bluuebunny/crossref_metadata_2025_split huggingface dataset:
MODL-44. DEVELOPMENT OF A NOVEL, PERSONALIZED DRUG SENSITIVITY SCORE TO ASSESS TUMOR KILLING AND TOXICITY WITHIN AN ORGANOTYPIC BRAIN SLICE CULTURE PLATFORM
Authors: Mann Breanna , Zhang Xiaopei , Bell Noah , Adefolaju Adebimpe , Thang Morrent , Dasari Rajaneekar , Kanchi Krishna , Valdivia Alain , Yang Yang , Buckley Andrew , Lettry Vivien , Quinsey Carolyn , Rauf Yasmeen , Kram David , Cassidy Noah , Vaziri Cyrus , Corcoran David L , Rego Stephen , Jiang Yuchao , Graves Lee M , Dunn Denise , Floyd Scott , Baldwin Albert , Hingtgen Shawn , Satterlee Andrew B 
Published: November 2023

Abstract
Development of new therapeutics for clinical use requires balancing tumor killing and off-target toxicity to normal tissue. We have established an organotypic brain slice culture (OBSC) platform which enables us to assess both on- and off-target drug effects via engraftment, treatment, and analysis of cell lines and uncultured patient brain tumor tissue. We have used OBSCs to test seven cell lines, ten patient tissues, and normal brain tissue against a panel of eleven different therapeutics. To determine a normalized comparison among drugs of differing potencies, we have established a drug sensitivity score (DSS) which combines both direct tumor killing via bioluminescence imaging and off-target toxicity via propidium iodide staining. Our ability to define these values independently allows us to generate normalized therapeutic window ratios for each drug-tumor-OBSC interaction. From these results, 11 different parameters, including those commonly used to define drug activity such as IC10, IC50, and area under the curve, were assessed and combined into a single ranked score which combines more than 100 data points. This algorithm enables relative comparisons among tumor responses to several drugs with less bias toward more potent compounds which produce correspondingly high off-target toxicity. Trends across DSSs for every tumor indicate that we can calculate scores throughout the entire scoring range. While we find that patient tumor tissue is generally more sensitive to treatment than cell lines, there is still a wide distribution of patient tumor sensitivities among tumor types and therapeutics. Additionally, our DSS can detect differences in tumor sensitivity after a single gene alteration in RAD18. In summary, our DSS algorithm and scoring system provides a summarized, normalized way to assess both on-target killing and off-target toxicity, allowing more comprehensive comparisons of drugs with varying potency.
MODL-46. RECAPITULATING CELLULAR HETEROGENEITY AND TREATMENT-SPECIFIC EFFECTS THROUGH SINGLE-CELL ANALYSIS OF PATIENT-DERIVED TUMOR SLICE CULTURE MODELS
Authors: Mohan Aditya , Bassett John , Jerry Jonathan , Yerrabelli Rushil , Blandford Emily , Mihalas Anca , Sampson John , Patel Anoop 
Published: November 2023

Abstract

INTRODUCTION
Malignant brain tumors are almost universally fatal despite standard-of-care (SOC) therapy with radiation (XRT) and temozolomide (TMZ). Low Grade Glioma (LGG) is a subclass of malignant glioma that can harbor an R132H mutation in Isocitrate Dehydrogenase 1 (IDH1). Extensive clinical trials have explored the clinical utility of IDH1 R132H mutation small molecule inhibitors such as ivosidenib and vorasidenib; however, the direct intracellular and intercellular effects of IDH1 R132H inhibition relative to SOC remain largely unknown. Objective This study examines these issues by developing a novel patient-specific tumor slice culture model to study the effects of both SOC and IDH1 R132H inhibition on IDH1 mutant glioma. Method En-bloc tumor samples from a patient with IDH mutant LGG undergoing surgery were sectioned into 400 um thick slices using a vibratome and cultured on porous microwell inserts for up to 14 days. Tumor slices were then either left untreated or treated with SOC (XRT/TMZ) or ivosidenib and harvested at various time points. Samples were hashed, and single-cell RNA sequencing was performed and analyzed. Result: Patient-derived tumor slice cultures were able to grow and were observed to contain heterogeneous cell populations, including tumor cells, astrocytes, neurons, oligodendrocytes, and microglia. When slice cultures were treated with SOC and ivosidenib treatment, separate tumor subpopulations were shown to be sensitive to either treatment. Furthermore, scRNA analysis revealed unique subpopulations that were insensitive to either treatment. We further demonstrate that slice cultures treated with Ivosidenib enriched for gene signatures related to protein translation and antigen processing. Intriguingly, we find that tumor cultures treated with ivosidenib abrogated the Notch signaling pathways between tumor-tumor and tumor-immune clusters.

CONCLUSION
Herein, we demonstrate that patient-derived tumor slice cultures are a viable strategy for understanding drug effects and tumor sensitivity to different therapies.
MODL-47. A NEW MOUSE MODEL OF IDH MUTATED GLIOMAS IDENTIFIES TUMOR CELLS OF ORIGIN AND DETERMINANTS OF SENSITIVITY TO IDH INHIBITORS
Authors: Laugesen Eric , Tian Ruxiao , Wu Annette , El Ghamrasni Samah , Levine Adrian , Aamir Zoya , Nobre Liana Figueiredo , Petrecca Kevin , McBrayer Samuel , Suva Mario , Hawkins Cynthia , Tabori Uri , Schramek Daniel , Mak Tak , Fortin Jerome 
Published: November 2023

Abstract
Driver mutations in IDH1 and IDH2 characterize a substantial proportion of diffuse gliomas. These tumors are typically of lower grade at diagnosis, but many eventually transform to more aggressive disease. Furthermore, there is a lack of effective curative treatments. Mutated IDH molecules acquire neomorphic enzymatic activity, favoring the synthesis of D-2-hydroxyglutarate (D-2-HG). Accumulation of this metabolite perturbs many cellular functions and drives gliomagenesis through incompletely understood mechanisms. IDH mutations are early events in gliomagenesis, but the identity of the initiating cell type has been debated. Here, using genetically engineered mice, we found that combining Idh1R132H and Trp53 loss in oligodendrocyte progenitors leads to fully penetrant development of diffuse gliomas. The tumors recapitulate the cardinal features of the corresponding human disease. While heterogeneous, the mouse Idh1R132H and Idh1WT tumors show distinct patterns of transcriptional alterations and oncogenic copy number variants. Mutant IDH itself is an attractive drug target, as it is clonally expressed and usually retained during tumor evolution, even though its relevance for disease progression has been questioned. Nevertheless, recent clinical trials have demonstrated clear, but variable, anti-tumor effects of mutant IDH inhibitors in patients. To better understand the mechanistic basis for heterogeneous responses to mutant IDH inhibition, we performed CRISPR/Cas9 functional genomic screens in cell lines derived from the mouse Idh1R132H;Trp53MUT tumors. These revealed interactions between the mutant IDH inhibitor vorasidenib and molecules related to astrocytic differentiation, Notch signaling, and cell growth and metabolism. The translational relevance of these findings was supported by molecular data from human tumors, patients treated with IDH inhibitors, and human-derived cell models. Overall, these studies nominate oligodendrocyte progenitors as candidate cells of origin for IDH mutated gliomas, and point to strategies that may enhance the efficacy of IDH inhibitors.
MODL-50. CLONAL EXPANSION OF SPONTANEOUS AND INJECTED TUMORS IN SYNGENEIC MOUSE MODELS OF GLIOBLASTOMA
Authors: Hall Courtney F , Pyczek Joanna , Ahn Bo Young , Chan Jennifer , Morrissy Sorana 
Published: November 2023

Abstract

INTRODUCTION
Glioblastoma (GBM) tumors are highly heterogenous and plastic. To better understand how tumors respond to treatment, it is important to use immunocompetent mouse models. We've created various mouse GBM models with common genetic mutations found in different subtypes of GBM, including classical, proneural, mesenchymal, and BRAF-driven.

METHODS
Using a combination of CRISPR and PiggyBac Transposon constructs, we injected plasmid mixtures into the ventricles of the mouse brain during the post-natal period. Electroporation was then used to enable the plasmids to enter nearby neural stem cells, which led to the spontaneous formation of tumors (spontaneous model). We collected tumor cells from these models and injected them into the adult mouse brain to create the injected mouse GBM model. Here we use spatial and single cell transcriptome profiling approaches to characterize these models at endpoint. Spatial transcriptome data was collected using the Visium 10X platform and tumor spots were deconvoluted from non-malignant spots using consensus non-negative matrix factorization. Copy number alterations (CNAs) were inferred using non-malignant spots and single-cell clusters as a reference.

RESULTS
We found that copy number states are largely homogenous within each sample, supporting an early population expansion in vivo. CNAs found in spontaneous tumors are also found in the matched injected tumors, which in turn harbour additional CNAs, suggesting that further selection occurs in vitro. Some of the CNAs include relevant cancer genes, suggesting the observed clonal expansions are potentially driven by additional somatic alterations that cooperate with the engineered driver mutations. Studying these models using orthogonal methods will allow us to discover alterations that synergize with the original drivers and delineate principles of GBM initiation and progression in an immune-competent environment.
A Pooled Analysis of 3 Phase II Trials of Salvage Nivolumab/Ipilimumab After Nivolumab in Renal Cell Carcinoma
Authors: McKay Rana R , Leucht Katharina , Xie Wanling , Jegede Opeyemi , Braun David A , Atkins Michael B , Grimm Marc-Oliver , Choueiri Toni K 
Published: November 2023

Abstract

Background
Nivolumab plus ipilimumab has demonstrated improved survival for treatment-naïve advanced clear cell renal cell carcinoma (RCC). A series of clinical trials evaluated the effect of salvage nivolumab plus ipilimumab in patients without an objective response to nivolumab. Given the size and heterogeneity of these studies, we performed a pooled analysis to better inform the activity of nivolumab plus ipilimumab after nivolumab.

Patients and Methods
Eligible patients included those with advanced clear cell RCC having received no prior immunotherapy. The primary objective was confirmed objective response rate (ORR) by investigator-assessment. Secondary objectives included progression-free survival (PFS) and overall survival (OS).

Results
The analysis included 410 patients with clear cell RCC, of whom 340 (82.9%) had IMDC intermediate/poor risk disease, and 137 (33.4%) had prior treatment. The 16-18-week ORR to nivolumab prior to nivolumab plus ipilimumab was 22.7% (n = 93), and best ORR to nivolumab was 25.1% (n = 103). Two hundred and thirty (56.1%) patients treated with nivolumab received nivolumab plus ipilimumab at a median of 16 weeks (IQR 9-19) after initiation of nivolumab [27.0% (n = 62) with stable disease and 73.0% (n = 168) with progressive disease to nivolumab]. The ORR to nivolumab plus ipilimumab was 12.6% (n = 29). Six-month PFS on nivolumab plus ipilimumab was 37% (95% CI, 27-47). Median follow-up was 34.3 months and 3-year OS was 59% (95% CI, 53-64) from nivolumab start.

Conclusion
A small subset of patients lacking a response to nivolumab derive benefit from salvage nivolumab plus ipilimumab. When possible, both drugs should be given in concomitantly, rather in an adaptive fashion.
The informal carer experience during the COVID-19 pandemic: mental health, loneliness, and financial (in)-security
Authors: Webb Edward J D , Meads David , Gardiner Clare 
Published: November 2023

Abstract
Informal caring is associated with many negative outcomes. COVID-19 caused societal disruption, which may have disproportionately impacted carers. Reducing inequalities requires knowing whether, and how, carers were impacted. COVID-19 Understanding Society survey participants who were informal household carers (IHCs) were matched with a non-IHC comparison group. Differences between the groups were assessed for mental health (measured using General Health Questionnaire, GHQ-12), loneliness, subjective financial security, whether behind with mortgage/rent payments or bills, household wealth changes, and whether receiving universal credit (UC). A total of 1617 IHCs were matched with 6684 comparators. IHCs’ GHQ-12 scores were 0.613 points higher; they experienced greater loneliness and worse subjective financial security. IHCs were significantly more likely to experience decreased household wealth and receive UC, but not to be behind with bills. IHC outcomes remained worse than comparators in September 2021. Spending longer caring, caring for a partner, and not being employed were associated with worse outcomes.
The event-driven nature of online political hostility: How offline political events make online interactions more hostile
Authors: Hebbelstrup Rye Rasmussen Stig , Petersen Michael Bang 
Published: November 2023

Abstract
Hostile interactions permeate political debates on social media, but what is driving the long-term developments in online political hostility? Prior research focuses on individual-level factors such as the dispositions of users or network-level factors such as echo chambers. Moving beyond these accounts, we develop and test an event-oriented explanation and demonstrate that over the course of the 2020 election year in the United States, all major shifts in political hostility on the social media platform Twitter were driven by external offline events. Importantly, these events were magnified by Twitter users within the most politically hostile and most ideologically homogeneous networks. Further contributing to the individual and network-oriented accounts, we show that divisive offline events mobilized individual users not already disposed for hostility and may have helped facilitate the formation of echo chambers. The dynamics of online interactions—including their level of hostility—seem crucially dependent on developments in the offline world.
Clinical Application of Umbilical Cord Mesenchymal Stem Cells Preserves β-cells in Type 1 Diabetes
Authors: Al Madhoun Ashraf , Koti Lubaina , Carrió Neus , Atari Maher , Al-Mulla Fahd 
Published: November 2023

Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease associated with complications that reduce the quality of life of affected individuals and their families. The therapeutic options for T1D are limited to insulin therapy and islet transplantation; these options are not focused on preserving β-cell function and endogenous insulin. Despite the promising outcomes observed in current clinical trials involving allogeneic Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) infusion for the management of T1D, the precise underlying mechanism of action remains to be elucidated. In this correspondence, we propose prospective mechanisms of action of WJ-MSCs that may be mediating their observed capability to preserve β-cell function and prevent T1D progression and provide recommendations for further investigations in clinical settings. We also highlight the efficacy of WJ-MSCs for therapeutic applications in comparison to other adult MSCs. Finally, we recommend the participation of muti-centers governed by international organizations to implement guidelines for the safe practice of cell therapy and patients’ welfare.
Wolfberry, Yam, and Chrysanthemum polysaccharides increased intestinal Akkermansia muciniphila abundance and hepatic YAP1 expression to alleviate DILI
Authors: Lu Junlan , Gong Yi , Gao Yuting , Yang Yanguang , Zhang Yuman , Zhang Zhiqin , Shi Xinli 
Published: November 2023

AbstractDrug‐induced liver injury (DILI) is frequently induced by high dose of acetaminophen (APAP) and is concomitant with disturbances of gut flora. Akkermansia muciniphila is beneficial for the repair of liver injury. Lycium barbarum polysaccharide, yam polysaccharide, and chrysanthemum polysaccharide all have anti‐inflammatory and antioxidation effects. The objective of this study is to investigate the potential of lycium barbarum polysaccharide, yam polysaccharide, and chrysanthemum polysaccharide (LYC) in improving DILI by increasing the abundance of A. muciniphila. Initially, screening for the optimal concentrations of wolfberry, yam, and chrysanthemum (WYC) or LYC to promote A. muciniphila proliferation in vitro and validated in antibiotic (ATB)‐treated KM mice. Subsequently, APAP‐induced DILI model in BALB/c mice were constructed to examine the treatment effects of LYC. Our findings indicate that the optimal concentration ratio of WYC was 2:3:2, and LYC was 1:1:1. WYC increased A. muciniphila proliferation in vitro and in ATB‐treated mice under this ratio. Meanwhile, LYC increased A. muciniphila abundance in vitro and the combination LYC with A. muciniphila promoted the proliferation of A. muciniphila in ATB‐treated mice. The overdose of APAP resulted in the impairment of the intestinal barrier function and subsequent leakage of lipopolysaccharide (LPS). Moreover, LYC increased A. muciniphila abundance, reduced intestinal inflammation and permeability, and upregulated the expression of the tight junction protein zonula occludens protein 1 (ZO‐1) and occludin contents in the gut. Lastly, LYC inhibited LPS leakage and upregulated hepatic YAP1 expression, ultimately leading to the repair of DILI.
Cellular ROS tolerance determines the effect of plumbagin on osteoclast differentiation
Authors: Sultanli Sevinj , Schneider Jakob , Burkart Sandy S. , Binder Marco , Kubatzky Katharina F. 
Published: November 2023

AbstractPlumbagin is used in traditional medicine because of its anti‐inflammatory and anti‐microbial properties. As a naphthoquinone, plumbagin triggers the production of reactive oxygen species (ROS). In vitro cancer studies showed that plumbagin triggers apoptosis in cancer cells through ROS production. As cancer‐mediated chronic inflammation can affect bone density, it was hypothesized that plumbagin might directly inhibit the formation of bone‐resorbing osteoclasts. We previously showed that the effect of plumbagin on osteoclastogenesis differed between bone marrow‐derived macrophages and the macrophage cell line RAW 264.7. Although RAW 264.7 macrophages are able to initiate the gene program required for osteoclastogenesis, only primary macrophages successfully differentiate into osteoclasts. Here, we show that RAW 264.7 cells are more sensitive toward plumbagin‐induced apoptosis. In the presence of plumbagin and the cytokine RANKL, which triggers ROS production to drive osteoclastogenesis, RAW 264.7 macrophages produce increased amounts of ROS and die. Addition of the ROS scavenger N‐acetyl cysteine prevented cell death, linking the failure to differentiate to increased ROS levels. RAW 264.7 cells show reduced expression of genes protective against oxidative stress, while primary macrophages have a higher tolerance toward ROS. Our data suggest that it is indispensable to consider cell (line)‐intrinsic properties when studying phytochemicals.
A training tool for clinicians in segmenting medical images to make 3D models
Authors: Chegini Soudeh , Tahim Arpan , Liu Mingjun , Edwards Eddie , Chooi Yean , Clarkson Matthew , Schilling Clare 
Published: November 2023

Introduction:
3D models produced from medical imaging can be used to plan treatment, design prosthesis, teach, and for communication. Despite the clinical benefit, few clinicians have experience of how 3D models are produced. This is the first study evaluating a training tool to teach clinicians to produce 3D models and reporting the perceived impact on their clinical practice.

Method:
Following ethical approval, 10 clinicians completed a bespoke training tool, comprising written and video material alongside online support. Each clinician and 2 technicians (included as control) were sent 3 CT scans and asked to produce 6 fibula 3D models using open-source software (3Dslicer). The produced models were compared to those produced by the technicians using Hausdorff distance calculation. Thematic analysis was used to study the postintervention questionnaire.

Results:
The mean Hausdorff distance between the final model produced by the clinicians and technicians was 0.65 mm ± SD 0.54 mm. The first model made by clinicians took a mean time of 1 hour 25 minutes and the final model took 16:04 minutes (5:00–46:00 minutes). 100% of learners reported finding the training tool useful and will employ it in future practice.

Discussion:
The training tool described in this article is able to successfully train clinicians to produce fibula models from CT scans. Learners were able to produce comparable models to technicians within an acceptable timeframe. This does not replace technicians. However, the learners perceived this training will allow them to use this technology in more cases, with appropriate case selection and they appreciate the limits of this technology.
HIV Care Continuum Among People Living With HIV and History of Arrest and Mental Health Diagnosis
Authors: Wiehe Sarah E. , Nelson Tammie L. , Aalsma Matthew C. , Rosenman Marc B. , Gharbi Sami , Fortenberry J. Dennis 
Published: November 2023

Objective:
Justice involvement and psychiatric comorbidities contribute to excess HIV morbidity, yet their interaction is poorly understood. We examined associations of this overlap with HIV outcomes among people living with HIV (PLWH).

Methods:
We conducted a retrospective cohort study of PLWH aged 13 years and older residing in Marion County (Indianapolis), IN, during 2018 (n = 5730) using linked HIV surveillance, arrest, and clinical data. We used univariable and multivariable regression to evaluate main and interaction effects of 2010–2017 arrest and mental health diagnosis on 2018 linkage to care (LTC), retention in care (RIC), and undetectable viral load (UVL).

Results:
LTC decreased among those with, versus without, an arrest (P = 0.02), although mental health diagnoses had no significant effect on LTC. When controlling for demographics and substance use disorder, analyses indicated a protective effect of arrest history on odds of RIC (adjusted odds ratio [aOR] = 1.54) and UVL (aOR = 1.26). Mental health diagnosis also increased odds of RIC (aOR = 2.02) and UVL (aOR = 1.95). Post hoc tests demonstrated that these results were mediated by outpatient care utilization, although an arrest or mental health diagnosis did increase odds of RIC among PLWH and a history of low outpatient utilization.

Conclusions:
Outpatient care utilization improves HIV outcomes, even among those with justice involvement and psychiatric comorbidities. Holistic approaches to care can increase utilization. Implementation of “no wrong door” approaches, such as integration of mental health care in the primary care setting, simplifies health care navigation and improves access. Among those arrested, access to a Behavioral Court program can improve, rather than disrupt, HIV care.