bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenomenological study of acoustic emissions generated by gear meshing in planetary gearboxes
Authors: Leaman Félix
Published: November 2024

This study explores the frequency content of the envelope spectrum of acoustic emission (AE) signals from planetary gearboxes. Since AE signals contain continuous AE and burst-type AE, it is important to determine how different types of amplitude modulation affect these components. Phenomenological simulations of the AE signals were conducted to analyze the influence of the modulations. This approach quantitatively determines how the different harmonics in the envelope spectrum change depending on the level and type of modulation. The modulations under analysis are sinusoidal and single square wave. The simulations indicate that sidebands at the planet gear pass frequency around the gear mesh components are mainly attributed to the modulation of AE bursts, while harmonics at the planet gear pass frequency are primarily attributed to the modulation of the continuous AE. An application case to a wind turbine gearbox is also presented. The study highlights the influence of normal modulations or fault-related modulations in the AE envelope spectra from planetary gearboxes. It provides meaningful insights for establishing AE technology as a consistent condition monitoring technique for planetary gearboxes. The main practical value of the research is providing guidelines for the correct interpretation of AE envelope spectra in planetary gearboxes, which is crucial for avoiding gear failures.
MLAD: Manifest and latent anomaly detection based on the integration of reconstruction and MLFP-KNN methods
Authors: Shao Pengyan , Lu Tongwei
Published: November 2024

In the realm of industrial manufacturing, anomaly detection technologies are essential for enhancing production efficiency. This paper aims to optimize the detection of anomalies in industrial manufacturing settings by introducing a novel framework manifest and latent anomaly detection (MLAD). Firstly, we redefine anomalies as manifest and latent, further subdividing the original categories of structural and logical anomalies. To address the issue of insufficient feature space information utilization in previous reconstruction-based methods, which led to inadequate detection of latent anomalies, we combine a reconstruction-based approach with the multi-layer feature pyramid k-nearest neighbors technique. Additionally, we introduce a Hybrid Attention mechanism to refine the autoencoder’s reconstruction process, thereby enhancing the detection of latent anomalies and increasing overall accuracy. Our experiments on the MVTec LOCO AD dataset demonstrate that MLAD achieves a significant improvement in anomaly detection, with an Image-level AUROC score of 90.8% and Pixel-level AU-sPRO of 79.3%. The integration of the Hybrid Attention mechanism significantly boosts the precision of anomaly detection, highlighting the effectiveness of our approach in enhancing industrial anomaly detection capabilities. The framework provides a more nuanced understanding of industrial defects, contributing valuable insights and practical improvements to the field of industrial anomaly detection.
Prediction of normal tissue complication probability for rat spinal cord tolerance following ion irradiations
Authors: Casali Alice , Ramos Ricardo Luis , Ballarini Francesca , Carante Mario Pietro
Published: November 2024

Objective. Currently, treatment planning in cancer hadrontherapy relies on dose-volume criteria and physical quantities constraints. However, incorporating biologically related models of tumor control probability and of normal tissue complication probability (NTCP) would help further minimizing adverse tissue reactions, and would allow achieving a more patient-specific strategy. The aim of this work was therefore the development of a mechanistic approach to predict NTCP for late tissue reactions following ion irradiation. Approach. A dataset on the tolerance of the rat spinal cord was considered, providing NTCP (for paresis of at least grade II) experimental data following irradiation by photons, protons, helium and carbon ions, under different fractionation schemes. The photon data were fit by a mechanistic NTCP model with four parameters, called Critical Element Model; this allowed fixing the two parameters that only depend on the tissue features. Afterwards, the two parameters depending on radiation quality were predicted by applying the BIophysical ANalysis of Cell death and chromosome Aberrations biophysical model, for each ion type and dose-averaged linear energy transfer value. Main results. The predicted NTCP curves for ion irradiation were tested against the ion experimental data, by Chi-Square and p-value calculations. The model passed a significance test at 1% for all the datasets, and 5% for 13 out of 16 datasets, thus showing a good predictive power. The Relative biological effectiveness (RBE) was also calculated and compared with the data for the endpoint of NTCP equal to 50

%

, and a considerable discrepancy with the commonly calculated RBE for cell survival was shown. Significance. This study highlights the importance of considering the endpoint of interest when computing the RBE, through the application of a NTCP model, and it represents a first step towards the development of an approach to improve treatment plan optimization in therapy. To this aim, the approach needs to be extended to other endpoints and to be applied to patients’ data.
Carbon quantum dots: synthesis, properties and multifaceted applications in biomedical imaging, environmental remediation and sensing technologies
Authors: Jebanisha B , Devi V N Meena
Published: November 2024

With a dimension of roughly 10 nm, carbon quantum dots (CQDs) are an intriguing family of carbon nanoparticles. Various fabrication techniques, such as ultrasonication, electrochemical oxidation, hydrothermal reaction, laser ablation, microwave irradiation and reflux lead to CQD synthesis through processes including pyrolysis, carbonization, oxidation and polymerization. Sustainable raw materials are often utilized, aligning with environmental concerns and waste reduction efforts. CQDs exhibit low toxicity, chemical inertness, remarkable biocompatibility and highly adjustable photoluminescence behaviour owing to their semiconductor-like properties and oxygen based functional groups. Their tiny particle sizes contribute to highly photoluminescent emissions and controllable fluorescence. In biomedical applications, CQDs show promise for imaging, drug delivery and sensing due to their biocompatibility and tunable optical properties. In environmental contexts, they hold potential for wastewater treatment, heavy metal detection and ion sensing leveraging their adsorption capabilities and photoluminescence. This review explores the synthesis methods, physical and chemical characteristics and diverse applications of CQDs particularly focusing on their potential in biomedical imaging, environmental remediation and sensing technologies.
Adiabatic propagation in nematic liquid crystals with competing nonlinearities
Authors: Du Mingxin , Pu Shaozhi , Zhang Meng , Sun Ying , Wang Xiaomeng
Published: November 2024

We theoretically investigate the influence of the variation of the nonlocal degree of the molecular orientation effect σ
1 and the nonlocal degree of the thermal effect σ
2 on beam propagation in nonlocal media with competing nonlinearities. According to the model proposed by JUNG P S, we find that variations in σ
1 and σ
2 have completely different effects on beam propagation in the medium. When σ
1 increases, the beam tends to broaden, whereas when σ
2 increases, the beam tends to compress. Numerical calculations, conducted using the split-step Fourier method, show that changes in σ
2 have a smaller effect on propagation compared to σ
1. Adiabatic propagation of the beam in nematic liquid crystals can be achieved if σ
1 changes gradually, but not if σ
1 changes abruptly. In contrast, adiabatic propagation can be realized with σ
2 whether it changes abruptly or gradually. The variational results are well confirmed by numerical simulations.
Mechanical performance of friction stir welded acrylonitrile butadiene styrene and polystyrene plates with and without multiwall carbon nanotubes: a comparative study
Authors: Kumar Balmiki , Kumar Sanjeev , Barma John Deb
Published: November 2024

Acrylonitrile Butadiene Styrene (ABS) and Polystyrene (PS) are utilized in high-performance automotive parts, robust consumer electronics, and advanced packaging solutions for improved durability and strength. Joining ABS and PS using Friction Stir Welding (FSW) significantly enhances the joint strength, material integrity, and performance, making it ideal for advanced engineering applications. Present paper investigates the effects of incorporating and deprived of multiwall carbon nanotubes (MWCNTs) during joining of the ABS and PS material. A cylindrical threaded tool is used to join the material at varying tool rotation speed (TRS) from 700 rpm to 1100 rpm with interval of 100 rpm and traverse speed (TS) from 0.1 mm s−1 to 0.5 mm s−1 with interval of 0.1 mm s−1. The Scanning Electron microscopy (SEM) and Fourier-Transform Infrared Spectroscopy (FTIR) analysis of welded samples is also performed. The results showed that optimal joints were formed at a TS of 0.1 mm s−1 and a TRS of 900 rpm with MWCNTs. Without MWCNTs, the maximum tensile strength and efficiency were achieved at a TS of 0.5 mm s−1 and TRS of 800 rpm. Tensile tests demonstrated a 39.16% increase in joint strength with the incorporation of MWCNTs in welded dissimilar thermoplastic materials, highlighting their potential to significantly enhance tensile strength.
Constraints on ultra-slow-roll inflation with the NANOGrav 15-Year dataset
Authors: Mu Bo , Liu Jing , Cheng Gong , Guo Zong-Kuan
Published: November 2024

Ultra-slow-roll (USR) inflation predicts an exponential amplification of scalar perturbations at small scales, which leads to a stochastic gravitational wave background (SGWB) through the coupling of the scalar and tensor modes at the second-order expansion of the Einstein equation. In this work, we search for such a scalar-induced SGWB from the NANOGrav 15-year (NG15) dataset, and find that the SGWB from USR inflation could explain the observed data.
The Bayes factors are 54 ± 5 for the USR inflation model alone and 68 ± 6 for the combined USR inflation plus supermassive black hole binaries (SMBHB) models.
We place constraints on the amplitude of the scalar power spectrum to P
Rp > 10-1.95 at 95% confidence level (C.L.) at the scale of k ∼ 20 pc-1. We find that log10
P
Rp degenerates with the peak scale log10
k
p.
We also obtain the parameter space allowed by the data in the USR inflationary scenario, where the e-folding numbers of the duration of the USR phase has a lower limit ΔN > 2.80 (95% C.L.) when the USR phase ends at N ≈ 20.
With astrophysically motivated priors, the NG15 dataset fits both the USR inflation model and SMBHB model equally well.
Simulation research of a borehole muon detector for deep vein exploration
Authors: Yin L. , Luo S. , Zeng G. , Wang K. , Feng S. , Feng S.Y. , Zhang H. , Feng C. , Wang X.
Published: November 2024

Natural muons are secondary particles generated through the
interaction of the universe's energetic proton stream with the
atmosphere. Their remarkable penetration capabilities and broad
energy spectrum allow them to traverse thousands of meters
underground. This inherent property renders them conducive to
imaging via the flux attenuation produced as muons penetrate large
objects. In the realm of earth science research, limitations of
underground space necessitate the development of novel detection
methodologies and instruments for imaging extensive subterranean
structures. Presently, researchers worldwide have developed and
evaluated numerous muon detectors, predominantly employing drilling
techniques. However, existing borehole detectors feature a high
number of readout channels and large diameters, resulting in
elevated manufacturing expenses and intricate electronic systems. In
this study, we propose a small-diameter detector with a reduced
number of readout channels, constructed using wedge-section plastic
scintillator strips and plastic scintillator arcs, and simulate the
detector performance in Geant4. Comparative analysis with
traditional rectangular-section plastic scintillator strip designs
reveals an enhancement in count rate, employing 176 read electronic
channels. The effect of the arc thickness of plastic scintillator on
the resolution of the zenith angle of the detector is simulated. The
results can provide guidance for the selection of the arc thickness
of plastic scintillator. Furthermore, simulated detection of
underground gold deposits demonstrates the detector's capability to
successfully invert images of subterranean gold deposits within a
specified timeframe.
Powering a molecular delivery system by harvesting energy from the leaf motion in wind
Authors: Armiento Serena , Bernacka-Wojcik Iwona , Dar Abdul Manan , Meder Fabian , Stavrinidou Eleni , Mazzolai Barbara
Published: November 2024

Smart agriculture tools as well as advanced studies on agrochemicals and plant biostimulants aim to improve crop productivity and more efficient use of resources without sacrificing sustainability. Recently, multiple advanced sensors for agricultural applications have been developed, however much less advancement is reported in the field of precise delivery of agriculture chemicals. The organic electronic ion pump (OEIP) enables electrophoretically-controlled delivery of ionic molecules in the plant tissue, however it needs external power-supplies complicating its application in the field. Here, we demonstrate that an OEIP can be powered by wind-driven leaf motion through contact electrification between a natural leaf and an artificial leaf. This plant-hybrid triboelectric nanogenerator (TENG) directly charges the OEIP, enabling proton delivery into a pH indicator solution, which triggers visible color changes as a proof-of-concept. The successful delivery of up to 44 nmol of protons was revealed by pH measurements after 17 h autonomous operation in air flow moving the plant and artificial leaves. Several control tests indicated that the proton delivery was powered uniquely by the charges generated during leaf fluttering. The OEIP-TENG combination opens the potential for targeted and self-powered long-term delivery of relevant chemicals in plants, with the possibility of enhancing growth and resistance to abiotic stressors.
Enhancing secrecy rates in visible-light communications with signal-dependent noise: exploring optical jamming technique
Authors: Al-Moliki Yahya M , Alqahtani Ali H , Alresheedi Mohammed T , Al-Harthi Yahya
Published: November 2024

This research investigates the security of a visible light communication (VLC) system in an indoor setting. The system consists of multiple transmitters (referred to as Alice), a legitimate receiver (referred to as Bob), and a passive adversary (referred to as Eve). A scheme is proposed to enhance secrecy by using optical jamming signals alongside the confidential signal, under constraints of nonnegativity and average optical intensity. The optical jamming signals follow a truncated Gaussian distribution to adhere to predefined constraints. The analysis takes into account both noise independent of the signal and noise dependent on the signal. The study obtains lower and upper bounds on secrecy rate through the application of the variational method, the dual expression of secrecy rate, and the notion of ‘the optimal input distribution that tends towards infinity’. An asymptotic analysis reveals a minimal performance difference between the upper and lower bounds under large optical intensity. Introducing a peak optical intensity constraint enables further scrutiny of both the exact and asymptotic secrecy-rate bounds. Numerical results are provided to validate the obtained secrecy-rate bounds.
What Do They Know of Cricket …?
Authors: Wagg Stephen
Published: November 2024

This chapter considers the politics of English cricket at the beginning of the 2020s, when the campaign to leave the European Union was the context for much atavistic political rhetoric. This in turn coincided, at state level and in the mainstream British media, with a growing hostility both to migrants and to ‘multiculturalism’—usually, in practice, the same thing. This can be understood as indicative of a long-drawn-out transition from one form of racism to another on the part of the British state. The chapter argues that both the public ruminations about ‘reclaiming’ the country and the restrictions triggered by the COVID-19 pandemic (much of the 2020 cricket season was cancelled and what professional cricket took place did so in the absence of spectators) highlighted processes that had been in train for some decades. The chapter considers these processes and their present and likely repercussions on English cricket.
‘One Team, One Nation’
Authors: Hildred Ben
Published: November 2024

In 2009, Sri Lanka emerged from a brutal, twenty-six-year-long civil war which created rifts that continue to be felt across the cultural landscape. In the ten years since the end of the conflict, various public figures have touted cricket as one method of fostering unity and reconciliation in the country. This chapter outlines the current context of cricket within Sri Lanka and places it within the wider global context of using sport for development and peace (SDP). Drawing from ethnographic research carried out in Colombo and Jaffna, the chapter examines these efforts to use cricket for reconciliatory purposes in an attempt to assess whether such an association is viable. In doing so, it focusses particularly on the use of cricket to forge a new national identity, one supposedly without ethnic, religious, or class boundaries, an idea encapsulated in the current Sri Lanka cricket slogan ‘One Team, One Nation’. While deemed unequivocally ‘good’ by stakeholders, the chapter shows how cricket is often rife with the same inequalities and problems that affect wider Sri Lankan society. Delving deeper into such inequalities reveals how sport inevitably occupies a paradoxical position in these contexts—in order to reconcile, it must divide. In examining the potential for cricket to forge a new national identity, the chapter contextualizes both concepts of reconciliation and concepts of cricket itself, conveying how on a deeper social level sport can come to create new meanings for the individual, presenting a potential re-configuration of ‘the national question’ for the future.
‘On Top of the World’ (?)
Authors: Westall Claire
Published: November 2024

This chapter reads the aesthetics of the 2019 Cricket World Cup against its 1999 predecessor, including the styles of play seen, the marketing efforts deployed, and the sales and ticketing approaches used to popularize these tournaments; tournaments that were mostly played in England. All this is set this within a longer story of cricketing Englishness, imperialism, and the growing need to ‘world’ the game in new ways. More specifically, though, the discussion compares the musical anthems and music videos used for the 1999 World Cup and those released for the return of the event in 2019. The chapter explores the way in which different ideas of Englishness, Britishness, success, and connection are attempted across the shift from 1999 to 2019 and also across the two 2019 pieces and their accompanying visuals. Where the Andrew ‘Freddie’ Flintoff’s singing and accompanying video offer a notably ‘down-to-earth’ and domestic vision of cricketing Englishness, moving through a number of seemingly ‘street’ locations and regional or specifically English scenes before arriving in London, the official tournament track by Loryn and Rudimental is a more explicitly urban, London-linked appeal to youthful celebration, attempting to call up the success of 2012 and mobilize the links between sport and public festival of that Olympic summer but with very little connection to contemporary cricketing culture. In this manner, the 2019 tournament, like the 1999 event before it, was marketed so as to make the world sit within an idea of Britishness, but only succeeded in retaining a sense of historically imperial Englishness which worked against more progressive ideas of a civic cricketing Englishness in and for England.
Women as Landscapes
Authors: Leonard-Fleckman Mahri
Published: November 2024

Chapter 5 explores scribal representations of Timnah and the Sorek Valley in the Samson cycle (Judges 13–16) and argues that female characters are scribal tools to depict and embody the region as elusive and liminal places. The chapter focuses on the unnamed woman around Timnah (Judges 14–15) and Delilah in the Sorek Valley (Judges 16). It also incorporates Tamar of Genesis 38 into the discussion, whose story takes place around a “Timnah” that may or may not be the Shephelah location. The chapter proposes that female characters in the Samson cycle are not subjects but rather geographical markers of a socially perplexing area. This chapter seeks to highlight the unknowability of these women and the Shephelah through feminist, spatial, and composition-historical analyses of their stories.
Elevated blood pressure variability is associated with an increased risk of negative health outcomes in adults aged 65 and above—a systematic review and meta-analysis
Authors: Saren Jordy , Debain Aziz , Loosveldt Fien , Petrovic Mirko , Bautmans Ivan
Published: November 2024

Background

The clinical relevance of blood pressure variability (BPV) is still unknown, despite increasing evidence associating BPV to negative health outcomes (NHOs). There is currently no gold standard to define high BPV and normal reference values for BPV are lacking.

Aim

The primary aim was to examine whether high BPV can predict NHO in adults aged ≥65. The predictive value of BPV was compared to mean BP (mBP) when both parameters were available.

Methods

PubMed and Web of Science were systematically screened; 49 articles (12 retrospective, 18 prospective and 19 cross-sectional studies) were included and evaluated for methodological quality. Meta-analyses were conducted to examine the association of BPV (and mBP when available) with NHO.

Results

Systolic BPV and systolic mBP seem to indicate at least comparable odds for cardiovascular disease (BPV: odds ratio (OR) = 1.33 (95% CI: 1.19–1.48, P < .00001) vs mBP: OR = 1.06 (95% CI: 1.03–1.09, P = .0002)) and cerebral deterioration (BPV: OR = 1.28 (95% CI: 1.17–1.41, P < .00001) vs mBP: OR = 1.06 (95% CI: 1.04–1.09, P < .00001)). Increased diastolic BPV was associated with higher odds of cerebral deterioration (OR = 1.18 (95% CI: 1.04–1.35), P = .01).

Conclusion

High systolic BPV and high systolic mBP are associated with 33% and 6% higher odds of cardiovascular disease in adults aged ≥65, respectively. High BPV is also related to an 18%–28% and 11% increased odds of cerebral deterioration and poor stroke recovery. An overview of cut-off values is provided for the most often reported BPV parameters in literature, which can be used as a guideline to identify elevated BPV in clinical practice.
Outcomes of a multidisciplinary approach to management of mavacamten in obstructive hypertrophic cardiomyopathy
Authors: Jensen Hanna , Yousif Zaid , Huynh Trina , Kraushaar Megan , Reed Marcy , Boarman Trista , Enciso Jorge Silva , Willeford Andrew
Published: November 2024

Purpose

Traditional treatments for obstructive hypertrophic cardiomyopathy (oHCM) include β-blockers, calcium channel blockers, and disopyramide. Mavacamten, a novel cardiac myosin inhibitor, is a promising oHCM therapy but has practical challenges limiting its use. This descriptive study aimed to describe a clinic workflow for mavacamten management in a real-world setting, addressing challenges such as cost, drug interactions, and monitoring requirements. The focus was on reducing patient-level costs while ensuring feasibility and efficiency.

A retrospective analysis was conducted on 34 patients with oHCM for whom mavacamten was considered between May 2022 and May 2023. The clinic workflow involved cardiologist assessment, pharmacist evaluation of drug interactions, enrollment in the mavacamten risk evaluation and mitigation strategy program, cost reduction measures, and initiation of monitoring through scheduled echocardiograms. Of the 34 patients, 21 (62%) were initiated on mavacamten and followed for up to 1 year on therapy. The median time from referral to prior authorization approval and first fill was 5 and 22 days, respectively. Patients demonstrated high adherence (99.1%) as measured by the proportion of days covered. Echocardiogram follow-up showed improvements in left ventricular outflow tract parameters with no patients having a decrease in left ventricular ejection fraction to less than 50%.

Conclusion

The described workflow effectively addressed challenges associated with mavacamten management, emphasizing roles for clinic personnel, cost reduction strategies, and structured patient monitoring. While the workflow’s specifics may need adaptation in different settings, this report provides valuable insights for clinics implementing structured mavacamten management approaches.
Superstitious–magical imaginings
Authors: Ichino Anna
Published: November 2024

According to a once-standard view, imagination has little or no role in action guidance: its motivating power, if any, is limited to pretence play. In recent years this view has been challenged by accounts that take imagination to motivate action also beyond pretence, for instance in the domain of religion and conspiracy-related thinking. Following this trend, I propose a new argument in favour of imagination’s motivating power based on a class of actions that has not yet received much consideration in the imagination literature: what I call ‘superstitious–magical actions’. These actions are extremely pervasive in our lives and reveal imagination’s motivating power to be larger than many take it to be. By analysing them I show not only that imagination motivates very often, but also how it does so – that is, what the dynamics of motivation by imagination are.
Selective IR measurement of fluorescent protein chromophore based on TFD-IR technique
Authors: Takahashi Hirona , Miyake Tomoya , Sakai Makoto
Published: November 2024

Recently, we developed a novel method based on the transient fluorescence detected IR (TFD-IR) technique to measure the IR spectra of fluorescent molecules in water. In this study, our method was applied for fluorescent proteins and succeeded in the selective IR measurement of chromophores of fluorescent proteins. It was found that the spectral feature of the TFD-IR spectra of TurboGFP and phiYFP, which have the same chromophore but different fluorescent wavelengths, is quite different. This might come from differences in the local structures of the chromophore that interact with the surrounding protein.
Sexual size dimorphism as a determinant of biting performance dimorphism in Anolis lizards
Authors: Toyama Ken S , Losos Jonathan B , Herrel Anthony , Mahler D Luke
Published: November 2024

Rensch’s rule describes a pattern of interspecific allometry in which sexual size dimorphism (SSD) increases with size among closely related species (i.e., among a group of related species, the largest ones tend to show more male-biased SSD). Sexual selection is often invoked to explain Rensch’s rule, as larger male body size is assumed to be favoured by sexual selection for increased fighting performance in contests for mating opportunities. Often, however, the correlation between size and performance is not well described. We studied a sexually selected performance trait, bite force in Anolis lizards, to determine whether patterns of SSD are linked to size-associated patterns of performance dimorphism at the macroevolutionary level, as expected under the sexual selection hypothesis for Rensch’s rule. Additionally, we tested whether allometric patterns of performance dimorphism differ between mainland and island species, as the latter have likely evolved under a stronger sexual selection regime. We found that SSD overwhelmingly explains the relationship between performance dimorphism and size in anoles, as expected under a sexual selection model for Rensch’s rule. However, residual performance dimorphism was higher in island than in mainland species, suggesting that these groups differ in performance dimorphism for reasons unrelated to size. Head size dimorphism was associated with residual performance dimorphism, but did not fully explain the difference in performance dimorphism between island and mainland species. Together, these findings highlight the need to interpret Rensch’s rule patterns of body size evolution cautiously, as allometric patterns of performance dimorphism and size dimorphism might not be equivalent.
10024- TB-2 COMBINATION THERAPY OF NOVEL MDM4 INHIBITOR CEP-1347 AND IONIZING RADIATION FOR MALIGNANT BRAIN TUMORS
Authors: Mitobe Yuta , Nakamura Kazuki , Sonoda Yukihiko , Kitanaka Chifumi
Published: November 2024

Radiation therapy represents the cornerstone treatment for malignant brain tumors, the majority of which express wild-type p53. Identification of drugs that promote ionizing-radiation (IR) induced activation of p53, therefore, is expected to help increase the efficacy of radiation therapy for these tumors. The growth inhibitory effects of CEP-1347, a known inhibitor of MDM4 expression, on malignant brain tumor cell lines expressing wild-type p53 were examined, alone or in combination with IR, by dye exclusion and/or colony formation assays. The effects of CEP-1347 on the p53 pathway, alone or in combination with IR, were examined by RT-PCR and Western blot analyses. The combination of CEP-1347 and IR activated p53 in malignant brain tumor cells and inhibited their growth more effectively than either alone. Mechanistically, CEP-1347 and IR each reduced MDM4 expression, but their combination did not result in further reduction. Instead, CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. Our findings show that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR besides inhibiting the expression of MDM4 and thus identify CEP-1347 as a promising radiosensitizer for malignant brain tumors expressing wild-type p53.
10166- ACT-9 TRANSLATING BASIC RESEARCH ON AD-REIC FOR RECURRENT GLIOBLASTOMA INTO AN INVESTIGATOR-INITIATED CLINICAL TRIAL
Authors: Otani Yoshihiro , Kurozumi Kazuhiko , Ishida Joji , Fujii Kentaro , Sasaki Tatsuya , Shimazu Yosuke , Oka Tetsuo , Hattori Yasuhiko , Tan Hironobu , Kumon Hiromi , Tanaka Shota
Published: November 2024

Glioblastoma is the most aggressive type of brain tumor, and the development of new treatments is urgently needed. A viral gene therapy incorporating the tumor suppressor gene REIC/Dkk-3 discovered at Okayama University was conducted from basic research to investigator-initiated clinical trials. Here, we present the results from basic research to clinical application.In 2014, we confirmed the antitumor effects of the first-generation Ad-REIC product, Ad-CAG-REIC, in both in vitro and in vivo experiments using human glioblastoma cells (Gene Ther, 2014). Subsequently, we developed the second-generation formulation, Ad-SGE-REIC, which enhances the expression of the REIC/Dkk-3 gene. Ad-SGE-REIC induced stronger endoplasmic reticulum stress and higher levels of cell death. In addition, Ad-SGE-REIC demonstrated a more potent antitumor effect than Ad-CAG-REIC in both immunodeficient models using human glioblastoma cells and immunocompetent models using mouse glioblastoma cells. Significant infiltration of CD8-positive and CD11c-positive cells were observed, suggesting immunogenic cell death (Sci Rep, 2016). Furthermore, the combination of Ad-SGE-REIC with Bevacizumab enhanced the therapeutic effect (PLoS One, 2022).Based on these results, we initiated a Phase 1/2a investigator-initiated clinical trial (jRCT2063190013, Future Oncol, 2020) for recurrent malignant glioma in 2019, supported by the AMED Translational Research Program Seeds C, and completed patient enrollment in 2022. We are currently evaluating the safety and efficacy of this trial. Additionally, since 2023, under the AMED P-PROMOTE, we have been exploring biomarkers for Ad-REIC. Ad-SGE-REIC has the potential to be a novel treatment for recurrent glioblastoma.
10178- ACT-11 A PHASE 1 STUDY OF LOMUSTINE MONOTHERAPY AND COMBINATION THERAPY WITH PROCARBAZINE, LOMUSTINE, AND VINCRISTINE IN JAPANESE PATIENTS WITH GLIOMA (LOMG)
Authors: Arakawa Yoshiki , Makino Yasuhide , Yamamoto Etsuko , Takeuchi Yasuhide , Takada Shigeki , Sano Noritaka , Tanji Masahiro , Mineharu Yohei , Yonezawa Atsushi
Published: November 2024

In the development of treatments for glioma, international clinical trials have demonstrated the efficacy of carmustine (BCNU), lomustine (CCNU), and methyl-CCNU against glioma. In Japan, nimustine (ACNU) has been developed and is used as a treatment for glioma. Internationally, compared to BCNU, the combination therapy of procarbazine, lomustine (CCNU), and vincristine (PCV therapy) has been confirmed to extend the survival period for glioma Grade 2/3, and numerous clinical trial results using PCV therapy have been accumulated. As a result, PCV therapy has become the standard treatment for Grade 2/3 oligodendroglioma and Grade 2 astrocytoma worldwide. However, lomustine is not approved in Japan, making it impossible to implement the standard treatment used overseas. Therefore, in 2019, the Japan Society for Neuro-Oncology submitted a request for the domestic development of lomustine to the ‘Meeting for the Evaluation of Unapproved Drugs and Indications with High Medical Needs.’ As a result of deliberation, it was determined in 2022 that clinical trial results involving Japanese subjects were necessary. Consequently, this physician-led trial was planned as a Phase I trial of lomustine, and the trial began in 2023. This report provides an overview and background of this clinical trial.
10312- ACT-20 A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH ADULT-TYPE DIFFUSE GLIOMA WITH AN IDH1/2 MUTATION (INDIGO): JAPAN SUBGROUP ANALYSIS
Authors: Arakawa Yoshiki , Mellinghoff Ingo K , van den Bent Martin J , Narita Yoshitaka , Mukasa Akitake , Saito Ryuta , Hirose Yuichi , Sugiyama Kazuhiko , Hashimoto Naoya , Tanaka Shota , Zhao Dan , Pandya Susan , Steelman Lori , Hassan Islam , Wen Patrick Y , Cloughesy Timothy F
Published: November 2024

INTRODUCTION

The Phase 3 INDIGO study (NCT04164901) evaluated vorasidenib, an oral, brain-penetrant, dual inhibitor of mutated isocitrate dehydrogenase 1/2 (mIDH1/2), in patients with mIDH1/2 diffuse glioma. The primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC) and key secondary endpoint of time to next intervention (TTNI) were met in the second interim analysis. In March 2023, the study was unblinded following committee recommendation. We present results for patients from Japan.

METHODS

Patients with grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (aged ≥12 years; Karnofsky Performance Status, ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy). Patients were randomized 1:1 to vorasidenib 40 mg or placebo daily in 28-day cycles.

RESULTS

In Japan, nine patients were randomized to placebo and seven to vorasidenib. At unblinding, all patients receiving placebo crossed over to vorasidenib. Study unblinding occurred in close succession to enrollment in Japan resulting in a short duration of placebo exposure. The Japan subgroup included all patients who received ≥1 dose of vorasidenib (n=16; median age, 44.0 years; oligodendroglioma, 10; astrocytoma: 6). As of March 2024, mean (SD) duration of vorasidenib exposure was 10.2 (3.0) months and 81.3% remained on treatment. No progression events per BIRC or deaths occurred. Median PFS and TTNI were not estimable: one patient received anticancer therapy and no other TTNI events occurred. All-grade adverse events occurring in >20% patients were increased alanine transferase (68.8%, Grade≥3: 25.0%), increased aspartate aminotransferase (56.3%; Grade≥3: 18.8%) and increased gamma-glutamyltransferase (31.3%, Grade≥3: 6.3%).

CONCLUSIONS

Vorasidenib is an effective targeted therapy for patients with mIDH1/2 diffuse glioma in this Japanese patient population. Findings are consistent with the statistically significant and clinically meaningful benefit of vorasidenib in the overall INDIGO study population.
10019- MPC-4 IN-HOUSE MOLECULAR DIAGNOSIS FOR THE ERA OF MOLECULAR STRATIFIED THERAPY OF GLIOMAS
Authors: Hata Nobuhiro , Fudaba Hirotaka , Momii Yasutomo , Anan Mitsuhiro , Fujiki Minoru
Published: November 2024

OBJECTIVE

Molecular diagnostics has become increasingly diverse since its formal adoption at WHO 2016 and then WHO 2021. In addition, with the forthcoming approval of molecular targeted therapies for IDH and BRAF, there is a need to explore molecular diagnostic systems that are compatible with clinical practice. While it is desirable to establish molecular diagnostic systems that can be completed within an institution for rapid post-diagnosis treatment, optimization of analytical methods with consideration of cost and simplicity is an important issue. We investigated the optimization of such molecular diagnostics at our institution.

METHODS

The author established an institutional molecular diagnostic system by combining MGMT methylation analysis by MS-PCR in addition to HRM analysis for point mutations of IDH1/2, BRAF, and H3, TERT promoter mutation analysis by Sanger sequencing, and MLPA using two different probe sets at a previous institution. After transferring to the current facility, we attempt to optimize molecular diagnostics within the facility with limited research funding.

RESULTS

The HRM system is low-cost, technically simple, and can detect stable results for IDH1/2, BRAF, and H3 mutations in a short time, and was easy to implement at the new facility. In addition, the newly developed MLPA probe set enabled single-step combined analysis of IDH, TERT, and MLPA methylation without bisulfite treatment. Given the usefulness of TERT as a molecular marker for glioblastoma and a surrogate marker for 1p19q, these two assays alone are now generally sufficient for the in-house molecular diagnosis of diffuse glioma in adults.

CONCLUSION

HRM and MLPA were suitable for the establishment of a sustainable molecular diagnostic system. Since the establishment of treatment strategies based on molecular diagnosis has become essential in recent years, and the optimization of an in-house molecular diagnosis system is desirable, so we will continue to study this issue.
10150- MPC-14 THE COMPARISON BETWEEN HISTOLOGICAL DIAGNOSIS, GENOME-WIDE DNA METHYLATION PROFILING AND INTEGRATED DIAGNOSIS FOR PEDIATRIC LOW-GRADE GLIOMA
Authors: Inoue Yohei , Yoshihiro Otani , Ishida Joji , Miyahira Akira , Yuko Hibiya , Matsushita Yuko , Satomi Kaishi , Fukuoka Kohei , Yamasaki Kai , Nakano Yoshiko , Yoshioka Takako , Hirato Junko , Tanaka Shota , Ichimura Koichi
Published: November 2024

INTRODUCTION

Genome-wide DNA methylation profiling is performed for pediatric low-grade glioma (pLGG) with diagnostic challenge. We compared histological diagnosis, DNA methylation profiling and integrated diagnosis for pLGG.

METHODS

We analyzed histology, molecular findings, DNA methylation profiling and integrated diagnosis of pLGG that were registered to the central diagnosis of Japan Children’s Cancer Group from March 2018 to June 2024 and underwent genome-wide DNA methylation profiling.

RESULTS

Fifty-eight cases were enrolled. Thirty-seven cases (64%) had calibrated scores of 0.84 or higher (match), and 21 cases (36%) had the scores below 0.84 (no match). Definitive diagnoses based on integrated diagnoses were achieved in 22 cases (59%) among the match cases, in 6 cases among the no match cases and in total 28 cases (48%). Tumor types of the 28 cases with definitive diagnoses were pilocytic astrocytoma (PA) in 16 cases, diffuse low-grade glioma, MAPK pathway-altered in 2 cases, subependymal giant cell astrocytoma in 2 cases, dysembryoplastic neuroepithelial tumour in 2 cases, and others in 6 cases. All 6 cases with definitive diagnoses among the no match cases were PA. Discrepancies between histological diagnosis and methylation class were observed in total 34 cases (match 17 cases, no match 17 cases). Among the 34 cases, definitive diagnoses were achieved in 8 cases (match 6 cases, no match 2 cases) and all the diagnoses supported the histological diagnoses. Twenty-one cases of the 34 cases were histologically diagnosed with unspecific tumor types like low-grade glioma or classified to MC Control tissue in DNA methylation profiling.

DISCUSSION/CONCLUSION

Genome-wide DNA methylation profiling was useful for pLGG matched to specific methylation class. Sixteen percents of the match cases showed discrepancy between histological diagnoses and methylation class, but supported histological diagnoses as definitive diagnoses, indicating the importance of integrated diagnosis.
10171- MPC-16 SCREENING OF NTRK FUSION IN JAPANESE CENTRAL NERVOUS SYSTEM TUMORS
Authors: Saito Tsuyoshi , Ura Ayako , Ashizawa Karin , Hayashi Takuo , Yao Takashi
Published: November 2024

NTRK fusions have been reported to be rare in cancers across various organs, except for certain types of tumors. NTRK fusion positive tumors are reported to be highly sensitive to TRK inhibitors such as Larotrectinib and Entrectinib. It is very important to identify patients who may have benefit from these inhibitors. In central nerve system (CNS) tumors, especially gliomas, the frequency of NTRK fusions has been reported to be approximately 2%, however, the frequency of NTRK fusions in CNS tumors of Japanese patients is unknown. Pan-trk IHC is useful to identify NTRK fusion tumors, however, the physiological expression of trks in neural tissues hamper the identification of CNS tumors with NTRK fusion by IHC. In this study, we employed quantitative PCR (qPCR)-based screening system of NTRK fusions in CNS tumors by evaluating the imbalanced expression of NTRK1-3. We performed Real-time qPCR for NTRK1, NTRK2 and NTRK3 in 390 cases of Japanese CNS tumors. Primers and probes were designed to recognize each 5’-side and 3’-side of NTRK1-3. Cases with imbalanced expression for either NTRK1-3 were further analyzed using NanoString gene expression assay containing probes for each 5’-side and 3’-side of NTRK1-3. Cases showing imbalanced expression were sent for target RNA sequences. We found a glioblastoma (GB) case (1%) with CKD5RAP2(ex22)-NTRK2(ex14) in-frame fusion among 96 consecutive Japanese GBs, and another GB with BCR(ex1)-NTRK2(ex10) out-of-frame fusion. NTRK fusion positive rate of glioblastoma in this study was similar to that of previous studies (1.1-2.6%). Imbalanced gene expression-based screening was considered to be useful to detect NTRK fusion in CNS tumors.
10016- NI-2 RADIOMICS ANALYSIS OF NON-ENHANCING LESIONS AFTER BEVACIZUMAB ADMINISTRATION IN RECURRENT GLIOBLASTOMA
Authors: Sanada Takahiro , Sato Hirotaka , Shimizu Takeshi , Saito Masato , Mitsui Nobuyuki , Hiroshima Satoru , Tanino Mishie , Kinoshita Manabu
Published: November 2024

INTRODUCTION

Identifying non-enhancing lesions (nCETs) in glioblastomas within the high-intensity area on T2/FLAIR is challenging. Bevacizumab (BEV) administration can reduce the size of contrast-enhancing lesions (CETs), which may correspond to the nCET. Elucidating these imaging features could enable visualization of non-enhancing lesions in glioblastomas. The current study aimed to investigate imaging features useful for identifying nCET by performing radiomic analysis on areas where CETs were transformed into nCET after BEV administration.

MATERIALS AND METHODS

The study included 25 patients with recurrent glioblastoma in which contrast-enhancing lesions on contrast-enhancing T1-weighted images shrank after BEV administration at the Asahikawa Medical University Hospital. FLAIR images, T2-weighted images, and ADC images were linearly transformed to the standard brain coordinate system with recommended signal correction. Regions of interest were defined as non-contrast T2/FLAIR areas (T2FL-H) before BEV administration (Pre-BEV) and reduced contrast enhancement areas (nCET) after BEV administration (Post-BEV). A total of 147 image features were extracted from Pre-BEV FLAIR images, T2-weighted images, and ADC images with T2FL-H and Post-BEV with nCET. The relationship between each imaging feature and T2FL-H or nCET was investigated.

RESULTS

Univariate analysis showed 81 statistically significant imaging features (p<0.05). FLAIR_GLRLMRln_SD exhibited the highest ability to discriminate between T2FL-H and nCET (n=40, AUC=0.9825, p<0.0001). An ideal cut-off for detecting nCET was FLAIR_GLRLMRln_SD < 332.4-354.0, with a sensitivity of 95% and specificity of 95%.

CONCLUSION

FLAIR_GLRLMRln_SD was able to most accurately identify areas where the contrast effect disappeared after BEV administration. It may be possible to accurately detect the nCET in glioblastomas by applying this image feature.
10122- NI-9 DEEP-LEARNING-BASED RECONSTRUCTION OF DIFFUSION WEIGHTED IMAGES OF MALIGNANT BRAIN TUMORS.
Authors: Sakaguchi Yusuke , Takahashi Satoshi , Ishiguro Naoaki , Suzuki Yuichi , Takami Hirokazu , Takahashi Masamichi , Takayanagi Shunsaku , Miyake Mototaka , Nomura Masashi , Kitagawa Yosuke , Tanaka Shota , Narita Yoshitaka , Saito Nobuhito , Hamamoto Ryuji
Published: November 2024

BACKGROUND

Diffusion Kurtosis Imaging (DKI) is increasingly used to diagnose malignant brain tumors by assessing non-Gaussian diffusion of water molecules, reflecting tissue microstructure. It aids in preoperative molecular classification and infiltration identification. However, its time-consuming process and complex analysis, requiring Diffusion Weighted Images (DWI) at b=0 and at least two distinct non-zero b-values across 15 axes, hinder its clinical adoption. This study aims to simplify this by using deep learning to reconstruct DWI (b=2000) from DWI (b=0, 1000).

MATERIALS & METHODS

We analyzed 157 malignant brain tumor cases from the University of Tokyo Hospital (2016-2023) using the ResViT model for reconstructing high-accuracy medical images, performing 5-fold cross-validation on 282,600 DWI sets. The reconstructed images were evaluated with the Structural Similarity Index Measure (SSIM) and Peak Signal-to-Noise Ratio (PSNR).

RESULTS

Reconstructed images showed SSIM and PSNR values of 0.956±0.007 and 31.46±1.05, respectively.

DISCUSSION

The deep learning-reconstructed DWI (b=2000) images were comparable to prior studies, suggesting potential for reduced DKI imaging time.