bluuebunny/crossref_metadata_2025_split huggingface dataset:
No evidence for αGal epitope transfer from media containing FCS onto human endothelial cells in culture
Authors: Ramm Robert , Hartmann Thorsten , Tudorache Igor , Haverich Axel , Hilfiker Andres 
Published: August 2015

AbstractBackgroundCurrent clinical applications of cell therapies and tissue engineered (TE) constructs aim to generate non‐immunogenic cells in the best‐case scenario of autologous origin. As the cells are cultured, it is theoretically possible that immunoreactive molecules present in xenogenic cell culture media components, such as fetal calf serum (FCS), are transmitted in the culturing process. This problem has propelled the search for xeno‐free culture media; however, in vitro culturing of many cell types, especially TE constructs which consist of several cell types, still relies to a great extent on FCS. In this study, we investigated the degree to which xenoantigens are transmitted to human endothelial cells (EC) cultured in medium containing FCS.MethodsHuman EC were isolated from pulmonary artery fragments and atrial appendage tissue samples by enzymatic digestion followed by magnetic‐activated cell separation (MACS) utilizing CD31 antibodies. The cells were cultured in EGM‐2 medium containing 10% FCS for several passages. Griffonia Simplicifolia Lectin I – Isolectin B4 (GSL I‐B4) was used to detect cell surface‐bound αGal epitopes either microscopically or flow cytometrically. Antibody binding to cells exposed to human sera prepared from healthy blood donors was investigated to detect surface‐located xenoantigens. An antibody‐dependent cytotoxicity assay was conducted with heat‐inactivated human serum supplemented with rabbit complement and analyzed by flow cytometry after staining for living and dead cells (LIVE/DEAD assay kit). In all experiments, cells cultured in EGM‐2 supplemented with 10% human serum (HS) served as controls.ResultsHuman EC were isolated and cultured successfully for ≥6 passages. GSL I‐B4 staining showed no difference between human EC cultured in FCS and in HS. In contrast to porcine EC which showed strong staining with GSL I‐B4 and binding of preformed human serum antibodies, human EC cultured in FCS media did not bind human antibodies from high titer anti‐αGal and anti‐Neu5GC antibody serum. Along these lines, the antibody‐dependent cytotoxicity assay showed that human EC cultures independent of FCS or HS usage were not affected, whereas about 40% of porcine EC did not survive.ConclusionDespite culturing cells in an environment containing xenoantigens, we were unable to demonstrate the translocation of xenogenic epitopes onto the surface of human EC or find an increased sensitivity in preformed human xenoantibody‐dependent complement activity. Therefore, our results suggest that the use of human cells for TE or cell therapy grown in cell culture systems complemented with FCS does not necessarily lead to an acute rejection reaction upon implantation.
Mitochondrial function in ageing: coordination with signalling and transcriptional pathways
Authors: Yin Fei , Sancheti Harsh , Liu Zhigang , Cadenas Enrique 
Published: August 2015

AbstractMitochondrial dysfunction entailing decreased energy‐transducing capacity and perturbed redox homeostasis is an early and sometimes initiating event in ageing and age‐related disorders involving tissues with high metabolic rate such as brain, liver and heart. In the central nervous system (CNS), recent findings from our and other groups suggest that the mitochondrion‐centred hypometabolism is a key feature of ageing brains and Alzheimer's disease. This hypometabolic state is manifested by lowered neuronal glucose uptake, metabolic shift in the astrocytes, and alternations in mitochondrial tricarboxylic acid cycle function. Similarly, in liver and adipose tissue, mitochondrial capacity around glucose and fatty acid metabolism and thermogenesis is found to decline with age and is implicated in age‐related metabolic disorders such as obesity and type 2 diabetes mellitus. These mitochondrion‐related disorders in peripheral tissues can impact on brain functions through metabolic, hormonal and inflammatory signals. At the cellular level, studies in CNS and non‐CNS tissues support the notion that instead of being viewed as autonomous organelles, mitochondria are part of a dynamic network with close interactions with other cellular components through energy‐ or redox‐sensitive cytosolic kinase signalling and transcriptional pathways. Hence, it would be critical to further understand the molecular mechanisms involved in the communication between mitochondria and the rest of the cell. Therapeutic strategies that effectively preserves or improve mitochondrial function by targeting key component of these signalling cascades could represent a novel direction for numerous mitochondrion‐implicated, age‐related disorders.
Analyzing the Tradeoffs Between Economies of Scale, Time-Value of Money, and Flexibility in Design Under Uncertainty: Study of Centralized Versus Decentralized Waste-to-Energy Systems
Authors: Cardin Michel-Alexandre , Hu Junfei 
Published: August 2015

This paper presents and applies a simulation-based methodology to assess the value of flexible decentralized engineering systems design (i.e., the ability to flexibly expand the capacity in multiple sites over time and space) under uncertainty. This work differs from others by analyzing explicitly the tradeoffs between economies of scale (EoS)—which favors designing large capacity upfront to reduce unit cost and accommodate high anticipated demand—and the time value of money—which favors deferring capacity investments to the future and deploying smaller modules to reduce unit cost. The study aims to identify the best strategies to design and deploy the capacity of complex engineered systems over time and improve their economic lifecycle performance in the face of uncertainty by exploiting the idea of flexibility. This study is illustrated using a waste-to-energy (WTE) system operated in Singapore. The results show that a decentralized design with the real option to expand the capacity in different locations and times improves the expected net present value (ENPV) by more than 30% under the condition of EoS α  = 0.8 and discount rate λ  = 8%, as compared to a fixed centralized design. The results also indicate that a flexible decentralized design outperforms other rigid designs under certain circumstances since it not only reduces transportation costs but also takes advantage of flexibility, such as deferring investment and avoiding unnecessary capacity deployment. The modeling framework and results help designers and managers better compare centralized and decentralized design alternatives facing significant uncertainty. The proposed method helps them analyze the value of flexibility (VOF) in small-scale urban environments, while considering explicitly the tradeoffs between EoS and the time-value of money.
Segmented slant hole collimator for stationary cardiac SPECT: Monte Carlo simulations
Authors: Mao Yanfei , Yu Zhicong , Zeng Gengsheng L. 
Published: August 2015

Purpose:This work is a preliminary study of a stationary cardiac SPECT system. The goal of this research is to propose a stationary cardiac SPECT system using segmented slant‐hole collimators and to perform computer simulations to test the feasibility. Compared to the rotational SPECT, a stationary system has a benefit of acquiring temporally consistent projections. The most challenging issue in building a stationary system is to provide sufficient projection view‐angles.Methods:A gate (geant4 application for tomographic emission) Monte Carlo model was developed to simulate a two‐detector stationary cardiac SPECT that uses segmented slant‐hole collimators. Each detector contains seven segmented slant‐hole sections that slant to a common volume at the rotation center. Consequently, 14 view‐angles over 180° were acquired without any gantry rotation. The NCAT phantom was used for data generation and a tailored maximum‐likelihood expectation‐maximization algorithm was used for image reconstruction. Effects of limited number of view‐angles and data truncation were carefully evaluated in the paper.Results:Simulation results indicated that the proposed segmented slant‐hole stationary cardiac SPECT system is able to acquire sufficient data for cardiac imaging without a loss of image quality, even when the uptakes in the liver and kidneys are high. Seven views are acquired simultaneously at each detector, leading to 5‐fold sensitivity gain over the conventional dual‐head system at the same total acquisition time, which in turn increases the signal‐to‐noise ratio by 19%. The segmented slant‐hole SPECT system also showed a good performance in lesion detection. In our prototype system, a short hole‐length was used to reduce the dead zone between neighboring collimator segments. The measured sensitivity gain is about 17‐fold over the conventional dual‐head system.Conclusions:The gate Monte Carlo simulations confirm the feasibility of the proposed stationary cardiac SPECT system with segmented slant‐hole collimators. The proposed collimator consists of combined parallel and slant holes, and the image on the detector is not reduced in size.
Easy View Care Maps as an alternative to the traditional specialist to GP clinic letter
Authors: Jaboli Maria Francesca , Rayne Timothy , Durcan Colette , Mason Isobel , Epstein Owen 
Published: August 2015

IntroductionIn most UK hospitals, clinical episodes are recorded with a letter sent to the referring general practitioners (GPs). This requires dictation, typing, proof-reading, correction, printing, sign-off and posting. We have used a mind map template to record the patient journey. We evaluated the GP responses to these Easy View Care Maps (EVCMs) and the cost comparison with the traditional GP letter.MethodsAn EVCM was prepared by a secretary using information available from the GP referral. The draft EVCM was available for the clinician to complete during the consultation with the patient. Three completed EVCMs were printed: one to be incorporated into the patient's notes; the second to be given to the patient; and a third copy posted to the GP. At follow-up, the EVCM was modified to reflect results. GP responses to EVCMs were sought by a postal questionnaire sent to 266 GPs. A comparative cost analysis was performed.ResultsOver 10 months, 568 EVCMs were used as the sole source of information recorded for the hospital file, patient and GP. The mean turnaround time for a dictated letter is 5.2 days while EVCM generation is immediate. Ninety per cent of GPs reported that they received the necessary information with 71% indicating acceptance as an alternative to the traditional letter. Net annual departmental saving was £31 344.ConclusionsEVCMs offer a new visual representation of the patient's journey. They are easy to follow and expose the clinician's thought processes. They provide an intuitive record at low cost.
Human trafficking and health: a cross-sectional survey of NHS professionals’ contact with victims of human trafficking
Authors: Ross Claire , Dimitrova Stoyanka , Howard Louise M , Dewey Michael , Zimmerman Cathy , Oram Siân 
Published: August 2015

Objectives(1) To estimate the proportion of National Health Service (NHS) professionals who have come into contact with trafficked people and (2) to measure NHS professionals’ knowledge and confidence to respond to human trafficking.DesignA cross-sectional survey.SettingFace-to-face mandatory child protection and/or vulnerable adults training sessions at 10 secondary healthcare provider organisations in England, and meetings of the UK College of Emergency Medicine.Participants782/892 (84.4%) NHS professionals participated, including from emergency medicine, maternity, mental health, paediatrics and other clinical disciplines.MeasuresSelf-completed questionnaire developed by an expert panel. Questionnaire asks about prior training and contact with potential victims of trafficking, perceived and actual human trafficking knowledge, confidence in responding to human trafficking, and interest in future human trafficking training.Results13% participants reported previous contact with a patient they knew or suspected of having been trafficked; among maternity services professionals this was 20.4%. However, 86.8% (n=679) reported lacking knowledge of what questions to ask to identify potential victims and 78.3% (n=613) reported that they had insufficient training to assist trafficked people. 71% (n=556), 67.5% (n=528) and 53.4% (n=418) lacked confidence in making appropriate referrals for men, women and children, respectively, who had been trafficked. 95.3% (n=746) of respondents were unaware of the scale of human trafficking in the UK, and 76.5% (n=598) were unaware that calling the police could put patients in more danger. Psychometric analysis showed that subscales measuring perceived knowledge, actual knowledge and confidence to respond to human trafficking demonstrated good internal consistency (Cronbach's αs 0.93, 0.63 and 0.64, respectively) and internal correlations.ConclusionsNHS professionals working in secondary care are in contact with potential victims of human trafficking, but lack knowledge and confidence in how to respond appropriately. Training is needed, particularly for maternity staff, on how to identify and respond to victims’ needs, including through making safe referrals.
Notch1 Activation or Loss Promotes HPV-Induced Oral Tumorigenesis
Authors: Zhong Rong , Bao Riyue , Faber Pieter W. , Bindokas Vytautas P. , Bechill John , Lingen Mark W. , Spiotto Michael T. 
Published: August 2015

Abstract
Viral oncogene expression is insufficient for neoplastic transformation of human cells, so human papillomavirus (HPV)–associated cancers will also rely upon mutations in cellular oncogenes and tumor suppressors. However, it has been difficult so far to distinguish incidental mutations without phenotypic impact from causal mutations that drive the development of HPV-associated cancers. In this study, we addressed this issue by conducting a functional screen for genes that facilitate the formation of HPV E6/E7–induced squamous cell cancers in mice using a transposon-mediated insertional mutagenesis protocol. Overall, we identified 39 candidate driver genes, including Notch1, which unexpectedly was scored by gain- or loss-of-function mutations that were capable of promoting squamous cell carcinogenesis. Autochthonous HPV-positive oral tumors possessing an activated Notch1 allele exhibited high rates of cell proliferation and tumor growth. Conversely, Notch1 loss could accelerate the growth of invasive tumors in a manner associated with increased expression of matrix metalloproteinases and other proinvasive genes. HPV oncogenes clearly cooperated with loss of Notch1, insofar as its haploinsufficiency accelerated tumor growth only in HPV-positive tumors. In clinical specimens of various human cancers, there was a consistent pattern of NOTCH1 expression that correlated with invasive character, in support of our observations in mice. Although Notch1 acts as a tumor suppressor in mouse skin, we found that oncogenes enabling any perturbation in Notch1 expression promoted tumor growth, albeit via distinct pathways. Our findings suggest caution in interpreting the meaning of putative driver gene mutations in cancer, and therefore therapeutic efforts to target them, given the significant contextual differences in which such mutations may arise, including in virus-associated tumors. Cancer Res; 75(18); 3958–69. ©2015 AACR.
Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition
Authors: Wiegmans Adrian P. , Yap Pei-Yi , Ward Ambber , Lim Yi Chieh , Khanna Kum Kum 
Published: August 2015

Abstract
The triple-negative breast cancer (TNBC) subtype represents a cancer that is highly aggressive with poor patient outcome. Current preclinical success has been gained through synthetic lethality, targeting genome instability with PARP inhibition in breast cancer cells that harbor silencing of the homologous recombination (HR) pathway. Histone deacetylase inhibitors (HDACi) are a class of drugs that mediate epigenetic changes in expression of HR pathway genes. Here, we compare the activity of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), the class I/IIa HDAC inhibitor valproic acid (VPA), and the HDAC1/2–specific inhibitor romidepsin (ROMI) for their capability to regulate DNA damage repair gene expression and in sensitizing TNBC to PARPi. We found that two of the HDACis tested, SAHA and ROMI, but not VPA, indeed inhibit HR repair and that RAD51, BARD1, and FANCD2 represent key proteins whose inhibition is required for HDACi-mediated therapy with PARP inhibition in TNBC. We also observed that restoration of BRCA1 function stabilizes the genome compared with mutant BRCA1 that results in enhanced polyploid population after combination treatment with HDACi and PARPi. Furthermore, we found that overexpression of the key HR protein RAD51 represents a mechanism for this resistance, promoting aberrant repair and the enhanced polyploidy observed. These findings highlight the key components of HR in guiding synthetic lethality with PARP inhibition and support the rationale for utilizing the novel combination of HDACi and PARPi against TNBC in the clinical setting. Mol Cancer Ther; 14(10); 2321–31. ©2015 AACR.
Abstract A09: CD138-negative myeloma cells regulate mechanical properties of bone marrow stromal cells through SDF-1/CXCR4/AKT signaling pathway.
Authors: Wu Dan , Guo Xinyi , Su Jing , Chen Ruoying , Berenzon Dmitriy , Bonin Keith , Guthold Martin , Zhao Weiling , Zhou Xiaobo 
Published: August 2015

Abstract
As the second most prevalent hematologic malignancy, multiple myeloma (MM) remains incurable and relapses due to intrinsic or acquired drug resistance. Therefore, new therapeutic strategies that target molecular mechanisms responsible for drug resistance are attractive. Interactions of tumor cells with their surrounding microenvironment impact tumor initiation, progression and metastasis, as well as patient prognosis. This cross-talk is bidirectional. Tumor cells can also attract or activate tumor-associated stromal cells by releasing cytokines to facilitate their growth, invasion and metastasis. The effect of myeloma cells on bone marrow stromal cells (BMSCs) has not been well studied.
In current study, we determined the effect of myeloma cells on the stiffness of BMSCs and explored the molecular mechanisms underlying these mechanical changes. Cell stiffness measurements were performed using a combined atomic force microscope (AFM)/inverted optical microscope. We found that higher stiffness of BMSCs was not a unique characteristic of BMSCs from MM patients (M-BMSCs). BMSCs from MGUS (Monoclonal gammopathy of undetermined significance) patients were also stiffer than the BMSCs from healthy volunteers (N-BMSCs). The stiffness of M-BMSCs was enhanced when cocultured with myeloma cells. In contrast, no changes were seen in myeloma cell-primed MGUS- and N-BMSCs. Interestingly, our data indicated that CD138- myeloma cells, but not CD138+ cells, regulated M-BMSC stiffness. SDF-1 was highly expressed in the CD138- myeloma subpopulation compared with that in CD138+ cells. Inhibition of SDF-1 using AMD3100 or knocking-down CXCR4 in M-BMSCs blocked CD138- myeloma cells-induced increase in M-BMSC stiffness, suggesting a crucial role of SDF-1/CXCR4. AKT inhibition attenuated SDF-1-induced increases in M-BMSC stiffness. These findings demonstrate, for the first time, CD138- myeloma cell-directed cross-talk with BMSCs and reveal that CD138- myeloma cells regulate M-BMSC stiffness through SDF-1/CXCR4/AKT signaling.
Citation Format: Dan Wu, Xinyi Guo, Jing Su, Ruoying Chen, Dmitriy Berenzon, Keith Bonin, Martin Guthold, Weiling Zhao, Xiaobo Zhou. CD138-negative myeloma cells regulate mechanical properties of bone marrow stromal cells through SDF-1/CXCR4/AKT signaling pathway. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A09.
Abstract A38: Remodeling of the malignant bone marrow niche represents a therapeutic target.
Authors: Campbell Timothy B. , Passegué Emmanuelle 
Published: August 2015

Abstract
Myeloproliferative neoplasms (MPNs) are malignant diseases of the hematopoietic stem cell (HSC). Targeting driver mutations in these diseases has had variable success. In chronic myelogenous leukemia (CML), targeting the BCR/ABL pathway has completely changed the way these patients are treated; however, there still remain a significant proportion of patients who have no targetable mutation for therapy and treatments centered on non-cell autonomous pathways of disease progression may have significant value. Previously, our lab showed that malignant myeloid cells from a mouse model of CML overexpressing BCR/ABL (BA mice) expand a remodeled mesenchymal stem cell (MSC) derived osteoblast population which leads to a fibrotic bone marrow (BM) niche and preserves malignant hematopoiesis (Schepers et al. Cell Stem Cell 2013; 13: 285-299). Disrupting the establishment of this fibrotic niche hopefully could delay clinical MPN progression and restore normal hematopoiesis. Bisphosphonates are known to act locally in the BM microenvironment on many cell types and improve the survival of patients with BM-involved disease, including multiple myeloma and breast cancer (Modi and Lentzsch. Leukemia 2012; 26:589-594). The focus of our current studies is to test the effect of zoledronic acid (ZA), a widely used bisphosphonate, on in vitro MSC fibrotic colony formation induced by malignant CML cells. Using whole BM from BA or control mice co-cultured with wild type MSCs, we found that ZA potently inhibited the increase in MSC colony formation induced by CML cells. The significant four-fold increase in MSC colony size (measured by cell number per colony) in BA co-cultures was completely negated by ZA at concentrations as low as 500 nM. The BA co-cultures were exquisitely sensitive to ZA and no breakthrough colonies were seen as compared to a 65 percent reduction in colony size in control co-cultures with 500 nM ZA. Our results suggest that zoledronic acid could be an interesting therapeutic compound to target the fibrotic BM niche in MPNs. Ongoing studies seek to understand the mechanism of action of ZA and to test its efficacy in preventing fibrosis and restoring a healthy BM niche in the BA model of CML. The goal is also to expand these results to other, more strongly fibrotic, mouse models of MPNs and human MPN samples.
Citation Format: Timothy B. Campbell, Emmanuelle Passegué. Remodeling of the malignant bone marrow niche represents a therapeutic target. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A38.