NF1 mutation drives neuronal activity-dependent initiation of optic glioma.

Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours. Although the role of neurons in tumour progression has previously been demonstrated, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood, raising  the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation.

Performance-Based Financing, Basic Packages of Health Services and User-Fee Exemption Mechanisms: An Analysis of Health-Financing Policy Integration in Three Fragile and Conflict-Affected Settings.

Background: As performance-based financing (PBF) is increasingly implemented across sub-Saharan Africa, some authors have suggested that it could be a 'stepping stone' for health-system strengthening and broad health-financing reforms. However, so far, few studies have looked at whether and how PBF is aligned to and integrated with national health-financing strategies, particularly in fragile and conflict-affected settings.

Objective: This study attempts to address the existing research gap by exploring the role of PBF with reference to: (1) user fees/exemption policies and (2) basic packages of health services and benefit packages in the Central African Republic, Democratic Republic of Congo and Nigeria.

Performance-based financing in three humanitarian settings: principles and pragmatism.

Background: Performance based financing (PBF) has been increasingly implemented across low and middle-income countries, including in fragile and humanitarian settings, which present specific features likely to require adaptation and to influence implementation of any health financing programme. However, the literature has been surprisingly thin in the discussion of how PBF has been adapted to different contexts, and in turn how different contexts may influence PBF. With case studies from three humanitarian settings (northern Nigeria, Central African Republic and South Kivu in the Democratic Republic of Congo), we examine why and how PBF has emerged and has been adapted to those unsettled and dynamic contexts, what the opportunities and challenges have been, and what lessons can be drawn.

Whole tumor RNA-sequencing and deconvolution reveal a clinically-prognostic PTEN/PI3K-regulated glioma transcriptional signature.

The concept that solid tumors are maintained by a productive interplay between neoplastic and non-neoplastic elements has gained traction with the demonstration that stromal fibroblasts and immune system cells dictate cancer development and progression. While less studied, brain tumor (glioma) biology is likewise influenced by non-neoplastic immune system cells (macrophages and microglia) which interact with neoplastic glioma cells to create a unique physiological state (glioma ecosystem) distinct from that found in the normal tissue. To explore this neoplastic ground state, we leveraged several preclinical mouse models of neurofibromatosis type 1 (NF1) optic glioma, a low-grade astrocytoma whose formation and maintenance requires productive interactions between non-neoplastic and neoplastic cells, and employed whole tumor RNA-sequencing and mathematical deconvolution strategies to characterize this low-grade glioma ecosystem as an aggregate of cellular and acellular elements.

Social accountability in primary health care in West and Central Africa: exploring the role of health facility committees.

Background: Social accountability has been emphasised as an important strategy to increase the quality, equity, and responsiveness of health services. In many countries, health facility committees (HFCs) provide the accountability interface between health providers and citizens or users of health services. This article explores the social accountability practices facilitated by HFCs in Benin, Guinea and the Democratic Republic of Congo.

The cell of origin dictates the temporal course of neurofibromatosis-1 (Nf1) low-grade glioma formation.

Low-grade gliomas are one of the most common brain tumors in children, where they frequently form within the optic pathway (optic pathway gliomas; OPGs). Since many OPGs occur in the context of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome, we have previously employed Nf1 genetically-engineered mouse (GEM) strains to study the pathogenesis of these low-grade glial neoplasms. In the light of the finding that human and mouse low-grade gliomas are composed of Olig2+ cells and that Olig2+ oligodendrocyte precursor cells (OPCs) give rise to murine high-grade gliomas, we sought to determine whether Olig2+ OPCs could be tumor-initiating cells for Nf1 optic glioma.

Increased Tissue Stiffness in Tumors from Mice with Neurofibromatosis-1 Optic Glioma.

Children with neurofibromatosis type 1 (NF1) cancer predisposition syndrome are prone to the development of low-grade brain tumors (gliomas) within the optic pathway (optic gliomas). One of the key obstacles to developing successful therapeutic strategies for these tumors is the striking lack of information about the mechanical properties that characterize these tumors relative to non-neoplastic optic nerve tissue. To study the physical changes that may occur when an optic nerve glioma is present, we employed atomic force microscopy to measure the stiffness of healthy versus tumor-bearing optic nerve tissue.

Defining the temporal course of murine neurofibromatosis-1 optic gliomagenesis reveals a therapeutic window to attenuate retinal dysfunction.

Background: Optic gliomas arising in the neurofibromatosis type 1 (NF1) cancer predisposition syndrome cause reduced visual acuity in 30%-50% of affected children. Since human specimens are rare, genetically engineered mouse (GEM) models have been successfully employed for preclinical therapeutic discovery and validation. However, the sequence of cellular and molecular events that culminate in retinal dysfunction and vision loss has not been fully defined relevant to potential neuroprotective treatment strategies.

Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma-induced retinal pathology.

Children with neurofibromatosis type 1 (NF1) develop low-grade brain tumors throughout the optic pathway. Nearly 50% of children with optic pathway gliomas (OPGs) experience visual impairment, and few regain their vision after chemotherapy. Recent studies have revealed that girls with optic nerve gliomas are five times more likely to lose vision and require treatment than boys.

Contextual signaling in cancer.

The formation and maintenance of an organism are highly dependent on the orderly control of cell growth, differentiation, death, and migration. These processes are tightly regulated by signaling cascades in which a limited number of molecules dictate these cellular events. While these signaling pathways are highly conserved across species and cell types, the functional outcomes that result from their engagement are specified by the context in which they are activated.

A Disintegrin and Metalloproteinase10 (ADAM10) Regulates NOTCH Signaling during Early Retinal Development.

ADAM10 and ADAM17 are two closely related members of the ADAM (a disintegrin and metalloprotease) family of membrane-bound sheddases, which proteolytically cleave surface membrane proteins. Both ADAM10 and ADAM17 have been implicated in the proteolytic cleavage of NOTCH receptors and as such regulators of NOTCH signaling. During retinal development, NOTCH signaling facilitates retinal neurogenesis by maintaining progenitor cells in a proliferative state and by mediating retinal cell fates.

NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1.

Neurofibromatosis type 1 (NF1) is a common neurogenetic condition characterized by significant clinical heterogeneity. A major barrier to developing precision medicine approaches for NF1 is an incomplete understanding of the factors that underlie its inherent variability. To determine the impact of the germline NF1 gene mutation on the optic gliomas frequently encountered in children with NF1, we developed genetically engineered mice harboring two representative NF1-patient-derived Nf1 gene mutations (c.

RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth.

Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance.

Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth.

Background: Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth.

The impact of coexisting genetic mutations on murine optic glioma biology.

Background: Children with the neurofibromatosis type 1 (NF1) tumor predisposition syndrome are prone to the development of optic pathway gliomas resulting from biallelic inactivation of the NF1 gene. Recent studies have revealed the presence of other molecular alterations in a small portion of these NF1-associated brain tumors. The purpose of this study was to leverage Nf1 genetically engineered mouse strains to define the functional significance of these changes to optic glioma biology.

Performance-based financing as a health system reform: mapping the key dimensions for monitoring and evaluation.

Background: Performance-based financing is increasingly being applied in a variety of contexts, with the expectation that it can improve the performance of health systems. However, while there is a growing literature on implementation issues and effects on outputs, there has been relatively little focus on interactions between PBF and health systems and how these should be studied. This paper aims to contribute to filling that gap by developing a framework for assessing the interactions between PBF and health systems, focusing on low and middle income countries.

ADAM17 transactivates EGFR signaling during embryonic eyelid closure.

Purpose: During mammalian embryonic eyelid closure ADAM17 has been proposed to play a role as a transactivator of epidermal growth factor receptor (EGFR) signaling by shedding membrane bound EGFR ligands. However, ADAM17 also sheds numerous other ligands, thus implicating ADAM17 in additional molecular pathways. The goal of this study was to experimentally establish the role of ADAM17 and determine ADAM17-mediated pathways essential for the embryonic eyelid closure.

Waved with open eyelids 2 (woe2) is a novel spontaneous mouse mutation in the protein phosphatase 1, regulatory (inhibitor) subunit 13 like (Ppp1r13l) gene.

Background: Waved with open eyelids 2 (woe2) is a novel autosomal recessive mouse mutation that arose spontaneously in our animal facility. Upon initial evaluation, mutant mice exhibited eyelids open at birth (EOB) and wavy fur phenotypes. The goals of this study were to phenotypically characterize the woe2 mice and to identify the gene harboring the mutation responsible for the woe2 phenotype.

The match between motivation and performance management of health sector workers in Mali.

Unlabelled: Human resources for health (HRH) play a central role in improving accessibility to services and quality of care. Their motivation influences this. In Mali, operational research was conducted to identify the match between motivation and the range and use of performance management activities.

Improved performance of seroconversion with a 4th generation HIV antigen/antibody assay.

Recently a new fourth generation microELISA for large scale blood screening has been described in which HIV p24 Ag detection was integrated in an anti-HIV-1/-2 and anti-HIV-1 group O assay based on a direct assay format: (Vironostika HIV Uni-Form II Ag/Ab (Van Binsbergen et al., (1998)). When compared to the third generation a-HIV assay (Vironostika HIV Uni-Form II plus O), the seroconversion window was narrowed with more than one week.

Strongly enhanced sensitivity of a direct anti-HIV-1/-2 assay in seroconversion by incorporation of HIV p24 ag detection: a new generation vironostika HIV Uni-Form II.

The clinical sensitivity of the current anti-HIV assays is based for an important part on their reactivity with seroconversion panels. The most sensitive assay closes the seroconversion window as much as possible, thereby reducing the risk of transmitting false negative donations obtained from individuals infected recently. Because of the absence of anti-HIV antibodies during the early phase of infection, the seroconversion window can be narrowed partially by detection of HIV p24 Ag.

Reactivity of a new HIV-1 group O third generation A-HIV-1/-2 assay with an unusual HIV-1 seroconversion panel and HIV-1 group O/group M subtyped samples.

It was shown previously that about 97% of the anti-HIV-1 group O strain-positive samples were detected by crossreaction with native HIV-1 gp160 (Van Binsbergen et al., Evaluation of a new third generation anti-HIV-1/anti-HIV-2 assay with increased sensitivity for HIV-1 group O, J. Virol.