tbuckley/cabot-search huggingface dataset:
Disruption of Ferroptosis Inhibition and Immune Evasion with Tumor‐Activatable Prodrug for Boosted Photodynamic/Chemotherapy Eradication of Drug‐Resistant Tumors
Authors: Tao Bi, Qixin Zhao, Ting Wang, Rui Huang, Bangguo Liu, Xinyue Liu, Yihuan Wang, Qin Sun, Yingcheng Yang, Zengjin Liu
Journal: Advanced Healthcare Materials (2024)

Breast cancer is a malignant tumor that threatens the life and health of women worldwide. As the first-line chemotherapy drug for breast cancer, doxorubicin (DOX) can inhibit the synthesis of RNA and DNA, and it exhibits strong inhibitory activity against breast cancer. However, drug-induced systemic toxicity and drug resistance can occur with DOX treatment. In this work, TSPO protein is identified as a promising target for overcoming drug resistance and we designed a novel BT-DOX/PDP conjugate to solve these problems in drug chemotherapy. It is found that BT-DOX/PDP can effectively downregulate TSPO1 protein and sensitize MCF-7/Adr to DOX. Furthermore, due to its positive charge, BT-DOX/PDP is readily loaded into puerarin (PUE), the resulting BT-DOX/PDP@PUE exhibited minimal systemic toxicity but enhanced antitumor activity in animal models, as compared with BT-DOX/PDP. This study demonstrates the advantages of combined chemotherapy and photodynamic therapy in overcoming drug resistance, which may be applied in the design of other photodynamic therapy-based conjugates to enhance antitumor therapy.
Understanding vaginal biofilms: The first step in harnessing antimicrobial nanomedicine
Authors: Sybil Obuobi, Nataša Škalko-Basnet
Journal: Journal of Controlled Release (2024)

In spite of multipurpose technologies offering broad-spectrum prevention for sexually transmitted infections (STIs) and contraception, the STIs incidences rise worldwide. The situation is even more alarming considering continuous rise in antimicrobial resistance (AMR) that limits therapy options. In this review we address the specific challenges of efficiently treating vaginal infections locally, at the infection site, by understanding the underlying barriers to efficient treatment such as vaginal biofilms. Knowledge on vaginal biofilms remains, up to now, rather scarce and requires more attention. We therefore propose a 'back to basics' insight that seeks to probe the complexity and role of the vaginal microbiota, its relationship with vaginal biofilms and implications to future therapeutic modalities utilizing advanced nano delivery systems. Our key objective is to highlight the interplay between biofilm, (nano)formulation and therapy outcome rather than provide an overview of all nanoformulations that were challenged against biofilms. We focused on the anatomy of the female reproductive organ and its physiological changes from birth, the unique vaginal microenvironment in premenopausal and postmenopausal women, vaginal biofilm infections and current nanomedicine-based approaches to treat infections in the vaginal site. Finally, we offer our perspectives on the current challenges associated with vaginal delivery and key considerations that can aid in the design and development of safer and potent products against persisting vaginal infections.
Corrigendum to “Residential exposure to transportation noise and risk of incident atrial fibrillation: a pooled study of 11 prospective Nordic cohorts” [The Lancet Regional Health – Europe, Volume 46, November 2024, 101091]
Authors: Jesse D Thacher, Nina Roswall, Mikael Ögren, Andrei Pyko, Agneta Åkesson, Anna Oudin, Annika Rosengren, Aslak H Poulsen, Charlotta Eriksson, David Segersson, Debora Rizzuto, Emilie Helte, Eva M Andersson, Gunn Marit Aasvang, Gunnar Engström, Hrafnhildur Gudjonsdottir, Jenny Selander, Jesper H Christensen, Jørgen Brandt, Karin Leander, Kim Overvad, Kristoffer Mattisson, Kristina Eneroth, Lara Stucki, Lars Barregard, Leo Stockfelt, Maria Albin, Mette K Simonsen, Ole Raaschou-Nielsen, Pekka Jousilahti, Pekka Tiittanen, Petter L S Ljungman, Steen S Jensen, Susanna Gustafsson, Tarja Yli-Tuomi, Thomas Cole-Hunter, Timo Lanki, Youn-Hee Lim, Zorana J Andersen, Göran Pershagen, Mette Sørensen
Journal: The Lancet Regional Health - Europe (2024)
World Pneumonia Day 2024: Fighting Pneumonia and Antimicrobial Resistance
Authors: Catia Cilloniz, Charles S. Dela Cruz, Guinevere Dy-Agra, Rodolfo S. Pagcatipunan, Catia Cilloniz, Anita Simonds, Kjeld Hansen, Josep Alouch, Heather Zar, Yoichi Nakanishi, Stephanie Levine, Mark Cohen, Charles Dela Cruz, Scott E. Evans, Maurizio Sanguinetti, Jordi Vila, Jesús Díez Manglano, Ricard Ferrer, Lucio Criado, José Polo García, Zaira Correcher, Carmen Terrazas, Carmen Muñoz-Almagro, Carolina Garcia-Vidal, Zeina Aoun, Juan Manuel Péricas, Israel Amirav, Rodrigo Torres-Castro
Journal: American Journal of Respiratory and Critical Care Medicine (2024)
CTIM-26. PHASE II STUDY OF AZELIRAGON IN COMBINATION WITH RADIATION THERAPY IN NEWLY DIAGNOSED PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Jiayi Huang, Manmeet Ahluwalia, John Boockvar, James Batiste, Jerry Jaboin, Dinesh Thotala, Lia Halasz, Nikhil Rammohan, Douglas Ney, Rachna Malani, Prakash Chinnaiyan, Rupesh R Kotecha, Minesh Mehta, Stephen Marcus
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Myeloid-derived suppressor cells (MDSCs) exacerbate immunosuppression and immune exhaustion in glioblastoma (GBM) and promote resistance to chemoradiotherapy. Preclinical data demonstrate that inhibiting the receptor for advanced glycation end-products (RAGE) pathway using azeliragon, when combined with radiation therapy (RT), can modulate MDSC accumulation in the tumor microenvironment and improve tumor control. CAN-401 is a phase II study evaluating the safety and preliminary clinical efficacy of combining azeliragon with RT for newly diagnosed IDH-wildtype MGMT-unmethylated glioblastoma (GBM). METHODS This multi-institutional, single-arm, open-label phase II study combines azeliragon with RT (60 Gy/30 fractions). Azeliragon is administered orally with a loading dose of 30 mg twice daily for 6 days before RT, followed by 20 mg daily during and after RT. If more than one dose-limiting toxicity occurs during the safety run-in of 6 patients, additional patients will be treated at de-escalated dose levels using the rolling six design. The study hypothesizes that azeliragon and RT will improve median progression-free survival (PFS) to 9.7 months compared to historical control of 5.7 months, corresponding to a hazard ratio of 0.58. The study aims to enroll 30 evaluable patients. RESULTS From December 2023 to May 2024, 10 patients were enrolled and treated with 20 mg of azeliragon daily, including 6 patients in the safety run-in. No dose-limiting toxicity was observed, hence no dose de-escalation was needed. The most common treatment-related adverse events (AEs) were grade 1, including fatigue and lymphopenia. There were no dose modifications or discontinuations due to treatment-related AEs. Enrollment is ongoing, and updated clinical outcomes will be reported. CONCLUSIONS Azeliragon at 20 mg per day with concurrent RT is well tolerated in patients with GBM. The phase II study is currently enrolling across 8 institutions in the United States (NCT05986851).
CTNI-11. A PHASE 1 OPEN-LABEL STUDY OF BRAF INHIBITOR ABM-1310 IN PATIENTS (PTS) WITH RECURRENT BRAF V600-MUTATED PRIMARY CNS TUMORS
Authors: Wenbin Li, Zhuang Kang, Shenglan Li, Feng Chen, Botao Zhang, Mengqian Huang, Zhongyuan Yang, Chen Chen, Zane Yang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND ABM-1310 is a blood-brain barrier penetrant BRAF inhibitor. Here we report interim results from our phase 1 study of ABM-1310. METHODS This is a dose-escalation plus expansions trial for adult pts with BRAF V600-mutated primary CNS tumors. In the dose-escalation, ABM-1310 is given at 150 or 200 mg twice a day (bid). In the expansion, ABM-1310 150 mg bid is administered. Study objectives include patient safety, maximum tolerated dose (MTD), preliminary efficacy and pharmacokinetics (PK). Clinical trial information: NCT05892653. RESULTS By May 6, 2024, 15 pts (7 male; median age 39 years old) have been treated. In the dose escalation: 4 pts received ABM-1310 150 mg bid, and another 7-pts received ABM-1310 200 mg bid. In the expansion, all 4 pts were given ABM-1310 at 150 mg bid. Among 14 efficacy evaluable pts, 3 had partial response (PR) (including one each of glioblastoma, WHO grade 2 and 3 pleomorphic xanthoastrocytoma) and 9 pts had stable disease as their best responses. Two pts have PR response for &amp;gt; 8 months and continue study treatment. All pts experienced treatment-related AEs. Common AEs were asymptomatic QT prolongation (n=11) and rash (n=10). Seven pts had grade 3 QT prolongation. There was no drug-related SAE. There was no ABM-1310 related dose limiting toxicity although a few pts had study treatment interruption or dose reduction. One patient discontinued prematurely due to asymptomatic Grade 3 QT prolongation. There were no drug-related deaths. The MTD for ABM-1310 was 200 mg bid, the recommended dose was 150 mg bid. In PK assessment, ABM-1310 drug exposure vs. dosage showed a linear proportional relationship. This trial is ongoing. CONCLUSIONS ABM-1310 was generally safe and tolerated. There were no new safety signals. Preliminary efficacy data demonstrate favorable anti-cancer activity in patients with recurrent BRAF V600-mutated primary CNS tumors.
CTNI-13. 18-FET-PET ENHANCED DIAGNOSIS OF PSEUDOPROGRESSION IN GLIOBLASTOMA IS AN INDEPENDENT PROGNOSTIC FACTOR FOR OVERALL SURVIVAL
Authors: Teresa Schmidt, Zeynep Oezdemir, Christoph Oster, Ulrich Sure, Ken Hermann, Martin Stuschke, Cornerlius Deuschl, Christoph Kleinschnitz, Michael Müther, Martin Glas, Sied Kebir
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Detecting pseudoprogression (PSP) in glioblastoma during first-line treatment remains challenging and has significant clinical implications for patient management. The detection of PSP has been shown feasible using FET-PET. The prognostic impact of FET-PET diagnosed PSP on overall survival is still uncertain, as retrospective studies provide limited insights due to the substantial differences in the distribution of prognostic factors between tumor progression (TP) and PSP groups. This study aims to address these uncertainties by leveraging advanced analysis techniques. METHODS Patients with newly diagnosed glioblastoma (WHO 2021) who underwent chemoradiation and contrast-enhanced MRI suspected for TP and subsequent FET-PET scan at Essen University Hospital were retrospectively evaluated. The modified Response Assessment in Neuro-Oncology (RANO) criteria were used to diagnose PSP. FET-PET analysis included mean (TBRmean) and maximum tumor-to-brain ratios (TBRmax). The two groups (TP/PSP) were balanced using a propensity score analysis including age at diagnosis, extent of resection, Karnofsky-Performance-Status Scale (KPS) and MGMT methylation status. Overall survival was predicted using Kaplan-Meier and multivariate analysis as well as conventional FET-PET parameters, PET/MRI volumetry, and FET/MRI-derived radiomics. An independent cohort was used for validation. RESULTS Out of the 165 patients analysed in this study, 38 were diagnosed with PSP. Following balancing analysis, our study cohort consisted of 40 patients (20 TP/20 PSP). Patients with PSP had a significantly longer mean overall survival (mOS) compared to those with TP (mOS TP 20.24 months; mOS PSP 33.25 months; p=0.0023). The multivariate Cox-Regression analysis confirmed PSP as a significant prognostic marker for overall survival (p=0.0153). Confirmation of these results on an independent validation cohort is pending and will be presented at the meeting. CONCLUSION This study shows that PSP is an independent prognostic factor for overall survival in newly diagnosed glioblastoma patients.
CTNI-27. SYSTEMIC DELIVERY OF LOW ENERGY RADIOFREQUENCY ELECTROMAGNETIC FIELDS FOR THE TREATMENT OF PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Olavo Feher, Caroline Chaul, Camila Bragança Xavier, Micelange Carvalho de Sousa, Leonardo Testagrossa, Maria Fernanda Barbosa de Medeiros, Luana Alencar Fernandes Sampaio, Rene Gansl, Rogerio Tuma, Sibele Meireles, Tatiana Zanesco, Antonio Iemma, Tiago Costa, Bertram Wiedenmann, Jack Tuszynski, Frederico Perego Costa
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tumor Treating Fields plus maintenance temozolomide (mTMZ) showed a survival advantage in the first-line glioblastoma (GBM) treatment. The survival benefit remains limited in patients with unmethylated MGMT gene promoter. The AutEMsys device emits low-energy amplitude modulated systemic electromagnetic fields (EMF) at patient specific frequencies. It is an outpatient procedure that can be integrated with mTMZ. METHODS This study involved a prospective compassionate access program targeting adult GBM patients using an intrabuccal EMF exposure via AutEMsys in addition to chemoRT+mTMZ. The program explored the effects on survival and patients’ reported quality-of-life (QOL) by EORTC-QL-C30. Patients underwent a 90-minute session of EMF exposure therapy repeated every 2 weeks until progression, deterioration in QOL or death. All patients had pathological specimens for diagnosis, IDH mutation status through NGS techniques, and MGMT promoter region methylation status. RESULTS 31 participants were enrolled, including 29 with GBM and 2 with diffuse midline glioma. 14 patients (45%) received EMF+chemoRT followed by EMF+mTMZ and 17 patients (55%) received EMF+mTMZ (post chemoRT). Survival time was measured from the start of mTMZ to the date of the last follow-up. The median overall survival (mOS) for all 31 patients was 26.0 months (95% CI: 14.4 – 37.2 months). Specifically for 21 patients with unmethylated MGMT, the mOS was 25.0 months (95% CI: 15.9 – 34.1 months). Similarly, for the 28 patients with IDH wildtype status, the mOS remained 26.0 months (95% CI: 9.6 – 42.4 months). The addition of AutEMsys with chemoRT+mTMZ demonstrated an improved role functioning in 79% of patients with 25% of these with &amp;gt;10-point score. CONCLUSION The AutEMsys device has shown promising initial results when added to chemoRT+mTMZ treatment of GBM. These findings warrant further prospective investigation and validation in a multicenter clinical trial setting.
BIOM-14. TRANSMEMBRANE WATER EFFLUX RATE (<i>K</i>IO) IS AN MRI-DETECTABLE BIOMARKER TO EVALUATE THE EFFICIENCY OF TTFIELDS TREATMENT ON GLIOBLASTOMA
Authors: Songtao Hu, Yinhang Jia, Qingping He, Jiaqi Chu, Yongjie Wang, Ruiliang Bai
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tumor Treating Fields (TTFields) has emerged as an effective treatment modality for Glioblastoma, shown to improve both OS and PFS. Yet how to monitor response to TTFields remains unclear. In this study, we proposed using transmembrane water efflux rate (kio), a non-invasive biomarker detectable in conventional MRI and reflecting cell membrane permeability, to assess the treatment efficiency of TTFields. METHODS U-87 MG human glioblastoma cell line were treated with TTFields at frequency of 200 kHz and varying field strengths of 0 V/cm, 0.8 V/cm, 1.2 V/cm and 1.6 V/cm using the inovitro system from Novocure. The measurement of kio was performed on a 0.5 T benchtop MRI system (Pure Devices GmbH) using a home-developed filter-exchange imaging (FEXI) sequence. Cell membrane morphology were quantitatively analysed using scanning electron microscopy. Patients with newly diagnosed glioblastoma (ndGBM) who underwent DCE-MRI before and after TTFields treatment were identified and the change of FEXI-kio value were analysed. RESULTS In the same frequency, the effect of TTFields on cancer cell proliferation is dependent on intensity, manifested a decrease in cell growth rate under high electric field intensity. As the TTFields electric field intensity increased, the cell membrane permeability (kio) also increased, exhibits a significant negative correlation with glioblastoma cell growth rate (p=0.031). Scanning electron microscopy reveals that TTFields can induce significant cell membrane pores, and the total surface area of membrane pores correlates significantly positively with FEXSY-kio index. DCE-MRI data obtained from 4 ndGBM before and after TTFields therapy showed that the FEXI-kio value is increased after TTFields treatment. CONCLUSION This study demonstrated that TTFields increases membrane permeability by inducing cell membrane holes, and kio is a promising non-invasive MRI biomarker to evaluate the efficiency of TTFields treatment.
CNSC-70. THE ROLE OF MAP4K4 IN TUMOR CELL INVASION OBSERVED IN A 3D IN VITRO MODEL OF PEDIATRIC GLIOBLASTOMA
Authors: Cesar Garcia, Ella Nettnin, Sophia Arana, Thien Nguyen, Maria Isabel Barros Guinle, Christy Wilson, Claudia K Petritsch, Michael C Bassik, Laura M Prolo
Journal: Neuro-Oncology (2024)

Abstract Several CNS tumors such as pediatric glioblastoma (pGBM), diffuse midline glioma (DMG), and medulloblastoma (MB) are characterized by local invasive spread and dissemination of tumor cells into surrounding brain tissue. As identified by our group in a genome-wide CRISPR screen and several others, MAP4K4 is a mediator of cell invasion in several cancers, including glioblastoma and medulloblastoma. Recently, we validated the pro-invasive role of MAP4K4 in a panel of pGBM cell lines. To further validate this finding in the context of pGBM cellular invasion, we performed 3D Matrigel timelapse invasion assays. We performed single- and multi-spheroid encapsulation to track spheroid invasion and cell-to-cell interactions between multiple spheroids. Tumor spheroids were cultured in a round-bottom, non-adherent well plate encapsulated in a Matrigel matrix and treated with a MAP4K4 small molecule inhibitor (PF06260933 dihydrochloride) or had a MAP4K4 knockout performed with Cas9 editing. Cell invasion was recorded over 72 hours and three-dimensional structures were stained for actin and imaged 10 days post-initial seeding. We show that MAP4K4 KO (p ~ 0.00033), small-molecule inhibition in the presence of a TGFB receptor agonist (SRI-011381), (p ~ 0.001) and with drug alone (p ~ 0.013) decreased spheroid invasion and prevented single-cell invasion of pGBM cells (SF188) into the matrix. More surprisingly, abrogation of MAP4K4 prevented individual spheroids in a multi-spheroid co-culture, from forming integrated glioma networks through the formation of tube-like structures in the matrix. Based on our initial findings, it appears that MAP4K4 is necessary for single-cell invasion into a three-dimensional matrix. It also appears that MAP4K4 is required for cell-to-cell connections to form between spheroids in the 3D environment to allow for the formation of higher-ordered and spatially organized structures. Future directions include studying how MAP4K4 allows for the formation of glioma tumor networks in pediatric GBM.
EPCO-13. HUMAN ENDOGENOUS RETROVIRUS (HERV) PLAYS A CRITICAL ROLE IN ONCOGENIC MECHANISM IN<i>IDH1</i>-WILD TYPE GLIOBLASTOMAS
Authors: William E Johnson, Prit Benny Malgulwar, Jason T Huse
Journal: Neuro-Oncology (2024)

Abstract IDH1-wildtype (WT) GBMs are the most common and aggressive tumors of the central nervous system (CNS), with a median survival rate of 12-15 months, and are resistant to clinical therapies due to their heterogenous molecular phenotype. In this study, we developed a pipeline to dissect the potential role of human endogenous retroviruses (HERVs) in patient derived glioma stem cells (GSCs) and integrated our findings with published epigenomic datasets for enhancers (H3K27ac), CTCF, and chromatin toplogy (Hi-C). We found high expression of several HERV transcripts in IDH1-WT GBMs as compared to IDH1-mutant variants. Epigenomic analysis of these upregulated HERVs showed association with both enhancer marks and CTCF deposition. Annotation of HERVs to their nearest genes, followed by Gene Set Enrichment Analysis (GSEA), identified involvement of actin-filament based mechanisms and regulation of immune phenotype. Integration of these findings identified MER61 (ERVMER61-1), a potential regulator of Interleukin-6 and showed alteration in chromatin looping and enhancer occupancy. To summarize, our work points to novel mechanisms of GBM pathogenesis, through involvement of HERVs in cell migratory and immune dysfunction, warranting further investigations into these oncogenic mechanism to identify and develop novel therapeutic options for GBM.
TMOD-24. DEVELOPMENT OF A 3D ORGANOTYPIC EXPLANT PLATFORM TO STUDY ONCOLYTIC VIRUS TREATMENT RESPONSE IN GLIOBLASTOMA
Authors: Zaki Abou-Mrad, Kenny Yu, Viviane Tabar
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Oncolytic viruses (OVs) are a promising strategy to induce an anti-tumor immune response in the lymphocyte-depleted environment of glioblastoma (GBM), however the mechanism of their oncolytic function is not well understood. Immune-intact experimental systems would be highly valuable in dissecting immune versus direct viral contribution to oncolysis. Here, we report on the development of an immune-intact organotypic explant (OE) model, amenable to perturbations and T-cell activity monitoring. METHODS OEs were made from fresh tumor samples and cultured in groups of 4-5. CAN-3310 OVs and T-cells were injected into each OE under a dissecting microscope. Cultured OEs were either fixed for immunofluorescence (IF) or dissociated into single-cell suspensions for flow cytometry and 5’ single-cell RNA (scRNA) and TCR sequencing. RESULTS Cultured OEs maintain the cellular density of the original tumor in both short- and long-term cultures. Ki67 IF shows that tumor cells retain their proliferative potential, allowing for renewal and repopulation. The TME, mainly microglia and macrophages, is maintained throughout culture. IF imaging of OV-treated OEs, 7 days post-treatment, shows significant GFP positivity in tumor cells demonstrating the feasibility of using OEs as an ex vivo model with OV. Additionally, autologous T-cells from the patient’s blood can survive in OEs, completing the TME with the equivalent of circulating T-cells. Finally, scRNA-seq of the original tumor and cultured OEs showed that the different cell types were represented at all time points. Tumor cell meta-module analysis showed an increase in hypoxic signatures recapitulating features of in vivo tumor cell growth. CONCLUSIONS OEs maintain tumor architecture and TME. OE co-culture with autologous T-cells allows us to better understand the oncolytic mechanisms of OVs. Future endeavors will include identifying expanded T-cell clones to create an OV-specific TCR repertoire. This OE system provides a new tool as an ex vivo platform to dissect glioma responses to therapy in a purely human system.