bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dasatinib reverses drug resistance by downregulating MDR1 and Survivin in Burkitt lymphoma cells
Authors: Tabata Mitsuki , Tsubaki Masanobu , Takeda Tomoya , Tateishi Keisuke , Tsurushima Katsumasa , Imano Motohiro , Satou Takao , Ishizaka Toshihiko , Nishida Shozo 
Published: March 2020

Abstract
Background
Current chemotherapies for Burkitt lymphoma (BL) have dramatically improved its clinical outcome. However, chemoresistance can lead to chemotherapy failure and very poor prognosis; thus, novel strategies are urgently required for patients with drug-resistant BL. To investigate the mechanisms underlying drug resistance in BL, we established drug-resistant BL cell lines: HS-Sultan/ADM (adriamycin-resistant), HS-Sultan/VCR (vincristine-resistant), HS-Sultan/DEX (dexamethasone-resistant), and HS-Sultan/L-PAM (melphalan-resistant).

Methods
Drug transporter and survival factor expression were investigated the using western blotting and real time polymerase chain reaction. Cell survival was analyzed by trypan blue dye exclusion method.

Results
The established cell lines acquired cross-resistance to adriamycin, vincristine, dexamethasone, and melphalan and exhibited 50% inhibitory concentration values 106-, 40-, 81-, and 45-fold higher than the parental cell lines, respectively. We found that protein and mRNA expression of MDR1 and Survivin were higher in drug-resistant BL cells than in the parent cells. Treatment with verapamil, an MDR1 inhibitor, or Survivin siRNA alongside each anti-cancer drug suppressed the proliferation of all drug-resistant BL cells. Src kinase activity was higher in all resistant cell lines than the parental cells; suppressing Src with dasatinib restored drug sensitivity by reducing MDR1 and Survivin expression.

Conclusions
MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.
Learning clinical reasoning: how virtual patient case format and prior knowledge interact
Authors: Kiesewetter Jan , Sailer Michael , Jung Valentina M. , Schönberger Regina , Bauer Elisabeth , Zottmann Jan M. , Hege Inga , Zimmermann Hanna , Fischer Frank , Fischer Martin R. 
Published: March 2020

Abstract
Introduction
Clinical reasoning has been fostered with varying case formats including the use of virtual patients. Existing literature points to different conclusions regarding which format is most beneficial for learners with diverse levels of prior knowledge. We designed our study to better understand which case format affects clinical reasoning outcomes and cognitive load, dependent on medical students’ prior knowledge.

Methods
Overall, 142 medical students (3 rd to 6 th year) were randomly assigned to either a whole case or serial cue case format. Participants worked on eight virtual patients in their respective case format. Outcomes included diagnostic accuracy, knowledge, and cognitive load.

Results
We found no effect of case format on strategic knowledge scores pre- vs post-test (whole case learning gain = 3, 95% CI. -.01 to .01, serial cue learning gain = 3, 95% CI. -.06 to .00 p = .50). In both case formats, students with high baseline knowledge (determined by median split on the pre-test in conceptual knowledge) benefitted from learning with virtual patients (learning gain in strategic knowledge = 5, 95% CI .03 to .09, p = .01) while students with low prior knowledge did not (learning gain = 0, 95%CI −.02 to .02). We found no difference in diagnostic accuracy between experimental conditions (difference = .44, 95% CI −.96 to .08, p = .22), but diagnostic accuracy was higher for students with high prior knowledge compared to those with low prior knowledge (difference = .8, 95% CI 0.31 to 1.35, p < .01). Students with low prior knowledge experienced higher extraneous cognitive load than students with high prior knowledge (multiple measurements, p < .01).

Conclusions
The whole case and serial cue case formats alone did not affect students’ knowledge gain or diagnostic accuracy. Students with lower knowledge experienced increased cognitive load and appear to have learned less from their interaction with virtual patients. Cognitive load should be taken into account when attempting to help students learn clinical reasoning with virtual patients, especially for students with lower knowledge.
Developing a toolkit for engagement practice: sharing power with communities in priority-setting for global health research projects
Authors: Pratt Bridget 
Published: March 2020

Abstract
Background
Communities’ engagement in priority-setting is a key means for setting research topics and questions of relevance and benefit to them. However, without attention to dynamics of power and diversity, their engagement can be tokenistic. So far, there remains limited ethical guidance on how to share power with communities, particularly those considered disadvantaged and marginalised, in global health research priority-setting. This paper generates a comprehensive, empirically-based “ethical toolkit” to provide such guidance, further strengthening a previously proposed checklist version of the toolkit. The toolkit places community engagement and power-sharing at the heart of priority-setting for global health research projects.

Methods
A two part method was used to generate a revised toolkit. Part one was conceptual, consisting of novel analysis of empirical data (previously collected as part of the same overall project) to identify additional concepts relevant to power-sharing between researchers and communities in global health research priority-setting. Part two was empirical, seeking feedback on the initial checklist version of the toolkit in interviews with researchers, ethicists, community engagement practitioners, and community organisation staff.

Results
The conceptual process identified two additional components of engagement and six additional features that affect who defines, who participates, and who is heard in research priority-setting. New ethical considerations related to sharing power in global health research priority-setting are articulated in relation to those components and features. Interviewees provided suggestions for revising the toolkit’s content and language. The implications of these suggestions and the analytic process for the toolkit are described.

Conclusions
The resultant toolkit is a reflective project planning aid for researchers and their community partners to employ before priority-setting is undertaken for global health research projects. It consists of three worksheets (to be completed collectively) and a companion document detailing how to use them. It is more comprehensive than the initial toolkit, as worksheet questions for discussion cover all phases of priority-setting.
An evaluation of paediatric tinnitus services in UK National Health Service audiology departments
Authors: Smith Harriet , Fackrell Kathryn , Kennedy Veronica , Barry Johanna G. , Broomhead Emily , Hoare Derek J. 
Published: March 2020

Abstract
Background
Whilst evidence indicates many children experience troublesome tinnitus, specialist services for children are far less established than those available for adults. To date, there is limited understanding of how paediatric tinnitus is managed in the UK, and to what extent current practice reflects what is recommended. This service evaluation aimed to 1) profile how tinnitus in children is managed in UK clinical practice, and assess to what extent care provided by services reflects advice included in the British Society of Audiology (BSA) Tinnitus in Children Practice Guidance, 2) collate clinician opinions on how services may be optimised, and 3) identify common problems experienced by children who present with bothersome tinnitus in clinic.

Methods
As part of a larger survey, eight questions regarding services for paediatric tinnitus were distributed to UK NHS audiology services via email and social media. Representatives from eighty-seven services responded between July and September 2017.

Results
Fifty-three percent of respondents reported that their department provided a paediatric tinnitus service. Among these services, there was widespread use of most BSA recommended assessments and treatments. Less widely used practices were the assessment of mental health (42%), and the use of psychological treatment approaches; cognitive behavioural therapy (CBT) (28%), mindfulness (28%), and narrative therapy (14%). There was varied use of measurement tools to assess tinnitus in children, and a minority of respondents reported using adult tinnitus questionnaires with children. Frequently reported tinnitus-related problems presented by children were sleep difficulties, concentration difficulties at school, situation-specific concentration difficulties, and emotional distress.

Conclusions
Approaches used to manage children with troublesome tinnitus in UK NHS services are largely consistent and reflective of the current practice guidance. However, findings from this study indicate specialist staff training, access to child-specific tools, and the treatment and referral of children with tinnitus-related psychological problems represent key areas in need of optimisation.
Pain-related fear in adolescents with chronic musculoskeletal pain: process evaluation of an interdisciplinary graded exposure program
Authors: Dekker C. , van Haastregt J. C. M. , Verbunt J. A. M. C. F. , de Jong J. R. , van Meulenbroek T. , Pernot H. F. M. , van Velzen A. D. , Bastiaenen C. H. G. , Goossens M. E. J. B. 
Published: March 2020

Abstract
Background
For studying the effectiveness of treatment, it is important to check whether a new treatment is performed as originally described in the study-protocol.

Objectives
To evaluate whether an interdisciplinary graded exposure program, for adolescents with chronic musculoskeletal pain reporting pain-related fear, was performed according to protocol, and whether it is feasible to implement the program in rehabilitation care.

Methods
A process evaluation where quantitative and qualitative data on participant characteristics (adolescents, parents and therapists), attendance and participants’ opinion on the program were collected, by means of registration forms, questionnaires and group interviews. To evaluate treatment fidelity, audio and video recordings of program sessions were analyzed.

Results
Thirty adolescents were offered the program, of which 23 started the program. Adolescents attended on average 90% of the sessions. At least one parent per adolescent participated in the program. Analysis of 20 randomly selected recordings of treatment sessions revealed that treatment fidelity was high, since 81% of essential treatment elements were offered to the adolescents. The program was considered client-centered by adolescents and family-centered by parents. Treatment teams wished to continue offering the program in their center.

Conclusion
The interdisciplinary graded exposure program was performed largely according to protocol, and therapists, adolescents and their parents had a favorable opinion on the program. Implementation of the program in rehabilitation care is considered feasible.

Trial registration
Clinicaltrials.gov ID: NCT02181725 (7 February 2014).
Neurological and psychiatric safety of tafenoquine in Plasmodium vivax relapse prevention: a review
Authors: Duparc Stephan , Chalon Stephan , Miller Scott , Richardson Naomi , Toovey Stephen 
Published: March 2020

Abstract
Background
Tafenoquine is an 8-aminoquinoline anti-malarial drug recently approved as a single-dose (300 mg) therapy for Plasmodium vivax relapse prevention, when co-administered with 3-days of chloroquine or other blood schizonticide. Tafenoquine 200 mg weekly after a loading dose is also approved as travellers’ prophylaxis. The development of tafenoquine has been conducted over many years, using various dosing regimens in diverse populations.

Methods
This review brings together all the preclinical and clinical data concerning tafenoquine central nervous system safety. Data were assembled from published sources. The risk of neuropsychiatric adverse events (NPAEs) with single-dose tafenoquine (300 mg) in combination with chloroquine to achieve P. vivax relapse prevention is particularly examined.

Results
There was no evidence of neurotoxicity with tafenoquine in preclinical animal models. In clinical studies in P. vivax relapse prevention, nervous system adverse events, mainly headache and dizziness, occurred in 11.4% (36/317) of patients with tafenoquine (300 mg)/chloroquine versus 10.2% (19/187) with placebo/chloroquine; and in 15.5% (75/483) of patients with tafenoquine/chloroquine versus 13.3% (35/264) with primaquine (15 mg/day for 14 days)/chloroquine. Psychiatric adverse events, mainly insomnia, occurred in 3.8% (12/317) of patients with tafenoquine/chloroquine versus 2.7% (5/187) with placebo/chloroquine; and in 2.9% (14/483) of patients with tafenoquine/chloroquine versus 3.4% (9/264) for primaquine/chloroquine. There were no serious or severe NPAEs observed with tafenoquine (300 mg)/chloroquine in these studies.

Conclusions
The risk:benefit of single-dose tafenoquine/chloroquine in P. vivax relapse prevention is favourable in the presence of malaria, with a low risk of NPAEs, similar to that seen with chloroquine alone or primaquine/chloroquine.
Fenobody and RANbody-based sandwich enzyme-linked immunosorbent assay to detect Newcastle disease virus
Authors: Ji Pinpin , Zhu Jiahong , Li Xiaoxuan , Fan Wenqi , Liu Qianqian , Wang Kun , Zhao Jiakai , Sun Yani , Liu Baoyuan , Zhou En-Min , Zhao Qin 
Published: March 2020

AbstractBackgroundTraditional sandwich enzyme-linked immunosorbent assay (ELISA) using polyclonal and monoclonal antibodies as reagents presents several drawbacks, including limited amounts, difficulty in permanent storage, and required use of a secondary antibody. Nanobodies can be easily expressed with different systems and fused with several tags in their tertiary structure by recombinant technology, thus offering an effective detection method for diagnostic purposes. Recently, the fenobody (ferritin-fused nanobody) and RANbody (nanobody-fused reporter) have been designed and derived from the nanobody for developing the diagnostic immunoassays. However, there was no report about developing the sandwich ELISA using the fenobody and RANbody as pairing reagents.ResultsA platform for developing a sandwich ELISA utilizing fenobody as the capture antibody and RANbody as the detection antibody was firstly designed in the study. Newcastle disease virus (NDV) was selected as the antigen, from which 13 NDV-specific nanobodies were screened from an immunized Bactrian camel. Then, 5 nanobodies were selected to produce fenobodies and RANbodies. The best pairing of fenobodies (NDV-fenobody-4, 800 ng/well) and RANbodies (NDV-RANbody-49, 1:10) was determined to develop the sandwich ELISA for detecting NDV. The detection limits of the assay were determined to be 22of hemagglutination (HA) titers and 10 ng of purified NDV particles. Compared with two commercial assays, the developed assay shows higher sensitivity and specificity. Meanwhile, it exhibits 98.7% agreement with the HA test and can detect the reference NDV strains belonging to Class II but not Class I.ConclusionsIn the presented study, the 13 anti-NDV nanobodies binding the NDV particles were first produced. Then, for the first time, the sandwich ELISA to detect the NDV in the different samples has been developed using the fenobody and RANbody as reagents derived from the nanobodies. Considering the rapidly increasing generation of nanobodies, the platform can reduce the cost of production for the sandwich ELISA and be universally used to develop assays for detecting other antigens.
Surface chemistry governs the sub-organ transfer, clearance and toxicity of functional gold nanoparticles in the liver and kidney
Authors: Li Xue , Wang Bing , Zhou Shuang , Chen Wei , Chen Hanqing , Liang Shanshan , Zheng Lingna , Yu Hongyang , Chu Runxuan , Wang Meng , Chai Zhifang , Feng Weiyue 
Published: March 2020

Abstract
Background
To effectively applied nanomaterials (NMs) in medicine, one of the top priorities is to address a better understanding of the possible sub-organ transfer, clearance routes, and potential toxicity of the NMs in the liver and kidney.

Results
Here we explored how the surface chemistry of polyethylene glycol (PEG), chitosan (CS), and polyethylenimine (PEI) capped gold nanoparticles (GNPs) governs their sub-organ biodistribution, transfer, and clearance profiles in the liver and kidney after intravenous injection in mice. The PEG-GNPs maintained dispersion properties in vivo, facilitating passage through the liver sinusoidal endothelium and Disse space, and were captured by hepatocytes and eliminated via the hepatobiliary route. While, the agglomeration/aggregation of CS-GNPs and PEI-GNPs in hepatic Kupffer and endothelial cells led to their long-term accumulation, impeding their elimination. The gene microarray analysis shows that the accumulation of CS-GNPs and PEI-GNPs in the liver induced obvious down-regulation of Cyp4a or Cyp2b related genes, suggesting CS-GNP and PEI-GNP treatment impacted metabolic processes, while the PEI-GNP treatment is related with immune responses.

Conclusions
This study demonstrates that manipulation of nanoparticle surface chemistry can help NPs selectively access distinct cell types and elimination pathways, which help to clinical potential of non-biodegradable NPs.
Enhancement of sciatic nerve regeneration with dual delivery of vascular endothelial growth factor and nerve growth factor genes
Authors: Fang Zhiwei , Ge Xuemei , Chen Xuan , Xu Yang , Yuan Wei-En , Ouyang Yuanming 
Published: March 2020

Abstract
Background
Peripheral nerve injury is one common clinical disease worldwide, in which sciatic nerve is anatomically the most challenging to regenerate given its length and large cross-sectional area. For the present, autologous nerve grafting remains to be the most ideal strategy when treating with sciatic nerve injury. However, this method sacrifices healthy nerves and requires highly intensive surgery, still calling for other advanced alternatives for nerve grafting.

Results
In this study, we utilized previously well-established gene delivery system to dually deliver plasmid DNA (pDNA) encoding vascular endothelial growth factor (VEGF) and nerve growth factor (NGF), exploring therapeutics for sciatic nerve injury. Low-molecular-weight branched polyethylenimine (bPEI) was constructed as the backbone structure of gene vectors, and it was further crosslinked to synthesize degradable polycations via the conjugation of dialdehydes. Potential synergistic effect between VEGF and NGF proteins were observed on rat sciatic nerve crush injury model in this study.

Conclusions
We concluded that dual delivery of plasmid VEGF and NGF as gene therapy could enhance sciatic nerve regeneration.
Accelerometer-measured physical activity and sedentary time in a cohort of US adults followed for up to 13 years: the influence of removing early follow-up on associations with mortality
Authors: Tarp Jakob , Hansen Bjørge Herman , Fagerland Morten Wang , Steene-Johannessen Jostein , Anderssen Sigmund Alfred , Ekelund Ulf 
Published: March 2020

Abstract
Background
Observational studies linking physical activity with mortality are susceptible to reverse causation bias from undiagnosed and prevalent diseases. Researchers often attempt to deal with reverse causation bias by excluding deaths occurring within the first 1 or 2 years from the analysis, but it is unclear if excluding deaths within this time-frame is sufficient to remove bias.

Methods
We examined associations between total and intensity-specific physical activity and sedentary time with all-cause mortality in a prospective cohort of 3542 individuals from the 2003–2006 NHANES cycles. In order to yield measures of association hypothesized as minimally influenced by reverse causation bias the primary analysis excluded individuals with < 5 years of follow-up. Accelerometer-measured physical activity was linked with recently updated vital status from the National Death Index with a median follow-up of 10.8 years.

Results
Hazard ratios (95% confidence intervals) were 0.74 (0.53, 1.04), 0.52 (0.37, 0.73), and 0.61 (0.38, 1.01) for ascending quartiles of total physical activity against the least active reference. Hazard ratios for ascending moderate-to-vigorous physical activity quartiles against the reference were 0.67 (0.47, 1.96), 0.67 (0.47, 0.95), and 0.68 (0.39, 1.18). Associations for light intensity physical activity and sedentary time were smaller in magnitude and all confidence intervals included unity. Total activity and moderate-to-vigorous physical activity hazard ratios from analyses only excluding deaths within the first 2 years were inflated by 13 and 26% relative to analysis restricted to ≥5 years of follow-up.

Conclusions
The pattern of associations suggested total physical activity and moderate-to-vigorous physical activity were associated with lower mortality after more than 10 years of follow-up and excluding the first 5 years of observation time to minimize the impact of reverse causation bias. Excluding deaths within the first 2 years appeared insufficient to minimize the impact of reserve causation bias.
Gastrointestinal mixed adenoneuroendocrine carcinoma: a population level analysis of epidemiological trends
Authors: Wang Jiakun , He Aoxiao , Feng Qian , Hou Ping , Wu Junjun , Huang Zhihao , Xiao Zhouqing , Sun Chi , Liao Wenjun , Wu Linquan 
Published: March 2020

Abstract
Background
The rise in incidence and mortality of gastrointestinal mixed adenoneuroendocrine carcinoma (MANEC) has not been well focused. The aim of our study was to examine epidemiological trends in incidence and incidence-based (IB) mortality of gastrointestinal MANEC at a population level.

Methods
The incidence and IB mortality of gastrointestinal MANEC as well as data on affected patients from 2000 to 2016 were obtained from the Surveillance, Epidemiology, and End Results database. Trends in incidence and IB mortality were assessed using Joinpoint regression. The Kaplan–Meier method and log-rank test were used for survival analysis. Cox proportional hazards regression was used to identify independent predictors of mortality.

Results
581 patients diagnosed with gastrointestinal MANEC were enrolled. Gastrointestinal MANEC incidence was 0.23 cases per 1,000,000 individuals in 2000 and 1.16 cases per 1,000,000 individuals in 2016, with an annual percent change (APC) of 8.0% (95% CI 5.7–10.3%, P < 0.05). IB mortality also showed a sustained increase (APC 12.9%, 95% CI 9.0–16.8%, P < 0.05). In Cox regression analysis, age at diagnosis, tumor grade and stage, lymph node metastasis, surgery, and tumor size were independently associated with mortality. Median survival was 75 months (95% CI 60–128 months). Median survival of appendiceal MANEC was significantly longer than that of cecal MANEC (115 vs. 31 months; P < 0.001).

Conclusions
We found a sustained and rapid increase both in incidence and IB mortality of gastrointestinal MANEC, manifesting that there has been no significant improvement in patient outcomes, nor progress in prevention and treatment. Additional resources should be devoted to gastrointestinal MANEC research.