bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Meaning and Measure of Concordance Factors in Phylogenomics
Authors: Lanfear Robert , Hahn Matthew W 
Published: October 2024

Abstract
As phylogenomic datasets have grown in size, researchers have developed new ways to measure biological variation and to assess statistical support for specific branches. Larger datasets have more sites and loci and therefore less sampling variance. While we can more accurately measure the mean signal in these datasets, lower sampling variance is often reflected in uniformly high measures of branch support—such as the bootstrap and posterior probability—limiting their utility. Larger datasets have also revealed substantial biological variation in the topologies found across individual loci, such that the single species tree inferred by most phylogenetic methods represents a limited summary of the data for many purposes. In contrast to measures of statistical support, the degree of underlying topological variation among loci should be approximately constant regardless of the size of the dataset. “Concordance factors” (CFs) and similar statistics have therefore become increasingly important tools in phylogenetics. In this review, we explain why CFs should be thought of as descriptors of topological variation rather than as measures of statistical support, and argue that they provide important information about the predictive power of the species tree not contained in measures of support. We review a growing suite of statistics for measuring concordance, compare them in a common framework that reveals their interrelationships, and demonstrate how to calculate them using an example from birds. We also discuss how measures of topological variation might change in the future as we move beyond estimating a single “tree of life” toward estimating the myriad evolutionary histories underlying genomic variation.
Clinical study on the utility of allergy tests to detect IgE-mediated anaphylaxis after diclofenac etalhyaluronate administration
Authors: Okayama Yoshimichi , Hayama Koremasa , Takada Shuhei , Muramatsu Dai , Nobuoka Yuji , Yagami Akiko 
Published: October 2024

ABSTRACT

Objectives
This study was conducted to investigate factors involved in anaphylaxis related to diclofenac etalhyaluronate (DEH) [product name: Joyclu® (JCL)] (containing DEH and macrogol 400), which is used to treat patients with osteoarthritis.

Methods
Patients with osteoarthritis were divided into two groups that had (experienced patients) or had not experienced anaphylactic symptoms after JCL administration (nonexperienced patients). Five tests performed to assess factors related to anaphylaxis consisted of a skin prick test as the primary endpoint and the other tests including basophil activation test, allergen-specific IgE tests using enzyme-linked immunosorbent assay or immunochromatographic kits, and genetic study were secondary endpoints.

Results
The skin prick test showed 4 (wheal)/7 (erythema) of 15 experienced patients and 0/3 of 19 nonexperienced patients were positive for any of the test reagents containing DEH. The basophil activation test showed two experienced patients were positive for test reagents containing DEH. DEH- and diclofenac-allergen-specific IgE were detected in 3 and 1 of 12 experienced patients, respectively. No clear results were shown in the other tests.

Conclusions
DEH may be the main factor involved in the development of anaphylaxis. The skin prick test was more sensitive than the basophil activation and allergen-specific IgE tests for identifying factors associated with anaphylaxis.
SpatialRef: a reference of spatial omics with known spot annotation
Authors: Cui Ting , Li Yan-Yu , Li Bing-Long , Zhang Han , Yu Ting-Ting , Zhang Jia-Ning , Qian Feng-Cui , Yin Ming-Xue , Fang Qiao-Li , Hu Zi-Hao , Yan Yu-Xiang , Wang Qiu-Yu , Li Chun-Quan , Shang De-Si 
Published: October 2024

Abstract
Spatial omics technologies have enabled the creation of intricate spatial maps that capture molecular features and tissue morphology, providing valuable insights into the spatial associations and functional organization of tissues. Accurate annotation of spot or domain types is essential for downstream spatial omics analyses, but this remains challenging. Therefore, this study aimed to develop a manually curated spatial omics database (SpatialRef, https://bio.liclab.net/spatialref/), to provide comprehensive and high-quality spatial omics data with known spot labels across multiple species. The current version of SpatialRef aggregates &gt;9 million manually annotated spots across 17 Human, Mouse and Drosophila tissue types through extensive review and strict quality control, covering multiple spatial sequencing technologies and &gt;400 spot/domain types from original studies. Furthermore, SpatialRef supports various spatial omics analyses about known spot types, including differentially expressed genes, spatially variable genes, Gene Ontology (GO)/KEGG annotation, spatial communication and spatial trajectories. With a user-friendly interface, SpatialRef facilitates querying, browsing and visualizing, thereby aiding in elucidating the functional relevance of spatial domains within the tissue and uncovering potential biological effects.
Mycobacterium smegmatis NucS-promoted DNA mismatch repair involves limited resection by a 5′-3′ exonuclease and is independent of homologous recombination and NHEJ
Authors: Rivera-Flores Iris V , Wang Emily X , Murphy Kenan C 
Published: October 2024

Abstract
The MutSL mismatch repair (MMR) systems in bacteria and eukaryotes correct mismatches made at the replication fork to maintain genome stability. A novel MMR system is represented by the EndoMS/NucS endonuclease from Actinobacterium Corynebacterium glutamicum, which recognizes mismatched substrates in vitro and creates dsDNA breaks at the mismatch. In this report, a genetic analysis shows that an M. smegmatis ΔnucS strain could be complemented by expression of wild type NucS protein, but not by one deleted of its last five amino acids, a region predicted to be critical for binding to the β-clamp at the replication fork. Oligo-recombineering was then leveraged to deliver defined mismatches to a defective hygromycin resistance gene on the M. smegmatis chromosome. We find that NucS recognizes and repairs G-G, G-T, and T-T mismatches in vivo, consistent with the recognition of these same mismatches in C. glutamicum in vitro, as well as mutation accumulation studies done in M. smegmatis. Finally, an assay that employs an oligo that promotes the generation of two mismatches in close proximity on the chromosome shows that a NucS-promoted cut is processed by a 5′–3′ exonuclease (or 5'-Flap endonuclease) and that NucS-promoted MMR is independent of both homologous recombination and non-homologous end-joining.
PL01.4.A COMPUTATIONAL HISTOPATHOLOGY ENABLES HIGH-GRANULARITY DIAGNOSTICS IN CNS TUMOURS
Authors: Shmatko A , Jin D , Patel A , Rahmanzade R , Wick W , Krieg S , Pfister S M , Jones D T W , von Deimling A , Gerstung M , Sahm F 
Published: October 2024

Abstract

BACKGROUND
The recent WHO classification of CNS tumours has increased the number of molecular markers recommended for making a WHO-compatible diagnosis. Particularly, DNA methylation-based classification pioneered by the Heidelberg MNP classifier has emerged as a powerful tool for CNS tumour diagnostics. However, high costs, both in terms of time and resources, along with the need for skilled personnel and expensive equipment, have limited the adoption of such techniques to larger centres. Computational methods like deep learning have proven useful in tasks such as tumour subtyping, identifying genetic alterations and predicting treatment responses. The recent advent of self-supervised learning and multiple-instance learning (MIL) has enhanced the accuracy and generalisation of these models, simultaneously reducing the dataset size requirements, thus bringing computational histopathology closer to clinical applications.

MATERIAL AND METHODS
To enable broader accessibility of precision diagnostics for CNS tumours and alleviate the need for molecular profiling, we introduce Paiean (Precision AI-enabled Neuropathology) - a computational histopathology pipeline that predicts the diagnostically relevant classes in line with the Heidelberg MNP classifier using only H&E stained whole-slide images (WSI). We designed a neural network architecture implemented in a MIL paradigm. Paiean employs a CTransPath pretrained feature extractor to identify and analyse relevant histological patterns and was fine-tuned on an in-house dataset of CNS tissue WSIs using the MoCo v3 contrastive objective. We trained the model on a dataset of 8,000 H&E stained FFPE WSIs with matched methylation data from the Dept. of Neuropathology, University Hospital Heidelberg. We validated the model on 5 independent external datasets. Additionally, we compared the model to evaluations by 9 board-certified pathologists from across the world.

RESULTS
Paiean could reliably predict 108 classes of CNS tumours in 72.19% cases. Moreover, for high-confidence predictions (confidence &gt; 0.5), the accuracy increased to 87.52%. We achieved an accuracy of 65.12% on the multi-center external datasets. The model outperformed the human evaluators by an average of 30.17%.

CONCLUSION
Our work demonstrates that deep learning can supplement conventional methods for molecular diagnostics in CNS tumours. Paiean requires only H&E WSI, covers 108 diagnostically relevant tumour types and has a turnaround time of under an hour from sample to result. We provide an interface that can be easily run on consumer-grade hardware without extensive bioinformatics expertise. Since H&E slides are readily used in routine tumour diagnostics worldwide, Paiean presents a rapid and cost-effective tool to incorporate molecular information into diagnostic decisions, thereby making precision medicine accessible worldwide.
JS03.7.A COMBINATION OF CDK4/6 AND MEK INHIBITION INCREASES ANTITUMOR EFFECTS IN PEDIATRIC HIGH-GRADE GLIOMA HARBORING BRAF MUTATION AND CDKN2A/B LOSS
Authors: Mayr L , Mager L , Lang A , Madlener S , Gabler L , Bruckner K , Machreich S , Jaunecker C , Senfter D , Kirchhofer D , Lämmerer A , Zeitler G , Dorfer C , Haberler C , Schwark K , Lau B , Müllauer L , Koschmann C , Berger W , Gojo J , Lötsch-Gojo D 
Published: October 2024

Abstract

BACKGROUND
Pediatric high-grade gliomas (pHGG) comprise a heterogenous group of tumors characterized by rapid growth and dismal overall survival. Besides maximum safe resection, irradiation and chemotherapy, molecularly-defined therapeutic interventions are still missing. BRAFV600E mutations are detected in 5-10% of pHGG and this subgroup frequently harbors a concurrent homozygous CDKN2A/B loss. Taking advantage of those molecular alterations is of utmost importance to improve overall survival in these patients. Thus, we hypothesize that a combination of MEK and CDK4/6 inhibition lead to prolonged anti-tumor effects in this patient subgroup when compared to monotherapy.

MATERIAL AND METHODS
Four HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss were tested for the efficacy of CDK4/6 inhibitor monotherapy (palbociclib, ribociclib, abemaciclib) and/or combined with the MEK inhibitor trametinib. Drug response, induction of apoptosis, cell cycle alterations and senescence were evaluated upon short- and long-term exposure using cell-based assays. Effects on intracellular signaling cascades were determined by western blot and immunostainings in cell and patient-derived xenograft (subcutaneous and orthotopic) models. Clinical efficacy of combined treatment was further investigated in one patient suffering from progressive metastatic BRAF-altered anaplastic pleomorphic xanthoastrocytoma (aPXA).

RESULTS
Besides trametinib, the investigated cell models showed the highest sensitivity to abemaciclib, thus we assumed that combination of these two inhibitors would be most suitable in vitro. The simultaneous application of both drugs induced apoptosis and the effect on tumor cell senescence was even superior with the combined treatment. Regarding signal transduction, solely the combination of MEK and CDK4/6 inhibitors reduced PI3K activation at the level of S6. To confirm our findings, in vivo experiments in PDX models were conducted. Significantly increased overall survival and antitumor effects were observed with the combination of both inhibitors when compared to single-agent treatment. Corroboratively, one patient suffering from progressive metastatic aPXA with BRAF mutation and CDKN2A/B loss was successfully treated with trametinib and ribociclib showing stable diseases for two years.

CONCLUSION
Summarizing, our results suggest that combined treatment with MEK and CDK4/6 inhibitors represent a promising treatment strategy in pHGG harboring simultaneous BRAF mutation and CDKN2A/B loss.
JS06.6.A COPENHAGEN GRADING FOR MENINGIOMA
Authors: Haslund-Vinding J L , Skjoth-Rasmussen J , Law I , Fugleholm K B , Meling T R , Poulsgaard L , Maier A D , Larsen V A , Forsse A , Henriksen O M , Madsen K , Mirian C , Poulsen F R , Förrander P , Santarius T , Bartek J J , Scheie D , Ziebell M , Kristensen B W , Mathiesen T 
Published: October 2024

Abstract

BACKGROUND
The extent of meningioma resection is the most fundamental risk factor for recurrence and exact knowledge of extent of resection is necessary for prognostication and for planning of adjuvant treatment. Currently used classifications are the EANO-grading and the Simpson grading. The former comprises radiological imaging with contrast-enhanced MRI and differentiation between “gross total removal” and “subtotal removal”, while the latter comprises a five-tiered differentiation of the surgeon’s impression of the extent of resection. The extent of resection of tumors is usually defined via analyses of resection margins but has until now not been implemented for meningiomas. PET/MRI imaging with 68Ga-DOTATOC allows more sensitive and specific imaging than MRI following surgery of meningiomas.

OBJECTIVE
To develop an objective grading system based on microscopic analyses of resection margins and sensitive radiological analyses to improve management of follow-up, adjuvant therapy and prognostication of meningiomas. Based on the rationale of resection-margin analyses as gold standard and superior imaging performance of 68Ga DOTATOC PET, we propose “Copenhagen Grading” for meningiomas.

PRELIMINARY RESULTS
Since April 2021, Copenhagen Grading has been implemented prospectively as a clinical standard at Rigshospitalet, Copenhagen, with 264 patients enrolled thus far. DOTATOC PET was used for follow-up in 212 subjects, while resection margin biopsies were obtained from 90 subjects. DOTATOC-PET revealed residual tumor in 33% (55/168) of cases where MRI results were inconclusive and in 28% (47/168) of cases where MRI showed no residual tumor.

CONCLUSION
Copenhagen Grading offers a comprehensive, logical, and reproducible means of defining resection extent, showing potential as the most sensitive and specific grading. Further long term evaluation of the clinical implication of biopsies and the cost-effectiveness of DOTATOC PET is necessary during the prospective implementation.
JS07.6.A MULTI-OMICS AND DRUG RESPONSE ASSESSMENTS IN LONGITUDINAL PATIENT AVATARS UNVEIL PATIENT-SPECIFIC RECURRENCE TRAJECTORIES AND DRUG SUSCEPTIBILITIES IN GLIOBLASTOMA
Authors: Lipsa A , Nosirov B , Ermini L , Hau A , Klein E , Yabo Y A , Mittelbronn M , Hertel F , Nazarov P V , Niclou S P , Golebiewska A 
Published: October 2024

Abstract

BACKGROUND
Glioblastomas (GBMs) have the worst prognosis of all adult brain tumours. Despite the aggressive standard-of-care, including surgery, radio- and chemotherapy, tumours inevitably recur and median survival remains at 18 months. GBMs exhibit complex changes at recurrence, although no common evolutionary trajectory has been identified yet. Such molecular evolution may lead to functional changes in drug response patterns. Investigations of longitudinal heterogeneity of paired primary-recurrent tumours using high resolution multi-omics profiling combined with functional investigations in matched patient avatars can provide clinically-relevant insights into tumour evolution at the individual patient level.

MATERIAL AND METHODS
We applied a cohort of longitudinal patient tumors and preclinical models derived thereof, propagated as primary organoids and orthotopic xenografts. Our cohort includes a unique collection of paired primary-recurrent patient avatars derived from 8 patients during their standard-of-care disease trajectory. We performed a comprehensive multi-omics profiling, including transcriptomics (bulk and single cell RNA-seq), epigenomics (DNA methylation arrays), genomics (targeted DNA-seq) and proteomics (LC-MS) to identify molecular evolution of tumors at recurrence. We further carried out an ex-vivo functional drug screen with a pharmacologically diverse 1482 compound library targeting cancer pathways and epigenetic modifiers.

RESULTS
High-resolution multi-omics analysis of longitudinal patient tumours and patient avatars identified patient-specific evolution of the primary tumours at recurrence following surgical resection and treatment pressure. While certain GBMs recurred without major molecular adaptation, others showed significant (epi)genetic and transcriptomic evolution towards new genetic clones and/or transcriptomic states. Majority of drug responses were similar in primary and recurrent tumours and were patient-specific. Interestingly, we observed selective susceptibilities to several epigenetic modifiers, especially Histone Deacetylase (HDAC) and Aurora Kinase (AURK) inhibitors in certain primary tumours, which were lost at recurrence.

CONCLUSION
Our study demonstrates the importance of combined omics and functional profiling to reveal clinical implications of longitudinal evolutionary trajectories in GBMs. Our findings imply that the impact of potentially effective drugs may differ between newly diagnosed and recurrent GBMs that might have implications in precision therapy strategies.
OS01.5.A MEASURABLE DISEASE AS BASELINE CRITERION FOR RESPONSE ASSESSMENT IN GLIOBLASTOMA TRIALS - A COMPARISON OF THE MRI-BASED (RANO 2.0) VERSUS PET-BASED (PET RANO 1.0) ASSESSMENT
Authors: Müller K J , Forbrig R , Reis J , Wiegand L , Barci E , Kunte S , Kaiser L , Schönecker S , Schichor C , Harter P , Thon N , von Baumgarten L , Preusser M , Albert N L 
Published: October 2024

Abstract

BACKGROUND
The baseline criterion for response assessment in IDH-wildtype glioblastoma relies on measuring contrast enhancement, known as ‘measurable disease’ on MRI. Recently, criteria based on amino acid PET have been proposed for response assessment in clinical glioblastoma trials (PET RANO 1.0 criteria). Here, we compare ‘measurable disease’ as defined by PET RANO 1.0 criteria with the standard MRI-based RANO 2.0 criteria in patients with newly diagnosed IDH-wildtype glioblastoma.

MATERIAL AND METHODS
In this retrospective single-center study, we identified patients with newly diagnosed IDH-wildtype glioblastoma who underwent [18F]FET PET and MRI after resection or biopsy (if non-operable) and before chemoradiotherapy. This timepoint aligns with the baseline recommended by PET RANO 1.0. Two independent investigators analyzed ‘measurable disease’ according to PET RANO 1.0 versus MRI-based RANO 2.0 criteria. Additionally, lesion size and uptake intensity, including maximal and mean target-to-background ratio (TBRmax, TBRmean) were assessed.

RESULTS
We evaluated 132 patients (median age 60.5 years, 40.2% females) with 87 cases after biopsy and 45 after resection. Using RANO 2.0, a total of 49/132 (37.1%) patients had measurable disease (median sum of maximum perpendicular diameters: 36.3mm). However, with PET RANO 1.0, a significantly higher proportion (117/132, 88.6%, p&lt;0.001) had measurable disease (median TBRmax: 3.4; median TBRmean: 2.0; median PET volume: 17.6cm3). None of the 15 patients without measurable disease on PET had measurable disease on MRI, while 68/83 (81.9%) of patients without measurable disease on MRI exhibited measurable disease on PET. Conclusion: PET RANO 1.0 identifies a significantly higher number of patients with ‘ measurable disease’ compared to conventional MRI-based criteria in the perioperative period of newly diagnosed glioblastoma. PET-based assessment may thus serve as a novel baseline parameter for evaluating treatment response and outcome in glioblastoma trials, that may allow enrollment of larger patient populations. Further validation in prospective trials is warranted.
OS02.6.A COORDINATION OF CARE IN THE CONTEXT OF PRIMARY BRAIN TUMOURS: HEALTHCARE PROFESSIONALS’ EXPLORATION OF THE UNSPOKEN IMPACT AND CLINICAL IMPLICATIONS
Authors: Jeon M S , Shaw J , Banks H , Legge D M , He S , Carlick T , Koh E S , Halkett G , Kelly B , Pinkham M B , Ownsworth T , Chan R J , Dhillon H 
Published: October 2024

Abstract

BACKGROUND
People with primary brain tumours (PwBT) and their families expereince high distress and face challenges navigating the disease, healthcare system, treatment, and/or survivorship. Coordination of care is an approach to achieving continuous, timely care according to individual care needs of PwBT. Within the Brain Cancer Rehabilitation, Assessment, Interventions for Survivorship Needs (BRAINS) program, we aimed to explore healthcare professionals’ (HCPs) practices and perceptions about neuro-oncology care coordination (NOCC).

MATERIAL AND METHODS
We conducted a qualitative study using semi-structured interviews via videoconferencing. Participants were HCPs involved in clinical neuro-oncology care. Interviews were audio-recorded and transcribed verbatim. Data were analysed thematically using interpretive description, following COREQ guidelines for conducting and reporting qualitative research.

RESULTS
We interviewed 12 HCPs from Australia and Aotearoa New Zealand between June and November 2023. The median interview duration was 58 minutes. Participants had a median of 13 years of clinical experience in neuro-oncology across medical, nursing, and allied health disciplines. NOCC models were not standardised. Often they were not clearly established and depended on HCPs’ knowledge, experience, and skillsets for triaging care or managing advanced illnesses. HCPs typically oversaw NOCC in either the neurosurgical or oncology care phases but not both. We identified five themes related to NOCC as perceived by HCPs: 1) Vulnerable and complex: PBT is a unique cancer generating pervasive, multifaceted disabilities; 2) Tailored coordination: Shaping and tailoring NOCC is in the best interests of PwBT and families; 3) Unfunded support: Care needs warrant unfunded proactive support; 4) Role limitations: Limited resources impact HCPs’ capacity to deliver the optimal standard of care; and 5) Emotionally demanding: HCPs manage emotional weight with limited support.

CONCLUSION
PwBT experience a unique and complex set of care needs requiring specialist skills and knowledge beyond general oncology care coordination. NOCC encompasses continuous coordination of multidisciplinary care to optimise functional living for PwBT. Recognising the NOCC role in managing a vast array of issues, better support infrastructure with training and resources for HCPs is needed to retain HCPs and prevent burnout, which will provide greater access to NOCC for PwBT and carers. The findings will inform further research to identify support, training and resource needs for HCPs and implement appropriate interventions.

FUNDING
The study is funded by the MRFF Australian Brain Cancer Mission Brain Cancer Survivorship Grant.