bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Manufacturability Evaluation of Complex Architectures by Laser Powder Bed Fusion Additive Manufacturing
Authors: McGregor Martine , Patel Sagar , Zhang Kevin , Yu Adam , Vlasea Mihaela , McLachlin Stewart 
Published: April 2024

Abstract
Additive manufacturing (AM) enables new possibilities for the design and manufacturing of complex metal architectures. Incorporating lattice structures into complex part geometries can enhance strength-to-weight and surface area-to-volume ratios for valuable components, particularly in industries such as medical devices and aerospace. However, lattice structures and their interconnections may result in unsupported down-skin surfaces, potentially limiting their manufacturability by metal AM technologies, such as laser powder bed fusion (LPBF). This study aimed to examine the correlation between down-skin surface area and the manufacturability of lattice structures fabricated using LPBF. Image processing algorithms were used to analyze down-skin surface areas of seven unique lattice designs and to devise quantitative metrics (such as down-skin surface area, discrete surface count, surface interconnectivity, down-skin ratio, over-print/under-print volumes, etc.) to evaluate LPBF manufacturability. The seven lattice designs were subsequently manufactured using maraging steel via LPBF and then examined using imaging using X-ray micro-computed tomography (XCT). The geometric accuracy of the lattice designs was compared with XCT scans of the manufactured lattices by employing a voxel-based image comparison technique. The results indicated a strong relationship between down-skin surface area, surface interconnectivity, and the manufacturability of a given lattice design. The digital manufacturability evaluation workflow was also applied to a medical device design, further affirming its potential industrial utility for complex geometries.
Prediction of Human Reaching Pose Sequences in Human–Robot Collaboration
Authors: Flowers Jared , Wiens Gloria 
Published: April 2024

Abstract
In human–robot collaboration, robots and humans must work together in shared, overlapping, workspaces to accomplish tasks. If human and robot motion can be coordinated, then collisions between robot and human can seamlessly be avoided without requiring either of them to stop work. A key part of this coordination is anticipating humans’ future motion so robot motion can be adapted proactively. In this work, a generative neural network predicts a multi-step sequence of human poses for tabletop reaching motions. The multi-step sequence is mapped to a time-series based on a human speed versus motion distance model. The input to the network is the human’s reaching target relative to current pelvis location combined with current human pose. A dataset was generated of human motions to reach various positions on or above the table in front of the human starting from a wide variety of initial human poses. After training the network, experiments showed that the predicted sequences generated by this method matched the actual recordings of human motion within an L2 joint error of 7.6 cm and L2 link roll–pitch–yaw error of 0.301 rad on average. This method predicts motion for an entire reach motion without suffering from the exponential propagation of prediction error that limits the horizon of prior works.
Flagellin-modulated inflammasome pathways characterize the human alveolar macrophage response to
Burkholderia pseudomallei
, a lung-tropic pathogen
Authors: Lovelace-Macon Lara , Baker Sarah M. , Ducken Deirdre , Seal Sudeshna , Rerolle Guilhem , Tomita Diane , Smith Kelly D. , Schwarz Sandra , West T. Eoin 
Published: April 2024

ABSTRACT

Melioidosis is an emerging tropical infection caused by inhalation, inoculation, or ingestion of the flagellated, facultatively intracellular pathogen
Burkholderia pseudomallei
. The melioidosis case fatality rate is often high, and pneumonia, the most common presentation, doubles the risk of death. The alveolar macrophage is a sentinel pulmonary host defense cell, but the human alveolar macrophage in
B. pseudomallei
infection has never been studied. The objective of this study was to investigate the host-pathogen interaction of
B. pseudomallei
infection with the human alveolar macrophage and to determine the role of flagellin in modulating inflammasome-mediated pathways. We found that
B. pseudomallei
infects primary human alveolar macrophages but is gradually restricted in the setting of concurrent cell death. Electron microscopy revealed cytosolic bacteria undergoing division, indicating that
B. pseudomallei
likely escapes the alveolar macrophage phagosome and may replicate in the cytosol, where it triggers immune responses. In paired human blood monocytes, uptake and intracellular restriction of
B. pseudomallei
are similar to those observed in alveolar macrophages, but cell death is reduced. The alveolar macrophage cytokine response to
B. pseudomallei
is characterized by marked interleukin (IL)-18 secretion compared to monocytes. Both cytotoxicity and IL-18 secretion in alveolar macrophages are partially flagellin dependent. However, the proportion of IL-18 release that is driven by flagellin is greater in alveolar macrophages than in monocytes. These findings suggest differential flagellin-mediated inflammasome pathway activation in the human alveolar macrophage response to
B. pseudomallei
infection and expand our understanding of intracellular pathogen recognition by this unique innate immune lung cell.
Supplementary Figure S3 from Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma
Authors: Habashy Karl J. , Dmello Crismita , Chen Li , Arrieta Victor A. , Kim Kwang-Soo , Gould Andrew , Youngblood Mark W. , Bouchoux Guillaume , Burdett Kirsten B. , Zhang Hui , Canney Michael , Stupp Roger , Sonabend Adam M. 
Published: April 2024

<p>Supplementary Figure 3. Paclitaxel and carboplatin exhibit synergy in vitro.
(A) Dose-response matrices illustrating the Loewe synergy score calculated for 11 glioma cell lines at clinically relevant PTX and CBDCA concentrations. (B) Bar charts showing the viability of cell lines treated with PTX, CBDCA, or a combination of both drugs at concentration that showed the highest synergy.</p>
Abstract LT03: C/EBPα Acts as an RNA Binding Protein Essential for, and Promotes End-Stage Macrophage Differentiation
Authors: Bassal Mahmoud A. , Zhang Yanzhou , Liu Yanjing V. , Camacho Virginia , Ummarino Simone , Welner Robert S. , Tenen Daniel G 
Published: April 2024

Abstract
The transcription factor C/EBPα is a well characterized DNA binding protein with essential functions in controlling and regulating myeloid differentiation and lipid metabolism. Herein, we describe C/EBPα’s separate and distinct RNA binding characteristics.
Using Chromatin RNA Immunoprecipitation, we identified that C/EBPα interacts primarily with RNA introns in both HL-60 and THP-1 cells, with a preference for a palindromic GC-rich binding motif. Structural prediction in conjunction with RNA electrophoretic mobility shift assays show that C/EBPα interacts with RNA through two previously undescribed domains located towards the proteins N terminus. These domains are distinct from C/EBPα’s DNA binding b-ZIP domain which is instead located on the proteins C terminus.
Mouse bone marrow transplantation and in vitro cytokine assays reveal that C/EBPα RNA binding appears to be essential for macrophage maturation but not neutrophil differentiation. To better understand these phenotypic differences, we expanded our observations into the transcriptomic space by utilizing single-cell CITE-Seq. In line with biochemical data, notable mature cell populations were absent when the C/EBPα’s RNA binding domains are excluded from the protein. Intriguingly, differential gene expression revealed strong, selective upregulation of Lipoprotein Lipase (Lpl) in monocyte, but not neutrophil populations. It has been previously reported that dysregulation of Lpl affects bone marrow monocyte progenitor differentiation and results in dysregulated cellular mobilization from the bone marrow, a phenotype that is commonly seen in cancers such as AML. The increased abundance of monocyte and neutrophil populations in the C/EBPα RNA deletion samples is therefore suggestive that C/EBPα RNA binding is critical in regulating terminal differentiation and mobilization circuits which may become dysregulated or perturbed in diseases such as AML.
On-going analyses are investigating the RNA velocity trajectory of captured cell populations in an attempt to better understand at which stage C/EBPα RNA binding becomes essential for terminal maturation and differentiation of select cell populations. Taken together though, we demonstrate that C/EBPα is also an RNA binding protein with unique functions distinct from its DNA binding activity that is essential for monocyte maturation, differentiation and mobilization.
Citation Format: Mahmoud A. Bassal, Yanzhou Zhang, Yanjing V. Liu, Virginia Camacho, Simone Ummarino, Robert S. Welner, Daniel G Tenen. C/EBPα Acts as an RNA Binding Protein Essential for, and Promotes End-Stage Macrophage Differentiation [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT03.
Abstract LT04: Dissecting Mediator Kinase Activity in Normal Tissue Homeostasis and Cancer
Authors: Dannappel Marius , Zhu Danxi , Sun Claire , Firestein Ron 
Published: April 2024

Abstract
Cyclin-dependent kinase 8 (CDK8) and its paralog CDK19, collectively known as Mediator kinase, are part of the multimeric Mediator complex that fine-tune gene expression programs on multiple levels, most notably by controlling transcription factor (TF) activity at promoter- and enhancer regions as well as organising the chromatin landscape. While Mediator kinases have been predominantly studied as a therapeutic target in cancer cells, their functions in a physiologically relevant context remain poorly understood. To study in vivo functions of Mediator, we developed a comprehensive suite of genetically engineered mouse models (GEMMs), including conditional floxed alleles (Cdk8fl/fl/Cdk19fl/fl) and kinase-dead knock-ins (Cdk8D173A/fl/Cdk19D173A/fl), enabling the analysis of scaffolding and kinase-dependent functions of this critical transcriptional module. Herein, we show that Mediator kinase has distinct kinase-dependent functions in modulating homeostasis and tissue lineage specification in diverse organs. Moreover, using a proteo-genomic approach we show that the Mediator Kinase module functionally interacts with the SWI/SNF complex to mediate transcriptional output. Collectively, our work expands the understanding of how Mediator Kinase regulates tissue homeostasis and provides a framework for considering how Mediator Kinase inhibition may be effectively employed in the clinical setting.
Citation Format: Marius Dannappel, Danxi Zhu, Claire Sun, Ron Firestein. Dissecting Mediator Kinase Activity in Normal Tissue Homeostasis and Cancer [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT04.
Abstract LT06: Understanding the Role of Mutant TP53 in Lung Cancer Using Novel Genetically Engineered Mouse Models
Authors: Chen Tianwei , Lieschke Elizabeth , Scott Leanne , Boyd Danielle , Sutherland Kate , Strasser Andreas , Kelly Gemma 
Published: April 2024

Abstract
The tumour suppressor gene TP53 (Trp53 in mouse) is mutated in ~50% of human cancers and this is associated with poor therapeutic responses. Mutant TP53 protein was reported to promote tumour development in three ways: (1) loss of function (LOF) effects which abrogate normal TP53-mediated cellular processes; (2) dominant negative effects (DNE); and (3) gain of function effects (GOF) whereby mutant TP53 proteins bind to and modulate the functions of proteins that are not impacted by wildtype TP53.
Despite extensive research efforts, the relative contributions of the LOF, DNE and GOF effects of mutant TP53 in cancer are largely unknown. This project aims to understand the relative importance of these three effects of TP53 mutant proteins in the initiation and sustained expansion of lung adenocarcinoma (LUAD). We will do this by using novel LUAD mouse models with switchable Trp53 status to trigger tumorigenesis through expression of mutant Trp53 and then conversion of mutant Trp53 either back to wildtype Trp53 or into a Trp53 knock-out state when desired. In vitro and in vivo studies were performed to investigate the immediate and long-term effects of different Trp53 status on tumour growth. Our data thus far show that conversion of mutant Trp53 back to wildtype Trp53 induced cellular senescence and cell cycle arrest in LUAD cells in vitro and substantially delayed tumour progression in vivo, which improved the overall survival of mice. In contrast, conversion of mutant Trp53 into a Trp53 knock-out state did not impair the sustained growth of these tumour cells either in vitro or in vivo. This suggest that the LOF but not GOF of mutant TRP53 is critical to sustain the expansion of lung cancer. These findings have important implications for the design of novel therapeutic approaches for cancers expressing mutant TP53.
Citation Format: Tianwei Chen, Elizabeth Lieschke, Leanne Scott, Danielle Boyd, Kate Sutherland, Andreas Strasser, Gemma Kelly. Understanding the Role of Mutant TP53 in Lung Cancer Using Novel Genetically Engineered Mouse Models [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT06.
Abstract LT08: Extracellular Vesicle Surface Display Enhances the Therapeutic Efficacy and Safety Profile of Cancer Immunotherapy
Authors: Jayasinghe Migara Kavishka , Tian Dawn Liu Xiao , Lay Yock Sin , Lee Chang Yu , Yeo Brendon Zhi Jie , Van Hoang Dong , Prajogo Rebecca Carissa , Peng Boya , Pham Thach Tuan , Nguyet Le Minh Thi 
Published: April 2024

Abstract
As our understanding of the complex interactions between the immune system and cancer has progressed, so has the identification of novel targets and ligands that can modulate effective anti-cancer immune responses. While immunotherapy has emerged as a mainstay in cancer therapy, its efficacy has been limited by the potential for off-target toxicity against normal body cells.
In this study, we present a nanoparticle-based delivery system that enhances the signaling efficacy of immunomodulatory ligands while concurrently limiting systemic toxicity. We demonstrate that extracellular vesicles (EVs), lipid bilayer enclosed nanoparticles released by cells, can be efficiently engineered to display multiple immunomodulatory ligands on their surface. Display of immunomodulatory ligands such as agonistic CD137 and CD40 antibodies on the EV surface significantly enhanced their therapeutic efficacy over equivalent doses of free ligands by inducing ligand multimerization, efficient receptor crosslinking and the formation of immune synapses. EVs conjugated with a complementary combination of immune stimulatory ligands and immune checkpoint inhibitors were able to shift the tumor immune milieu towards an anti-tumorigenic phenotype in a lung metastatic melanoma allograft and suppress tumor progression to a greater extent than an equivalent dose of free ligands. We also demonstrate the ability of EVs to co-deliver intraluminally loaded TLR agonists which synergize with surface displayed agonistic CD40 antibodies to induce effective anti-tumor responses and tumor regression in a metastatic autochthonous cell-derived model of PDAC. Remarkably, we also observed that EV-associated immunotherapeutics were limited in their biodistribution to the tumor microenvironment, resulting in significantly lower off-target toxicity than treatment with free ligands.
In summary, we present an EV-based delivery approach that allows the use of potent cancer immunotherapy combinations to achieve superior anti-tumor responses at significantly lower doses with less side-effects than is possible with conventional administration methods for cancer immunotherapy.
Citation Format: Migara Kavishka Jayasinghe, Dawn Liu Xiao Tian, Yock Sin Lay, Chang Yu Lee, Brendon Zhi Jie Yeo, Dong Van Hoang, Rebecca Carissa Prajogo, Boya Peng, Thach Tuan Pham, Minh Thi Nguyet Le. Extracellular Vesicle Surface Display Enhances the Therapeutic Efficacy and Safety Profile of Cancer Immunotherapy [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT08.
Abstract P15: Aberrant Non-canonical NF-κB Signalling Reprograms the Epigenome Landscape to Drive Oncogenic Transcriptomes in Multiple Myeloma
Authors: Ang Daniel A. , Carter Jean-Michel , Deka Kamalakshi , Tan Joel H.L. , Zhou Jianbiao , Chen Qingfeng , Chng Wee Joo , Harmston Nathan , Li Yinghui 
Published: April 2024

Abstract
Activation of the NF-κB pathway is recognized to be necessary for the survival and progression of haematological cancers including Multiple Myeloma (MM). In particular, recurrent genetic lesions resulting in the chronic induction of non-canonical NF-κB (ncNF-κB) signalling have been exclusively linked to MM. Such mutations among patients are associated with significant proliferative and metastatic advantages and have been causally linked to treatment resistance. How the constitutive activity of ncNF-κB transcription factors can support such adaptations in this common haematological malignancy has been a fundamental question in cancer. In this study, we captured the epigenomic landscape of patient-derived MM cell lines harbouring recurrent NF-κB activating mutations through perturbation of nfkb2/p52 and integrated these cis-regulatory changes with MM patient epigenome data. Here, we find that sustained NF-κB/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis-regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a novel p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-κB signalling potentiates transcriptional programs beneficial for multiple myeloma progression.
Citation Format: Daniel A. Ang, Jean-Michel Carter, Kamalakshi Deka, Joel H.L. Tan, Jianbiao Zhou, Qingfeng Chen, Wee Joo Chng, Nathan Harmston, Yinghui Li. Aberrant Non-canonical NF-κB Signalling Reprograms the Epigenome Landscape to Drive Oncogenic Transcriptomes in Multiple Myeloma [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P15.
Abstract P20: Unveiling the Influence of Tumor Microenvironment and Spatial Heterogeneity on Temozolomide Resistance in Glioblastoma using an Advanced Human in vitro Model of the Blood-brain Barrier and Glioblastoma
Authors: Lam Maxine SY , Aw Joey JY , Tan Damien , Vijayakumar Ragavi , Lim Hui Yi Grace , Yada Swathi , Pang Qing You , Barker Nick , Tang Carol , Ang Beng Ti , Sobota Radoslaw M. , Pavesi Andrea 
Published: April 2024

Abstract
Glioblastoma (GBM) is the most common primary malignant brain cancer in adults, with a dismal prognosis of 15 months. This is despite decades of research and improvements in surgery and radiotherapy. Temozolomide (TMZ) is the only first-in-line chemotherapeutic; however, resistance is frequent and multifactorial. While many molecular and genetic factors have been linked to TMZ resistance, the role of the solid tumor morphology and the tumor microenvironment (TME), particularly the blood-brain barrier (BBB), is unknown. Complex 3D in vitro models are able to recapitulate aspects of clinical disease such as the tumor microenvironment, such that research into the role of the TME and how it affects tumor biology and therapy resistance can be studied more easily and accurately. We have developed a complex 3D in vitro model for GBM and its surrounding BBB, that recapitulates important clinical features such as a dense tumor core with tumor cells that invade along the perivascular space; and a perfusable BBB with a physiological permeability with morphology that is altered in the presence of a tumor spheroid. We demonstrate that TMZ sensitivity decreases with increasing cancer cell spatial organization, and that the BBB can contribute to TMZ resistance. Proteomic analysis of cultured microtissues using low volume sample workflows revealed proteins linked to aggressive tumors and TMZ resistance. Notably, proteomic analysis revealed a potential role for cell cycle proteins in TMZ resistance. Preliminary data with tumor spheroids formed by patient derived GBM progenitor cells revealed a similar trend of an increase in proteins associated with tumor aggressiveness upon co-culture with a BBB. The data demonstrate the utility of combining complex physiological in vitro models and next generation mass spectrometry for interrogating the tumour microenvironment, tumor biology and accurate in vitro therapy validation.
Citation Format: Maxine SY Lam, Joey JY Aw, Damien Tan, Ragavi Vijayakumar, Hui Yi Grace Lim, Swathi Yada, Qing You Pang, Nick Barker, Carol Tang, Beng Ti Ang, Radoslaw M. Sobota, Andrea Pavesi. Unveiling the Influence of Tumor Microenvironment and Spatial Heterogeneity on Temozolomide Resistance in Glioblastoma using an Advanced Human in vitro Model of the Blood-brain Barrier and Glioblastoma [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P20.