bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 32: Data-driven inference of crosstalk in the tumor microenvironment
Authors: Ghoshdastider Umesh , Naeini Marjan , Rohatgi Neha , Solai Sundar , Nguyen Tin , Revkov Egor , Skanderup Anders 
Published: August 2020

Abstract
Signaling between cancer and nonmalignant (stromal) cells in the tumor microenvironment (TME) is key to tumorigenesis, yet challenging to decipher from tumor transcriptomes. Here, we report an unbiased, data-driven approach to deconvolute bulk tumor transcriptomes and predict crosstalk between ligands and receptors on cancer and stromal cells in the TME of 20 solid tumor types. Our approach recovers known transcriptional hallmarks of cancer and stromal cells and is concordant with single-cell and immunohistochemistry data, underlining its robustness. Pan-cancer analysis reveals previously unrecognized features of cancer-stromal crosstalk. We find that autocrine cancer cell crosstalk varied between tissues but often converged on known cancer signaling pathways. In contrast, many stromal crosstalk interactions were highly conserved across tumor types. Interestingly, the immune checkpoint ligand PD-L1 was overexpressed in stromal rather than cancer cells across all tumor types. Moreover, we predicted and experimentally validated aberrant ligand and receptor expression in cancer cells of basal and luminal breast cancer, respectively. Collectively, our findings validate a data-driven method for tumor transcriptome deconvolution and establish a new resource for hypothesis generation and downstream functional interrogation of the TME in tumorigenesis and disease progression.
Citation Format: Umesh Ghoshdastider, Marjan Naeini, Neha Rohatgi, Sundar Solai, Tin Nguyen, Egor Revkov, Anders Skanderup. Data-driven inference of crosstalk in the tumor microenvironment [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 32.
Abstract 37: Computational analysis of the KRAS G13D colorectal cancer response to EGFR inhibition with an alternatively parameterized model
Authors: McFall Thomas , Stites Edward C. 
Published: August 2020

Abstract
Controversially, KRAS G13D colorectal cancer patients have been reported to benefit from treatment with the EGFR inhibitor cetuximab. That EGFR inhibitors could somehow reduce signaling through a constitutively active KRAS mutant has been taken as inconsistent with known mechanisms of RAS biology. Through a combination of computational modeling and experimentation, we recently demonstrated that EGFR inhibition results in a reduction of wild-type (HRAS and NRAS) signaling in KRAS G13D colon cancer cells, but not in colon cancer cells with the other common KRAS mutants, G12D and G12V. We demonstrated this in multiple colon cancer cell lines, and we developed the hypothesis originally from our mathematical model of oncogenic RAS signal regulation adapted to biochemical rate constants for the KRAS G13D mutant. Here, we develop and analyze an alternatively parameterized version of the computational model. Analysis of this alternative model similarly suggests that EGFR inhibition causes a greater reduction of wild-type RAS signal in KRAS G13D cancers. This further substantiates our findings, analogous to demonstration in an additional cell line or an additional mouse model. In addition to reinforcing our proposed mechanism, this work also further demonstrates the power of mechanism-based computational models of protein network biochemistry in personalized cancer medicine.
Note: This abstract was not presented at the conference.
Citation Format: Thomas McFall, Edward C. Stites. Computational analysis of the KRAS G13D colorectal cancer response to EGFR inhibition with an alternatively parameterized model [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 37.
Abstract 38: Molecular determinants of drug response in TNBC cell lines
Authors: Merrill Nathan M. , Lachacz Eric J. , Vandecan Nathalie M. , Ulintz Peter J. , Bao Li Wei , Lloyd John P. , Morikawa Aki , Merajver Sofia D. , Soellner Matthew B. 
Published: August 2020

Abstract
Triple-negative breast cancer (TNBC) is one of the deadliest forms of breast cancer due to limited treatment options beyond conventional chemotherapy. TNBC constitutes approximately 10-20% of total breast cancer cases in the US; however, TNBC tends to be more aggressive, higher grade, and have a poorer prognosis than other forms of breast cancer. While oncogenic aberrations have been identified in TNBC, such as the PI3K/AKT/mTOR pathway that is misregulated in ~25% of tumors, there is a general lack of predictive markers of therapeutic efficacy to identify subsets of patients most likely to positively respond to a given targeted or conventional therapy. Simply relying on mutation status is undependable, as some patients without PI3K mutations respond to PI3K inhibitors and some patients with PI3K mutations do not respond. Thus, there is a critical need for biomarkers of drug efficacy in TNBC to help design precision medicine clinical trials based on systematically derived predictive biomarkers. To fill this gap, we devised a strategy to identify biomarkers of drug efficacy in TNBC. Using 23 TNBC cell lines, drug sensitivity scores (DSS3) were determined across a panel of investigational drugs and drugs approved for other indications. Molecular readouts were generated for each cell line using RNA sequencing, RNA targeted panels, DNA sequencing, and functional proteomics. DSS3 values were correlated with molecular readouts using an FDR-corrected significance cutoff of p* &lt; 0.05 and yielded molecular determinant panels that predict anti-TNBC efficacy. Molecular determinant panels were obtained from 12 drugs that were prioritized on the basis of their efficacy. Six molecular determinant panels were obtained by correlating DSS3 with molecular readouts. We found that coinhibiting correlated pathways led to robust synergy across many cell lines. Together, our work presents an integrated method to identify biomarkers of drug efficacy in TNBC, where DNA predictions correlate poorly with drug response. Furthermore, we outline a framework to identify optimal companion drugs for combination therapy.
Citation Format: Nathan M. Merrill, Eric J. Lachacz, Nathalie M. Vandecan, Peter J. Ulintz, Li Wei Bao, John P. Lloyd, Aki Morikawa, Sofia D. Merajver, Matthew B. Soellner. Molecular determinants of drug response in TNBC cell lines [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 38.
Abstract 43: Clinical implications of real-world data on plasma circulating tumor DNA in gynecologic cancer patients
Authors: Charo Lindsey Michelle , Eskander Ramez N. , Okamura Ryosuke , Patel Sandip , Nikanjam Mina , Layman Richard , Piccioni David E. , Kato Shamei , McHale Michael , Kurzrock Razelle 
Published: August 2020

Abstract
Molecular characterization of individual cancers is increasingly important in dictating prognostic factors and directing therapy. Next-generation sequencing of blood-derived circulating tumor DNA (ctDNA) offers less invasive, more convenient collection and a more real-time representation of a tumor and its molecular heterogeneity than tissue-based analysis. However, little is known about the clinical implications of ctDNA assessment in gynecologic cancer. We report the clinicopathologic and genomic information for 105 gynecologic cancer patients with ctDNA analysis, including 78 patients with tissue-based sequencing, who were enrolled in Profile Related Evidence Determining Individualized Cancer Therapy (PREDICT, NCT02478931). Tumors in our cohort included ovarian (47.6%), uterine (35.2%), cervical (12.4%), vulvar or vaginal (2.9%), and gynecologic cancer of unknown primary (1.9%). The majority of patients (74.3%) had at least one characterized alteration on ctDNA analysis. The most common alterations were in the following genes: TP53 (N=59, 56.2% of patients), PIK3CA (N=26, 24.8%), KRAS (N=14, 13.3%), BRAF (N=10, 9.5%), ERBB2 (N=8, 7.6%), and MYC (N=8, 7.6%). Higher total percentage of ctDNA was associated with worse overall survival (HR 2.18, p=0.008), and therapy matched to ctDNA genomic alterations (N = 33 patients) independently predicted improved overall survival (HR 0.34, p=0.007) as compared to unmatched therapy (N = 28 patients). Tissue and ctDNA genomic results showed high concordance unaffected by temporal or spatial factors. This study provides evidence for the utility of ctDNA in determining outcome and individualizing cancer therapy in patients with gynecologic cancer.
Citation Format: Lindsey Michelle Charo, Ramez N. Eskander, Ryosuke Okamura, Sandip Patel, Mina Nikanjam, Richard Layman, David E. Piccioni, Shamei Kato, Michael McHale, Razelle Kurzrock. Clinical implications of real-world data on plasma circulating tumor DNA in gynecologic cancer patients [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 43.
Abstract IA23: ctDNA as predictive biomarkers for response and toxicity with immunotherapy
Authors: Siu Lillian L. 
Published: August 2020

Abstract
Immune checkpoint blockade (ICB) with anti-PD1/PD-L1 antibodies provides clinical benefit to a subset of cancer patients. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. Limited data exist to show how serial circulating tumor (ct)DNA testing may perform as a predictive biomarker in patients receiving immune checkpoint blockade. In an investigator-initiated phase II study of the anti-PD1 antibody pembrolizumab in patients with advanced solid tumors (INSPIRE; NCT02644369), we collected plasma samples at baseline and prior to every third cycle. These samples were retrospectively analyzed using a validated patient-specific, amplicon-based sequencing assay to detect and quantify ctDNA levels at each plasma time point. In total, 94 patients with serial ctDNA collections in five cohorts of solid tumors received single-agent pembrolizumab 200 mg IV ever 3 weeks. Levels of ctDNA at serial time points and the change from baseline were correlated with overall survival (OS), progression-free survival (PFS), objective response rate (ORR by RECIST v1.1), and clinical benefit rate (CBR, CR + PR + SD &gt; 6 cycles). Response was measured by RECIST v1.1. Across the five cancer cohorts, median number of pembrolizumab cycles received was 3 and median follow-up was 13.8 months. Baseline ctDNA concentration correlated with multiple efficacy measures. This association became stronger across the cohorts when considering ctDNA kinetics after treatment initiation. An early reduction in ctDNA levels (at about 6-7 weeks) was strongly correlated with OS, PFS, ORR, and CBR. Sustained ctDNA clearance during treatment preceded durable clinical response. Strikingly, all 14 patients with ctDNA clearance during treatment were alive with a median of 27.5 months follow-up. These results demonstrate the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB for advanced solid tumors of diverse histologies. Limited by the number of patients with grade 2 or higher immune-related adverse events (irAEs, 23/94 patients, 24%), no correlation was seen between irAE and cell-free DNA levels in the INSPIRE cohort. Currently we are planning interventional ICB studies using early ctDNA dynamics as predictive biomarkers.
Citation Format: Lillian L. Siu. ctDNA as predictive biomarkers for response and toxicity with immunotherapy [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 IA23.
Polar wolf optimization algorithm for solving optimal reactive power problem
Authors: Lenin Kanagasabai 
Published: August 2020

<span>This paper proposes polar wolf optimization (PWO) algorithm to solve the optimal reactive power problem. Proposed algorithm enthused from actions of polar wolves. Leader’s wolves which denoted as </span>x<sub>α</sub> <span>are accountable for taking judgment on hunting, resting place, time to awaken etc. second level is </span>x<sub>β</sub> <span>those acts when there is need of substitute in first case. Then </span>x<sub>γ</sub> <span>be as final level of the wolves. In the modeling social hierarchy is developed to discover the most excellent solutions acquired so far. Then the encircling method is used to describe circle-shaped vicinity around every candidate solutions. In order to agents work in a binary space, the position modernized accordingly. Proposed PWO algorithm has been tested in standard IEEE 14, 30, 57,118,300 bus test systems and simulation results show the projected algorithms reduced the real power loss considerably.</span>
Racial Differences in the Use of Aortic Valve Replacement for Treatment of Symptomatic Severe Aortic Valve Stenosis in the Transcatheter Aortic Valve Replacement Era
Authors: Matthew Brennan J. , Leon Martin B. , Sheridan Paige , Boero Isabel J. , Chen Qinyu , Lowenstern Angela , Thourani Vinod , Vemulapalli Sreekanth , Thomas Kevin , Wang Tracy Y. , Peterson Eric D. 
Published: August 2020

Background
Aortic valve replacement (AVR) is a life‐saving treatment for patients with symptomatic severe aortic valve stenosis. We sought to determine whether transcatheter AVR has resulted in a more equitable treatment rate by race in the United States.

Methods and Results

A total of 32 853 patients with symptomatic severe aortic valve stenosis were retrospectively identified via Optum’s deidentified electronic health records database (2007–2017). AVR rates in non‐Hispanic Black and White patients were assessed in the year after diagnosis. Multivariate Fine‐Gray hazards models were used to evaluate the likelihood of AVR by race, with adjustment for patient factors and the managing cardiologist. Time‐trend and 1‐year symptomatic severe aortic valve stenosis survival analyses were also performed. From 2011 to 2016, the rate of AVR increased from 20.1% to 37.1%. Overall, Black individuals were less likely than Whites to receive AVR (22.9% versus 31.0%; unadjusted hazard ratio [HR], 0.70; 95% CI, 0.62–0.79; fully adjusted HR, 0.76; 95% CI, 0.67–0.85). Yet, during 2015 to 2016, AVR racial differences were attenuated (29.5% versus 35.2%; adjusted HR, 0.86; 95% CI, 0.74–1.02) because of greater uptake of transcatheter AVR in Blacks than Whites (53.4% of AVRs versus 47.3%;
P
=0.128). Untreated patients had significantly higher 1‐year mortality than those treated (adjusted HR, 0.57; 95% CI, 0.53–0.61), which was consistent by race (interaction
P
value=0.52).

Conclusions
Although transcatheter AVR has increased the use of AVR in the United States, treatment rates remain low. Black patients with symptomatic severe aortic valve stenosis were less likely than White patients to receive AVR, yet these differences have recently narrowed.
Morphological Bottleneck: The Case of Russian Heritage Speakers
Authors: Mikhaylova Anna 
Published: August 2020

The Bottleneck Hypothesis (Slabakova, 2008) assumes functional morphology to be a particular challenge in second language (L2) acquisition whereas acquisition of syntax and semantics to be unproblematic. I propose, following Polinsky (2011), that functional morphology can be seen as an acquisitional bottleneck for heritage language (hl) speakers as well. Russian verbal aspect is known to be problematic in bilingual Russian children (Anstatt, 2008; Gupol, 2009), in adult foreign language learners (Slabakova, 2005, Nossalik, 2009) and in Russian heritage speakers of low (Polinsky, 2008) and even near-native fluency (Laleko, 2010).
This comprehension study tested fluent and literate English dominant hl speakers of Russian on their interpretation of lexical and grammatical aspect. The findings suggest that the semantics and syntax of aspect were unproblematic, but aspectual morphology played both a facilitative and a hindering role in the comprehension of aspectual distinctions. In the untimed Semantic Entailments task, where participants chose the most logical continuation of an utterance, the morphological complexity of secondary imperfectives coupled with their semantic complexity, hindered hl interpretations. In contrast, in the Stop-Making-Sense self-paced reading task, in which participants read sentences one word at a time, the idiosyncratic morphology marking lexical aspect hindered hl processing, while the regular mechanism of marking grammatical aspect facilitated it.
Wittmann Patch
Authors: Nemec Hannah M. , Benjamin Christie D. , Montgomery Anne , Vaughn Danny M. 
Published: August 2020

Introduction Damage control laparotomy (DCL) is a life-saving surgical technique, but the resultant open abdomen (OA) carries serious morbidity/mortality. Many methods are utilized to manage OAs, but discrepancy exists in distinguishing closure from coverage techniques. We observed a difference in our DCL patient outcomes managed with the Wittmann Patch (WP) closure device versus the more popular ABThera (AB) coverage device. We hypothesized that the WP contributed to an improved fascial closure rate of the OAs after DCL. Methods A retrospective review of OAs managed with the AB or WP at our Level 1 trauma center was performed using billing codes to capture DCL patients from 2011 to 2019. Patients were divided into AB alone or WP groups. Major endpoints included primary fascial closure (PFC) and delayed fascial closure (DFC, fascial closure after greater than 7 days). Results 189 patients were identified as AB and 38 as WP. Rates of death before closure, age, gender, and Injury Severity Score were similar in both groups. PFC = 81%-90% for AB versus WP, respectively. Excluding patients with preexisting hernias PFC = 87%-100% for AB versus WP ( P < .05) and DFC = 44%-100% for AB versus WP ( P ≤ 0.001). WP had a statistically higher rate of PFC and DFC. There was a decreased incidence of complications in the WP versus AB group. Conclusions While not well reported in the peer-reviewed literature, the application of the WP for management of the OA is an active form of pursuing PFC when compared with the AB, a coverage device. Our interinstitutional results have demonstrated superior PFC and DFC rates and fewer complications, in patients managed with the WP compared with the AB.
Opioid Use After Inguinal and Ventral Hernia Repair
Authors: Millard Jessica L. , Moraney Robyn , Childs Jordan C. , Ewing Joseph A. , Carbonell Alfredo M. , Cobb William S. , Warren Jeremy A. 
Published: August 2020

Background Recent data on opioid consumption indicate that patients typically require far less than is prescribed. Prisma Health Upstate Hernia Center adopted standardized postoperative prescribing after hernia repair and began tracking patient-reported opioid utilization. The aim of this study is to evaluate patient opioid use after hernia repair in order to guide future prescribing. Methods All patients who underwent primary ventral (umbilical and epigastric), incisional, and inguinal hernia repair between February and May 2019 were reviewed. Patients reported the number of opioid pills taken at their first postoperative visit and documented either in the progress note or in the Americas Hernia Society Quality Collaborative (AHSQC) patient-reported outcomes (PRO) questionnaire. All demographic, operative, and outcomes data were captured prospectively in the AHSQC. Opioid use reported as milligram morphine equivalents (MME). Results A total of 162 surgeries were performed during the study period, and 107 had patient-reported opioid use for analysis. Inguinal hernia repair was performed in 36 patients, 10 primary ventral hernia repairs, and 61 incisional hernia repairs. No opioid use was reported in 63.9% of inguinal hernias, 60% of primary ventral hernias, and 20% of incisional hernias. Inguinal hernia patients consumed a mean of 10.5 MME, primary ventral patients 11 MME, and incisional hernia patients 78.5 MME. Conclusion Patients require little to no opioid after primary ventral or inguinal hernia repair and opioid-free surgery is feasible. Incisional hernia is more heterogenous, but the majority of patients still required less opioid than previously thought.
Comparisons of Spatiotemporal and Ground Reaction Force Components of Gait Between Individuals with Congenital Vision Loss and Sighted Individuals
Authors: Majlesi Mahdi , Farahpour Nader , Robertson Gordon E. 
Published: August 2020

Introduction: The understanding of abnormalities in biomechanical parameters of gait in individuals with vision loss (i.e., blindness or low vision) has clinical importance. The aims of this study were to compare the spatiotemporal and ground reaction force variables of sighted individuals with those with vision loss. Methods: Ten sighted males and 10 young males with congenital vision loss were recruited. A Vicon motion analysis system with four cameras and two Kistler force plates was used to quantify spatiotemporal and ground reaction force components of both groups during walking without shoes. Sighted individuals walked in eyes-open and eyes-closed conditions. Results: Results showed that the stride and step length, walking speed, the vertical and posterior–anterior reaction forces in heel contact and push-off phase, and the impulse of the control group during walking with the open- and closed-eyes conditions were significantly smaller than those in persons with vision loss ( p < .05). Discussion: Vision loss is associated with decreased step and stride length, slower walking, and smaller propulsive reaction force. These kinematic and kinetics alterations suggest an adaptation to a new neuromuscular response for dynamic postural control as a result of lack of vision. These alterations in the long term may result in rigidity and muscle weakness. Implications for practitioners: A rehabilitation program to enhance mobility and strength is suggested for individuals with vision loss.