bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ex Vivo Molecular Rejuvenation Improves the Therapeutic Activity of Senescent Human Cardiac Stem Cells in a Mouse Model of Myocardial Infarction
Authors: Avolio Elisa , Gianfranceschi Giuseppe , Cesselli Daniela , Caragnano Angela , Athanasakis Emmanouil , Katare Rajesh , Meloni Marco , Palma Anita , Barchiesi Arianna , Vascotto Carlo , Toffoletto Barbara , Mazzega Elisa , Finato Nicoletta , Aresu Giuseppe , Livi Ugolino , Emanueli Costanza , Scoles Giacinto , Beltrami Carlo Alberto , Madeddu Paolo , Beltrami Antonio Paolo 
Published: May 2014

Abstract
Cardiac stem cells (CSC) from explanted decompensated hearts (E-CSC) are, with respect to those obtained from healthy donors (D-CSC), senescent and functionally impaired. We aimed to identify alterations in signaling pathways that are associated with CSC senescence. Additionally, we investigated if pharmacological modulation of altered pathways can reduce CSC senescence in vitro and enhance their reparative ability in vivo. Measurement of secreted factors showed that E-CSC release larger amounts of proinflammatory cytokine IL1β compared with D-CSC. Using blocking antibodies, we verified that IL1β hampers the paracrine protective action of E-CSC on cardiomyocyte viability. IL1β acts intracranially inducing IKKβ signaling, a mechanism that via nuclear factor-κB upregulates the expression of IL1β itself. Moreover, E-CSC show reduced levels of AMP protein kinase (AMPK) activating phosphorylation. This latter event, together with enhanced IKKβ signaling, increases TORC1 activity, thereby impairing the autophagic flux and inhibiting the phosphorylation of Akt and cAMP response element-binding protein. The combined use of rapamycin and resveratrol enhanced AMPK, thereby restoring downstream signaling and reducing IL1β secretion. These molecular corrections reduced E-CSC senescence, re-establishing their protective activity on cardiomyocytes. Moreover ex vivo treatment with rapamycin and resveratrol improved E-CSC capacity to induce cardiac repair upon injection in the mouse infarcted heart, leading to reduced cardiomyocyte senescence and apoptosis and increased abundance of endogenous c-Kit+ CSC in the peri-infarct area. Molecular rejuvenation of patient-derived CSC by short pharmacologic conditioning boosts their in vivo reparative abilities. This approach might prove useful for refinement of CSC-based therapies. Stem Cells 2014;32:2373–2385
Engineering the Human Thymic Microenvironment to Support Thymopoiesis In Vivo
Authors: Chung Brile , Montel-Hagen Amélie , Ge Shundi , Blumberg Garrett , Kim Kenneth , Klein Sam , Zhu Yuhua , Parekh Chintan , Balamurugan Arumugam , Yang Otto O. , Crooks Gay M. 
Published: May 2014

Abstract
A system that allows manipulation of the human thymic microenvironment is needed both to elucidate the extrinsic mechanisms that control human thymopoiesis and to develop potential cell therapies for thymic insufficiency. In this report, we developed an implantable thymic microenvironment composed of two human thymic stroma populations critical for thymopoiesis; thymic epithelial cells (TECs) and thymic mesenchyme (TM). TECs and TM from postnatal human thymi were cultured in specific conditions, allowing cell expansion and manipulation of gene expression, before reaggregation into a functional thymic unit. Human CD34+ hematopoietic stem and progenitor cells (HSPC) differentiated into T cells in the aggregates in vitro and in vivo following inguinal implantation of aggregates in immune deficient mice. Cord blood HSPC previously engrafted into murine bone marrow (BM), migrated to implants, and differentiated into human T cells with a broad T cell receptor repertoire. Furthermore, lentiviral-mediated expression of vascular endothelial growth factor in TM enhanced implant size and function and significantly increased thymocyte production. These results demonstrate an in vivo system for the generation of T cells from human HSPC and represent the first model to allow manipulation of gene expression and cell composition in the microenvironment of the human thymus. Stem Cells 2014;32:2386–2396
Selection Via Pluripotency-Related Transcriptional Screen Minimizes the Influence of Somatic Origin on iPSC Differentiation Propensity
Authors: Hartjes Katherine A. , Li Xing , Martinez-Fernandez Almudena , Roemmich Alexa J. , Larsen Brandon T. , Terzic Andre , Nelson Timothy J. 
Published: May 2014

Abstract
The value of induced pluripotent stem cells (iPSCs) within regenerative medicine is contingent on predictable and consistent iPSC differentiation. However, residual influence of the somatic origin or reprogramming technique may variegate differentiation propensity and confound comparative genotype/phenotype analyses. The objective of this study was to define quality control measures to select iPSC clones that minimize the influence of somatic origin on differentiation propensity independent of the reprogramming strategy. More than 60 murine iPSC lines were derived from different fibroblast origins (embryonic, cardiac, and tail tip) via lentiviral integration and doxycycline-induced transgene expression. Despite apparent equivalency according to established iPSC histologic and cytomorphologic criteria, clustering of clonal variability in pluripotency-related gene expression identified transcriptional outliers that highlighted cell lines with unpredictable cardiogenic propensity. Following selection according to a standardized gene expression profile calibrated by embryonic stem cells, the influence of somatic origin on iPSC methylation and transcriptional patterns was negated. Furthermore, doxycycline-induced iPSCs consistently demonstrated earlier differentiation than lentiviral-reprogrammed lines using contractile cardiac tissue as a measure of functional differentiation. Moreover, delayed cardiac differentiation was predominately associated with upregulation in pluripotency-related gene expression upon differentiation. Starting from a standardized pool of iPSCs, relative expression levels of two pluripotency genes, Oct4 and Zfp42, statistically correlated with enhanced cardiogenicity independent of somatic origin or reprogramming strategy (R2 = 0.85). These studies demonstrate that predictable iPSC differentiation is independent of somatic origin with standardized gene expression selection criteria, while the residual impact of reprogramming strategy greatly influences predictable output of tissue-specification required for comparative genotype/phenotype analyses. Stem Cells 2014;32:2350–2359
A Novel Oncogenic Role of Inositol Phosphatase SHIP2 in ER-Negative Breast Cancer Stem Cells: Involvement of JNK/Vimentin Activation
Authors: Fu Chiung-Hui , Lin Ruey-Jen , Yu John , Chang Wen-Wei , Liao Guo-Shiou , Chang Wen-Ying , Tseng Ling-Ming , Tsai Yi-Fang , Yu Jyh-Cherng , Yu Alice L. 
Published: May 2014

Abstract
Overexpression of SH2-containing-5′-inositol phosphatase-2 (SHIP2) correlates with poor survival in breast cancer. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here, we showed that the percentage of SHIP2+ cells was positively correlated with that of CD24−CD44+ cells in 60 breast cancer specimens. Among 20 estrogen receptor (ER)-negative samples, 17 had greater SHIP2 expression in CD24−CD44+ subpopulation than the remaining subpopulation. Data mining of microarray analysis of 295 breast tumors showed a significant correlation of higher SHIP2 expression with distant metastasis. Examination of patient-derived mouse xenografts revealed that SHIP2 protein and its tyrosine 1135 phosphorylation were significantly higher in BCSCs, identified as CD24−CD44+ or aldehyde dehydrogenase (ALDH+), than non-BCSCs. SHIP2 silencing or inhibitor of SHIP2 phosphatase significantly decreased mammosphere-forming efficiency, ALDH+ subpopulation in vitro and tumorigenicity of BCSCs in vivo. Overexpression of SHIP2 enhanced the expression of epithelial–mesenchymal transition markers including vimentin (VIM), which was mainly expressed in ER-negative breast cancer cells with higher level in mammospheres than monolayer culture. Ablation of c-Jun N-terminal kinase 1 (JNK1), JNK2, or VIM diminished the increased ALDH+ population and tumorigenicity, induced by SHIP2 overexpression. BCSCs displayed greater expression of phospho-JNK than non-BCSCs and silencing of JNK suppressed SHIP2-mediated upregulation of VIM. Furthermore, SHIP2 overexpression enhanced Akt activation, but Akt inhibition failed to influence SHIP2-induced phospho-JNK/VIM upregulation. In conclusion, SHIP2 plays a key role in BCSCs of ER-negative breast cancers through activation of Akt and JNK with upregulation of VIM and may serve as a target for therapy directed at BCSCs. Stem Cells 2014;32:2048–2060
Importance of Cell-Cell Contact in the Therapeutic Benefits of Cardiosphere-Derived Cells
Authors: Xie Yucai , Ibrahim Ahmed , Cheng Ke , Wu Zhijun , Liang Wenbin , Malliaras Konstantinos , Sun Baiming , Liu Weixin , Shen Deliang , Cheol Cho Hee , Li Taosheng , Lu Lin , Lu Guoping , Marbán Eduardo 
Published: May 2014

Abstract
Cardiosphere-derived cells (CDCs) effect therapeutic regeneration after myocardial infarction (MI) both in animal models and in humans. Here, we test the hypothesis that cell-cell contact plays a role in mediating the observed therapeutic benefits of CDCs, above and beyond conventional paracrine effects. Human CDCs or vehicle were injected into immunodeficient (SCID) mouse hearts during acute MI. CDC transplantation augmented the proportion of cycling (Ki67+) cardiomyocytes and improved ventricular function. CDC-conditioned media only modestly augmented the percentage of Ki67+ cardiomyocytes (&gt;control but &lt;CDCs), but did not improve pump function. When neonatal rat ventricular myocytes (NRVMs) were cocultured with human CDCs in vitro, the percentage of cycling NRVMs (Ki67+ or BrdU+ nuclei) increased relative to solitary NRVM culture. To further dissect the relative contributions of soluble factors versus contact-dependent mechanisms, we compared CDCs grown with NRVMs in a transwell contact-free system versus admixed coculture. The percentage of cycling NRVMs was higher in admixed coculture than in the contact-free system. Pretreatment with inhibitors of MEK and PI3K, or with β1 integrin neutralizing antibody, blocked the ability of CDCs to promote myocyte cycling. While conditioned media are not inert, direct apposition of CDCs to cardiomyocytes produces greater enhancement of cardiomyocyte proliferation in vitro and in vivo, and improves function post-MI. Intact cardiomyocyte β1 integrin signaling is necessary for the contact-dependent cardioproliferative effects of CDCs. Stem Cells 2014;32:2397–2406
Elements for Adequate Informed Consent in the Surgical Context
Authors: Abaunza Hernando , Romero Klaus 
Published: May 2014

Abstract
Given a history of atrocities and violations of ethical principles, several documents and regulations have been issued by a wide variety of organizations. They aim at ensuring that health care and clinical research adhere to defined ethical principles. A fundamental component was devised to ensure that the individual has been provided the necessary information to make an informed decision regarding health care or participation in clinical research. This article summarizes the history and regulations for informed consent and discusses suggested components for adequate consent forms for daily clinical practice in surgery as well as clinical research.
High Survival in Patients Operated for Small Isolated Liver Metastases from Gastric Cancer: A Multi‐institutional Study
Authors: Komeda Koji , Hayashi Michihiro , Kubo Shoji , Nagano Hiroaki , Nakai Takuya , Kaibori Masaki , Wada Hiroshi , Takemura Shigekazu , Kinoshita Masahiko , Koga Chikato , Matsumoto Masataka , Sakaguchi Tatsuma , Inoue Yoshihiro , Hirokawa Fumitoshi , Kwon A‐Hon , Uchiyama Kazuhisa 
Published: May 2014

AbstractBackgroundAlthough several studies have reported the outcomes of surgery for the treatment of liver metastases of gastric cancer (GLM), indications for liver resection for gastric metastases remain controversial. This study was designed to identify prognostic determinants that identify operable hepatic metastases from gastric cancer and to evaluate the actual targets of surgical therapy.MethodsRetrospective analysis was performed on outcomes for 24 consecutive patients at five institutions who underwent gastrectomy for gastric cancer followed by curative hepatectomy for GLM between 2000 and June 2012.ResultsOverall 5‐year survival and median survival were 40.1 % and 22.3 months, respectively. Uni‐ and multivariate analyses showed that liver metastatic tumour size less than 5 cm was the most important predictor of overall survival (OS, p = 0.03). Four patients survived >5 years. Repeat hepatectomy was performed in three patients. Two of these patients have remained disease‐free since the repeat hepatectomy.ConclusionsGLM patients with metastatic tumour diameter less than 5 cm maximum are the best candidates for hepatectomy. Hepatic resection should be considered as an option for gastric cancer patients with liver metastases.
Japanese D3 Lymph Node Dissection in Low Rectal Cancer with Inferior Mesenteric Lymph Node Metastases
Authors: Ubukata Mamiko , Itabashi Michio , Kameoka Shingo 
Published: May 2014

AbstractBackgroundThere is currently no consensus on the significance of Japanese D3 lymph node dissection in low rectal cancer with inferior mesenteric lymph node (IMLN) metastasis. This is partly because, despite a number of studies on the subject, cases of IMLN metastasis are relatively rare, and there are few cases of curative resection because of metastasis to other organs. A retrospective study involving a large number of patients was conducted.
MethodsThe subjects were 2,743 patients registered in the national registry of the Japanese Society for Cancer of the Colon and Rectum. The data were analyzed for (1) prognostic factors for IMLN metastasis, and (2) outcomes in R0 cases with IMLN metastasis.ResultsIn the control group, 67 patients (2.7 %) were considered positive for IMLN metastasis. The outcomes in the 35 R0 cases with IMLN metastasis were 50.8 % for 5‐year relapse‐free survival (RFS) and 61.9 % for 5‐year overall survival (OS), which were each better than for R1+R2 cases (5‐year RFS 16.1 %, p = 0.0001; 5‐year OS 26.7 %, p = 0.0002). The outcomes for R0 cases (total metastatic lymph nodes ≥7) with IMLN metastasis (5‐year RFS 53.9 %, 5‐year OS 68.8 %) did not differ significantly from those for IMLN(−) cases (5‐year RFS 54.6 %, 5‐year OS 57.1 %) (RFS: p = 0.9515, OS: p = 0.4621).ConclusionsIt was confirmed that cases of IMLN metastasis in low rectal cancer tend to have a large total number of metastatic lymph nodes, but if curative resection can be performed, a good prognosis can be expected. These results demonstrate the value of radical Japanese D3 lymph node dissection in low rectal cancer with IMLN metastasis.
Investigation of Micellization and Vesiculation of Conjugated Linoleic Acid by Means of Self‐Assembling and Self‐Crosslinking
Authors: Fan Ye , Fang Yun , Ma Lin , Jiang Hang 
Published: May 2014

AbstractBioactive and biocompatible conjugated linoleic acid (CLA) has been only considered as a food or medicine ingredient due to its rare natural occurrence. In this work, the surface activities and pH‐induced self‐assembling behaviors of the semi‐synthetic CLA molecules into micelles or vesicles were systematically investigated. First, the self‐assembling of CLA was studied in detail, and it was found that aside from temperature and ionic strength, pH is the prominent factor affecting the self‐assembling of CLA. Moreover, stable CLA ufasomes (unsaturated fatty acid liposomes) in uniform size were obtained by self‐crosslinking of the CLA ufasomes, and the morphologies of the crosslinked CLA assemblies were recorded by transmission electron microscopy, which made known the pH‐induced formation of the CLA ufasomes or the CLA micelles. The crosslinked CLA assemblies presented improved properties such as a higher calcium stability, a lower lime soap dispersing requirement and a better solubilization ability than that of the CLA molecules themselves or the pre‐crosslinked linoleic acids. These investigations could be helpful for comprehensively understanding effects of environment factors on self‐assembling behaviors of conjugated fatty acids and responsive polymerization of polymerizable surfactants.
Lipidomics Reveals Mitochondrial Membrane Remodeling Associated with Acute Thermoregulation in a Rodent with a Wide Thermoneutral Zone
Authors: Pan Qian , Li Min , Shi Yao‐Long , Liu Huwei , Speakman John R. , Wang De‐Hua 
Published: May 2014

AbstractMongolian gerbils (Meriones unguiculatus) have high physiological flexibility in response to acute temperature changes, and have the widest thermoneutral zone (TNZ, 26.5–38.9 °C) reported among small mammals. At the upper critical temperature (Tuc, 38.9 °C), body temperatures of gerbils were significantly increased (39–41 °C) while metabolic rates were maintained at the basal level. In contrast, below the lower critical temperature (Tlc, 26.5 °C), metabolism was elevated and body temperature stable. Rapid changes in mitochondrial membrane lipidome were hypothesized to play an important role during acute thermoregulation of gerbils. Taking advantage of a recent lipidomic technique, we examined changes in the membrane phospholipids environment and free fatty acids (FFA) production in mitochondria between 38 and 27 °C (in the TNZ), and between 27 and 16 °C (below the TNZ). At 38 °C, acute heat stress elicited distinct remodeling in mitochondrial membrane lipidome which related to a potential decrease in mitochondrial respiration and membrane fluidity compared to 27 °C. At 16 °C, a sharply decreased unsaturation index and increased chain lengths were detected in mitochondrial FFA production both in muscle and brown adipose tissue. Our results suggest that mitochondrial membrane lipid remodeling may stabilize membrane function and activity of respiration related membrane protein to maintain a stable metabolic rate at Tuc, and improve heat production by decomposing less fluid fatty acid conjugates of membrane lipids under acute cold exposure. These data therefore imply an important role of membrane remodeling during acute thermoregulation in a non‐hibernating endotherm.
Thalamic Stroke: Precursors and Outcomes for Ten Patients
Authors: Freeland Johanna , Levi Christopher , Hunter Mick 
Published: May 2014

Objective: The purpose of this study was to examine susceptibility factors in thalamic stroke, as well as outcomes in order to identify rehabilitation needs.Methods: Ten patients with thalamic stroke were interviewed and administered the Audio Recorded Cognitive Screen. Magnetic resonance imaging (MRI) scans were examined to determine location and size of the lesion, as well as basilar artery size and anatomical variances in the circle of Willis.Results: Risk factors such as high cholesterol, high blood pressure and pre-existing heart conditions were identified. Circle of Willis variations were found in 6 of the 10 participants, with MR angiography indicating that the posterior communication artery was absent or failed to join the posterior cerebral artery. Basilar artery diameter measurements were no larger than normal. All participants reported post-stroke changes, including decreased coordination and mobility, poor balance, reduced energy, memory deficits and mood changes. Participants’ overall scores on cognitive tests were significantly lower than age-matched norms. Performance on the test domains of memory, fluency, language and attention were all significantly below age norms.Conclusions: The variability of outcome measures demonstrates the difficulty of defining patterns of relationship between risk factors and severity of functional sequelae in thalamic stroke.
‘The televising of science is a process of television’: establishing Horizon, 1962–1967
Authors: BOON TIMOTHY 
Published: May 2014

AbstractBBC Television's Horizon series, fifty years old on 2 May 2014, despite its significance to the history of the public culture of science, has been little studied. This microhistorical account follows the gestation and early years of the programme, demonstrating how it established a social and cultural account of science. This was a result of televisual factors, notably the determination to follow the format of the successful arts television programme Monitor. It illuminates how the processes of television production, with a handful of key participants – Aubrey Singer, Gerald Leach, Philip Daly, Gordon Rattray Taylor, Ramsay Short, Michael Peacock and Robert Reid – established the format of the programme. This occurred over seventeen months of prior preparation followed by three troubled years of seeking to establish a stable form. This was finally achieved in 1967 when the programme adopted a film documentary approach after extended attempts at making it as a studio-based magazine programme. The story has implications for understanding the social accounts of science that were circulating in the key decade of the 1960s.
A fuzzy multi-stage path-planning method for a robot in a dynamic environment with unknown moving obstacles
Authors: Mobadersany Pooya , Khanmohammadi Sohrab , Ghaemi Sehraneh 
Published: May 2014

SUMMARYPath planning is one of the most important fields in robotics. Only a limited number of articles have proposed a practical way to solve the path-planning problem with moving obstacles. In this paper, a fuzzy path-planning method with two strategies is proposed to navigate a robot among unknown moving obstacles in complex environments. The static form of the environment is assumed to be known, but there is no prior knowledge about the dynamic obstacles. In this situation, an online and real-time approach is essential for avoiding collision. Also, the approach should be efficient in natural complex environments such as blood vessels. To examine the efficiency of the proposed algorithm, a drug delivery nanorobot moving in a complex environment (blood vessels) is supposed. The Monte Carlo simulation with random numbers is used to demonstrate the efficiency of the proposed approach, where the dynamic obstacles are assumed to appear in exponentially distributed random time intervals.
Heterogeneity in the smoking response to health shocks by out-of-pocket spending risk
Authors: Richards Michael R. , Marti Joachim 
Published: May 2014

AbstractAn existing literature demonstrates that adverse changes to health can lead to improvements in health behaviors. Although the exact explanations for these empirical findings are debated, some posit that individuals learn about their true health risks through health shocks. Updated health risk information can then induce changes in health behaviors. While we follow a learning framework, we argue that past work has neglected the role of health insurance and medically related financial risk within this decision making context. Using longitudinal data from 11 European countries, we investigate the impact of a new cardiovascular (CV) health shock on smoking decisions among older adults and examine whether personal exposure to medical spending risk influences the smoking response. We then explore two potential mechanisms for this link: larger updates to health risk beliefs and higher medical expenditures to incentivize behavior change. We find that CV shocks impact the propensity to smoke, with relatively more impact among individuals with high financial risk exposure to medical spending. We also see larger increases in out-of-pocket expenditures following a shock for this group – consistent with the latter mechanism for behavior change.