bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA001: Harnessing evolutionary dynamics for control and cure of metastatic cancers
Authors: Gatenby Robert 
Published: May 2022

Abstract
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

Abstract
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

Abstract
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

Abstract
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.
Abstract IA019: Resolving the paradigm of the pre-existing resistance to targeted therapy, and the fitness costs associate with resistance: In vitro and theoretical evidence using an evolutionary game theoretic approach
Authors: Scott Jacob G. 
Published: May 2022

Abstract
Therapeutic strategies for tumor control have traditionally assumed that maximizing reduction in tumor volume correlates with clinical efficacy. Unfortunately, this rapid decrease in tumor burden is almost invariably followed by the emergence of therapeutic resistance. Evolutionary based treatment strategies attempt to delay resistance via judicious treatments that maintain a significant treatable subpopulation. While these strategies have shown promise in recent clinical trials, they often rely on biological conjecture and intuition to derive parameters. To bridge this gap, we recently developed an in vitro assay to directly measure the parameters of the underlying evolutionary game played between cancer cells under therapy. Using this assay we have subsequently directly observed competitive exclusion in non-small cell lung cancer cells – a necessary, but not sufficient condition for adaptive therapy. Intrinsic to this finding lies another advance: one which helps us settle the long standing paradox of pre-existing resistance and fitness costs associated with resistance mutations. In particular, if a cost of resistance exists, how can a less fit mutant persist in a population long enough for a treatment to be given to expose its increased fitness? To answer this, we show experimental and theoretical results that help explain this paradox which we posit submit should be generalizable outside cancer and applicable across the kingdoms of life where eco-evolutionary dynamics are at play.
Citation Format: Jacob G. Scott. Resolving the paradigm of the pre-existing resistance to targeted therapy, and the fitness costs associate with resistance: In vitro and theoretical evidence using an evolutionary game theoretic approach [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 IA019.
Abstract IA020: Dynamics of response and resistance to cancer therapy
Authors: Bozic Ivana 
Published: May 2022

Abstract
Despite the effectiveness of many cancer therapies in reducing tumor burden for significant amounts of time in a subset of patients, primary and acquired resistance to treatment remain one of the biggest challenges in the effort to cure cancer. Successful management, or prevention, of resistance requires deciphering the mechanisms by which it arises, and in particular whether it stems from pre-existing cell populations or arises de novo during therapy. Using evolutionary principles and mathematical techniques together with patient data, we aim to develop a precise mathematical understanding of the dynamics of response and resistance to various cancer therapies, including targeted therapies and immunotherapy. Our work shows that therapies that maximize the killing rate of cancer cells may not be optimal, and that instead the parameters determining the fraction of resistant cells and their growth rate have a larger effect on the long-term control of cancer.
Citation Format: Ivana Bozic. Dynamics of response and resistance to cancer 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 IA020.
Abstract IA022: Exploiting immune surveillance to target colorectal cancer evolution and mutability
Authors: Bardelli Alberto 
Published: May 2022

Abstract
The emergence of drug resistance limits the efficacy of targeted therapies in human tumors. Strategies to prevent or overcome resistance are essential to design the next generation of clinical trials. The prevalent view is that resistance is a fait accompli: when treatment is initiated, cancers already contain drug-resistant mutant cells. Notably, bacteria exposed to antibiotics transiently increase their mutation rates (adaptive mutability) thus improving chances of survival. We studied colorectal cancer (CRC) to assess whether tumor cells similarly exploit adaptive mutability to evade therapeutic pressure. We found that EGFR and BRAF inhibition activates stress-induced mutagenesis through downregulation of MMR and HR DNA repair effectors, and concomitant up-regulation of error-prone polymerases in drug-tolerant persister cells resulting in increased mutation rates. Overcoming drug resistance, therefore, means considering as a target not “only” individual oncogenes but also the evolving nature of human tumors. One possibility is to unleash the ability of the immune system to recognize mutations induced by therapy. We tested this possibility in syngeneic mouse models of CRC. Our findings indicate that inactivation of DNA repair mechanisms and manipulation of mutational loads can trigger immune surveillance and prolonged therapeutic responses.
Citation Format: Alberto Bardelli. Exploiting immune surveillance to target colorectal cancer evolution and mutability [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 IA022.
Abstract IA025: Decoding breast cancer evolution with single cell genomics
Authors: Navin Nicholas 
Published: May 2022

Abstract
I will discuss our efforts to develop and apply single cell DNA sequencing technologies to study breast cancer progression and evolution. We have developed a method called Acoustic Cell Tagmentation (ACT) which can provide high-throughput single cell copy number profiling of hundreds of cells in parallel at single-molecule resolution. We have applied this approach to study copy number evolution in Triple-negative breast cancer, which has revealed a ‘transient instability’ model of early copy number evolution, after the acquisition of TP53 mutations and genome doubling. We have also developed a computational toolkit called CopyKit to analyze single cell DNA sequencing data, and applied it to study metastasis in breast and colon cancer, as well as the spatial organization of subclones in metastatic tumors. Collectively these studies and tools provide new insights into the evolution of chromosome aberrations in human tumors.
Citation Format: Nicholas Navin. Decoding breast cancer evolution with single cell genomics [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 IA025.
Abstract PR013: Oct4 and Sox2 induce cellular transition of glioma stem cells to an immune suppressive, regulatory T cell-like state
Authors: Johnson Amanda , Korleski Jack , Laterra John , Lopez-Bertoni Hernando 
Published: May 2022

Abstract
Solid malignancies, including GBM, contain small subsets of cells that display stem-like properties (i.e. glioma stem cells or GSCs) and act as key determinants of therapeutic resistance and tumor recurrence. Mechanisms of GSC immune escape are considered fundamental to clinical GBM growth and recurrence. GBM cells escape antitumor immunity by modifying the tumor microenvironment by secreting immune-suppressive factors and recruiting anti-inflammatory/pro-oncogenic cells (e.g. T-regulatory cells, M2-like macrophages). However, whether subsets of GSCs can mimic T-reg-like functions by expressing proteins associated with T-reg immune-suppression remains unknown. Single-cell RNA sequencing analysis of GBM neurospheres revealed a previously unrecognized Oct4/Sox2high/FOXP3− cell subpopulation with high expression of TGFb1, CD39, CD73, PD-L1, and Galectin-1, a gene expression fingerprint typically associated with T-reg cells and their immune suppressive functions within the tumor microenvironment. Bioinformatics analysis of public databases shows that the above-mentioned genes are enriched in the mesenchymal GBM subtype and highly correlated with CD44 and TGFb type II receptor (TGFBR2) expression in both clinical GBM and primary GSCs. Mechanistically, Oct4 and Sox2 were found to directly induce TGFBR2 transcription concurrent with chromatin architectural changes (i.e. heterochromatin-to-euchromatin transition) involving the TGFBR2 gene. Transgenic TGFBR2 expression increased neurosphere cell growth capacity, upregulated expression of T-reg-like effector genes and enriched for CD44+ GSCs. Functionally, neurospheres expressing transgenic Oct4/Sox2 or transgenic TGFBR2 possess increased immunosuppressive capacity, and pharmacological inhibition of TGFBR2 depleted CD44+ GSCs and reduced immunosuppression in T-cell co-cultures. Taken together, we show that reprogramming events initiated by Oct4 and Sox2 induce a CD44+/FOX3P− GSC cell subset with a T-reg-like immunosuppressive transcriptional profile via a TGFBR2-dependent mechanism. This research provides the first description of such neoplastic cells in any malignancy and has high potential translational impact since targeting these tumor cell subsets and their immunosuppressive mechanisms may be critical to the successful development of GBM immunotherapies.
Citation Format: Amanda Johnson, Jack Korleski, John Laterra, Hernando Lopez-Bertoni. Oct4 and Sox2 induce cellular transition of glioma stem cells to an immune suppressive, regulatory T cell-like state [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 PR013.
Surgical Timing in Patients With Infective Endocarditis and With Intracranial Hemorrhage: A Systematic Review and Meta‐Analysis
Authors: Musleh Rita , Schlattmann Peter , Caldonazo Túlio , Kirov Hristo , Witte Otto W. , Doenst Torsten , Günther Albrecht , Diab Mahmoud 
Published: May 2022

Background
Intracranial hemorrhage (ICH) is one of the main causes for lack of surgery in patients with infective endocarditis (IE), despite the presence of surgical indications. We aimed to evaluate the impact of early surgery in patients with IE and with ICH on postoperative neurological deterioration and all‐cause mortality and to elucidate the risk of 30‐day mortality in patients who were denied surgery.

Methods and Results
Three libraries (MEDLINE, EMBASE, and Cochrane Library) were assessed. The primary outcome was all‐cause mortality, and the secondary outcome was neurological deterioration. Inverse variance method and random model were performed. We identified 16 studies including 355 patients. Nine studies examined the impact of surgical timing (early versus late) and were included in the meta‐analysis. Only one study examined the fate of patients with IE and with ICH who were treated conservatively despite having an indication for cardiac surgery, showing higher mortality rates than those who underwent surgery (11.8% versus 2.5%). We found no significant association between early surgery, regardless of its definition, and a higher mortality (odds ratio [OR], 1.69; 95% CI, 0.95–3.02). Early surgery was associated with higher risk for neurological deterioration (OR, 2.00; 95% CI, 1.10–3.65).

Conclusions
Cardiac surgery for IE within 30 days of ICH was not associated with higher mortality, but with an increased rate of neurological deterioration. The 30‐day mortality in patients with IE and with ICH who were denied surgery has not yet been sufficiently investigated. This patient group should be analyzed in future studies in more detail.
London Fog: A Century of Pollution and Mortality, 1866–1965
Authors: Hanlon W. Walker 
Published: May 2022

Abstract
This study draws on London’s long experience with air pollution in order to improve our understanding of the overall effects of pollution exposure and how and why these effects evolve as locations develop. I compare uniquely detailed new mortality data covering 1866 to 1965 to the timing of London’s famous fog events, which trapped emissions in the city. I show that air pollution was a major contributor to mortality in London over this period and that it interacted strongly with specific infectious diseases. As a consequence of this interaction, reductions in the infectious disease burden substantially altered the health costs of pollution.
Real-world effectiveness after initiating fremanezumab treatment in US patients with episodic and chronic migraine or difficult-to-treat migraine
Authors: Driessen Maurice T. , Cohen Joshua M. , Thompson Stephen F. , Patterson-Lomba Oscar , Seminerio Michael J. , Carr Karen , Totev Todor I. , Sun Rochelle , Yim Erica , Mu Fan , Ayyagari Rajeev 
Published: May 2022

Abstract
Background
Fremanezumab, a fully humanized monoclonal antibody (mAb; IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), is approved for the preventive treatment of migraine in adults. The efficacy and safety of fremanezumab for migraine prevention have been demonstrated in randomized, double-blind, placebo-controlled trials. Real-world effectiveness data are needed to complement clinical trial data. This study assessed the effectiveness of fremanezumab across different subgroups of adult patients with episodic migraine (EM), chronic migraine (CM), or difficult-to-treat (DTT) migraine in real-world clinical settings.

Methods
This retrospective, panel-based online chart review used electronic case report forms. Patient inclusion criteria were a physician diagnosis of EM or CM; age ≥ 18 years at the time of first fremanezumab initiation; ≥ 1 dose of fremanezumab treatment; ≥ 1 follow-up visit since first initiation; and ≥ 2 measurements of monthly migraine days (MMD; with 1 within a month before or at first initiation and ≥ 1 after first initiation). Changes in MMD and monthly headache days were assessed during the follow-up period. These endpoints were evaluated in subgroups of patients by migraine type (EM/CM) and in subgroups with DTT migraine (diagnosis of medication overuse [MO], major depressive disorder [MDD], generalized anxiety disorder [GAD], or prior exposure to a different CGRP pathway–targeted mAb [CGRP mAb]).

Results
Data were collected from 421 clinicians and 1003 patients. Mean (percent) reductions from baseline in MMD at Month 6 were − 7.7 (77.0%) in EM patients, − 10.1 (68.7%) in CM patients, − 10.8 (80.6%) in the MO subgroup, − 9.9 (68.3%) in the MDD subgroup, − 9.5 (66.4%) in the GAD subgroup, and − 9.0 (68.7%) in the prior CGRP mAb exposure subgroup. Improvements in MDD or GAD severity were reported by 45.5% and 45.8% of patients with comorbid MDD or GAD, respectively.

Conclusions
In this real-world study, fremanezumab demonstrated effectiveness for migraine regardless of migraine type or the presence of factors contributing to DTT migraine (MO, GAD, MDD, or prior exposure to a different CGRP mAb).