bluuebunny/crossref_metadata_2025 huggingface dataset:
Smoking Cessation Prevalence and Inequalities in the United States: 2014-2019
Authors: Leventhal Adam M , Dai Hongying , Higgins Stephen T
Published: November 2021

Background

Smoking is a leading cause of premature death and health inequities in the United States.

Methods

We estimated cross-sectional prevalence of smoking cessation indicators among US adult recent smokers (n = 43 602) overall and by sociodemographic subgroups in the Current Population Survey Tobacco Use Supplement 2014-2015 and 2018-2019 timepoints. Respondents reported past-year quit smoking interest, attempts, sustained (successful) cessation for 6 or more months and use of e-cigarettes or behavioral or pharmacological cessation treatments to quit smoking.

Results

Past-year quit smoking attempts declined slightly from 2014-2015 (52.9%) to 2018-2019 (51.3%) overall. Quit interest (pooled = 77.1%) and sustained cessation (pooled = 7.5%) did not change across timepoints. Among smokers making past-year quit attempts, 34.4% reported using cessation treatments in 2018-2019, and using e-cigarettes to quit smoking declined from 2014-2015 (33.3%) to 2018-2019 (25.0%). Several non-White (vs White) racial and ethnic groups had higher prevalence of quit interest and attempts but lower prevalence of sustained cessation or using e-cigarettes or treatments to quit. Income, education, employment, and metropolitan residence were positively associated with sustained cessation. Sociodemographic inequalities in sustained cessation and most other outcomes did not change across timepoints.

Conclusions

Although about half of US adult smokers made past-year quit attempts from 2014 to 2019, only 7.5% reported sustained cessation, and most who made quit attempts did not report using cessation treatments. Sociodemographic inequalities in cessation were pervasive and not entirely correspondent with sociodemographic variation in motivation to quit. Smoking cessation prevalence and inequalities did not improve from 2014 to 2019. Encouraging quit attempts and equitable access to smoking cessation aids are public health priorities.
Cancer Microbiology
Authors: DiMaio Daniel , Emu Brinda , Goodman Andrew L , Mothes Walther , Justice Amy
Published: November 2021

Microbes play important roles in cancer from direct carcinogenic effects to their use in treatment. Cancers caused by microorganisms account for approximately 15% of cancers, primarily in low- and middle-income countries. Unique features of infectious carcinogens include their transmissibility, mutability, and specific immune interactions, which provide challenges and opportunities for cancer prevention and treatment. For these agents, infection control through exposure reduction, antivirals, antibiotics, and vaccines is cancer control. In addition, developing evidence suggests that microorganisms including the human microbiome can indirectly modulate cancer formation and influence the effectiveness and toxicity of cancer treatments. Finally, microorganisms themselves can be used to prevent or treat cancer. The convergence of these factors signals the emergence of a new field, cancer microbiology. Recognition of cancer microbiology will spur research, stimulate cross-disciplinary training, inform drug development, and improve public health.
Crouching TIGER, hidden structure: Exploring the nature of linguistic data using TIGER values
Authors: Syrjänen Kaj , Maurits Luke , Leino Unni , Honkola Terhi , Rota Jadranka , Vesakoski Outi
Published: November 2021

In recent years, techniques such as Bayesian inference of phylogeny have become a standard part of the quantitative linguistic toolkit. While these tools successfully model the tree-like component of a linguistic dataset, real-world datasets generally include a combination of tree-like and nontree-like signals. Alongside developing techniques for modeling nontree-like data, an important requirement for future quantitative work is to build a principled understanding of this structural complexity of linguistic datasets. Some techniques exist for exploring the general structure of a linguistic dataset, such as NeighborNets, δ scores, and Q-residuals; however, these methods are not without limitations or drawbacks. In general, the question of what kinds of historical structure a linguistic dataset can contain and how these might be detected or measured remains critically underexplored from an objective, quantitative perspective. In this article, we propose TIGER values, a metric that estimates the internal consistency of a genetic dataset, as an additional metric for assessing how tree-like a linguistic dataset is. We use TIGER values to explore simulated language data ranging from very tree-like to completely unstructured, and also use them to analyze a cognate-coded basic vocabulary dataset of Uralic languages. As a point of comparison for the TIGER values, we also explore the same data using δ scores, Q-residuals, and NeighborNets. Our results suggest that TIGER values are capable of both ranking tree-like datasets according to their degree of treelikeness, as well as distinguishing datasets with tree-like structure from datasets with a nontree-like structure. Consequently, we argue that TIGER values serve as a useful metric for measuring the historical heterogeneity of datasets. Our results also highlight the complexities in measuring treelikeness from linguistic data, and how the metrics approach this question from different perspectives.
Roles of the wound hormone jasmonate in plant regeneration
Authors: Zhang Guifang , Liu Wu , Gu Zewei , Wu Shasha , E Yilan , Zhou Wenkun , Lin Jinxing , Xu Lin
Published: November 2021

Plants have remarkable abilities to regenerate in response to wounding. How wounding triggers rapid signal transduction to induce a cellular response is a key topic for understanding the molecular mechanism of plant regeneration. An increasing body of evidence indicates that jasmonate, a hormone that is produced rapidly in response to wounding, plays multiple roles in different plant regeneration processes. In this review, we summarize recent advances on the roles of jasmonate in tissue repair, the formation of wound-induced callus, de novo organ regeneration, and somatic embryogenesis. Physiological and molecular analyses indicate that jasmonate can regulate stem cell activities, cell proliferation, cell fate transition, and auxin production, thereby contributing to plant regeneration. In addition, jasmonate is strictly controlled in plant cells via restriction of the jasmonate concentration and its signalling pathway in a spatial and temporal manner during regeneration. Overall, jasmonate acts as the hormone linking wounding to distinct types of regeneration in plants.
Regulatory mechanisms underlying cuticular wax biosynthesis
Authors: Lee Saet Buyl , Suh Mi Chung
Published: November 2021

Plants are sessile organisms that have developed hydrophobic cuticles that cover their aerial epidermal cells to protect them from terrestrial stresses. The cuticle layer is mainly composed of cutin, a polyester of hydroxy and epoxy fatty acids, and cuticular wax, a mixture of very-long-chain fatty acids (>20 carbon atoms) and their derivatives, aldehydes, alkanes, ketones, alcohols, and wax esters. During the last 30 years, forward and reverse genetic, transcriptomic, and biochemical approaches have enabled the identification of key enzymes, transporters, and regulators involved in the biosynthesis of cutin and cuticular waxes. In particular, cuticular wax biosynthesis is significantly influenced in an organ-specific manner or by environmental conditions, and is controlled using a variety of regulators. Recent studies on the regulatory mechanisms underlying cuticular wax biosynthesis have enabled us to understand how plants finely control carbon metabolic pathways to balance between optimal growth and development and defense against abiotic and biotic stresses. In this review, we summarize the regulatory mechanisms underlying cuticular wax biosynthesis at the transcriptional, post-transcriptional, post-translational, and epigenetic levels.
Optimizing the Impact of Pragmatic Clinical Trials for Veteran and Military Populations: Lessons From the Pain Management Collaboratory
Authors: Ali Joseph , Antonelli Margaret , Bastian Lori , Becker William , Brandt Cynthia A , Burgess Diana J , Burns Amy , Cohen Steven P , Davis Alison F , Dearth Christopher L , Dziura Jim , Edwards Rob , Erdos Joe , Farrokhi Shawn , Fritz Julie , Geda Mary , George Steven Z , Goertz Christine , Goodie Jeffrey , Hastings Susan N , Heapy Alicia , Ilfeld Brian M , Katsovich Lily , Kerns Robert D , Kyriakides Tassos C , Lee Allison , Long Cynthia R , Luther Stephen L , Martino Steve , Matheny Michael E , McGeary Don , Midboe Amanda , Pasquina Paul , Peduzzi Peter , Raffanello Michael , Rhon Daniel , Rosen Marc , Esposito Elizabeth Russell , Scarton Dylan , Hastings Susan N , Seal Karen , Silliker Norman , Taylor Sakasha , Taylor Stephanie L , Tsui Megan , Wright Fred S , Zeliadt Steven
Published: November 2021

Pragmatic clinical trials (PCTs) are well-suited to address unmet healthcare needs, such as those arising from the dual public health crises of chronic pain and opioid misuse, recently exacerbated by the COVID-19 pandemic. These overlapping epidemics have complex, multifactorial etiologies, and PCTs can be used to investigate the effectiveness of integrated therapies that are currently available but underused. Yet individual pragmatic studies can be limited in their reach because of existing structural and cultural barriers to dissemination and implementation. The National Institutes of Health, Department of Defense, and Department of Veterans Affairs formed an interagency research partnership, the Pain Management Collaboratory. The partnership combines pragmatic trial design with collaborative tools and relationship building within a large network to advance the science and impact of nonpharmacological approaches and integrated models of care for the management of pain and common co-occurring conditions. The Pain Management Collaboratory team supports 11 large-scale, multisite PCTs in veteran and military health systems with a focus on team science with the shared aim that the “whole is greater than the sum of the parts.” Herein, we describe this integrated approach and lessons learned, including incentivizing all parties; proactively offering frequent opportunities for problem-solving; engaging stakeholders during all stages of research; and navigating competing research priorities. We also articulate several specific strategies and their practical implications for advancing pain management in active clinical, “real-world,” settings.
Implementation of a clinical decision rule for selecting empiric treatment for invasive aspergillosis in a setting with high triazole resistance
Authors: van de Peppel Robert J , van Grootveld Rebecca , Hendriks Bart J C , van Paassen Judith , Bernards Sandra , Jolink Hetty , Koopmans Julia G , von dem Borne Peter A , van der Beek Martha T , de Boer Mark G J
Published: November 2021

World-wide, emerging triazole resistance increasingly complicates treatment of invasive aspergillosis (IA). In settings with substantial (>10%) prevalence of triazole resistance, empiric combination therapy with both a triazole and liposomal amphotericin B (LAmB) can be considered because of the low yields of susceptibility testing. To avoid toxicity while optimizing outcome, a strategy with monotherapy would be preferable. A newly designed treatment algorithm based on literature and expert consensus provided guidance for empiric monotherapy with either voriconazole or LAmB. Over a four and a half year period, all adult patients in our hospital treated for IA were included and patient data were collected. An independent committee reviewed the attributability of death to IA for each patient. Primary outcomes were 30- and 100-day crude mortality and attributable mortality. In total, 110 patients were treated according to the treatment algorithm. Fifty-six patients (51%) were initially treated with voriconazole and 54 patients (49%) with LAmB. Combined attributable and contributable mortality was 13% within 30 days and 20% within 100 days. Treatment switch to LAmB was made in 24/56 (43%) of patients who were initially treated with voriconazole. Combined contributable and attributable 100-day mortality in this subgroup was 21% and was not increased when compared with patients initially treated with LAmB (P = 0.38). By applying a comprehensive clinical decision algorithm, an antifungal-sparing regime was successfully introduced. Further research is warranted to explore antifungal treatment strategies that account for triazole-resistance.

Lay summary

Due to resistance of Aspergillus against triazoles, combination therapy with liposomal amphotericin B (LAmB) is applied more often as primary therapy against invasive aspergillosis. This study presents the results of a decision tool which differentiated between triazole or LAmB monotherapy.
Dynamical ejecta of neutron star mergers with nucleonic weak processes – II: kilonova emission
Authors: Just O , Kullmann I , Goriely S , Bauswein A , Janka H-T , Collins C E
Published: November 2021

The majority of existing results for the kilonova (or macronova) emission from material ejected during a neutron-star (NS) merger is based on (quasi-) one-zone models or manually constructed toy-model ejecta configurations. In this study, we present a kilonova analysis of the material ejected during the first $\sim 10\,$ ms of a NS merger, called dynamical ejecta, using directly the outflow trajectories from general relativistic smoothed-particle hydrodynamics simulations, including a sophisticated neutrino treatment and the corresponding nucleosynthesis results, which have been presented in Part I of this study. We employ a multidimensional two-moment radiation transport scheme with approximate M1 closure to evolve the photon field and use a heuristic prescription for the opacities found by calibration with atomic-physics-based reference results. We find that the photosphere is generically ellipsoidal but augmented with small-scale structure and produces emission that is about 1.5–3 times stronger towards the pole than the equator. The kilonova typically peaks after $0.7\!-\!1.5\,$ d in the near-infrared frequency regime with luminosities between $3\!-\!7\times 10^{40}\,$ erg s−1 and at photospheric temperatures of $2.2\!-\!2.8\times 10^3\,$ K. A softer equation of state or higher binary-mass asymmetry leads to a longer and brighter signal. Significant variations of the light curve are also obtained for models with artificially modified electron fractions, emphasizing the importance of a reliable neutrino-transport modelling. None of the models investigated here, which only consider dynamical ejecta, produces a transient as bright as AT2017gfo. The near-infrared peak of our models is incompatible with the early blue component of AT2017gfo.
ACACIA: a new method to produce on-the-fly merger trees in the ramses code
Authors: Ivkovic Mladen , Teyssier Romain
Published: November 2021

The implementation of ACACIA, a new algorithm to generate dark matter halo merger trees with the Adaptive Mesh Refinement code RAMSES, is presented. The algorithm is fully parallel and based on the Message Passing Interface. As opposed to most available merger tree tools, it works on the fly during the course of the N-body simulation. It can track dark matter substructures individually using the index of the most bound particle in the clump. Once a halo (or a sub-halo) merges into another one, the algorithm still tracks it through the last identified most bound particle in the clump, allowing to check at later snapshots whether the merging event was definitive, or whether it was only temporary, with the clump only traversing another one. The same technique can be used to track orphan galaxies that are not assigned to a parent clump anymore because the clump dissolved due to numerical overmerging. We study in detail the impact of various parameters on the resulting halo catalogues and corresponding merger histories. We then compare the performance of our method using standard validation diagnostics, demonstrating that we reach a quality similar to the best available and commonly used merger tree tools. As a proof of concept, we use our merger tree algorithm together with a parametrized stellar-mass-to-halo-mass relation and generate a mock galaxy catalogue that shows good agreement with observational data.
Is the birth of PSR J0538+2817 accompanied by a gamma-ray burst?
Authors: Xu Fan , Geng Jin-Jun , Wang Xu , Li Liang , Huang Yong-Feng
Published: November 2021

Recently, the Five-hundred-meter Aperture Spherical radio Telescope measured the three-dimensional velocity of PSR J0538+2817 with respect to its associated supernova remnant S147 and found a possible spin–velocity alignment for this pulsar. Here, we show that the high velocity and the spin–velocity alignment of this pulsar can be explained by the so-called electromagnetic rocket mechanism. In this framework, the pulsar is kicked in the direction of the spin axis, which naturally explains the spin–velocity alignment. We scrutinize the evolution of the pulsar and show that the kick process can create a highly relativistic jet at the opposite direction of the kick velocity. The lifetime and energetics of the jet is estimated. It is argued that the jet can generate a gamma-ray burst (GRB). The long-term dynamical evolution of the jet is calculated. It is found that the shock radius of the jet should expand to about 32 pc at present, which is well consistent with the observed radius of the supernova remnant S147 (32.1 ± 4.8 pc). Additionally, our calculations indicate that the current velocity of the GRB remnant should be about 440 km s−1, which is also roughly consistent with the observed blast-wave velocity of the remnant of S147 (500 km s−1).
The challenge of simulating the star cluster population of dwarf galaxies with resolved interstellar medium
Authors: Hislop Jessica M , Naab Thorsten , Steinwandel Ulrich P , Lahén Natalia , Irodotou Dimitrios , Johansson Peter H , Walch Stefanie
Published: November 2021

We present results on the star cluster properties from a series of high resolution smoothed particles hydrodynamics (SPH) simulations of isolated dwarf galaxies as part of the griffin project. The simulations at sub-parsec spatial resolution and a minimum particle mass of 4 M⊙ incorporate non-equilibrium heating, cooling, and chemistry processes, and realize individual massive stars. The simulations follow feedback channels of massive stars that include the interstellar-radiation field variable in space and time, the radiation input by photo-ionization and supernova explosions. Varying the star formation efficiency per free-fall time in the range ϵff = 0.2–50${{\ \rm per\ cent}}$ neither changes the star formation rates nor the outflow rates. While the environmental densities at star formation change significantly with ϵff, the ambient densities of supernovae are independent of ϵff indicating a decoupling of the two processes. At low ϵff, gas is allowed to collapse more before star formation, resulting in more massive, and increasingly more bound star clusters are formed, which are typically not destroyed. With increasing ϵff, there is a trend for shallower cluster mass functions and the cluster formation efficiency Γ for young bound clusters decreases from $50 {{\ \rm per\ cent}}$ to $\sim 1 {{\ \rm per\ cent}}$ showing evidence for cluster disruption. However, none of our simulations form low mass (<103 M⊙) clusters with structural properties in perfect agreement with observations. Traditional star formation models used in galaxy formation simulations based on local free-fall times might therefore be unable to capture star cluster properties without significant fine tuning.
On the nature of the X-ray pulsar XTE J1859+083 and its broad-band properties
Authors: Salganik Alexander , Tsygankov Sergey S , Djupvik Anlaug A , Karasev Dmitri I , Lutovinov Alexander A , Buckley David A H , Gromadzki Mariusz , Poutanen Juri
Published: November 2021

This work is devoted to the study of the broad-band 0.8–79 keV spectral and timing properties of the poorly studied X-ray pulsar XTE J1859+083 during its 2015 outburst based on the data from the NuSTAR and Swift observatories. We show that the source pulse profile has complex shape that depends on the energy band. Pulse fraction of XTE J1859+083 has constant value around 35 per cent in the broad energy band, this behaviour is atypical for X-ray pulsars. At the same time its energy spectrum is typical of this class of objects and has a power-law shape with an exponential cutoff at high energies. No cyclotron absorption line was discovered in the source spectrum. On the basis of indirect method and the absence of a cyclotron line, an estimation was made for the magnetic field strength as less than 5 × 1011 G or belonging to the interval from 5 × 1012 to $2.0^{+0.9}_{-1.2}\times 10^{13}$ G. Data from the NOT and SALT telescopes as well as optical and IR sky surveys allowed us also to study the nature of its optical companion. We have proposed and studied new possible candidates for the optical companion of XTE J1859+083 and the most likely candidate was identified. The results of the optical and IR photometry and spectroscopy of these possible companions showed that the system is a Be X-ray binary, showing Brγ, He i, and strong H α spectral lines.
MRI-active inner regions of protoplanetary discs – II. Dependence on dust, disc, and stellar parameters
Authors: Jankovic Marija R , Mohanty Subhanjoy , Owen James E , Tan Jonathan C
Published: November 2021

Close-in super-Earths are the most abundant exoplanets known. It has been hypothesized that they form in the inner regions of protoplanetary discs, out of the dust that may accumulate at the boundary between the inner region susceptible to the magneto-rotational instability (MRI) and an MRI-dead zone further out. In Paper I, we presented a model for the viscous inner disc which includes heating due to both irradiation and MRI-driven accretion; thermal and non-thermal ionization; dust opacities; and dust effects on ionization. Here, we examine how the inner disc structure varies with stellar, disc, and dust parameters. For high accretion rates and small dust grains, we find that: (1) the main sources of ionization are thermal ionization and thermionic and ion emission; (2) the disc features a hot, high-viscosity inner region, and a local gas pressure maximum at the outer edge of this region (in line with previous studies); and (3) an increase in the dust-to-gas ratio pushes the pressure maximum outwards. Consequently, dust can accumulate in such inner discs without suppressing the MRI, with the amount of accumulation depending on the viscosity in the MRI-dead regions. Conversely, for low accretion rates and large dust grains, there appears to be an additional steady-state solution in which: (1) stellar X-rays become the main source of ionization; (2) MRI-viscosity is high throughout the disc; and (3) the pressure maximum ceases to exist. Hence, if planets form in the inner disc, larger accretion rates (and thus younger discs) are favoured.
Detecting the proposed CH4–CO2 biosignature pair with the James Webb Space Telescope: TRAPPIST-1e and the effect of cloud/haze
Authors: Mikal-Evans Thomas
Published: November 2021

It is widely anticipated that the James Webb Space Telescope (JWST) will be transformative for exoplanet studies. It has even been suggested that JWST could provide the first opportunity to search for biosignatures in an alien atmosphere using transmission spectroscopy. This claim is investigated, specifically for the proposed anoxic biosignature pair CH4–CO2. The most favourable known target is adopted (TRAPPIST-1e), with an assumed atmospheric composition similar to the Archean Earth. Compared to previous studies, a more systematic investigation of the effect that cloud/haze layers have on the detectability of CH4 and CO2 is performed. In addition to a clear atmosphere scenario, cloud/haze layers are considered at eight pressure levels between 600 and 1 mbar. These pressures cover a plausible range for H2O cloud and photochemical haze, based on observations of solar system atmospheres and physical models of tidally locked planets such as TRAPPIST-1e, although no assumptions regarding the cloud/haze-layer composition are made in this study. For the clear atmosphere and cloud/haze-layer pressures of 600–100 mbar, strong (5σ) detections of both CH4 and CO2 are found to be possible with approximately 5–10 co-added transits measured using the Near Infrared Spectrograph (NIRSpec) prism, assuming a dry stratosphere. However, approximately 30 co-added transits would be required to achieve the same result if a cloud/haze layer is present at 10 mbar. A cloud/haze layer at 1 mbar would prevent the detection of either molecule with the NIRSpec prism for observing programmes up to 50 transits (>200 h of JWST time), the maximum considered.
Gravitational waves from tidal disruption events: an open and comprehensive catalog
Authors: Toscani Martina , Lodato Giuseppe , Price Daniel J , Liptai David
Published: November 2021

We present an online, open, and comprehensive template library of gravitational waveforms produced during the tidal disruptions of stars by massive black holes, spanning a broad space of parameters. We build this library thanks to a new feature that we implement in the general relativistic version of phantom, a smoothed particle hydrodynamics code for three dimensional simulations in general relativity. We first perform a series of numerical tests to show that the gravitational wave (GW) signal obtained is in excellent agreement with the one expected from theory. This benchmark is done for well studied scenarios (such as binary stellar systems). We then apply our code to calculate the GW signals from tidal disruption events, finding that our results are consistent with the theoretical estimates obtained in previous studies for selected parameters. We illustrate interesting results from the catalog, where we stress how the gravitational signal is affected by variations of some parameters (like black hole spin, stellar orbital eccentricity, and inclination). The full catalog is available online. It is intended to be a living catalog.
Discrepancy between SAA and CRP levels linked to the difference of SAA/CRP ratio in the patients with early rheumatoid arthritis
Authors: Uda Hiroshi , Ebisu Rika , Maeda Keiji , Saiki Osamu
Published: November 2021

Objectives

Indeed, serum amyloid A (SAA) and C-reactive protein (CRP) reportedly seem to have moderate correlation, but discrepancies between CRP and SAA levels have often been reported in patients with early rheumatoid arthritis (ERA). This study aimed to determine the reasons for this discrepancy.

Methods

ERA patients (n = 206) were enrolled and treated with anti-RA drugs. Clinical features and disease activities were estimated. CRP and SAA levels were monitored, and the SAA/CRP ratio was compared. Correlations between CRP and SAA levels in individuals and between individuals and disease activity scores were examined.

Results

In a follow-up study, the SAA/CRP ratio remained almost constant over time in the same patients. However, SAA/CRP ratios differed widely between patients (0.233–106.3). In patients with high SAA/CRP ratios (>6.52), many (26.2%) had abnormal SAA values only. In patients with low SAA/CRP ratios (<6.52), not a few (6.8%) exhibited abnormal CRP values only.

Conclusions

The SAA/CRP ratio remained virtually constant in the same patients but differed dramatically between patients, which clarifies the discrepancy between CRP and SAA levels. CRP is the better marker in low-ratio patients but not in high-ratio patients; the SAA/CRP ratio is critical for its interpretation.
Surgical treatment of wrist joint dysfunction in rheumatoid arthritis: A report of two cases
Authors: Kumagai Kosuke , Takemura Yoshinori , Okumura Noriaki , Amano Yasutaka , Yayama Takafumi , Mimura Tomohiro , Mori Kanji , Barrett-Jolley Richard , Imai Shinji
Published: November 2021

In rheumatoid arthritis (RA), it is important to actively treat wrist dysfunction to improve patient outcomes. Herein, we report two cases of wrist dysfunction in RA patients who required partial wrist fusion soon after drug initiation. Case 1: A 38-year-old woman was referred to our hospital because of left wrist joint pain. At the time of examination, swelling and tenderness of the left wrist joint were observed. After 6 months of medication, no improvement in symptoms was noted; therefore, partial wrist fusion was performed. Case 2: A 38-year-old woman was referred to our hospital because of right wrist joint pain. A plain X-ray image showed fusion of the carpal bones. Due to previous failure of drug treatment, the patient opted for arthrodesis. The postoperative course was good in both cases, and the pain improved. In these cases of monoarthritic RA, synovitis and bone destruction were observed, but blood tests showed no features of active disease, and drug treatment was ineffective. In such cases, early surgical treatment should be considered, rather than continuing conservative treatment, to ensure the best outcomes.
Identification and characterization of histones inPhysarum polycephalumevidence a phylogenetic vicinity of Mycetozoans to the animal kingdom
Authors: Poulet Axel , Mishra Laxmi Narayan , Téletchéa Stéphane , Hayes Jeffrey J , Jacob Yannick , Thiriet Christophe , Duc Céline
Published: November 2021

Physarum polycephalum belongs to Mycetozoans, a phylogenetic clade apart from the animal, plant and fungus kingdoms. Histones are nuclear proteins involved in genome organization and regulation and are among the most evolutionary conserved proteins within eukaryotes. Therefore, this raises the question of their conservation in Physarum and the position of this organism within the eukaryotic phylogenic tree based on histone sequences. We carried out a comprehensive study of histones in Physarum polycephalum using genomic, transcriptomic and molecular data. Our results allowed to identify the different isoforms of the core histones H2A, H2B, H3 and H4 which exhibit strong conservation of amino acid residues previously identified as subject to post-translational modifications. Furthermore, we also identified the linker histone H1, the most divergent histone, and characterized a large number of its PTMs by mass spectrometry. We also performed an in-depth investigation of histone genes and transcript structures. Histone proteins are highly conserved in Physarum and their characterization will contribute to a better understanding of the polyphyletic Mycetozoan group. Our data reinforce that P. polycephalum is evolutionary closer to animals than plants and located at the crown of the eukaryotic tree. Our study provides new insights in the evolutionary history of Physarum and eukaryote lineages.
EPCO-07. HYBRID NEURO-GLIAL CELLULAR ARCHITECTURE IN HIGH-GRADE GLIOMA DRIVEN BY H3-G34R MUTATION
Authors: Laffy Julie , Nomura Masashi , He Chen , Bussema Lillian , Slyper Michal , Hover Laura , Gritsch Simon , Regev Aviv , Baker Suzanne , Tirosh Itay , Suva Mario
Published: November 2021

High-grade gliomas (HGG) with histone H3.3 G34R mutation are rare intractable tumours in the cerebral hemispheres that preferentially affect adolescents and young adults, but have unknown mechanisms of neuroanatomical specificity and tumourigenesis. Here, we performed single-nucleus RNA-sequencing of twenty patient samples, encompassing twelve tumours with G34R mutation and eight H3.3 wildtype HGGs, age- and location-matched. Both classes of HGG were heterogeneous, with malignant cells in multiple states, recapitulating neural and glial developmental trajectories. G34R HGG is distinguished by lack of malignant cells in the oligodendroglial lineage, and aberrant expression of neuronal programs superimposed over cellular states, resulting in hybrid glio-neuronal malignant programs. Singe-cell barcoding supports plasticity between cellular states in HGG with multiple possible transitions. CRISPR-correction of G34R in HGG models followed by scRNA-seq supports that the G34R mutation directly drives these aberrant programs. Our study provides a framework for studying the origin and tumourigenesis of paediatric gliomas.
EPCO-15. SPATIAL-TRANSCRIPTOMICS REVEALS UNIQUE MOLECULAR FEATURES OF FLUORESCENCE-SORTED 5-AMINOLEVULINIC ACID+ INFILTRATIVE TUMOR CELLS ASSOCIATED WITH RECURRENCE AND POOR SURVIVAL IN GLIOBLASTOMA
Authors: Andrieux Geoffroy , Das Tonmoy , Smith Stuart , Rahman Ruman , Chakraborty Sajib
Published: November 2021

Spatiotemporal heterogeneity of glioblastoma (GBM) originating from genomic and transcriptional variation in spatially distinct sites, may contribute to subtype switching in GBM prior to and upon recurrence. Fluorescence-guided neurosurgical resection utilizing 5-aminolevulinic acid (5ALA) has enabled the isolation of infiltrative margin tumor cells (5ALA+ cells) from a background of non-neoplastic cells. To falsify the hypothesis that the 5ALA+ subpopulation(s) is defined by a unique cellular state, we have explored the spatial-transcriptomic (ST) landscape to interrogate molecular signatures unique to infiltrating 5ALA+ cells in comparison to GBM core, rim, and invasive margin non-neoplastic cells. ST analysis reveals that GBM molecular subtype plasticity is not restricted to recurrence, but manifests regionally in a cell-type-specific manner. Whilst GBM core and rim are highly enriched with Classical and Proneural subtypes, 5ALA+ cells are uniquely enriched with the Mesenchymal subtype (MES). Upregulation of the wound response pathway in 5ALA+ cells implicate hijacking of the wound healing pathway of neural cells to promote tumor growth. Exon-intron split analysis revealed an upregulation of exonic counts for MES and wound-response genes in 5ALA+ cells, implying that these genes are under active post-transcriptional control. Network analysis suggests that wound response genes, including chemokine CCL2 that recruits regulatory T-cells and monocytic myeloid-derived suppressor cells, are controlled by an IRF8-mediated transcriptional program in 5ALA+ cells. A higher stemness signature both in 5ALA+ cells and non-neoplastic cells of the invasive margin emphasizes the role of this microenvironment in stemness acquisition and defines 5ALA+ cells as a rare sub-population of GBM stem cells. Finally, we establish a link between the unique molecular-signatures of 5ALA+ cells, and poor survival and GBM recurrence. Characterization of the 5ALA+ infiltrative sub-population offers an opportunity to develop more effective GBM treatments and urges focus away from the GBM proliferative core, upon which failed targeted therapies have been predicated.
EPCO-17. METHYLATION ANALYSIS OF MATCHED PRIMARY AND RECURRENT IDHmt ASTROCYTOMA; AN UPDATE FROM THE GLIOMA LONGITUDINAL ANALYSIS NL (GLASS-NL) CONSORTIUM
Authors: Vallentgoed Wies , Niers Anneke , van  Garderen Karin , van den Bent Martin , Draaisma Kaspar , de Heer Iris , Kouwenhoven Mathilde , Kros Johan , Martin Ivonne , Robe Pierre , Smits Marion , Tesileanu Mircea , van Thuijl Hinke , Verhaak Roel , Westerman Bart , van de Wiel Mark , Ylstra Bauke , de Leng Wendy , Wesseling Pieter , French Pim
Published: November 2021

The GLASS-NL consortium, was initiated to gain insight into the molecular mechanisms underlying glioma evolution and to identify markers of progression in IDH-mutant astrocytomas. Here, we present the first results of genome-wide DNA-methylation profiling of GLASS-NL samples. 110 adult patients were identified with an IDH-mutant astrocytoma at first diagnosis. All patients underwent a surgical resection of the tumor at least twice, separated by at least 6 months (median 40.9 months (IQR: 24.0, 64.7). In 37% and 18% of the cases, patients were treated with radiotherapy or chemotherapy respectively, before surgical resection of the recurrent tumor. DNA-methylation profiling was done on 235 samples from 103 patients (102 1st, 101 2nd, 29 3rd, and 3 4th resection). Copy number variations were also extracted from these data. Methylation classes were determined according to Capper et al. Overall survival (OS) was measured from date of first surgery. Of all primary tumors, the methylation-classifier assigned 85 (87%) to the low grade subclass and 10 (10%) to the high grade subclass. The relative proportion of high grade tumors increased ~three-fold at tumor recurrence (32/101, 32%) and even further in the second recurrence (15/29, 52%). Methylation classes were prognostic, both in primary and recurrent tumors. The overall DNA-methylation levels of recurrent samples was lower than that of primary samples. This difference is explained by the increased number of high grade samples at recurrence, since near identical DNA-methylation levels were observed in samples that remained low grade. In an unsupervised analysis, DNA-methylation data derived from primary and first recurrence samples of individual patients mostly (79%) cluster together. Recurrent samples that do not cluster with their primary tumor, form a separate group with relatively low genome-wide DNA-methylation. Our data demonstrate that methylation profiling identifies a shift towards a higher grade at tumor progression coinciding with reduced genome-wide DNA-methylation levels.
EPCO-29. GENOMIC PROFILING OF SPORADIC MULTIPLE MENINGIOMAS
Authors: Erson-Omay Zeynep , Barak Tanyeri , Vetsa Shaurey , Nadar Arushii , Miyagishima Danielle , Yalcin Kanat , Aguilera Stephanie , Mishra-Gorur Ketu , McGuone Declan , Fulbright Robert , Gunel Murat , Moliterno-Gunel Jennifer
Published: November 2021

INTRODUCTION

In rare cases, sporadic meningiomas can occur as multiple tumors in the same patient without a known germline mutation. While the underlying mechanism that leads to the formation of these multiple lesions has been hypothesized to be monoclonal or independent, the genomic profiles to support these theories remain understudied.

METHODS

Patients with an absence of family history of meningioma and prior radiation history with multiple metachronous meningiomas were included. All tissue underwent whole exome sequencing and analysis of somatic single nucleotide variations (SNV), small insertion/deletion (INDEL) events together with copy number variations (CNV) was performed. The genomic findings were correlated with clinical data.

RESULTS

A cohort of 13 meningiomas and one dural specimen, from five individuals was studied. The majority (9/13 tumors) of tumors had NF2 mutation/Chr22 loss. Four out of 5 cases had a monoclonal origination, whereas one case displayed an independent clonal formation. The somatic profile of dura was unrevealing. In contrast to the current understanding, we found monoclonal formation of multiple meningiomas is not exclusive to NF2 driven cases, as non-NF2 mutated meningiomas can too display a monoclonal etiology. Moreover, multiple monoclonal-originating lesions did not always display a homogenous profile, but rather exhibited heterogeneity through branching evolution, where some lesions acquired genomic alterations associated with aggressive behavior. The histological characterization of multiple meningioma cases does not necessarily overlap with the genomic clustering.

CONCLUSION

To our knowledge, this is the first study to use unbiased comprehensive genomic methods to reveal the heterogeneity of multiple meningioma genomic profiles. Our extensive genomic characterization of this cohort revealed that monoclonal formation can be observed both in NF2 and non-NF2 mutant meningiomas and can introduce heterogeneity. Therefore, in order to understand the full scope of each individual’s disease, detailed genomic profiling of all lesions, when possible, should be performed.
EPCO-32. IDENTIFICATION OF PROGNOSTIC CHORDOMA SUBGROUPS USING DNA METHYLATION SIGNATURES IN TISSUE AND PLASMA
Authors: Zuccato Jeffrey , Patil Vikas , Mansouri Sheila , Liu Jeffrey , Nassiri Farshad , Mamatjan Yasin , Chakravarthy Ankur , Karimi Shirin , Almeida Joao Paulo , Bernat Anne-Laure , Hasen Mohammed , Khan Shahbaz , Kislinger Thomas , Sinha Namita , Froelich Sébastien , Adle-Biassette Homa , Aldape Kenneth , De Carvalho Daniel , Zadeh Gelareh
Published: November 2021

BACKGROUND

Chordomas are malignant bone cancers arising from the skull-base and spine that are rare but cause devastating central nervous system morbidities. Survival is highly variable despite surgery and radiotherapy as 10% live under 1 year and 30-35% survive over 20 years. There are currently no reliable prognostic factors and this limits our ability to tailor patient treatment to their risk. Accordingly, this work identifies epigenetic prognostic chordoma subgroups that are detectable non-invasively through plasma methylomes to guide treatment.

METHODS

A total of 68 chordoma surgical specimens resected between 1996-2018 across three international centres underwent DNA methylation profiling. Cell-free methylated tumor DNA immunoprecipitation and high-throughput sequencing was performed on available matched plasma samples.

RESULTS

Two stable tumor clusters were identified through consensus clustering of tissue methylation data. Clusters had statistically significantly different disease-specific survivals (log-rank p=0.0062) independent of clinical factors in a multivariable Cox analysis (HR=16.5, 95%CI: 2.8-96, p=0.0018). The poorer-performing “Immune-infiltrated” cluster had genes hypomethylated at promoters, typically resulting in transcription, within immune-related pathways and higher immune cell abundance within tumors. The better-performing “Cellular” cluster showed higher tumor cellularity plus cell-to-cell interaction and extracellular matrix pathway hypomethylation. Fifty chordoma-versus-other binomial generalized linear models built using plasma methylome data distinguished chordomas from meningiomas and spinal metastases, as representative clinical differential diagnoses, in random left-out 20% testing sets (mean AUROC=0.84, 95%CI: 0.52-1.00). Plasma-based methylation signatures were highly correlated with tissue-based signals within both poor-performing (median r=0.69, 95%CI: 0.66-0.72) and better-performing cluster tumors (median r=0.67, 95%CI: 0.62-0.72).

CONCLUSIONS

The first identification of two distinct prognostic epigenetic chordoma subgroups is shown here with “Immune-infiltrated” tumors having a poorer prognosis than “Cellular” tumors. Plasma methylomes can be utilized for non-invasive chordoma diagnosis and subtyping. This work may transform chordoma treatment decision-making by guiding surgical planning in advance to match resection aggressiveness with patient prognosis.
EPCO-33. CELL-TYPE PROPORTION DECONVOLUTION OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS FROM SINGLE NUCLEI RNA-seq UNCOVERS UNDERLYING TRANSCRIPTOMIC CHANGES FROM BULK TUMOR RNA-seq COMPARED TO NORMAL BRAIN
Authors: Lee Min Kyung , Azizgolshani Nasim , Kolling Fred , Nguyen Lananh , Zanazzi George , Christensen Brock
Published: November 2021

Identifying transcriptomic alterations in pediatric central nervous system (pCNS) tumors often relies on transcriptomic profiles from bulk tissue RNA-sequencing that can be confounded by varying cell type proportions across tumor and normal brain tissues. We utilized single nuclei RNA-sequencing (snRNA-seq) and bulk RNA-seq in 33 pCNS tumors and 3 non-diseased pediatric brain tissue samples collected from the Norris Cotton Cancer Center to identify variation in gene expression in bulk tissue attributed to overrepresentation of specific cell-type populations when determining differentially expressed genes comparing pCNS tumors to normal pediatric brain tissues. snRNA-seq of 43,515 nuclei (mean = 1,209 nuclei/sample) revealed large proportions of astrocytes (median = 0.45, range = 0.24–0.93) and oligodendrocytes (median = 0.37, range = 0.00–0.66) in pCNS tumors. Compared to normal pediatric brain, proportions of astrocytes were significantly higher (P = 9.2E-03) and neurons were significantly lower (P = 9.4E-03) in pCNS tumors. Differential expression analyses comparing bulk RNA-sequencing data from pCNS tumors to normal pediatric brain identified 902 additional differentially expressed genes (# DE genes = 1,802) when adjusting for astrocyte and neuron proportions compared with unadjusted analysis (# DE genes = 900). In cell-type proportion unadjusted analysis, top DE genes included astrocyte-specific markers, GFAP and CIITA, both of which were found to be not significantly differentially expressed in cell-type proportion adjusted analysis. Indeed, pathways enrichment analysis revealed DE genes in unadjusted models were associated with processes of the neurons and astrocytes such as interferon signaling and postsynaptic signal transmission. After adjustment for astrocyte and neuron proportions, DE genes were associated with defensins and DNA replication-related processes. Our results highlight new potential biological pathways essential in pCNS tumors and indicate the significance of the distribution of varying cell types in tissue samples when conducting studies to investigate transcriptomic alterations in bulk tissue of pCNS tumors.
BIOM-12. DEVELOPMENT OF 5-ALA BASED LIQUID BIOPSY FOR THE NON-INVASIVE DIAGNOSIS OF GLIOBLASTOMA
Authors: Yekula Anudeep , Hsia Tiffaney , Balaj Leonora , Carter Bob
Published: November 2021

INTRODUCTION

Tumor specificity of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence is widely applied for fluorescence-guided surgery (FGS) in gliomas. We recently showed the feasibility of detecting tumour-specific fluorescent PpIX extracellular vesicles (EVs) derived from the plasma of glioblastoma (GBM) patients undergoing 5-ALA based fluorescence-guided surgery. Here, we further develop methods to characterize, sort and study fluorescent PpIX EVs in plasma of patients with glioma.

METHODS

We used imaging flow cytometry and Astrios EQ nanoFACS to characterize and sort PpIX EVs, respectively. Downstream RNA analysis utilized transcriptome sequencing analysis and droplet digital PCR (EGFRvIII mRNA).

RESULTS

All GBM cell lines (Gli36vIII, U87, Gli36 WT) dosed with 5-ALA demonstrated PpIX fluorescence, and released PpIX positive EVs. There was a high correlation between fluorescence in cells and the number of PpIX EVs released (r2=0.9). We sorted 100,000 PpIX EVs from Gli36vIII cells dosed with 5-ALA and detected 65 copies and 24 copies of mutant EGFRvIII mRNA and wildtype EGFR mRNA per 100,000 EVs, respectively. RNAseq analysis of the sorted PpIX EVs showed expression patterns reflective of parent cells. Furthermore, 100,000 sorted PpIX EVs from the plasma of a patient with EGFRvIII glioma yielded 22 copies of EGFRvIII mRNA while < 5 copies were detected in 1ml of plasma and healthy control plasma, demonstrating the tumor-specific nature of PpIX EVs. Finally, we performed transcriptome analysis on 250,000 PpIX EVs each from 8 patients undergoing 5-ALA based FGS. We identified several mRNAs including Gli3, STAG2, ELF3, PHLPP1 which play an important role in cancer.

CONCLUSION

The ability to sort and characterize tumor specific PpIX EVs following 5-ALA administration opens new avenues for liquid biopsy-based glioma diagnosis.