Miracle-dz/UniFAR-FTUs huggingface dataset:
Standardized orthotopic xenografts in zebrafish reveal glioma cell-line-specific characteristics and tumor cell heterogeneity

ABSTRACT Glioblastoma (GBM) is a deadly brain cancer, for which few effective drug treatments are available. Several studies have used zebrafish models to study GBM, but a standardized approach to modeling GBM in zebrafish was lacking to date, preventing comparison of data across studies. Here, we describe a new, standardized orthotopic xenotransplant model of GBM in zebrafish. Dose-response survival assays were used to define the optimal number of cells for tumor formation. Techniques to measure tumor burden and cell spread within the brain over real time were optimized using mouse neural stem cells as control transplants. Applying this standardized approach, we transplanted two patient-derived GBM cell lines, serum-grown adherent cells and neurospheres, into the midbrain region of embryonic zebrafish and analyzed transplanted larvae over time. Progressive brain tumor growth and premature larval death were observed using both cell lines; however, fewer transplanted neurosphere cells were needed for tumor growth and lethality. Tumors were heterogeneous, containing both cells expressing stem cell markers and cells expressing markers of differentiation. A small proportion of transplanted neurosphere cells expressed glial fibrillary acidic protein (GFAP) or vimentin, markers of more differentiated cells, but this number increased significantly during tumor growth, indicating that these cells undergo differentiation in vivo. By contrast, most serum-grown adherent cells expressed GFAP and vimentin at the earliest times examined post-transplant. Both cell types produced brain tumors that contained Sox2+ cells, indicative of tumor stem cells. Transplanted larvae were treated with currently used GBM therapeutics, temozolomide or bortezomib, and this resulted in a reduction in tumor volume in vivo and an increase in survival. The standardized model reported here facilitates robust and reproducible analysis of glioblastoma tumor cells in real time and provides a platform for drug screening. Summary: This zebrafish xenotransplant model of glioblastoma enables in vivo imaging of tumor cells and rapid screening for anti-glioma agents. It provides standardization of a model that is easily replicated across laboratories.
Just Say “I Don't”: Lack of Concordance Between Teen Report and Biological Measures of Drug Use

BACKGROUND: Prevalence estimates of illicit drug use by teens are typically generated from confidential or anonymous self-report. While data comparing teen self-report with biological measures are limited, adult studies identify varying degrees of under-reporting. METHODS: Hair analyses for cocaine, opiates and marijuana were compared to confidential teen self- and parent-reported teen drug use in a longitudinal cohort of >400 high-risk urban teens and parents. RESULTS: Both teens and parents substantially underreported recent teen cocaine and opiate use. However, compared with parents, teens were more likely to deny biomarker-verified cocaine use. Teen specimens (hair) were 52 times more likely to identify cocaine use compared with self-report. Parent hair analyses for cocaine and opiate use were 6.5 times and 5.5 times, respectively, more likely to indicate drug use than were parental self-report. The lack of concordance between self-report and bioassay occurred despite participant's knowledge that a “certificate of confidentiality” protected both teen and adult participants, and that the biological specimens would be tested for drugs. CONCLUSIONS: These findings confirm prior reports of adult under-reporting of their own drug use while extending our understanding of teen's self-admitted drug use. The lack of concordance between teen self- or parent-reported teen drug use and biomarkers confirm our concerns that both teen- and parent-reported teen drug use is limited, at least for youth in high-risk urban settings. Methods of ascertainment other than self- or parent-report must be considered when health care providers, researchers and public health agencies attempt to estimate teen drug-use prevalence.
Seizure control through genetic and pharmacological manipulation of Pumilio in Drosophila: a key component of neuronal homeostasis

ABSTRACT Epilepsy is a significant disorder for which approximately one-third of patients do not respond to drug treatments. Next-generation drugs, which interact with novel targets, are required to provide a better clinical outcome for these individuals. To identify potential novel targets for antiepileptic drug (AED) design, we used RNA sequencing to identify changes in gene transcription in two seizure models of the fruit fly Drosophila melanogaster. The first model compared gene transcription between wild type (WT) and bangsenseless1 (parabss), a gain-of-function mutant in the sole fly voltage-gated sodium channel (paralytic). The second model compared WT with WT fed the proconvulsant picrotoxin (PTX). We identified 743 genes (FDR≤1%) with significant altered expression levels that are common to both seizure models. Of these, 339 are consistently upregulated and 397 downregulated. We identify pumilio (pum) to be downregulated in both seizure models. Pum is a known homeostatic regulator of action potential firing in both flies and mammals, achieving control of neuronal firing through binding to, and regulating translation of, the mRNA transcripts of voltage-gated sodium channels (Nav). We show that maintaining expression of pum in the CNS of parabss flies is potently anticonvulsive, whereas its reduction through RNAi-mediated knockdown is proconvulsive. Using a cell-based luciferase reporter screen, we screened a repurposed chemical library and identified 12 compounds sufficient to increase activity of pum. Of these compounds, we focus on avobenzone, which significantly rescues seizure behaviour in parabss flies. The mode of action of avobenzone includes potentiation of pum expression and mirrors the ability of this homeostatic regulator to reduce the persistent voltage-gated Na+ current (INaP) in an identified neuron. This study reports a novel approach to suppress seizure and highlights the mechanisms of neuronal homeostasis as potential targets for next-generation AEDs. Summary: Next-generation anticonvulsant compounds potentiate the activity of the neuronal homeostatic regulator Pumilio.
A novel mode of induction of the humoral innate immune response in Drosophila larvae

ABSTRACT Drosophila adults have been utilized as a genetically tractable model organism to decipher the molecular mechanisms of humoral innate immune responses. In an effort to promote the utility of Drosophila larvae as an additional model system, in this study, we describe a novel aspect of an induction mechanism for innate immunity in these larvae. By using a fine tungsten needle created for manipulating semi-conductor devices, larvae were subjected to septic injury. However, although Toll pathway mutants were susceptible to infection with Gram-positive bacteria as had been shown for Drosophila adults, microbe clearance was not affected in the mutants. In addition, Drosophila larvae were found to be sensitive to mechanical stimuli with respect to the activation of a sterile humoral response. In particular, pinching with forceps to a degree that might cause minor damage to larval tissues could induce the expression of the antifungal peptide gene Drosomycin; notably, this induction was partially independent of the Toll and immune deficiency pathways. We therefore propose that Drosophila larvae might serve as a useful model to analyze the infectious and non-infectious inflammation that underlies various inflammatory diseases such as ischemia, atherosclerosis and cancer. Editors' choice: Drosophila larvae represent a useful model of infectious inflammation and sterilely induced humoral innate response, which are relevant for disorders associated with chronic inflammation.
Birth Before 39 Weeks' Gestation Is Associated With Worse Outcomes in Neonates With Heart Disease

BACKGROUND: Recent studies have revealed increased morbidity and mortality rates in term neonates without birth defects who were delivered before 39 weeks of completed gestation. We sought to determine if a similar association exists between gestational age at delivery and adverse outcomes in neonates with critical congenital heart disease, with particular interest in those born at 37 to 38 weeks' gestation. PATIENTS AND METHODS: We studied 971 consecutive neonates who had critical congenital heart disease and a known gestational age and were admitted to our cardiac ICU from 2002 through 2008. Gestational age was stratified into 5 groups: >41, 39 to 40, 37 to 38, 34 to 36, and <34 completed weeks. Multivariate logistic regression analyses were used to evaluate mortality and a composite morbidity variable. Multivariate Poisson regression was used to evaluate duration of ventilation, intensive care, and hospitalization. RESULTS: Compared with the referent group of neonates who were delivered at 39 to 40 completed weeks' gestation, neonates born at 37 to 38 weeks had increased mortality (6.9% vs 2.6%; adjusted P = .049) and morbidity (49.7% vs 39.7%; adjusted P = .02) rates and tended to require a longer duration of mechanical ventilation (adjusted P = .05). Patients born after 40 or before 37 weeks also had greater adjusted mortality rates, and those born before 37 weeks had increased morbidity rates and required more days of mechanical ventilation and intensive care. CONCLUSIONS: For neonates with critical congenital heart disease, delivery before 39 weeks' gestation is associated with greater mortality and morbidity rates and more resource use. With respect to neonatal mortality, the ideal gestational age for delivery of these patients may be 39 to 40 completed weeks.
Chemotherapy for Early-Stage Breast Cancer: A Paradigm in Flux

Breast cancer is the most common malignancy among women in the United States. A reduction in breast cancer mortality has been observed over recent years and is in part attributable to general use of adjuvant chemotherapy and trastuzumab. Besides the addition of specific therapeutic agents, the therapy of early-stage breast cancer has benefited from dose-dense approaches, identification of molecular markers, and translational research innovations such as prognostic gene expression assays. Treatment recommendations for adjuvant breast cancer chemotherapy are traditionally guided by results from clinical studies reflecting a general population; however, molecular and genomic information can potentially enable clinicians to formulate more refined therapeutic decisions. These advances also generate further questions regarding situations where application of therapy is necessary to optimize efficacy and circumstances where sparing therapy is appropriate. Taken together, the advances made through early-stage breast cancer chemotherapy positions us closer to fulfilling the promise of personalized medicine. This article reviews the recent progress of adjuvant chemotherapy and trastuzumab in breast cancer.
What do carers of people with psychosis need from mental health services? Exploring the views of carers, service users and professionals

The development of anti-psychotic medications and deinstitutionalization has shifted the primary focus of mental health treatment from hospital to the community. As a consequence, carers have become an integral part of the care system (Thornicroft and Tansella, 2005). Historically, interventions for families with people with psychosis have tended to focus on service user outcomes that attempt to reduce or prevent relapse (Askey et al., 2007). As a consequence, carers often feel ignored or marginalized by services (Shepherd et al., 1995; Beck and Minghella, 1998; Henwood, 1998). This problem has recently been recognized, and it has been highlighted that there is a need for more involvement with carers of clients with mental illness (DoH, 1999). However, there continues to be a lack of knowledge about carers' needs and how professionals specifically meet carers' needs (Chambers et al., 2001). This article presents the results of a study aimed at exploring the views and experiences of carers, service users and professionals with regard to what carers of people with psychosis need from mental health services. It will initially review the literature on carer burden and needs, as well as interventions such as family intervention and carers' assessments/care plans which have been developed to address carer needs.
Transition Delay Fault Test Pattern Generation Considering Supply Voltage Noise in a SOC Design

Due to shrinking technology, increasing functional frequency and density, and reduced noise margins with supply voltage scaling, the sensitivity of designs to supply voltage noise is increasing. The supply noise is much larger during at-speed delay test compared to normal circuit operation since large number of transitions occur within a short time frame. Existing commercial ATPG tools do not consider the excessive supply noise that might occur in the design during test pattern generation. In this paper, we first present a case study of a SOC design and show detailed IR-drop analysis, measurement and its effects on design performance during at-speed test. We then propose a novel method to measure the average power of at-speed test patterns, referred to as switching cycle average power (SCAP). A new practical pattern generation methodology is proposed to generate supply noise tolerant delay test patterns using existing capabilities in commercial ATPG tools. The results demonstrate that the new patterns generated using our technique will minimize the supply noise effects on path delay.
Strategies to Address Appropriate Fluoroquinolone Use in the Hospital

Purpose Strategies to optimally use fluoroquinolones in the hospital setting are reviewed. Summary Fluoroquinolones possess broad-spectrum antimicrobial coverage and are widely used to treat a variety of infections including some serious, life-threatening conditions. Overuse and inappropriate use of fluoroquinolones has led to rapid emergence of fluoroquinolone-resistant organisms as well as multidrug-resistant pathogens. Preserving the fluoroquinolone class is important, especially given the lack of new antibiotics currently in clinical development. Maintaining the fluoroquinolone class as a therapeutic option requires the successful implementation of guidelines to promote appropriate, optimal use of these agents. Among many recommendations to control the growing problem of antimicrobial resistance, antimicrobial stewardship programs offer the most comprehensive solution to gain appropriate antimicrobial prescribing. Effective programs include selection of the most effective agents, specific dosages, frequency of administration, routes of administration, and duration of therapy. Additionally, a dual fluoroquinolone formulary, which typically incorporates one respiratory fluoroquinolone and ciprofloxacin, has been employed to increase the diversity of fluoroquinolone treatment and thus reduce the selective antimicrobial pressure. A combination of antimicrobial stewardship programs and a dual formulary option has been demonstrated to be a good approach to optimize the use of fluoroquinolones in the hospital. Two successful experiences in applying such strategies have been reported; in both cases the empiric fluoroquinolone prescribing was reduced. Conclusion Implementation of aggressive optimization strategies such as the combined use of antimicrobial stewardship programs and a dual fluoroquinolone formulary may maintain the efficacy of fluoroquinolones and preserve their utility for future patients.
Decreased Insulin Secretion in Women with Previous Gestational Diabetes Mellitus

Objectives: Gestational diabetes mellitus (GDM) affects 2%–4% of the all pregnant women, and it is a major risk factor for development of type 2 DM. We performed this cross-sectional study to determine whether there were defects in insulin secretory capacity or insulin sensitivity in women with previous GDM. Methods: On 6–8 weeks after delivery, 75 g oral glucose tolerance test was performed in 36 women with previous GDM and 19 non-pregnant control women matched with age and weight. Intravenous glucose tolerance test was performed on 10–14 weeks after delivery. Insulin secretory capacity measured as the acute insulin response to glucose (AIRg) and insulin sensitivity as minimal model derived sensitivity index (SI) were obtained. AIRg×SI (β-cell disposition index) was used as an index of β-cell function. Results: Women with previous GDM were classified into normal glucose tolerance (postpartum-NGT, n=19) and impaired glucose tolerance (postpartum-IGT, n=17). Postpartum fasting glucose levels were significantly higher in postpartum-IGT compared to postpartum-NGT and control (P<0.05). AIRg×SI was significantly lower in postpartum-IGT compared to control (P<0.05). SI was lower in postpartum-NGT and postpartum-IGT compared to control, but the difference did not have the statistical significance. Frequency of parental history of type 2 diabetes was significantly greater in postpartum-IGT compared to postpartum-NGT (P<0.05). Conclusion: Women with previous GDM showed impaired insulin secretion although their glucose tolerance states were restored to normal. It suggests impaired early insulin secretion may be a major pathophysiologic factor for development of type 2 DM, and this defect may be genetically determined. (Ewha Med J 2015;38(1):30-35)
Filaments made from A- and B-type lamins differ in structure and organization

Lamins are intermediate filament proteins and the major component of the nuclear lamina. Current views of the lamina are based on the remarkably regular arrangement of lamin LIII in amphibian oocyte nuclei. We have re-examined the LIII lamina and propose a new interpretation of its organization. Rather than consisting of two perpendicular arrays of parallel filaments, we suggest that the oocyte lamina consists of parallel filaments that are interconnected in register to give the impression of a second set of perpendicular filaments. We have also used the oocyte system to investigate the organization of somatic lamins. Currently, it is not feasible to examine the organization of somatic lamins in situ because of their tight association with chromatin. It is also difficult to assemble vertebrate lamin filaments in vitro. Therefore, we have used the oocyte system, where exogenously expressed somatic B-type and A-type lamins assemble into filaments. Expression of B-type lamins induces the formation of intranuclear membranes that are covered by single filament layers. LIII filaments appear identical to the endogenous lamina, whereas lamin B2 assembles into filaments that are organized less precisely. Lamin A induces sheets of thicker filaments on the endogenous lamina and significantly increases the rigidity of the nuclear envelope.
The BARRIERS scale: Does it 'fit' the current NHS research culture?

The BARRIERS scale was developed in the US as a method of identifying the main barriers to research utilisation reported by nurses. However, its appropriateness for assessing such barriers in the UK is not clear. The current drive for evidence-based practice makes it desirable to assess the availability of an instrument to measure the progress of nurses who have implemented research. Information about the appropriateness of the BARRIERS scale for use in the UK would allow its potential as a monitoring instrument to be assessed. This paper is a section of a wider study aimed at producing a general picture of the underlying types of barrier to the implementation of research findings. Objectives included exploring those factors which acted as barriers to research implementation; assessing the construct validity and the internal consistency of the BARRIERS scale in the UK; and identifying barriers which might be excluded or added in future studies. A census survey of practice nurses and nurses from two hospital and two community trusts within one health authority, and one community trust from another health authority, was undertaken. The BARRIERS questionnaire was sent by mail to 4,501 nurses, with a 44.6% response rate. Exploratory factor analysis was used to identify key factors underlying the 29 items of the BARRIERS scale which acted as barriers to the utilisation of research findings. Four factors were identified, which were conceptualised as: the benefits, quality and accessibility of research, and resources for implementation. These were similar, but not identical, to factors identified in the original US study. One factor appeared mainly to be concerned with critical appraisal, which could be considered to be a facilitator rather than a barrier. More than one-fifth of the original items were not included in the UK model. Under-reported (mainly research issues) and additional barriers (mainly organisational issues) were identified. The four-factor solution was roughly comparable with that derived in the US, although fewer items were retained (22 instead of 28), and some of the factors were conceptually a little different. It was concluded that the internal reliability of the four-factor solution was fair. The scale may not be suitable for use in the UK without further development: a scale which includes positive as well as negative aspects of research culture, with a greater emphasis on organizational issues, may be more useful.
Arabidopsis SMG7 protein is required for exit from meiosis

Meiosis consists of two nuclear divisions that are separated by a short interkinesis. Here we show that the SMG7 protein, which plays an evolutionarily conserved role in nonsense-mediated RNA decay (NMD) in animals and yeast, is essential for the progression from anaphase to telophase in the second meiotic division in Arabidopsis. Arabidopsis SMG7 is an essential gene, the disruption of which causes embryonic lethality. Plants carrying a hypomorphic smg7 mutation exhibit an elevated level of transcripts containing premature stop codons. This suggests that the role of SMG7 in NMD is conserved in plants. Furthermore, hypomorphic smg7 alleles render mutant plants sterile by causing an unusual cell-cycle arrest in anaphase II that is characterized by delayed chromosome decondensation and aberrant rearrangement of the meiotic spindle. The smg7 phenotype was mimicked by exposing meiocytes to the proteasome inhibitor MG115. Together, these data indicate that SMG7 counteracts cyclin-dependent kinase (CDK) activity at the end of meiosis, and reveal a novel link between SMG7 and regulation of the meiotic cell cycle.