Gene network exploration of crosstalk between apoptosis and autophagy in chronic myelogenous leukemia

Copyright © 2015 Fengfeng Wang et al. Background. Gene expression levels change to adapt the stress, such as starvation, toxin, and radiation. The changes are signals transmitted through molecular interactions, eventually leading to two cellular fates, apoptosis and autophagy. Due to genetic variations, the signals may not be effectively transmitted to modulate apoptotic and autophagic responses. Such aberrant modulation may lead to carcinogenesis and drug resistance. The balance between apoptosis and autophagy becomes very crucial in coping with the stress. Though there have been evidences illustrating the apoptosis-autophagy interplay, the underlying mechanism and the participation of the regulators including transcription factors (TFs) and microRNAs (miRNAs) remain unclear. Results. Gene network is a graphical illustration for exploring the functional linkages and the potential coordinate regulations of genes. Microarray dataset for the study of chronic myeloid leukemia was obtained from Gene Expression Omnibus. The expression profiles of those genes related to apoptosis and autophagy, including MCL1, BCL2, ATG, beclin-1, BAX, BAK, E2F, cMYC, PI3K, AKT, BAD, and LC3, were extracted from the dataset to construct the gene networks. Conclusion. The network analysis of these genes explored the underlying mechanisms and the roles of TFs and miRNAs for the crosstalk between apoptosis and autophagy.Link_to_subscribed_fulltex

Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity

S31-201 (NSC 74859) is a chemical probe inhibitor of Stat3 activity, which was identified from the National Cancer Institute chemical libraries by using structure-based virtual screening with a computer model of the Stat3 SH2 domain bound to its Stat3 phosphotyrosine peptide derived from the x-ray crystal structure of the Stat3 beta homodimer. S31-201 inhibits Stat3-Stat3 complex formation and Stat3 DNA-binding and transcriptional activities. Furthermore, S31-201 inhibits growth and induces apoptosis preferentially in tumor cells that contain persistently activated Stat3. Constitutively climerized and active Stat3C and Stat3 SH2 domain rescue tumor cells from S31-201-induced apoptosis. Finally, S31-201 inhibits the expression of the Stat3-regulated genes encoding cyclin D1, BcI-xL, and survivin and inhibits the growth of human breast tumors in vivo. These findings strongly suggest that the antitumor activity of S31-201 is mediated in part through inhibition of aberrant Stat3 activation and provide the proof-of-concept for the potential clinical use of Stat3 inhibitors such as S31-201 in tumors harboring aberrant Stat3

Perfusion and Metabolic Neuromonitoring during Ventricular Taps in Infants with Post-Hemorrhagic Ventricular Dilatation.

Post-hemorrhagic ventricular dilatation (PHVD) is characterized by a build-up of cerebral spinal fluid (CSF) in the ventricles, which increases intracranial pressure and compresses brain tissue. Clinical interventions (i.e., ventricular taps, VT) work to mitigate these complications through CSF drainage; however, the timing of these procedures remains imprecise. This study presents Neonatal NeuroMonitor (NNeMo), a portable optical device that combines broadband near-infrared spectroscopy (B-NIRS) and diffuse correlation spectroscopy (DCS) to provide simultaneous assessments of cerebral blood flow (CBF), tissue saturation (

Inter-hemispheric EEG coherence analysis in Parkinson's disease : Assessing brain activity during emotion processing

Parkinson’s disease (PD) is not only characterized by its prominent motor symptoms but also associated with disturbances in cognitive and emotional functioning. The objective of the present study was to investigate the influence of emotion processing on inter-hemispheric electroencephalography (EEG) coherence in PD. Multimodal emotional stimuli (happiness, sadness, fear, anger, surprise, and disgust) were presented to 20 PD patients and 30 age-, education level-, and gender-matched healthy controls (HC) while EEG was recorded. Inter-hemispheric coherence was computed from seven homologous EEG electrode pairs (AF3–AF4, F7–F8, F3–F4, FC5–FC6, T7–T8, P7–P8, and O1–O2) for delta, theta, alpha, beta, and gamma frequency bands. In addition, subjective ratings were obtained for a representative of emotional stimuli. Interhemispherically, PD patients showed significantly lower coherence in theta, alpha, beta, and gamma frequency bands than HC during emotion processing. No significant changes were found in the delta frequency band coherence. We also found that PD patients were more impaired in recognizing negative emotions (sadness, fear, anger, and disgust) than relatively positive emotions (happiness and surprise). Behaviorally, PD patients did not show impairment in emotion recognition as measured by subjective ratings. These findings suggest that PD patients may have an impairment of inter-hemispheric functional connectivity (i.e., a decline in cortical connectivity) during emotion processing. This study may increase the awareness of EEG emotional response studies in clinical practice to uncover potential neurophysiologic abnormalities

Multi-Modality Therapeutics with Potent Anti-Tumor Effects: Photochemical Internalization Enhances Delivery of the Fusion Toxin scFvMEL/rGel

BACKGROUND: There is a need for drug delivery systems (DDS) that can enhance cytosolic delivery of anti-cancer drugs trapped in the endo-lysosomal compartments. Exposure of cells to specific photosensitizers followed by light exposure (photochemical internalization, PCI) results in transfer of agents from the endocytic compartment into the cytosol. METHODOLOGY AND PRINCIPAL FINDINGS: The recombinant single-chain fusion construct scFvMEL/rGel is composed of an antibody targeting the progenitor marker HMW-MAA/NG2/MGP/gp240 and the highly effective toxin gelonin (rGel). Here we demonstrate enhanced tumor cell selectivity, cytosolic delivery and anti-tumor activity by applying PCI of scFvMEL/rGel. PCI performed by light activation of cells co-incubated with scFvMEL/rGel and the endo-lysosomal targeting photosensitizers AlPcS(2a) or TPPS(2a) resulted in enhanced cytotoxic effects against antigen-positive cell lines, while no differences in cytotoxicity between the scFvMEL/rGel and rGel were observed in antigen-negative cells. Mice bearing well-developed melanoma (A-375) xenografts (50-100 mm(3)) were treated with PCI of scFvMEL/rGel. By 30 days after injection, approximately 100% of mice in the control groups had tumors>800 mm(3). In contrast, by day 40, 50% of mice in the PCI of scFvMEL/rGel combination group had tumors<800 mm(3) with no increase in tumor size up to 110 days. PCI of scFvMEL/rGel resulted in a synergistic effect (p<0.05) and complete regression (CR) in 33% of tumor-bearing mice (n = 12). CONCLUSIONS/SIGNIFICANCE: This is a unique demonstration that a non-invasive multi-modality approach combining a recombinant, targeted therapeutic such as scFvMEL/rGel and PCI act in concert to provide potent in vivo efficacy without sacrificing selectivity or enhancing toxicity. The present DDS warrants further evaluation of its clinical potential

Advancing the application of systems thinking in health: managing rural China health system development in complex and dynamic contexts

Background: This paper explores the evolution of schemes for rural finance in China as a case study of the long and complex process of health system development. It argues that the evolution of these schemes has been the outcome of the response of a large number of agents to a rapidly changing context and of efforts by the government to influence this adaptation process and achieve public health goals. Methods:The study draws on several sources of data including a review of official policy documents and academic papers and in-depth interviews with key policy actors at national level and at a sample of localities. Results: The study identifies three major transition points associated with changes in broad development strategy and demonstrates how the adaptation of large numbers of actors to these contextual changes had a major impact on the performance of the health system. Further, it documents how the Ministry of Health viewed its role as both an advocate for the interests of health facilities and health workers and as the agency responsible for ensuring that government health system objectives were met. It is argued that a major reason for the resilience of the health system and its ability to adapt to rapid economic and institutional change was the ability of the Ministry to provide overall strategy leadership. Additionally, it postulates that a number of interest groups have emerged, which now also seek to influence the pathway of health system development. Conclusions: This history illustrates the complex and political nature of the management of health system development and reform. The paper concludes that governments will need to increase their capacity to analyze the health sector as a complex system and to manage change processes.UKaid: DFI

Effects of Dopamine on Sensitivity to Social Bias in Parkinson's Disease

Patients with Parkinson's disease (PD) sometimes develop impulsive compulsive behaviours (ICBs) due to their dopaminergic medication. We compared 26 impulsive and 27 non-impulsive patients with PD, both on and off medication, on a task that examined emotion bias in decision making. No group differences were detected, but patients on medication were less biased by emotions than patients off medication and the strongest effects were seen in patients with ICBs. PD patients with ICBs on medication also showed more learning from negative feedback and less from positive feedback, whereas off medication they showed the opposite effect

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

MCOIN: a novel heuristic for determining transcription factor binding site motif width

BACKGROUND: In transcription factor binding site discovery, the true width of the motif to be discovered is generally not known a priori. The ability to compute the most likely width of a motif is therefore a highly desirable property for motif discovery algorithms. However, this is a challenging computational problem as a result of changing model dimensionality at changing motif widths. The complexity of the problem is increased as the discovered model at the true motif width need not be the most statistically significant in a set of candidate motif models. Further, the core motif discovery algorithm used cannot guarantee to return the best possible result at each candidate width. RESULTS: We present MCOIN, a novel heuristic for automatically determining transcription factor binding site motif width, based on motif containment and information content. Using realistic synthetic data and previously characterised prokaryotic data, we show that MCOIN outperforms the current most popular method (E-value of the resulting multiple alignment) as a predictor of motif width, based on mean absolute error. MCOIN is also shown to choose models which better match known sites at higher levels of motif conservation, based on ROC analysis. CONCLUSIONS: We demonstrate the performance of MCOIN as part of a deterministic motif discovery algorithm and conclude that MCOIN outperforms current methods for determining motif width