bluuebunny/crossref_metadata_2025 huggingface dataset:
Partisan Bias in Political Judgment
Authors: Ditto Peter H. , Celniker Jared B. , Siddiqi Shiri Spitz , Güngör Mertcan , Relihan Daniel P.
Published: September 2024

This article reviews empirical data demonstrating robust ingroup favoritism in political judgment. Partisans display systematic tendencies to seek out, believe, and remember information that supports their political beliefs and affinities. However, the psychological drivers of partisan favoritism have been vigorously debated, as has its consistency with rational inference. We characterize decades-long debates over whether such tendencies violate normative standards of rationality, focusing on the phenomenon of motivated reasoning. In light of evidence that both motivational and cognitive factors contribute to partisan bias, we advocate for a descriptive approach to partisan bias research. Rather than adjudicating the (ir)rationality of partisan favoritism, future research should prioritize the identification and measurement of its predictors and clarify the cognitive mechanisms underlying motivated political reasoning. Ultimately, we argue that political judgment is best evaluated by a standard of ecological rationality based on its practical implications for individual well-being and functional democratic governance.
Ankle torque variance is a better indicator of balance control performance than plantar perceptual sensitivity threshold
Authors: Viseux Frederic J. F. , Billot Maxime , Handrigan Grant , Simoneau Martin
Published: September 2024

Plantar cutaneous information contributes to balance control by modulating motor commands, but plantar perceptual sensitivity is a suboptimal indicator of balance performance. Multiple sensory cues encode whole body dynamics, guiding sensorimotor mechanisms to minimize body sway variability. Ankle torque variance is proposed as a superior measure for explaining balance control performance and evaluating the sensorimotor loop’s functioning in balance control.
Mapping Community‐Based Services for Social Prescribing for Children and Young People Living with Obesity across South Yorkshire
Authors: Garside Megan , Homer Catherine , Dayson Christopher , Dowrick Lorna , Pickering Katie , Wright Neil
Published: September 2024

Background. High numbers of young people are living with obesity in England, with associated negative impacts on their mental and physical health. Social prescribing involves professionals referring individuals to community‐based services to provide additional health and well‐being support. Social prescribing may be a helpful way to provide holistic support to young people living with obesity alongside weight management services. However, there is a need to better understand the availability of community‐based services that could provide this support. Aims. This study aimed to explore the process for mapping community‐based services to be part of a social prescribing offer within children’s specialist weight management services in one region of England and to provide an understanding of the availability of community‐based services in this region that are accessible for this population. Method. Community‐based services providing physical activity opportunities to young people in an area local to a specialist weight management service (South Yorkshire) were mapped using a mixed methods approach, including scoping of online resources and meetings with relevant contacts. Services were identified and reviewed against criteria developed through stakeholder engagement to assess suitability for young people living with obesity. Results. A total of 933 community‐based services were identified across South Yorkshire between January and June 2023. Scoping and suitability assessment of these services took 6 months. There was often limited information provided about services, particularly relating to costs. Nineteen services met all suitability criteria. Conclusion. It requires time and capacity to identify relevant community‐based services as part of a social prescribing offering. Although a high number of services were identified, few of these were suitable for young people living with obesity. Consideration should be given to how young people can be supported to access services, as well as how services can be supported to meet the needs of young people living with severe obesity.
POCT Detection of Pseudomonas aeruginosa by PGM and Application of Preventing Nosocomial Infection of Bronchoscopy
Authors: Wen Tao , Ning Houqi , Yang Yinping , Zhang Jinze
Published: September 2024

Background. The primary pathogen responsible for bronchoscope contamination is Pseudomonas aeruginosa. Conventional techniques for bronchoscopy disinfection and pathogen identification methods are characterized by time‐consuming and operation complexly. The objective of this research is to establish a prompt and precise method for the identification of Pseudomonas aeruginosa, with the ultimate goal of mitigating the risk of nosocomial infections linked to this pathogen. Methods. The magnetic nanoparticles (MNPs) were synthesized in a single step, followed by the optimization of the coating process with antibodies and invertase to produce the bifunctionalized IMIc. Monoclonal antibodies were immobilized on microplates for the specific capture and enrichment of Pseudomonas aeruginosa. Upon the presence of Pseudomonas aeruginosa, the monoclonal antibodies, the test sample, and the IMIc formed sandwich structures. The subsequent addition of a sucrose solution allowed for the detection of glucose produced through invertase hydrolysis by a personal glucose meter, enabling quantitative assessment of Pseudomonas aeruginosa concentration. Results. TEM image demonstrates that the MNPs exhibit a consistent spherical shape. NTA determined that the grain diameter of magnetic nanoparticles was 200 nm. FTIR spectrum revealed the successful modification of two carboxyl groups on the MNPs. The optimization of the incubation pH of the microplate‐coated antibody was 7. The optimization of the incubation time of the microplate‐coated antibody was 2 h. The optimization of the ligation pH for the polyclonal antibody was 5. Reaction times of polyclonal antibodies linked to magnetic beads was 1 h. The pH of invertase linked by magnetic beads was 4. Conclusion. This article presents a novel qualitative and quantitative immunoassay for point‐of‐care monitoring of P. aeruginosa utilizing PGM as a readout. The PGM represents a convenient and accurate quantitative detection method suitable for potential clinical diagnostic applications.
A Novel AC Green Plug Switched Filter Scheme for Low Impact Efficient V2G Battery Charging Stations
Authors: Bloul Albe M. , Sharaf Adel M. , Aly Hamed H. , Gu Jason
Published: September 2024

In this paper, a novel switched/modulated capacitor filter scheme is proposed for enhancing vehicle‐to‐house (V2G) battery‐charging stations utilized in electric vehicles (EVs). The novel approach is tested on two controllers with a classical optimized PID controller. The technique, which employs modified multimode weighted charging modes for fast charging, improved power quality, and minimal inrush currents, results in reduced voltage transients on the DC side and less harmonics on the AC side. An intercoupled DC‐AC capacitor interface that features dual complementary switching modes is used by the switched modulated filter as a way to provide optimal pulsing in both the tuned‐arm filter and capacitive compensator modes of operations. This switched intercoupled AC‐DC filter compensation approach leads to enhanced power usage in EVs, along with lower AC‐DC voltage transients and inrush currents.
Figure S6 from A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis
Authors: White Brian S. , Woo Xing Yi , Koc Soner , Sheridan Todd , Neuhauser Steven B. , Wang Shidan , Evrard Yvonne A. , Chen Li , Foroughi pour Ali , Landua John D. , Mashl R. Jay , Davies Sherri R. , Fang Bingliang , Raso Maria Gabriela , Evans Kurt W. , Bailey Matthew H. , Chen Yeqing , Xiao Min , Rubinstein Jill C. , Sanderson Brian J. , Lloyd Michael W. , Domanskyi Sergii , Dobrolecki Lacey E. , Fujita Maihi , Fujimoto Junya , Xiao Guanghua , Fields Ryan C. , Mudd Jacqueline L. , Xu Xiaowei , Hollingshead Melinda G. , Jiwani Shahanawaz , Acevedo Saul , Davis-Dusenbery Brandi N. , Robinson Peter N. , Moscow Jeffrey A. , Doroshow James H. , Mitsiades Nicholas , Kaochar Salma , Pan Chong-xian , Carvajal-Carmona Luis G. , Welm Alana L. , Welm Bryan E. , Govindan Ramaswamy , Li Shunqiang , Davies Michael A. , Roth Jack A. , Meric-Bernstam Funda , Xie Yang , Herlyn Meenhard , Ding Li , Lewis Michael T. , Bult Carol J. , Dean Dennis A. , Chuang Jeffrey H.
Published: September 2024

Figure S6
Figure S13 from A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis
Authors: White Brian S. , Woo Xing Yi , Koc Soner , Sheridan Todd , Neuhauser Steven B. , Wang Shidan , Evrard Yvonne A. , Chen Li , Foroughi pour Ali , Landua John D. , Mashl R. Jay , Davies Sherri R. , Fang Bingliang , Raso Maria Gabriela , Evans Kurt W. , Bailey Matthew H. , Chen Yeqing , Xiao Min , Rubinstein Jill C. , Sanderson Brian J. , Lloyd Michael W. , Domanskyi Sergii , Dobrolecki Lacey E. , Fujita Maihi , Fujimoto Junya , Xiao Guanghua , Fields Ryan C. , Mudd Jacqueline L. , Xu Xiaowei , Hollingshead Melinda G. , Jiwani Shahanawaz , Acevedo Saul , Davis-Dusenbery Brandi N. , Robinson Peter N. , Moscow Jeffrey A. , Doroshow James H. , Mitsiades Nicholas , Kaochar Salma , Pan Chong-xian , Carvajal-Carmona Luis G. , Welm Alana L. , Welm Bryan E. , Govindan Ramaswamy , Li Shunqiang , Davies Michael A. , Roth Jack A. , Meric-Bernstam Funda , Xie Yang , Herlyn Meenhard , Ding Li , Lewis Michael T. , Bult Carol J. , Dean Dennis A. , Chuang Jeffrey H.
Published: September 2024

Figure S13
Figure S11 from A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis
Authors: White Brian S. , Woo Xing Yi , Koc Soner , Sheridan Todd , Neuhauser Steven B. , Wang Shidan , Evrard Yvonne A. , Chen Li , Foroughi pour Ali , Landua John D. , Mashl R. Jay , Davies Sherri R. , Fang Bingliang , Raso Maria Gabriela , Evans Kurt W. , Bailey Matthew H. , Chen Yeqing , Xiao Min , Rubinstein Jill C. , Sanderson Brian J. , Lloyd Michael W. , Domanskyi Sergii , Dobrolecki Lacey E. , Fujita Maihi , Fujimoto Junya , Xiao Guanghua , Fields Ryan C. , Mudd Jacqueline L. , Xu Xiaowei , Hollingshead Melinda G. , Jiwani Shahanawaz , Acevedo Saul , Davis-Dusenbery Brandi N. , Robinson Peter N. , Moscow Jeffrey A. , Doroshow James H. , Mitsiades Nicholas , Kaochar Salma , Pan Chong-xian , Carvajal-Carmona Luis G. , Welm Alana L. , Welm Bryan E. , Govindan Ramaswamy , Li Shunqiang , Davies Michael A. , Roth Jack A. , Meric-Bernstam Funda , Xie Yang , Herlyn Meenhard , Ding Li , Lewis Michael T. , Bult Carol J. , Dean Dennis A. , Chuang Jeffrey H.
Published: September 2024

Figure S11
Figure S1 from A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis
Authors: White Brian S. , Woo Xing Yi , Koc Soner , Sheridan Todd , Neuhauser Steven B. , Wang Shidan , Evrard Yvonne A. , Chen Li , Foroughi pour Ali , Landua John D. , Mashl R. Jay , Davies Sherri R. , Fang Bingliang , Raso Maria Gabriela , Evans Kurt W. , Bailey Matthew H. , Chen Yeqing , Xiao Min , Rubinstein Jill C. , Sanderson Brian J. , Lloyd Michael W. , Domanskyi Sergii , Dobrolecki Lacey E. , Fujita Maihi , Fujimoto Junya , Xiao Guanghua , Fields Ryan C. , Mudd Jacqueline L. , Xu Xiaowei , Hollingshead Melinda G. , Jiwani Shahanawaz , Acevedo Saul , Davis-Dusenbery Brandi N. , Robinson Peter N. , Moscow Jeffrey A. , Doroshow James H. , Mitsiades Nicholas , Kaochar Salma , Pan Chong-xian , Carvajal-Carmona Luis G. , Welm Alana L. , Welm Bryan E. , Govindan Ramaswamy , Li Shunqiang , Davies Michael A. , Roth Jack A. , Meric-Bernstam Funda , Xie Yang , Herlyn Meenhard , Ding Li , Lewis Michael T. , Bult Carol J. , Dean Dennis A. , Chuang Jeffrey H.
Published: September 2024

Figure S1
TR-107, an Agonist of Caseinolytic Peptidase Proteolytic Subunit, Disrupts Mitochondrial Metabolism and Inhibits the Growth of Human Colorectal Cancer Cells
Authors: Giarrizzo Michael , LaComb Joseph F. , Patel Hetvi R. , Reddy Rohan G. , Haley John D. , Graves Lee M. , Iwanowicz Edwin J. , Bialkowska Agnieszka B.
Published: September 2024

Oxidative phosphorylation is an essential metabolic process for cancer proliferation and therapy resistance. The ClpXP complex maintains mitochondrial proteostasis by degrading misfolded proteins. Madera Therapeutics has developed a class of highly potent and selective small-molecule activators (TR compounds) of the ClpXP component caseinolytic peptidase proteolytic subunit (ClpP). This approach to cancer therapy eliminates substrate recognition and activates nonspecific protease function within mitochondria, which has shown encouraging preclinical efficacy in multiple malignancies. The class-leading compound TR-107 has demonstrated significantly improved potency in ClpP affinity and activation and enhanced pharmacokinetic properties over the multitargeting clinical agent ONC201. In this study, we investigate the in vitro efficacy of TR-107 against human colorectal cancer cells. TR-107 inhibited colorectal cancer cell proliferation in a dose- and time-dependent manner and induced cell cycle arrest at low nanomolar concentrations. Mechanistically, TR-107 downregulated the expression of proteins involved in the mitochondrial unfolded protein response and mitochondrial DNA transcription and translation. TR-107 attenuated oxygen consumption rate and glycolytic compensation, confirming inactivation of oxidative phosphorylation and a reduction in total cellular respiration. Multiomics analysis of treated cells indicated a downregulation of respiratory chain complex subunits and an upregulation of mitophagy and ferroptosis pathways. Further evaluation of ferroptosis revealed a depletion of antioxidant and iron toxicity defenses that could potentiate sensitivity to combinatory chemotherapeutics. Together, this study provides evidence and insight into the subcellular mechanisms employed by colorectal cancer cells in response to potent ClpP agonism. Our findings demonstrate a productive approach to disrupting mitochondrial metabolism, supporting the translational potential of TR-107.
Abstract A006 Targeting boundary cap cells leads to mouse Smarcb1-deficient peripheral nerve tumors recapitulating human peripheral rhabdoid tumors
Authors: HAN Zhi-Yan , Andrianteranagna Mamy , Fitte-Duval Stéphanie , Manriquez Valeria , Frah Magali , Bouarich Rachida , Turcynski Sandrina , Tauziède-Espariat Arnault , Beccaria Kevin , Masliah-Planchon Julien , Bourneix Christine , Guillemot Delphine , Reynaud Stéphanie , Pierron Gaelle , Veyssiere Maëva , Hoare Owen , Chauvin Céline , Thomson Grégory , Surdez Didier , Varlet Pascale , Dufour Christelle , Dangouloff-Ros Volodia , Waterfall Joshua J. , Piaggio Eliane , Delattre Olivier , Topilko Piotr , Bourdeaut Franck
Published: September 2024

Malignant rhabdoid tumors (MRT) are rare aggressive tumors of infancy characterized by the biallelic inactivation of SMARCB1. Their lineage of origin remains uncertain, but increasing evidence suggest a neural-crest origin. By analyzing the transcriptome of MRT occurring in peripheral and cranial nerves, we observe that their expression profiling was not distinct from any other tumor localization. We therefore investigated whether the development of Smarcb1-deficient tumors emerging from embryonic precursors of peripheral nerves in mice could recapitulate human MRT. we generated conditional Smarcb1 knockout in the Prss56-Cre mouse strain thereby targeting boundary cap cells which are neural crest derived Schwann cell precursor. All Smarcb1Flox/Flox;Prss56Cre+/+ showed ataxia within a median of two months, due to the development of massive intracranial tumor in the ponto-cerebellum angle. Smarcb1Flox/Flox;Prss56Cre+/- mainly developed paraplegia related to nerve root tumors, within a median delay of 7 months. Interestingly, transcriptome profiling confirmed the good correlation between mouse peripheral nerve tumors and human MRT; intracranial tumors in this new model correlated with MYC-ATRTs but with some specific features not observed in their human counterparts. All tumors harbored a significant immune infiltration, with some clonal T-cell expansion. Altogether, the Smarcb1Flox/Flox;Prss56-Cre mouse tumors offer a new model for human MRT and promising perspectives for immune-based innovative treatments.

Citation Format: Zhi-Yan HAN, Mamy Andrianteranagna, Stéphanie Fitte-Duval, Valeria Manriquez, Magali Frah, Rachida Bouarich, Sandrina Turcynski, Arnault Tauziède-Espariat, Kevin Beccaria, Julien Masliah-Planchon, Christine Bourneix, Delphine Guillemot, Stéphanie Reynaud, Gaelle Pierron, Maëva Veyssiere, Owen Hoare, Céline Chauvin, Grégory Thomson, Didier Surdez, Pascale Varlet, Christelle Dufour, Volodia Dangouloff-Ros, Joshua J. Waterfall, Eliane Piaggio, Olivier Delattre, Piotr Topilko, Franck Bourdeaut. Targeting boundary cap cells leads to mouse Smarcb1-deficient peripheral nerve tumors recapitulating human peripheral rhabdoid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A006.
Abstract A009 Single cell transcriptomic signature of Li-Fraumeni Syndrome soft tissue sarcomas
Authors: Kissoondoyal Ashby , Malkin David
Published: September 2024

Li-Fraumeni Syndrome (LFS) is a genetic predisposition disorder associated with pathogenic germline Tp53 mutations. A subset of LFS-associated neoplasms occurs at an increased risk within the first 5 years of life, with the most common being soft tissue sarcomas (STS). Histological characterization of STS is one of the primary approaches to guiding treatment. However, the heterogeneity of STS has necessitated a further understanding of the molecular etiology of these tumors. Examining sarcomas using a single-cell transcriptomic approach has shown unique subsets of cells with dysregulations in cell fate and differentiation. Within LFS-associated tumors, including LFS-STS a major event in tumorigenesis is the copy-neutral loss of heterozygosity (LOH). LOH was determined to occur much earlier than cancer onset in LFS, suggesting a dormancy period from the LOH until tumorigenesis; cancer-defining events in LFS are likely occurring prenatally. During embryogenesis, Tp53 is involved in differentiation and pluripotency regulation, as well as cell cycle control and apoptosis. Here we hypothesize that the emergence of STS in LFS mice is associated with distinct disturbances in the cell fate and differentiation pathways. Specifically, there will be deficits in cell fate determination and the organization of cells across multiple cell types in LFS-Sarcomas. Single-cell RNAseq was performed on spontaneous tumors and healthy matched muscle tissue from male and female C57BL/6J Trp53R172H/WT mice. Cell types were determined based on differential gene expression between clusters defined by principal component analysis. Despite tumor heterogeneity between mice, there were consistent disruptions of developmental pathways among tumor cells. Moreover, when comparing matched cell types across tumor and healthy muscle tissue we observed dysregulation of pathways promoting tumorigenesis, and cell fate determination in cells originating from tumor tissue. For the first time to our knowledge, this study examines the single-cell transcriptome of LFS-STS. Current literature has speculated on the presence of an early precancer state of LFS-associated tumors. This study will provide evidence to determine whether this precancer state can be determined in tumor samples, and identify elements that constitute this state. Moreover, we will determine changes in supporting non-tumor cells and whether they also exhibit dysregulations in cell state and differentiation. Together these findings will hopefully contribute to improvements in molecular subtyping across STS, and particularly within LFS individuals.

Citation Format: Ashby Kissoondoyal, David Malkin. Single cell transcriptomic signature of Li-Fraumeni Syndrome soft tissue sarcomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A009.
Abstract A043 Plasma circulating proteomic markers are associated with metastatic spread and outcome in osteosarcoma
Authors: Audinot Baptiste , Drubay Damien , Da Costa Maria Eugenia , Beaudry Gael Moquin , Jimenez Marta , Geoerger Birgit , Gaspar Nathalie , Abbou Samuel , Marchais Antonin
Published: September 2024

Background: Osteosarcoma is the most frequent bone cancer in children and young adults. Histological response and control of primary metastases are the main prognostic clinical factors, but are insufficient to identify the ∼30% of hard-to-treat patients and are not predictive of the response to combinations of chemotherapies or biological treatments. Our aim was to evaluate if circulating proteomic analyses could predict tumor progression. Methods: 88 plasma samples from newly diagnosed patients with osteosarcoma in the OS2006 trial were sequenced using the OLINK Explore panel (3072 proteins) and 88 more coming from the SARCOME13 trial will be used as a validation cohort. Results: Principal component analysis defined co-circulating proteins associated to critical biological pathways involved in osteosarcoma oncogenesis, such as cell adhesion, cell survival/growth, bone formation and extracellular matrix organization. Cox survival analysis associated circulating bone formation pathway with OS(HR=1.10 [1.03;1.17], p=0.006) and PFS(HR=1.12 [1.05;1.19], p=<0.001). These circulating pathways were also associated with presence of metastases at diagnosis (odd ratio = 1.33 [1.12;1.72], p=0.006). These results are being validated on SARCOME13 data. Conclusion: Proteomic plasma markers quantification in patients with osteosarcoma at diagnosis capture a biological signal significantly associated to prognosis and the presence of metastasis at diagnosis.

Citation Format: Baptiste Audinot, Damien Drubay, Maria Eugenia Da Costa, Gael Moquin Beaudry, Marta Jimenez, Birgit Geoerger, Nathalie Gaspar, Samuel Abbou, Antonin Marchais. Plasma circulating proteomic markers are associated with metastatic spread and outcome in osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A043.
Abstract A062 Therapeutic targeting of the SAGA KAT module impairs MYCN-amplified neuroblastoma growth through reduction of the MYCN oncogenic gene expression program
Authors: Mabe Nathaniel W. , Malone Clare F. , Forman Alexandra B. , Alexe Gabriela , Engel Kathleen L. , Chen Ying-Jiun C. , Soeung Melinda , Salhotra Silvi , Basanthakumar Allen , Liu Bin , Dent Sharon YR , Stegmaier Kimberly
Published: September 2024

Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity. While direct targeting of transcription factors is difficult, one method to circumvent this problem is to target co-factors and chromatin complexes that are necessary for their oncogenic function. To evaluate protein complex dependencies enriched in MYCN-amplified neuroblastoma, a disease of dysregulated development driven by aberrant expression of an oncogenic expression program, we curated a list of protein complexes using the CORUM database and mined the Dependency Map using single sample gene set enrichment analysis. This analysis identified the KAT module of the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as a selective dependency in MYCN-amplified neuroblastoma. Loss of SAGA complex activity in neuroblastoma through both genetic knockout and induced protein degradation of the lysine acetyltransferase (KAT) module subunit TADA2B resulted in a global reduction of histone lysine acetylation and impaired neuroblastoma cell growth. Genetic knockout of TADA2B did not impair the growth of pediatric sarcoma cell lines, suggesting that SAGA loss-of-function is not broadly deleterious. Furthermore, SAGA loss-of-function reduced MYCN binding to chromatin, resulting in suppression of the MYCN-driven gene expression program and impaired cell cycle progression. Importantly, the SAGA complex is pharmacologically targetable in vitro and in vivo with GSK-699, a PROTAC that induces proteolysis of both KAT2A and KAT2B paralogs. As observed with genetic knockout studies, loss of SAGA activity through KAT2A/B degradation reduced the MYCN-driven transcriptional signature and impaired cell cycle progression. Our findings expand our understanding of the chromatin complexes that maintain the oncogenic transcriptional state in MYCN-amplified neuroblastoma and suggest therapeutic potential for inhibitors of SAGA KAT activity in MYCN-amplified neuroblastoma.

Citation Format: Nathaniel W. Mabe, Clare F. Malone, Alexandra B. Forman, Gabriela Alexe, Kathleen L. Engel, Ying-Jiun C. Chen, Melinda Soeung, Silvi Salhotra, Allen Basanthakumar, Bin Liu, Sharon YR Dent, Kimberly Stegmaier. Therapeutic targeting of the SAGA KAT module impairs MYCN-amplified neuroblastoma growth through reduction of the MYCN oncogenic gene expression program [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A062.
Abstract A073 Epigenetic control of neuroblastoma differentiation through inhibition of the histone acetyltransferases KAT6A and KAT6B
Authors: Weichert-Leahey Nina , Look Thomas
Published: September 2024

Retinoic acid re-organizes the enhancers regulating the expression of these key transcription factors in neuroblastoma and establishes a new differentiated cell state characterized by MYCN downregulation and proliferative arrest. However, the epigenetic and growth suppressing effects of retinoic acid are completely reversible in vitro, leading to cell proliferation. We sought to determine if retinoid-induced differentiation can be forced to progress to terminal neuronal maturation by the addition of inhibitors of enzymes modifying the epigenome. We conducted a drug screen using more than 450 epigenetic modifiers to treat neuroblastoma cells either with each compound alone or in combination with retinoic acid to determine whether any compound augments the antiproliferative effects of retinoic acid. We found that an inhibitor of the histone acetyltransferases KAT6A/B synergistically inhibits neuroblastoma growth in combination with retinoic acid in vitro and enhances neuroblastoma differentiation. We used a xenograft model of retinoid-sensitive neuroblastoma cells in mice to test if the combination treatment with isotretinoin and a KAT6 inhibitor is more effective than isotretinoin alone to induce permanent neuroblastoma differentiation in vivo. We found that isotretinoin is very effective in suppressing neuroblastoma proliferation, however its effects are completely reversible upon drug removal leading to rapid tumor re-growth. In contrast, when isotretinoin is combined with a KAT6 inhibitor, tumors cannot re-grow after isotretinoin removal and remain differentiated. In conclusion, our studies nominate KAT6A/B inhibition combined with isotretinoin as a promising approach to improve outcome for patients with neuroblastoma.

Citation Format: Nina Weichert-Leahey, Thomas Look. Epigenetic control of neuroblastoma differentiation through inhibition of the histone acetyltransferases KAT6A and KAT6B [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A073.
Abstract A080 PRC1/BMI1 activity alters chromatin accessibility to regulate differentiation in atypical teratoid rhabdoid tumors
Authors: Alimova Irina Irina , Murdock Gillian , Pierce Angela M. , Wang Dong , Dahl Nathan , Venkataraman Sujatha , Vibhakar Rajeev
Published: September 2024

Atypical Teratoid Rhabdoid Tumor (ATRT) is a highly aggressive pediatric brain tumor and characterized by SMARCB1 deletion. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. We performed an RNAi-based functional genomic screen to identify key epigenetic regulators that co-operate with SMARCB1 loss and contribute to tumorigenesis in ATRT. 406 genes associated with epigenetic regulation in patient derived ATRT cell lines were targeted. This screen identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as one of the top targets essential for ATRT cell growth. Using RNA-seq and ChIP-Seq analysis we demonstrated that BMI1 co-operates with SMARCB1 deletion to suppress transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. In SMARCB1 deficient cells BMI1 forms a partial PRC1 complex devoid of DNA binding components. We found that genetic inactivation of BMI1 suppresses ATRT cell clonogenicity in vitro and decreases S-phase length. By Doxycycline-inducible SMARCB1 re-expression system we revealed activation of proapoptotic proteins p16 and p21. With immunoprecipitation for BMI1, followed by mass spectrometry analysis we demonstrated that re-expression of SMARCB1 activates two PRC1 chromatin localizing components CBX4 and CBX8. Moreover, inhibition of BMI1 significantly prolongs mice survival and decreases tumor size as evaluated by IVIS imaging system and T2-MRI. Thus, we demonstrated that SMARCB1 deletion results in reprograming of BMI1 chromatin occupancy away from lineage specification by altering the components of the PRC1 complex and that PRC1/BMI1 inhibition is a novel therapeutic approach in ATRT.

Citation Format: Irina Irina Alimova, Gillian Murdock, Angela M. Pierce, Dong Wang, Nathan Dahl, Sujatha Venkataraman, Rajeev Vibhakar. PRC1/BMI1 activity alters chromatin accessibility to regulate differentiation in atypical teratoid rhabdoid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A080.
Abstract B008: Decoding the primary site-specific regulation of rhabdomyosarcoma metastasis
Authors: Hebron Katie E. , Isanogle Kristine , Edmondson Elijah F. , James Amy , Difilippantonio Simone , Yohe Marielle E.
Published: September 2024

The prognosis for patients with high-risk rhabdomyosarcoma (RMS), a pediatric sarcoma characterized in part by defective skeletal muscle (myogenic) differentiation, has remained stagnant at <30% for over forty years. With >15% of patients presenting at diagnosis with metastasis, a defining factor of high-risk disease, there is an urgent need for new therapies. Some primary tumor locations are associated with a higher incidence of metastasis and poorer outcomes. However, the biology (and potential for therapeutic intervention) driving this prognostic factor is poorly defined.To analyze the influence of the primary tumor location on RMS invasion and metastasis, we evaluated cell line xenografts (CDX) implanted in a favorable site, the tongue, versus an unfavorable site, the hindlimb. We evaluated invasion and metastasis from each primary tumor site by histopathology and measured gene expression changes by bulk RNAseq.Despite the tongue being deemed a favorable primary site, perineural invasion or intravascular tumor emboli (60% versus 0%), sentinel lymph node metastasis (25-100% versus 0%), and clinically significant lung metastases (>10% lung area or symptomatic mice; 20% versus 0%) were observed more frequently in tongue xenograft-bearing mice than hindlimb xenograft-bearing mice. The expression of myogenic differentiation markers is higher in tongue CDX than in hindlimb CDX, but expression of these markers is reduced upon metastasis. These phenotypes are maintained when cells are returned to 2D culture, suggesting a stable shift in the differentiation state. Interestingly, CDX of sentinel lymph node metastasis-derived cells were more invasive and metastatic than parental CDX when implanted in the tongue, but not when implanted in the hindlimb.Our work, the first direct evaluation of RMS invasion and metastasis by primary tumor location, demonstrates that the primary tumor location influences RMS metastasis and that tumor cell-intrinsic properties alone are insufficient to increase invasion and metastasis. Ongoing work aims to identify the mechanisms by which the primary tumor microenvironment regulates invasion, enhancing our understanding of the biology of RMS metastasis and offering an opportunity to employ a precision medicine-based approach to targeting metastasis.

Citation Format: Katie E. Hebron, Kristine Isanogle, Elijah F. Edmondson, Amy James, Simone Difilippantonio, Marielle E. Yohe. Decoding the primary site-specific regulation of rhabdomyosarcoma metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B008.
Abstract B046: Addressing inequities in pediatric solid tumors: Insights from Hispanics in Puerto Rico
Authors: Ruiz-Perez Carolyn M. , Rivera-Valentín Rocío K.
Published: September 2024

Introduction: Pediatric solid tumors are a diverse group of rare cancers that occur in children. Recent advancements in therapy, such as immunotherapy, targeted therapy, and precision medicine, have shown promise in improving treatment outcomes for these cancers. Moreover, health disparities in the incidence and mortality rates of pediatric solid tumors have been reported between US racial/ethnic groups, where Hispanics and African ethnicities present higher rates of incidence and metastatic disease. Despite disparities observed in pediatric solid tumors among US Hispanics, no information exists for Puerto Rican Hispanic children with cancer. Thus, this study aims to understand and describe the epidemiology of a Hispanic population of pediatric patients diagnosed with solid tumors living in Puerto Rico. Methods: Age-adjusted incidence rates (IR) and mortality rates (MR) for specific childhood cancers (ages 0-19) were estimated using data obtained from the Incidence Case File from the Puerto Rico Central Cancer Registry for the period 2009-2020. Results: During this period, 666[MS1]pediatric patients were diagnosed with cancer, with malignant bone tumors comprising 4.7% of cases and with an age-adjusted incidence rate of 6.0 cases per million. Among pediatric patients with malignant bone tumors, 34.6% presented with regional disease and 23.1% presented with distant metastatic disease at diagnosis. The mortality rate for pediatric cancers involving bone and joints was 2.4 cases per million. Conclusions: This is a first-of-its-kind analysis in a Hispanic cohort of pediatric solid tumor patients in Puerto Rico. Understanding the disparities in solid pediatric tumors within this Hispanic population is crucial for developing targeted interventions that improve diagnosis, treatment, and survival rates for these children who face other disparities, including limited access to specialized care and economic barriers, among others. Publishing this data is essential as it raises awareness, guides resource allocation, and informs policy decisions to address healthcare inequities. Future studies should explore risk factors and differential gene expression. Acknowledgement: The authors extend gratitude to the Biostatistics and Bioinformatics Core of the UPR Comprehensive Cancer Center and the PR Central Cancer Registry for collaborating in our research.

Citation Format: Carolyn M. Ruiz-Perez, Rocío K. Rivera-Valentín. Addressing inequities in pediatric solid tumors: Insights from Hispanics in Puerto Rico [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B046.
Abstract B078: Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy
Authors: Walker Faye M. , Sobral Lays Martin , Danis Etienne , Sanford Bridget , Balakrishnan Ilango , Wang Dong , Pierce Angela , Karam Sana , Serkova Natalie J. , Foreman Nicholas K. , Venkataraman Sujatha , Dowell Robin , Vibhakar Rajeev , Dahl Nathan A.
Published: September 2024

Background: Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-mediated promoter proximal pause-release of Pol II is a conserved regulatory mechanism for synchronous transcriptional induction best described in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Design/Method: In order to examine the dynamics of chromatin reorganization following radiotherapy, we performed a combination of ChIP-, ATAC-, and RNA-seq in model systems of diffuse intrinsic pontine glioma (DIPG) and other pediatric high-grade gliomas (pHGG) following IR exposure. We interrogated IR-induced gene expression in the presence or absence of PTEFb blockade, including both mechanistic and functional consequences of concurrent inhibition or genetic depletion. We utilized culture models with live cell imaging to assess the therapeutic synergy of PTEFb inhibition with IR, as well as the therapeutic index of this intervention relative to normal controls. Finally, we employed orthotopic models of pHGG treated with conformal radiotherapy and CNS-penetrant PTEFb inhibitors in order to assess tolerability and anti-tumor effect in vivo. Results: Rapid genome-wide redistribution of active chromatin features and PTEFb facilitates Pol II pause-release to drive nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of PTEFb imparts a transcription elongation defect, abrogating canonical adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival.Conclusion: These studies reveal a central role for PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies.

Citation Format: Faye M. Walker, Lays Martin Sobral, Etienne Danis, Bridget Sanford, Ilango Balakrishnan, Dong Wang, Angela Pierce, Sana Karam, Natalie J. Serkova, Nicholas K. Foreman, Sujatha Venkataraman, Robin Dowell, Rajeev Vibhakar, Nathan A. Dahl. Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B078.
Supplementary Figure 8 from Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan
Published: September 2024

Supplementary Figure 8
Supplementary Figure 6 from Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan
Published: September 2024

Supplementary Figure 6
Visual Outcome after Anti-Vascular Epithelial Growth Factor Therapy Using New Classification of Diabetic Macular Edema by Optical Coherence Tomography
Authors: Zhao Jiawei , Zhu Weiye , Cui Xiao , Xu Bing , Shen Ni , Song Hongyuan , Shen Wei
Published: September 2024

Introduction: The aim of the study was to examine alterations in visual acuity in patients with diabetic macular edema (DME), classified according to the TCED-HFV optical coherence tomography (OCT) system, following anti-vascular epithelial growth factor (VEGF) therapy. Methods: The medical records of patients with DME receiving anti-VEGF therapy were retrospectively reviewed. Patients were divided into four groups according to the TCED-HFV OCT classification. Patient demographic and clinical characteristics and best-corrected visual acuity (BCVA) before and after treatment were compared among the groups. Results: The BCVA before treatment was 0.49 ± 0.18, 0.81 ± 0.41, 0.83 ± 0.41, and 0.82 ± 0.49 in the early DME, advanced DME, severe DME, and atrophic maculopathy groups, respectively. The BCVA in the early DME group was therefore significantly lower than that in the other three groups (p = 0.042). After treatment, the BCVA improved to 0.15 ± 0.17, 0.52 ± 0.31, 0.62 ± 0.32, and 0.69 ± 0.47 in the early DME, advanced DME, severe DME, and atrophic maculopathy groups, respectively (p < 0.005). There were some differences among patients in the four groups in terms of the duration of diabetes, percentage of hemoglobin A1c, and duration of hypertension. Conclusion: The TCED-HFV OCT classification of patients with DME is exact and functional and can allow the severity of DME, and its response to anti-VEGF therapy, to be estimated.
Detecting Longitudinal Trends between Passively Collected Phone Use and Anxiety among College Students
Authors: Gyorda Joseph A. , Lekkas Damien , Jacobson Nicholas C.
Published: September 2024

Introduction: Existing theories and empirical works link phone use with anxiety; however, most leverage subjective self-reports of phone use (e.g., validated questionnaires) that may not correspond well with true behavior. Moreover, most works linking phone use with anxiety do not interrogate associations within a temporal framework. Accordingly, the present study sought to investigate the utility of passively sensed phone use as a longitudinal predictor of anxiety symptomatology within a population particularly vulnerable to experiencing anxiety. Methods: Using data from the GLOBEM study, which continuously collected longitudinal behavioral data from a college cohort of N = 330 students, weekly PHQ-4 anxiety subscale scores across 3 years (2019–2021) were paired with median daily phone use records from the 2 weeks prior to anxiety self-report completion. Phone use was operationalized through unlock duration which was passively curated via Apple’s “Screen Time” feature. GPS-tracked location data was further utilized to specify whether an individual’s phone use was at home or away from home. Within-individual and temporal associations between phone use and anxiety were modeled within an ordinal mixed-effects logistic regression framework. Results: While there was no significant association between anxiety levels and either median total phone use or median phone use at home, participants in the top quartile of median phone use away from home were predicted to exhibit clinically significant anxiety levels 20% more frequently than participants in the bottom quartile during the first study year; however, this association weakened across successive years. Importantly, these associations remained after controlling for age, physical activity, sleep, and baseline anxiety levels and were not recapitulated when operationalizing phone use with unlock frequency. Conclusions: These findings suggest that phone use may be leveraged as a means of mitigating or coping with anxiety in social situations outside the home, while pandemic-related developments may also have attenuated this behavior later in the study. Nevertheless, the present results suggest promise in interrogating a larger suite of objectively measured phone use behaviors within the context of social anxiety.
Effect of Dialysis on Structural Brain Connectivity in Patients with End-Stage Renal Disease
Authors: Choi Byeongo , Heo Chang Min , Yi Jiyae , Lee Dong Ah , Lee Yoo Jin , Park Sihyung , Kim Yang Wook , Ko Junghae , Park Bong Soo , Park Kang Min
Published: September 2024

Introduction: Patients with end-stage renal disease (ESRD) are known to have reduced structural and functional brain connectivity in the brain regions associated with cognitive function. However, the effect of dialysis on brain connectivity remains unclear. This study aimed to evaluate the effects of dialysis on structural brain connectivity in patients with ESRD. Methods: This prospective study included 20 patients with ESRD in the pre-dialysis stage and 35 healthy controls. The patients underwent T2-weighted and three-dimensional T1-weighted magnetic resonance imaging before and 3 months after dialysis initiation. Moreover, the cortical thickness was calculated. We applied graph theoretical analysis to calculate the structural covariance network based on cortical thickness. We compared the cortical thickness and structural covariance network of patients with ESRD in the pre-dialysis stage with those of healthy controls and with those of patients with ESRD in the post-dialysis stage. Results: The mean cortical thickness in both hemispheres was lower in patients with ESRD in the pre-dialysis stage than in healthy controls (2.296 vs. 2.354, p = 0.030; 2.282 vs. 2.362, p = 0.004, respectively) and was higher in patients with ESRD in the post-dialysis stage than in those in the pre-dialysis stage (2.333 vs. 2.296, p = 0.001; 2.322 vs. 2.282, p = 0.002, respectively). Analysis of the structural covariance network revealed that the assortative coefficient was lower in patients with ESRD in the pre-dialysis stage than in healthy controls (−0.062 vs. −0.031, p = 0.029) and was higher in patients with ESRD in the post-dialysis stage than in those in the pre-dialysis stage (−0.002 vs. −0.062, p = 0.042). Conclusion: We observed differences in the cortical thickness and structural covariance networks before and after dialysis in patients with ESRD. This indicates that dialysis affects structural brain connectivity, contributing to the understanding of the pathophysiological mechanism of cognitive function alterations resulting from dialysis in patients with ESRD.