bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth of rhombohedral insulin crystals and in vitro modeling of their dissolution in the blood stream
Authors: Nanev C. N. , Dimitrov I. L. , Hodzhaoglu F. V.
Published: December 2010

Insulin is the only protein that is secreted in a crystalline form in a human healthy body. To mimic the secretion process we used NaCl salting‐out to growing tiny rhombohedral Zn‐insulin crystals. The dissolution of the insulin crystals is of special interest for the therapeutical praxis, because the human body is supplied with the physiologically active monomers of the insulin through dissolution of the crystalline granules secreted in the pancreatic β‐cells. Sets of tiny rhombohedral Zn‐insulin crystals, which resembled the granules secreted in the β‐cells, were subjected to dissolution in blood plasma and model solutions. The impacts of the solution composition, flow rate, pH and ionic strength on the insulin crystal dissolution were investigated. The effect of the blood plasma was determinant because it dissolved the rhombohedral Zn‐insulin crystals almost instantly, while the effects of solution's physicochemical characteristics were of minor importance. In addition, we found that the presence of abundant zinc ions suppressed the dissolution of the insulin crystals. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Preparation of calcium sulfate whiskers using waste calcium chloride by reactive crystallization
Authors: Song Xingfu , Zhang Lina , Zhao Jingcai , Xu Yanxia , Sun Ze , Li Ping , Yu Jianguo
Published: December 2010

Calcium sulfate whiskers, owing to its good thermal stability, chemical resistance and good compatibility with rubber and plastics, has a strong potential in the application of polymer reinforcing composite materials. This work deals with the preparation of calcium chloride whiskers by reactive crystallization process with sulfuric acid and calcium chloride discharged from Solvay process. Firstly, the orthogonal experiments were carried out using both CaCl2 and H2SO4 in analytic grade as feedstock, and the reactive crystallization conditions were optimized, which included reaction temperature, reactant concentration, reaction time and stirring speed. Based on the optimized reactive crystallization conditions, the new process for the preparation of calcium chloride whiskers was studied using the reactive crystallization process with sulfuric acid and calcium chloride discharged from Solvay process, and the effects of impurity ions in the waste solutions on the growth of whiskers were evaluated. It was found that calcium sulfate whiskers with stable and structured fine crystals (its aspect ratio up to 190) can be prepared using waste CaCl2 in Solvay process. The experimental results will provide the valuable information for the reasonable disposal of waste CaCl2 solution from Solvay process. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Cataloging the interactome of small molecules and the human proteome
Authors: Gurwitz David
Published: December 2010

Recent advances in computational power permit accurate in silico predictions of the interactions between small molecules and protein targets. Countless studies have been published about such interactions and about computational tools for predicting drug—target interactions. What is still missing, and would greatly facilitate drug design and development, is a comprehensive and open database allowing the extraction of information on the predicted interactions (interactome) between small molecules and the human proteome. Ideally, such a catalog should include the entire repertoires of published small natural and synthetic compounds and each member of the human proteome. This would be a huge undertaking requiring massive public support. The PubChem database at the National Center for Biotechnology Information may serve as a fine starting point for embarking on such a massive project. Drug Dev Res 72: 1–3, 2011. © 2010 Wiley‐Liss, Inc.
Molecular simulations for the evaluation of binding free energies in lead optimization
Authors: Noy Efrat , Senderowitz Hanoch
Published: December 2010

The ability to predict, through computer simulation, the free energy of binding between drug‐like ligands and their biological target(s) is one of the most difficult yet rewarding tasks in computer‐aided drug design (CADD) efforts. Successful and consistent predictions are likely to have a profound effect on the efficiency of hit discovery and lead optimization campaigns. However, the route to achieving this goal is paved with challenges resulting from the complexity of the binding process and from the ability to simulate it, given contemporary computational tools. In this review we present the challenges faced by binding free energy simulations within the context of lead optimization, survey the main tools currently in use for performing such calculations, and discuss their applications and performance based on selected examples. Our main conclusion is that despite great progress and numerous success cases, free energy simulations have yet to mature in order to become an integral component of the arsenal of tools available to practitioners in the field of lead optimization. Drug Dev Res 72: 36–44, 2011. © 2010 Wiley‐Liss, Inc.
Machine learning in drug discovery and development
Authors: Wale Nikil
Published: December 2010

In‐silico tools and computational techniques have become an integral part of pharmaceutical research. These techniques are now used extensively at various phases during the drug development process. Such tools perform a wide range of functions from retrieving and analyzing data to sophisticated computational models for many biological and chemical processes in drug discovery. Among them, machine‐learning techniques are becoming especially popular because of their emphasis on obtaining accurate predictions. In this overview, we discuss the increasing role of Machine Learning in Drug Discovery. Since this field has close connections with the field of Statistics, we will first describe similarities and differences between these fields. We will then highlight various domains and problems within drug discovery that are utilizing machine‐learning technology to improve and speed up the drug discovery process. Drug Dev Res 72: 112–119, 2011.  © 2010 Wiley‐Liss, Inc.
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

The 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

The 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

The 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

As 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

Testicular 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

MicroRNAs 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

Background

This study was performed to define prognostic factors and management of minor salivary gland carcinoma of the oral cavity and oropharynx .

Methods

Retrospective 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.

Results

Seventy‐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.

Conclusions

Tumor 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

The 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

The 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

Interleukin (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.
Improving the rate of success for underrepresented racial minorities in STEM fields: Insights from a national project
Authors: Hurtado Sylvia , Newman Christopher B. , Tran Minh C. , Chang Mitchell J.
Published: December 2010

In this chapter, we summarize findings and offer implications from the first phase of a national longitudinal study of undergraduate STEM majors conducted by the Higher Education Research Institute at UCLA.
High‐performing institutions and their implications for studying underrepresented minority students in STEM
Authors: Museus Samuel D. , Liverman Deborah
Published: December 2010

Researchers studying underrepresented minority students in STEM can learn much from the examination of successful cases. In this chapter, authors discuss how the analysis of high‐performing institutions can inform future research on students of color in STEM.
Early‐warning analysis for currency crises in emerging markets: A revisit with fuzzy clustering
Authors: Marghescu Dorina , Sarlin Peter , Liu Shuhua
Published: December 2010

Currency 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

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

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.
Nfatc2 is a primary response gene of nell-1 regulating chondrogenesis in ATDC5 cells
Authors: Chen Weiwei , Zhang Xinli , Siu Ronald K , Chen Feng , Shen Jia , Zara Janette N , Culiat Cymbeline T , Tetradis Sotirios , Ting Kang , Soo Chia
Published: December 2010

Nell-1 is a growth factor required for normal skeletal development and expression of extracellular matrix proteins required for bone and cartilage cell differentiation. We identified the transcription factor nuclear factor of activated T cells (Nfatc2) as a primary response gene of Nell-1 through a microarray screen, with validation using real-time polymerase chain reaction (PCR). We investigated the effects of recombinant Nell-1 protein on the chondrogenic cell line ATDC5 and primary mouse chondrocytes. The osteochondral transcription factor Runx2 was investigated as a possible intermediary between Nell-1 and Nfatc2 using adenoviral overexpression of wild-type and dominant-negative Runx2. Nell-1 transiently induced both transcription and translation of Nfatc2, an effect inhibited by transduction of dominant-negative Runx2, suggesting that Runx2 was necessary for Nfatc2 induction. Differentiation assays revealed inhibitory effects of Nell-1 on ATDC5 cells. Although proliferation was unaffected, expression of chondrocyte-specific genes was decreased, and cartilage nodule formation and proteoglycan accumulation were suppressed. siRNA knockdown of Nfatc2 significantly reversed these inhibitory effects. To elucidate the relationship between Nell-1, Runx2, and Nfatc2 in vivo, their presence and distribution were visualized in femurs of wild-type and Nell1-deficient mice at both neonatal and various developmental stages using immunohistochemistry. All three proteins colocalized in the perichondrium of wild-type femurs but stained weakly or were completely absent in Nell1-deficient femurs at neonatal stages. Thus Nfatc2 likely plays an important role in Nell-1-mediated osteochondral differentiation in vitro and in vivo. To our knowledge, this is the first demonstration that Nfatc2 is a primary response gene of Nell-1. © 2011 American Society for Bone and Mineral Research.
Selective venous catheterization for the localization of phosphaturic mesenchymal tumors
Authors: Andreopoulou Panagiota , Dumitrescu Claudia E , Kelly Marilyn H , Brillante Beth A , Cutler Peck Carolee M , Wodajo Felasfa M , Chang Richard , Collins Michael T
Published: December 2010

Tumor-induced osteomalacia (TIO) is characterized by renal phosphate wasting, hypophosphatemia, and aberrant vitamin D3 metabolism and is caused by fibroblast growth factor 23 (FGF-23)–producing mesenchymal tumors, which are often difficult to locate. We investigated the utility of selective venous sampling in tumor localization. The primary endpoint was identification of the FGF-23 concentration ratio between the venous drainage of the tumor bed and the general circulation that was diagnostic of the location of an FGF-23-secreting tumor. Fourteen subjects underwent 15 sampling procedures after functional and anatomic imaging studies. Subjects fit into three imaging categories: no suspicious site, multiple sites, and single site (positive controls). FGF-23 levels were measured by ELISA. Suspicious tumors were resected for diagnosis, confirmation, and cure. In subjects with a positive venous sampling study and subsequent cure, a minimum ratio of 1.6 was diagnostic. In 7 of 14 subjects there was suggestive imaging, a diagnostic ratio, and an associated TIO tumor (true positive). Four of these required complicated resection procedures. In 4 of 14 subjects with no suspicious site on imaging studies, an FGF-23 diagnostic ratio was not detected (true negative). Biopsy or resection of a single lesion in 2 of 14 subjects with a diagnostic ratio failed to identify a TIO tumor (false positive). A diagnostic FGF-23 ratio was absent in 1 of 14 subjects whose tumor was a single highly suspicious lesion on imaging studies (false negative). These data yield a sensitivity of 0.87 [95% confidence interval (CI) 0.47–0.99] and a specificity of 0.71 (95% CI 0.29–0.96). Selective venous sampling for FGF-23 was particularly useful in subjects with multiple suspicious sites or an anatomically challenging planned resection but not in the absence of a suspicious lesion on imaging studies. © 2011 American Society for Bone and Mineral Research.
Genome-scale techniques highlight the epigenome and redefine fundamental principles of gene regulation
Authors: Pike J Wesley
Published: December 2010

The regulation of gene expression represents one of the most fundamental of biologic processes that controls cellular proliferation, differentiation, and function. Recent technological advances in genome-wide annotation together with bioinformatic/computational analyses have contributed significantly to our understanding of transcriptional regulation at the epigenomic and regulomic levels. This perspective outlines the techniques that are being utilized and summarizes a few of the outcomes. © 2011 American Society for Bone and Mineral Research.
Cross-sectional analysis of the association between fragility fractures and bone microarchitecture in older men: The STRAMBO study
Authors: Szulc Pawel , Boutroy Stéphanie , Vilayphiou Nicolas , Chaitou Ali , Delmas Pierre D , Chapurlat Roland
Published: December 2010

Areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) identifies 20% of men who will sustain fragility fractures. Thus we need better fracture predictors in men. We assessed the association between the low-trauma prevalent fractures and bone microarchitecture assessed at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 920 men aged 50 years of older. Ninety-eight men had vertebral fractures identified on the vertebral fracture assessment software of the Hologic Discovery A device using the semiquantitative criteria, whereas 100 men reported low-trauma peripheral fractures. Men with vertebral fractures had poor bone microarchitecture. However, in the men with vertebral fractures, only cortical volumetric density (D.cort) and cortical thickness (C.Th) remained significantly lower at both the radius and tibia after adjustment for aBMD of ultradistal radius and hip, respectively. Low D.cort and C.Th were associated with higher prevalence of vertebral fractures regardless of aBMD. Severe vertebral fractures also were associated with poor trabecular microarchitecture regardless of aBMD. Men with peripheral fractures had poor bone microarchitecture. However, after adjustment for aBMD, all microarchitectural parameters became nonsignificant. In 15 men with multiple peripheral fractures, trabecular spacing and distribution remained increased after adjustment for aBMD. Thus, in men, vertebral fractures and their severity are associated with impaired cortical bone, even after adjustment for aBMD. The association between peripheral fractures and bone microarchitecture was weaker and nonsignificant after adjustment for aBMD. Thus bone microarchitecture may be a determinant of bone fragility in men, which should be investigated in prospective studies. © 2011 American Society for Bone and Mineral Research.
Electronic ground states and vibrational frequency shifts of diatomic ligands in heme adducts
Authors: Liu Yang , Sun Huai
Published: December 2010

DFT calculations were carried out to study heme complexes with diatomic ligand (CO, NO, or O2) and trans‐imidazole ligand. The optimized electronic ground states of CO, NO, and O2 adducts are singlet, doublet, and open‐shell singlet, respectively. For O2 adduct, the open‐shell singlet is slightly lower in energy than the close‐shell singlet. However, important differences are found in optimized structures and vibrational frequencies. Particularly, the trans‐imidazole‐induced frequency up‐shift of the FeO(O) stretching mode can be predicted only with the open‐shell singlet as ground state. An analysis of normal modes confirms that the up‐shifts in the bent (NO and O2) adducts are mainly due to mixing of FeX(O) stretching mode with FeXO bending coordinate. Our study of binding mechanism indicates that a secondary source of the upshifts is the diminished weakening of the FeX(O) bonds. The FeX(O) bond strengths are modulated by σ competition mechanism, which weakens the FeX(O) bond and σ–π cooperation mechanism, which only exists in the bent adducts and enforce the FeX(O) bond. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011
Theory for trivial trajectory parallelization of multicanonical molecular dynamics and application to a polypeptide in water
Authors: Ikebe Jinzen , Umezawa Koji , Kamiya Narutoshi , Sugihara Takanori , Yonezawa Yasushige , Takano Yu , Nakamura Haruki , Higo Junichi
Published: December 2010

Trivial trajectory parallelization of multicanonical molecular dynamics (TTP‐McMD) explores the conformational space of a biological system with multiple short runs of McMD starting from various initial structures. This method simply connects (i.e., trivially parallelizes) the short trajectories and generates a long trajectory. First, we theoretically prove that the simple trajectory connection satisfies a detailed balance automatically. Thus, the resultant long trajectory is regarded as a single multicanonical trajectory. Second, we applied TTP‐McMD to an alanine decapeptide with an all‐atom model in explicit water to compute a free‐energy landscape. The theory imposes two requirements on the multiple trajectories. We have demonstrated that TTP‐McMD naturally satisfies the requirements. The TTP‐McMD produces the free‐energy landscape considerably faster than a single‐run McMD does. We quantitatively showed that the accuracy of the computed landscape increases with increasing the number of multiple runs. Generally, the free‐energy landscape of a large biological system is unknown a priori. The current method is suitable for conformational sampling of such a large system to reduce the waiting time to obtain a canonical ensemble statistically reliable. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011
Growth factors controlling ovarian functions
Authors: Sirotkin Alexander V.
Published: December 2010

The present review demonstrates an important role of different growth factors (of insulin‐like growth factors, epidermal growth factors, vascular endothelial growth factor, thrombopoietin, erytropoietin, hepatocyte growth factor, and growth factors of Hedgehog, Wnt and Notch families) in control of different ovarian functions—ovarian cell proliferation, apoptosis, folliculogenesis, luteogenesis, oogenesis, release of hormones, response to upstream hormonal regulators, fertility and, in some cases, in development of ovarian disorders. The possibility of practical application of these growth factors for characterization, prediction, and regulation the ovarian state is demonstrated. J. Cell. Physiol. 226: 2222–2225, 2011. © 2010 Wiley‐Liss, Inc.
Knockdown of CITED2 using short‐hairpin RNA sensitizes cancer cells to cisplatin through stabilization of p53 and enhancement of p53‐dependent apoptosis
Authors: Wu Zchong‐Zcho , Sun Nian‐Kang , Chao Chuck C.‐K.
Published: December 2010

CITED2 is a transcriptional modulator which has been implicated in human oncogenesis. In the present study, we examined whether CITED2 is also involved in the resistance of cancer cells to the chemotherapeutic drug cisplatin. We first observed that knockdown of CITED2 using short‐hairpin RNA sensitized non‐tumorigenic HEK293 cells to cisplatin. Sensitization to cisplatin following knockdown of CITED2 was also observed in cervical carcinoma HeLa cells and in cisplatin‐resistant HeLa cells, thereby showing that acquired cisplatin resistance could be reversed by CITED2 knockdown. This sensitization response was dependent on the status of p53 since efficient sensitization was observed in p53‐positive hepatocellular carcinoma (HCC) Sk‐Hep‐1 cells, whereas a negligible response was produced in the two p53‐defective cell lines HCC Mahlavu and lung cancer H1299. In contrast, overexpression of CITED2 decreased sensitivity of HEK293 cells to cisplatin, while moderate resistance was produced in HeLa cells. Overexpression of CITED2 also decreased sensitivity to cisplatin in p53‐defective H1299 cells when exogenous p53 expression was re‐introduced. We observed that knockdown of CITED2‐induced CBP/p300‐mediated p53 acetylation (Lys373) in HEK293 cells, thereby leading to a decrease of p53 ubiquitination and subsequent accumulation of the p53 protein. Notably, the effects of CITED2 knockdown on p53 accumulation and the increase of p53's target Bax were more pronounced after treatment with cisplatin. Based on these results, we propose that a combination of cisplatin and CITED2 shRNA may represent an effective treatment against p53‐sensitive cancer cells. J. Cell. Physiol. 226: 2415–2428, 2011. © 2010 Wiley‐Liss, Inc.
Utilization of laser‐assisted analytical methods for monitoring of lead and nutrition elements distribution in fresh and dried Capsicum annuum l. leaves
Authors: Galiová Michaela , Kaiser Jozef , Novotný Karel , Hartl Martin , Kizek Rene , Babula Petr
Published: December 2010

Laser induced breakdown spectroscopy (LIBS) and laser ablation inductively coupled plasma mass spectrometry (LA‐ICP‐MS) have been applied for high‐resolution mapping of accumulation and distribution of heavy metal (lead) and nutrition elements (potassium, manganese) in leaves of Capsicum annuum L. samples. Lead was added in a form of Pb(NO3)2 at concentration up to 10 mmol L−1 into the vessels that contained tap water and where the 2‐months old Capsicum annuum L. plants were grown another seven days. Two dimensional maps of the elements are presented for both laser‐assisted analytical methods. Elemental mapping performed on fresh (frozen) and dried Capsicum annuum L. leaves are compared. Microsc. Res. Tech., 2011. © 2010 Wiley‐Liss, Inc.
An efficient and clean Michael addition of indoles to electron‐deficient olefins under solvent‐ and catalyst‐free condition
Authors: Liu Xiong‐Li , Xue Dong , Zhang Zun‐Ting
Published: December 2010

An efficient Michael addition of indoles to electron‐deficient olefins under solvent‐ and catalyst‐free condition afforded biologically important 3‐substituted indole derivatives in good to excellent yields was reported. The acidic NH proton of indole plays a key role in Michael addition of indoles to electron‐deficient olefins. This very simple procedure provides an efficient and clean process for the synthesis of indole derivatives. J. Heterocyclic Chem., (2011).
Comparative internal structure of dorsal lips and radiolar appendages in sabellidae (Polychaeta) and phylogenetic implications
Authors: Capa María , Nogueira João Miguel de Matos , Rossi Maíra Cappellani Silva
Published: December 2010

Fan worms (Sabellidae) possess paired modified prostomial structures at the base of the radiolar crown, dorso‐lateral to the mouth, called dorsal lips. The dorsal lips are involved in the sorting of particles collected by the radiolar crown. The range of variation in the morphology of dorsal lips is extensive, and probably this is not only due to adaptations to different environments and feeding preferences but also due to phylogenetic constraints. In this study, we describe and compare the morphology of dorsal lips in a range of sabellid taxa based on histological cross‐sections of these structures, and compare our data and terminology with those of previous studies. Dorsal lips are maintained erect in most taxa by a modified radiole fused to them known as dorsal radiolar appendage. We suggest that dorsal radiolar appendages with an internal supporting axis (cellular or acellular) and probably also the ventral lips are synapomorphies of the family. J. Morphol., 2011. © 2010 Wiley‐Liss, Inc.
Portal vein embolization (prior to major hepatectomy) effects on regeneration, resectability, and outcome
Authors: Abdalla Eddie K.
Published: December 2010

Portal vein embolization (PVE) is used to increase the volume and function of the liver that will remain after extensive liver resection. Operative outcomes are improved in properly selected patients who undergo PVE and experience adequate future liver remnant (FLR) hypertrophy. Absolute volume and volume change of the FLR after PVE (interpreted in context of liver disease) predict adequate liver function postresection. Oncologic outcomes following resection in patients with appropriately applied PVE are excellent. J. Surg. Oncol. 2010;102:960–967. © 2010 Wiley‐Liss, Inc.
Outcomes of laparoscopic hepatic resection for colorectal cancer metastases
Authors: Nguyen Kevin Tri , Geller David A.
Published: December 2010

The role of laparoscopic liver resection for cancer remains controversial. This review summarizes the expanding literature on outcomes of minimally invasive hepatic resection for colorectal cancer liver metastases. Four recent studies (in more than 300 patients) show 5‐year overall‐survival rates of 46–64%, which are comparable to results in modern open hepatic resection series. The advantages of laparoscopic liver resection include smaller incisions, less pain, less narcotic requirements, and shorter length of stay. J. Surg. Oncol. 2010;102:975–977. © 2010 Wiley‐Liss, Inc.
Optimum imaging of colorectal metastases
Authors: Grand David J. , Beland Michael , Noto Richard B. , Mayo‐Smith William
Published: December 2010

Dramatic improvements in diagnostic imaging have developed with and enabled increasingly sophisticated treatments for metastatic colorectal cancer. Advances in therapeutic techniques, such as surgical resection and percutaneous therapies, demand that diagnostic imaging provide an accurate assessment of disease burden as well as precise localization. In this article, we present the current state‐of‐the‐art of diagnostic imaging for evaluation of metastatic colorectal cancer. J. Surg. Oncol. 2010;102:909–913. © 2010 Wiley‐Liss, Inc.