bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer incidence and mortality patterns in women with anorexia nervosa
Authors: Karamanis Georgios , Skalkidou Alkistis , Tsakonas Georgios , Brandt Lena , Ekbom Anders , Ekselius Lisa , Papadopoulos Fotios C.
Published: October 2013

Caloric restriction in animals is an effective way to reduce carcinogenesis. Anorexia nervosa (AN) is considered a model of extreme caloric restriction in humans. The aim of our study was to assess cancer incidence and mortality in women with AN. A total of 6,009 women with at least one inpatient treatment for AN during the period 1973–2003 were included in the study. Standardized incidence ratios (SIR) and standardized mortality ratios (SMR) were calculated. Overall, there was no statistically significant difference in cancer incidence compared to women in the general population. At a statistically significant or borderline significant level, a higher incidence for lung cancer and cancer of lymphoid, hematopoietic and related tissue was observed along with a reduced breast cancer incidence. Women with AN had twice as high mortality from cancer in general, and more specifically from melanoma, cancers of genital organs and cancers of ill‐defined, secondary and unspecified sites. The increased lung cancer incidence may be due to smoking habits among women with AN. The worse prognosis with higher mortality from melanoma, cancers of genital organs and cancers of ill‐defined, secondary and unspecified sites may be explained by AN‐specific attitudes toward seeking medical care, adherence to treatment or worse biological precondition due to starvation and cachexia.
Additive effect of the AZGP1, PIP, S100A8 and UBE2C molecular biomarkers improves outcome prediction in breast carcinoma
Authors: Parris Toshima Z. , Kovács Anikó , Aziz Luaay , Hajizadeh Shahin , Nemes Szilárd , Semaan May , Forssell‐Aronsson Eva , Karlsson Per , Helou Khalil
Published: October 2013

The deregulation of key cellular pathways is fundamental for the survival and expansion of neoplastic cells, which in turn can have a detrimental effect on patient outcome. To develop effective individualized cancer therapies, we need to have a better understanding of which cellular pathways are perturbed in a genetically defined subgroup of patients. Here, we validate the prognostic value of a 13‐marker signature in independent gene expression microarray datasets (n = 1,141) and immunohistochemistry with full‐faced FFPE samples (n = 71). The predictive performance of individual markers and panels containing multiple markers was assessed using Cox regression analysis. In the external gene expression dataset, six of the 13 genes (AZGP1, NME5, S100A8, SCUBE2, STC2 and UBE2C) retained their prognostic potential and were significantly associated with disease‐free survival (p < 0.001). Protein analyses refined the signature to a four‐marker panel [AZGP1, Prolactin‐inducible protein (PIP), S100A8 and UBE2C] significantly correlated with cycling, high grade tumors and lower disease‐specific survival rates. AZGP1 and PIP were found in significantly lower levels in invasive breast tissue as compared with adjacent normal tissue, whereas elevated levels of S100A8 and UBE2C were observed. A predictive model containing the four‐marker panel in conjunction with established clinical variables outperformed a model containing the clinical variables alone. Our findings suggest that deregulated AZGP1, PIP, S100A8 and UBE2C are critical for the aggressive breast cancer phenotype, which may be useful as novel therapeutic targets for drug development to complement established clinical variables.
Tropism of the in situ growth from biopsies of childhood neuroectodermal tumors following transplantation into experimental teratoma
Authors: Jamil Seema , Hultman Isabell , Cedervall Jessica , Ali Rouknuddin Q. , Fuchs Gabriel , Gustavsson Bengt , Asmundsson Jurate , Sandstedt Bengt , Kogner Per , Ährlund‐Richter Lars
Published: October 2013

Experimental teratoma induced from human pluripotent stem cells with normal karyotype can be described as a failed embryonic process and includes besides advanced organoid development also large elements of tissue with a prolonged occurrence of immature neural components. Such immature components, although benign, exhibit strong morphological resemblance with tumors of embryonic neuroectodermal origin. Here, we demonstrate that biopsy material from childhood tumors of neural embryonic origin transplanted to mature experimental teratoma can show an exclusive preference for matching tissue. Tumor specimens from five children with; Supratentorial primitive neuroectodermal tumor (sPNET); Pilocytic astrocytoma of the brainstem; Classic medulloblastoma; peripheral primitive neuroectodermal tumor (pPNET) or neuroblastoma (NB), respectively, were transplanted. Analysis of up to 120 sections of each tumor revealed an engraftment for three of the transplanted tumors: pPNET, sPNET, and NB, with a protruding growth from the latter two that were selected for detailed examination. The histology revealed a strict tropism with a non‐random integration into what morphologically appeared as matched embryonic microenvironment recuperating the patient tumor histology. The findings suggest specific advantages over xenotransplantation and lead us to propose that transplantation to the human embryonic microenvironment in experimental teratoma can be a well‐needed complement for preclinical in vivo studies of childhood neuroectodermal tumors.
Sequence‐dependent combination therapy with doxorubicin and a survivin‐specific small interfering RNA nanodrug demonstrates efficacy in models of adenocarcinoma
Authors: Ghosh Subrata K. , Yigit Mehmet V. , Uchida Masashi , Ross Alana W. , Barteneva Natalie , Moore Anna , Medarova Zdravka
Published: October 2013

The clinical management of cancer reflects a balance between treatment efficacy and toxicity. While typically, combination therapy improves response rate and time to progression compared with sequential monotherapy, it causes increased toxicity. Consequently, in cases of advanced cancer, emerging guidelines recommend sequential monotherapy, as a means to enhance quality of life. An alternative approach that could overcome nonspecific toxicity while retaining therapeutic efficacy, involves the combination of chemotherapy with targeted therapy. In the current study, we tested the hypothesis that combination therapy targeting survivin (BIRC5) and low‐dose doxorubicin (Dox) will show enhanced therapeutic potential in the treatment of cancer, as compared to monotherapy with Dox. We demonstrate in both in vitro and in vivo models of breast cancer that combination therapy with a low dose of Dox and an anti‐survivin siRNA nanodrug (MN‐siBIRC5) is superior to mono‐therapy with either low‐ or high‐dose Dox alone. Importantly, therapeutic efficacy showed prominent sequence dependence. Induction of apoptosis was observed only when the cells were treated with Dox followed by MN‐siBIRC5, whereas the reverse sequence abrogated the benefit of the drug combination. In vivo, confirmation of successful sequence dependent combination therapy was demonstrated in a murine xenograft model of breast cancer. Finally, to determine if the observed effect is not limited to breast cancer, we extended our studies to a murine xenograft model of pancreatic adenocarcinoma and found similar outcomes as shown for breast cancer.
Downregulation of microRNA‐15b by hepatitis B virus X enhances hepatocellular carcinoma proliferation via fucosyltransferase 2‐induced Globo H expression
Authors: Wu Chen‐Shiou , Yen Chia‐Jui , Chou Ruey‐Hwang , Chen Jia‐Ni , Huang Wei‐Chien , Wu Chung‐Yi , Yu Yung‐Luen
Published: October 2013

Globo H, a cancer‐associated carbohydrate antigen, is highly expressed in various types of cancers. However, the role of Globo H in hepatocellular carcinoma (HCC) remains elusive. In our study, we performed glycan microarray analysis of 134 human serum samples to explore anti‐Globo H antibody changes and found that Globo H is upregulated in hepatitis B virus (HBV)‐positive HCC. Similarly, immunohistochemistry showed that Globo H expression was higher in tumors compared to normal tissues. In addition, fucosyltransferase 2 (FUT2), the main synthetic enzyme of Globo H, was also increased in HCC cells overexpressing HBV X protein (HBX). HBX plays an important role in promoting cell proliferation and may be related to increased levels of FUT2 and Globo H. Furthermore, using microRNA profiling, we observed that microRNA‐15b (miR‐15b) was downregulated in patients with HCC and confirmed association of FUT2 expression with expression of its product, Globo H. Therefore, our results suggest that HBX suppressed the expression of miR‐15b, which directly targeted FUT2 and then increased levels of Globo H to enhance HCC cell proliferation. Additionally, proliferation of HBX‐overexpressing HCC cells was significantly inhibited by treatment with Globo H antibody in vitro. In xenograft animal experiments, we found that overexpression of miR‐15b effectively suppressed tumor growth. The newly identified HBX/miR‐15b/FUT2/Globo H axis suggests one possible molecular mechanism of HCC cell proliferation and represents a new potential therapeutic target for HCC treatment.
Unstable genomes elevate transcriptome dynamics
Authors: Stevens Joshua B. , Liu Guo , Abdallah Batoul Y. , Horne Steven D. , Ye Karen J. , Bremer Steven W. , Ye Christine J. , Krawetz Stephen A. , Heng Henry H.
Published: October 2013

The challenge of identifying common expression signatures in cancer is well known, however the reason behind this is largely unclear. Traditionally variation in expression signatures has been attributed to technological problems, however recent evidence suggests that chromosome instability (CIN) and resultant karyotypic heterogeneity may be a large contributing factor. Using a well‐defined model of immortalization, we systematically compared the pattern of genome alteration and expression dynamics during somatic evolution. Co‐measurement of global gene expression and karyotypic alteration throughout the immortalization process reveals that karyotype changes influence gene expression as major structural and numerical karyotypic alterations result in large gene expression deviation. Replicate samples from stages with stable genomes are more similar to each other than are replicate samples with karyotypic heterogeneity. Karyotypic and gene expression change during immortalization is dynamic as each stage of progression has a unique expression pattern. This was further verified by comparing global expression in two replicates grown in one flask with known karyotypes. Replicates with higher karyotypic instability were found to be less similar than replicates with stable karyotypes. This data illustrates the karyotype, transcriptome, and transcriptome determined pathways are in constant flux during somatic cellular evolution (particularly during the macroevolutionary phase) and this flux is an inextricable feature of CIN and essential for cancer formation. The findings presented here underscore the importance of understanding the evolutionary process of cancer in order to design improved treatment modalities.
Impact of technology on cytology outcome in cervical cancer screening of young and older women
Authors: Rask J. , Lynge E. , Franzmann M. , Hansen B. , Hjortebjerg A. , Rygaard C. , Schledermann D. , Wåhlin A. , Rebolj M.
Published: October 2013

Little is known about age‐dependent variation in outcomes of cervical cytology with modern technologies. This population‐based study evaluated age‐dependent changes after routine implementation of ThinPrep and SurePath technology in two independent laboratories, and controlled for time trends in a third laboratory using manually read conventional cytology continually. Data were collected from the Danish National Health Care Registers. For each laboratory, we compared proportions of abnormal cytology defined as atypical squamous cells of undetermined significance or worse (ASCUS+) by age and technology phase. The study included 489,960 cytological samples with no recent abnormality from women aged 23–59 years, routinely screened between 1998 and 2007. Implementation of SurePath liquid‐based cytology (LBC) was followed by an increase in abnormal cytology in women aged 23–29 years from 4.6 to 6.1%, relative proportion (RP): 1.31 [95% confidence interval (CI): 1.08–1.61], and a decrease in women aged 45–59 years from 2.9 to 2.0%, RP: 0.71 (95% CI: 0.60–0.83). Implementation of ThinPrep LBC was followed by a decrease in abnormal cytology both in women aged 23–29 years from 7.7 to 6.8%, RP: 0.89 (95% CI: 0.78–1.02) and in women aged 45–59 years from 3.4 to 1.0%, RP: 0.30 (95% CI: 0.24–0.37). With implementation of imaging‐assisted reading, regardless of the brand of technology, the proportion of abnormality increased by around 30% in all age groups (range from 19 to 41%). In the laboratory with unchanged technology no trends in abnormality proportions were observed. The impact of LBC implementation on cytological abnormality proportions varied considerably across age groups.
Cancer‐associated autoantibodies to MUC1 and MUC4—A blinded case–control study of colorectal cancer in UK collaborative trial of ovarian cancer screening
Authors: Pedersen Johannes W. , Gentry‐Maharaj Aleksandra , Nøstdal Alexander , Fourkala Evangelia‐Ourania , Dawnay Anne , Burnell Matthew , Zaikin Alexey , Burchell Joy , Papadimitriou Joyce Taylor , Clausen Henrik , Jacobs Ian , Menon Usha , Wandall Hans H.
Published: October 2013

Recent reports suggest that autoantibodies directed to aberrantly glycosylated mucins, in particular MUC1 and MUC4, are found in patients with colorectal cancer. There is, however, limited information on the autoantibody levels before clinical diagnosis, and their utility in cancer screening in the general population. In our study, we have generated O‐glycosylated synthetic MUC1 and MUC4 peptides in vitro, to mimic cancer‐associated glycoforms, and displayed these on microarrays. The assay's performance was tested through an initial screening of serum samples taken from patients at the time of colorectal cancer diagnosis and healthy controls. Subsequently, the selected biomarkers were evaluated in a blinded nested case–control study using stored serum samples from among the 50,640 women randomized to the multimodal arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), where women gave annual blood samples for several years. Cases were 97 postmenopausal women who developed colorectal cancer after recruitment and were age‐matched to 97 women without any history of cancer. MUC1‐STn and MUC1‐Core3 IgG autoantibodies identified cases with 8.2 and 13.4% sensitivity, respectively, at 95% specificity. IgA to MUC4 glycoforms were unable to discriminate between cases and controls in the UKCTOCS sera. Additional analysis was undertaken by combining the data of MUC1‐STn and MUC1‐Core3 with previously generated data on autoantibodies to p53 peptides, which increased the sensitivity to 32.0% at 95% specificity. These findings suggest that a combination of antibody signatures may have a role as part of a biomarker panel for the early detection of colorectal cancer.
POSTPARTUM BLUES: A MARKER OF EARLY NEONATAL ORGANIZATION?
Authors: Bydlowski Sarah , Lalanne Christophe , Golse Bernard , Vaivre‐Douret Laurence
Published: October 2013

Postpartum blues may promote a certain openness to emotional exchange between mother and her infant. Groups of mothers were assembled according to various types of emotional expression demonstrated during early postpartum. Links between mothers’ groups and newborns’ neuropsychomotor characteristics were assessed. Twenty‐one mother–infant dyads were included at maternity wards. A semistructured interview was established to identify symptoms of the blues and classify mothers into clinical groups: ordinary and emotionally mixed postpartum blues (OB); sad, intense, and lasting blues; or without blues. Newborns were examined using the Neonatal Behavioral Assessment Scale (T.B. Brazelton & J.K. Nugent, ). Cluster analysis revealed a two‐class structure, where 78% of women with OB were found to belong to the same class, with a higher median score on newborn “hand‐to‐mouth activity” which correlated to self‐quieting activity, heightened regulation of awake states, decreased need for adult support, better defensive movements, greater attentiveness, and diminished irritability. The acquired faculties demonstrated by newborns whose mothers experience OB reflect a distinct skillset of neuropsychomotor maturity.
CONSTRUCTING OPTIMAL DENSITY FORECASTS FROM POINT FORECAST COMBINATIONS
Authors: Gaglianone Wagner Piazza , Lima Luiz Renato
Published: October 2013

Decision makers often observe point forecasts of the same variable computed, for instance, by commercial banks, IMF and the World Bank, but the econometric models used by such institutions are frequently unknown. This paper shows how to use the information available on point forecasts to compute optimal density forecasts. Our idea builds upon the combination of point forecasts under general loss functions and unknown forecast error distributions. We use real‐time data to forecast the density of US inflation. The results indicate that the proposed method materially improves the real‐time accuracy of density forecasts vis‐à‐vis those from the (unknown) individual econometric models. Copyright © 2013 John Wiley & Sons, Ltd.
Identification of metabolomic biomarkers for drug‐induced acute kidney injury in rats
Authors: Uehara Takeki , Horinouchi Akira , Morikawa Yuji , Tonomura Yutaka , Minami Keiichi , Ono Atsushi , Yamate Jyoji , Yamada Hiroshi , Ohno Yasuo , Urushidani Tetsuro
Published: October 2013

Nephrotoxicity is a common side effect observed during both nonclinical and clinical drug development investigations. The present study aimed to identify metabolomic biomarkers that could provide early and sensitive indication of nephrotoxicity in rats. Metabolomic analyses were performed using capillary electrophoresis–time‐of‐flight mass spectrometry on rat plasma collected at 9 and 24 h after a single dose of 2‐bromoethylamine or n‐phenylanthranilic acid and at 24 h after 7 days of repeated doses of gentamicin, cyclosporine A or cisplatin. Among a total of 169 metabolites identified, 3‐methylhistidine (3‐MH), 3‐indoxyl sulfate (3‐IS) and guanidoacetate (GAA) were selected as candidate biomarkers. The biological significance and reproducibility of the observed changes were monitored over time in acute nephrotoxicity model rats treated with a single dose of cisplatin, with the glomerular filtration rate monitored by determination of creatinine clearance. Increased plasma levels of 3‐MH and 3‐IS were related to a decline in glomerular filtration due to a renal failure. In contrast, the decrease in plasma GAA, which is synthesized from arginine and glycine in the kidneys, was considered to reflect decreased production due to renal malfunction. Although definitive validation studies are required to confirm their usefulness and reliability, 3‐MH, 3‐IS and GAA may prove to be valuable plasma biomarkers for monitoring nephrotoxicity in rats. Copyright © 2013 John Wiley & Sons, Ltd.
Integrated testing and assessment approaches for skin sensitization: a commentary
Authors: Roberts David W. , Patlewicz Grace Y.
Published: October 2013

A Bayesian integrated testing strategy (ITS) approach, aiming to assess skin sensitization potency, has been presented, in which data from various types of in vitro assays are integrated and assessed in combination for their ability to predict in vivo skin sensitization data. Here we discuss this approach and compare it to our quantitative mechanistic modeling (QMM) approach based on physical organic chemistry. The main findings of the Bayesian study are consistent with our chemistry‐based approach and our previously published assessment of the key determinants of sensitization potency, in particular the relatively high predictive value found for chemical reactivity data and the relatively low predictive value for bioavailability parameters. As it stands at present the Bayesian approach does not utilize the full range of predictive capability that is already available, and aims only to assign potency categories rather than numerical potency values per se. In contrast, for many chemicals the QMM approach can already provide numerical potency predictions. However, the Bayesian approach may have potential for those chemicals where a chemistry modeling approach cannot provide a complete answer (e.g. pro‐electrophiles whose in cutaneo activation cannot currently be modeled confidently). Nonetheless, our main message is of the importance of leveraging chemistry insights and read‐across approaches to the fullest extent possible. Copyright © 2013 John Wiley & Sons, Ltd.
Rate control of cell sheet recovery by incorporating hydrophilic pattern in thermoresponsive cell culture dish
Authors: Kumashiro Yoshikazu , Matsunaga Teruyuki , Muraoka Megumi , Tanaka Nobuyuki , Itoga Kazuyoshi , Kobayashi Jun , Tomiyama Yumiko , Kuroda Masatoshi , Shimizu Tatsuya , Hashimoto Iwao , Umemura Kazuo , Yamato Masayuki , Okano Teruo
Published: October 2013

Thready stripe‐polyacrylamide (PAAm) pattern was fabricated on a thermoresponsive poly(N‐isopropylacrylamide) (PIPAAm) surface, and their surface properties were characterized. A PIPAAm surface spin‐coated with positive photoresist was irradiated through a 5 µm/5 µm or a 10 µm/10‐µm black and white striped photomask, resulting in the radical polymerization of AAm on the photoirradiated area. After staining with Alexa488 bovine serum albumin, the stripe‐patterned surface was clearly observed and the patterned surface was also observed by a phase contrast image of an atomic force microscope. NIH‐3T3 (3T3) single cells were able to be cultured at 37°C on the patterned surfaces as well as on a PIPAAm surface without pattern, and the detachment of adhered cells was more rapidly from the patterned surface after reducing temperature. Furthermore, the rate of detachment of 3T3 confluent cell sheet on the patterned surface was accelerated, compared with on a conventional PIPAAm surface under the static condition. The rate control of cell sheet recovery should contribute the preservations of cell phenotype and biological functions of cell sheet for applying to clinical trials. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2849–2856, 2014.
A novel peptide‐modified and gene‐activated biomimetic bone matrix accelerating bone regeneration
Authors: Pan Haitao , Zheng Qixin , Yang Shuhua , Guo Xiaodong , Wu Bin , Zou Zhenwei , Duan Zhixia
Published: October 2013

The osteogenic differentiation of bone marrow stromal cells (BMSCs) can be regulated by systemic or local growth factor, especially by transforming growth factor beta 1 (TGF‐β1). However, how to maintain the bioactivity of exogenous TGF‐β1 is a great challenge due to its short half‐life time. The most promising solution is to transfer TGF‐β1 gene into seed cells through transgenic technology and then transgenic cells to continuously secret endogenous TGF‐β1 protein via gene expression. In this study, a novel non‐viral vector (K)16GRGDSPC was chemically linked to bioactive bone matrices PLGA‐[ASP‐PEG]n using cross‐linker to construct a novel non‐viral gene transfer system. TGF‐β1 gene was incubated with this system and subsequently rabbit‐derived BMSCs were co‐cultured with this gene‐activated PLGA‐[ASP‐PEG]n, while co‐cultured with PLGA‐[ASP‐PEG]n modified with (K)16GRGDSPC only and original PLGA‐[ASP‐PEG]n as control. Thus we fabricated three kinds of composites: Group A (BMSCs‐TGF‐β1DNA‐(K)16GRGDSPC‐PLGA‐[ASP‐PEG]n composite); Group B (BMSCs‐(K)16GRGDSPC‐PLGA‐[ASP‐PEG]n composite); and Group C (BMSCs‐PLGA‐[ASP‐PEG]n composite). TGF‐β1 and other osteogenic phenotype markers of alkaline phosphatase, osteocalcin, osteopontin and type I collagen in Group A were all significantly higher than the other two groups ex vivo. In vivo, 15‐mm long segmental rabbit bone defects were created and randomly implanted the aforementioned composites separately, and then fixed with plate‐screws. The results demonstrated that the implants in Group A significantly accelerated bone regeneration compared with the other implants based on X‐rays, histological and biomechanical examinations. Therefore, we conclude this novel peptide‐modified and gene‐activated biomimetic bone matrix of TGF‐β1DNA‐(K)16GRGDSPC‐PLGA‐[ASP‐PEG]n is a very promising scaffold biomaterial for accelerating bone regeneration. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2864–2874, 2014.
Structural and physicochemical aspects of silica encapsulated ZnO quantum dots with high quantum yield and their natural uptake in HeLa cells
Authors: Depan D. , Misra R. D. K.
Published: October 2013

Photoluminescent semiconductor quantum dots (QDs) are of significant interest for bioimaging and fluorescence labeling. In this regard, we describe here the design of high sensitivity and high specificity non‐toxic ZnO QDs (∼5 nm) with long‐term stability of up to 12 months. The embedding of ZnO QDs on silica nanospheres led to significant increase in photoluminescence intensity rendering them highly bright QD‐based probes. The QDs were characterized in vitro with respect to cancer cells (HeLa) and evaluated in terms of viability, fluorescence and cytoskeletal organization. The immobilization of ZnO QDs on silica nanospheres promoted the internalization and enhanced fluorescence emission of HeLa cells. The fluorescence emission from QDs was stable for 3 days, indicating excellent stability toward photobleaching. Cytoskeletal reorganization was observed after internalization of QDs such that the ZnO QDS on silica nanospheres resulted in broadening of the actin cytoskeleton. The study underscores that ZnO QDs immobilized on Si nanospheres are promising for tracking cancer cells in cell therapy. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2934–2941, 2014.
Reticulated bioactive scaffolds with improved textural properties for bone tissue engineering: Nanostructured surfaces and porosity
Authors: Ramiro‐Gutiérrez M. Lourdes , Will Julia , Boccaccini Aldo R. , Díaz‐Cuenca Aránzazu
Published: October 2013

Organised nanoporous SBA‐15 type silica precursor (SP) particulate material has been processed into three‐dimensional macroporous, reticulated structures using a novel strategy consisting of blending increasing percentages of SP with a SiO2‐CaO‐P2O5 (80Si15Ca5P) mesoporous bioactive glass (MBG) sol. The procedure successfully produced consolidated and functionally competent open‐cell scaffolds while preserving the nanoporous order of the SP. Scaffolds were prepared using four different (MBG)/(SP) ratios. These structures were then characterized using field emission gun scanning electron microscopy, X‐ray diffraction (XRD), nitrogen adsorption‐desorption measurements, and compressive strength testing. Open‐cell interconnected structures with dual macro (150–500 μm) and nano (4–6 nm)‐organised porosity were produced. Both the textural and mechanical properties were found to improve with increasing SBA‐15 content. The in vitro bioactive response using simulated body fluid confirmed high reactivity for all prepared scaffolds. In addition, the SBA‐15 containing scaffolds exhibited a superior ability to delay the pH‐triggered lysozyme release with antibiotic activity. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2982–2992, 2014.
Surface‐modified functionalized polycaprolactone scaffolds for bone repair: In vitro and in vivo experiments
Authors: Jensen Jonas , Rölfing Jan Hendrik Duedal , Svend Le Dang Quang , Kristiansen Asger Albæk , Nygaard Jens Vinge , Hokland Lea Bjerre , Bendtsen Michael , Kassem Moustapha , Lysdahl Helle , Bünger Cody Eric
Published: October 2013

A porcine calvaria defect study was carried out to investigate the bone repair potential of three‐dimensional (3D)‐printed poly‐ε‐caprolactone (PCL) scaffolds embedded with nanoporous PCL. A microscopic grid network was created by rapid prototyping making a 3D‐fused deposition model (FDM‐PCL). Afterward, the FDM‐PCL scaffolds were infused with a mixture of PCL, water, and 1,4‐dioxane and underwent a thermal‐induced phase separation (TIPS) followed by lyophilization. The TIPS process lead to a nanoporous structure shielded by the printed microstructure (NSP‐PCL). Sixteen Landrace pigs were divided into two groups with 8 and 12 weeks follow‐up, respectively. A total of six nonpenetrating holes were drilled in the calvaria of each animal. The size of the cylindrical defects was h 10 mm and Ø 10 mm. The defects were distributed randomly using following groups: (a) NSP‐PCL scaffold, (b) FDM‐PCL scaffold, (c) autograft, (d) empty defect, (a1) NSP‐PCL scaffold + autologous mononuclear cells, and (a2) NSP‐PCL scaffold + bone morphogenetic protein 2. Bone volume to total volume was analyzed using microcomputed tomography (µCT) and histomorphometry. The µCT and histological data showed significantly less bone formation in the NSP‐PCL scaffolds in all three variations after both 8 and 12 weeks compared to all other groups. The positive autograft control had significantly higher new bone formation compared to all other groups except the FDM‐PCL when analyzed using histomorphometry. The NSP‐PCL scaffolds were heavily infiltrated with foreign body giant cells suggesting an inflammatory response and perhaps active resorption of the scaffold material. The unmodified FDM‐PCL scaffold showed good osteoconductivity and osseointegration after both 8 and 12 weeks. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2993–3003, 2014.
Toll‐like receptors‐2 and 4 are overexpressed in an experimental model of particle‐induced osteolysis
Authors: Valladares Roberto D. , Nich Christophe , Zwingenberger Stefan , Li Chenguang , Swank Katherine R. , Gibon Emmanuel , Rao Allison J. , Yao Zhenyu , Goodman Stuart B.
Published: October 2013

Aseptic loosening secondary to particle‐associated periprosthetic osteolysis remains a major cause of failure of total joint replacements (TJR) in the mid‐ and long term. As sentinels of the innate immune system, macrophages are central to the recognition and initiation of the inflammatory cascade, which results in the activation of bone resorbing osteoclasts. Toll‐like receptors (TLRs) are involved in the recognition of pathogen‐associated molecular patterns and danger‐associated molecular patterns. Experimentally, polymethylmethacrylate and polyethylene (PE) particles have been shown to activate macrophages via the TLR pathway. The specific TLRs involved in PE particle‐induced osteolysis remain largely unknown. We hypothesized that TLR‐2, ‐4, and ‐9 mediated responses play a critical role in the development of PE wear particle‐induced osteolysis in the murine calvarium model. To test this hypothesis, we first demonstrated that PE particles caused observable osteolysis, visible by microCT and bone histomorphometry when the particles were applied to the calvarium of C57BL/6 mice. The number of TRAP positive osteoclasts was significantly greater in the PE‐treated group when compared to the control group without particles. Finally, using immunohistochemistry, TLR‐2 and TLR‐4 were highly expressed in PE particle‐induced osteolytic lesions, whereas TLR‐9 was downregulated. TLR‐2 and ‐4 may represent novel therapeutic targets for prevention of wear particle‐induced osteolysis and accompanying TJR failure. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 3004–3011, 2014.
High‐strength poly(para‐phenylene) as an orthopedic biomaterial
Authors: Frick Carl P. , DiRienzo Amy L. , Hoyt Anthony J. , Safranski David L. , Saed Mohand , Losty Eric J. , Yakacki Christopher M.
Published: October 2013

Poly(para‐phenylene) (PPP) exhibits exceptional mechanical strength, stiffness, toughness, and chemical inertness, although it is not currently used in any biomedical applications. The purpose of this study is to serve as a preliminary investigation into the potential of PPP as a biomaterial in orthopedic load‐bearing applications. Nuclear magnetic resonance (NMR) analysis confirmed a polymer structure composed of an aromatic backbone and side groups. Tensile PPP specimens along with samples from several other polymers often used for orthopedic applications were elongated to failure after being soaked in phosphate buffered saline (PBS) for 1 h, 1 day, 1 week, 2 weeks, 1 month, and more than 1 year. Results showed that PBS absorption of the PPP plateaued at 1 week at values of ∼0.7 wt % and remained within one standard deviation when soaked for over 1 year. PBS absorption did not affect elastic modulus (5.0 GPa), yield strength (141 MPa), fracture strength (120 MPa) and strain‐to‐failure (17%) more than one standard deviation. Zero‐to‐tension fatigue testing established an endurance limit of approximately 35 MPa, which was relatively insensitive to frequency (1–10 Hz). Eagle's minimum essential medium (MEM) elution assay with fibroblasts confirmed that the PPP was noncytotoxic. Relative to other polymers used for load‐bearing biomedical applications, PPP displays promising mechanical properties that remain stable in aqueous solution. Lastly, prototype PPP and polyetheretherketone (PEEK) bone plates were manufactured and tested, with the PPP plate showing a 38% higher maximum tensile load before failure. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 3122–3129, 2014.
Undifferentiated human adipose‐derived stromal/stem cells loaded onto wet‐spun starch–polycaprolactone scaffolds enhance bone regeneration: Nude mice calvarial defect in vivo study
Authors: Carvalho Pedro P. , Leonor Isabel B. , Smith Brenda J. , Dias Isabel R. , Reis Rui L. , Gimble Jeffrey M. , Gomes Manuela E.
Published: October 2013

The repair of large bony defects remains challenging in the clinical setting. Human adipose‐derived stromal/stem cells (hASCs) have been reported to differentiate along different cell lineages, including the osteogenic. The objective of the present study was to assess the bone regeneration potential of undifferentiated hASCs loaded in starch‐polycaprolactone (SPCL) scaffolds, in a critical‐sized nude mice calvarial defect. Human ASCs were isolated from lipoaspirate of five female donors, cryopreserved, and pooled together. Critical‐sized (4 mm) calvarial defects were created in the parietal bone of adult male nude mice. Defects were either left empty, treated with an SPCL scaffold alone, or SPCL scaffold with human ASCs. Histological analysis and Micro‐CT imaging of the retrieved implants were performed. Improved new bone deposition and osseointegration was observed in SPCL loaded with hASC engrafted calvarial defects as compared to control groups that showed little healing. Nondifferentiated human ASCs enhance ossification of nonhealing nude mice calvarial defects, and wet‐spun SPCL confirmed its suitability for bone tissue engineering. This study supports the potential translation for ASC use in the treatment of human skeletal defects. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 3102–3111, 2014.
Designing colon‐specific delivery systems for anticancer drug‐loaded nanoparticles: An evaluation of alginate carriers
Authors: Ma Yiming , Coombes Allan G. A.
Published: October 2013

Incorporation of drug‐loaded nanoparticles (NPs) in colon‐specific delivery systems shows potential for raising local drug concentrations, tumor targeting and improving chemotherapy. Alginate microcapsules (15–80 µm diameter) containing insoluble Eudragit® RS NPs as models were characterized precisely in terms of NP loading and release kinetics. High NP loading (22%, w/w of the dried microcapsules) combined with negligible release in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) suggested that high concentrations of NPs could be transported to the colon. However, NP aggregation was confirmed at extremely low concentration (0.0003%, w/v) in alginate solution (0.007%, w/v) and after release from alginate microcapsules. Indomethacin, a model anticolorectal cancer drug, was encapsulated in pH‐responsive Eudragit® S100 NPs (116 nm, 5%, w/w drug loading) using the nanoprecipitation method. Approximately 90% of the drug load was released from the NPs in SGF and SIF before transfer to simulated colon fluid (SCF). However, incorporation of NPs in 2 mm alginate pellets resulted in a significantly higher fraction of the drug load (around 60%) being available for release in SCF. Delivery of isolated NPs to the colon for interaction with and uptake by cancer cells requires elimination of NP‐excipient interactions that promote NP aggregation. NP‐loaded alginate carriers, meanwhile, offer a promising strategy for delivery of anticancer drugs to tumor sites in the colon and reducing systemic side effects. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 3167–3176, 2014.
Bonding between oxide ceramics and adhesive cement systems: A systematic review
Authors: Papia Evaggelia , Larsson Christel , du Toit Madeleine , von Steyern Per Vult
Published: October 2013

The following aims were set for this systematic literature review: (a) to make an inventory of existing methods to achieve bondable surfaces on oxide ceramics and (b) to evaluate which methods might provide sufficient bond strength. Current literature of in vitro studies regarding bond strength achieved using different surface treatments on oxide ceramics in combination with adhesive cement systems was selected from PubMed and systematically analyzed and completed with reference tracking. The total number of publications included for aim a was 127 studies, 23 of which were used for aim b. The surface treatments are divided into seven main groups: as‐produced, grinding/polishing, airborne particle abrasion, surface coating, laser treatment, acid treatment, and primer treatment. There are large variations, making comparison of the studies difficult. An as‐produced surface of oxide ceramic needs to be surface treated to achieve durable bond strength. Abrasive surface treatment and/or silica‐coating treatment with the use of primer treatment can provide sufficient bond strength for bonding oxide ceramics. This conclusion, however, needs to be confirmed by clinical studies. There is no universal surface treatment. Consideration should be given to the specific materials to be cemented and to the adhesive cement system to be used. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 102B: 395–413, 2014.
The development of an in vitro test method for predicting the abrasion resistance of textile and metal components of endovascular stent grafts
Authors: Yao Tong , Choules Brian D. , Rust Jon P. , King Martin W.
Published: October 2013

Implantable endovascular stent grafts have become a frequent option for the treatment of abdominal and thoracic aneurysms. Given that such devices are permanent implants, the question of long‐term biostability needs to be addressed. This article describes the development of an in vitro stent graft abrasion test method between the graft fabric and metal stent of an endovascular device. Three endpoints were established to determine the abrasion resistance between the fabric and stent surfaces after a predetermined number of abrasion cycles. During initial testing, two types of graft fabric materials, multifilament woven polyester fabric and monofilament woven polyester fabric, and two types of stent materials, laser cut nitinol stents and regular nitinol stent wire, were evaluated under dry and wet conditions. The results have shown that this test method is viable for testing the relative abrasion resistance of the components of endovascular stent grafts. The abrasion resistance of both fabrics was lower in a wet environment compared to being tested dry. Additionally, the multifilament polyester fabric had better abrasion resistance than the monofilament polyester fabric. The laser cut nitinol stent was more aggressive in creating holes and breaking yarns, while the regular nitinol stent wire caused a greater loss in fabric strength. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 102B: 488–499, 2014.
Tailoring of antibacterial Ag nanostructures on TiO2 nanotube layers by magnetron sputtering
Authors: Uhm Soo‐Hyuk , Song Doo‐Hoon , Kwon Jae‐Sung , Lee Sang‐Bae , Han Jeon‐Geon , Kim Kyoung‐Nam
Published: October 2013

To reduce the incidence of postsurgical bacterial infection that may cause implantation failure at the implant–bone interface, surface treatment of titanium implants with antibiotic materials such as silver (Ag) has been proposed. The purpose of this work was to create TiO2 nanotubes using plasma electrolytic oxidation (PEO), followed by formation of an antibacterial Ag nanostructure coating on the TiO2 nanotube layer using a magnetron sputtering system. PEO was performed on commercially pure Ti sheets. The Ag nanostructure was added onto the resulting TiO2 nanotube using magnetron sputtering at varying deposition rates. Field emission scanning electron microscopy and transmission electron microscopy were used to characterize the surface, and Ag content on the TiO2 nanotube layer was analyzed by X‐ray diffraction and X‐ray photoelectron spectroscopy. Scanning probe microscopy for surface roughness and contact angle measurement were used to indirectly confirm enhanced TiO2 nanotube hydrophilicity. Antibacterial activity of Ag ions in solution was determined by inductively coupled plasma mass spectrometry and antibacterial testing against Staphylococcus aureus (S. aureus). In vitro, TiO2 nanotubes coated with sputtered Ag resulted in significantly reduced S. aureus. Cell viability assays showed no toxicity for the lowest sputtering time group in the osteoblastic cell line MC3T3‐E1. These results suggest that a multinanostructured layer with a biocompatible TiO2 nanotube and antimicrobial Ag coating is a promising biomaterial that can be tailored with magnetron sputtering for optimal performance. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 102B: 592–603, 2014.
Vitamin D3 Dose Requirement to Raise 25-Hydroxyvitamin D to Desirable Levels in Adolescents: Results from a Randomized Controlled Trial
Authors: Al-Shaar Laila , Mneimneh Rania , Mona Nabulsi  , Maalouf Joyce , Fuleihan Ghada El-Hajj
Published: October 2013

Several organizations issued recommendations on desirable serum 25-hydroxy vitamin D [25(OH)D] levels and doses of vitamin D needed to achieve them. Trials allowing the formulation of evidence-based recommendations in adolescents are scarce. We investigated the ability of two doses of vitamin D3 in achieving recommended vitamin D levels in this age group. Post hoc analyses on data from a 1-year double-blind trial that randomized 336 Lebanese adolescents, aged 13 ± 2 years, to placebo, vitamin D3 at 200 IU/day (low dose), or 2000 IU/day (high dose). Serum 25(OH)D level and proportions of children achieving levels ≥20 ng/mL and 30 ng/mL were determined. At baseline, mean 25(OH)D was 15 ± 7 ng/mL, 16.4 ± 7 ng/mL in boys, and 14 ± 8 ng/mL in girls, p = 0.003, with a level ≥20 ng/mL in 18% and ≥30 ng/mL in 5% of subjects. At 1 year, mean levels were 18.6 ± 6.6 ng/mL in the low-dose group, 17.1 ± 6 ng/mL in girls, and 20.2 ± 7 ng/mL in boys, p = 0.01, and 36.3 ± 22.3 ng/mL in the high-dose group, with no sex differences. 25(OH)D increased to ≥20 ng/mL in 34% of children in the low-dose and 96% in the high-dose group, being higher in boys in the low-dose arm only; it remained ≥30 ng/mL in 4% of children in the low-dose arm but increased to 64% in the high-dose arm. Baseline 25(OH)D level, body mass index (BMI), and vitamin D dose assigned were the most significant predictors for reaching a 25(OH)D level ≥20 ng/mL and 30 ng/mL. A daily dose of 2000 IU raised 25(OH)D level ≥20 ng/mL in 96% of adolescents (98% boys versus 93% girls). Dose-response studies are needed to determine in a definitive manner the daily allowance of vitamin D for Middle Eastern adolescents with a similar profile. © 2014 American Society for Bone and Mineral Research.
Nanotopographical Effects on Mesenchymal Stem Cell Morphology and Phenotype
Authors: Tsimbouri Penelope , Gadegaard Nikolaj , Burgess Karl , White Kate , Reynolds Paul , Herzyk Pawel , Oreffo Richard , Dalby Matthew J.
Published: October 2013

There is a rapidly growing body of literature on the effects of topography and critically, nanotopography on cell adhesion, apoptosis and differentiation. Understanding the effects of nanotopography on cell adhesion and morphology and the consequences of cell shape changes in the nucleus, and consequently, gene expression offers new approaches to the elucidation and potential control of stem cell differentiation. In the current study we have used molecular approaches in combination with immunohistology and transcript analysis to understand the role of nanotopography on mesenchymal stem cell morphology and phenotype. Results demonstrate large changes in cell adhesion, nucleus and lamin morphologies in response to the different nanotopographies. Furthermore, these changes relate to alterations in packing of chromosome territories within the interphase nucleus. This, in turn, leads to changes in transcription factor activity and functional (phenotypical) signalling including cell metabolism. Nanotopography provides a useful, non‐invasive tool for studying cellular mechanotransduction, gene and protein expression patterns, through effects on cell morphology. The different nanotopographies examined, result in different morphological changes in the cyto‐ and nucleo‐skeleton. We propose that both indirect (biochemical) and direct (mechanical) signalling are important in these early stages of regulating stem cell fate as a consequence of altered metabolic changes and altered phenotype. The current studies provide new insight on cell–surface interactions and enhance our understanding of the modulation of stem cell differentiation with significant potential application in regenerative medicine. J. Cell. Biochem. 115: 380–390, 2014. © 2013 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals, Inc.
Specific In Situ Detection of Murine Indoleamine 2, 3‐Dioxygenase
Authors: Thomas Sunil , DuHadaway James , Prendergast George C. , Laury‐Kleintop Lisa
Published: October 2013

Indoleamine 2,3‐dioxygenase‐1 (IDO1) catabolizes the essential amino acid tryptophan, acting as a modifier of inflammation and immune tolerance. Recent work has implicated IDO1 in many human diseases, including in cancer, chronic infection, autoimmune disorders, and neurodegenerative disease, stimulating a major surge in preclinical and clinical studies of its pathogenic functions. In the mouse, IDO1 is expressed widely but in situ detection of the enzyme in murine tissues has been unreliable due to the lack of specific antibodies that do not also react with tissues from animals that are genetically deficient in IDO1. Such probes are crucial to establish cellular mechanisms since IDO1 appears to act in different cell types depending on disease context, but reliable probes have been elusive in the field. In this report, we address this issue with the development of IDO1 monoclonal antibody 4B7 which specifically recognizes the murine enzyme in tissue sections, offering a reliable tool for immunohistology in preclinical disease models. J. Cell. Biochem. 115: 391–396, 2014. © 2013 Wiley Periodicals, Inc.