Cell Motil. Cytoskeleton, 2008. © 2008 Wiley‐Liss, Inc.
Regulation of polarity in cells devoid of actin bundle system after treatment with inhibitors of myosin II activity
Authors: Shutova Maria S. , Alexandrova Antonina Y. , Vasiliev Jury M.
Published: July 2008

Interplay of two cytoskeletal systems ‐ microfilaments and microtubules is essential for directional cell movement. To better understand the role of those cytoskeletal systems in polarization of cells, rat fibroblasts were incubated with drugs inhibiting activity of myosin II: blebbistatin and Y‐27632. Both drugs led to disappearance of actin‐myosin bundles and mature focal cell‐matrix adhesions but did not affect polarization and directional motility. The rate of motility even increased after inhibitor treatment. The characteristic feature of inhibitor‐treated fibroblasts was collapse of the cytoplasm accompanied by bundling of microtubules that led to transformation of lamellae into long immobile tails. The only exception was the leading anterior lamella which was not transformed into the tail and supported directional movement of the cell. The tail at the cell rear determined the position of anterior lamella and direction of locomotion. Depolymerization of microtubules by colcemid stopped directional locomotion of inhibitor‐treated cells. These data show that integrity of the microtubular system provides the basic mechanism of polarization and orientation which is only modified by interactions with actin‐myosin system and cell‐substrate adhesions. We suggest that the position of bundled tail microtubules and dispersed microtubules in leading lamella determine polarization in cells lacking stress fibers and focal adhesions. Thus, polarization is based on microtubule‐dependent mechanisms both in non‐contractile and contractile cells. These mechanisms could switch dependent on circumstances as fibroblasts may acquire non‐contractile phenotype, not only after direct inhibition of myosin II but also in certain conditions of microenvironment [Rhee et al., 2007, 104:5425–5430]. Cell Motil. Cytoskeleton 2008. © 2008 Wiley‐Liss, Inc.
Cortactin branches out: Roles in regulating protrusive actin dynamics
Authors: Ammer Amanda Gatesman , Weed Scott A.
Published: July 2008

Since its discovery in the early 1990's, cortactin has emerged as a key signaling protein in many cellular processes, including cell adhesion, migration, endocytosis, and tumor invasion. While the list of cellular functions influenced by cortactin grows, the ability of cortactin to interact with and alter the cortical actin network is central to its role in regulating these processes. Recently, several advances have been made in our understanding of the interaction between actin and cortactin, providing insight into how these two proteins work together to provide a framework for normal and altered cellular function. This review examines how regulation of cortactin through post‐translational modifications and interactions with multiple binding partners elicits changes in cortical actin cytoskeletal organization, impacting the regulation and formation of actin‐rich motility structures. Cell Motil. Cytoskeleton 2008. © 2008 Wiley‐Liss, Inc.
β‐tubulin isotype classes II and V expression patterns in nonsmall cell lung carcinomas
Authors: Cucchiarelli Valeria , Hiser Laree , Smith Hilda , Frankfurter Anthony , Spano Anthony , Correia John J. , Lobert Sharon
Published: July 2008

Previous studies suggest that β‐tubulin isotype protein levels could be useful as indicators of nonsmall cell lung cancer (NSCLC) aggressiveness. However, measurement of protein amounts in tissue samples by staining techniques is semiquantitative at best. Since technologies for measuring mRNA levels have become more efficient and quantitative, we wanted to determine whether β‐tubulin message levels may be useful as biomarkers. Quantitative real‐time RT‐PCR was used to measure the seven classes of β‐tubulin isotypes, stathmin and MAP4 mRNA levels in 64 NSCLC and 12 normal lung tissue samples. We found significantly higher fractions of β‐tubulin classes II and V mRNA compared to the other isotypes in all lung tumor samples (P < 0.05). In addition, the ratio of β‐tubulin classes II/V mRNA was significantly higher in NSCLCs compared to normal lung tissues (P < 0.001). The data suggest that the ratio of β‐tubulin classes II and V mRNA could be useful as a biomarker for NSCLC tumor differentiation and/or NSCLC aggressiveness. Furthermore, the ratio of MAP4 to stathmin mRNA was found to be higher in diseased lung tissues compared to normal lung tissues, suggesting this ratio might also be used as a clinically relevant biomarker for NSCLCs. Cell Motil. Cytoskeleton 2008. © 2008 Wiley‐Liss, Inc.
The knock‐out of ARP3a gene affects F‐actin cytoskeleton organization altering cellular tip growth, morphology and development in moss Physcomitrella patens
Authors: Finka Andrija , Saidi Younousse , Goloubinoff Pierre , Neuhaus Jean‐Marc , Zrÿd Jean‐Pierre , Schaefer Didier G.
Published: July 2008

The seven subunit Arp2/3 complex is a highly conserved nucleation factor of actin microfilaments. We have isolated the genomic sequence encoding a putative Arp3a protein of the moss Physcomitrella patens. The disruption of this ARP3A gene by allele replacement has generated loss‐of‐function mutants displaying a complex developmental phenotype. The loss‐of function of ARP3A gene results in shortened, almost cubic chloronemal cells displaying affected tip growth and lacking differentiation to caulonemal cells. In moss arp3a mutants, buds differentiate directly from chloronemata to form stunted leafy shoots having differentiated leaves similar to wild type. Yet, rhizoids never differentiate from stem epidermal cells. To characterize the F‐actin organization in the arp3a‐mutated cells, we disrupted ARP3A gene in the previously described HGT1 strain expressing conditionally the GFP‐talin marker. In vivo observation of the F‐actin cytoskeleton during P. patens development demonstrated that loss‐of‐function of Arp3a is associated with the disappearance of specific F‐actin cortical structures associated with the establishment of localized cellular growth domains. Finally, we show that constitutive expression of the P. patens Arp3a and its Arabidopsis thaliana orthologs efficiently complement the mutated phenotype indicating a high degree of evolutionary conservation of the Arp3 function in land plants. Cell. Motil. Cytoskeleton, 2008. © 2008 Wiley‐Liss, Inc.
Role of nonmuscle myosin IIB and N‐RAP in cell spreading and myofibril assembly in primary mouse cardiomyocytes
Authors: Lu Shajia , Horowits Robert
Published: July 2008

We investigated the role of nonmuscle myosin heavy chain (NMHC) IIB in cultured embryonic mouse cardiomyocytes by specific knockdown using RNA interference. NMHC IIB protein levels decreased 90% compared with mock‐transfected cells by 3 days post transfection. NMHC IIB knockdown resulted in a slow decrease in N‐RAP protein levels over 6 days with no change in N‐RAP transcript levels. N‐RAP is a scaffold for α‐actinin and actin assembly during myofibrillogenesis, and we quantitated myofibril accumulation by morphometric analysis of α‐actinin organization. Between 3 and 6 days, NMHC IIB knockdown was accompanied by the abolishment of cardiomyocyte spreading. During this period the rate of myofibril accumulation steadily decreased, correlating with the slowly decreasing levels of N‐RAP. Between 6 and 8 days NMHC IIB and N‐RAP protein levels recovered, and cardiomyocyte spreading and myofibril accumulation resumed. Inhibition of proteasome function using MG132 led to accumulation of excess N‐RAP, and the secondary decrease in N‐RAP that otherwise accompanied NMHC IIB knockdown was abolished. The results show that NMHC IIB knockdown led to decreased N‐RAP levels through proteasome‐mediated degradation. Furthermore, these proteins have distinct functional roles, with NMHC IIB playing a role in cardiomyocyte spreading and N‐RAP functioning in myofibril assembly. Cell Motil. Cytoskeleton 2008. Published 2008 Wiley‐Liss, Inc.
Living microlens arrays
Authors: Zimberlin Jessica A. , Wadsworth Patricia , Crosby Alfred J.
Published: July 2008

Both individual cells and sheets of cells exert traction forces on the substrate and these forces have been investigated using a wide range of methods. Here we compare the mechanical properties of fibroblasts and epithelial cells using a novel surface geometry. Living cells are added to a thin film of polystyrene [PS] attached to a substrate of crosslinked poly(dimethyl siloxane) [PDMS] microwells. The contractile nature of the cells attached to the surface and the compliance of the PDMS surface geometry allows the PS thin film to buckle, forming arrays of convex microlenses. The resulting curvature of the microlenses allows us to determine the applied strain of growing cell sheets. We report that a monolayer of epithelial cells exerts more stress on the substrate than fibroblasts and attribute this to the collective behavior of the epithelium. By subsequently adding different chemical triggers to the system, the contractile nature of the cells changes, thus modifying the focal length of the microlenses. Together, these findings demonstrate the importance of studying the mechanics of cell sheets and also introduce a new design paradigm for advanced materials, offering great promise for a range of applications. Cell Motil. Cytoskeleton 2008. © 2008 Wiley‐Liss, Inc.
Solid‐State Forms of Sodium Valproate, Active Component of the Anticonvulsant Drug Epilim
Authors: Petruševski Gjorgi , Naumov Panče , Jovanovski Gligor , Bogoeva‐Gaceva Gordana , Ng Seik Weng
Published: July 2008

The results of the first detailed and systematic investigation of the solid‐state forms of sodium valproate, one of the most potent and widely used anticonvulsant medicines, are presented. By using wet and dry methods, eight solid forms of varying stability in air were obtained and characterized. Three extremely hygroscopic polycrystalline hydrates, Na(C8H15O2)⋅H2O (form A), Na(C8H15O2)⋅x H2O (form B), and Na(C8H15O2)⋅y H2O (form D), three acid‐stabilized stoichiometric solvates, Na3(C8H15O2)3(C8H16O2)⋅H2O (form C), Na(C8H15O2)(C8H16O2) (form E), and Na3(C8H15O2)3(C8H16O2)⋅2 H2O (form F), the pure anhydrous salt Na(C8H15O2) (form H), and an additional unstable thermal intermediate Na3(C8H15O2)3(C8H16O2)0.5 (form G) were prepared. Under ambient conditions, forms A and B as well as the commercially available compound appear as very hygroscopic white powders. Form C is less hygroscopic, while forms E and F are stable and are not hygroscopic. Partial stabilization of forms A and B can be achieved by evacuation and pressing, which results in a lower hydrate D, or after a heating–cooling cycle, resulting in crystallization of the anhydrous salt H. Addition of one molecule of valproic acid and saturation with one molecule of water of forms A and B results in the less hygroscopic form C. Addition to form C of a second water molecule affords form F, which is not hygroscopic and is indefinitely stable. The symmetric structure and medium alkyl chain length of the valproate ion are some of the probable reasons for the presence of a number of solid solvates: in its most stable conformation, the valproate ion cannot simultaneously pack efficiently and interact strongly through the negatively charged carboxylate group without leaving voids in the crystalline lattice. The conformational flexibility of the aliphatic chains probably aids the penetration of water molecules, which results in a strong affinity for the absorption of water.
The First Step into the Brain: Uptake of NIO‐PBCA Nanoparticles by Endothelial Cells in vitro and in vivo, and Direct Evidence for their Blood–Brain Barrier Permeation
Authors: Weiss Clemens K. , Kohnle Maria‐Verena , Landfester Katharina , Hauk Thomas , Fischer Dietmar , Schmitz‐Wienke Julia , Mailänder Volker
Published: July 2008

By using fluorescent polysorbate 80 coated poly(n‐butylcyanoacrylate) (PBCA) nanoparticles in an in vivo study, direct evidence was found for the presence of nanoparticles entering the brain and retina of rats. The nanoparticles, prepared with a miniemulsion process, were labeled in situ with a fluorescent dye and coated with polysorbate 80. After preparation the particle size, ζ potential, and the molecular weight distribution were determined. BMEC cells were used as an in vitro model for the BBB. The cells showed significant uptake of the particles, but no transcytosis could be observed in vitro. After applying the particles to the animals at two concentrations, cryosections of the brains and retinas were prepared. Regarding the sections of the rats that received the lower dose, co‐localization of the applied fluorescent particles and the stained endothelial cells could be detected in the brain and retina, indicating particle internalization in the endothelial cells. Applied at higher doses, the particles could be detected within the brain and retina with few co‐localized signals, suggesting passage through the blood–brain and blood–retina barriers.
NMR and the uncertainty principle: How to and how not to interpret homogeneous line broadening and pulse nonselectivity. III. Uncertainty?
Authors: Szántay Csaba
Published: July 2008

Following the treatments presented in Parts I and II, I herein discuss in more detail the popular notion that the frequency of a monochromatic RF pulse as well as that of a monochromatic FID is “in effect” uncertain due to the (Heisenberg) Uncertainty Principle, which also manifests itself in the fact that the FT‐spectrum of these temporal entities is spread over a nonzero frequency band. In Part III, I continue my preliminary review of some further fundamental concepts, such as the Heisenberg and Fourier Uncertainty Principles, that are needed to understand whether or not the NMR linewidth and the RF excitation bandwidth have anything to do with “uncertainty”. The article then culminates in re‐addressing our Two NMR Problems in a more conscientious frame of mind by using a more refined formalism. The correct interpretation of these problems will be discussed in Part IV. © 2008 Wiley Periodicals, Inc. Concepts Magn Reson Part A 32A: 302–325, 2008.
Laplacian eigenfunctions in NMR. I. A numerical tool
Authors: Grebenkov Denis S.
Published: July 2008

A geometrical confinement considerably affects the diffusive motion of the nuclei and the consequent signal attenuation under inhomogeneous magnetic fields. In this article, we illustrate the use of Laplacian eigenfunctions to describe this effect. Starting from the classical Bloch‐Torrey equation, we obtain the free induction decay (FID) and the spin‐echo or gradient‐echo signal in a compact matrix form. Each attenuation mechanism (restricted diffusion, gradient dephasing, surface or bulk relaxation) is represented by a matrix which is constructed from the Laplace operator eigenbasis and thus depending only on the geometry of the confinement. In turn, the physical parameters (free diffusion coefficient, gradient intensity, surface or bulk relaxivity) characterize the “strengths” of the underlying attenuation mechanisms and naturally appear as coefficients in front of these matrices. Once the Laplacian eigenfunctions for a given confinement are found (analytically or numerically), further computation of the macroscopic signal is more accurate and much faster than by using conventional simulation methods. The matrix technique is actually a simple numerical tool to deal with arbitrary gradient waveforms, including simple or stimulated, single or multiple spin echoes. We illustrate its efficiency by considering restricted diffusion in simple domains: a slab, a cylinder, and a sphere. In a companion paper, we shall focus on theoretical advances achieved by using Laplacian eigenfunctions. © 2008 Wiley Periodicals, Inc. Concepts Magn Reson Part A 32A: 277–301, 2008.
The impact of socioeconomic status on survival after cancer in the United States
Authors: Byers Tim E. , Wolf Holly J. , Bauer Katrina R. , Bolick‐Aldrich Susan , Chen Vivien W. , Finch Jack L. , Fulton John P. , Schymura Maria J. , Shen Tiefu , Van Heest Scott , Yin Xiang
Published: July 2008

BACKGROUND.

Understanding the ways in which socioeconomic status (SES) affects mortality is important for defining strategies to eliminate the unequal burden of cancer by race and ethnicity in the United States.

METHODS.

Disease stage, treatment, and 5‐year mortality rates were ascertained by reviewing medical records, and SES was determined by analyzing income and education at the census tract level for 4844 women with breast cancer, 4332 men with prostate cancer, and 4422 men and women with colorectal cancer who were diagnosed in 7 U.S. states in 1997.

RESULTS.

Low SES was associated with more advanced disease stage and with less aggressive treatment for all 3 cancers. The hazard ratio (HR) for 5‐year all‐cause mortality associated with low SES was elevated after a diagnosis of breast cancer when the analysis was adjusted for age (HR, 1.59; 95% confidence interval [CI], 1.35‐1.87). Adjustment for mediating factors of race/ethnicity, comorbid conditions, cancer stage, and treatment reduced the association. The age‐adjusted mortality risk associated with low SES was elevated after a diagnosis of prostate cancer (HR, 1.33; 95% CI, 1.13‐1.57), and multivariate adjustments for mediating factors also reduced that association. There was less association between SES and mortality after a diagnosis of colorectal cancer. For all 3 cancer sites, low SES was a much stronger predictor of mortality among individuals aged <65 years and among individuals from racial/ethnic minority groups.

CONCLUSIONS.

The current results indicated that low SES is a risk factor for all‐cause mortality after a diagnosis of cancer, largely because of a later stage at diagnosis and less aggressive treatment. These findings support the need to focus on SES as an underlying factor in cancer disparities by race and ethnicity. Cancer 2008. © 2008 American Cancer Society.
Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004
Authors: Zhou Yuhong , Wang Haijun , Fang Wenjing , Romaguer Jorge E. , Zhang Yanxia , Delasalle Kay B. , Kwak Larry , Yi Qing , Du Xianglin L. , Wang Michael
Published: July 2008

BACKGROUND.

Mantle cell lymphoma (MCL) is a distinct subtype of B‐cell non‐Hodgkin's lymphoma. To the authors' knowledge, little is known regarding its incidence patterns and associated factors. The purpose of the current study was to examine the incidence of MCL over a period of 13 years and to identify the factors associated with the incidence patterns.

METHODS.

Patients diagnosed with MCL between 1992 and 2004 were identified from the Surveillance, Epidemiology, and End Results (SEER) Tumor registries. SEER*Stat statistical software was used for analysis.

RESULTS.

Of the 87,166 patients diagnosed with non‐Hodgkin's lymphoma during the 13‐year period between 1992 and 2004, 2459 (2.8%) had confirmed MCL. The overall incidence of MCL (per 100,000) was 0.55, which increased with age: 0.07 in patients aged <50 years, 2.97 in patients aged 70 to 79 years, and 2.78 in those aged ≥80 years. The age‐adjusted incidence rate increased from 0.27 of 100,000 in 1992 to 0.69 of 100,000 in 2004, and the annual percent change was 5.87% (P < .05). The median age at diagnosis was 68 years. The incidence of MCL was higher in men (0.84 of 100,000) than in women (0.34 of 100,000) (P < .05), and was higher in Caucasians (0.61 of 100,000) than in African Americans (0.32 of 100,000). Late‐stage (III‐IV) MCL was diagnosed in 74.6% of patients. There were significant geographic variations noted (P < .05).

CONCLUSIONS.

The incidence of MCL increased from 1992 to 2004, and was significantly higher in men, in Caucasians, and patients aged ≥50 years. Most patients were diagnosed with late‐stage MCL, and there also were considerable geographic variations observed in incidence rate. Cancer 2008. © 2008 American Cancer Society.
The influence of serial prostate‐specific antigen (PSA) screening on the PSA velocity at diagnosis
Authors: Martin Neil E. , Chen Ming‐Hui , Catalona William J. , Loeb Stacy , Roehl Kimberly A. , D'Amico Anthony V.
Published: July 2008

BACKGROUND.

A prostate‐specific antigen (PSA) velocity (PSAV) >2 ng/mL during the year before diagnosis has been associated with an increased risk of prostate cancer‐specific mortality (PCSM) after radical prostatectomy (RP) or radiation therapy. The objective of the current study was to examine whether the proportion of men with a PSAV >2 ng/mL per year has changed significantly during the PSA era.

METHODS.

The authors evaluated 1095 men from a prospective prostate cancer screening study who underwent RP between 1989 and 2002. For the purposes of this analysis, clinicopathologic features were compared between men who were treated during the following 3 periods: before 1995, from 1995 to 1998, and after 1998. Logistic regression analysis was used to evaluate for an association between the year of diagnosis and the proportion of men with a PSAV >2 ng/mL per year.

RESULTS.

Two hundred sixty‐two of 1095 men (24%) had a PSAV >2 ng/mL per year. There was a statistically significant reduction in the proportion of men presenting with a PSAV >2 ng/mL per year over the study period. Specifically, 35% of men presented with a PSAV >2 ng/mL per year in the early period compared with only 22% and 12% in the middle and late periods, respectively (P < .001). Over the studied periods, there also was a significantly greater proportion of men with >2 PSA values obtained before diagnosis (P < .001).

CONCLUSIONS.

Men who were screened serially with PSA were less likely to present with a PSAV >2 ng/mL per year. This association lends support to the hypothesis that serial PSA‐based screening may lead to a decrease in PCSM. Cancer 2008. © 2008 American Cancer Society.
Kinase domain point mutations in Philadelphia chromosome‐positive acute lymphoblastic leukemia emerge after therapy with BCR‐ABL kinase inhibitors
Authors: Jones Dan , Thomas Deborah , Yin C. Cameron , O'Brien Susan , Cortes Jorge E. , Jabbour Elias , Breeden Megan , Giles Francis J. , Zhao Weiqiang , Kantarjian Hagop M.
Published: July 2008

BACKGROUND.

BCR‐ABL kinase domain (KD) mutations are detected in approximately 45% of patients with imatinib‐resistant chronic myeloid leukemia. Patterns of KD mutations in Philadelphia chromosome (Ph)‐positive acute lympho‐ blastic leukemia (ALL) are less well studied.

METHODS.

The authors assessed KD mutations in patients with recurrent Ph‐positive ALL after treatments that included 1 or more kinase inhibitors (n = 24 patients) or no prior kinase inhibitor (KI) therapy (n = 12 patients).

RESULTS.

ABL KD mutations were detected by direct sequencing in 15 of 17 patients (88%) who had recurrent Ph‐positive ALL and received prior imatinib (n = 16) or dasatinib (n = 1) treatment and in 6 of 7 patients (86%) who had resistant/recurrent tumors treated with ≥2 KIs compared with 0 of 12 patients with recurrent Ph‐positive ALL who never received KIs. A restricted set of mutations was observed, mostly Y253H and T315I, and were detected on average 10 months after KI initiation, and mutations were not detected in the initial tumor samples before KI therapy in 12 patients who were assessed. Using a more sensitive pyrosequencing method, mutations were not detected at codons 315 and 253 in the diagnostic samples from those 12 patients or in 30 patients with Ph‐positive ALL who never developed recurrent disease.

CONCLUSIONS.

ABL KD mutations, especially at codons 315 and 253, emerged at the time of disease recurrence in the vast majority of patients who had Ph‐positive ALL and received maintenance KI therapy. Thus, the authors concluded that ongoing KI exposure may alter the patterns of recurrence and favor the outgrowth of clones with KI‐resistant mutations. Cancer 2008. © 2008 American Cancer Society.
Pilot clinical trial of localized concurrent chemoradiation therapy for locally advanced hepatocellular carcinoma with portal vein thrombosis
Authors: Han Kwang‐Hyub , Seong Jinsil , Kim Ja Kyung , Ahn Sang Hoon , Lee Do Yun , Chon Chae Yoon
Published: July 2008

BACKGROUND.

Patients with advanced hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) have a particularly grave prognosis. In the current study, an attempt was made to localize chemoradiation therapy (CCRT) followed by hepatic arterial infusion chemotherapy (HAIC) in patients with locally advanced HCC with PVT and good reserve liver function. The objective of the current study was to evaluate the therapeutic effect of localized CCRT followed by HAIC as a new treatment modality for these patients.

METHODS.

Between January 1998 and December 2003, 40 patients were recruited. Concurrent regional chemotherapy using an intra‐arterial implanted port plus localized external beam radiotherapy was performed with a total of 45 gray (Gy) over 5 weeks with conventional fractionation and hepatic arterial infusion of 5‐fluorouracil (5‐FU), which was administered during the first and fifth weeks of radiotherapy. One month after localized CCRT, HAIC with 5‐FU and cisplatin was administered every 4 weeks.

RESULTS.

One month after localized CCRT, an objective response was observed on the intention‐to‐treat analysis in 18 of 40 patients (45%). The actuarial 3‐year overall survival rate was 24.1% and the median survival time was 13.1 months from the start of radiation treatment. Responders after localized CCRT demonstrated significantly better survival (P = .033) than nonresponders.

CONCLUSIONS.

The substantial response rate as well as median survival time noted in the current study encourages the use of this new approach in patients with locally advanced HCC with PVT. Cancer 2008. © 2008 American Cancer Society.
Triplet combination of gemcitabine, paclitaxel, and carboplatin followed by maintenance 5‐fluorouracil and folinic acid in patients with metastatic nasopharyngeal carcinoma
Authors: Leong Swan Swan , Wee Joseph , Rajan Sandeep , Toh Chee Keong , Lim Wan Teck , Hee Siew Wan , Tay Miah Hiang , Poon Donald , Tan Eng Huat
Published: July 2008

BACKGROUND.

Nasopharyngeal carcinoma (NPC) is a disease that is highly responsive to various chemotherapeutic agents. In the metastatic setting, 2‐drug combination chemotherapy generally provides a response rate of 55% to 75%, and median survival of 10 to 12 months. The objective of the current study was to assess the efficacy of a 3‐drug combination followed by maintenance treatment in patients with metastatic NPC.

METHODS.

Patients with metastatic NPC were treated with a combination of gemcitabine at a dose of 1000 mg/m2, paclitaxel at a dose of 70 mg/m2, and carboplatin at an area under the concentration‐time‐curve (AUC) of 2.5 on Days 1 and 8 every 21 days. Patients who achieved partial or complete response continued to receive weekly 5‐fluorouracil at a dose of 450 mg/m2 and leucovorin at a dose of 30 mg/m2 for 48 weeks.

RESULTS.

Twenty‐eight patients were recruited. Twenty‐two (79%) patients had ≥2 sites of disease. Toxicities were mainly from bone marrow suppression, with 79% grade 3/4 neutropenia, 32% grade 3/4 anemia, and 29% grade 3/4 thrombocytopenia (according to the National Cancer Institute Common Toxicity Criteria). The overall response rate to the 3‐drug regimen was 86%, with a complete response rate of 11%. The median duration of response was 8 months and the median overall survival was 22 months.

CONCLUSIONS.

This regimen of a 3‐drug combination followed by maintenance is feasible and has demonstrated an encouraging response rate and overall survival. Cancer 2008. © 2008 American Cancer Society.
The phosphorylated membrane estrogen receptor and cytoplasmic signaling and apoptosis proteins in human breast cancer
Authors: Mintz Paul J. , Habib Nagy A. , Jones Louise J. , Giamas Georgios , Lewis Jacqueline S. , Bowen Rebecca L. , Coombes R. Charles , Stebbing Justin
Published: July 2008

BACKGROUND.

Estrogens play a central role in breast cancer development, and the estrogen receptor‒α (ERα) remains the single most important predictor of breast cancer prognosis. Therefore, it is crucial to elucidate pathways that may contribute to ER signaling in clinical specimens.

METHODS.

Using extracts of fresh invasive ERα‐positive invasive breast carcinomas, ductal carcinoma in situ, and normal glandular breast tissue, the authors performed Western blot analyses of the membrane‐bound ER, 1 of its phosphorylated isoforms, and cytosolic fractions from the same specimens, examining associated proteins (Akt/mitogen‐activated protein kinase pathways). Western blot analysis and immunocapture for the apoptosis and survival factors Bcl‐2 agonist of death (BAD)/Bcl‐2 and BAD/Bcl‐xL were also performed.

RESULTS.

To the authors' knowledge, this is the first study to report that ERα was phosphorylated in the plasma membrane fractions derived from patients' invasive breast carcinomas. This was associated with a predominance of phosphorylated BAD and a relative reduction in Bcl‐2 compared with both normal tissue and ductal carcinoma in situ, although such studies in fresh tissue did not corroborate these findings. The authors also demonstrated that the BAD/Bcl‐2 and BAD/Bcl‐xL complexes characterized the invasive carcinoma state.

CONCLUSIONS.

A phosphorylated form of the membrane ER was found to characterize the invasive cancer state. This was associated with a reduction in BAD/Bcl‐2 and BAD/Bcl‐xl. These data implicate the membrane ERα as the in vivo receptor responsible for transcription‐independent cellular responses to estrogens. Cancer 2008. © 2008 American Cancer Society.
Combined treatment with pegylated interferon–α‐2a and dacarbazine in patients with advanced metastatic melanoma
Authors: Hauschild Axel , Dummer Reinhard , Ugurel Selma , Kaehler Katharina C. , Egberts Friederike , Fink Wolfram , Both‐Skalsky Jeannine , Laetsch Barbara , Schadendorf Dirk
Published: July 2008

BACKGROUND.

Dacarbazine (DTIC) and pegylated interferon (IFN)–α‐2a have both demonstrated some efficacy as single agents in metastatic melanoma. To the authors' knowledge, the current study is the first to test a combination of these 2 agents in a phase 2 trial.

METHODS.

Twenty–eight patients with stage IV melanoma without brain metastases were treated with DTIC (at a dose of 850 mg/m2 every 3 weeks) combined with weekly pegylated IFN–α‐2a at a dose of 180 μg. The study was initiated to evaluate the efficacy and tolerability of the combination. The primary study endpoint was objective response.

RESULTS.

Twenty–five patients were evaluable for response. Two patients (8.0%) achieved a complete response that continued for >480 days and 746 days, respectively. Four patients (16.0%) demonstrated a partial response, and another patient experienced stable disease. Six of 7 nonprogressive patients had either not received treatment or had not developed disease progression during adjuvant IFN treatment for stage II/III disease. The median duration of response was 236 days, the median progression‐free survival was 56 days, and the overall survival time was 403 days. Few grade 3 toxicities and only 1 grade 4 toxicity were observed (according to National Cancer Institute Common Toxicity Criteria).

CONCLUSIONS.

The combination of DTIC and pegylated IFN–α‐2a was found to be well tolerated in patients with metastatic melanoma. The response rate of 24%, including 2 long‐lasting complete responses, is encouraging, but must be confirmed in larger trials. Cancer 2008. © 2008 American Cancer Society.
Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system
Authors: Kawano June , Tanizawa Yukio , Shinoda Koh
Published: July 2008

Wolfram syndrome (OMIM 222300) is a neurodegenerative disorder defined by insulin‐dependent diabetes mellitus and progressive optic atrophy. This syndrome has been attributed to mutations in the WFS1 gene, which codes for a putative multi‐spanning membrane glycoprotein of the endoplasmic reticulum. The function of WFS1 (wolframin), the distribution of this protein in the mammalian visual system, and the pathogenesis of optic atrophy in Wolfram syndrome are unclear. In this study we made a detailed analysis of the distribution of Wfs1 mRNA and protein in the normal mouse visual system by using in situ hybridization and immunohistochemistry. The mRNA and protein were observed in the retina, optic nerve, and brain. In the retina, Wfs1 expression was strong in amacrine and Müller cells, and moderate in photoreceptors and horizontal cells. In addition, it was detectable in bipolar and retinal ganglion cells. Interestingly, moderate Wfs1 expression was seen in the optic nerve, particularly in astrocytes, while little Wfs1 was expressed in the optic chiasm or optic tract. In the brain, moderate Wfs1 expression was observed in the zonal, superficial gray, and intermediate gray layers of the superior colliculus, in the dorsomedial part of the suprachiasmatic nucleus, and in layer II of the primary and secondary visual cortices. Thus, Wfs1 mRNA and protein were widely distributed in the normal mouse visual system. This evidence may provide clues as to the physiological role of Wfs1 protein in the biology of vision, and help to explain the selective vulnerability of the optic nerve to WFS1 loss‐of‐function. J. Comp. Neurol. 510:1–23, 2008. © 2008 Wiley‐Liss, Inc.
Distinct molecular pathways for development of telencephalic interneuron subtypes revealed through analysis of Lhx6 mutants
Authors: Zhao Yangu , Flandin Pierre , Long Jason E. , Cuesta Melissa Dela , Westphal Heiner , Rubenstein John L.R.
Published: July 2008

Here we analyze the role of the Lhx6 lim‐homeobox transcription factor in regulating the development of subsets of neocortical, hippocampal, and striatal interneurons. An Lhx6 loss‐of‐function allele, which expresses placental alkaline phosphatase (PLAP), allowed analysis of the development and fate of Lhx6‐expressing interneurons in mice lacking this homeobox transcription factor. There are Lhx6+;Dlx+ and Lhx6−;Dlx+ subtypes of tangentially migrating interneurons. Most interneurons in Lhx6PLAP/PLAP mutants migrate to the cortex, although less efficiently, and exhibit defects in populating the marginal zone and superficial parts of the neocortical plate. By contrast, migration to superficial parts of the hippocampus is not seriously affected. Furthermore, whereas parvalbumin+ and somatostatin+ interneurons do not differentiate, NPY+ interneurons are present; we suggest that these NPY+ interneurons are derived from the Lhx6−;Dlx+ subtype. Striatal interneurons show deficits distinct from pallial interneurons, including a reduction in the NPY+ subtype. We provide evidence that Lhx6 mediates these effects through promoting expression of receptors that regulate interneuron migration (ErbB4, CXCR4, and CXCR7), and through promoting the expression of transcription factors either known (Arx) or implicated (bMaf, Cux2, and NPAS1) in controlling interneuron development. J. Comp. Neurol. 510:79–99, 2008. © 2008 Wiley‐Liss, Inc.
Regional and cellular localization of the CXCl12/SDF‐1 chemokine receptor CXCR7 in the developing and adult rat brain
Authors: Schönemeier Bastian , Kolodziej Angela , Schulz Stefan , Jacobs Stefan , Hoellt Volker , Stumm Ralf
Published: July 2008

The chemokine stromal cell‐derived factor‐1 (SDF‐1) regulates neuronal development via the chemokine receptor CXCR4. In the adult brain the SDF‐1/CXCR4 system was implicated in neurogenesis, neuromodulation, brain inflammation, tumor growth, and HIV encephalopathy. Until the recent identification of RDC1/CXCR7 as the second SDF‐1 receptor, CXCR4 was considered to be the only receptor for SDF‐1. Here we provide the first map of CXCR7 mRNA expression in the embryonic and adult rat brain. At embryonic stages, CXCR7 and CXCR4 were codistributed in the germinative zone of the ganglionic eminences, caudate putamen, and along the routes of GABAergic precursors migrating toward the cortex. In the cortex, CXCR7 was identified in GABAergic precursors and in some reelin‐expressing Cajal‐Retzius cells. Unlike CXCR4, CXCR7 was abundant in neurons forming the cortical plate and sparse in the developing dentate gyrus and cerebellar external germinal layer. In the adult brain, CXCR7 was expressed by blood vessels, pyramidal cells in CA3, and mature dentate gyrus granule cells, which is reminiscent of the SDF‐1 pattern. CXCR7 and CXCR4 overlapped in the wall of the four ventricles. Further neuronal structures expressing CXCR7 comprised the olfactory bulb, accumbens shell, supraoptic and ventromedial hypothalamic nuclei, medial thalamus, and brain stem motor nuclei. Also, GLAST‐expressing astrocytes showed signals for CXCR7. Thus, CXCR4 and CXCR7 may cooperate or act independently in SDF‐1‐dependent neuronal development. In mature neurons and blood vessels CXCR7 appears to be the preponderant SDF‐1‐receptor. Indexing terms: J. Comp. Neurol. 510:207–220, 2008. © 2008 Wiley‐Liss, Inc.
Spatiotemporal distribution of proteoglycans in the developing rat's barrel field and the effects of early deafferentation
Authors: Bahia Carlomagno Pacheco , Houzel Jean‐Christophe , Picanço‐Diniz Cristovam Wanderley , Pereira Antonio
Published: July 2008

The isolectin Vicia villosa B4 (VV) selectively recognizes N‐acetyl‐galactosamine‐terminal glycoconjugates that form perineuronal nets (PNNs) around a subset of neurons in the cerebral cortex. PNNs are thought to participate in the guidance of incoming thalamic axons and in the posterior stabilization and maintenance of synaptic contacts. Here we examine the spatial and temporal distribution of biotinylated VV in tangential sections through layer IV of the posteromedial barrel subfield in the primary somatosensory cortex (PMBSF) of rats ranging from postnatal day (P)3 to P60, which underwent unilateral deafferentation of whiskers at birth. In the afferented hemisphere, labeling first appears at P5, with a diffuse distribution, probably associated with neuropil, inside PMBSF barrels. VV distribution remains diffuse during the following week, and declines around P17. From P24 onward, however, proteoglycans form PNNs around cell bodies preferentially localized in septal regions of the PMBSF. In the contralateral, deafferented PMBSF the diffuse labeling also appears on P5, but first develops into elongated, homogeneous stripes, which disappear after P24, leaving only scattered cell bodies along layer IV. Our results indicate that proteoglycans appear simultaneous to barrel formation in the developing rat while segregation of PNNs to septal cells might be driven by afferent activity. J. Comp. Neurol. 510:145–157, 2008. © 2008 Wiley‐Liss, Inc.
Anatomical and neurochemical characterization of dopaminergic interplexiform processes in mouse and rat retinas
Authors: Witkovsky Paul , Gábriel Robert , Križaj David
Published: July 2008

Dopaminergic (DA) neurons of mouse and rat retinas are of the interplexiform subtype (DA‐IPC), i.e., they send processes distally toward the outer retina, exhibiting numerous varicosities along their course. The primary question we addressed was whether distally located DA‐IPC varicosities, identified by tyrosine hydroxylase (TH) immunoreactivity, had the characteristic presynaptic proteins associated with calcium‐dependent vesicular release of neurotransmitter. We found that TH immunoreactive varicosities in the outer retina possessed vesicular monoamine transporter 2 and vesicular GABA transporter, but they lacked immunostaining for any of nine subtypes of voltage‐dependent calcium channel. Immunoreactivity for other channels that may permit calcium influx such as certain ionotropic glutamate receptors and canonical transient receptor potential channels (TRPCs) was similarly absent, although DA‐IPC varicosities did show ryanodine receptor immunoreactivity, indicating the presence of intracellular calcium stores. The synaptic vesicle proteins sv2a and sv2b and certain other proteins associated with the presynaptic membrane were absent from DA‐IPC varicosities, but the vesicular SNARE protein, vamp2, was present in a fraction of those varicosities. We identified a presumed second class of IPC that is GABAergic but not dopaminergic. Outer retinal varicosities of this putative GABAergic IPC did colocalize synaptic vesicle protein 2a, suggesting they possessed a conventional vesicular release mechanism. J. Comp. Neurol. 510:158–174, 2008. © 2008 Wiley‐Liss, Inc.
Comparative study of the distribution of the α‐subunits of voltage‐gated sodium channels in normal and axotomized rat dorsal root ganglion neurons
Authors: Fukuoka Tetsuo , Kobayashi Kimiko , Yamanaka Hiroki , Obata Koichi , Dai Yi , Noguchi Koichi
Published: July 2008

We compared the distribution of the α‐subunit mRNAs of voltage‐gated sodium channels Nav1.1–1.3 and Nav1.6–1.9 and a related channel, Nax, in histochemically identified neuronal subpopulations of the rat dorsal root ganglia (DRG). In the naïve DRG, the expression of Nav1.1 and Nav1.6 was restricted to A‐fiber neurons, and they were preferentially expressed by TrkC neurons, suggesting that proprioceptive neurons possess these channels. Nav1.7, ‐1.8, and ‐1.9 mRNAs were more abundant in C‐fiber neurons compared with A‐fiber ones. Nax was evenly expressed in both populations. Although Nav1.8 and ‐1.9 were preferentially expressed by TrkA neurons, other α‐subunits were expressed independently of TrkA expression. Actually, all IB4+ neurons expressed both Nav1.8 and ‐1.9, and relatively limited subpopulations of IB4+ neurons (3% and 12%, respectively) expressed Nav1.1 and/or Nav1.6. These findings provide useful information in interpreting the electrophysiological characteristics of some neuronal subpopulations of naïve DRG. After L5 spinal nerve ligation, Nav1.3 mRNA was up‐regulated mainly in A‐fiber neurons in the ipsilateral L5 DRG. Although previous studies demonstrated that nerve growth factor (NGF) and glial cell‐derived neurotrophic factor (GDNF) reversed this up‐regulation, the Nav1.3 induction was independent of either TrkA or GFRα1 expression, suggesting that the induction of Nav1.3 may be one of the common responses of axotomized DRG neurons without a direct relationship to NGF/GDNF supply. J. Comp. Neurol. 510:188–206, 2008. © 2008 Wiley‐Liss, Inc.