bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved Survival in Rhesus Macaques Immunized with Modified Vaccinia Virus Ankara Recombinants Expressing Simian Immunodeficiency Virus Envelope Correlates with Reduction in Memory CD4+T-Cell Loss and Higher Titers of Neutralizing Antibody
Authors: Ourmanov Ilnour , Kuwata Takeo , Goeken Robert , Goldstein Simoy , Iyengar Ranjani , Buckler-White Alicia , Lafont Bernard , Hirsch Vanessa M. 
Published: March 2009

ABSTRACTPrevious studies demonstrated that immunization of macaques with simian immunodeficiency virus (SIV) Gag-Pol and Env recombinants of the attenuated poxvirus modified vaccinia virus Ankara (MVA) provided protection from high viremia and AIDS following challenge with a pathogenic strain of SIV. Although all animals became infected, plasma viremia was significantly reduced in animals that received the MVA-SIV recombinant vaccines compared with animals that received nonrecombinant MVA. Most importantly, the reduction in viremia resulted in a significant increase in median and cumulative survival. Continued analysis of these animals over the subsequent 9 years has shown that they maintain a survival advantage, although all but two of the macaques have progressed to AIDS. Importantly, improved survival correlated with preservation of memory CD4+T cells in the peripheral blood. The greatest survival advantage was observed in macaques immunized with regimens containing SIV Env, and the titer of neutralizing antibodies to the challenge virus prior to or shortly following challenge correlated with preservation of CD4+T cells. These data are consistent with a role for neutralizing antibodies in nonsterilizing protection from high viremia and associated memory CD4+T-cell loss.
Angiotensinogen Delays Angiogenesis and Tumor Growth of Hepatocarcinoma in Transgenic Mice
Authors: Vincent François , Bonnin Philippe , Clemessy Maud , Contrerès Jean-Olivier , Lamandé Noël , Gasc Jean-Marie , Vilar José , Hainaud Patricia , Tobelem Gérard , Corvol Pierre , Dupuy Evelyne 
Published: March 2009

Abstract
Angiotensinogen, a member of the serpin family, is involved in the suppression of tumor growth and metastasis. To investigate whether human angiotensinogen protects against tumor progression in vivo, we established an original bitransgenic model in which transgenic mice expressing human angiotensinogen (Hu-AGT-TG mice) were crossed with a transgenic mouse model of hepatocellular carcinoma (HCC-TG mice). Bitransgenic mice overexpressing human angiotensinogen (HCC/Hu-AGT-TG) had a significantly longer survival time than the HCC-TG mice and a reduction of both tumor growth and blood flow velocities in the liver. This antitumor effect of angiotensinogen is related to a reduced angiogenesis, impaired expression of endothelial arterial markers (active Notch4, Delta-like 4 ligand, and ephrin B2) with a decrease of arterial vessel density in HCC/Hu-AGT-TG mice liver. Overexpression of human angiotensinogen decreases angiogenesis, and prevents tumor sinusoids from remodeling and arterialization, thus delaying tumor progression in vivo. [Cancer Res 2009;69(7):2853–60]
Modulation of Caspase-Independent Cell Death Leads to Resensitization of Imatinib Mesylate–Resistant Cells
Authors: Lavallard Vanessa J. , Pradelli Ludivine A. , Paul Audrey , Bénéteau Marie , Jacquel Arnaud , Auberger Patrick , Ricci Jean-Ehrland 
Published: March 2009

Abstract
Imatinib mesylate is widely used for the treatment of patients with chronic myelogenous leukemia (CML). This compound is very efficient in killing Bcr-Abl–positive cells in a caspase-dependent manner. Nevertheless, several lines of evidence indicated that caspase-mediated cell death (i.e., apoptosis) is not the only type of death induced by imatinib. The goal of our study was to evaluate the importance of the newly described caspase-independent cell death (CID) in Bcr-Abl–positive cells. We established in several CML cell lines that imatinib, in conjunction with apoptosis, also induced CID. CID was shown to be as efficient as apoptosis in preventing CML cell proliferation and survival. We next investigated the potential implication of a recently identified mechanism used by cancer cells to escape CID through overexpression of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We showed here, in several CML cell lines, that GAPDH overexpression was sufficient to induce protection from CID. Furthermore, imatinib-resistant Bcr-Abl–positive cell lines were found to spontaneously overexpress GAPDH. Finally, we showed that a GAPDH partial knockdown, using specific short hairpin RNAs, was sufficient to resensitize those resistant cells to imatinib-induced cell death. Taken together, our results indicate that CID is an important effector of imatinib-mediated cell death. We also established that GAPDH overexpression can be found in imatinib-resistant Bcr-Abl–positive cells and that its down-regulation can resensitize those resistant cells to imatinib-induced death. Therefore, drugs able to modulate GAPDH administered together with imatinib could find some therapeutic benefits in CML patients. [Cancer Res 2009;69(7):3013–20]
A Novel Prostate Cancer Susceptibility Locus at 19q13
Authors: Hsu Fang-Chi , Sun Jielin , Wiklund Fredrik , Isaacs Sarah D. , Wiley Kathleen E. , Purcell Lina D. , Gao Zhengrong , Stattin Pär , Zhu Yi , Kim Seong-Tae , Zhang Zheng , Liu Wennuan , Chang Bao-Li , Walsh Patrick C. , Duggan David , Carpten John D. , Isaacs William B. , Grönberg Henrik , Xu Jianfeng , Zheng S. Lilly 
Published: March 2009

Abstract
A two-stage genome-wide association study (GWAS) of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative identified single nucleotide polymorphisms (SNP) in 150 regions across the genome that may be associated with prostate cancer (PCa) risk. We filtered these results to identify 43 independent SNPs where the frequency of the risk allele was consistently higher in cases than in controls in each of the five CGEMS study populations. Genotype information for 22 of these 43 SNPs was obtained either directly by genotyping or indirectly by imputation in our PCa GWAS of 500 cases and 500 controls selected from a population-based case-control study in Sweden [Cancer of the Prostate in Sweden (CAPS)]. Two of these 22 SNPs were significantly associated with PCa risk (P &lt; 0.05). We then genotyped these two SNPs in the remaining cases (n = 2,393) and controls (n = 1,222) from CAPS and found that rs887391 at 19q13 was highly associated with PCa risk (P = 9.4 × 10−4). A similar trend of association was found for this SNP in a case-control study from Johns Hopkins Hospital (JHH), albeit the result was not statistically significant. Altogether, the frequency of the risk allele of rs887391 was consistently higher in cases than controls among each of seven study populations examined, with an overall P = 3.2 × 10−7 from a combined allelic test. A fine-mapping study in a 110-kb region at 19q13 among CAPS and JHH study populations revealed that rs887391 was the most strongly associated SNP in the region. Additional confirmation studies of this region are warranted. [Cancer Res 2009;69(7):2720–3]
Triggering of Toll-like Receptor 4 Expressed on Human Head and Neck Squamous Cell Carcinoma Promotes Tumor Development and Protects the Tumor from Immune Attack
Authors: Szczepanski Miroslaw J. , Czystowska Malgorzata , Szajnik Marta , Harasymczuk Malgorzata , Boyiadzis Michael , Kruk-Zagajewska Aleksandra , Szyfter Witold , Zeromski Jan , Whiteside Theresa L. 
Published: March 2009

AbstractToll-like receptors (TLR) expressed on inflammatory cells play a key role in host defense against pathogens, benefiting the host. TLR are also expressed on tumor cells. To evaluate the role of TLR in tumor cells, we investigated TLR4 signaling effects on human head and neck squamous cell carcinoma (HNSCC). Tumor tissues were obtained from 27 patients with laryngeal and 12 with oral cavity cancers. Normal mucosa was obtained from 10 patients with nonneoplastic disorders. Smears for bacteria were taken from all patients during surgery. TLR4 expression in tumors and HNSCC cell lines (PCI-1, PCI-13, and PCI-30) was detected by reverse transcription-PCR and immunohistochemistry. Cell growth, apoptosis, nuclear factor-κB (NF-κB) translocation, and MyD88 and IRAK-4 expression, as well as Akt phosphorylation were measured following tumor cell exposure to the TLR4 ligand lipopolysaccharide (LPS). Tumor cell sensitivity to NK-92–mediated lysis was evaluated in 4-hour 51Cr-release assays. Cytokine levels in HNSCC supernatants were measured in Luminex-based assays. TLR4 was expressed in all tumors, HNSCC cell lines, and normal mucosa. The TLR4 expression intensity correlated with tumor grade. LPS binding to TLR4 on tumor cells enhanced proliferation, activated phosphatidylinositol 3-kinase/Akt pathway, up-regulated IRAK-4 expression, induced nuclear NF-κB translocation, and increased production (P &lt; 0.05) of interleukin (IL)-6, IL-8, vascular endothelial growth factor, and granulocyte macrophage colony-stimulating factor. TLR4 triggering protected tumor cells from lysis mediated by NK-92 cells. TLR4 ligation on tumor cells supports HNSCC progression. [Cancer Res 2009;69(7):3105–13]
Inhibition of NOTCH Signaling by Gamma Secretase Inhibitor Engages the RB Pathway and Elicits Cell Cycle Exit in T-Cell Acute Lymphoblastic Leukemia Cells
Authors: Rao Sudhir S. , O'Neil Jennifer , Liberator Cole D. , Hardwick James S. , Dai Xudong , Zhang Theresa , Tyminski Edyta , Yuan Jing , Kohl Nancy E. , Richon Victoria M. , Van der Ploeg Lex H.T. , Carroll Pamela M. , Draetta Giulio F. , Look A. Thomas , Strack Peter R. , Winter Christopher G. 
Published: March 2009

Abstract
NOTCH signaling is deregulated in the majority of T-cell acute lymphoblastic leukemias (T-ALL) as a result of activating mutations in NOTCH1. Gamma secretase inhibitors (GSI) block proteolytic activation of NOTCH receptors and may provide a targeted therapy for T-ALL. We have investigated the mechanisms of GSI sensitivity across a panel of T-ALL cell lines, yielding an approach for patient stratification based on pathway activity and also providing a rational combination strategy for enhanced response to GSI. Whereas the NOTCH1 mutation status does not serve as a predictor of GSI sensitivity, a gene expression signature of NOTCH pathway activity does correlate with response, and may be useful in the selection of patients more likely to respond to GSI. Furthermore, inhibition of the NOTCH pathway activity signature correlates with the induction of the cyclin-dependent kinase inhibitors CDKN2D (p19INK4d) and CDKN1B (p27Kip1), leading to derepression of RB and subsequent exit from the cell cycle. Consistent with this evidence of cell cycle exit, short-term exposure of GSI resulted in sustained molecular and phenotypic effects after withdrawal of the compound. Combination treatment with GSI and a small molecule inhibitor of CDK4 produced synergistic growth inhibition, providing evidence that GSI engagement of the CDK4/RB pathway is an important mechanism of GSI action and supports further investigation of this combination for improved efficacy in treating T-ALL. [Cancer Res 2009;69(7):3060–8]
MUC1-Induced Transcriptional Programs Associated with Tumorigenesis Predict Outcome in Breast and Lung Cancer
Authors: Khodarev Nikolai N. , Pitroda Sean P. , Beckett Michael A. , MacDermed Dhara M. , Huang Lei , Kufe Donald W. , Weichselbaum Ralph R. 
Published: March 2009

Abstract
The Mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in diverse human malignancies including breast and lung cancer. Although MUC1 modulates the activity of several transcription factors, there is no information regarding the effects of MUC1 on global gene expression patterns and the potential role of MUC1-induced genes in predicting outcome for cancer patients. We have developed an experimental model of MUC1-induced transformation that has identified the activation of gene families involved in oncogenesis, angiogenesis, and extracellular matrix remodeling. A set of experimentally derived MUC1-induced genes associated with tumorigenesis was applied to the analysis of breast and lung adenocarcinoma cancer databases. A 35-gene MUC1-induced tumorigenesis signature predicts significant decreases in both disease-free and overall survival in patients with breast (n = 295) and lung (n = 442) cancers. The data show that the MUC1 oncoprotein contributes to the regulation of genes that are highly predictive of clinical outcome in breast and lung cancer patients. [Cancer Res 2009;69(7):2833–7]
Clinical and Biological Effects of Valproic Acid as a Histone Deacetylase Inhibitor on Tumor and Surrogate Tissues: Phase I/II Trial of Valproic acid and Epirubicin/FEC
Authors: Munster Pamela , Marchion Douglas , Bicaku Elona , Lacevic Mira , Kim Jongphil , Centeno Barbara , Daud Adil , Neuger Anthony , Minton Susan , Sullivan Daniel 
Published: March 2009

Abstract
Purpose: The aim was to study the biological and molecular effects of the histone deacetylase (HDAC) inhibitor, valproic acid, in patients with solid tumor malignancies.
Experimental Design: A phase I dose escalation of valproic acid given on days 1 to 3 followed by epirubicin (day 3) was followed by a dose expansion of valproic acid combined with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100). Pharmacodynamic and pharmacokinetic studies entailed valproic acid and epirubicin plasma levels and their interaction, the effects of valproic acid on histone acetylation in peripheral blood mononuclear cells (PBMC) and tumor cells at baseline and day 3, and baseline expression of HDAC2 and HDAC6 as therapeutic targets.
Results: Forty-four patients were enrolled in the phase I part, with a disease-specific cohort expansion of 15 breast cancer patients (median age, 55 years; range, 28-66 years) receiving 120 mg/kg/day valproic acid followed by FEC100. Partial responses were seen in 9 of 41 (22%) patients during the phase I part. Objective responses were seen in 9 of 14 (64%) evaluable patients at the dose expansion with a median number of 6 administered cycles. Predominant toxicities were valproic acid–associated somnolence and epirubicin-induced myelosuppression. Valproic acid plasma levels were associated with short-term, reversible depletion of WBC and neutrophils within 48 hours. Histone acetylation in tumor samples and in PBMCs correlated with valproic acid levels and was further linked to baseline HDAC2 but not to HDAC6 expression.
Conclusion: Valproic acid is a clinically relevant HDAC inhibitor, and PBMCs may serve as a surrogate for tumor histone acetylation in solid tumor malignancies. HDAC2 should be further considered as a relevant therapeutic target.
Microarray Analysis of Early Stage Serous Ovarian Cancers Shows Profiles Predictive of Favorable Outcome
Authors: Berchuck Andrew , Iversen Edwin S. , Luo Jingqin , Clarke Jennifer P. , Horne Hisani , Levine Douglas A. , Boyd Jeff , Alonso Miguel A. , Secord Angeles Alvarez , Bernardini Marcus Q. , Barnett Jason C. , Boren Todd , Murphy Susan K. , Dressman Holly K. , Marks Jeffrey R. , Lancaster Johnathan M. 
Published: March 2009

Abstract
Purpose: Although few women with advanced serous ovarian cancer are cured, detection of the disease at an early stage is associated with a much higher likelihood of survival. We previously used gene expression array analysis to distinguish subsets of advanced cancers based on disease outcome. In the present study, we report on gene expression of early-stage cancers and validate our prognostic model for advanced-stage cancers.
Experimental Design: Frozen specimens from 39 stage I/II, 42 stage III/IV, and 20 low malignant potential cancers were obtained from four different sites. A linear discriminant model was used to predict survival based upon array data.
Results: We validated the late-stage survival model and show that three of the most differentially expressed genes continue to be predictive of outcome. Most early-stage cancers (38 of 39 invasive, 15 of 20 low malignant potential) were classified as long-term survivors (median probabilities 0.97 and 0.86). MAL, the most differentially expressed gene, was further validated at the protein level and found to be an independent predictor of poor survival in an unselected group of advanced serous cancers (P = 0.0004).
Conclusions: These data suggest that serous ovarian cancers detected at an early stage generally have a favorable underlying biology similar to advanced-stage cases that are long-term survivors. Conversely, most late-stage ovarian cancers seem to have a more virulent biology. This insight suggests that if screening approaches are to succeed it will be necessary to develop approaches that are able to detect these virulent cancers at an early stage.
Dietary Omega-3 Fatty Acids, Cyclooxygenase-2 Genetic Variation, and Aggressive Prostate Cancer Risk
Authors: Fradet Vincent , Cheng Iona , Casey Graham , Witte John S. 
Published: March 2009

Abstract
Purpose: Dietary intake of long-chain ω-3 (LC n-3) polyunsaturated fatty acids may reduce inflammation and in turn decrease risk of prostate cancer development and progression. This potential effect may be modified by genetic variation in cyclooxygenase-2 (COX-2), a key enzyme in fatty acid metabolism and inflammation.
Experimental Design: We used a case-control study of 466 men diagnosed with aggressive prostate cancer and 478 age- and ethnicity-matched controls. Diet was assessed with a semiquantitative food frequency questionnaire, and nine COX-2 tag single nucleotide polymorphisms (SNP) were genotyped. We used logistic regression models to estimate odds ratios (OR) for association and interaction.
Results: Increasing intake of LC n-3 was strongly associated with a decreased risk of aggressive prostate cancer (Ptrend ≤ 0.0001). The OR (95% confidence interval) for prostate cancer comparing the highest with the lowest quartile of n-3 intake was of 0.37 (0.25-0.54). The LC n-3 association was modified by SNP rs4648310 (+8897 A/G), flanking the 3′ region of COX-2 (Pinteraction = 0.02). In particular, the inverse association was even stronger among men with this variant SNP. This reflected the observation that men with low LC n-3 intake and the variant rs4648310 SNP had an increased risk of disease (OR, 5.49; 95% confidence interval, 1.80-16.7), which was reversed by increasing intake of LC n-3.
Conclusions: Dietary LC n-3 polyunsaturated fatty acids appear protective for aggressive prostate cancer, and this effect is modified by the COX-2 SNP rs4648310. Our findings support the hypothesis that LC n-3 may impact prostate inflammation and carcinogenesis through the COX-2 enzymatic pathway.
Variable Clinical Presentations of Nasal and Waldeyer Ring Natural Killer/T-Cell Lymphoma
Authors: Li Ye-Xiong , Liu Qing-Feng , Fang Hui , Qi Shu-Nan , Wang Hua , Wang Wei-Hu , Song Yong-Wen , Lu Jiade , Jin Jing , Wang Shu-Lian , Liu Yue-Ping , Lu Ning , Liu Xin-Fan , Yu Zi-Hao 
Published: March 2009

AbstractPurpose: To determine the clinical characteristics, prognosis, and treatment outcome for patients with nasal natural killer (NK)/T-cell lymphoma (N-NKTL) and Waldeyer ring NK/T-cell lymphoma (WR-NKTL).Experimental Design: A total of 145 patients with N-NKTL and 95 patients with WR-NKTL were compared.Results: Compared with N-NKTL, WR-NKTL exhibited distinct differences in clinical features with a propensity for nodal involvement, more advanced stages, low elevated lactate dehydrogenase, intermediate chemosensitivity, and a favorable prognosis. Compared with patients with WR-NKTL, patients with N-NKTL were associated with a lower overall response (54% versus 89%) and higher persistent or progressive disease after initial chemotherapy (46% versus 11%; P = 0.000). The 5-year overall survival and progression-free survival rates were 67% and 56% for N-NKTL and 65% and 47% for WR-NKTL, respectively. Patients with stage II WR-NKTL showed favorable prognosis compared with those with stage II N-NKTL. Compared with radiotherapy alone, patients with early-stage WR-NKTL that received radiotherapy and chemotherapy showed a superior progression-free survival and improved overall survival. In contrast, the addition of chemotherapy to radiotherapy did not provide any survival benefit for patients with early-stage N-NKTL.Conclusions: N-NKTL and WR-NKTL represent heterogeneous groups with variable clinical features, responses, prognosis, and treatment options.
Top–Down Attentional Control in Parkinson's Disease: Salient Considerations
Authors: Cools Roshan , Rogers Robert , Barker Roger A. , Robbins Trevor W. 
Published: March 2009

Abstract
Cognitive dysfunction in Parkinson's disease (PD) has been hypothesized to reflect a failure of cortical control. In keeping with this hypothesis, some of the cognitive deficits in PD resemble those seen in patients with lesions in the lateral pFC, which has been associated with top–down attentional control. However, there is no direct evidence for a failure of top–down control mechanisms in PD. Here we fill this gap by demonstrating disproportionate control by bottom–up attention to dimensional salience during attentional set shifting. Patients needed significantly more trials to criterion than did controls when shifting to a low-salient dimension while, remarkably, needing significantly fewer trials to criterion than did controls when shifting to a high-salient dimension. Thus, attention was captured by bottom–up attention to salient information to a greater extent in patients than in controls. The results provide a striking reinterpretation of prior set-shifting data and provide the first direct evidence for a failure of top–down attentional control, resembling that seen after catecholamine depletion in the pFC.
On the Derivation of Material Thermal Properties Representative of Heterogeneous Urban Neighborhoods
Authors: Salamanca F. , Krayenhoff E. S. , Martilli A. 
Published: March 2009

Abstract
An important question arises when modeling a heterogeneous landscape (e.g., an urbanized area) with a mesoscale atmospheric model. The surface within a grid cell of the model (which has a typical dimension of one or more kilometers) can be composed of patches of surfaces of different character. The total sensible heat flux in the grid cell, then, is the aggregate of the heat fluxes from each individual surface, each one with a unique thermal response arising from its thermal properties, among other factors. Current methods to estimate the sensible heat flux consider only one (in the case of flat terrain) or three (roof, walls, and ground, for urban areas) active surfaces with thermal properties that are ideally representative of the materials present in the grid cell. The question is then how to choose the representative thermal properties such that the heat flux computed by the model most closely approximates the aggregate of the fluxes from the different patches. In this work a new way to average building material thermal properties for urban canopy parameterizations is presented, and a suite of idealized numerical simulations demonstrates its superiority to two more standard averages. Moreover, this novel approach points to a new way of determining physical properties that are representative of heterogeneous zones.