tbuckley/cabot-search huggingface dataset:
IMMU-35. TARGETING THE AHR IMMUNOMETABOLIC HUB DURING VIROIMMUNOTHERAPY OF GLIOMAS
Authors: Andres R Lopez-Rivas, Andrew G Gillard, Akhila Parthasarathy, Dong H Shin, Marc Garcia-Moure, Lethan A Hampton, Jiasen He, Hong Jiang, Xuejun Fan, Derek Wainwright, Francisco J Quintana, Juan Fueyo, Candelaria Gomez-Manzano
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) poses a significant therapeutic challenge in oncology. Recent clinical trials have shown the feasibility of virotherapy to treat patients with GBM. Our laboratory developed an oncolytic adenovirus termed Delta-24-RGD that has been tested in clinical trials for recurrent GBM patients with encouraging results (NCT00805376, NCT02798406). These clinical studies, together with preclinical data, showed that the efficacy of Delta-24-RGD was due to direct tumor cell oncolysis and indirect activation of anti-tumor immune response. To further leverage this immune component, our group generated Delta-24-RGDOX, an armed version of Delta-24-RGD expressing the T-cell activator OX40-L, which exhibits a superior anti-cancer effect. In this project, we aim to further boost the effectiveness of Delta-24-RGDOX by targeting factors that maintain the immunosuppressive characteristic of gliomas. Specifically, we identified the environmental sensor and transcription factor Aryl Hydrocarbon Receptor (AhR) as one of the immunosuppressive factors. We show that AhR is overexpressed in GBM surgical specimens compared to healthy brain tissue, and high AhR expression correlates with poorer survival in glioma patients. Immunofluorescence staining of glioma cells treated with Delta-24-RGDOX demonstrated that AhR translocates to the nucleus, and qPCR showed that translocation resulted in the enhanced transcription of AhR-responsive elements. Additionally, bulk RNA-seq reveals that in vivo glioma models treated with Delta-24-RGDOX exhibit activation of the AhR pathway network. This unexpected and paradoxical activation may be responsible for immune suppression mechanisms, which might hinder the effect of Delta-24-RGDOX. Based on these data, we combined two innovative strategies, the oncolytic virus Delta-24-RGDOX and AhR inhibitors. Survival analysis in immunocompetent models of gliomas treated with this combined therapy showed the greatest therapeutic benefit compared to monotherapy controls. These findings highlight the critical role of AhR activation triggered by Delta-24-RGDOX and position AhR as a potential therapeutic target for enhancing the efficacy of oncolytic adenovirus therapy in GBM.
miR-24-3p secreted as extracellular vesicle cargo by cardiomyocytes inhibits fibrosis in human cardiac microtissues
Authors: Giorgia Senesi, Alessandra M Lodrini, Shafeeq Mohammed, Simone Mosole, Jesper Hjortnaes, Rogier J A Veltrop, Bela Kubat, Davide Ceresa, Sara Bolis, Andrea Raimondi, Tiziano Torre, Paolo Malatesta, Marie-José Goumans, Francesco Paneni, Giovanni G Camici, Lucio Barile, Carolina Balbi, Giuseppe Vassalli
Journal: Cardiovascular Research (2024)

Cardiac fibrosis in response to injury leads to myocardial stiffness and heart failure. At the cellular level, fibrosis is triggered by the conversion of cardiac fibroblasts (CF) into extracellular matrix-producing myofibroblasts. miR-24-3p regulates this process in animal models. Here, we investigated whether miR-24-3p plays similar roles in human models.
Toward harnessing biodiversity–ecosystem function relationships in fungi
Authors: Kadri Runnel, Leho Tedersoo, Franz-Sebastian Krah, Meike Piepenbring, J F Scheepens, Henner Hollert, Sarah Johann, Nele Meyer, Claus Bässler
Journal: Trends in Ecology & Evolution (2024)

Fungi are crucial for terrestrial ecosystems, yet the role of fungal diversity in ecosystem functions remains unclear. We synthesize fungal biodiversity and ecosystem function (BEF) relationships, focusing on plant biomass production, carbon storage, decomposition, and pathogen or parasite resistance. The observed BEF relationships for these ecosystem functions vary in strength and direction, complicating generalizations. Strong positive relationships are generally observed when multiple ecosystem functions are addressed simultaneously. Often, fungal community composition outperforms species richness in predicting ecosystem functions. For more comprehensive fungal BEF research, we recommend studying natural communities, considering the simultaneous functions of a broader array of fungal guilds across spatiotemporal scales, and integrating community assembly concepts into BEF research. For this, we propose a conceptual framework and testable hypotheses.
Dementia
Authors: Esther S. Oh
Journal: Annals of Internal Medicine (2024)

Dementia, or major neurocognitive disorder, is defined as a decline in 1 or more cognitive domains that causes impairment in everyday function. Alzheimer disease is the most common type of dementia in the United States, with an estimated 6.9 million adults who have Alzheimer disease and are 65 years or older. This article discusses the latest findings in preventing cognitive decline. It also discusses dementia screening, diagnosis, treatment, and the quality of life for persons with dementia and their caregivers.
Clinical Tools to Assess Functional Capacity During Risk Assessment Before Elective Noncardiac Surgery
Authors: Julian F. Daza, Tyler R. Chesney, Juan F. Morales, Yuanxin Xue, Sandra Lee, Leandra A. Amado, Bianca Pivetta, Arnaud R. Mbadjeu Hondjeu, Rachel Jolley, Calvin Diep, Shabbir M.H. Alibhai, Peter M. Smith, Erin D. Kennedy, Elizabeth Racz, Luke Wilmshurst, Duminda N. Wijeysundera
Journal: Annals of Internal Medicine (2024)

Functional capacity is critical to preoperative risk assessment, yet guidance on its measurement in clinical practice remains lacking.
Misuse of Race in the Interpretation of HbA<sub>1c</sub>
Authors: Elizabeth Selvin
Journal: Annals of Internal Medicine (2024)

Hemoglobin A1c (HbA1c) is a diagnostic test for diabetes and the standard measure used to monitor glycemic control. Arising from observations of racial differences in the absolute levels of HbA1c, guidelines and experts have recommended that race or ethnicity be "taken into consideration" when using HbA1c to diagnose diabetes or make treatment decisions (1). Some experts have stated that HbA1c is a "less accurate" or "inappropriate" diagnostic test in certain racial or ethnic groups, and there have been many calls for the use of race-specific HbA1c cut points. However, such recommendations raise concerns about the inappropriate use …
Enhanced CRISPR-Cas9 RNA system delivery using cell penetrating peptides-based nanoparticles for efficient in vitro and in vivo applications
Authors: Veronica Guzman Gonzalez, Audrey Grunenberger, Olivier Nicoud, Elodie Czuba, Julien Vollaire, Véronique Josserand, Xavier Le Guével, Nail Desai, Jean-Luc Coll, Gilles Divita, Virginie Faure
Journal: Journal of Controlled Release (2024)

CRISPR-Cas9 system has emerged as a revolutionary gene-editing tool with huge therapeutic potential for addressing the underlying genetic causes of various diseases, including cancer. However, there are challenges such as the delivery method that must be overcome for its clinical application. In addition to the risk of nuclease degradation and rapid clearance of the CRISPR-Cas9 system by macrophages, the large size of Cas9, the high anionic charge density and hydrophilic nature of the RNA hinder their intracellular delivery and overall gene transfection efficiency. In this study, we engineered a novel Peptide-Based Nanoparticles ADGN for the delivery of long RNA. ADGN peptides can form stable self-assembled nanoparticles with CRISPR-Cas9 RNA. They have the ability to cross the cell membrane of various cell types, exhibiting a preference for cancer cells that overexpress laminin receptor and safeguard RNA prior their delivery into the cytoplasm. We demonstrate that ADGN peptides significantly promote CRISPR-Cas9 mediated knockout of the luciferase gene in vitro achieving 60 % efficiency with a preference for G insertion at the targeted site of luciferase gene. Moreover, we have provided evidence that these nanoparticles can also be systemically intravenously administrated in vivo in mice to deliver a functional CRISPR-Cas9 system to tumoral lung cells orthotopically implanted in the mouse, resulting in an effective gene knockout in mice. We also demonstrated that the in vivo distribution of ADGN-RNA is influenced by its peptides to RNA molar ratio. This study introduces a promising new Peptide-Based Nanoparticles for delivering CRISPR-Cas9 system in its RNA form applicable in both in vitro and in vivo models.
Comparison of first-line chemotherapy regimens in unresectable locally advanced or metastatic pancreatic cancer: a systematic review and Bayesian network meta-analysis
Authors: Luca Mastrantoni, Marta Chiaravalli, Alexia Spring, Viria Beccia, Armando Di Bello, Cinzia Bagalà, Maria Bensi, Diletta Barone, Giovanni Trovato, Giulia Caira, Giulia Giordano, Emilio Bria, Giampaolo Tortora, Lisa Salvatore
Journal: The Lancet Oncology (2024)
Trends in the incidence of young-adult-onset diabetes by diabetes type: a multi-national population-based study from an international diabetes consortium
Authors: Dianna J Magliano, Lei Chen, Jedidiah I Morton, Agus Salim, Bendix Carstensen, Edward W Gregg, Meda E Pavkov, Martti Arffman, Helen M Colhoun, Kyoung Hwa Ha, Tomoaki Imamura, György Jermendy, Dae Jung Kim, Zoltán Kiss, Didac Mauricio, Stuart J McGurnaghan, Yuichi Nishioka, Sarah H Wild, Klas Winell, Jonathan E Shaw
Journal: The Lancet Diabetes & Endocrinology (2024)
FRET verification of crucial interaction sites in RhoA regulation mediated by RhoGDI
Authors: Hui Li, Jia Guo, Yujie Xing, Linhong Deng, Mingxing Ouyang
Journal: Med-X (2024)

Abstract The small GTPase Rho family are the major factors in mediating actin cytoskeleton dynamics. Rho-specific guanine nucleotide dissociation inhibitors (RhoGDIs) serve as important negative regulators by complexing with inactive Rho into the cytoplasm. However, how these two molecules interact still needs experimental verification. Based on fluorescence resonance energy transfer (FRET) measurements, we would demonstrate crucial sites in RhoGDI and RhoA for this regulatory role. Cotransfection of RhoGDI markedly reduced RhoA or Cdc42 activity in airway smooth muscle (ASM) cells, while D185R-RhoGDI mutant reversed this decrease, indicating that RhoGDI Asp 185 residue is essential for the molecular interaction. R68D-RhoA (mutation in the switch II region) resulted in a deficiency in RhoGDI regulation, while TV37/38NG-RhoA (in the switch I region) displayed low RhoA activity. Hence, the Arg 68 site in RhoA is indispensable for regulation by RhoGDI, and Thr 37 Val 38 site is important for maintaining RhoA activity. Additionally, microtubule but not actin cytoskeleton showed inhibitory role in RhoA activity, while the dissolution of either cytoskeleton did not change the regulatory role of RhoGDI. In checking the downstream effect, reduction of RhoA activity induced by PDGF stimulation or RhoGDI decreased cellular stress fibers. In this study, FRET visualization was applied to have experimentally demonstrated the interaction sites and crucial role of RhoGDI in regulating RhoA activity. Graphical Abstract
Cellular mechanisms of combining innate immunity activation with PD-1/PD-L1 blockade in treatment of colorectal cancer
Authors: Qi Xie, Xiaolin Liu, Rengyun Liu, Jingxuan Pan, Jing Liang
Journal: Molecular Cancer (2024)

PD-1/PD-L1 blockade therapies have displayed extraordinary clinical efficacy for melanoma, renal, bladder and lung cancer; however, only a minority of colorectal cancer (CRC) patients benefit from these treatments. The efficacy of PD-1/PD-L1 blockade in CRC is limited by the complexities of tumor microenvironment. PD-1/PD-L1 blockade immunotherapy is based on T cell-centered view of tumor immunity. However, the onset and maintenance of T cell responses and the development of long-lasting memory T cells depend on innate immune responses. Acknowledging the pivotal role of innate immunity in anti-tumor immune response, this review encapsulates the employment of combinational therapies those involve PD-1/PD-L1 blockade alongside the activation of innate immunity and explores the underlying cellular mechanisms, aiming to harnessing innate immune responses to induce long-lasting tumor control for CRC patients who received PD-1/PD-L1 blockade therapy.
Gas embolism in double-balloon endoscopic retrograde cholangiography with carbon dioxide insufflation
Authors: Yuki Kawasaki, Susumu Hijioka, Yoshikuni Nagashio, Mark Chatto, Takuji Okusaka, Yutaka Saito
Journal: Endoscopy (2024)

Gas embolism during endoscopy is a rare but potentially fatal adverse event. Some risk factors, such as biliary procedures and gastrointestinal reconstruction have been cited [1]. The use of carbon dioxide (CO2) insufflation is effective in preventing gas embolism, although a few cases of gas embolism with CO2 insufflation during balloon-assisted endoscopic retrograde cholangiography (ERC) have been reported [2] [3].
Robotic endoscopic resection: the next revolution in therapeutic endoscopy is already here!
Authors: Jérémie Jacques
Journal: Endoscopy (2024)

En bloc resection of large superficial colorectal lesions offers significant advantages. Beyond enabling the treatment of early submucosal cancers with a low risk of lymph node metastasis, it also helps prevent recurrence, reducing the need for regular, costly, and stressful colonoscopy follow-ups for patients [1]. Additionally, this approach simplifies the optical diagnostic phase, eliminating the need to identify subtle mucosal and vascular pattern irregularities. Instead, it focuses on detecting amorphous areas, for which endoscopic resection may be contraindicated owing to a high probability of deep cancer infiltration. Furthermore, considering the environmental impact of transporting patients for their colonoscopy follow-ups [2], the strategy of en bloc resection as a one-time procedure appears more ecologically sustainable. Such follow-up colonoscopies also impair significantly work productivity [3]. So, despite these clear advantages for en bloc resection, why does piecemeal endoscopic mucosal resection (EMR) remain the most widely used technique in many countries?
Endoscopic ultrasound-guided gastroenterostomy for the treatment of gastric outlet obstruction secondary to acute pancreatitis
Authors: Andreas Wannhoff, Andrew Canakis, Reem Z. Sharaiha, Farimah Fayyaz, Christoph Schlag, Neil Sharma, Ismaeil Elsayed, Mouen A. Khashab, Todd H. Baron, Karel Caca, Shayan S. Irani
Journal: Endoscopy (2024)

Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is a minimally invasive technique for treating gastric outlet obstruction (GOO). The aim of this study was to assess the outcomes of EUS-GE in managing benign GOO caused by duodenal stenosis in patients with acute pancreatitis.
EXTH-71. A MECHANISTIC INVESTIGATION INTO AUGER THERAPY: 2-DIMENSIONAL THIN-FILMS TO CHARACTERIZE THERAPEUTIC RANGE<i>IN VITRO</i>
Authors: Jacob Al-Husseini, Meenakshi Upreti, Joseph Ha, Rex Moats, David Koos, Ethan Fong, Clark Baker, Archie Spindler, Malkiat Johal, Peter Chiarelli
Journal: Neuro-Oncology (2024)

Abstract Metallic nanoparticles can improve the accuracy and effectiveness of conventional radiotherapy in the treatment of solid tumors through a light-matter interaction known as the Auger effect. In this work, we present the assembly of an iron oxide (Fe3O4) nanoparticle (NPs) layer within a biocompatible polyelectrolyte film using ionic self-assembly to enable the spatial separation of NPs from their target cells. Films exhibited uniform nanoparticle coverage as well as strong stability in cell culture conditions. To investigate the applicability of NMDR with non-internalized NPs, conditions with (NP-PEM) and without (PEM) embedded nanoparticles were used to evaluate the therapeutic effect of physically separated nanoparticles on cells cultured on the film surface via a measure of intracellular reactive oxygen (ROS) generation and histone phosphorylation (yH2AX) after irradiation from a 137Cesium source. Cells cultured on NP-PEM demonstrated a 78.4% increase in ROS generation when compared to cells cultured on PEM films. When adjusting for cell count, NP-PEM films induce 70.5% greater ROS generation. In investigating nanoparticle-mediated deposition of radiation (NMDR), these films allow for the determination of the extent of the therapeutic effect when NPs are not internalized into their targeted cells, potentially providing indications with respect to off-target effects. Cells were irradiated on films with nanoparticle distances from 25.9 nm to 97.5 nm to interrogate the NMDR effect size at a range of distances. yH2AX phosphorylation exhibited an exponential decay until 69.8 nm, where there was no difference when compared to nanoparticle-free films. This work highlights the ability of iron oxide NPs to deliver NMDR at a known, quantifiable distance, providing insights for further translational applications.
EXTH-65. EXPLORING ANTIHISTAMINES TO TREAT GLIOBLASTOMA
Authors: Poonam Yadav, Raghupathy Vengoji, David Doss, Maneesh Jain, Surinder Batra, Nicole Shonka
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive and lethal primary malignant brain tumor with a 5-year survival of 6.8%. Interestingly, people with allergies, atopy, or asthma are less likely to develop GBM. A recent study recognized that high histamine receptor 1 (HRH1) expression is inversely related to overall and progression-free survival. METHODS We used a bioinformatics tool, iLINCS, which, after analyzing 99 GBM and 38 healthy samples, identified 36 drugs that can reverse GBM signatures. Based on the concordance score and blood-brain barrier permeability, we selected brompheniramine (Brom), a first-generation HRH1 antagonist, as a potential candidate. HRH1 expression analysis was done on human and mouse GBM cell lines by immunoblotting. The effect of Brom alone or in combination with temozolomide (TMZ) was investigated on proliferation, DNA damage and apoptosis in human (U118 and U251) and three syngeneic (EGFRvIII, p16-/- &amp; GFAP Cre, PTEN+/-, p53R172H+/-, EGFRvIII &amp; GFAP Cre, PTEN-/-, p53R172H-/- &amp; GFAP Cre) cell lines. GBM orthograft mouse models were used to test the efficacy of combination therapy. RESULTS HRH1 is highly expressed in human and syngeneic GBM cells. This expression is further increased in TMZ-resistant cells. Interestingly, the addition of histamine, induced TMZ resistance in GBM cells. TMZ with Brom decreases proliferation in mouse and human GBM cells, and Brom is non-toxic to non-transformed cells. Combination treatment increases DNA damage and decreases the DNA repair mechanism, possibly by downregulating the expression of O6methylguanine-DNA methyltransferase (MGMT). In the GBM orthograft mouse model, the combination therapy reduced tumor volume and significantly increased survival compared to single-agent treatment. CONCLUSIONS Brom is non-toxic; Brom, in combination with TMZ, enhanced the anti-tumor efficacy of TMZ both in in vitro and in vivo GBM models. Further studies in spontaneous mouse models are planned.
EXTH-75. IMMUNOVIROTHERAPY WITH PP2A AND PD-1 INHIBITION IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Kyung-Don Kang, Stephen Frederico, Aaron Fan, Sam Gary, Zhuo Zhang, Li Zhou, James Markert, Joshua Bernstock, Gregory Friedman
Journal: Neuro-Oncology (2024)

Abstract Pediatric high-grade gliomas (HGGs) represent a significant clinical challenge with poor survival rates. Engineered oncolytic herpes simplex virus (oHSV) has shown potential in several clinical trials at targeting HGGs through their direct lytic effect and induction of an immune response. We have learned from our clinical trial experience (NCT02457845) that a critical barrier to more durable response is augmenting and sustaining the anti-tumor immune response generated by oHSV. LB-100, a protein phosphatase 2A (PP2A) inhibitor, is known to enhance T-cell activity. We hypothesized that LB-100 with anti-PD-1 therapy would overcome the immunosuppressive barriers, enhancing the immunotherapeutic effects of oHSV and improve survival in an immunocompetent murine model. We investigated the therapeutic impact of clinically available, next-generation oHSV, M002, which expresses murine interleukin-12, combined with LB-100 and PD-1 inhibition compared to M002 with LB-100 or anti-PD-1 antibody, each therapy alone, or control by measuring median survival and changes in the tumor immune microenvironment. The triple combination of M002, LB-100, and anti-PD-1 antibody significantly extended median survival compared to control (45 days vs 22.5 days, P=0.001) or each treatment alone, and compared to M002 and LB-100 (44 days vs 28 days, P=0.017) or M002 and anti-PD-1 (45.5 days vs 41 days, P=0.023). This increase in survival was correlated with a robust increase in CD45+ immune cell infiltration and a reduction in T-regulatory cells. We will further investigate the changes in the tumor microenvironment to better understand the specific contributions of different immune cell populations. These data support the hypothesis that LB-100 enhances the efficacy of oHSV by amplifying T-cell-mediated immune responses against tumor cells. This combination therapy demonstrates a promising strategy that warrants further exploration and potential clinical application, emphasizing the critical role of targeting multiple aspects of immune regulation to enhance the efficacy of oncolytic virotherapy in pediatric tumors.
NIMG-49. IMAGING PREDICTIVE FACTORS OF BRAIN ADHESION IN SUPRATENTORIAL MENINGIOMA
Authors: Shingo Tanaka, Sho Tamai, Masashi Kinoshita, Mitsutoshi Nakada
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVES 80 % of meningioma are benign and are classified as WHO grade 1. However, meningioma frequently adheres to surrounding brain and make tumor detach difficult during surgery. This study retrospectively analyzed the adhesion of meningioma to the brain based on preoperative MR images and operative findings. METHODS We retrospectively reviewed 238 tumor planes of 60 supratentorial meningioma cases with WHO grade 1 (parasagittal: 15, convexity: 20, falcine: 7, sphenoidal ridge 13 and frontal base 5) underwent surgical treatment. The tumor adhesion to the surrounding brain was defined during surgery as the rupture of arachnoid membrane or leaving tumor capsule due to tight adhesion. The location of MRI image was identified during surgery and verified reference to operation video postoperatively. We assessed following items, tumor diameter, T2 hyper rim, T1 hypo rim, FLAIR hypo rim and brain edema of surrounding tumor. We performed univariate analysis for each item with and without adhesion, and extracted predictors for tumor adhesion by logistic regression analysis. RESULTS We confirmed 127 tumor planes without adhesion and 111 tumor planes adhered to surrounding brain. The cutoff value obtained from the ROC curve for tumor adhesion and tumor diameter was 2.3 cm. In univariate analysis, tumor diameter ≧ 2.3 cm, T2 hyper rim, T1 hypo rim, FLAIR hypo rim and brain edema of surrounding tumor were significantly associated with adhesion. In logistic regression analysis, tumor diameter ≧ 2.3 cm (odds ratio (OR) 2.7, P = 0.02), T2 hyper rim (OR 0.04, P &amp;lt; 0.001), and brain edema of surrounding tumor (OR 25, P &amp;lt; 0.001) were significantly independent predictive factors for tumor adhesion. CONCLUSION Meningioma adhesion to surrounding brain might be predicted by tumor diameter ≧2.3 cm, T2 hyper rim, and brain edema of surrounding tumor.