bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B026: Simulations of cancer evolution predict relative benefits of synergistic and non-synergistic drug combinations for combating different landscapes of drug-resistance
Authors: Saputra Elysia , Tucker-Kellogg Lisa 
Published: May 2022

Abstract
Cancer therapies often have short duration of success due to the development of drug-resistance, which motivates research into anti-evolutionary therapies. A popular strategy is to combine two drugs, particularly if they have synergistic (greater-than-additive) efficacy. However, therapies that cause synergistic suppression of drug-sensitive cells will also suffer from synergistic release of drug-resistant cells, when drug-resistance arises. Not yet understood is the impact of partial drug-resistance and semi-resistant phenotypes on the speed of clonal expansion under combination therapy. In this work, we perform computational modeling to compare the growth rates of heterogeneous populations of cells, when drug-resistance is a binary (all-or-nothing) phenotype, versus when it is a spectrum of partially-sensitive phenotypes. We ask whether the type and granularity of drug-resistance levels in the drug-resistance landscape affects the relative outcome of using synergistic versus non-synergistic drug combinations. We observe that if drug-resistance can develop via rapid, “plastic” phenotypic transitions, then synergistic drugs provide long-lasting suppression of resistance than additive drugs (when dosed to have equal initial efficacy). Conversely, if drug-resistance develops via slow acquisition of phenotypic changes (e.g., requiring multiple genomic lesions), then synergistic drugs promote faster evolution of drug-resistance than additive drugs. When studying how synergism affects evolution, we found that cells escaping a synergistic treatment would be more likely to develop “asymmetric resistance” toward one drug (with greater sensitivity toward the other drug). In contrast, cells escaping antagonistic treatments would be more likely to develop symmetric resistance (equal levels of resistance) toward both drugs. Our findings suggest that after a synergistic treatment, a post-relapse tumor would be more likely to retain sensitivity to one of the drugs used, compared with equivalent relapse after non-synergistic combination treatment. Thus, theoretical modeling can provide testable predictions that complement the hypotheses arising from experiments.
Citation Format: Elysia Saputra, Lisa Tucker-Kellogg. Simulations of cancer evolution predict relative benefits of synergistic and non-synergistic drug combinations for combating different landscapes of 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 B026.
Abstract B031: Metabolism-epigenetics interplay drives cancer cell persistence during receptor tyrosine kinase inhibition
Authors: El-Kenawi Asmaa , Berglund Anders , Brown Joel , Gatenby Robert 
Published: May 2022

Abstract
Receptor tyrosine kinase inhibitors (TKI) are effective anti-cancer treatments. However, evolution of resistance almost inevitably occurs due to pre-existing mutations or development of therapy-tolerant persister cells. Here, we combined time-lapse imaging with longitudinal DNA/RNA sequencing, metabolomics and genome-wide DNA methylation profiling to decipher mechanisms of TKI-induced persisters. Whole exome sequencing demonstrated that persisters were genetically indistinguishable from their parental counterparts, suggesting non-genetic mechanisms were involved. Using untargeted metabolomics, we uncovered that persisters were deficient in methionine metabolism intermediates, including S-(5'-adenosyl)-L-homocysteine (SAH), a major determinant DNA methylation. Examining the consumption of a panel of isotope labeled extracellular amino acids indicated that persisters don’t exhibit deregulation in methionine and cysteine transport. Instead, persisters preferentially consume methionine and cystine to support their survival. Profiling of wide-genome DNA methylation suggested that these metabolic changes was associated with a unique global DNA hypermethylation. We then discovered that promotor regions of genes encoding a range of trace element transporters were uniquely hypermethylated. Through further functional analysis, we then unraveled that these metabolic and epigenetic changes collectively facilitate emergence of a phenotype characterized by methionine/cystine-dependent resistance to osmotic stress. Thus, evolution of TKI resistance can develop by metabolism-dependent epigenetic modifications. Unraveling the detailed mechanisms of these metabolic and epigenetic strategies in cancer cell persisters is crucial to prevent cancer recurrence.
Citation Format: Asmaa El-Kenawi, Anders Berglund, Joel Brown, Robert Gatenby. Metabolism-epigenetics interplay drives cancer cell persistence during receptor tyrosine kinase inhibition [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 B031.
Abstract B038: Blockade of c-met signaling to circumvent radioresistance-associated metastasis in head and neck cancer
Authors: Dou Juan , Lang Liwei , Chen Georgia , Saba Nabil F. , Teng Yong 
Published: May 2022

Abstract
One of the significant clinical challenges in head and neck cancer (HNC) treatment is a high rate of recurrence and metastasis after radiotherapy. Once tumor metastasis occurs following radiotherapy, the prognosis of HNC patients is extremely poor. However, the failure of radiotherapy for cancers is closely related to various factors, and the underlying mechanism remains unclear. We report here that c-Met is the most activated receptor tyrosine kinases in HNC cells once they develop radioresistance. Inactivation of c-Met dramatically attenuates the increased metastatic potential gained in HNC radioresistant cells, leading to tumor regression. Cancer stem cells (CSC) have been confirmed to be in a quiescent state in most established tumors. Mechanistically, the quiescent CSC population can be “awakened” by hyperactive c-Met signaling in radiation, which in turn initiates proliferation and differentiation to potentiate a series of malignant phenotypes. Most importantly, knockdown c-Met by shRNAs or inactivating it by c-Met inhibitor SU11274 reduces the population of “awakened” CSCs and suppresses metastasis, leading to increased sensitivity of HNC radioresistant cells to radiation. These novel findings highlight the importance of additional c-Met blockade in radiotherapy and suggest that combined targeting of c-Met and radiotherapy could be a promising strategy to improve the care for patients with HNC.
Citation Format: Juan Dou, Liwei Lang, Georgia Chen, Nabil F. Saba, Yong Teng. Blockade of c-met signaling to circumvent radioresistance-associated metastasis in head and neck 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 B038.
Abstract IA004: Tracking population heterogeneity and chemoresistance with functionalized cell barcodes
Authors: Brock Amy 
Published: May 2022

Abstract
Heterogeneity across individual cancer cells and clonal populations impacts growth rate, tumor composition, and response to therapy. To improve treatment, new tools are required to measure and control the contributions of diverse cell subpopulations. Our team has developed a high-complexity expressed barcode system, ClonMapper, that integrates expressed cell barcoding with single-cell RNA-sequencing and clonal isolation to characterize and track subpopulation trajectories. Using this approach, we uncovered subsets of cells from cell models with distinct transcriptional signatures and chemotherapy survivorship trajectories. To gain a deeper understanding of the process of clonal diversification, we profiled clones and retrieved sub-clones over the course of expansion and treatment. Supervised learning indicated that clonal subpopulations have characteristic transcriptomic signatures that are well-conserved under a variety of therapeutic perturbations. By providing the capability for systematic dissection of complex clonal dynamics, ClonMapper enables the delineation of an underlying engine of clonal diversification in cancer cell populations and refines our understanding of clonal identity.
Citation Format: Amy Brock. Tracking population heterogeneity and chemoresistance with functionalized cell barcodes [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 IA004.
Tubular IL-1β Induces Salt Sensitivity in Diabetes by Activating Renal Macrophages
Authors: Veiras Luciana C. , Bernstein Ellen A. , Cao DuoYao , Okwan-Duodu Derick , Khan Zakir , Gibb David R. , Roach Arantxa , Skelton Rachel , Williams Ryan M. , Bernstein Kenneth E. , Giani Jorge F. 
Published: May 2022

Background:
Chronic renal inflammation has been widely recognized as a major promoter of several forms of high blood pressure including salt-sensitive hypertension. In diabetes, IL (interleukin)-6 induces salt sensitivity through a dysregulation of the epithelial sodium channel. However, the origin of this inflammatory process and the molecular events that culminates with an abnormal regulation of epithelial sodium channel and salt sensitivity in diabetes are largely unknown.

Methods:
Both in vitro and in vivo approaches were used to investigate the molecular and cellular contributors to the renal inflammation associated with diabetic kidney disease and how these inflammatory components interact to develop salt sensitivity in db/db mice.

Results:
Thirty-four-week-old db/db mice display significantly higher levels of IL-1β in renal tubules compared with nondiabetic db/+ mice. Specific suppression of IL-1β in renal tubules prevented salt sensitivity in db/db mice. A primary culture of renal tubular epithelial cells from wild-type mice releases significant levels of IL-1β when exposed to a high glucose environment. Coculture of tubular epithelial cells and bone marrow-derived macrophages revealed that tubular epithelial cell-derived IL-1β promotes the polarization of macrophages towards a proinflammatory phenotype resulting in IL-6 secretion. To evaluate whether macrophages are the cellular target of IL-1β in vivo, diabetic db/db mice were transplanted with the bone marrow of IL-1R1 (IL-1 receptor type 1) knockout mice. db/db mice harboring an IL-1 receptor type 1 knockout bone marrow remained salt resistant, display lower renal inflammation and lower expression and activity of epithelial sodium channel compared with db/db transplanted with a wild-type bone marrow.

Conclusions:
Renal tubular epithelial cell-derived IL-1β polarizes renal macrophages towards a proinflammatory phenotype that promotes salt sensitivity through the accumulation of renal IL-6. When tubular IL-1β synthesis is suppressed or in db/db mice in which immune cells lack the IL-1R1, macrophage polarization is blunted resulting in no salt-sensitive hypertension.
Predicting Residual Angina After Chronic Total Occlusion Percutaneous Coronary Intervention: Insights from the OPEN‐CTO Registry
Authors: Butala Neel M. , Tamez Hector , Secemsky Eric A. , Grantham J. Aaron , Spertus John A. , Cohen David J. , Jones Philip , Salisbury Adam C. , Arnold Suzanne V. , Harrell Frank , Lombardi William , Karmpaliotis Dimitrios , Moses Jeffrey , Sapontis James , Yeh Robert W. 
Published: May 2022

Background
Given that percutaneous coronary intervention (PCI) of a chronic total occlusion (CTO) is indicated primarily for symptom relief, identifying patients most likely to benefit is critically important for patient selection and shared decision‐making. Therefore, we identified factors associated with residual angina frequency after CTO PCI and developed a model to predict postprocedure anginal burden.

Methods and Results
Among patients in the OPEN‐CTO (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures) registry, we evaluated the association between patient characteristics and residual angina frequency at 6 months, as assessed by the Seattle Angina Questionnaire Angina Frequency Scale. We then constructed a prediction model for angina status after CTO PCI using ordinal regression. Among 901 patients undergoing CTO PCI, 28% had no angina, 31% had monthly angina, 30% had weekly angina, and 12% had daily angina at baseline. Six months later, 53% of patients had a ≥20‐point increase in Seattle Angina Questionnaire Angina Frequency Scale score. The final model to predict residual angina after CTO PCI included baseline angina frequency, baseline nitroglycerin use frequency, dyspnea symptoms, depressive symptoms, number of antianginal medications, PCI indication, and presence of multiple CTO lesions and had a C index of 0.78. Baseline angina frequency and nitroglycerin use frequency explained 71% of the predictive power of the model, and the relationship between model components and angina improvement at 6 months varied by baseline angina status.

Conclusions
A 7‐component OPEN‐AP (OPEN‐CTO Angina Prediction) score can predict angina improvement and residual angina after CTO PCI using variables commonly available before intervention. These findings have implications for appropriate patient selection and counseling for CTO PCI.
Concomitant Hepatorenal Dysfunction and Malnutrition in Valvular Heart Surgery: Long‐Term Prognostic Implications for Death and Heart Failure
Authors: Tse Yi‐Kei , Chandramouli Chanchal , Li Hang‐Long , Yu Si‐Yeung , Wu Mei‐Zhen , Ren Qing‐Wen , Chen Yan , Wong Pui‐Fai , Sit Ko‐Yung , Chan Daniel Tai‐Leung , Ho Cally Ka‐Lai , Au Wing‐Kuk , Li Xin‐Li , Tse Hung‐Fat , Lam Carolyn S. P. , Yiu Kai‐Hang 
Published: May 2022

Background
Strategies to improve long‐term prediction of heart failure and death in valvular surgery are urgently needed because of an increasing number of procedures globally. This study sought to report the prevalence, changes, and prognostic implications of concomitant hepatorenal dysfunction and malnutrition in valvular surgery.

Methods and Results

In 909 patients undergoing valvular surgery, 3 groups were defined based on hepatorenal function (the modified model for end‐stage liver disease excluding international normalized ratio score) and nutritional status (Controlling Nutritional Status score): normal hepatorenal function and nutrition (normal), hepatorenal dysfunction or malnutrition alone (mild), and concomitant hepatorenal dysfunction and malnutrition (severe). Overall, 32%, 46%, and 19% of patients were classified into normal, mild, and severe groups, respectively. Over a 4.1‐year median follow‐up, mild and severe groups incurred a higher risk of mortality (hazard ratio [HR], 3.17 [95% CI, 1.40–7.17] and HR, 9.30 [95% CI, 4.09–21.16], respectively), cardiovascular death (subdistribution HR, 3.29 [95% CI, 1.14–9.52] and subdistribution HR, 9.29 [95% CI, 3.09–27.99]), heart failure hospitalization (subdistribution HR, 2.11 [95% CI, 1.25–3.55] and subdistribution HR, 3.55 [95% CI, 2.04–6.16]), and adverse outcomes (HR, 2.11 [95% CI, 1.25–3.55] and HR, 3.55 [95% CI, 2.04–6.16]). Modified model for end‐stage liver disease excluding international normalized ratio and controlling nutritional status scores improved the predictive ability of European System for Cardiac Operative Risk Evaluation (area under the curve: 0.80 versus 0.73,
P
<0.001) and Society of Thoracic Surgeons score (area under the curve: 0.79 versus 0.72,
P
=0.004) for all‐cause mortality. One year following surgery (n=707), patients with persistent concomitant hepatorenal dysfunction and malnutrition (severe) experienced worse outcomes than those without.

Conclusions
Concomitant hepatorenal dysfunction and malnutrition was frequent and strongly linked to heart failure and mortality in valvular surgery.
CENIT (Impact of Cardiac Exercise Training on Lipid Content in Coronary Atheromatous Plaques Evaluated by Near‐Infrared Spectroscopy): A Randomized Trial
Authors: Vesterbekkmo Elisabeth Kleivhaug , Madssen Erik , Aamot Aksetøy Inger‐Lise , Follestad Turid , Nilsen Hans Olav , Hegbom Knut , Wisløff Ulrik , Wiseth Rune 
Published: May 2022

Background
The effect of physical exercise on lipid content of coronary artery plaques is unknown. With near infrared spectroscopy we measured the effect of high intensity interval training (HIIT) on lipid content in coronary plaques in patients with stable coronary artery disease following percutaneous coronary intervention.

Methods and Results

In CENIT (Impact of Cardiac Exercise Training on Lipid Content in Coronary Atheromatous Plaques Evaluated by Near‐Infrared Spectroscopy) 60 patients were randomized to 6 months supervised HIIT or to a control group. The primary end point was change in lipid content measured as maximum lipid core burden index at 4 mm (maxLCBI
4mm
). A predefined cutoff of maxLCBI
4mm
>100 was required for inclusion in the analysis. Forty‐nine patients (HIIT=20, usual care=29) had maxLCBI
4mm
>100 at baseline. Change in maxLCBI
4mm
did not differ between groups (−1.2, 95% CI, −65.8 to 63.4,
P
=0.97). The estimated reduction in maxLCBI
4mm
was −47.7 (95% CI, −100.3 to 5.0,
P
=0.075) and −46.5 (95% CI, −87.5 to −5.4,
P
=0.027) after HIIT and in controls, respectively. A negative correlation was observed between change in peak oxygen uptake (VO
2peak
) and change in lipid content (Spearman’s correlation −0.44,
P
=0.009). With an increase in VO
2peak
above 1 metabolic equivalent task, maxLCBI
4mm
was on average reduced by 142 (−8 to −262), whereas the change was −3.2 (154 to −255) with increased VO
2peak
below 1 metabolic equivalent task.

Conclusions

Six months of HIIT following percutaneous coronary intervention did not reduce lipid content in coronary plaques compared with usual care. A moderate negative correlation between increase in VO
2peak
and change in lipid content generates the hypothesis that exercise with a subsequent increase in fitness may reduce lipid content in coronary atheromatous plaques.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02494947.
Clinical Prediction Models for Heart Failure Hospitalization in Type 2 Diabetes: A Systematic Review and Meta‐Analysis
Authors: Razaghizad Amir , Oulousian Emily , Randhawa Varinder Kaur , Ferreira João Pedro , Brophy James M. , Greene Stephen J. , Guida Julian , Felker G. Michael , Fudim Marat , Tsoukas Michael , Peters Tricia M. , Mavrakanas Thomas A. , Giannetti Nadia , Ezekowitz Justin , Sharma Abhinav 
Published: May 2022

Background
Clinical prediction models have been developed for hospitalization for heart failure in type 2 diabetes. However, a systematic evaluation of these models’ performance, applicability, and clinical impact is absent.

Methods and Results
We searched Embase, MEDLINE, Web of Science, Google Scholar, and Tufts’ clinical prediction registry through February 2021. Studies needed to report the development, validation, clinical impact, or update of a prediction model for hospitalization for heart failure in type 2 diabetes with measures of model performance and sufficient information for clinical use. Model assessment was done with the Prediction Model Risk of Bias Assessment Tool, and meta‐analyses of model discrimination were performed. We included 15 model development and 3 external validation studies with data from 999 167 people with type 2 diabetes. Of the 15 models, 6 had undergone external validation and only 1 had low concern for risk of bias and applicability (Risk Equations for Complications of Type 2 Diabetes). Seven models were presented in a clinically useful manner (eg, risk score, online calculator) and 2 models were classified as the most suitable for clinical use based on study design, external validity, and point‐of‐care usability. These were Risk Equations for Complications of Type 2 Diabetes (meta‐analyzed c‐statistic, 0.76) and the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (meta‐analyzed c‐statistic, 0.78), which was the simplest model with only 5 variables. No studies reported clinical impact.

Conclusions
Most prediction models for hospitalization for heart failure in patients with type 2 diabetes have potential concerns with risk of bias or applicability, and uncertain external validity and clinical impact. Future research is needed to address these knowledge gaps.
Heart Transplantation in Children With Down Syndrome
Authors: Godown Justin , Fountain Darlene , Bansal Neha , Ameduri Rebecca , Anderson Susan , Beasley Gary , Burstein Danielle , Knecht Kenneth , Molina Kimberly , Pye Sherry , Richmond Marc , Spinner Joseph A. , Watanabe Kae , West Shawn , Reinhardt Zdenka , Scheel Janet , Urschel Simon , Villa Chet , Hollander Seth A. 
Published: May 2022

Background
Children with Down syndrome (DS) have a high risk of cardiac disease that may prompt consideration for heart transplantation (HTx). However, transplantation in patients with DS is rarely reported. This project aimed to collect and describe waitlist and post– HTx outcomes in children with DS.

Methods and Results

This is a retrospective case series of children with DS listed for HTx. Pediatric HTx centers were identified by their participation in 2 international registries with centers reporting HTx in a patient with DS providing detailed demographic, medical, surgical, and posttransplant outcome data for analysis. A total of 26 patients with DS were listed for HTx from 1992 to 2020 (median age, 8.5 years; 46% male). High‐risk or failed repair of congenital heart disease was the most common indication for transplant (N=18, 69%). A total of 23 (88%) patients survived to transplant. All transplanted patients survived to hospital discharge with a median posttransplant length of stay of 22 days. At a median posttransplant follow‐up of 2.8 years, 20 (87%) patients were alive, 2 (9%) developed posttransplant lymphoproliferative disorder, and 8 (35%) were hospitalized for infection within the first year. Waitlist and posttransplant outcomes were similar in patients with and without DS (
P
=non‐significant for all).

Conclusions
Waitlist and post‐HTx outcomes in children with DS selected for transplant listing are comparable to pediatric HTx recipients overall. Given acceptable outcomes, the presence of DS alone should not be considered an absolute contraindication to HTx.