bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMIC-75. ICAM-1 PROMOTES AN IMMUNOSUPPRESSIVE LANDSCAPE IN GLIOBLASTOMAS BY REGULATING THE PHENOTYPIC POLARIZATION STATE OF TUMOR ASSOCIATED MACROPHAGES
Authors: Gandhi Shreya , Devaraja Kaviya , Mansouri Sheila , Zadeh Gelareh 
Published: November 2024

Abstract
Glioblastoma (GBM) is a fatal adult CNS tumor, with a median overall survival of 12-15 months. Intercellular adhesion molecule 1 (ICAM-1) is a cell adhesion molecule whose expression is significantly greater in the mesenchymal transcriptional subtype of GBMs, whereby it is prognostic. We have previously shown that when ICAM-1 is knocked out in the tumor microenvironment (TME) of immune-competent GBM-bearing mice, these mice showed prolonged overall survival and reduced tumor volume. It is yet to be determined how ICAM-1 expression affects infiltration and functional polarization of tumor-associated macrophages (TAMs) and other immune cells in GBM, and if we can suppress the infiltration of M2-like TAMs into the TME by inhibiting ICAM-1. We used a mouse glioma model with and without knockout (KO) of the ICAM-1 gene and intracranially injected GL261 cells. ICAM-1 KO mice survived longer and had reduced tumor volume relative to wildtype, with survival and volume differences being rescued upon ICAM-1 bone marrow reconstitution. Upon endpoint, we performed cytometry by time-of-flight, and found that ICAM-1 KO tumors harbored a reduction in helper T cells, Tregs, and cytotoxic T cells, but an increased proportion in double-negative T cells relative to ICAM-1 WT tumors. ICAM-1 KO tumors also demonstrated an increased proportion of M1-like TAMs relative to M2-like. These results were validated upon administration of ISIS-3082 to tumor models, an antisense oligonucleotide for which a human-specific form has been fast-track approved for other diseases, that targets ICAM-1 transiently in peripheral immune cells prior to TME infiltration. These findings suggest that ICAM-1 expression influences immune cell infiltration, potentially modulates the functional state of TAMs towards a M1-like state, and that ICAM-1 may be targeted in TAMs to ‘reeducate’ them before entering the TME. This may be translated into clinical practice and combined with standards-of-care to render GBMs more sensitive to treatment.
TMIC-84. MOLECULAR EVOLUTION OF THE TUMOR AND ITS MICROENVIRONMENT AT RECURRENCE
Authors: Hashemi Elaheh , R.L Akshaya , Kumar Anupam , Voong Viva , Wang Lin Lin , Diaz Aaron , Phillips Joanna 
Published: November 2024

Abstract
Changes in the glioma immune microenvironment at recurrence may contribute to disease progression and therapeutic resistance. In prior studies we demonstrated that the circumscribed glioma, pleomorphic xanthoastrocytoma (PXA), was relatively immune enriched including activated cytotoxic CD8+ T cells and Iba1+ microglia/macrophages. While PXA are often low-grade, a significant fraction can recur and progress to higher grade. To determine how the tumor and its immune microenvironment changes with recurrence, we examined a cohort of tumors from patients with multiple resections. Using single-nucleus RNA sequencing (snRNAseq) and spatial molecular imaging we investigate the temporal changes in the tumor and its microenvironment. To begin, we analyzed samples from three patients with paired initial and recurrent tumor. A total of 22,465 immune and non-immune cells were analyzed. Compared to the initial, the recurrent tumor tended to have decreased numbers of T cells and T cells had lower expression of CD2 and GZMA. Pathway analysis for DE genes in TAMs demonstrated enrichment of genes associated with NTRK signaling, while pathways related to aerobic respiration and mitochondrial translation were decreased suggesting a less inflammatory phenotype. Tumor cells at recurrence demonstrated decreased expression of CD274 (PD-L1) and of the chemokine CXCL14, previously identified as a factor driving an anti-tumor CD8+ T cell response. In a cohort of 5 patients with paired initial and recurrent tumors, we observed increased numbers of CD163+ TAMs. Together these data suggest changes in the tumor-associated immune response at recurrence that may be relevant to therapy. Using murine models for the disease we are investigating the factors that regulate these changes.
TMOD-07. DEVELOPMENT AND CHARACTERIZATION OF A SPINAL CORD DIFFUSE MIDLINE GLIOMA MODEL
Authors: Hernandez-Osuna Reyes , Lacalle Andrea , Gonzalez-Huarriz Marisol , Marco-Sainz Javier , Palacios Daniel , Nuin Sara , Morales Sandra , Perez-Larraya Jaime Gallego , Patiño-García Ana , Phoenix Timothy , Hernandez-Lain Aurelio , Lassaletta Alvaro , Blasco Luis , Quincoces Gemma , Collantes Maria , Solano Palma , Alonso Marta M , Labiano Sara 
Published: November 2024

Abstract
Diffuse midline gliomas (DMGs) are very aggressive central nervous system tumors that occur mainly in children and adolescents. Most DMGs develop in the brainstem, but they can also be found in the thalamus and the spinal cord, the latter comprising 4% of all DMGs. Despite advances in current treatments, the outcome for DMG patients remains extremely poor. The success of immunotherapy in other tumors encourages its translation to DMGs, for which the understanding of the tumor immune microenvironment (TIME) is imperative. The field counts with several murine DMG models in the pontine and thalamic locations. However, there is a paucity of spinal cord models. Thus, in this work, we have generated an orthotopic syngeneic model of H3K27M spinal cord DMG by injecting the tumor cells directly into the spinal cord under the T2 vertebra. We monitored tumor growth by bioluminescence and PET using 18F-FDG and 11C-methionine. As the tumor grew, we observed human-like symptoms in the mice, such as hemiplegia and hemiparesis. TIME characterization showed that this tumor model is mainly infiltrated by macrophages and almost devoid of lymphocytes. We are currently delving into the phenotype of these populations by scRNAseq and spatial transcriptomics. In addition, we are comparing our findings with human samples (n=15) to assess whether our model mimics human disease and can serve as a bonafide model of this tumor location. As a proof of concept, treatment of spinal DMG-bearing mice with a TIM-3 antagonist antibody, previously described as effective in pontine DMG-bearing mice, increased the median overall survival. We showed by microPET imaging that anti-TIM-3 administration into the brain ventricles diffuses to the tumor. These results open a path for the characterization of the spinal cord DMG TIME and for testing preclinical treatments in this new model.
TMOD-22. MULTIREGION BIOPSIES AND CORRESPONDING NEUROSPHERE CULTURES REVEAL SPATIAL DIVERGENCE IN GLIOBLASTOMA EVOLUTION
Authors: Salatino Roberto , Geisberg Jacob , Onubogu Ugoma , Romero-Toledo Arantxa , Oakes Banjamin , Szentirmai Oszkar , McDonald Thomas , Michor Franziska , Janiszewska Michalina 
Published: November 2024

Abstract
Spatial organization of normal tissues is key for their function, yet the role of distribution of distinct clones of cancer cells in tumor is not usually studied as a potential vulnerability in cancer. This is of particular interest in glioblastoma (GBM), in which extensive intratumor heterogeneity hampers effectiveness of treatment. To better understand tumor evolution and the complexity of cancer ecosystem in GBM, we performed profiling of biopsies collected from MRI-defined regions of the tumors, spanning the surface, tumor core and deep tumor margins, which drive local recurrence after surgery. To test how spatially distinct biopsies differ in their cancer cell composition and to assess the tumor microenvironment heterogeneity, we took advantage of 5-ALA metabolite fluorescence, which accumulates in GBM cells and allows the surgeon to visualize cancer under blue light. We used it to separate cancer cells (predominantly 5-ALAhigh) from tumor microenvironment (5-ALAlow) and subjected the fractions to bulk and single cell transcriptomics, respectively. We found a gradient of cellular states associated with location in the tumor, with the deep margin samples having more 5-ALAlow cancer cells and generally less defined phenotype. We have also developed neurosphere cultures from our collection of spatially distant biopsies. Despite the selection pressure of the in vitro culture conditions, cells from different regions of the tumor adopted different morphologies, suggesting retention of some of their differential features. The differences between cultures were reflected in metabolism, proliferation, and differential sensitivity to a drug panel. Whole exome sequencing and transcriptomic analysis were also performed to identify the selection bottleneck of culture conditions, establish evolutionary trajectory of the distinct regions and neurosphere cultures, and test how strongly our cultures represent both the 5-ALAhigh and 5-ALAlow subpopulations of GBM cells. Our study identified properties associated with different spatial locations within GBM tumors, which will help uncover the cellular and microenvironmental dependencies that could lead to novel therapeutic targets for this highly heterogeneous tumor.
The Privacy–Equality Synthesis: Framing Reproductive Rights in India
Authors: Pillai Gauri 
Published: November 2024

Abstract
Reproductive rights are typically framed as engaging one’s constitutional right to privacy. However, with increasing contestations around the right to privacy, the right to equality has been proposed as an alternate frame. Often, a choice tends to be constructed between the two. Challenging this, some argue for both privacy and equality to be included in framing constitutional reproductive rights. This approach places emphasis on the combined presence of the two rights. Indian constitutional law offers a third, distinct possibility, moving beyond mere rights addition to reading rights in ‘synthesis’. The synthesis pays close attention to the site of dynamic rights interaction, highlighting the effects of the rights on one another. This method of rights analysis, and its latent potential, remains dormant within constitutional doctrine in India. Resurrecting it, and studying examples of abortion and maternal mortality, I frame reproductive rights through the synthesis between privacy and equality. In functioning as a magnifier, a catalyst and a backstop, the synthesis alters the constitutional imagination of reproductive rights in India while, simultaneously, advancing an insightful paradigm for constitutional reproductive rights globally and rights analyses generally.
Protracted Magma Evolution and Transcrustal Magmatic Plumbing System Architecture at Erta Ale Volcano (Afar, Ethiopia)
Authors: Pin Juliette , Chazot Gilles , France Lydéric , Abily Bénédicte , Gurenko Andrey , Bertrand Hervé , Loppin Alexandra 
Published: November 2024

Abstract
The Afar region is one of the only places on Earth where magmatic continental rifting and associated ongoing break-up processes are exposed onshore. The several active magmatic segments there are characterized by contrasted morphologies, crustal thicknesses, magma production rates, and magma-tectonic styles. In the Erta Ale Range rift segment, extension is magmatically accommodated, making the range the ideal place to study the magmatic behavior of a mature rift segment. Erta Ale Range comprises sub-segments with magma compositions ranging from basalts to rhyolites, but only the Erta Ale Volcano (EAV) sub-segment is active, where only basaltic compositions have been reported so far. Here, we show for the first time protracted differentiation at EAV that is not expressed volcanically at the surface, but is rather accessible via unique cognate gabbroic and microgabbroic blocks, and recorded by mixing with erupted basaltic magmas. These cognate samples record previously unknown mushy and evolved parts of the EAV plumbing system. To constrain their origin and evolution, we measured the major and trace element compositions of the bulk rocks, interstitial glasses, and melt inclusions. We also measured the oxygen isotopic compositions of olivine crystals, interstitial glasses, and melt inclusions. By combining these results with textural relationships and oxy-thermo-barometry calculations, we discuss magma differentiation and storage conditions, as well as magmatic interactions during transport through the crust. Comparison of our results with rhyolite-MELTS thermodynamic models highlights that protracted fractional crystallization is the main process of magma evolution, and when associated with reactive porous flow is capable of forming the evolved compositions observed (up to 75 wt.% SiO2). We also use the model outputs to quantify distinct steps of igneous differentiation in both shallow and deep crustal reservoirs, and we highlight significant interactions with hydrothermally altered wall rocks. We discuss this model within the geological contexts of the Erta Ale Range rift segment and the larger Afar region, and highlight contrasts with mature oceanic systems to argue that the region is not in the final stages of continental break-up.
Deficiency of TET2-mediated KMT2D self-transcription confers a targetable vulnerability in hepatocellular carcinoma
Authors: Jin Yuting , Rao Keqiang , Zheng Jiaojiao , Zhang Xinchao , Luo Yi , He Jing 
Published: November 2024

Abstract
Hepatocellular carcinoma (HCC) has become a leading cause of cancer-related mortality worldwide. Conventional therapies tend to exacerbate comorbidities, liver dysfunction, and relapse, rendering an urgent demand for novel strategy for management of HCC. Here, we reported that DNA dioxygenase TET2 collaborates with histone methyltransferase KMT2D to enable transcription of KMT2D and ARID1A in HCC. Mechanistically, KMT2D and ARID1A are the major epigenetic targets of TET2 through RNA-seq analysis. Moreover, KMT2D recruits TET2 to facilitate self-transcription via oxidation of 5-methylcytosine in promoter, thereby maintaining expression of ARID1A. Physiologically, KMT2D was identified as a tumor suppressor and mediates the antitumor effect of vitamin C in HCC. Tumors with depleted KMT2D present growth advantage over control group. Vitamin C is able to impair tumor growth, which is compromised by deficiency of KMT2D. Furthermore, loss of KMT2D sensitizes HCC tumors to cisplatin with reduced tumor weight and high level of DNA damage. Ultimately, TET2–KMT2D axis correlates with prognosis of patients with HCC. Patients with high amounts of TET2 and KMT2D present better outcome. Our findings not only put forth a heretofore unrecognized mechanism underlying cross-talk between TET2 and KMT2D in mediating self-transcription of KMT2D, but also propose a targetable vulnerability for HCC therapy on the basis of TET2–KMT2D axis.
Partisan belief in new misinformation is resistant to accuracy incentives
Authors: Stein Jonas , Keuschnigg Marc , van de Rijt Arnout 
Published: November 2024

Abstract
One explanation for why people accept ideologically welcome misinformation is that they are insincere. Consistent with the insincerity hypothesis, past experiments have demonstrated that bias in the veracity assessment of publicly reported statistics and debunked news headlines often diminishes considerably when accuracy is incentivized. Many statements encountered online, however, constitute previously unseen claims that are difficult to evaluate the veracity of. We hypothesize that when confronted with unfamiliar content, unsure partisans will form sincere beliefs that are ideologically aligned. Across three experimental studies, 1,344 conservative and liberal US participants assessed the veracity of 20 politically sensitive statements that either confirmed or contradicted social science evidence only known to experts. As hypothesized, analyses show that incentives failed to correct most ideological differences in the perceived veracity of statements. Sixty six to 78% of partisan differences in accuracy assessment persisted even when monetary stakes were raised beyond levels in prior studies. Participants displayed a surprising degree of confidence in their erroneous beliefs, as bias was not reduced when participants could safely avoid rating statements they were unsure about, without monetary loss. These findings suggest limits to the ability of disciplining interventions to reduce the expression of false statements, because many of the targeted individuals sincerely believe them to be true.
Transcriptomic Analysis of the Amygdala in Subjects with Schizophrenia, Bipolar Disorder and Major Depressive Disorder Reveals Differentially Altered Metabolic Pathways
Authors: Zhang Xiaolu , Valeri Jake , Eladawi Mahmoud A , Gisabella Barbara , Garrett Michael R , Vallender Eric J , McCullumsmith Robert , Pantazopoulos Harry , O’Donovan Sinead M 
Published: November 2024

Abstract

Background and Hypothesis
The amygdala, crucial for mood, anxiety, fear, and reward regulation, shows neuroanatomical and molecular divergence in psychiatric disorders like schizophrenia, bipolar disorder and major depression. This region is also emerging as an important regulator of metabolic and immune pathways. The goal of this study is to address the paucity of molecular studies in the human amygdala. We hypothesize that diagnosis-specific gene expression alterations contribute to the unique pathophysiological profiles of these disorders.

Study Design
We used a cohort of subjects diagnosed with SCZ, BPD or MDD, and nonpsychiatrically ill control subjects (n = 15/group), together with our bioinformatic 3-pod analysis consisting of full transcriptome pathway analysis, targeted pathway analysis, leading-edge gene analysis and iLINCS perturbagen analysis.

Study Results
We identified altered expression of metabolic pathways in each disorder. Subjects with SCZ displayed downregulation of mitochondrial respiration and nucleotide metabolism pathways. In comparison, we observed upregulation of mitochondrial respiration pathways in subjects with MDD, while subjects with BPD displayed enrichment of pathways involved in carbohydrate metabolism. Several pathways associated with brain metabolism including immune system processes and calcium ion transport were also differentially altered between diagnosis groups.

Conclusion
Our findings suggest metabolic pathways, including downregulation of energy metabolism pathways in SCZ and upregulation of energy metabolism pathways in MDD, are uniquely altered in the amygdala in these disorders, which may impact approaches for therapeutic strategies.
Continuation versus Interruption of Buprenorphine/Naloxone in Adult Veterans Undergoing Surgery: Examination of Postoperative Pain and Opioid Utilization in a National Retrospective Cohort Study
Authors: Hitt James M. , Elkin Peter L. , de Leon-Casasola Oscar A. 
Published: November 2024

Background:
Prescription rates for buprenorphine in opioid use disorder are increasing, and recent guidelines recommend its continuation during and after surgery; however, evidence from clinical outcome studies is limited. The authors tested the hypotheses (1) that perioperative continuation of buprenorphine does not result in higher pain scores and (2) that this approach does not result in higher supplemental postoperative opioid requirements.

Methods:
The Veterans Affairs Corporate Data Warehouse was queried for patients who underwent surgery while being prescribed buprenorphine/naloxone for opioid use disorder between 2010 and 2020. Analysis of the prescription record was used to infer buprenorphine management, and a 3:1 matched control set of patients without buprenorphine prescriptions was generated. The authors examined patients who continued buprenorphine, patients who had buprenorphine interrupted, and control patients. The primary outcome was time-weighted average postoperative pain scores from inpatient and outpatient sources within 72 h of surgery. The secondary outcome was postoperative average daily morphine equivalent opioid requirements within 2 weeks of surgery.

Results:
A total of 1,881 surgical procedures in 1,673 patients taking buprenorphine for opioid use disorder were included; these procedures were matched to 5,748 control patients (5,775 procedures) without a buprenorphine prescription. Among the 1,881 procedures, 1,186 (63%) continued buprenorphine through the perioperative period, while 695 (37%) interrupted buprenorphine. Pain scores (± SD) were clinically similar for all three groups (4.1 ± 1.9 control [n = 3,284], 4.9 ± 2.0 continued buprenorphine [n = 662], and 5.5 ± 1.7 interrupted buprenorphine [n = 419]; P < 0.001). Patients who continued buprenorphine did not require significantly more supplemental opioids as compared to controls (39.7 ± 1.9 mg morphine equivalents/day vs. 36.5 ± 0.7; P = 0.23), and patients who interrupted buprenorphine received more supplemental opioids than those who continued it (74.2 ± 4.5 mg morphine equivalents/day vs. 39.7 ± 1.9, respectively; P < 0.001).

Conclusions:
Continuation of buprenorphine is not associated with higher average pain scores or postoperative opioid requirements, supporting recently published guidelines.
Comparative Analysis of Surgical Outcomes in Separation Surgery vs. Anterior Reconstruction for Metastatic Epidural Spinal Cord Compression
Authors: Amelink Jantijn J.G.J. , Pierik Robertus J.B. , Groot Olivier Q. , Shin John H. , Verlaan Jorrit-Jan , Tobert Daniel G. 
Published: November 2024

Study Design.
Retrospectively matched case-control study

Objective.
To compare intraoperative and postoperative outcomes between separation surgery and corpectomy with anterior reconstruction for patients with metastatic epidural spinal cord compression (MESCC).

Summary of Background Data.
The primary goal of surgery for MESCC is to preserve and improve neurological function. Separation surgery may offer a less invasive alternative that still achieves neurological decompression and restores biomechanical stability, enabling surgeons to forego more invasive surgeries, such as corpectomy with anterior reconstruction. However, there is limited literature comparing these two surgical methods.

Methods.
Fifty-six patients aged 18 years or older who underwent either separation surgery followed by stereotactic body radiation therapy (n=28) or corpectomy with anterior reconstruction (n=28) for MESCC from 2017 to 2022 were included. Outcomes included estimated blood loss, operating time, intraoperative blood transfusion and complications. The Mann-Whitney U test was used for continuous data, and Fisher’s exact test for categorical data.

Results.
Patients undergoing separation surgery compared with anterior reconstruction experienced less blood loss (median 500 ml [IQR 300-1,000] vs. 925 ml [IQR 500-1,425]; P=0.036) and shorter operating times (median 214 minutes [IQR 164-281] vs. 286 minutes [IQR 220-328]; P=0.028). Intraoperative blood transfusion occurred in seven patients (25%) in the separation surgery group versus 14 patients (50%) in the anterior reconstruction group (P=0.10). There were no significant differences between both groups with regard to duration of hospitalization, complications, postoperative transfusions, reoperations, or survival (P<0.05).

Conclusion.
Separation surgery was found to have less blood loss and shorter operating times compared with corpectomy with anterior reconstruction. These findings suggest that separation surgery may be a viable therapeutic alternative for MESCC patients currently undergoing more invasive surgical approaches. Future studies should prospectively compare separation surgery and corpectomy with anterior reconstruction to provide additional evidence on their relative effectiveness in managing local tumor control.

Level of evidence:
Treatment benefits, Level IV