bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-Nucleotide Polymorphisms of DNA Damage Response Genes Are Associated with Overall Survival in Patients with Pancreatic Cancer
Authors: Okazaki Taro , Jiao Li , Chang Ping , Evans Douglas B. , Abbruzzese James L. , Li Donghui
Published: April 2008

Purpose: The goals of this study were to determine if single-nucleotide polymorphisms in DNA damage repair genes and cell cycle regulating genes affect clinical response to combined gemcitabine radiation therapy and the overall survival (OS) of patients with pancreatic cancer.

Experimental Design: We evaluated six single-nucleotide polymorphisms of the ATM, ATM and Rad3-related (ATR), CHEK1, and CHEK2 genes in 119 patients with potentially resectable pancreatic cancer who were enrolled in clinical trials at The University of Texas M. D. Anderson Cancer Center from February 1999 to January 2006, with follow-up until February 2007. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. Genotypes were determined and tested for associations with OS by Kaplan-Meier estimation, the log-rank test, and Cox regression analysis. P values of ≤0.05 were considered significant.

Results: The ATM G60A and CHEK1 G35A genotypes were significant (P < 0.05), and the ATR C340T genotype borderline significantly (P = 0.079) associated with OS. The hazard ratio of CHEK1 35AA was 2.01 (95% confidence interval, 1.20-3.37; P = 0.007) compared with CHEK1 35GG/GA with adjustments for race, sex, diabetes status, CA19-9 level, and success of tumor resection. A significant combined genotype effect was observed between ATM 60GA/GG, ATR 340CT/CC, and CHEK1 35AA with median OS times of 31.0, 16.2, and 10.5 months for patients carrying ≤1, 2, and 3 deleterious alleles, respectively (P = 0.004).

Conclusions: These observations suggest that polymorphic variations of DNA damage response genes affect clinical response to gemcitabine radiation therapy and OS of patients with resectable pancreatic cancer.
Glioma Proliferation as Assessed by 3‘-Fluoro-3’-Deoxy-l-Thymidine Positron Emission Tomography in Patients with Newly Diagnosed High-Grade Glioma
Authors: Ullrich Roland , Backes Heiko , Li Hongfeng , Kracht Lutz , Miletic Hrvoje , Kesper Kristina , Neumaier Bernd , Heiss Wolf-Dieter , Wienhard Klaus , Jacobs Andreas H.
Published: April 2008

Purpose: The aim of this study was to investigate the relationship between the in vivo derived kinetic parameters of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) and the proliferation rate measured in vitro by Ki-67 staining in patients with newly diagnosed high-grade gliomas.

Experimental Design: Thirteen patients with newly diagnosed high-grade gliomas were investigated with 18F-FLT and methyl-11C- l-methionine (11C-MET) positron emission tomography (PET) and T1-, Gd-T1–, and T2-weighted magnetic resonance imaging on consecutive days. Tracer kinetic parameters of 18F-FLT as well as the standardized uptake value and the tumor-to-background (T/B) ratio of 18F-FLT and 11C-MET were determined. Data of kinetic modeling, standardized uptake value, and T/B values derived from 18F-FLT-PET were compared with T/B values derived from 11C-MET-PET and to the in vitro proliferation marker Ki-67.

Results: A significant correlation was observed between the metabolic rate constant Ki and the proliferation index as measured by Ki-67 immunostaining [Ki, r = 0.79 (P = 0.004)]. Also, the phosphorylation rate constant k3 correlated with Ki-67 [k3, r = 0.76 (P = 0.006)], whereas the rate constant for transport through the blood brain barrier K1 showed a weaker correlation with Ki-67 [K1, r = 0.62 (P = 0.044)]. No significant correlation between 11C-MET and 18F-FLT uptake ratios and Ki-67 was observed.

Conclusions: This study shows that kinetic analysis of 18F-FLT tracer uptake is essential for the in vivo assessment of tumor proliferation in high-grade gliomas, whereas uptake ratios of 11C-MET and 18F-FLT failed to correlate with the in vitro determined proliferation marker. Thus, kinetic analysis of 18F-FLT might provide an accurate method for the assessment of early response to glioma treatment in the future.
New Pansomatostatin Ligands and Their Chelated Versions: Affinity Profile, Agonist Activity, Internalization, and Tumor Targeting
Authors: Ginj Mihaela , Zhang Hanwen , Eisenwiener Klaus-Peter , Wild Damian , Schulz Stefan , Rink Hans , Cescato Renzo , Reubi Jean Claude , Maecke Helmut R.
Published: April 2008

Purpose: Somatostatin receptor (sst) targeting is an established method to image and treat sst-positive tumors. Particularly, neuroendocrine tumors express the receptor subtype 2 in high density, but sst1, sst3, sst4, and sst5 are also expressed to some extent in different human tumors. Currently used targeting peptides mainly have sst2 affinity. We aimed at developing (radio)peptides that bind with high affinity to all receptor subtypes.

Experimental Design: Carbocyclic octapeptides were coupled with macrocyclic chelators for radiometal labeling. Affinity, internalization, and agonist potencies were determined on sst1- to sst5-expressing cell lines. Biodistribution was determined on nude mice bearing HEK-sst2 or AR4-2J and HEK-sst3 tumors.

Results: High affinity to all receptor subtypes was found. YIII-KE88 showed agonistic properties at all five sst receptor subtypes as it inhibits forskolin-stimulated cyclic AMP production. Surprisingly, very low or even absent sst2 receptor internalization was found compared with currently clinically established octapeptides, whereas the sst3 internalization was very efficient. Biodistribution studies of [111In]KE88 and [67Ga]KE88/[68Ga]KE88 reflected the in vitro data. In nude mice with s.c. implanted sst2 (HEK-sst2, AR4-2J)-expressing and sst3 (HEK-sst3)-expressing tumors, high and persistent uptake was found in sst3-expressing tumors, whereas the uptake in the sst2-expressing tumors was lower and showed fast washout. The kidney uptake was high but blockable by coinjection of lysine.

Conclusion: This peptide family shows pansomatostatin potency. As radiopeptides, they are the first to show a full pansomatostatin profile. Despite some drawback, they should be useful for imaging sst2-expressing tumors with short-lived radiometals, such as 68Ga, at early time points and for sst3-expressing tumors at later time points with longer-lived radiometals, such as 64Cu or 86Y.
Tumor-Targeting Nanocomplex Delivery of Novel Tumor Suppressor RB94 Chemosensitizes Bladder Carcinoma CellsIn vitroandIn vivo
Authors: Pirollo Kathleen F. , Rait Antonina , Zhou Qi , Zhang Xin-qiao , Zhou Jain , Kim Chang-Soo , Benedict William F. , Chang Esther H.
Published: April 2008

Purpose: RB94, a truncated form of RB110, has enhanced tumor suppressor potency and activity against all tumor types tested to date including bladder carcinoma. However, efficient, systemic delivery of the gene encoding RB94 specifically to tumors, is an obstacle to clinical application as an anticancer therapeutic. We have developed a systemically given, nanosized liposome DNA delivery system that specifically targets primary and metastatic disease. The ability of RB94, delivered via this nanocomplex, to sensitize bladder carcinoma to chemotherapy in vitro and in vivo was assessed.

Experimental Design: The nanocomplex is an RB94 plasmid encapsulated by a cationic liposome, the surface of which is decorated with a tumor-targeting moiety, either transferrin (Tf/Lip/RB94) or an antitransferrin receptor single-chain antibody fragment (TfRScFv/Lip/RB94). The ability of the complex to sensitize human bladder carcinoma HTB-9 cells to chemotherapeutics was assessed in vitro by XTT assay. In vivo tumor specificity and efficacy were tested in mice carrying HTB-9 tumors by PCR and tumor growth inhibition, respectively.

Results: Transfection with Tf/Lip/RB94 significantly sensitized HTB-9 cells to chemotherapeutic agents in vitro. Tumor specificity of the complex was shown in an orthotopic bladder tumor model by immunohistochemistry and PCR. Moreover, in mice bearing subcutaneous HTB-9 tumors, the combination of systemically given Tf/Lip/RB94 or TfRScFv/Lip/RB94 plus gemcitabine resulted in significant (P < 0.0005) tumor growth inhibition/regression and induction of apoptosis.

Conclusions: Use of our tumor-targeting nanocomplex to specifically deliver the potent tumor suppressor RB94 efficiently to tumors has potential as a more effective treatment modality for genitourinary and other cancers.
Anemia Is a Significant Prognostic Factor in Local Relapse-Free Survival of Premenopausal Primary Breast Cancer Patients Receiving Adjuvant Cyclophosphamide/Methotrexate/5-Fluorouracil Chemotherapy
Authors: Dubsky Peter , Sevelda Paul , Jakesz Raimund , Hausmaninger Hubert , Samonigg Hellmut , Seifert Michael , Denison Ursula , Mlineritsch Brigitte , Steger Günther , Kwasny Werner , Stöger Herbert , Bartsch Rupert , Stierer Michael , Taucher Susanne , Fridrik Michael , Schippinger Walter , Greil Richard , Pötter Richard , Gnant Michael ,   for the Austrian Breast and Colorectal Cancer Study Group
Published: April 2008

Purpose: To determine the effects of anemia on local relapse-free, relapse-free, and overall survival (LRFS, RFS, and OS, respectively) in premenopausal, primary breast cancer patients receiving adjuvant polychemotherapy, and to determine which conventional prognostic factors affected these outcomes.

Experimental Design: Four hundred twenty-four premenopausal patients with early-stage primary breast cancer and hormone receptor–expressing tumors were treated with i.v. cyclophosphamide/methotrexate/5-fluorouracil (CMF) polychemotherapy as part of an adjuvant phase III trial (Austrian Breast and Colorectal Cancer Study Group Trial 5). The influence of anemia (hemoglobin <12 g/dL) on LRFS, RFS, and OS was evaluated in a retrospective analysis.

Results: Of 424 patients, 77 (18.2%) developed anemia on CMF chemotherapy. After a median follow-up time of 5 years, 8.9% of nonanemic patients had local relapse compared with 19.6% of anemic patients (P = 0.0006). Although mastectomy was associated with anemia (26% versus 13.7% in breast conserving surgery; P = 0.002), multivariate analysis did not show mastectomy per se to be a significant risk factor for LRFS. Age, lymph node status, and hemoglobin had an independent significant influence on LRFS (P < 0.005). Anemic patients had a relative risk of 2.96 (95% confidence interval, 1.41-6.23) for developing local relapse in comparison with nonanemic patients.

Conclusion: Premenopausal breast cancer patients who developed anemia during the CMF regimen had significantly worse LRFS. In Austrian Breast and Colorectal Cancer Study Group Trial 5, anemia may have contributed to an almost doubled incidence of local recurrence in the chemotherapy arm. Molecular targets associated with tumor hypoxia and distinct from erythropoiesis should receive further attention in experimental and clinical settings.
18F-Fluoro-2-Deoxy-Glucose Uptake Predicts Clinical Outcome in Patients with Gefitinib-Treated Non–Small Cell Lung Cancer
Authors: Na Im Il , Byun Byung Hyun , Kang Hye Jin , Cheon Gi Jeong , Koh Jae Soo , Kim Cheol Hyeon , Choe Du Hwan , Ryoo Baek-Yeol , Lee Jae Cheol , Lim Sang Moo , Yang Sung Hyun
Published: April 2008

Purpose: To evaluate response and survival according to 18F-fluoro-2-deoxy-glucose uptake at presentation in patients with gefitinib-treated non–small cell lung cancer.

Experimental Design: We retrospectively analyzed 84 positron emission tomography/computed tomography findings. Patient characteristics, response rates, and survivals were evaluated according to the maximum standardized uptake value (SUV) of primary tumor. The cutoff value of SUVs was obtained from receiver operating characteristic analysis.

Results: The response rate (RR) was higher for never-smokers (41%) than ever-smokers (9%; P = 0.001). Patients with adenocarcinoma showed higher RR than those with other tumor histopathology (35% versus 9%; P = 0.009). The SUV was significantly lower in patients who were never-smokers (P = 0.005), patients with adenocarcinoma (P < 0.001), and female patients (P = 0.017). Patients with a low SUV showed higher RR compared with those with a high SUV (53% versus 18%; P = 0.003). Prolonged progression-free survival was observed in patients with low SUVs compared with those with high SUVs (median, 33.1 weeks versus 8.6 weeks; P = 0.003). While controlling for performance status, smoking history, and pathology, the high SUV conferred unfavorable outcome (hazard ratio, 2.3; P = 0.012). In terms of overall survival, a low SUV was associated with favorable outcome in univariate analysis (P = 0.011). Patients with a low SUV showed prolonged survival in multivariate analysis (P = 0.043).

Conclusions: These results suggest that low SUVs at presentation can predict favorable response and survival in gefitinib-treated non–small cell lung cancer patients.
Human Leukocyte Antigen Class I, MHC Class I Chain-Related Molecule A, and CD8+/Regulatory T-Cell Ratio: Which Variable Determines Survival of Cervical Cancer Patients?
Authors: Jordanova Ekaterina S. , Gorter Arko , Ayachi Ouissam , Prins Frans , Durrant Lindy G. , Kenter Gemma G. , van der Burg Sjoerd H. , Fleuren Gert Jan
Published: April 2008

Purpose: To investigate the effect of intraepithelial tumor-infiltrating lymphocytes (ieTIL) and their ligands expressed by cervical tumor cells on the outcome of cervical cancer patients.

Experimental Design: The prognostic value of ieTILs was investigated in 115 cases of cervical cancer. T-cell subsets, CD57+ cells, and regulatory T cells (Treg) were enumerated. The associations of these different ieTIL subtypes with human leukocyte antigen (HLA) class I and MHC class I chain-related molecule A (MICA) expression were determined in relation to clinical variables and patient survival.

Results: Survival analysis showed that a high number of intraepithelial Treg (FoxP3+), a low CD8+/regulatory T-cell ratio, and a weak HLA-A expression were all associated with worse survival (P = 0.034, 0.025, and 0.033, respectively, log-rank test). Further stratification of patient groups based on HLA-A-MICA expression and HLA-A-MICA-CD8+/Treg ratio revealed an even poorer survival (P = 0.005). In a multivariate Cox analysis, low CD8+/Treg ratio (P = 0.047), weak HLA-A-MICA expression (P = 0.003), and weak HLA-A-MICA expression combined with low CD8+/Treg ratio (P = 0.002) were all found to be independent unfavorable prognostic predictors in cervical carcinoma (hazard ratios, 2.7, 4.0, and 4.9, respectively).

Conclusion: Weak HLA-A-MICA expression combined with low CD8+/Treg ratio reveals a patient group with the poorest survival in cervical cancer. As a single variable, low CD8+/Treg ratio was a significant independent unfavorable prognostic factor.
DTS-108, A Novel Peptidic Prodrug of SN38: In vivo Efficacy and Toxicokinetic Studies
Authors: Meyer-Losic Florence , Nicolazzi Céline , Quinonero Jérôme , Ribes Fabien , Michel Matthieu , Dubois Vincent , de Coupade Catherine , Boukaissi Matthieu , Chéné Anne-Sophie , Tranchant Isabelle , Arranz Valérie , Zoubaa Imane , Fruchart Jean-Sébastien , Ravel Denis , Kearsey Jonathan
Published: April 2008

Purpose: Irinotecan is a prodrug converted to the active cytotoxic molecule SN38 predominantly by the action of liver carboxylesterases. The efficacy of irinotecan is limited by this hepatic activation that results in a low conversion rate, high interpatient variability, and dose-limiting gastrointestinal toxicity. The purpose of this study was to evaluate a novel peptidic prodrug of SN38 (DTS-108) developed to bypass this hepatic activation and thus reduce the gastrointestinal toxicity and interpatient variability compared with irinotecan.

Experimental Design: SN38 was conjugated to a cationic peptide (Vectocell) via an esterase cleavable linker. The preclinical development plan consisted of toxicity and efficacy evaluation in a number of different models and species.

Results: The conjugate (DTS-108) is highly soluble, with a human plasma half-life of 400 minutes in vitro. Studies in the dog showed that DTS-108 liberates significantly higher levels of free SN38 than irinotecan without causing gastrointestinal toxicity. In addition, the ratio of the inactive SN38-glucuronide metabolite compared with the active SN38 metabolite is significantly lower following DTS-108 administration, compared with irinotecan, which is consistent with reduced hepatic metabolism. In vivo efficacy studies showed that DTS-108 has improved activity compared with irinotecan. A significant dose-dependent antitumoral efficacy was observed in all models tested and DTS-108 showed synergistic effects in combination with other clinically relevant therapeutic agents.

Conclusions: DTS-108 is able to deliver significantly higher levels of SN38 than irinotecan, without the associated toxicity of irinotecan, resulting in an increased therapeutic window for DTS-108 in preclinical models. These encouraging data merit further preclinical and clinical investigation.
Curcumin Sensitizes Human Colorectal Cancer Xenografts in Nude Mice to γ-Radiation by Targeting Nuclear Factor-κB–Regulated Gene Products
Authors: Kunnumakkara Ajaikumar B. , Diagaradjane Parmeswaran , Guha Sushovan , Deorukhkar Amit , Shentu Shujun , Aggarwal Bharat B. , Krishnan Sunil
Published: April 2008

Purpose: How colorectal cancer develops resistance to γ-radiation is not fully understood, but the transcription factor nuclear factor-κB (NF-κB) and NF-κB–regulated gene products have been proposed as mediators. Because curcumin, a component of turmeric (Curcuma longa), has been shown to suppress NF-κB activation, whether it can sensitize the colorectal cancer to γ-radiation was investigated in colorectal cancer xenografts in nude mice.

Experimental Design: We established HCT 116 xenograft in nude mice, randomized into four groups, and treated with vehicle (corn oil), curcumin, γ-radiation, and curcumin in combination with γ-radiation. NF-κB modulation was ascertained using electrophoretic mobility shift assay and immunohistochemistry. Markers of proliferation, angiogenesis, and invasion were monitored by immunohistochemistry and Western blot analysis.

Results: Curcumin significantly enhanced the efficacy of fractionated radiation therapy by prolonging the time to tumor regrowth (P = 0.02) and by reducing the Ki-67 proliferation index (P < 0. 001). Moreover, curcumin suppressed NF-κB activity and the expression of NF-κB–regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase-9, and vascular endothelial growth factor), many of which were induced by radiation therapy and mediate radioresistance. The combination of curcumin and radiation therapy also suppressed angiogenesis, as indicated by a decrease in vascular endothelial growth factor and microvessel density (P = 0.002 versus radiation alone).

Conclusion: Collectively, our results suggest that curcumin potentiates the antitumor effects of radiation therapy in colorectal cancer by suppressing NF-κB and NF-κB–regulated gene products, leading to inhibition of proliferation and angiogenesis.
Regulation of Hematopoietic Stem Cells by the Steel Factor/KIT Signaling Pathway
Authors: Kent David , Copley Michael , Benz Claudia , Dykstra Brad , Bowie Michelle , Eaves Connie
Published: April 2008

Understanding the intrinsic pathways that regulate hematopoietic stem cell (HSC) proliferation and self-renewal responses to external signals offers a rational approach to developing improved strategies for HSC expansion for therapeutic applications. Such studies are also likely to reveal new targets for the treatment of human myeloid malignancies because perturbations of the biological processes that control normal HSC self-renewal divisions are believed to drive the propagation of many of these diseases. Here, we review recent findings that point to the importance of using stringent functional criteria to define HSCs as cells with longterm repopulating activity and evidence that activation of the KIT receptor and many downstream effectors serve as major regulators of changing HSC proliferative and self-renewal behavior during development.
Effects of Tobacco Smoke on Gene Expression and Cellular Pathways in a Cellular Model of Oral Leukoplakia
Authors: Gümüş Zeynep H. , Du Baoheng , Kacker Ashutosh , Boyle Jay O. , Bocker Jennifer M. , Mukherjee Piali , Subbaramaiah Kotha , Dannenberg Andrew J. , Weinstein Harel
Published: April 2008

In addition to being causally linked to the formation of multiple tumor types, tobacco use has been associated with decreased efficacy of anticancer treatment and reduced survival time. A detailed understanding of the cellular mechanisms that are affected by tobacco smoke (TS) should facilitate the development of improved preventive and therapeutic strategies. We have investigated the effects of a TS extract on the transcriptome of MSK-Leuk1 cells, a cellular model of oral leukoplakia. Using Affymetrix HGU133 Plus 2 arrays, 411 differentially expressed probe sets were identified. The observed transcriptome changes were grouped according to functional information and translated into molecular interaction network maps and signaling pathways. Pathways related to cellular proliferation, inflammation, apoptosis, and tissue injury seemed to be perturbed. Analysis of networks connecting the affected genes identified specific modulated molecular interactions, hubs, and key transcription regulators. Thus, TS was found to induce several epidermal growth factor receptor (EGFR) ligands forming an EGFR-centered molecular interaction network, as well as several aryl hydrocarbon receptor–dependent genes, including the xenobiotic metabolizing enzymes CYP1A1 and CYP1B1. Notably, the latter findings in vitro are consistent with our parallel finding that CYP1A1 and CYP1B1 levels were increased in oral mucosa of smokers. Collectively, these results offer insights into the mechanisms underlying the procarcinogenic effects of TS and raise the possibility that inhibitors of EGFR or aryl hydrocarbon receptor signaling will prevent or delay the development of TS-related tumors. Moreover, the inductive effects of TS on xenobiotic metabolizing enzymes may help explain the reduced efficacy of chemotherapy, and suggest targets for chemopreventive agents in smokers.
A Prediction Model for Lung Cancer Diagnosis that Integrates Genomic and Clinical Features
Authors: Beane Jennifer , Sebastiani Paola , Whitfield Theodore H. , Steiling Katrina , Dumas Yves-Martine , Lenburg Marc E. , Spira Avrum
Published: April 2008

Lung cancer is the leading cause of cancer death due, in part, to lack of early diagnostic tools. Bronchoscopy represents a relatively noninvasive initial diagnostic test in smokers with suspect disease, but it has low sensitivity. We have reported a gene expression profile in cytologically normal large airway epithelium obtained via bronchoscopic brushings, which is a sensitive and specific biomarker for lung cancer. Here, we evaluate the independence of the biomarker from other clinical risk factors and determine the performance of a clinicogenomic model that combines clinical factors and gene expression.

Training (n = 76) and test (n = 62) sets consisted of smokers undergoing bronchoscopy for suspicion of lung cancer at five medical centers. Logistic regression models describing the likelihood of having lung cancer using the biomarker, clinical factors, and these data combined were tested using the independent set of patients with nondiagnostic bronchoscopies. The model predictions were also compared with physicians' clinical assessment.

The gene expression biomarker is associated with cancer status in the combined clinicogenomic model (P < 0.005). There is a significant difference in performance of the clinicogenomic relative to the clinical model (P < 0.05). In the test set, the clinicogenomic model increases sensitivity and negative predictive value to 100% and results in higher specificity (91%) and positive predictive value (81%) compared with other models. The clinicogenomic model has high accuracy where physician assessment is most uncertain.

The airway gene expression biomarker provides information about the likelihood of lung cancer not captured by clinical factors, and the clinicogenomic model has the highest prediction accuracy. These findings suggest that use of the clinicogenomic model may expedite more invasive testing and definitive therapy for smokers with lung cancer and reduce invasive diagnostic procedures for individuals without lung cancer.
Dietary Energy Balance Modulates Signaling through the Akt/Mammalian Target of Rapamycin Pathways in Multiple Epithelial Tissues
Authors: Moore Tricia , Beltran Linda , Carbajal Steve , Strom Sara , Traag Jeanine , Hursting Stephen D. , DiGiovanni John
Published: April 2008

The prevalence of obesity, an established risk factor for several types of cancer, has increased steadily over the past several decades in the United States. New targets and strategies for offsetting the effect of obesity on cancer risk are urgently needed. In the present study, we examined the effect of dietary energy balance manipulation on steady-state signaling in multiple epithelial tissues, with a focus on the Akt and mammalian target of rapamycin (mTOR) pathways. For these experiments, male FVB/N and C57BL/6 and female ICR mice were maintained on a control (10 kcal% fat) diet, a diet-induced obesity (DIO; 60 kcal% fat) regimen, or a 30% calorie restriction (CR) regimen for 15 to 17 weeks. Relative to the control group, the DIO regimen increased, whereas CR decreased, circulating insulin-like growth factor-I (IGF-I) as has previously been reported. Western blot analyses showed that the DIO regimen enhanced, whereas CR inhibited, activation of Akt and mTOR, regardless of epithelial tissue or genetic background. In contrast, activation of AMP-activated protein kinase was modulated by dietary energy balance manipulation in the liver but not in the epidermis or dorsolateral prostate. Western blot analyses of epidermal extracts taken from ICR mice also revealed reduced activation of both the IGF-I receptor and epidermal growth factor receptor in CR mice, compared with control mice or mice maintained on the DIO regimen. Taken together, these novel findings suggest that dietary energy balance modulates signaling through cell-surface receptors (i.e., IGF-I receptor and epidermal growth factor receptor), affecting activation of multiple downstream pathways including Akt and mTOR, thus providing important dietary and pharmacologic targets for disrupting the obesity-cancer link.
Leukocyte Integrin Mac-1 Promotes Acute Cardiac Allograft Rejection
Authors: Shimizu Koichi , Libby Peter , Shubiki Rica , Sakuma Masashi , Wang Yunmei , Asano Kenichi , Mitchell Richard N. , Simon Daniel I.
Published: April 2008

Background—

In allograft rejection, recipient leukocytes and alloantibodies first target donor endothelial cells. Although the leukocyte integrin Mac-1 (α
Mβ2
, CD11b/CD18) facilitates cell–cell interactions among leukocytes and interactions between leukocytes and endothelial cells or platelets, its role in allograft survival and vasculopathy is incompletely defined.

Methods and Results—

This study examined parenchymal rejection and graft arterial disease after total allomismatched cardiac transplantation (BALB/c donor heart and B6 recipients) in wild-type (WT) and Mac-1-deficient (Mac-1
−/−
) recipients. Recipient Mac-1 deficiency attenuated parenchymal rejection and significantly prolonged cardiac allograft survival from 8.3±1.3 days in WT recipient allografts (n=18) to 13.8±2.3 days in Mac-1
−/−
recipient allografts (n=6;
P
<0.0001). Accumulation of neutrophils and macrophages significantly decreased in Mac-1
−/−
compared with WT recipients. Adoptive transfer of WT but not Mac-1
−/−
macrophages to Mac-1
−/−
recipients exacerbated parenchymal rejection and reduced allograft survival; in contrast, adoptive transfer of WT neutrophils did not affect graft survival. Mac-1
−/−
macrophages expressed significantly lower levels of costimulatory molecules both in vivo and in vitro, and mixed lymphocyte reaction using alloantigen-primed Mac-1
−/−
macrophages resulted in significantly lower antigen-presenting function than for WT macrophages. Tumor necrosis factor-α production also fell in cultures with Mac-1
−/−
macrophages. Despite attenuation of acute rejection, recipient Mac-1-deficiency did not prevent late graft arterial disease.

Conclusions—

These studies demonstrate critical participation of Mac-1 in alloresponses during cellular allograft rejection. These observations establish a molecular target for modulating recipient responses to prolong graft survival.
Conditional FKBP12.6 Overexpression in Mouse Cardiac Myocytes Prevents Triggered Ventricular Tachycardia Through Specific Alterations in Excitation- Contraction Coupling
Authors: Gellen Barnabas , Fernández-Velasco María , Briec François , Vinet Laurent , LeQuang Khai , Rouet-Benzineb Patricia , Bénitah Jean-Pierre , Pezet Mylène , Palais Gael , Pellegrin Noémie , Zhang Andy , Perrier Romain , Escoubet Brigitte , Marniquet Xavier , Richard Sylvain , Jaisser Fréderic , Gómez Ana María , Charpentier Flavien , Mercadier Jean-Jacques
Published: April 2008

Background—

Ca
2+
release from the sarcoplasmic reticulum via the ryanodine receptor (RyR2) activates cardiac myocyte contraction. An important regulator of RyR2 function is FKBP12.6, which stabilizes RyR2 in the closed state during diastole. β-Adrenergic stimulation has been suggested to dissociate FKBP12.6 from RyR2, leading to diastolic sarcoplasmic reticulum Ca
2+
leakage and ventricular tachycardia (VT). We tested the hypothesis that FKBP12.6 overexpression in cardiac myocytes can reduce susceptibility to VT in stress conditions.

Methods and Results—

We developed a mouse model with conditional cardiac-specific overexpression of FKBP12.6. Transgenic mouse hearts showed a marked increase in FKBP12.6 binding to RyR2 compared with controls both at baseline and on isoproterenol stimulation (0.2 mg/kg IP). After pretreatment with isoproterenol, burst pacing induced VT in 10 of 23 control mice but in only 1 of 14 transgenic mice (
P
<0.05). In isolated transgenic myocytes, Ca
2+
spark frequency was reduced by 50% (
P
<0.01), a reduction that persisted under isoproterenol stimulation, whereas the sarcoplasmic reticulum Ca
2+
load remained unchanged. In parallel, peak I
Ca,L
density decreased by 15% (
P
<0.01), and the Ca
2+
transient peak amplitude decreased by 30% (
P
<0.001). A 33.5% prolongation of the caffeine-evoked Ca
2+
transient decay was associated with an 18% reduction in the Na
+
-Ca
2+
exchanger protein level (
P
<0.05).

Conclusions—

Increased FKBP12.6 binding to RyR2 prevents triggered VT in normal hearts in stress conditions, probably by reducing diastolic sarcoplasmic reticulum Ca
2+
leak. This indicates that the FKBP12.6-RyR2 complex is an important candidate target for pharmacological prevention of VT.
Rapid Endothelial Turnover in Atherosclerosis-Prone Areas Coincides With Stem Cell Repair in Apolipoprotein E–Deficient Mice
Authors: Foteinos Georgios , Hu Yanhua , Xiao Qingzhong , Metzler Bernhard , Xu Qingbo
Published: April 2008

Background—

Recently, it has been shown that stem/progenitor cells may repair damaged/lost endothelial cells in vein grafts and wire-injured arteries. In the present study, we investigated endothelial cell turnover and regeneration in apolipoprotein E (apoE)
−/−
/transgenic mice carrying LacZ genes driven by an endothelial TIE2 promoter.

Methods and Results—

To assess cell proliferation on the surface of aortas in apoE
−/−
mice and wild-type controls, BrdU was injected into the tail vein and labeled on en face preparation. BrdU-positive cells on the aortas were observed occasionally in wild-type mice and frequently at sites prone to lesion development in apoE
−/−
mice (0.18±0.1% versus 1.12±0.2%;
P
<0.001). Endothelial integrity tests demonstrated that the areas with high rate of cell turnover displayed Evans blue leakage, low levels of VE-cadherin expression, and increased cell attachment, as evidenced by Evans blue dye injection, immunostaining, and scanning electron microscopy, respectively. Furthermore, immunostaining for CD34, Sca-1, Flk-1, and CD133 indicated that ≈3% to 5% of total cells on the aorta were positive in apoE
−/−
mice. En face double labeling using Ki-67 and progenitor markers revealed that 30% to 50% of progenitor
+
cells expressed Ki-67, indicating a state of proliferation. To clarify the origin of endothelial progenitor cells participating in endothelial repair in apoE
−/−
mice, a chimeric mouse model was created by bone marrow transplantation between apoE
−/−
and LacZ
+/+
/apoE
−/−
mice. Ten months after bone marrow transplantation, ≈3% to 4% of total cells in the lesion-prone areas were β-gal positive in apoE
−/−
with apoE
−/−
/TIE2-LacZ bone marrow mice. When cells of aortas from chimeric mice were cultivated on Matrigel-coated plates, a capillary-like structure was found, which showed β-gal/CD31 or β-gal/von Willebrand factor double positivity. By a combined analysis of laser dissection microscopy and nest reverse transcription polymerase chain reaction, it was found that β-gal
+
cells were mainly expressing CD31 and CD144.

Conclusions—

Our findings provide the first quantitative data on endothelial turnover and repair by progenitor cells that are, at least in part, derived from bone marrow during development of atherosclerosis in apoE
−/−
mice.
Cardiac Sodium Channel (
SCN5A
) Variants Associated with Atrial Fibrillation
Authors: Darbar Dawood , Kannankeril Prince J. , Donahue Brian S. , Kucera Gayle , Stubblefield Tanya , Haines Jonathan L. , George Alfred L. , Roden Dan M.
Published: April 2008

Background—

Genetic studies have identified ion channel gene variants in families segregating atrial fibrillation (AF), the most common arrhythmia in clinical practice. Here, we tested the hypothesis that vulnerability to AF is associated with variation in
SCN5A
, the gene encoding the cardiac sodium channel.

Methods and Results—

We resequenced the entire
SCN5A
coding region in 375 subjects with either lone AF (n=118) or AF associated with heart disease (n=257). Controls (n=360) from the same population were then genotyped for the presence of mutations or rare variants identified in the AF cases. In 10 probands (2.7%), 8 novel variants not found in the control population (0%;
P
=0.001) were identified. All variants affect highly conserved residues in the SCN5A protein. In 6 families with >1 affected member, the novel variant cosegregated with AF. We also identified 11 rare missense variants in 12 probands (3.2%) that have previously been associated with inherited arrhythmia syndromes (eg, congenital long-QT syndrome and Brugada syndrome).

Conclusions—

Mutations or rare variants in
SCN5A
may predispose patients with or without underlying heart disease to AF. The findings of the present study expand the clinical spectrum of disorders of the cardiac sodium channel to include AF and represent important progress toward molecular phenotyping and directed rather than empirical therapy for this common arrhythmia.
Increase in Carotid Intima-Media Thickness in Grade I Hypertensive Subjects
Authors: Puato Massimo , Palatini Paolo , Zanardo Marco , Dorigatti Francesca , Tirrito Carmen , Rattazzi Marcello , Pauletto Paolo
Published: April 2008

We studied 74 never-treated grade I hypertensive subjects aged 18 to 45 years and 20 normotensive control subjects to define the rate of increase in carotid intima-media thickness (IMT) and the potential role played by the various risk factors. IMT was assessed as mean IMT and as maximum IMT in the right and left common carotid artery, carotid bulb, and internal carotid artery at baseline and at the 5-year follow-up. In grade I hypertensive subjects, both mean IMT and mean of maximum IMT were significantly higher compared with baseline values. Compared with normotensive subjects, both mean IMT and maximum IMT increased significantly (at least
P
<0.01) in each carotid artery segment. The increase in cumulative IMT was 3.4-fold for mean IMT and 3.2-fold for mean of maximum IMT. Levels of mean arterial pressure at 24-hour monitoring and total serum cholesterol were factors potentially linked to the increment in mean IMT and mean of maximum IMT. Age was also relevant for the increment in mean of maximum IMT, whereas body mass index played some role in the increment of mean IMT. During the follow-up, mean IMT and mean of maximum IMT increased to a greater degree in white-coat hypertensive subjects (n=35) and sustained hypertensive subjects (n=39) than in normotensive control subjects. No differences were found between white-coat hypertensive subjects and sustained hypertensive subjects for both mean IMT and maximum IMT. Levels of mean arterial pressure at 24-hour monitoring affected the increment in IMT in both white-coat hypertensive subjects and sustained hypertensive subjects. In conclusion, our findings indicate that carotid IMT is greater and grows faster in white-coat hypertensive subjects than in normotensive subjects without significant differences with sustained hypertensive patients.
Four Years of Tropical ERA-40 Vorticity Maxima Tracks. Part I: Climatology and Vertical Vorticity Structure
Authors: Kerns Brandon , Greene Kantave , Zipser Edward
Published: April 2008

Using the 40-yr European Centre for Medium-Range Weather Forecasts Re-Analysis (ERA-40), vorticity maxima (VM) have been manually tracked and classified as developing and nondeveloping. The VM are identified on Hovmöller plots for June–October 1998–2001, within 0°–35°N, 140°–10°W. Over 600 low-level and midlevel VM are tracked. The ERA-40 VM track climatology compares favorably with previous knowledge about easterly waves. Some new results have also been found. The VM are not equivalent to easterly waves, so it is important to distinguish between the large-scale wave and the embedded VM. Unlike waves, individual VM leaving Africa generally do not survive to cross the entire Atlantic. Unlike waves, which can cross Central America, most individual east Pacific VM originate in the east Pacific. Genesis productivity is defined as the fraction of nontropical cyclone VM that eventually develop. It reaches 50% in the eastern North Pacific (EPAC) and 30% in the Atlantic, where there is geographical separation between the locations of maximum nondeveloping and pregenesis track density. There is a strong gradient in daily genesis potential (DGP) near 10°N, associated with weaker upper-level anticyclonic vorticity equatorward of 10°N. The maximum genesis productivity is obtained north of 10°N, where the upper-anticyclonic vorticity and DGP are higher. Finally, there is no obvious distinction in VM strength between developing VM prior to genesis and nondeveloping VM. A major factor is the minimum vorticity threshold for VM as opposed to cloud clusters.
Scientific Productivity, Web Visibility and Citation Patterns in Sixteen Nordic Sociology Departments
Authors: Aaltojärvi Inari , Arminen Ilkka , Auranen Otto , Pasanen Hanna-Mari
Published: April 2008

Science is being published increasingly on the web. In this article, we explore how Nordic sociology is represented on Google Scholar (GS), what its output and impact is, and what factors explain it. Our data consist of faculty in 16 Nordic sociology departments in March 2005. The distribution of their publications and citations is skewed. Thirteen per cent of scholars do not appear on GS, whereas only 15 per cent have more than 5 publications. Of scholars with at least 1 publication ( n = 240), 75 per cent have at most 10 citations. Both the number of web hits (web visibility) and citations are influenced by the gender of the faculty member, type and age of publication. Web visibility, citations and position are mutually reinforcing. Departmental effect is greater in web visibility than citations. International publications have started to dominate the social sciences, international monographs being particularly frequently cited. The remaining salience of books shows that sociology is still a distinct form of knowledge. The exclusive use of refereed articles and direct comparisons with the natural sciences ignore important aspects of the social sciences. In all, while GS produces findings similar to those in citation databases such as the SSCI, some systematic differences exist. No individual method for measuring scientific output is objective.
Terrorism and Everyday Life in Beirut 2005
Authors: Borell Klas
Published: April 2008

Although the psychological stress created by terror has been extensively researched, little has been written about the subjective experience of living with terror. How do people perceive risk and how do they adjust their daily lives? The Lebanese capital Beirut suffered from a wave of bomb attacks following the assassination of Lebanon's former Prime Minister Rafik Hariri on 14 February 2005. In order to examine people's reactions and ways of coping with these events, 14 focus group interviews ( n = 77) were conducted in targeted areas. The findings suggest that Beirutis could no longer rely on the taken-for-granted routines of daily life. By changing their routes to school or work and avoiding public places, they restricted their daily activities. However, the data also suggest that targeted people attempted to normalize their everyday lives. Two strategies were employed. The first can be described as bracketing in time and space, which means that people tried to benefit from periods they perceived as moments of reprieve, and that they defined business and private space as safe havens. Bracketing can also be described as re-normalization, i.e. as an attempt to return to the previous state of `normality'. The other strategy can be described as crisis normalization and means that the new evaluations of the risks and new patterns of action adopted, which originally deviated from people's established routines, themselves became routinized.
Mobility and Territorial Belonging
Authors: Gustafson Per
Published: April 2008

Much existing research assumes that there is an opposition between mobility and territorial belonging, so that mobile persons tend to have a weak sense of belonging whereas persons with a strong sense of belonging are less willing than others to move. Some studies, however, suggest that mobility may coexist with or even reinforce territorial belonging. This article uses Swedish survey data to introduce two important qualifications to this discussion. First, it shows that different kinds of mobility—daily commuting, long-distance travel, residential mobility, and international migration—are differently related to people's sense of belonging. Second, by examining local, regional, national, and European belonging, it shows that the relationship between mobility and belonging is to some extent a matter of territorial scale.
Gender Differences in Gifted and Average-Ability Students
Authors: Preckel Franzis , Goetz Thomas , Pekrun Reinhard , Kleine Michael
Published: April 2008

This article investigates gender differences in 181 gifted and 181 average-ability sixth graders in achievement, academic self-concept, interest, and motivation in mathematics. Giftedness was conceptualized as nonverbal reasoning ability and defined by a rank of at least 95% on a nonverbal reasoning subscale of the German Cognitive Abilities Test. Mathematical achievement was measured by teacher-assigned grades and a standardized mathematics test. Self-concept, interest, and motivation were assessed by questionnaire. In both ability groups, boys earned significantly higher test scores but there were no gender differences in grades. Girls scored lower on measures of academic self-concept, interest, and motivation. Gender differences were larger in gifted than in average-ability students. Ability group differences for self-concept and interest were only found for boys in favor of the gifted. Results support the assumption that gender differences in self-concept, interest, and motivation in mathematics are more prevalent in gifted than in average-ability students.
Academically Talented Students' Attitudes Toward Service in the Community
Authors: Webster Nicole S. , Worrell Frank C.
Published: April 2008

In this study, the authors examined participation rates in, and attitudes toward, service in community settings in a sample of 936 academically talented adolescents. Results indicated that about 50% of the participants participated in both classroom-sponsored and organization-sponsored service activities, with female students reporting higher rates than male students. Participation rates increased with increases in socioeconomic status, and rates in organization-sponsored activities increased across grade levels. Attitudes toward service were generally positive, with female students having more positive attitudes than male students. These findings mirror results from studies of non-identified students and suggest that differences in participation rates in service activities may be reflecting differences in economic circumstances that allow for participation.
When and Where I Enter
Authors: Hubbard LaRese C.
Published: April 2008

Anna Julia Cooper provides an important, though often overlooked, Africana intellectual history and philosophy in the field of Africana Studies generally and Black women’s history particularly. Many of the studies on Anna Julia Cooper’s life and philosophy have been done outside of the discipline of Africology, and as a result, her work has primarily been placed in the feminist and literary studies field. While it can be stated that her speeches and writings have greatly contributed to the growth of these philosophies, Cooper’s most fundamental and least recognized intellectual contribution is to the establishment and advancement of the Afrocentric discourse. There is an urgent need to recover and reclaim Anna Julia Cooper, her foremothers, and contemporaries who have not been thoroughly discussed within Africana studies as agents of cultural change in their communities and at large. In this article, Cooper’s intellectual thought is situated at the center and examined for its significance to the discourse and development of Africana studies.
Rediscovering the “Lost” Roman Caesar
Authors: Asante Molefi Kete , Ismail Shaza
Published: April 2008

The aim of this article is to rescue, as much as possible, the history of the African Roman Emperor Lucius Septimius Severus in order to adequately place him, with his considerable faults and achievements, in the continental record of Africa. Thus, the authors present the reader with a general overview of the life and career of Severus, emphasizing the African character of his experience and that of his companions who worked to secure him the position of Emperor of Rome. They then interrogate the “identity” issues surrounding Severus’s history in order to rediscover his place in the history of the Roman Empire.
African Americans and Homelessness
Authors: Johnson Roberta Ann
Published: April 2008

The story of African Americans is usually absent from the mainstream textbook study of homeless people. This research begins to address this absence. It provides an overview by using eight distinct historic experiences—the colonial period, Civil War period, cowboys of the west, the tramping years, the Black migration north, the depression years and New Deal, urban renewal, and deindustrialization of the American economy—to begin the process of more fully describing the experience of Black homelessness in America.