bluuebunny/crossref_metadata_2025_split huggingface dataset:
Representative pure risk estimation by using data from epidemiologic studies, surveys, and registries: estimating risks for minority subgroups
Authors: Wang Lingxiao , Li Yan , Graubard Barry I , Katki Hormuzd A 
Published: November 2023

AbstractRepresentative risk estimation is fundamental to clinical decision-making. However, risks are often estimated from non-representative epidemiologic studies, which usually under-represent minorities. Model-based methods use population registries to improve external validity of risk estimation but assume hazard ratios are generalisable from samples to the target finite population. ‘Pseudoweighting’ methods improve representativeness of studies by using an external probability-based survey as the reference, but the resulting estimators can be biased due to propensity model misspecification and inefficient due to highly variable pseudoweights or small sample sizes of minorities in the cohort and/or survey. We propose a two-step pseudoweighting procedure that post-stratifies the event rates among age/race/sex strata in the pseudoweighted cohort to the population rates, to produce efficient and robust pure risk estimation (i.e. a cause-specific absolute risk in the absence of competing events). For developing an all-cause mortality risk model representative for the USA, our findings suggest that hazard ratios for minorities are not generalisable, and that surveys can have inadequate numbers of events for minorities. Post-stratification on event rates is crucial for obtaining reliable risk estimation for minority subgroups.
Uncovering root compaction response mechanisms: new insights and opportunities
Authors: Pandey Bipin K , Bennett Malcolm J 
Published: November 2023

Abstract
Compaction disrupts soil structure, reducing root growth, nutrient and water uptake, gas exchange, and microbial growth. Root growth inhibition by soil compaction was originally thought to reflect the impact of mechanical impedance and reduced water availability. However, using a novel gas diffusion-based mechanism employing the hormone ethylene, recent research has revealed that plant roots sense soil compaction. Non-compacted soil features highly interconnected pore spaces that facilitate diffusion of gases such as ethylene which are released by root tips. In contrast, soil compaction stress disrupts the pore network, causing ethylene to accumulate around root tips and trigger growth arrest. Genetically disrupting ethylene signalling causes roots to become much less sensitive to compaction stress. Such new understanding about the molecular sensing mechanism and emerging root anatomical traits provides novel opportunities to develop crops resistant to soil compaction by targeting key genes and their signalling pathways. This expert view discusses these recent advances and the molecular mechanisms associated with root–soil compaction responses.
Progressive disseminated histoplasmosis: The experience in one non-endemic medical center
Authors: Li Lucy X , Rajack Shakila Tenkayala Abdul , Ostrander Darin , Datta Kausik , Totten Marissa , Avery Robin K , Zhang Sean X , Marr Kieren A , Permpalung Nitipong 
Published: November 2023

Abstract
Histoplasmosis, the most common endemic mycosis in North America, presents in a myriad of ways, spanning the spectrum from self-limiting pneumonia to progressive disseminated histoplasmosis (PDH). Toward better describing contemporary histoplasmosis syndromes, risks, and outcomes, this single-center retrospective cohort study was performed (2009–2019). The population who developed PDH was similar to that with other forms of histoplasmosis (OFH) except for higher rates of preexisting immunocompromising conditions (91.3% vs. 40%, P &lt; .001) and a trend toward receiving more chronic immunosuppression (65.2% vs. 33.3%, P = .054) compared to those with OFH. Diagnosis was most frequently achieved by urinary or serum antigen positivity. People with PDH more frequently tested positive compared to those with OFH, but negative tests did not rule out histoplasmosis. Median time to diagnosis was prolonged among people with both PDH and OFH (32 vs. 31 days, respectively). Following diagnosis, people with PDH received more liposomal amphotericin (78.3% vs. 20%, P &lt; .001). Subsequent survival at 90 and 365 days and treatment response were similar in both groups. Patients with PDH were more often hospitalized (95.7% vs. 60%, P = .006); however, once admitted, there were no differences in hospital length of stay or intensive care unit admission rate. The challenges of diagnosing histoplasmosis based on clinical presentation alone highlight the need for heightened awareness of these entities especially given the recent reports on expanded endemicity and delays in diagnosis.
Neutron star mass in dark matter clumps
Authors: Deliyergiyev Maksym , Del Popolo Antonino , Le Delliou Morgan 
Published: November 2023

ABSTRACT
This paper investigates a hypothesis proposed in previous research relating neutron star (NS) mass and its dark matter (DM) accumulation. As DM accumulates, NS mass decreases, predicting lower NS masses toward the Galactic centre. Due to limited NSs data near the Galactic centre, we examine NSs located within DM clumps. Using the CLUMPY code simulations, we determine the DM clumps distribution, with masses from 10 to 108 M⊙ and scales from 10−3 to 10 kpc. These clumps’ DM exhibit a peak at the centre, tapering toward the outskirts, resembling our Galaxy’s DM distribution. We analyse these DM clumps’ NS mass variations, considering diverse DM particle masses and galaxy types. We find relatively stable NS mass within 0.01 – 5 kpc from the clump centre. This stability supports the initial hypothesis, particularly for NSs located beyond 0.01 kpc from the clump centre, where NS mass reaches a plateau around 0.1 kpc. Nevertheless, NS mass near the clump’s periphery reveals spatial dependence: NS position within DM clumps influences its mass in Milky Way-type galaxies. Moreover, this dependence varies with the DM model considered. In summary, our study investigates the proposed link between NS mass and DM accumulation by examining NSs within DM clumps. While NS mass remains stable at certain distances from the clump centre, spatial dependencies arise near the clump’s outer regions, contingent on the specific DM model.
Pithoviruses Are Invaded by Repeats That Contribute to Their Evolution and Divergence from Cedratviruses
Authors: Rigou Sofia , Schmitt Alain , Alempic Jean-Marie , Lartigue Audrey , Vendloczki Peter , Abergel Chantal , Claverie Jean-Michel , Legendre Matthieu 
Published: November 2023

Abstract
Pithoviridae are amoeba-infecting giant viruses possessing the largest viral particles known so far. Since the discovery of Pithovirus sibericum, recovered from a 30,000-yr-old permafrost sample, other pithoviruses, and related cedratviruses, were isolated from various terrestrial and aquatic samples. Here, we report the isolation and genome sequencing of 2 Pithoviridae from soil samples, in addition to 3 other recent isolates. Using the 12 available genome sequences, we conducted a thorough comparative genomic study of the Pithoviridae family to decipher the organization and evolution of their genomes. Our study reveals a nonuniform genome organization in 2 main regions: 1 concentrating core genes and another gene duplications. We also found that Pithoviridae genomes are more conservative than other families of giant viruses, with a low and stable proportion (5% to 7%) of genes originating from horizontal transfers. Genome size variation within the family is mainly due to variations in gene duplication rates (from 14% to 28%) and massive invasion by inverted repeats. While these repeated elements are absent from cedratviruses, repeat-rich regions cover as much as a quarter of the pithoviruses genomes. These regions, identified using a dedicated pipeline, are hotspots of mutations, gene capture events, and genomic rearrangements that contribute to their evolution.
ANGI-01. INDUCIBLE CAS9 IN PATIENT-DERIVED CULTURES OF IDH WILDTYPE GLIOBLASTOMA WITH DISTINCT GROWTH CHARACTERISTICS
Authors: Kundu Soumi , Yildirim Irem , Voukelatou Faidra , Stockgard Rebecka , Krona Cecilia , Nelander Sven 
Published: November 2023

Abstract
To identify new treatment opportunities for IDH wildtype glioblastoma, it is essential to establish robust methods to evaluate candidate genes in patient-derived cells. Here, we report initiative to establish large-scale candidate gene evaluation by CRISPR-Cas9 using well characterized cells from the Uppsala Human Glioma Cell Culture biobank. Previously, we have characterized fully the HGCC cultures (n = 100) in terms of multi-omics, and by systematic injection as patient-derived orthotopic xenografts. Here, we report a procedure to introduce doxycycline-inducible Cas9 into cultures from our biobank. This allows for temporally controlled target gene ablation in patient-derived cells with known growth characteristics. As proof-of-concept, we describe the derivation of clonal Cas9-inducible cells in the cell lines U3013MG (proneural, bulk forming) and U3180MG (classical, diffuse-growing). The Cas9 induction and editing efficiency was evaluated by ablation of the gene encoding the cell surface marker CD44, for which we transduced the Cas9-inducible clones with CD44 dual sgRNA vector and treated then with doxycycline over time, evaluating CD44 knockout by longitudinal flow cytometry. From a library of 106 clones, we identified the best performing clones, as evaluated by CD44 loss at day 21. Ten out of 64 clones assessed, showed potent Cas9 activity, estimating a drop in CD44 levels by 40-60% after 21 days of doxycycline treatment. The amount of editing by inducible Cas9 was higher with CD44 sgRNA administered by lentivirus than by electroporation. To ensure that the Cas9-inducible patient-derived cell lines have reproducible tumor phenotypes and did not divert from their parental growth pattern, they were transplanted orthotopically into athymic nude mice. We also validated the activity of Cas9ind in vivo by checking the editing of CD44 expression in one of our clones. The established procedure provides a basis for large-scale single-gene and pooled in vivo CRISPR studies of IDH wildtype glioblastomas with distinct invasive characteristics.
ANGI-07. GLIOBLASTOMA WITH BONY METASTATIC DISEASE IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1: A CASE REPORT
Authors: Shah Trusha , Hutchens Troy , Yang Jonathan , Graber Jerome 
Published: November 2023

Abstract
Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor predisposition syndrome causing diffuse neurofibromas, plexiform neurofibromas, and in a minority of patients malignant peripheral nerve sheath tumors (MPNST) and gliomas. Gliomas from NF1 typically present early in life and can be grade 1-4, with higher grades less frequent. Malignant gliomas associated with NF1 have a different molecular landscape compared to sporadic gliomas. Extracranial spread of gliomas is extremely rare for reasons unknown, but renal transplants from gliomas patients have resulted in clonal gliomas in organ recipients. We present here the first reported case of extracranial metastases of GBM to bone in a 21 year old male with NF1. At the age of 18, he was diagnosed with a high-grade astrocytoma consistent with GBM (IDH wildtype, MGMT unmethylated). This was 2 years following a diagnosis of a right neck plexiform neurofibroma. His GBM was initially treated with six cycles of temozolomide. Following temozolomide he underwent another resection (1.5 years after initial surgery) due to tumor recurrence. Resection was followed by proton radiation therapy and selumetinib, a MEK inhibitor approved for treatment of plexiform neurofibromas in NF1. The selumetinib did reduce his plexiform neurofibroma, but did not have an apparent effect on his GBM. Selumetinib was stopped five months after initiation due to increased tumor burden and he began lomustine, followed by bevacizumab and etoposide at next recurrence. About 2.5 years after his initial GBM diagnosis, he had low back pain and imaging showed multiple sites of bony metastases. Pathology confirmed extracranial spread of GBM.
ANGI-09. UNRAVELING THE INVOLVEMENT OF BAIAP2 AND CDC42 IN MEDULLOBLASTOMA PATHOGENESIS
Authors: Ruiz Luz , Jangde Nitish , Suter Robert , Ayad Nagi 
Published: November 2023

Abstract
The most common malignant pediatric brain tumor is medulloblastoma. Despite advancements in treatment, medulloblastoma survivors have significant long-term medical side effects and increased all-cause mortality. That is why novel, more effective, and safe treatments are direly necessary. One treatment challenge is that medulloblastoma tumors can disseminate via the bloodstream and cerebrospinal fluid leading to a poorer prognosis. The underlying mechanisms that promote metastasis and invasion in medulloblastoma are not clearly understood. One method we used to identify potential key regulators in the pathogenesis of medulloblastoma is by analyzing microarray and single-cell RNA sequencing data. We mined publicly-available datasets along with our data from genetically engineered models of medulloblastoma to identify differentially expressed genes compared to non-tumor brain cells. We identified BAIAP2 and CDC42 to be differentially expressed and have higher expression in medulloblastoma compared to other brain cancers. BAIAP2 and CDC42 are known to be implicated in migration and invasion. Extensive literature demonstrates an interaction between BAIAP2 and CDC42 in multiple cell types. However, this interaction has yet to be thoroughly studied in medulloblastoma. We hypothesize that CDC42 interacts with BAIAP2 in medulloblastoma cells to facilitate tumor pathogenesis. To further investigate this, we conducted siRNA-mediated gene knockdown of BAIAP2 and CDC42 in ONS-76 cells. We determined that BAIAP2 and CDC42 are highly expressed in medulloblastoma, and knockdown of BAIAP2 modulates CDC42 expression. Further, we determined that cell proliferation and migration were reduced upon BAIAP2 and CDC42 knockdown. Our findings suggest that BAIAP2 and CDC42 have a role in the migration and proliferation of medulloblastoma ONS-76 cells. Altogether, these findings indicate BAIAP2 and CDC42 as possible targets for future studies.
BIOM-27. CELL-FREE DNA-BASED LIQUID BIOPSIES FOR THE REAL-TIME TRACKING OF TUMOR BURDEN AND TREATMENT RESPONSE IN GLIOBLASTOMA
Authors: Mankame Sharvari , Kyriakidou Maria , Tang Nanyun , Reid George , Berens Michael , Brown Christine , Portnow Jana , Barthel Floris 
Published: November 2023

Abstract
Cell-free DNA (cfDNA) are short fragments of DNA that are released by apoptotic or necrotic cells into bodily fluids. It has emerged as a potential diagnostic tool allowing for the detection and analysis of tumor-derived biomarkers in cancer. Despite the detailed view provided by clinical imaging, its inability to quantify tumor burden and distinguish between pseudo-progression and pseudo-response poses a challenge for patients. In this study, we sought to investigate the effectiveness of cfDNA as a liquid biopsy tool to track tumor burden and disease progression in real time in different glioblastoma models and through different types of biofluids. To examine the feasibility of cfDNA-based tumor tracking we cultivated several patient-derived glioblastoma lines, purified cfDNA and performed sequencing. Further analysis revealed that dead cells were associated with an elevated cfDNA yield and altered fragment size profiles. Genomic sequencing revealed consistent variants shared across serial cfDNA timepoints, strengthening the suggestion that cfDNA can be used as a non-invasive biomarker. In order to demonstrate the clinical implications of our methodology, we collected a preliminary batch of n = 43 longitudinal intraventricular cerebrospinal fluid (CSF) samples from a patient that underwent CAR-T treatment over the span of two years. We observed a marked increase in cfDNA yield post-treatment compared to samples taken prior to treatment administration. Furthermore, cfDNA-based estimates of tumor burden measured as allele fraction specific to the tumor, tracked with clinical imaging-based tumor size estimates. These preliminary findings provide compelling evidence supporting the clinical utility of cfDNA analysis in monitoring the effectiveness and dynamics of CAR-T treatment. By tracking cfDNA levels in CSF, we can identify patterns reflecting treatment response and aid in assessing the therapeutic efficiency of CAR-T treatment in glioma patients. Further investigations with larger patient cohorts and more comprehensive data analysis to validate these findings are actively underway.
BIOM-31. TARGETED DNA SEQUENCING OF RECURRENT GLIOBLASTOMA IDENTIFIES MOLECULAR FACTORS ASSOCIATED WITH CLINICAL OUTCOMES
Authors: Al-Adli Nadeem , Chen William , Young Jacob , Mirchia Kanish , Peeran Zain , Braunstein Steve , Perry Arie , de Groot John , Raleigh David , Costello Joseph , Berger Mitchel , Vasudevan Harish 
Published: November 2023

Abstract

PURPOSE
The goal of our project was to define the molecular features of recurrent glioblastoma (rGBM) and their prognostic significance.

METHODS
We retrospectively reviewed 121 consecutive glioblastoma patients who underwent re-resection at a single institution from 2016-2021. Primary treatment in all patients included maximal safe resection followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ). Capture-based targeted DNA sequencing for point mutations and copy number analysis was performed on all re-resection samples. Overall (OS) and progression-free survival (PFS) from re-resection were analyzed with the Kaplan-Meier method and Cox regression analyses.

RESULTS
Median age at first recurrence was 57 years (range, 27-78) and follow up from re-resection was 11 months. Salvage therapy comprised re-irradiation (n = 52, 43%), temozolomide (TMZ) (n = 39, 32%), lomustine (n = 47, 39%), and/or bevacizumab (n = 22, 18%). Median OS and PFS were 12.1 and 4.4 months, respectively. Median tumor mutation burden (TMB) was 4 mut/Mb (range, 1-650), average unstable microsatellite sites (MSI) were 1.16% (range, 0-20), and MGMT was methylated in 71 (59%) patients. Longer OS was found after postoperative TMZ (19.1 vs. 9.1), KPS &gt; 70 (13.6 vs. 11.1), and/or re-irradiation (12.6 vs. 8.4) (p&lt; .05). On multivariate analysis, TMZ (HR 0.2, 0.079-0.48), re-irradiation (HR 0.27, 0.12-0.58), and mutations in PDGFRA (HR 0.24, 0.067-0.83) or PTEN (HR 2.3, 1.1-4.8) genes were associated with longer OS after re-resection (p&lt; .05). Multivariate predictors of re-irradiation response included MSI &gt;1.16 (HR 0.25, 0.084-0.75), and mutations in PDGFRA (HR 0.04, 0.005-0.33), TERT (HR 0.16, 0.033-0.78), or PIK3R1 (HR 0.18, 0.041-0.8) genes. In the 46 matched primary/recurrent tumors, 40 (87%%) had a change in a mutation and 9 (20%) demonstrated hypermutation, of which 4 (44%) had mismatch repair deficiencies.

CONCLUSIONS
Our study outlines the molecular factors associated with survival and response to re-irradiation in rGBM as well as, the molecular differences between primary/recurrent samples.
BIOM-42. LONGITUDINAL IMMUNE PROFILES OF LOWER GRADE ADULT GLIOMA PATIENTS
Authors: Guerra Geno , Francis Stephen , Molinaro Annette , Taylor Jennie , Warrier Gayathri , Bracci Paige , Rice Terri , Hansen Helen , McCoy Lucie , Clarke Jennifer , Wiencke John , Wrensch Margaret 
Published: November 2023

Abstract
Immune dysregulation is a known characteristic of glioma, however there is little known about the peripheral immune status of lower-grade (LrGG) glioma patients across the course of disease. Using immunomethylomic (deconvoluted blood DNA methylation) data from the UCSF Immune Profiles Study, we explore changes in patient peripheral blood immune cell profiles in newly diagnosed and recurrent LrGG patients. For patients receiving radiation (RT) and temozolomide (TMZ) (n = 75), blood is collected pre-RT/TMZ, post-RT/TMZ, before, during, and after adjuvant TMZ (if applicable). For patients followed only by MRI (n = 53) and those with other treatment plans (n = 67), blood is collected at MRIs, and if applicable, before radiation. For all patients, blood is also collected before new treatment intervention. For patients (LrGG IDH mutated) with paired pre- and post-surgery samples (n = 139), we observed a significant post-surgery increase in the count of memory B-cells (p = 1.7e-5), neutrophils (p = 0.0001), basophils (p = 8.7e-5), monocytes (p = 0.0001), and T-regulatory cells (p = 0.0001) along with a significant decrease in natural killer cells (p = 0.0003). Treatment was also associated with altered patient immune profiles. The use of dexamethasone was associated with an increased count of B-memory (p = 0.0001) and B-naïve cells (p = 0.0001), monocytes (p = 2.1e-5), and neutrophils (p = 3.7e-6) post-surgery. Patients receiving chemoradiation (n = 12) exhibited significant and temporally sustained decreases in B-memory (p &lt; 0.0001), B-naïve (p = 0.005), CD4 naïve cells (p = 0.002), and in neutrophils (p = 0.001). Patient follow-up, data collection, and further analyses are ongoing. These results shed light on the dynamic and variable immune changes in LrGG patients and provide a guide for future prognostic and therapeutic studies.
BIOM-43. LOSS OF NF1 PROTEIN EXPRESSION IS A POOR PROGNOSTIC BIOMARKER IN A SUBSET OF IDH-WILDTYPE GLIOBLASTOMA
Authors: Chang Michael , Chinnasamy Viveka , Ioannou Maria , Rodriguez Fausto , Lucas Calixto-Hope , Schreck Karisa 
Published: November 2023

Abstract

BACKGROUND
Loss of NF1, a tumor suppressor and negative regulator of RAS signaling, is common in IDH-wildtype glioblastoma and occurs through two primary mechanisms – genomic inactivation or proteasomal degradation. NF1 loss is associated with poor clinical outcomes but may also confer sensitivity to MEK inhibitors in some tumors. No clinically validated biomarker for NF1 loss exists, limiting clinical development of therapeutics for these patients. Here, we describe an immunohistochemical biomarker for NF1 expression in IDH-wildtype glioblastoma.

METHODS
We constructed a tissue microarray of 73 genomically-characterized glioblastoma treated at Johns Hopkins - 45 NF1-wildtype and 28 NF1-mutant. Immunohistochemistry was performed to assess NF1 expression, then correlated with clinical and genomic characteristics.

RESULTS
Among NF1-mutant tumors, NF1 expression was lost in 17 specimens (77%) and retained in 5 (23%). Among NF1-wildtype tumors, NF1 expression was lost in 11 (25%), equivocal in 3 (7%), and retained in 30 (68%). Loss of NF1 expression was mutually exclusive with EGFR alterations (p = 0.034) but co-occurred with alterations in TSC2 (p = 0.02) and PIK3R1 (p = 0.049), consistent with our larger genomic patient dataset (n = 277). Loss of NF1 expression was associated with decreased median overall survival (7.3 vs 14.4 months, p = 0.027), even after correcting for prognostic variables (age, MGMT promoter methylation, extent of resection, treatment). This survival difference was driven by the subset of patients with intact genomic NF1 but loss of NF1 expression. Median overall survival in this subset (n = 11) compared to the rest of the cohort (n = 49) was 4.1 vs 13.2 months (p&lt; 0.0001). Cox proportional hazards model correcting for prognostic variables revealed HR 5.4 (95%CI 1.94-15, p = 0.001) associated with loss of NF1 expression.

CONCLUSION
Loss of NF1 expression assessed by immunohistochemistry, particularly when paired with genomically-intact NF1, correlates with inferior outcomes in patients with glioblastoma. These results will need to be validated in a larger cohort.