bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 84: Single-cell transcriptional analysis of multiple myeloma bone marrow aspirates using particle-templated instant partition sequencing (PIPseq)
Authors: Katzenelenbogen Yonatan , Zada Mor , Meltzer Robert , Fontanez Kristina , Amit Ido 
Published: April 2023

Abstract
Single-cell RNA-seq technologies have dramatically evolved in recent years. Despite these advances, the field faces some significant limitations in the versatility of current single cell technologies. These limitations include speed, ease of use, and the ability to sample both vast and minimal numbers of cells in a single batch - particularly in human samples. The PIPseq approach is based on Particle-templated Instant Partitions (PIPs) that allow single-cell encapsulation and barcoding using uniform droplet emulsions with minimal lab hardware. PIPseq is particularly effective for routine, high-throughput analysis of multiple myeloma bone marrow biopsies. Patients with multiple myeloma undergo a series of treatments aimed at depleting their malignant plasma cells (PC). Nevertheless, a high rate of relapse is observed despite low PC levels detected in the bone marrow (BM). Deep molecular profiling of the cellular pathways of rare PC, as well as their unique microenvironment, may shed light on the mechanisms underlying resistance to conventional therapies. As part of an ongoing clinical research, a bone marrow sample from a patient with multiple myeloma was molecularly characterized using the PIPseq T2 3’ Single Cell RNA Kit. Two distinct cell populations from a frozen BM biopsy were sorted into the T2 PIPseq tube: CD45+ cells (tumor microenvironment; TME) and rare malignant PC. In spite of the limited number of cells in the biopsy, PIPseq analysis clearly resolved both the malignant PC and the TME, demonstrating its utility for extensive analyses of fresh or frozen clinical myeloma samples.
Citation Format: Yonatan Katzenelenbogen, Mor Zada, Robert Meltzer, Kristina Fontanez, Ido Amit. Single-cell transcriptional analysis of multiple myeloma bone marrow aspirates using particle-templated instant partition sequencing (PIPseq) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 84.
Abstract 853: The impact of normal tissue density on tumor growth and evolution in a 3D whole-tumor model of lung cancer
Authors: Bravo Rafael Ramon , Robertson-Tessi Mark , Anderson Alexander R. , Gatenby Robert , Antonia Scott , Gray Jhanelle , Beg Amer , Schabath Matthew 
Published: April 2023

Abstract
We developed a novel modeling paradigm to specifically recapitulate 3D tissue at the resolution of CT imaging and yet capture single cell information: the population-based model (PBM). This PBM method allowed us to seed a model with individual cells that operate at the CT scale of cubic millimeters and grow to the scale of 10 cubic centimeters or more.
We used our PBM to investigate how well-known tumor traits of increased resource consumption and angiogenesis maybe differentially selected by a growing tumor in different densities of normal tissue. We found that tumor phenotypes that reduced consumption and increased angiogenesis grew the fastest in low density normal tissue, and vice versa in high density normal tissue.
We ran parameter sweeps of this model using temporal patient data from the NLST dataset, which consisted of untreated tumors in the low-density lung periphery. We saw that specific movement rate and proliferation rate parameters were required to fit the growth speed of the tumors, while a low consumption and high angiogenic phenotype was required to fit the radial density distribution of the tumors.
Citation Format: Rafael Ramon Bravo, Mark Robertson-Tessi, Alexander R. Anderson, Robert Gatenby, Scott Antonia, Jhanelle Gray, Amer Beg, Matthew Schabath. The impact of normal tissue density on tumor growth and evolution in a 3D whole-tumor model of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 853.
Abstract 855: Model-informed drug design (MIDD) exploration of a theoretical CD47xTAA bispecific antibody using available data from magrolimab, an anti-CD47 monoclonal antibody
Authors: Pace Emily A. , Millard Bjorn L. 
Published: April 2023

Abstract
Purpose: The goal of this study is to outline the process and utility of using fit-for-purpose, semi-mechanistic PK/PD modeling to inform the design of a theoretical CD47 bispecific antibody targeted to a generic tumor-associated antigen (CD47xTAA bsAb) with improved efficacy, tolerability, and PK compared to single target anti-CD47 therapies. Approach: To help guide the CD47xTAA bsAb design, a 3-compartment human model was built to include a target-mediated drug disposition (TMDD) component from CD47 expressed on red blood cells (RBC), white blood cells (WBC), and cells in the peripheral compartment. The model was parameterized using available literature data and calibrated against magrolimab human PK data that exhibited potential TMDD. The magrolimab model was used to identify key CD47 receptor occupancy (RO) thresholds associated with tolerability (the priming dose threshold) and efficacy (the recommended Phase 2 dose/RP2D threshold). Next, assumed drug properties and TAA expression levels for a CD47xTAA bsAb were implemented in a similar human model and drug PK and doses required to match key CD47 RO thresholds were explored across a range of single-arm binding affinities. Results: The calibrated magrolimab model projected target engagement levels on RBCs and WBCs and showed rapid antibody-induced CD47 pruning on RBCs that is consistent with clinical PD measurements. At TAA binding affinities that produce sufficient binding to tumor antigen, the model predicts that lowering the CD47 binding affinity allows for a higher starting dose that matches the priming threshold, while lowering the dose required to match the RP2D threshold. The model also shows that lowering the binding affinity to CD47 may improve PK exposure in the tumor compartment by reducing systemic CD47 TMDD. Conclusions: This modeling exercise demonstrates how semi-mechanistic PK/PD models can be used in model-informed drug design (MIDD) by leveraging the targeting advantage of avid bispecific antibody therapies and by using publicly available preclinical and clinical data. Furthermore, these model projections can help inform future studies with bispecific CD47 drug candidates.
Citation Format: Emily A. Pace, Bjorn L. Millard. Model-informed drug design (MIDD) exploration of a theoretical CD47xTAA bispecific antibody using available data from magrolimab, an anti-CD47 monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 855.
Abstract 86: Chemotherapy-induced microenvironmental changes promote dormant breast cancer cell outgrowth in adipose tissue
Authors: Ren Qihao , Ye Jiayu , Yuan Xiaoyu , Stewart Sheila 
Published: April 2023

Abstract
Despite the high 5-year survival rate for early-stage breast cancer patients, late recurrence of the disease remains a major challenge. Breast cancer can recur in approximately 20-25% of patients months to decades after an initial diagnosis, and there are few biomarkers that predict which patients will suffer from the recurrent disease. Unfortunately, this means clinicians and their patients must take a frustrating wait-and-see approach. Notably, disseminated tumor cells (DTCs) are frequently detected in early-stage breast cancer patients, and their presence predicts a higher chance of recurrence. However, why some patients with DTCs recur while others do not remains a mystery. Previous work has suggested that changes in the tumor microenvironment (TME) play an important role in the maintenance of tumor cell dormancy. When assessing the impact of doxorubicin (DOXO), a chemotherapeutic agent often used to treat breast cancer patients, on the TME, we noted that DOXO treatment led to the activation of dormant breast cancer cells in the visceral adipose tissue. Moreover, in accordance with the clinical observation that obese patients suffer a higher risk of cancer recurrence, we found that diet-induced obesity further exacerbated DOXO ability to reactivate dormant breast cancer cells in adipose tissue and this reactivation was associated with robust macrophage infiltration. These findings were interesting in light of our observation that tumor cells can metastasize to visceral fat depots in breast cancer patients. To understand why macrophages were recruited to the adipose tissue and how they led to tumor cell reactivation, we profiled the microenvironmental changes in visceral fat from Veh- and Doxo- treated mice using single-cell RNA-sequencing and found that the infiltrating macrophages exhibited unique pro-inflammatory and lipid-regulatory phenotypes. Our study provides novel insights into how TME impacts breast cancer dormancy and also highlights the importance of adipose tissue as a unique reservoir that potentiates cancer relapse.
Citation Format: Qihao Ren, Jiayu Ye, Xiaoyu Yuan, Sheila Stewart. Chemotherapy-induced microenvironmental changes promote dormant breast cancer cell outgrowth in adipose tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 86.
Abstract 861: Modelling the role of EGFR mutation in the initiation of never-smoker lung cancer
Authors: Coggan Helena M. , Weeden Clare E. , Dalwadi Mohit , Swanton Charles , Pearce Philip , Page Karen M. 
Published: April 2023

Abstract
Genetic mutations associated with never-smoker lung cancer frequently appear in normal lung tissue, in both cancer and non-cancer patients. It is unclear what circumstances are required for a mutation to fix in healthy tissue and eventually lead to a tumor. To investigate this, alveolar type-II murine cells were grown in a 3D nutrient system, forming spheroidal clusters. The volumes of these clusters were measured at 7 and 14 days and a mathematical model was devised to describe their growth. In the absence of an EGFR mutation, variations in growth between clusters can be explained by a skew-normal distribution of initial division rates. These rates decline exponentially as the clusters age, and the decline rate is the same across clusters. When cells possess an epidermal growth factor receptor (EGFR) mutation or are grown in the presence of interleukin-1 beta (il-1b) growth factor, clusters form more complex shapes, which we believe may be driven by branching processes and cell-cell interactions. Accordingly, more complex models are needed to explain their development. This work lays the groundwork for new, parameterized models of mutational spread in lung tissue, and a deeper understanding of the role of mutation in carcinogenesis.
Citation Format: Helena M. Coggan, Clare E. Weeden, Mohit Dalwadi, Charles Swanton, Philip Pearce, Karen M. Page. Modelling the role of EGFR mutation in the initiation of never-smoker lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 861.
Abstract 862: Pairwise and higher-order epistatic effects among somatic cancer mutations across oncogenesis of lung adenocarcinoma
Authors: Alfaro-Murillo Jorge A. , Dasari Krishna , Townsend Jeffrey P. 
Published: April 2023

Abstract
The somatic evolution of cancer depends on the rate at which new mutations are acquired, as well as the selective pressure acting on them. Further, mutual exclusivity or co-occurrence of mutations suggests that variants can exert antagonistic or synergistic epistatic effects on the selection of new mutations, contributing to a complex landscape of evolutionary trajectories. Estimation of pairwise and higher-order epistatic effects—essential to estimation of the trajectory of likely cancer genotoypes—has remained a challenge. We have developed a continuous-time Markov chain model that enables the estimation of mutation origination and fixation (flux), dependent on somatic cancer genotype. Coupling the continuous-time Markov chain model with a deconvolution approach provides estimates of underlying mutation rates and selection across the trajectory of oncogenesis. We demonstrate computation of fluxes and selection coefficients in a somatic evolutionary model of lung adenocarcinoma informed by a compilation of samples from multiple data sets including The Cancer Genome Atlas and the AACR Project GENIE. The approach enables inference of the most likely routes of site-specific variant evolution and estimation of the selection strength operating on each step along the route, a key component of what we need to know to develop and implement personalized cancer therapies. Finally, by comparing smoker and nonsmoker tumor cohorts, we reveal and describe distinct evolutionary trajectories, influenced not only by differential mutation, but also by the differential physiological effects that smoking can have on the selective regime of lung tissue. These distinctions disambiguate the physiological and mutational influences of smoking and can inform personalized treatment of the two groups.
Citation Format: Jorge A. Alfaro-Murillo, Krishna Dasari, Jeffrey P. Townsend. Pairwise and higher-order epistatic effects among somatic cancer mutations across oncogenesis of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 862.
Abstract 87: The role of miro1-mediated mitochondrial positioning in the development and metastasis of breast cancer
Authors: Gravelle Randi , McCoy Margaret , Shannon Nathaniel , Chang Martin , Cunniff Brian 
Published: April 2023

Abstract
Miro1 is an outer mitochondrial membrane protein that links mitochondria to motor protein complexes to support subcellular mitochondrial trafficking. Preliminary observations and published work has established that metastatic breast cancer cells have increased expression of Miro1 in comparison to breast cancer cells with low metastatic potential. Furthermore, tumors from breast cancer patients with high Miro1 expression have poorer survival rates compared to patients harboring tumors with low Miro1 expression. This data suggests that Miro1 has a functional role in aggressive breast cancers although this has not been widely studied or confirmed in advanced preclinical models. The objective of our research is to investigate the role of Miro1 in breast cancer tumorigenesis and metastasis. We hypothesize that that Miro1-mediated mitochondrial dynamics support subcellular signaling events driving cell migration, invasion, and tumorigenesis. To examine the function of Miro1 in promoting metastatic phenotypes in vitro, we generated human breast cancer cell lines (MDA-MB-231, MDA-MB-468, T-47d, and MCF7) with Miro1 knockdown using adenoviral shRNA. Knockdown of Miro1 to levels greater than 50% of that in control cells resulted in mitochondria sequestered around the nucleus and reduced cell migration. Additionally, MDA-MB-231 cells with ≥50% Miro1 knockdown resulted in a significant decrease in cell invasion through Matrigel coated membranes in transwell invasion assays. Our research has also uncovered altered phosphorylation of key cell migration and stress-response proteins including vinculin, focal adhesion kinase and ERK ½ when Miro1 is knocked down. To investigate the role of Miro1 in vivo, we generated a novel transgenic mouse model with inducible, tissue specific Miro1 deletion in mammary epithelial cells with concurrent polyomavirus middle T-antigen oncogene activation. We found that when breast cancer formation is induced utilizing the transgenic middle-T antigen system, our control mice form tumors at all mammary gland sites and have metastasis to the lungs. Conversely, mice with concurrent Miro1 deletion and middle T- antigen activation fail to develop tumors. This data suggests that Miro1 has a functional role in both mammary tumor onset and tumor cell migration and invasion, providing a possible new biomarker of tumor status and pathway for therapeutic intervention.
Citation Format: Randi Gravelle, Margaret McCoy, Nathaniel Shannon, Martin Chang, Brian Cunniff. The role of miro1-mediated mitochondrial positioning in the development and metastasis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 87.
Abstract 871: Accurate estimation of open chromatin and intrinsic biases in bulk and single-cell CUT&Tag data
Authors: Hu Sheng'en , Chen Qingying , Zang Chongzhi 
Published: April 2023

Abstract
Histone modifications (HM) and transcription factors (TF) are aberrantly regulated in the pathogenesis of humans and are a major class of cancer cell dependencies. Precise detection of HM and TF binding genome-wide is essential for a better understanding of cancer epigenetics. Cleavage Under Targets & Tagmentation (CUT&Tag) is an easy and low-cost epigenomic profiling method that can be performed on a low number of cells and on the single-cell level. A large number of CUT&Tag datasets have been generated in cancer samples, providing a valuable resource. Unbiased analysis of CUT&Tag data is important for cancer epigenetics research. CUT&Tag experiments rely on the hyperactive transposase Tn5 for tagmentation. We performed integrative analysis of CUT&Tag and other high-throughput data, and found that Tn5 is subject to intrinsic sequence insertion biases (intrinsic biases). Preference of Tn5 captured reads toward chromatin accessibility regions (open chromatin biases) also confound the distribution of CUT&Tag reads. Both sources of biases confound the analysis of CUT&Tag data, especially for factors that are not expected to associate with accessible chromatin. High sparsity of single-cell data makes the effect of both biases more substantial compared to bulk data. We present a computational model for accurate characterization and quantitative estimation of biases in CUT&Tag data. This model paved the way for further development of computational tools for improving both bulk and single-cell CUT&Tag data analysis.
Citation Format: Sheng'en Hu, Qingying Chen, Chongzhi Zang. Accurate estimation of open chromatin and intrinsic biases in bulk and single-cell CUT&Tag data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 871.
Abstract 879: Exosomal mRNAs secreted from pancreatic cancer (PC) cell lines might include good candidates of biomarkers of PC patients
Authors: Rong Yuhan , Okubo Naoki , Fukui Risa , Suzuki Akihiro , Sato Motokazu , Tokuhisa Motohiko , Takeda Yuma , Kobayashi Noritoshi , Endo Itaru , Ichikawa Yasushi 
Published: April 2023

Abstract
Background: Exosomal mRNAs secreted from cancer cells are regarded as important messengers in communication system between cells. In PC, some exosomal RNAs from patients’ plasma were expected as biomarkers of PC. However, exosomes in the blood of cancer patients are not derived only from cancer cells. Relationship of RNAs produced in cancer cells and those secreted into exosomes is still unclear. In this study, we evaluated relationships between mRNAs in PC cell lines and those of exosomes secreted into supernatant and determined candidates for PC biomarkers from cancer specific exosomal mRNAs.
Material and Method: Three PC cell lines (PANC-1, MIAPaCa-2 and Capan-1) were used. Three studies were performed for each cell line. After 48h serum-free culture, the supernatants were collected, and exosomes were isolated by ultracentrifugation. The remaining cells in the culture dish were also collected and mRNAs were extracted. RNA-seq was performed for mRNAs extracted from cell and exosomal RNAs extracted from supernatant. Data was analyzed by R (version 4.2.1).
Results: In MIAPaCa-2, expression of cellular mRNAs and corresponding exosomal mRNAs showed strong correlation (R was higher than 0.7). In the other 2 cell lines, they showed moderate correlation (R was higher than 0.5). Then, expression of mRNA in the cells was approximately reflected in those in the exosomes. However, some mRNAs showed high expression in exosome and low expression in the cell. We focused on these mRNAs, and then, performed a differential analysis of the whole raw RNA data by using TCC package of R and found differentially expressed mRNAs.
Conclusion: Comparing with data of GEO database showing exosomal mRNA extracted from healthy volunteers, we finally find candidates of cancer specific exosomal mRNAs of PC.
Citation Format: Yuhan Rong, Naoki Okubo, Risa Fukui, Akihiro Suzuki, Motokazu Sato, Motohiko Tokuhisa, Yuma Takeda, Noritoshi Kobayashi, Itaru Endo, Yasushi Ichikawa. Exosomal mRNAs secreted from pancreatic cancer (PC) cell lines might include good candidates of biomarkers of PC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 879.