bluuebunny/crossref_metadata_2025 huggingface dataset:
CARRIER-DENSITY DEPENDENCE OF THE EXCHANGE COUPLING BETWEEN MAGNETIC IONS AND CONDUCTION BAND ELECTRONS IN HEAVILY n-TYPE Zn(1-x)MnxSe AND OPTICALLY PUMPED Cd(1-x)MnxTe
Authors: LENTZE M. , GRABS P. , GEURTS J. , RÖNNBURG K. , MOHLER E. , ROSKOS H.
Published: May 2007

We report on the analysis of the influence of carrier concentration on the exchange coupling between conduction band electrons and Mn d-electrons in diluted magnetic semiconductors. For this analysis we employed (i) electronic spin-flip Raman spectroscopy on heavily n-doped ( Zn , Mn ) Se , (ii) time-resolved Faraday rotation on optically pumped ( Cd , Mn ) Te . With increasing carrier density, a reduction of the exchange energy N0α up to 30 % is observed. It is explained by a weakening of the ferromagnetic character of the coupling of conducton-band electrons to the Mn d-electrons by an admixture of an antiferromagnetic (p-d) coupling contribution to the ferromagnetic (s-d) one for q ≠ 0.
OPEN PROBLEMS IN THE HYDRODYNAMICAL APPROACH TO RELATIVISTIC HEAVY ION COLLISIONS
Authors: KODAMA T. , KOIDE T. , DENICOL G. S. , MOTA P.
Published: May 2007

We discuss some open problems in hydrodynamical approach to the relativistic heavy ion collisions. In particular, we propose a new, very simple alternative approach to the relativistic dissipative hydrodynamics of Israel and Stewart.
DILEPTON PRODUCTION IN HEAVY ION REACTIONS
Authors: FAESSLER AMAND , FUCHS CHRISTIAN
Published: May 2007

We present a unified description of the vector meson and dilepton production in elementary and in heavy ion reactions. The production of vector mesons is described via the excitation of nucleon resonances. Medium effects in heavy ion reactions are discussed.
QUANTUM TELEPORTATION WITH PAIR-COHERENT STATES
Authors: GÁBRIS AURÉL , AGARWAL GIRISH S.
Published: May 2007

Recently, it has been argued that all presently performed continuous variable quantum teleportation experiments could be explained using a local hidden variable theory. In this paper, we study a modification of the original protocol which requires a fully quantum mechanical explanation even when coherent states are teleported. Our calculations of the fidelity of teleportation using a pair-coherent state under ideal conditions suggest that fidelity above the required limit of 1/2 may be achievable in an experiment also.
QUANTUM NONLOCALITY OF POLARIZATION-MOMENTUM HYPER-ENTANGLED STATES
Authors: BARBIERI M. , DE MARTINI F. , MATALONI P. , VALLONE G.
Published: May 2007

We present two experimental tests of nonlocality, namely the Bell's inequalities and the "All Versus Nothing" (AVN) proof, performed with a two photon hyper-entangled state, entangled in polarization and momentum. These states, which double the extension of the available qubits, are engineered by a simple experimental method which uses linear optics and a single Type I nonlinear crystal. The AVN test of local realism represents a generalization of the GHZ to the case of two entangled particles and two observers.
THE GAUGE SYMMETRY OF THE THIRD KIND AND QUANTUM MECHANICS AS AN INFRARED LIMIT
Authors: ELZE HANS-THOMAS
Published: May 2007

We introduce functional degrees of freedom by a new gauge principle related to the phase of the wave functional. Thus, quantum mechanical systems are dissipatively embedded into a nonlinear classical dynamical structure. There is a necessary fundamental length, besides an entropy/area parameter, and standard couplings. For states that are sufficiently spread over configuration space, quantum field theory is recovered.
TOWARDS A QUANTUM ALGORITHM FOR THE PERMANENT
Authors: MARZUOLI ANNALISA , RASETTI MARIO
Published: May 2007

We resort to considerations based on topological quantum field theory to outline the development of a possible quantum algorithm for the evaluation of the permanent of a 0 - 1 matrix. Such an algorithm might represent a breakthrough for quantum computation, since computing the permanent is considered a "universal problem", namely, one among the hardest problems that a quantum computer can efficiently handle.
HOW "HOT" ARE MIXED QUANTUM STATES?
Authors: PARFIONOV GEORGE , ZAPATRIN ROMÀN R.
Published: May 2007

Given a mixed quantum state ρ of a qudit, we consider any observable M as a kind of "thermometer" in the following sense. Given a source which emits pure states with certain distributions, we select distributions such that the appropriate average value of the observable M is equal to the average Tr M ρ of M in the state ρ. Among those distributions we find the most typical, namely, having the highest differential entropy. We call this distribution the conditional Gibbs ensemble as it turns out to be a Gibbs distribution characterized by a temperature-like parameter β. The expressions establishing the liaisons between the density operator ρ and its temperature parameter β are provided. Within this approach, the uniform mixed state has the highest "temperature," which tends to zero as the state in question approaches a pure state.
Pramlintide treatment reduces 24-h caloric intake and meal sizes and improves control of eating in obese subjects: a 6-wk translational research study
Authors: Smith Steven R. , Blundell John E. , Burns Colleen , Ellero Cinzia , Schroeder Brock E. , Kesty Nicole C. , Chen Kim S. , Halseth Amy E. , Lush Cameron W. , Weyer Christian
Published: May 2007

Evidence from rodent studies indicates that the β-cell-derived neurohormone amylin exerts multiple effects on eating behavior, including reductions in meal size, intake of highly palatable foods, and stress-induced sucrose consumption. To assess the effect of amylin agonism on human eating behavior we conducted a randomized, blinded, placebo-controlled, multicenter study investigating the effects of the amylin analog pramlintide on body weight, 24-h caloric intake, portion sizes, “fast food” intake, and perceived control of eating in 88 obese subjects. After a 2-day placebo lead-in, subjects self-administered pramlintide (180 μg) or placebo by subcutaneous injection 15 min before meals for 6 wk without concomitant lifestyle modifications. Compared with placebo, pramlintide treatment elicited significant mean reductions from baseline in body weight on day 44 (−2.1 ± 0.3 vs. +0.1 ± 0.4%, P < 0.001), 24-h caloric intake (−990 ± 94 vs. −243 ± 126 kcal on day 3, P < 0.0001; −680 ± 86 vs. −191 ± 161 kcal on day 43, P < 0.01), portion sizes, and caloric intake at a “fast food challenge” (−385 ± 61 vs. −109 ± 88 kcal on day 44, P < 0.05). Pramlintide treatment also improved perceived control of eating, as demonstrated by a 45% placebo-corrected reduction in binge eating scores ( P < 0.01). The results of this translational research study confirm in humans various preclinical effects of amylin agonism, demonstrating that pramlintide-mediated weight loss in obese subjects is accompanied by sustained reductions in 24-h food intake, portion sizes, fast food intake, and binge eating tendencies.
Ischemic preconditioning prevents in vivo hyperoxygenation in postischemic myocardium with preservation of mitochondrial oxygen consumption
Authors: Zhu Xuehai , Liu Bin , Zhou Shaotang , Chen Yeong-Renn , Deng Yuanmu , Zweier Jay L. , He Guanglong
Published: May 2007

Ischemic preconditioning (IPC) strongly protects against ischemia-reperfusion injury; however, its effect on subsequent myocardial oxygenation is unknown. Therefore, we determine in an in vivo mouse model of regional ischemia and reperfusion (I/R) if IPC attenuates postischemic myocardial hyperoxygenation and decreases formation of reactive oxygen/nitrogen species (ROS/RNS), with preservation of mitochondrial function. The following five groups of mice were studied: sham, control (I/R), ischemic preconditioning (IPC + I/R, 3 cycles of 5 min coronary occlusion/5 min reperfusion) and IPC + I/R NG-nitro-l-arginine methyl ester treated, and IPC + I/R eNOS knockout mice. I/R and IPC + I/R mice were subjected to 30 min regional ischemia followed by 60 min reperfusion. Myocardial Po2and redox state were monitored by electron paramagnetic resonance spectroscopy. In the IPC + I/R, but not the I/R group, regional blood flow was increased after reperfusion. Po2upon reperfusion increased significantly above preischemic values in I/R but not in IPC + I/R mice. Tissue redox state was measured from the reduction rate of a spin probe, and this rate was 60% higher in IPC than in non-IPC hearts. Activities of NADH dehydrogenase (NADH-DH) and cytochrome c oxidase (CcO) were reduced in I/R mice after 60 min reperfusion but conserved in IPC + I/R mice compared with sham. There were no differences in NADH-DH and CcO expression in I/R and IPC + I/R groups compared with sham. After 60 min reperfusion, strong nitrotyrosine formation was observed in I/R mice, but only weak staining was observed in IPC + I/R mice. Thus IPC markedly attenuates postischemic myocardial hyperoxygenation with less ROS/RNS generation and preservation of mitochondrial O2metabolism because of conserved NADH-DH and CcO activities.
Endotoxin-induced maturation of monocytes in preterm fetal sheep lung
Authors: Kramer Boris W. , Joshi Shubhada N. , Moss Timothy J. M. , Newnham John P. , Sindelar Richard , Jobe Alan H. , Kallapur Suhas G.
Published: May 2007

The fetal lung normally contains immature monocytes and very few mature macrophages. The chorioamnionitis frequently associated with preterm birth induces monocyte influx into the fetal lung. Previous studies demonstrated that monocytes in the developing lung can mediate lung injury responses that resemble BPD in humans. We hypothesized that chorioamnionitis would induce maturation of immature monocytes in the fetal lung. Groups of three to seven time-mated ewes received saline or 10 mg of endotoxin ( Escherichia coli 055:B5) in saline by intra-amniotic injection for intervals from 1 to 14 days before operative delivery at 124 days of gestational age. Monocytic cells from lung tissue were recovered using Percoll gradients. Monocytic cells consistent with macrophages were identified morphologically and by myosin heavy chain class II expression. An increase in macrophages was preceded by induction of granulocyte-macrophage colony-stimulating factor in the lung and subsequent activation of the transcription factor PU.1. The production of IL-6 by monocytes/macrophages in response to endotoxin challenge in vitro increased 7 and 14 days after exposure to intra-amniotic endotoxin. Recombinant TNF-α induced IL-6 production by lung monocytic cells exposed to intra-amniotic endotoxin but not in control cells. Monocytic phagocytosis of apoptotic neutrophils also increased 7 and 14 days after exposure to intra-amniotic endotoxin. Intra-amniotic endotoxin induced lung monocytes to develop into functionally mature cells consistent with macrophages. These findings have implications for lung immune responses after exposure to chorioamnionitis.
Anti-IL-8 autoantibody:IL-8 immune complexes suppress spontaneous apoptosis of neutrophils
Authors: Fudala Rafal , Krupa Agnieszka , Matthay Michael A. , Allen Timothy C. , Kurdowska Anna K.
Published: May 2007

Our previous studies demonstrated that a significant fraction of interleukin-8 (IL-8) in lung fluids from patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) is associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 immune complexes). Neutrophils have been implicated in the pathogenesis of ALI/ARDS, and moreover, it is well-established that apoptosis of neutrophils is delayed in patients with ALI/ARDS. The aim of this study was, therefore, to examine the role of anti-IL-8:IL-8 immune complexes in modulating spontaneous apoptosis of normal human neutrophils. Apoptosis was assessed by evaluating morphological changes, measuring enzymatic activity of caspase-3, and determining the extent of DNA degradation. We found that samples containing anti-IL-8:IL-8 immune complexes but not samples from which these complexes were removed inhibited neutrophil apoptosis. Furthermore, the former samples or effectively anti-IL-8:IL-8 complexes induced an increase in the level of antiapoptotic protein, Bcl-XL. In contrast, levels of proapoptotic proteins Bax and Bak were decreased in the same conditions. Activity of both caspase-3 and caspase-9 was also suppressed by anti-IL-8:IL-8 complex-containing samples. Finally, we established that IgG receptor, FcγRIIa, mediates antiapoptotic activity of anti-IL-8:IL-8 complexes and that the key components of the FcγRIIa signaling pathway, Src, Syk, PI3 kinase, and ERK, may be involved in regulation of neutrophil apoptosis by the complexes. These studies demonstrate for the first time that anti-IL-8:IL-8 immune complexes have the ability to prolong neutrophil life.
A 10-Gene Classifier for Distinguishing Head and Neck Squamous Cell Carcinoma and Lung Squamous Cell Carcinoma
Authors: Vachani Anil , Nebozhyn Michael , Singhal Sunil , Alila Linda , Wakeam Elliot , Muschel Ruth , Powell Charles A. , Gaffney Patrick , Singh Bhuvanesh , Brose Marcia S. , Litzky Leslie A. , Kucharczuk John , Kaiser Larry R. , Marron J. Stephen , Showe Michael K. , Albelda Steven M. , Showe Louise C.
Published: May 2007

Purpose: The risk of developing metastatic squamous cell carcinoma for patients with head and neck squamous cell carcinoma (HNSCC) is very high. Because these patients are often heavy tobacco users, they are also at risk for developing a second primary cancer, with squamous cell carcinoma of the lung (LSCC) being the most common. The distinction between a lung metastasis and a primary LSCC is currently based on certain clinical and histologic criteria, although the accuracy of this approach remains in question.

Experimental Design: Gene expression patterns derived from 28 patients with HNSCC or LSCC from a single center were analyzed using penalized discriminant analysis. Validation was done on previously published data for 134 total subjects from four independent Affymetrix data sets.

Results: We identified a panel of 10 genes (CXCL13, COL6A2, SFTPB, KRT14, TSPYL5, TMP3, KLK10, MMP1, GAS1, and MYH2) that accurately distinguished these two tumor types. This 10-gene classifier was validated on 122 subjects derived from four independent data sets and an average accuracy of 96% was shown. Gene expression values were validated by quantitative reverse transcription-PCR derived on 12 independent samples (seven HNSCC and five LSCC). The 10-gene classifier was also used to determine the site of origin of 12 lung lesions from patients with prior HNSCC.

Conclusions: The results suggest that penalized discriminant analysis using these 10 genes will be highly accurate in determining the origin of squamous cell carcinomas in the lungs of patients with previous head and neck malignancies.
Tumor-Specific Efficacy of Transforming Growth Factor-βRI Inhibition in Eker Rats
Authors: Laping Nicholas J. , Everitt Jeffrey I. , Frazier Kendall S. , Burgert Mark , Portis Melisa J. , Cadacio Caprice , Gold Leslie I. , Walker Cheryl L.
Published: May 2007

Purpose: Transforming growth factor β (TGF-β), which generally stimulates the growth of mesenchymally derived cells but inhibits the growth of epithelial cells, has been proposed as a possible target for cancer therapy. However, concerns have been raised that whereas inhibition of TGF-β signaling could be efficacious for lesions in which TGF-β promotes tumor development and/or progression, systemic pharmacologic blockade of this signaling pathway could also promote the growth of epithelial lesions.

Experimental Design: We examined the effect of a TGF-β inhibitor on mesenchymal (leiomyoma) and epithelial (renal cell carcinoma) tumors in Eker rats, which are genetically predisposed to develop these tumors with a high frequency.

Results: Blockade of TGF-β signaling with the ALK5/type I TGF-βR kinase inhibitor, SB-525334, was efficacious for uterine leiomyoma; significantly decreasing tumor incidence and multiplicity, and reducing the size of these mesenchymal tumors. However, SB-525334 was also mitogenic and antiapoptotic for epithelial cells in the kidney and exacerbated the growth of epithelial lesions present in the kidneys of these animals.

Conclusion: Although pharmacologic inhibition of TGF-β signaling with SB-525334 may be efficacious for mesenchymal tumors, inhibition of this signaling pathway seems to promote the development of epithelial tumors.
Improved Oral Delivery ofN-(4-Hydroxyphenyl)Retinamide with a Novel LYM-X-SORB Organized Lipid Complex
Authors: Maurer Barry J. , Kalous Ondrej , Yesair David W. , Wu Xiaqin , Janeba Jitka , Maldonado Vanessa , Khankaldyyan Vazgen , Frgala Tomas , Sun Bee-Chun , McKee R. Travis , Burgess Stephen W. , Shaw Walter A. , Reynolds C. Patrick
Published: May 2007

Purpose: Fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] is a cytotoxic retinoid that suffers from a wide interpatient variation in bioavailability when delivered orally in a corn oil capsule. The poor bioavailability of the capsule formulation may have limited responses in clinical trials, and the large capsules are not suitable for young children. To support the hypothesis that a novel organized lipid matrix, LYM-X-SORB, can increase the oral bioavailability of fenretinide, fenretinide in LYM-X-SORB matrix and in a powderized LYM-X-SORB formulation was delivered to mice.

Experimental Design: Fenretinide was delivered orally to mice as the contents of the corn oil capsule, in LYM-X-SORB matrix (4-HPR/LYM-X-SORB matrix) or in a LYM-X-SORB matrix powderized with sugar and flour (4-HPR/LYM-X-SORB oral powder). Levels of 4-HPR, and its principal metabolite, N-(4-methoxyphenyl)retinamide, were assayed in plasma and tissues.

Results: In a dose-responsive manner, from 120 to 360 mg/kg/d, delivery to mice of 4-HPR in LYM-X-SORB matrix, or as 4-HPR/LYM-X-SORB oral powder, increased 4-HPR plasma levels up to 4-fold (P < 0.01) and increased tissue levels up to 7-fold (P < 0.01) compared with similar doses of 4-HPR delivered using capsule contents. Metabolite [N-(4-methoxyphenyl)retinamide] levels mirrored 4-HPR levels. Two human neuroblastoma murine xenograft models showed increased survival (P < 0.03), when treated with 4-HPR/LYM-X-SORB oral powder, confirming the bioactivity of the formulation.

Conclusions: 4-HPR/LYM-X-SORB oral powder is a novel, oral drug delivery formulation, suitable for pediatric use, which warrants further development for the delivery of fenretinide in the treatment of cancer. A phase I clinical trial in pediatric neuroblastoma is in progress.
Cyclooxygenase 2 Expression in Rectal Cancer Is of Prognostic Significance in Patients Receiving Preoperative Radiotherapy
Authors: de Heer Pieter , Gosens Marleen J.E.M. , de Bruin Elza C. , Dekker-Ensink N. Geeske , Putter Hein , Marijnen Corrie A.M. , van den Brule Adriaan J.C. , van Krieken J. Han J.M. , Rutten Harm J.T. , Kuppen Peter J.K. , van de Velde Cornelis J.H. ,   for the Dutch Colorectal Cancer Group
Published: May 2007

Purpose: To determine the effect of cyclooxygenase (COX)-2 expression on clinical behavior in irradiated and nonirradiated rectal carcinomas.

Experimental Design: Tumor samples were collected from 1,231 patients of the Dutch TME trial, in which rectal cancer patients were treated with standardized surgery and randomized for preoperative short-term (5 × 5 Gy) radiotherapy or no preoperative radiotherapy. Tissue microarrays were constructed from primary tumor material, and COX-2 expression was assessed by immunohistochemistry. Tumor cell apoptosis was determined by M30 immunostaining.

Results: A high level of COX-2 expression after radiotherapy was associated with low levels of tumor cell apoptosis (P = 0.001). COX-2 expression had no significant effect on patient survival or tumor recurrence in nonirradiated tumors. However, in patients receiving preoperative radiotherapy, high level of COX-2 expression was associated with higher incidence of distant recurrences [P = 0.003; hazard ratio (HR), 1.7; 95% confidence interval (95% CI), 1.2-2.5] and shorter disease-free survival (P = 0.002; HR, 1.8; 95% CI, 1.2-2.5) and overall survival (P = 0.009; HR, 1.5; 95% CI, 1.1-2.0), independent of patient age, tumor stage, tumor location, or the presence of tumor cells in the circumferential resection margin.

Conclusions: A high level of COX-2 expression after preoperative radiotherapy in resection specimens is associated with apoptosis resistance, high distant recurrence rates, and a poor prognosis in rectal cancer.
E1A, E1B Double-Restricted Adenovirus with RGD-Fiber Modification Exhibits Enhanced Oncolysis for CAR–Deficient Biliary Cancers
Authors: Wakayama Mariko , Abei Masato , Kawashima Rei , Seo Emiko , Fukuda Kuniaki , Ugai Hideo , Murata Takehide , Tanaka Naomi , Hyodo Ichinosuke , Hamada Hirofumi , Yokoyama Kazunari K.
Published: May 2007

Purpose: Cancers of biliary system represent highly malignant diseases of dismal prognosis. We have previously introduced AxdAdB3, an E1A, E1B double-restricted oncolytic adenovirus, which showed excellent oncolytic efficacy for approximately half of the biliary cancer lines with an enhanced safety to normal cells. The purpose of this study was to evaluate whether RGD-fiber modification (AxdAdB3-F/RGD), which enables integrin-dependent infection, can improve the infectivity and efficacy of AxdAdB3 for biliary cancers.

Experimental Design: Expressions of adenoviral receptors, coxsackievirus adenovirus receptor (CAR) and integrins (αvβ3 and αvβ5), were compared with the level of infectivity of LacZ-expressing replication-defective adenoviruses with wild-type fibers or RGD-modified fibers in a panel of biliary cancer cell lines in vitro. Viral replication and cytotoxicity in vitro of AxdAdB3-F/RGD, a novel E1A, E1B double-restricted replication-selective adenovirus with RGD-modified fibers, were compared with those of its parent virus, AxdAdB3, in various biliary cancer cells and in normal cells. In vivo antitumor effects of these oncolytic viruses were compared in a xenograft tumor model.

Results: Expression of CAR significantly correlated with the adenovirus infectivity, whereas integrin αvβ5 was abundantly expressed in almost all biliary cancer cells. Whereas AxdAdB3 effectively replicated and lysed only the biliary cancer cells with a preserved expression of CAR, AxdAdB3-F/RGD exhibited efficient replication and potent oncolysis in both CAR-positive and CAR-negative biliary cancer cells. AxdAdB3-F/RGD showed attenuated replication and little cytopathy in human normal cells (i.e., hepatocytes, WI-38 cells) as well as AxdAdB3. Furthermore, in nude mice with s.c. xenografts of CAR-deficient human biliary cancer, i.t. AxdAdB3-F/RGD therapy caused a marked inhibition of tumor growth.

Conclusions: The RGD-fiber modification strategy enhanced the infectivity, replication, and oncolytic effects of the E1A, E1B double-restricted oncolytic adenovirus for CAR-deficient biliary cancers. In addition, it preserved the merit of excellent safety of the double-restricted virus for normal cells. These results suggest a potential use of this agent for the treatment of biliary cancers.
Microsatellite Instability Markers for Identifying Early-Onset Colorectal Cancers Caused by Germ-Line Mutations in DNA Mismatch Repair Genes
Authors: Mead Leeanne J. , Jenkins Mark A. , Young Joanne , Royce Simon G. , Smith Letitia , St. John D. James B. , Macrae Finlay , Giles Graham G. , Hopper John L. , Southey Melissa C.
Published: May 2007

Purpose: Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes.

Experimental Design: Invasive primary tumors from a population-based sample of 107 cases of colorectal cancer diagnosed before age 45 years and tested for germ-line mutations in MLH1, MSH2, MSH6, and PMS2 and MMR protein expression were screened for MSI using the National Cancer Institute panel and an expanded 10-microsatellite marker panel.

Results: The National Cancer Institute five-marker panel system scored 31 (29%) as NCIMSI-High, 13 (12%) as NCIMSI-Low, and 63 (59%) as NCIMS-Stable. The 10-marker panel classified 18 (17%) as 10MSI-High, 17 (16%) as 10MSI-Low, and 72 (67%) as 10MS-Stable. Of the 26 cancers that lacked the expression of at least one MMR gene, 24 (92%) were positive for some level of MSI (using either microsatellite panel). The mononucleotide repeats Bat26, Bat40, and Myb were unstable in all 10MSI-High cancers and all MLH1 and MSH2 mutation carriers (100% sensitive). Bat40 and Bat25 were unstable in all tumors of MSH6 mutation carriers (100% sensitive). Bat40 was unstable in all MMR gene mutation carriers (100% sensitive). By incorporating seven mononucleotide repeats markers into the 10-marker panel, we were able to distinguish the carriers of MSH6 mutations (all scored 10MSI-Low) from the MLH1 and MSH2 mutation carriers (all scored 10MSI-High).

Conclusions: In early-onset colorectal cancer, a microsatellite panel containing a high proportion of mononuclear repeats can distinguish between tumors caused by MLH1 and MSH2 mutations from those caused by MSH6 mutations.
Immunization of High-Risk Breast Cancer Patients with Clustered sTn-KLH Conjugate plus the Immunologic Adjuvant QS-21
Authors: Gilewski Teresa A. , Ragupathi Govind , Dickler Maura , Powell Shemeeakah , Bhuta Sonal , Panageas Kathy , Koganty R. Rao , Chin-Eng Jeannette , Hudis Clifford , Norton Larry , Houghton Alan N. , Livingston Philip O.
Published: May 2007

Purpose: To determine the clinical toxicities and antibody response against sTn and tumor cells expressing sTn following immunization of high-risk breast cancer patients with clustered sTn-KLH [sTn(c)-KLH] conjugate plus QS-21.

Experimental Design: Twenty-seven patients with no evidence of disease and with a history of either stage IV no evidence of disease, rising tumor markers, stage II (≥4 positive axillary nodes), or stage III disease received a total of five injections each during weeks 1, 2, 3, 7, and 19. Immunizations consisted of sTn(c)-KLH conjugate containing 30, 10, 3, or 1 μg sTn(c) plus 100 μg QS-21. Induction of IgM and IgG antibodies against synthetic sTn(c) and natural sTn on ovine submaxillary mucin were measured before and after therapy. Fluorescence-activated cell sorting analyses assessed reactivity of antibodies to LSC and MCF-7 tumor cells.

Results: The most common toxicities were transient local skin reactions at the injection site and mild flu-like symptoms. All patients developed significant IgM and IgG antibody titers against sTn(c). Antibody titers against ovine submaxillary mucin were usually of lower titers. IgM reactivity with LSC tumor cells was observed in 21 patients and with MCF-7 cells in 13 patients. There was minimal IgG reactivity with LSC cells.

Conclusion: Immunization with sTn(c)-KLH conjugate plus QS-21 is well tolerated and immunogenic in high-risk breast cancer patients. Future trials will incorporate sTn(c) as a component of a multiple antigen vaccine.
Vascular Endothelial Growth Factor and Its Relationship to Inflammatory Mediators
Authors: Angelo Laura S. , Kurzrock Razelle
Published: May 2007

Inflammation occurs in response to host injury or infection, as the result of an autoimmune disease, or in response to the development of a tumor. Although the immune system may be helpful in fighting the tumor, it may also fuel the tumorigenic process. In fact, recent data suggest a strong link between chronic inflammation, angiogenesis, and the development of cancer. For example, inflammation and scarring caused by recurring infections with Mycobacterium tuberculosis may be a cause for cancers of the lung. Inflammatory breast cancer exhibits increased angiogenesis and lymphangiogenesis and has a higher metastatic potential than noninflammatory breast cancer. Nonsteroidal anti-inflammatory drugs have been proposed as preventives for the development of colon carcinoma and ovarian cancer. Inhibition of nuclear factor-κB contributes to the proposed mechanism of action. Inflammatory cytokines, including interleukin-6, serve as autocrine and paracrine growth factors for several cancers, and high levels of these cytokines may correlate with a poor prognosis and increased production of angiogenic factors. The state of the art of our understanding of this critical interaction is reviewed.
The Graft Content of Donor T Cells Expressing γδTCR+ and CD4+foxp3+ Predicts the Risk of Acute Graft versus Host Disease after Transplantation of Allogeneic Peripheral Blood Stem Cells from Unrelated Donors
Authors: Pabst Caroline , Schirutschke Holger , Ehninger Gerhard , Bornhäuser Martin , Platzbecker Uwe
Published: May 2007

Purpose: Recently, high numbers of regulatory T cells within the stem cell graft were described to be associated with less graft-versus-host disease (GVHD) after related peripheral blood stem cell transplantation (PBSCT). Studies in mice also suggest a distinct role of γδTCR+ T cells in mediating GVHD. Therefore, the aim of this study was to define the yet-unknown role of regulatory and γδTCR+ T cells in human PBSCT from unrelated donors.

Experimental Design: The frequency of both T-cell subsets within the graft was analyzed in 63 patients receiving unrelated allogeneic PBSCT. The respective amounts were quantified by flow cytometry and PCR and further correlated with clinical outcome.

Results: The grafts contained a median of 11.2 × 106/kg CD4+foxp3+ and 9.8 × 106/kg γδTCR+ T cells, respectively. Patients receiving more CD4+foxp3+ cells had a lower cumulative incidence of acute GVHD II-IV (44% versus 65%, P = 0.03). Interestingly, in patients who received higher concentrations of donor γδTCR+ T cells, acute GVHD II-IV was more frequent (66% versus 40%, P = 0.02). In multivariate analysis, only the graft concentration of γδTCR+ T cells (P = 0.002) and a positive cytomegalovirus status of the recipient (P = 0.03) were significantly associated with the occurrence of acute GVHD II-IV.

Conclusion: Graft composition of T-cell subsets seems to affect the outcome of patients receiving allogeneic PBSCT from unrelated donors. Therefore, selective manipulation or add-back of particular subsets might be a promising strategy to reduce the incidence of GVHD.
Microtubule-Associated Proteins as Targets in Cancer Chemotherapy
Authors: Bhat Kumar M.R. , Setaluri Vijayasaradhi
Published: May 2007

Natural and synthetic compounds that disrupt microtubule dynamics are among the most successful and widely used cancer chemotherapeutic agents. However, lack of reliable markers that predict sensitivity of cancers to these agents and development of resistance remain vexing issues. There is accumulating evidence that a family of cellular proteins that are associated with and alter the dynamics of microtubules can determine sensitivity of cancer cells to microtubule-targeting agents and play a role in tumor cell resistance to these agents. This growing family of microtubule-associated proteins (MAP) includes products of oncogenes, tumor suppressors, and apoptosis regulators, suggesting that alteration of microtubule dynamics may be one of the critical events in tumorigenesis and tumor progression. The objective of this review is to integrate the knowledge on these seemingly unrelated proteins that share a common function and examine their relevance to microtubule-targeting therapies and highlight MAPs-tubulin-drug interactions as a novel avenue for new drug discovery. Based on the available evidence, we propose that rational microtubule-targeting cancer therapeutic approaches should ideally include proteomic profiling of tumor MAPs before administration of microtubule-stabilizing/destabilizing agents preferentially in combination with agents that modulate the expression of relevant MAPs.
Magnetic Resonance Imaging Determination of Tumor Grade and Early Response to Temozolomide in a Genetically Engineered Mouse Model of Glioma
Authors: McConville Patrick , Hambardzumyan Dolores , Moody Jonathan B. , Leopold Wilbur R. , Kreger Alicia R. , Woolliscroft Michael J. , Rehemtulla Alnawaz , Ross Brian D. , Holland Eric C.
Published: May 2007

Purpose: The median survival for patients diagnosed with glioblastoma multiforme, the most common type of brain tumor, is less than 1 year. Animal glioma models that are more predictive of therapeutic response in human patients than traditional models and that are genetically and histologically accurate are an unmet need. The nestin tv-a (Ntv-a) genetically engineered mouse spontaneously develops glioma when infected with ALV-A expressing platelet-derived growth factor, resulting in autocrine platelet-derived growth factor signaling.

Experimental Design: In the Ntv-a genetically engineered mouse model, T2-weighted and T1-weighted, contrast-enhanced magnetic resonance images were correlated with histology, glioma grade (high or low), and survival. Magnetic resonance imaging (MRI) was therefore used to enroll mice with high-grade gliomas into a second study that tested efficacy of the current standard of care for glioma, temozolomide (100 mg/kg qdx5 i.p., n = 13).

Results: The Ntv-a model generated a heterogeneous group of gliomas, some with high-grade growth rate and histologic characteristics and others with characteristics of lower-grade gliomas. We showed that MRI could be used to predict tumor grade and survival. Temozolomide treatment of high-grade tv-a gliomas provided a 14-day growth delay compared with vehicle controls. Diffusion MRI measurement of the apparent diffusion coefficient showed an early decrease in cellularity with temozolomide, similar to that observed in humans.

Conclusions: The use of MRI in the Ntv-a model allows determination of glioma grade and survival prediction, distribution of mice with specific tumor types into preclinical trials, and efficacy determination both by tumor growth and early apparent diffusion coefficient response.
Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles
Authors: Hegde Priti S. , Rusnak David , Bertiaux Melissa , Alligood Krystal , Strum Jay , Gagnon Robert , Gilmer Tona M.
Published: May 2007

Lapatinib (GW572016) is a small-molecule dual inhibitor of epidermal growth factor receptor (ErbB1) and ErbB2 receptor kinase activities currently in phase III clinical trials. We used phosphoprotein and microarray analyses to carry out targeted pathway studies of phosphorylation and gene expression changes in human breast cancer cell lines in the presence or absence of lapatinib. Studies were done in four breast cancer cell lines, two of which were responsive and two of which were nonresponsive to lapatinib. Responsive cell lines, BT474 and SKBr3, constitutively overexpress ErbB2 and show an IC50 of 25 or 32 nmol/L for lapatinib, respectively. In contrast, nonresponsive MDA-MB-468 and T47D cells expressed a low basal level of ErbB2 and showed IC50 values in the micromolar range. Cells responsive to lapatinib exhibited strong differential effects on multiple genes in the AKT pathway. After 12 h of exposure to 1.0 μmol/L of lapatinib, AKT1, MAPK9, HSPCA, IRAK1, and CCND1 transcripts were down-regulated 7- to 25-fold in responsive BT474 and SKBr3 cells. In contrast, lapatinib weakly down-regulated the AKT pathway in nonresponsive breast cancer cell lines (<5-fold down-regulation of most genes in the pathway). Furthermore, the proapoptotic gene FOXO3A, which is negatively regulated by AKT, was up-regulated 7- and 25-fold in lapatinib-responsive SKBr3 and BT474 cells, respectively. Phosphorylated Akt and Akt-mediated phosphorylation of FOXO3A also decreased in responsive breast cancer cell lines exposed to lapatinib. Gene expression profiling also revealed that lapatinib stimulated the expression of estrogen and progesterone receptors and modulated the expression of genes involved in cell cycle control, glycolysis, and fatty acid metabolism. In BT474 and T47D cells, which expressed moderate basal levels of the estrogen and progesterone receptors, 1.0 μmol/L of lapatinib induced expression by 7- to 11-fold. These data provide insight into the mechanism of action of lapatinib in breast cancer cells. [Mol Cancer Ther 2007;6(5):1629–40]
Classification of anti-estrogens according to intramolecular FRET effects on phospho-mutants of estrogen receptor α
Authors: Zwart Wilbert , Griekspoor Alexander , Rondaij Mariska , Verwoerd Desiree , Neefjes Jacques , Michalides Rob
Published: May 2007

Anti-estrogen resistance is a major clinical problem in the treatment of breast cancer. In this study, fluorescence resonance energy transfer (FRET) analysis, a rapid and direct way to monitor conformational changes of estrogen receptor α (ERα) upon anti-estrogen binding, was used to characterize resistance to anti-estrogens. Nine different anti-estrogens all induced a rapid FRET response within minutes after the compounds have liganded to ERα in live cells, corresponding to an inactive conformation of the ERα. Phosphorylation of Ser305 and/or Ser236 of ERα by protein kinase A (PKA) and of Ser118 by mitogen-activated protein kinase (MAPK) influenced the FRET response differently for the various anti-estrogens. PKA and MAPK are both associated with resistance to anti-estrogens in breast cancer patients. Their respective actions can result in seven different combinations of phospho-modifications in ERα where the FRET effects of particular anti-estrogen(s) are nullified. The FRET response provided information on the activity of ERα under the various anti-estrogen conditions as measured in a traditional reporter assay. Tamoxifen and EM-652 were the most sensitive to kinase activities, whereas ICI-182,780 (Fulvestrant) and ICI-164,384 were the most stringent. The different responses of anti-estrogens to the various combinations of phospho-modifications in ERα elucidate why certain anti-estrogens are more prone than others to develop resistance. These data provide new insights into the mechanism of action of anti-hormones and are critical for selection of the correct individual patient-based endocrine therapy in breast cancer. [Mol Cancer Ther 2007;6(5):1526–33]
Induction of p21 protein protects against sulforaphane-induced mitotic arrest in LNCaP human prostate cancer cell line
Authors: Herman-Antosiewicz Anna , Xiao Hui , Lew Karen L. , Singh Shivendra V.
Published: May 2007

Previous studies have indicated that d,l-sulforaphane (SFN), a synthetic cancer chemopreventive analogue of cruciferous vegetable-derived isomer (−)-1-isothiocyanato-(4R)-(methylsulfinyl)-butane, activates a checkpoint kinase 2 (Chk2)–dependent G2-M phase cell cycle arrest in p53-deficient human prostate cancer cells. Because p53 is a downstream target of Chk2 kinase and known to regulate G2-M transition by transcriptional regulation of cyclin-dependent kinase (Cdk) inhibitor p21Cip1/Waf1 (p21), the present study was undertaken to determine the role of p21 in SFN-induced cell cycle arrest using wild-type p53–expressing cell line LNCaP. The SFN treatment caused a modest increase in S phase fraction and a marked increase in G2-M fraction in LNCaP cells in a concentration- and time-dependent manner. The SFN-induced S phase arrest correlated with a reduction in protein levels of cyclin D1, cyclin E, Cdk4, and Cdk6, whereas activation of the G2-M checkpoint was accompanied by induction of cyclin B1 and down-regulation of Cdk1 and Cdc25C protein levels. The SFN-treated LNCaP cells were also arrested in mitosis as revealed by immunofluorescence microscopy and increased Ser10 phosphorylation of histone H3, a sensitive marker for mitotic cells. The SFN treatment increased activating phosphorylation of Chk2 (Thr68) that was accompanied by induction of p53 and p21. The SFN-induced mitotic arrest was statistically significantly increased by small interfering RNA–based knockdown of p21. However, p21 protein knockdown did not have any appreciable effect on SFN-induced cytoplasmic histone-associated DNA fragmentation (apoptosis). In conclusion, the present study indicates that induction of p21 protects against SFN-induced mitotic arrest in LNCaP cells. [Mol Cancer Ther 2007;6(5):1673–81]
Biglycan Deficiency Causes Spontaneous Aortic Dissection and Rupture in Mice
Authors: Heegaard Anne-Marie , Corsi Alessandro , Danielsen Carl Christian , Nielsen Karina L. , Jorgensen Henrik L. , Riminucci Mara , Young Marian F. , Bianco Paolo
Published: May 2007

Background—

For the majority of cases, the cause of spontaneous aortic dissection and rupture is unknown. An inherited risk is associated with Marfan syndrome, Ehlers-Danlos syndrome type IV, and loci mapped to diverse autosomal chromosomes. Analysis of pedigrees however has indicated that it may be also inherited as an X-linked trait. The biglycan gene, found on chromosome X in humans and mice, encodes a small leucine-rich proteoglycan involved in the integrity of the extracellular matrix. A vascular phenotype has never been described in mice deficient in the gene for small leucine-rich proteoglycans. In the breeding of BALB/cA mice homozygous for a null mutation of the biglycan gene, we observed that 50% of biglycan-deficient male mice died suddenly within the first 3 months of life.

Methods and Results—

Necropsies revealed a major hemorrhage in the thoracic or abdominal cavity, and histology showed aortic rupture that involved an intimal and medial tear as well as dissection between the media and adventitia. By transmission electron microscopy and biomechanical testing, the aortas of biglycan-deficient mice showed structural abnormalities of collagen fibrils and reduced tensile strength. Similar collagen fibril changes were observed in male as well as in female biglycan-deficient mice, which implies a role of additional determinants such as gender-related response to stress in the development of this vascular catastrophe only in male mice.

Conclusions—

The spontaneous death of biglycan-deficient male mice from aortic rupture implicates biglycan as essential for the structural and functional integrity of the aortic wall and suggests a potential role of biglycan gene defects in the pathogenesis of aortic dissection and rupture in humans.
Diagnostic Miscues in Congenital Long-QT Syndrome
Authors: Taggart Nathaniel W. , Haglund; Carla M. , Tester David J. , Ackerman Michael J.
Published: May 2007

Background—

Long-QT syndrome (LQTS) is a potentially lethal cardiac channelopathy that can be mistaken for palpitations, neurocardiogenic syncope, and epilepsy. Because of increased physician and public awareness of warning signs suggestive of LQTS, there is the potential for LQTS to be overdiagnosed. We sought to determine the agreement between the dismissal diagnosis from an LQTS subspecialty clinic and the original referral diagnosis.

Methods and Results—

Data from the medical record were compared with data from the outside evaluation for 176 consecutive patients (121 females, median age 16 years, average referral corrected QT interval [QTc] of 481 ms) referred with a diagnosis of LQTS. After evaluation at Mayo Clinic’s LQTS Clinic, patients were categorized as having definite LQTS (D-LQTS), possible LQTS (P-LQTS), or no LQTS (No-LQTS). Seventy-three patients (41%) were categorized as No-LQTS, 56 (32%) as P-LQTS, and only 47 (27%) as D-LQTS. The yield of genetic testing among D-LQTS patients was 78% compared with 34% for P-LQTS and 0% among No-LQTS patients (
P
<0.0001). The average QTc was greater in either D-LQTS or P-LQTS than in No-LQTS (461 versus 424 ms,
P
<0.0001). Vasovagal syncope was more common among the No-LQTS subset (28%) than the P-LQTS/D-LQTS group (8%;
P
=0.04). Determinants for discordance (ie, positive outside diagnosis versus No-LQTS) included overestimation of QTc, diagnosing LQTS on the basis of “borderline” QTc values, and interpretation of a vasovagal fainting episode as an LQTS-precipitated cardiac event.

Conclusions—

Diagnostic concordance was present for less than one third of the patients who sought a second opinion. Two of every 5 patients referred with the diagnosis of LQTS departed without such a diagnosis. Miscalculation of the QTc, misinterpretation of the normal distribution of QTc values, and misinterpretation of symptoms appear to be responsible for most of the diagnostic miscues.
Risk Factors for the Progression of Coronary Artery Calcification in Asymptomatic Subjects
Authors: Kronmal Richard A. , McClelland Robyn L. , Detrano Robert , Shea Steven , Lima João A. , Cushman Mary , Bild Diane E. , Burke Gregory L.
Published: May 2007

Background—

The Multi-Ethnic Study of Atherosclerosis (MESA) provides an opportunity to study the association of traditional cardiovascular risk factors with the incidence and progression of coronary artery calcium (CAC) in a large community-based cohort with no evidence of clinical cardiovascular disease.

Methods and Results—

Follow-up CAC measurements were available for 5756 participants with an average of 2.4 years between scans. The incidence of newly detectable CAC averaged 6.6% per year. Incidence increased steadily across age, ranging from <5% annually in those <50 years of age to >12% in those >80 years of age. Median annual change in CAC for those with existing calcification at baseline was 14 Agatston units for women and 21 Agatston units for men. Most traditional cardiovascular risk factors were associated with both the risk of developing new incident coronary calcium and increases in existing calcification. These included age, male gender, white race/ethnicity, hypertension, body mass index, diabetes mellitus, glucose, and family history of heart attack. Factors also existed that were related only to incident CAC risk, such as low- and high-density lipoprotein cholesterol and creatinine. Diabetes mellitus had the strongest association with CAC progression for blacks and the weakest for Hispanics, with intermediate associations for whites and Chinese.

Conclusions—

This is the first large multiethnic study reporting on the incidence and progression of CAC. Standard coronary risk factors were generally related to both CAC incidence and progression. Whites had more incident CAC and CAC progression than the other 3 racial/ethnic groups. Except for diabetes mellitus, risk factor relationships were similar across racial/ethnic groups.
Influence of Acute and Chronic Mineralocorticoid Excess on Endothelial Function in Healthy Men
Authors: Nietlispach Fabian , Julius Barbara , Schindler Ruth , Bernheim Alain , Binkert Christoph , Kiowski Wolfgang , Brunner-La Rocca Hans Peter
Published: May 2007

Aldosterone has rapid nongenomic effects in the human vasculature. However, data are not uniform and little is known about chronic effects of aldosterone. Therefore, we investigated acute and chronic effects of elevated aldosterone levels on endothelial function in the forearm vasculature of healthy men. In a first crossover study, the effects of arterial aldosterone infusion in ascending doses (3.3 to 55 pmol/min per 1000 mL forearm volume) on forearm blood flow were investigated in 8 healthy men (26±2 years). In a second study, endothelium-dependent (acetylcholine; 0.08, 0.275, and 2.75 μmol/min per 1000 mL) and endothelium-independent (sodium nitroprusside 0.02 μmol/min per 1000 mL) vasodilation and basal nitric oxide formation (forearm blood flow response to blockade by
N
G
-monomethyl-
l
-arginine 8 μmol/min per 1000 mL) were tested in 10 healthy men (age 30±5 years) at baseline, during infusion of 55 pmol/1000 mL per min aldosterone (acute effects), and after 0.3 mg/d oral fludrocortisone for 2 weeks (chronic effects) on separate days. Forearm blood flow was assessed by venous occlusion plethysmography. No change in forearm blood flow was seen with aldosterone infusion alone. Acute coinfusion of aldosterone increased vasodilation to sodium nitroprusside by 93% (
P
<0.01) and to acetylcholine by 60% (
P
=0.14). Response to
N
G
-monomethyl-
l
-arginine did not change. After 2 weeks of oral fludrocortisone, response to acetylcholine was enhanced by 72% compared with baseline (
P
=0.03). Additionally, response to
N
G
-monomethyl-
l
-arginine was enhanced by 80% compared with baseline (
P
=0.05). Aldosterone acutely enhances vasodilation to exogenous nitric oxide whereas mineralocorticoid excess for 2 weeks enhances basal nitric oxide bioactivity and improves endothelium dependent, nitric oxide–mediated vasodilation in the forearm vasculature of healthy men.