bluuebunny/crossref_metadata_2025 huggingface dataset:
Antagonism of specific corticotropin-releasing factor receptor subtypes selectively modifies weight loss in restrained rats
Authors: Chotiwat Christina , Harris Ruth B. S.
Published: October 2008

Rats exposed to 3 h of restraint stress on each of 3 days (RRS) lose weight on the days of RRS and gain weight at the same rate as controls after stress ends, but do not return to the weight of controls. RRS rats also show an exaggerated endocrine response to subsequent novel stressors. Studies described here tested the effects of corticotropin-releasing factor receptor (CRFR) antagonism on RRS-induced weight loss, hypophagia, and corticosterone release during mild stress in the postrestraint period. Weight loss was not prevented by either peripheral or third-ventricle administration of a CRFR1 antagonist, antalarmin, before each restraint. Antalarmin did, however, allow recovery of body weight in the poststress period. Third-ventricle administration of a CRFR2 antagonist, antisauvagine 30, had no effect in RRS rats but caused sustained weight loss in control animals. Surprisingly, third-ventricle administration of the nonselective CRFR antagonist, astressin, caused hypophagia and reversible weight loss in control rats. It had no effect in RRS rats. None of the antagonists modified the corticosterone response to RRS or to mild stress in the post-RRS period, but antalarmin suppressed corticosterone during the period of restraint in Control rats. These results suggest that CRFR1 activation is required for the initiation of events that lead to a prolonged down-regulation of body weight in RRS rats. The sustained reduction in body weight is independent of the severity of hypophagia on the days of restraint and of RRS-induced corticosterone release.
Effect of gonadectomy on AgRP-induced weight gain in rats
Authors: Goodin Sean Z. , Keichler Alicia R. , Smith Marissa , Wendt Donna , Strader April D.
Published: October 2008

Agouti-related peptide (AgRP), the endogenous antagonist to the melanocortin 3 and 4 receptors, elicits robust hyperphagia and weight gain in rodents when administered directly into the central nervous system. The relative influence of AgRP to cause weight gain in rodents partially depends on the activity level of the melanocortin agonist-producing proopiomelanocortin neurons. Both proopiomelanocortin and AgRP neurons within the arcuate nucleus receive energy storage information from circulating peripheral signals such as leptin and insulin. Another modulator of AgRP activity includes the cell surface molecule syndecan-3. Because leptin and insulin affect food intake in a sexually dimorphic way in rodents and syndecan-3-deficient mice regulate adiposity levels through distinct physiological mechanisms, we hypothesized that AgRP-induced weight gain would also be sexually dimorphic in rats. In the present study, the behavioral and physiological effects of centrally-administered AgRP in male and female were investigated. In male rats, AgRP (1 nmol) induced 5 days ( P < 0.0001) of significantly elevated feeding compared with vehicle-treated controls, while females displayed 3 days of hyperphagia ( P < 0.05). However, 1 wk after the injection, both male and female rats gained the same percent body weight (6%). Interestingly, female rats exhibited a greater reduction in energy expenditure (vo2) following AgRP compared with male rats ( P < 0.05). Removal of the gonads did not alter cumulative food intake in male or female rats but did attenuate the dramatic reduction in Vo2 exhibited by females. Both intact and gonadectomized rats demonstrated significantly increased respiratory quotient supporting the anabolic action of AgRP ( P < 0.01). These findings are novel in that they reveal sex-specific underlying physiology used to achieve weight gain following central AgRP in rats.
Tumor necrosis factor-α induces renal vasoconstriction as well as natriuresis in mice
Authors: Shahid Mohd , Francis Joseph , Majid Dewan S. A.
Published: October 2008

Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of hypertension and renal injury. However, the direct effects of TNF-α on renal hemodynamic and excretory function are not yet clearly defined. We examined the renal responses to infusion of TNF-α (0.33 ng·g−1·min−1) in anesthetized mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearance. The urine was collected from a cannula inserted into the bladder. Following the 60-min control clearance period, TNF-α infusion was initiated and 15 min were given for stabilization followed by another 60-min clearance period. TNF-α alone ( n = 7) caused decreases in RBF (7.9 ± 0.3 to 6.4 ± 0.3 ml·min−1·g−1) and GFR (1.04 ± 0.06 to 0.62 ± 0.08 ml·min−1·g−1) as well as increases in absolute (0.8 ± 0.3 to 1.4 ± 0.3 μmol·min−1·g−1) and fractional excretion of sodium (0.5 ± 0.2 to 1.5 ± 0.4%) without affecting arterial pressure. TNF-α also increased 8-isoprostane excretion (8.10 ± 1.09 to 11.13 ± 1.34 pg·min−1·g−1). Pretreatment with TNF-α blocker etanercept (5 mg/kg sc; 24 and 3 h before TNF-α infusion; n = 6) abolished these responses. However, TNF-α induced an increase in RBF and caused attenuation of the GFR reduction in mice pretreated with superoxide (O2−) scavenger tempol (2 μg·g−1·min−1; n = 6). Pretreatment with nitric oxide (NO) synthase inhibitor nitro-l-arginine methyl ester (0.1 μg·g−1·min−1; n = 6) resulted in further enhancement in vasoconstriction while natriuresis remained unaffected in response to TNF-α. These data suggest that TNF-α induces renal vasoconstriction and hypofiltration via enhancing the activity of O2−and thus reducing the activity of NO. The natriuretic response to TNF-α is related to its direct effects on tubular sodium reabsorption.
Epibatidine Application In Vitro Blocks Retinal Waves Without Silencing All Retinal Ganglion Cell Action Potentials in Developing Retina of the Mouse and Ferret
Authors: Sun Chao , Speer Colenso M. , Wang Guo-Yong , Chapman Barbara , Chalupa Leo M.
Published: October 2008

Epibatidine (EPI), a potent cholinergic agonist, disrupts acetylcholine-dependent spontaneous retinal activity. Early patch-clamp recordings in juvenile ferrets suggested that EPI blocks all retinal ganglion cell (RGC) action potentials when applied to the retina. In contrast, recent experiments on the developing mouse that relied on multielectrode array (MEA) recordings reported that EPI application decorrelates the activity of neighboring RGCs and eliminates retinal waves while preserving the spiking activity of many neurons. The different techniques used in previous studies raise the question of whether EPI has different effects on RGC activity in mouse compared with that in ferret. A resolution of this issue is essential for interpreting the results of developmental studies that relied on EPI to manipulate retinal activity. Our goal was to compare the effects of EPI on the spontaneous discharges of RGCs in mouse and ferret using 60-electrode MEA as well as patch-clamp recordings during the developmental stage when retinal waves are driven by acetylcholine in both species. We found that in both mouse and ferret EPI decorrelates RGC activity and eliminates retinal waves. However, EPI does not block all spontaneous activity in either species. Instead, our whole cell recordings reveal that EPI silences more than half of all RGCs while significantly increasing the activity of the remainder. These results have important implications for interpreting the results of previous studies that relied on this cholinergic agonist to perturb retinal activity.
Astrocytes as the Glucose Shunt for Glutamatergic Neurons at High Activity: An In Silico Study
Authors: Occhipinti Rossana , Somersalo Erkki , Calvetti Daniela
Published: October 2008

The question of the preferred substrate of glutamatergic neurons at high neural activity has been vibrantly debated for over a decade since the classical hypothesis (CH) of the primacy of glucose has been challenged by the astrocyte-neuron lactate shuttle hypothesis (ANLSH), which replaces the primacy of glucose with astrocyte produced lactate. We perform Bayesian Flux Balance Analysis (BFBA) with a new mathematical model of cellular brain energetics, comprising detailed biochemical pathways in and between astrocytes and glutamatergic neurons and partitioning of each cell type into cytosol and mitochondria. Supported by the results of our in silico studies, which are in remarkable agreement with previously published results, we posit the Glucose Shunt Hypothesis (GSH) that during high activity, the inhibition of the phosphofructokinase (PFK) enzyme in neuron impairs neuronal glycolysis, enabling the process by which lactate effluxed by astrocytes is taken up by glutamatergic neurons, whereas at low activity, glucose remains the preferred substrate for neurons. We postulate that the ANLS is a shunt utilized by glutamatergic neurons to bypass their glycolysis impaired by the inhibition of PFK in connection with increased oxidative phosphorylation at high neuronal activity.
The Unique Nature of Mg2+Channels
Authors: Moomaw Andrea S. , Maguire Michael E.
Published: October 2008

Considering the biological abundance and importance of Mg2+, there is a surprising lack of information regarding the proteins that transport Mg2+, the mechanisms by which they do so, and their physiological roles within the cell. The best characterized Mg2+channel to date is the bacterial protein CorA, present in a wide range of bacterial species. The CorA homolog Mrs2 forms the mitochondrial Mg2+channel in all eukaryotes. Physiologically, CorA is involved in bacterial pathogenesis, and the Mrs2 eukaryotic homolog is essential for cell survival. A second Mg2+channel widespread in bacteria is MgtE. Its eukaryotic homologs are the SLC41 family of carriers. Physiological roles for MgtE and its homologs have not been established. Recently, the crystal structures for the bacterial CorA and MgtE Mg2+channels were solved, the first structures of any divalent cation channel. As befits the unique biological chemistry of Mg2+, both structures are unique, unlike that of any other channel or transporter. Although structurally quite different, both CorA and MgtE appear to be gated in a similar manner through multiple Mg2+binding sites in the cytosolic domain of the channels. These sites essentially serve as Mg2+“sensors” of cytosolic Mg2+concentration. Many questions about these channels remain, however, including the molecular basis of Mg2+selectivity and the physiological role(s) of their eukaryotic homologs.
The Role of FXR in Disorders of Bile Acid Homeostasis
Authors: Eloranta Jyrki J. , Kullak-Ublick Gerd A.
Published: October 2008

As ligands for the nuclear receptor FXR, bile acids regulate their own synthesis, transport, and conjugation, thus protecting against bile acid toxicity. Recently, the role of genetic variants in FXR itself, FXR target genes, and regulators of FXR in the pathophysiology of the liver and intestine has become increasingly evident.
IL12RB2 and ABCA1 Genes Are Associated with Susceptibility to Radiation Dermatitis
Authors: Isomura Minoru , Oya Natsuo , Tachiiri Seiji , Kaneyasu Yuko , Nishimura Yasumasa , Akimoto Tetsuo , Hareyama Masato , Sugita Tadasi , Mitsuhashi Norio , Yamashita Takashi , Aoki Masahiko , Sai Heitetsu , Hirokawa Yutaka , Sakata Koh-ichi , Karasawa Kumiko , Tomida Akihiro , Tsuruo Takashi , Miki Yoshio , Noda Tetsuo , Hiraoka Masahiro
Published: October 2008

Purpose: Severe acute radiation dermatitis is observed in approximately 5% to 10% of patients who receive whole-breast radiotherapy. Several factors, including treatment-related and patient-oriented factors, are involved in susceptibility to severe dermatitis. Genetic factors are also thought to be related to a patient's susceptibility to severe dermatitis. To elucidate genetic polymorphisms associated with a susceptibility to radiation-induced dermatitis, a large-scale single-nucleotide polymorphism (SNP) analysis using DNA samples from 156 patients with breast cancer was conducted.

Experimental Design: Patients were selected from more than 3,000 female patients with early breast cancer who received radiotherapy after undergoing breast-conserving surgery. The dermatitis group was defined as patients who developed dermatitis at a National Cancer Institute Common Toxicity Criteria grade of ≥2. For the SNP analysis, DNA samples from each patient were subjected to the genotyping of 3,144 SNPs covering 494 genes.

Results: SNPs that mapped to two genes, ABCA1 and IL12RB2, were associated with radiation-induced dermatitis. In the ABCA1 gene, one of these SNPs was a nonsynonymous coding SNP causing R219K (P = 0.0065). As for the IL12RB2 gene, the strongest association was observed at SNP-K (rs3790568; P = 0.0013). Using polymorphisms of both genes, the probability of severe dermatitis was estimated for each combination of genotypes. These analyses showed that individuals carrying a combination of genotypes accounting for 14.7% of the Japanese population have the highest probability of developing radiation-induced dermatitis.

Conclusion: Our results shed light on the mechanisms responsible for radiation-induced dermatitis. These results may also contribute to the individualization of radiotherapy.
Activation of the RAF/Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase Pathway Mediates Apoptosis Induced by Chelerythrine in Osteosarcoma
Authors: Yang Rui , Piperdi Sajida , Gorlick Richard
Published: October 2008

Purpose: Chelerythrine, a widely used broad-range protein kinase C inhibitor, induces apoptosis in many cell types. In this study, the mechanism of chelerythrine-induced apoptosis in osteosarcoma was investigated.

Experimental Design: Signaling pathways activated by chelerythrine in osteosarcoma were detected by Western blots. Impacts of RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK MAPK on apoptosis and cell survival were studied using genetic approaches and pharmacologic pathway–specific inhibitors.

Results: Osteosarcoma cells underwent apoptosis rapidly after treatment with chelerythrine. Three parallel MAPKs pathways, including the ERKs, c-Jun NH2 kinases, and p38, were activated by chelerythrine in a dose-dependent and time-dependent fashion. For the ERKs, the activation was evident at the earliest time point tested (2 minutes) and sustained for >4 hours. Introduction of a dominant-negative H-RAS mutant (17N) partially attenuated ERK activation and delayed the onset of apoptosis induced by chelerythrine. The ERK activation and apoptotic effects of chelerythrine were greatly abrogated by the pharmaceutical inhibitors of MEK, but not by those of c-Jun NH2 kinase or p38. Moreover, osteosarcoma cells were sensitized to chelerythrine by transient transfection with wild-type MEK1 or constitutively active MEK1 and became resistant with dominant-negative MEK1. Other protein kinase C inhibitors, including GF109203X or Gö6976, did not cause ERK activation or apoptosis in the same timeframe tested.

Conclusion: In osteosarcoma, chelerythrine-induced apoptosis is mediated through activation of the RAF/MEK/ERK pathway. These findings suggest that activating the ERK MAPK, as opposed to inhibiting it, may be a therapeutic strategy in osteosarcoma.
DNA Double-Strand Break Repair of Blood Lymphocytes and Normal Tissues Analysed in a Preclinical Mouse Model: Implications for Radiosensitivity Testing
Authors: Rübe Claudia E. , Grudzenski Saskia , Kühne Martin , Dong Xiaorong , Rief Nicole , Löbrich Markus , Rübe Christian
Published: October 2008

Purpose: Radiotherapy is an effective cancer treatment, but a few patients suffer severe radiation toxicities in neighboring normal tissues. There is increasing evidence that the variable susceptibility to radiation toxicities is caused by the individual genetic predisposition, by subtle mutations, or polymorphisms in genes involved in cellular responses to ionizing radiation. Double-strand breaks (DSB) are the most deleterious form of radiation-induced DNA damage, and DSB repair deficiencies lead to pronounced radiosensitivity. Using a preclinical mouse model, the highly sensitive γH2AX-foci approach was tested to verify even subtle, genetically determined DSB repair deficiencies known to be associated with increased normal tissue radiosensitivity.

Experimental Design: By enumerating γH2AX-foci in blood lymphocytes and normal tissues (brain, lung, heart, and intestine), the induction and repair of DSBs after irradiation with therapeutic doses (0.1-2 Gy) was investigated in repair-proficient and repair-deficient mouse strains in vivo and blood samples irradiated ex vivo.

Results: γH2AX-foci analysis allowed to verify the different DSB repair deficiencies; even slight impairments caused by single polymorphisms were detected similarly in both blood lymphocytes and solid tissues, indicating that DSB repair measured in lymphocytes is valid for different and complex organs. Moreover, γH2AX-foci analysis of blood samples irradiated ex vivo was found to reflect repair kinetics measured in vivo and, thus, give reliable information about the individual DSB repair capacity.

Conclusions: γH2AX analysis of blood and tissue samples allows to detect even minor genetically defined DSB repair deficiencies, affecting normal tissue radiosensitivity. Future studies will have to evaluate the clinical potential to identify patients more susceptible to radiation toxicities before radiotherapy.
Establishment of Patient-Derived Non–Small Cell Lung Cancer Xenografts as Models for the Identification of Predictive Biomarkers
Authors: Fichtner Iduna , Rolff Jana , Soong Richie , Hoffmann Jens , Hammer Stefanie , Sommer Anette , Becker Michael , Merk Johannes
Published: October 2008

Purpose: It was the aim of our study to establish an extensive panel of non-small cell lung cancer (NSCLC) xenograft models useful for the testing of novel compounds and for the identification of biomarkers.

Experimental Design: Starting from 102 surgical NSCLC specimens, which were obtained from primarily diagnosed patients with early-stage tumors (T2/T3), 25 transplantable xenografts were established and used for further investigations.

Results: Early passages of the NSCLC xenografts revealed a high degree of similarity with the original clinical tumor sample with regard to histology, immunohistochemistry, as well as mutation status. The chemotherapeutic responsiveness of the xenografts resembled the clinical situation in NSCLC with tumor shrinkage obtained with paclitaxel (4 of 25), gemcitabine (3 of 25), and carboplatin (3 of 25) and lower effectiveness of etoposide (1 of 25) and vinorelbine (0 of 11). Twelve of 25 NSCLC xenografts were >50% growth inhibited by the anti-epidermal growth factor receptor (EGFR) antibody cetuximab and 6 of 25 by the EGFR tyrosine kinase inhibitor erlotinib. The response to the anti-EGFR therapies did not correlate with mutations in the EGFR or p53, but there was a correlation of K-ras mutations and erlotinib resistance. Protein analysis revealed a heterogeneous pattern of expression. After treatment with cetuximab, we observed a down-regulation of EGFR in 2 of 6 sensitive xenograft models investigated but never in resistant models.

Conclusion: An extensive panel of patient-derived NSCLC xenografts has been established. It provides appropriate models for testing marketed as well as novel drug candidates. Additional expression studies allow the identification of stratification biomarkers for targeted therapies.
Phase I Combination Study of Trabectedin and Doxorubicin in Patients with Soft-Tissue Sarcoma
Authors: Blay Jean-Yves , von Mehren Margaret , Samuels Brian L. , Fanucchi Michael P. , Ray-Coquard Isabelle , Buckley Brigid , Gilles Leen , Lebedinsky Claudia , Elsayed Yusri A. , Le Cesne Axel
Published: October 2008

Purpose: To determine the dose of trabectedin plus doxorubicin with granulocyte colony-stimulating factor support associated with manageable neutropenia and acceptable dose-limiting toxicities (DLT) in patients with recurrent or persistent soft-tissue sarcoma.

Methods: In this phase I, open-label, multicenter trial, patients previously treated with 0-1 prior chemotherapy regimens excluding doxorubicin, an Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function received a 10- to 15-min i.v. infusion of doxorubicin 60 mg/m2 immediately followed by a 3-h i.v. infusion of trabectedin 0.9 to 1.3 mg/m2 on day 1 of a 3-week cycle. Because four of the first six patients experienced DLT-defining neutropenia during cycle 1, all subsequent patients received primary prophylactic granulocyte colony-stimulating factor. The maximum tolerated dose was the highest dose level with six or more patients in which less than one-third of the patients experienced severe neutropenia or DLT. Blood was collected during cycle 1 for pharmacokinetic analyses. Adverse events, tumor response, and survival were assessed.

Results: Patients (N = 41) received a median of six cycles of treatment (range, 2-13). The maximum tolerated dose was trabectedin 1.1 mg/m2 and doxorubicin 60 mg/m2. Common grade 3/4 treatment-emergent adverse events were neutropenia (71%), alanine aminotransferase increase (46%), and thrombocytopenia (37%). Overall, 5 (12%) patients achieved a partial response and 34 (83%) maintained stable disease. Median progression-free survival was 9.2 months. Doxorubicin and trabectedin pharmacokinetics were not altered substantially with concomitant administration.

Conclusion: The combination of doxorubicin 60 mg/m2 followed by trabectedin 1.1 mg/m2 every 21 days is safe and active in patients with soft-tissue sarcoma.
Clinical Determinants of Response to Irinotecan-Based Therapy Derived from Cell Line Models
Authors: Allen Wendy L. , Coyle Vicky M. , Jithesh Puthen V. , Proutski Irina , Stevenson Leanne , Fenning Cathy , Longley Daniel B. , Wilson Richard H. , Gordon Michael , Lenz Heinz-Josef , Johnston Patrick G.
Published: October 2008

Purpose: In an attempt to identify genes that are involved in resistance to SN38, the active metabolite of irinotecan (also known as CPT-11), we carried out DNA microarray profiling of matched HCT116 human colon cancer parental cell lines and SN38-resistant cell lines following treatment with SN38 over time.

Experimental Design: Data analysis identified a list of genes that were acutely altered in the parental cells following SN38 treatment as well as constitutively altered in the SN38-resistant cells.

Results: Independent validation of 20% of these genes by quantitative reverse transcription-PCR revealed a strong correlation with the microarray results: Pearson's correlation was 0.781 (r2 = 0.61, P < 0.000001) for those genes that were acutely altered in the parental setting following SN38 treatment and 0.795 (r2 = 0.63, P < 0.000002) for those genes that were constitutively altered in the SN38-resistant cells. We then assessed the ability of our in vitro-derived gene list to predict clinical response to 5-fluorouracil/irinotecan using pretreatment metastatic biopsies from responding and nonresponding colorectal cancer patients using both unsupervised and supervised approaches. When principal components analysis was used with our in vitro classifier gene list, a good separation between responding and nonresponding patients was obtained, with only one nonresponding and two responding patients separating with the incorrect groups. Supervised class prediction using support vector machines algorithm identified a 16-gene classifier with 75% overall accuracy, 81.8% sensitivity, and 66.6% specificity.

Conclusions: These results suggest that in vitro-derived gene lists can be used to predict clinical response to chemotherapy in colorectal cancer.
Von Hippel-Lindau–Coupled and Transcription-Coupled Nucleotide Excision Repair–Dependent Degradation of RNA Polymerase II in Response to Trabectedin
Authors: Aune Gregory J. , Takagi Kazutaka , Sordet Olivier , Guirouilh-Barbat Josée , Antony Smitha , Bohr Vilhelm A. , Pommier Yves
Published: October 2008

Purpose: Ecteinascidin 743 (Et743; trabectedin, Yondelis) has recently been approved in Europe for the treatment of soft tissue sarcomas and is undergoing clinical trials for other solid tumors. Et743 selectively targets cells proficient for TC-NER, which sets it apart from other DNA alkylating agents. In the present study, we examined the effects of Et743 on RNA Pol II.

Experimental Design and Results: We report that Et743 induces the rapid and massive degradation of transcribing Pol II in various cancer cell lines and normal fibroblasts. Pol II degradation was abrogated by the proteasome inhibitor MG132 and was dependent on TC-NER. Cockayne syndrome (CS) cells and xeroderma pigmentosum (XP) cells (XPD, XPA, XPG, and XPF) were defective in Pol II degradation, whereas XPC cells whose defect is limited to global genome NER in nontranscribing regions were proficient for Pol II degradation. Complementation of the CSB and XPD cells restored Pol II degradation. We also show that cells defective for the VHL complex were defective in Pol II degradation and that complementation of those cells restores Pol II degradation. Moreover, VHL deficiency rendered cells resistant to Et743-induced cell death, a similar effect to that of TC-NER deficiency.

Conclusion: These results suggest that both TC-NER–induced and VHL-mediated Pol II degradation play a role in cell killing by Et743.
Cyclin D1–Specific Cytotoxic T Lymphocytes Are Present in the Repertoire of Cancer Patients: Implications for Cancer Immunotherapy
Authors: Kondo Eisei , Maecker Britta , Weihrauch Martin R. , Wickenhauser Claudia , Zeng WanYong , Nadler Lee M. , Schultze Joachim L. , von Bergwelt-Baildon Michael S.
Published: October 2008

Purpose: Cyclin D1, a key cell cycle regulator, is overexpressed in multiple types of cancer. Such tumor-associated genes may be useful targets for cancer immunotherapy. Nevertheless, it had previously been suggested that efficient T cells recognizing cyclin D1-derived epitopes are absent from the repertoire because of thymic deletion. We attempted to induce autologous CTL from healthy donors and patients with cyclin D1-overexpressing tumors using a highly efficient T-cell expansion system based on CD40-activated B cells as antigen-presenting cells.

Experimental Design: Cyclin D1-derived, HLA-A*0201–restricted epitopes were predicted by multiple computer algorithms, screened in HLA-A2-binding assays, and used for T-cell stimulation. The generated CTL lines and clones were analyzed by IFN-γ enzyme-linked immunosorbent spot assay or cytolysis assay.

Results: After screening, at least two naturally processed and presented HLA-A*0201–binding cyclin D1 epitopes were identified. CTL specific for these epitopes could be successfully generated from HLA-A2+ donors. T cells efficiently recognized target cells pulsed with the cognate peptide and cyclin D1-expressing tumor cell lines in an HLA-A*0201–restricted manner. More importantly, HLA-A*0201–matched, primary cyclin D1+ tumor cells were efficiently recognized by cyclin D1-specific CTL. These CTL could be generated from patients with mantle cell lymphoma and cyclin D1+ colon cancer.

Conclusions: These results underscore that cyclin D1 needs to be considered as a target for broad-based antitumor immunotherapy.
JC Virus Infection in Colorectal Neoplasia That Develops after Liver Transplantation
Authors: Selgrad Michael , Koornstra Jan Jacob , Fini Lucia , Blom Marloes , Huang Rong , DeVol Edward B. , Boersma-van Ek Wytske , Dijkstra Gerard , Verdonk Robert C. , de Jong Steven , Goel Ajay , Williams Sharenda L. , Meyer Richard L. , Haagsma Elizabeth B. , Ricciardiello Luigi , Boland C. Richard
Published: October 2008

Purpose: Liver transplant recepients (LTRs) have an increased risk of colorectal neoplasia. The mechanism responsible for this is unknown. JCV encodes for TAg and has been implicated in colorectal carcinogenesis. We hypothesized that the use of immunosuppression in LTRs facilitates activation of JCV and is responsible for the increased risk of neoplasia.

Experimental Design: JCV TAg DNA and protein expression were determined in normal colonic epithelium (n = 15) and adenomatous polyps (n = 26) from LTRs and compared with tissue samples from control patients (normal colon, n = 21; adenomas, n = 40). Apoptosis and proliferation were determined by M30 and Ki-67 immunoreactivity, respectively.

Results: JCV TAg DNA was found in 10 of 15 (67%) of normal colonic mucosa from LTRs compared with 5 of 21 (24%) of control normal mucosa (P = 0.025). JCV TAg DNA was detected in 16 of 26 (62%) of the adenomas from LTRs and in 20 of 40 (50%) of control adenomas. JCV TAg protein was expressed in 13 of 26 (50%) adenomas from LTRs versus 2 of 40 (5%) of adenomas from controls (P < 0.001). In adenomas from LTRs, the mean proliferative activity was higher compared with controls (60.3 ± 3.2% versus 42.7 ± 2.8%, P < 0.001), whereas mean apoptotic indices were lower in LTRs (0.29 ± 0.08% versus 0.39 ± 0.06%, P = 0.05).

Conclusions: The presence of JCV in the colorectal mucosa and adenomas from LTRs, in concert with the use of immunosuppressive agents, suggests that JCV may undergo reactivation, and the subsequent TAg protein expression might explain the increased risk of colorectal neoplasia in LTRs.
A Phase 1 Dose-Escalation Study of Irinotecan in Combination with 17-Allylamino-17-Demethoxygeldanamycin in Patients with Solid Tumors
Authors: Tse Archie N. , Klimstra David S. , Gonen Mithat , Shah Manish , Sheikh Tahir , Sikorski Rachel , Carvajal Richard , Mui Janet , Tipian Caroll , O'Reilly Eileen , Chung Ki , Maki Robert , Lefkowitz Robert , Brown Karen , Manova-Todorova Katia , Wu Nian , Egorin Merrill J. , Kelsen David , Schwartz Gary K.
Published: October 2008

Purpose: Both heat shock protein 90 (Hsp90) and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors.

Experimental Design: During the dose escalation phase, patients received i.v. irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity.

Results: Twenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity at dose level 4 (100 mg/m2 irinotecan and 375 mg/m2 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by the coadministration of irinotecan, and vice versa. There was no partial response, although tumor shrinkage was observed in six patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P = 0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G2-M cell cycle checkpoint, and cell death could be shown in tumor biopsy samples obtained at the MTD.

Conclusions: The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m2 irinotecan and 300 mg/m2 17AAG.
Regression of Drug-Resistant Lung Cancer by the Combination of Rosiglitazone and Carboplatin
Authors: Girnun Geoffrey D. , Chen Liang , Silvaggi Jessica , Drapkin Ronny , Chirieac Lucian R. , Padera Robert F. , Upadhyay Rabi , Vafai Scott B. , Weissleder Ralph , Mahmood Umar , Naseri Elnaz , Buckley Stephanie , Li Danan , Force Jeremy , McNamara Kate , Demetri George , Spiegelman Bruce M. , Wong Kwok-Kin
Published: October 2008

Purpose: Current therapy for lung cancer involves multimodality therapies. However, many patients are either refractory to therapy or develop drug resistance. KRAS and epidermal growth factor receptor (EGFR) mutations represent some of the most common mutations in lung cancer, and many studies have shown the importance of these mutations in both carcinogenesis and chemoresistance. Genetically engineered murine models of mutant EGFR and KRAS have been developed that more accurately recapitulate human lung cancer. Recently, using cell-based experiments, we showed that platinum-based drugs and the antidiabetic drug rosiglitazone (PPARγ ligand) interact synergistically to reduce cancer cell and tumor growth. Here, we directly determined the efficacy of the PPARγ/carboplatin combination in these more relevant models of drug resistant non–small cell lung cancer.

Experimental Design: Tumorigenesis was induced by activation of either mutant KRAS or EGFR. Mice then received either rosiglitazone or carboplatin monotherapy, or a combination of both drugs. Change in tumor burden, pathology, and evidence of apoptosis and cell growth were assessed.

Results: Tumor burden remained unchanged or increased in the mice after monotherapy with either rosiglitazone or carboplatin. In striking contrast, we observed significant tumor shrinkage in mice treated with these drugs in combination. Immunohistochemical analyses showed that this synergy was mediated via both increased apoptosis and decreased proliferation. Importantly, this synergy between carboplatin and rosiglitazone did not increase systemic toxicity.

Conclusions: These data show that the PPARγ ligand/carboplatin combination is a new therapy worthy of clinical investigation in lung cancers, including those cancers that show primary resistance to platinum therapy or acquired resistance to targeted therapy.
Tumor-Specific Urinary Matrix Metalloproteinase Fingerprinting: Identification of High Molecular Weight Urinary Matrix Metalloproteinase Species
Authors: Roy Roopali , Louis Gwendolyn , Loughlin Kevin R. , Wiederschain Dmitri , Kilroy Susan M. , Lamb Carolyn C. , Zurakowski David , Moses Marsha A.
Published: October 2008

Purpose: We have previously reported that matrix metalloproteinases MMP-2, MMP-9, and the complex MMP-9/NGAL can be detected in urine of patients with a variety of cancers including prostate and bladder carcinoma. In addition, we also detected several unidentified urinary gelatinase activities with molecular weights >125 kDa. The objective of the current study was to identify these high molecular weight (HMW) species, determine their potential as predictors of disease status, and ask whether a tumor-specific pattern existed based on urinary MMP analysis.

Experimental Design: Chromatography, zymography, and mass spectrometry was used to identify HMW gelatinase species of ∼140, 190, and >220 kDa in urine of cancer patients. To determine whether a tumor-specific pattern of appearance existed among the MMPs detected, we analyzed the urine of 189 patients with prostate or bladder cancer and controls.

Results: The ∼140, >220 kDa, and ∼190 HMW gelatinase species were identified as MMP-9/tissue inhibitor of metalloproteinase 1 complex, MMP-9 dimer, and ADAMTS-7, respectively. The frequency of detection of any MMP species was significantly higher in urine from prostate and bladder cancer groups than controls. MMP-9 dimer and MMP-9 were independent predictors for distinguishing between patients with prostate and bladder cancer (P < 0.001 for each) by multivariable analysis.

Conclusions: This study is the first to identify a tumor-specific urinary MMP fingerprint that may noninvasively facilitate identification of cancer presence and type. This information may be of diagnostic and prognostic value in the detection and/or clinical monitoring of disease progression and therapeutic efficacy in patients with bladder or prostate cancer.
The Influence of Business and Industry NGOs in the Negotiation of the Kyoto Mechanisms: the Case of Carbon Capture and Storage in the CDM
Authors: Vormedal Irja
Published: October 2008

This article examines the role of business and industry NGOs (BINGOs) within the international climate negotiations. It develops a typology of BINGOs operating in the regime, and a framework for assessing the influence of these organizations. The framework is applied to a case study of the negotiation of carbon capture and storage technologies as a Kyoto Protocol mitigation option. In contrast to previous research, the article illustrates the existence of formal and informal networks among BINGOs, a variety of national delegations and international institutions, and demonstrates how these networks are tactically invoked in the effort to influence specific negotiation processes and outcomes. It is argued that BINGO activities influenced negotiations on regulatory design, and that a plausible explanation of business influence in this context lies in the notion of corporate technological power.
The Ageing Populations of Europe — Implications for Health Systems and Patients' Rights
Authors: Rynning Elisabeth
Published: October 2008

Europe is facing a trend of demographic and social change that is likely to have a significant impact on our health systems in the coming decades. The primary concerns are related to the double challenge of population ageing and population decline. These changes will result in a shrinking workforce to handle the steadily increasing healthcare needs of the very old, who will constitute the fastest growing segment of the population. A number of strategies to meet this challenge are suggested and implemented, not least at the EU level. Adaptation of European health systems to the new situation also makes it necessary to revisit familiar medico-legal issues, in order to clarify and consolidate a number of already established patients' rights.
Dynamic Mechanical Performances of Polyester—Clay Nanocomposite Thick Films
Authors: Lucignano Carmine , Quadrini Fabrizio , Santo Loredana
Published: October 2008

Dynamic mechanical properties of polyester—montmorillonite nanocomposite thick films, prepared by the in situ intercalative polymerization method, were evaluated in a tensile mode. A fast fabrication procedure was chosen to allow industrial applications. A total time less than 1 h was sufficient to obtain a thick film which could be cut for the specimen preparation. The final films had a thickness of 250 μm and a nano-clay content ranging from 0 to 10 wt%. A differential scanning calorimeter was used to investigate the effect of the clay content on the resin polymerization kinetics whereas tensile tests were performed to make a comparison with dynamic mechanical results. The maximum in the mechanical performances was obtained at the clay content of 1 wt% at which an increase of about 55% for the storage modulus was measured in comparison with the unfilled resin.
Consolidation of U-Nyte® Epoxy-Coated Carbon-Fiber Composites via Temperature-Controlled Resistive Heating
Authors: Sarles Stephen A. , Leo Donald J.
Published: October 2008

Temperature-controlled internal resistive heating creates on-command rigidizable materials for structural consolidation of ultra-lightweight, inflatable space structures. A PAN-based carbon fiber tow coated with a novel, low cure-temperature thermosetting resin (Hydrosize U-Nyte® Set 201 epoxy binder) was investigated for consolidation through internal resistive heating. Precise, proportional-integral (PI) temperature tracking was achieved for controlled sample heating and used to prescribe intelligently-designed curing profiles to cause resin consolidation and curing. Rigidized samples were evaluated by measuring the increase in bending stiffness as well as verifying resin cure completion through DSC. The permanent strength gained through active rigidization via internal resistive heating was demonstrated on a small, inflatable structure.
Towards Development of a Self-Healing Composite using a Mendable Polymer and Resistive Heating
Authors: Jong Se Park  , Takahashi Kosuke , Guo Zhanhu , Wang Ying , Bolanos Ed , Hamann-Schaffner Christine , Murphy Erin , Wudl Fred , Hahn H. Thomas
Published: October 2008

Mendomers are a group of polymers that are mendable upon heating. Specifically, cracks in these polymers have been shown to heal themselves when heated close to the glass transition temperature. The main mechanism behind the healing is the thermally reversible Diels—Alder reaction, where a dicyclopentadiene unit in the polymer backbone breaks apart into two cyclopentadiene terminal groups, which then reunite upon heating. The present study investigates the feasibility of using a mendomer as a matrix for re-mending composites reinforced with graphite fibers. The graphite fibers are used as electrical conductors to provide the necessary heat to the polymer. Specimens were prepared by spreading a monomer, called mendomer, powder on a graphite/epoxy laminate substrate and curing in a vacuum oven. Microcracks were introduced by bending the substrate coupon, and the latter was heated by applying electric currents. The healing behavior was confirmed by disappearance of microcracks that were observed with an optical microscope and a scanning electron microscope (SEM).
Factors Influencing Differences between Survey and Market-based Environmental Value Measures
Authors: Hite Diane
Published: October 2008

A unique US database combining survey and housing data is used to obtain household-level stated and market-based willingness-to-pay (WTP) measures to avoid living near landfills. Systematic differences are found between individuals with zero and positive stated WTP, suggesting that a double hurdle model be used. Positive stated WTP is related to whether a respondent donated to an environmental organisation or lives downwind from an open landfill, while zero WTP is associated with age, high education levels or high ranking of house location. WTP difference (survey—hedonic) depends positively on respondents' consideration of a landfill prior to home purchase, toxic air release levels, relative valuation of neighbourhood and environmental characteristics and donations to environmental organisations; WTP difference is highly negatively associated with age and high levels of education.
Assessing the Effectiveness of Human Capital Investments on the Regional Unemployment Rate in the United States: 1990 and 2000
Authors: Nistor Adela
Published: October 2008

This article evaluates the effect of human capital investment—for example, expenditures on education, training, and employment—on regional unemployment rates in the United States. State-level unemployment rates are estimated using the spatial lag fixed effects model with spatial correlation of regional unemployment rates for 1990 and 2000. The results show that unemployment rates can be decreased by a policy of state-level human capital investment. A $100 per capita human capital investment in a state is expected to decrease the unemployment rate by 0.63 percent. Human capital investment has a negative impact on a state's unemployment as long as the yearly average state net migration rate is greater than −1.6 percent. A maximum of 1.6 percent of a state's population can out-migrate on average in a year for human capital expenditures to be associated with a decrease in the state's unemployment rate. If a state's net migration rate is less than −1.6 percent of its population, human capital expenditures have a positive effect on unemployment.
From Practice to Praxis
Authors: Blodgett Amy T. , Schinke Robert J. , Fisher Leslee A. , Wassengeso George Clifton , Peltier Duke , Ritchie Stephen , Pickard Patricia
Published: October 2008

Through research grounded in praxis, sport psychologists can seek to understand and then help meet the motivational needs of sport participants from marginalized cultures. The present report unveils the recommendations of 23 elite Canadian Aboriginal athletes and subsequent community meetings with an Aboriginal community regarding how to enhance sport programming and increase enrollment of youth within a First Nations reserve. Data were analyzed inductively with the coding of themes developed by community consensus, reflecting barriers to sport participation and recommendations regarding how programming can be refined through training strategies with youth participants, parents, and sport and recreation staff. Recommendations include educating youth about the value of persistence and success, encouraging coaches to foster positive beliefs, and integrating Aboriginal role models.
Orientalism in the Mirror
Authors: Cooper Melinda
Published: October 2008

This article reflects on the convergence of revolutionary anti-capitalism and moral fundamentalism in the contemporary Islamic revival. It is concerned more generally with the recurrent appeal to fundamental value — of a sexual, genealogical or economic kind — in the history of anti-imperial and anti-capitalist movements. Exploring the tradition of Islamist philosophies of finance, the article suggests that Islamic political theology is unique in its ability to separate absolute law from territory ( pace Schmitt). Transgressing the boundaries of nation-state postcolonialism, it thereby relocates absolute value, and hence absolute prohibition, in the realm of the sexual and the divine.
`China Who Makes and Fakes'
Authors: Pang Laikwan
Published: October 2008

This is a study of the semiotics of counterfeit products. Beginning with an analysis of a number of piracy-related activities taking place in China, I look at how and why China is understood by the world as a pirate nation. Through a careful reading of the counterfeit product as a material object, my study aims at demythologizing the relation between China and piracy, and I relate the logic of the counterfeit to the logic of capitalism. I argue that piracy is a result of global capitalism rather than to do with the character of a particular people, and I demonstrate the urgent need to establish a politics of mimetic reading, which refuses to be shut down by capitalist discourse, such as that produced by the intellectual property rights regime.
The role of parents in children's musical development
Authors: Mcpherson Gary E.
Published: October 2008

A framework for studying parent—child interactions is proposed, based on evidence that parents play a pivotal role in their children's musical development. It is suggested that the goals and aspirations that parents hold impact on the styles and practices they adopt during interactions with their children. Importantly, the model proposes a feedback loop in which child and socio-contextual characteristics interact with parenting goals, styles and practices to help shape children's musical competence and achievement, their sense of musical identity and accomplishment, and their continuing desire to participate, exert effort, overcome obstacles and succeed musically.
Orchestral performance and the footprint of mindfulness
Authors: Langer Ellen , Russel Timothy , Eisenkraft Noah
Published: October 2008

Two studies were designed to test the hypothesis that actively creating novel distinctions and sonically portraying them during the performance of orchestral music is preferable to attempting to re-create a past performance. The data suggest that orchestral musicians preferred creating music when they were encouraged to mindfully incorporate subtle nuances into their performance. When audience members were played recordings of both types of performance, a significant majority expressed a preference for the performances that were created in a mindful state. Individual attention to novel distinctions and subtle nuances appears to alter the process of creative ensemble performance and lead to music that is more enjoyable to perform and hear.
Coping Difficulties After Hospitalization
Authors: Fitzgerald Miller Judith , Piacentine Linda B. , Weiss Marianne
Published: October 2008

Coping difficulties of 113 adults 3 weeks after hospital discharge were identified using the Post-Discharge Coping Difficulty Scale and a brief focused telephone interview (11-item guide). Overall, low difficulty scores were reported ( M = 23.9, SD = 18.2, range = 0 to 100). Qualitative data reveal specific coping difficulties in the categories of stressors, specific difficulties, caring for self, managing the condition, family, advice needed, contact with the health care system, and what they wished they knew before discharge. A core theme of biographical reconstruction emerged.