bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA11: Overcoming immune evasion in pediatric brain tumors
Authors: Garancher Alexandra , Suzuki Hiromichi , Haricharan Svasti , Masihi Meher B. , Rusert Jessica M. , Norris Paula S. , Carrette Florent , Romero Megan M. , Morrissy Sorana A. , Skowron Patryk , Cavalli Florence M.G. , Farooq Hamza , Ramaswamy Vijay , Morcavallo Alaide , Henderson Jacob J. , Olson James M. , Cho Yoon-Jae , Li Xiao-Nan , Chesler Louis , Marra Marco A. , Becher Oren J. , Bradley Linda M. , Ware Carl F. , Taylor Michael D. , Wechsler-Reya Robert J. 
Published: August 2020

Abstract
Many immunotherapies act by enhancing T-cell killing of tumor cells. Cytotoxic T cells recognize antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. Our studies suggest that medulloblastomas and high-grade gliomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. Treatment with tumor necrosis factor or lymphotoxin beta receptor agonist rescues expression of Erap1, Tap1, and MHC-I on p53 mutant tumor cells. In vivo, TNF treatment prolongs survival and markedly augments the efficacy of the immune checkpoint inhibitor anti-PD-1. These studies identify p53 as a key regulator of immune evasion in vivo and suggest that TNF could be used to enhance sensitivity of p53-mutant tumors to immunotherapy.
Citation Format: Alexandra Garancher, Hiromichi Suzuki, Svasti Haricharan, Meher B. Masihi, Jessica M. Rusert, Paula S. Norris, Florent Carrette, Megan M. Romero, Sorana A. Morrissy, Patryk Skowron, Florence M.G. Cavalli, Hamza Farooq, Vijay Ramaswamy, Alaide Morcavallo, Jacob J. Henderson, James M. Olson, Yoon-Jae Cho, Xiao-Nan Li, Louis Chesler, Marco A. Marra, Oren J. Becher, Linda M. Bradley, Carl F. Ware, Michael D. Taylor, Robert J. Wechsler-Reya. Overcoming immune evasion in pediatric brain tumors [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 IA11.
Abstract IA15: Tissue-agnostic development of TRK inhibitors for pediatric cancer
Authors: Laetsch Theodore W. 
Published: August 2020

Abstract
Fusions involving in the NTRK1, NTRK2, and NTRK3 genes that encode the TRKA, TRKB, and TRKC neurotrophin receptors (TRK fusions) occur across a wide range of cancers in children and adults. These fusions result in constitutive expression and ligand-independent activation of the TRK kinase. TRK fusions are pathognomonic for certain rare cancers, including infantile fibrosarcoma and cellular congenital mesoblastic nephroma, and occur at a lower frequency across a range of more common cancers in children including soft-tissue sarcomas, gliomas, and leukemias. Recently, larotrectinib was FDA approved for the treatment of TRK fusion solid tumors in children and adults, representing the first kinase inhibitor to receive FDA histology-agnostic approval for the treatment of cancer. This approval was based on a combined analysis of three clinical trials, including an ongoing pediatric phase 1/2 trial that demonstrated a 94% response rate in 34 children with TRK fusion-positive solid tumors. Remarkably, due to nearly concurrent development in pediatrics and adults, more than 30% of the patients with TRK fusion solid tumors treated with larotrectinib on clinical trials to date have been children. Other TRK inhibitors are also in pediatric development, including entrectinib and LOXO-195, and clinical trials of additional agents including repotrectinib are planned. Entrectinib, which also antagonizes ROS1 and ALK, was reported to induce responses in 11/11 children whose tumors harbored fusions of the TRK, ROS1 or ALK genes. LOXO-195 and repotrectinib have the potential to antagonize resistance mutations that can develop during treatment with first-generation TRK inhibitors, and we reported a 45% response rate to LOXO-195 among 20 patients enrolled to either single-patient treatment protocols or an ongoing pediatric and adult phase 1 study who harbored a TRK kinase resistance mutation. In this talk, I will review the data on the use of TRK inhibitors for TRK fusion cancers in children, discuss unanswered questions related to the use of TRK inhibitors in children and planned clinical trials designed to address these, and highlight the challenges and opportunities that arise when studying novel therapies for rare, molecularly defined diseases.
Citation Format: Theodore W. Laetsch. Tissue-agnostic development of TRK inhibitors for pediatric cancer [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 IA15.
Abstract IA19: Genomic analysis of osteosarcoma: Insights into tumor evolution and therapy response
Authors: Sweet-Cordero E. Alejandro 
Published: August 2020

Abstract
While significant progress has been made in most other cancers to advance targeted therapy, there has been essentially no change in our approach to treatment of osteosarcoma in over 30 years. Osteosarcomas exhibit an extremely complex genome characterized by multiple copy number changes and structural alterations. Using patient-derived xenografts and primary tumors, we are employing whole-genome sequencing (WGS) and RNAseq to characterize the evolution of this disease with a goal of understanding how evolutionary constraints can identify targetable vulnerabilities. We have identified a number of potential subtypes of osteosarcoma based on copy number alterations and defined how these copy number alterations can be exploited for therapeutic benefit using a large and clinically annotated patient-derived xenograft (PDX) collection. A key current effort is to identify novel genome-informed combination therapies for this disease. To facilitate this work, we have developed a panel of cell lines derived from PDX models, which have also be characterized with regards to their genomic characteristics. We have used these cell lines to screen for response to a wide variety of drugs with the goal of matching response to specific genomic characteristics. Lastly, we are using PDX models to study the process of metastatic progression and have identified a possible role for the enzyme ENPP1 in osteosarcoma metastasis.
Citation Format: E. Alejandro Sweet-Cordero. Genomic analysis of osteosarcoma: Insights into tumor evolution and therapy response [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 IA19.
Abstract IA21: Blocking purine synthesis in cancer promotes response to immunotherapy
Authors: Erez Ayelet , Ruppin Eytan , Keshet Rom , Lee Joo Sang 
Published: August 2020

Abstract
Nucleotide imbalance promotes mutagenesis in multiple types of cancer. We have previously shown that nucleotide imbalance favoring pyrimidines leads to mutational bias, which promotes the generation of immunogenic neoantigens that respond to ICT. We now find that tumors with high purine bias demonstrate a novel asymmetric genomic signature, consisting of transversion mutations manifested at the DNA, RNA, and protein level. This metabolic alteration leads to presentation of less immunogenic neoantigens and to decreased response to immune checkpoint inhibitors independent of mutational load. Reversing the nucleotide imbalance to favor pyrimidines improves the response to immunotherapy. Our data firmly establish that beyond mutational load and tumor heterogeneity, purine/pyrimidine bias is a strong determinant of the response to immunotherapy. Importantly, our findings suggest that we can metabolically manipulate tumor mutations to improve patients’ response to immunotherapy.
Citation Format: Ayelet Erez, Eytan Ruppin, Rom Keshet, Joo Sang Lee. Blocking purine synthesis in cancer promotes response to immunotherapy [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 IA21.
Abstract IA26: The need for evidence-based survivorship care
Authors: Kremer Leontien 
Published: August 2020

Abstract
The 5-year survival for children with cancer has increased enormously. However, years after treatment, childhood cancer survivors are at high risk for developing health and psychosocial long-term side effects due to their previous cancer treatment. The impacts on morbidity, mortality, and society are significant. These impacts can be reduced by optimal long-term follow-up of survivors. Survivorship care that is focused on the detection of treatable disease at an early phase will improve quality of life of survivors by timely interventions. The International Guideline Harmonisation Group (ighg.org) developed evidence-based guidelines for many late effects. However, implementing these guidelines has proven challenging. The availability of follow-up care for adult survivors varies considerably, and many clinics do not offer survivorship care for adult survivors of childhood cancer. High-quality survivorship care requires a multidisciplinary care infrastructure, implementation of guidelines, and development of a survivorship care plan with a detailed summary of treatment and specific knowledge on late effects. This presentation will focus on the translation of knowledge to guidelines and the need for survivorship care.
Citation Format: Leontien Kremer. The need for evidence-based survivorship care [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 IA26.
Effects of Inhibition of Nitric Oxide Synthase on Muscular Arteries During Exercise: Nitric Oxide Does Not Contribute to Vasodilation During Exercise or in Recovery
Authors: O'Gallagher Kevin , Shabeeh Husain , Munir Shahzad , Roomi Ali , Jiang Benyu , Guilcher Antoine , Brett Sally , Chowienczyk Philip 
Published: August 2020

Background

Basal release of nitric oxide (
NO
) from the vascular endothelium regulates the tone of muscular arteries and resistance vasculature. Effects of
NO
on muscular arteries could be particularly important during exercise when shear stress may stimulate increased
NO
synthesis.

Methods and Results

We investigated acute effects of
NO
synthase inhibition on exercise hemodynamics using

N
G

‐monomethyl‐
l
‐arginine (
l
‐
NMMA
), a nonselective
NO
synthase ‐inhibitor. Healthy volunteers (n=10, 5 female, 19–33 years) participated in a 2‐phase randomized crossover study, receiving
l
‐
NMMA
(6 mg/kg, iv over 5 minutes) or placebo before bicycle exercise (25–150 W for 12 minutes). Blood pressure, cardiac output (measured by dilution of soluble and inert tracers) and femoral artery diameter were measured before, during, and after exercise. At rest,
l
‐
NMMA
reduced heart rate (by 16.2±4.3 bpm relative to placebo,
P
<0.01), increased peripheral vascular resistance (by 7.0±1.4 mmHg per L/min,
P
<0.001), mean arterial blood pressure (by 8.9±3.5 mmHg,
P
<0.05), and blunted an increase in femoral artery diameter that occurred immediately before exercise (change in diameter: 0.14±0.04 versus 0.32±0.06 mm after
l
‐
NMMA
and placebo,
P
<0.01). During/after exercise
l
‐
NMMA
had no significant effect on peripheral resistance, cardiac output, or on femoral artery diameter.

Conclusions

These results suggest that
NO
plays little role in modulating muscular artery function during exercise but that it may mediate changes in muscular artery tone immediately before exercise.
Relationship Between Depressive Symptoms and Health Status in Peripheral Artery Disease: Role of Sex Differences
Authors: Jelani Qurat‐ul‐ain , Mena‐Hurtado Carlos , Burg Matthew , Soufer Robert , Gosch Kensey , Jones Philip G. , Spertus John A. , Safdar Basmah , Smolderen Kim G. 
Published: August 2020

Background
The association of depressive symptoms with health status in peripheral artery disease (PAD) is understudied. No reports of differential impact on women have been described.

Methods and Results

The PORTRAIT (Patient‐Centered Outcomes Related to Treatment Practices in Peripheral Artery Disease Investigating Trajectories) registry enrolled 1243 patients from vascular specialty clinics with new or worsening PAD symptoms. Depressive symptoms were assessed at baseline and 3 months using the 8‐Item Patient Health Questionnaire (score ≥10 indicating clinically relevant depressive symptoms). Disease‐specific and generic health status were measured by Peripheral Artery Questionnaire and EQ‐5D Visual Analogue Scale at baseline and 3, 6, and 12 months. An adjusted general linear model for repeated measures was constructed for baseline and 3‐, 6‐, and 12‐month health status outcomes by depressive symptoms at baseline. Differences by sex were tested with interaction effects. The mean age was 67.6±9.4 years with 38% (n=470) women. More women than men (21.1% versus 12.9%;
P
<0.001) presented with severe depressive symptoms. In the adjusted model, patients with depressive symptoms had worse health status at each time point (all
P
<0.0001). Results were similar for EQ‐5D Visual Analogue Scale scores. The magnitude in 1‐year change in health status scores did not differ by sex. Depressive symptoms explained 19% of the association between sex differences in 1‐year Peripheral Artery Questionnaire summary scores.

Conclusions
Women with PAD have a high burden of depressive symptoms. Depressive symptoms were associated with a strikingly worse disease‐specific health status recovery path over the year following PAD diagnosis in men and women. Developing and testing interventions to address depressive symptoms in PAD are urgently needed.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01419080.
Relationship Between Motor Skills, Balance, and Physical Activity in Children with CHARGE Syndrome
Authors: Perreault Melanie , Haibach-Beach Pamela , Lieberman Lauren , Foster Elizabeth 
Published: August 2020

Introduction: Children with CHARGE syndrome often show delays in balance and motor skills due to multisensory impairments. Research also suggests that children with CHARGE syndrome have fewer opportunities to engage in physical activity. However, little research has examined the relationship among all of these variables. Thus, the purpose of this study was to examine the relationship between balance, motor skills, and physical activity. Methods: Participants consisted of 37 children with CHARGE syndrome aged 3–16 years who could walk independently. Parents of each child with CHARGE syndrome completed a demographics questionnaire and the Physical Activity Questionnaire for Children or Adolescents. Their child completed the Mini-BEST balance test and five motor skills (run, jump, slide, kick, and throw) from the Test of Gross Motor Development II. Results: Results indicate that anticipatory control had significant positive correlations with all five motor skills, sensory orientation with three motor skills, and reactive postural control and dynamic gait with two motor skills. Running was the only variable that had a significant positive correlation with physical activity. Discussion: The findings indicate that balance, especially anticipatory control, plays an important role in fundamental motor skills of children with CHARGE syndrome. There is also a strong connection between physical activity and running competence for this population; however, since this is based on a correlational analysis, the direction of the relationship is unclear. Implications for practitioners: Physical education teachers should work with students with CHARGE syndrome on increasing balance and motor skill performance to give them the competence and confidence to engage in physical activity. Moreover, parents can help by engaging in physical activity with their child at an early age and seeking out additional physical activity opportunities for their child outside of the physical education and school setting.
Impact of Health Literacy on Medication Engagement Among Adults With Diabetes in the United States: A Systematic Review
Authors: Chima Charles C. , Abdelaziz Aya , Asuzu Chisom , Beech Bettina M. 
Published: August 2020

Purpose The purpose of this systematic review is to assess evidence of a relationship between health literacy and medication engagement (formerly referred to as medication adherence) among adults with diabetes mellitus in the United States. Methods Literature searches were conducted in PubMed, Ovid Medline, CINAHL, Embase, PsycInfo, and Scopus from the inception of each database to April 2020. Studies were included if they met all of the following criteria: (1) conducted in the United States, (2) the population of interest was adults ≥18 years with a diagnosis of type 1 or type 2 diabetes, (3) medication engagement was an outcome variable, (4) a direct and not a mediating relationship between health literacy and medication engagement was assessed, (5) a quantifiable measure of association was reported, and (6) a full-text journal article or dissertation was available. Quality of published evidence was graded according to Joanna Briggs Institute Critical Appraisal Checklists appropriate for the respective study designs identified. Results Thirteen articles from 11 unique studies were retained in the review, most of which used a cross-sectional design. Four out of 11 studies found a direct positive association between health literacy and medication engagement. Two of the 4 studies with positive findings had significant methodological shortcomings. Conclusions There is some evidence that health literacy is associated with medication engagement among adults with diabetes in the United States. Properly designed and executed longitudinal studies are needed to better elucidate the relationship between health literacy and medication engagement among adults with diabetes.
Technology Integration: The Role of the Diabetes Care and Education Specialist in Practice
Authors: Isaacs Diana , Cox Carla , Schwab Kathy , Oser Tamara K. , Rinker Joanne , Mason Mary Jo , Greenwood Deborah A. , Albanese-O’Neill Anastasia 
Published: August 2020

Purpose Technology is rapidly evolving and has become an integral component of diabetes care. People with diabetes and clinicians are harnessing a variety of technologies, including connected blood glucose meters, continuous glucose monitors, insulin pumps, automated insulin delivery systems, data-sharing platforms, telehealth, remote monitoring, and smartphone mobile applications to improve clinical outcomes and quality of life. Although diabetes technology use is associated with improved outcomes, this is enhanced when the person using it is knowledgeable and actively engaged; simply wearing the device or downloading an app may not automatically translate into health benefits. The diabetes care and education specialist (DCES) has a central role in defining and establishing a technology-enabled practice setting that is efficient and sustainable. The purpose of this article is to describe the role of the DCES in technology implementation and to demonstrate the value of diabetes technology in both the care of the individual and as a tool to support population-level health improvements. Conclusion By following the recommendations in this article, DCESs can serve as technology champions in their respective practices and work to reduce therapeutic inertia while improving health outcomes and providing patient-centered care for the populations they serve.
The Use of Human Lymphocytes for the In Vitro Estimation of Acute Toxicity of Ten Chemicals from the MEIC List
Authors: Skaanild Mette Tingleff , Clausen Jørgen 
Published: August 2020

The acute cytotoxicity of ten chemicals included in the MEIC (multicentre evaluation of in vitro cytotoxicity) list has already been estimated in various cell lines, e.g. primary rat hepatocytes, HeLa cells, human hepatoma cells, and 3T3 and mouse fibroma cells. In the present study, primary cultures of human lymphocytes, with or without an S9-mix (microsomes), were used to assay for in vitro toxicity. The cultured cells were initially treated with different concentrations of the respective drugs for 24 hours. Then cellular enzymatic activity was estimated using two assay systems, namely, measurement of cytosolic LDH activity and the mitochondrial (diaphorase) MTT test. Since the biological significance of the assay of LC50 values is dependent upon the slope of the dose-response curves, the results are expressed as LC20, LC50 and LC80 values in μM for the ten drugs. A Spearman rank correlation analysis revealed a significant correlation between the results from the two assays in both cell culture systems (r=1.00 and r=0.99). The LC50 values found in the lymphocyte cultures, both with and without an S9-mix, correlated well with the results previously found using primary cultures of hepatocytes and HeLa cells.
Prognostic value of the TGFβ1 rs4803455 single nucleotide polymorphism in small cell lung cancer
Authors: Ayala de Miguel Pablo , Enguix-Riego María Valle , Cacicedo Jon , Delgado Blas David , Perez Marco , Praena-Fernández Juan Manuel , Quintana Cortés Laura , Borrega García Pablo , del Campo Eleonor Rivin , Lopez Guerra Jose Luis 
Published: August 2020

Background: Small cell lung cancer (SCLC) is one of the greatest therapeutic challenges of oncology. Potential associations between single nucleotide polymorphisms in heat shock protein β1 (HSPB1) and transforming growth factor β1 (TGFβ1) and survival have been investigated. Methods: A prospective multicenter study of 94 patients with SCLC treated between 2013 and 2016 was conducted. Clinical, tumour-related, therapeutic, and genetic (9 SNPs of TGFβ1 gene and 5 of HSPB1 gene) variables were analyzed. Results: The cohort included 77 men and 17 women with a median age of 61 years. Eighty percent presented with limited stage at diagnosis and received thoracic radiation with a median dose of 45 Gy (twice-daily radiation in 42%). Forty-seven percent received concurrent platinum-based chemotherapy and 57% received prophylactic cranial irradiation (PCI). Overall survival (OS) was 34% at 2 years and 16% at 3 years. In multivariate analysis, the rs4803455:CA genotype of the TGFβ1 gene showed a statistically significant association with lower disease-free survival (DFS; hazard ratio [HR] 3.13; confidence interval [CI] 1.19–8.17; p = 0.020) and higher local recurrence (HR 3.80; CI 1.37–10.5; p = 0.048), and a marginal association with lower OS (HR 1.94; CI 0.98–3.83; p = 0.057). A combined analysis showed that patients receiving PCI and carrying the rs4803455:CA genotype had statistically significant lower OS ( p < 0.001) and DFS ( p < 0.001) than patients receiving PCI and carrying the rs4803455:AA genotype. Conclusions: Genetic analysis showed the CA genotype of TGFβ1 SNP rs4803455 was associated with worse prognosis in patients with SCLC and could be considered as a potential biomarker.