bluuebunny/crossref_metadata_2025 huggingface dataset:
MODL-07. NF1 MUTATION IN OLIGODENDROCYTE PRECURSOR CELLS INDUCES PRENEOPLASTIC LESIONS IN THE BRAIN
Authors: Pan Yuan , Hysinger Jared , Yalçın Belgin , Lennon James , Raghavan Preethi , Schindler Nicole , Anastasaki Corina , Chatterjee Jit , Mount Christopher , Nagaraja Surya , Scheaffer Suzanne , Attardi Laura , Gutmann David , Monje Michelle
Published: November 2023

Oligodendrocyte precursor cells (OPCs) are progenitor cells that give rise to oligodendrocytes in the central nervous system throughout the lifespan. Transcriptomic and lineage tracing studies suggest that OPCs may be the putative cell of origin for many gliomas in children and adults. While children with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome typically develop optic pathway and brainstem gliomas, as many as 50% of children develop gliomas in other brain regions using radiologic criteria. Relevant to these gliomas, discrete patches of hyperdense OPCs were found in the brains of Nf1+/- mice. The OPCs within the lesions display a transient increase in proliferation and hypercellularity. When the brains of mice carrying different heterozygous NF1 patient derived germline Nf1 gene mutations were examined, hyperdense OPC lesions were only seen in mice whose Nf1 mutations also predispose to optic gliomas. Mechanistically, monoallelic KRAS hyperactivation also results in similar OPC hyperdense lesions. Moreover, OPC-specific Nf1-heterozygous mice display similar lesions, while OPC-specific Nf1-knockout results in generalized OPC hyperdensity throughout the entire brain. Taken together, these data suggest the existence of a preneoplastic state conferred by Nf1 mutation in OPCs and establish a tractable model system to explore the transition to glioma in children with NF1.
MODL-13. DEVELOPMENT OF TUMOR TREATING FIELDS (TTFIELDS) ARRAYS FOR TREATMENT OF HEAD TUMORS IN MICE MODELS
Authors: Zbidat Sewar , Blat Roni , Sellevoll Mariell , Gabay Martin , Schlachet Inbar , Cahal Shay , Davidi Shiri , Tzchori Itai , Haber Adi , Giladi Moshe , Palti Yoram
Published: November 2023

INTRODUCTION

Glioblastoma (GBM) is the most common malignant brain tumor. Tumor Treating Fields (TTFields) therapy is an approved treatment for GBM, delivered continuously by two array pairs placed on the skin surrounding the tumor region. Currently, most GBM animal models are based on mice. Since arrays for TTFields application to the mouse head are lacking, GBM-TTFields in vivo studies are limited. The small dimensions and specific geometries of the mouse head make the development of such arrays challenging.

METHODS

We tested different array layouts to identify one that will optimally accommodate the geometries of the mouse head while minimally restricting head movement. Additionally, we investigated adhesive tapes for array attachment to the skin, to allow good adherence and hence provide efficient treatment delivery. To validate that the selected array layout delivers therapeutic field intensity to the desired region, we performed simulations and fields measurements.

RESULTS

To overcome the issue of small head size we developed a layout in which the arrays on the head were divided into two smaller disks, with the opposing arrays situated on the mouse torso. We also identified a thin and transparent adhesive tape that facilitated the correct positioning of the arrays on the mouse head, offered good tackiness, and allowed for easy removal without leaving residual adhesive on the skin. The arrays met the minimum treatment requirements: field intensity ≥ 1 V/cm RMS, current ≥ 50 mA, usage ≥ 75%.

CONCLUSIONS

Our newly developed mouse head arrays are a flexible construct, that adheres strongly to the skin to enable efficient electric field delivery. By facilitating TTFields delivery to the heads of mice, we will expand the scope of GBM treatment research and will contribute to further advance this field.
MODL-17. OBESOGENIC DIET INCREASES NF1-OPTIC PATHWAY GLIOMA FORMATION THROUGH EFFECTS ON THE TUMOR CELL OF ORIGIN
Authors: Chan Ambrose , Zhang Kailong , Martin Gemma , Bano Sabiha , Avery Wang , Sarvika Mahto , Gutmann David , Brossier Nicole
Published: November 2023

Rates of both pediatric low-grade glioma and obesity have been rising in the U.S., and children of obese mothers have increased rates of several tumor types, including brain tumors. Importantly, obesity in the U.S. is largely dietary-driven, given the prevalence of high fat and high sugar (HFHS) diets. High-fat diet exposure can promote proliferation of embryonic neuroglial progenitor cells (NPCs), which animal modeling suggests are potential cells of origin for low-grade glioma. Together, these data suggested that in utero exposure to an obesogenic diet might affect the formation of pediatric brain tumors. Using preclinical models of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, in which optic pathway gliomas (Nf1-OPGs) arise from NPCs in the developing third ventricular zone (TVZ), we sought to determine whether maternal obesogenic exposure would increase glioma formation through intrinsic effects on the tumor cell of origin. We demonstrated that progeny from obese dams exposed to HFHS diet during and preceding gestation had increased proliferation and glial differentiation of WT and Nf1-mutant TVZ NPCs. Progeny of non-obese dams exposed to this diet during gestation demonstrate a similar phenotype, suggesting these effects are related to maternal diet rather than weight. Obesogenic diet exposure (Ob) also increased glioma penetrance in two low-penetrance murine models of Nf1-OPG. Moreover, we demonstrated that Ob mice developed earlier tumor onset with elevated Erk activity in a high-penetrance Nf1-OPG model. In contrast, when obesogenic diet was introduced postnatally, only 11% of mice showed accelerated tumor formation. Ob-exposed nerves also displayed elevated levels of activated Stat3, consistent with upregulation of the IL6/Jak/Stat3 pathway with HFHS diet exposure. These findings establish maternal obesogenic diet as a risk for pediatric glioma formation, in part through in utero effects on the tumor cell of origin, and identify the MAPK and IL6/Jak/Stat3 pathways as targets for further investigation.
MODL-18. ESTABLISHMENT OF A NOVEL HUMANIZED PERIPHERAL BLOOD MONONUCLEAR CELL (HU-PBMC) MOUSE MODEL TO EVALUATE LYMPHOCYTE INVOLVEMENT IN GLIOBLASTOMA AND ITS TREATMENT
Authors: Deshpande Krutika , Kwang Denna , Cadiente Marvin , Delany Jasmine , Ahmed Taufeeq , McDonald Bailey , Wang Xi , Barrette Anne Marie , Sun Dongxu
Published: November 2023

Glioblastoma (GBM) has traditionally been classified as an ‘immune cold’ tumor, characterized by strong immunosuppression, low mutational burden, and few presentable antigens. However, lack of standard-of-care improvement and the discovery of targetable immune-modulatory biomarkers like PD-1/PD-L1 and CTLA4 in the GBM microenvironment has prompted clinical trials to explore immune checkpoint inhibition (ICI) efficacy in patients, with moderate responses in specific patient subsets. To better characterize ICI in GBM, and to match prospective patients to suitable therapeutics, it is necessary to establish preclinical GBM mouse models that incorporate the lymphocytic milieu as xenograft and syngeneic models are unable to replicate the immune responses seen in humans. We have established a novel humanized PBMC mouse model that recapitulates human GBM pathology in the brain, supports and maintains systemic and intracranial human T cell engraftment in the presence of GBM tumors, and allows for a suitable timeline for preclinical testing of therapeutics prior to onset of GVHD. In our study, orthotopic GBM-bearing NSG mice showed successful human CD45+ engraftment in the blood (~20%) and brain (~5%) 2 weeks post intravenous implantation of hu-PBMCs. Restricted tumor growth was observed, indicating initial responsiveness of human immune cells to GBM. Engraftment remained unaffected upon treatment with temozolomide (GBM standard of care), and persisted over 6 weeks (brain ~40%, blood ~70%) before GVHD onset (week 7). ~90% of the hCD45+ population was CD3+, indicating robust T cell engraftment, which was further characterized into CD4+ and CD8+ subsets and by activation status (HLA-DR, CD45RA/RO, PD-1, FOXP3 etc) within the tumor-bearing brain and blood. Anti-PD-1 inhibitor efficacy was also tested in engrafted animals to observe ICI potential in GBM. This humanized mouse provides a powerful translational model to evaluate T cell responses in tumor pathology and immunotherapy in GBM and potentially other primary or secondary brain malignancies.
MODL-36. EX VIVO GSC CULTURES RETAIN PATIENT-UNIQUE HALLMARK GENE EXPRESSIONS AND PREDICT PATIENT RESPONSE TO TMZ MORE SPECIFICALLY THAN MGMT PROMOTER STATUS
Authors: Ntafoulis Ioannis , Kleijn Anne , Ju Jie , Jimenez-Cowell Kevin , Fabro Federica , Klein Michelle , Yen Romain Tching Chi , Balvers Rutger , Kers Trisha , Kros Johan , Lawler Sean , Kremer Andreas , Li Yunlei , Stubbs Andrew , van den Bent Martin , Dirven Clemens , Leenstra Sieger , Lamfers Martine ,   GLIOTRAIN Consortium
Published: November 2023

BACKGROUND

Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ).

METHODS

DNA and RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Drug response readouts were related to clinical parameters of corresponding patients and whole-transcriptome data.

RESULTS

Tumor DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. Patient-specific hallmark gene expression levels were retained in vitro. Functional screening for TMZ sensitivity yielded three response categories (responders, intermediates and non-responders) which significantly correlated with patient survival, therewith providing a more specific response prediction than the binary MGMT marker. Transcriptome analysis of GSCs and parental tissues identified 121 genes related to TMZ sensitivity and overall survival, of which 21, including MGMT, could be validated in external datasets.

CONCLUSION

GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma patients.
MODL-37. MODELING REVERSIBLE TUMORIGENESIS IN CEREBRAL ORGANOIDS
Authors: Graham Maya , Codega Paolo , Campos Carl , Nandakumar Subhiksha , Rosenblum Marc , Antonescu Cristina , Grogan Meaghan , Benhamida Jamal , Bale Tejus , von Deimling Andreas , Socci Nicholas , Mellinghoff Ingo
Published: November 2023

Human cerebral organoids have emerged as a new approach to modeling the role of cancer-associated genes in tumorigenesis ex vivo. Here, we asked whether high-grade tumorigenesis in cerebral organoids is a reversible process. Using inducible cassettes carrying key oncogenic mutations histone H3K27M, dominant negative p53 and activated PDGFRA, we show that their expression in cerebral organoids reproducibly drives high grade malignant transformation in vitro and in vivo, including in orthotopic xenografts. We characterize this transformation as a fusion-negative rhabdomyosarcoma (FN-RMS) phenotype and identify a putative FN-RMS cell-of-origin in cerebral organoids. Finally, we show this transformation is dependent on persistent transgenic oncogene expression, as oncogene withdrawal causes complete tumor regression. These findings demonstrate that cerebral organoids may be used to pinpoint previously unappreciated and distinct roles of different mutations in tumor development and maintenance.
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

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

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

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

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

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

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

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

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

Drug‐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

Plumbagin 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.
Anti-Clogging Effect of Continuous Hemodiafiltration With Blood Recirculation
Authors: Nishimori Kazuhisa , Kasuno Kenji , Takahashi Naoki , Nishimura Fumihiro , Shimamoto Yuki , Kimura Hideki , Iwano Masayuki
Published: November 2023

Pediatric dialysis requires low flow from the body, but greater flow is needed to prevent clogging. As a solution, we developed a new continuous hemodiafiltration system with blood recirculation (CHDF-R), which enables separate settings for blood flow from the body and to the hemofilter. We compared CHDF-R with conventional continuous hemodiafiltration (CHDF) of bovine plasma and blood by monitoring the transmembrane pressure (TMP) and observing the hemofilter membrane surface. When using bovine plasma, the postdialysis TMP with CHDF-R was significantly lower than with CHDF (median CHDF, 23.7; median CHDF-R, 18.1; p = 0.029). Likewise, when using bovine blood, the postdialysis TMP was also significantly lower with CHDF-R than with CHDF (median CHDF, 150; median CHDF-R, 100; p = 0.029). Moreover, the area of clogged membrane was significantly smaller with CHDF-R than with CHDF, and the inner membrane surface showed less material deposition with CHDF-R than CHDF. CHDF-R thus appears to suppress accumulation of clogging substances by producing higher shear stress within hollow fiber membranes.
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.
Telomere-to-telomere assembly by preserving contained reads
Authors: Kamath Sudhanva Shyam , Bindra Mehak , Pal Debnath , Jain Chirag
Published: November 2023

Automated telomere-to-telomere (T2T)de novoassembly of diploid and polyploid genomes remains a formidable task. A string graph is a commonly used assembly graph representation in the overlap-based algorithms. The string graph formulation employs graph simplification heuristics, which drastically reduce the count of vertices and edges. One of these heuristics involves removing the reads contained in longer reads. However, this procedure is not guaranteed to be safe. In practice, it occasionally introduces gaps in the assembly by removing all reads that cover one or more genome intervals. The factors contributing to such gaps remain poorly understood. In this work, we mathematically derived the frequency of observing a gap near a germline and a somatic heterozygous variant locus. Our analysis shows that (i) an assembly gap due to contained read deletion is an order of magnitude more frequent in Oxford Nanopore reads than PacBio HiFi reads due to differences in their read-length distributions, and (ii) this frequency decreases with an increase in the sequencing depth. Drawing cues from these observations, we addressed the weakness of the string graph formulation by developing the RAFT assembly algorithm. RAFT addresses the issue of contained reads by fragmenting reads and producing a more uniform readlength distribution. The algorithm retains spanned repeats in the reads during the fragmentation. We empirically demonstrate that RAFT significantly reduces the number of gaps using simulated datasets. Using real Oxford Nanopore and PacBio HiFi datasets of the HG002 human genome, we achieved a twofold increase in the contig NG50 and the number of haplotype-resolved T2T contigs compared to Hifiasm.
Ultrasound-guided Photoacoustic image Annotation Toolkit in MATLAB (PHANTOM) for preclinical applications
Authors: Sweeney Allison , Arora Aayush , Edwards Skye , Mallidi Srivalleesha
Published: November 2023

Depth-dependent fluence-compensation in photoacoustic (PA) imaging is paramount for accurate quantification of chromophores from deep tissues. Here we present a user-friendly toolkit named PHANTOM (PHotoacoustic ANnotation TOolkit for MATLAB) that includes a graphical interface and assists in the segmentation of ultrasound-guided PA images. We modelled the light source configuration with Monte Carlo eXtreme and utilized 3D segmented tissues from ultrasound to generate fluence maps to depth compensate PA images. The methodology was used to analyze PA images of phantoms with varying blood oxygenation and results were validated with oxygen electrode measurements. Two preclinical models, a subcutaneous tumor and a calcified placenta, were imaged and fluence-compensated using the PHANTOM toolkit and the results were verified with immunohistochemistry. The PHANTOM toolkit provides scripts and auxiliary functions to enable biomedical researchers not specialized in optical imaging to apply fluence correction to PA images, enhancing accessibility of quantitative PAI for researchers in various fields.
Memory control deficits in the sleep-deprived human brain
Authors: Harrington Marcus O. , Karapanagiotidis Theodoros , Phillips Lauryn , Smallwood Jonathan , Anderson Michael C. , Cairney Scott A.
Published: November 2023

Sleep disturbances are associated with intrusive memories, but the neurocognitive mechanisms underpinning this relationship are poorly understood. Here, we show that an absence of sleep disrupts prefrontal inhibition of memory retrieval, and that the overnight restoration of this inhibitory mechanism is predicted by time spent in rapid eye movement (REM) sleep. The functional impairments arising from sleep loss are linked to a behavioural deficit in the ability to suppress unwanted memories, and coincide with a deterioration of deliberate patterns of self-generated thought. We conclude that sleep deprivation gives rise to intrusive memories via the disruption of neural circuits governing mnemonic inhibitory control, which may rely on REM sleep.
Hypoxia evokes a sequence of raphe-pontomedullary network operations for inspiratory drive amplification and gasping
Authors: Nuding Sarah C. , Segers Lauren S. , Iceman Kimberly E. , O’Connor Russell , Dean Jay B. , Valarezo Pierina A. , Shuman Dale , Solomon Irene C. , Bolser Donald C. , Morris Kendall F. , Lindsey Bruce G.
Published: November 2023

Hypoxia can trigger a sequence of breathing-related behaviors, from tachypnea to apneusis to apnea and gasping, an autoresuscitative behavior that, via large tidal volumes and altered intrathoracic pressure, can enhance coronary perfusion, carotid blood flow, and sympathetic activity, and thereby coordinate cardiac and respiratory functions. We tested the hypothesis that hypoxia-evoked gasps are amplified through a disinhibitory microcircuit within the inspiratory neuron chain and a distributed efference copy mechanism that generates coordinated gasp-like discharges concurrently in other circuits of the raphe-pontomedullary respiratory network. Data were obtained from 6 decerebrate, vagotomized, neuromuscularly-blocked, and artificially ventilated adult cats. Arterial blood pressure, phrenic nerve activity, end-tidal CO2, and other parameters were monitored. Hypoxia was produced by ventilation with a gas mixture of 5% O2in nitrogen (N2). Neuron spike trains were recorded at multiple pontomedullary sites simultaneously and evaluated for firing rate modulations and short-time scale correlations indicative of functional connectivity. Experimental perturbations evoked reconfiguration of raphe-pontomedullary circuits during tachypnea, apneusis and augmented bursts, apnea, and gasping. The functional connectivity, altered firing rates, efference copy of gasp drive, and coordinated step increments in blood pressure reported here support a distributed brain stem network model for amplification and broadcasting of inspiratory drive during autoresuscitative gasping that begins with a reduction in inhibition by expiratory neurons and an initial loss of inspiratory drive during hypoxic apnea.
The trade-off between growth and risk in Kelly’s gambling and beyond
Authors: Cavallero S. , Rousselot A. , Pugatch R. , Dinis L. , Lacoste D.
Published: November 2023

We study a generalization of Kelly’s horse model to situations where gambling on horses other than the winning horse does not lead to a complete loss of the investment. In such a case, the odds matrix is non-diagonal, a case which is of special interest for biological applications. We derive a trade-off for this model between the mean growth rate and the volatility as a proxy for risk. We show that this trade-off is related to a game-theoretic formulation of this problem developed previously. Since the effect of fluctuations around the average growth rate is asymmetric, we also study how the risk-growth trade-off is modified when risk is evaluated more accurately by the probability of the gamble’s ruin.
Quantification of healthspan in aging mice: Introducing FAMY and GRAIL
Authors: Lamming Dudley W.
Published: November 2023

The population around the world is graying, and as many of these individuals will spend years suffering from the burdens of age associated diseases, understanding how to increase healthspan, defined as the period of life free from disease and disability, is an urgent priority of geroscience research. The lack of agreed-upon quantitative metrics for measuring healthspan in aging mice has slowed progress in identifying interventions that do not simply increase lifespan, but also healthspan. Here, we define FAMY (Frailty-Adjusted Mouse Years) and GRAIL (Gauging Robust Aging when Increasing Lifespan) as new summary statistics for quantifying healthspan in mice. FAMY integrates lifespan data with longitudinal measurements of a widely utilized clinical frailty index, while GRAIL incorporates these measures and also adds information from widely utilized healthspan assays and the hallmarks of aging. Both metrics are conceptually similar to quality-adjusted life years (QALY), a widely-utilized measure of disease burden in humans, and can be readily calculated from data acquired during longitudinal and cross-sectional studies of mouse aging. We find that interventions generally thought to promote health, including calorie restriction, robustly improve healthspan as measured by FAMY and GRAIL. Finally, we show that the use of GRAIL provides new insights, and identify dietary restriction of protein or isoleucine as interventions that robustly promote healthspan but not longevity in female HET3 mice. We suggest that the routine integration of these measures into studies of aging in mice will allow the identification and development of interventions that promote healthy aging even in the absence of increased lifespan.
Using Multivariate Pattern Analysis to Increase Effect Sizes for Event-Related Potential Analyses
Authors: Carrasco Carlos Daniel , Bahle Brett , Simmons Aaron Matthew , Luck Steven J.
Published: November 2023

Multivariate pattern analysis approaches can be applied to the topographic distribution of event-related potential (ERP) signals to ‘decode’ subtly different stimulus classes, such as different faces or different orientations. These approaches are extremely sensitive, and it seems possible that they could also be used to increase effect sizes and statistical power in traditional paradigms that ask whether an ERP component differs in amplitude across conditions. To assess this possibility, we leveraged the open-source ERP CORE dataset and compared the effect sizes resulting from conventional univariate analyses of mean amplitude with two multivariate pattern analysis approaches (support vector machine decoding and the cross-validated Mahalanobis distance, both of which are easy to compute using open-source software). We assessed these approaches across seven widely studied ERP components (N170, N400, N2pc, P3b, lateral readiness potential, error related negativity, and mismatch negativity). Across all components, we found that multivariate approaches yielded effect sizes that were as large or larger than the effect sizes produced by univariate approaches. These results indicate that researchers could obtain larger effect sizes, and therefore greater statistical power, by using multivariate analysis of topographic voltage patterns instead of traditional univariate analyses in many ERP studies.
Distinct and interdependent functions of three RING proteins regulate recombination during mammalian meiosis
Authors: Ito Masaru , Yun Yan , Kulkarni Dhananjaya S , Sandhu Sumit , Nunez Briana , Hu Linya , Lee Kevin , Lim Nelly , Hirota Rachel , Prendergast Rowan , Huang Cynthia , Huang Ivy , Hunter Neil
Published: November 2023

During meiosis, each pair of homologous chromosomes becomes connected by at least one crossover, as required for accurate segregation, and adjacent crossovers are widely separated thereby limiting total numbers. In coarsening models, this crossover patterning results from nascent recombination sites competing to accrue a limiting pro-crossover RING-domain protein (COR) that diffuses between synapsed chromosomes. Here we delineate the localization dynamics of three mammalian CORs in mouse and determine their interdependencies. RNF212, HEI10 and a new member RNF212B show divergent spatiotemporal dynamics along synapsed chromosomes, including profound differences in spermatocytes and oocytes, that are not easily reconciled by elementary coarsening models. Contrasting mutant phenotypes and genetic requirements indicate that RNF212B, RNF212, and HEI10 play distinct but interdependent functions in regulating meiotic recombination and coordinating the events of meiotic prophase-I by integrating signals from DNA breaks, homolog synapsis, the cell-cycle, and incipient crossover sites.