tbuckley/cabot-search huggingface dataset:
Intratracheal Budesonide Mixed With Surfactant for Extremely Preterm Infants
Authors: Brett J. Manley, C. Omar F. Kamlin, Susan M. Donath, Kate L. Francis, Jeanie L. Y. Cheong, Peter A. Dargaville, Jennifer A. Dawson, Susan E. Jacobs, Pita Birch, Steven M. Resnick, Georg M. Schmölzer, Brenda Law, Risha Bhatia, Katinka P. Bach, Koert de Waal, Javeed N. Travadi, Pieter J. Koorts, Mary J. Berry, Kei Lui, Victor S. Rajadurai, Suresh Chandran, Martin Kluckow, Elza Cloete, Margaret M. Broom, Michael J. Stark, Adrienne Gordon, Vinayak Kodur, Lex W. Doyle, Peter G. Davis, Christopher J. D. McKinlay, Bernice Mills, Li Huang, Kim Dalziel, Rodney Wilson, Scott Morris, Ajit Aiyappan, Tim Cochrane, Arun Nair, Renae Allen, Tim Schindler, Tara Crawford, Callum Gately ( Gately, Yip Wai Yan, Krishna Revanna, Chua Mei Chien, Polglase Polglase, Stuart Hooper, Huda Ismail, Christine Gilmartin, Wirawan Jeong
Journal: JAMA (2024)

Bronchopulmonary dysplasia (BPD) is a common adverse outcome in extremely preterm infants born at less than 28 weeks' gestation. Systemic corticosteroids are effective against BPD but may be associated with adverse outcomes. Corticosteroids given directly into the lungs may be effective and safer.
Letter to Editor: Prevalence of subclinical hypothyroidism and longitudinal thyroid stimulating hormone changes in youth with metabolic dysfunction-associated steatotic liver disease: an observational study
Authors: Anna Di Sessa, Emanuele Miraglia del Giudice
Journal: Hepatology (2024)

Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy Correspondence University of Campania Luigi Vanvitelli, Department of Woman, Child and General and Specialized Surgery. Email: [email protected]
Letter to the editor: Quality indicators and the safety profile of endoscopic intervention in patients with bleeding esophageal varices
Authors: Jake E. Krige, Eduard G. Jonas, Marc M. Bernon
Journal: Hepatology (2024)

Surgical Gastroenterology and HPB Unit, Department of Surgery, University of Cape Town Health Sciences Faculty, and Groote Schuur Hospital, Anzio Road, Observatory, Cape Town, 7925, South Africa Correspondence Jake E. Krige, Surgical Gastroenterology, Department of Surgery, University of Cape Town Health Sciences Faculty, Anzio Road, Observatory, Cape Town, 7925, South Africa. Email: [email protected]
Letter to the editor : Association of hepatitis delta virus infection and hepatocellular carcinoma, hepatic decompensation, all-cause and liver-related death in a national cohort
Authors: Ziyi He, Chenxi Wang, Huichuan Tian
Journal: Hepatology (2024)

1Department of Oncology, The Second Affiliated Hospital of Tianjin University of Chinese Medicine, Tianjin, 300250, China 2Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, 999078, China Correspondence Huichuan Tian, Faculty of Chinese Medicine, Macau University of Science and Technology. Email: [email protected]
Reply: Association of hepatitis delta virus infection and hepatocellular carcinoma, hepatic decompensation, all-cause and liver-related death in a national cohort
Authors: Binu V. John, Dustin Bastaich, Bassam Dahman
Journal: Hepatology (2024)

1Division of Gastroenterology and Hepatology, Miami VA Medical System, and Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, FL 2Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 3Department of Health Policy, Virginia Commonwealth University, Richmond, VA Correspondence Binu V. John, Associate Professor, University of Miami Miller School of Medicine, Miami VA Health System, Miami FL 33125. Email: [email protected]
Sex-Specific Effects of <i>MTSS1</i> Downregulation on Dilated Cardiomyopathy
Authors: Dongwook Choe, Megan Burke, Jeffrey A. Brandimarto, Ingrid Marti-Pamies, Jaime Yob, Yifan Yang, Michael P. Morley, Theodore G. Drivas, Sharlene Day, Michael Levin, Scott Damrauer, Xiao Wang, Thomas P. Cappola
Journal: Circulation (2024)
EXTH-28. DEVELOPING A NOVEL INJECTABLE IMMUNOTHERAPEUTIC GEL FOR ENCAPSULATION OF NATURAL KILLER CELLS FOR POST-SURGICAL GLIOBLASTOMA TREATMENT
Authors: Chiungyin Huang, Pinyuan Chen, Kuochen Wei
Journal: Neuro-Oncology (2024)

Abstract Malignant brain tumors are one of the leading causes of death among all cancers. Approximately 40,000 people are diagnosed with malignant brain tumors every year. Among these patients, 15,000 cases are glioblastoma (GBM) with a very poor prognosis; even after aggressive surgical resection and adjuvant chemo/radiotherapy, the median survival is only 14.6 months. The major reason for poor prognosis is the blood-brain barrier, which prevents therapeutic agents from reaching the target area. Therefore, there are only a few choices of drugs available for brain tumor treatment. To date, temozolomide (TMZ) and the Gliadel wafer have been clinically used as standard chemotherapy agents after brain tumor resection. However, drug resistance to TMZ and the poor drug diffusion rate of the Gliadel wafer still result in ineffective suppression of residual cancer cells. To overcome the above-mentioned difficulties in clinical brain tumor treatment, in situ self-crosslinking multifunctional hydrogels was developed to carry natural killer cells (NK cells) and radiosensitizers as a novel brain tumor treatment system. Unlike traditional hydrogels catalyzed by pH value or temperature, this new system is stable and consistent as an immune cell carrier. We used fibrinogen, thrombin, and alginic acid as the backbone of the in situ self-crosslinking hydrogel, tested the properties of the synthesized hydrogel, and analyzed the gel-formation time and swelling rate. The release rate of NK cells was also examined. In a brain tumor animal model, the use of hydrogel-NK cells significantly inhibited tumor proliferation and prolonged animal survival time. In conclusion, this therapeutic hydrogel carrying NK cells can serve as a novel post-operation adjuvant therapeutic tool for malignant brain tumors.
EXTH-27. POLYCOMB OVERACTIVITY DRIVES TUMORIGENESIS IN AGGRESSIVE CUSHING’S DISEASE
Authors: David Asuzu, Dustin Mullaney, Shyama Bhatt, Debjani Mandal, Dragan Maric, Abdel Elkahloun, Prashant Chittiboina
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Aggressive Cushing’s disease (CD) tumors (Ki67 &amp;gt; 3%) exhibit rapid growth, poor postsurgical outcomes, and resistance to conventional therapies. Polycomb group (PcG) proteins are canonical epigenetic silencers that can drive tumor aggressiveness. We asked if PcG underlies rare but fatal pituitary tumor progression. METHODS We performed paired multiome analysis (single nucleus RNAseq and ATACseq) in 5 aggressive CD adenomas, and adjacent normal gland. We verified protein expression with multiplexed immunohistochemistry (mIHC) and PcG activity by H3K27me3 ChIPseq. Aggressive murine pituitary tumor cells ATT20 were treated using PcG inhibitors (DZNep, tazemetostat), HDAC inhibitor (vorinostat), or siRNA (Ezh2, Suz12). PcG binding to the POMC promoter was assessed by reverse chromatin immunoprecipitation (rChIP). We treated one patient off-label with oral vorinostat 400mg daily for 6 days prior to radiation. RESULTS PcG loci (EZH2 and EED) were more accessible in aggressive CD adenoma versus normal gland corticotrophs, and EZH2, SUZ12 and EED mRNA was robustly overexpressed. mIHC confirmed SUZ12, EZH2 and H3K27me3 overexpression, and ChIPseq confirmed polycomb overactivity in aggressive CD adenomas. Polycomb inhibition by DZNep, vorinostat, or siRNAs led to proliferative arrest and Pomc suppression in ATT20 cells (P &amp;lt; 0.05 versus controls). Vorinostat enriched Suz12 at the Pomc promoter (P &amp;lt; 0.01), confirming direct silencing. In a patient with aggressive CD and hypercortisolemia despite two prior surgeries, a single course of vorinostat decreased cortisol (24mcg/dL to 7.5mcg/dL) and ACTH (63.7pg/mL to 44.9pg/mL) prior to radiation therapy initiation. CONCLUSIONS PcG hyperactivity is associated with a more aggressive CD phenotype. We report here the therapeutic potential of HDAC inhibition against aggressive CD adenomas in a first-in-human application.
PATH-30. CLINICAL OUTCOMES AND PREDICTIVE BIOMARKERS FOR IDH-WILDTYPE GLIOBLASTOMAS DEVELOPING HYPERMUTATION FOLLOWING TEMOZOLOMIDE TREATMENT
Authors: Jacob Young, Calixto-Hope Lucas, Nadeem Al-Adli, Rohit Gupta, Ramin Morshed, Jasper Wu, Ajay Ravindranathan, Anny Shai, Nancy Ann Oberheim-Bush, Jennie Taylor, John de Groot, Javier Villanueva-Meyer, Melike Pekmezci, Arie Perry, Andy Bollen, Philip Theodosopoulos, Manish Aghi, Edward Chang, Shawn Hervey-Jumper, David Raleigh, Aaron Diaz, Joseph Costello, Jennifer Clarke, Nicholas Butowski, Joanna Phillips, Susan Chang, Mitchel Berger, David Solomon
Journal: Neuro-Oncology (2024)

Abstract Current standard of care for IDH-wildtype glioblastoma (GBM) includes maximal safe resection, adjuvant radiation, and chemotherapy with the alkylating agent temozolomide. A subset of gliomas treated with temozolomide develop somatic hypermutation with a predominance of C&amp;gt;T transitions due to the alkylation effects on DNA. However, the frequency of occurrence, clinical ramifications, and predictive biomarkers for developing temozolomide-induced hypermutation (TMZ-HM) in GBM are unknown. Here we performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent GBM from 106 patients. Seven patients (7%) developed hypermutation at time of first recurrence, while an additional five patients (5%) developed hypermutation at a subsequent recurrence. Patients who developed TMZ-HM had a significantly longer interval between initial surgery and first recurrence (27.8 vs. 9.9 months, p&amp;lt;0.001). In contrast to IDH-mutant gliomas where TMZ-HM is associated with poor prognosis, those patients with IDH-wildtype GBM who developed TMZ-HM had significantly longer overall survival from both initial surgery (67.9 vs. 20.3 months, p&amp;lt;0.001) and from time of recurrence after development of hypermutation (30.9 vs. 9.5 months, p=0.001). There was no difference in oncogenic alteration frequency in initial GBM that subsequently developed TMZ-HM. However, 4 specific CpG sites out of 12 total interrogated sites in the promoter region of MGMT (a DNA repair enzyme) and 5 specific CpG sites in the promoter region of KCNQ1DN (a negative regulator of c-Myc) were significantly more hypermethylated in those GBM that developed TMZ-HM. We then generated a weighted risk score across these CpG sites that can be used to prospectively identify GBM likely to develop TMZ-HM associated with favorable survival. In summary, patients with GBM that develop TMZ-HM follow a more favorable clinical course, and specific MGMT and KCNQ1DN promoter hypermethylation patterns could serve as a biomarker to identify these patients who may potentially benefit from extended alkylating chemotherapy treatment.
EXTH-26. EXPLORING THE ROLE OF ANDROGEN RECEPTOR SIGNALING IN GLIOBLASTOMA IN AN ORTHOTOPIC ANIMAL MODEL
Authors: Sofia R E Mason, Sylvia Chung, Laveniya Satgunaseelan, Cerys McCool, Beatriz Perez-San Juan, Shabarni Gupta, Ashraf Zaman, Bryan W Day, Rachel Dear, Hao-Wen Sim, Jeff Holst, Christine L Chaffer
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Gliomas, particularly glioblastoma which is the most common and deadly type, frequently express androgen receptors (AR). We systematically characterized AR expression in low- and high-grade gliomas to investigate whether disrupting AR signaling with readily available blood-brain-barrier penetrant drugs could improve treatment. METHODS Low- and high-grade glioma samples were stained for AR by immunohistochemistry, with AR-expression correlated to grade and sex. Localization of AR and the influence of dihydrotestosterone (DHT) and anti-androgens in glioblastoma cell line (U251) were determined by immunofluorescence and immunoblot. Building on previous in vitro data, we used an orthotopic AR-positive patient-derived model (RN1) to test the efficacy of seviteronel, a blood-brain-barrier penetrant anti-androgen. RESULTS Two thirds of biopsy samples were positive for AR expression by IHC (n=25/39). AR expression correlated with increasing tumor grade (p&amp;lt;0.05) but was similar between sexes (p=0.94). Anti-androgens enzalutamide and seviteronel prevented DHT-induced nuclear translocation of AR; however, seviteronel did so to a lesser extent, as measured by immunofluorescence and immunoblot. In the mouse model, seviteronel significantly improved survival compared to vehicle (n=12, 36.0 vs 27.5 days, p=0.03), and demonstrated reduced Ki67 expression in tumors at the endpoint (68.9% vs 85.0%, p&amp;lt;0.001). Combining seviteronel with temozolomide limited tumor growth as measured by bioluminescence imaging, but did not significantly extend survival compared to temozolomide alone (n=16, 63.5 vs 56.5 days, p=0.37). Adding seviteronel to radiotherapy did not extend survival compared to radiotherapy alone (n=16, 33.0 vs 39.0 days, p=0.19). CONCLUSIONS Targeting AR signaling with blood-brain-barrier penetrant anti-androgens may represent a promising biomarker-directed therapeutic strategy. The mechanisms underlying the effects of seviteronel are being further investigated through affinity-purification mass spectrometry analysis and CUT&amp;RUN sequencing of untreated and treated glioma cells. Additional animal experiments are underway to examine the role of biological sex and the glioma immune microenvironment on the efficacy of anti-androgens in vivo.
DDDR-49. REPURPOSING OF THE ANTI-VIRAL DRUG RIBAVIRIN AS A POTENTIAL MENINGIOMA THERAPEUTIC
Authors: Joshua Casaos, Travis Perryman, Maya Harary, Jeremie Vitte, Shilp Shah, Brian Na, Marco Giovannini, Richard Everson
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION High grade meningiomas provide significant challenges to treatment. Recent works have demonstrated meningiomas to express higher levels of the epigenetic regulator enhancer of zeste homolog 2 (EZH2), as well as the protein eIF4E, a key player in translation. These two molecules are demonstrated targets of the well tolerated antiviral drug, ribavirin, which has recently shown promise as an anti-neoplastic agent. Based on these findings we sought to investigate the effect of ribavirin on meningioma tumorigenesis utilizing in vitro and in vivo meningioma models. METHODS Several immortalized human meningioma cell lines, three immortalized mouse meningioma cell lines, and a panel of human primary cell cultures were assessed. Cell proliferation, cell colony formation, clonogenic assay, and cell death were assessed. Furthermore, we tested ribavirin efficacy in vivo utilizing two aggressive high grade syngeneic orthotopic allograft meningioma models in FVB WT mice. RESULTS We provide evidence that ribavirin significantly impairs meningioma cell growth and proliferation, and induces cell death in vitro. Most importantly, we demonstrate that ribavirin alone significantly improves the survival of mice orthotopically implanted with MGS2 cells. Ribavirin-treated animals exhibited a significantly increased median survival (67 days) compared to controls (41 days; p=0.0009;) in an orthotopic convexity meningioma xenograft model. Furthermore, ribavirin treatment resulted in increased survival in an orthotopic skull base meningioma xenograft model. CONCLUSION Our work establishes that ribavirin is effective against meningioma in vitro and in vivo. Ribavirin treatment reduced proliferation in all cell lines tested, in both high and low grade models, induced cell death, and prolonged survival in two aggressive in vivo models, potentially via modulation of the EZH2 and eIF4E pathways. Given the lack of medical therapy for high grade meningiomas, these findings provide a framework for further investigation into ribavirin’s effects on meningioma tumorigenesis, and demonstrate ribavirin as a potential new therapeutic option in the treatment of meningioma.
PATH-33. THE IMPACT OF THE MOLECULAR CLASSIFICATION IN HISTOLOGICALLY DIAGNOSED GLIOBLASTOMAS
Authors: Yoshiki Arakawa, Takeshi Kawauchi, Yasuhide Makino, Asako Katsuma, Ema Yoshioka, Tomoko Shofuda, Daisuke Kanematsu, Etsuko Yamamoto, Shigeki Takada, Noritaka Sano, Masahiro Tanji, Yohei Mineharu, Yonehiro Kanemura
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Glioblastomas have been diagnosed based on traditional histological findings (necrosis, microvascular proliferation) and molecular genetic findings (IDH-wildtype, H3-wildtype, TERT promoter mutation, EGFR amplification, +7/−10 chromosome copy-number changes). Thus, IDH-wildtype and H3-wildtype glioblastomas can be classified into those with molecular genetic findings (defined as molecular glioblastoma) and those with only histological findings (defined as non-molecular glioblastoma). We re-evaluated the molecular genetics of patients diagnosed histologically with glioblastoma at our institution and examined their characteristics. METHODS A total of 275 cases diagnosed histologically as glioblastoma between December 2000 and March 2022 were included. Sanger sequencing (IDH1/2, Histone H3, TERTp) and MLPA for copy number analysis (PDGFRA, EGFR, CDKN2A, PTEN, MDM2, CDK4, TP53) were performed. The genetic analysis results and survival periods were analyzed. RESULTS Among the 275 cases, 151 initial glioblastomas met the criteria of IDH wild-type and H3 wild-type. Genetic analysis results that could be evaluated were obtained in 89 of these cases. TERT promoter mutation was present in 43 cases (48%), with 37% (16 cases) showing EGFR amplification and 19% (8 cases) showing EGFR gain/PTEN loss (+7/-10) simultaneously. On the other hand, TERT promoter wild-type was found in 45 cases (51%), with EGFR amplification in only 1 case (2%) and EGFR ain/PTEN loss in 4 cases (9%), and these 5 cases were judged to correspond to molecular glioblastoma. Adding one case with TERT promoter evaluation failure but EGFR amplification, the integrated molecular/non-molecular glioblastoma cases were 49 (55%)/40 (45%), revealing that both tumor types exist in nearly equal proportions. Survival curve analysis showed that median overall survivals of molecular and non-molecular glioblastoma were 17 and 29 months, respectively, showing a two-fold difference, and non-molecular glioblastoma had significantly better prognosis (P=0.0136). CONCLUSION It was revealed that tumors diagnosed as glioblastoma based on conventional histological findings can be broadly classified into molecular and non-molecular glioblastoma, with significant differences in prognosis.
EXTH-41. COMBINATION TREATMENT WITH RAF/MEK AND FAK INHIBITION ENHANCES TUMOR GROWTH INHIBITION IN MENINGIOMA
Authors: Nazanin Ijad, Katie L Waller, Erika Yamazawa, Naema Nayyar, Elizabeth J Summers, Christian Migliarese, Evanthia Galanis, Brett L Carlson, Jann N Sarkaria, Hiroaki Wakimoto, Rachael A Vaubel, Priscilla K Brastianos
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with meningiomas who have progressed after multimodal treatments face a significant shortage of viable therapeutic options. Recent advancements in the molecular understanding of meningiomas have identified the FAK and RAF/MEK signaling pathways as potential promising targets for progressive meningiomas. METHODS In vitro, we tested two human meningioma cell lines, IOMM-Lee (NF2 wild-type and CDKN2A loss) and CH157-MN (NF2 mutant). The cells were plated in Matrigel-coated wells, treated with defactinib (FAK inhibitor), VS-6766 (RAF/MEK inhibitor, avutometinib) and the combination over a 7-day period and assessed for cell viability using the CellTiter-Glo 3D assay. In vivo, we tested the efficacy of the FAK inhibitor VS-4718 (possessing favorable pharmacokinetic properties in mice) and RAF/MEK inhibitor VS-6766, both given daily via oral gavage, in athymic nude mice bearing IOMM-Lee or CH157-MN tumors. RESULTS In the matrigel assay, VS-6766 suppressed IOMM-Lee and CH157-MN cells in a dose dependent manner. The drug combination was mostly additive in IOMM-Lee cells. However, CH157-MN cells showed a strong synergistic response across all drug concentrations tested. In the IOMM-Lee flank tumor model, VS-4718 alone had no effect, while VS-6766 alone or in combination significantly reduced tumor growth and extended median survival from 25 days to 47 days (p &amp;lt; 0.05). In the CH157 flank tumor model, VS-4718 monotherapy did not affect tumor growth or survival, but VS-6766 monotherapy slowed tumor growth and increased median survival from 10 days to 31 days (p &amp;lt; 0.001). Combining both drugs further reduced tumor growth and extended median survival to 42 days (p &amp;lt; 0.001). CONCLUSION Treatment with FAK and RAF/MEK inhibitors showed synergistic or combination effects in the NF2 mutant CH157-MN model in vitro and in vivo. RAF/MEK inhibitor monotherapy was effective for the IOMM-Lee model (NF2 wild-type), without clear benefit of combining with the FAK inhibitor. Investigations in intracranial tumor models are underway.
EPCO-18. DECIPHERING SPATIAL DIVERSITY OF GLIOBLASTOMA GENETIC ARCHITECTURE
Authors: Junyi Zhang, Tanvi Joshi, Dolores Hambardzumyan, Dieter Henrik Heiland
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is hallmarked by profound inter- and intratumoral heterogeneity. Current research has mapped key genetic drivers to distinct transcriptional profiles within GBM. Nevertheless, the intricate interactions between genetic alterations and spatial-transcriptional heterogeneity remain elusive. We utilized nestin-Tva C57BL/6 mice to induce de novo GBM via oncogene overexpression alongside shRNA-mediated silencing or deletion of tumor suppressors. We modeled critical driver mutations: PDGFB, NF1, and EGFR. Employing 10X Genomics platform for single-cell RNA sequencing, combined with spatially resolved transcriptomics and proteomics (Nanostring GeoMx), we integrated data using both horizontal (mutual nearest neighbors) and vertical (weighted nearest neighbors) approaches, analyzed through the SPATA2 software. Advanced computational techniques, including graph neural networks and single-cell deconvolution, were leveraged to unravel the genotypic and spatial variability within tumors and their microenvironments. Our findings uncover persistent cellular heterogeneity across diverse genetic contexts. However, specific genetic mutations precipitated distinct dominant transcriptional states: NF1 and EGFR mutations drove mesenchymal and astrocytic-like states, respectively, whereas PDGFB fostered a neural progenitor/cell-like state. These transcriptional shifts were closely linked to unique microenvironmental modifications, such as elevated neuronal signaling in PDGFB-driven GBMs and significant immune infiltration in NF1 and EGFR models. Through weighted co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA) paired with spatial-niche deconvolution, we identified a mesenchymal transition leading to an immunosuppressive microenvironment in NF1-loss driven GBMs and increased lymphocyte presence around blood vessels in EGFR-amplified GBMs. These patterns were consistent with human spatially resolved transcriptomic data, emphasizing the genetic complexity and heterogeneity of human GBMs. Our genetically engineered mouse models serve as a robust platform for dissecting GBM with defined genetic mutations. Leveraging sophisticated analytical techniques and computational modeling, this study underscores the profound interplay between genetic drivers and the tumor microenvironment, paving the way for targeted therapeutic strategies and precision medicine in GBM.