bluuebunny/crossref_metadata_2025_split huggingface dataset:
Magnitude and Phenotype of Cellular Immune Responses Elicited by Recombinant Adenovirus Vectors and Heterologous Prime-Boost Regimens in Rhesus Monkeys
Authors: Liu Jinyan , Ewald Bonnie A. , Lynch Diana M. , Denholtz Matthew , Abbink Peter , Lemckert Angelique A. C. , Carville Angela , Mansfield Keith G. , Havenga Menzo J. , Goudsmit Jaap , Barouch Dan H. 
Published: March 2008

ABSTRACT

Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for human immunodeficiency virus type 1 (HIV-1) and other pathogens have been shown to elicit antigen-specific cellular immune responses. Rare serotype rAd vectors have also been constructed to circumvent preexisting anti-Ad5 immunity and to facilitate the development of novel heterologous rAd prime-boost regimens. Here we show that rAd5, rAd26, and rAd48 vectors elicit qualitatively distinct phenotypes of cellular immune responses in rhesus monkeys and can be combined as potent heterologous prime-boost vaccine regimens. While rAd5-Gag induced primarily gamma interferon-positive (IFN-γ
+
) and IFN-γ
+
/tumor necrosis factor alpha
+
(TNF-α
+
) T-lymphocyte responses, rAd26-Gag and rAd48-Gag induced higher proportions of interleukin-2
+
(IL-2
+
) and polyfunctional IFN-γ
+
/TNF-α
+
/IL-2
+
T-lymphocyte responses. Priming with the rare serotype rAd vectors proved remarkably effective for subsequent boosting with rAd5 vectors. These data demonstrate that the rare serotype rAd vectors elicited T-lymphocyte responses that were phenotypically distinct from those elicited by rAd5 vectors and suggest the functional relevance of polyfunctional CD8
+
and CD4
+
T-lymphocyte responses. Moreover, qualitative differences in cellular immune responses may prove critical in determining the overall potency of heterologous rAd prime-boost regimens.
Hypoxia-Inducible Factor-1 Target Genes as Indicators of Tumor Vessel Response to Vascular Endothelial Growth Factor Inhibition
Authors: Dang Duyen T. , Chun Sang Y. , Burkitt Kyunghee , Abe Masako , Chen Shaowei , Havre Pamela , Mabjeesh Nicola J. , Heath Elisabeth I. , Vogelzang Nicholas J. , Cruz-Correa Marcia , Blayney Douglas W. , Ensminger William D. , Croix Brad St. , Dang Nam H. , Dang Long H. 
Published: March 2008

Abstract
Antiangiogenic therapy improves survival in patients with advanced stage cancers. Currently, there are no reliable predictors or markers for tumor vessel response to antiangiogenic therapy. To model effective antiangiogenic therapy, we disrupted the VEGF gene in three representative cancer cell lines. HCT116 xenografts had low proportions of endothelial tubes covered by pericytes that stained with α-smooth muscle actin (SMA) antibody. Upon disruption of VEGF, HCT116VEGF−/− xenografts had significantly decreased tumor microvessel perfusion compared with their parental counterparts. Furthermore, HCT116VEGF−/− xenografts mounted a tumor-reactive response to hypoxia, characterized by the induction of hypoxia-inducible factor-1 (HIF-1) target genes. One highly induced protein was DPP4, a measurable serum protein that has well-described roles in cancer progression. In contrast, LS174T and MKN45 tumor xenografts had high proportion of endothelial tubes that were covered by SMA+ pericytes. Upon disruption of VEGF, LS174TVEGF−/− and MKN45VEGF−/− xenografts maintained tumor microvessel perfusion. As such, there were no changes in intratumoral hypoxia or HIF-1α induction. Together, these data show that the extent of tumor vessel response to angiogenic inhibition could be correlated with (a) the preexisting coverage of tumor endothelial tubes with SMA+ pericytes and (b) differential tumor induction of HIF-1 target genes. The data further show that DPP4 is a novel marker of HIF-1 induction. Altogether, these preclinical findings suggest novel clinical trials for predicting and monitoring tumor vessel responses to antiangiogenic therapy. [Cancer Res 2008;68(6):1872–80]
Adjuvant Therapy with Small Hairpin RNA Interference Prevents Non–Small Cell Lung Cancer Metastasis Development in Mice
Authors: Bulk Etmar , Hascher Antje , Liersch Ruediger , Mesters Rolf M. , Diederichs Sven , Sargin Bülent , Gerke Volker , Hotfilder Marc , Vormoor Josef , Berdel Wolfgang E. , Serve Hubert , Müller-Tidow Carsten 
Published: March 2008

Abstract
Development of distant metastasis is the major reason for cancer-related deaths worldwide. Adjuvant therapy approaches after local therapies are most effective when specific targets are inhibited. Recently, we identified S100P overexpression as a strong predictor for metastasis development in early-stage non–small cell lung cancer (NSCLC) patients. Here, we show that S100P overexpression increased angiogenesis in and metastasis formation from s.c. xenotransplants of NSCLC cells. Plasmid-derived short hairpin RNAs (shRNA) were developed as specific adjuvant therapy. I.v. injected shRNA against S100P significantly decreased S100P protein expression in xenograft tumors and inhibited tumor angiogenesis in vivo. Metastasis formation 8 weeks after primary tumor resection was significantly reduced. Lung metastases developed in 31% of mice treated with S100P-targeting shRNAs compared with 64% in control shRNA–treated mice (P &lt; 0.05). These findings suggest that RNA interference–based therapy approaches can be highly effective in the adjuvant setting. [Cancer Res 2008;68(6):1896–904]
Chemopreventive Effect of Silymarin on Liver Pathology in HBV X Protein Transgenic Mice
Authors: Wu Yi-Fang , Fu Shu-Ling , Kao Cheng-Heng , Yang Chu-Wen , Lin Chao-Hsiung , Hsu Ming-Ta , Tsai Ting-Fen 
Published: March 2008

Abstract
There are currently limited therapeutic regimens available for effective treatment of hepatocellular carcinoma (HCC). Silymarin is a naturally derived polyphenolic antioxidant with hepatoprotective properties and is very widely used in clinical application; however, effect of silymarin on spontaneous HCC has not been studied. Silymarin was evaluated for its efficacy against spontaneous carcinogenesis using the HBV X protein (HBx) transgenic model. Silymarin was p.o. given to the HBx transgenic mice from 4 to 6 weeks of age. Our data indicated that silymarin has therapeutic effects on the early stages of liver damage, reversing fatty changes and recovering liver histopathology in a dose-dependent manner. To study the chemopreventive effects on the later stages of carcinogenesis, the mice at 13 months were split into a precancerous group and a group with significant liver carcinogenesis. After silymarin was given to the precancerous mice from 13 to 16 months of age, in contrast to an 80% incidence of HCC development in the untreated transgenic mice, no HCC was detected in any of these mice. Nonetheless, small hyperplastic nodules were detected in 86% of these precancerous mice. In the second group with notable HCC, silymarin was unable to block cancer progression. Although silymarin did not affect HBx expression, intracellular reactive oxygen species levels were decreased, cell proliferation was stimulated, and hepatocyte ultrastructure was found to significantly recover. In conclusion, silymarin exerts beneficial effects on the early stages of liver pathogenesis, preventing and delaying liver carcinogenesis. This drug should be considered as a potential chemopreventive agent for HBV-related hepatocarcinogenesis. [Cancer Res 2008;68(6):2033–42]
Tumor Cell Dependence on Ran-GTP–Directed Mitosis
Authors: Xia Fang , Lee Connie W. , Altieri Dario C. 
Published: March 2008

Abstract
Deregulated cell division is a hallmark of cancer, but whether tumor cells become dependent on specific mitotic mechanisms is not known. Here, we show that the small GTPase Ran, a regulator of mitotic spindle formation, is differentially overexpressed in human cancer as compared with normal tissues, in vivo. Acute silencing of Ran in various tumor cell types causes aberrant mitotic spindle formation, mitochondrial dysfunction, and apoptosis. This pathway does not require p53, Bax, or Smac, but is controlled by survivin as a novel Ran target in cancer. Conversely, loss of Ran in normal cells is well tolerated and does not result in mitotic defects or loss of cell viability. Therefore, tumor cells can become dependent on Ran signaling for cell division, and targeting this pathway may provide a novel and selective anticancer strategy. [Cancer Res 2008;68(6):1826–33]
Proteinase-Activated Receptor-1–Triggered Activation of Tumor Progression Locus-2 Promotes Actin Cytoskeleton Reorganization and Cell Migration
Authors: Hatziapostolou Maria , Polytarchou Christos , Panutsopulos Dimitrios , Covic Lidija , Tsichlis Philip N. 
Published: March 2008

Abstract
Tumor progression locus 2 (Tpl2), a mitogen-activated protein kinase kinase kinase (MAP3K) that is activated by provirus insertion in retrovirus-induced rodent lymphomas and mammary adenocarcinomas, is known to transduce Toll-like receptor, interleukin 1, tumor necrosis factor α, and CD40 signals and to play an important role in inflammation. Here we show that Tpl2 is also required for the transduction of cell migration and gene expression signals originating in the G-protein–coupled receptor proteinase-activated receptor 1 (PAR1). PAR1 signals transduced by Tpl2 activate Rac1 and focal adhesion kinase, and they are required for reorganization of the actin cytoskeleton and cell migration. PAR1 expressed in fibroblasts can be triggered by proteinases produced by tumor cells, and PAR1 expressed in tumor cells can be triggered by proteinases produced by fibroblasts. These data suggest that signals that regulate cell migration and gene expression flow between stromal and tumor cells in both directions and that Tpl2 plays a pivotal role in this process. [Cancer Res 2008;68(6):1851–61]
Genome-Wide Analysis of the Homeobox C6 Transcriptional Network in Prostate Cancer
Authors: McCabe Colleen D. , Spyropoulos Demetri D. , Martin David , Moreno Carlos S. 
Published: March 2008

Abstract
Homeobox transcription factors are developmentally regulated genes that play crucial roles in tissue patterning. Homeobox C6 (HOXC6) is overexpressed in prostate cancers and correlated with cancer progression, but the downstream targets of HOXC6 are largely unknown. We have performed genome-wide localization analysis to identify promoters bound by HOXC6 in prostate cancer cells. This analysis identified 468 reproducibly bound promoters whose associated genes are involved in functions such as cell proliferation and apoptosis. We have complemented these data with expression profiling of prostates from mice with homozygous disruption of the Hoxc6 gene to identify 31 direct regulatory target genes of HOXC6. We show that HOXC6 directly regulates expression of bone morphogenic protein 7, fibroblast growth factor receptor 2, insulin-like growth factor binding protein 3, and platelet-derived growth factor receptor α (PDGFRA) in prostate cells and indirectly influences the Notch and Wnt signaling pathways in vivo. We further show that inhibition of PDGFRA reduces proliferation of prostate cancer cells, and that overexpression of HOXC6 can overcome the effects of PDGFRA inhibition. HOXC6 regulates genes with both oncogenic and tumor suppressor activities as well as several genes such as CD44 that are important for prostate branching morphogenesis and metastasis to the bone microenvironment. [Cancer Res 2008;68(6):1988–96]
Rictor and Integrin-Linked Kinase Interact and Regulate Akt Phosphorylation and Cancer Cell Survival
Authors: McDonald Paul C. , Oloumi Arusha , Mills Julia , Dobreva Iveta , Maidan Mykola , Gray Virginia , Wederell Elizabeth D. , Bally Marcel B. , Foster Leonard J. , Dedhar Shoukat 
Published: March 2008

Abstract
An unbiased proteomic screen to identify integrin-linked kinase (ILK) interactors revealed rictor as an ILK-binding protein. This finding was interesting because rictor, originally identified as a regulator of cytoskeletal dynamics, is also a component of mammalian target of rapamycin complex 2 (mTORC2), a complex implicated in Akt phosphorylation. These functions overlap with known ILK functions. Coimmunoprecipitation analyses confirmed this interaction, and ILK and rictor colocalized in membrane ruffles and leading edges of cancer cells. Yeast two-hybrid assays showed a direct interaction between the NH2- and COOH-terminal domains of rictor and the ILK kinase domain. Depletion of ILK and rictor in breast and prostate cancer cell lines resulted in inhibition of Akt Ser473 phosphorylation and induction of apoptosis, whereas, in several cell lines, depletion of mTOR increased Akt phosphorylation. Akt and Ser473P-Akt were detected in ILK immunoprecipitates and small interfering RNA–mediated depletion of rictor, but not mTOR, inhibited the amount of Ser473P-Akt in the ILK complex. Expression of the NH2-terminal (1–398 amino acids) rictor domain also resulted in the inhibition of ILK-associated Akt Ser473 phosphorylation. These data show that rictor regulates the ability of ILK to promote Akt phosphorylation and cancer cell survival. [Cancer Res 2008;68(6):1618–24]
Tumor-Specific T-Cell Memory: Clearing the Regulatory T-Cell Hurdle
Authors: Côté Anik L. , Usherwood Edward J. , Turk Mary Jo 
Published: March 2008

Abstract
Antitumor immune responses can be stimulated by interfering with regulatory T-cell (Treg) function. However, this effect is short lived unless T-cell memory to tumor antigens can be generated. Our recent studies show that Treg cells not only limit primary responses to tumor/self-antigens in tumor-bearing hosts but also prevent the natural generation of T-cell memory to such antigens. Here, we discuss the role of Treg cells in suppressing T-cell memory after surgical excision of tumors and the potential clinical benefits of overcoming this suppression. [Cancer Res 2008;68(6):1614–7]
New Models for Motor Control
Authors: Altman Jennifer S. , Kien Jenny 
Published: March 2008

What do a prototype robot (Brooks 1989) and a model for the control of behavioral choice in insects (Altman and Kien 1987a) have in common? And what do they share with a scratching cat (Shadmehr 1989)? The answer is distributed control systems that do not depend on a central command center for the execution of behavioral outputs. The first two in particular are examples of a growing trend to replace the long-held concept of linear hierarchical control of motor output with one of decentralized, distributed control, with inputs at many levels and the output a consensus of the activity in several centers. Brooks (1989) describes a six-legged machine that, in its most advanced form, can walk over rough terrain and prowl around following a source of warmth, such as a person. The six legs, chosen as a compromise between stability and ease of coordination, give the robot a superficial resemblance to an insect — but the similarity goes deeper. The modular control system, designed strictly on engineering principles for maximum efficiency and economy, bears a striking similarity to the model we have proposed elsewhere (Altman and Kien 1987a) to describe the organization of the motor system in insects such as the locust. In both systems, the same set of components can generate different behaviors, depending on the context, and similar principles govern the generation of different levels of behavior, from movements of a single leg to coordinated responses of the whole beast. Neither requires a single center for integrating all sensory information and conflicts tend to be resolved by consensus at the motor level.
The Vapnik-Chervonenkis Dimension: Information versus Complexity in Learning
Authors: Abu-Mostafa Yaser S. 
Published: March 2008

When feasible, learning is a very attractive alternative to explicit programming. This is particularly true in areas where the problems do not lend themselves to systematic programming, such as pattern recognition in natural environments. The feasibility of learning an unknown function from examples depends on two questions: 1. Do the examples convey enough information to determine the function? 2. Is there a speedy way of constructing the function from the examples? These questions contrast the roles of information and complexity in learning. While the two roles share some ground, they are conceptually and technically different. In the common language of learning, the information question is that of generalization and the complexity question is that of scaling. The work of Vapnik and Chervonenkis (1971) provides the key tools for dealing with the information issue. In this review, we develop the main ideas of this framework and discuss how complexity fits in.
Modeling Orientation Discrimination at Multiple Reference Orientations with a Neural Network
Authors: Devos M. , Orban G. A. 
Published: March 2008

We trained a multilayer perceptron with backpropagation to perform stimulus orientation discrimination at multiple references using biologically plausible values as input and output. Hidden units are necessary for good performance only when the network must operate at multiple reference orientations. The orientation tuning curves of the hidden units change with reference. Our results suggest that at least for simple parameter discriminations such as orientation discrimination, one of the main functions of further processing in the visual system beyond striate cortex is to combine signals representing stimulus and reference.
Removing Time Variation with the Anti-Hebbian Differential Synapse
Authors: Mitchison Graeme 
Published: March 2008

I describe a local synaptic learning rule that can be used to remove the effects of certain types of systematic temporal variation in the inputs to a unit. According to this rule, changes in synaptic weight result from a conjunction of short-term temporal changes in the inputs and the output. Formally,This is like the differential rule proposed by Klopf (1986) and Kosko (1986), except for a change of sign, which gives it an anti-Hebbian character. By itself this rule is insufficient. A weight conservation condition is needed to prevent the weights from collapsing to zero, and some further constraint—implemented here by a biasing term—to select particular sets of weights from the subspace of those which give minimal variation. As an example, I show that this rule will generate center-surround receptive fields that remove temporally varying linear gradients from the inputs.
IgG regulates the CD1 expression profile and lipid antigen-presenting function in human dendritic cells via FcγRIIa
Authors: Smed-Sörensen Anna , Moll Markus , Cheng Tan-Yun , Loré Karin , Norlin Anna-Carin , Perbeck Leif , Moody D. Branch , Spetz Anna-Lena , Sandberg Johan K. 
Published: March 2008

Abstract
Dendritic cells (DCs) process and present bacterial and endogenous lipid antigens in complex with CD1 molecules to T cells and invariant natural killer T (NKT) cells. However, different types of DCs, such as blood myeloid DCs and skin Langerhans cells, exhibit distinct patterns of CD1a, CD1b, CD1c, and CD1d expression. The regulation of such differences is incompletely understood. Here, we initially observed that monocyte-derived DCs cultured in an immunoglobulin-rich milieu expressed CD1d but not CD1a, CD1b, and CD1c, whereas DCs cultured in the presence of low levels of immunoglobulins had an opposite CD1 profile. Based on this, we tested the possibility that immunoglobulins play a central role in determining these differences. IgG depletion and intravenous immunoglobulin (IVIg) add-in experiments strongly supported a role for IgG in directing the CD1 expression profile. Blocking experiments indicated that this effect was mediated by FcγRIIa (CD32a), and quantitative polymerase chain reaction data demonstrated that regulation of the CD1 profile occurred at the gene expression level. Finally, the ability of DCs to activate CD1-restricted NKT cells and T cells was determined by this regulatory effect of IgG. Our data demonstrate an important role for FcγRIIa in regulating the CD1 antigen presentation machinery of human DCs.
Testing the Coulomb/Accessible Surface Area solvent model for protein stability, ligand binding, and protein design
Authors: am Busch Marcel Schmidt , Lopes Anne , Amara Najette , Bathelt Christine , Simonson Thomas 
Published: March 2008

Abstract

Background
Protein structure prediction and computational protein design require efficient yet sufficiently accurate descriptions of aqueous solvent. We continue to evaluate the performance of the Coulomb/Accessible Surface Area (CASA) implicit solvent model, in combination with the Charmm19 molecular mechanics force field. We test a set of model parameters optimized earlier, and we also carry out a new optimization in this work, using as a target a set of experimental stability changes for single point mutations of various proteins and peptides. The optimization procedure is general, and could be used with other force fields. The computation of stability changes requires a model for the unfolded state of the protein. In our approach, this state is represented by tripeptide structures of the sequence Ala-X-Ala for each amino acid type X. We followed an iterative optimization scheme which, at each cycle, optimizes the solvation parameters and a set of tripeptide structures for the unfolded state. This protocol uses a set of 140 experimental stability mutations and a large set of tripeptide conformations to find the best tripeptide structures and solvation parameters.

Results
Using the optimized parameters, we obtain a mean unsigned error of 2.28 kcal/mol for the stability mutations. The performance of the CASA model is assessed by two further applications: (i) calculation of protein-ligand binding affinities and (ii) computational protein design. For these two applications, the previous parameters and the ones optimized here give a similar performance. For ligand binding, we obtain reasonable agreement with a set of 55 experimental mutation data, with a mean unsigned error of 1.76 kcal/mol with the new parameters and 1.47 kcal/mol with the earlier ones. We show that the optimized CASA model is not inferior to the Generalized Born/Surface Area (GB/SA) model for the prediction of these binding affinities. Likewise, the new parameters perform well for the design of 8 SH3 domain proteins where an average of 32.8% sequence identity relative to the native sequences was achieved. Further, it was shown that the computed sequences have the character of naturally-occuring homologues of the native sequences.

Conclusion
Overall, the two CASA variants explored here perform very well for a wide variety of applications. Both variants provide an efficient solvent treatment for the computational engineering of ligands and proteins.
Effects of cyclic nucleotides on midgut infections and maturation of T. b. brucei in G. m. morsitans
Authors: MacLeod Ewan T , Maudlin Ian , Welburn Susan C 
Published: March 2008

Abstract
Cyclic nucleotide signalling through cyclic adenosine monophosphate (cAMP) is thought to play an important role in the transformation of the long slender (dividing) form to the short-stumpy (arrested) form in the mammalian bloodstream but the role of cyclic nucleotides in the tsetse-based part of the trypanosome life cycle is unknown. In a series of in vivo experiments, it was found that cyclic guanosine monophosphate (cGMP) but not cAMP could induce significantly higher rates of midgut infection in tsetse. Continuous feeding of either cGMP or cAMP to tsetse had no effect on rates of maturation of established midgut infections suggesting that these two parts of the life cycle in tsetse are not linked.