bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of Edge Computing and Blockchain in Smart Agriculture System
Authors: Feng Yuhan
Published: May 2022

The development of Internet technology provides a lot of convenience for the promotion of smart agriculture. At present, smart agriculture has gradually realized unmanned and automatic management, which can realize monitoring, supervision, and real-time image monitoring. However, the data in smart agriculture system cannot be guaranteed to be complete and vulnerable to attack. Based on this, this paper studies and analyzes the application of edge computing and blockchain in smart agriculture systems. Based on the simple analysis of the development of smart agriculture, the edge computing framework and the advantages of blockchain are used to build the framework system of smart agriculture. The classical architecture of edge computing and the confidentiality of blockchain are used to realize the analysis and storage of data. In view of the shortcomings of crop image overlap detection, it is proposed to detect the overlapping area and determine the feature points to analyze the image based on the edge computing and hash algorithm. In terms of data integrity, based on the advantages of blockchain, an edge data detection method based on short signature is proposed, and experiments are designed to analyze the accuracy and effectiveness of the algorithm. The simulation results show that the image mosaic algorithm can extract the contour information of the image and realize the fast image matching. The edge data integrity calculation based on short signature can meet the requirements and shorten the response time.
Construction of Human Resource Management System Based on Enterprise Data Analysis Model
Authors: Deng Hua , Huang Haiying
Published: May 2022

With the development of social economy and the increasing maturity of information technology, we should actively explore and carry out digital transformation practice in the field of human resources to achieve accurate, scientific, and standardized management of the core management affairs of enterprises, in order to meet the needs of enterprises for human resource management and help enterprises to bring human resource management into the development channel of data. This design uses the human resource data analysis method and designs the human resource data analysis model that meets the actual demand. Based on this model, a data statistical analysis subsystem is designed to construct the human resource management system architecture, and the overall structure of human resources and the division of functional modules are described in detail. Through data analysis model to analyze employee salary, the results show that basic salary accounts for 58% of the salary structure, and the amount of performance salary accounts for 38% of the total amount of salary. Compensation and welfare are closely related to labour cost, and the colour of labour cost proportion represents the quadrant position, which can effectively inform and warn information. The data analysis model provides the basis for human resource management and lays the data foundation for enterprises to formulate human resource management policies.
Insights into the Major Metabolites Involved in the Underground Floral Differentiation of Erythronium japonicum
Authors: Wang Hongtao , Zhu Junyi , Zhang Lifan , Shen Peng , Xiao Zi , Zhao Rengui
Published: May 2022

Background. Erythronium japonicum Decne (Liliaceae) is an early spring ephemeral with an underground initial floral differentiation stage. The flowering mechanism is crucial in ornamental plants due to the associated economic value. Therefore, this study is aimed at exploring the metabolic landscape during floral differentiation, including flower primordium, perianth, stamen, and the pistil differentiation period, in E. japonicum coupled with a conjoint analysis of the metabolome and transcriptome. Using ultraperformance liquid chromatography‐tandem mass spectrometry, we identified 586 metabolites from 13 major metabolite classes. Comparative metabolomics between different floral developmental stages revealed several abundant metabolites during the respective phases. Upaccumulation of p‐coumaroylputrescine, scopoletin, isorhoifolin, cosmosiin, genistin, and LysoPC 15 : 0 emphasized the significance of these compounds during flower development. Furthermore, previously identified DEGs, viz., EARLY FLOWERING 3, Flowering locus K, PHD finger-containing protein, and zinc finger SWIM domain-containing protein for floral differentiation, depicted a high correlation with lipid, flavonoid, and phenolics accumulation during floral developmental stages. Conclusions. Together, the results improve our interpretation of the underground floral development in E. japonicum.
Characterization of Fabricated Gold‐Doped ZnO Nanospheres and Their Use as a Photocatalyst in the Degradation of DR‐31 Dye
Authors: Verma Neha , Jagota Vishal , Alguno Arnold C. , Alimuddin  , Rakhra Manik , Kumar Pawan , Dugbakie Betty Nokobi
Published: May 2022

Water contamination is a significant issue in the modern day, caused by the textile dying business, and it has a detrimental impact on living organisms. We report on the manufacture of gold‐doped ZnO nanospheres using a simple heat treatment approach and the use of ZnO nanoparticles as photocatalysts for the degradation of methyl orange dye. To increase this degrading activity, Au was utilised as a modifier, and their temperature quenching effect was noticed. One of the most efficient electron grabbers in the conduction band is Au ion. The novelty of this recent research is that it has found that anatase to rutile phase transformation is promoted, and the highest transformation was achieved by using 1.0% of Au, which proves Au‐doped ZnO‐based nanoparticles are best for this degradation of dyes. The structural, morphological, optical, electrical, and photocatalytic characteristics of the synthesised nanocatalysts were determined. These nanoparticles have a grain size of 45‐75 nm. Photocatalytic activity was investigated using UV‐Vis spectra, and a significant absorption peak of about 482 nm was discovered. With increasing frequency, the dielectric constant and frequency of the produced nanoparticles drop. The kinetic analysis yields a rate constant of 0.0165 min-1 for nanosphere‐like particles. At a concentration of 1% Au, the produced nanoparticles degrade the dye completely in 150 minutes when exposed to UV light.
Role and Utility of Mixed Reality Technology in Laparoscopic Partial Nephrectomy: Outcomes of a Prospective RCT Using an Indigenously Developed Software
Authors: Gadzhiev Nariman , Semeniakin Igor , Morshnev Aleksandr , Alcaraz Antonio , Gauhar Vineet , Okhunov Zhamshid
Published: May 2022

Objective. To develop a software for mixed reality (MR) anatomical model creation and study its intraoperative clinical utility to facilitate laparoscopic partial nephrectomy. Materials and Methods. After institutional review board approval, 47 patients were prospectively randomized for LPN into two groups: the control group (24 patients) underwent operation with an intraoperative ultrasound (US) control and the experimental group (23 patients) with smart glasses HoloLens 2 (Microsoft, Seattle, WA, USA). Our team has developed an open-source software package called “HLOIA,” utilization of which allowed to create and use during surgery the MR anatomical model of the kidney with its vascular pedicle and tumor. The study period extended from June 2020 to February 2021 where demographic, perioperative, and pathological data were collected for all qualifying patients. The objective was to assess the utility of a MR model during LPN and through a 5-point Likert scale questionnaire, completed by the surgeon, immediately after LPN. Patient characteristics were tested using the chi-square test for categorical variables and Student’s t-test or Mann–Whitney test for continuous variables. Results. Comparison of the variables between the groups revealed statistically significant differences only in the following parameters: the time for renal pedicle exposure and the time from the renal pedicle to the detection of tumor localization (

p
<
0.001

), which were in favor of the experimental group. The surgeon’s impression of the utility of the MR model by the proposed questionnaire demonstrated high scores in all statements. Conclusions. Developed open-source software “HLOIA” allowed to create the mixed reality anatomical model by operating urologist which is when used with smart glasses has shown improvement in terms of time for renal pedicle exposure and time for renal tumor identification without compromising safety.
Delusions of a Magic Man Shared by Codependent Twin Sisters
Authors: Shaikh Anam , Lai Randy
Published: May 2022

Folie à deux has been called double insanity or shared psychotic disorder. In this report, we describe the case of twin sisters who presented with identical delusions. Both sisters reported a “magic man” lived in their bodies and made them weak. Both underwent treatment with similar medications: the primary case with risperidone and the secondary case with paliperidone. The delusions of the primary case slowly abated with antipsychotics, whereas those of the secondary case completely resolved within a short duration after admission when the twins were separated in different hospital units.
Clinical Evaluation of Antiphospholipase A2 Receptor IgG4 level and Its IgG4‐to‐IgG Ratio Based on Quantitative Immunoassays in Idiopathic Membranous Nephropathy
Authors: Zhang Yi , Huang Yiqing , Huang Biao , Chen Xiaolei , Zhou Bin , Zou Pei , Wang Liang , Liu Xiaobin , Sheng Huiming , Xie Minhao
Published: May 2022

Background. Phospholipase A2 receptor (PLA2R), located at the membrane of glomerular podocyte, is the major autoantigen of idiopathic membranous nephropathy (IMN), and its antibodies with a predominant IgG4 subclass lead to pathological lesions. Further studies could be performed to validate the clinical values of PLA2R‐IgG, PLA2R‐IgG4, and PLA2R‐IgG4‐to‐IgG ratios, as ultrasensitive and quantitative immunoassays for PLA2R antibodies have been well established in our previous work. Methods. A cohort of 58 IMN patients, 30 of whom were followed from 3 to 42 months, was assessed for serum PLA2R‐IgG and ‐IgG4 levels, and the ratio of PLA2R‐IgG4/‐IgG combined with relative clinicopathological indicators. Results. Serum PLA2R‐IgG4 level was significantly correlated with glomerular PLA2R staining. In addition, it was strongly correlated with PLA2R‐IgG and its ratio. PLA2R‐IgG and ‐IgG4 levels were both correlated with high‐density lipoprotein and erythrocyte sedimentation rates. The ratio at the first diagnosis can predict the remission, and its efficacy overmatched PLA2R‐IgG4. In the survival curves, negative results for the ratio or PLA2R‐IgG4 at the first diagnosis demonstrated higher remission rates. Conclusion. Serum PLA2R‐IgG4 concentration may replace renal PLA2R immunohistochemistry in IMN diagnosis. We propose that the PLA2R‐IgG4‐to‐IgG ratio and PLA2R‐IgG4 could be novel indicators for remission prediction in clinical practice.
Anticonvulsant Activity of trans‐Anethole in Mice
Authors: da Guedes Erika , Ribeiro Leandro Rodrigo , Carneiro César Alves , Santos Aline Matilde Ferreira , Brito Monteiro Álefe , de Andrade Humberto Hugo Nunes , Castro Ricardo Dias , Barbosa Flávio Freitas , Barbosa Filho José Maria , de Almeida Reinaldo Nóbrega , Stiebbe Salvadori Mirian Graciela
Published: May 2022

Epilepsy is a chronic neurological disorder affecting 1‐2% of world population, and one‐third of patients are refractory to pharmacological treatment. This fact has stimulated research for new antiepileptic drugs and natural products have been an important source. trans‐Anethole (TAN) is a phenylpropanoid, component of some essential oils, extracted from plants, and its effects have been little studied. Therefore, this study is aimed at investigating the TAN effect in classic seizure models and evaluate the electroencephalographic (EEG) profile of animals treated with this substance. For this, Swiss male mice (Mus musculus) were used, and the lethal dose was evaluated and subsequently submitted to the test maximal electroshock (MES), the pentylenetetrazole‐ (PTZ) induced seizure test, and the EEG profile. Initially, the LD50 for TAN was estimated in 1000 mg/kg (i.p.) dose and there was no sign of acute toxicity or death. In the MES test, TAN 300, i.p. (12.00 ± 2.9 s) and 400 mg/kg, i.p. (9.00 ± 4.4 s) doses was able to decrease tonic seizures duration induced by electric discharge (0.5 mA, 150 pulses/s, for 0.5 s). In the PTZ test (75 mg/kg, i.p.), TAN 400 mg/kg, i.p. increased the latency to myoclonic jerks (80.0 (56.0–134.0)), the latency totonic‐clonic seizures (900.0 (861.0–900.0) and decrease seizure duration (0.0 (0.0–10.0)). No deaths were found in this groups compared to vehicle. EEG analysis showed an amplitude decrease of waves (ratio of baseline) in TAN 300 (1.82 ± 0.23) and 400 mg/kg (1.06 ± 0.16) groups. In this way, TAN at 400 mg/kg was able to inhibit and/or attenuate seizures by increasing the time for the onset of spasms and convulsions, as reducing the duration of seizures. The EEG profile corroborate with this results showing a reduction in the amplitude of waves compared to the PTZ group. Thus, TAN showed an anticonvulsant effect in all experimental models performed, behavioral and electroencephalographic.
Liver Colonization by Colorectal Cancer Metastases Requires YAP-Controlled Plasticity at the Micrometastatic Stage
Authors: Heinz Maria C. , Peters Niek A. , Oost Koen C. , Lindeboom Rik G.H. , van Voorthuijsen Lisa , Fumagalli Arianna , van der Net Mirjam C. , de Medeiros Gustavo , Hageman Joris H. , Verlaan-Klink Ingrid , Borel Rinkes Inne H.M. , Liberali Prisca , Gloerich Martijn , van Rheenen Jacco , Vermeulen Michiel , Kranenburg Onno , Snippert Hugo J.G.
Published: May 2022

Micrometastases of colorectal cancer can remain dormant for years prior to the formation of actively growing, clinically detectable lesions (i.e., colonization). A better understanding of this step in the metastatic cascade could help improve metastasis prevention and treatment. Here we analyzed liver specimens of patients with colorectal cancer and monitored real-time metastasis formation in mouse livers using intravital microscopy to reveal that micrometastatic lesions are devoid of cancer stem cells (CSC). However, lesions that grow into overt metastases demonstrated appearance of de novo CSCs through cellular plasticity at a multicellular stage. Clonal outgrowth of patient-derived colorectal cancer organoids phenocopied the cellular and transcriptomic changes observed during in vivo metastasis formation. First, formation of mature CSCs occurred at a multicellular stage and promoted growth. Conversely, failure of immature CSCs to generate more differentiated cells arrested growth, implying that cellular heterogeneity is required for continuous growth. Second, early-stage YAP activity was required for the survival of organoid-forming cells. However, subsequent attenuation of early-stage YAP activity was essential to allow for the formation of cell type heterogeneity, while persistent YAP signaling locked micro-organoids in a cellularly homogenous and growth-stalled state. Analysis of metastasis formation in mouse livers using single-cell RNA sequencing confirmed the transient presence of early-stage YAP activity, followed by emergence of CSC and non-CSC phenotypes, irrespective of the initial phenotype of the metastatic cell of origin. Thus, establishment of cellular heterogeneity after an initial YAP-controlled outgrowth phase marks the transition to continuously growing macrometastases.

Significance:

Characterization of the cell type dynamics, composition, and transcriptome of early colorectal cancer liver metastases reveals that failure to establish cellular heterogeneity through YAP-controlled epithelial self-organization prohibits the outgrowth of micrometastases.

See related commentary by LeBleu, p. 1870
Abstract A001: Modeling cancer’s ecological and evolutionary dynamics
Authors: Bukkuri Anuraag , Pienta Kenneth J. , Hockett Ian , Austin Robert H. , Hammarlund Emma U. , Amend Sarah R. , Brown Joel S.
Published: May 2022

We present a theoretical modeling framework, called the G function, to understand cancer speciation, diversification, and environmental adaptation. The G function integrates both the ecology and evolution of cancer and has been used in evolutionary ecology. However, the G function has not yet been widely applied to problems in cancer. Here, we build the G-function framework from fundamental Darwinian principles and discuss how cancer is inherently an evolutionary game. We begin with a simple model of cancer growth and add on components of cancer cell competition and drug resistance. To aid in exploration of eco-evolutionary modeling with this approach, we also present a user-friendly online tool. We argue that G-functions are useful to understand the games cancer plays in a biologically mechanistic fashion.

Citation Format: Anuraag Bukkuri, Kenneth J. Pienta, Ian Hockett, Robert H. Austin, Emma U. Hammarlund, Sarah R. Amend, Joel S. Brown. Modeling cancer’s ecological and evolutionary dynamics [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 A001.
Abstract A005: Transcriptional profiling of tumor heterogeneity and chemoresistance in small cell lung cancer
Authors: Wollenzien Hannah , Afeworki Yohannes , Kareta Michael S.
Published: May 2022

Small Cell Lung Cancer (SCLC) is often a heterogeneous tumor, where multiple populations of phenotypically different cells exist and contribute differentially to tumor dynamics. This tumor is characterized by a very low 2- year survival rate, high metastatic rates, and rapid acquisition of chemoresistance. Beyond first-line chemotherapy, targeted treatment options are scarce, and none take in to consideration the complex genetics of the tumor. The heterogeneous nature of this tumor makes it difficult to study and to treat, as current attempts to understand tumor dynamics use a bulk approach that averages the contribution of all cells within a tumor. This work uses a cellular barcoding lineage tracing approach combined with single-cell RNA sequencing (scRNA-seq) to understand tumor heterogeneity and evolution of SCLC in both a xenograft of human SCLC cell lines and an in vivo system using a genetically modified mouse model with alterations in the same driver genes as the majority of humans with SCLC. Tumors are sampled pre-growth, post-growth and metastasis, and pre- and post- chemotherapy. By paring the barcode populations that exist in samples over time, in metastasis, or in chemoresistance, a clonal evolution map of growth, metastasis, and chemoresistance can be generated, based on shared barcodes and convergent or divergent transcriptomic profiles. In validation of scRNA-seq data, we have identified the cancer testis antigens (CTA) PAGE5 and GAGE2A as markers of chemoresistance in human SCLC. CTAs have been successfully targeted in other tumor types and may be a promising avenue for targeted therapy in SCLC. In mouse tumors, we have identified an AP-1-high population of early tumor cells that are maintained throughout the course of the disease. The knowledge gained in this work will pave the way for the identification of new therapeutic targets for SCLC.

Citation Format: Hannah Wollenzien, Yohannes Afeworki, Michael S. Kareta. Transcriptional profiling of tumor heterogeneity and chemoresistance in small cell lung 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 A005.
Abstract A010: Integration of clonal composition and tumor heterogeneity reveals novel evolutionary states and intervention targets in ovarian cancer
Authors: Lahtinen Alexandra , Lavikka Kari , Li Yilin , Jamalzadeh Sanaz , Virtanen Anni , Lehtonen Rainer , Carpén Olli , Hietanen Sakari , Huhtinen Kaisa , Häkkinen Antti , Hynninen Johanna , Oikkonen Jaana , Hautaniemi Sampsa
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 (PR003) of the Conference Proceedings.

Citation Format: Alexandra Lahtinen, Kari Lavikka, Yilin Li, Sanaz Jamalzadeh, Anni Virtanen, Rainer Lehtonen, Olli Carpén, Sakari Hietanen, Kaisa Huhtinen, Antti Häkkinen, Johanna Hynninen, Jaana Oikkonen, Sampsa Hautaniemi. Integration of clonal composition and tumor heterogeneity reveals novel evolutionary states and intervention targets 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 A010.
Abstract A023: Progression and regression dynamics of bivalve transmissible neoplasia in the soft-shell clam (Mya arenaria) after both natural and experimental exposure
Authors: Giersch Rachael M. , Yonemitsu Marisa A. , Hart Samuel F.M. , Metzger Michael J.
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 (PR017) of the Conference Proceedings.

Citation Format: Rachael M. Giersch, Marisa A. Yonemitsu, Samuel F.M. Hart, Michael J. Metzger. Progression and regression dynamics of bivalve transmissible neoplasia in the soft-shell clam (Mya arenaria) after both natural and experimental exposure [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 A023.
Abstract B001: Developing adaptive therapy to suppress the evolution of treatment resistance in high-grade serous ovarian cancer
Authors: Hockings Helen , Lockley Michelle , Graham Trevor , Lakatos Eszter , Huang Weini
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 (PR015) of the Conference Proceedings.

Citation Format: Helen Hockings, Michelle Lockley, Trevor Graham, Eszter Lakatos, Weini Huang. Developing adaptive therapy to suppress the evolution of treatment resistance in high-grade serous 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 B001.
Abstract B004: Adaptive therapy in preclinical models of hormone-refractory breast cancer
Authors: Seyedi Sareh , Maley Carlo
Published: May 2022

The goal of this study was to test whether adaptive therapy works in preclinical mouse models with hormone-refractory breast cancer and compare adaptive therapy with standard therapy. Specifically, we tested whether the drugs gemcitabine and/or capecitabine can control the MCF7 cancer cell line which is resistant to palbociclib and fulvestrant. We treated MCF7 resistant breast cancers growing orthotopically in the mammary fat pads of NSG immunodeficient mice with gemcitabine, capecitabine, or both drugs together. In the combined drug treatment, we switched drugs in every application (every 3 days) (“ping-pong”) or applied the drugs together (in tandem). In both single and multi-drug therapy, we applied drugs by either adjusting their doses or applying intermittently. We measured tumor size by bioluminescence imaging and caliper. We saw a reduction in the tumor burden of most mice treated with adaptive therapy along with prolonging overall survival. We found that the combination of gemcitabine and capecitabine in both intermittent and dose adjustment protocols significantly increased the survival of mice in comparison to standard therapy when we applied the drugs in a ping-pong strategy. The combination therapy in tandem was less successful compared to dose adjustment, but better than standard therapy in increasing overall survival. Moreover, we had several weeks off-treatment in most of the mice when the tumor was under the threshold, therefore lower drug doses were used. Among single drug therapies, capecitabine dose adjustment protocol was better than using both intermittent and the maximum tolerated dose in terms of increasing overall survival of mice and accumulating less dose of the drug. However, the capecitabine intermittent treatment was better compared to the capecitabine maximum tolerated dose. In contrast, there were no significant differences between adaptive protocols and standard therapy. However, in both intermittent and dose adjustment protocols we had several weeks off-treatment in most of the mice, so lower drug doses were used. In conclusion, we found that lower drug doses can be used under adaptive therapy, once the tumor is controlled. We had several weeks off- treatment for some cases and we saw a continued decline in tumor size. Overall, adaptive therapy strategies could prolong progression-free survival besides reduction in the tumor burden.

Citation Format: Sareh Seyedi, Carlo Maley. Adaptive therapy in preclinical models of hormone-refractory breast 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 B004.
Abstract B005: Uncovering polygenic signatures of Ewings Sarcoma drug sensitivity during the evolution of resistance
Authors: Lin-Rahardja Kristi , Scarborough Jessica , Hitomi Masahiro , Scott Jacob
Published: May 2022

Evolution of chemotherapeutic resistance can cause treatment failure in patients with metastatic Ewings sarcoma (EWS). As resistance to the first-line therapy evolves, there is potential for the tumor to develop sensitivities to other chemotherapeutic agents besides the active treatment. This concept is known as collateral sensitivity, and it presents an opportunity for medical providers to plan more effective treatment regimens. However, it can be difficult to predict due to the stochastic nature of evolution. By analyzing gene expression patterns among independent populations of an EWS cell line that have repeatedly evolved collateral responses, we aim to extract a collection of gene signatures, or sets of genes, that will predict states of collateral sensitivity against various existing chemotherapies. To accomplish this, we will treat independently evolving replicates of an EWS cell line (A673) with the standard of care therapy (alternating combinations of vincristine, doxorubicin, cyclophosphamide, and etoposide and cyclophosphamide) to evolve resistance. Throughout this treatment regimen, we will regularly screen for collateral sensitivity against 128 chemotherapeutic agents and perform bulk RNA-sequencing. When collateral sensitivity against a drug is observed in multiple replicates, we will utilize the RNA-sequencing data to extract gene signatures using differential expression analysis. The signatures will then be validated using patient-derived xenografts collected in our lab as well as from collaborators. When completed, the sizable archive of sensitivity signatures we expect to assemble could greatly streamline the process of treatment planning for EWS patients, especially those with advanced disease. When a patient's response to primary therapy begins to decline, RNA- sequencing can be performed on a tumor biopsy, gene expression patterns can be compared with the validated signature library, and the most appropriate drug for the individual patient can be determined and used for subsequent treatment. This proposed method of treatment planning mitigates the need for excessive treatment regimens that are not guaranteed to be effective for every patient, thereby expanding the reach of precision medicine and potentially improving outcomes for EWS patients.

Citation Format: Kristi Lin-Rahardja, Jessica Scarborough, Masahiro Hitomi, Jacob Scott. Uncovering polygenic signatures of Ewings Sarcoma drug sensitivity during the evolution of resistance [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 B005.
Abstract B006: Evolutionary Tumor Board: Implementing dynamic personalized therapy using evolutionary theory and mathematical modeling for clinical decision support
Authors: Robertson-Tessi Mark , Brown Joel , Poole Maria , Luddy Kimberly , Marusyk Andriy , Gallaher Jill , West Jeffrey , Johnson Matthew , Enderling Heiko , Makanji Rikesh , Farinhas Joaquim , Gatenby Robert , Reed Damon , Chung Christine , Anderson Alexander
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 (PR010) of the Conference Proceedings.

Citation Format: Mark Robertson-Tessi, Joel Brown, Maria Poole, Kimberly Luddy, Andriy Marusyk, Jill Gallaher, Jeffrey West, Matthew Johnson, Heiko Enderling, Rikesh Makanji, Joaquim Farinhas, Robert Gatenby, Damon Reed, Christine Chung, Alexander Anderson. Evolutionary Tumor Board: Implementing dynamic personalized therapy using evolutionary theory and mathematical modeling for clinical decision support [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 B006.
Abstract B008: Man vs machine: Crowdsourcing vs deep learning of adaptive therapy strategies
Authors: Bravo Rafael R. , Peterson Brenden K. , Robertson-Tessi Mark , Faissol Daniel M. , Anderson Alexander R.A.
Published: May 2022

Cancer Crusade is a citizen science game in which players design treatment strategies to influence a virtual tumor growth model. The treatment regimens that the players construct are collected and sent to an online database for analysis, which may give insights into clinically effective adaptive strategies. In parallel, a machine learning-based approach was applied to the game to find optimal treatment policies, and the optimized therapy approaches generated are compared to those generated by the human players. For the core game engine in Cancer Crusade, we started with a previously published hybrid cellular automata model of tumor metabolism and growth. The original model was used to study how tumor cells evolve acid-mediated invasion and the impact of treatment on these metabolic processes. We expanded the model by adding more drugs and cell phenotypes, including drug-resistant cells. The game was released on mobile platforms and has been generating data from plays for several years. The treatment strategies were analyzed using dendrogram clustering to find key decision differences and profile their relative performance. We also performed network analysis to observe treatment transitions. These analyses indicated several effective adaptive strategies, which tended to oscillate between chemotherapy and a pro-angiogenic drug, or chemotherapy and a hypoxia-activated prodrug, or combinations of all three of these drugs. These results parallel a machine learning (Q-learning) approach to the problem, which yielded a preferred strategy based on chemotherapy combined with a pro-angiogenic drug. The existence of several human-discovered alternative strategies suggests that in general human players may offer greater variety of successful strategies via citizen science games than Q-learning. The human and machine learning approaches also excelled in different areas. Human players tended to use less drug overall, and perform best on less aggressive tumors, while the Q-learning approach used more drug overall and performed best on more aggressive tumors.

Citation Format: Rafael R. Bravo, Brenden K. Peterson, Mark Robertson-Tessi, Daniel M. Faissol, Alexander R.A. Anderson. Man vs machine: Crowdsourcing vs deep learning of adaptive therapy strategies [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 B008.
Abstract B016: Selection and reprogramming contribute to the evolution of targeted therapy resistance
Authors: Velde Robert Vander , Shaffer Sydney
Published: May 2022

Targeted therapies provide substantial benefits to cancer patients by shrinking and controlling tumors. However, the long-term efficacy of targeted therapy is limited by the development of resistance. Once a tumor is fully resistant, it continues to grow despite the presence of the targeted therapy, leading to disease relapse in the patient. When the therapy is first applied, a number of studies have now shown that there is initially a selection for cells that are able to tolerate the drug (termed “tolerant cells”). This contrasts with selection of fully resistant cells. More recently our studies have suggested that the transition from tolerance to resistance is not binary and involves multiple changes. These changes can be propelled by the stochastic generation of heritable heterogeneity followed by selection (Darwinian evolution), by long-term changes in signaling networks (reprogramming) and by combinations of these two. The contribution of these factors determines the usefulness of strategies using either evolutionary dynamics (such as reducing population size or changing selective pressures on tumor cells) or therapies that alter cell states (such as inhibiting or activating key signaling nodes). We are using colony assays and developing barcoding techniques to address the role of selection and clonality in the evolution of full resistance to BRAF inhibitors in melanoma from a tolerant state. Early results show a rapid increase in fitness (relative to surviving tolerant cells) suggesting a role for selection immediately after the first selective event. These changes are followed by slow changes that may be the result of mostly reprogramming. This implies that strategies that manipulate evolutionary dynamics are most effective early in resistance evolution while later changes can be manipulated by altering signaling nodes.

Citation Format: Robert Vander Velde, Sydney Shaffer. Selection and reprogramming contribute to the evolution of targeted therapy resistance [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 B016.
Abstract B030: Mimicking the evolution of doxorubicin resistance in triple negative breast cancer
Authors: Pearson Kashenya , Everett Terrence , Rorie Checo J.
Published: May 2022

Chemotherapy resistance presents a major challenge in the treatment of triple negative breast cancer (TNBC), which is characterized by low or no expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor-2 (HER2). Because TNBC tumors do not express these receptors, there has been little to no advancement in the establishment of drug therapies to specifically target this breast cancer subtype. Additionally, unfavorable side effects and drug resistance reveal an urgent need for safer, more effective therapeutic options. In this study, we aim to mimic cancer recurrence by establishing doxorubicin (DOX) resistance in TNBC cell lines, HCC1806 and HCC70 and investigate the effect on cell survival, cell migration, and changes in gene expression. Here we show that TNBC cell growth was sustained after pulse treatments with increasing concentrations of DOX. HCC1806 and HCC70 cells treated with DOX titrants (0.5 µM-2.0 µM) demonstrate cell growth sustainability after 3h treatments. The DOX-treated TNBC cells also demonstrate anti-migratory potential. RNA sequencing analysis show that IL6, TP53, and TNFSF12 are uniquely expressed after 24h exposure to 0.5uM DOX. We plan to further investigate the roles these genes play in chemoresistance. Understanding changes in the gene network, as a result of doxorubicin-resistance, may help to establish biomarkers that could represent targets for drug therapies to overcome chemoresistance in TNBC.

Citation Format: Kashenya Pearson, Terrence Everett, Checo J. Rorie. Mimicking the evolution of doxorubicin resistance in triple negative breast 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 B030.
Abstract B033: 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

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR0081) of the Conference Proceedings.

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 B033.
Abstract B034: Targeting cellular plasticity-driven metabolic adaptation to overcome chemoresistance in GBM
Authors: Ahmed Atique U. , Shireman Jack M. , Atash Fatemeh , Lee Gina , Ali Eunus S. , Saathoff Miranda R. , Park Cheol H. , Savchuk Sol , Baisiwala Shivani , Miska Jason , Lesniak Maciej S. , James C. David , Stupp Roger , Kumthekar Priya , Horbinski Craig M. , Ben-Sahra Issam
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 (PR011) of the Conference Proceedings.

Citation Format: Atique U. Ahmed, Jack M. Shireman, Fatemeh Atash, Gina Lee, Eunus S. Ali, Miranda R. Saathoff, Cheol H. Park, Sol Savchuk, Shivani Baisiwala, Jason Miska, Maciej S. Lesniak, C. David James, Roger Stupp, Priya Kumthekar, Craig M. Horbinski, Issam Ben-Sahra. Targeting cellular plasticity-driven metabolic adaptation to overcome chemoresistance in GBM [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 B034.
Abstract IA001: Harnessing evolutionary dynamics for control and cure of metastatic cancers
Authors: Gatenby Robert
Published: May 2022

Although most metastatic cancers now have at least one effective therapy, evolution of resistance almost invariably leads to treatment failure and patient death. While often viewed as the result of a “resistance mutation,” many cancer cell resistance strategies simply involve increased expression of genes (e.g., xenobiotic metabolism) already in the human genome. Furthermore, clinical treatments to block the resistance mechanism (e.g. the MDR proteins) have generally been unsuccessful reflecting the multiplicity of available strategies. In an evolutionary context, however, the mere presence of a resistant phenotype is not sufficient for treatment failure. Rather, tumor progression requires proliferation of the resistant phenotype at a rate sufficient to produce the billions of cells necessary for clinically evident progressive disease. Importantly, the necessary molecular, cellular, and population dynamics necessary for cancer progression during treatment are deeply connected because there are often significant phenotypic costs from synthesis, maintenance, and operation of the molecular machinery of resistance that can reduce cellular proliferation and invasion particularly in the substrate-poor environment often present in clinical cancers. Evolution-based cancer treatment assumes that resistant phenotypes are invariably present prior to initiation of therapy and seeks to exploit evolutionary dynamics to delay or prevent proliferation of these cells. A specific example of this approach is adaptive therapy which is used in clinical settings in which cure is not achievable. Similar to widely accepted practices in pest management, adaptive therapy reduces or periodically withdraws treatment to maintain a stable population of treatment-sensitive cells that can use their fitness advantage (i.e. absence of the cost of resistance) to suppress proliferation of resistant phenotypes. This approach has been investigated in both pre-clinical and clinical conditions. A clinical trial in metastatic castrate-resistant prostate cancer (mCRPC) has been completed and will be discussed. Finally, when cure from a cancer treatment is possible but rare, evolutionary dynamics, based on observations in Anthropocene extinctions, can theoretically be used to increase the probability of complete eradication of the malignant population.

Citation Format: Robert Gatenby. Harnessing evolutionary dynamics for control and cure of metastatic cancers [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 IA001.
Abstract IA003: Darwinian and non-Darwinian evolution of cancer drug resistance
Authors: Gerlinger Marco
Published: May 2022

Many highly effective cancer drugs are available for the treatment of solid tumors but resistance almost invariably develops. The ability of cancers to acquire drug resistance by Darwinian evolution is widely accepted. Recently, cellular and microenvironmental plasticity were discovered as additional processes that can lead to drug resistance. I will discuss drug resistance evolution in colorectal cancer and show the need for a comprehensive framework that integrates Darwinian and non-Darwinian evolution in order to understand and address drug resistance evolution.

Citation Format: Marco Gerlinger. Darwinian and non-Darwinian evolution of cancer drug resistance [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 IA003.
Abstract IA015: Exploring how competition can be leveraged to improve adaptive therapy in metastatic prostate cancer
Authors: Brady-Nicholls Renee , Enderling Heiko
Published: May 2022

Prostate cancer remains the most prevalent cancer in men in the US. While continuous first-line hormone treatment at maximum tolerable dose is the standard of care, continuous treatment often selects for the resistant phenotypes resulting in castration resistant disease. Second-line hormone therapy options, such as abiraterone acetate (AA), have been proven effective for metastatic castration resistant prostate cancer (mCRPC). Adaptive AA, whereby treatment is cycled on and off using patient-specific treatment triggers, has been shown to be effective at reducing toxicity and prolonging time to progression. It is hypothesized that cycling through treatment allows sensitive cells to competitively suppress resistant cells, thereby increasing the amount of time that treatment is effective. It has been proposed that there exists a subset of patients for which this competition can be enhanced through slight modifications to adaptive AA. Here, we investigate this by calibrating a simple mathematical model to longitudinal prostate-specific antigen data from 16 mCRPC patients undergoing adaptive AA. Model parameters are used to simulate modified adaptive therapy and compare against conventional adaptive therapy. Model simulations show that modified adaptive therapy can extend time to progression, while reducing the cumulative dose patients receive. This is a promising first step in improving patient care, particularly in those patients who do not respond well to conventional adaptive therapy.

Citation Format: Renee Brady-Nicholls, Heiko Enderling. Exploring how competition can be leveraged to improve adaptive therapy in metastatic prostate 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 IA015.
Abstract IA018: Rare cell variability and drug resistance in cancer
Authors: Shaffer Sydney
Published: May 2022

Even within a clonal cancer, individual cells have different responses to drugs; while some cells may be sensitive to a therapy and die, other cells from the same tumor can be resistant and continue to grow. Methods such as single-cell RNA-sequencing provide a snapshot into the underlying molecular variability responsible for different single-cell phenotypes. However, the missing dimension from such end-point based methods is time. Single-cell RNA-seq provides just one time point of gene expression, but does not capture the dynamics of how gene expression states change with time. In this talk, I will present an experimental and computational approach to capture the timescales of gene expression states and their relationship to therapy resistance. Here, we leverage high-throughput cellular barcoding and single-cell RNA-sequencing to track gene expression for thousands of cells and to predict the time for which these gene expression states persist in single cells. These techniques uncover the TGFB pathway as an inducer of the gene expression states that prime melanoma cells for resistance to BRAF/MEK inhibitors. Further, I will present a strategy for overcoming resistance through targeting the pre-existing cellular states that ultimately give rise to drug resistance.

Citation Format: Sydney Shaffer. Rare cell variability and drug resistance in 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 IA018.