bluuebunny/crossref_metadata_2025_split huggingface dataset:
De-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses CML cell apoptosis and contributes to Imatinib resistance
Authors: Nie Zi-Yuan , Yao Min , Yang Zhan , Yang Lin , Liu Xiao-Jun , Yu Jing , Ma Ying , Zhang Nan , Zhang Xiao-Yan , Liu Meng-Han , Jiang Ling-Ling , Luo Jian-Min 
Published: January 2020

Abstract
Background
STAT5 plays an important role in the transformation of hematopoietic cells by BCR-ABL. However, the downstream target genes activated by STAT5 in chronic myeloid leukemia (CML) cells remain largely unclear. Here, we investigated the mechanistic functional relationship between STAT5A-regulated microRNA and CML cell apoptosis.

Methods
The expression of USP15, Caspase-6, STAT5A-regulated miR-202-5p and STAT5A was detected by qRT-PCR and Western blotting in CML cell lines and PBMCs of CML patients. Cell apoptosis was evaluated by flow cytometry. Both gain- and loss-of-function experiments were used to investigate the roles of USP15, miR-202-5p and STAT5A in CML. Luciferase reporter assay detected the effect of miR-202-5p on USP15 expression. Xenograft animal model was used to test the effect of anti-miR-202-5p and pimozide on K562 cell xenograft growth.

Results
USP15 expression was significantly downregulated in CML cell lines and PBMCs of CML patients. Depletion of USP15 increased, whereas overexpression of USP15 reduced the resistance of CML cells to Imatinib. Further, decreased deubiquitinating activity of USP15 by USP15 downregulation led to reduced caspase-6 level, thus attenuating CML cell apoptosis. Mechanistically, miR-202-5p was upregulated in K562G cells and negatively regulated USP15 expression by directly targeting USP15 3′-UTR. Correspondingly, upregulation of miR-202-5p enhanced the resistance of CML cells to Imatinib by inhibiting cell apoptosis. Importantly, STAT5A was upregulated in CML cells and directly activated miR-202-5p transcription by binding to the pre-miR-202 promoter. Pimozide induced CML cell apoptosis and significantly reduced K562 cell xenograft growth in vivo by blocking STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis.

Conclusions
we provide the first evidence that de-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses the apoptosis of CML cells, targeting this pathway might be a promising therapeutic approach for the treatment of CML.
Musashi2 promotes EGF-induced EMT in pancreatic cancer via ZEB1-ERK/MAPK signaling
Authors: Sheng Weiwei , Shi Xiaoyang , Lin Yiheng , Tang Jingtong , Jia Chao , Cao Rongxian , Sun Jian , Wang Guosen , Zhou Lei , Dong Ming 
Published: January 2020

Abstract
Background
Our previous study showed Musashi2 (MSI2) promoted chemotherapy resistance and pernicious biology of pancreatic cancer (PC) by down-regulating Numb and p53. We further explored the novel molecular mechanism involving its oncogenic role in PC development.

Methods
We investigated the potential role and mechanism of MSI2 in EGF-induced EMT in PC in vitro and vivo.

Results
EGF enhanced EGFR (epidermal growth factor receptor) phosphorylation, induced EMT and activated ZEB1-ERK/MAPK signaling in 2 PC cells. However, MSI2 silencing reversed EGF stimulated function, including inhibiting EGF-promoted EMT-like cell morphology and EGF-enhanced cell invasion and migration. Meanwhile, MSI2 silencing inhibited EGF-enhanced EGFR phosphorylation at tyrosine 1068 and reversed EGF-induced change of the key proteins in EMT and ZEB1-ERK/MAPK signaling (ZEB1, E-cad, ZO-1, β-catenin, pERK and c-Myc). Additionally, MSI2 was co-stained and co-immunoprecipitated with ZEB1, pERK and c-Myc in PC cells by IF and co-IP, implying a close interaction between them. In vivo, MSI2 silencing inhibited pancreatic tumor size in situ and distant liver metastases. A close relationship of MSI2 with EMT and ZEB1-ERK/MAPK signaling were also observed in vivo and human PC samples, which coordinately promoted the poor prognosis of PC patients.

Conclusions
MSI2 promotes EGF-induced EMT in PC via ZEB1-ERK/MAPK signaling.
International randomised controlled trial for the treatment of newly diagnosed EWING sarcoma family of tumours – EURO EWING 2012 Protocol
Authors: Anderton Jennifer , Moroz Veronica , Marec-Bérard Perrine , Gaspar Nathalie , Laurence Valerie , Martín-Broto Javier , Sastre Ana , Gelderblom Hans , Owens Cormac , Kaiser Sophie , Fernández-Pinto Melissa , Fenwick Nicola , Evans Abigail , Strauss Sandra , Whelan Jeremy , Wheatley Keith , Brennan Bernadette 
Published: January 2020

Abstract
Background
Although there have been multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT) and these have been conducted over many years and involved many international cooperative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens: (1) vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or busulfan and mephalan (VAI/VAC/BuMel) consolidation and (2) vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or busulfan and mephalan (IE/VC/VAI/BuMel) consolidation (randomisation 1, or R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome.

Methods
EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomly assigned at two different time points: at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes or metastases (or both), and achievement of local control at the end of treatment.

Discussion
This study will establish which is the “standard regimen” of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and consider that international cooperation is needed to provide answers in a timely manner.

Trial registration
Registered with EudraCT number 2012-002107-17 on 26 February 2012. Registered with ISRCTN number 92192408 on 4 November 2013.
Infection control and risk factors for acquisition of carbapenemase-producing enterobacteriaceae. A 5 year (2011–2016) case-control study
Authors: Segagni Lusignani Luigi , Presterl Elisabeth , Zatorska Beata , Van den Nest Miriam , Diab-Elschahawi Magda 
Published: January 2020

Abstract
Background
Carbapenemase-producing enterobacteriaceae (CPE) are a major threat for severely ill patients. However, only limited data on the epidemiology and on evidence-based infection prevention and control measures are available. The aim of this study was to investigate the epidemiology of patients with CPE, characterizing the CPE isolates by their resistance mechanisms and genetic similarity, to explore risk factors for their acquisition, and to evaluate the effectiveness of the current CPE infection control measures.

Methods
A retrospective case-control study was performed using data from 2011 to 2016 in a 1800-bed academic hospital in Central Europe, where risk-based screening at patients´ admission is performed. Carbapenem resistance mechanisms of all carbapenem resistant enterobacteriaceae from patients admitted during this period were investigated. Clinical data of the CPE-positive patients were analysed and compared to a matched control group (case-control ratio of 1:3). We performed univariate and multivariate statistical analysis to identify risk factors for CPE acquisition.

Results
Of 621,623 admitted patients in the study period, 75 patients with carriage of carbapenem resistant enterobacteriaceae were included (0.12/1000 admittances). Carbapenemase-encoding genes were detected in 77.3% (58/75) of patients with carbapenem-resistant enterobacteriaceae. The enzyme blaOXA-48 was found in 34.5% (20/58), blaKPC in 29.3% (17/58), blaNDM enzymes in 20.7% (12/58) and blaVIM in 8.6% (5/58) of the isolates. The overall mortality among CPE patients was 25.9% (15/58) and attributable mortality of CPE was 53.3% (8/15). Multivariate analysis revealed four risk factors to be independent predictors of CPE carriage: the length of hospital admission > 20 days (AOR: 4.9, 95% CI: 1.4–15.5; P <  0.001), hospital admission within the previous year (AOR: 22.3, 95% CI: 3.9–88.4; P <  0.001), exposure to a healthcare facility in a country with high or unknown carbapenem-resistant enterobacteriaceae prevalence 3 months before admission (AOR: 11.8, 95% CI: 2.2–63.2; P <  0.01) and the use of antibiotics longer than 10 days (AOR: 5.2, 95% CI: 1.4–35.9; P <  0.05). The current risk-based screening strategy at hospital admission could not identify 37 (63.8%) of the 58 CPE-positive patients. Epidemiological investigation and genotyping revealed that no outbreaks due to CPE occurred during this period.

Conclusion
Overall, the CPE carriage rate in patients was very low, the attributable mortality, however, is alarming (53%). BlaOXA-48 and blaKPC were the main cause of carbapenem resistance in enterobacteriaceae. Although the strict application of standard infection control measures was effective for prevention of outbreaks in this setting, an enlarged risk based targeted screening strategy has to be implemented.
Effect of the micro-environment on α-synuclein conversion and implication in seeded conversion assays
Authors: Candelise Niccolo , Schmitz Matthias , Thüne Katrin , Cramm Maria , Rabano Alberto , Zafar Saima , Stoops Erik , Vanderstichele Hugo , Villar-Pique Anna , Llorens Franc , Zerr Inga 
Published: January 2020

Abstract
Background
α-Synuclein is a small soluble protein, whose physiological function in the healthy brain is poorly understood. Intracellular inclusions of α-synuclein, referred to as Lewy bodies (LBs), are pathological hallmarks of α-synucleinopathies, such as Parkinson’s disease (PD) or dementia with Lewy bodies (DLB).

Main body
Understanding of the molecular basis as well as the factors or conditions promoting α-synuclein misfolding and aggregation is an important step towards the comprehension of pathological mechanism of α-synucleinopathies and for the development of efficient therapeutic strategies. Based on the conversion and aggregation mechanism of α-synuclein, novel diagnostic tests, such as protein misfolding seeded conversion assays, e.g. the real-time quaking-induced conversion (RT-QuIC), had been developed. In diagnostics, α-synuclein RT-QuIC exhibits a specificity between 82 and 100% while the sensitivity varies between 70 and 100% among different laboratories. In addition, the α-synuclein RT-QuIC can be used to study the α-synuclein-seeding-characteristics of different α-synucleinopathies and to differentiate between DLB and PD.

Conclusion
The variable diagnostic accuracy of current α-synuclein RT-QuIC occurs due to different protocols, cohorts and material etc.. An impact of micro-environmental factors on the α-synuclein aggregation and conversion process and the occurrence and detection of differential misfolded α-synuclein types or strains might underpin the clinical heterogeneity of α-synucleinopathies.
Warming-induced permafrost thaw exacerbates tundra soil carbon decomposition mediated by microbial community
Authors: Feng Jiajie , Wang Cong , Lei Jiesi , Yang Yunfeng , Yan Qingyun , Zhou Xishu , Tao Xuanyu , Ning Daliang , Yuan Mengting M. , Qin Yujia , Shi Zhou J. , Guo Xue , He Zhili , Van Nostrand Joy D. , Wu Liyou , Bracho-Garillo Rosvel G. , Penton C. Ryan , Cole James R. , Konstantinidis Konstantinos T. , Luo Yiqi , Schuur Edward A. G. , Tiedje James M. , Zhou Jizhong 
Published: January 2020

AbstractBackgroundIt is well-known that global warming has effects on high-latitude tundra underlain with permafrost. This leads to a severe concern that decomposition of soil organic carbon (SOC) previously stored in this region, which accounts for about 50% of the world’s SOC storage, will cause positive feedback that accelerates climate warming. We have previously shown that short-term warming (1.5 years) stimulates rapid, microbe-mediated decomposition of tundra soil carbon without affecting the composition of the soil microbial community (based on the depth of 42684 sequence reads of 16S rRNA gene amplicons per 3 g of soil sample).ResultsWe show that longer-term (5 years) experimental winter warming at the same site altered microbial communities (p< 0.040). Thaw depth correlated the strongest with community assembly and interaction networks, implying that warming-accelerated tundra thaw fundamentally restructured the microbial communities. Both carbon decomposition and methanogenesis genes increased in relative abundance under warming, and their functional structures strongly correlated (R2> 0.725,p< 0.001) with ecosystem respiration or CH4flux.ConclusionsOur results demonstrate that microbial responses associated with carbon cycling could lead to positive feedbacks that accelerate SOC decomposition in tundra regions, which is alarming because SOC loss is unlikely to subside owing to changes in microbial community composition.
Referee height influences decision making in British football leagues
Authors: McCarrick Dane , Brewer Gayle , Lyons Minna , Pollet Thomas V. , Neave Nick 
Published: January 2020

Abstract
Background
Male height is positively associated with social dominance, and more agonistic/competitive behaviours. However, the ‘Napoleon complex’ or ‘small man syndrome’ suggests that smaller males are more assertive and punitive to compensate for lack of height and social dominance. Here, we assess possible relationships between height and punitive behaviours in a real-world setting.

Methods
Using a non-experimental correlational design, we analysed data on 61 male association football referees from four professional leagues in England, and explored relationships between their height and punitive behaviours in the form of yellow cards, red cards and penalties given during an entire season.

Results
Overall there was no effect of referee height on fouls awarded. However, there was a main effect of height on yellow cards awarded, with shorter referees issuing more yellow cards. The same effect was found for red cards and penalties, though this was moderated by league. In the lower leagues, more red cards and penalties were awarded by relatively shorter referees, but in the higher leagues more red cards and penalties were awarded by relatively taller referees.

Conclusions
These findings from real-life public dominance encounters show that height is associated with punitive behaviours, but is sensitive to context.
Correlation between urinary biomarker and organ failure in patients with sepsis and patients after esophagectomy: a prospective observational study
Authors: Mitaka Chieko , Ishibashi Chika , Kawagoe Izumi , Hashimoto Takashi , Takahashi Makoto , Satoh Daizoh , Inada Eiichi 
Published: January 2020

Abstract
Background
Neutrophil gelatinase-associated lipocalin (NGAL) is a diagnostic marker for acute kidney injury (AKI). NGAL expression is highly induced not only in kidney injury but also in bacterial infection, inflammation, and cancer. The factors regulating NGAL expression are proinflammatory cytokines, and plasma NGAL levels have been increased in septic shock. However, there are no reports of urine neutrophil gelatinase-associated lipocalin (uNGAL) levels after open esophagectomy.

Methods
We prospectively enrolled critically ill patients, including patients with sepsis (n = 45) and patients who underwent open esophagectomy (n = 40). We compared vital signs, PaO2/FIO2, serum C-reactive protein (CRP) levels, acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score, and uNGAL levels between the sepsis group and the esophagectomy group. Then, we investigated whether uNGAL is associated with the severity of illness and organ failure, and whether uNGAL is a reliable screening test for AKI.

Results
The median uNGAL levels, APACHE II score, SOFA score, and serum CRP levels were significantly (p < 0.001) higher in the sepsis group than in the esophagectomy group on ICU day 1. In the sepsis group, uNGAL levels were significantly (p < 0.05) correlated with APACHE II score and SOFA score on intensive care unit (ICU) day 1, 2, and 3. In the esophagectomy group, uNGAL levels were significantly (p < 0.05) correlated with SOFA score on ICU day 3 and 4. In the sepsis group, 1 patient developed AKI stage 2 and 6 patients developed AKI stage 3. No patients developed AKI in the esophagectomy group. In a total of 85 patients of this study, 80 patients had an abnormal value of uNGAL and only 7 patients (8.7%) of those 80 patients developed AKI.

Conclusions
uNGAL levels were correlated with the severity of illness and organ failure in critically ill patients. The value of uNGAL increases under the surgical and inflammatory responses, thereby losing a significance of a screening test of AKI in critically ill patients.
Change theory and theory of change: what’s the difference anyway?
Authors: Reinholz Daniel L. , Andrews Tessa C. 
Published: January 2020

AbstractThis commentary focuses on the difference between a theory of change and change theory, as it relates to systemic change projects in STEM higher education. A theory of change is project-specific and related to evaluation. It makes the underlying rationale of a project explicit, which supports planning, implementation, and assessment of the project. In addition, a theory of change is often required by funding agencies as part of grant proposals. In contrast, change theories represent theoretical and empirically grounded knowledge about how change occurs that goes beyond any one project. Ideally, a theory of change is informed by change theories. This essay describes the connections between a theory of change and change theory and provides examples of how change theory can inform a project’s theory of change. Grounding projects in change theory allows change agents to draw on existing knowledge and to better contribute to our collective knowledge about how to achieve meaningful change in STEM higher education.
Comparative omics of CCM signaling complex (CSC)
Authors: Abou-Fadel Johnathan , Smith Mark , Falahati Kamran , Zhang Jun 
Published: January 2020

Abstract
Background
Cerebral cavernous malformations (CCMs), a major neurosurgical condition, characterized by abnormally dilated intracranial capillaries, result in increased susceptibility to stroke. KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3) have been identified as causes of CCMs in which at least one of them is disrupted in most familial cases. Our goal is to identify potential biomarkers and genetic modifiers of CCMs, using a global comparative omics approach across several in vitro studies and multiple in vivo animal models. We hypothesize that through analysis of the CSC utilizing various omics, we can identify potential biomarkers and genetic modifiers, by systemically evaluating effectors and binding partners of the CSC as well as second layer interactors.

Methods
We utilize a comparative omics approach analyzing multiple CCMs deficient animal models across nine independent studies at the genomic, transcriptomic, and proteomic levels to dissect alterations in various signaling cascades.

Results
Our analysis revealed a large set of genes that were validated across multiple independent studies, suggesting an important role for these identified genes in CCM pathogenesis.

Conclusion
This is currently one of the largest comparative omics analysis of CCM deficiencies across multiple models, allowing us to investigate global alterations among multiple signaling cascades involved in both angiogenic and non-angiogenic events and to also identify potential biomarker candidates of CCMs, which can be used for new therapeutic strategies.
Post-stroke sleep disorders in Egyptian patients by using simply administered questionnaires: a study from Ain Shams University
Authors: Mansour Alia H. , Ayad Maged , El-Khayat Naglaa , El Sadek Ahmed , Alloush Taha K. 
Published: January 2020

Abstract
Introduction
Stroke is a leading cause of disability worldwide with grave morbidity and mortality. Sleep and stroke have a definite intermingling neuropathological relationship, so along with expeditious acute management, efficient secondary prevention and consistent rehabilitation, sleep disorders’ management has a hand in offering a medical service up to the mark.

Objective
Screening of sleep disorders’ prevalence in patients who survived a previous stroke by applying simple questionnaires and to determine the correlation between these disorders and stroke’s demographic, clinical, and risk factor variables.

Methods
Cross-sectional prospective study on 75 stroke patients from stroke outpatient clinic and all patients were subjected to answer a sheet of sleep questionnaire, Pittsburg Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Apnea/Hypopnea Index (AHI), Arabic versions. Results
A total of 70.6 % were found to have sleep disorders, 61.6% had poor sleep quality, 20% had a severe degree of excessive day time sleepiness (EDS). Sleep disorders were more prevalent in the moderate severity of stroke by NIHSS and in the first 1–4 weeks. There was no correlation between the occurrence of sleep disorders and the site of the lesion.

Conclusion
Sleep disorders are broadly prevalent after a stroke. Resulting damage impedes the functional outcome. Simple questionnaires are easy applicable methods for screening of such disorders in post-stroke patients. Guidelines needed regarding screening and management of sleep disorders after a stroke.
Heart versus brain: a case of ictal asystole in temporal lobe epilepsy
Authors: Yassin Ahmed , Aldabbour Belal , Bagić Anto , Urban Alexandra 
Published: January 2020

Abstract
Background
Ictal asystole is a rare phenomenon. Most reported cases are in persons with long-standing focal epilepsy originating from the temporal lobe. Its occurrence may complicate the clinical presentation or delay diagnosis, and it is thought to be associated with increased risk of sudden unexpected death in epilepsy.

Case presentation
We report the case of a 55-year-old female person with epilepsy who suffered ictal asystole for 10 s while under monitoring at the Epilepsy Monitoring Unit. We then review briefly the pathophysiology and current management modalities for this phenomenon.

Discussion
The first step in management of this condition is usually the optimization of anti-seizure drugs. In our case, a 2-year fall-free period was achieved with optimization of medical treatment. Pacemaker implantation can also be attempted to prevent ictal asystole-related falls and injury, while refractory cases may benefit from epilepsy surgery in terms of both seizure control and prevention of ictal asystole.