bluuebunny/crossref_metadata_2025 huggingface dataset:
Local gene expression in nerve endings
Authors: Crispino Marianna , Chun Jong Tai , Cefaliello Carolina , Perrone Capano Carla , Giuditta Antonio
Published: July 2013

At the Nobel lecture for physiology in 1906, Ramón y Cajal famously stated that “the nerve elements possess reciprocal relationships in contiguity but not in continuity,” summing up the neuron doctrine. Sixty years later, by the time the central dogma of molecular biology formulated the axis of genetic information flow from DNA to mRNA, and then to protein, it became obvious that neurons with extensive ramifications and long axons inevitably incur an innate problem: how can the effect of gene expression be extended from the nucleus to the remote and specific sites of the cell periphery? The most straightforward solution would be to deliver soma‐produced proteins to the target sites. The influential discovery of axoplasmic flow has supported this scheme of protein supply. Alternatively, mRNAs can be dispatched instead of protein, and translated locally at the strategic target sites. Over the past decades, such a local system of protein synthesis has been demonstrated in dendrites, axons, and presynaptic terminals. Moreover, the local protein synthesis in neurons might even involve intercellular trafficking of molecules. The innovative concept of glia‐neuron unit suggests that the local protein synthesis in the axonal and presynaptic domain of mature neurons is sustained by a local supply of RNAs synthesized in the surrounding glial cells and transferred to these domains. Here, we have reviewed some of the evidence indicating the presence of a local system of protein synthesis in axon terminals, and have examined its regulation in various model systems. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 74: 279–291, 2014
Identifying novel phenotypes of vulnerability and resistance to activity‐based anorexia in adolescent female rats
Authors: Barbarich‐Marsteller Nicole C. , Underwood Mark D. , Foltin Richard W. , Myers Michael M. , Walsh B. Timothy , Barrett Jeffrey S. , Marsteller Douglas A.
Published: July 2013

Objective

Activity‐based anorexia is a translational rodent model that results in severe weight loss, hyperactivity, and voluntary self‐starvation. The goal of our investigation was to identify vulnerable and resistant phenotypes of activity‐based anorexia in adolescent female rats.

Method

Sprague‐Dawley rats were maintained under conditions of restricted access to food (N = 64; or unlimited access, N = 16) until experimental exit, predefined as a target weight loss of 30–35% or meeting predefined criteria for animal health. Nonlinear mixed effects statistical modeling was used to describe wheel running behavior, time to event analysis was used to assess experimental exit, and a regressive partitioning algorithm was used to classify phenotypes.

Results

Objective criteria were identified for distinguishing novel phenotypes of activity‐based anorexia, including a vulnerable phenotype that conferred maximal hyperactivity, minimal food intake, and the shortest time to experimental exit, and a resistant phenotype that conferred minimal activity and the longest time to experimental exit.

Discussion

The identification of objective criteria for defining vulnerable and resistant phenotypes of activity‐based anorexia in adolescent female rats provides an important framework for studying the neural mechanisms that promote vulnerability to or protection against the development of self‐starvation and hyperactivity during adolescence. Ultimately, future studies using these novel phenotypes may provide important translational insights into the mechanisms that promote these maladaptive behaviors characteristic of anorexia nervosa. © 2013 Wiley Periodicals, Inc. (Int J Eat Disord 2013; 46:737–746)
Carbon monoxide decreases endosome–lysosome fusion and inhibits soluble antigen presentation by dendritic cells to T cells.
Authors: Tardif Virginie , Riquelme Sebastián A. , Remy Séverine , Carreño Leandro J. , Cortés Claudia M. , Simon Thomas , Hill Marcelo , Louvet Cédric , Riedel Claudia A. , Blancou Philippe , Bach Jean‐Marie , Chauveau Christine , Bueno Susan M. , Anegon Ignacio , Kalergis Alexis M.
Published: July 2013

Heme oxygenase‐1 (HO‐1) inhibits immune responses and inflammatory reactions via the catabolism of heme into carbon monoxide (CO), Fe2+, and biliverdin. We have previously shown that either induction of HO‐1 or treatment with exogenous CO inhibits LPS‐induced maturation of dendritic cells (DCs) and protects in vivo and in vitro antigen‐specific inflammation. Here, we evaluated the capacity of HO‐1 and CO to regulate antigen presentation on MHC class I and MHC class II molecules by LPS‐treated DCs. We observed that HO‐1 and CO treatment significantly inhibited the capacity of DCs to present soluble antigens to T cells. Inhibition was restricted to soluble OVA protein, as no inhibition was observed for antigenic OVA‐derived peptides, bead‐bound OVA protein, or OVA as an endogenous antigen. Inhibition of soluble antigen presentation was not due to reduced antigen uptake by DCs, as endocytosis remained functional after HO‐1 induction and CO treatment. On the contrary, CO significantly reduced the efficiency of fusion between late endosomes and lysosomes and not by phagosomes and lysosomes. These data suggest that HO‐1 and CO can inhibit the ability of LPS‐treated DCs to present exogenous soluble antigens to naïve T cells by blocking antigen trafficking at the level of late endosome–lysosome fusion.
Plasma and urine metabolic fingerprinting of type 1 diabetic children
Authors: Balderas Claudia , Rupérez Francisco Javier , Ibañez Elena , Señorans Javier , Guerrero‐Fernández Julio , Casado Isabel González , Gracia‐Bouthelier Ricardo , García Antonia , Barbas Coral
Published: July 2013

Type 1 diabetes mellitus is one of the most common chronic disorders of childhood. The metabolic control is lost due to the lack of insulin, which is the main treatment for the disease. Nevertheless, long‐term complications appear even under good glycemic control. Metabolomics, an emerging strategy, can help in diagnosis, prognosis, and monitoring of metabolic disorders. The objective of the present study was to investigate the alterations in plasma (by LC‐MS) and urine (CE‐MS) of type 1 diabetic children that were under insulin treatment and good glycemic control. Even without remarkable biochemical differences between the two groups (diabetic and control) except for glucose level and glycosilated hemoglobin, metabolomic tools were able to capture subtle metabolic differences. The main changes in plasma were associated to lipidic metabolism (nonesterified fatty acids, lysophospholipids, and other derivatives of fatty acids), and some markers of the differential activity of the gut microflora were also found (bile acids, p‐cresol sulfate). In urine, changes associated to protein and amino acid metabolism were found (amino acids, their metabolites and derivatives), and among them one advanced glycation end product (carboxyethylarginine) and one early glycation end product (fructosamine) were excreted in higher proportion in the diabetic group.
Synthesis of uniform poly(d,l‐lactide) and poly(d,l‐lactide‐co‐glycolide) microspheres using a microfluidic chip for comparison
Authors: Yang Chih‐Hui , Huang Keng‐Shiang , Grumezescu Alexandru Mihai , Wang Chih‐Yu , Tzeng Shian‐Chiuan , Chen Szu‐Yu , Lin Yu‐Hsin , Lin Yung‐Sheng
Published: July 2013

Applications of poly(l‐lactide) (PLA) and poly(d,l‐lactide‐co‐glycolide) (PLGA) microspheres are widely used in the biomedical and pharmaceutical fields. The effects of PLA/PLGA on microsphere properties when using conventional particulate preparation methods are not easily defined due to the uncontrollable particle size and size distribution. This study was aimed to synthesize uniform PLA and PLGA microspheres using a phenol formaldehyde resin‐based microfluidic chip, which has the advantage of being solvent‐resistant, flexible, and is readily disassembled for cleaning. The proposed chip can rapidly fabricate reproducible PLA and PLGA microspheres. Uniform emulsion droplets can be achieved by hydrodynamic flow focusing. After solvent evaporation, the free‐flowing PLA and PLGA microspheres have a high level of morphological uniformity and size, allowing for a clear comparison of material effects. The results indicate that the sizes of the PLA and PLGA microspheres for the various flow rates of dispersed/continuous phases are very similar. The PLA/PLGA materials do not have a significant effect on particle size, but the particle surface indicates a different morphology. The result of the cytotoxicity evaluation shows no difference between PLA and PLGA and ensures the biocompatibility of both prepared PLA and PLGA microspheres for biomedical and pharmaceutical applications in the future.
Modal analysis of pile‐supported structures during seismic liquefaction
Authors: Lombardi Domenico , Bhattacharya Subhamoy
Published: July 2013

The purpose of this paper is to investigate the effects of liquefaction on modal parameters (frequency and damping) of pile‐supported structures. Four physical models, consisting of two single piles and two 2 × 2 pile groups, were tested in a shaking table where the soil surrounding the pile liquefied because of seismic shaking. The experimental results showed that the natural frequency of pile‐supported structures may decrease considerably owing to the loss of lateral support offered by the soil to the pile. On the other hand, the damping ratio of structure may increase to values in excess of 20%. These findings have important design consequences: (a) for low‐period structures, substantial reduction of spectral acceleration is expected; (b) during and after liquefaction, the response of the system may be dictated by the interactions of multiple loadings, that is, horizontal, axial and overturning moment, which were negligible prior to liquefaction; and (c) with the onset of liquefaction due to increased flexibility of pile‐supported structure, larger spectral displacement may be expected, which in turn may enhance P‐delta effects and consequently amplification of overturning moment. Practical implications for pile design are discussed. Copyright © 2013 John Wiley & Sons, Ltd.
Seismic evaluation of the shear behavior in reinforced concrete bridge columns including effect of vertical accelerations
Authors: Lee Hyerin , Mosalam Khalid M.
Published: July 2013

The effect of vertical excitation on shear capacity of reinforced concrete columns is important. Field evidences, analytical studies and static or hybrid simulations suggested that excessive tension or tensile strain of the column may lead to shear strength degradation, and therefore vertical excitation can be one of the causes of shear failure. This paper describes an experimental study consisting of shaking table tests on reduced‐scale bridge columns. Results of the tests indicate that tension in the columns has the potential to degrade the shear capacity, which is mainly due to the degradation of the concrete contribution to this capacity. The presented computational results and code evaluations also support this shear strength degradation. The presented dynamic tests contribute to better understanding of the effect of vertical excitation on the shear failure, which is one of the most critical brittle failure mechanisms. Copyright © 2013 John Wiley & Sons, Ltd.
The Impact of Co‐Location of Securities Exchanges' and Traders' Computer Servers on Market Liquidity
Authors: Frino Alex , Mollica Vito , Webb Robert I.
Published: July 2013

This study examines the impact of allowing traders to co‐locate their servers near exchange servers on the liquidity of futures contracts traded on the Australian Securities Exchange. It provides evidence of an increase in proxies for high‐frequency trading activity following the introduction of co‐location. There is strong evidence of a decrease in bid–ask spreads and an increase in market depth after the introduction of co‐location. We conclude that the introduction of co‐location enhances liquidity. We conjecture that co‐location improves the efficiency with which liquidity providers (including market maker high‐frequency traders) are able to make markets. © 2013 Wiley Periodicals, Inc. Jrl Fut Mark 34:20–33, 2014
Estimation of atmospheric nutrient inputs to the Atlantic Ocean from 50°N to 50°S based on large‐scale field sampling: Iron and other dust‐associated elements
Authors: Baker A. R. , Adams C. , Bell T. G. , Jickells T. D. , Ganzeveld L.
Published: July 2013

Atmospheric inputs of mineral dust supply iron and other trace metals to the remote ocean and can influence the marine carbon cycle due to iron's role as a potentially limiting micronutrient. Dust generation, transport, and deposition are highly heterogeneous, and there are very few remote marine locations where dust concentrations and chemistry (e.g., iron solubility) are routinely monitored. Here we use aerosol and rainwater samples collected during 10 large‐scale research cruises to estimate the atmospheric input of iron, aluminum, and manganese to four broad regions of the Atlantic Ocean over two 3 month periods for the years 2001–2005. We estimate total inputs of these metals to our study regions to be 4.2, 17, and 0.27 Gmol in April–June and 4.9, 14, and 0.19 Gmol in September–November, respectively. Inputs were highest in regions of high rainfall (the intertropical convergence zone and South Atlantic storm track), and rainfall contributed higher proportions of total input to wetter regions. By combining input estimates for total and soluble metals for these time periods, we calculated overall percentage solubilities for each metal that account for the contributions from both wet and dry depositions and the relative contributions from different aerosol types. Calculated solubilities were in the range 2.4%–9.1% for iron, 6.1%–15% for aluminum, and 54%–73% for manganese. We discuss sources of uncertainty in our estimates and compare our results to some recent estimates of atmospheric iron input to the Atlantic.
Evidence of active dinitrogen fixation in surface waters of the eastern tropical South Pacific during El Niño and La Niña events and evaluation of its potential nutrient controls
Authors: Dekaezemacker J. , Bonnet S. , Grosso O. , Moutin T. , Bressac M. , Capone D.G.
Published: July 2013

Biological N2 fixation rates were quantified in the Eastern Tropical South Pacific (ETSP) during both El Niño (February 2010) and La Niña (March–April 2011) conditions, and from Low‐Nutrient, Low‐Chlorophyll (20°S) to High‐Nutrient, Low‐Chlorophyll (HNLC) (10°S) conditions. N2 fixation was detected at all stations with rates ranging from 0.01 to 0.88 nmol N L−1 d−1, with higher rates measured during El Niño conditions compared to La Niña. High N2 fixations rates were reported at northern stations (HNLC conditions) at the oxycline and in the oxygen minimum zone (OMZ), despite nitrate concentrations up to 30 µmol L−1, indicating that inputs of new N can occur in parallel with N loss processes in OMZs. Water‐column integrated N2 fixation rates ranged from 4 to 53 µmol N m−2 d−1 at northern stations, and from 0 to 148 µmol m−2 d−1 at southern stations, which are of the same order of magnitude as N2 fixation rates measured in the oligotrophic ocean. N2 fixation rates responded significantly to Fe and organic carbon additions in the surface HNLC waters, and surprisingly by concomitant Fe and N additions in surface waters at the edge of the subtropical gyre. Recent studies have highlighted the predominance of heterotrophic diazotrophs in this area, and we hypothesize that N2 fixation could be directly limited by inorganic nutrient availability, or indirectly through the stimulation of primary production and the subsequent excretion of dissolved organic matter and/or the formation of micro‐environments favorable for heterotrophic N2 fixation.
Physical constraints for temperature biases in climate models
Authors: Bellprat O. , Kotlarski S. , Lüthi D. , Schär C.
Published: July 2013

In general, biases of climate models depend upon the climate state (i.e., are nonstationary). Recent studies have shown that the adoption of a stationary temperature bias can lead to an overestimation of projected summer warming in southern Europe. It has also been proposed to use a bias correction that increases linearly with temperature. While such an assumption is well‐justified for near‐term projections, one wonders whether and at what temperature this relation levels off if it does. Here we show, using regional climate model simulations of the ENSEMBLES project and from a single‐model perturbed physics ensemble, that the linear bias assumption breaks down at high model temperatures, followed by a transition to a constant bias relation. This transition is apparent in strongly biased model simulations and supported using a pseudo‐reality approach. We show that soil moisture scarcity explains a large degree of summer temperature biases across both ensembles and that the limits of soil moisture depletion are responsible for the transition. A linear temperature bias correction therefore potentially over‐corrects summer warming, and implicitly assumes unphysical relations between soil moisture and temperature, in particular when considering high‐emission scenarios. We conclude that a physically consistent and time‐dependent temperature bias correction considering the state of the soil would increase the robustness of bias correction and reduce the uncertainty of 21st century summer warming.
Basin‐scale transport of heat and fluid induced by earthquakes
Authors: Wang Chi‐Yuen , Wang Lee‐Ping , Manga Michael , Wang Chung‐Ho , Chen Chieh‐Hung
Published: July 2013

Large earthquakes are known to cause widespread changes in groundwater flow, yet their relation to subsurface transport is unknown. Here we report systematic changes in groundwater temperature after the 1999 Mw7.6 Chi‐Chi earthquake in central Taiwan, documented by a dense network of monitoring wells over a large (17,000 km2) alluvial fan near the epicenter. Analysis of the data reveals a hitherto unknown system of earthquake‐triggered basin‐wide groundwater flow, which scavenges geothermal heat from depths, changing groundwater temperature across the basin. The newly identified earthquake‐triggered groundwater flow may have significant implications on postseismic groundwater supply and quality, contaminant transport, underground repository safety, and hydrocarbon production.
Spatial trends in synoptic rainfall in southern Australia
Authors: Risbey James S. , Pook Michael J. , McIntosh Peter C.
Published: July 2013

This work assesses spatial and temporal changes in rainfall in southern Australia over the period 1990–2009. Rainfall is assessed by season and according to the synoptic system generating the rainfall. Rainfall decreases over the period across much of the southwest, with the most significant decrease occurring around 2000. These changes are associated with frontal and cutoff systems. Frontal systems dominate the timing and changes of rainfall in western Tasmania. In the southeast, the timing and magnitude of rainfall changes are more closely associated with cutoff systems and show consistent decreases in the early 1990s. The largest reductions in rainfall in the southeast are in the Alpine region and are due to cutoffs and fronts and exhibit seasonal and spatial variations consistent with the climatologies of these systems.
Long‐term care services expenditure projection in South Korea from 2015 to 2050
Authors: Kim Nayoung
Published: July 2013

South Korea has been undergoing significant change in its population structure over the past three decades. Within 10 years, South Korean baby‐boomers will reach the age of 65 years and accelerate this change. This trend in population structure is crucial, because an aging population may increase medical demand, especially that for long‐term care (LTC) services, which would create a financial burden on society.

This study estimates total LTC expenditure in South Korea from 2015 to 2050 by modifying the method proposed by the UK Personal Social Science Research Unit, the seminal study on projecting costs of LTC services. Using population data from the projections of the Korean Statistical Information Service, I stratify the projected population by gender and age, using the groups 65–69, 70–74, 75–79 and 80 or over and divide LTC services into two categories, namely facility and home care.

South Korea's total LTC expenditure is predicted to continuously increase and then reach 4.2% of GDP in 2050. Expenditure on LTC services for women is higher than that for men. Moreover, the increase in total expenditure is dramatic after 2040 for home‐based services but is constant for facility services. This study shows that the presence of baby‐boomers heavily influences LTC expenditure in South Korea. Copyright © 2013 John Wiley & Sons, Ltd.
Liberalising trade in health services: constraints and prospects for South Asian countries
Authors: Khatun Fahmida , Ahamad Mazbahul
Published: July 2013

This paper attempts to examine the prospects and challenges associated with liberalising trade in health services in five South Asian countries, namely Bangladesh, India, Nepal, Pakistan and Sri Lanka. Country‐specific secondary information, a brief literature review of empirical studies and debriefing sessions with key stakeholders are employed to explore the issues related to liberalising health services trade. The health sectors in India, Nepal and Pakistan are scheduled under General Agreement on Trade in Services (GATS) classification, whereas those in Bangladesh and Sri Lanka are not. In Bangladesh, there is opportunity for investment in joint venture hospitals under Mode 3. Nonetheless, India is the largest trader in health services under all four modes. In Sri Lanka, cross‐border trade in healthcare services is found to be insignificant. Moreover, expertise in eye treatment in Nepal could also attract foreign investment in medical services under Mode 3. In contrast, Pakistan exhibits no potential under Mode 4, because of a lack of healthcare professionals. In this view, the prospects of trade in health services within the South Asian region under the four GATS modes are constrained by infrastructural, regulatory, perception‐related, logistical and cultural problems. Considering the level of development and commercial opportunities, regional integration in the health sector could be explored in such areas as telemedicine, medical tourism, cross‐border investment and capacity building of health personnel. These developments call for stronger and pro‐active government‐to‐government collaboration in the South Asian Association of Regional Cooperation (SAARC) region in a transparent and accountable manner. Copyright © 2013 John Wiley & Sons, Ltd.
Polymorphisms in DNA repair genes, recreational physical activity and breast cancer risk
Authors: McCullough Lauren E. , Santella Regina M. , Cleveland Rebecca J. , Millikan Robert C. , Olshan Andrew F. , North Kari E. , Bradshaw Patrick T. , Eng Sybil M. , Terry Mary Beth , Shen Jing , Crew Katherine D. , Rossner Pavel , Teitelbaum Susan L. , Neugut Alfred I. , Gammon Marilie D.
Published: July 2013

The mechanisms driving the inverse association between recreational physical activity (RPA) and breast cancer risk are complex. While exercise is associated with increased reactive oxygen species production it may also improve damage repair systems, particularly those that operate on single‐strand breaks including base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR). Of these repair pathways, the role of MMR in breast carcinogenesis is least investigated. Polymorphisms in MMR or other DNA repair gene variants may modify the association between RPA and breast cancer incidence. We investigated the individual and joint effects of variants in three MMR pathway genes (MSH3, MLH1 and MSH2) on breast cancer occurrence using resources from the Long Island Breast Cancer Study Project. We additionally characterized interactions between RPA and genetic polymorphisms in MMR, BER and NER pathways. We found statistically significant multiplicative interactions (p < 0.05) between MSH2 and MLH1, as well as between postmenopausal RPA and four variants in DNA repair (XPC‐Ala499Val, XPF‐Arg415Gln, XPG‐Asp1104His and MLH1‐lle219Val). Significant risk reductions were observed among highly active women with the common genotype for XPC (OR = 0.54; 95% CI, 0.36–0.81) and XPF (OR = 0.62; 95% CI, 0.44–0.87), as well as among active women who carried at least one variant allele in XPG (OR = 0.46; 95% CI, 0.29–0.77) and MLH1 (OR = 0.46; 95% CI, 0.30–0.71). Our data show that women with minor alleles in both MSH2 and MLH1 could be at increased breast cancer risk. RPA may be modified by genes in the DNA repair pathway, and merit further investigation.
Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update
Authors: Duffy M.J. , Lamerz R. , Haglund C. , Nicolini A. , Kalousová M. , Holubec L. , Sturgeon C.
Published: July 2013

Biomarkers currently play an important role in the detection and management of patients with several different types of gastrointestinal cancer, especially colorectal, gastric, gastro‐oesophageal junction (GOJ) adenocarcinomas and gastrointestinal stromal tumors (GISTs). The aim of this article is to provide updated and evidence‐based guidelines for the use of biomarkers in the different gastrointestinal malignancies. Recommended biomarkers for colorectal cancer include an immunochemical‐based fecal occult blood test in screening asymptomatic subjects ≥50 years of age for neoplasia, serial CEA levels in postoperative surveillance of stage II and III patients who may be candidates for surgical resection or systemic therapy in the event of distant metastasis occurring, K‐RAS mutation status for identifying patients with advanced disease likely to benefit from anti‐EGFR therapeutic antibodies and microsatellite instability testing as a first‐line screen for subjects with Lynch syndrome. In advanced gastric or GOJ cancers, measurement of HER2 is recommended in selecting patients for treatment with trastuzumab. For patients with suspected GIST, determination of KIT protein should be used as a diagnostic aid, while KIT mutational analysis may be used for treatment planning in patients with diagnosed GISTs.
Oncolytic effects of parvovirus H‐1 in medulloblastoma are associated with repression of master regulators of early neurogenesis
Authors: Lacroix Jeannine , Schlund Franziska , Leuchs Barbara , Adolph Kathrin , Sturm Dominik , Bender Sebastian , Hielscher Thomas , Pfister Stefan M. , Witt Olaf , Rommelaere Jean , Schlehofer Jörg R. , Witt Hendrik
Published: July 2013

Based on extensive pre‐clinical studies, the oncolytic parvovirus H‐1 (H‐1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high‐risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H‐1PV on MB cells in vitro and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non‐transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H‐1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H‐1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H‐1PV. H‐1PV induced down‐regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H‐1PV infection. H‐1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus.
Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial‐to‐mesenchymal transition
Authors: Roepman Paul , Schlicker Andreas , Tabernero Josep , Majewski Ian , Tian Sun , Moreno Victor , Snel Mireille H , Chresta Christine M , Rosenberg Robert , Nitsche Ulrich , Macarulla Teresa , Capella Gabriel , Salazar Ramon , Orphanides George , Wessels Lodewyk FA , Bernards Rene , Simon Iris M
Published: July 2013

In most colorectal cancer (CRC) patients, outcome cannot be predicted because tumors with similar clinicopathological features can have differences in disease progression and treatment response. Therefore, a better understanding of the CRC biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for other patients. Based on unsupervised classification of whole genome data from 188 stages I–IV CRC patients, a molecular classification was developed that consist of at least three major intrinsic subtypes (A‐, B‐ and C‐type). The subtypes were validated in 543 stages II and III patients and were associated with prognosis and benefit from chemotherapy. The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: epithelial‐to‐mesenchymal transition, deficiency in mismatch repair genes that result in high mutation frequency associated with microsatellite instability and cellular proliferation. A‐type tumors, observed in 22% of the patients, have the best prognosis, have frequent BRAF mutations and a deficient DNA mismatch repair system. C‐type patients (16%) have the worst outcome, a mesenchymal gene expression phenotype and show no benefit from adjuvant chemotherapy treatment. Both A‐type and B‐type tumors have a more proliferative and epithelial phenotype and B‐types benefit from adjuvant chemotherapy. B‐type tumors (62%) show a low overall mutation frequency consistent with the absence of DNA mismatch repair deficiency. Classification based on molecular subtypes made it possible to expand and improve CRC classification beyond standard molecular and immunohistochemical assessment and might help in the future to guide treatment in CRC patients.
Incorporation of growth factor loaded microspheres into polymeric electrospun nanofibers for tissue engineering applications
Authors: Selcan Gungor‐Ozkerim P. , Balkan Timucin , Kose Gamze T. , Sezai Sarac A. , Kok Fatma N.
Published: July 2013

Nanofibrous double‐layer matrices were prepared by electrospinning technique with the bottom layer formed from PCL (poly‐ε‐caprolactone)/PLLA (poly‐l‐lactic acid) nanofibers and the upper layer from PCL/Gelatin nanofibers. Bottom layer was designed to give mechanical strength to the system, whereas upper layer containing gelatin was optimized to improve the cell adhesion. Gelatin microspheres were incorporated in the middle of two layers for controlled growth factor delivery. Successful fabrication of the blend nanofibers were shown by spectroscopy. Scanning electron microscopy results demonstrated that bead‐free nanofibers with uniform morphology could be obtained by 10% w/v concentrations of PCL/PLLA and PCL/Gelatin solutions. Microspheres prepared by 15% gelatin concentration and cross‐linked with 7.5% glutaraldehyde solution were chosen after in vitro release studies for the incorporation to the double‐layer matrices. The optimized conditions were used to prepare fibroblast growth factor‐2 (FGF‐2) loaded microspheres. Preliminary cell culture studies showed that the FGF‐2 could be actively loaded into the microspheres and enhanced the cell attachment and proliferation. The complete system had a slow degradation rate in saline (18% weight loss in 2 months) and it could meanwhile preserve its integrity. This sandwich system prevented microsphere leakage from the scaffold, and the hydrophilic and bioactive nature of the fibers at the upper layer promoted cell attachment to the surface. PLLA/PCL layer, on the other hand, improved the mechanical properties of the system and enabled better handling. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 1897–1908, 2014.
Elastic properties of human posterior eye
Authors: Chen Kinon , Rowley Adrian P. , Weiland James D. , Humayun Mark S.
Published: July 2013

This study examines the elastic properties of the human posterior retina, choroid, and sclera. Twenty‐four human eyes from 30‐ to 74‐year‐old donors were obtained from an eye bank. Vertically and horizontally oriented tissue strips of the retina, choroid, and sclera (ideally n = 12 in each group) were harvested from the posterior eyes. Their thicknesses were estimated optically. The samples were stretched at 1 mm/s in 37°C saline. Stress and strain were obtained from the mechanical tests, and then the transition stress, transition strain, toe modulus, and heel modulus were calculated. Statistical analysis was performed for comparison between groups. Linear regression analyses were used to explore the relationship between the mechanical parameters and age. We found that the stress–strain relationship of the retina, choroid, and sclera were nonlinear. Except for the retinal transition strain (p = 0.0124), no statistical difference was found between the vertical and horizontal meridian in the mechanical parameters (p > 0.05). Furthermore, weak relationship was observed between some of the mechanical parameters and the donors' age. Our results suggest that there is significant anisotropy in the retina, and mechanical properties of each layer may change with age. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2001–2007, 2014.
Cell‐penetrating peptides: Achievements and challenges in application for cancer treatment
Authors: Shin Meong Cheol , Zhang Jian , Min Kyoung Ah , Lee Kyuri , Byun Youngro , David Allan E. , He Huining , Yang Victor C.
Published: July 2013

One of the major hurdles to cure cancer lies in the low potency of currently available drugs, which could eventually be solved by using more potent therapeutic macromolecules, such as proteins or genes. However, although these macromolecules possess greater potency inside the cancer cells, the barely permeable cell membrane remains a formidable barrier to exert their efficacy. A widely used strategy is to use cell penetrating peptides (CPPs) to improve their intracellular uptake. Since the discovery of the first CPP, numerous CPPs have been derived from natural or synthesized products. Both in vitro and in vivo studies have demonstrated that those CPPs are highly efficient in transducing cargoes into almost all cell types. Therefore, to date, CPPs have been widely used for intracellular delivery of various cargoes, including peptides, proteins, genes, and even nanoparticles. In addition, recently, based on the successes of CPPs in cellular studies, their applications in vivo have been actively pursued. This review will focus on the advanced applications of CPP‐based in vivo delivery of therapeutics (e.g., small molecule drugs, proteins, and genes). In addition, we will highlight certain updated applications of CPPs for intracellular delivery of nanoparticulate drug carriers, as well as several “smart” strategies for tumor targeted delivery of CPP‐cargoes. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 575–587, 2014.
MC3T3‐E1 and RAW264.7 cell response to hydroxyapatite and alpha‐type alumina adsorbed with bovine serum albumin
Authors: Kawashita Masakazu , Hayashi Jumpei , Kudo Tada‐aki , Kanetaka Hiroyasu , Li Zhixia , Miyazaki Toshiki , Hashimoto Masami
Published: July 2013

Initial cell responses following implantation are important for inducing osteoconductivity. We investigated cell adhesion, spreading, and proliferation in response to native and bovine serum albumin (BSA)‐adsorbed disc of hydroxyapatite (HA) or alpha‐type alumina (α‐Al2O3) using mouse MC3T3‐E1 osteoblastic cells and mouse RAW264.7 macrophages. The adsorbed BSA inhibited adhesion and spreading of MC3T3‐E1 cells, but did not affect MC3T3‐E1 cell proliferation on HA and α‐Al2O3 substrates. Thus, MC3T3‐E1 cells quickly adhere to original HA before cell binding is impeded by adsorption of BSA in quantities sufficient to inhibit the adhesion of MC3T3‐E1 cells. The adsorbed BSA inhibits adhesion of RAW264.7 cells to α‐Al2O3, but not to HA. BSA adsorption does not affect RAW264.7 cell spreading and proliferation on both HA and α‐Al2O3 substrates. Thus, BSA adsorbed on HA stimulates a different cell response than α‐Al2O3. Moreover, quick adherence of osteoblast cells and monocyte‐macrophage lineage cells plays a role in HA osteoconductivity. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 1880–1886, 2014.
Considerations in binding diblock copolymers on hydrophilic alginate beads for providing an immunoprotective membrane
Authors: Spasojevic Milica , Bhujbal Swapnil , Paredes Genaro , de Haan Bart J. , Schouten Arend J. , de Vos Paul
Published: July 2013

Alginate‐based microcapsules are being proposed for treatment of many types of diseases. A major obstacle however in the successes is that these capsules are having large lab‐to‐lab variations. To make the process more reproducible, we propose to cover the surface of alginate capsules with diblock polymers that can form polymer brushes. In the present study, we describe the stepwise considerations for successful application of diblock copolymer of polyethylene glycol (PEG) and poly‐L‐lysine (PLL) on the surface of alginate beads. Special procedures had to be designed as alginate beads are hydrophilic and most protocols are designed for hydrophobic biomaterials. The successful attachment of diblock copolymer and the presence of PEG blocks on the surface of the capsules were studied by fluorescence microscopy. Longer time periods, that is, 30–60 min, are required to achieve saturation of the surface. The block lengths influenced the strength of the capsules. Shorter PLL blocks resulted in less stable capsules. Adequate permeability of the capsules was achieved with poly(ethylene glycol)‐block‐poly(L‐lysine hydrochloride) (PEG454‐b‐PLL100) diblock copolymers. The capsules were a barrier for immunoglobulin G. The PEG454‐b‐PLL100 capsules have similar mechanical properties as PLL capsules. Minor immune activation of nuclear factor κB in THP‐1 monocytes was observed with both PLL and PEG454‐b‐PLL100 capsules prepared from purified alginate. Our results show that we can successfully apply block copolymers on the surface of hydrophilic alginate beads without interfering with the physicochemical properties. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 1887–1896, 2014.
Microstructural effects on the wear behavior of a biomedical as‐cast Co‐27Cr‐5Mo‐0.25C alloy exposed to pulsed laser melting
Authors: Acevedo‐Dávila J. L. , López H. F. , Cepeda‐Rodríguez F. , Rodriguez‐Reyes M. , García‐Vazquez F. , Hernández‐Garcia H. M.
Published: July 2013

In this work, the effect of pulsed laser melting on the exhibited microstructure and properties of a cast Co‐27Cr‐5Mo‐0.25C alloy was investigated. In particular, properties such as surface hardness and wear behavior of the laser modified microstructure were determined as a function of the implemented laser melting parameters. It was found that laser melting promotes significant grain refinement while preventing the precipitation of coarse carbide phases. Apparently, a refined dendritic grain structure develops which is surrounded by a fine carbide distribution in the interdendritic regions. Moreover, the high‐temperature face centered cubic (FCC) phase remains untransformed at room temperature. Hardness measurements and wear testing using a Pin‐On‐Disk tribological machine indicate that the modified laser surfaces exhibit both, high wear resistance and high microhardness when compared with the untreated as‐cast Co‐27Cr‐5Mo‐0.25C alloy. In particular, it was found that the laser modified surfaces exhibit improved wear and friction properties comparable to the ones found in Co‐Cr‐Mo alloys with a predominantly hexagonal closest packed (HCP) matrix. However, surface defects associated with the laser process can be detrimental for the improved wear performance and they should be considered in identifying the proper laser parameters in alloy melting. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2008–2016, 2014.
The structurally effect of surface coated rhamnogalacturonan I on response of the osteoblast‐like cell line SaOS‐2
Authors: Svava Rikke , Gurzawska Katarzyna , Yihau Yu , Haugshøj Kenneth Brian , Dirscherl Kai , Levery Steven B. , Jørgensen Niklas Rye , Gotfredsen Klaus , Damager Iben , Ulvskov Peter , Jørgensen Bodil
Published: July 2013

Osseointegration is important when implants are inserted into the bone and can be improved by biochemical surface coating of the implant. In this paper enzymatically modified rhamnogalacturonan I (RG‐I) from apple and lupin was used for biochemical coating of aminated surfaces and the importance of the quality of RG‐I, the nature of the binding, the fine structure of RG‐I, and its effect on SaOS‐2 cell line cultured on coated surfaces was investigated. SaOS‐2 cells are osteoblast‐like cells and a well‐established in vitro model of bone‐matrix forming osteoblasts. Purification by gel filtration could remove small fragments of galacturonic acid (GalA) and binding studies showed that the purity of the RG‐I molecules was important for the quality of the coating. The structure of RG‐I and osteoblast‐like cells' viability were positively correlated so that high content of 1,4‐linked galactose (Gal) and a low content of arabinose in the RG‐I molecules favored cell viability. These results indicate that coating of implants with RG‐I affect osseointegration positively. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 1961–1971, 2014.
A review of integrating electroactive polymers as responsive systems for specialized drug delivery applications
Authors: Pillay Viness , Tsai Tong‐Sheng , Choonara Yahya E. , du Toit Lisa C. , Kumar Pradeep , Modi Girish , Naidoo Dinesh , Tomar Lomas K. , Tyagi Charu , Ndesendo Valence M. K.
Published: July 2013

Electroactive polymers (EAPs) are promising candidate materials for the design of drug delivery technologies, especially in conditions where an “on–off” drug release mechanism is required. To achieve this, EAPs such as polyaniline, polypyrrole, polythiophene, ethylene vinyl acetate, and polyethylene may be blended into responsive hydrogels in conjunction with the desired drug to obtain a patient‐controlled drug release system. The “on–off” drug release mechanism can be achieved through the environmental‐responsive nature of the interpenetrating hydrogel‐EAP complex via (i) charged ions initiated diffusion of drug molecules; (ii) conformational changes that occur during redox switching of EAPs; or (iii) electroerosion. These release mechanisms are not exhaustive and new release mechanisms are still under investigation. Therefore, this review seeks to provide a concise incursion and critical overview of EAPs and responsive hydrogels as a strategy for advanced drug delivery, for example, controlled release of neurotransmitters, sulfosalicyclic acid from cross‐linked hydrogel, and vaccine delivery. The review further discusses techniques such as linear sweep voltammetry, cyclic voltammetry, impedance spectroscopy, and chronoamperometry for the determination of the redox capability of EAPs. The future implications of the hydrogel‐EAP composites include, but not limited to, application toward biosensors, DNA hybridizations, microsurgical tools, and miniature bioreactors and may be utilized to their full potential in the form of injectable devices as nanorobots or nanobiosensors. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2039–2054, 2014.
Photoinitiated chemical vapor deposition of cytocompatible poly(2‐hydroxyethyl methacrylate) films
Authors: McMahon Brian J. , Pfluger Courtney A. , Sun Bing , Ziemer Katherine S. , Burkey Daniel D. , Carrier Rebecca L.
Published: July 2013

Poly(2‐hydroxyethyl methacrylate) (pHEMA) is a widely utilized biomaterial due to lack of toxicity and suitable mechanical properties; conformal thin pHEMA films produced via chemical vapor deposition (CVD) would thus have broad biomedical applications. Thin films of pHEMA were deposited using photoinitiated CVD (piCVD). Incorporation of ethylene glycol diacrylate (EGDA) into the pHEMA polymer film as a crosslinker, confirmed via Fourier transform infrared spectroscopy and X‐ray photoelectron spectroscopy, resulted in varied swelling and degradation behavior. 2‐Hydroxyethyl methacrylate‐only films showed significant thickness loss (up to 40%), possibly due to extraction of low‐molecular‐weight species or erosion, after 24 h in aqueous solution, whereas films crosslinked with EGDA (9.25–12.4%) were stable for up to 21 days. These results differ significantly from those obtained with plasma‐polymerized pHEMA, which degraded steadily over a 21‐day period, even with crosslinking. This suggests that the piCVD films differ structurally from those fabricated via plasma polymerization (plasma‐enhanced CVD). piCVD pHEMA coatings proved to be good cell culture materials, with Caco‐2 cell attachment and viability comparable to results obtained on tissue‐culture polystyrene. Thus, thin film CVD pHEMA offers the advantage of enabling conformal coating of a cell culture substrate with tunable properties depending on method of preparation and incorporation of crosslinking agents. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2375–2382, 2014.
Development and assessment of a biodegradable solvent cast polyester fabric small‐diameter vascular graft
Authors: Melchiorri Anthony J. , Hibino Narutoshi , Brandes Zachary R. , Jonas Richard A. , Fisher John P.
Published: July 2013

Adjusting the mechanical properties of polyester‐based vascular grafts is crucial to achieving long‐term success in vivo. Although previous studies using a fabric‐based approach have achieved some success, a central issue with pure poly(lactic acid) (PLA) or poly(glycolic acid) (PGA) grafts sealed with poly(dl‐caprolactone‐co‐lactic acid) (P(CL/LA)) has been stenosis. Intimal hyperplasia, a leading cause of stenosis, can be caused by the mechanical incompatibility of synthetic vascular grafts. Investigating the performance of poly(glycolic‐co‐lactic acid) (PGLA) grafts could lead to insight into whether graft stenosis stems from mechanical issues such as noncompliance and unfavorable degradation times. This could be achieved by examining grafts with tunable mechanical properties between the ranges of such properties in pure PGA and PLA‐based grafts. In this study, we examined PGLA‐based grafts sealed with different P(CL/LA) solutions to determine the PGLA‐P(CL/LA) grafts' mechanical properties and tissue functionality. Cell attachment and proliferation on graft surfaces were also observed. For in vivo assessment, grafts were implanted in a mouse model. Mechanical properties and degradation times appeared adequate compared to recorded values of vessels used in autograft procedures. Initial neotissue formation was observed in the grafts and patency maintained during the pilot study. This study presents a ∼1‐mm diameter degradable graft demonstrating suitable mechanical properties and in vivo pilot study success, enabling further investigation into the tuning of mechanical properties to reduce complications in degradable polyester fabric‐based vascular grafts. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 1972–1981, 2014.