Barriers and facilitating factors influencing implementation of occupational therapy home assessment recommendations: A mixed methods systematic review.

INTRODUCTION: Low implementation rates of occupational therapy home assessment recommendations have previously been reported. The objective was to identify and describe the barriers and facilitating factors that influence implementation of home assessment recommendations. METHODS: A mixed methods systematic review consisting of studies involving adults living in the community who received an occupational therapy home assessment was conducted. Seven databases were last searched in August 2021. Study quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools (SUMARI) dependent on study design. Data synthesis followed the convergent integrated approach. Findings were mapped to the theoretical Capability Opportunity Motivation Behaviour (COM-B) model of health behaviour change. RESULTS: From 5,540 citations, 22 articles met the criteria for the systematic review. Implementation of occupational therapy home assessment recommendations ranged between 55% and 90%. Six synthesised findings were identified. Capability barriers included a patient's cognitive and physical ability. Motivation barriers included a perceived lack of need and stigma; patient reported decreased involvement and lack of choice. Opportunity barriers included limited family or carer involvement, carer stress, level of service provision available, including funding, therapy dosage and timing and environmental restrictions. Overall facilitators included patient-centred care, including choice and understanding need, individualised tailored recommendations, involvement of families and carers, provision of written record and strategies to support implementation. Results were limited by methodological weaknesses in identified studies and heterogeneity in the definition and measurement of implementation impacting on comparison. Specific intervention components were often poorly described. CONCLUSION: The theoretical model elucidates priority factors to address for promoting implementation of home assessment recommendations. Future high-quality research clearly defining intervention components is required to support short- and long-term implementation of recommendations in the home environment. Behaviour change techniques could be utilised to support home assessment practices in future research.

A pilot study to assess short-term physiologic outcomes of transitioning infants with severe bronchopulmonary dysplasia from ICU to two subacute ventilators.

INTRODUCTION: This study was designed to evaluate short-term physiologic outcomes of transitioning neonates with bronchopulmonary dysplasia (BPD) from intensive care unit (ICU) ventilators to both the Trilogy 202 (Philips Healthcare, Andover, MA) and LTV 1200 (CareFusion, Yorba Linda, CA) subacute ventilators. METHODS: Six infants with BPD requiring tracheostomies for support with a neonatal-specific ICU ventilator underwent placement of esophageal balloon catheters, airway pressure transducers, flow sensors, oxygen saturation (SpO2), and end tidal carbon dioxide (PETCO2) monitors. Noninvasive gas exchange, airflow, and airway and esophageal pressures (PES) were recorded following 20 min on the ICU ventilator. The infants were placed on the Trilogy 202 and LTV 1200 ventilators in random order at identical settings as the ICU ventilator. We measured noninvasive gas exchange, pressure-rate product (respiratory rate × ΔPES), ventilator response times, and the percentage of spontaneous breaths that triggered the ventilator at 20 min in each subject while being supported with each of the different subacute ventilators. RESULTS: The mean (SD) weight of the six infants was 4.983 (0.56) kg. There were no differences in heart rate (p = 0.51) or SpO2 (p = 0.97) but lower PETCO2, ΔPES, respiratory rate, pressure rate-product, response times, and greater percentage of subject initiated breaths that triggered the ventilator (p < 0.05) was observed with the Trilogy 202 than the LTV 1200. All six infants transitioned successfully from the ICU ventilator to the Trilogy 202 ventilator. CONCLUSION: In this small group of infants with BPD, the Trilogy 202 ventilator performed better than the LTV 1200. The improved subject efforts, per cent subject triggering, and response times observed with the Trilogy are likely related to differences in triggering algorithms, location of triggering mechanisms, and gas delivery system performance within the ventilators. These pilot data may be useful for informing future clinical study design and understanding differences in the level of support provided by different subacute ventilators in infants with BPD.

Inhaled Treprostinil Drug Delivery During Mechanical Ventilation and Spontaneous Breathing Using Two Different Nebulizers.

OBJECTIVES: To determine the feasibility of delivering inhaled treprostinil during mechanical ventilation and spontaneous unassisted ventilation using the Tyvaso Inhalation System and the vibrating mesh nebulizer. We sought to compare differences in fine particle fraction, and absolute inhaled treprostinil mass delivered to neonatal, pediatric, and adult models affixed with a face mask, conventional, and high-frequency ventilation between Tyvaso Inhalation System and with different nebulizer locations between Tyvaso Inhalation System and vibrating mesh nebulizer. DESIGN: Fine particle fraction was first determined via impaction with both the Tyvaso Inhalation System and vibrating mesh nebulizer. Next, a test lung configured with neonatal, pediatric, and adult mechanics and a filter to capture medication was attached to a realistic face model during spontaneous breathing or an endotracheal tube during conventional ventilation and high-frequency oscillator ventilator. Inhaled treprostinil was then nebulized with both the Tyvaso Inhalation System and vibrating mesh nebulizer, and the filter was analyzed via high-performance liquid chromatography. Testing was done in triplicate. Independent two-sample t tests were used to compare mean fine particle fraction and inhaled mass between devices. Analysis of variance with Tukey post hoc tests were used to compare within device differences. SETTING: Academic children's hospital aerosol research laboratory. MEASUREMENTS AND MAIN RESULTS: Fine particle fraction was not different between the Tyvaso Inhalation System and vibrating mesh nebulizer (0.78 ± 0.04 vs 0.77 ± 0.08, respectively; p = 0.79). The vibrating mesh nebulizer delivered the same or greater inhaled treprostinil than the Tyvaso Inhalation System in every simulated model and condition. When using the vibrating mesh nebulizer, delivery was highest when using high-frequency oscillator ventilator in the neonatal and pediatric models, and with the nebulizer in the distal position in the adult model. CONCLUSIONS: The vibrating mesh nebulizer is a suitable alternative to the Tyvaso Inhalation System for inhaled treprostinil delivery. Fine particle fraction is similar between devices, and vibrating mesh nebulizer delivery meets or exceeds delivery of the Tyvaso Inhalation System. Delivery for infants and children during high-frequency oscillator ventilator with the vibrating mesh nebulizer may result in higher than expected dosages.

Surgical checklist application and its impact on patient safety in pediatric surgery.

BACKGROUND: Surgical care is an essential component of health care of children worldwide. Incidences of congenital anomalies, trauma, cancers and acquired diseases continue to rise and along with that the impact of surgical intervention on public health system also increases. It then becomes essential that the surgical teams make the procedures safe and error proof. The World Health Organization (WHO) has instituted the surgical checklist as a global initiative to improve surgical safety. AIMS: To assess the acceptance, application and adherence to the WHO Safe Surgery Checklist in Pediatric Surgery Practice at a university teaching hospital. MATERIALS AND METHODS: In a prospective study, spanning 2 years, the checklist was implemented for all patients who underwent operative procedures under general anesthesia. The checklist identified three phases of an operation, each corresponding to a specific period in the normal flow of work: Before the induction of anesthesia ("sign in"), before the skin incision ("time out") and before the patient leaves the operating room ("sign out"). In each phase, an anesthesiologist,-"checklist coordinator," confirmed that the anesthesia, surgery and nursing teams have completed the listed tasks before proceeding with the operation and exit. The checklist was used for 3000 consecutive patients. RESULTS: No major perioperative errors were noted. In 54 (1.8%) patients, children had the same names and identical surgical procedure posted on the same operation list. The patient identification tag was missing in four (0.1%) patients. Mention of the side of procedures was missing in 108 (3.6%) cases. In 0.1% (3) of patients there was mix up of the mention of side of operation in the case papers and consent forms. In 78 (2.6%) patients, the consent form was not signed by parents/guardians or the side of the procedure was not quoted. Antibiotic orders were missing in five (0.2%) patients. In 12 (0.4%) cases, immobilization of the patients was suboptimal, which led to displacement of diathermy grounding pad. In 54 (1.8%) patients, the checklist was not used at all. In 76 (2.5%) patients the checklist was found to be incompletely filled. CONCLUSIONS: Our study supports the use of the checklist as an essential safety tool and reinforcement of the same. The checklist may act as a valuable prompt to focus the team, to ensure that even the simple things have been cared for.

Effects of sequential osteoporosis treatments on trabecular bone in adult rats with low bone mass.

UNLABELLED: We used an osteopenic adult ovariectomized (OVX) rat model to evaluate various sequential treatments for osteoporosis, using FDA-approved agents with complementary tissue-level mechanisms of action. Sequential treatment for 3 months each with alendronate (Aln), followed by PTH, followed by resumption of Aln, created the highest trabecular bone mass, best microarchitecture, and highest bone strength. INTRODUCTION: Individual agents used to treat human osteoporosis reduce fracture risk by ∼ 50-60%. As agents that act with complementary mechanisms are available, sequential therapies that mix antiresorptive and anabolic agents could improve fracture risk reduction, when compared with monotherapies. METHODS: We evaluated bone mass, bone microarchitecture, and bone strength in adult OVX, osteopenic rats, during different sequences of vehicle (Veh), parathyroid hormone (PTH), Aln, or raloxifene (Ral) in three 90-day treatment periods, over 9 months. Differences among groups were evaluated. The interrelationships of bone mass and microarchitecture endpoints and their relationship to bone strength were studied. RESULTS: Estrogen deficiency caused bone loss. OVX rats treated with Aln monotherapy had significantly better bone mass, microarchitecture, and bone strength than untreated OVX rats. Rats treated with an Aln drug holiday had bone mass and microarchitecture similar to the Aln monotherapy group but with significantly lower bone strength. PTH-treated rats had markedly higher bone endpoints, but all were lost after PTH withdrawal without follow-up treatment. Rats treated with PTH followed by Aln had better bone endpoints than those treated with Aln monotherapy, PTH monotherapy, or an Aln holiday. Rats treated initially with Aln or Ral, then switched to PTH, also had better bone endpoints, than monotherapy treatment. Rats treated with Aln, then PTH, and returned to Aln had the highest values for all endpoints. CONCLUSION: Our data indicate that antiresorptive therapy can be coupled with an anabolic agent, to produce and maintain better bone mass, microarchitecture, and strength than can be achieved with any monotherapy.

Zooming in on Long Non-Coding RNAs in Ewing Sarcoma Pathogenesis.

Ewing sarcoma (ES) is a rare aggressive cancer of bone and soft tissue that is mainly characterized by a reciprocal chromosomal translocation. As a result, about 90% of cases express the EWS-FLI1 fusion protein that has been shown to function as an aberrant transcription factor driving sarcomagenesis. ES is the second most common malignant bone tumor in children and young adults. Current treatment modalities include dose-intensified chemo- and radiotherapy, as well as surgery. Despite these strategies, patients who present with metastasis or relapse still have dismal prognosis, warranting a better understanding of treatment resistant-disease biology in order to generate better prognostic and therapeutic tools. Since the genomes of ES tumors are relatively quiet and stable, exploring the contributions of epigenetic mechanisms in the initiation and progression of the disease becomes inevitable. The search for novel biomarkers and potential therapeutic targets of cancer metastasis and chemotherapeutic drug resistance is increasingly focusing on long non-coding RNAs (lncRNAs). Recent advances in genome analysis by high throughput sequencing have immensely expanded and advanced our knowledge of lncRNAs. They are non-protein coding RNA species with multiple biological functions that have been shown to be dysregulated in many diseases and are emerging as crucial players in cancer development. Understanding the various roles of lncRNAs in tumorigenesis and metastasis would determine eclectic avenues to establish therapeutic and diagnostic targets. In ES, some lncRNAs have been implicated in cell proliferation, migration and invasion, features that make them suitable as relevant biomarkers and therapeutic targets. In this review, we comprehensively discuss known lncRNAs implicated in ES that could serve as potential biomarkers and therapeutic targets of the disease. Though some current reviews have discussed non-coding RNAs in ES, to our knowledge, this is the first review focusing exclusively on ES-associated lncRNAs.

Factors Affecting EWS-FLI1 Activity in Ewing's Sarcoma.

Ewing's sarcoma family tumors (ESFT) are characterized by specific chromosomal translocations, which give rise to EWS-ETS chimeric proteins. These aberrant transcription factors are the main pathogenic drivers of ESFT. Elucidation of the factors influencing EWS-ETS expression and/or activity will guide the development of novel therapeutic agents against this fatal disease.

Mechanisms, Diagnosis and Treatment of Bone Metastases.

Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients' quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. We also highlight current and innovative approaches to biologically targeted therapy and immunotherapy. In particular, we discuss the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications. Multiple signaling pathways have been described to contribute to metastatic spread to the bone of specific cancer entities, with most knowledge derived from the study of breast and prostate cancer. However, it is likely that similar mechanisms are involved in different types of cancer, including multiple myeloma, primary bone sarcomas and neuroblastoma. The metastatic rate-limiting interaction of tumor cells with the various cellular and noncellular components of the bone-marrow niche provides attractive therapeutic targets, which are already partially exploited by novel promising immunotherapies.

Barriers and facilitators influencing adherence to occupational therapy home assessment recommendations: a mixed methods systematic review protocol.

OBJECTIVE: To identify and describe the barriers and facilitators that influence adherence to recommendations provided as part of an occupational therapy home assessment. INTRODUCTION: Home assessments, including environmental interventions, are commonly used by occupational therapists. Home assessment recommendations aim to support a patient's independence in their occupational roles and improve safety in the home. Research evaluating home assessments and adherence to recommended strategies is limited. However, low adherence has been associated with poorer outcomes including falls, deconditioning, and decreased function. This research aims to synthesize factors that influence adherence to home assessment recommendations. INCLUSION CRITERIA: This review will consider all qualitative and quantitative studies that report on adherence to recommendations provided during occupational therapy home assessments. Studies will include adults (>18) and/or their caregivers, who live in the community and receive an occupational therapy home assessment. METHODS: A mixed methods systematic review will be undertaken. Eight databases will be searched for studies published in English reporting on adherence following home assessments completed by occupational therapists published after January 2000. Study quality will be assessed using standardized JBI critical appraisal tools dependent on study design. Data extraction will be performed using a standardized tool, followed by data transformation. Data synthesis will follow the convergent integrated approach. All findings will be tabulated to explore factors that influence adherence. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020159233.

YAP/TAZ inhibition reduces metastatic potential of Ewing sarcoma cells.

Ewing sarcoma (EwS) is a highly metastatic bone cancer characterized by the ETS fusion oncoprotein EWS-FLI1. EwS cells are phenotypically highly plastic and switch between functionally distinct cell states dependent on EWS-FLI1 fluctuations. Whereas EWS-FLI1high cells proliferate, EWS-FLI1low cells are migratory and invasive. Recently, we reported activation of MRTFB and TEAD, effectors of RhoA and Hippo signalling, upon low EWS-FLI1, orchestrating key steps of the EwS migratory gene expression program. TEAD and its co-activators YAP and TAZ are commonly overexpressed in cancer, providing attractive therapeutic targets. We find TAZ levels to increase in the migratory EWS-FLI1low state and to associate with adverse prognosis in EwS patients. We tested the effects of the potent YAP/TAZ/TEAD complex inhibitor verteporfin on EwS cell migration in vitro and on metastasis in vivo. Verteporfin suppressed expression of EWS-FLI1 regulated cytoskeletal genes involved in actin signalling to the extracellular matrix, effectively blocked F-actin and focal-adhesion assembly and inhibited EwS cell migration at submicromolar concentrations. In a mouse EwS xenograft model, verteporfin treatment reduced relapses at the surgical site and delayed lung metastasis. These data suggest that YAP/TAZ pathway inhibition may prevent EwS cell dissemination and metastasis, justifying further preclinical development of YAP/TAZ inhibitors for EwS treatment.

Synthesis and surface control of colloidal Cr3+-doped SnO2 transparent magnetic semiconductor nanocrystals.

The synthesis of colloidal Cr(3+)-doped SnO(2) nanocrystals prepared under mild conditions via a hydrolysis method is described. We show by means of nanocrystal surface ligand exchange that even under mild reaction conditions a significant fraction of the dopant ions reside on the nanocrystal surfaces. Two different approaches aimed at achieving internal dopant incorporation-surface-bound dopant complexation and isocrystalline shell growth-are described and compared. While free-standing nanocrystals are paramagnetic, the films prepared from the same nanocrystals exhibit ferromagnetic ordering at room temperature. The measured magnetization is associated with structural defects formed at the interfaces of nanocrystals in their films, and discussed in terms of the defect-related itinerant-electron-mediated mechanism. The observed ferromagnetism is compared to ferromagnetism in Cr(3+)-doped In(2)O(3) nanocrystalline films. These results demonstrate the possibility of controlling surface structure and composition of doped oxide nanocrystals using different approaches. Furthermore, this work emphasizes the importance of surface structure and composition in tailoring properties of doped multifunctional transparent conducting oxide nanostructures.

CPT coding patterns at nurse-managed health centers: data from a national survey.

Nurse-managed health centers (NMHCs) play an important role in delivering health care services to a wide range of communities and often serve as our nation's safety net providers. Unfortunately, NMHCs struggle to remain in business for a variety of reasons, including underdeveloped business practices. Until now, NMHCs had only data from the Centers for Medicare and Medicaid Services and the Medical Group Management Assocation for comparison with coding patterns in individual centers. This article is the first published report of national data for NMHCs that is available for comparison. Providers need to possess financial acumen to remain open for business. Assessment of CPT coding patterns is a key strategy to support long-term sustainability.

Incidentally Diagnosed Alport Syndrome in a Patient with Drug-Induced Vasculitis.

A 53-year-old woman is admitted with a serum creatinine of 16 mg/dl. Seven months earlier, she was diagnosed with heart failure and started on several medications, including Hydralazine. Laboratory studies revealed the presence of dual Anti-Neutrophil Cytoplasmic Antibodies (anti-MPO and anti-PR3), anti-nuclear and anti-histone antibodies. The clinical diagnosis was Drug-Induced ANCA Vasculitis (DIAV). Kidney histology, however, did not reveal crescents, but showed characteristic features of Alport's syndrome.

Physiologic Effects of 3 Different Neonatal Volume-Targeted Ventilation Modes in Surfactant-Deficient Juvenile Rabbits.

BACKGROUND: Different brands of volume-targeted modes may vary the location of tidal volume (VT) monitoring and whether peak inspiratory pressure is adjusted based on inspiratory, expiratory, or leak-compensated VT. These variables may result in different levels of support provided to patients, especially when an endotracheal tube (ETT) leak is present. We hypothesized that there would be no differences in gas exchange, triggering, or work of breathing between volume-targeted modes of 3 different brands of equipment in a surfactant-deficient, spontaneously breathing animal model with and without an ETT leak. METHODS: Twelve rabbits (mean ± SD 1.61 ± 0.20 kg) were sedated, anesthetized, intubated, lavaged with 0.9% saline solution, and randomized in a crossover design so that each animal was supported by 3 different volume-targeted modes at identical settings with and without an ETT leak. After 30 min, arterial blood gas, VT, and esophageal and airway pressure were recorded for each condition, and pressure-rate product and percentage of successfully triggered breaths were calculated. RESULTS: Gas exchange and the pressure-rate product were not different between the ventilators in the absence of an ETT leak. When an ETT leak was introduced, volume-guarantee modes allowed a higher percentage of triggered breaths and peak inspiratory pressure, which resulted in higher minute ventilation, pH, and lower PaCO2 than the pressure-regulated volume control mode (P < .05). CONCLUSIONS: When a moderate ETT leak was present, volume-targeted modes that used proximal VT monitoring and triggering with adaptive leak compensation capabilities appeared more effective in providing ventilation support than did a ventilator that used measurements obtained from the back at the ventilator and does not have leak compensation.

Retraction Note: Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Smooth muscle-targeted knockout of connexin43 enhances neointimal formation in response to vascular injury.

OBJECTIVE: Vascular disease alters and reduces connexin expression and a reduction in connexin 43 (Cx43) expression diminishes the extent of atherosclerosis observed in a high-cholesterol diet murine model. We hypothesized that connexins might play a role in the smooth muscle cell response to vascular injury. METHODS AND RESULTS: We therefore studied a line of smooth muscle cell-specific, Cx43 gene knockout mice (SM Cx43 KO) in which the carotid arteries were injured, either by vascular occlusion or by a wire injury. In the SM Cx43 KO mice both types of injury manifested accelerated growth of the neointima and of the adventitia. Isolated vascular smooth muscle cells from the SM Cx43 KO mice grew at a slightly faster rate in culture, and to marginally higher saturation densities than those of control mice, but these changes were not adequate to explain the large changes in the injured vessels. CONCLUSIONS: These observations provide direct evidence that smooth muscle Cx43 gap junctions play a multi-faceted role in modulating the in vivo growth response of vascular smooth muscle cells to vascular injury.

The conversion to metered-dose inhaler with valved holding chamber to administer inhaled albuterol: a pediatric hospital experience.

BACKGROUND: Metered-dose inhalers with valved holding chambers (MDI-VHCs) have been shown to be equivalent to small-volume nebulizers (SVNs) for the delivery of bronchodilators in children. At Seattle Children's Hospital and Regional Medical Center we sought to implement the conversion from SVN to MDI-delivered albuterol in nonintubated patients receiving intermittent treatments. METHODS: There were 4 distinct interventions used to plan and implement this conversion program: (1) literature review, (2) product selection, (3) policy and operational changes, and (4) staff training. Bronchodilator administration guidelines and clinical pathways for asthma and bronchiolitis were revised to recommend MDI-VHC use in lieu of SVNs. Computerized physician order sets were amended to indicate MDI-VHC as the preferred method of delivering inhaled albuterol in children with asthma and bronchiolitis. Data from administrative case mix files and computerized medication delivery systems were used to assess the impact of our program. RESULTS: MDI-VHC utilization increased from 25% to 77% among all non-intensive-care patients receiving albuterol, and from 10% to 79% among patients with asthma (p < 0.001). Duration of stay among patients with asthma was unchanged after conversion to MDI-VHC (p = 0.53). CONCLUSIONS: Our program was very successful at promoting the use of MDI-VHC for the administration of albuterol in our pediatric hospital. Duration of stay among patients with asthma did not change during or since the implementation of this program.

Single-chain antibodies to the EWS NH(2) terminus structurally discriminate between intact and chimeric EWS in Ewing's sarcoma and interfere with the transcriptional activity of EWS in vivo.

The chimeric protein EWS-FLI1, arising from chromosomal translocation in Ewing's sarcoma family tumors (ESFT), acts as an aberrant tumorigenic transcription factor. The transforming activity of EWS-FLI1 minimally requires an ETS DNA binding domain and the EWS NH(2) terminus. Proteins interacting with the EWS portion differ between germ-line and chimeric EWS despite their sharing identical sequences in this domain. We explored the use of the phage display technology to isolate anti-EWS-FLI1 specific single-chain antibody fragments (scFvs). Using recombinant EWS-FLI1 as bait, 16 independent specific antibody clones were isolated from combinatorial phage display libraries, of which six were characterized in detail. Despite differing in their complementarity-determining region sequences, all six scFvs bound to the same epitope spanning residues 51 to 75 within the shared minimal transforming EWS domain. Whereas all six scFvs bound efficiently to cellular EWS, reactivity with ESFT-expressed EWS-FLI1 was weak and restricted to denatured protein. One scFv, scFv-I85, when expressed as an intrabody, efficiently suppressed EWS-dependent coactivation of hepatocyte nuclear factor 4- and OCT4-mediated transcription in vivo but no effect on known EWS-FLI1 target genes was observed. These data suggest that a prominent EWS epitope exposed on recombinant EWS-FLI1 structurally differs between germ-line and chimeric EWS in mammalian cells and that this region is functionally involved in the transcriptional activity of EWS. Thus, we have generated a tool that will prove useful to specifically differentiate between normal and rearranged EWS in functional studies.

Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers.

Ewing sarcoma (EwS) is an aggressive pediatric bone cancer in need of more effective therapies than currently available. Most research into novel targeted therapeutic approaches is focused on the fusion oncogene EWSR1-FLI1, which is the genetic hallmark of this disease. In this study, a broad range of 3,325 experimental compounds, among them FDA approved drugs and natural products, were screened for their effect on EwS cell viability depending on EWS-FLI1 expression. In a network-based approach we integrated the results from drug perturbation screens and RNA sequencing, comparing EWS-FLI1-high (normal expression) with EWS-FLI1-low (knockdown) conditions, revealing novel interactions between compounds and EWS-FLI1 associated biological processes. The top candidate list of druggable EWS-FLI1 targets included genes involved in translation, histone modification, microtubule structure, topoisomerase activity as well as apoptosis regulation. We confirmed our in silico results using viability and apoptosis assays, underlining the applicability of our integrative and systemic approach. We identified differential sensitivities of Ewing sarcoma cells to BCL-2 family inhibitors dependent on the EWS-FLI1 regulome including altered MCL-1 expression and subcellular localization. This study facilitates the selection of effective targeted approaches for future combinatorial therapies of patients suffering from Ewing sarcoma.

Correction: Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation.

Since publication of the article, the authors became aware that Figure 6(A,D) contained errors in the bands and loading controls. The newly compiled Figure 6A and 6D is given below.