bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA50: Genetic testing, treatment and mortality after diagnosis of breast cancer or ovarian cancer: The SEER-GeneLINK Initiative
Authors: Kurian Allison W. 
Published: August 2020

Abstract
Cancer registries enable research on cancer incidence and outcomes in a real-world setting, with broad relevance for the general population. Since only 3% of adult cancer patients in the United States are treated in clinical trials, cancer registries offer crucial insight into the treatment and survival of the other 97%. While highly informative in terms of patient demographics, cancer incidence, and survival, cancer registries lack key clinical details necessary to assess treatment quality and prognostic factors: notably, genetic testing results, specific therapies and patient-reported outcomes. In recent work, we have developed novel data linkage approaches to augment the information value of the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) registry. These linkages have enhanced our understanding of breast cancer and ovarian cancer from genetic risk assessment through treatment, recurrence, and mortality. I will discuss the SEER-GeneLINK initiative, in which we have collaborated with genetic testing laboratories to link the results of germline genetic testing to SEER registry records of breast cancer and ovarian cancer patients. Furthermore, we have surveyed these patients and their attending physicians about key aspects of genetic testing. We are now extending this work to encompass cascade genetic testing of patients' relatives. Our aim is to identify gaps and disparities in cancer care, in order to inform interventions that will improve care quality. Recent results on the use, correlates, and results of genetic testing on the population level will be presented.
Citation Format: Allison W. Kurian. Genetic testing, treatment and mortality after diagnosis of breast cancer or ovarian cancer: The SEER-GeneLINK Initiative [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA50.
Abstract 13: Clinical trial outcomes for cancer drug combinations can be predicted using cancer cell line monotherapy screens and a model of independent drug action
Authors: Ling Alexander , Huang R. Stephanie 
Published: August 2020

Abstract
Drug combinations are a cornerstone of cancer therapy; however, the vast number of possible drug combinations makes it infeasible to experimentally evaluate all of these possibilities when identifying new therapies. For example, testing all possible 4-drug combinations for 200 compounds in 100 cell lines would require more than 6 billion experiments. To solve this problem, efforts have been made to develop computational models capable of accurately predicting drug combination efficacy without the need to experimentally test all of them. While these models have traditionally aimed to predict drug synergy, recent evidence has emerged suggesting that many cancer drug combinations may derive their efficacy from independent drug action (IDA), where patients only receive benefit from the single most effective drug in a drug combination. In light of these findings, we developed IDACombo, a computational method that uses IDA to predict the efficacy of drug combinations based on monotherapy data from high-throughput cancer cell line drug screens. We have demonstrated that IDACombo predictions closely agree with measured drug combination efficacies both in vitro (Pearson’s correlation = 0.94 when comparing predicted efficacies to measured efficacies for &gt;5,000 combinations) and in a systematically selected set of clinical trials (accuracy &gt;88% for predicting progression-free survival/time to progression or overall survival benefit in 26 first-line therapy trials). This work provides a framework for translating monotherapy cell line screening data into clinically meaningful efficacy predictions for hundreds of thousands of 2-drug combinations and millions of combinations of 3 or more drugs.
Citation Format: Alexander Ling, R. Stephanie Huang. Clinical trial outcomes for cancer drug combinations can be predicted using cancer cell line monotherapy screens and a model of independent drug action [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 13.
Abstract 20: Targeting difficult targets with lysine-covalent ligands: Expanding the druggable space for covalent drugs
Authors: Pellecchia Maurizio 
Published: August 2020

Abstract
Oncology drugs osimertinib, ibrutinib, neratinib, and afatinib have all been approved in very recent years by the FDA, and all target a cysteine that is present in proximity to the binding site of their respective targets. More recently, Amgen reported on AMG 510 as a first-in-class investigational drug designed to selectively and irreversibly target the KRAS G12C protein. These drugs rely on acrylamides moieties strategically incorporated in their chemical structures to selectively and efficiently react with binding site cysteine residues. Obviously, the approach is limited to drug targets that present a cysteine residue in proximity to the binding site, which often is not the case. This druggable target space for covalent drugs is called the Cysteinome. My laboratory has been developing and applying novel strategies aimed at deriving potent, selective, cell-permeable, and efficacious covalent therapeutics by designing agents that can selectively react with lysine residues (1,2). The approach relies on introducing stable aryl-fluorosulfates or sulfonyl-fluorides in drug leads to selectively and efficiently react with lysine residues. Because lysines are more ubiquitously found within the binding pocket of the target oncogenes, the approach defines a much larger target space for covalent drugs: the Lysinome. In addition, I will demonstrate that the approach is amenable also to tackle difficult targets such as those involving protein-protein interactions (PPIs). Hence, our work widens the available target space beyond cysteine and also allows the development of novel drug candidates against PPIs, which represent an untapped large class of therapeutic targets in oncology. Examples will include potent and selective Lys-covalent agents targeting antiapoptotic proteins in the IAP and Bcl-2 families of proteins, including particularly exciting, yet to be published results.
References: 1. Gambini L, Baggio C, Udompholkul P, Jossart J, Salem AF, Perry JJP, Pellecchia M. Covalent inhibitors of protein-protein interactions targeting lysine, tyrosine, or histidine residues. J Med Chem 2019;13;62(11):5616-27. 2. Baggio C, Udompholkul P, Gambini L, Salem AF, Jossart J, Perry JJP, Pellecchia M. Aryl-fluorosulfate-based lysine covalent pan-inhibitors of apoptosis protein (IAP) antagonists with cellular efficacy. J Med Chem 2019;Oct. 8. doi: 10.1021/acs.jmedchem.9b01108.
Citation Format: Maurizio Pellecchia. Targeting difficult targets with lysine-covalent ligands: Expanding the druggable space for covalent drugs [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 20.
Abstract 22: Toward automated design of mutant-selective tyrosine kinase inhibitors using dynamic pharmacophore mapping and machine learning
Authors: Brown Benjamin P. , Mendenhall Jeffrey , Lovly Christine , Meiler Jens 
Published: August 2020

Abstract
Receptor tyrosine kinases (RTKs) constitute one of the most significant classes of oncologic therapeutic targets. For over a decade, all-atom molecular simulations have been employed to probe the determinants of tyrosine kinase inhibitor (TKI) selectivity. Today, we recognize that sequence and dynamical differences in key regions of kinases, such as the glycine-rich loop, DFG-motif, hinge-binding domain, and gatekeeper region, all contribute to the variability in TKI potency and selectivity across the kinome. This knowledge led to the structure-based rational design of the TKI osimertinib, which preferentially binds to the EGFR-T790M resistance mutant over wild-type EGFR. More recently, we demonstrated that a newly-identified EGFR osimertinib resistance mutation, G724S, develops in specific sequence variants of Ex19Del, but not in L858R, and we were able to attribute these differences to detailed changes in EGFR dynamics. Here, we present a strategy that leverages differences in protein dynamics between mutants to guide the design of mutant-selective inhibitors. Our algorithm employs machine learning-guided Monte Carlo-Metropolis (MCM) sampling of medicinal chemistry modifications to small-molecule scaffolds. The molecules are iteratively filtered through a pharmacophore map of the protein-ligand complex, where the softness of the edges scales with a molecular dynamics-derived measure of each residue’s flexibility with respect to the ligand.
Citation Format: Benjamin P. Brown, Jeffrey Mendenhall, Christine Lovly, Jens Meiler. Toward automated design of mutant-selective tyrosine kinase inhibitors using dynamic pharmacophore mapping and machine learning [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 22.
Abstract 44: Monitoring of ctDNA burden from noncoding DNA
Authors: Yu Guo , Poh Zhong Wee , Zhu Guanhua , Tan Iain , Ng Sarah , Tan Patrick , Skanderup Anders 
Published: August 2020

Abstract
Our understanding of mutations in noncoding DNA is still nascent across most cancer types. Similarly, the potential clinical utility of noncoding DNA in cancer liquid biopsy assays remains mostly unexplored. Here, we identify high-frequency noncoding mutation hotspots in whole genomes from hundreds of gastrointestinal tumors and show that these mutations can be detected in liquid biopsy samples from cancer patients. We demonstrate how profiling of noncoding mutation hotspots can significantly increase the accuracy of ctDNA burden estimation, with minimal impact on sequencing cost, when paired with existing targeted cfDNA assays. Our results suggest that targeted NGS liquid biopsy assays should target both protein-coding and noncoding mutations when estimation and monitoring of ctDNA burden is a key clinical endpoint.
Citation Format: Guo Yu, Zhong Wee Poh, Guanhua Zhu, Iain Tan, Sarah Ng, Patrick Tan, Anders Skanderup. Monitoring of ctDNA burden from noncoding DNA [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 44.
Anticoagulant Therapy in Initially Low‐Risk Patients With Nonvalvular Atrial Fibrillation Who Develop Risk Factors
Authors: Choi Sun Young , Kim Moo Hyun , Lee Kwang Min , Cho Young‐Rak , Park Jong Sung , Kim Seong Woo , Kim Jin Kyung , Chung Matthew , Yun Sung‐Cheol , Lip Gregory Y. H. 
Published: August 2020

Background

The CHA
2
DS
2
‐VASc score has been validated for stroke risk prediction in patients with atrial fibrillation (AF). Antithrombotic therapy is not recommended for low‐risk patients with AF (CHA
2
DS
2
‐VASc 0 [male] or 1 [female]). We studied a cohort of initially low‐risk patients with AF in relation to their development of incident comorbidities and their treatment on oral anticoagulation therapy.

Methods and Results

We assessed data from 14 441 low‐risk patients with AF (CHA
2
DS
2
‐VASc score of 0 [male] or 1 [female]) using the Korean National Health Insurance Service database, in relation to their development of incident stroke risk factors and adverse outcomes. The clinical end point was the occurrence of ischemic stroke, major bleeding, all‐cause death, or the composite outcome (ischemic stroke + major bleeding + all‐cause death). In our cohort, 2615 (29.1%) male and 1650 (30.3%) female patients acquired at least 1 new stroke risk factor during a mean follow‐up of 2.0 years. Among the patients with an increasing CHA
2
DS
2
‐VASc score ≥1, male and female patients treated with oral anticoagulants had a significantly lower risk of ischemic stroke (male: hazard ratio [HR], 0.62 [95% CI, 0.44–0.82;
P
=0.003]; female: HR, 0.65 [95% CI, 0.47–0.84;
P
=0.007]), all‐cause death (male: HR, 0.67 [95% CI, 0.49–0.88;
P
=0.009]; female: HR, 0.82 [95% CI, 0.63–1.02;
P
=0.185]), and composite outcomes (male: HR, 0.78 [95% CI, 0.61–0.95;
P
=0.042]; female: HR, 0.79 [95% CI, 0.62–0.96;
P
=0.045]) than patients not treated with oral anticoagulants.

Conclusions
Approximately 30% of patients acquired ≥1 stroke risk factor over a 2‐year follow‐up period. Low‐risk patients with AF should be regularly reassessed to adequately identify those with incident stroke risk factors that would merit thromboprophylaxis for the prevention of stroke and the composite outcome.
Impact of Long‐Term Burden of Body Mass Index and Blood Pressure From Childhood on Adult Left Ventricular Structure and Function
Authors: Liu Yang , Yan Yinkun , Jiang Tingbo , Li Shengxu , Guo Yajun , Fernandez Camilo , Barshop Rupert , Bazzano Lydia , He Jiang , Chen Wei 
Published: August 2020

Background
Data are limited regarding the relationship between the life‐course burden of risk factors and adult cardiac function. This study sought to examine the impact of long‐term burden of body mass index (BMI) and blood pressure (BP) levels on changes in adult left ventricular (LV) structure and function in a community‐based cohort.

Methods and Results

The longitudinal study cohort consisted of 1108 adult patients (726 White; 41.9% men; mean age, 48.2 years in the last survey) who had been examined 4 to 16 times for BMI and BP and echocardiographic LV structure and function in adulthood, with a mean follow‐up period of 38.8 years. The area under the curve was used as a measure of long‐term burden of BMI and BP. Adult LV mass index was significantly associated with childhood and adulthood BMI and systolic BP (SBP), and their area under the curve values (β=0.07–0.37;
P
<0.05 for all). Adult LV ejection fraction was negatively associated with childhood BMI (β=−0.08), adult BMI (β=−0.07) and BMI area under the curve (β=−0.07) (
P
<0.05 for all); the effects of SBP measures were not significant. Adult E/A ratio was negatively associated with adulthood SBP (β=−0.13;
P
<0.01) and total area under the curve of SBP (β=−0.13;
P
<0.01). E/e′ ratio was positively associated with BMI and SBP measures. The effects of diastolic BP measures were substantially similar to those of SBP measures. Participants with LV hypertrophy, eccentric hypertrophy, and concentric hypertrophy had significantly lower LV ejection fraction and higher E/e′ ratio.

Conclusions
These observations provide strong evidence that early‐life adiposity and BP levels and their life‐course cumulative burdens are associated with subclinical changes in adult LV structure and function in the general population.
100 Robotic Distal Pancreatectomies: The Future at Hand
Authors: Rosemurgy Alexander S. , Luberice Kenneth , Krill Emily , Castro Miguel , Espineira Gabriel Rivera , Sucandy Iswanto , Ross Sharona 
Published: August 2020

Introduction This study was undertaken to examine 100 consecutive robotic distal pancreatectomies with splenectomies, and to compare our outcomes to predicted outcomes as calculated using the American college of surgeons national surgical quality improvement program (ACS NSQIP) Surgical Risk Calculator and to the outcomes contained within NSQIP. Methods Outcomes were compared with predicted outcomes, calculated using the ACS NSQIP Surgical Risk Calculator, and with outcomes documented in NSQIP for distal pancreatectomy. For illustrative purposes, data are presented as median (mean ± SD). Results Patients who underwent robotic distal pancreatectomy were of age 67 (63 ± 13.4) years with a BMI of 29 (29 ± 6.3) kg/m2, with 49% being women. Operative duration was 242 (265 ± 112.2) minutes and estimated blood loss was 110 (211 ± 233.9) mL. Predicted outcomes were similar to those reported in NSQIP. Our actual outcomes were significantly superior to the predicted outcomes for serious complication, any complication, surgical site infection, sepsis, and length of stay. Compared to NSQIP outcomes, our actual outcomes for serious complication, any complication, surgical site infection, sepsis, and delayed gastric emptying were significantly superior. Twelve percent of operations were converted to “open.” There were 3 deaths within 30 days, similar to predicted outcomes. Deaths were due to sepsis (2) and respiratory failure (1). Conclusion Our patients’ predicted outcomes were the same as national outcomes; our patients were not a select group. However, their actual outcomes were like or significantly superior than those predicted by NSQIP or reported in NSQIP. We believe that the robot has the future of distal pancreatectomy with or without splenectomy.
Effectiveness of Lateral Auditory Collision Warnings: Should Warnings Be Toward Danger or Toward Safety?
Authors: Chen Jing , Šabić Edin , Mishler Scott , Parker Cody , Yamaguchi Motonori 
Published: August 2020

Objective The present study investigated the design of spatially oriented auditory collision-warning signals to facilitate drivers’ responses to potential collisions. Background Prior studies on collision warnings have mostly focused on manual driving. It is necessary to examine the design of collision warnings for safe takeover actions in semi-autonomous driving. Method In a video-based semi-autonomous driving scenario, participants responded to pedestrians walking across the road, with a warning tone presented in either the avoidance direction or the collision direction. The time interval between the warning tone and the potential collision was also manipulated. In Experiment 1, pedestrians always started walking from one side of the road to the other side. In Experiment 2, pedestrians appeared in the middle of the road and walked toward either side of the road. Results In Experiment 1, drivers reacted to the pedestrian faster with collision-direction warnings than with avoidance-direction warnings. In Experiment 2, the difference between the two warning directions became nonsignificant. In both experiments, shorter time intervals to potential collisions resulted in faster reactions but did not influence the effect of warning direction. Conclusion The collision-direction warnings were advantageous over the avoidance-direction warnings only when they occurred at the same lateral location as the pedestrian, indicating that this advantage was due to the capture of attention by the auditory warning signals. Application The present results indicate that drivers would benefit most when warnings occur at the side of potential collision objects rather than the direction of a desirable action during semi-autonomous driving.
Divergent Thinking: The Performance of Students with Visual Impairments on Abstract and Scenario-Based Tasks and Their Correlates
Authors: Zebehazy Kim T. , Weber Rachel C. , Murphy Meagan , Ghani Aisha 
Published: August 2020

Introduction: Divergent thinking is a crucial component of effective problem-solving. This study investigated the divergent thinking of students with visual impairments (i.e., blindness or low vision) in three countries and explored the correlates of their performance on two tasks. Methods: A sample of 52 students with visual impairments completed two divergent thinking tasks, one traditional Alternate Uses task, and one scenario-based task created for this study. Each student’s teacher of students with visual impairments completed a questionnaire containing demographic, curriculum, and student characteristics. Results: Of the correlates examined, teacher-rated academic independence, working on grade level, number of expanded core curriculum (ECC) areas of instruction currently received, and ongoing receipt of assistive technology instruction were significantly related to task performance. Discussion: Findings demonstrate the strong relationship between real-life problem-solving, divergent thinking, and academic functioning in students with visual impairments. Further investigation is needed about the relationship between aspects of problem-solving instruction and student outcomes as they relate to divergent thinking. Implications for practitioners: Given the connection of divergent thinking to overall problem-solving ability, teachers should assess these skills in students. Using similar scenario-based real-life tasks, they can also incorporate practice opportunities for divergent thinking within ECC instruction.
Association Between Dissatisfaction With Care and Diabetes Self-Care Behaviors, Glycemic Management, and Quality of Life of Adults With Type 2 Diabetes Mellitus
Authors: Dalal Jugal , Williams Joni S. , Walker Rebekah J. , Campbell Jennifer A. , Davis Kimberly S. , Egede Leonard E. 
Published: August 2020

Purpose The purpose of the study was to examine the associations between patient dissatisfaction and diabetes outcomes among patients with type 2 diabetes. Methods Primary data from 615 adults with type 2 diabetes from 2 adult primary care clinics completed validated questionnaires. Patient dissatisfaction was measured by asking participants to what degree over the past 12 months were they very dissatisfied with the care they received from their primary care provider. Diabetes outcomes included self-care behaviors, quality of life, and A1C. A1C was abstracted from the medical record. Multiple linear regression models were used to assess associations between patient dissatisfaction, self-care, blood glucose, and quality of life. Results After adjusting for covariates, this study demonstrated that higher patient dissatisfaction was significantly associated with poor general diet, worse blood glucose levels, and lower mental component score for quality of life. Conclusions In patients with type 2 diabetes, patient dissatisfaction had a significant association with higher blood glucose levels, poor general diet, and low quality of life. Demographic factors driving patient dissatisfaction included young age, low income, and low health literacy. Future studies should investigate how to address patient satisfaction in an effort to improve health outcomes.