bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibodies Produced in Response to a Live-Attenuated Dengue Vaccine Are Functional in Activating the Complement System
Authors: Nascimento Eduardo J M , Norwood Brooke , Kpamegan Eloi , Parker Allan , Fernandes Jesuina , Perez-Guzman Erick , Tricou Vianney , Braun Ralph , Sharma Mayuri , Dean Hansi J
Published: December 2022

Background

Antibody-driven complement system (CS) activation has been associated with protection against symptomatic dengue virus (DENV) infection. Aggregation, opsonization, lysis, and phagocytosis are mechanisms triggered by antibody-antigen immunocomplexes following fixation of the component 1q (C1q) and activation of the classical pathway. As a result, DENV neutralization and clearance are facilitated, whereas antibody-dependent enhancement of infection is inhibited. We investigated the ability of antibodies produced in response to Takeda's dengue vaccine candidate, TAK-003, to fix C1q and activate CS.

Methods

Serum samples were collected from seronegative and seropositive participants in a phase 2 clinical trial (DEN-203), pre- and postvaccination. Samples were evaluated for the presence of complement-fixing antibodies (CFAs) against DENV using a Luminex multiplex-based immunoassay.

Results

TAK-003 elicited production of CFAs against all 4 DENV serotypes, which persisted for 1 year postvaccination, irrespective of baseline serostatus. CFA levels were correlated with neutralizing antibody titers and virus-binding total IgG and IgG1 concentrations. Furthermore, efficiency of CFA fixation was greater in samples with higher polyclonal IgG avidity.

Conclusions

These results indicate that antibodies produced after TAK-003 vaccination are functional in both activating CS and neutralizing virus infection by all DENV serotypes, which may contribute to efficacy of TAK-003.

Clinical Trials Registration

NCT01511250.
Oxidative DNA Damage by N4-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir
Authors: Kobayashi Hatasu , Mori Yurie , Ahmed Sharif , Hirao Yuichiro , Kato Shinya , Kawanishi Shosuke , Murata Mariko , Oikawa Shinji
Published: December 2022

Molnupiravir is an antiviral agent recently used for treating coronavirus disease 2019 (COVID-19). Here, we demonstrate that N4-hydroxycytidine (NHC), a molnupiravir metabolite, treated with cytidine deaminase (CDA) induced Cu(II)-mediated oxidative DNA damage in isolated DNA. A colorimetric assay revealed hydroxylamine generation from CDA-treated NHC. The site specificity of DNA damage also suggested involvement of hydroxylamine in the damage. Furthermore, Cu(I) and H2O2 play an important role in the DNA damage. We propose oxidative DNA damage via CDA-mediated metabolism as a possible mutagenic mechanism of NHC, highlighting the need for careful risk assessment of molnupiravir use in therapies for viral diseases, including COVID-19.
Current challenges for evaluating mobile health applications
Authors: Alon Noy , Torous John
Published: December 2022

As mobile health applications continue to proliferate without clear regulation, the need for app evaluation frameworks to offer guidance to patients and clinicians also expands. However, this expanding number of app evaluation frameworks itself can be a source of confusion and often contradictory recommendations. In pursuit of better frameworks that offer innovation for app evaluation, we present 4 challenges that app evaluation frameworks must overcome as well as examples from our own experience toward overcoming them. The recommendations are applicable to all health apps from any field of medicine, although we use examples from mental health as they are illustrative.
Effects of nursing a large litter and ovarian response to gonadotropins at weaning on subsequent fertility in first parity sows
Authors: Arend Lidia S , Vinas Raquel F , Silva Gustavo S , Lower Aaron J , Connor Joseph F , Knox Robert V
Published: December 2022

Post-weaning fertility failures occur more often in parity 1 (P1) sows due to high metabolic demands for lactation and their inability to meet energy requirements for maintenance, growth, and reproduction. We hypothesized that body condition loss occurs more frequently in P1 sows nursing a large litter, resulting in impairment of ovarian follicle development during lactation and post-weaning, which can negatively impact estrus and subsequent fertility. At 24 h post-farrowing, P1 sows (n = 123) were assigned to treatment (TRT) based on sow weight and the number of functional teats to receive a high number (HN, 15 to 16) or low number (LN, 12) of nursing piglets. At weaning, sows in each TRT were assigned to receive PG600 or None (Control). During lactation, sow body measures were obtained and ovarian follicles were assessed in mid-lactation and post-weaning. Lactation data were analyzed for the effects of TRT, and fertility data after weaning were assessed for TRT x PG600, but there were no interactions (P > 0.10). During lactation, 22.2 % of HN sows lost ≥ 4 piglets due to death or removal, and so these sows were excluded from further analysis. The HN sows were lighter (−6.2 kg), had less backfat (−1.0 mm), had lower body condition score (−0.4), and lost more nursing piglets (−1.2) than LN sows (P < 0.05). However, HN sows weaned more pigs (14.0) than LN sows (11.0). There was no effect of TRT on wean to estrus interval (4.2 d), but the interval was 0.5 days shorter for PG600 (P = 0.004) than control. There were no effects of TRT or PG600 on estrus within seven days after weaning (87.3 %), but PG600 induced smaller (P = 0.002) follicles at estrus (6.7 mm) than control (7.3 mm). In the subsequent parity, there were no effects of TRT or PG600 on farrowing rate (93.9%) and total born (13.2). Overall, HN sows lost more piglets and body condition but still weaned more pigs without any detrimental effects on subsequent reproductive performance.
Source Area of the Immigrant Population of Beet Webworm (Lepidoptera: Crambidae) in Northern Xinjiang, China
Authors: Mamut Marzeya , Wang Hui-Qing , Li Jing , Ji Rong , Chen Xiao
Published: December 2022

The beet webworm, Loxostege sticticalis (Linnaeus) (Lepidoptera: Crambidae), is a destructive pest inhabiting the northern temperate zone. In Xinjiang, China, this species has only occasionally infested certain areas, but has been causing severe damage since 2005. Early studies showed that most of the outbreak populations in northern Xinjiang are immigrant populations. However, the specific source area is still unknown. In this study, we determined the source area of the immigrant population of L. sticticalis in northern Xinjiang from 2010 to 2013 using daily monitoring data of L. sticticalis adults; we explained the causation of why an overwintering area of L. sticticalis could build up in Central Asia. Results showed that the direct source area of L. sticticalis in northern Xinjiang was eastern Kazakhstan, and the initial source area could be traced further to Altai Krai, Russia. Both regions were located at the foothills of the westernmost portion of Altai Mountains. The thermal conditions in these regions could not support L. sticticalis development for two generations before 1990. Hence, a few cocoons could be formed in the autumn. Influenced by global warming, L. sticticalis in these regions could complete two whole generations most years after 2001. The increased generation number, combined with sufficient precipitation, and mountainous terrain in the westernmost portion of Altai Mountains have created an overwintering area for L. sticticalis.
Decellularized extracellular matrix as scaffold for cancer organoid cultures of colorectal peritoneal metastases
Authors: Varinelli Luca , Guaglio Marcello , Brich Silvia , Zanutto Susanna , Belfiore Antonino , Zanardi Federica , Iannelli Fabio , Oldani Amanda , Costa Elisa , Chighizola Matteo , Lorenc Ewelina , Minardi Simone P , Fortuzzi Stefano , Filugelli Martina , Garzone Giovanna , Pisati Federica , Vecchi Manuela , Pruneri Giancarlo , Kusamura Shigeki , Baratti Dario , Cattaneo Laura , Parazzoli Dario , Podestà Alessandro , Milione Massimo , Deraco Marcello , Pierotti Marco A , Gariboldi Manuela
Published: December 2022

Peritoneal metastases (PM) from colorectal cancer (CRC) are associated with poor survival. The extracellular matrix (ECM) plays a fundamental role in modulating the homing of CRC metastases to the peritoneum. The mechanisms underlying the interactions between metastatic cells and the ECM, however, remain poorly understood, and the number of in vitro models available for the study of the peritoneal metastatic process is limited. Here, we show that decellularized ECM of the peritoneal cavity allows the growth of organoids obtained from PM, favoring the development of three-dimensional (3D) nodules that maintain the characteristics of in vivo PM. Organoids preferentially grow on scaffolds obtained from neoplastic peritoneum, which are characterized by greater stiffness than normal scaffolds. A gene expression analysis of organoids grown on different substrates reflected faithfully the clinical and biological characteristics of the organoids. An impact of the ECM on the response to standard chemotherapy treatment for PM was also observed. The ex vivo 3D model, obtained by combining patient-derived decellularized ECM with organoids to mimic the metastatic niche, could be an innovative tool to develop new therapeutic strategies in a biologically relevant context to personalize treatments.
Adverse Drug Reactions to Anti-infectives in Hospitalized Children: A Multicenter Study in Brazil
Authors: Feitosa Ramos Sheila , de Barros Fernandes Thais , Carlos Araújo Dyego , Rodrigues Furtado Leitzke Luísa , Gomes Alexandre Júnior Ronaldo , Morais de Araújo Janaína , Sales de Souza Júnior Alcidésio , Heineck Isabela , Maria de França Fonteles Marta , Osorio-de-Castro Claudia G S , Bracken Louise E , Peak Matthew , Pereira de Lyra Junior Divaldo , Costa Lima Elisangela
Published: December 2022

Introduction

Adverse drug reactions (ADRs) to anti-infectives affect especially hospitalized children and contribute to increased morbidity, mortality, length of stay, and costs in healthcare systems.

Objective

To assess ADRs associated with anti-infective use in Brazilian hospitalized children.

Methods

A prospective cohort study was conducted in 5 public hospitals over 6 months. Children aged 0–11 years and 11 months who were hospitalized for more than 48 h and prescribed anti-infectives for over 24 h were included.

Results

A total of 1020 patients met the inclusion criteria. Of these, 152 patients experienced 183 suspected ADRs. Most reactions were related to the gastrointestinal system (65.6%), followed by skin reactions (18.6%). Most reactions were classified as probable causality (58.5%), moderate severity (61.1%), and unavoidable (56.2%). Our findings showed that ADRs were associated with increased length of stay (P < .001), increased length of therapy (P < .015), increased days of therapy (P = .038), and increased number of anti-infectives prescribed per patient (P < .001).

Conclusion

Almost 15% of hospitalized children exposed to anti-infectives presented suspected ADRs. Their occurrence was classified as probable, of moderate severity, and unavoidable. ADRs were significantly influenced by the length of hospital stay and the number of anti-infectives prescribed per patient.
Plant tRNA functions beyond their major role in translation
Authors: Chery Marjorie , Drouard Laurence
Published: December 2022

Transfer RNAs (tRNAs) are well known for their essential function as adapters in delivering amino acids to ribosomes and making the link between mRNA and protein according to the genetic code. Besides this central role in protein synthesis, other functions are attributed to these macromolecules, or their genes, in all living organisms. This review focuses on these extra functions of tRNAs in photosynthetic organisms. For example, tRNAs are implicated in tetrapyrrole biosynthesis, mRNA stabilization or transport, and priming the reverse transcription of viral RNAs, and tRNA-like structures play important roles in RNA viral genomes. Another important function of tRNAs in regulating gene expression is related to their cleavage allowing the production of small non-coding RNAs termed tRNA-derived RNAs. Here, we examine in more detail the biogenesis of tRNA-derived RNAs and their emerging functions in plants.
On the Jacobi capture origin of binaries with applications to the Earth-Moon system and black holes in galactic nuclei
Authors: Boekholt Tjarda C N , Rowan Connar , Kocsis Bence
Published: December 2022

Close encounters between two bodies in a disc often result in a single orbital deflection. However, within their Jacobi volumes, where the gravitational forces between the two bodies and the central body become competitive, temporary captures with multiple close encounters become possible outcomes: a Jacobi capture. We perform three-body simulations in order to characterize the dynamics of Jacobi captures in the plane. We find that the phase space structure resembles a Cantor-like set with a fractal dimension of about 0.4. The lifetime distribution decreases exponentially, while the distribution of the closest separation follows a power law with index 0.5. In our first application, we consider the Jacobi capture of the Moon. We demonstrate that both tidal captures and giant impacts are possible outcomes. The impact speed is well approximated by a parabolic encounter, while the impact angles follow that of a uniform beam on a circular target. Jacobi captures at larger heliocentric distances are more likely to result in tidal captures. In our second application, we find that Jacobi captures with gravitational wave dissipation can result in the formation of binary black holes in galactic nuclei. The eccentricity distribution is approximately superthermal and includes both prograde and retrograde orientations. We conclude that dissipative Jacobi captures form an efficient channel for binary formation, which motivates further research into establishing the universality of Jacobi captures across multiple astrophysical scales.
Dust motion and possibility of dust growth in a growing circumstellar disk
Authors: Koga Shunta , Machida Masahiro N
Published: December 2022

We calculate the evolution of a star-forming cloud core using a three-dimensional resistive magnetohydrodynamics simulation, treating dust grains as Lagrangian particles, to investigate the dust motion in the early star formation stage. We prepare six different-sized set of dust particles in the range ad = 0.01–$1000\, \mu$m, where ad is the dust grain size. In a gravitationally collapsing cloud, a circumstellar disk forms around a protostar and drives a protostellar outflow. Almost all the small dust grains (ad ≲ 10–$100\, \mu$m) initially distributed in the region θ0 ≲ 45° are ejected from the center by the outflow, where θ0 is the initial zenith angle relative to the rotation axis, whereas only a small number of the large dust grains ($a_{\rm d} \gtrsim 100\, \mu$m) distributed in the region are ejected. All other grains fall onto either the protostar or disk without being ejected by the outflow. Regardless of the dust grain size, the behavior of the dust motion is divided into two trends after dust particles settle into the circumstellar disk. The dust grains reaching the inner disk region from the upper envelope preferentially fall onto the protostar, while those reaching the outer disk region or disk outer edge from the envelope can survive without an inward radial drift. These surviving grains can induce dust growth. Thus, we expect that the outer disk regions could be a favored place of planet formation.
The Solar system test for the general modified gravity theories
Authors: Chan Man Ho , Lee Chak Man
Published: December 2022

In the past few decades, various versions of modified gravity theories were proposed to mimic the effect of dark matter. Compared with the conventional Newtonian or relativistic dynamics, these theories contain some extra apparent force terms in the dynamical equations to replace the role of dark matter. Generally speaking, the extra apparent force terms usually scale with radius so that the effect would be significant only on large scale to explain the missing mass in galaxies or galaxy clusters. Nevertheless, the apparent effect may still be observable in small structures like the Solar system. In this paper, we derive analytic general formulae to represent the contribution of the precession angle of the planets in the Solar system due to the general modified gravity theories, in which the extra apparent force terms can be written in a power law of radius r or an exponential function in r. We have tested three popular modified gravity theories, the modified Newtonian dynamics (MOND), the emergent gravity (EG), and the modified gravity. In particular, based on the Solar system data, we have constrained the parameters involved for two popular general interpolating functions used in MOND. Our results can be generally applied to both of the modified inertia and modified gravity versions of MOND.
Moving groups across Galactocentric radius with Gaia DR3
Authors: Lucchini Scott , Pellett Emil , D’Onghia Elena , Aguerri J Alfonso L
Published: December 2022

The kinematic plane of stars near the Sun has proven an indispensable tool for untangling the complexities of the structure of our Milky Way (MW). With ever improving data, numerous kinematic ‘moving groups’ of stars have been better characterized, and new ones continue to be discovered. Here we present an improved method for detecting these groups using MGwave, a new open-source 2D wavelet transformation code that we have developed. Our code implements similar techniques to previous wavelet software; however, we include a more robust significance methodology and also allow for the investigation of underdensities, which can eventually provide further information about the MW’s non-axisymmetric features. Applying MGwave to the latest data release from Gaia (DR3), we detect 47 groups of stars with coherent velocities. We reproduce the majority of the previously detected moving groups in addition to identifying three additional significant candidates: one within Arcturus, and two in regions without much substructure at low VR. Finally, we have followed these associations of stars beyond the Solar neighbourhood from Galactocentric radius of 6.5–10 kpc. Most detected groups are extended throughout radius indicating that they are streams of stars possibly due to non-axisymmetric features of the MW.
Combining photometry and astrometry to improve orbit retrieval of directly imaged exoplanets
Authors: Bruna Margaret , Cowan Nicolas B , Sheffler Julia , Haggard Hal M , Bourdon Audrey , Mâlin Mathilde
Published: December 2022

Future missions like Roman, HabEx, and LUVOIR will directly image exoplanets in reflected light. While current near-infrared direct imaging searches are only sensitive to young, self-luminous planets whose brightness is independent of their orbital phase, reflected light direct imaging will reveal changes in planet brightness throughout an orbit due to phase variations. One of the first objectives will be determining the planet’s orbit via astrometry, the projected position of the planet with respect to its host star in the sky plane. We show that phase variations can significantly improve the accuracy and precision of orbital retrieval with two or three direct images. This would speed up the classification of exoplanets and improve the efficiency of subsequent spectroscopic characterization. We develop a forward model to generate synthetic observations of the 2D astrometry and the planet/star flux ratio. Synthetic data are fitted with Keplerian orbits and Henyey–Greenstein phase variations to retrieve orbital and phase parameters. For astrometric uncertainties of 0.01 au in projected separation and flux ratio uncertainties of 10−12, using photometry in orbit retrieval improves the accuracy of semimajor axis by 47 per cent for two epochs and 61 per cent for three epochs if the phase curves have a known shape, but unknown amplitude. In a realistic scenario where phase curve shape and amplitude are a priori unknown, photometry improves accuracy by 16 per cent for two epochs and 50 per cent for three epochs. In general, we find that if the planetary flux is measured to better than 10σ at multiple epochs, it usefully contributes to orbit retrieval.
The flat entropy profile at the outskirts of the Abell 2244 galaxy cluster
Authors: Andreon S , Moretti A , Böhringer H , Castagna F
Published: December 2022

Entropy is an advantageous diagnostics to study the thermodynamic history of the intracluster plasma of galaxy clusters. We present the entropy profile of the Abell 2244 galaxy cluster derived both exclusively using X-ray data from the low-background Swift XRT telescope and using the Planck y data. The entropy profile derivation using X-rays only is robust at least to the virial radius because the cluster brightness is large compared to the X-ray background at low energies, the temperature is strongly bounded by the lack of cluster X-ray photons at energies kT > 3 keV, and the XRT background is low, stable, and understood. In the observed solid angle, about one quadrant, the entropy radial profile deviates from a power law at the virial radius, mainly because of a sharp drop in the cluster temperature. This bending of the entropy profile is confirmed when X-ray spectral information is replaced by the Compton map. Clumping and non-thermal pressure support are insufficient to restore a power-law entropy profile because they are bound to be small by: (i) the agreement between mass estimates from different tracers (gas and galaxies), (ii) the agreement between entropy profile determinations based on combinations of observables with different sensitivities and systematics, and (iii) the low value of clumping as estimated using the azimuthal scatter and the gas fraction. Based on numerical simulations, ion–electron equilibration is also insufficient to restore a linear entropy profile. Therefore, the bending of the entropy profiles seems to be robustly derived and witnesses the theoretically predicted decrease in the inflow through the virial boundary.
Characterization of the spatial distribution of metals and profile of metalloprotein complexes in a mouse model of repetitive mild traumatic brain injury
Authors: Juan Sydney M A , Daglas Maria , Gunn Adam P , Lago Larissa , Adlard Paul A
Published: December 2022

Metal dyshomeostasis is a well-established consequence of neurodegenerative diseases and traumatic brain injury. While the significance of metals continues to be uncovered in many neurological disorders, their implication in repetitive mild traumatic brain injury remains uncharted. To address this gap, we characterized the spatial distribution of metal levels (iron, zinc, and copper) using laser ablation–inductively coupled plasma–mass spectrometry, the profile of metal-binding proteins via size exclusion chromatography–inductively coupled plasma–mass spectrometry and the expression of the major iron storing protein ferritin via western blotting. Using a mouse model of repetitive mild traumatic brain injury, 3-month-old male and female C57Bl6 mice received one or five impacts (48 h apart). At 1 month following 5× TBI (traumatic brain injury), iron and ferritin levels were significantly elevated in the contralateral cortex. There was a trend toward increased iron levels in the entire contralateral hemisphere and a reduction in contralateral cortical iron-binding proteins following 1× TBI. No major changes in zinc levels were seen in both hemispheres following 5× or 1× TBI, although there was a reduction in ipsilateral zinc-binding proteins following 5× TBI and a contralateral increase in zinc-binding proteins following 1× TBI. Copper levels were significantly increased in both hemispheres following 5× TBI, without changes in copper-binding proteins. This study shows for the first time that repetitive mild TBI (r-mTBI) leads to metal dyshomeostasis, highlighting its potential involvement in promoting neurodegeneration, which provides a rationale for examining the benefit of metal-targeting drugs, which have shown promising results in neurodegenerative conditions and single TBI, but have yet to be tested following r-mTBI.
Vitamin K supplementation and bone mineral density in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial
Authors: Levy-Schousboe Karin , Marckmann Peter , Frimodt-Møller Marie , Peters Christian D , Kjærgaard Krista D , Jensen Jens D , Strandhave Charlotte , Sandstrøm Hanne , Hitz Mette F , Langdahl Bente , Vestergaard Peter , Brasen Claus L , Schmedes Anne , Madsen Jonna S , Jørgensen Niklas R , Frøkjær Jens B , Frandsen Niels E , Petersen Inge , Hansen Ditte
Published: December 2022

Background

Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis.

Methods

In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1–L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status.

Results

After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo −0.023 g/cm2 [95% confidence interval (CI) −0.039 to −0.008]}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented [mean difference of changes between groups 0.050 g/cm2 (95% CI 0.015–0.085)]. No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants.

Conclusion

Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis.
SPDR-5 ESTABLISHMENT OF A CONTINUOUS CULTURE METHOD FOR MENINGIOMAS AND THE EFFECTS OF THE GREM2-BMP SIGNALLING PATHWAY ON PROLIFERATION AND ANGIOGENESIS
Authors: Yokogami Kiyotaka , Mizuguchi Asako , Watanabe Takashi , Matsumoto Fumitaka , Yamashita Shinji , Takeshima Hideo
Published: December 2022

Purpose

Meningiomas are closely related to osteogenesis, including calcification and hyperostosis at the site of attachment. Signaling pathways involved in tumor formation and extension of meningioma have not yet been elucidated. Treatment options include surgical removal and radiotherapy, but there are no reports of effective drug treatment. This is due to the difficulty of culturing non-malignant meningiomas, which has made basic experiments difficult. In this study, we established a continuous culture method for meningiomas and investigated the signaling pathways involved in meningioma growth.

Methods

67 consecutive cases of meningiomas treated in our department for three years from Apr, 2019 to March, 2022. Primary continuous culture was performed by modifying the conditional reprogramming (CR) method. Sixty-four cases were studied, excluding three cases in which culture was abandoned due to contamination. The mean age was 62.6 years, Grade 3 (6%), Grade 2 (14%) and Grade 1 (80%). These were used to observe morphology, proliferation and genetic analysis involved in angiogenesis.

Results

1) Sustained culture lasted an average of 150 days with no differences between Grades; 2) Inhibition of BMP signaling involved in osteogenesis suppressed cell proliferation regardless of Grade, and the IC50 of the inhibitor suggested the involvement of the receptor ALK3; 3) We identified GREM2 as upstream regulator of BMP signals 4) GREM2 is highly expressed in menigotherial meningiomas and immunostaining showed strong expression around whole and calcified areas. 5) GREM2 expression is negatively correlated with MIB-1 L.I., so overexpression of GREM2 in malignant meningioma cells decreased ID, which is involved in proliferation downstream of BMP signaling, and increased angiogenic factor VEGFA, which is involved in proliferation.

Conclusion

A method for the continuous culture of meningiomas was established. Using this experimental system, we identified the involvement of the GREM2-BMP signaling pathway in proliferation and angiogenesis in meningiomas as well as calcification.
GEN-13 PAIRED MUTATIONAL ANALYSIS IN SECONDARY NERVOUS SYSTEM LYMPHOMA AND PCNSL SYSTEMIC RELAPSE REVEALS DRIVER MUTATION CANDIDATES IN THE CENTRAL NERVOUS SYSTEM
Authors: Sasaki Nobuyoshi , Kume Satoshi , Tateishi Kensuke , Nakamura Taishi , Ibayashi Kenji , Yamagishi Yuki , Saito Kuniaki , Kobayashi Keiichi , Matsushita Yuko , Hibiya Yuko , Kitahara Mai , Suzuki Saki , Nagano Reiko , Yamashita Satoshi , Nakatomi Hirofumi , Shiokawa Yoshiaki , Ichimura Koichi , Nagane Motoo
Published: December 2022

Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin lymphoma confined to the brain, eyes, and the spinal cord. The mechanism of central nervous system (CNS) tropism in PCNSL has not been fully elucidated. Diffuse large B cell lymphomas (DLBCLs) occasionally present with distant recurrence, which can involve inside and outside the CNS. Secondary central nervous system lymphomas (SCNSLs) are CNS relapse of systemic lymphoma. PCNSLs also rarely present with systemic relapse. We have previously reported in our study of whole exome sequencing that PCNSLs harbor frequent mutations in genes of B cell receptor pathway members and aberrant somatic hypermutation (aSHM) target genes. Although several genetic alterations were identified as more frequent in PCNSLs compared with systemic lymphomas, specific genetic alterations which serve as the driver for CNS tropism in PCNSLs has not been identified. In order to search for mutations which might serve as driver mutations in the CNS, we have performed targeted sequencing in paired samples from patients with recurrent lymphomas, either SCNSLs or PCNSL systemic relapses, using Ion Torrent multiplex PCR. Mutational profiles were compared between the primary and recurrent tumor. Six cases (four SCNSL cases and two PCNSL systemic relapse cases) were analyzed. Of note, in the SCNSL cases, several de novo mutations were enriched only among the recurrent CNS tumors. Among these mutations, BTG2 mutations were observed in 3/4 (75%), and B2M and KLHL14 mutations were observed in 2/4 (50%) cases. In the two PCNSL systemic relapse cases, KMT2D mutations were enriched only in the recurrent systemic tumors. It is suggested that these de novo mutations in the recurrent CNS tumors might serve as driver mutations in the CNS. Further analysis in larger cohorts, and functional studies are required in order to validate these findings.
ET-7 EVALUATION OF HYPOXIA-TARGETING RADIOPHARMACEUTICAL64CU-ATSM FOR PET MONITORING WITH LOCAL THERAPY IN HIGH-GRADE GLIOMA MODEL
Authors: Yoshii Yukie , Hihara Fukiko , Matsumoto Hiroki , Igarashi Chika , Tachibana Tomoko , Shinada Mitsuhiro , Ming-Rong Zhang , Oshima Akito , Sato Hidemitsu , Narita Yoshitaka , Kurihara Hiroaki , Yamamoto Tetsuya , Higashi Tatsuya , Tateishi Kensuke
Published: December 2022

World Health Organization (WHO)-defined central nervous system (CNS) grade 4 high-grade gliomas (HGGs) are highly aggressive brain cancers characterized by the presence of hypoxia within a rapidly-growing tumor mass. Due to invasion to the surrounding brain parenchyma, these tumors commonly recur locally, despite aggressive surgical resection, and new therapeutic approaches are required for local tumor control. Here, we show a positron emission tomography (PET) integrated local therapy (PETx), to target HGGs. This technique consists of a one-step local theranostic application, followed by PET monitoring, with a hypoxia-targeting radiopharmaceutical 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM). We examined the safety and therapeutic potential of 64Cu-ATSM PETx for HGG patient-derived xenograft (PDX) tumors, which recapitulated the parent tumor phenotype of high expression of hypoxia-inducible factor-1α and BNIP3, biomarkers of tissue hypoxia. Biodistribution, dosimetry, and toxicity studies of 64Cu-ATSM local administration determined the maximum tolerated dose (MTD) to be 3.7 MBq in mouse. PETx using the MTD dose of 64Cu-ATSM indicated high tumor penetration, distribution, and retention of 64Cu-ATSM in PDX tumors, as compared to sham-treated mice. The 64Cu-ATSM PETx promoted DNA double-strand breaks, followed by apoptosis in tumors, and extensively prolonged overall survival with tolerable systemic toxicity. These findings indicate the potential of 64Cu-ATSM PETx to induce high uptake in the hypoxic tumor microenvironment, and strong therapeutic effects in PDX models. These findings establish 64Cu-ATSM PETx as a potential novel theranostic approach to facilitate local control of WHO CNS grade 4 HGGs.
BOT-3 GENOME-WIDE ASSOCIATION STUDY OF INTRACRANIAL GERM CELL TUMORS: A COMMON DELETION ATBAK1 ATTENUATES THE ENHANCER ACTIVITY AND CONFERS RISK FOR THE BRAIN TUMORS IN CHILDREN ADOLESCENTS AND YOUNG ADULTS
Authors: Terashima Keita , Sonehara Kyuto , Kimura Yui , Nakano Yoshiko , Ozawa Tatsuya , Takahashi Meiko , Suzuki Ken , Fujii Takashi , Matsushita Yuko , Tomiyama Arata , Suzuki Tomonari , Yamaguchi Shigeru , Miwa Tomoru , Sasaki Hikaru , Kitagawa Masashi , Ohe Naoyuki , Fukai Junya , Ogiwara Hideki , Kawamura Atsufumi , Miyawaki Satoru , Matsuda Fumihiko , Kiyakawa Nobutaka , Ichimura Koichi , Nishikawa Ryo , Okada Yukinori
Published: December 2022

Intracranial germ cell tumors (IGCTs) are rare brain tumors that mainly occur in children, adolescents and young adults with a particularly high incidence in East Asian populations. The biological basis of these tumors is still largely unknown. We conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry by using Infinium Asian Screening Array and other molecular biology methods. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10−9, odds ratio = 2.46 [95% CI: 1.83-3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. Expression quantitative trait locus (eQTL) analysis using the GTEx dataset reveals that the risk allele of rs3831846 has a down-regulating effect on BAK1 expression in a wide range of tissues. Further in-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity. BAK1 is a pro-apoptotic member of the BCL-2 family, thus our results suggested that the risk allele may contribute to IGCTs predisposition through down-regulating BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10-4, Spearman’s ρ = 0.48). Of the 57 loci, 11 exhibit significant association with IGCTs and these loci were implicated in a broad range of biological pathways, including KIT/KITLG signaling, apoptosis regulation, and telomerase activity. The risk allele frequency of rs3831846 is higher in east Asia than Europe (0.49 vs. 0.20), which may provide a partial explanation for the ethnic difference in incidence. Nevertheless, our results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.
ACT-4 EXPLORATORY PET EVALUATION OF BORON NEUTRON CAPTURE THERAPY FOR MALIGNANT GLIOMA REFRACTORY TO BEVACIZUMAB
Authors: Furuse Motomasa , Nihei Keiji , Kawabata Shinji , Ryo Hiramatsu , Nonoguchi Naosuke , Soeda Fumihiko , Ito Yuri , Takeno Satoshi , Aihara Teruhito , Takami Toshihiro , Miyatake Shin-Ichi , Ono Koji , Wanibuchi Masahiko
Published: December 2022

Background

We previously reported a phase II trial of accelerator-based boron neutron capture therapy (BNCT) for patients with malignant glioma, which showed a long median overall survival of 18.9 months. However, median progression-free survival was 0.9 months. In this trial, bevacizumab was permitted to use after progressive disease. The reason of discrepance between a short progression-free survival and a long overall survival was speculated that progression disease included pseudoprogression. But, efficacy of add-on bevacizumab on overall survival was not ignored.

Methods

The present study was approved by the Osaka Medical and Pharmaceutical University certificated review board and registered for Japan Registry of Clinical Trial (jRCTs051220019). Twenty-one patients who had malignant glioma refractory to bevacizumab treatment were planned to enroll in the study. The primary endpoint was a response rate of boronophenylalanine positron emission tomography. The secondary endpoints were a response rate of magnetic resonance image and safety.

Conclusion

Patients have been enrolled from June 2022. The efficacy of BNCT for malignant glioma could be elucidated by PET evaluation of tumor viability after BNCT.
ACT-20 PHASE 1/2, PROSPECTIVE, INTERNATIONAL MULTI-CENTER STUDY TO ESTABLISH THE SAFETY AND FEASIBILITY OF BLOOD-BRAIN-BARRIER DISRUPTION COMBINED WITH CARBOPLATIN FOR RECURRENT GLIOBLASTOMA; FIRST CLINICAL EXPERIENCE IN JAPAN
Authors: Kijima Noriyuki , Kanemoto Manabu , Oshino Satoru , Tani Naoki , Hosomi Koichi , Okita Yoshiko , Hirayama Ryuichi , Tachi Tetsuro , Kuroda Hideki , Utsuki Rena , Kagawa Naoki , Kishima Haruhiko
Published: December 2022

The prognosis for glioblastoma is still very poor despite intensive treatment by surgery, radiation, and chemotherapy. One of the reasons for poor prognosis of glioblastoma is blood-brain-barrier (BBB), which limits the delivery of chemotherapeutic agents to the brain. Focused ultrasound (FUS) therapy is approved for essential tremor and Parkinson disease in Japan and preclinical studies suggest low-intensity focused ultrasound (LIFU) administered with microbubbles (MB) can disrupt BBB and can improve the delivery of chemotherapeutic agents. Thus, currently, focused ultrasound therapy has gained attention in neuro-oncology and a number of clinical trials using FUS for the treatment of glioblastoma are underway. Our institutions (Osaka University Hospital and Saito Yukoukai Hospital) are the first in Japan to join the international multicenter study to examine the safety and feasibility of BBB disruption by FUS and MB combined with intravenous carboplatin for the treatment of recurrent glioblastoma. We are planning to enroll one recurrent glioblastoma patient for this study soon. BBB disruption strategies using FUS and MB for the treatment of neuro-oncological disease has potentials to improve the outcome of patients and many clinical trials will be performed in future.
RT-3 TREATMENT RESULTS OF AVAGAMMA THERAPY FOR RECURRENT GLIOBLASTOMA COMBINED WITH GAMMA KNIFE AND BEVACIZUMAB
Authors: Sato Kenichi , Asanome Taku , Ishida Yuuki , Sugio Hironori , Takanashi Masami , Nakamura Hirohiko
Published: December 2022

Purpose

We report the treatment results of AVAgamma therapy combining gamma knife (GK) and bevacizumab (Bev) for recurrent glioblastoma.

Subjects

From August 2013 to July 2022, 56 patients with recurrent glioblastoma treated with AVAgamma therapy as salvage therapy at the time of relapse after initial treatment. When the irradiation volume of GK was 15 ml or less, a single irradiation with a marginal dose of 20 to 26 Gy was performed. More than that received a single marginal dose of 12-15 Gy in two fractions or 8 Gy in three fractions. The mean therapeutic marginal dose was 23.9 Gy. Bev was administered 10 mg / kg or 15 mg / kg 1 to 10 times after GK.

Methods

Median progression-free survival (mPFS) and median survival (mOS) from AVAgamma treatment, and mOS and 5-year survival rate from initial treatment were compared with historical controls (GK group: 30 patients) who received only GK at the time of recurrence.

Results

The mPFS from AVAgamma therapy was 6 months, PFS-6m was 39%, OS-6m was 76%, and mOS was 10 months. The mOS from initial treatment was 25 months, which was prolonged compared to 21 months in the GK group (p=0.05). The 5-year survival rate for recurrent glioblastoma was 5% in the GK group and 22% in the AVAgamma group (p=0.04). The 5-year survival rate for glioblastoma with KPS is 70% or more at recurrence was 0% in the GK group and 33% in the AVAgamma group (p=0.017).

Discussion

Combined use of Bev with GK was considered to provide local control of recurrent lesions and prolong life prognosis in patients with good KPS at the time of recurrence.

Conclusion

AVAgamma therapy is thought to prolong the survival of recurrent glioblastoma and play an important role as salvage treatment.
RT-4 WORLD'S FIRST HEMISPHERE-SHAPE BRAIN-DEDICATED PET FOR SMALL LESION DETECTION
Authors: Takahashi Miwako , Akamatsu Go , Yamaki Tomohiro , Onodera Shinji , Yamaya Taiga
Published: December 2022

Positron emission tomography (PET) is useful to detect malignant tumors by imaging glucose or amino acid metabolism. Whole-body PET with the detector arrangement in a large diameter is currently used for brain imaging, however, the detector arrangement in small diameter is better for brain imaging. Stereotactic radiosurgery (SRS) treats brain tumor with maintaining cognitive function. Therefore, it needs more dedicated PET to identify small lesions and their localization. Then, we developed the world's first brain-dedicated PET with detectors arranged in a hemisphere of 28 cm diameter, attaining 2.2 mm in spatial resolution. This development was performed with ATOX CO., LTD and the brain-dedicated PET has been commercialized as VrainTM. Ten normal volunteers (22 - 45 age male) underwent 18FDG-PET using a whole-body PET (Discovery MI, GE) and the brain-PET for 10-min each, which were started 30-min and 45-min after FDG injection, respectively. A phantom with 10-22 diameter hot spheres and background (radioactivity ratio, 4:1) was also acquired by both PET systems, then estimated the radioactivity ratio in case of 2-mm diameter hot sphere. As a results, the inferior colliculus, substantia nigra, red nucleus, and brain stem raphe nucleus were identified with the brain-PET. The inferior colliculus was identified with the whole-body PET, but other nuclei were not. Based on phantom study, it was estimated that radioactivity in a 2-mm diameter sphere was measured with 1.4 - 2.9 times higher contrast than whole-body PET. The substantia nigra and the red nucleus has 5.0-6.0mm in short diameter on MRI T2WI axial image. The raphe nucleus extends laterally to 2.5mm on postmortem brain specimens. We concluded that our brain-dedicated PET can identify approximately 2.5mm diameter tumor clearly and will be particularly useful in SRS.
RT-7 DIFFERENTIATION AND TREATMENT OF RECURRENCE AND RADIATION NECROSIS IN THE TREATMENT OF MALIGNANT GLIOMAS
Authors: Tsuzuki Shunsuke , Nitta Masayuki , Saito Taiichi , Maruyama Takashi , Koriyama Shunichi , Kuwano Atsushi , Tamura Manabu , Ikuta Soko , Kawamata Takakazu , Muragaki Yoshihiro
Published: December 2022

Background

In the course of treatment of malignant gliomas, the appearance of contrast-enhanced lesions and surrounding T2/FLAIR high-signal after treatment is often experienced. There is no modality that can reliably diagnose whether the lesion is a recurrence or a response to treatment, including radiation necrosis. Furthermore, the choice of treatment modality is often difficult, such as reexcision, stereotactic irradiation, Avastin. Very few reports have examined the relationship between the irradiation field and histology.

Methods

Thirty-seven lesions in 30 patients who underwent repeat resection of malignant gliomas at our institution from October 2019 to December 2021 were analyzed retrospectively. Based on postoperative pathology, the patients were classified into two groups: recurrence group and radiation necrosis group.In each group, age, gender, histology at initial surgery, IDH status, radiation and chemotherapy, TNR of Methionine-PET, and the number of days after the end of treatment until the appearance of contrast lesions were considered.

Results

The recurrence group consisted of 20 patients with 26 lesions, mean age 48 years, male/female = 13/7, pathology was GBM 13, DA 1, AA 3, AO 2, AE 1, TNR 3.33 (1.41-6.32), and time to contrast appearance 547 (14-2427) days. PDT in combination with initial surgery was seen in 9 patients.The necrosis group consisted of 10 patients with 11 lesions, mean age 47 years, male/female = 4/6, pathology GBM 5, AA 2, AO 1, PXA 2. TNR 2.51 (1.20-3.75), 318 (24-678) days to contrast appearance, 2 patients had PDT.

Conclusions

Radiation necrosis tended to have lower TNR and shorter time to lesion appearance than recurrence, but no significant difference was observed. Improvement of diagnostic accuracy with modalities is desirable, and unnecessary irradiation is highly likely to contribute to ADL deterioration such as leukoencephalopathy and higher functional impairment.
RT-8 POST-IRRADIATION COURSE OF GLIOMAS OF THALAMUS AND BRAINSTEM
Authors: Yuri Shimizu , Narita Yoshitaka , Ichimura Koichi , Miyakita Yasuji , Ohno Makoto , Takahashi Masamichi , Yanagisawa Syunsuke , Shima Satoshi , Kojima Kanako , Kashihara Tairo , Takahashi Kana , Inaba Koji , Itami Jyun , Igaki Hiroshi
Published: December 2022

Objective

We retrospectively reviewed the post-irradiation course of cases treated with radiotherapy for the gliomas involving thalamus or brainstem.

Methods

Thirty-seven gliomas involving thalamus or brainstem treated with radiotherapy from 2007 to 2021 in our hospital were included. Median age was 47 (19-79) years, and KPS at the start of irradiation was 80% or less in 26 cases. Tumor localization was thalamus only/brainstem only/both thalamus and brainstem for 20/9/8 cases. Two cases did not undergo biopsy, and the others underwent surgery before irradiation. Two cases underwent partial excision of the lesion near the thalamus, 6 cases underwent partial excision from other than the thalamus-brainstem, and 27 cases underwent biopsy only. The pathological diagnosis based on the WHO classification at the time of surgery was glioblastoma (GBM) in 8 cases, high-grade glioma other than glioblastoma (HGG) in 23 cases (including 9 cases of diffuse midline glioma K27M), and low-grade glioma (LGG) in 6 cases.

Results

Median observation period was 16(2-66) months. Median PFS/median OS/5-year OS rate were 13 months/25 months/20% in all 37 cases. Median PFS was 66/18/7 months for LGG/ HGG/ GBM, and 5-year OS was 75/16/15%. Symptomatic cerebral edema associated with tumor growth was observed in one GBM 9 months after irradiation. In HGG, 7/23 cases underwent the VP shunting before irradiation, and one case who underwent ventriculostomy before irradiation had a VP shunting created for worsening hydrocephalus 3 months after irradiation. In one case of GBM, a VP shunt was created immediately after surgery.

Conclusions

Compared to the past reports of gliomas, it was suggested that the localization in thalamic brainstem was a factor for a worse prognosis in HGG.