bluuebunny/crossref_metadata_2025 huggingface dataset:
TMIC-66. SPATIALLY RESOLVED METABOLIC INTERACTIONS IN THE GBM MICROENVIRONMENT
Authors: Chakraborty Avirup , Feier Diana , Silver Aryeh , Yang Changlin , Fu Dongtao , Rahman Maryam , Sarkisian Matthew , Huang Jianping , Harrison Jeffrey , Mitchell Duane , Deleyrolle Loic
Published: November 2023

Glioblastoma (GBM) contains cell populations with distinct metabolic requirements, with fast-cycling cells (FCCs) harnessing aerobic glycolysis, and treatment-resistant slow-cycling cancer stem cells (SCCs) preferentially engaging in lipid metabolism. The interaction between immune and tumor cells, and how tumor metabolic heterogeneity shapes the immune landscape in GBM has yet to be understood. Our study allows for the molecular and spatial decoding of the heterogeneity within the GBM microenvironment, with a specific focus on unraveling the metabolic links that underlie the interplay between SCCs and the immune compartment. Our work indicates a new paradigm of communication in the TME of GBM, where SCCs play a pivotal role in shifting the tumor milieu toward an immunosuppressive phenotype, in part by recruiting specific tumor-promoting immune cells that stimulate SCC-driven tumor progression and provide metabolic support to these treatment-resistant cells. Our study delineates these metabolic communications and assesses the potential therapeutic effect of disrupting these interactions to treat GBM. The insights generated from this project uncover fundamental principles of the emerging connections between the tumor microenvironment, cell metabolism, anti-tumor immunity, and associated therapeutic vulnerabilities. In conclusion, our study provides a novel understanding of the role of metabolic interactions in the development of drug and immune resistant GBM. These findings suggest that targeting metabolic interactions, specifically between SCCs and tumor-associated immune suppressive cells, may be a promising therapeutic strategy for GBM.
TMIC-82. SPATIAL AND SINGLE-CELL PROTEOMIC LANDSCAPING OF THE HYPOXIC MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Mansouri Sheila , Gandhi Shreya , Zaidi Mark , Singh Olivia , Karimi Shirin , Lombard Phoebe , Dvorkin-gheva Anna , Valesquez Carlos , Ali Hafsah , Devaraja Kaviya , Sosa Julio , Patil Vikas , Wei Qinxqia , Wu Ronald , Li Mira , Cheung May , Voisin Mathew , Gao Andrew , Hedley David , Aldape Kenneth , Wouters Bradley , Zadeh Gelareh
Published: November 2023

Glioblastoma (GBM) is a fatal adult solid tumour with median overall survival of 18-20 months post-diagnosis; contributing factors to therapeutic inefficacy include acquisition of genomic alterations post-therapy, immune evasion, deregulated hypervascularization, and tumor microenvironmental factors such as hypoxia. Combined with extensive inter- and intra-tumoral heterogeneity at bulk and single-cell level, hypoxia contributes to a gradient of molecular alterations that are specific to different cell populations that make up tumour bulk and reside in specific niches. Hitherto, high-dimensional histopathologic analyses of hypoxic regions within GBM tissue have not been performed. We took a combined spatial and single-cell proteomic profiling approach to investigate the histopathologic features of hypoxia by leveraging a unique clinical study wherein the exogenous hypoxia marker, pimonidazole (PIMO), was administered to GBM-patients preoperatively. Tissue specimens were subjected to imaging mass cytometry, high-resolution imaging, and serial immunohistochemistry using a panel of markers associated with cellular hallmarks of hypoxia, metabolism, proliferation, stemness, angiogenesis, and immune cell types. Our findings showed that PIMO staining is associated with histopathologic features of hypoxia and correlates with specific metabolic, immune, and stemness markers in GBM; specific lymphocyte populations were depleted from hypoxic regions alongside alterations in macrophagic and microglial landscape in a niche-specific manner; hypoxia reduced the proportion of proliferating glioma initiating cells and altered the proliferative, transcriptional, and translational capacity of different cell populations; microvessel density was reduced in hypoxic microenvironment. Cytometry by time-of-flight further validated the altered proportions of specific immune cell types enriched in hypoxic populations of GBM microenvironment. Our study is the first to report use of PIMO to interrogate spatial, single-cell, and phenotypic architecture associated with tissue hypoxia and altered expression of biomarkers associated with hypoxia/glycolysis, immune infiltration, proliferation, and stemness. Identification of targetable biomarkers and mediators of hypoxia-driven habitats in GBM may provide direction for future immunotherapeutic research.
TMIC-86. SPATIAL ORGANIZATION OF THE PEDIATRIC HIGH-GRADE GLIOMA TUMOR-IMMUNE LANDSCAPE
Authors: van den Broek Thijs , Hoogendijk Raoull , Kranendonk Mariëtte , Ruiz Cristian , Megchelenbrink Wout L , Lammers Julie , Ries Mario G , Hoving Eelco , van der Lugt Jasper , Rios Anne C , Stunnenberg Hendrik , van Vuurden Dannis , Zomer Anoek
Published: November 2023

BACKGROUND

Advances in cellular immunotherapies have shown promising results for brain tumors, including pediatric-type diffuse high-grade gliomas (pHGG). A comprehensive understanding of the tumor-immune microenvironment (TME) is essential for efficient target identification and novel therapeutic strategies. The interplay between cells and their spatial localization within the TME may affect immune cell phenotype and function. We characterized these interactions and phenotypes by single-cell (SC) spatial proteomic analysis.

METHODS

Thirty-two tissue biopsies of pHGGs were collected from the Princess Máxima Center biobank consisting of 14 diffuse midline gliomas, H3K27-altered (DMG) and 18 other pHGGs. Three cores per biopsy were assembled in a tissue micro-array (TMA). A cyclical multiplex immunofluorescence antibody staining technique by means of chemical antibody-removal was applied to the TMA sections. This resulted in hyperplexed images enabling detailed mapping of the spatial organization. Survival data of patients was collected retrospectively. Clusters of interacting cells were detected using cellular neighborhood (CN) analysis and SC distance analysis.

RESULTS

SC analysis revealed a large fraction of myeloid cells in the TME, up to 21% of total cells within a tumor, characterized by expression of IBA1 and CD68. We also identified some significant differences in the composition and spatial organization of DMGs compared to other pHGGs. More specifically, DMG biopsies showed lower abundance of CD163+/CD206+ immunosuppressive myeloid cells compared to other pHGGs (p< 0.001). Additionally, the presence of T cells was significantly lower in DMGs compared to other pHGGs (p< 0.001). CN analysis revealed a higher occurrence of myeloid/astrocyte-like neighborhoods in pHGGs other than DMG. The presence of this cluster in these tumors is associated with higher risk of dying (p< 0.05). Thus, the combination of our spatial proteomic SC technology framework and unique patient sample collection will offer essential insights into the cellular interplay in the TME, and its influence on patient outcomes.
MODL-04. ESTABLISHMENT OF TUMOR MICROENVIRONMENT-PRESERVING ORGANOID MODEL FROM PATIENTS WITH INTRACRANIAL MENINGIOMA
Authors: Ahn Stephen
Published: November 2023

Although meningioma is the most common primary brain tumor, treatments depend only on the surgery and radiotherapy, and recurrent meningiomas have no standard therapeutic options due to a lack of clinically relevant research models. Current meningioma cell lines or organoids cannot reflect biological features of patients’ tumors since they undergo transformation along culture and consist of only tumor cells without microenvironment. Here, we firstly established patient-derived meningioma organoids (MNOs) preserving diverse cell types of tumor microenvironment, including endothelial cells and macrophage/microglia cells. Exclusion of the enzymatic dissociation-reaggregation steps endowed MNOs with original histology and tumor microenvironment. In addition, we used liquid media culture system instead of embedding into Matrigel, thus easy-to-handle, cost-efficient, and time-saving. MNOs maintained their functionality and morphology after long-term culture ( > 9 wk) and repeated cryopreserving-recovery cycles. The similarity between MNOs and their corresponding parental tumors were confirmed by both immunohistochemistry and whole-exome sequencing. As a representative application, we utilized MNOs in drug screening, and mifepristone, an antagonist of progesterone receptor, showed prominent antitumor efficacy in respect to viability, invasiveness, and protein expression. Taken together, our MNO model overcame limitations of previous meningioma models and showed superiority in terms of resemblance with parental tumors. Thus, we expect that our model can facilitate translational research of identifying and selecting drugs for meningioma in the era of precision medicine.
MODL-14. IMAGING, HISTOLOGICAL AND MOLECULAR CHARACTERIZATION AND COMPARISON OF POST-ABLATION RECURRENT TUMOR WITH THE PRIMARY TUMOR IN A PRECLINICAL GLIOBLASTOMA MODEL
Authors: Nagaraja Tavarekere , Datta Indrani , Morosini Natalia , Bartlett Seamus , Ayloo Bhargav , Cabral Glauber , Avritt Faith , Hasselbach Laura , Parasar Parveen , deCarvalho Ana , Singh Jaspreet , Knight Robert , Brown Stephen , Ewing James , Noushmehr Houtan , Lee Ian
Published: November 2023

Recurrent glioblastoma (rGBM) is highly aggressive and invasive. A reliable preclinical model that recapitulates these features is not presently available. The objective was to generate a preclinical rGBM model, characterize and compare its imaging, histological and molecular signatures in comparison to the primary tumor. Immune-suppressed, RNU/RNU female rats were implanted with U251N tumor cells in one brain hemisphere (n=33). Tumor progression in all rats was followed by longitudinal dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI). In 24 rats the tumor was ablated under diffusion-weighted imaging (DWI)-guided laser interstitial thermal therapy (LITT) at post-implantation 2-weeks. Cohorts from twenty ablated rats were euthanized at post-LITT 24 h, 2- and 4-weeks and, along with 5 unablated controls, used for hematoxylin and eosin (H&E) and Ki67 staining. Tissues from 4 other unablated and 4 recurrent tumors at post-LITT 2-weeks were used for RNAseq. All the rats survived the LITT procedure. Unablated controls showed increased tumor burden by post-implantation 2 weeks and were euthanized. In the LITT group, MRI showed little tumor tissue at 24 h, evidence of recurrence at 2 weeks and significant tumor tissue at 4 weeks and matched with histological evidence for tumor recurrence. Compared to the primary tumor, H&E staining showed increased vascular hyperplasia, mitotic bodies and hypoxic regions with pseudopalisading necrosis in the recurrent tumor. Increased KI67 staining in recurrent tumors suggested higher rates of proliferation and evidence of infiltration into host tissue. Pathway analyses demonstrated differentially expressed genes in the canonical pathways of hypoxia-inducible factor-alpha (HIF-1α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and OX40 signaling. The genes for the following functions were significantly affected: cell cycle, cellular movement and cell morphology. Reliable preclinical rGBM models are few. These data suggest that this model replicates the features of human rGBM and can be useful in testing putative anti-glioma therapies.
MODL-30. UTILIZING SERUM-FREE CO-CULTURE MODELS FOR IN-VITRO MODELING OF TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA
Authors: Alrefai Hasan , Kumar Manoj , Nassour Lauren , Schanel Taylor , Beierle Andee , Anderson Joshua , Hicks Patricia , Willey Christopher
Published: November 2023

BACKGROUND

The GBM tumor microenvironment consists of various cancerous and non-cancerous cells that influence GBM growth, invasion, angiogenesis, and resistance to chemoradiation. In-vitro models of GBM often lack multiple cell types. Some addressed this by using multicellular models with macrophages and astrocytes; however, these models employ serum-containing media, which causes GBM brain-tumor initiating cells to lose their stem-like properties. Moreover, these models use IL-4/13 polarized macrophages (M2), despite tumor-associated macrophages (TAMs) not adhering to the M2 phenotype. Thus, there is a need to develop physiologically accurate in-vitro models of GBM.

METHODS

We transitioned THP-1 monocytes from serum-containing RPMI 1640 to serum-free TheraPEAKTM X-VIVOTM-15 media. Monocytes were stimulated towards a macrophage-like state with PMA and polarized by co-culturing with GBM patient-derived xenograft (PDX) lines using transwell inserts. Macrophage polarization was characterized through cytokine arrays, invasion, angiogenesis, and phagocytosis assays, comparing them to resting (M0), pro-inflammatory (M1), and M2 macrophages.

RESULTS

THP-1 monocytes grown in X VIVO-15 media exhibited similar proliferation rates to those in RPMI 1640 for up to 48 hours. However, at 72 hours, there was a slight decrease in proliferation rates in X VIVO-15 media (p< 0.0001). Macrophages polarized by the GBM PDX line, JX39P-RT, did not exhibit the cytokine expression profile of any other group. M2 macrophages displayed higher phagocytic capacity (25%) of JX39P-RT compared to M0, M1, and TAMs (< 15%, p< 0.01). M1 macrophages showed significantly higher invasion rates than M0, M2, and JX39P-polarized TAMs.

CONCLUSIONS

We have demonstrated a serum-free method by which we can polarize macrophages towards a GBM-supportive phenotype that differs molecularly and functionally from M0, M1, and M2 macrophages. This high-fidelity method of modeling TAMs in GBM will aid in the development and testing of innate immunomodulatory therapeutics that may one day enter the clinic in hopes of improving GBM outcomes
MODL-35. BIOENGINEERED HYDROGEL AND BLOOD BRAIN BARRIER-ON-A-CHIP SYSTEM TO STUDY GLIAL CELL ACTIVATION AND BLOOD BRAIN BARRIER DYSFUNCTION IN GLIOBLASTOMA
Authors: dePalma Thomas , Hughes Kennedy , Fraas David , Tawfik Marie , Hisey Colin , Skardal Aleksander
Published: November 2023

Treatments for glioblastoma (GBM) are limited leading to short patient life expectancies after diagnosis. Current preclinical models of GBM fail to accurately replicate the function of the blood brain barrier (BBB) and the extreme heterogeneity of the GBM tumor hindering the drug development process. Therefore, there is a pressing need for improved model systems to study how different GBM subpopulations interact with glial cells and the BBB. To build such a model, we first focused on designing a 3D extracellular matrix-based hydrogel biomaterial that would support human astrocytes and a functional BBB. The hydrogel chosen for these studies is composed of functionalized hyaluronic acid (HA) and gelatin and has similar mechanical properties to the human brain. Using confocal imaging and qPCR, we have shown that astrocytes encapsulated in this hydrogel have greater branching and express fewer markers of activation compared to astrocytes grown in commonly used 3D biomaterials such as collagen I and Matrigel. Treatment with inflammatory cytokines and GBM cell derived extracellular vesicles (EVs) revealed that astrocytes in this environment display the activation and inflammatory phenotypes observed in vivo in GBM. Next, this hydrogel biomaterial was deployed in a bioengineered BBB-on-a-chip. We have shown that this system supports the formation of 3D microvessel structures with human brain endothelial cells, pericytes, and astrocytes that accurately mimic the function of the human BBB. Studies using this BBB-on-a-chip have shown that invasive glioma stem cells alter BBB permeability influencing the transport of certain therapeutics to the tumor site. We are now beginning to test how various subpopulations of GBM tumor cells behave in this model and how changes to glial cells and the BBB impact drug delivery and efficacy. This study shows that engineered in vitro models can provide critical insight into disease mechanisms and inform treatment design in GBM.
MODL-45. UNDERSTANDING OLIGODENDROCYTE PROGENITOR CELL CONTRIBUTION TO GLIOMAGENESIS USING A NOVEL PHARMACOGENETIC ABLATION TOOL
Authors: Xing Lulu , Lancero Hope , Hambardzumyan Dolores , Merson Tobias , Petritsch Claudia
Published: November 2023

In the central nervous system (CNS), gliomas represent almost 50% of all pediatric tumors and due to their complex histological and biological heterogeneity, aggressive standard treatment consisting of surgery and chemoradiotherapy remains ineffective. As a result, more biologically based therapies are urgently needed and this requires a deeper knowledge of the etiology and biology of gliomas, which can arise from oligodendrocyte progenitor cells (OPCs). OPCs are the most proliferative cell type in the CNS, and upon oncogenic mutations in OPCs, they exhibit defective asymmetric divisions with a concomitant increase in symmetrical renewal, leading to aberrant growth of OPCs prior to malignancy. Although OPC-like cells frequently found in human glioma significantly contribute to tumor heterogeneity and malignancy, how resident tumor-infiltrating OPCs functionally integrate into the tumor cell networks within the tumor microenvironment remains unknown. However, in order to address this critical gap in knowledge of the field, a novel mouse model of conditional OPC ablation must be used to overcome methodological challenges of most current approaches that often result in partial and transient OPC ablation, which limits our understanding of long-term function of OPCs. Here, we have successfully developed a novel pharmacogenetic model of conditional OPC ablation, eliminating 98.6% of all OPCs throughout the mouse brain for up to 12 days post ablation. This novel mouse model of complete OPC ablation can be combined with intracranial injection of tumor cells in order to reveal the longitudinal and spatial functional roles and the necessity for resident OPCs in the tumor context. Understanding the OPC-tumor cell crosstalk by using our state-of-the-art approach at both cellular and molecular levels will have significant clinical implications for improving treatment for patients with pediatric gliomas.
MODL-49. NEW MURINE GLIOBLASTOMA STEM-LIKE CELL MODELS
Authors: Kardani Kimia , Ghouse Shanawaz Mohammed , Hara Toshiro , Soda Yasushi , Stemmer-Rachamimov Anat , Wakimoto Hiroaki , Rabkin Samuel
Published: November 2023

BACKGROUND

There is a dearth of mouse glioblastoma (GBM) preclinical models in immunocompetent mice for the development of immunotherapeutic agents. In this study, we characterized five murine GBM stem-like cell (GSC) models derived from lentivirus induced tumors in transgenic mice that are driven by the activation of the Nf1-Ras MAP kinase signalling pathway due to HRasV12 or NF1 shRNA, and inactivation of Tp53.

METHODS

Murine GSC lines, 005, NF53, RIG, C1, and C3, were cultured as spheres in serum-free stem cell media. Whole exome sequencing (WES) was conducted to quantify single nucleotide polymorphisms (SNPs) using the C57BL/6J genome as reference. Stem cell properties were characterized by in vitro assays and tumorigenicity was examined by intracerebral implantation into C57BL/6 mice. Brain tissues were processed for histological analysis, such as immunohistochemistry, or for FACS to examine markers of stemness and tumor-infiltrating immune cells.

RESULTS

WES identified a large variation in coding sequence SNPs, likely due to the mixed backgrounds of the parental mice, with 005 having the highest number of SNPs, and C1 and C3 the lowest. All GSC lines were capable of clonogenic sphere formation, indicative of self-renewal, and showed varying levels of cell surface CD133. In vivo, all the GSCs efficiently established tumors that were histologically consistent with malignant glioma with strong CD44 expression. Median survival varied, ranging from 27 days (005) to 82 days (C1), upon 20,000-cell implantation. CD68+ macrophages were consistently dominant in the tumor microenvironment, while C1 and C3 exhibited fewer CD4+ and CD8+ T cells.

CONCLUSIONS

Despite the similar molecular strategy used to generate these GBMs, we observed a range of tumor phenotypes and immune microenvironmental profiles. These models can serve as valuable tools for studying GBM biology and exploring immunotherapeutic strategies. Keywords: Glioblastoma, glioblastoma stem-like cell (GSC), genetically engineered mouse models, Tumor microenvironment.
Longitudinal characteristics of T2-FLAIR mismatch in IDH-mutant astrocytomas: Relation to grade, histopathology, and overall survival in the GLASS-NL cohort
Authors: van Garderen Karin A , Vallentgoed Wies R , Lavrova Anna , Niers Johanna M , de Leng Wendy W J , Hoogstrate Youri , de Heer Iris , Ylstra Bauke , van Dijk Erik , Klein Stefan , Draaisma Kaspar , Robe Pierre A J T , Verhaak Roel G W , Westerman Bart A , French Pim J , van den Bent Martin J , Kouwenhoven Mathilde C M , Kros Johan M , Wesseling Pieter , Smits Marion
Published: November 2023

Background

The T2-FLAIR mismatch sign is defined by signal loss of the T2-weighted hyperintense area with Fluid-Attenuated Inversion Recovery (FLAIR) on magnetic resonance imaging, causing a hypointense region on FLAIR. It is a highly specific diagnostic marker for IDH-mutant astrocytoma and is postulated to be caused by intercellular microcystic change in the tumor tissue. However, not all IDH-mutant astrocytomas show this mismatch sign and some show the phenomenon in only part of the lesion. The aim of the study is to determine whether the T2-FLAIR mismatch phenomenon has any prognostic value beyond initial noninvasive molecular diagnosis.

Methods

Patients initially diagnosed with histologically lower-grade (2 or 3) IDH-mutant astrocytoma and with at least 2 surgical resections were included in the GLASS-NL cohort. T2-FLAIR mismatch was determined, and the growth pattern of the recurrent tumor immediately before the second resection was annotated as invasive or expansive. The relation between the T2-FLAIR mismatch sign and tumor grade, microcystic change, overall survival (OS), and other clinical parameters was investigated both at first and second resection.

Results

The T2-FLAIR mismatch sign was significantly related to Grade 2 (80% vs 51%), longer post-resection median OS (8.3 vs 5.2 years), expansive growth, and lower age at second resection. At first resection, no relation was found between the mismatch sign and OS. Microcystic change was associated with areas of T2-FLAIR mismatch.

Conclusions

T2-FLAIR mismatch in IDH-mutant astrocytomas is correlated with microcystic change in the tumor tissue, favorable prognosis, and Grade 2 tumors at the time of second resection.
Comparison of Publications on Heated Tobacco Products With Conventional Cigarettes and Implied Desirability of the Products According to Tobacco Industry Affiliation: A Systematic Review
Authors: Suzuki Harumitsu , Aono Naoki , Zhang Yan , Yuri Kuniko , Bassole Epse Brou Maggy Audrey Murielle , Takemura Shigeki , Higashiyama Aya , Tabuchi Takahiro , Fujiyoshi Akira
Published: November 2023

Introduction

Heated tobacco products (HTPs) have been advertised as “reduced-harm” tobacco products compared to conventional cigarettes (CC); however, no direct evidence supporting HTPs being desirable for human health exists. A previous systematic review reported that evidence on HTPs published in 2017 or earlier was primarily drawn from industry-related papers. We aimed to investigate whether tobacco industry-affiliated studies are more likely to conclude that HTPs are more desirable than CC.

Methods

PubMed and Ichushi-Web were searched up to March 15, 2022, for studies on HTPs published in 2017 or after. We selected studies that assessed any measures of HTPs and CC, including secondary analyses using gray literature in English or Japanese. We excluded review articles except for a meta-analysis that met the aforementioned criteria. Data on the authors’ affiliations, grant, conflict of interest, category of research subjects, and interpretation were extracted. Research members in two groups independently assessed the papers; discrepancies were solved by discussion between the groups.

Results

Overall, 134 studies met the criteria. Eighty-seven (64.9%) of them were affiliated with the tobacco industry. Of the 134 studies, 56.3% (49/87) of the industry-affiliated studies versus 19.1% (9/47) of nonindustry-affiliated studies concluded that HTPs were more desirable than CC (p < .01). No study investigated clinically relevant outcomes, such as disease occurrence.

Conclusions

Publications on HTPs in the biomedical literature from January 2017 to March 2022 were dominated by tobacco industry-affiliated studies. More than half of them concluded that HTPs were more desirable than CC compared to independent studies.

Implications

Tobacco industry advertises HTPs as “reduced-harm” tobacco products compared to CC. HTP users tend to consider HTPs as alternative tobacco products less harmful than CC (ie, products for “harm reduction”). Our results demonstrated that papers written by tobacco industry-affiliated authors concluded that HTPs were more desirable than CC compared to papers by independent authors. However, all their judgments were based on surrogate outcomes. Surrogate outcomes are not necessarily linked to clinically relevant outcomes such as disease occurrence. Further studies on HTPs using clinically relevant outcomes are warranted by independent authors from tobacco industry.
Predictors of Detectable Viremia, Outcomes, and Implications for Management of People Living With HIV Who Are Receiving Antiretroviral Therapy in Southern Nigeria
Authors: Akpan Uduak U , Nwanja Esther N , Badru Titilope , Toyo Otoyo E , Idemudia Augustine M , Sanwo Olusola , Okeke Pius Nwaokoro , Gana Bala , Idem Saade , Idiong Helen M , Khamofu Hadiza G , Bateganya Moses H
Published: November 2023

Background

This study examined the prevalence and factors associated with detectable viremia, as well as clinical outcomes among people with HIV (PWH) receiving antiretroviral therapy (ART) who initially achieved viral suppression in 2 southern states in Nigeria.

Methods

The retrospective cohort study used data from the electronic medical records of 96 comprehensive ART centers. PWH were followed up who achieved viral suppression (viral load [VL] ≤50 copies/mL) upon starting ART based on the first VL test. We examined the presence of detectable viremia in follow-up VL results, graded by the absolute VL count from the second and third consecutive VL tests as follows: transient viremia (second follow-up VL, 51–999 copies/mL; third, ≤50 copies/mL), persistent viremia (second follow-up VL, 51–999 copies/mL or ≥1000 copies/mL; third, >50 copies/mL), and virologic failure (second and third follow-up VL, >1000 copies/mL). We analyzed demographic and clinical factors associated with detectable viremia using logistic regression analysis on Stata 14.

Results

Overall, 15 050 PWH had achieved viral suppression following ART initiation (median age, 34 years; 71.3% female). On follow-up, 3101 (20.6%) had a viremic event: 11.6%, transient viremia; 8.8%, persistent viremia; 0.2%, virologic failure. Shorter duration of ART (P < .001), being 0 to 14 years of age (P < .001), and not being enrolled in a differentiated service delivery model (P < .001) were significantly associated with detectable viremia.

Conclusions

Our study shows that people who initially attain vial suppression upon starting ART remain at risk of detectable viremia.
A New England?
Authors: Searle G R
Published: November 2023

G. R. Searle's absorbing narrative history breaks conventional chronological barriers to carry the reader from England in 1886, the apogee of the Victorian era with the nation poised to celebrate the empress queen's golden jubilee, to 1918, as the 'war to end all wars' drew to a close leaving England to come to terms with its price - above all in terms of human life, but also in the general sense that things would never be the same again. This was an age of extremes: a period of imperial pomp and circumstance, with a political elite preoccupied with display and ceremony, alongside the growing cult of the simple life; the apogee of imperialism with its idealization of war on the one hand, the start of the Labour Party, a socialist renaissance, and welfare politics on the other; and a radical challenging of traditional gender stereotypes in the face of the prevailing cult of masculinity. Under Professor Searle's historical microscope, all the details of daily life spring into sharp relief. Half-forgotten figures such as Edward Carpenter, Vesta Tilley, and Edward Carson take their place on stage beside Oscar Wilde, the Pankhursts and Lloyd George. Motoring and aviation, to become such an intrinsic part of life within the next decades, had their beginnings in this period as pastimes for the rich. From the wretched slums of England's great cities to their bustling docks and factories, from the grand portals of Westminster to the violent political challenges of the Ulster Unionists and the militant suffrage movement, from Blackpool's tower and beach packed with holidaymakers to the trenches of the Western Front, the energy, creativity, and often destructive turmoil of the years 1886-1918 are brought into focus in this magisterial history. THE NEW OXFORD HISTORY OF ENGLAND The aim of the New Oxford History of England is to give an account of the development of the country over time. It is hard to treat that development as just the history which unfolds within the precise boundaries of England, and a mistake to suggest that this implies a neglect of the histories of the Scots, Irish, and Welsh. Yet the institutional core of the story which runs from Anglo-Saxon times to our own is the story of a state-structure built round the English monarchy and its effective successor, the Crown in Parliament. While the emphasis of individual volumes in the series will vary, the ultimate outcome is intended to be a set of standard and authoritative histories, embodying the scholarship of a generation.
Intuition, Iteration, Induction
Authors: van Atten Mark
Published: November 2023

Brouwer’s view on induction has relatively recently been characterised as one on which it is not only intuitive (as expected) but functional, by van Dalen. He claims that Brouwer’s ‘Ur-intuition’ also yields the recursor. Appealing to Husserl’s phenomenology, I offer an analysis of Brouwer’s view that supports this characterisation and claim, even if assigning the primary role to the iterator instead. Contrasts are drawn to accounts of induction by Poincaré, Heyting, and Kreisel. On the phenomenological side, the analysis provides an alternative to that in Tieszen’s Mathematical Intuition, and confirms a view of Gödel on his Dialectica Interpretation.
Arabidopsis TETRASPANIN8 mediates exosome secretion and glycosyl inositol phosphoceramide sorting and trafficking
Authors: Liu Ningjing , Hou Lipan , Chen Xin , Bao Jingjing , Chen Fangyan , Cai Wenjuan , Zhu Huixian , Wang Lingjian , Chen Xiaoya
Published: November 2023

Sphingolipids are components of plant membranes, and their heterogeneous distribution gives different membrane systems distinct properties. For example, glycosyl inositol phosphoceramides (GIPCs), 1 major type of sphingolipids, aggregate in the outer layer of the plasma membrane (PM), as well as in extracellular vesicles (EVs), including the small (30 to 100 nm) EVs termed exosomes. How these sphingolipids are sorted and trafficked is not clear. In this work, we report that Arabidopsis thaliana TETRASPANIN8 (TET8) acts as a sphingolipid carrier and thus regulates the export of GIPCs from the Golgi apparatus. TET8 recognized the coat protein complex I (COPI) subunit γ2-COPI and moved to its proper location in the PM; this recognition required the TET8 C-terminal tail. Deleting the C-terminal tail of TET8 largely restricted its roles in GIPC transport and endosomal trafficking. Further, we show that TET8 affects EV secretion in association with GIPCs. Thus, our findings shed light on GIPC transport and the molecular machinery involved in EV biogenesis.
Long small RNA76113 targets CYCLIC NUCLEOTIDE-GATED ION CHANNEL 5 to repress disease resistance in rice
Authors: Zheng Liyu , Yu Yiyang , Zheng Ying , Wang Yaxin , Wu Na , Jiang Chunhao , Zhao Hongwei , Niu Dongdong
Published: November 2023

Small RNAs are widely involved in plant immune responses. However, the role of long small RNAs (25 to 40 nt) in monocot plant disease resistance is largely unknown. Here, we identified a long small RNA (lsiR76113) from rice (Oryza sativa) that is downregulated by Magnaporthe oryzae infection and targets a gene encoding CYCLIC NUCLEOTIDE-GATED CHANNEL 5 (CNGC5). The cngc5 mutant lines were more susceptible to M. oryzae than the wild type, while knocking down lsiR76113 in transgenic rice plants promoted pathogen resistance. A protoplast transient expression assay showed that OsCNGC5 promotes Ca2+ influx. These results demonstrate that OsCNGC5 enhances rice resistance to rice blast by increasing the cytosolic Ca2+ concentration. Importantly, exogenous Ca2+ application enhanced rice M. oryzae resistance by affecting reactive oxygen species (ROS) production. Moreover, cngc5 mutants attenuated the PAMP-triggered immunity response, including chitin-induced and flg22-induced ROS bursts and protein phosphorylation in the mitogen-activated protein kinase cascade, indicating that OsCNGC5 is essential for PAMP-induced calcium signaling in rice. Taken together, these results suggest that lsiR76113-mediated regulation of Ca2+ influx is important for PTI responses and disease resistance in rice.
Goblet cell interactions reorient bundled mucus strands for efficient airway clearance
Authors: Bos Meike F , Ermund Anna , Hansson Gunnar C , de Graaf Joost
Published: November 2023

The respiratory tract of larger animals is cleared by sweeping bundled strands along the airway surface. These bundled strands can be millimetric in length and consist of MUC5B mucin. They are produced by submucosal glands, and upon emerging from these glands, the long axis of the bundled strands is oriented along the cilia-mediated flow toward the oral cavity. However, after release, the bundled strands are found to have turned orthogonal to the flow, which maximizes their clearance potential. How this unexpected reorientation is accomplished is presently not well understood. Recent experiments suggest that the reorientation process involves bundled strands sticking to MUC5AC mucus threads, which are tethered to the goblet cells. Such goblet cells are present in small numbers throughout the airway epithelium. Here, we develop a minimal model for reorientation of bundled mucus strands through adhesive interactions with surface goblet cells. Our simulations reveal that goblet cell interactions can reorient the bundled strands within 10 mm of release—making reorientation on the length scale of the tracheal tube feasible—and can stabilize the orthogonal orientation. Our model also reproduces other experimental observations such as strong velocity fluctuations and significant slow-down of the bundled strand with respect to the cilia-mediated flow. We further provide insight into the strand turning mechanism by examining the effect of strand shape on the impulse exerted by a single goblet cell. We conclude that goblet cell–mediated reorientation is a viable route for bundled strand reorientation, which should be further validated in future experiment.
The Haunted Island: Medieval History and the Old English Elegies in Brenda Chamberlain’s Tide-race (1962)
Authors: Brooks Francesca
Published: November 2023

This article explores the relationship between Tide-race, a 1962 memoir by the Welsh poet and artist Brenda Chamberlain, and medieval culture and literature on Ynys Enlli. Written in the decades after the Second World War when Chamberlain had left mainland Wales, Tide-race is a memoir of the artist’s time on Enlli living with its small community of fishermen and farmers. In contrast to other works of twentieth-century island literature, I argue, Chamberlain rejected dominant, medieval patriarchal histories of Enlli, refusing to read the island as a male monastic site, or as a Welsh nationalist or cultural space. Tide-race is a medieval modern text that is deeply ambivalent about what medieval culture means for modern conceptions of identity, specifically Welshness and womanhood. Chamberlain’s late modernist work has been neglected because of her status as a Welsh woman writer working outside of the centres of modernism, and she has never been considered in the context of Medievalism Studies. By bringing archival material from the Brenda Chamberlain papers at the National Library of Wales together with the published memoir, this article brings to light an unremarked upon interest in Old English literature and traces the development of Chamberlain’s medievalism in the post-war period. Although her use of the Old English elegies—The Wanderer, The Seafarer and The Wife’s Lament—has remained unnoticed by Chamberlain’s critics, these early medieval poems are translated and adapted in her prose in ways that allow her to exorcize old grudges and challenge masculine ideals.
Clinical safety and narcolepsy-like symptoms of dual orexin receptor antagonists in patients with insomnia: a systematic review and meta-analysis
Authors: Na Hyun-jin , Jeon Nakyung , Staatz Christine E , Han Nayoung , Baek In-hwan
Published: November 2023

Study Objectives

Dual orexin receptor antagonists (DORAs) are emerging treatments for insomnia. This meta-analysis study aimed to assess the safety of FDA-approved DORAs (suvorexant, lemborexant, and daridorexant), focusing on narcolepsy-like symptoms associated with these drugs.

Methods

Five prominent databases were searched to identify randomized controlled trials (RCTs) on this topic. Primary safety outcomes included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Excessive daytime sleepiness (EDS), sleep paralysis, and hallucinations were categorized as adverse events (AEs)-related narcolepsy-like symptoms.

Results

Eleven RCTs with 7703 patients were included. DORAs were associated with a higher risk of TEAEs (risk ratio [RR], 1.09; 95% confidence interval [CI], 1.03 to 1.15) and treatment-related TEAEs (RR, 1.69; 95% CI: 1.49 to 1.92) when compared to placebo. The DORA group exhibited a significantly higher risk of EDS (RR, 2.15; 95% CI: 1.02 to 4.52) and sleep paralysis (RR, 3.40; 95% CI: 1.18 to 9.80) compared to the placebo group.

Conclusion

This meta-analysis achieved a comparative evaluation of the clinical safety and tolerability of FDA-approved DORAs for primary insomnia, specifically focusing on AEs-related narcolepsy-like symptoms. This study contributes to understanding the safety profile of FDA-approved DORAs for treating insomnia.
Serv/eillance: Cops, Queers, and Clinics in Segregated Chicago
Authors: Dana Lydia
Published: November 2023

The Chicago Police Department’s community policing program partners with several LGBTQ service providers in and around Chicago’s white middle class “gayborhood.” These organizations make strange bedfellows for law enforcement, given that many of their clients are queer and trans people of color (QTPOC) and, indeed, targets of policing and gentrification projects. This study draws on eighteen months of ethnography and in-depth interviews to examine motivations and consequences of these inter-agency unions. The study finds that non-governmental organizations (NGOs) are incorporated into racialized policing strategies through mechanisms ranging from contractual agreement to implicit expectation. While NGOs resist directly criminalizing their QTPOC clients, some discourage them from lingering around service centers, effectively making them invisible in the white gayborhood. Findings demonstrate that in a post-welfare police state, sexual health governance is racially and economically circumscribed, as well as mediated, by institutional intimacies between governmental and non-governmental agencies. I argue that LGBTQ service provision is situated within a multilevel monitoring system, a structure I term “serv/eillance.” Providing services to LGBTQ+POC becomes conditioned on state surveillance, while receiving services is conditioned on being surveilled, by police or by proxy.
Australian tax arrangements for trusts: Section 100A of the Income Tax Assessment Act (1936) Cth
Authors: Morrison David
Published: November 2023

The reason taxpayers make arrangements is because they are able to suit themselves, as well as their and business and investment purposes. Such arrangements are as many and varied as there are taxpayers. It is impossible for a legislator, especially in relation to taxation, which by its very nature is a by-product of being free to so arrange, to set out, or prescribe in detail what is and what is not acceptable, except in the clearest of cases. The use of trusts causes the Commissioner of Taxation some concern and the ATO arguably starts with the position that those using trusts are doing so to lessen their taxation burden. Trusts, however, are used for a variety of personal and commercial purposes. It is the case that taxation considerations are increasingly considered to be a part of the equation. The difficulties around the application of section 100A are causing no little consternation for taxpayers and their advisors, not in the least because the Australian Revenue authorities have taken considerable time to issue their view, while at the same time pursuing taxpayers for alleged breaches of the provision.
Lead and cadmium co-exposure modified PC12 viability and ER stress: study from a 3 × 3 factorial design
Authors: Su Xiao , Wang Ruike , Wu Yingying , Yang Mingzhi , Ba Yue , Huang Hui
Published: November 2023

Background

Although exposure to individual metal does exhibit its toxicity, combined exposures provide a more effective representation of the toxic effects of different heavy metal exposures on public health as well as ecosystems. Furthermore, there are few studies on composite exposure to low concentrations of heavy metals, which is more consistent with real-life exposure. The purpose of this study was to explore the neurotoxicity induced by combined exposure to low concentrations of Lead (Pb) and cadmium (Cd) and the potential interaction of their mixture in vitro.

Methods

PC12 cells were incubation with the corresponding concentration of cadmium chloride and/or lead acetate. Viability of PC12 cells was measured by CCK8 assay after 12, 24 and 48h incubation. Next, We measured the ROS, mitochondrial membrane potential (MMP) and apoptosis produced by different treated cells using ROS assay kit, JC-1 MMP assay kit and annexin V-FITC/propidium iodide (PI) apoptosis assay kit, respectively. Expression of proteins related to PI3K/AKT and endoplasmic reticulum (ER) stress in PC12 cells were tested by western blotting. Our study was the first to analyze the interaction between Pb and Cd using a 3 × 3 factorial design approach to observe neurotoxicity.

Results

The results showed that the combined exposure of them was more cytotoxic than the single metal. The activation of PI3K/AKT signaling pathway and several parameters related to oxidative stress and ER stress were significantly altered in combined exposure to low concentrations of Pb and Cd compared with the Pb or Cd. Regarding apoptosis and ER stress, a synergistic interaction between Pb and Cd was evident. Moreover, evoked ER stress as a mechanism involved in the apoptosis of PC12 cells by the combined exposure to Pb and Cd.

Conclusion

The present study provides a theoretical basis used for the toxicological assessment of metal mixtures induced neurotoxicity of concern in terms of public health, and more effective control measures should be taken for the environmental pollution caused by various mixed heavy metals discharged from industry and agriculture.
MAGI2 ameliorates podocyte apoptosis of diabetic kidney disease through communication with TGF‐β‐Smad3/nephrin pathway
Authors: Wang Tingli , Li Chen , Wang Xiaofei , Liu Fang
Published: November 2023

Podocytes, the key component of the glomerular filtration barrier (GFB), are gradually lost during the progression of diabetic kidney disease (DKD), severely compromising kidney functionality. The molecular mechanisms regulating the survival of podocytes in DKD are incompletely understood. Here, we show that membrane‐associated guanylate kinase inverted 2 (MAGI2) is specifically expressed in renal podocytes, and promotes podocyte survival in DKD. We found that MAGI2 expression was downregulated in podocytes cultured with high‐glucose in vitro, and in kidneys of db/db mice as well as DKD patients. Conversely, we found enforced expression of MAGI2 via AAV transduction protected podocytes from apoptosis, with concomitant improvement of renal functions. Mechanistically, we found that MAGI2 deficiency induced by high glucose levels activates TGF‐β signaling to decrease the expression of anti‐apoptotic proteins. These results indicate that MAGI2 protects podocytes from cell death, and can be harnessed therapeutically to improve renal function in diabetic kidney disease.
Regional Ventilation–Perfusion Matching by Electrical Impedance Tomography After Single Lung Transplant
Authors: Scaravilli Vittorio , Colombo Sebastiano Maria , Fumagalli Jacopo , Mauri Tommaso , Zanella Alberto , Rosso Lorenzo , Grasselli Giacomo
Published: November 2023

Single lung transplantation (LUTX) can be the last therapeutic option for a growing cohort of patients suffering from end-stage respiratory failure. Postoperative ventilatory management of single LUTX recipients is challenged by the coexistence of the diseased native lung and a healthy—but fragile—graft. In this case report, in a single LUTX recipient with idiopathic pulmonary fibrosis, regional ventilation (

), perfusion (

), and

/

matching and subsequent measurement of shunt fraction (Qs/Qt) and alveolar dead space (Vd/Vt) were obtained by integrating electrical impedance tomography (EIT) with volumetric capnography and pulmonary thermodilution technique. Although the preoperative pulmonary scintigraphy showed predominant right lung perfusion (79.8% vs. 20.2%), the EIT documented the postoperative re-establishment of

between the lungs (demonstrating the adequate functioning of vascular anastomoses), the diversion of

to the graft and similar global Qs/Qt (17%) and Vd/Vt (29%) between native and graft lung. Electrical impedance tomography mapping allowed regional Qs/Qt and Vd/Vt assessment: the native right lung had a completely deranged distribution of

and

(Qs/Qt 25%, Vd/Vt 46%), whereas the graft showed normal coupling of

and

(Qs/Qt 8%, Vd/Vt 12%). Electrical impedance tomography may allow noninvasive, repeatable, bedside assessments of the lung

/

coupling after single LUTX.