Comprehensive analysis of the ErbB receptor family in pediatric nervous system tumors and rhabdomyosarcoma.

BACKGROUND: There is a paucity of knowledge regarding pediatric biomarkers, including the relevance of ErbB pathway aberrations in pediatric tumors. We investigated the occurrence of ErbB receptor aberrations across different pediatric malignancies, to identify patterns of ErbB dysregulation and define biomarkers suitable for patient enrichment in clinical studies. PROCEDURE: Tissue samples from 297 patients with nervous system tumors and rhabdomyosarcoma were analyzed for immunohistochemical expression or gene amplification of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Exploratory analyses of HER3/HER4 expression, and mRNA expression of ErbB receptors/ligands (NanoString) were performed. Assay validation followed general procedures, with additional validation to address Clinical Laboratory Improvement Amendments (CLIA) requirements. RESULTS: In most tumor types, samples with high ErbB receptor expression were found with heterogeneous distribution. We considered increased/aberrant ErbB pathway activation when greater than or equal to two EGFR/HER2 markers were simultaneously upregulated. ErbB pathway dysregulation was identified in ∼20%-30% of samples for most tumor types (medulloblastoma/primitive neuroectodermal tumors 31.1%, high-grade glioma 27.1%, neuroblastoma 22.7%, rhabdomyosarcoma 23.1%, ependymoma 18.8%), 4.2% of diffuse intrinsic pontine gliomas, and no recurrent or refractory low-grade astrocytomas. In medulloblastoma/primitive neuroectodermal tumors and neuroblastoma, this was attributed mainly to high EGFR polysomy/HER2 amplification, whereas EGFR gene amplification was observed in some high-grade glioma samples. EGFR/HER2 overexpression was most prevalent in ependymoma. CONCLUSIONS: Overexpression and/or amplification of EGFR/HER2 were identified as potential enrichment biomarkers for clinical trials of ErbB-targeted drugs.

Connecting healthcare professionals in Central America through management and leadership development: a social network analysis.

BACKGROUND: Leadership and management training has become increasingly important in the education of health care professionals. Previous research has shown the benefits that a network provides to its members, such as access to resources and information, but ideas for creating these networks vary. This study used social network analysis to explore the interactions among Central American Healthcare Initiative (CAHI) Fellowship alumni and learn more about information sharing, mentoring, and project development activities among alumni. The CAHI Fellowship provides leadership and management training for multidisciplinary healthcare professionals to reduce health inequities in the region. Access to a network was previously reported as one of the top benefits of the program. RESULTS: Information shared from the work of 100 CAHI fellows from six countries, especially within the same country, was analyzed. Mentoring relationships clustered around professions and project types, and networks of joint projects clustered by country. Mentorship, which CAHI management promoted, and joint project networks, in which members voluntarily engaged, had similar inclusiveness ratios. CONCLUSION: Social networks are strategic tools for health care leadership development programs to increase their impact by promoting interactions among participants. These programs can amplify intergenerational and intercountry ties by organizing events, provide opportunities for alumni to meet, assign mentors, and support collaborative action groups. Collaborative networks have great value to potentiate health professionals' leadership and management capabilities in a resource-constrained setting, such as the Global South.

Maintaining essential health services during a pandemic: lessons from Costa Rica's COVID-19 response.

Studies on COVID-19 usually focus on health system responses to decrease the rate of COVID-19 infection and death, but patients with other diseases also require access to health services during the pandemic. This paper describes the structures and processes by which the Costa Rican Social Security Fund (CCSS) changed in response to the COVID-19 pandemic, which helped to sustain essential health services (EHSs). We conducted a desk review of the local literature and semistructured qualitative interviews with key informants from the CCSS. We found that the CCSS implemented changes in structure, such as creating a specialised COVID-19 centre and hiring additional interim health workers. The CCSS also implemented changes in processes, including leveraging its integrated network to optimise its resources and support alternative care modalities. These changes generated changes in outputs and outcomes that helped sustain EHSs for non-COVID-19 patients. These interventions were possible primarily due to Costa Rica's underlying health system, particularly its integrated nature with a single institution in charge of healthcare provision financed through mandatory health insurance, a unique digital medical record system and a contingency fund.

New refrigerants and system configurations for vapor-compression refrigeration.

The high global warming potential of current refrigerants in cooling equipment based on the vapor-compression cycle has triggered a major effort to find and implement more environmentally benign alternatives. Here, we review the basics of the vapor-compression cycle together with the safety, environmental, and thermodynamic constraints that have led to the current and next generation of refrigerants. The development of new fluids has focused on fluorinated olefins, known as hydrofluoroolefins (HFOs), and blends that contain HFOs. Many of these are slightly flammable, presenting trade-offs between safety and environmental considerations. Engineers also have options with a resurgence of the "natural refrigerants" (ammonia, carbon dioxide, propane, and isobutane). Innovative system designs that reduce the required quantity of refrigerant may allow a wider choice of refrigerants.

Management training in global health education: a Health Innovation Fellowship training program to bring healthcare to low-income communities in Central America.

BACKGROUND: Interprofessional education is increasingly recognized as essential for health education worldwide. Although effective management, innovation, and entrepreneurship are necessary to improve health systems, business schools have been underrepresented in global health education. Central America needs more health professionals trained in health management and innovation to respond to health disparities, especially in rural communities. OBJECTIVE: This paper explores the impact of the Health Innovation Fellowship (HIF), a new training program for practicing health professionals offered jointly by the Central American Healthcare Initiative and INCAE Business School, Costa Rica. Launched in 2014, HIF's goal is to create a network of highly trained interdisciplinary health professionals in competencies to improve health of Central American communities through better health management. METHODS: The program's fellows carried out innovative healthcare projects in their local regions. The first three annual cohorts (total of 43 fellows) represented all health-related professions and sectors (private, public, and civil society) from six Central American countries. All fellows attended four 1-week, on-site modular training sessions, received ongoing mentorship, and stayed connected through formal and informal networks and webinars through which they exchange knowledge and support each other. CAHI stakeholders supported HIF financially. RESULTS: Impact evaluation of the three-year pilot training program is positive: fellows improved their health management skills and more than 50% of the projects found either financial or political support for their implementation. CONCLUSIONS: HIF's strengths include that both program leaders and trainees come from the Global South, and that HIF offers a platform to collaborate with partners in the Global North. By focusing on promoting innovation and management at a top business school in the region, HIF constitutes a novel capacity-building effort within global health education. HIF is a capacity-building effort that can be scaled up in the region and other low- and middle-income countries.

Orphan Drug Regulation: A missed opportunity for children and adolescents with cancer.

BACKGROUND: Oncology represents a major sector in the field of orphan drug development in Europe. The objective was to evaluate whether children and adolescents with cancer benefited from the Orphan Drug Regulation. METHODS: Data on orphan drug designations (ODDs) and registered orphan drugs from 8th August 2000 to 10th September 2016 were collected from the Community Register of medicinal products for human use. Assessment history, product information and existence of paediatric investigation plans were searched and retrieved from the European Medicine Agency website. RESULTS: Over 16 years, 272 of 657 oncology ODDs (41%) concerned a malignant condition occurring both in adults and children. The five most common were acute myeloid leukaemia, high-grade glioma, acute lymphoblastic leukaemia, graft-versus-host disease and soft-tissue sarcomas. 74% of 31 marketing authorisations (MAs) for an indication both in adults and children (26 medicines) had no information for paediatric use in their Summary of Product Characteristics (SmPC) at the time of the first MA. Furthermore, 68% still have no paediatric information in their most recently updated SmPC, at a median of 7 years after. Only 15 ODDs (2%) pertained to a malignancy occurring specifically in children and only two drugs received an MA: Unituxin for high-risk neuroblastoma and Votubia for sub-ependymal giant-cell astrocytoma. CONCLUSION: The Orphan Drug Regulation failed to promote the development of innovative therapies for malignancies occurring in children. Major delays and waivers occurred through the application of the Paediatric Medicines Regulation. The European regulatory environment needs to be improved to accelerate innovation for children and adolescents dying of cancer.

GADD153 and 12-lipoxygenase mediate fenretinide-induced apoptosis of neuroblastoma.

The synthetic retinoid fenretinide induces apoptosis of neuroblastoma cells and in vitro acts synergistically with chemotherapeutic drugs used to treat neuroblastoma. The mechanisms of fenretinide-induced cell death of neuroblastoma cells are complex, involving cellular signaling pathways as yet incompletely defined but, in part, involving the generation of reactive oxygen species (ROS). In an attempt to characterize the mechanism of action of fenretinide, cDNA array filters were screened to identify apoptotic genes regulated in response to treatment of SH-SY5Y cells with fenretinide. Expression of the stress-induced transcription factor, GADD153, was up-regulated at both the protein and mRNA levels in response to fenretinide. Overexpression of GADD153 increased apoptosis in the presence and absence of fenretinide, whereas reduced expression of GADD153 by expression of antisense DNA abrogated the response to fenretinide. Although fenretinide is a partial retinoic acid receptor (RAR)-beta/gamma agonist, RARbeta/gamma antagonists did not block the induction of GADD153 by fenretinide; conversely, the induction of GADD153 was blocked by antioxidants. Enzyme inhibitors were used to identify pathways mediating the ROS-dependent effects of fenretinide: inhibitors of phospholipase A(2) and lypoxygenases (LOX), and specific inhibitors of 12-LOX, but not 5-LOX or 15-LOX, inhibited the induction of ROS, apoptosis, and GADD153 in response to fenretinide. The inhibition of ROS and apoptosis was reversed by the addition of the 12-LOX products, 12 (S)-hydroperoxyeicosatetraenoic acid (12-HpETE) and 12 (S)-hydroxyeicosatetraenoic acid (12-HETE). Fenretinide did not increase free arachidonic acid levels, but increased LOX activity without a detectable increase in 12-LOX protein. These results suggest that fenretinide induces apoptosis via RAR-dependent and -independent pathways in which the RAR-independent pathway is characterized by a fenretinide-dependent increase in 12-LOX activity, leading to the induction of GADD153. The targeting of 12-LOX and/or GADD153 in neuroblastoma cells may thus present a novel pathway for the development of drugs inducing apoptosis of neuroblastoma with improved tumor specificity.

Creating a unique, multi-stakeholder Paediatric Oncology Platform to improve drug development for children and adolescents with cancer.

Seven years after the launch of the European Paediatric Medicine Regulation, limited progress in paediatric oncology drug development remains a major concern amongst stakeholders - academics, industry, regulatory authorities, parents, patients and caregivers. Restricted increases in early phase paediatric oncology trials, legal requirements and regulatory pressure to propose early Paediatric Investigation Plans (PIPs), missed opportunities to explore new drugs potentially relevant for paediatric malignancies, lack of innovative trial designs and no new incentives to develop drugs against specific paediatric targets are some unmet needs. Better access to new anti-cancer drugs for paediatric clinical studies and improved collaboration between stakeholders are essential. The Cancer Drug Development Forum (CDDF), previously Biotherapy Development Association (BDA), with Innovative Therapy for Children with Cancer Consortium (ITCC), European Society for Paediatric Oncology (SIOPE) and European Network for Cancer Research in Children and Adolescents (ENCCA) has created a unique Paediatric Oncology Platform, involving multiple stakeholders and the European Union (EU) Commission, with an urgent remit to improve paediatric oncology drug development. The Paediatric Oncology Platform proposes to recommend immediate changes in the implementation of the Regulation and set the framework for its 2017 revision; initiatives to incentivise drug development against specific paediatric oncology targets, and repositioning of drugs not developed in adults. Underpinning these changes is a strategy for mechanism of action and biology driven selection and prioritisation of potential paediatric indications rather than the current process based on adult cancer indications. Pre-competitive research and drug prioritisation, early portfolio evaluation, cross-industry cooperation and multi-compound/sponsor trials are being explored, from which guidance for innovative trial designs will be provided.

International Intercomparison of Solar UVR Spectral Measurement Systems in Melbourne in 2013.

Monitoring ambient solar UVR levels provides information on how much there is in both real time and historically. Quality assurance of ambient measurements of solar UVR is critical to ensuring accuracy and stability and this can be achieved by regular intercomparisons of spectral measurement systems with those of other organizations. In October and November of 2013 a solar UVR spectroradiometer from Public Health England (PHE) was brought to Melbourne for a campaign of intercomparisons with a new Bentham spectrometer of Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) and one at the Australian Bureau of Meteorology (BOM), supported by New Zealand's National Institute for Water and Atmosphere (NIWA). Given all three spectroradiometers have calibrations that are traceable to various national standards, the intercomparison provides a chance to determine measurement uncertainties and traceability that support UV measurement networks in Australia, New Zealand and the UK. UV Index measurements from all three systems were compared and ratios determined for clear sky conditions when the scans from each instrument were within 2 min of each other. While wavelengths below 305 nm showed substantial differences between the PHE unit and the two other systems, overall the intercomparison results were encouraging, with mean differences in measured UV Index between the BOM/NIWA and those of PHE and ARPANSA of <0.1% and 7.5%, respectively.

Induction of GADD153 and Bak: novel molecular targets of fenretinide-induced apoptosis of neuroblastoma.

Unlike 13-cis retinoic acid, the synthetic retinoid fenretinide induces apoptosis of neuroblastoma cells and in vitro acts synergistically with the chemotherapeutic drugs, cisplatin, etoposide and carboplatin. The stress-induced transcription factor GADD153 and the Bcl2-related protein Bak are upregulated in response to fenretinide. Although fenretinide is a partial retinoic acid receptor (RAR)-beta/gamma agonist, RARbeta/gamma antagonists do not block the induction of GADD153 or Bak by fenretinide. Conversely, the induction of GADD153 and Bak is blocked by antioxidants. Neither GADD153 or Bak were induced by chemotherapeutic agents but over expression of GADD153 results in increased sensitivity to fenretinide-induced apoptosis. Therefore, fenretinide induces apoptosis via RAR-dependent and -independent pathways in which the RAR-independent pathway is characterised by the reactive oxygen species-dependent induction of GADD153 and Bak. The targeting of GADD153 and Bak in neuroblastoma cells may be novel pathways for the development of drugs inducing apoptosis of neuroblastoma with improved tumour specificity.

Autonomous portable solar ultraviolet spectroradiometer (APSUS) - a new CCD spectrometer system for localized, real-time solar ultraviolet (280-400 nm) radiation measurement.

Terrestrial solar ultraviolet (UV) radiation has significant implications for human health and increasing levels are a key concern regarding the impact of climate change. Monitoring solar UV radiation at the earth's surface is therefore of increasing importance. A new prototype portable CCD (charge-coupled device) spectrometer-based system has been developed that monitors UV radiation (280-400 nm) levels at the earth's surface. It has the ability to deliver this information to the public in real time. Since the instrument can operate autonomously, it is called the Autonomous Portable Solar Ultraviolet Spectroradiometer (APSUS). This instrument incorporates an Ocean Optics QE65000 spectrometer which is contained within a robust environmental housing. The APSUS system can gather reliable solar UV spectral data from approximately April to October inclusive (depending on ambient temperature) in the UK. In this study the new APSUS unit and APSUS system are presented. Example solar UV spectra and diurnal UV Index values as measured by the APSUS system in London and Weymouth in the UK in summer 2012 are shown.

Effect of altitude on solar UVR and spectral and spatial variations of UV irradiances measured inWagrain, Austria in winter.

Ultraviolet radiation spectral irradiance was measured at different altitudes on horizontal and tilted planes in different azimuth directions on cloudless days in Austria, in March 2010, within the Impact of Climatic and Environmental factors on Personal Ultraviolet Radiation Exposure project framework. The presented results demonstrate variations of the UVB, UVA and biologically effective spectral irradiance measured on inclined and horizontal surfaces with east, west and south azimuth directions of the vertical surface and the angular position of a detector.

Temperature correction of UV spectral solar measurements for ICEPURE project.

UV solar spectra have been measured, using a double-grating spectroradiometer, during population studies carried out across Europe for the EC Framework 7 funded ICEPURE project on the impact of climatic and environmental factors on personal UV radiation exposure and human health. Spectral field measurements have been conducted at ambient temperatures which varied between 11.5 and 33.5 °C. This temperature variation might affect instrument performance. The effect of ambient temperature was quantified and verified, and a model for temperature correction of spectral data is presented.

Serum angiogenic profile of patients with glioblastoma identifies distinct tumor subtypes and shows that TIMP-1 is a prognostic factor.

Angiogenesis plays a key role in glioblastoma biology and antiangiogenic agents are under clinical investigation with promising results. However, the angiogenic profiles of patients with glioblastoma and their clinical significance are not well understood. Here we characterize the serum angiogenic profile of patients with glioblastoma, and examine the prognostic significance of individual angiogenic factors. Serum samples from 36 patients with glioblastoma were collected on admission and simultaneously assayed for 48 angiogenic factors using protein microarrays. The data were analyzed using hierarchical cluster analysis. Vessel morphology was assessed histologically after immunostaining for the pan-endothelial marker CD31. Tumor samples were also immunostained for tissue inhibitor of metalloproteinase-1 (TIMP-1). Cluster analysis of the serum angiogenic profiles revealed 2 distinct subtypes of glioblastoma. The 2 subtypes had markedly different tumor microvessel densities. A low serum level of TIMP-1 was associated with significantly longer survival independent of patient age, performance status, or treatment. The serum angiogenic profile in patients with glioblastoma mirrors tumor biology and has prognostic value. Our data suggest the serum TIMP-1 level as an independent predictor of survival.

Growth and DNA damage-inducible transcription factor 153 mediates apoptosis in response to fenretinide but not synergy between fenretinide and chemotherapeutic drugs in neuroblastoma.

Fenretinide induces apoptosis of neuroblastoma cells in vitro and interacts synergistically with the chemotherapeutic drugs cisplatin and etoposide. The stress-inducible transcription factor known as growth and DNA damage (GADD)-inducible transcription factor 153 is induced in response to fenretinide and in other cell types modulates apoptosis via pro- and antiapoptotic members of the BCL2 family. Because BCL2-family proteins are important in apoptosis induced by chemotherapeutic drugs, GADD153 may be a key mediator of synergy between fenretinide and chemotherapeutic drugs. To investigate this, GADD153 cDNA in sense and antisense orientations was stably transfected into SH-SY5Y neuroblastoma cells using a tetracycline-inducible vector. Increased expression of GADD153 raised the background level of apoptosis and increased apoptosis induced by fenretinide or the chemotherapeutic drugs cisplatin and etoposide. However, there was no increase in synergy between fenretinide and chemotherapeutic drugs. Conversely, expression of antisense-GADD153 virtually abolished the induction of apoptosis in response to fenretinide but overall had no significant effect on apoptosis induced by chemotherapeutic drugs. The effect of antisense-GADD153 on synergy between chemotherapeutic drugs and fenretinide varied with the drug used: there was no effect on synergy between fenretinide and cisplatin, but the combination of fenretinide with etoposide became antagonistic. These results suggest that mechanisms mediating synergy between fenretinide and chemotherapeutic drugs lie upstream of GADD153.

Mechanisms of free-radical induction in relation to fenretinide-induced apoptosis of neuroblastoma.

The mechanisms of fenretinide-induced cell death of neuroblastoma cells are complex, involving signaling pathways mediated by free radicals or reactive oxygen species (ROS). The aim of this study was to identify mechanisms generating ROS and apoptosis of neuroblastoma cells in response to fenretinide. Fenretinide-induced ROS or apoptosis of SH-SY5Y or HTLA 230 neuroblastoma cells were not blocked by Nitro l-argenine methyl ester (l-NAME), an inhibitor of nitric oxide synthase. Flavoprotein-dependent superoxide-producing enzymes such as NADPH oxidase were also not involved in fenretinide-induced apoptosis or ROS generation. Similarly, ketoconazole, a cytochrome P450 inhibitor, and inhibitors of cyclooxygenase (COX) were also ineffective. In contrast, inhibition of phospholipase A(2) or lipoxygenases (LOX) blocked the induction of ROS and apoptosis in response to fenretinide. Using specific inhibitors of LOX, blocking 12-LOX but not 5- or 15-LOX inhibited both fenretinide-induced ROS and apoptosis. The effects of eicosatriynoic acid, a specific 12-LOX inhibitor, were reversed by the addition of the 12-LOX products, 12 (S)-hydroperoxyeicosatetraenoic acid and 12 (S)-hydroxyeicosatetraenoic acid. The targeting of 12-LOX in neuroblastoma cells may thus be a novel pathway for the development of drugs inducing apoptosis of neuroblastoma with improved tumor specificity.