bluuebunny/crossref_metadata_2025 huggingface dataset:
Forecasting Electricity Power Generation of Pawan Danavi Wind Farm, Sri Lanka, Using Gene Expression Programming
Authors: Herath Damayanthi , Jayasinghe Jeevani , Rathnayake Upaka
Published: May 2022

This paper presents the development of a wind power forecasting model based on gene expression programming (GEP) for one of the major wind farms in Sri Lanka, Pawan Danavi. With the ever-increasing demand for renewable power generation, Sri Lanka has started harnessing electricity from wind power. Though the initial establishment cost of wind farms is high, the analyses clearly showcased the economic sustainability of wind power generation in long term. In this context, forecasting the wind power generation at Sri Lankan wind farms is important in many ways. However, limited research has been carried out in Sri Lanka to predict the wind power generation against the changing climate. Therefore, to overcome this research gap, a model was developed to forecast wind power generation against two climatic factors, viz. on-site wind speed and ambient temperature. The results showcased the robustness and accuracy of the proposed GEP-based forecasting model (with R2 = 0.92, index of agreement = 0.98, and RMSE = 259 kW). Moreover, the results of the study were compared against three different forecasting models and found comparable in terms of the model accuracy. The GEP-based model is advantageous over machine learning techniques due to its capability in deriving a mathematical expression. As an acceptable relationship was found between wind power generation and climatic factors, the proposed model facilitates the future projection of wind power generations with forecasted climatic factors. Though the application of GEP in the field of wind power generation is reported in a few research publications, this is the first research in which GEP is employed to model the power generation with respect to weather indices. The proposed prediction model is advantageous than machine learning models as the relationship between the wind power and the weather indices can be expressed.
p
-Adic Riesz Potential and Its Commutators on Morrey-Herz Spaces
Authors: Shi Yanlong , Shi Yafeng , Chen Shenbao
Published: May 2022

In this paper, we establish the boundedness of

p

-adic Riesz potential on Morrey-Herz spaces, as well as the

λ

-central BMO estimates for multilinear commutators of

p

-adic Riesz potential on Morrey-Herz spaces.
Waiting Behavior and Arousal in Different Levels of Crowd Density: A Psychological Experiment with a “Tiny Box”
Authors: Beermann Mira , Sieben Anna
Published: May 2022

Crowd density, defined as persons per square meter, is a basic measuring unit for describing and analyzing crowd dynamics and for planning pedestrian infrastructure. However, little is known about the relationship between crowd density and psychological stress and well-being. This study uses an experimental approach to determine whether higher crowd densities result in higher levels of stress in participants. In this experiment, which was a case study at the university, participants (N = 29) wait in a wooden box of 1 m2 for three minutes. Two, four, six, or eight participants are present simultaneously in the box. It is varied whether participants are supposed to remain silent or to speak with each other. Stress is conceptualized as arousal and measured as skin conductance level/electrodermal activity (EDA). A questionnaire is administered after the experiment, and the positioning of participants in the box is videotaped. The results show that the correlation between crowd density and physiological arousal is more complex than expected. The specific social situation in the box appears to play a more important role than merely the number of people waiting there. Furthermore, our data indicate a temporal trend: participants seem to adapt to the crowd density in the box. Video data analysis reveals that participants choose their positioning and orientation in the box carefully, but that this social choreography works less smoothly in higher densities. This study shows promising results for using EDA as a measurement of arousal in the context of crowd research. However, the limitations of this method and the experiments conducted are also discussed in detail to further improve this approach.
Dropout Rate Prediction of Massive Open Online Courses Based on Convolutional Neural Networks and Long Short-Term Memory Network
Authors: Tang Xingqiu , Zhang Hao , Zhang Ni , Yan Huan , Tang Fangfang , Zhang Wei
Published: May 2022

Massive open online courses (MOOC) is characterized by large scale, openness, autonomy, and personalization, attracting increasingly students to participate in learning and gaining recognition from more and more people. This paper proposes a network model based on convolutional neural networks and long short-term memory network (CNN-LSTM) for MOOC dropout prediction task. The model selects 43-dimensional behavioral features as input from students’ learning activity logs and adopts the CNN model to automatically extract continuous features over a period of time from students’ learning activity logs. At the same time, considering the time sequence of students’ learning behavior characteristics, a MOOC dropout prediction model was established by using long short-term memory network to obtain students’ learning status at different time steps. The algorithm proposed in this chapter was trained and evaluated on the public dataset provided by the KDD Cup 2015 competition. Compared with the dropout prediction methods based on LSTM and CNN-RNN, the model improved the AUC by 2.7% and 1.4%, respectively. The result in this paper is a good predictor of dropout rates and is expected to provide teaching aid to teachers.
Basketball Motion Posture Recognition Based on Recurrent Deep Learning Model
Authors: Liu FeiPeng , Zhang Wei
Published: May 2022

In order to improve the training effect of athletes and effectively identify the movement posture of basketball players, we propose a basketball motion posture recognition method based on recurrent deep learning. A one-dimensional convolution layer is added to the neural network structure of the deep recurrent Q network (DRQN) to extract the athlete pose feature data before the long short-term memory (LSTM) layer. The acceleration and angular velocity data of athletes are collected by inertial sensors, and the multi-dimensional motion posture features are extracted from the time domain and frequency domain, respectively, and the posture recognition of basketball is realized by DRQN. Finally, the new reinforcement learning algorithm is trained and tested in a time-series-related environment. The experimental results show that the method can effectively recognize the basketball motion posture, and the average accuracy of posture recognition reaches 99.3%.
The Bioinformatical Identification of Potential Biomarkers in Heart Failure Diagnosis and Treatment
Authors: Sheng Xiaodong , Jin Xiaoqi , Liu Yanqi , Fan Tao , Zhu Zongcheng , Jin Jing , Zheng Guanqun , Chen Zhixian , Lu Min , Wang Zhiqiang
Published: May 2022

Background. Heart failure (HF) is defined as the inability of the heart’s systolic and diastolic function to properly discharge blood flow from the veins to the heart. The goal of our research is to look into the possible mechanism that causes HF. Methods. The GSE5406 database was used for screening the differentially expressed genes (DEGs). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI) network were applied to analyze DEGs. Besides, cell counting Kit-8 (CCK-8) was conducted to observe the knockdown effect of hub genes on cell proliferation. Results. Finally, 377 upregulated and 461 downregulated DEGs came out, enriched in the extracellular matrix organization and gap junction. According to GSEA results, Hoft cd4 positive alpha beta memory t cell bcg vaccine age 18–45 yo id 7 dy top 100 deg ex vivo up, Sobolev t cell pandemrix age 18–64 yo 7 dy dn, and so on were significantly related to gene set GSE5406. 7 hub genes, such as COL1A1, UBB, COL3A1, HSP90AA1, MYC, STAT3 and MAPK1, were selected from PPI networks. CCK-8 indicated silencing of STAT3 promoted the proliferation of H9C2 cells and silencing of UBB inhibited the proliferation of H9C2 cells. Conclusion. Our analysis reveals that COL1A1, UBB, COL3A1, HSP90AA1, MYC, STAT3, and MAPK1 might promote the progression of HF and become the biomarkers for diagnosis and treatment of HF.
Association of Endothelin-Converting Enzyme and Endothelin-1 Gene Polymorphisms with Essential Hypertension in Malay Ethnics
Authors: Salim Elnaz , Ramachandran Vasudevan , Ansari Neda , Ismail Patimah , Mohamed Mohd Hazmi , Mohamad Nur Afiqah , Inche Mat Liyana Najwa
Published: May 2022

Objectives. Endothelin-1 (ET-1), the most potent endogenous vasoconstrictor, generated by enzymatic cleavage catalyzed by an endothelin-converting enzyme (ECE), plays a significant role in the regulation of hypertension. Methods. This study investigates the effect of endothelin-1 (Lys198Asn/rs5370) and ECE (rs212526 C/T) gene polymorphisms with essential hypertension (EH) among Malay ethnics. To determine the association of gene polymorphism, 177 hypertensives and controls (196) were genotyped using Taqman method. Results. A significant difference was observed in ET-1 rs5370 and ECE rs212526 gene polymorphisms between EH and control subjects (

P
<
0.001

). A significantly high body mass index (BMI), waist-to-hip ratio, fasting plasma glucose, hemoglobin A1c, systolic and diastolic blood pressure, and lipid profiles were observed among the EH patients when compared to controls (

P
<
0.05

). Moreover, T allele (rs5370) carriers in males have a high risk for EH. There was no significant association between gender in ECE C/T polymorphisms (

P
>
0.05

). Conclusion. Based on our result, it is evident that the T allele of ET-1 rs5370 polymorphism and C allele of ECE rs212526 have a significant genetic risk factor in EH among Malay subjects, and BMI and age are associated with hypertension.
Abstract A002: Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer
Authors: Challoner Benjamin R. , Woolston Andrew , Lau David , Buzzetti Marta , Barber Louise J. , Lund Tom , Sansano Harold B. , von Loga Katharina , Lázare-Iglesias Héctor , Begum Ruwaida , Crux Richard , Cunningham David , Chau Ian , Starling Naureen , Ruiz-Bañobre Juan , Dhillon Tony , Gerlinger Marco
Published: May 2022

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR012) of the Conference Proceedings.

Citation Format: Benjamin R. Challoner, Andrew Woolston, David Lau, Marta Buzzetti, Louise J. Barber, Tom Lund, Harold B. Sansano, Katharina von Loga, Héctor Lázare-Iglesias, Ruwaida Begum, Richard Crux, David Cunningham, Ian Chau, Naureen Starling, Juan Ruiz-Bañobre, Tony Dhillon, Marco Gerlinger. Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A002.
Abstract A003: Genome evolution of a transmissible cancer in the soft-shell clam (Mya arenaria)
Authors: Hart Samuel F.M. , Giersch Rachael M. , Yonemitsu Marisa A. , Beal Brian , Goff Stephen P. , Metzger Michael J.
Published: May 2022

A small number of transmissible cancer lineages exist in which cancer cells metastasize repeatedly to new hosts and live past the death of their original hosts. Transmissible cancers have been observed in the dog, Tasmanian devil, and most recently in numerous bivalves species, including one lineage that has spread through the soft-shell clam (Mya arenaria) population along the east coast of North America. We assembled a highly contiguous 1.2 Gb soft-shell clam reference genome and characterized the genome evolution of this transmissible cancer lineage. Our analyses confirm that all cancer samples descended from a single founder clam, but cluster in two geographically separated sub-lineages. In both sub-lineages, we observe high somatic mutation density, widespread copy number gain, structural rearrangement and transposable element activity, all indicative an unstable cancer genome. We also discovered a novel mutational signature generating mutations at a stable rate, predicting the cancer to be 344 to 877 years old and indicating it spread undetected long before it was first observed in the 1970s.

Citation Format: Samuel F.M. Hart, Rachael M. Giersch, Marisa A. Yonemitsu, Brian Beal, Stephen P. Goff, Michael J. Metzger. Genome evolution of a transmissible cancer in the soft-shell clam (Mya arenaria) [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A003.
Abstract A008: TP53 field defects in uterine fluid are associated with ovarian cancer risk
Authors: Risques Rosana , Smith Thomas H. , Norgaard Zachary K. , Katz Roniz , Lo Fang Yin , Schmidt Elizabeth K. , Higgins Jacob E. , Filipits Martin , Labidi-Galy Intidhar , Cibula David , Dostálek Lukáš , Jelenek Gabriel , Plch Magdalena , Bouda Jiří , Mustea Alexander , Condic Mateja , Grill Sabine , Gleeson Noreen , Oppelt Peter , Pristauz-Telsnigg Gunda , Vanderstichele Adriaan , Obrecht Siel , Rosenthal Adam , Speiser Paul , Salk Jesse
Published: May 2022

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR005) of the Conference Proceedings.

Citation Format: Rosana Risques, Thomas H. Smith, Zachary K. Norgaard, Roniz Katz, Fang Yin Lo, Elizabeth K. Schmidt, Jacob E. Higgins, Martin Filipits, Intidhar Labidi-Galy, David Cibula, Lukáš Dostálek, Gabriel Jelenek, Magdalena Plch, Jiří Bouda, Alexander Mustea, Mateja Condic, Sabine Grill, Noreen Gleeson, Peter Oppelt, Gunda Pristauz-Telsnigg, Adriaan Vanderstichele, Siel Obrecht, Adam Rosenthal, Paul Speiser, Jesse Salk. TP53 field defects in uterine fluid are associated with ovarian cancer risk [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A008.
Abstract A011: Deciphering clonal evolution under chemotherapy in high-risk neuroblastoma using patient derived models
Authors: Andersson Natalie , Nuñez Adriana Mañas , Aaltonen Kristina , Hansson Karin , Seger Alexandra , Radke Katarzyna , Esfandyari Javanshir , Bexell Daniel , Gisselsson David
Published: May 2022

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR001) of the Conference Proceedings.

Citation Format: Natalie Andersson, Adriana Mañas Nuñez, Kristina Aaltonen, Karin Hansson, Alexandra Seger, Katarzyna Radke, Javanshir Esfandyari, Daniel Bexell, David Gisselsson. Deciphering clonal evolution under chemotherapy in high-risk neuroblastoma using patient derived models [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A011.
Abstract A015: Inferring phylogenetic trees based on copy number aberrations from methylation array
Authors: Ding Chuling , Herrero Javier
Published: May 2022

Background: The development of methylation array platforms has allowed large scale studies on cancer epigenomes. Apart from intended analyses on methylation patterns, it is also possible to infer copy number profiles by leveraging the signal from methylation array data. To disentangle complex mixtures of phylogenetically related clones, it is best to jointly analyze different samples (different regions, timepoints, etc.) from the same tumor. However, current methods for studying copy number aberrations (CNAs) from methylation arrays consider tumor samples independently. In this project, we introduce Multi-Sample EPIC Phylogenetic Reconstruction (MultiSEPhyR), aiming to investigate the copy number profiles and clonal compositions from multi-sample methylation array data. Material and methods: As part of the GCGR (Glioma Cellular Genetic Resource; gcgr.org.uk) project, we analyze 53 samples from 26 cases with multiple methylation array data of primary glioblastomas, tumor-derived cell lines and xenograft re-derived cell lines. Copy Number Aberrations (CNAs) called from the methylation array data are validated using WGS data from a subset of the cohort. By jointly clustering the segmented LogR ratios from related samples, we can define tumor clones based on clustered CNA events. We use a two-step approach, where we firstly identify clonal events to obtain sample purity and tumor ploidy and use these values to subsequently infer the copy number state and the clonality of the remaining events. Results and Discussions: On a simulated dataset, MultiSEPhyR could accurately estimate sample purity and identify both clonal and sub-clonal CNA events. We then apply our method on GCGR dataset and show similar extent of intra-tumor heterogeneity in primary glioblastomas and derived cell lines. We also investigate clonal dynamics in each case. In the cell lines, while the heterogeneity is well captured, some sub-clonal CNA events may exhibit significantly different clonality compared to the primary glioblastomas. For example, we observe a clonal expansion of the clones harboring a deletion in chromosome 6 in xenograft re-derived cell lines. Conclusion We present a systematic way to call CNAs and resolve clonal compositions from methylation array data, leading to a cost-efficient way to study tumor evolution.

Citation Format: Chuling Ding, Javier Herrero. Inferring phylogenetic trees based on copy number aberrations from methylation array [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A015.
Abstract A018: Lung cancer associated DNA Damageome reveals a genome destabilizing role of Aquaporin 3
Authors: Xia Jun , Lin Mu , Song Zhuoyi , Fernandes Gail , Rosenberg Susan , Amos Chris
Published: May 2022

Lung cancer is a multifactorial disease caused by both environmental exposures and genetic factors. Genome and transcriptome-wide association studies (GWAS and TWAS) successfully identified many genetic variants and candidate causal genes associated with lung cancer. However, the lack of functional studies of these genes remains a major bottleneck to clinical translation. Recently, we discovered that large networks of evolutionarily conserved DNA damageome proteins (DDPs) promote DNA damage and genome instability. Here, we discovered a lung cancer-associated DNA damageome network. We further discovered that one of the lung cancer DDPs, Aquaporin 3 (AQP3), can promote ROS dependent DNA damage upon overproduction. Furthermore, it potentiates DNA damage by a low dose of arsenic exposure, creating unique double strand break hotspots which help predict mutational signatures. We screened for high endogenous DNA damage levels for more than 40 TWAS and GWAS-nominated candidates using high-throughput single cell-based flow cytometric assays. We optimized and performed Mre11-Cut&Tag (Cleavage Under Targets and Tagmentation) to map double strand breaks, which are the most deleterious form of DNA damage. In addition, we used END-Seq to provide a much higher resolution of the DSB map and uncovered hotspots in arsenic-detoxifying genes. We are implementing duplex sequencing to map the mutational signatures caused by arsenic and the arsenic-Aquaporin 3 interaction. Our study brings function to endogenous DNA damage and DNA damageome proteins that interact with environmental toxicants. Mechanistic insights into how low-dose arsenic interacts with risk genes yield critical knowledge for the prevention, diagnosis, and treatment of arsenic-associated diseases. We also uncovered several early biomarkers to potentially predict the long-term health impacts of arsenic.

Citation Format: Jun Xia, Mu Lin, Zhuoyi Song, Gail Fernandes, Susan Rosenberg, Chris Amos. Lung cancer associated DNA Damageome reveals a genome destabilizing role of Aquaporin 3 [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A018.
Abstract A019: Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential (CHIP) using fluctuating methylation clocks
Authors: Schenck Ryan O. , Jakobsen Niels Asger , Turati Virginia , Shibata Darryl , Vyas Paresh , Leedham Simon , Anderson Alexander R.A.
Published: May 2022

Clonal hematopoiesis (CH), such as clonal hematopoiesis of indeterminant potential (CHIP), is diagnosed based on somatic genomic alterations in the absence of hematologic malignancy. At present, CHIP is diagnosed using peripheral blood, where putative driver point mutations and small insertions/deletions whose variant allele frequency is greater or equal to two percent. Generally, the prevalence of CH increases as an individual ages and conveys a risk for progression to a malignancy. CH is thought to be driven by the underlying hematopoietic stem cells of an unknown quantity, with estimates in the literature for stem cell numbers differing by orders of magnitude. Previously, we developed a method using fluctuating CpG (fCpG) sites to serve as a fluctuating methylation clock to uncover stem cell dynamics in glandular tissues and orthogonally validated our method using publicly available datasets of human blood from normal cohorts and malignant cohorts. Here we expand on this work by presenting 38 new patients with distinct VAF groups from 1-2% VAF up to greater than 10% VAF for putative drivers with corresponding DNA methylation profiles using the Illumina EPIC array platform. We identify fCpG from our normal and CHIP cohorts to train and validate a machine learning approach that allows us to diagnose CHIP without DNA sequencing. Importantly, our approach allows for the identification of patients who may have CH driven by structural variants such as copy number alterations. We use this method to evaluate two publicly available methylation datasets of reportedly normal patients (n=656 and n=732) showing that evidence of CHIP can be found in 19% and 29% of these datasets, respectively. We then evaluate copy number differences in burden within our CHIP cohort and these newly identified CHIP cohorts. Using a mechanistic model of hematopoietic stem cells containing fCpGs we examine the temporal dynamics of competing founder CHIP drivers and the number of stem cells in the hematopoietic stem cell compartment.

Citation Format: Ryan O. Schenck, Niels Asger Jakobsen, Virginia Turati, Darryl Shibata, Paresh Vyas, Simon Leedham, Alexander R.A. Anderson. Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential (CHIP) using fluctuating methylation clocks [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A019.
Abstract A020: Multi-species regulatory analysis of osteosarcoma to reduce clinical trial failure rates
Authors: Torabi Tina Salehi , Gottipati Soumya , Kahveci Tamer , Graim Kiley
Published: May 2022

Osteosarcoma is a rare pediatric cancer characterized by poor prognosis and a high likelihood of metastasis, for which no systemic treatments have been successfully developed in the past 30 years [1]. The lack of effective biologically relevant osteosarcoma tumor models is a significant obstacle to the development of effective therapeutics [2]. Therefore, developing a framework that addresses this issue is essential in further advancing therapeutics studies. We postulate that a comparative genomics approach, evaluating whole-transcriptome osteosarcoma response in species closely related to humans, would highlight immune and other differences in each species that will better guide the design of human therapeutics. To investigate this, we compile RNA-seq data from studies of mice, human, and canine osteosarcoma [3], and perform an integrated analysis of disease in these three species. We build a tri-species multi-layer network of regulatory interactions in osteosarcomas to identify evolutionary links between osteosarcomas. Each layer of our network represents the interactions in one species, and the integrated network captures interactions preserved across species. We perform enrichment analysis on these networks and statistically evaluate differences between the topologies of the regulatory networks of these three species, investigating the functional impact of species-specific interactions and how each affects drug response. Additionally, we survey the literature to identify mutations in osteosarcomas from each species, and calculate diffusion scores for mutated genes in each layer of the network compared to genes mutated in osteosarcoma. As future work, we aim to utilize our comparative genomics approach and leverage the differences between interaction networks of related species to compute the likelihood of identifying early-stage therapeutic trials that will fail in later stages, thus avoiding costly experiments and guiding drug development.

Citation Format: Tina Salehi Torabi, Soumya Gottipati, Tamer Kahveci, Kiley Graim. Multi-species regulatory analysis of osteosarcoma to reduce clinical trial failure rates [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A020.
Abstract A028: Selective pressures on bone cancer evolution and treatment resistance emerging from the interactions with the bone ecosystem
Authors: Basanta David , Lynch Conor , Miller Anna , Bishop Ryan
Published: May 2022

The bone is the organ of origin of several types of cancer including multiple myeloma, as well as a host to many metastatic lesions such as those characterizing prostate and breast cancer. The evolutionary dynamics that drive primary and metastatic progression in the bone, as well as those that explain the emergence of resistance to treatments such as proteosome inhibitors and hormonal deprivation therapies, result from the interactions between the tumor and the bone ecosystem. Models that can capture the complex ecological interactions in the bone are key to define the selective pressures underpinning somatic evolution in the bone. Our approach combines computational agent-based models with both in vitro and pre-clinical models in order to shed lights on some open questions in regard to tumor-stromal interactions. As well as the integration of biological and computational models, our approach is hypotheses-driven and captures the homeostasis of the bone that emerges from the interactions of key cellular species such as osteoblasts and osteoclasts. We have explored our models to investigate explore how prostate cancer cells can successfully initiate metastases in the bone, novel therapeutic approaches to treat bone metastatic prostate cancer, explore the emergence of treatment resistance in multiple myeloma and tease apart the contribution of environmentally-mediated drug resistance from cell-intrinsic resistance to proteosome inhibitors.

Citation Format: David Basanta, Conor Lynch, Anna Miller, Ryan Bishop. Selective pressures on bone cancer evolution and treatment resistance emerging from the interactions with the bone ecosystem [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A028.
Abstract A034: Bayesian adaptive design for phase I drug combination trials
Authors: Yuan Ying , Liu Suyu
Published: May 2022

Drug combination therapy is the most commonly used approach to overcome acquired resistance to cancer therapy. Designing phase I drug combination trials faces several challenges beyond the conventional single-agent dose escalation studies, e.g., two-dimensional dose space and partial order in toxicity. In this presentation, we will overview novel Bayesian adaptive designs for drug combination trials. In particularly, we will focus on model-assisted designs that are simply to implement, while yielding superior operating characteristics. Trial example and software will be provided to illustrate the application of the novel designs.

Citation Format: Ying Yuan, Suyu Liu. Bayesian adaptive design for phase I drug combination trials [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A034.
Abstract B007: Design and construction of evolutionary-guided "selection gene drive" therapy
Authors: Leighow Scott M. , Inam Haider , Pritchard Justin R.
Published: May 2022

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR014) of the Conference Proceedings.

Citation Format: Scott M. Leighow, Haider Inam, Justin R. Pritchard. Design and construction of evolutionary-guided "selection gene drive" therapy [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B007.
Abstract B009: Integrating mathematical modelling and wet-lab experiments to examine the scope for adaptive treatment scheduling of PARP inhibitors in ovarian cancer
Authors: Strobl Maximilian , Damaghi Mehdi , Martin Alexandra , Byrne Samantha , Robertson-Tessi Mark , Gatenby Robert , Wenham Robert , Maini Philip , Anderson Alexander R.A.
Published: May 2022

PARP inhibitors (PARPis) represent a great advancement in the treatment of ovarian cancer, yet these drugs often fail after a few months due to emerging drug resistance. A recent clinical trial in prostate cancer showed that evolutionary-inspired, adaptive drug scheduling significantly delayed time to progression. This approach adaptively skipped treatment to maintain a pool of drug-sensitive cells that suppressed resistant cells through competition. Here, we present results from a combined modelling and experimental study in which we investigated whether adaptive therapy could delay resistance to the PARPi olaparib in ovarian cancer.We performed a series of in vitro experiments in which we used Incucyte Zoom time-lapse microscopy to characterize the cell population dynamics under different PARPi schedules. Leveraging these data we developed an ordinary differential equation mathematical model of treatment response, and used this model to test different plausible adaptive treatment schedules. Our model can accurately predict the in vitro treatment dynamics, even to new schedules, and suggests that treatment modifications need to be carefully timed, or one risks losing control over tumor growth, even in the absence of any resistance. This is because multiple rounds of cell division are required for cells to acquire sufficient DNA damage to induce apoptosis. As a result, adaptive therapy algorithms that modulate treatment but never completely withdraw it are predicted to perform better in this setting than strategies based on treatment interruptions. Subsequent experiments confirm this prediction in vivo. To conclude, we present preliminary work aiming at investigating the scope for clinical translation of our results by confronting our model with longitudinal CA-125 data from 53 ovarian cancer patients receiving olaparib at Moffitt. Overall, this study contributes to a better understanding of the impact of scheduling on treatment outcome for PARPis, and showcases some of challenges involved in developing adaptive therapies for new treatment settings.

Citation Format: Maximilian Strobl, Mehdi Damaghi, Alexandra Martin, Samantha Byrne, Mark Robertson-Tessi, Robert Gatenby, Robert Wenham, Philip Maini, Alexander R.A. Anderson. Integrating mathematical modelling and wet-lab experiments to examine the scope for adaptive treatment scheduling of PARP inhibitors in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B009.
Abstract B015: Eco-evolutionary dynamics of poly-aneuploid cancer cells: A life history model
Authors: Bukkuri Anuraag , Pienta Kenneth J. , Austin Robert H. , Hammarlund Emma U. , Amend Sarah R. , Brown Joel S.
Published: May 2022

Despite major advances in cancer research over the last several decades, advanced cancers largely remain incurable due to the evolution of resistance. Recent experimental evidence suggests that a poly-aneuploid cancer cell (PACC) state may contribute to the emergence of therapeutic resistance by allowing cancer cells to avoid the effects of and adapt to extreme environmental stressors. The PACC state is enabled when aneuploid cells undergo whole genome doubling but subsequently bypass mitosis, cytokinesis, or both. We create a novel mathematical framework for modeling the eco-evolutionary dynamics of state-structured populations and use this framework to construct a model of cancer populations with an aneuploid and a PACC state. Using in silico simulations, we explore how the PACC state allows cancer cells to 1) survive extreme environmental conditions by exiting the cell cycle after S phase and protecting genomic material and 2) aid in adaptation to environmental stressors by increasing the cancer cell's evolvability (ability to generate heritable variation) through the increase in genomic content that accompanies polyploidization. In doing so, we demonstrate the ability of the PACC state to contribute to therapeutic resistance and stress the importance of targeting PACC populations for improved therapeutic outcomes.

Citation Format: Anuraag Bukkuri, Kenneth J. Pienta, Robert H. Austin, Emma U. Hammarlund, Sarah R. Amend, Joel S. Brown. Eco-evolutionary dynamics of poly-aneuploid cancer cells: A life history model [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B015.
Abstract IA006: Somatic mutation in normal tissues
Authors: Martincorena Iñigo
Published: May 2022

Somatic mutations underpin cancer development and have been speculated to contribute to ageing and a range of diseases. Over the past decade, the ability to sequence cancer genomes has transformed our understanding of the genetics and evolution of a wide range of cancers. However, owing to technical limitations, much less is known about the earliest steps of cancer and how cells in our tissues accumulate mutations during normal ageing. In this talk, I will summarize our recent work to unravel the extent of somatic mutation and clonal selection in normal tissues. I will also discuss how recent technological developments are opening new frontiers in this nascent field.

Citation Format: Iñigo Martincorena. Somatic mutation in normal tissues [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA006.
Abstract IA007: Outcompeting cancer in the intestine
Authors: Vermeulen Louis
Published: May 2022

Cancers develop in a stepwise fashion as mutations in oncogenes and tumor suppressor genes accumulate. The mutations provide the cells in which they occur typically an advantage over the surrounding wild type neighbors, resulting in clonal expansion. Understanding the nature of the competitive benefit of oncogenic cells might result in the identification of targets for prevention of cancer. In particular in individuals affected by hereditary cancer syndromes, in which the initiating mutations are well-described, this is a promising strategy. I will discuss our work on intestinal carcinogenesis and the impact on stem cell properties of mutations associated with familial cancer syndromes affecting the gut. In particular I will discuss how inactivation of the tumor suppressor gene APC, which is affected in individuals suffering from Familial Adenomatous Polyposis (FAP), generates supercompetitor cells that actively suppress their neighbors. As we will see, the uncovered mechanism directly suggests a potent chemopreventive strategy that is currently being tested in a proof-of-concept clinical trial in FAP individuals.

Citation Format: Louis Vermeulen. Outcompeting cancer in the intestine [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA007.
Abstract IA023: Selection for a glycolytic phenotype
Authors: Damaghi Mehdi
Published: May 2022

In early breast carcinogenesis, neoplastic cells grow in multiple layers towards the lumens of ducts, which subjects the periluminal cells to harsh conditions of low oxygen, low pH, and nutrient deprivation. Adaptation to these harsh conditions is a pre-requisite for survival of incipient tumor cells and also responsible for selecting cells with a more aggressive phenotype. Based on the first principle of Darwinian evolution, common phenotypes of cancer cells must have conferred a selective advantage at some point during their evolutionary trajectory. Adaptations are initially acute and reversible, but eventually Darwinian selection results in cells with hardwired phenotypes. A prominent example of this is aerobic glycolysis, or the Warburg Effect (WE), wherein cells are hard-wired to ferment glucose, even in the presence of oxygen. WE provides and evolutionary advantage which leads to higher fitness of the cancer cells, who have acquired mechanisms of adaptation, such as autophagy and lysosome redistribution. Notably, a WE is highly correlated with a cancer’s metastatic potential and poor outcome. Hence, a major question in carcinogenesis is: “What are the mechanisms by which a harsh microenvironment eventually selects for hard-wired (heritable) phenotypes, such as a WE?”. Rather than simply selection of pre-existing phenotypes, we contend that the microenvironment actively induces phenotypic diversity through a systematic set of epigenetic and genetic alterations.

Citation Format: Mehdi Damaghi. Selection for a glycolytic phenotype [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA023.
Abstract IA024: The role of the epigenome and phenotypic plasticity in colorectal cancer evolution
Authors: Graham Trevor A.
Published: May 2022

The evolutionary dynamics of colorectal metastasis and the role of the epigenome in disease progression remain to be fully determined. We have used multi-region, multi-omic profiling (DNA, RNA and chromatin), together with computational modelling, of a prospectively collected cohort of primary CRCs (pCRCs) and DNA and RNA analysis of a retrospective series of metastatic CRCs (mCRCs) to define pCRC biology and track clonal evolution from primary tumour to metastasis. Computational analysis of multi-region sequencing data provided a sensitive test confirming subclonal selection is rare in pCRCs. We detected substantial epigenetic rewiring at the outset of pCRC formation, implicating changes in chromatin accessibility in the initial genesis of CRCs. Using DNA to trace clonal ancestry and overlaying RNA to measure gene expression phenotypes, we observe widespread gene expression changes without underlying clonal selection, indicative that pCRC cells are phenotypically plastic. In mCRCs, we observe that the karyotype of the primary tumour is often not substantially modified in metastasis, across multiple organs, through treatment and over substantial periods of time. This is suggestive that stabilising selection, acting on copy number alterations, constrains karyotype evolution. Paired analysis of DNA and RNA in metastasis indicate that the phenotypic plasticity persists during metastatic spread. Epigenetic rewiring and phenotypic plasticity play potentially causative roles in the genesis and progression of colorectal cancer.

Citation Format: Trevor A. Graham. The role of the epigenome and phenotypic plasticity in colorectal cancer evolution [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA024.
Abstract PR008: Immunosuppressive niche engineering at the onset of human colorectal cancer
Authors: Gatenbee Chandler D. , Baker Ann-Marie , Schenck Ryan O. , Strobl Maximilian , West Jeffrey , Robertson-Tessi Mark , Graham Trevor A. , Anderson Alexander R.A.
Published: May 2022

The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently detected and surgically removed. Here, we demonstrate a key role for the immune response in tumor initiation by studying tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and multi-region exome sequencing and neoantigen prediction in a total of 62 patient samples. Modelling indicates there are several potential routes to malignancy, each of which uniquely sculpts tumor ecology and intra-tumor antigenic heterogeneity (aITH). In patient samples, the immune microenvironment was characterized using the spatial distribution of 17 markers across registered whole-slide images, as well as patterns of intra-lesion aITH measured using multi-region exome sequencing and neoantigen prediction. The patient data were best described by a model where adenomas that become immunogenic early on do not progress to CRC because they are under immune control; progression therefore proceeds in adenomas with low immunogenicity. In these tumors, immune suppression is initially low, but gradually an immunosuppressive niche that is depleted in CD8+ cytotoxic T cells expands. There was little evidence for immune blockade (PD-L1 expression) in tumor initiation or progression. These results suggest that re-engineering the immunosuppressive niche may prove to be an effective immunotherapy in CRC.

Citation Format: Chandler D. Gatenbee, Ann-Marie Baker, Ryan O. Schenck, Maximilian Strobl, Jeffrey West, Mark Robertson-Tessi, Trevor A. Graham, Alexander R.A. Anderson. Immunosuppressive niche engineering at the onset of human colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR008.
Large Parathyroid Tumor 8 Years after Thyroid Surgery: A Case Report
Authors: Ratniece Madara , Tauvena Elina , Pavlovics Sergejs , Niciporuka Rita , Liepa Mara , Prieditis Peteris , Ozolins Arturs , Gardovskis Janis , Radzina Maija , Narbuts Zenons
Published: May 2022

This report represents an unusually large parathyroid carcinoma (PC) mimicking thyroid nodule recurrence after hemithyroidectomy. PC is a rare endocrine malignancy accounting for less than 1% of hyperparathyroidism cases. This is the first case report where contrast-enhanced ultrasound (CEUS) was performed on a PC. A 63-year-old female presented with an enlarged mass on the left side of the neck. In 2012, left-side hemithyroidectomy was done due to a benign goiter. In 2020, laboratory analysis showed markedly elevated parathyroid hormone and calcium. Multiparametric neck ultrasonography was performed including B-mode, color Doppler, shear wave elastography, and CEUS. Computed tomography revealed an irregular mass in proximity to the trachea, esophagus, and dislocation of the common carotid artery. Perifocal fatty tissue appeared normal. Scintigraphy displayed a suspected parathyroid tumor or a suspected left lobe nodule of thyroid. Based on the biochemical diagnosis of primary hyperparathyroidism and radiological examinations, a suspected parathyroid tumor was considered. Intraoperative findings demonstrated an unusually large 9 × 6 cm tumor (84 g) adjacent to the common carotid artery anterolaterally and the recurrent laryngeal nerve medially. Pathohistological examination revealed a tumor solid in structure, with focal necrosis penetrating the capsule. Immunohistochemical analysis was positive for chromogranin, CD56, and Ki-67 (8–10%) and negative for CK20 and CK7. The morphological and immunohistochemical results correspond to PC. PC is a challenging diagnosis requiring a multidisciplinary approach, especially in the case of previous neck surgery. The only curative treatment for PC is radical surgery. Lifelong monitoring of PCs is mandatory due to the high recurrence rate.
Intermittent and Unilateral Chorioretinal Folds due to Combined Chiari 1 Malformation and Basilar Invagination
Authors: Tesfaw Alemu Kerie , Batra Nikhil N. , Phan Cong T. , Woldegiorgis Workayehu Kebede , Melesse Mulusew Asferaw
Published: May 2022

We report the case of a 35-year-old female with combined Chiari 1 malformation and basilar invagination, who presented with intermittent conjunctival chemosis and unilateral chorioretinal folds that were temporally correlated. She denied any flashes, floaters, eye redness, or pain. She also denied nausea or vomiting. Clinical exam and optical coherence tomography imaging revealed conjunctival chemosis and chorioretinal folds in the left eye. Subsequent magnetic resonance imaging of the brain and the orbits were consistent with combined Chiari 1 malformation and basilar invagination. The unilateral and intermittent chorioretinal folds and conjunctival chemosis presentation of combined Chiari 1 malformation and basilar invagination is unusual. To the best of our knowledge, this is the first case to be reported with this unique clinical presentation. It is most important to be aware that unilateral and intermittent chorioretinal folds associated with conjunctival chemosis may be signs of intracranial disease.