bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

Abstract
N-terminal processing by methionine aminopeptidases (MetAP) is a crucial step in the maturation of proteins during protein biosynthesis. Small-molecule inhibitors of MetAP2 have antiangiogenic and antitumoral activity. Herein, we characterize the structurally novel MetAP2 inhibitor M8891. M8891 is a potent, selective, reversible small-molecule inhibitor blocking the growth of human endothelial cells and differentially inhibiting cancer cell growth. A CRISPR genome-wide screen identified the tumor suppressor p53 and MetAP1/MetAP2 as determinants of resistance and sensitivity to pharmacologic MetAP2 inhibition. A newly identified substrate of MetAP2, translation elongation factor 1-alpha-1 (EF1a-1), served as a pharmacodynamic biomarker to follow target inhibition in cell and mouse studies. Robust angiogenesis and tumor growth inhibition was observed with M8891 monotherapy. In combination with VEGF receptor inhibitors, tumor stasis and regression occurred in patient-derived xenograft renal cell carcinoma models, particularly those that were p53 wild-type, had Von Hippel-Landau gene (VHL) loss-of-function mutations, and a mid/high MetAP1/2 expression score.
Data from Effects of Combined Therapeutic Targeting of AXL and ATR on Pleural Mesothelioma Cells
Authors: Hirai Soichi , Yamada Tadaaki , Katayama Yuki , Ishida Masaki , Kawachi Hayato , Matsui Yohei , Nakamura Ryota , Morimoto Kenji , Horinaka Mano , Sakai Toshiyuki , Sekido Yoshitaka , Tokuda Shinsaku , Takayama Koichi
Published: February 2024

Abstract
Few treatment options exist for pleural mesothelioma (PM), which is a progressive malignant tumor. However, the efficacy of molecular-targeted monotherapy is limited, and further therapeutic strategies are warranted to treat PM. Recently, the cancer cell-cycle checkpoint inhibitors have attracted attention because they disrupt cell-cycle regulation. Here, we aimed to establish a novel combinational therapeutic strategy to inhibit the cell-cycle checkpoint kinase, ATR in PM cells. The siRNA screening assay showed that anexelekto (AXL) knockdown enhanced cell growth inhibition when exposed to ATR inhibitors, demonstrating the synergistic effects of the ATR and AXL combination in some PM cells. The AXL and ATR inhibitor combination increased cell apoptosis via the Bim protein and suppressed cell migration when compared with each monotherapy. The combined therapeutic targeting of AXL and ATR significantly delayed regrowth compared with monotherapy. Thus, optimal AXL and ATR inhibition may potentially improve the PM outcome.
Abstract A053: Dynamic regulation of pyruvate carboxylase is required for immune evasion and pulmonary metastasis
Authors: Coleman Mike , Cotul Eylem Kulkoyluoglu , Teegarden Dorothy , Hursting Stephen , Wendt Mike K
Published: February 2024

Metabolic plasticity is an important mediator of tumor cell survival, growth in various microenvironments, and immune evasion. We present a dimorphic role for for the metabolic enzyme pyruvate carboxylase (PC) in pulmonary metastatic versus primary mammary tumors. Specifically, we demonstrate that PC is essential for metastatic outgrowth in the lungs. In contrast, depletion of PC in tumor cells promotes primary tumor growth. This affect was only observed in immune competent animals, leading us to address the hypothesis that repression of PC can suppress anti-tumor immunity. Exploring key differences between the pulmonary and mammary environments we demonstrate that hypoxia potently downregulated PC. Metabolomic analyses demonstrated that in the absence of PC, tumor cells produce more lactate and undergo less oxidative phosphorylation. Inhibition of lactate metabolism was sufficient to restore T cell populations to PC-depleted mammary tumors and drastcially inhibited primary tumor growth. Along these line, forced overexpression of PC decreased lactate production, increased immune inflitation, and prevented initiation of pulmonary metastases. These findings highlight a key contextual role for PC-directed lactate production as a metabolic nexus connecting hypoxia and antitumor immune suppression in primary tumors and intiating pulmonary metastases. However, following immune evasion and initiation of metastasis the return of PC expression is required for propagation of macroscopic pulmonary metastases.

Citation Format: Mike Coleman, Eylem Kulkoyluoglu Cotul, Dorothy Teegarden, Stephen Hursting, Mike K Wendt. Dynamic regulation of pyruvate carboxylase is required for immune evasion and pulmonary metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A053.
Abstract A070: Examining patient-specific responses to PARP inhibitors in a novel, human induced pluripotent stem cell-based model of breast cancer
Authors: Weddle Carly , Burridge Paul
Published: February 2024

Patient-derived human induced pluripotent stem cells (hiPSCs) are a powerful tool for disease modeling because hiPSCs provide a scalable source of cells that retain patient-specific genomic variants. Recently, somatic cell reprogramming has been applied to modeling cancer: cancer cells are reprogrammed into hiPSCs, then re-differentiated into the relevant cancer cell lineage. hiPSCs derived from cancer cells retain tumor- and subclone-specific genomic variants and drug sensitivities, providing a unique tool to deconstruct the contributions of tumor heterogeneity to drug response. While hiPSCs have been shown to model various hematological malignancies, no study to date has examined the potential of hiPSCs to model breast cancer. We demonstrate for the first time that primary human breast cancer cells can be reprogrammed into hiPSCs by transiently overexpressing canonical reprogramming factors. Using an optimized reprogramming methodology, we generated a biobank of >200 hiPSC lines from 10 breast tumor samples, including hormone receptor positive, HER2 positive, and triple negative breast tumors. Breast tumor-derived hiPSCs retain patient-specific oncogenic variants. Additionally, we present a protocol to differentiate hiPSCs into mammary epithelial cells (hiPSC-MECs) and mammary-like organoids for in vitro disease modeling. hiPSC-MECs are proliferative and exhibit a gene expression profile that closely resembles primary MECs. Finally, we demonstrate that this breast tumor model can be used to assess patient-specific responses to PARP inhibitors. We show that hiPSC-MECs derived from BRCA1 and BRCA2 mutant tumors are deficient in homology-directed repair and are more sensitive to PARP inhibitor treatment. This work establishes the foundation of hiPSCs as a novel disease modeling platform for breast cancer and highlights the potential of tumor-derived hiPSCs to predict patient and subclone-specific drug responses.

Citation Format: Carly Weddle, Paul Burridge. Examining patient-specific responses to PARP inhibitors in a novel, human induced pluripotent stem cell-based model of breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A070.
Abstract A074: Targeting dormant disseminated tumor cells and their permissive niche by pro-resolving mediators derived from resolution-phase macrophages
Authors: Gilon Odelya , Weidenfeld Keren , Samara Hadell , Feuermann Yonatan , Schif-Zuck Sagie , Butenko Sergei , Sabo Edmond , Ariel Amiram , Barkan Dalit
Published: February 2024

Metastatic breast cancer can recur years after primary tumor resection and adjuvant therapy and appears to arise from quiescent disseminated tumor cells (QDTC) that persist at distant sites and resist conventional therapies. To date there are no treatments to target QDTCs. Previously, the fibrotic-like microenvironment enriched with Type I collagen (Col-I) was shown to be required for the switch of QDTC to metastatic outgrowth in lungs of mice. Here, we examined whether soluble mediators secreted by ex-vivo generated pro-resolving CD11blow macrophages (CM-Mres) will reinstate resolution of inflammation thus inhibiting the establishment of the fibrotic-like-niche and in turn prevent the emergence of QDTC to metastatic outgrowth. Our findings indicate that CM-Mres promoted immune silencing of alveolar macrophages at the metastatic site where dormant DTCs reside. Immune silencing is one of the hallmarks of resolution of inflammation. Furthermore, CM-Mres inhibited the establishment of a fibrotic-like niche resulting in the inhibition of the metastatic outgrowth in vitro and in vivo. This was due to inhibition of fibroblasts differentiation to myofibroblasts independent of TGFbeta1 canonical signaling and abolishment of Col-I expression. Furthermore, CM-Mres deactivated myofibroblasts as part of the resolution process by inducing an increase in reactive oxygen species (ROS) via activation of NADPH oxidase. This in turn induced DNA damage leading to Go/G1 arrest and intrinsic apoptosis. Similarly, apoptosis mediated by oxidative stress was induced by CM-Mres in dormant and outbreaking QDTCs. Taken together our results demonstrate for the first time that by reinstating resolution of inflammation via physiological mediators, secreted by pro-resolving macrophages, can prevent metastatic outgrowth of QDTCs at their permissive site. Since conventional therapies fail to eradicate dormant DTCs and their transition to clinical metastasis, our findings hold great promise in the quest to identify novel strategies to prevent or treat recurrent metastatic disease.

Citation Format: Odelya Gilon, Keren Weidenfeld, Hadell Samara, Yonatan Feuermann, Sagie Schif-Zuck, Sergei Butenko, Edmond Sabo, Amiram Ariel, Dalit Barkan. Targeting dormant disseminated tumor cells and their permissive niche by pro-resolving mediators derived from resolution-phase macrophages [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A074.
Abstract A090: Gender Disparities in the National Institutes of Health Funding for Breast Oncology
Authors: Ukrani Janta , Sohail Aruba , Khan Sarah , Zahid Ibrahim , Farooq Muhammad Zain , Jaglal Michael Vishal
Published: February 2024

Introduction As a matter of course, there has been an under-representation of women in academic medicine, resulting in discriminatory distribution of research grants. This study examines the trend of funding allocation of R01 grants in Breast oncology by the National Institutes of Health with specific focus on the distribution of funding between gender. Methods The data were retrieved from the NIH RePORTER (Research Portfolio Online Reporting Tools Expenditure) using breast oncology-related search terms from 2018-2021. The gender was categorized using Genderize. The number of citations, publications, H-index, and seniority were obtained from Scopus and Web of Science in December 2022. Consumer Price Index was used to adjust funding amount to 2021 equivalent U.S. dollars. Linear regression was used for analysis. Results A total of 885 NIH-funded R01 grants amounting to $444.6 million were awarded for breast oncology research. Women (n=390; 44.1% [95% CI: 40.8%-47.3%]) received relatively fewer grants than men (n=495; 55.9% [95% CI: 52.7%-59.2%]). From 2018-2021, there was a significant increase in the number of grants awarded among both men (90 to 155, p<0.01) and women (71 to 115, p=0.036). Similarly, there was a significant increase in the grant amount (in millions) awarded among men (43.4 to 76.5, p<0.01) but not in women (36.7 to 56.1, p=0.11). Of the 212 co-PIs, 133 (62.7% [95% CI: 56.2%-69.2%]) were men and 76 (37.3% [95% CI: 30.8%-43.8%]) were women. There was no significant difference in h-index (48 vs 44, p=0.12), number of publications (158 vs 138, p=0.08), and citations (13272 vs 8092, p=0.06) between the male and female PIs. Funding amount was significantly associated with number of publications (β=0.35, p<0.01), seniority (β=0.25, p<0.01) and institution (p<0.01). Conclusion Our analysis shows continued gender disparity as only 44% of total R01 grants were awarded towards females for breast oncology between the fiscal years 2018 to 2021. Though the proportion of discrepancy is lower as compared to other malignancies. A collaborative effort is still needed to bridge the gap and advance gender equality.

Citation Format: Janta Ukrani, Aruba Sohail, Sarah Khan, Ibrahim Zahid, Muhammad Zain Farooq, Michael Vishal Jaglal. Gender Disparities in the National Institutes of Health Funding for Breast Oncology [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A090.
Abstract B017: Elucidating the role of CPPED1 in triple-negative breast cancer
Authors: Zomorrodinia Talieh
Published: February 2024

Triple-negative breast cancer (TNBC) represents a daunting challenge in clinical oncology due to its aggressive nature and limited treatment options. In light of this unmet need, our research efforts are to gain comprehensive insights into the mechanisms underlying TNBC and explore novel therapeutic strategies. We have identified an enzyme, calcineurin-like phosphoesterase domain-containing protein 1 (CPPED1), that functions as a phosphatase targeting phospho-serine/threonine residues and is amplified in breast cancer. While previous studies on bladder cancer linked CPPED1 to promoting cell death, our preliminary findings in TNBC cell lines, MDA-MB-231 and HS578T, present a contrasting role. Knockdown of CPPED1 in TNBC cell lines leads to reduced cell colony formation and increased apoptosis, indicating its role in promoting cell proliferation in TNBC. Analysis of human patient data from TCGA also shows that expression of CPPED1 is associated with poor survival in both ER+ and ER- breast cancer. These observations hint at CPPED1's potential to exhibit diverse molecular characteristics depending on the cancer type. By thoroughly elucidating the molecular mechanisms and functional role of CPPED1 in breast cancer, our research holds promise in guiding the development of targeted and more effective treatments tailored to address the challenges posed by TNBC.

Citation Format: Talieh Zomorrodinia. Elucidating the role of CPPED1 in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B017.
Abstract IA13: Molecular and genomic mechanisms of estrogen signaling and gene regulation in breast cancer
Authors: Kraus W. Lee
Published: February 2024

Transcriptional enhancers function as nucleation sites for the assembly of transcription-regulating complexes across the genome, which act to drive cell type-specific patterns of gene expression. Although many features of active enhancers [e.g., H3K4me1, H3K27ac, enrichment of p300/CBP and Mediator, and production of enhancer RNAs (eRNAs)] have been defined by genomic assays, the roles of these features in estrogen receptor alpha (ERa) enhancer function are not well understood. We are interested in how the molecular underpinnings of ERa enhancer formation and activity control the gene expression programs that drive breast cancer phenotypes and responses to therapeutic agents. We have used a variety of molecular, biochemical, genomic, genetic, and computational approaches to determine the following aspects of ERa enhancers biology in hormone-responsive breast cancer cells: (1) where ERa enhancers are formed across the genome, (2) the kinetics of ERa enhancer formation and disassembly, (3) the influence of genetic variation on ERa enhancer function, (4) the role of the enhancer features noted above in ERa enhancer function, and (5) how protein complexes and small polypeptides serve as coregulators to drive ERa transcriptional activity. Our current focus has been on eRNAs, which are poorly characterized noncoding RNAs that are thought to regulate enhancer function and gene expression. We have identified a ~40 nucleotide functional eRNA regulatory motif (FERM) present in many estrogen-regulated eRNAs that promotes gene expression by increasing ERα recruitment and stimulating p300-catalyzed H3K27 acetylation. In addition, we have been examining how the dose of estrogen impacts the efficiency of enhancer assembly by ERα. Finally, we have been exploring the role of PARP1, a ubiquitous chromatin-associated regulator, and small polypeptides derived from “non-coding” RNAs, control ERa enhancer function. In all cases, we perform analyses to link enhancer function to gene expression outcomes and breast cancer biology. Collectively, our results demonstrate the biological and mechanistic roles of eRNAs in breast cancer. This work is supported by grants from the NIH/NIDDK (DK058110) and CPRIT (RP160319) to W.L.K.

Citation Format: W. Lee Kraus. Molecular and genomic mechanisms of estrogen signaling and gene regulation in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA13.
Abstract A025: Adaptive therapy: Leveraging evolutionary dynamics for colorectal cancer management in vivo
Authors: Richker Harley I. , Marquez-Alcaraz Gissel , Maley Carlo
Published: February 2024

Therapeutic resistance to chemotherapy is frequently the proximate cause of cancer treatment failure and, ultimately, patient mortality. Evolutionary therapies have been developed to address this problem and potentially reduce toxicities. The most successful strategy to date, adaptive therapy (AT), is designed to use chemosensitive cells to out-compete and suppress the chemoresistant cells. However, detailed observations to elucidate the mechanisms of AT's success are lacking. Typically, AT involves lowering the dose of the chemotherapy, thereby reducing toxicity and preserving the immune system. We are evaluating AT for the first time in colorectal cancer, using syngeneic orthotopic xenograft models. This project marks several firsts: 1) sensitive and resistant clones will be tracked longitudinally, 2) AT will be tested with a targeted therapy (MRTX1133), 3) AT will be tested in an immune competent model, 4) multiple drugs will be used for AT, and 5) extinction therapy will be tested in mice. We will employ genetic barcodes and differential luciferase tagging to track the tumor cell subpopulations longitudinally. Currently, we are conducting an in-vivo pilot experiment to validate our protocol, emphasizing tumor engraftment efficacy and tracking cell subpopulations. Additionally, we are investigating the potential of Lactobacillus acidophilus to inhibit tumor growth, augment chemotherapy, and bolster immune response in colorectal cancer.

Citation Format: Harley I. Richker, Gissel Marquez-Alcaraz, Carlo Maley. Adaptive therapy: Leveraging evolutionary dynamics for colorectal cancer management in vivo [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A025.
Abstract B041: Identification of m3C modification sites within mRNAs of pancreatic cancer cells by long-read direct RNA sequencing
Authors: Mitsutomi Shuhei , Sugawara Anzu , Takahashi Kenji , Mizukami Yusuke , Akimitsu Nobuyoshi , Taniue Kenzui
Published: February 2024

Chemical modification is a precise and effective way to control the biogenesis, stability, and function of biological molecules, such as nucleic acids, proteins, and lipids. More than 170 different types of modifications have been discovered in coding and non-coding RNAs, constituting a diverse RNA modification landscape, called epitranscriptome. RNA modifications were mediated by three types of proteins: writers, erasers, and readers. Recently, RNA modification machinery has been dysregulated in several types of cancers and may be promising targets for cancer therapy. 3-methylcytidine (m3C), which is catalyzed by METTL2A, 2B, 6, and 8, is found at position 32 of cytoplasmic tRNAs in organisms ranging from yeast to humans, however, their functions and regulatory machinery in mRNA and non-coding RNA has not been clarified because there were no effective anti- m3C antibodies. Here we discovered that the expression of m3C writers was higher in pancreatic tumors than in noncancerous tissues. We further found that METTL2A expression is associated with a poor prognosis in pancreatic cancer patients. We also showed that METTL2A depletion led to a reduction in the growth of AsPC1 cells. We next attempted to identify the m3C sites in cellular transcripts regulated by METTL2A in AsPC1 cells using long-read direct RNA sequencing. We corrected the transcriptome using ESPRESSO and searched for the RNA modifications using Nanocompore. We then found that METTL2A targets the NYCYN motif in mRNAs and mitochondrial rRNAs. Moreover, we found that transcripts with METTL2A-mediated m3C modification were upregulated in AsPC-1 cells knocked down by METTL2A. Our study provides evidence for METTL2A-mediated down-regulation of target mRNAs via m3C modification in the survival of pancreatic tumor cells.

Citation Format: Shuhei Mitsutomi, Anzu Sugawara, Kenji Takahashi, Yusuke Mizukami, Nobuyoshi Akimitsu, Kenzui Taniue. Identification of m3C modification sites within mRNAs of pancreatic cancer cells by long-read direct RNA sequencing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B041.
Abstract IA006: Leveraging the extreme selection induced by therapeutic bottlenecks to subvert resistance via identifying evolutionarily-informed targets for orthogonal immunotherapy
Authors: Fisk J. Nic , Politi Katerina , Gettinger Scott , Townsend Jeffrey P
Published: February 2024

Evolutionary dynamics underlie carcinogenesis, with tumor cells constantly adapting, resulting in cell populations that outgrow their non-tumor cell neighbors, evade treatment, and ultimately lead to death. Well-designed therapies to treating cancer induce immense and specific selection. The heterogenous cancer cell population either goes extinct or continues to evolve during and in response to the therapeutically induced bottleneck, leading to a subsequent selective sweep and newfound prominence of cells exhibiting the resistance phenotype. However, this bottleneck period provides a unique opportunity wherein the diversity of cells constituting the tumor is predictably reduced. Here, we introduce a framework to quantify the selection upon variants before, during, and after the therapeutic bottleneck, facilitating richer understanding of the mechanisms by which therapeutic resistance is acquired. We additionally couple measures of selection intensity with the prediction of neoantigens in a cohort of patients to identify potential orthogonal targets for immunotherapy. The result is a schema for leveraging predictability induced by the primary therapeutic bottleneck to drive the remnant tumor cell population to extinction. Finally, we demonstrate the utility of this schema in mutant EGFR lung adenocarcinoma.

Citation Format: J. Nic Fisk, Katerina Politi, Scott Gettinger, Jeffrey P Townsend. Leveraging the extreme selection induced by therapeutic bottlenecks to subvert resistance via identifying evolutionarily-informed targets for orthogonal immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA006.
Abstract IA013: Using genetic ancestry in genomics of tumor evolution
Authors: Davis Melissa B.
Published: February 2024

The burgeoning field of genomic science, particularly in the context of cancer research, has undergone a transformative shift with the incorporation of genetic ancestry in understanding tumor evolution. The work of Melissa B. Davis highlights this paradigm shift, revealing how biases within genomic data, primarily due to the underrepresentation of diverse ethnic groups, have historically influenced our understanding of cancer disparities. Davis's research emphasizes the critical importance of including diverse ethnic groups in genomic studies, not merely as a token inclusion but as a rigorous scientific necessity. Her research demonstrates that by integrating genetic ancestry into the study of tumor biology, we can gain a more comprehensive understanding of cancer's evolution and behavior. This approach is instrumental in identifying unique genetic markers and pathways influenced by ancestry, which may contribute to differences in cancer incidence, progression, and treatment response among different populations. Davis's work thus represents a significant stride towards personalized medicine, where treatment strategies can be tailored not just to the individual's genetic makeup but also to their ancestral background. This shift in focus towards a more inclusive genomic science has the potential to bridge the gap in cancer care disparities. By acknowledging and addressing these disparities, research spearheaded by scientists like Davis paves the way for more equitable healthcare outcomes. The inclusion of genetic ancestry in the study of tumor evolution is more than a scientific advancement; it's a step towards justice and equity in healthcare, ensuring that all groups benefit equally from the advancements in cancer research and treatment.

Citation Format: Melissa B. Davis. Using genetic ancestry in genomics of tumor evolution [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA013.
Abstract PR016: Topology of the tumor microenvironment: Integrating imaging, modeling, and topological data analysis
Authors: Barker-Clarke Rowan , Gray Jason M. , Scott Jacob G.
Published: February 2024

Cancer evolution involves multiple stochastic processes across many scales. In addition to genomic and transcriptomic changes, hallmarks of cancer within solid tumors include the malignant co-evolution of the tumor microenvironment. Although the evaluation of tissue architecture plays a key role in pathologist staging, the automated extraction of additional structural features remains far from translation to the clinic. However, one particularly effective novel methodology for extracting patterns from these clinical images is topological data analysis(TDA). TDA is a field that studies the shape of data and its connectedness using concepts from geometric and algebraic topology. Recent work using topological data analysis has allowed the extraction of image features. Such features have been associated with clinical outcomes in both the analysis of H&E images in prostate cancer and CT images in lung cancer. We set out to question how the topological features of tissues, including tumor and stromal composition, evolve during treatment and between original sites and metastasis. To analyze this we use a combination of tissue sections, imaging, and cell-automata models and persistent homology and cubical persistence techniques from TDA. We apply certain topological methods for the first time to tissue images (H&E) and to the output of spatial simulations. We focus specifically on analyzing the evolution of topological features in ovarian and lung cancer and compare our features to 2D and 3D simulations (HAL) with varying game theoretical interactions as well as comparing features across tissues from matched primary and metastatic sites. We find that several topological features are conserved between primary and metastatic sites and some feature evolution is replicated in simulation.

Citation Format: Rowan Barker-Clarke, Jason M. Gray, Jacob G. Scott. Topology of the tumor microenvironment: Integrating imaging, modeling, and topological data analysis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR016.
Supplementary Figure 2 from PKCδ Regulates Chromatin Remodeling and DNA Repair through SIRT6
Authors: Affandi Trisiani , Haas Ami , Ohm Angela M. , Wright Gregory M. , Black Joshua C. , Reyland Mary E.
Published: February 2024

Supplementary Figure 2. PKCð regulates expression of genes required for DNA repair.
Supplementary Figure 5 from SOX10 Loss Sensitizes Melanoma Cells to Cytokine-Mediated Inflammatory Cell Death
Authors: Rosenbaum Sheera R. , Caksa Signe , Stefanski Casey D. , Trachtenberg Isabella V. , Wilson Haley P. , Wilski Nicole A. , Ott Connor A. , Purwin Timothy J. , Haj Jelan I. , Pomante Danielle , Kotas Daniel , Chervoneva Inna , Capparelli Claudia , Aplin Andrew E.
Published: February 2024

Cytokine treatment leads to caspase cleavage in SOX10-knockout cells
Supplementary Figure 1 from Integrating Clinical Cancer and PTM Proteomics Data Identifies a Mechanism of ACK1 Kinase Activation
Authors: Balasooriya Eranga R. , Madhusanka Deshan , López-Palacios Tania P. , Eastmond Riley J. , Jayatunge Dasun , Owen Jake J. , Gashler Jack S. , Egbert Christina M. , Bulathsinghalage Chanaka , Liu Lu , Piccolo Stephen R. , Andersen Joshua L.
Published: February 2024

Machine learning model predicts cancer driver mutations.
Overcoming Clinical Resistance to EZH2 Inhibition Using Rational Epigenetic Combination Therapy
Authors: Kazansky Yaniv , Cameron Daniel , Mueller Helen S. , Demarest Phillip , Zaffaroni Nadia , Arrighetti Noemi , Zuco Valentina , Kuwahara Yasumichi , Somwar Romel , Ladanyi Marc , Qu Rui , de Stanchina Elisa , Dela Cruz Filemon S. , Kung Andrew L. , Gounder Mrinal M. , Kentsis Alex
Published: February 2024

Epigenetic dependencies have become evident in many cancers. On the basis of antagonism between BAF/SWI-SNF and PRC2 in SMARCB1-deficient sarcomas, we recently completed the clinical trial of the EZH2 inhibitor tazemetostat. However, the principles of tumor response to epigenetic therapy in general, and tazemetostat in particular, remain unknown. Using functional genomics and diverse experimental models, we define molecular mechanisms of tazemetostat resistance in SMARCB1-deficient tumors. We found distinct acquired mutations that converge on the RB1/E2F axis and decouple EZH2-dependent differentiation and cell-cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest, suggests a general mechanism for effective therapy, and provides prospective biomarkers for therapy stratification, including PRICKLE1. On the basis of this, we develop a combination strategy to circumvent tazemetostat resistance using bypass targeting of AURKB. This offers a paradigm for rational epigenetic combination therapy suitable for translation to clinical trials for epithelioid sarcomas, rhabdoid tumors, and other epigenetically dysregulated cancers.

Significance:

Genomic studies of patient epithelioid sarcomas and rhabdoid tumors identify mutations converging on a common pathway for response to EZH2 inhibition. Resistance mutations decouple drug-induced differentiation from cell-cycle control. We identify an epigenetic combination strategy to overcome resistance and improve durability of response, supporting its investigation in clinical trials.

See related commentary by Paolini and Souroullas, p. 903.

This article is featured in Selected Articles from This Issue, p. 897
Gut Mycobiota Dysbiosis Is Associated with Melanoma and Response to Anti–PD-1 Therapy
Authors: Szóstak Natalia , Handschuh Luiza , Samelak-Czajka Anna , Tomela Katarzyna , Pietrzak Bernadeta , Schmidt Marcin , Galus Łukasz , Mackiewicz Jacek , Mackiewicz Andrzej , Kozlowski Piotr , Philips Anna
Published: February 2024

Recent research indicates that gut microbiota may be vital in the advancement of melanoma. In this study, we found that melanoma patients exhibited a distinct gut mycobiota structure compared with healthy participants. Candida albicans, Candida dubliniensis, and Neurospora crassa were more abundant in samples from patients with melanoma, whereas Saccharomyces cerevisiae and Debaryomyces hansenii were less abundant. During anti–PD-1 treatment, the relative amount of Malassezia restricta and C. albicans increased. A higher level of Saccharomyces paradoxus was associated with a positive response to anti–PD-1 treatment, whereas a higher level of Tetrapisispora blattae was associated with a lack of clinical benefits. High levels of M. restricta and C. albicans, elevated serum lactate dehydrogenase, and being overweight were linked to increased risk of melanoma progression and poorer response to anti–PD-1 treatment. Thus, this study has revealed melanoma-associated mycobiome dysbiosis, characterized by altered fungal composition and fungi species associated with a higher risk of melanoma progression, identifying a role for the gut mycobiome in melanoma progression.
Table S7 from Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses
Authors: Napoli Marco , Deshpande Avani A. , Chakravarti Deepavali , Rajapakshe Kimal , Gunaratne Preethi H. , Coarfa Cristian , Flores Elsa R.
Published: February 2024

List of transcriptional factor motifs differentially enriched in the 3 groups of TAp63-specific direct target genes, ∆Np63-specific direct target genes, and common direct target genes. For the analysis of the transcription factor motifs only the 2 kb regions surrounding the p63 peaks in each of the 3 groups of genes were considered.
Table S6 from Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses
Authors: Napoli Marco , Deshpande Avani A. , Chakravarti Deepavali , Rajapakshe Kimal , Gunaratne Preethi H. , Coarfa Cristian , Flores Elsa R.
Published: February 2024

List of identified metabolites detected via liquid chromatography-high resolution mass spectrometry in TAp63-/- vs. WT mouse epidermal cells.
Supplementary Figure S2 from Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses
Authors: Napoli Marco , Deshpande Avani A. , Chakravarti Deepavali , Rajapakshe Kimal , Gunaratne Preethi H. , Coarfa Cristian , Flores Elsa R.
Published: February 2024

Identification of ∆Np63 and TAp63 regulated transcriptomes
Long-Term Follow-Up of a Case of Severe Hyperglycemia Requiring Hospitalization after Third Dose of Teprotumumab: A Case Report
Authors: Mehta Preeya , Angell Trevor , LeTran Vivian , Lin Michael , Nguyen Annie , Zhang-Nunes Sandy
Published: February 2024

Introduction: In 2020, teprotumumab became the first FDA-approved treatment for thyroid eye disease (TED). In clinical trials, hyperglycemia had been described as mild and controlled with medication. We present a case that occurred in 2020 of a 67-year-old male with TED and pre-existing glucose intolerance, who was hospitalized with severe hyperglycemia (1,059 mg/dL) after three doses of teprotumumab. Case Presentation: This patient’s HbA1c was in the pre-diabetic range (6.3%) 6 months prior to initiating teprotumumab. After three doses, the patient was hospitalized with hyperosmolar hyperglycemic nonketotic syndrome and an HbA1c of 11.7%. He was diagnosed with type 2 diabetes mellitus and treated with insulin aspart mixed 70/30. He remained on this regimen for 14 months with an A1c of 6.0%. He then self-discontinued the insulin, with an A1c 4 months later measuring 5.5%. The patient’s latest HbA1c approximately two and a half years after hospitalization was 6.1% on no medications. Conclusion: It appears that teprotumumab was a trigger for this transient case of diabetes, and detecting those that have underlying glucose intolerance ahead of time is important. We recommend blood glucose levels for patients with pre-diabetes prior to and ideally in the first few days after each infusion, to help determine patients at a greater risk for adverse hyperglycemic outcomes. A glucometer may be valuable for patients to self-monitor while on teprotumumab. If fasting blood glucose is ≥126 mg/dL or non-fasting glucose is >200 mg/dL, patients should be referred for further diabetes assessment and possible treatment initiation.
Successful Retrieval of a Broken Aspiration Needle Penetrated into the Right Pulmonary Artery: A Case Report with Experience Sharing
Authors: Tang Fei , Zhu Feng , Wang Bin , Dong Zhe , Yu Yao , Li Yuan , Lyu Liping , Ma Dongchun
Published: February 2024

Introduction: Endobronchial ultrasound-guided transbronchial needle aspiration is increasingly used as a minimally invasive procedure in clinical settings. It is generally regarded as a safe procedure with high diagnostic accuracy. However, a complication involving a needle fracture that penetrated a nearby artery has not been reported during this procedure. Case Presentation: A male patient, 58 years of age, underwent endobronchial ultrasound-guided transbronchial needle aspiration for a mediastinal lymph node biopsy at a local hospital. The aspiration needle fractured and penetrated from the right middle segmental bronchus into the right pulmonary artery. The patient was then transferred to our hospital. After conducting repeated chest imaging examinations to confirm the presence of the foreign body and holding multidisciplinary team consultations, we first inserted a deflated balloon catheter near the puncture site in the right middle segmental bronchus. Following the needle retrieval through a flexible bronchoscope, the balloon catheter was inflated to ensure local hemostasis. Follow-up evaluations revealed no further complications for this patient. Conclusion: Intragenic vascular injury can occur during endobronchial ultrasound-guided transbronchial needle aspiration. Careful pre-procedure preparations should be planned to minimize complications. In patients experiencing complications due to needle penetration, consultation and coordination with a multidisciplinary team are essential to ensure the safe retrieval of the broken needle.
O narrador benjaminiano no conto “meu tio o iauaretê: rememoração no conto rosiano como experiência autêntica
Authors: Nascimento Esaú Brilhante do
Published: February 2024

O objetivo deste trabalho é entender a rememoração no conto como uma tentativa de “salvar” os fenômenos históricos, em uma experiência autêntica. A forma literária de Guimarães Rosa, nesse caso, seu projeto linguístico, é a possibilidade dessa outra forma de narrar. Para isso, usaremos a análise dialética de Walter Benjamin em “O Narrador” e seu diagnóstico sobre o fim da narrativa tradicional, exatamente para apresentar no conto uma busca por uma narração que consiga dar conta dos fenômenos apresentados.
Heranças ancestrais em O sumiço da Santa, de Jorge Amado: oralidade, provérbios, rituais e religião de matriz africana
Authors: Ferretti Fransueiny Pereira Fleischmann , Leonardeli Poliana Bernabé
Published: February 2024

Este artigo tem o objetivo de evidenciar as heranças ancestrais presentes na obra amandiana O sumiço da Santa (1988). A ancestralidade africana movimenta o enredo da obra representando a sociedade de Salvador. A partir de uma pesquisa bibliográfica, este artigo analisa trechos que destacam a oralidade, o culto à religião de matriz africana, a utilização de provérbios e os rituais presentes nos terreiros e no cotidiano das pessoas. Utilizou-se estudos de Hambaté Bâ (2010), Lopes e Simas (2020) e Pierre Verger (1997).
Tereza Batista cansada de guerra: um olhar feminista acerca da personagem
Authors: Gerasch Larissa , Felippi Ângela Cristina Trevisan
Published: February 2024

Este trabalho analisa, a partir de uma pesquisa bibliográfica, a personagem Tereza Batista, do romance Tereza Batista cansada de guerra (1972), de Jorge Amado. O contexto no qual a obra foi produzida e a sua relação com o feminismo atual foram levados em consideração, assim como a influência da maternidade e da sexualidade na construção da identidade feminina. A análise da obra permitiu uma leitura contemporânea feminista a partir de uma perspectiva interseccional.
O espaço entre o imaginativo e o factual: venturas e desventudas de dois meninos pela Bahia, de Jorge Amado, e a Angola, de Ondjaki
Authors: Moreira Cristiane Aparecida Francisca
Published: February 2024

Este artigo pretende fazer uma reflexão a respeito das possíveis representações da infância, em suas múltiplas nuances, vividas dentro de um espaço físico adverso devido a motivações sociais e/ou políticas. Para isso, faremos uma análise comparativa entre os romances Capitães da Areia, do escritor brasileiro Jorge Amado e Bom dia, Camaradas, do autor angolano Ondjaki. Nesse sentido, pretendemos entender como essas infâncias são retratadas no âmbito da chamada literatura engajada ou literatura de resistência.
Jorge Amado: pós-produção e intermídia a partir de Capitães da Areia
Authors: Saraiva Filismina Fernandes , Leite Gildeci de Oliveira , Araújo Nerivaldo Alves , Fernandes Alexandre de Oliveira
Published: February 2024

Tratar-se-á neste texto de aspectos da pós-produção e intermídia através do ressurgimento da canção “Capitão de Areia”, inspirada na obra literária “Capitães da Areia” de Jorge Amado (2008). Para tanto foram utilizados os métodos bibliográfico e netnográfico, pensando a realidade de maneira qualitativa. Constatou-se a contribuição da pós-produção e da intermídia no reviver tanto da canção, quanto do romance e ainda mais para afirmar a atualidade e a pertinência contemporânea da obra romanesca.
Direitos de decisão, percepção facilitadora de indicadores de desempenho e empoderamento psicológico: Quase-experimento de campo com operadores de call center
Authors: Bordin Maximilian Zanelato , Mendonça Neto Octávio Ribeiro de , Aguiar Andson Braga de , Oyadomari José Carlos Tiomatsu
Published: February 2024

Este estudo conduz um quase-experimento de campo para examinar benefícios individuais da delegação de direitos de decisão para operadores de call center. O grupo experimental foi composto por 25 operadores de um call center de pós-venda que tiveram ampliado seus direitos de decisão; para fins de comparabilidade, foram selecionados como grupo de controle 20 operadores de outro call center da própria empresa que não sofreram alterações em seus direitos de decisão. Relativamente ao grupo de controle, o grupo experimental apresentou aumento de percepção facilitadora dos indicadores de desempenho e de empoderamento psicológico. Adicionalmente, parte do benefício de maior empoderamento psicológico causado por maior nível de direitos de decisão é explicado pela maior percepção facilitadora dos indicadores de desempenho. A principal implicação prática destes resultados é que organizações interessadas em ampliar o sentimento de empoderamento psicológico de seus colaboradores podem encontrar nos controles gerenciais um mecanismo efetivo para essa finalidade.
Nudge: Empurrando para longe o gerenciamento de resultados
Authors: Moreira Caritsa Scartaty , Sousa Rossana Guerra de , Martins Orleans Silva , Aguiar Andson Braga de
Published: February 2024

This research aimed to verify the effects of using nudges in reduction of earnings management. The study was classified as a between-subjects experiment. The sample consisted of 40 accountants.  Descriptive statistics, Analysis of Variance, Structural Equation Model, and mean tests were used for data analysis and interpretation. The results revealed three main findings, as support for the developed hypotheses. First, the level of earnings management by accounting professionals is lower in the presence of nudges than in their absence; second, the level of earnings management by accounting professionals is lower in the presence of an injunctive nudge issued by the leader than in its absence; and third, there is no difference in the level of earnings management by accounting professionals when the descriptive nudge is issued by the leader, compared to the absence of it.
Operários da cena: a divisão e a organização do trabalho cenotécnico
Authors: Nosella Berilo Luigi Deiró , Nascimento Priscila de Souza Chagas do
Published: February 2024

Este artigo aborda o ofício da cenotécnica, compreendido como um sistema operacional ativo nas realizações dos eventos teatrais, seja na organização do espaço cênico, seja na construção e operação dos aparatos cenográficos. Partimos das questões “o que é a cenotécnica?”, “o que faz a cenotécnica?” e “como se faz a cenotécnica?”, em adição a fatores como tempo, etapas, espaços, máquinas e ferramentas de trabalho, que são relacionados ao sujeito que os manipulam: o trabalhador cenotécnico. Foram analisados documentos legais, bibliografias e entrevistas produzidas com cenotécnicos atuantes na cidade de São Paulo que iniciaram suas carreiras na década de 1970. Tal conjunto investigativo compôs a pesquisa de mestrado que resultou na dissertação intitulada Cenotecnia, a criação dos operários da cena: um estudo sobre as funções dos trabalhadores cenotécnicos da cidade de São Paulo.
Preeclampsia Associated Differences in the Placenta, Fetal Brain, and Maternal Heart Can Be Demonstrated Antenatally: An Observational Cohort Study Using MRI
Authors: Hall Megan , de Marvao Antonio , Schweitzer Ronny , Cromb Daniel , Colford Kathleen , Jandu Priya , O’Regan Declan P , Ho Alison , Price Anthony , Chappell Lucy C. , Rutherford Mary A. , Story Lisa , Lamata Pablo , Hutter Jana
Published: February 2024

BACKGROUND:

Preeclampsia is a multiorgan disease of pregnancy that has short- and long-term implications for the woman and fetus, whose immediate impact is poorly understood. We present a novel multiorgan approach to magnetic resonance imaging (MRI) investigation of preeclampsia, with the acquisition of maternal cardiac, placental, and fetal brain anatomic and functional imaging.

METHODS:

An observational study was performed recruiting 3 groups of pregnant women: those with preeclampsia, chronic hypertension, or no medical complications. All women underwent a cardiac MRI, and pregnant women underwent a placental-fetal MRI. Cardiac analysis for structural, morphological, and flow data were undertaken; placenta and fetal brain volumetric and T2* (which describes relative tissue oxygenation) data were obtained. All results were corrected for gestational age. A nonpregnant cohort was identified for inclusion in the statistical shape analysis.

RESULTS:

Seventy-eight MRIs were obtained during pregnancy. Cardiac MRI analysis demonstrated higher left ventricular mass in preeclampsia with 3-dimensional modeling revealing additional specific characteristics of eccentricity and outflow track remodeling. Pregnancies affected by preeclampsia demonstrated lower placental and fetal brain T2*. Within the preeclampsia group, 23% placental T2* results were consistent with controls, these were the only cases with normal placental histopathology. Fetal brain T2* results were consistent with normal controls in 31% of cases.

CONCLUSIONS:

We present the first holistic assessment of the immediate implications of preeclampsia on maternal heart, placenta, and fetal brain. As well as having potential clinical implications for the risk stratification and management of women with preeclampsia, this gives an insight into the disease mechanism.