bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+ T Cell and NK Cell Interplay Key to Regression of MHC Class Ilow Tumors upon TLR7/8 Agonist Therapy
Authors: Doorduijn Elien M. , Sluijter Marjolein , Salvatori Daniela C. , Silvestri Serenella , Maas Saskia , Arens Ramon , Ossendorp Ferry , van der Burg Sjoerd H. , van Hall Thorbald 
Published: June 2017

Abstract
One of the next challenges in cancer immunotherapy is the resistance of tumors to T-cell–based treatments through loss of MHC class I. Here, we show that under these circumstances, the Toll-like receptor (TLR)-7/8 ligand imiquimod, but not the TLR3 ligand poly I:C or TLR9 ligand CpG, mediated an effective antitumor response. The rejection of these immune-escaped cancers was mediated by NK cells and CD4+ T cells, whereas activated CD8+ T cells were dispensable. Application of the innate immune stimulator at a distant site activated NK cells and thereby elicited tumor-specific T-cell responses in tumor-bearing mice. Mechanistically, imiquimod activated NK cells to kill tumor cells, resulting in release of tumor antigens and induction of tumor-specific CD4+ T cells. These T helper cells provoked a strong induction of CXCL9 and CXCL10 in the tumor environment. Simultaneously, imiquimod induced the expression of the cognate chemokine receptor CXCR3 on peripheral lymphocytes. This ignited intratumoral CD4+ T-cell infiltration and accumulation, which was critical for tumor rejection; CXCR3 blocking antibodies mitigated the clinical response. In the effector phase, NK cell recruitment to tumors and their activation depended on CD4+ T cells. Together, we have uncovered a potent immune axis of tumor-specific CD4+ T cells and NK cells that eliminates escaped MHC-Ilow tumors. Cancer Immunol Res; 5(8); 642–53. ©2017 AACR.
Monocyte-Derived Dendritic Cells with Silenced PD-1 Ligands and Transpresenting Interleukin-15 Stimulate Strong Tumor-Reactive T-cell Expansion
Authors: Van den Bergh Johan M.J. , Smits Evelien L.J.M. , Berneman Zwi N. , Hutten Tim J.A. , De Reu Hans , Van Tendeloo Viggo F.I. , Dolstra Harry , Lion Eva , Hobo Willemijn 
Published: June 2017

Abstract
Although allogeneic stem cell transplantation (allo-SCT) can elicit graft-versus-tumor (GVT) immunity, patients often relapse due to residual tumor cells. As essential orchestrators of the immune system, vaccination with dendritic cells (DC) is an appealing strategy to boost the GVT response. Nevertheless, durable clinical responses after DC vaccination are still limited, stressing the need to improve current DC vaccines. Aiming to empower DC potency, we engineered monocyte-derived DCs to deprive them of ligands for the immune checkpoint regulated by programmed death 1 (PD-1). We also equipped them with interleukin (IL)-15 “transpresentation” skills. Transfection with short interfering (si)RNA targeting the PD-1 ligands PD-L1 and PD-L2, in combination with IL15 and IL15Rα mRNA, preserved their mature DC profile and rendered the DCs superior in inducing T-cell proliferation and IFNγ and TNFα production. Translated into an ex vivo hematological disease setting, DCs deprived of PD-1 ligands (PD-L), equipped with IL15/IL15Rα expression, or most effectively, both, induced superior expansion of minor histocompatibility antigen–specific CD8+ T cells from transplanted cancer patients. These data support the combinatorial approach of in situ suppression of the PD-L inhibitory checkpoints with DC-mediated IL15 transpresentation to promote antigen-specific T-cell responses and, ultimately, contribute to GVT immunity. Cancer Immunol Res; 5(8); 710–5. ©2017 AACR.
Study Comparing Vein Integrity and Clinical Outcomes in Open Vein Harvesting and 2 Types of Endoscopic Vein Harvesting for Coronary Artery Bypass Grafting
Authors: Krishnamoorthy Bhuvaneswari , Critchley William R. , Thompson Alexander J. , Payne Katherine , Morris Julie , Venkateswaran Rajamiyer V. , Caress Ann L. , Fildes James E. , Yonan Nizar 
Published: June 2017

Background:
Current consensus statements maintain that endoscopic vein harvesting (EVH) should be standard care in coronary artery bypass graft surgery, but vein quality and clinical outcomes have been questioned. The VICO trial (Vein Integrity and Clinical Outcomes) was designed to assess the impact of different vein harvesting methods on vessel damage and whether this contributes to clinical outcomes after coronary artery bypass grafting.

Methods:

In this single-center, randomized clinical trial, patients undergoing coronary artery bypass grafting with an internal mammary artery and with 1 to 4 vein grafts were recruited. All veins were harvested by a single experienced practitioner. We randomly allocated 300 patients into closed tunnel CO
2
EVH (n=100), open tunnel CO
2
EVH (n=100), and traditional open vein harvesting (n=100) groups. The primary end point was endothelial integrity and muscular damage of the harvested vein. Secondary end points included clinical outcomes (major adverse cardiac events), use of healthcare resources, and impact on health status (quality-adjusted life-years).

Results:

The open vein harvesting group demonstrated marginally better endothelial integrity in random samples (85% versus 88% versus 93% for closed tunnel EVH, open tunnel EVH, and open vein harvesting;
P
<0.001). Closed tunnel EVH displayed the lowest longitudinal hypertrophy (1% versus 13.5% versus 3%;
P
=0.001). However, no differences in endothelial stretching were observed between groups (37% versus 37% versus 31%;
P
=0.62). Secondary clinical outcomes demonstrated no significant differences in composite major adverse cardiac event scores at each time point up to 48 months. The quality-adjusted life-year gain per patient was 0.11 (
P
<0.001) for closed tunnel EVH and 0.07 (
P
=0.003) for open tunnel EVH compared with open vein harvesting. The likelihood of being cost-effective, at a predefined threshold of £20 000 per quality-adjusted life-year gained, was 75% for closed tunnel EVH, 19% for open tunnel EVH, and 6% for open vein harvesting.

Conclusions:
Our study demonstrates that harvesting techniques affect the integrity of different vein layers, albeit only slightly. Secondary outcomes suggest that histological findings do not directly contribute to major adverse cardiac event outcomes. Gains in health status were observed, and cost-effectiveness was better with closed tunnel EVH. High-level experience with endoscopic harvesting performed by a dedicated specialist practitioner gives optimal results comparable to those of open vein harvesting.

Clinical Trial Registration:

URL:
https://www.isrctn.com
. International Standard Randomised Controlled Trial Registry Number: 91485426.
Mild Cognitive Impairment and Changes in Everyday Function Over Time: The Importance of Evaluating Both Speed and Accuracy
Authors: Lassen-Greene Caroline L. , Steward Kayla , Okonkwo Ozioma , Porter Ellen , Crowe Michael , Vance David E. , Griffith H. Randall , Ball Karlene , Marson Daniel C. , Wadley Virginia G. 
Published: June 2017

Objectives: Research estimates that a significant percentage of individuals with mild cognitive impairment (MCI) experience functional difficulties. In addition to reduced accuracy on measures of everyday function, cross-sectional research has demonstrated that speed of performing instrumental activities of daily living (IADLs) is slowed in individuals with MCI. The present study investigated whether baseline and longitudinal changes in speed and accuracy of IADL performance differed between persons with MCI and cognitively normal peers. Design: Linear mixed models were used to estimate the group differences in longitudinal performance on measures of IADLs. Setting: Assessments were conducted at university and medical research centers. Participants: The sample consisted of 80 participants with MCI and 80 control participants who were enrolled in the Alzheimer’s Disease Research Center’s Measuring Independent Living in the Elderly Study. Measurements: Instrumental activities of daily living speed and accuracy were directly assessed using selected domains of the Financial Capacity Instrument, the Timed IADL assessment, and driving-related assessments (Useful Field of View, Road Sign Test). Results: Individuals with MCI performed worse on speed and accuracy measures of IADLs in comparison to cognitively normal peers and demonstrated significantly steeper rates of decline over three years in either speed or accuracy in all domains assessed. Conclusion: Both speed and accuracy of performance on measures of IADL are valuable indices for early detection of functional change in MCI. The performance pattern may reflect a trade-off between speed and accuracy that can guide clinical recommendations for maintaining patient independence.
Human Cortical Neuronal Cell Line (Hcn-1): Further in Vitro Characterization and Suitability for Brain Transplantation
Authors: Poltorak Maciej , Isono Mitsuo , Freed William J. , Ronnett Gabriele V. , Snyder Solomon H. 
Published: June 2017

The human neuronal cell-1 (HCN-1) line has recently been established. Under favorable conditions, these cells differentiate into mature neuronal phenotypes. Here we report on further characterization of these cells. Cultured HCN-1 cells express fibronectin immunoreactivity and grow well on fibronectin substrate but do not respond to human bFGF. In the undifferentiated state, some HCN-1 cells show MHC class I antigen expression. After differentiation, HCN-1 cells and their processes are MHC class I negative. On the other hand, interferon-γ stimulation enhances MHC class I expression but does not induce MHC class II immunoreactivity. Our in vitro data indicate that HCN-1 cells express mixed characteristics, including both neuronal and mesenchymal markers, and are consistent with the suggestion that the HCN-1 cell line resembles an immature neuroepithelial cell precursor with a complex origin.One possible application of the use of the HCN-1 cells includes intracerebral transplantation. We also examined the survival of dissociated HCN-1 cells implanted into rat brain parenchyma. The host animals were not immunosuppressed. Despite expression of MHC class I antigens, small clusters of HCN-1 cells survived in the rat brain. These xenografts did not induce distinct immunological responses within the host brain tissue. Surviving HCN-1 cells demonstrated similar features to those observed in culture.Our preliminary results suggest that the HCN-1 cell line would be suitable for intracerebral transplantation in primates or humans. However, it may be that short-term host immunosuppression or addition of HCN-1 cell differentiation factors would be beneficial for enhanced cell survival.
Assessment of inhibitory effects on major human cytochrome P450 enzymes by spasmolytics used in the treatment of overactive bladder syndrome
Authors: Dahlinger Dominik , Aslan Sevinc , Pietsch Markus , Frechen Sebastian , Fuhr Uwe 
Published: June 2017

Background: The objective of this study was to examine the inhibitory potential of darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium chloride on the seven major human cytochrome P450 enzymes (CYP) by using a standardized and validated seven-in-one cytochrome P450 cocktail inhibition assay. Methods: An in vitro cocktail of seven highly selective probe substrates was incubated with human liver microsomes and varying concentrations of the seven test compounds. The major metabolites of the probe substrates were simultaneously analysed using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Enzyme kinetics were estimated by determining IC50 and Ki values via nonlinear regression. Obtained Ki values were used for predictions of potential clinical impact of the inhibition using a static mechanistic prediction model. Results: In this study, 49 IC50 experiments were conducted. In six cases, IC50 values lower than the calculated threshold for drug–drug interactions (DDIs) in the gut wall were observed. In these cases, no increase in inhibition was determined after a 30 min preincubation. Considering a typical dosing regimen and applying the obtained Ki values of 0.72 µM (darifenacin, 15 mg daily) and 7.2 µM [propiverine, 30 mg daily, immediate release (IR)] for the inhibition of CYP2D6 yielded a predicted 1.9-fold and 1.4-fold increase in the area under the curve (AUC) of debrisoquine (CYP2D6 substrate), respectively. Due to the inhibition of the particular intestinal CYP3A4, the obtained Ki values of 14 µM of propiverine (30 mg daily, IR) resulted in a predicted doubling of the AUC for midazolam (CYP3A4 substrate). Conclusions: In vitro/ in vivo extrapolation based on pharmacokinetic data and the conducted screening experiments yielded similar effects of darifenacin on CYP2D6 and propiverine on CYP3A4 as obtained in separately conducted in vivo DDI studies. As a novel finding, propiverine was identified to potentially inhibit CYP2D6 at clinically occurring concentrations.
Co-constructed health narratives during a ‘media event’: The case of the first Dutch Twitter heart operation
Authors: Adams Samantha , Schiffers Puck 
Published: June 2017

Objective This article examines the relationship between microblogging and the development of health narrative through the lens of an institution-initiated media event, the first live-tweeted heart operation in the Netherlands. It specifically addresses the question, how does health narrative take shape on a microblog and other (social) media, through the combination of self-initiated status updates, reactions to questions and short conversations with followers? Methods A combination of qualitative and quantitative data analysis was used to identify prominent themes in the tweets and trace the complex process by which the narrative took shape. The results presented here are derived from the qualitative analysis. Results There are four recurring health narrative themes in the tweets: (a) new challenges to professionalism; (b) mutual exchanges of information, support and advice; (c) increasingly personal (and public) details; and (d) questions about ‘resuming normalcy’. The special nature of this case also reveals interesting features, such as the multiple narrative starting points and the phenomenon of ‘tweeting by proxy’, and raises a number of critical questions regarding this type of use of social media in healthcare. Conclusions In the discussion we reflect on whether/how microblogged health narratives are really ‘new’ and on the implications of this single case for understanding the relationship between social media, health narrative and the changing relationships between information technologies, actors and institutions. We further examine this case as an example of what Lupton has deemed the ‘digital patient experience economy’, in reference to patients increasingly being encouraged to post experiences of their illness and encounters with the healthcare system to online platforms, where these shared experiences become valorised and monetised.
Circular external fixation and cemented PMMA spacers for the treatment of complex tibial fractures and infected nonunions with segmental bone loss
Authors: van Niekerk Andries H , Birkholtz Franz F , de Lange Phillip , Tetsworth Kevin , Hohmann Erik 
Published: June 2017

Purpose: The purpose of this study was to compare the outcome of combined circular external fixation and cemented polymethylmethacrylate (PMMA) spacer application between a cohort of patients with grade 3 open fractures and infected tibial nonunions and concomitant segmental bone loss. Methods: The study was designed as a retrospective cohort study. All patients who were treated for complex tibial fractures or infected nonunions with segmental bone loss between 2009 and 2013 were included if they were aged between 16 years and 60 years, sustained acute traumatic grade 3 open tibial fractures, presented with infected nonunion, and were followed up for a minimum of 12 months. Patients with a history of ipsilateral tibial fractures, contralateral lower extremity fractures, polytrauma, chest, or abdominal trauma and patients with head injuries were excluded. Both groups were treated with aggressive debridement, circular external fixation, and antibiotic-impregnated PMMA spacer. Outcome measures were the time in the external fixator (EFT) and the external fixation index (EFI). Results: Twenty-four patients with a mean age of 32 ± 14.7 years were included. Twelve patients with a mean age of 32 + 14 years and a mean bone defect of 82 + 36 mm were treated for acute complex grade 3 open tibial fractures, and 12 patients with a mean age of 35.1 + 15.7 years and a mean bone defect of 50 + 26 mm were treated for infected nonunions. There was no significant difference ( p = 0.44) between the groups for EFT (249 ± 99 days—tibial fractures; 255 ± 142 days—infected nonunion). There were significant between group differences ( p = 0.027) for EFI (37.3 ± 9.1 cm/days—tibial fractures; 56 ± 14.5 cm/days—infected nonunion). Conclusion: The findings of this study suggest that patients were treated for infected nonunion with segmental bone loss using circular external fixation, distraction osteogenesis, and antibiotic-impregnated PMMA spacers, and the spacers may not offer any advantage over a conventional approach using the principles of osteogenesis only. In contrast, antibiotic-impregnated spacers for open tibial trauma were advantageous and reduced the EFI considerably.
An aptamer-based targeted delivery of miR-26a protects mice against chemotherapy toxicity while suppressing tumor growth
Authors: Tanno Toshihiko , Zhang Peng , Lazarski Christopher A. , Liu Yang , Zheng Pan 
Published: June 2017

Key Points
miR-26a is a key regulator for apoptosis of cancer cells and hematopoietic toxicity of chemotherapy. A novel chimera with an anti-KIT aptamer and miR-26a can selectively deliver microRNA to cancer cells and HSPCs.
Accessibility to health services among migrant workers in the Northeast of Thailand
Authors: Khongthanachayopit Suprawee , Laohasiriwong Wongsa 
Published: June 2017

Background. There is an increasing trend of trans-border migration from neighboring countries to Thailand. According to human rights laws, everyone must have access to health services, even if they are from other nationalities. However, a small minority of health personnel in Thailand discriminate against immigrant workers, as they are from a lower financial bracket. Methods. This cross-sectional study aims to determine the prevalence of accessibility to health services and factors associated with access to health services among migrant workers who work along the Northeast border of Thailand. A total of 621 legal migrant workers were randomly selected to respond to a structured questionnaire about the satisfaction of health services, using the 5As of health services: availability; accessibility; accommodation; affordability; acceptability. Associations between independent variables and access to health services were analysed using multiple logistic regression analysis. Results. The results indicated that the majority of these registered migrant workers were female (63.9%) with an average age of 29± 8.61 years old, and were married (54.3%). Most of the workers worked at restaurants (80%), whereas only 20% were in agricultural sectors. Only 14% (95% CI: 11-17%) of migrant workers had access to health services. The factors that were significantly associated with accessibility to health service experienced ill health during the past one year (OR = 2.48; 95%CI; 1.54–3.97; p-value<0.001); have been married (OR = 2.32; 95% CI: 1.40 – 3.90; p-value <0.001). Conclusions. Most of the migrant workers could not access health services. The ones who did access health services were married or ill.
Comercio interregional de bienes manufacturados en los países de la Alianza del Pacífico desde la Teoría de Linder
Authors: Ovando Aldana Wendy , Canales García Rosa Azalea , Munguía Vázquez Gabriela 
Published: June 2017

Derivadas de la restructuración económica de finales del siglo XX, la lógica del mercado y la apertura comercial se han convertido en los ejes rectores del sistema capitalista. La disminución de las barreras al comercio internacional y los acuerdos comerciales son mecanismos que permiten la promoción del libre comercio. La Alianza del Pacífico representa una iniciativa de integración regional de reciente creación y a cinco años de su firma es necesaria una evaluación. El objetivo de esta investigación es analizar la evolución del comercio de bienes manufacturados entre las naciones de la Alianza del Pacífico. Para alcanzar dicho objetivo, esta investigación se basa en la Teoría de Linder que establece que el comercio de bienes manufacturados será más intensivo entre países de similar ingreso per cápita. Se realizó un estudio descriptivo con datos de la United Nations Conference on Trade and Development (UNCTAD) y posteriormente se empleó un modelo gravitacional modificado. Con base en la evidencia empírica se establece que el comercio de bienes manufacturados entre las nacionesde la Alianza del Pacífico es marginal. Los países signatarios presentan mayor comerciocon otras naciones, principalmente Estados Unidos y China, aun cuando las distancias geográficas con estos países son mayores.
The Norm Prohibiting the Chewing of Coca Leaf: From the International System to the Colombian State
Authors: Fernandez Lopez Julian Andres 
Published: June 2017

Este artículo trata sobre el proceso de adopción de los tratados internacionales de drogas en el orden jurídico interno colombiano. La ley internacional establece que los únicos usos lícitos para las substancias que son objeto de vigilancia, como es elcaso de la hoja de coca, son los medicinales y científicos. Por lo tanto, la masticación de hoja de coca realizada por las comunidades indígenas andinas debe ser eliminada. El Estado colombiano ha firmado y ratificado estos tratados internacionales y tiene la responsabilidad de respetar sus compromisos internacionales. Sin embargo, siendo una nación multicultural con dos sistemas formales e igualitarios de derecho (el indígena y la jurisdicción ordinaria) y con el incremento de la participación de las comunidades indígenas en la política colombiana la tarea produce una confrontación. El Estado colombiano se encuentra frente a un dilema: por un lado, cumplir con sus obligaciones jurídicas internacionales y por el otro respetar los derechos de las comunidades indígenas.
De Walter White a Heisenberg: el camino del (anti)héroe en la sociedad del riesgo
Authors: Aguado Peláez Delicia 
Published: June 2017

El nuevo milenio revitaliza las tesis de ulrich beck (2008) y su sociedad del riesgo a través de dos grandes acontecimientos que golpean a Estados unidos en el arranque del siglo XXI: los atentados del 11 de septiembre —y sus consecuencias— y la gran recesión. Precisamente en este ambiente de incertidumbre se desarrolla uno de los momentos de mayor esplendor para las producciones dramáticas estadounidenses conocida como la tercera Edad Dorada de la televisión. Este doble contexto es el punto de partida de la presente investigación que se centra en el papel de la ficción en la reproducción de la sensación de miedo. Así pues, el estudio se centra en Breaking Bad (AMC, 2008-2013), uno de los grandes éxitos de esta época de calidad e innovación. De esta forma, y haciendo uso del análisis de contenido cualitativo, se estudia la influencia de la sociedad del riesgo a partir del impacto del miedo en la trama, prestando especial atención a la construcción del personaje principal y su consecuente evolución hacia el antiheroísmo. Una investigación que revela la importancia de la ficción a la hora de explicar y reproducir el presente ambiente de incertidumbre.