Translational Efforts Research Articles

"It's All Sort of Cool and Interesting…but What Do I Do With It?" A Qualitative Study of Stroke Survivors' Perceptions of Surface Electromyography.

Background: Stroke is one of the most common neurologic injuries worldwide. Over decades, evidence-based neurorehabilitation research and advancements in wireless, wearable sensor design have supported the deployment of technologies to facilitate recovery after stroke. Surface electromyography (sEMG) is one such technology, however, clinical application remains limited. To understand this translational practice gap and improve clinical uptake, it is essential to include stakeholder voices in an analysis of neurorehabilitation practice, the acceptability of current sEMG technologies, and facilitators and barriers to sEMG use in the clinic and the community. The purpose of this study was to foreground the perspectives of stroke survivors to gain a better understanding of their experiences in neurorehabilitation, the technologies they have used during their recovery, and their opinions of lab-designed and commercially-available sEMG systems.Methods: A qualitative, phenomenological study was completed. In-depth, semi-structured interviews were conducted with eight stroke survivors (age range 49–78 years, 6 months to 12 years post-stroke) and two caregivers from a large metropolitan region. A demonstration of four sEMG systems was provided to gather perceptions of sensor design, features and function, and user interface. Interviews were audio-recorded, transcribed verbatim, and coded for analysis using constant comparison until data saturation was reached.Results: Three themes emerged from the data: (1) “Surface EMG has potential….but…” highlights the recognition of sEMG as a valuable tool but reveals a lack of understanding and need for clear meaning from the data; (2) “Tracking incremental progress over days or years is important” highlights the persistence of hope and potential benefit of sEMG in detecting small changes that may inform neurorehabilitation practice and policy; and (3) “Neurorehabilitation technology is cumbersome” highlights the tension between optimizing therapy time and trying new technologies, managing cost, logistics and set-up, and desired technology features.Conclusion: Further translation of sEMG technology for neurorehabilitation holds promise for stroke survivors, but sEMG system design and user interface needs refinement. The process of using sEMG technology and products must be simple and provide meaningful insight to recovery. Including stroke survivors directly in translational efforts is essential to improve uptake in clinical environments.

Abstract PO-065: National Clinical Trials Network biobanking during the COVID-19 pandemic

Abstract The National Cancer Institute (NCI) has a large portfolio of ongoing cancer clinical trials that involve biospecimen collection and are supported by the NCI-funded National Clinical Trials Network (NCTN) Biospecimen Banks located across the United States and Canada. At the start of the COVID-19 pandemic, NCTN biobanks rapidly responded to staffing consequences of state- and institution-issued stay-at-home orders. Many of the NCTN biobanks were deemed essential by their institutions, allowing for limited and/or socially distanced operations. NCTN biobanks quickly worked with NCI and their respective groups to advise participating sites of changes to usual biospecimen collection procedures in order to accommodate limited staffing at the biobanks. In many instances, participating sites were navigating their own institutional process change due to the pandemic. NCTN cancer clinical trials experienced an approximate 40% decrease in enrollment from March 11 to May 19, 2020, compared to the same time frame in 2019. Likewise, NCTN biobanks saw an approximate 40% and 60% decrease in biospecimen receipt and distribution, respectively. The decrease in biospecimen receipt was likely due to two factors: (1) participating site COVID-19 policies limiting patient enrollment on NCI cancer clinical trials and/or biospecimen collection for those trials, and (2) NCTN biobank requests for participating sites to hold nonurgent and/or nonmandatory biospecimens during the initial phase of the pandemic. Decrease in biospecimen distributions was mainly due to receiving laboratory closures as dictated by their institutional COVID-19 policies. On May 20, 2020, all states had begun initial reopening phases to some extent. At this time, several, but not all, NCTN biobanks had begun measured return to full operations, following institutional guidance. NCTN biobanks are making numerous considerations toward returning to full operations and will continue to work with NCI and their respective groups to responsibly collect and distribute biospecimens collected during the COVID-19 pandemic. Likely, some patients enrolled on NCTN cancer clinical trials may have had clinical or subclinical COVID-19 at the time of biospecimen collection. Additionally, biospecimens will be collected on two recently activated NCI COVID-19 studies: (1) the NCI COVID-19 in Cancer Patients Study (NCCAPS): A Longitudinal Natural History Study (NCT04387656), and (2) a tocilizumab treatment trial for COVID-19-related acute respiratory distress syndrome in cancer patients (NCT04370834). Retrospective annotation of these biospecimens may provide a unique resource for translational research efforts and will also be a needed caveat for interpreting biomarker studies conducted using these biospecimens, as the impact of COVID-19 on various biomarkers is currently unknown. Citation Format: Heather A. Lankes, Mark A. Watson, Richard C. Jordan, Nilsa C. Ramirez, Ignacio I. Wistuba, Lois Shepherd, Irina A. Lubensky, Hala Makhlouf. National Clinical Trials Network biobanking during the COVID-19 pandemic [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-065.

Do Coordinated Knowledge Translation Campaigns Persuade Radiation Oncologists to Use Single-Fraction Radiation Therapy Compared With Multiple-Fraction Radiation Therapy for Bone Metastases?

Although level 1 evidence supports the use of single-fraction radiation therapy (SFRT) compared with multiple-fraction radiation therapy (MFRT) for the palliative management of bone metastases, SFRT is underused. In early 2017, the Canadian Partnership Against Cancer and CancerCare Manitoba undertook a comprehensive knowledge translation campaign in Manitoba, Canada featuring educational outreach visits, local consensus meetings, and audit and feedback interventions to encourage greater use of SFRT. This study assessed the impact of this campaign on SFRT use and identified variables associated with MFRT usage. This retrospective, population-based cohort study identified all patients treated with palliative radiation therapy for bone metastases in Manitoba, Canada, from January 1, 2017, to December 31, 2017, using the provincial radiation therapy database. Baseline characteristics were extracted and tabulated by fractionation schedule. The proportion of patients treated with SFRT in 2017 (postintervention) was compared with the 2016 (preintervention) levels. Univariable and multivariable logistic regression analyses were performed to identify risk factors associated with MFRT use. In 2017, 927 patients received palliative radiation therapy for bone metastasis, of which 548 (59.1%) received SFRT, a 21.1% absolute increase in SFRT use compared with 2016 levels (38.0%). With use of multivariable analysis, variables associated with receipt of MFRT included: complicated bone metastasis, soft tissue extension, hematological primary malignancy, and treatment at a subsidiary center. The comprehensive knowledge translation campaign carried out in Manitoba resulted in a significant increase in SFRT use for bone metastases. Continued audit/feedback strategies are recommended to further reinforce knowledge translation efforts supporting SFRT use in the future.

Stroke rehabilitation research translation in Australia: a survey of clinical trialists

Purpose Translation of findings from stroke trials into clinical practice remains low. Little is known about planned translation activities from the perspective of trialists who generate the evidence. This study aims to investigate perceptions of Australian stroke clinical trialists’ about implementation of their findings into practice, and what translation activities they embedded into trial protocols. Materials and method A descriptive cohort design and electronic survey was conducted. Three databases were searched to identify Australian stroke rehabilitation trials published between 2007 and 2017. Corresponding authors of the included trials were invited to complete an anonymous online survey about implementation of their trial intervention. Results Fifty-one trialists were invited to participate and 38 completed the survey (74% response rate). The majority (79%) considered their trial results to be clinically significant and 68% had pre-planned knowledge translation activities. The most common planned translation activities were publication (89%), conference presentation (87%), and feedback of results to target audiences (58%). Mixed opinions were evident regarding when and how to design knowledge translation activities for inclusion in trial protocols. Stroke rehabilitation trialists rely mostly on anecdotal reports about implementation of trial interventions, with few formally measuring uptake. Implications for rehabilitation The most common knowledge translation activities planned for by researchers are publication of findings in academic journals, and conference presentations. Mixed opinions exist regarding when and how to design for knowledge translation activities in trial protocols. Limited formal measurement of intervention uptake is completed. Further implementation research is required to support and measure effective translation efforts when embedded into trial protocols.

Factors associated with avoidable interhospital transfers for children with a minor head injury.

Children with minor head injuries (MHI) are routinely transferred to a pediatric trauma center for definitive care. Unwarranted transfers result in minimal benefit to the patient and add substantially to healthcare costs. The purpose of this study is to explore the factors associated with avoidable interhospital transfers of children with MHI. We conducted a retrospective cohort study of children <18years of age transferred to our pediatric emergency department (PED) for MHI between January 2013 and December 2018. Patients transferred for non-accidental trauma, and those with a history of coagulopathies, underlying neurological conditions, intraventricular shunts and developmental delay were excluded. Transfers were categorized as avoidable if none of the following interventions were required at our PED: procedural sedation, anticonvulsant initiation, subspecialty consultation, intensive care unit admission or hospital admission for ≥2 nights, intubation or operative intervention. We collected demographics, injury mechanism, neuroimaging results, interventions performed and PED disposition. Binary logistic regression was conducted to provide adjusted associations between patient characteristics and the risk of avoidable interhospital transfers. We analyzed 1078 transfers for MHI, of which 450 (42%) transfers were classified as avoidable. Children in the avoidable transfer group tended to be younger, less likely to have experienced loss of consciousness, and more likely to belong to the the group at lowest risk for a clinically important traumatic brain injury (ciTBI). Our multivariable model determined that children less than 2years of age (OR=1.75; 95% CI=1.3-2.37), low-risk group for ciTBI (OR=1.66; 95% CI=1.22-0.1), and a positive head CT at the transferring hospital (OR=0.06; 95% CI=0.02-0.1) were all significantly associated with avoidable transfers. There is a high rate of avoidable transfers in children with MHI. Focused interventions targeting risk factors associated with avoidable transfers may reduce unwarranted interhospital transfers.

Mobilizing foreign language students for multilingual crisis translation in Shanghai

Abstract This paper examines the multilingual translation efforts of a group of university student volunteers during the COVID-19 outbreak in Shanghai. Data were collected through semi-structured interviews of the volunteer team leader, team members, and a local community health worker. Findings identified time constraints, limited language proficiency, and limited technical knowledge as the major challenges confronting the university volunteers. In order to overcome the challenges, they worked in close collaboration and used translingual and network strategies to facilitate prompt and high-quality crisis translation. Findings suggest that foreign language university students in local universities may serve as readily available multilingual resources and can be mobilized in prompt response to the grassroots multilingual needs of the local community in times of crisis. The paper ends with implications for measures and strategies to enhance effective emergency language service and crisis communication for global multilingual cities.

Abstract 4280: Potential molecular biomarkers of response to eribulin in patients with leiomyosarcoma

Abstract Background. The recent randomized phase 3 trial Eisai Study 309 evaluated efficacy of eribulin (ERI) compared to dacarbazine (DTIC) in advanced liposarcoma (LPS) and leiomyosarcoma (LMS). Improved overall survival (OS) in ERI-treated patients led to US and EU regulatory approval of ERI for LPS, but not in LMS where DTIC has clinically relevant activity. As part of the translational effort in this trial we have now explored the molecular profile of LMS tumors from North American study sites, in order to identify potential predictive molecular factors for treatment with ERI. Material and Methods. From 82 archival primary tumor or metastatic LMS samples collected prior to study entry, 78 specimens were available for low-coverage whole genome sequencing. We analyzed copy number alterations (CNAs) and performed whole exome sequencing (WES) for mutational profiling. Forty patients received experimental treatment with ERI, while 38 were treated with DTIC. Treatment response was evaluated using RECIST v1.1; disease control was defined as complete/partial response and stable disease. Results. Overall 111 focal CNAs were observed in the entire group of LMS, including 55 gains and 56 loses. Gain of 17q12 was the most common CNA (43/78 cases; 55.1%) observed in the entire group analyzed, with 26 samples showing high level amplification. MYOCD is a suggested target of 17q12 gains in LMS, encodes myocardin which induces smooth muscle differentiation and promotes cell migration. In the ERI-treated group, gains of 4q26, 20p12.2, 13q13.3, 8q22.2, 8q13.2 and loss of 1q44 had a negative impact on progression-free survival (PFS) (p&amp;lt;0.05; log rank test), while loss of 2p12 was a positive prognosticator. Gains of 4q22.1 and losses of 3q14.2, 2q14.1 and 11q25 had a negative impact on OS in ERI-treated patients. Using WES we detected an average of 266.1 (143-626) nonsynonymous substitutions and 4.7 indels (0-16) per sample, with an average of 11.5 (0-28) variants affecting Cancer Consensus Genes. The most commonly mutated genes in analyzed samples were TP53 (38%), MUC16 (31%) and ATRX (17%). In ERI-treated patients, the presence of ATRX mutations was more frequently observed in patients progressing on ERI (7/20 in patients with PD vs. 1/20 in group with disease control; p=0.0435). The presence of ATRX mutation had a negative impact on both PFS and OS. TP53 mutations were associated with longer PFS, and these mutations were more frequently observed in patients achieving disease control, although this was not statistically significant (11/20 vs. 5/20). ATRX andTP53 mutations were not linked with clinical benefit/response to DTIC. Conclusions. LMS has a complex genetic background, with multiple CNAs and mutations affecting genes implicated in tumorigenesis. We identified several molecular changes with potential impact on disease control and survival of LMS patients treated with ERI. These observations require further prospective validation. Citation Format: Agnieszka Wozniak, Bram Boecks, Elodie Modave, Amy Weaver, Diether Lambrechts, Bruce A. Littlefield, Patrick Schöffski. Potential molecular biomarkers of response to eribulin in patients with leiomyosarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4280.

Abstract 445: Integrated proteogenomic characterization across seven histological types of pediatric brain tumors

Abstract We performed a comprehensive proteogenomic analysis across seven major types of childhood brain tumors for a deeper understanding of their functional biology. Whole genome seq, RNAseq, quantitative proteomic and phosphoproteomic profiling were performed on 219 fresh frozen tumor samples representing the histologic diagnoses of: low grade astrocytoma (93), ependymoma (32), high grade astrocytoma (26), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16) and atypical teratoid rhabdoid tumor (12). Characterization of the tumor microenvironment through multi-omics based deconvolution analyses revealed 5 distinct tumor clusters associated with different populations of infiltrating immune cells: Cold-medullo, Cold-mixed, Epithelial, Neuronal and Hot. The two cold-tumor clusters have the lowest immune cell infiltration, one characterized by the enrichment of medulloblastoma tumors; while the other is a mixture of ependymoma, ATRT, HGG and medulloblastoma. The Epithelial group, on the other hand, was enriched in craniopharyngioma samples, an epithelium derived tumor. Interestingly, the RNA levels of PD-1 and CTLA4 were significantly upregulated in this Epithelial group, confirming that craniopharingioma could potentially benefit from anti PD-1 and/or CTLA-4 therapies as previously reported. LLG and ganglioglioma were allocated into two groups of Neuronal and Hot, the former characterized by the presence of neuronal cells, and the latter by the presence of macrophages, microglia, and dendritic cells. Adenosine producers (e.g., ENTPD1 and NT5E), which act as inhibitory immune checkpoint molecular, showed up-regulation in the Hot cluster based on both RNAseq and proteome data, suggesting patients in this group might benefit from adenosine reducing treatments. Among LGG tumors, there is a significant difference between microglial and macrophage polarization across BRAF statuses: BRAF-fusion promoted more pro-regenerative (immune suppressive) microglia than pro-inflammatory microglia, while BRAF-V600E promoted more pro-regenerative macrophages than pro-inflammatory macrophages, implying different immunosuppressive mechanisms in the BRAF-V600E and fusion tumors. This study reports the first large-scale deep comprehensive proteogenomic analysis crossing traditional histologic boundaries to uncover foundational pediatric brain tumor biology relating to tumor microenvironment. The incorporation of the proteomic and phosphoproteomic dimension into this large-scale multi-omic study adds functional insight that helps drive translational efforts. Citation Format: Francesca Petralia, Nicole Tignor, Boris Reva, Pichai Raman, Shrabanti Chowdhury, Dmitry Rykunov, Azra Krek, Weiping Ma, Jiayi Ji, Xiaoyu Song, Yuankun Zhu, Jo Lynne Rokita, Antonio Colaprico, Anna Calinawan, Jeffrey R. Whiteaker, Richard G. Ivey, Zeynep Gumus, Selim Kalayci, Gonzalo L. Garcia, Seungyeul Yoo, Lizabeth Katsnelson, Ying Wang, Jacob J. Kennedy, Uliana J. Voytovich, Lei Zhao, Felipe Leprevost, Hui-Yin Chang, Krutika S. Gaonkar, Elizabeth M. Appert, Ximena Cuellar, Jena Lilly, Jun Zhu, Eric E. Schadt, Medhi Mesri, Emily Boja, Tara Hiltka, Henry Rodriguez, Li Ding, Antonio Iavarone, Maciej Wiznerowicz, Alexey I. Nesvizhskii, David Fenyo, Steven Gygi, Amanda Paulovich, Adam C. Resnick, Phillip B. Storm, Brian Rood, Pei Wang, Children's Brain Tumor Tissue Consortium and Clinical Proteomic Tumor Analysis Consortium. Integrated proteogenomic characterization across seven histological types of pediatric brain tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 445.

Abstract 3445: Immuno-transcriptomic profiling identifies actionable genomic alterations in pediatric solid malignancies

Abstract Malignancy remains the leading cause of disease-related death in children. To identify potential tumor-driving molecular targets and characterize immunogenomic profiles in pediatric cancers, we performed RNA-seq analysis on a cohort of 788 pediatric solid tumors across 14 different diagnoses in conjunction with additional 147 normal tissues for comparison. Sequencing data were analyzed for expressed mutations, fusion events, and expressional patterns, providing therapeutic targets and rich cancer biology for these childhood cancers. Furthermore, we describe a comprehensive and in-depth immunogenomic landscape of these solid tumors including immune cell infiltrate, neoepitope analysis from expressed mutations and fusions, expressional patterns of clinically relevant immune checkpoint genes, expression of tumor-specific genes as potential pharmacological or immunological targets, and T cell receptor repertoire. Across the cohort, we observed a striking correlation between the expressed neoepitope burden in tumors and enrichment of the effector immune signatures. Intriguingly, canonical fusions (e.g. EWS-FLI1) contribute a disproportionally large number of neoepitopes in these typically low mutational tumors. Histology-specific immunogenomic patterns are also apparent. Several of the pediatric cancers such as alveolar soft part sarcoma and osteosarcoma exhibit rich immune cell infiltration and evidence for activated T cell activities, whereas others such as Wilms tumors and synovial sarcoma generally have a very low T cell infiltration. In addition, we demonstrated a significant positive correlation between tumor-infiltrating CD8+ T cells and overall survival in patients with osteosarcoma, revealing the clinical importance of these tumor-infiltrating immune cells in these childhood cancers. Moreover, an orthogonal evaluation of immunopeptidome in osteosarcoma, a cancer type displaying high immune infiltrates, confirmed our transcriptomic findings on potential targetable tumor-specific genes. Finally, we took an adoptive cell therapy-based approach to target a tumor-specific gene PRAME identified by our transcriptomic and immunopeptidomic studies and showed significant in-vitro cytotoxicity using T cells expressing TCRs specifically targeting PRAME in osteosarcoma U2OS cells. Therefore, we demonstrate that RNA-seq is a powerful tool to identify clinically relevant and histology-specific genomic alterations and translationally relevant immunogenomic patterns for pediatric cancers. This study also represents one of the largest of its type to date and provides a framework for future translational efforts in pediatric cancer. Citation Format: Jun S. Wei, Andrew S. Brohl, Sivasish Sindiri, David Milewski, Young K. Song, Sushma Nagaraj, Vineela Gangalapudi, Xinyu Wen, Marc Ladanyi, Javed Khan. Immuno-transcriptomic profiling identifies actionable genomic alterations in pediatric solid malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3445.

Effect of Previous Translations on Retranslation: A Case Study of Russian-Dutch Literary Translation

As Outi Paloposki and Kaisa Koskinen (2010) correctly stated in their article on the “fine line between retranslating and revising”, the exact relationship of a text with the previous translation(s) cannot always be determined, even if the most recent translation is presented (in the paratext to the edition) as a ‘retranslation’, ‘re-edition’ or ‘revision’. Indeed, in practice the “labels” of “(re)translation, (…) revisions, adaptations and retellings” are “hard to separate and cover different contents” in different circumstances (Van Coillie 2014).&#x0D; In this paper I will try to study the effect of a first or previous translation on the process of retranslating. In order to do that I will compare a number of literary translations with their predecessors. Literary translations are specifically chosen here because they are probably more often retranslated than other types of texts. Moreover, the style of the translated text is presumably more important than for other genres, which allows me to mutually compare the translations not only at lexical and syntactic, but also at stylistic level.&#x0D; In order to visualize the effect of a previous translation on a retranslation I will compare a number of Dutch translations of Russian literary works with their retranslations. On the one hand, I will compare three recent retranslations with older translations of the same work, ordered and published by the same publishing house, and explicitly announced to the reader as a ‘refreshed’ and reworked translation of the previous one. In these particular cases the retranslators were fully aware of the existence of another translation and the explicit reference to ‘retranslation’ virtually forced them to use the previous translation as a starting point. In order to avoid the influence of (1) the changing translation strategies throughout time, and (2) the possible idiosyncratic peculiarities of the specific translation strategy of one particular (but not representative) translator, I will use translations made by three different translators and published in approximately the same period.&#x0D; On the other hand, I will investigate two Dutch translations of the same Russian literary work, that were made independently from each other and were published virtually on the same day, as the translators were unaware of each other’s translation effort. In this case the ‘previous’ (the term is not really applicable in this case) translation could not have had any effect on the ‘retranslation’, which makes it an interesting case to compare with the three genuine ‘retranslations’.&#x0D; Special attention will be drawn to the differences in the translator’s decisions at lexical, syntactical and stylistic level. More specifically, the analysis will include a quantitative and qualitative approach. I will establish the amount of overlap in lexical, syntactical and stylistic choices in the four pairs of texts, and will try to find whether the retention or substitution of certain terms and linguistic features can be explained.

Rational discovery of molecular glue degraders via scalable chemical profiling.

Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts. Here, we describe a scalable strategy toward glue degrader discovery that is based on chemical screening in hyponeddylated cells coupled to a multi-omics target deconvolution campaign. This approach led us to identify compounds that induce ubiquitination and degradation of cyclin K by prompting an interaction of CDK12-cyclin K with a CRL4B ligase complex. Notably, this interaction is independent of a dedicated substrate receptor, thus functionally segregating this mechanism from all described degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify degraders with nonobvious mechanisms and thus empower future drug discovery efforts.

The Impact of Anodal tDCS on the Attentional Networks as a Function of Trait Anxiety and Depressive Symptoms: A Preregistered Double-Blind Sham-Controlled Experiment.

ObjectiveAttention is a multifaceted construct, including three distinct attentional networks: the alerting, orienting, and executive conflict networks. Recently, researchers have started to envision strategies to enhance the attentional networks, and transcranial Direct Current Stimulation (tDCS) has emerged as a promising tool to do so, especially regarding the executive conflict network. On the other hand, other research lines have suggested that anodal tDCS might yield more substantial impacts among depressive and anxious participants.MethodIn this preregistered study, we thus examined two questions. First, we wanted to replicate previous observations and tested whether anodal tDCS does improve the executive conflict network's efficiency. Second, we set out to clarify the impact of anxiety and depressive symptoms on this effect. To do so, we adopted a double-blind within-subject protocol in an unselected sample (n = 50) and delivered a single session of anodal— applied over the dorsolateral part of the left prefrontal cortex—versus sham tDCS during the completion of a task assessing the attentional networks. We assessed anxiety and depressive symptoms at baseline.Results and ConclusionsAlthough there were no significant direct effects of tDCS on the attentional networks, we found that the higher the levels of depression and trait anxiety, the larger the executive conflict network's enhancement during tDCS. By highlighting the importance of trait anxiety and depression when considering the impact of tDCS on the attentional networks, this study fulfills a valuable niche in clinical neuroscience, wherein preclinical data provide critical clues for larger, more definitive future translational efforts.

Does dissemination of guidelines alone increase the use of palliative single-fraction radiotherapy? Initial report of a longitudinal change management campaign at a provincial cancer program.

Despite level 1 evidence demonstrating the equivalence of single-fraction radiotherapy (sfrt) and multiple-fraction radiotherapy (mfrt) for the palliation of painful bone metastases, sfrt remains underused. In 2015, to encourage the sustainable use of palliative radiation oncology resources, CancerCare Manitoba disseminated, to each radiation oncologist in Manitoba, guidelines from Choosing Wisely Canada (cwc) that recommend sfrt. We assessed whether dissemination of the guidelines influenced sfrt use in Manitoba in 2016, and we identified factors associated with mfrt. All patients treated with palliative radiotherapy for bone metastasis in Manitoba from 1 January 2016 to 31 December 2016 were identified from the provincial radiotherapy database. Patient, treatment, and disease characteristics were extracted from the electronic medical record and tabulated by fractionation schedule. Univariable and multivariable logistic regression analyses were performed to identify risk factors associated with mfrt. In 2016, 807 patients (mean age: 70 years; range: 35-96 years) received palliative radiotherapy for bone metastasis, with 69% of the patients having uncomplicated bone metastasis. The most common primary malignancies were prostate (27.1%), lung (20.6%), and breast cancer (15.9%). In 62% of cases, mfrt was used-a proportion that was unchanged from 2015. On multivariable analysis, a gastrointestinal [odds ratio (or): 5.3] or lung primary (or: 3.3), complicated bone metastasis (or: 4.3), and treatment at a subsidiary site (or: 4.4) increased the odds of mfrt use. Dissemination of cwc recommendations alone did not increase sfrt use by radiation oncologists in 2016. A more comprehensive knowledge translation effort is therefore warranted and is now underway to encourage increased uptake of sfrt in Manitoba.

The Epistemological Break in Economics: What Does the Public Know About the Economy and What Do Economists Know About the Public?

Economics is characterized by an epistemological break: a discontinuity, between everyday and scientific understandings. An extensive empirical literature proves the so-called economic ignorance of the public. This has created a disdain for the public among economists and provided an argument for more influence of experts. We demonstrate that this empirical literature privileges scientific economic knowledge over other types of economics knowledge, and thus merely proves the existence of the epistemological break. In its place we argue for the simultaneous existence of different types of economic knowledge, held by economic actors (the public) and economists (the experts). Economics should seek convergence between these bodies of knowledge, through translation efforts. We demonstrate that Wicksteed and Ostrom have tried this and suggest further constructive steps following Boltanski’s work in sociology. We argue that economics without an epistemological break has the potential to improve economics education, and mutual understanding between economists and the public.

Early Assessment of Integrated Knowledge Translation Efforts to Mobilize Sex Workers in Their Communities

Researchers have recently increased their efforts to find more effective strategies to reduce the gap between the production of academic knowledge and its uptake in policy and practice. We focus attention on sex workers in Canada who have limited access to societal resources and are hampered by punitive laws prohibiting their work. The initial aim of our study was to work with sex worker organizations and allied agencies to develop a training program for sex workers to help them understand Canada’s most recent criminal justice approach to adult sex commerce. What has emerged from our integrated knowledge translation process during the first year of the study’s operation has been a change to a broader focus on mobilizing sex workers around their occupational and social rights. In this paper, we first give an overview of recent changes in Canada’s prostitution laws and then report qualitative findings from interviews with members of our partner organizations. Interviewees appreciated the change in research direction and the emergent collaborative process among themselves and the authors, but also noted challenges regarding shifting research timelines, balancing power between themselves and the academic researchers, and reaching consensus on research plans among community partners themselves. We discuss the findings in relation to successful knowledge translation strategies that aim to ensure the research questions we ask, and the empirical processes we engage in, are advantageous to those we aim to benefit.

The FGF/FGFR system in the physiopathology of the prostate gland.

Fibroblast growth factors (FGFs) are a family of proteins possessing paracrine, autocrine, or endocrine functions in a variety of biological processes, including embryonic development, angiogenesis, tissue homeostasis, wound repair, and cancer. Canonical FGFs bind and activate tyrosine kinase FGF receptors (FGFRs), triggering intracellular signaling cascades that mediate their biological activity. Experimental evidence indicates that FGFs play a complex role in the physiopathology of the prostate gland that ranges from essential functions during embryonic development to modulation of neoplastic transformation. The use of ligand- and receptor-deleted mouse models has highlighted the requirement for FGF signaling in the normal development of the prostate gland. In adult prostate, the maintenance of a functional FGF/FGFR signaling axis is critical for organ homeostasis and function, as its disruption leads to prostate hyperplasia and may contribute to cancer progression and metastatic dissemination. Dissection of the molecular landscape modulated by the FGF family will facilitate ongoing translational efforts directed toward prostate cancer therapy.

Providing multilingual logistics communication in COVID-19 disaster relief

Abstract Translation is an important means of enabling access to information in an emergency response. Increasingly, volunteer translators have been using social media platforms to self-organize and carry out urgent translation tasks that effectively complement official disaster relief efforts. However, the role of crowdsourced translations and the capacity of volunteer translators in reducing the impact of disasters remain underestimated and therefore understudied. Based on semi-structured interviews with five volunteer translators and online observation of their translation practices, this study investigates the role of a volunteer-driven crowdsourced translation effort in facilitating the donation and procurement of medical supplies between Wuhan and the world. By addressing the real challenges of urgent crisis communication in Wuhan in the early stages of the pandemic, this study draws attention to the need to integrate information and communication technologies with multilingual resources for disaster relief. In addition, it calls for the inclusion of multilingual logistics in national emergency preparation, response and recovery plans.

Abstract PR17: Immunogenomic landscape of pediatric solid malignancies

Abstract Malignancy remains the leading cause of disease-related death in children. To identify potential tumor-driving molecular targets and immunogenomic profiles in pediatric cancers, we performed RNA-seq analysis on a cohort of 788 pediatric solid malignant tumors across 14 different diagnoses in conjunction with additional 147 normal tissues for comparison. Sequencing data were analyzed for expressed mutations, fusion events, and expressional patterns, providing therapeutic targets and rich cancer biology for these childhood cancers. Furthermore, we describe immunogenomic features of these solid tumors including immune cell infiltrate, neoantigen expression, expression of immunomodulatory molecules, and T-cell receptor repertoire. Across the cohort, we observed a striking correlation between the expressed neoantigen burden in tumors and enrichment of the effector immune signatures. Histology-specific immunogenomic patterns were also apparent. Several of the pediatric cancers such as alveolar soft part sarcoma and osteosarcoma exhibit rich immune cell infiltration and evidence for activated T-cell activities, whereas others such as Wilms’ tumors and synovial sarcoma generally have a very low T-cell infiltration. We demonstrate that RNA-seq is a powerful tool to identify clinically relevant and histology-specific recurrent mutations, novel oncogenic fusions, and translationally relevant immunogenomic patterns for pediatric cancers. This study also represents one of the largest of its type to date and provides a framework for future translational efforts in pediatric cancer. This abstract is also being presented as Poster A69. Citation Format: Jun S. Wei, Andrew S. Brohl, Sivasish Sindiri, Young K. Song, Sushma Najaraj, Vineela Gangalapudi, Xinyu Wen, Marc Ladanyi, Javed Khan. Immunogenomic landscape of pediatric solid malignancies [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr PR17.

Development of a Genome-Wide Oligonucleotide Microarray Platform for Detection of DNA Copy Number Aberrations in Feline Cancers.

The utility of the domestic cat as a model system for biomedical studies was constrained for many years by the absence of a comprehensive feline reference genome sequence assembly. While such a resource now exists, the cat continues to lag behind the domestic dog in terms of integration into the ‘One Health’ era of molecular medicine. Stimulated by the advances being made within the evolving field of comparative cancer genomics, we developed a microarray platform that allows rapid and sensitive detection of DNA copy number aberrations in feline tumors using comparative genomic hybridization analysis. The microarray comprises 110,456 unique oligonucleotide probes anchored at mean intervals of 22.6 kb throughout the feline reference genome sequence assembly, providing ~350-fold higher resolution than was previously possible using this technique. We demonstrate the utility of this resource through genomic profiling of a feline injection-site sarcoma case, revealing a highly disrupted profile of DNA copy number imbalance involving several key cancer-associated genes including KIT, TP53, PTEN, FAS and RB1. These findings were supported by targeted fluorescence in-situ hybridization analysis, which identified major alterations in chromosome structure, including complex intrachromosomal reorganization events typical of those seen in aggressive soft-tissue sarcomas of other species. We then characterized a second mass that was identified at a nearby site in the same patient almost 12 months later. This mass demonstrated a remarkably conserved genomic profile consistent with a recurrence of the original tumor; however the detection of subtle differences reflected evolution of the tumor over time. These findings exemplify the diverse potential of this microarray platform to incorporate domestic cat cancers into comparative and translational research efforts in molecular oncology.

A Systematic Review of Methods Used for Confounding Adjustment in Observational Economic Evaluations in Cardiology Conducted between 2013 and 2017.

Background. Observational economic evaluations (i.e., economic evaluations in which treatment allocation is not randomized) are prone to confounding bias. Prior reviews published in 2013 have shown that adjusting for confounding is poorly done, if done at all. Although these reviews raised awareness on the issues, it is unclear if their results improved the methodological quality of future work. We therefore aimed to investigate whether and how confounding was accounted for in recently published observational economic evaluations in the field of cardiology. Methods. We performed a systematic review of PubMed, Embase, Cochrane Library, Web of Science, and PsycInfo databases using a set of Medical Subject Headings and keywords covering topics in "observational economic evaluations in health within humans" and "cardiovascular diseases." Any study published in either English or French between January 1, 2013, and December 31, 2017, addressing our search criteria was eligible for inclusion in our review. Our protocol was registered with PROSPERO (CRD42018112391). Results. Forty-two (0.6%) out of 7523 unique citations met our inclusion criteria. Fewer than half of the selected studies adjusted for confounding (n = 19 [45.2%]). Of those that adjusted for confounding, propensity score matching (n = 8 [42.1%]) and other matching-based approaches were favored (n = 8 [42.1%]). Our results also highlighted that most authors who adjusted for confounding rarely justified their methodological choices. Conclusion. Our results indicate that adjustment for confounding is often ignored when conducting an observational economic evaluation. Continued knowledge translation efforts aimed at improving researchers' knowledge regarding confounding bias and methods aimed at addressing this issue are required and should be supported by journal editors.