bluuebunny/crossref_metadata_2025 huggingface dataset:
Deciphering signatures of natural selection via deep learning
Authors: Qin Xinghu , Chiang Charleston W K , Gaggiotti Oscar E
Published: September 2022

Identifying genomic regions influenced by natural selection provides fundamental insights into the genetic basis of local adaptation. However, it remains challenging to detect loci under complex spatially varying selection. We propose a deep learning-based framework, DeepGenomeScan, which can detect signatures of spatially varying selection. We demonstrate that DeepGenomeScan outperformed principal component analysis- and redundancy analysis-based genome scans in identifying loci underlying quantitative traits subject to complex spatial patterns of selection. Noticeably, DeepGenomeScan increases statistical power by up to 47.25% under nonlinear environmental selection patterns. We applied DeepGenomeScan to a European human genetic dataset and identified some well-known genes under selection and a substantial number of clinically important genes that were not identified by SPA, iHS, Fst and Bayenv when applied to the same dataset.
Updated review of advances in microRNAs and complex diseases: taxonomy, trends and challenges of computational models
Authors: Huang Li , Zhang Li , Chen Xing
Published: September 2022

Since the problem proposed in late 2000s, microRNA–disease association (MDA) predictions have been implemented based on the data fusion paradigm. Integrating diverse data sources gains a more comprehensive research perspective, and brings a challenge to algorithm design for generating accurate, concise and consistent representations of the fused data. After more than a decade of research progress, a relatively simple algorithm like the score function or a single computation layer may no longer be sufficient for further improving predictive performance. Advanced model design has become more frequent in recent years, particularly in the form of reasonably combing multiple algorithms, a process known as model fusion. In the current review, we present 29 state-of-the-art models and introduce the taxonomy of computational models for MDA prediction based on model fusion and non-fusion. The new taxonomy exhibits notable changes in the algorithmic architecture of models, compared with that of earlier ones in the 2017 review by Chen et al. Moreover, we discuss the progresses that have been made towards overcoming the obstacles to effective MDA prediction since 2017 and elaborated on how future models can be designed according to a set of new schemas. Lastly, we analysed the strengths and weaknesses of each model category in the proposed taxonomy and proposed future research directions from diverse perspectives for enhancing model performance.
Letter to the editor: evaluating computational tools for lncRNA identification on independent datasets
Authors: Zheng Hansi , Li Xiaoman , Hu Haiyan
Published: September 2022

The authors of the BASiNET tool claim that the survey paper ‘A systematic evaluation of computational tools for lncRNA identification’ incorrectly evaluates the BASiNET tool. Here, we point out that the survey paper correctly evaluates the BASiNET tool and why the evaluation should not be carried out as BASiNET authors suggest.
Vessel wall imaging: a promising enhancement in the management of inflammatory intracranial vasculopathy
Authors: Yang Dixon , Elkind Mitchell S V
Published: September 2022

This scientific commentary refers to ‘Vessel wall magnetic resonance and arterial spin labelling imaging in the management of presumed inflammatory intracranial arterial vasculopathy’, by Benjamin et al. (https://doi.org/10.1093/braincomms/fcac157).
Odors associated with neonatal experiences with the dam have enhanced anxiolytic effects in rat
Authors: Mochizuki-Kawai Hiroko , Ichitani Yukio , Ayabe-Kanamura Saho , Yamada Kazuo
Published: September 2022

Odor stimuli are widely reported to promote relaxation and reduce anxiety in humans and rodents. However, it remains unclear if this anxiolytic efficacy can be further enhanced by association with positive experiences. Therefore, we compared the effects of a novel odor to a familiar odor previously paired with a positive experience on anxiety-like behaviors in rats. One group of Wistar–Imamichi female and male pups was exposed to an odor stimulus with their dams during postnatal days (PNDs) 8–12, whereas another control group was exposed to perfused air during the same period. Starting on PND 42, all animals were examined in the open field test (OFT) and elevated plus maze (EPM) test during exposure to scent-free air (vehicle), a novel odor, or the positive-familiar odor from postnatal exposure. In the EPM, female rats entered open arms with all 4 paws (complete entry) more frequently and spent more time on open arms during exposure to the positive-familiar odor than during exposure to air or a novel odor, whereas partial open arm entries with forepaws only were increased during exposure to both novel and positive-familiar odors compared to air. In contrast, male rats demonstrated no significant increase in open arm activity during positive-familiar odor exposure, but did show equally reduced grooming frequency during novel and familiar-positive odor exposure in the OFT. Exposure to positive-familiar odors may be an effective and safe method for anxiety reduction, especially in females.
Clinical Implementation of Routine Whole-genome Sequencing for Hospital Infection Control of Multi-drug Resistant Pathogens
Authors: Forde Brian M , Bergh Haakon , Cuddihy Thom , Hajkowicz Krispin , Hurst Trish , Playford E Geoffrey , Henderson Belinda C , Runnegar Naomi , Clark Julia , Jennison Amy V , Moss Susan , Hume Anna , Leroux Hugo , Beatson Scott A , Paterson David L , Harris Patrick N A
Published: September 2022

Background

Prospective whole-genome sequencing (WGS)-based surveillance may be the optimal approach to rapidly identify transmission of multi-drug resistant (MDR) bacteria in the healthcare setting.

Methods

We prospectively collected methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), carbapenem-resistant Acinetobacter baumannii (CRAB), extended-spectrum beta-lactamase (ESBL-E), and carbapenemase-producing Enterobacterales (CPE) isolated from blood cultures, sterile sites, or screening specimens across three large tertiary referral hospitals (2 adult, 1 paediatric) in Brisbane, Australia. WGS was used to determine in silico multi-locus sequence typing (MLST) and resistance gene profiling via a bespoke genomic analysis pipeline. Putative transmission events were identified by comparison of core genome single nucleotide polymorphisms (SNPs). Relevant clinical meta-data were combined with genomic analyses via customised automation, collated into hospital-specific reports regularly distributed to infection control teams.

Results

Over 4 years (April 2017 to July 2021) 2660 isolates were sequenced. This included MDR gram-negative bacilli (n = 293 CPE, n = 1309 ESBL), MRSA (n = 620), and VRE (n = 433). A total of 379 clinical reports were issued. Core genome SNP data identified that 33% of isolates formed 76 distinct clusters. Of the 76 clusters, 43 were contained to the 3 target hospitals, suggesting ongoing transmission within the clinical environment. The remaining 33 clusters represented possible inter-hospital transmission events or strains circulating in the community. In 1 hospital, proven negligible transmission of non-multi-resistant MRSA enabled changes to infection control policy.

Conclusions

Implementation of routine WGS for MDR pathogens in clinical laboratories is feasible and can enable targeted infection prevention and control interventions.
Validation of an LC-MS/MS Method Using Solid-Phase Extraction for the Quantification of 1-84 Parathyroid Hormone: Toward a Candidate Reference Measurement Procedure
Authors: Farré-Segura Jordi , Le Goff Caroline , Lukas Pierre , Cobraiville Gaël , Fillet Marianne , Servais Anne-Catherine , Delanaye Pierre , Cavalier Etienne
Published: September 2022

Background

Parathyroid hormone (PTH) measurement is important for patients with disorders of calcium metabolism, including those needing bone-turnover monitoring due to chronic kidney disease–mineral bone disorder. There are currently 2 generations of PTH immunoassays on the market, both having cross-reactivity issues and lacking standardization. Therefore, we developed an LC-MS/MS higher-order method for PTH analysis.

Methods

The method was calibrated against the international standard for 1-84 PTH (WHO 95/646). Antibody-free sample preparation with the addition of an isotope-labeled internal standard was performed by solid-phase extraction. Extracts were analyzed by LC-MS/MS. EDTA-K2 plasma was used throughout the development and validation. Bias and uncertainty sources were tested according to ISO 15193. Clinical Laboratory Standards Institute guidelines and reference measurement procedures were consulted for the design of the validation. Patient samples and external quality controls were compared between LC-MS/MS and 2 third-generation immunoassays.

Results

The method was validated for 1-84 PTH from 5.7 to 872.6 pg/mL. The interassay imprecision was between 1.2% and 3.9%, and the accuracy ranged from 96.2% to 103.2%. The measurement uncertainty was <5.6%. The comparison between LC-MS/MS and the immunoassays showed a proportional bias but moderate to substantial correlation between methods.

Conclusions

This LC-MS/MS method, which is independent of antibodies, is suitable for a wide range of PTH concentrations. The obtained analytical performance specifications demonstrate that development of a reference measurement procedure will be possible once a higher order reference standard is available.
Coronary subclavian steal syndrome causing acute coronary syndrome: a case report
Authors: Carmona Adrien , Marchandot Benjamin , Sagnard Mylene , Morel Olivier
Published: September 2022

Background

Myocardial infarction on non-occluded coronary artery represents a very specific subset of acute coronary syndrome (ACS). Coronary subclavian steal syndrome (CSSS) is defined by a left subclavian artery stenosis in case of (i) left internal mammary artery (LIMA) used to bypass left anterior descending artery (LAD) and (ii) >75% stenosis of the left subclavian artery prior to the origin of the LIMA to LAD graft. Here we report the case of a CSSS causing ACS.

Case summary

A 71-year-old man with history of LIMA to LAD coronary artery bypass surgery was admitted to the nephrology intensive care unit for acute kidney injury requiring dialysis. Due to rapid deterioration, altered left ventricular ejection fraction and elevated c-troponin levels, an urgent coronary angiography was performed. It revealed a subtotal occlusion of the left subclavian artery prior to the origin of the LIMA to LAD graft. This was responsible for a severely altered coronary flow in the LIMA and LAD. Revascularization of the proximal left subclavian artery with a stent was performed, enabling instant recovery of distal coronary flows.

Discussion

ACS due to CSSS in this report highlights the complexity of the cardio–renal interaction. Patients with coronary artery bypass graft and chronic kidney disease commonly exhibit a higher risk for severe progression of atherosclerosis at multiple sites. CSSS treatments include secondary prevention measures and revascularization (if indicated) such as an endovascular approach.
Randomized evaluation of redo ablation procedures of atrial fibrillation with focal impulse and rotor modulation-guided procedures: the REDO-FIRM study
Authors: Spitzer Stefan G , Miller John M , Sommer Philipp , Szili-Torok Tamas , Reddy Vivek Y , Nölker Georg , Williams Chris , Sarver Anne , Wilber David J
Published: September 2022

Aims

REDO-FIRM evaluated safety and effectiveness of conventional vs. focal impulse and rotor modulation (FIRM)-guided ablation of recurrent persistent or paroxysmal atrial fibrillation (AF) after an initial AF ablation procedure.

Methods and results

This prospective, multicentre, randomized study included patients with a single prior AF ablation, but with recurrent AF and reconnected pulmonary veins (PVs). Conventional ablation generally included PV re-isolation; however, additional ablation was permitted per physician discretion. In the FIRM arm, beyond PV re-isolation, basket catheter-based FIRM mapping created dynamic animations of putative rotors, which were targeted for ablation. Between May 2016 and July 2019, 269 subjects were randomized, with 243 subjects completing 12-month follow-up. Ablation beyond re-pulmonary vein isolation, the FIRM vs. Conventional arms did not differ significantly: cavo-tricuspid isthmus –9.0% vs. 15.3%, caval vein isolation –1.5% vs. 0.8%, non-PV trigger –2.2% vs. 3.8%, other –11.9% vs. 13.0%. Single procedure 12-month freedom from AF/atrial tachycardia/atrial flutter-recurrence was 63.3% (76/120) vs. 59.0% (72/122) in the FIRM and Conventional arms (P = 0.3503). Efficacy was similar in the paroxysmal and persistent AF subgroups (P = 0.22 and P = 0.48). The 10-day and 12-month safety endpoints were achieved in 93.3% vs. 93.8% (P = 0.89) and 88.4% vs. 93.4% (P = 0.22) in the FIRM and Conventional arms, respectively.

Conclusions

In REDO-FIRM, as compared to standard ablation, FIRM-guided ablation did not provide additional efficacy in redo ablation procedures, but FIRM-guided ablation was equally safe. Additional studies are necessary to identify any potential population able to benefit from FIRM-guided ablation.
Comparison analysis of the ETAS model with Gutenberg–Richter (GR), Tapered-GR and characteristic magnitude distributions
Authors: Spassiani I , Yaghmaei-Sabegh S , Console R , Falcone G , Murru M
Published: September 2022

In this paper, we carry out a comparison analysis of the Epidemic Type Aftershock Sequence (ETAS) model for the earthquake process, embedded with the three main exponential-type distributions adopted in practical applications to describe the magnitudes of seismic events, that are, the Gutenberg–Richter (GR), the tapered Gutenberg–Richter (TGR) and the CHaracteristic (CH) frequency–magnitude distributions (FMDs). The first law is a pure-power decreasing function, while both the other two introduce a more rapid decay in the tail of the distribution: a soft taper in the TGR model and a sharp cut-off in the CH one. To perform the comparison, we first investigate some theoretical features of the ETAS model with CH-distributed magnitudes (ETAS-CH), which have not been deeply analysed in the literature as much as for ETAS-TGR and ETAS-GR. In particular, we explicitly compute the branching ratio, we analyse its asymptotics in relation to its parameters, and we derive the proper stability conditions. We then move to the comparison among the three ETAS-GR, ETAS-TGR and ETAS-CH processes, to highlight differences and similarities. This is done by carrying out both a theoretical analysis, mainly focused on the three models’ branching ratios and the relative sensitivity, and a simulation analysis of realistic synthetic catalogues to compare the processes’ numbers, events’ magnitude distribution and temporal evolution. The results we obtained show that the ETAS-TGR and ETAS-CH processes have very similar features. They both have also less restrictive non-explosion conditions than for ETAS-GR; in fact, differently from this latter case, their branching ratios exist for any value of the parameters and are lower than the one of ETAS-GR, to which they converge for large magnitudes.
SlWRKY45 interacts with jasmonate-ZIM domain proteins to negatively regulate defense against the root-knot nematodeMeloidogyne incognitain tomato
Authors: Huang Huang , Zhao Wenchao , Qiao Hui , Li Chonghua , Sun Lulu , Yang Rui , Ma Xuechun , Ma Jilin , Song Susheng , Wang Shaohui
Published: September 2022

Parasitic root-knot nematodes (RKNs) cause a severe reduction in crop yield and seriously threaten agricultural production. The phytohormones jasmonates (JAs) are important signals regulating resistance to multiple biotic and abiotic stresses. However, the molecular mechanism for JAs-regulated defense against RKNs in tomato remains largely unclear. In this study, we found that the transcription factor SlWRKY45 interacted with most JA-ZIM domain family proteins (JAZs), key repressors of the JA signaling. After infection by the RKN Meloidogyne incognita, the slwrky45 mutants exhibited lower gall numbers and egg numbers per gram of roots than wild type, whereas overexpression of SlWRKY45 attenuated resistance to Meloidogyne incognita. Under M. incognita infection, the contents of jasmonic acid (JA) and JA-isoleucine (JA-Ile) in roots were repressed by SlWRKY45-overexpression. Furthermore, SlWRKY45 bound to and inhibited the promoter of the JA biosynthesis gene ALLENE OXIDE CYCLASE (AOC), and repressed its expression. Overall, our findings revealed that the SlJAZ-interaction protein SlWRKY45 attenuated RKN-regulated JA biosynthesis and repressed defense against the RKN M. incognita in tomato.
The evolving personal, professional and physical impact on healthcare professionals during three COVID-19 waves: A cross-sectional study
Authors: Seys Deborah , Peeters Bart , Doggen Kris , Vanhaecht Kris
Published: September 2022

Background

The COVID-19 pandemic has led to huge pressure on not only healthcare systems, but also on healthcare professionals.

Objective

As the pandemic continues, the aim of this study is to evaluate how 10 reactions of healthcare professionals evolved during the first 18 months of COVID-19.

Methods

A repeated cross-sectional study was performed with eight measurement points between April 2020 and September 2021 in Belgium. Participants were asked how frequently (on a scale of 0–10) they experienced positive and negative reactions during normal circumstances and during past week, referred to as before and during COVID-19, respectively. These reactions were stress, fatigue, difficulty sleeping, muscle strain, hypervigilance, leaving profession, headache, doubting knowledge and skills, flashbacks and fear.

Results

In total, 13 308 respondents were included in our study. During both the first (March 2020) and second COVID-19 peak (November 2020), the measured personal, professional and physical reactions were significantly higher compared to before COVID-19. The third wave in April 2021 was shorter and less severe with regard to hospital admissions and deaths, yet an important impact on healthcare professionals could still be observed. ‘Fatigue,’ ‘stress,’ ‘difficulty sleeping’ and ‘muscle strain’ are the most worrying reactions in September 2021, which are increasing compared to the previous measurements.

Conclusion

Our results showed that acute stress reactions decreased over time but that chronic stress reactions and professional reactions, such as ‘intent to leave,’ increased. Healthcare organizations and policy makers should realize that 18 months after the start of COVID-19 almost all of the measured reactions continue to be more prevalent than before COVID-19. Moreover, the continuous increase over the last three measurement periods of the number of healthcare professionals who want to leave their profession is alarming. Continuous follow-up of the personal, professional and physical reactions is more than necessary.
Legal, Mythic, and Divine Violence: Post-secular Entanglements in Walter Benjamin’s ‘Toward the Critique of Violence’
Authors: Holte Stine
Published: September 2022

Walter Benjamin’s essay ‘Toward the Critique of Violence’ (1921) has in the past decades been central to important debates within post-secular philosophical thought. This article explores the intricate connections between legal, mythic, and divine violence in Benjamin’s essay, in light of some of his other theological, literary, and political works from the same period. It suggests that the idea of a ‘divine law-annihilating violence’ should be read in light of Benjamin’s claim that a ‘critique of violence is the philosophy of its history’. This implies amongst other things a critique of the dogma of the sanctity of mere life underlying both the Greek and the Christian tradition.
Performing ‘Art for the People’: Politics, Spectatorship, and Schoenberg’s Music at the Berlin VolksbÜhne
Authors: Carrasco Clare
Published: September 2022

In early 1920, a performance of Arnold Schoenberg’s Chamber Symphony sponsored by the Berlin Volksbühne (People’s Theatre) set off a dialogue of remarkable vehemence and duration in the musical press. Writing as spectators of what they imagined to be a working-class audience, professional music critics framed the event as a musical performance that itself was a carefully staged piece of political theatre. Their accounts detail and debate the use of casting, symbols, and rituals to enact a ‘leftist’ agenda in which Schoenberg’s music was not the subversive project of a radical few, but a legitimate exemplar of ‘art for the people’—the motto of the Volksbühne. By engaging with the recent ‘performative turn’ in studies of the Weimar Republic, this article presents a rich microhistory of this experimental concert and its afterlife in the press, revealing vital connections to broader practices of political performativity in Weimar democracy.
Multiple locations of near-infrared coronal lines in NGC 5548
Authors: Kynoch Daniel , Landt Hermine , Dehghanian Maryam , Ward Martin J , Ferland Gary J
Published: September 2022

We present the first intensive study of the variability of the near-infrared coronal lines in an active galactic nucleus (AGN). We use data from a 1-yr-long spectroscopic monitoring campaign with roughly weekly cadence on NGC 5548 to study the variability in both emission line fluxes and profile shapes. We find that in common with many AGN coronal lines, those studied here are both broader than the low-ionizaton forbidden lines and blueshifted relative to them, with a stratification that implies an origin in an outflow interior to the standard narrow line region. We observe for the first time [S viii] and [Si vi] coronal line profiles that exhibit broad wings in addition to narrow cores, features not seen in either [S ix] or [Si x]. These wings are highly variable, whereas the cores show negligible changes. The differences in both the profile shapes and variability properties of the different line components indicate that there are at least two coronal line regions in AGN. We associate the variable, broad wings with the base of an X-ray heated wind evaporated from the inner edge of the dusty torus. The coronal line cores may be formed at several locations interior to the narrow line region: either along this accelerating, clumpy wind or in the much more compact outflow identified with the obscurer and so emerging on scales similar to the outer accretion disc and broad-line region.
Detecting and analysing the topology of the cosmic web with spatial clustering algorithms I: methods
Authors: Kelesis Dimitrios , Basilakos Spyros , Papadopoulou Lesta Vicky , Fotakis Dimitris , Efstathiou Andreas
Published: September 2022

In this paper, we explore the use of spatial clustering algorithms as a new computational approach for modelling the cosmic web. We demonstrate that such algorithms are efficient in terms of computing time needed. We explore three distinct spatial methods which we suitably adjust for (i) detecting the topology of the cosmic web and (ii) categorizing various cosmic structures as voids, walls, clusters, and superclusters based on a variety of topological and physical criteria such as the physical distance between objects, their masses, and local densities. The methods explored are (1) a new spatial method called Gravity Lattice; (2) a modified version of another spatial clustering algorithm, the abacus; and (3) the well known spatial clustering algorithm hdbscan. We utilize hdbscan in order to detect cosmic structures and categorize them using their overdensity. We demonstrate that the abacus method can be combined with the classic dtfe method to obtain similar results in terms of the achieved accuracy with about an order of magnitude less computation time. To further solidify our claims, we draw insights from the computer science domain and compare the quality of the results with and without the application of our method. Finally, we further extend our experiments and verify their effectiveness by showing their ability to scale well with different cosmic web structures that formed at different redshifts.
Finite-temperature effects in dynamical spacetime binary neutron star merger simulations: validation of the parametric approach
Authors: Raithel Carolyn A , Espino Pedro , Paschalidis Vasileios
Published: September 2022

Parametric equations of state (EoSs) provide an important tool for systematically studying EoS effects in neutron star merger simulations. In this work, we perform a numerical validation of the M*-framework for parametrically calculating finite-temperature EoS tables. The framework, introduced by Raithel et al., provides a model for generically extending any cold, β-equilibrium EoS to finite temperatures and arbitrary electron fractions. In this work, we perform numerical evolutions of a binary neutron star merger with the SFHo finite-temperature EoS, as well as with the M*-approximation of this same EoS, where the approximation uses the zero-temperature, β-equilibrium slice of SFHo and replaces the finite-temperature and composition-dependent parts with the M*-model. We find that the approximate version of the EoS is able to accurately recreate the temperature and thermal pressure profiles of the binary neutron star remnant, when compared to the results found using the full version of SFHo. We additionally find that the merger dynamics and gravitational wave signals agree well between both cases, with differences of $\lesssim 1\!-\!2\,{\textrm{per cent}}$ introduced into the post-merger gravitational wave peak frequencies by the approximations of the EoS. We conclude that the M*-framework can be reliably used to probe neutron star merger properties in numerical simulations.
Rotavirus RNA chaperone mediates global transcriptome-wide increase in RNA backbone flexibility
Authors: Coria Aaztli , Wienecke Anastacia , Knight Michael L , Desirò Daniel , Laederach Alain , Borodavka Alexander
Published: September 2022

Due to genome segmentation, rotaviruses must co-package eleven distinct genomic RNAs. The packaging is mediated by virus-encoded RNA chaperones, such as the rotavirus NSP2 protein. While the activities of distinct RNA chaperones are well studied on smaller RNAs, little is known about their global effect on the entire viral transcriptome. Here, we used Selective 2′-hydroxyl Acylation Analyzed by Primer Extension and Mutational Profiling (SHAPE-MaP) to examine the secondary structure of the rotavirus transcriptome in the presence of increasing amounts of NSP2. SHAPE-MaP data reveals that despite the well-documented helix-unwinding activity of NSP2 in vitro, its incubation with cognate rotavirus transcripts does not induce a significant change in the SHAPE reactivities. However, a quantitative analysis of mutation rates measured by mutational profiling reveals a global 5-fold rate increase in the presence of NSP2. We demonstrate that the normalization procedure used in deriving SHAPE reactivities from mutation rates can mask an important global effect of an RNA chaperone. Analysis of the mutation rates reveals a larger effect on stems rather than loops. Together, these data provide the first experimentally derived secondary structure model of the rotavirus transcriptome and reveal that NSP2 acts by globally increasing RNA backbone flexibility in a concentration-dependent manner.
KS05.7.A Characterization of the immune composition of extreme long-term survivors with malignant glioma at single-cell level
Authors: Decraene B , Antoranz A , Verbeke T , Nazari P , Solie L , Dubroja N , Derweduwe M , De Smet F , De Vleeschouwer S
Published: September 2022

Background

Glioblastoma Multiforme (GBM) remains the most common malignant primary brain tumor with a dismal prognosis that rarely exceeds beyond two years despite extensive therapy, which consists of maximal safe surgical resection, radiotherapy and/or chemotherapy. Recently, it has become clear that GBM is not one homogeneous entity and that both intra-and intertumoral heterogeneity contribute significantly to differences in tumoral behavior which may consequently be responsible for differences in survival. Strikingly and in spite of its dismal prognosis, small fractions of GBM patients seem to display extended survival compared to the large majority of patients. The underlying mechanisms for this peculiarity remain largely unknown however, even though emerging data suggest that both cancer cell-autonomous and microenvironmental factors and their interplay probably play an important role.

Material and Methods

We used high-dimensional, multiplexed immunohistochemistry to spatially, and cytometry by time-of-flight to quantitively characterize the cell constitution and interactions within the tumor microenvironment (TME) in 21 extreme long-term survivors (living over ten years since primary diagnosis or five years after recurrence) and 42 deeply matched short-term controls (living under 1.5 year) on a single cell level. For all tumors (epi-)genetic data was also collected.

Results

We identified a high level of both inter-and intrapatient heterogeneity defined by several distinct tumor niches, as well as described interactions within these niches and with the surrounding infiltrating immune cells of the TME. By linking patient characteristics with the heterogeneous immune composition we are building an immune stratification that can be linked to patient survival in GBM.

Conclusion

Generating an immune stratification for GBM will allow us to identify immune characteristics responsible for longer or even exceptional survival, as well as thoroughly identify tumor components that may serve as a potential target for personalized treatment strategies. Therefore, this study is also an essential initial step towards such clinical trials which alter the TME in a favorable way with a personalized modulation strategy.
OS06.5.A Investigating safety and efficacy of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma - the PriCoTTF phase I/II trial
Authors: Kebir S , Lazaridis L , Schmidt T , Oster C , Feldheim J , Glas M , Pierscianek D , Proescholdt M , Hau P , Grosu A , Krex D , Scheffler B , Kleinschnitz C , Pöttgen C , Stuschke M
Published: September 2022

Background

The EF-14 phase III trial demonstrated improved survival for patients with newly diagnosed glioblastoma (nGBM) when TTFields therapy was added to adjuvant temozolomide chemotherapy. TTFields at 200 kHz are applied to the tumor utilizing arrays on the patients’ scalp. In preclinical studies, a synergistic inhibiting effect on glioblastoma cell proliferation was found for the combination of TTFields and radiotherapy. Based on these findings, we conduct the phase I/II PriCoTTF trial in adult nGBM patients to investigate the safety and efficacy of TTFields therapy initiated prior and concomitant to radiochemotherapy.

Material and Methods

Per study protocol, TTFields therapy is initiated following surgery and completed wound healing. Continuing throughout radiochemotherapy and adjuvant chemotherapy, TTFields therapy is used for approximately 9 months in total with TTFields rechallenge allowed at recurrence. Radiotherapy is conducted with arrays applied on the patients’ scalp. A total recruitment of 33 patients was sought, with 20 patients in arm A receiving normo-fractionated radiotherapy, and 13 elderly patients in arm B receiving hypo-fractionated radiotherapy. Safety and tolerance are the study’s primary endpoint, analyzed by a selection of pre-specified treatment-limiting toxicities (TLTs).

Results

A total of 33 patients have been enrolled. Patients' characteristics were mostly typical for glioblastoma, except for a rather low fraction of patients with gross total resection (GTR, 22.5%). The distribution of adverse events of common toxicity criteria (CTC) grade 3 or higher was comparable to that of established glioblastoma trials. Notably, skin toxicity of CTC grade 3 or higher was quite uncommon (n=2, 6%). As no patient developed TLTs, the study's primary endpoint was met. Median TTFields treatment duration was 8.4 months. Overall survival data was not mature enough (event rate 48%) to allow for a definite conclusion. Notably, on multivariable Cox regression, the number of days with TTFields adherence of more than 23 hours was independently associated with overall survival (HR 0.96, 95% confidence interval 0.93 - 0.99, p=0.008).

Conclusion

The PriCoTTF trial met its primary endpoint indicating that combined TTFields and radiotherapy is safe and well tolerated. High-grade skin toxicity was quite uncommon and the patients with high TTFields adherence seem to perform particularly well. An extended follow-up is required to provide first estimates regarding putative efficacy. At that point in time, the reduced overall TTFields duration and fraction of patients with GTR need to be factored in.
OS08.6.A Novel role of ARF4-mediated retrograde trafficking as a driver of chemoresistance in GBM
Authors: Budhiraja S , Baisiwala S , Perrault E , Cho S , Dara G , Nandoliya K , Zolp A , Chen L , Dmello C , Park C , Sonabend A , Ahmed A
Published: September 2022

Background

Glioblastoma (GBM) is the most common type of adult malignant brain tumor, with a median survival of only 21 months. This is partly due to the high rate of resistance to conventional therapy, including temozolomide (TMZ), leading to recurrence rates close to 100%. To identify the unknown genes driving the development of this resistance, we performed a genome-wide CRISPR knockout screen comparing a DMSO-treated population with a TMZ-treated population over 14 days. Results showed substantial enrichment of ~200 novel genes, including a previously unstudied gene ARF4—involved in retrograde trafficking to the nucleus. Here, we set out to characterize the mechanism by which ARF4 may be acting to promote chemoresistance.

Material and Methods

A whole-genome CRISPR-Cas9 sensitivity screen as well as a variety of in vitro and in vivo experiments, such as live-cell imaging, cell viability assays, and western blotting were conducted.

Results

Initial investigation into ARF4 showed significant elevations in expression at RNA and protein levels (p<0.05) in recurrent patient tumors, as well as a significant survival benefit in patient datasets when downregulated (p<0.05). Knocking out ARF4 resulted in significantly heightened sensitivity to TMZ in multiple GBM patient-derived xenograft lines and extended survival compared to the controls (p<0.01) in vivo. Further investigation via live-cell imaging of transferrin receptors, a retrograde transport marker, revealed that ARF4-knockdowns significantly inhibited retrograde trafficking, while ARF4-overexpressions resulted in an untenable increase in retrograde trafficking in vitro. This effect was also seen in TMZ-treated cells, which displayed enhanced trafficking dynamics, suggesting that ARF4-mediated retrograde trafficking is elevated during therapy to drive nuclear localization of key chemoresistance-promoting factors. We then performed an unbiased proteomics screen to identify which genes were being uniquely transported to the nucleus as a product of ARF4-mediated retrograde trafficking, which revealed enrichment of the EGFR signaling pathway in particular. Validation experiments confirmed a decrease in EGFR trafficking and nuclear EGFR expression in ARF4-knockdowns and an increase in EGFR trafficking and nuclear EGFR expression in ARF4-overexpression and TMZ-treated GBM cells. Furthermore, nuclear DNA-PK, a DNA repair protein known to be transcriptionally activated by EGFR, was similarly found to be downregulated in ARF4-knockdown conditions and elevated in ARF4-overexpression and TMZ-treated conditions.

Conclusion: Here, we show that ARF4 may be responsible for promoting chemoresistance through altered retrograde trafficking of EGFR specifically. Thus, our study has yielded a promising and novel therapeutic target for GBM, a disease desperately in need of new therapeutic strategies.
P01.08.A Perioperative Levetiracetam for seizure prophylaxis in seizure naive brain tumor patients with focus on neurocognitive functioning
Authors: Konrath E , Marhold F , Kindler W , Scheichel F , Popadic B , Blauensteiner K , Calabek-Wohinz B , Freydl E , Weber M , Ristl R , Hainz K , Sherif C , Oberndorfer S
Published: September 2022

Background

In seizure-naive brain tumor patients, the efficacy of perioperative prophylactic antiepileptic drugtreatment remains controversial. In case of administration, the common preferred drug is levetiracetam (LEV) because of its favorable pharmacological profile. Research to date has not sufficiently determined how LEV affects cognition in the short term as it does in the perioperative period. The objective of this prospective study was to examine the neurocognitive functioning of seizure-naive brain tumor patients after receiving LEV perioperatively.

Material and methods

Patients with supratentorial brain tumor undergoing surgery received LEV three days before until seven days after surgery as seizure prophylaxis. Cognitive functioning (NeuroCogFX), LEV plasma-levels, hematotoxicity, side-effects, as well as health-related quality of life (HRQoL, Qolie31), were recorded preoperatively before (Baseline) and after onset of LEV (Pre-Op), 4-6 days postoperatively (Post-Op) and 21 days postoperatively (Follow-Up).

Results

No significant changes in cognitive functioning and HRQoL were seen after onset of preoperative LEV. There was a significant improvement of NeuroCogFX total-score at Follow-Up (p=0.004) compared to Baseline. The overall-score Qolie31 showed simultaneous improvement patterns as cognitive functioning (p< 0.001). The most frequent side effect related to study drug was somnolence (in 24% of patients).

Conclusion

Following LEV therapy, a significant improvement of cognitive functioning, as well as an improvement in HRQoL, were detected postoperatively. This is presumably due to the debulking effect of the surgery. Nevertheless, LEV has no detrimental effect on cognitivefunctioning in the perioperative phase in seizure-naive brain tumor patients.
P03.08.B Proton Therapy and recurrent Lower Grade Glioma: clinical and radiological aspects, intraoperative findings and histo-pathological features
Authors: Conti Nibali M , Rossi M , Sciortino T , Gay L , Lopci E , Fernandes B , Rudà R , Bello L
Published: September 2022

Background

Radiation therapy (RT) plays a central role in management of central nervous system disease, in particular in the multimodality management of low(er) and high-grade CNS gliomas. New strategy that involved Proton Therapy (PT) have been experienced in the last years. No data are available about re-surgery of lesion irradiated with protons.

Material and Methods

We reviewed our single Unit experience of re-surgery of Lower-Grade Glioma patients that received, in their neuro-oncological history, a treatment with PT. We collect clinical data, intra-operative findings, histopathological features and oncological and clinical outcome after surgery.

Results

We collected three cases of young with an IDH1-mutated tumor that underwent to Proton Therapy (PT). In two cases PT was performed due to progression of disease, in one case as adjuvant therapy after first surgical treatment. In all cases we performed surgery within three years after PT. All patients complained drug resistant epilepsy after PT with symptom relief after surgery and one patient complained a spine fracture due to corticosteroids intake to control radionecrosis’s symptoms after PT. In the pre-operative work-up all patient performed a 11-C-Methionin PET scan that revealed an increase of tracer uptake in the suspected area of tumor progression. In one case advanced MRI protocol with PWI was performed to further distinguish and sample area of pseudoprogression and tumor progression. In two patients area of gliosis and necrosis was find at the histological examination.

Conclusion

Our experience, although limited to three case, provided a clinical and radiological example of the small cohort of patients that performed surgery after a Prothon Radiotherapy. Clinical presentation was heterogenous except a poor seizure control. Despite time elapsed since PT, areas of radionecrosis were found in the histopathological samples of 2/3 of patients. Moreover, we need to collect more data to draw a complete picture in this complex field.
P05.02.A 18F-FACBC PET/MRI in diagnostic assessment of gliomas
Authors: Pedersen L K
Published: September 2022

Background and Theory

MRI and histopathological tissue sampling are routinely done as part of the diagnostic work-up of patients with glioma. MRI provides anatomical images with high resolution and excellent soft-tissue contrast. But this modality has limitations in identifying tumor grade, true tumor extension and differentiate viable tumor tissue from treatment induced changes. PET can provide quantitative information of cellular activity and metabolism, and may therefore have additional value compared to MRI alone.

Objective

The aim of this study was to find the sensitivity of [18F]FACBC PET in gliomas, and evaluate if PET imaging with this tracer can improve differentiation between low-and high-grade gliomas.

Methods

Patients with suspicion of primary (n=19) or recurrent gliomas (n=8) were recruited to this study from St. Olavs hospital, Trondheim University Hospital, Trondheim, and from the University Hospital of North Norway, Tromsø. PET acquisitions (30-45 min post injection) using the amino acid radiotracer [18F]FACBC (3 MBq/kg) were performed simultaneously to MRI acquisitions (T1 with and without contrast, FLAIR, and UTE for attenuation correction. The sensitivity of [18F]FACBC PET in glioma detection was assessed using histopathology as reference. Tumor-to-background ratios (TBRs) were compared to tumor subtype and grade to assess the diagnostic value of this tracer for glioma diagnostics.

Results

Histopathology revealed 2 WHO grade 1 gliomas (pilocytic astrocytoma n=1, pilocytic astrocytoma/ganglioglioma n=1), 7 WHO grade 2 gliomas(astrocytoma n=4, oligodendroglioma n=3), 7 WHO grade 3 gliomas(astrocytoma n=5, oligodendroglioma n=2) and 12 WHO grade 4 tumors(astrocytoma n=1, glioblastoma n=11). [18F]FACBC PET provided a sensitivity of 74.1% in the detection of gliomas. PET uptake was observed in all grade 4 tumors, 5/7 grade 3 tumors, 2/7 grade 2 tumors, and all grade 1 tumors. TBRpeak was high with a median value of 9.4 (range: 2.1-34.9) in PET positive tumors. Only tumors with a TBRpeak > 2.0 were detected with [18F]FACBC PET. TBRpeak was highest for grade 1 gliomas with a median value of 20.6, and increased significantly from grade 2 to grade 4 tumors with median values of 1.7 (grade 2), 6.2 (grade 3) and 12.4 (grade 4) (Kruskal-Wallis, p=0.001).

Conclusion

[18F]FACBC PET demonstrated high uptake in the majority of gliomas, and there was a clear tendency to higher uptake in the higher grade tumors. [18F]FACBC PET may be useful in the differentiation between glioms grades and subtypes. A future study using the same patient data will be performed to evaluate the assessment of [18F]FACBC PET in neurosurgical treatment planning. Image-localized biopsies from different regions of each tumor will be correlated to fused PET/MRI images to evaluate if [18F]FACBC PET can be used to guide surgical resection and to improve accuracy in histopathological tissue sampling.
P06.07.A Natural killer cells lyse glioblastoma stem cells and increase their sensitivity to chemotherapy
Authors: Breznik B , Ko M , Chen P , Senjor E , Majc B , Novak M , Habič A , Jewett A
Published: September 2022

Background

Glioblastoma is the most common and lethal brain tumor in the adult population and immunotherapy is playing an increasingly central role in the treatment of many cancers. Nevertheless, the search for effective immunotherapeutic approaches for glioblastoma patients continues. In this study, we aimed to explore the therapeutic potential of allogeneic highly activated super-charged natural killer (NK) cells in glioblastoma.

Material and Methods

Chromium release- and calcein release-based cytotoxicity assays, ELISA, ELISPOT, and multiplex cytokine assays were used to determine NK cell cytotoxicity against glioblastoma stem cells (GSCs) and secretion of cytokines. Cell surface marker expression using flow cytometry and cell growth in vitro and in vivo were measured to determine GSC phenotype. NK cell killing and penetration in 3D were measured using confocal microscopy of GSC tumorospheres.

Results

Super-charged NK cells efficiently lysed patient-derived GSCs in 2D and 3D models potentially reversing the immunosuppression observed in patients. NK-cells secreted IFN-γ, upregulated GSC surface expression of CD54 and MHC class I and increased sensitivity of GSCs to chemotherapeutic drugs. Co-localization of NK cells with GBM cells in perivascular niches in glioblastoma tissues and their direct contact with GSCs in tumorospheres suggests their ability to infiltrate glioblastoma tumors and target GSCs.

Conclusion

Allogeneic super-charged NK cells appear to be a potential therapeutic approach for glioblastoma by selectively killing therapy-resistant cancer stem cell population, increasing their immune-related surface markers and enhancing their sensitivity to chemotherapy. Due to GSC heterogeneity and plasticity personalized immunotherapeutic strategies should be developed to effectively target glioblastomas.