bluuebunny/crossref_metadata_2025_split huggingface dataset:
A geostatistical analysis of multiscale metallicity variations in galaxies – I. Introduction and comparison of high-resolution metallicity maps to an analytical metal transport model
Authors: Metha Benjamin , Trenti Michele , Chu Tingjin 
Published: September 2021

ABSTRACTThanks to recent advances in integral field spectroscopy, modern surveys of nearby galaxies are capable of resolving metallicity maps of H ii regions down to scales of ∼50 pc. However, statistical analyses of these metallicity maps has seldom gone beyond fitting basic linear regressions and comparing parameters to global galaxy properties. In this paper (the first of a series), we introduce techniques from spatial statistics that are well suited for detailed analysis of both small- and large-scale metallicity variations within the interstellar medium (ISM) of local galaxies. As a first application, we compare the observed structure of small-scale metallicity fluctuations within seven local galaxies observed by the Physics at High Angular resolution in Nearby GalaxieS (PHANGS) collaboration to predictions from a stochastic, physically motivated, analytical model developed by Krumholz & Ting. We show that while the theoretical model underestimates the amount of correlated scatter in the galactic metallicity distributions by 3–4 orders of magnitude, it provides good estimates of the physical scale of metallicity correlations. We conclude that the ISM of local spiral galaxies is far from homogeneous, with regions of size ∼1 kpc showing significant departures from the mean metallicity at each galactocentric radius.
Structural dissection of sequence recognition and catalytic mechanism of human LINE-1 endonuclease
Authors: Miller Ian , Totrov Max , Korotchkina Lioubov , Kazyulkin Denis N , Gudkov Andrei V , Korolev Sergey 
Published: September 2021

Abstract
Long interspersed nuclear element-1 (L1) is an autonomous non-LTR retrotransposon comprising ∼20% of the human genome. L1 self-propagation causes genomic instability and is strongly associated with aging, cancer and other diseases. The endonuclease domain of L1’s ORFp2 protein (L1-EN) initiates de novo L1 integration by nicking the consensus sequence 5′-TTTTT/AA-3′. In contrast, related nucleases including structurally conserved apurinic/apyrimidinic endonuclease 1 (APE1) are non-sequence specific. To investigate mechanisms underlying sequence recognition and catalysis by L1-EN, we solved crystal structures of L1-EN complexed with DNA substrates. This showed that conformational properties of the preferred sequence drive L1-EN’s sequence-specificity and catalysis. Unlike APE1, L1-EN does not bend the DNA helix, but rather causes ‘compression’ near the cleavage site. This provides multiple advantages for L1-EN’s role in retrotransposition including facilitating use of the nicked poly-T DNA strand as a primer for reverse transcription. We also observed two alternative conformations of the scissile bond phosphate, which allowed us to model distinct conformations for a nucleophilic attack and a transition state that are likely applicable to the entire family of nucleases. This work adds to our mechanistic understanding of L1-EN and related nucleases and should facilitate development of L1-EN inhibitors as potential anticancer and antiaging therapeutics.
PL02.3. A Phenotypic heterogeneity and plasticity as resistance mechanisms in Glioblastoma
Authors: Yabo Y Y , Oudin A , Skupin A , Nazarov P V , Niclou S P , Golebiewska A 
Published: September 2021

Abstract

BACKGROUND
Glioblastomas are among the most heterogeneous tumors, which hampers patient stratification and development of effective therapies. Glioblastomas create a dynamic ecosystem, where heterogeneous tumor cells interact with the tumor microenvironment to establish different niches. Upon tumor growth, Glioblastoma cells manifest remarkable plasticity and respond flexibly to selective pressures by transiting towards states favorable to the new tumor microenvitonment. How this phenotypic plasticity contributes to treatment resistance is currently less clear. The exact nature of treatment resistant, tolerant and sensitive Glioblastoma cells remains unresolved. Further studies at the single cell level are needed to reveal transient and long-term signatures of the resistant states.

MATERIAL AND METHODS
To investigate long-term phenotypic changes upon treatment at the single cell level we performed single cell RNA-seq (scRNA-seq) on the longitudinal patient-derived xenograft (PDOX) models derived from Glioblastoma patient tumors prior and after the standard-of-care treatment. In addition, direct treatment of PDOXs with temozolomide combined with scRNA-seq allowed revealing short-term transcriptomic changes both in tumor cells and in the mouse-derived cells forming tumor microenvironment. Advanced computational algorithms, including reference-free deconvolution methods, were applied to reveal treatment resistance signatures and master regulators of the identified treatment-resistant subpopulations.

RESULTS
We show that PDOX models recapitulate all the major cell types and transcriptional programs reported in Glioblastoma patient samples, providing clinically relevant models for investigating treatment resistance signatures of tumor cells and associated tumor microenvironment. Analysis of treatment naïve and treated Glioblastomas at the single cell level revealed presence of pre-existing treatment resistant states as well as newly established resistant subpopulatons. Certain transcriptomic changes are preserved long term, regardless of the lack of genetic evolution of the tumor cells.

CONCLUSION
Phenotypic plasticity is an important factor contributing to resistance mechanisms in Glioblastoma. Key molecular regulators of tumor cell plasticity towards treatment resistance states represent novel targets for future combinatory treatments.
PL02.4.A Chromosome 1p19q codeletion frequency, but not survival, varies according to the IDH mutation subtypes: analysis of 1050 IDH-mutated diffuse gliomas
Authors: Picca A , Berzero G , Di Stefano A , Trabelsi N , Bielle F , Sanson M 
Published: September 2021

Abstract

BACKGROUND
recurring hotspot mutations in isocitrate dehydrogenase (IDH) 1 enzymes, and to a lesser extent IDH2, are the main oncogenic alteration in most of lower-grade diffuse gliomas and a subset of grade 4 gliomas. Although most commonly represented by the IDH1R132H mutation, non-canonical IDH1/2-nonR132H mutations are present in about 10% of cases. As the neomorphic enzymatic activity can vary depending on the type of the hotspot mutation, a different biological behaviour may be inferred. Nevertheless, the prognostic significance of the different IDH1/2 mutations remains a matter of debate.

MATERIAL AND METHODS
we queried the OncoNeuroTek tumor bank (Pitié-Salpêtrière Hospital, Paris) to identify all registered cases of IDH-mutated diffuse gliomas. Most relevant clinical and molecular data were collected.

RESULTS
We identified 1050 IDH mutated diffuse gliomas (481 grade 2 [46%], 459 grade 3 [44%], and 110 grade 4 [10%]), of which 1007 (96%) were IDH1 mutated (934 IDH1R132H [89%] and 73 IDH-nonR132H [7%]) and 43 (4%) were IDH2 mutated (24 IDH2R172K [2%] and 19 IDH2-nonR172K [2%]). The chromosomes 1p/19q codeletion was more frequent in IDH2-mutated tumors (25/42 [60%] versus 350/918 [38%] in IDH1-mutated cases, p=0.005). Nevertheless, only IDH2R172K mutation was associated with the codeletion (18/24 [75%], versus 7/18 [39%] in IDH2-nonR172K-mutated tumors, p=0.02). IDH1-nonR132H tumors showed the lowest rate of 1p/19q codeletion (9/69 [13%], versus 341/849 [40%] in IDH1R132H-mutated cases, p&lt;0.001). At the time of observation, 536 patients were deceased (51%), with a median overall survival (OS) of 115 months (mo., 95% CI 108–125 mo.). Median follow up for censored patients was 77 mo. Codeleted patients had a significantly longer OS compared to non-codeleted ones (179 vs. 96 mo., p&lt;0.001). No significant differences in survival were seen when stratifying according to IDH mutation type (115 mo. for IDH1R132H vs. 136 mo. for IDH1-nonR132H vs. 112 mo. for IDH2R172K vs. 150 mo. for IDH2-nonR172K, p=0.8). No differences were seen when restricting the analysis to codeleted or not-codeleted patients only, respectively. In a multivariate analysis including the main prognostic factors (age, sex, preoperative performance status, tumor grade, surgical resection, midline location, 1p/19q codeletion, and p16 homozygous deletion), no survival difference was associated with any of the IDH mutation subtype.

CONCLUSION
although significantly different rates of 1p/19q codeletion were seen according to the four main IDH mutation subgroups, these groups does not associate with different survival profiles in our cohort.
KS01.6.A Comparative analysis of the immune compartment in human glioblastoma and IDH-mutant WHO grade 4 astrocytoma reveals profound differences in microglia phenotypes
Authors: Sankowski R , Friedrich M , Bunse L , Heiland H H , Platten M , Prinz M 
Published: September 2021

Abstract

BACKGROUND
Glioblastoma (GBM) are the most common primary brain tumors. If untreated the average survival is around 12–18 months. Unfortunately, despite extensive research efforts, the therapeutic options remain limited. One major aspect complicating therapeutic development is an immunosuppressive tumor microenvironment. Isocitrate dehydrogenase (IDH)-mutant, WHO grade 4 astrocytomas appear histologically indistinguishable from GBM, but show significantly longer survival times. IDH mutations lead to changes in the tumor microenvironment with accrual of the neometabolite R-2-hydroxyglutarate. Previous studies on bulk transcriptomes have shown differences in the immune compartment of both tumor entities that were linked to the differences in clinical behavior.

MATERIAL AND METHODS
We have conducted high-dimensional comparative analyses of the myeloid compartment in surgically resected human GBM and IDH-mutant WHO grade 4 astrocytomas using single-cell RNA-Sequencing and immunohistochemistry. Histologically normal brain regions from epilepsy patients were used as controls. For analysis, whole-cell suspensions were prepared from freshly resected tumors or controls. Fluorescence activated cell sorting was used for myeloid cell enrichment. Samples were processed using the high-sensitivity single-cell RNA sequencing protocol CEL-Seq2. Seurat and StemID2 algorithms were used for clustering, differential gene expression and pseudotime analysis. Protein validation was achieved using immunohistochemistry.

RESULTS
We identified profound transcriptional changes of glioma-associated microglia in GBM with respect to control brain samples. Namely, we observed a global upregulation of major histocompatibility complex associated genes in GBM across all clusters. Additionally, we identified distinct myeloid subsets with phagocytic, hypoxia-associated and chemotactic transcriptomic signatures. Pseudotime analysis finely resolved transitional cell states. These changes were dramatically attenuated in IDH-mutant WHO grade 4 astrocytomas. The myeloid cells in these tumors resembled homeostatic microglia and showed an increased expression of cytokine and chemokine genes.

CONCLUSION
Here, we present a high-dimensional transcriptomic atlas of the myeloid compartment in human GBM and IDH-mutant WHO grade 4 astrocytomas. The identified differences point towards targeted therapeutic options via the modulation of the tumor microenvironment.
OS05.9.A Short-term fasting in glioma patients - Analysis of diet diaries and metabolic parameters of the ERGO2 trial
Authors: Voss M , Wenger K J , von Mettenheim N , Bojunga J , Vetter M , Diehl B , Gerlach R , Ronellenfitsch M W , Franz K , Harter P N , Hattingen E , Steinbach J P , Rödel C , Rieger J 
Published: September 2021

Abstract

BACKGROUND
The prospective, randomized ERGO2 trial investigated the effect of fasting / calorie restricted ketogenic diet (KD-IF) on re-irradiation for recurrent brain tumors (Clinicaltrials.gov number: NCT01754350). The study did not meet its primary endpoint of improved progression-free survival in comparison to a standard diet (SD). We here report the results of the quality of life questionnaire, neurocognition testing, detailed analysis of the diet diaries and the alterations of metabolic parameters.

MATERIAL AND METHODS
50 Patients were randomized 1:1 to re-irradiation combined with either SD or KD-IF. The KD-IF schedule included 3 days of ketogenic diet (KD: 21–23 kcal/kg/d, carbohydrate intake limited to 50 g/d), followed by 3 days of fasting and again 3 days of KD. Follow-up included examination of cognition, quality of life and serum samples.

RESULTS
The 20 patients who completed KD-IF met the prespecified goals for calorie and carbohydrate restriction. In these, a decrease in leptin and insulin and an increase in uric acid was observed. The SD group had a lower calorie intake of 21 kcal/kg/d than the expected 30 kcal/kg/d. Neither quality of life nor cognition were affected by the diet. Low glucose emerged as a significant prognostic parameter in a best responder analysis.

CONCLUSION
The strict caloric goals of the ERGO2 trial could be achieved by patients with recurrent brain tumor. The unexpected lower calorie intake of the SD group might have hampered the interpretation of the trial. However, the short diet schedule already led to significant metabolic alterations, suggesting that short-term dietary interventions might be therapeutically useful, possibly combined with other modalities.
OS10.8.A The effectiveness of antiepileptic drug duotherapies in glioma patients: a multicenter observational cohort study
Authors: van der Meer P B , Dirven L , Fiocco M , Vos M , Kouwenhoven M C M , van den Bent M J , Taphoorn M J B , Koekkoek J A F 
Published: September 2021

Abstract

BACKGROUND
About 30% of glioma patients need an add-on antiepileptic drug (AED) due to uncontrolled seizures on AED monotherapy. This study aimed to determine whether levetiracetam combined with valproic acid (LEV+VPA), a commonly prescribed duotherapy, is more effective than other duotherapy combinations including either LEV or VPA in glioma patients.

MATERIAL AND METHODS
In this multicenter retrospective observational cohort study, treatment failure (i.e. replacement by or addition of a new AED, or withdrawal of an AED) for any reason was the primary outcome. Secondary outcomes included: 1) treatment failure due to uncontrolled seizures; and 2) treatment failure due to adverse effects. Time to treatment failure was defined as the time from the start of AED duotherapy until the time of treatment failure. Multivariable Cox proportional hazard models were estimated to study the association between risk factors and treatment failure. The maximum duration of follow-up was 36 months.

RESULTS
A total of 1435 patients were treated with first-line monotherapy LEV or VPA, of which 355 patients received AED duotherapy after they had treatment failure due to uncontrolled seizures on monotherapy. LEV+VPA was prescribed in 66% (236/355) and other AED duotherapy combinations including LEV or VPA in 34% (119/355) of patients. Patients using other duotherapy versus LEV+VPA had higher risk of treatment failure for any reason (cause-specific hazard ratio [csHR]=1.50 [95%CI=1.07–2.12], p=0.020), treatment failure due to uncontrolled seizures (csHR=1.73 [95%CI=1.10–2.73], p=0.018). There were no differences in failure due to adverse effects (csHR=0.88 [95%CI=0.47–1.67]), p=0.703) between the two groups.

CONCLUSION
This observational cohort study suggests that LEV+VPA has better efficacy than other AED combinations. Similar toxicities were experienced in the two groups.
OS14.4.A The Neuroplastic Potential of the Human Brain before and After Glioma Surgery: Towards “Interventional Neurorehabilitation
Authors: Poologaindran A , Romero-Garcia R , Hart M , Young I , Santarius T , Price S , Sinha R , Profyris C , Profyris C , Erez Y , Teo C , Sughrue M , Suckling J 
Published: September 2021

Abstract

INTRODUCTION
The human brain is a highly neuroplastic ‘complex’ network: it self-organises without a hard blueprint, adapts to evolving circumstances, and can withstand insults. However, similar to other naturally occurring networks, brain networks can only endure a finite amount of damage before cognitive processes are affected. In this study, we first sought to establish the brain networks governing domain-general cognition (DGC) in healthy individuals across the lifespan. We then sought to map, track, and potentially rehabilitate networks governing DGC through connectomics and non-invasive brain stimulation (NIBS) when damaged by low-grade gliomas (LGG) and surgical oncology.

METHODS
Using MRI and cognitive data from n=629 individuals (aged 18–88, Female= 51%), we assessed the structural, functional, and topological relevance of the spatially-distributed multiple-demand (MD) system for DGC. Next, in n=17 patients undergoing glioma surgery, we longitudinally acquired connectomic and cognitive data at multiple time points: pre-surgery and post-surgery Day 1, Month 3, Month 12. In an independent cohort of n=34 patients, we sought to establish the safety profile for “interventional neurorehabilitation”: connectome-driven NIBS in the acute post-operative period to accelerate cognitive recovery.

RESULTS
In healthy individuals, the MD system across multiple scales of biological organisation was positively associated with higher-order cognition (Catell’s fluid intelligence). In our patients, pre-operative LGG infiltration into the structural MD system was negatively associated with the number of long-term cognitive deficits, suggesting a functional reorganisation. Mixed-effects modelling demonstrated the resilience of the functional MD system to infiltration and resection, while the early post-operative period was critical for effective neurorehabilitation. Graph analyses revealed increased perioperative modularity can distinguish patients with long-term cognitive improvements at one-year follow-up. Finally, NIBS within two weeks post-craniotomy had a 90% (n=31/34) recruitment rate into the trial. There were no seizures or serious complications due to NIBS in this patient population. Transient headaches and tingling were reported in a minority of patients.

CONCLUSION
For the first time, we elucidate long-term cognitive and network trajectories following LGG surgery while establishing a positive safety-profile for NIBS in the acute post-operative period. We argue that “mesoscale” brain mapping serves as a robust biomarker for intervention-related plasticity for future clinical trials. While we performed these experiments in the context of neurosurgery, connectomics and NIBS could be adopted across diverse neuro-oncological care pathways (i.e. chemotherapy/radiation).
OS14.6.A GlioCova: Defining patient safety events for brain tumour patients undergoing neurosurgery
Authors: Mauricaite R , Le Calvez K , Brodbelt A , Bottle A , Williams M 
Published: September 2021

Abstract

BACKGROUND
Surgery is associated with a risk of adverse events (e.g. venous thrombosis). These have been used to define the OECD Patient Safety Event (PSE) indicators (41 diagnostic codes), but not in the brain tumour population. The GlioCova project uses English linked national cancer data on all 51,775 adult primary brain tumour patients (2013–2018).

MATERIAL AND METHODS
We identified all glioblastoma patients having surgery for their tumour and noted the 100 most common ICD-10 diagnostic codes within 30 days of surgery, excluding previous medical conditions, brain tumour diagnosis codes and OECD-defined codes. Potential post-surgical complications were reviewed by a group of experienced clinicians. We reviewed these “novel PSE codes” in all brain tumour patients re-admitted after surgery. We looked at the co-occurrence between our novel and OECD codes and combined them to form the final PSE list.Patients readmitted within 30 days were divided into those without codes (“PSE-free”), and those with at least one PSE code during admission or readmission. We examined age, length of stay, in-hospital and 30-day mortality and assessed statistical significance using Welch’s t-test and a two sample Z-test for proportions.

RESULTS
29,135 patients underwent neurosurgery, of whom 8,361 (28.7%) were readmitted within 30 days. We identified 32 novel PSE codes. 1,319 (16%) patients had an OECD code, 5,524 (66%) had a novel code, and 2,098 (25%) patients were PSE-free. 83% of patients who had an OECD PSE code also had a novel code. Patients in the PSE group were older (median age = 60 years) than the PSE-free group (57 years). Length of stay was longer in patients who had a PSE after surgery (median = 7 days) and after readmission (5 days) compared with PSE-free after surgery (4 days), at readmission (0 days). More patients died in hospital after readmission in the PSE group (4.7%) compared with no-PSE (2.7%). 30-day mortality after surgery was similar in both groups (2.5% PSE-free, 3.1% PSE group). All differences were highly statistically significant (p&lt;0.0001).

CONCLUSION
We identified 32 novel patient safety event codes following surgery in the brain tumour population. Patients with these diagnostic codes had an elevated LOS and in-hospital death rate. Using brain tumour specific PSE codes captures many more events than the existing list of OECD codes.