bluuebunny/crossref_metadata_2025_split huggingface dataset:
In silico augmentation of the drug development pipeline: examples from the study of acute inflammation
Authors: An Gary , Bartels John , Vodovotz Yoram 
Published: December 2010

AbstractThe clinical translation of promising basic biomedical findings, whether derived from reductionist studies in academic laboratories or as the product of extensive high‐throughput and high‐content screens in the biotechnology and pharmaceutical industries, has reached a period of stagnation in which ever higher research and development costs are yielding ever fewer new drugs. Systems biology and computational modeling have been touted as potential avenues by which to break through this logjam. However, few mechanistic computational approaches are used in a manner that is fully cognizant of the inherent clinical realities in which the drugs developed through this ostensibly rational process will be ultimately used. This article presents a translational systems biology approach to inflammation. This approach is based on the use of mechanistic computational modeling centered on inherent clinical applicability, namely that a unified suite of models can be applied to generate in silico clinical trials, individualized computational models as tools for personalized medicine, and rational drug and device design based on disease mechanism. Drug Dev Res 72: 187–200, 2011.   © 2010 Wiley‐Liss, Inc.
Water‐Soluble Transition‐Metal‐Phthalocyanines as Singlet Oxygen Photosensitizers in Ene Reactions
Authors: D'Ambrosio Primiano , Tonucci Lucia , d'Alessandro Nicola , Morvillo Antonino , Sortino Salvatore , Bressan Mario 
Published: December 2010

AbstractThe capability of platinum, palladium and ruthenium sulfophthalocyanines (PtPcS, PdPcS and RuPcS) to act as singlet oxygen [1O2(1Δg)] photosensitizers in ene reactions in aqueous medium has been investigated by combining time‐resolved and steady‐state techniques. Laser flash photolysis experiments with nanosecond time resolution revealed the population of the lowest excited triplet state in the case of PtPcS and PdPcS upon light excitation. In both cases, this transient is effectively quenched by molecular oxygen leading to the formation of 1O2(1Δg) with a quantum yield ΦΔ = 0.24, as unequivocally demonstrated by time‐resolved near‐infrared luminescence. In contrast, RuPcS did not photosensitize 1O2(1Δg), in accordance with the lack of population of the precursor excited triplet state. These metal–sulfophthalocyanines (MPcSs) were further tested in the ene reaction. In line with the photophysical results, PtPcS and PdPcS photosensitized the formation of hydroperoxide by 1O2(1Δg) addition to the target α,β‐unsaturated carboxylic derivatives whereas RuPcS was totally inactive in this respect. Supporting the MPcSs on Amberlite® apparently made the ene reaction more rapid.
A rational sediment transport scaling relation based on dimensionless stream power
Authors: Eaton Brett C. , Church M. 
Published: December 2010

AbstractThe concept of stream channel grade – according to which a stream channel reach will adjust its gradient, S, in order to transport the imposed sediment load having magnitude Qb and characteristic grain size Db, with the available discharge Q (Mackin, 1948, Geological Society of America Bulletin 59: 463–512; Lane, 1955, American Society of Civil Engineers, Proceedings 81: 1–17) is one of the most influential ideas in fluvial geomorphology. Herein, we derive a scaling relation that describes how externally imposed changes in either Qb or Q can be accommodated by changes in the channel configuration, described by the energy gradient, mean flow depth, characteristic grain size and a parameter describing the effect of bed surface structures on grain entrainment. One version of this scaling relation is based on the dimensionless bed material transport parameter (W*) presented by Parker and Klingeman (1982, Water Resources Research 18: 1409–1423). An equivalent version is based on a new dimensionless transport parameter (E*) using dimensionless unit stream power. This version is nearly identical to the relation based on W*, except that it is independent of flow resistance. Both versions of the scaling relation are directly comparable to Lane's original relation. In order to generate this stream power‐based scaling relation, we derived an empirical transport function relation relating E* to dimensionless stream power using data from a wide range of stable, bed load‐dominated channels: the form of that transport function is based on the understanding that, while grain entrainment is related to the forces acting on the bed (described by dimensionless shear stress), sediment transport rate is related to the transfer of momentum from the fluid to the bed material (described by dimensionless stream power). Copyright © 2010 John Wiley & Sons, Ltd.
A simple model accounting for the uptake, transport, and deposition of wind‐eroded mineral particles in the hyperarid coastal Atacama Desert of northern Chile
Authors: Alfaro Stephane C. , Flores‐Aqueveque Valentina , Foret Gilles , Caquineau Sandrine , Vargas Gabriel , Rutllant Jose A. 
Published: December 2010

AbstractAs previously observed in marine sediments collected downwind of African or South American continental sources, recent studies of sediment cores collected at the bottom of Mejillones Bay in north Chile (23°S) show a laminated structure in which the amount of particles of aeolian origin and their size create significant differences between the layers. This suggests inter‐annual to inter‐decadal variations in the strength of the local southerly winds responsible for (1) the erosion of the adjacent hyperarid surface of the Mejillones Pampa, and (2) the subsequent transport of the eroded particles towards the bay. A simple model accounting for the vertical uptake, transport, and deposition of the particles initially set into motion by wind at the surface of the pampa is proposed. This model, which could be adapted to other locations, assumes that the initial rate of (vertical) uptake is proportional to the (horizontal) saltation flux quantified by means of White's equation, that particles are lifted to a height (H), increasing with the magnitude of turbulence, and that sedimentation progressively removes the coarsest particles from the air column as it moves towards the bay. In this model, the proportionality constant (A) linking the vertical flux of particles with the horizontal flux, and the injection height (H) control the magnitude and size distribution of the deposition flux in the bay. Their values are determined using the wind speed measured over the pampa and the size distribution of particles collected in sediment traps deployed in the bay as constraints. After calibration, the model is used to assess the sensitivity of the deposition flux to the wind intensity variations. The possibility of performing such quantitative studies is necessary for interpreting precisely the variability of the aeolian material in the sediment cores collected at the bottom of Mejillones Bay. Copyright © 2010 John Wiley & Sons, Ltd.
Minimum regions of genomic imbalance in stage I testicular embryonal carcinoma and association of 22q loss with relapse
Authors: Gilbert Duncan C. , McIntyre Alan , Summersgill Brenda , Missiaglia Edoardo , Goddard Neil C. , Chandler Ian , Huddart Robert A. , Shipley Janet 
Published: December 2010

AbstractTesticular germ cell tumors (TGCT) are the most frequent solid tumor to affect young adult males and are histologically divided into seminomas and nonseminomas (NS). NS comprise undifferentiated embryonal carcinoma (EC) and differentiated tumors with embryonic (teratoma) or extra‐embryonic (choriocarcinoma, yolk sac tumor) features. In contrast to other subtypes, EC have uniform cellular morphology and lack normal cell infiltrates, ideal for nucleic acid profiling. EC are under‐represented in previous studies due to their relative rarity. To gain insights into NS tumorigenesis, metastatic dissemination and potential markers of relapse, a full tiling path BAC platform was used to obtain array comparative genomic hybridization (aCGH) profiles from 32 formalin fixed paraffin embedded stage I EC samples from patients with follow‐up data. In addition to identifying regions previously described in TGCT, novel minimum overlapping regions of gain at 6p21.33, 10q11.21, and 22q13.32 and loss at 22q12.2 were defined and confirmed by fluorescence in situ hybridization analyses. Specifically, the region at 6p21.33 included OCT3/4, the expression of which is involved in the maintenance of pluripotency and the 10q11.21 region contains the gene encoding the RAS activating factor RASGEF1A, the expression of which was demonstrably increased in RNA extracted from these samples. The region of loss at 22q12.2 was more frequently seen in tumors that relapsed and protein expression of genes from 22q12.2 included PIK3IP1, a negative regulator of PI3 kinase signaling was reduced. These data support the role for genes involved in pluripotency and RAS/PI3K signaling in EC development and progression. © 2010 Wiley‐Liss, Inc.
MicroRNAs and colon and rectal cancer: Differential expression by tumor location and subtype
Authors: Slattery Martha L. , Wolff Erica , Hoffman Michael D. , Pellatt Daniel F. , Milash Brett , Wolff Roger K. 
Published: December 2010

AbstractMicroRNAs are thought to have an impact on cell proliferation, apoptosis, stress responses, maintenance of stem cell potency, and metabolism and are, therefore, important in the carcinogenic process. In this study, we examined 40 colon tumors, 30 rectal tumors, and 30 normal tissue samples (10 proximal colon, 10 distal colon, and 10 rectal paired with cancer cases) to examine miRNA expression profiles in colon and rectal tumors. MiRNA expression levels were adjusted for multiple comparisons; tumor tissue was compared with noncancerous tissue from the same site. A comparison of normal tissue showed 287 unique miRNAs that were significantly differentially expressed at the 1.5‐fold level and 73 with over a two‐fold difference in expression between colon and rectal tissue. Examination of miRNAs that were significantly differentially expressed at the 1.5‐fold level by tumor phenotype showed 143 unique miRNAs differentially expression for microsatellite instability positive (MSI+) colon tumors; 129 unique miRNAs differentially expressed for CpG Island Methylator Phenotype positive (CIMP+) colon tumors; 135 miRNAs were differentially expressed forKRAS2‐mutated colon tumors, and 139 miRNAs were differentially expressed forTP53‐mutated colon tumors. Similar numbers of differentially expressed miRNAs were observed for rectal tumors, although the miRNAs differentially expressed differed. There were 129 unique miRNAs for CIMP+, 143 unique miRNAs forKRAS2‐mutated, and 136 unique miRNAs forTP53‐mutated rectal tumors. These results suggest the importance of miRNAs in colorectal cancer and the need for studies that can confirm these results and provide insight into the diet, lifestyle, and genetic factors that influence miRNA expression. © 2010 Wiley‐Liss, Inc.
Prognostic factors in patients with minor salivary gland carcinoma of the oral cavity and oropharynx
Authors: Carrillo José F. , Maldonado Federico , Carrillo Liliana C. , Ramirez‐Ortega Margarita C , Pizano Juan G. Gómez , Melo C. , Chanona José G , Luna‐Ortiz K. , Ocaña Luis F. Oñate 
Published: December 2010

AbstractBackgroundThis study was performed to define prognostic factors and management of minor salivary gland carcinoma of the oral cavity and oropharynx .MethodsRetrospective analyses of patients with salivary gland carcinoma of the oral cavity or oropharynx, treated in 1989 to 2006. Statistics included univariate analyses to identify prognostic factors associated with disease‐free survival (DFS) and disease‐specific survival. A multivariate analysis model was constructed by the Cox method.ResultsSeventy‐seven patients constituted our cohort. Significant prognostic factors regarding DFS and disease‐specific survival in univariate analyses comprised tumor size, surgical margins, grade, lymph node status, and Karnofsky status and T classification. A multivariate model identified tumor size, grade, surgical margins, and lymph node status significant regarding DFS.ConclusionsTumor size, grade, surgical margins, and lymph node status could be used for a rational design of treatment strategies in these rare tumors. © 2010 Wiley Periodicals, Inc. Head Neck, 2010
Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma
Authors: Chan King Chi , Ko Josephine Mun Yee , Lung Hong Lok , Sedlacek Radislav , Zhang Zeng‐Feng , Luo Dian‐Zhong , Feng Zhen‐Bo , Chen Shuang , Chen Honglin , Chan Kwok Wah , Tsao Sai Wah , Chua Daniel Tsin‐tien , Zabarovsky Eugene R. , Stanbridge Eric J. , Lung Maria Li 
Published: December 2010

AbstractThe association of Matrix metalloproteinase‐19 (MMP19) in the development of nasopharyngeal carcinoma (NPC) was identified from differential gene profiling, which showed MMP19 was one of the candidate genes down‐regulated in the NPC cell lines. In this study, quantitative RT‐PCR and Western blot analysis showed MMP19 was down‐regulated in all seven NPC cell lines. By tissue microarray immunohistochemical staining, MMP19 appears down‐regulated in 69.7% of primary NPC specimens. Allelic deletion and promoter hypermethylation contribute to MMP19 down‐regulation. We also clearly demonstrate that the catalytic activity of MMP19 plays an important role in antitumor and antiangiogenesis activities in comparative studies of the wild‐type and the catalytically inactive mutant MMP19. In the in vivo tumorigenicity assay, only the wild‐type (WT), but not mutant, MMP19 transfectants suppress tumor formation in nude mice. In the in vitro colony formation assay, WT MMP19 dramatically reduces colony‐forming ability of NPC cell lines, when compared to the inactive mutant. In the tube formation assay of human umbilical vein endothelial cells and human microvascular endothelial cells (HMEC‐1), secreted WT MMP19, but not mutant MMP19, induces reduction of tube‐forming ability in endothelial cells with decreased vascular endothelial growth factor (VEGF) in conditioned media detected by enzyme‐linked immunosorbent assay (ELISA). The anti‐angiogenic activity of WT MMP19 is correlated with suppression of tumor formation. These results now clearly show that catalytic activity of MMP19 is essential for its tumor suppressive and anti‐angiogenic functions in NPC.
The adult stem cell marker Musashi‐1 modulates endometrial carcinoma cell cycle progression and apoptosis via Notch‐1 and p21WAF1/CIP1
Authors: Götte Martin , Greve Burkhard , Kelsch Reinhard , Müller‐Uthoff Heike , Weiss Kristin , Kharabi Masouleh Behzad , Sibrowski Walter , Kiesel Ludwig , Buchweitz Olaf 
Published: December 2010

AbstractThe RNA‐binding protein Musashi‐1 has been proposed to maintain stem cell function during development and regenerative processes as a modulator of the Notch‐1 signaling pathway. Musashi‐1 expression is upregulated in endometrial carcinoma, however, its pathogenetic role in this tumor entity is unknown. Here we investigate the functional impact and mode of action of Musashi‐1 on endometrial carcinoma cell behaviour in vitro. Aldehyde dehydrogenase‐1 activity and side population (SP) measurement by Hoechst dye exclusion revealed that the Ishikawa endometrial carcinoma cell line contains a pool of putative cancer stem cells. Musashi‐1 expression is 20.8‐fold upregulated in SP+ compared to SP‐ and equally distributed between ALDH+ and ALDH‐ cell pools. siRNA‐mediated knockdown of Musashi‐1 mRNA expression lead to an altered expression of the signaling receptor Notch‐1 and its downstream targets, the transcription factor Hes‐1 and the cell cycle regulators p21WAF1/CIP1 and cyclin B1, as determined by Western blotting and quantitative real‐time PCR. Flow cytometric and ELISA analyses revealed that Musashi‐1‐mediated modulation of these factors exerted an antiproliferative effect on the cell cycle, and increased apoptosis in endometrial carcinoma cells. We conclude that Ishikawa cells contain a subpopulation of cells with stem cell‐like properties. Musashi‐1 modulates endometrial carcinoma cell cycle progression and apoptosis via the stemness‐related factors Notch‐1, Hes‐1 and p21WAF1/CIP1, thus emerging as a novel future target for endometrial carcinoma therapy.
Antitumor activity of IL‐2/anti‐IL‐2 mAb immunocomplexes exerts synergism with that of N‐(2‐hydroxypropyl)methacrylamide copolymer‐bound doxorubicin conjugate due to its low immunosuppressive activity
Authors: Tomala Jakub , Chmelova Helena , Strohalm Jiri , Ulbrich Karel , Sirova Milada , Rihova Blanka , Kovar Marek 
Published: December 2010

AbstractInterleukin (IL)‐2 has been approved for treatment of metastatic renal cancer and malignant melanoma. However, its unfavorable pharmacologic properties, severe side effects and the negative role of IL‐2 in maintaining T regulatory cells are severe drawbacks. It has been shown that immunocomplexes of IL‐2 and certain anti‐IL‐2 mAbs possess selective and high stimulatory activity in vivo. Here, we show that IL‐2/S4B6 mAb immunocomplexes expand not only CD122high subsets and newly activated CD8+ T cells but also natural killer T cells and γδ T cells. Further, we demonstrate that natural killer (NK) cells expanded by IL‐2/S4B6 mAb immunocomplexes in vivo have high cytolytic activity, which can be further increased by coadministration of IL‐12. We also demonstrate that IL‐2/S4B6 mAb immunocomplexes possess noticeable antitumor activity in two syngeneic mouse tumor models, namely BCL1 leukemia and B16F10 melanoma, but only if administered early in tumor progression. To effectively treat established tumors, we administered the tumor‐bearing mice first with N‐(2‐hydroxypropyl)methacrylamide copolymer‐bound doxorubicin conjugate, and subsequently with IL‐2/S4B6 mAb immunocomplexes alone or with IL‐12 to induce an efficient antitumor immune response. Importantly, we show that the conjugate has significantly lower immunosuppressive activity than free doxorubicin when using dosage with comparable antitumor activity, thus eliminating the majority of tumor cells while leaving the immune system mostly unimpaired for stimulation with IL‐2/S4B6 mAb immunocomplexes. Indeed, we demonstrate that the conjugate and IL‐2/S4B6 mAb immunocomplexes together have synergistic antitumor activity.
Early‐warning analysis for currency crises in emerging markets: A revisit with fuzzy clustering
Authors: Marghescu Dorina , Sarlin Peter , Liu Shuhua 
Published: December 2010

AbstractCurrency crises, also often called balance‐of‐payment crises, occur when massive capital outflows force a country to devalue or float its currency. The world‐wide integration of capital markets since the 1980s and 1990s has increased the degree of capital mobility, which also determined a substantial turbulence in foreign exchange markets and frequent currency crises. In this paper, we explore advanced supporting instruments for predicting currency crises, based on an empirical study of the currency crisis episodes in 23 emerging markets around the world during the second half of last century. More specifically, we investigate the usefulness of prediction models built based on the fuzzy c‐means method. First we build clustering models that partition data into a certain number of overlapping natural groups. Thereafter, we classify the data clusters into early‐warning clusters and tranquil clusters. We compare the performance of our models with a conventional c‐means clustering model and a benchmark probit model. The results show that the proposed models achieve a similar level of out‐of‐sample performance as the probit model and c‐means model. The fuzzy approach also introduces additional explanatory advantages into the early‐warning analysis process. Copyright © 2010 John Wiley & Sons, Ltd.
BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment
Authors: Leblanc Elisabeth , Trensz Frédéric , Haroun Sonia , Drouin Geneviève , Bergeron Éric , Penton Christopher M , Montanaro Federica , Roux Sophie , Faucheux Nathalie , Grenier Guillaume 
Published: December 2010

Abstract
Heterotopic ossification (HO) is defined as the formation of bone inside soft tissue. Symptoms include joint stiffness, swelling, and pain. Apart from the inherited form, the common traumatic form generally occurs at sites of injury in damaged muscles and is often associated with brain injury. We investigated bone morphogenetic protein 9 (BMP-9), which possesses a strong osteoinductive capacity, for its involvement in muscle HO physiopathology. We found that BMP-9 had an osteoinductive influence on mouse muscle resident stromal cells by increasing their alkaline phosphatase activity and bone-specific marker expression. Interestingly, BMP-9 induced HO only in damaged muscle, whereas BMP-2 promoted HO in skeletal muscle regardless of its state. The addition of the soluble form of the ALK1 protein (the BMP-9 receptor) significantly inhibited the osteoinductive potential of BMP-9 in cells and HO in damaged muscles. BMP-9 thus should be considered a candidate for involvement in HO physiopathology, with its activity depending on the skeletal muscle microenvironment. © 2011 American Society for Bone and Mineral Research.
Hyperlipidemia induces resistance to PTH bone anabolism in mice via oxidized lipids
Authors: Sage Andrew P , Lu Jinxiu , Atti Elisa , Tetradis Sotirios , Ascenzi Maria-Grazia , Adams Douglas J , Demer Linda L , Tintut Yin 
Published: December 2010

Abstract
In hyperlipidemia, oxidized lipids accumulate in vascular tissues and trigger atherosclerosis. Such lipids also deposit in bone tissues, where they may promote osteoporosis. We found previously that oxidized lipids attenuate osteogenesis and that parathyroid hormone (PTH) bone anabolism is blunted in hyperlipidemic mice, suggesting that osteoporotic patients with hyperlipidemia may develop resistance to PTH therapy. To determine if oxidized lipids account for this PTH resistance, we blocked lipid oxidation products in hyperlipidemic mice with an ApoA-I mimetic peptide, D-4F, and the bone anabolic response to PTH treatment was assessed. Skeletally immature Ldlr−/− mice were placed on a high-fat diet and treated with D-4F peptide and/or with intermittent PTH(1–34) injections. As expected, D-4F attenuated serum lipid oxidation products and tissue lipid deposition induced by the diet. Importantly, D-4F treatment attenuated the adverse effects of dietary hyperlipidemia on PTH anabolism by restoring micro–computed tomographic parameters of bone quality—cortical mineral content, area, and thickness. D-4F significantly reduced serum markers of bone resorption but not bone formation. PTH and D-4F, together but not separately, also promoted bone anabolism in an alternative model of hyperlipidemia, Apoe−/− mice. In normolipemic mice, D-4F cotreatment did not further enhance the anabolic effects of PTH, indicating that the mechanism is through its effects on lipids. These findings suggest that oxidized lipids mediate hyperlipidemia-induced PTH resistance in bone through modulation of bone resorption. © 2011 American Society for Bone and Mineral Research.