bluuebunny/crossref_metadata_2025 huggingface dataset:
Controlling jumps through latches in small jumping robots
Authors: Divi Sathvik , St. Pierre Ryan , Foong Hui Min , Bergbreiter Sarah
Published: September 2023

Small jumping robots can use springs to maximize jump performance, but they are typically not able to control the height of each jump owing to design constraints. This study explores the use of the jumper’s latch, the component that mediates the release of energy stored in the spring, as a tool for controlling jumps. A reduced-order model that considers the dynamics of the actuator pulling the latch and the effect of spring force on the latch is presented. This model is then validated using high speed video and ground reaction force measurements from a 4g jumper. Both the model and experimental results demonstrate that jump performance in small insect-inspired resource-constrained robots can be tuned to a range of outputs using latch mediation, despite starting with a fixed spring potential energy. For a fixed set of input voltages to the latch actuator, the results also show that a jumper with a larger latch radius has greater tunability. However, this greater tunability comes with a trade-off in maximum performance. Finally, we define a new metric, ‘Tunability Range,’ to capture the range of controllable jump behaviors that a jumper with a fixed spring compression can attain given a set of control inputs (i.e. latch actuation voltage) to choose from.
Urban moisture and dry islands: spatiotemporal variation patterns and mechanisms of urban air humidity changes across the globe
Authors: Huang Xinjie , Song Jiyun
Published: September 2023

Urbanization-induced atmospheric moisture changes, embodied as urban moisture island (UMI) and urban dry island (UDI) effects, are not as thoroughly understood as the urban heat island (UHI) effects, despite their significant influence on human comfort and well-being. This paper offers the first systematic review and quantitative meta-analysis of global urban–rural humidity contrasts, aiming to advance our comprehension of the mechanisms, intensity, patterns, and implications of urban humidity changes. The meta-analysis compiles observational data from 34 studies across 33 cities. It reveals that mid-latitude cities predominantly exhibit moderate UMI and UDI effects, and cities with low mean annual precipitation and distinct dry/wet seasons, however, exhibit extreme UMI and UDI effects. The diurnal cycle analysis presents more pronounced UMI effects at night, largely due to increased evapotranspiration and delayed dewfall linked with UHI. On a seasonal scale, UDI effects dominate in spring, while UMI effects peak in winter for mid-latitude cities and in summer for low-latitude cities. In addition, city characteristics such as topography, morphology, and size significantly shape urban–rural humidity contrasts. Coastal cities are subject to sea-breeze circulation, importing moisture from sea to land, whereas mountainous cities can accumulate humidity and precipitation due to geographical barriers and vertical airflow. High-density urban areas generally experience heightened UMI effects due to restricted airflow and ventilation. Larger cities with higher populations contribute to increased UMI effects, particularly in winter, due to stronger anthropogenic moisture sources. This paper also discusses multi-dimensional humidity impacts and strategies for humidity-sensitive urban planning in the context of climate change. It identifies critical gaps in current research, paving the way for future exploration into urban humidity changes.
High resolution spatial mapping of the electrocaloric effect in a multilayer ceramic capacitor using scanning thermal microscopy
Authors: Baxter Olivia E , Kumar Amit , Gregg J Marty , McQuaid Raymond G P
Published: September 2023

Scanning thermal microscopy (SThM) is emerging as a powerful atomic force microscope based platform for mapping dynamic temperature distributions on the nanoscale. To date, however, spatial imaging of temperature changes in electrocaloric (EC) materials using this technique has been very limited. We build on the prior works of Kar-Narayan et al (2013 Appl. Phys. Lett.
102 032903) and Shan et al (2020 Nano Energy
67 104203) to show that SThM can be used to spatially map EC temperature changes on microscopic length scales, here demonstrated in a commercially obtained multilayer ceramic capacitor. In our approach, the EC response is measured at discrete locations with point-to-point separation as small as 125 nm, allowing for reconstruction of spatial maps of heating and cooling, as well as their temporal evolution. This technique offers a means to investigate EC responses at sub-micron length scales, which cannot easily be accessed by the more commonly used infrared thermal imaging approaches.
From clean room to machine room: commissioning of the first-generation BrainScaleS wafer-scale neuromorphic system
Authors: Schmidt Hartmut , Montes José , Grübl Andreas , Güttler Maurice , Husmann Dan , Ilmberger Joscha , Kaiser Jakob , Mauch Christian , Müller Eric , Sterzenbach Lars , Schemmel Johannes , Schmitt Sebastian
Published: September 2023

The first-generation of BrainScaleS, also referred to as BrainScaleS-1, is a neuromorphic system for emulating large-scale networks of spiking neurons. Following a ‘physical modeling’ principle, its VLSI circuits are designed to emulate the dynamics of biological examples: analog circuits implement neurons and synapses with time constants that arise from their electronic components’ intrinsic properties. It operates in continuous time, with dynamics typically matching an acceleration factor of 10 000 compared to the biological regime. A fault-tolerant design allows it to achieve wafer-scale integration despite unavoidable analog variability and component failures. In this paper, we present the commissioning process of a BrainScaleS-1 wafer module, providing a short description of the system’s physical components, illustrating the steps taken during its assembly and the measures taken to operate it. Furthermore, we reflect on the system’s development process and the lessons learned to conclude with a demonstration of its functionality by emulating a wafer-scale synchronous firing chain, the largest spiking network emulation ran with analog components and individual synapses to date.
Dark-centred umbels in Apiaceae: diversity, development and evolution
Authors: Claßen-Bockhoff Regine , Celep Ferhat , Ajani Yousef , Frenken Lisa , Reuther Kerstin , Doğan Musa
Published: September 2023

The wild carrot (Daucus carota) is famous for its dark flowers in the umbel centre. Several studies have been conducted to figure out their functional significance, but the evolution of the dark centre remains an enigma. In the present paper, we consider all known apioid species with dark-centred umbels to get a deeper understanding of their biology and evolution. Based on herbaria studies, literature and field work, we reconstructed the distribution area of 10 species (7 genera, 6 clades) of Apiaceae-Apioideae. To recognize homology of the dark structures, developmental studies were conducted in Artedia squamata and Echiophora trichophylla Field studies included architecture, flower morph distribution (andromonoecy) and flowering sequence within the plants, abundancy and behaviour of umbel visitors and preliminary manipulation experiments (removal/adding of dark structures). The dark structures are not homologous to each other. In the Daucus alliance, central flowers or umbellets are conspicuous, whereas in other species dark brush-like (A. squamata) or club-shaped structures (Dicyclophora persica, Echinophora trichophylla, Tordylium aegyptiacum, T. cappadocicum) develop from a naked receptacle. Species are andromonoecious, have a modular architecture and flower in multicyclic protandrous sequence. Among the many umbel visitors, beetles were the most abundant group. Only visitors found on umbels in both flowering phases were recognized as possible pollinators. Manipulation experiments indicated that the dark structures influence the behaviour of some, but not all umbel visitors. In Echinophora trichophylla, a massive gall infection was observed. It is evident that the dark structures evolved several times in parallel. The brush- and club-shaped structures are interpreted as the results of mutations affecting umbel development. Dark umbel centres are most likely stabilized by selection due to their general adaptive function. Their appearance in an area known as a hotspot of beetle pollination gives rise to the assumption that they may act as beetle marks.
Surgical Anatomy of the Ligamentous Attachments in the Superoposterior Scalp Region
Authors: Bran Greg , Van Genechten Maarten
Published: September 2023

Background

Hairline-lowering surgery has become increasingly popular in recent years, but little investigation into the surgical anatomy of the scalp has been performed.

Objectives

The aim of this study was to describe findings based on clinical observation and anatomic study of ligamentous attachments in the superoposterior region of the scalp.

Methods

Six fresh cadaveric heads were dissected to identify connective tissue structures in the superoposterior scalp region. The areas of interest were along the sagittal suture towards the lambda, the obelion, and around the lambdoid suture. The location and dimensions of identified connective tissue attachments were documented with reference to described skeletal landmarks.

Results

Three distinct structures could be identified: (1) a cylindrical structure that sits at the posterior end of the sagittal suture with the parietal foramina in its base. This ligamentous structure extends from the pericranium into the galea, causes dimpling in the skin, and contains emissary veins. As this fulfills the criteria for an osseocutaneous retaining ligament, the term “cranial retaining ligament” is proposed. (2) Anterior to this ligament a connective tissue thickening was identified running along the sagittal suture and blending into the ligament, for which the term “sagittal adhesion” is proposed. (3) Another adhesion was identified just superior to the lambdoid suture, posterior to the retaining ligament, for which the term “supralambdoid adhesion” is proposed.

Conclusions

Identification and better understanding of ligamentous structures in the superoposterior scalp allows for a safer and more effective advancement of the scalp in hairline-lowering surgery, which is a benefit to both patients and surgeons.
aenmd: annotating escape from nonsense-mediated decay for transcripts with protein-truncating variants
Authors: Klonowski Jonathan , Liang Qianqian , Coban-Akdemir Zeynep , Lo Cecilia , Kostka Dennis
Published: September 2023

DNA changes that cause premature termination codons (PTCs) represent a large fraction of clinically relevant pathogenic genomic variation. Typically, PTCs induce transcript degradation by nonsense-mediated mRNA decay (NMD) and render such changes loss-of-function alleles. However, certain PTC-containing transcripts escape NMD and can exert dominant-negative or gain-of-function (DN/GOF) effects. Therefore, systematic identification of human PTC-causing variants and their susceptibility to NMD contributes to the investigation of the role of DN/GOF alleles in human disease. Here we present aenmd, a software for annotating PTC-containing transcript-variant pairs for predicted escape from NMD. aenmd is user-friendly and self-contained. It offers functionality not currently available in other methods and is based on established and experimentally validated rules for NMD escape; the software is designed to work at scale, and to integrate seamlessly with existing analysis workflows. We applied aenmd to variants in the gnomAD, Clinvar, and GWAS catalog databases and report the prevalence of human PTC-causing variants in these databases, and the subset of these variants that could exert DN/GOF effects via NMD escape.

Availability and implementation

aenmd is implemented in the R programming language. Code is available on GitHub as an R-package (github.com/kostkalab/aenmd.git), and as a containerized command-line interface (github.com/kostkalab/aenmd_cli.git).
Comment on ‘Treatment of moderate-to-severe alopecia areata with baricitinib in preadolescent children’
Authors: Buontempo Michael G , Sicco Kristen Lo , Shapiro Jerry
Published: September 2023

In this response to a recent article on the off-label use of baricitinib for paediatric alopecia areata (AA), we raise additional points regarding the relationship between viral infections and AA relapse on Janus kinase inhibitor (JAKi) therapy, and the potential benefits of concomitant oral minoxidil therapy in mitigating the risk of relapse during JAKi dose reduction or discontinuation.
Genetic risks of Alzheimer’s by APOE and MAPT on cortical morphology in young healthy adults
Authors: Huang Weijie , Zeng Jianmin , Jia Lina , Zhu Dajiang , O’Brien John , Ritchie Craig , Shu Ni , Su Li
Published: September 2023

Genetic risk factors such as APOE ε4 and MAPT (rs242557) A allele are associated with amyloid and tau pathways and grey matter changes at both early and established stages of Alzheimer’s disease, but their effects on cortical morphology in young healthy adults remain unclear. A total of 144 participants aged from 18 to 24 underwent 3T MRI and genotyping for APOE and MAPT to investigate unique impacts of these genetic risk factors in a cohort without significant comorbid conditions such as metabolic and cardiovascular diseases. We segmented the cerebral cortex into 68 regions and calculated the cortical area, thickness, curvature and folding index for each region. Then, we trained machine learning models to classify APOE and MAPT genotypes using these morphological features. In addition, we applied a growing hierarchical self-organizing maps algorithm, which clustered the 68 regions into 4 subgroups representing different morphological patterns. Then, we performed general linear model analyses to estimate the interaction between APOE and MAPT on cortical patterns. We found that the classifiers using all cortical features could accurately classify individuals carrying genetic risks of dementia outperforming each individual feature alone. APOE ε4 carriers had a more convoluted and thinner cortex across the cerebral cortex. A similar pattern was found in MAPT A allele carriers only in the regions that are vulnerable for early tau pathology. With the clustering analysis, we found a synergetic effect between APOE ε4 and MAPT A allele, i.e. carriers of both risk factors showed the most deviation of cortical pattern from the typical pattern of that cluster. Genetic risk factors of dementia by APOE ε4 and MAPT (rs242557) A allele were associated with variations of cortical morphology, which can be observed in young healthy adults more than 30 years before Alzheimer’s pathology is likely to occur and 50 years before dementia symptoms may begin.
Comment on ‘Permethrin-unresponsive scabies in London, UK: a wake-up call’
Authors: Potestio Luca , Scalvenzi Massimiliano , Martora Fabrizio , Costanzo Luca , Gallo Lucia
Published: September 2023

Regarding scabies management, permethrin is the most prescribed first-line treatment. However, cases of treatment resistance have been reported, leading to the need for new drugs.
Comment on ‘An A–Z guide for dermatologists on how to critically appraise an abstract’
Authors: Nwabudike Lawrence Chukwudi
Published: September 2023

A–Z critical appraisal begins with the Title (A), which should accurately reflect the contents of the work and ends with the References (Z), when relevant, reflecting the breadth of the authors’ research into the subject matter at hand.
Feminist Commitments Towards a Horizontal Women, Peace, and Security Critical Learning Community
Authors: Luttrell-Rowland Mikaela , Prandini Assis Mariana , Segalo Puleng ,   The Women Peace and Security Collective, Afkar Nasser , Ikasilon Agnes , Mulibinge Aline Sifa , Apendeki Alphonsine , Ayoola-Amale Ayo , Rinyu Bantar Samuela , Ochongo Beatrice Sharon , Mukade Bridget Sharon , Chongwain Christelle Bay , Mushayi Constance , Chea Florence Munteh , Chinzete Gillian , Nfoh Jennet , Yarima Jennifer , Abdulrazaq Kabirat , Abubakar Kaltume , Gbowee Leymah , Matlakala Limpho , Matlakala Lineo , Kalake Makhotso , Makhele Mamello , Sedziafa Margaret , Mutisi Martha , Juan Mary , Hassan Mazahir Ali , Osei-Konadu Mercy , Fine Michelle , Abdulrazaq Muibat , Abdi Nuria , Alfadil Omima , Kavata Racheal , Abubaker Rasha , Yuyada Riya Williams , Faida Rose , Ochieng Ruth , wa Mwilambwe Seya , Auma Susy , Katooko Sylvia , Madziro Tatenda , Abdalla Zaki Varna Joseph
Published: September 2023

This paper features the process whereby an experimental Women, Peace, and Security (WPS) program fostered a critical learning community around peace and security across 13 countries and with 40 women. It addresses the epistemological questions of doing research in collective ways (with and among activists/scholars), the axiological challenge of recognizing and embracing counter-expertise, and the possibilities for incorporating values and practices of care as well as non-extractivism in producing and disseminating knowledge. By articulating the core ethical principles that emerged from this experience, the paper suggests a critical feminist epistemological commitment in taking seriously grassroots women's knowledge in peace and security processes, rather than what is often done in both policy and academy: prescribing their needs from above, interpreting their knowledge from the outside, and advising what problems to tackle and how to live.
Phase 1b safety and pharmacokinetics of intravenous and oral fosmanogepix in patients with acute myeloid leukaemia and neutropenia
Authors: Cornely Oliver A , Ostermann Helmut , Koehler Philipp , Teschner Daniel , Limburg Endrik , Kramer William G , Barbat Sara H , Tawadrous Margaret , Hodges Michael R
Published: September 2023

Objectives

Fosmanogepix (APX001), a first-in-class, intravenous (IV) and oral (PO) antifungal prodrug, is being developed to treat invasive fungal diseases (IFDs). Manogepix (APX001A; active moiety) targets fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, inhibiting cell wall synthesis causing loss of viability. This open-label, multicentre, Phase 1b study in patients with AML and neutropenia (absolute neutrophil count <500 cells/μL; >10 days) undergoing chemotherapy aimed to assess tolerability, safety and pharmacokinetics (PK) of IV and PO fosmanogepix.

Methods

Of 21 adult AML patients undergoing remission induction chemotherapy, 10 received IV fosmanogepix (600 mg; q24h) and 11 received oral fosmanogepix (500 mg; q24h) over 14 days, with a 28 day follow-up. Patients also received remission induction chemotherapy [sequential high-dose cytarabine and mitoxantrone (S-HAM) or 7 + 3 regimen] for AML and IFD prophylaxis (posaconazole). A two-compartmental PK model from previous studies in healthy volunteers was fitted to manogepix plasma data.

Results

Of 26 fosmanogepix-related adverse events (AEs; IV: 14; PO: 12) in 9 (42.9%) patients [IV: 5 (50%); PO: 4 (36.4%)], none were serious or resulted in fosmanogepix discontinuation. Most frequently occurring fosmanogepix-related AEs were Grade 1/2 nausea [four events in three patients (14.3%)]; vomiting, ALT increase, and delirium [two events; two patients (9.5%) each]. One patient experienced fosmanogepix-related Grade 3 hypertension. Dose-corrected geometric mean ratio of AUC (PO-to-IV) was 95%. Elimination half-lives (∼2 days) were consistent with prior studies in healthy volunteers.

Conclusions

Fosmanogepix was safe and well tolerated in AML patients with neutropenia receiving remission induction chemotherapy. Safety and PK profiles were comparable to healthy volunteers.
Decision Theory without Luminosity
Authors: Isaacs Yoaav , Levinstein Benjamin A
Published: September 2023

Our decision-theoretic states are not luminous. We are imperfectly reliable at identifying our own credences, utilities and available acts, and thus can never be more than imperfectly reliable at identifying the prescriptions of decision theory. The lack of luminosity affords decision theory a remarkable opportunity — to issue guidance on the basis of epistemically inaccessible facts. We show how a decision theory can guarantee action in accordance with contingent truths about which an agent is arbitrarily uncertain. It may seem that such advantages would require dubiously adverting to externalist facts that go beyond the internalism of traditional decision theory, but this is not so. Using only the standard repertoire of decision-theoretic tools, we show how to modify existing decision theories to take advantage of this opportunity. These improved decision theories require agents to maximize conditional expected utility — expected utility conditional upon an agent’s actual decision situation. We call such modified decision theories ‘self-confident’. These self-confident decision theories have a distinct advantage over standard decision theories: their prescriptions are better.
The energy and dynamics of trapped radiative feedback with stellar winds
Authors: Geen Sam , Bieri Rebekka , de Koter Alex , Kimm Taysun , Rosdahl Joakim
Published: September 2023

In this paper, we explore the significant, non-linear impact that stellar winds have on H ii regions. We perform a parameter study using three-dimensional radiative magnetohydrodynamic simulations of wind and ultraviolet radiation feedback from a 35 M⊙ star formed self-consistently in a turbulent, self-gravitating cloud, similar to the Orion Nebula (M42) and its main ionizing source θ1 Ori C. Stellar winds suppress early radiative feedback by trapping ionizing radiation in the shell around the wind bubble. Rapid breakouts of warm photoionized gas (‘champagne flows’) still occur if the star forms close to the edge of the cloud. The impact of wind bubbles can be enhanced if we detect and remove numerical overcooling caused by shocks crossing grid cells. However, the majority of the energy in the wind bubble is still lost to turbulent mixing between the wind bubble and the gas around it. These results begin to converge if the spatial resolution at the wind bubble interface is increased by refining the grid on pressure gradients. Wind bubbles form a thin chimney close to the star, which then expands outwards as an extended plume once the wind bubble breaks out of the dense core the star formed in, allowing them to expand faster than a spherical wind bubble. We also find wind bubbles mixing completely with the photoionized gas when the H ii region breaks out of the cloud as a champagne flow, a process we term ‘hot champagne’.
Can massive stars form in low mass clouds?
Authors: Smith Jamie D , Jaffa Sarah E , Krause Martin G H
Published: September 2023

The conditions required for massive star formation are debated, particularly whether massive stars must form in conjunction with massive clusters. Some authors have advanced the view that stars of any mass (below the total cluster mass) can form in clusters of any mass with some probability (random sampling). Others pointed out that the scatter in the determinations of the most massive star mass for a given cluster mass was consistent with the measurement error, such that the mass of the most massive star was determined by the total cluster mass (optimal sampling). Here, we investigate the relation between cluster mass (Mecl) and the maximum stellar mass (Mmax) using a suite of SPH simulations. Varying cloud mass and turbulence random seed results in a range of cluster masses which we compare with their respective maximum star masses. We find that more massive clusters will have, on average, higher mass stars with this trend being steeper at lower cluster masses ($M_{max} \propto M_ {ecl}^{0.31}$ for $M_ {ecl}\lt 500\, \mathrm{M}_{\odot }$) and flattening at higher cluster masses ($M_ {max} \propto M_ {ecl}^{0.11}$ for $M_ {ecl}\gt 500\, \mathrm{M}_{\odot }$). This rules out purely stochastic star formation in our simulations. Significant scatter in the maximum masses with identical initial conditions also rules out the possibility that the relation is purely deterministic (that is that a given cluster mass will result in a specific maximum stellar mass). In conclusion our simulations disagree with both random and optimal sampling of the initial mass function.
SN 2021gno: a calcium-rich transient with double-peaked light curves
Authors: Ertini K , Folatelli G , Martinez L , Bersten M C , Anderson J P , Ashall C , Baron E , Bose S , Brown P J , Burns C , DerKacy J M , Ferrari L , Galbany L , Hsiao E , Kumar S , Lu J , Mazzali P , Morrell N , Orellana M , Pessi P J , Phillips M M , Piro A L , Polin A , Shahbandeh M , Shappee B J , Stritzinger M , Suntzeff N B , Tucker M , Elias-Rosa N , Kuncarayakti H , Gutiérrez C P , Kozyreva A , Müller-Bravo T E , Chen T -W , Hinkle J T , Payne A V , Székely P , Szalai T , Barna B , Könyves-Tóth R , Bánhidi D , Bíró I B , Csányi I , Kriskovits L , Pál A , Szabó Zs , Szakáts R , Vida K , Vinkó J , Gromadzki M , Harvey L , Nicholl M , Paraskeva E , Young D R , Englert B
Published: September 2023

We present extensive ultraviolet (UV) and optical photometric and optical spectroscopic follow-up of supernova (SN) 2021gno by the ‘Precision Observations of Infant Supernova Explosions’ (POISE) project, starting less than 2 d after the explosion. Given its intermediate luminosity, fast photometric evolution, and quick transition to the nebular phase with spectra dominated by [Ca ii] lines, SN 2021gno belongs to the small family of Calcium-rich transients. Moreover, it shows double-peaked light curves, a phenomenon shared with only four other Calcium-rich events. The projected distance from the centre of the host galaxy is not as large as other objects in this family. The initial optical light-curve peaks coincide with a very quick decline of the UV flux, indicating a fast initial cooling phase. Through hydrodynamical modelling of the bolometric light curve and line velocity evolution, we found that the observations are compatible with the explosion of a highly stripped massive star with an ejecta mass of $0.8\, M_\odot$ and a 56Ni mass of 0.024 M⊙. The initial cooling phase (first light-curve peak) is explained by the presence of an extended circumstellar material comprising ∼$10^{-2}\, {\rm M}_{\odot }$ with an extension of $1100\, R_{\odot }$. We discuss if hydrogen features are present in both maximum-light and nebular spectra, and their implications in terms of the proposed progenitor scenarios for Calcium-rich transients.
Reconceptualizing Music Therapy in Acute Mental Health Settings Part I: A Descriptive Overview of Single-Session Therapy
Authors: Silverman Michael J
Published: September 2023

Single-session therapy (SST) is a collaborative, direct, and transparent approach to providing treatment that emphasizes service users having active and empowered roles in determining the focus, solutions, and extent of the therapy. Clinicians developed SST as many adult mental health service users only receive a single session of therapy. Service users tend to be satisfied with SST and often chose to not return for additional sessions. SST emphasizes the strengths, resources, and resilience of service users and increases treatment access while limiting costs. Some of the impetus for SST is based on research indicating that rapid improvement tends to occur early in treatment with additional sessions being less impactful. In Part I, I provide a descriptive overview and synthesis of the SST literature. I conclude Part I by naming assumptions of long-term therapy and SST. In Part II, I describe approaches to conducting SST, apply SST to music therapy, and provide a critical reflection of SST.
Engineered lentivirus-derived nanoparticles (LVNPs) for delivery of CRISPR/Cas ribonucleoprotein complexes supporting base editing, prime editing and in vivo gene modification
Authors: Haldrup Jakob , Andersen Sofie , Labial Alexander Rafael LaVilla , Wolff Jonas Holst , Frandsen Frederik Plum , Skov Thomas Wisbech , Rovsing Anne Bruun , Nielsen Ian , Jakobsen Thomas Stax , Askou Anne Louise , Thomsen Martin K , Corydon Thomas J , Thomsen Emil Aagaard , Mikkelsen Jacob Giehm
Published: September 2023

Implementation of therapeutic in vivo gene editing using CRISPR/Cas relies on potent delivery of gene editing tools. Administration of ribonucleoprotein (RNP) complexes consisting of Cas protein and single guide RNA (sgRNA) offers short-lived editing activity and safety advantages over conventional viral and non-viral gene and RNA delivery approaches. By engineering lentivirus-derived nanoparticles (LVNPs) to facilitate RNP delivery, we demonstrate effective administration of SpCas9 as well as SpCas9-derived base and prime editors (BE/PE) leading to gene editing in recipient cells. Unique Gag/GagPol protein fusion strategies facilitate RNP packaging in LVNPs, and refinement of LVNP stoichiometry supports optimized LVNP yield and incorporation of therapeutic payload. We demonstrate near instantaneous target DNA cleavage and complete RNP turnover within 4 days. As a result, LVNPs provide high on-target DNA cleavage and lower levels of off-target cleavage activity compared to standard RNP nucleofection in cultured cells. LVNPs accommodate BE/sgRNA and PE/epegRNA RNPs leading to base editing with reduced bystander editing and prime editing without detectable indel formation. Notably, in the mouse eye, we provide the first proof-of-concept for LVNP-directed in vivo gene disruption. Our findings establish LVNPs as promising vehicles for delivery of RNPs facilitating donor-free base and prime editing without formation of double-stranded DNA breaks.
PL02.3.A NRG ONCOLOGY STUDY BN007: RANDOMIZED PHASE II/III TRIAL OF IPILIMIUMAB (IPI) PLUS NIVOLUMAB (NIVO) VS. TEMOZOLOMIDE (TMZ) IN MGMT-UNMETHYLATED (UMGMT) NEWLY DIAGNOSED GLIOBLASTOMA (NGBM)
Authors: Lassman A B , Polley M C , Iwamoto F M , Sloan A E , Wang T J C , Aldape K D , Wefel J S , Gondi V , Gutierrez A N , Manasawala M , Gilbert M R , Sulman E P , Wolchok J D , Greene R M , Neil E C , Lukas R V , Goldlust S A , Snuderl M , Dignam J J , Won M , Movsas B , Mehta M P
Published: September 2023

BACKGROUND

New therapies are especially needed for uMGMT nGBM. NRG Oncology BN002 (phase I) demonstrated safety and preliminary efficacy of Ipi+Nivo for nGBM, leading to BN007 as phase II/III.

METHODS

Adults with uMGMT nGBM (WHO 2016) and KPS ≥ 70 were randomized to RT and concurrent and adjuvant Ipi+Nivo or TMZ, stratified by glioma-recursive partitioning analysis class (RPA), intent to use tumor-treating fields (NCT04396860). Phase II primary endpoint was progression-free survival (PFS), powered 95% to detect a hazard ratio (HR) ≤0.58 with 1-sided 0.15 significance after 100 events. If p<0.15, then phase III would accrue with overall survival (OS) as primary endpoint. Corticosteroids were disallowed at Ipi+Nivo start. Histology, biomarkers, and PFS were assessed centrally.

RESULTS

Among 374 patients screened, 159 were randomized in phase II (79 Ipi+Nivo, 80 TMZ). Demographics (age median 60 years, range 28-79; male 66%, white 88%, not Hispanic/Latino 89%), KPS (90-100 61%), extent of resection (gross total 65% per local PI), and RPA (III 10%, IV 73%, V 17%) were well-balanced between arms. After 100 PFS events, the pre-planned phase II analysis demonstrated no improvement for Ipi+Nivo vs. TMZ [median 7.7 (95% CI: 6.5, 8.5) vs. 8.5 (95% CI: 7.1, 10.4) months; HR 1.47 (95% CI: 0.98-2.2); 1-sided p=0.96]. OS is immature (>50% alive, 13.7 months median follow-up) but without observed difference between arms [median ~13 months each; HR 0.95 (95% CI: 0.61-1.49); 1-sided p=0.36]. On the Ipi+Nivo arm, treatment-related grade 3, 4, and 5 events were reported in 26 (33.3%), 4 (5.1%), and 2 (2.6%; colitis and autoimmune disorder, n=1 each) patients.

CONCLUSION

Ipi+Nivo did not improve PFS for uMGMT nGBM. Accrual permanently closed after phase II. No new safety signals were identified. Molecular analyses and survival follow-up are ongoing. Funded by NCI Grants U10CA180868, U10CA180822, U24CA196067 (NRG Oncology Operations, SDMC, Specimen Bank).
KS01.5.A LATE BREAKING ABSTRACT: LONG-TERM FOLLOW-UP OF PATIENTS WITH NEWLY DIAGNOSED IDH-MUTANT ASTROCYTOMA AFTER IDH1-VAC TREATMENT
Authors: Bunse L , Lindner K , Wick A , Poschke I , Freitag A , Edelmann D , Lanz L , Breckwoldt M , Sahm F , Schmitt A , Schnell O , Hense J , Misch M , Krex D , Denk M , Steinbach J , von Deimling A , Schmitt M , Tabatabai G , Bendszus M , Wick W , Platten M
Published: September 2023

BACKGROUND

The Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), a multicenter, single-arm, open-label, first-in-human phase I trial, met its primary endpoints in demonstrating safety and immunogenicity of a long peptide vaccine targeting IDH1(R132H) (IDH1-vac) added to standard of care in 32 patients with newly diagnosed World Health Organization (WHO) Grade 3 (n=21) and 4 (n=11) IDH1(R132H)+ astrocytomas (ClinicalTrials.gov identifier NCT02454634).

MATERIAL AND METHODS

Here, we report on the clinical and immunological long-term follow-up of NOA16. Data cut-off was May 2023.

RESULTS

Six-year progression-free and survival rates of patients in the safety data set were 0.47 (CI: 0.29 - 0.63) and 0.66 (CI: 0.46 - 0.79), respectively. Six-year progression-free and survival rates in the Grade 3 population were 0.52 (CI: 0.30 - 0.71) and 0.67 (CI: 0.43 - 0.83), respectively. Six-year progression-free and survival rates in the Grade 4 population were 0.55 (CI: 0.23 - 0.78) and 0.62 (CI: 0.28 - 0.84), respectively. Six-year progression-free and survival rates in patients with complete resection (n=17) were 0.82 (CI: 0.55 - 0.94) and 0.88 (CI: 0.61 - 0.97), respectively. Calculated via the Simon-Makuch method, patients in the immunogenicity dataset (n=30) with immune responses (IR) had six-year progression-free and survival rates of 0.46 (0.26 - 0.64) and 0.75 (CI: 0.55 - 0.87), respectively. Two patients without IR showed progressive disease (PD) within two years of first diagnosis and died within 3 years of first diagnosis. In one-year landmark analyses, best mutation-specific B cell response at the time point of last vaccination or later was associated with a favorable clinical course, suggesting a relevant but differential response to repetitive therapeutic vaccination regimes.

CONCLUSION

This data supports a randomized clinical trial of IDH-vac in patients with newly diagnosed IDH-mutant gliomas. A booster treatment regime should be considered as continuous source of IDH1R132H-reactive T cells.
JS09.6.A ASSESSMENT OF RESPONSE TO REGORAFENIB IN RECURRENT GLIOMA PATIENTS USING FET PET AND MRI INCLUDING ADC VALUES
Authors: Werner J , Lohmann P , Kabbasch C , Wollring M M , Tscherpel C , Stoffels G , Goldbrunner R , Langen K , Fink G R , Galldiks N
Published: September 2023

BACKGROUND

The phase 2 REGOMA trial suggested that glioblastoma patients treated with the multikinase inhibitor regorafenib at first progression have significantly longer overall survival than patients treated with lomustine. Here, we evaluated the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and MRI for the evaluation of response to regorafenib in recurrent glioma patients.

MATERIAL AND METHODS

Twenty patients (age range, 30-72 years) with CNS WHO grade 3 or 4 gliomas (glioblastoma, 85%) at recurrence were treated according to the REGOMA trial with regorafenib at 160 mg/d for the first three weeks of each 4-week cycle, with individual dose adjustment according to toxicity. FET PET and MRI were performed at baseline and follow-up after the second cycle. Static FET PET parameters comprised tumor-to-brain ratios (TBR) and metabolic tumor volumes (MTV). Parameters derived from dynamic FET PET acquisition were time-to-peak and slope. MRI response assessment was based on RANO criteria. Additionally, mean and minimum apparent diffusion coefficients (ADC) were obtained from diffusion-weighted MRI. FET PET parameters and ADC thresholds were defined using ROC analyses to predict an overall survival of ≥ 6 months. The predictive values of FET PET parameters, ADC values, and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates.

RESULTS

Patients received a median of three regorafenib cycles (range, 2-10 cycles). After treatment initiation, the median follow-up was 8.6 months (range, 3.2-27.3 months). The median number of previous treatment lines was two (range, 1-4 lines). At the time of data analysis, 17 patients (85%) had died. After two cycles of regorafenib, a regorafenib-induced reduction of mean TBR values by ≥ 10% predicted a longer overall survival (9.9 vs. 5.3 months; P=0.023). Interestingly, absolute mean TBR values ≤ 2.0 at follow-up were prognostic and associated with longer OS (10.6 vs. 4.5 months; P=0.007). In contrast, MTV, dynamic PET parameters, RANO criteria, and ADC values were not predictive for response or prognostic (all P>0.05). Multivariate survival analyses revealed that relative mean TBR changes were most potent in predicting response to regorafenib (P=0.038; HR, 0.246) and absolute mean TBR values for prognostication (P<0.001; HR, 0.005).

CONCLUSION

Data suggest that FET PET parameters are clinically valuable for identifying responders to regorafenib early after treatment initiation and helpful for prognostication. MRI parameters, including ADC values, do not appear to add valuable information in this context.
P01.05.A COGNITIVE OUTCOMES IN ADULT MENINGIOMA PATIENTS AFTER SURGERY WITH OR WITHOUT RADIOTHERAPY
Authors: De Roeck L , Coolkens L , De Vleeschouwer S , Sleurs C , Lambrecht M
Published: September 2023

BACKGROUND

Meningioma patients often report cognitive complaints after therapy, profoundly impacting health-related quality of life. However, prevalence of these cognitive sequelae is inconsistent across trials. Moreover, meningioma patients often suffer from severe anxiety after treatment compared to healthy controls, possibly adversely affecting cognition.

MATERIAL AND METHODS

In this cohort study, 41 adult WHO grade 1 and 2 meningioma patients underwent comprehensive cognitive testing, covering the domains of memory, executive functioning, visuomotor functioning, attention, and language. Cognitive scores were transformed into z-scores using normative data adjusted for age, education, and sex. Patients were categorized as cognitively impaired if at least 2 tests scores differed ≥ - 1.5 SD or if at least 1 test score differed ≥ - 2.0 SD from the reference mean. Moreover, all patients filled out an online self-report inventory, assessing anxiety. Anxiety, age at diagnosis and treatment modality were included as predictors in a linear regression model per cognitive domain. Bonferroni correction was applied to correct for multiple testing.

RESULTS

In this cohort, 26 out of 41 patients showed cognitive impairment (63,4%) and the same number reported to have higher anxiety levels compared to the norm. Patients performed worse than the norm in cognitive domains of language and visuomotor functioning. No significant differences were found in cognitive outcomes regarding therapy, being either surgery (n=31) or surgery followed by cranial radiotherapy (n=10). Age at time of diagnosis was the only significant predictor of language (p=.005) and attention (p=.015) performance, with worse performance in case of diagnosis at younger age. No impact of anxiety nor treatment modality was found in this study.

CONCLUSION

More than half of meningioma patients showed to be cognitively impaired after surgery with or without radiotherapy treatment, mostly in domains of language and visuomotor functioning. Younger patients could be affected more by language and attention difficulties in their daily lives. Given their more active stage in life, this can have an important impact. This effect was independent of emotional functioning. These findings will need to be validated in larger prospective longitudinal trials.
P02.06.B DIELECTRIC PROPERTIES OF INTRACRANIAL TUMORS
Authors: Proescholdt M , Haj A , Schebesch K , Doenitz C , Hoehne J , Schmidt N
Published: September 2023

BACKGROUND

Recently, tumor treating fields (TTFields) were established for the treatment of newly diagnosed glioblastoma (GBM). One of the most crucial parameters defining the treatment efficacy of TTFields is the electric field intensity, which depends on the dielectric properties of the tumor tissue. In this study we determined the dieclectric properties of brain tumors by analyzing resected tissue following a fast acquisition protocol. In GBM patients, histological analysis for cellularity, vascularization and myelin content was performed. In addition, sensitivity analyses for specific parameters (tissue hydration, temperature, and saline irrigation) were conducted.

MATERIAL AND METHODS

A cohort of 130 patients with tumors of different histology and malignancy grade have been recruited (meningioma: n=36; brain metastases n=29; low grade glioma n=7; anaplastic glioma = 12; other= 7; glioblastoma n=39, all treated with TTFields). Tissue samples were placed into a cylindrical cell with a known diameter. The impedance was recorded at frequencies 20Hz-1MHz using a software specifically developed for this study. The measured impedance was translated into dielectric properties of the sample (conductivity and relative permittivity) based on the parallel plate model. Myelin, which is the most powerful electric isolator in the brain, was assessed in GBM samples by luxol fast blue staining, and quantified in a three-tier scale. To assess the impact of tissue conditions on the measurements, probes were warmed to 35 degree Celsius, dehydrated or irrigated with 0.9% saline solution.

RESULTS

We found significant differences between the conductivity of different types of tumors with meningiomas showing the lowest and GBM tissue exhibiting the highest conductivity values. GBM samples with very high median conductivity values displayed a consistently lower myelin content. In addition, GBM patients with particularly high conductivity had a significantly shorter overall survival (log rank analysis, p = 0.024). While tissue temperature had no detectable effects on the dielectric properties in GBM, saline irrigation tissue hydration significantly affected the results.

CONCLUSION

The dielectric properties of intracranial tumors depend on histological class and malignancy grade. GBM patients with high conductivity values showed a significantly poorer prognosis, indicating this parameter as potential marker for TTF efficacy.
P02.20.B PLASMA MEMBRANE-ASSOCIATED 70 KDA HEAT SHOCK PROTEIN (HSP70) INVOLVED IN GLIOBLASTOMA CELLS INVASION AS A TARGET FOR TUMOR THERANOSTICS
Authors: Shevtsov M , Yudintceva N , Bobkov D , Tagaeva R , Samochernykh K , Kim A , Nechaeva A , Fedorov E , Fedorov V , Nazaralieva E , Ten A , Combs S E
Published: September 2023

BACKGROUND

Heat shock proteins (HSPs) represent a large family of highly conserved proteins serving as molecular chaperones that play an important role in intracellular homeostasis. Apart from their intracellular localization, members of various HSPs families such as HSP70 have been reported to be expressed on the plasma membrane of malignant cells, including glioblastoma multiforme (GBM). However, the role of the membrane-bound protein Hsp70 has not yet been investigated in the pathophysiology of GBM.

MATERIAL AND METHODS

mHsp70 expression as related to GBM cell invasive potential was analyzed in biopsies obtained from neurooncological patients using CellVoyager CQ1 Benchtop High-Content Analysis System (Yokogawa) and inverted confocal microscopy (Leica Microsystems). Application of membrane-associated chaperone for targeted therapies was assessed in the intracranial human NCH644, NCH421k, and U87 GBM models in immunodeficient mice employing various chaperone inhibitors (i.e., JG-98, MKT-077, pifithrin-μ (PES)) as a monotherapy or in combination with a single dose of stereotactic irradiation (10Gy) (SARRP).

RESULTS

Live-cell imaging of the patient-derived biopsies demonstrated the increased cellular density of mHsp70+ GBM cells particularly in the tissue along the tumor-brain margin. Time-lapse evaluation of the tumor sample further proved the migration of mHsp70+ cells into the surrounding normal brain tissues. Subsequent high-powered multiplex immunofluorescence analysis (Akoya Biosystems) confirmed significantly increased single-cell infiltration of mHsp70+ tumor cells (also positively stained for Nestin, Oct4, and SOX2) in the normal brain tissues. When mHsp70 inhibitors were applied in GBM animal models as a monotherapy or in combination with radiotherapy dramatic inhibition of tumor progression (as shown by MRI) and increased animal survival were observed.

CONCLUSION

Expression of the mHsp70 on the plasma membrane of GBM cells corresponds to the highly invasive potential of the tumor cells in neuro-oncological patients. Administration of the HSP70 small molecular inhibitors significantly decreased the GBM growth and invasion thus prolonging the overall survival of tumor-bearing mice. Further development of mHsp70-targeted agents represents a promising approach in treatment of multiforme glioblastoma.
P03.09.B LOW DOSE BATH FROM RADIOSURGERY TO SURROUNDING NORMAL BRAIN IN TREATMENT OF BRAIN METASTASES COULD STERILIZE BRAIN AND INHIBIT RECURRENCES
Authors: Mader T , Bhutto S , Tranter J , Martins Gomes L F , Hawkins M , Spyridonidis A , Baumert B G
Published: September 2023

BACKGROUND

Stereotactic radiosurgery and fractionated stereotactic radiotherapy (SRS/fSRT) are standard treatments for brain metastases. Each SRS/fSRT plan has a low-dose penumbra outside the high dose area, which multiplies if multiple metastases are irradiated and results in a low-dose bath in healthy brain tissue. We hypothesize that a certain dose of the low-dose bath can sterilize brain tissue and prevent local recurrences. We present first data of an ongoing project.

MATERIAL AND METHODS

Data of fifty-three patients with brain metastases treated with single fraction SRS or fractionated fSRT at our institute between 2020 and 2022 were reviewed retrospectively. All patients with at least one cranial follow-up MRI after 3 months were evaluated. Follow-up MRI scans were fused to the original treatment plans. New metastases in the isodose-volumes of 10 Gy-, 8 Gy-, 6 Gy-, 4 Gy-, and 2 - Gy were identified and evaluated. Mean doses, on the site of the new lesions, received from SRS/fSRT were tabulated summarized and analyzed.

RESULTS

Six of the 53 patients met the inclusion criteria. Five patients developed recurrent brain metastases out-of-field within 2-4 months of follow-up. One metastasis was observed outside the irradiation field. One patient developed no new metastases. With decreasing isodose levels an increasing number of new metastases were observed: In the reconstructed volume of 10Gy (V10Gy), V8Gy and V6Gy two metastases each, no metastases in the V4Gy and 5 metastases in the V2Gy. No toxicities were observed.

CONCLUSION

Our data suggest a trend towards a benefit that the low-dose bath as part of the penumbra of stereotactic radiotherapy sterilizes brain tissue. Especially, brain regions receiving doses of 4 Gy or more had fewer new lesions compared to regions that received less than 4 Gy. This should be further validated prospectively in larger patient populations, in clinical trials with combination of CNS-accessible immunotherapy like Osimertinib. Indications for whole brain radiotherapy could be further reduced. Low dose spillage with manageable risks might be sufficient to treat microscopic brain metastases in the future.