bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1145: Therapeutic drug monitoring of Sunitinib in real-world patients
Authors: Ferrer Laurent , Chauvin Jonathan , Deville Dr Jean-Laurent , Ciccolini Joseph 
Published: June 2022

Abstract
Therapeutic Drug Monitoring (TDM) with model-based adaptive dosing is expected to quickly ensure that exposure levels of anticancer agents are in the adequate range of plasma concentrations. Here, we have compared such TDM + in silico approach with empirical changes in dosing performed upon clinical signs in patients with metastatic renal cell carcinoma treated with Sunitinib. A total of 31 patients were monitored in our institute. All patients were treated with a standard starting dose of 50 mg QD following the 4/2 schedule. Sunitinib and n-desethyl sunitinib trough levels were assayed at steady state by a fully validated LC-MS/MS analysis. A PK-pop model with Bayesian estimate implemented on Monolix helped to identify individual PK parameters from a single time-point. Two different target exposures were considered (i.e., trough levels comprised between 50 and 100 ng/ml or 0-24h AUC comprised between 1250 and 2150 ng/ml.h). The PK model enabled to simulate both trough levels and 0-24h AUC from a single sample, regardless of the sampling time. Overall, dosing was modified empirically in about 54% of the patients after treatment started, mostly (46%) for reducing the dosing after that toxicities showed. Clinical benefit (i.e., stable disease + partial response + complete reponse) was achieved in 54% of patients but treatment discontinuation was observed in 58% of the patients eventually, mostly because of severe side-effects. A relationship between baseline exposure levels and early onset treatment-related toxicities was found. Because of the various changes in dosing, no such relationship was found between baseline exposure levels and efficacy evaluated at 3 months. TDM showed that only 45% of the patients were in the right window for trough levels (i.e., 50-100 ng/ml) and only 26% when considering AUC as the target exposure (i.e., 1200-2150 ng/ml.h). Consequently, the PK/PD model would have suggested to rapidly customize dosing in a much larger part of the patients (i.e., 84% with respect to the target AUCs). Importantly, Sunitinib dosing was empirically reduced only in 41% patients who displayed early-onset severe toxicities, whereas modelling would have immediately proposed to cut the dosing in more than 80% of those patients, thus suggesting that the safety of Sunitinib could have been improved when using our model. Although performed on a limited number of patients, this real-world study supports the hypothesis that TDM associated with PK modelling could help the prescriber to identify the best Sunitinib dosing in a quicker way than empirical change in dosing.
Citation Format: Laurent Ferrer, Jonathan Chauvin, Dr Jean-Laurent Deville, Joseph Ciccolini. Therapeutic drug monitoring of Sunitinib in real-world patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1145.
Abstract 1150: Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351
Authors: Donnette Melanie , Hamimed Mourad , Ciccolini Joseph , Costello Regis , Delassus Laure , Venton Geoffroy , Fanciullino Raphaelle 
Published: June 2022

Abstract
CPX-351 is a liposomal form encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia (AML) patients. Cytidine Deaminase (CDA) catabolizes free cytarabine in the liver, but to what extent it could affect as well the pharmacokinetics of liposomal cytarabine is yet to be investigated. Here we have studied the pharmacokinetics (PK) of released, liposomal and total cytarabine using a population-modeling approach in adult AML patients treated with CPX-351. Impact of CDA status (i.e., Poor Metabolizer (PM) vs. Extensive Metabolizer (EM)) on cytarabine exposure levels (AUC, trough levels, Cmax) and PK parameters were analyzed. All patients showed febrile neutropenia and one toxic-death was observed. Overall response rate was 75%. The ratio free:total cytarabine monitored in our patients was higher than expected (i.e., 47%). Inter-individual variability on pharmacokinetics parameters and subsequent exposure levels was &gt;60%. A trend towards severe toxicities was observed in patients with higher exposure of cytarabine. Results showed that liposomal CPX-351 led to sustained exposure with reduced clearance (Cl = 0.16 L/h) and prolonged half-life (T1/2 = 28 h). Of note, liposomes were observed transiently in bone marrow on D15, with cytarabine levels 2.3-time higher than in plasma. Sequencing CDA gene was not contributive and CDA status was primarily evaluated upon phenotyping patients. PM status was found in 77% of the patients with a marked impact on cytarabine PK parameters, i.e., PM patients had higher exposure than EM patients (AUC: 5536 vs. 1784 ng/mL.h), prolonged half-life (T1/2: 33.9 vs. 13.7 h), and reduced clearance (Cl: 0.12 vs. 0.29 L/h). This pilot study suggests that despite being encapsulated in a liposomal vehicle as CPX-351, cytarabine fate in the body is highly dependent upon CDA activity, suggesting that liver metabolism is only partly skipped by the nanoparticle. Here, CDA status proved to have a major impact on cytarabine PK and possibly safety in AML patients treated with CPX-351. Indeed PM patients displayed higher exposure levels with higher risk for severe non-hematological toxicities. This study suggests that CDA status could be used as a covariate to customize CPX-351 dosing in AML patients.
Citation Format: Melanie Donnette, Mourad Hamimed, Joseph Ciccolini, Regis Costello, Laure Delassus, Geoffroy Venton, Raphaelle Fanciullino. Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1150.
Abstract 1159: Predicting clinical drug responses using a few-shot learning-based interpretable AI
Authors: Park Sungjoon , Singhal Akshat , Silva Erica , Kreisberg Jason F. , Ideker Trey 
Published: June 2022

Abstract
High-throughput screens have generated large amounts of data characterizing how thousands of cell lines respond to hundreds of anti-cancer therapies. However, predictive drug response models trained using data from cell lines often fail to translate to clinical applications. Here, we focus on two key issues to improve clinical performance: 1) Transferability: the ability of predictive models to quickly adapt to clinical contexts even with a limited number of samples from patients, and 2) Interpretability: the ability to explain how drug-response predictions are being made given an individual patient’s genotype. Notably, an interpretable AI model can also help to identify biomarkers of treatment response in individual patients. By leveraging new developments in meta-learning and interpretable AI, we have developed an interpretable drug response prediction model that is trained on large amounts of data from experiments using cell lines and then transferred to clinical applications. We assessed our model’s clinical utility using AACR Project GENIE data, which contains mutational profiles from tumors and the patient’s therapeutic responses. We have demonstrated the feasibility of applying our AI-driven predictive model to clinical settings and shown how this model can support clinical decision making for tumor boards.
Citation Format: Sungjoon Park, Akshat Singhal, Erica Silva, Jason F. Kreisberg, Trey Ideker. Predicting clinical drug responses using a few-shot learning-based interpretable AI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1159.
Abstract 1171: Genotoxic preventive potential of ethanol leaves extract of Annona muricata on N-Nitroso-N-ethylurea pro-leukaemia carcinogen in mice by bone marrow micronucleus assay
Authors: Akanni Olufemi Emmanuel , Bamisaye Eunice Oluwaseyi , Fashina Sunday Anthony , Abdulraheem Fatai Adesina , Fadiora Solomon Olufemi 
Published: June 2022

Abstract
Background: Genotoxicity which is an important indicator of DNA damage, repair and cell rejuvenation has been a predisposing factor to cancer development evidenced by bone marrow suppression in leukemia and studies have proven the effect of several agents inclusive of natural products to induce, prevent and treat genotoxicity through experimental models and clinical trials.
Aim:The genotoxic preventive potential of Annona muricata ethanol leaves extract on N-nitroso-N-ethylurea (NEU) pro-leukemia carcinogen in mice model using micronuclei formation in bone marrow was assessed.
Materials and Methods: 48 mice weighing 18-24g were randomly divided into six groups of eight mice each comprising of the; mice intravenously administered 20mg/kg of NEU 48 hourly 3 times (A); 80mg/kg of NEU 48 hourly 3 times (B); negative control fed with feed and water only (C); 0.2ml (0.1g/ml) ethanolic leaves extract of Annona muricata for 3 weeks prior to administration of low dose of NEU (D); 0.2ml (0.1g/ml) ethanolic extract of Annona muricata for 3 weeks prior to administration of high dose of NEU (E); and Annona muricata (ethanolic leaves extract) and commercial diet for adverse/toxicity group (F). After six weeks of last exposure, animals were ethically sacrificed, bone marrow harvested, smeared, stained using MayGrumwald and number of micronucleus polychromatic erythrocyte (MNPCEs) were determined microscopically.Result: Groups exposed to various dosage of the NEU yielded significantly increased MNPCEs with group B producing higher MNPCEs than A. The groups treated with extract displayed a significant reduction in the MNPCEs despite the prior exposure concentrations of NEU. The adverse group displayed no difference in MNPCEs when compared with the negative control (Table 1).
Conclusion: The extract displayed profound capacity to prevent genotoxicity thereby alleviating leukemia condition and it is well tolerated.
Week Number Groups (Mean±Standard deviation of MNPCE) A B C D E F 2 14.13±0.56 50.45±2.31 4.52±0.34 6.15±0.49 17.11±1.11 4.53±0.45 3 15.01±0.18 53.77±1.95 4.61±0.67 7.85±0.98 20.34±2.34 4.62±0.23 4 16.11±0.22 56.95±2.01 4.91±0.88 8.01±1.01 25.11±1.67 5.63±0.45 5 19.64±1.68 68.23±1.56 4.82±0.75 10.07±0.67 30.54±2.34 5.92±0.67
Citation Format: Olufemi Emmanuel Akanni, Eunice Oluwaseyi Bamisaye, Sunday Anthony Fashina, Fatai Adesina Abdulraheem, Solomon Olufemi Fadiora. Genotoxic preventive potential of ethanol leaves extract of Annona muricata on N-Nitroso-N-ethylurea pro-leukaemia carcinogen in mice by bone marrow micronucleus assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1171.
Abstract 118: BACH1 is an oxygen-sensitive mediator of the hypoxia response in triple-negative breast cancer
Authors: Dann Christopher M. , Nguyen Long C. , Yang Dongbo , Wynne Joseph P. , Valdespino Andrea , Stock Letícia , Rosner Marsha R. 
Published: June 2022

Abstract
Triple-negative breast cancer (TNBC) is an aggressive solid tumor characterized by a hypoxic phenotype that promotes metastatic progression and resistance to therapy. The canonical cellular response to hypoxia is largely driven by hypoxia inducible factors (HIFs) that stimulate transcription of genes related to angiogenesis, cancer stem cells, cell survival, and glucose and iron metabolism. There is growing evidence that several factors, in addition to HIFs, contribute to the tumor hypoxia response. Thus, identifying novel mechanisms that regulate this cellular response in addition to the HIFs is key to our understanding of hypoxia and could have direct clinical impact. High expression of BTB and CNC homology 1 (BACH1), a heme-regulated bZIP transcription factor, drives metastatic progression in various cancers including TNBC. While BACH1 has been shown to be induced under hypoxia in some cell lines, its regulation and role in hypoxia signaling, specifically with regards to cancer cells, is poorly understood. Here we report a novel regulatory pathway of the tumor hypoxia response in TNBC. We show that BACH1 is post-translationally prolyl-hydroxylated by the HIF prolyl-hydroxylases (PHDs) in an oxygen-dependent and NRF2/HMOX1-independent manner. Hypoxic exposure thus stabilizes BACH1 protein and enhances its DNA binding activity at loci of both canonical and hypoxia-specific downstream targets. We further show that BACH1 regulates the hypoxia response by promoting expression of both HIF-dependent and HIF-independent hypoxia-induced genes in TNBC cells. Our findings describe BACH1 as a novel oxygen-sensitive effector of the hypoxia response in TNBC that represents an alternative target for attenuating hypoxia-induced, pro-metastatic signaling and therapeutic resistance.
Citation Format: Christopher M. Dann, Long C. Nguyen, Dongbo Yang, Joseph P. Wynne, Andrea Valdespino, Letícia Stock, Marsha R. Rosner. BACH1 is an oxygen-sensitive mediator of the hypoxia response in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 118.
Abstract 1198: Discovering novel bispecific antibody targets through the mining of large-scale bulk and single cell RNA-seq databases
Authors: Chekalin Eugene , Paithankar Shreya , Chen Bin 
Published: June 2022

Abstract
Bispecific antibodies (bsAbs) that bind two distinct surface proteins in cancer cells are emerging as an appealing therapeutic strategy in cancer immunotherapy. Among thousands of surface proteins, experimentally identifying the best target pairs that are expressed only in cancer cells, but not in normal cells, is costly and time-consuming. The open bulk RNASeq and single-cell (sc)RNASeq offers a great resource to identify novel bispecific targets. Bulk RNASeq has been widely explored to identify therapeutic targets and biomarkers, resulting in voluminous data for various cancers and normal tissues, but the mixture of cell types in bulk RNASeq could not characterize the precise expression of targets in cancer cells, resulting in considerable false positives. scRNASeq provides a high resolution of target expression in individual cells, however, the challenges in solving the dropout issue and cell type classification hinder the direct use of scRNASeq in bsAbs target identification. Utilizing the OCTAD database consisting of over 20,000 bulk RNASeq samples, we proposed an approach that identifies target pairs that separate tumors from healthy the most, taking into account cluster heterogeneity, the distance between tumors and healthy as well as the angle between potential markers. Among the top pairs in Hepatocellular Carcinoma (HCC), CD33~PLVAP, for example, was a false positive because CD33 is myeloid and lymphoid cell lineage-specific. We thus assembled a scRNAseq database of healthy vital organs containing 39361 cells to aid selection. By comparing their expression with the expression of 18000 malignant cells predicted from 72000 cells of eight HCC samples, we identified target pairs that mostly express on the surface of the malignant HCC cells and had low or zero expression in vital organs. The most promising marker pair was GPC3~MUC13, presenting on the surface of over 30% of malignant HCC cells, with very low expression in vital organs. We further developed an R package to navigate the bsAbs target selection from open bulk RNASeq and scRNASeq.
Citation Format: Eugene Chekalin, Shreya Paithankar, Bin Chen. Discovering novel bispecific antibody targets through the mining of large-scale bulk and single cell RNA-seq databases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1198.
Abstract 1201: GenomeCruzer: A tool for interactive 3D visualization and analysis of multidimensional cancer omics
Authors: Isella Claudio , Corsi Riccardo , Elhasnaoui Jamal , Bertotti Andrea , Vezzadini Luca , Medico Enzo 
Published: June 2022

Abstract
In cancer genomics, integrative analysis of data obtained from biological samples of patient cohorts requires handling large groups of patients, each with molecular data of different type for thousands of genes, such as expression, mutation, copy number, and others.
Currently available tools allow visualization and analysis of such complex data, however forcing the user to work with partial views due to the amount of information. Also, these systems usually involve somewhat laborious procedures, so that for a complete analysis of the information it is often necessary to use many tools in sequence.
Here we present GenomeCruzer, a software for 3D interactive visualization and analysis of multidimensional omic data sets (e.g. gene expression, methylation, copy number alteration). GenomeCruzer is particularly useful to quickly achieve clinical and biological insight, providing easy integration and interactive visualization of genomic data of any kind. GenomeCruzer has the dual objectives of representing large amounts of genomic data in an easily readable way, allowing interactive analysis and providing visual results in real-time. Powerful graphics also allow simultaneous display of different types of values for the same objects, through multiple dimensions and customizable visual metaphors. The user can navigate this 3D environment and interact with the different elements, which constitute a representation of the starting datasets, building analysis paths and using statistical tools e.g. for the comparison of groups to highlight correlations.
In conclusion, GenomeCruzer enables users without bioinformatics background to browse, analyse and interpret complex omics datasets for multiple groups of patients and genes simultaneously, extracting clinical correlates and biological knowledge.
Citation Format: Claudio Isella, Riccardo Corsi, Jamal Elhasnaoui, Andrea Bertotti, Luca Vezzadini, Enzo Medico. GenomeCruzer: A tool for interactive 3D visualization and analysis of multidimensional cancer omics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1201.
Abstract 1219: Unraveling alternative polyadenylation in prostate cancer with CORE-PAD
Authors: Imada Eddie L. , Wilks Christopher , Langmead Ben , Marchionni Luigi 
Published: June 2022

Abstract
Mechanisms that control gene expression at the RNA level are often referred to as post-transcriptional regulation (PTR) mechanisms. Splicing and polyadenylation (PA) are well-known examples of PTR that can regulate not only gene expression but also their function. Alternative Polyadenylation (APA) has already been shown to be essential to many biological processes (e.g., proliferation, cell differentiation, etc) and has also been implicated in the development and progression of multiple diseases (e.g., cancer, hematological and immune disorders, etc.). Although several sequencing methods have been developed to sequence only the transcript termination site (TTS), the number of publicly available data derived from these methods is extremely limited in comparison to traditional RNA-Seq data. To overcome this limitation, we created a new framework - Compositional Regression of Polyadenylation Differences (CORE-PAD) - for the study of differential APA events using traditional bulk RNA-seq data. Through simulated data, we showed that CORE-PAD has higher accuracy than other methods (accuracy = 0.98) in detecting APA events. We applied CORE-PAD across prostate cancer (PCa) samples with impaired CDK12 and “wild” samples. We found multiple genes presented differential PA site usage, including DNA repair genes. Most notably, we notice that many genes that exhibit differential APA were not differentially expressed at gene level, meaning they are potentially “silent drivers” that cannot be capture through standard differential gene expression analysis. These findings highlight the importance of studying APA, which can help shed light into another layer of regulation occurring between transcription and translation. This is especially important since these events can be source of neoantigens or targeted mRNA degradation which could be explore for new treatments. Finally, the CORE-PAD framework was designed to take advantage of our recently published recount3 resource making over 750,000 RNA-Seq samples of human and mouse origin readily available for analysis, enabling studies of APA across thousands of phenotypes in an accurate and accessible way.
Citation Format: Eddie L. Imada, Christopher Wilks, Ben Langmead, Luigi Marchionni. Unraveling alternative polyadenylation in prostate cancer with CORE-PAD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1219.