tbuckley/cabot-search huggingface dataset:
Abstract A029 Investigating the role of environmental toxicant exposures and STAG2 loss in sarcomagenesis
Authors: Rachael Kohrn, Joyce Ohm
Journal: Cancer Research (2024)

Abstract Humans are exposed to a variety of environmental toxicants which have been implicated in contributing to cancer development. A possible explanation for this link is that adaptive epigenetic changes occur in stem cell populations upon toxicant exposure. These cells are particularly vulnerable during developmental stages, leading to abnormal gene expression later in life. Environmental exposures have been associated with the initiation of sarcoma development. This study will focus on Ewing Sarcoma (ES), as this malignancy has a low mutational burden relative to other cancer types and is thought to be linked to agricultural chemicals. We are also focusing on stromal antigen 2 (STAG2), which is found to be frequently mutated in ES in addition to multiple other tumor types. Patients with STAG2-mutated ES have higher rates of metastatic disease and worse outcomes, but the reason for this remains poorly understood. STAG2 plays a role in the regulation of genomic organization, DNA repair, and modulation of replication stress (RS). It has also been shown that STAG2 loss may lead to dysregulation of the cGAS-STING pathway, which is critical for tumor immunosurveillance. We are testing the effects of environmental toxicants in mesenchymal stem cells (MSCs), the putative cell of origin for ES and many other sarcomas. We have successfully used CRISPR/Cas9 to generate STAG2 knockout MSCs. With this model, we are testing the effects of STAG2 loss and toxicant exposure on levels of RS, epigenomic instability, and innate immune suppression in MSCs. Our results indicate that these toxicants alter the cell cycle dynamics of MSCs, and that these alterations change depending on STAG2 status. We have also observed changes in the DNA damage response of STAG2-mutant MSCs when exposed to environmental toxicants. Interestingly, effects were seen even at sub-lethal doses that may reflect common, low-level exposures. We believe that our data will contribute to the understanding of the mechanism by which environmental toxicants facilitate malignant transformation of Ewing sarcoma and other pediatric sarcomas. Citation Format: Rachael Kohrn, Joyce Ohm. Investigating the role of environmental toxicant exposures and STAG2 loss in sarcomagenesis [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 A029.
Abstract B081: EWS::FLI1 alters DNA damage induced protein dynamics at the RNAPII CTD
Authors: Aiola Stoja, Xiaoping Xu, David S Libich, Alexander J. R. Bishop
Journal: Cancer Research (2024)

Abstract Ewing sarcoma (EwS) is an aggressive pediatric bone cancer with limited treatment options, highlighting a drastic need for novel therapeutics. EwS is driven by translocation of the EWSR1 low complexity domain and most often the DNA binding domain of FLI1, making up the oncogenic fusion protein EWS::FLI1. Accumulating evidence suggests that EWS::FLI1 alters the biophysical properties of EWS and EWS::FLI1 phase separated condensates. We have previously shown that EWS::FLI1 prevents the release of the double strand break (DSB) repair protein BRCA1 from RNA Polymerase II (RNAPII) complexes, inhibiting BRCA1 mediated DSB repair. However, how EWS::FLI1 alters protein dynamics at the RNAPII complexes is not understood. In this work we show that EWS::FLI1 co-localization to RNAPII C-Terminal Domain (CTD) protein hubs causes enhanced phase separation, imitating a hardening of RNAPII CTD condensates. Additionally, we find that treatment with DNA damaging agents decreases BRCA1 occupancy at RNAPII CTD protein hubs. Expression of EWS::FLI1 in this in cellulo system suggests inhibition of BRCA1 release from RNAPII phase separated entities upon DNA damage. Overall, this data indicates that EWS::FLI1 mediated changes in phase state alters heterotypic protein-protein interactions at the RNAPII complexes. Furthermore, we find that RNAPII CTD phase separated entities are refractory to THZ1 drug treatment. This underscores the physiological significance condensate biology plays in drug efficacy and drug resistance. In conclusion, our results prompt further investigation into EWS::FLI1 affects on protein-protein interactions at RNAPII condensates. Our findings are novel as we look at heterotypic phase condensate biology in cellulo, whereas most phase studies are conducted in vitro and focus on homotypic interactions. Moreover, though much work was conducted on BRCA1 and RNAPII interaction and damage-induced release in the 1990s and early 2000s, little is understood about the relationship of BRCA1 and RNAPII and certainly not in the context of EWS::FLI1. Importantly, this work provides a basis for the physiological role of condensate biology in EWS::FLI1 mediated BRCA1 and RNAPII protein-protein dynamics. Citation Format: Aiola Stoja, Xiaoping Xu, David S Libich, Alexander J. R. Bishop. EWS::FLI1 alters DNA damage induced protein dynamics at the RNAPII CTD [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 B081.
Abstract IA003: Genetic predisposition to pediatric cancer: the long way from discovery to surveillance guidelines
Authors: Franck Bourdeaut
Journal: Cancer Research (2024)

Abstract Pediatric cancers are estimated to be related to a genetic predisposition in about 8 to 10% of cases. This estimation mostly relies on already discovered cancer predisposing genes. However, the numerous new cancer predisposing genes that have been discovered in the past decade thanks to high throughput sequencing in vast cohort of pediatric patients illustrate that new genes may still be unravelled. Moreover, the frequency of early post-zygotic mosaicism is being readdressed thanks to more dedicated sequencing and research. The actual clinical impact of all those discoveries is the main challenge for the community: defining the penetrance, delineating the cancer spectrum and therefore the appropriate surveillance, and setting up innovative follow-up techniques are necessary. Here, we’ll describe recent findings on brain tumor predisposing genes (ELP1 and SMARCB1, among others) to illustrate the increasing recognition of genetic predisposition in pediatric cancers and how the clinical translation of these laboratory findings remain challenging at clinical and ethical levels. Citation Format: Franck Bourdeaut. Genetic predisposition to pediatric cancer: the long way from discovery to surveillance guidelines [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 IA003.
Abstract B080: Survivorship care models for childhood cancer survivors in low- and middle-income countries: A scoping review
Authors: Celine Lecce, Avram E. Denburg, Sumit Gupta, Alexandra Martiniuk, Ariel Qi
Journal: Cancer Research (2024)

Abstract Childhood cancer survivors require specific care that includes monitoring for late effects of cancer therapy. Current knowledge on how to deliver survivorship care is based on experience in high-income countries, which may not be applicable to other settings. We thus conducted a scoping review to characterize and describe the models of survivorship care available to childhood cancer survivors in low- and middle-income countries (LMICs). Fifty-one studies were selected from a comprehensive literature search of 8 electronic and 2 grey-literature databases followed by title, abstract, and full-text screening. Elements of survivorship care were categorized within the domains of the Quality of Cancer Survivorship Care Framework using representative Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers guidelines for childhood cancer survivors. The Quality of Cancer Survivorship Care Framework is comprised of 5 domains related to survivorship care services, and 4 domains related to health care delivery. From the 51 studies chosen for data extraction, 61 LMICs were identified. Of these 61 LMICs, only 11 countries reported having active survivorship care services. The most reported services in the included papers from LMICs are related to the surveillance and management of chronic medical conditions and psychosocial effects. Of the countries that that reported survivorship services, literature from India reported on the four fundamental health care delivery domains identified by the Quality Cancer Survivorship Care Framework, which include clinical structure, communication and decision-making, care coordination, and patient/caregiver experience. Additionally, 8 of the 11 countries publishing about their survivorship care documented access to specialty medical care and healthcare professionals for childhood cancer survivors, such as onco-endocrinologists and psychologists. There are patient, clinician, and health system-related barriers to developing and implementing survivorship care in LMICs. Efforts to optimize the delivery of survivorship care include increased patient and family education about treatment late effects, optimized healthcare provider staffing, staff education, and training, and implementation of standardized practice guidelines that are resource-stratified and therefore applicable in multiple settings. Citation Format: Celine Lecce, Avram E. Denburg, Sumit Gupta, Alexandra Martiniuk, Ariel Qi. Survivorship care models for childhood cancer survivors in low- and middle-income countries: A scoping review [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 B080.
Correspondence on ‘EULAR recommendations for the management of systemic lupus erythematosus: 2023 update’ by Fanouriakis<i>et al</i>
Authors: Jordan Elizabeth Roberts, Nayimisha Balmuri, Joyce C Chang, Jennifer Cooper, Onengiya Harry, Rebecca Hetrick, Jim Jarvis, Andrea M Knight, Laura B Lewandowski, Tamar B Rubinstein, Rebecca Sadun, William Daniel Soulsby, Scott Wenderfer, Jennifer M P Woo
Journal: Annals of the Rheumatic Diseases (2024)
Abstract B040: Rural-urban differences in multiple symptoms occurrence in pediatric cancer survivors after treatment completion in Nebraska, United States
Authors: Krishtee Napit, Don Coulter, Katrina Cordts, Daisy Dai, Evi Farazi, Shinobu Watanabe-Galloway
Journal: Cancer Research (2024)

Abstract Background Pediatric cancer is the leading cause of death by disease among children. With advanced treatments, survivors are living longer. However, they often experience multiple symptoms even after the treatment completion. Little is known about whether rural-urban residences are associated with multiple symptoms occurrence in pediatric cancer survivors. Methods We conducted a cross-sectional study of 130 pediatric cancer survivors aged 10-25 who completed treatment within eight years from 2 major hospitals in Nebraska. We used a survey to collect data during their hospital visit and the validated Memorial Symptom Assessment Scale tool to collect information on 30 symptoms. We used the PedsQoL instrument to measure the quality of life. We conducted a multiple linear regression model to find the association between rurality and multiple symptoms and to identify factors associated with multiple symptoms at a level of significance with a p-value of less than 0.05 and an adjusted beta coefficient. Results The mean age of participants was 15.00, the mean year since diagnosis and treatment completion was 4.52 and 2.92, respectively, and the mean number of symptoms was 6.18.Difficulty concentrating (49.23%), lack of energy (46.92%), and feeling drowsy (46.92%) were the most common symptoms. The mean total quality of life score was 82.16 out of 100. In the unadjusted model, the association of residence and multiple symptoms was not found to be significant, but when adjusted for possible confounders such as age, race, ethnicity, education, diagnosis, body mass index, health-related quality of life, the association was found to be significant indicating there are a higher number of symptoms in pediatric cancer survivors residing in rural areas compared to urban areas. Quality of life is also poorer when the number of symptoms is higher. Conclusion Even after the treatment completion, multiple symptoms occur in pediatric cancer survivors, and the number of symptoms is higher for those residing in rural areas.Further exploration is needed because of the higher number of symptoms in those residing in rural areas. The association of multiple symptoms with other neighborhood-level socio-demographic indices, such as the area deprivation index, should also be assessed. Citation Format: Krishtee Napit, Don Coulter, Katrina Cordts, Daisy Dai, Evi Farazi, Shinobu Watanabe-Galloway. Rural-urban differences in multiple symptoms occurrence in pediatric cancer survivors after treatment completion in Nebraska, United States [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 B040.
Abstract B060: Clonal composition of αβ and γδ T cells in primary human neuroblastoma tumors – Is every child unique?
Authors: Bronte Manouk Verhoeven, Kewei Ye, Jakob Stenman, Per Kogner, John Inge Johnsen, Oscar Bedoya Reina, Taras Kreslavskiy, Ninib Baryawno
Journal: Cancer Research (2024)

Abstract Alpha beta (ab) T cells are immune cells that play a key role in the adaptive immune system. Over the years many different ab T cell subtypes have been defined including cells with anti-tumor cytotoxic functions. Gamma delta (gd) T cells are considered the bridge between innate and adaptive immunity. While rules of antigen recognition by gd T cells remain poorly understood, this recognition takes place in the absence of classical antigen presentation on MHC molecules. In neuroblastoma (NB), the most common and deadly extracranial tumor in children, different subtypes of T cells have been identified in the tumor microenvironment (TME) and their presence is correlated to improved prognosis. However, it remains unknown whether T cells in the TME have clonally expanded, and if yes, which antigens they recognize. Our aim is thus to uncover the clonal composition of T cells in primary human NB tumors including to elucidate ligand recognition in gd T cells. To address these questions, we performed flow cytometry analysis to elucidate gd T cell composition in 14 patient samples, and additionally performed single-cell (sc) RNA/VDJ-seq experiments to characterize clonal composition and functional states of ab and gd T cells infiltrating NB tumors from 11 patients for which 4 had a matched blood sample. In patients' blood, as expected, most gd T cells detected were Vg9Vd2+ cells. In contrast, the majority of detected infiltrating gd T cells in NB tumors were Vd1+ cells. scRNA/VDJ-seq experiments revealed prominent clonal expansion of both ab and gd T cells varying between patients. Clonal expansion was particularly prominent for gd T cells in one female intermediate risk patient’s tumor where nearly half of the cells represented one of the two top expanded clones with unique Vd1 and Vd3 TCRs. Interestingly, we detected Vd1/ Vd3 expanded clones with both a clear cytotoxic signature and with a possible wound healing phenotype. Taken together, drastic clonal expansion of both ab and gd T cells in NB suggests that these cells may recognize antigens present in the TME providing possibilities for immunotherapy. Citation Format: Bronte Manouk Verhoeven, Kewei Ye, Jakob Stenman, Per Kogner, John Inge Johnsen, Oscar Bedoya Reina, Taras Kreslavskiy, Ninib Baryawno. Clonal composition of αβ and γδ T cells in primary human neuroblastoma tumors – Is every child unique [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 B060.
Abstract A062 Therapeutic targeting of the SAGA KAT module impairs MYCN-amplified neuroblastoma growth through reduction of the MYCN oncogenic gene expression program
Authors: 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
Journal: Cancer Research (2024)

Abstract 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.
Introduction to the <i>Diagnostics in Periodontology and Implant Dentistry</i> issue
Authors: Denis F. Kinane, Michael M. Bornstein
Journal: Periodontology 2000 (2024)

Abstract Chronic inflammatory periodontal disease and its related condition, peri‐implant disease, are highly prevalent globally and require accurate and speedy diagnosis. The focus of this volume dedicated to diagnostics is to cover modern enhancements in accuracy, simplicity and speed. An international assortment of experts has been tasked with reviewing defined areas of current best practice as well innovation in the field of periodontitis and peri‐implantitis diagnostics. Periodontitis and peri‐implantitis are irreversible, chronic, cumulative conditions propagated by bacteria and host factors, which involve soft and hard tissue changes, and these changes are measured in the diagnostic process. Clinically relevant modifications to the healthy state are detected using clinical, radiological and laboratory or point of care testing, and these testing approaches are critically reviewed at length in this state‐of‐the‐art resume of periodontal diagnostics.
Integrating mTOR Inhibition and Photodynamic Therapy Based on Carrier‐Free Nanodrugs for Breast Cancer Immunotherapy
Authors: Jinzhao Liu, Qingyang Lyu, Meicen Wu, Yang Zhou, Tianyi Wang, Yichi Zhang, Ni Fan, Chang Yang, Weiping Wang
Journal: Advanced Healthcare Materials (2024)

Abstract Conventional photodynamic therapy (PDT) in cancer treatment needs to utilize oxygen to produce reactive oxygen species to eliminate malignant tissues. However, oxygen consumption in tumor microenvironment exacerbates cancer cell hypoxia and may promote vasculature angiogenesis. Since the mammalian target of rapamycin (mTOR) signaling pathway plays a vital role in endothelial cell proliferation and fibrosis, mTOR inhibitor drugs hold the potential to reverse hypoxia‐evoked angiogenesis for improved PDT effect. In this study, a carrier‐free nanodrug formulation composed of Torin 1 as mTORC1/C2 dual inhibitor and Verteporfin as a photosensitizer and Yes‐associated protein inhibitor is developed. These two drug molecules can self‐assemble into stable nanoparticles through π–π stacking and hydrophobic interactions with good long‐term stability. The nanodrugs can prompt synergistic apoptosis, combinational anti‐angiogenesis, and strong immunogenic cell death effects upon near‐infrared light irradiation in vitro. Furthermore, the nanosystem also exhibits improved antitumor effect, anti‐cancer immune response, and distant tumor inhibition through tumor microenvironment remodeling in vivo. In this way, the nanodrugs can reverse PDT‐elicited angiogenesis and promote cancer immunotherapy to eliminate tumor tissues and prevent metastasis. This nanosystem provides insights into integrating mTOR inhibitors and photosensitizers for safe and effective breast cancer treatment in clinical settings.
Impact of Drug Conjugation Site and Corona Chemistry on the Therapeutic Activity of Polymer Nanorod – Drug Conjugates
Authors: Nicole M. Warne, Cameron J. Nowell, Mai P. Tran, John R. Finnegan, Orlagh M. Feeney, Kristian Kempe
Journal: Advanced Healthcare Materials (2024)

Abstract Biocompatible rod‐shaped nanoparticles of controlled length can be produced through the heat‐induced “living” seeded crystallization‐driven self‐assembly (CDSA) of poly(2‐isopropyl‐2‐oxazoline)‐containing block copolymers. With a hydrophilic poly(2‐methyl‐2‐oxazine) or poly(2‐methyl‐2‐oxazoline) corona, these nanorods have proven non‐cytotoxic, non‐hemolytic, and ideal for use as a polymer‐based drug delivery system. This study demonstrates a facile, one‐pot method for the synthesis of mycophenolic acid (MPA)‐conjugated block copolymer “unimers” for use in seeded CDSA. Through altering block order during sequential monomer addition cationic ring‐opening polymerization (CROP), MPA is conjugated to either the chain end of the core‐forming or corona‐forming block. This allows bioactive polymer nanorods to be prepared with MPA positioned at either the periphery of the corona, or at the core‐corona interface of the nanorod formed during seeded CDSA. In vitro, these nanorods arrest growth in human T and B lymphocytes, with reduced effect in “off‐target” monocytes when compared with unconjugated MPA. Furthermore, the conjugation of MPA to the core‐corona interface of the nanorods leads to a slower release and reduced cytostatic effect. This study offers a robust investigation into the effect of steric hindrance and corona chemistry on the therapeutic potential of drug‐conjugated CDSA nanorods and demonstrates the potential of poly(2‐oxazoline)/poly(2‐oxazine)‐based CDSA nanomaterials as effective drug delivery platforms.