tbuckley/cabot-search huggingface dataset:
RBIO-06. STEREOTACTIC RADIOSURGERY ENHANCES T-CELL RECEPTOR REPERTOIRES AND INDUCES IMMUNOGENICITY IN BRAIN METASTASIS
Authors: Kazutaka Fukumura, Alexandre Reuben, Peixin Jiang, Sherise D Ferguson, Debra N Yeboa, Jason T Huse
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastasis is a frequent and deadly complication of systemic malignancy. The incidence rate is increasing and the prognosis remains poor, in contrast to recent advances in the management of systemic malignancy. Our previous work revealed an immunosuppressive microenvironment in brain metastasis and correlation between T-cell status and patient outcomes, shared across the primary tumor histologies. Therefore, we hypothesize that induction of immunogenicity has potential to improve brain metastasis patient outcome. METHODS Pre-operative stereotactic radiosurgery (SRS) (n = 44) and post-operative SRS (n = 47) brain metastasis specimens were collected from an ongoing clinical trial (MDACC protocol 2018-0552) designed to determine optimal timing of SRS for the treatment of brain metastasis. The patient materials were extracted DNA and RNA, and subjected to T-cell receptor (TCR) repertoire sequencing and mRNA-seq to interrogate radiation-induced immunogenicity. RESULTS In a preliminary analysis of the first 21 specimens, Gene Set Enrichment Analysis revealed that SRS significantly enhanced multiple immune-related signaling pathways including interferon response, along with apoptotic pathways, in brain metastasis. We also found that TCR signaling and PD-1 signaling was upregulated by radiotherapy. TCR repertoire analysis further identified increased density and diversity of TCRs induced by SRS treatment. Profiling of the remaining sample set is currently ongoing. CONCLUSIONS In light of our previous finding regarding the correlation between immune status and outcomes of patients with brain metastases, reversing immunosuppression in brain metastasis could be a key factor on patient prognosis and treatment. Our TCR repertoire and mRNA sequencing analyses with pre-operative and post-operative SRS brain metastasis cohorts support a role for radiation-induced immunogenicity, pointing to a prospective therapeutic approach for brain metastasis management.
STEM-07. UNVEILING THE ROLE OF HYPOXIA AND TAM-SECRETED TGF-Β1 IN PROMOTING GLIOMA STEM CELL MAINTENANCE VIA YAP/TAZ ACTIVATION IN GLIOBLASTOMA PERI-NECROTIC NICHE
Authors: Ling-Kai Shih, Tomasz Gruchala, Jiabo Li, Nicholas Lam, Daniel Brat
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is a highly malignant brain tumor with rapid growth and poor outcomes. In the tumor microenvironment (TME), necrosis triggers significant reshaping and rapid progression, marked by tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) accumulation in peri-necrotic zones. Analysis of Ivy-GAP and single-cell RNA-Seq data revealed consistent Hippo pathway activation in the hypoxic peri-necrotic zone, despite canonical stem-cell transcription factors such as SOX2, OLIG2, and FOXM1 not being upregulated. We hypothesize that Hippo transcription activation may promote GSC stemness via direct effects of hypoxia and/or TAM-secreted cytokines. Exposing patient-derived GBM neurospheres to 1% hypoxia increased nuclear YAP1 and TAZ expression, along with CYR61, a Hippo pathway readout, compared to normoxia at 48 hours. Single-cell RNA-Seq identified potential hypoxia-regulated genes upstream of YAP/TAZ, including Zyxin, upregulated in 1% hypoxia-treated cultures, possibly facilitating nuclear YAP/TAZ transport. Culturing GBM cells with primary macrophage-conditioned media activated Hippo transcription, with TGF-β1 identified as a hypoxia-specific driver of malignant cell gene expression with single-cell RNA-Seq analysis using NichenetR. Treating GBM cells with TGF-β1 increased CYR61 expression, signifying Hippo transcription activation. Furthermore, we showed that hypoxia and TGF-β1 synergistically maintained GSCs with extreme limiting dilution assays. In the immunocompetent RCAS/tv-a mouse model, Verteporfin, a YAP/TAZ inhibitor, significantly reduced tumor size and prolonged mouse lifespan. TAZ knockdown similarly extended lifespan and reduced tumor growth, with flow cytometry showing a decrease in CD133/CD44 positive GSC populations in knockdown mice. These findings suggest the conclusion that hypoxia and TAM-secreted TGF-β1 directly stimulate YAP/TAZ activation and potentially promote GSC stemness in the GBM peri-necrotic niche.
EPCO-32. PROSPECTIVE GERMLINE SEQUENCING OF PATIENTS WITH GLIOMAS, GLIONEURONAL OR NEURONAL TUMORS
Authors: Andrew Lin, Subhiksha Nandakumar, Miika Mehine, Yelena Kemel, Diana Mandelker, Matthias Karajannis, Sameer Farouk Sait, Igor Gavrilovic, Elena Pentsova, Lauren Schaff, Jacqueline Stone, Craig Nolan, Adrienne Boire, Christian Grommes, Bianca Santomasso, Eli Diamond, Jessica Wilcox, Anna Piotrowski, Thomas Kaley, Robert Young, Brandon Imber, Cameron Brennan, Nelson Moss, Viviane Tabar, Marc Rosenblum, Tejus Bale, Lisa DeAngelis, Ingo Mellinghoff, Michael Berger, Zsofia Stadler, Nicholas Schultz
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Several genetic syndromes have been linked to the development of central nervous system (CNS) tumors; however, the prevalence and clinical significance of germline pathogenic variants in this population remain unclear. METHODS 2,367 patients with a glioma, glioneuronal, or neuronal tumor (WHO grade 1-4) ages 0.2-93.8 years underwent tumor and matched normal sequencing with MSK-IMPACT. Germline variants and copy-number variants affecting 90 well-established cancer predisposing genes were analyzed; the presence of biallelic inactivation was determined using FACETS. RESULTS Eleven percent harbored germline pathogenic mutations in high-, moderate-, and low-penetrance genes. High- and moderate-penetrance genes included CHEK2 (n=32, 1.3%), BRCA2 (n=10; 0.4%), TP53 (n=9; 0.4%), NF1 (n=6; 0.2%), and mismatch repair (MMR) genes (n=20, 0.9%). Low-penetrance genes included monoallelic MUTYH (n=42; 1.8%) and the APC I1307K variant (n=28, 1.2%). Biallelic inactivation was found in all tumors from patients with germline TP53 and NF1 mutations, with lower rates in tumors from patients with a germline MMR alteration (53%). Biallelic inactivation was rare among patients with a germline mutation in homologous recombination pathway (HRD) genes (27%), and in the aforementioned low-penetrance APC (15.3%) and MUTYH (10.2%) variants. All patients with biallelic inactivation of an MMR gene were hypermutated. Biallelic inactivation of MMR genes and TP53 were observed in IDH-mutant astrocytoma and IDH-WT gliomas, while biallelic inactivation of NF1 and somatic IDH1/2 mutation were mutually exclusive. When examining the age at diagnosis among patients with germline alterations, tumors with biallelic inactivation were diagnosed at a younger age compared to tumors with monoallelic alterations (37.7 vs 51.6 years, p=0.002). CONCLUSION Clinical germline sequencing identifies a germline mutation in a high proportion of patients with CNS tumors. Biallelic inactivation was most commonly identified in tumors from patients with germline TP53 or NF1 mutations and were less common in patients with a germline MMR alteration.
IMMU-61. THE LAST OF US: A FUNGI BASED DENDRITIC CELL VACCINE
Authors: Kevin Artiga, Alex Valenzuela, Mitchell Hsu, Herui Wang, Juan Ye, Zhengping Zhuang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults. The current standard treatment for newly diagnosed GBM involves maximal surgical resection followed by radiotherapy and temozolomide. Despite these interventions, the median overall survival for GBM patients remains approximately 15 months, highlighting the critical need for innovative therapeutic approaches. OBJECTIVE Our laboratory has previously developed a subcutaneous autologous tumor vaccine incorporating irradiated (IR) tumor cells with phagocytosis-stimulating ligands (Mannan-BAM), toll-like receptor (TLR) agonists, and an immunostimulant anti-CD40 antibody (collectively termed MBT). This combination has shown efficacy in mouse models of colon carcinoma, breast cancer, melanoma, and, more recently, gliomas. Our study aimed to create a dendritic cell (DC) vaccine using this strategy. METHODS To evaluate whether MBT could induce the maturation of DCs in vitro, we harvested BMDCs from mice and co-cultured them in the presence of MBT-tagged irradiated tumor cells. We then analyzed the maturation markers using flow cytometry and assessed cytokine production via ELISA. To test the efficacy of this approach in vivo, we utilized two different murine glioma models (SB28 and GL261). RESULTS Using flow cytometry, we observed a significant upregulation of important co-stimulatory molecules. Additionally, ELISA analysis demonstrated that MBT-treated DCs significantly increased the secretion of Type 1 cytokines while limiting the secretion of the regulatory cytokine IL-10. MBT-primed DCs combined with immune checkpoint inhibitor PD-1 increased mouse survival in a glioma model compared to WT mice. However, mice eventually succumbed to cerebral edema. Histology demonstrated significant treatment effects. CONCLUSION Our results demonstrate that MBT effectively matures DCs ex-vivo. Further research is required to immunophenotype the response to vaccination in glioma models and explore ways to overcome resistance.
TMIC-06. TUMOR ASSOCIATED MACROPHAGES DRIVE TUMOR PROGRESSION AND ARE TRANSCRIPTIONALLY SHAPED BY HISTONE MUTATIONS IN DIFFUSE MIDLINE GLIOMA
Authors: James Ross, Montserrat Puigdelloses-Vallcorba, Gonzalo Pinero, Nishant Soni, Wes Thomason, John DeSisto, Angelo Angione, Nadejda Tsankova, Maria Castro, Matthew Schniederjan, Nitin Wadhwani, G Praveen Raju, Peter Morgenstern, Oren Becher, Adam Green, Alexander Tsankov, Dolores Hambardzumyan
Journal: Neuro-Oncology (2024)

Abstract Little progress has been made to delineate the inflammatory microenvironment in pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG). We utilize molecularly defined human samples and immunocompetent mouse models to study how tumor location and genetic driver mutations influence the tumor microenvironment (TME). We first induced tumors of each pHGG/DMG molecular subtype (H3WT, H3G34R, H3.1K27M, H3.3K27M) into both the cortical hemisphere and midline of separate mice and performed survival studies and flow cytometry. The main driving factor shaping the immune landscape and survival is the driver mutation, not tumor location. Next, we performed single cell RNA sequencing on murine H3WT cortical pHGG, H3WT DMG, H3.1 and H3.3K27M DMGs, paired with multiplex flow cytometry. H3K27M DMGs have sparse T cell infiltration and limited T cell recruiting chemokine production. The main non-neoplastic cell type in all tumors was infiltrating myeloid cells and microglia. H3WT DMGs had the greatest myeloid cell and monocyte-derived macrophage (MDM) infiltration, while H3.3K27M DMGs were enriched for microglia. Disease associated gene signatures were found in tumor-associated macrophages (TAMs) that are found in other neurodegenerative diseases, marked by down-regulation of inflammatory signaling, interferon responses, and up-regulation of metabolism-related pathways. H3.3K27M DMGs were enriched for disease-associated TAMs. These gene signatures were then identified in human pHGG/DMG scRNA sequencing data. CD16 monocytes and microglia were enriched for diseased signatures, while CD14 monocytes were pro-inflammatory. We demonstrate that reprogramming this diseased signature in mice results in increased T cell infiltration and extension of survival in H3K27M DMG. Last, through pharmacologic inhibition of CCR1 and CCR5, we demonstrate preventing TAM infiltration in DMG results in enhanced survival, comparable to radiation therapy. Together, this work provides the foundation for developing immunotherapies targeted at specific subgroups of pHGG and DMGs, such as CAR-T-cell, oncolytic viral therapy, and checkpoint blockade.
INNV-19. MULTIMODAL THERAPY FOR BRAF V600E MUTANT MELANOMA BRAIN METASTASES: CHARACTERIZATION OF CHRONOLOGICAL TREATMENT STRATEGIES AND ASSOCIATIONS WITH OVERALL SURVIVAL
Authors: Michael Rooney, Lily Erickson, Hesham Alghodhaifi, Andrew Elliott, Hannah Green, Holly Langshaw, Bikash Panthi, Wasif Talpur, Sara Thrower, Victoria White, Caroline Chung
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND B-raf proto-oncogene (BRAF)-mutant melanoma brain metastases (BRAF MBM) are associated with poor prognosis. Amidst our large institutional experience treating patients with BRAF MBM with multimodality therapy, our aim was to identify disease and treatment-related prognostic features, accounting for longitudinal sequence of events, to inform clinical decision-making. METHODS We retrospectively reviewed electronic health records of 100 patients with primary cutaneous melanoma diagnosed with BRAF MBM. Demographic, disease, and clinical factors including treatment sequencing were tabulated. Descriptive statistics were used to summarize the study population and non-parametric tests were used to evaluate differences across groups. A multivariable Cox regression identified factors associated with overall survival (OS) following BRAF MBM diagnosis. RESULTS Median follow-up was 22 months and median OS was 33.5 months. Patients received an average [standard deviation (SD)] of 3.36 [1.06] unique therapies. After adjustment for covariates, greater number of brain metastases at initial diagnosis (hazard ratio (HR) 2.3 [1.14-4.62], p=0.01 for 3-10 metastases and HR 2.54 [1.01-6.36], p=0.04 for &amp;gt;10 metastases, respectively), receipt of combination IO and targeted therapy prior to BRAF MBM diagnosis (HR 2.91 [1.08-7.86], p=0.03), and receipt of no unique subsequent therapy after initial management strategy (HR 3.89 [1.48-10.16], p=0.005) were significantly associated with worse OS. CONCLUSIONS Despite heterogeneity in individual treatment sequences, patients with greater intracranial disease burden and those receiving combination targeted and immunotherapy prior to BRAF MBM diagnoses had the worst outcomes. Dynamic changes in therapy resistance may inform optimal treatment strategies for individuals with BRAF MBM.
EULAR points to consider for patient education in physical activity and self-management of pain during transitional care
Authors: Javier Courel-Ibáñez, Rafael Prieto-Moreno, Erica Briones-Vozmediano, Patrocinio Ariza-Vega, Saskya Angevare, Jordi Anton, Ilaria Bini, Daniel Clemente, Matilde Correia, Wendy Costello, Diederik De Cock, Andrea Domján, Leticia Leon, Andréa Marques, Kirsten Minden, Ana Filipa Mourão, Aurélie Najm, Seza Ozen, Georgina Pimentel, Zainab Saleem, Tomas Vetrovsky, Nico M Wulffraat, Andrea Zacarias Crovato, Yeliz Prior, Loreto Carmona, Fernando Estévez-López
Journal: Annals of the Rheumatic Diseases (2024)

A EULAR task force was convened to develop points to consider (PtC) for patient education in physical activity and self-management of pain in young people with juvenile-onset rheumatic and musculoskeletal diseases during transitional care.
In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy
Authors: Robert L Bowman, Andrew J Dunbar, Tanmay Mishra, Wenbin Xiao, Michael R Waarts, Inés Fernández Maestre, Shira E Eisman, Louise Cai, Shoron Mowla, Nisargbhai Shah, Angela Youn, Laura Bennett, Suean Fontenard, Shreeya Gounder, Anushka Gandhi, Michael Bowman, Kavi O'Connor, Zachary Zaroogian, Pablo Sánchez-Vela, Anthony R Martinez Benitez, Matthew Werewski, Young Park, Isabelle S Csete, Aishwarya Krishnan, Darren Lee, Nayla Boorady, Chad R Potts, Matthew T Jenkins, Sheng F Cai, Martin P Carroll, Sara E Meyer, Linde A Miles, P Brent Ferrell, Jennifer J Trowbridge, Ross L Levine
Journal: Cancer Cell (2024)
Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion
Authors: Rei Kudo, Anton Safonov, Catherine Jones, Enrico Moiso, Jonathan R. Dry, Hong Shao, Sharanya Nag, Edaise M. da Silva, Selma Yeni Yildirim, Qing Li, Elizabeth O’Connell, Payal Patel, Marie Will, Atsushi Fushimi, Marimar Benitez, Martina Bradic, Li Fan, Harikrishna Nakshatri, Dhivya R. Sudhan, Christopher R. Denz, Jorge S. Reis-Filho, Shom Goel, Andrew Koff, Britta Weigelt, Qamar J. Khan, Pedram Razavi, Sarat Chandarlapaty
Journal: Cancer Cell (2024)
Democratise and decolonise to decarbonise: how to reap health and climate benefits of transport infrastructure in Africa
Authors: Tolu Oni, Meelan Thondoo, Hastings Chikoko
Journal: BMJ (2024)

<b>Tolu Oni and colleagues</b> argue that building healthy low carbon transport infrastructure in Africa's rapidly growing cities requires addressing historical contexts, confronting power imbalances, and claiming transport as a social good
Abortion dominant, but health sidelined: the road to Trump’s win
Authors: Joanne Silberner
Journal: BMJ (2024)

Donald Trump is the new US president after an ill tempered campaign that saw abortion dominate on the Democratic side but healthcare a minor part of the overall election discourse. <b>Joanne Silberner</b> reports on the medical issues that were debated—and what this may bode for the new president's agenda
Intraoperative Conduction Mapping to Reduce Postoperative Atrioventricular Block in Complex Congenital Heart Disease
Authors: Edward T O'Leary, Eric N Feins, Jocelyn Davee, Christopher W Baird, Rebecca Beroukhim, Pedro J Del Nido, Audrey Dionne, Kimberlee Gauvreau, David M Hoganson, John K Triedman, Edward P Walsh, Meena Nathan, Sitaram M Emani, Elizabeth S DeWitt
Journal: Journal of the American College of Cardiology (2024)
Potassium ion channel modulation at cancer-neural interface enhances neuronal excitability in epileptogenic glioblastoma multiforme
Authors: Ye Zhang, Wei Duan, Lingchao Chen, Junrui Chen, Wei Xu, Qi Fan, Shuwei Li, Yuandong Liu, Shidi Wang, Quansheng He, Xiaohui Li, Yang Huang, Haibao Peng, Jiaxu Zhao, Qiangqiang Zhang, Zhixin Qiu, Zhicheng Shao, Bo Zhang, Yihua Wang, Yang Tian, Yousheng Shu, Zhiyong Qin, Yudan Chi
Journal: Neuron (2024)
Transcutaneous spinal cord stimulation neuromodulates pre- and postsynaptic inhibition in the control of spinal spasticity
Authors: Karen Minassian, Brigitta Freundl, Peter Lackner, Ursula S Hofstoetter
Journal: Cell Reports Medicine (2024)

Aside from enabling voluntary control over paralyzed muscles, a key effect of spinal cord stimulation is the alleviation of spasticity. Dysfunction of spinal inhibitory circuits is considered a major cause of spasticity. These circuits are contacted by Ia muscle spindle afferents, which are also the primary targets of transcutaneous lumbar spinal cord stimulation (TSCS). We hypothesize that TSCS controls spasticity by transiently strengthening spinal inhibitory circuit function through their Ia-mediated activation. We show that 30 min of antispasticity TSCS improves activity in post- and presynaptic inhibitory circuits beyond the intervention in ten individuals with traumatic spinal cord injury to normative levels established in 20 neurologically intact individuals. These changes in circuit function correlate with improvements in muscle hypertonia, spasms, and clonus. Our study opens the black box of the carryover effects of antispasticity TSCS and underpins a causal role of deficient post- and presynaptic inhibitory circuits in spinal spasticity.
Simulated misuse of large language models and clinical credit systems
Authors: James T Anibal, Hannah B Huth, Jasmine Gunkel, Susan K Gregurick, Bradford J Wood
Journal: npj Digital Medicine (2024)

In the future, large language models (LLMs) may enhance the delivery of healthcare, but there are risks of misuse. These methods may be trained to allocate resources via unjust criteria involving multimodal data - financial transactions, internet activity, social behaviors, and healthcare information. This study shows that LLMs may be biased in favor of collective/systemic benefit over the protection of individual rights and could facilitate AI-driven social credit systems.
Personalized MRD Assessment in Peri-surgical ctDNA for Prognostic Prediction in Hepatocellular Carcinoma
Authors: Jie Hu, Haoran Tang, Can-Can Jia, Xiang-Yu Zhang, Ying Xu, Jin-Peng Tan, Jia Fan, Shidong Jia, Jian Zhou
Journal: Clinical Cancer Research (2024)

Detecting residual disease is a critical clinical requirement in the peri-surgical management of patients with resectable hepatocellular carcinoma (HCC). Previous studies focused on specific genomic regions exhibiting limited sensitivity and failed to meet the minimal residual disease (MRD) testing threshold. We introduce a next-generation sequencing (NGS) based assay, informed by baseline samples, facilitating MRD detection in hepatectomized HCC patients and offering prognostic predictions.
Human <i>ITGAV</i> variants are associated with immune dysregulation, brain abnormalities, and colitis
Authors: Sina Ghasempour, Neil Warner, Rei Guan, Marco M. Rodari, Danton Ivanochko, Ryder Whittaker Hawkins, Ashish Marwaha, Jan K. Nowak, Yijing Liang, Daniel J. Mulder, Lorraine Stallard, Michael Li, Daniel D. Yu, Fred G. Pluthero, Vritika Batura, Mo Zhao, Iram Siddiqui, Julia E.M. Upton, Jessie M. Hulst, Walter H.A. Kahr, Roberto Mendoza-Londono, Fabienne Charbit-Henrion, Lies H. Hoefsloot, Anis Khiat, Diana Moreira, Eunice Trindade, Maria do Céu Espinheira, Isabel Pinto Pais, Marjolein J.A. Weerts, Hannie Douben, Daniel Kotlarz, Scott B. Snapper, Christoph Klein, James J. Dowling, Jean-Philippe Julien, Marieke Joosten, Nadine Cerf-Bensussan, Spencer A. Freeman, Marianna Parlato, Tjakko J. van Ham, Aleixo M. Muise
Journal: The Journal of Experimental Medicine (2024)

Integrin heterodimers containing an Integrin alpha V subunit are essential for development and play critical roles in cell adhesion and signaling. We identified biallelic variants in the gene coding for Integrin alpha V (ITGAV) in three independent families (two patients and four fetuses) that either caused abnormal mRNA and the loss of functional protein or caused mistargeting of the integrin. This led to eye and brain abnormalities, inflammatory bowel disease, immune dysregulation, and other developmental issues. Mechanistically, the reduction of functional Integrin αV resulted in the dysregulation of several pathways including TGF-β-dependent signaling and αVβ3-regulated immune signaling. These effects were confirmed using immunostaining, RNA sequencing, and functional studies in patient-derived cells. The genetic deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation. Taken together, the ITGAV variants identified in this report caused a previously unknown human disease characterized by brain and developmental defects in the case of complete loss-of-function and atopy, neurodevelopmental defects, and colitis in cases of incomplete loss-of-function.