bluuebunny/crossref_metadata_2025 huggingface dataset:
Serotonergic dysfunction impairs locomotor coordination in spinal muscular atrophy
Authors: Delestrée Nicolas , Semizoglou Evangelia , Pagiazitis John G , Vukojicic Aleksandra , Drobac Estelle , Paushkin Vasilissa , Mentis George Z
Published: September 2023

Neuromodulation by serotonin regulates the activity of neuronal networks responsible for a wide variety of essential behaviours. Serotonin (or 5-HT) typically activates metabotropic G protein-coupled receptors, which in turn initiate second messenger signalling cascades and induce short and long-lasting behavioural effects. Serotonin is intricately involved in the production of locomotor activity and gait control for different motor behaviours. Although dysfunction of serotonergic neurotransmission has been associated with mood disorders and spasticity after spinal cord injury, whether and to what extent such dysregulation is implicated in movement disorders has not been firmly established.

Here, we investigated whether serotonergic neuromodulation is affected in spinal muscular atrophy (SMA), a neurodegenerative disease caused by ubiquitous deficiency of the SMN protein. The hallmarks of SMA are death of spinal motor neurons, muscle atrophy and impaired motor control, both in human patients and mouse models of disease. We used a severe mouse model of SMA, that closely recapitulates the severe symptoms exhibited by type I SMA patients, the most common and most severe form of the disease. Together, with mouse genetics, optogenetics, physiology, morphology and behavioural analysis, we report severe dysfunction of serotonergic neurotransmission in the spinal cord of SMA mice, both at early and late stages of the disease. This dysfunction is followed by reduction of 5-HT synapses on vulnerable motor neurons.

We demonstrate that motor neurons innervating axial and trunk musculature are preferentially affected, suggesting a possible cause for the proximo-distal progression of disease, and raising the possibility that it may underlie scoliosis in SMA patients. We also demonstrate that the 5-HT dysfunction is caused by SMN deficiency in serotonergic neurons in the raphe nuclei of the brainstem. The behavioural significance of the dysfunction in serotonergic neuromodulation is underlined by inter-limb discoordination in SMA mice, which is ameliorated when selective restoration of SMN in 5-HT neurons is achieved by genetic means.

Our study uncovers an unexpected dysfunction of serotonergic neuromodulation in SMA and indicates that, if normal function is to be restored under disease conditions, 5-HT neuromodulation should be a key target for therapeutic approaches.
Fast ripples reflect increased excitability that primes epileptiform spikes
Authors: Weiss Shennan A , Fried Itzhak , Engel Jerome , Sperling Michael R , Wong Robert K S , Nir Yuval , Staba Richard J
Published: September 2023

The neuronal circuit disturbances that drive inter-ictal and ictal epileptiform discharges remain elusive. Using a combination of extra-operative macro-electrode and micro-electrode inter-ictal recordings in six pre-surgical patients during non-rapid eye movement sleep, we found that, exclusively in the seizure onset zone, fast ripples (200–600 Hz), but not ripples (80–200 Hz), frequently occur <300 ms before an inter-ictal intra-cranial EEG spike with a probability exceeding chance (bootstrapping, P < 1e−5). Such fast ripple events are associated with higher spectral power (P < 1e−10) and correlated with more vigorous neuronal firing than solitary fast ripple (generalized linear mixed-effects model, P < 1e−9). During the intra-cranial EEG spike that follows a fast ripple, action potential firing is lower than during an intra-cranial EEG spike alone (generalized linear mixed-effects model, P < 0.05), reflecting an inhibitory restraint of intra-cranial EEG spike initiation. In contrast, ripples do not appear to prime epileptiform spikes. We next investigated the clinical significance of pre-spike fast ripple in a separate cohort of 23 patients implanted with stereo EEG electrodes, who underwent resections. In non-rapid eye movement sleep recordings, sites containing a high proportion of fast ripple preceding intra-cranial EEG spikes correlate with brain areas where seizures begin more than solitary fast ripple (P < 1e−5). Despite this correlation, removal of these sites does not guarantee seizure freedom. These results are consistent with the hypothesis that fast ripple preceding EEG spikes reflect an increase in local excitability that primes EEG spike discharges preferentially in the seizure onset zone and that epileptogenic brain regions are necessary, but not sufficient, for initiating inter-ictal epileptiform discharges.
Neutrophil extracellular traps are involved in the occurrence of interstitial lung disease in a murine experimental autoimmune myositis model
Authors: Bai Ling , Zhu Jiarui , Ma Wenlan , Li Feifei , Zhao Peipei , Zhang Sigong
Published: September 2023

The excessive formation of neutrophil extracellular traps (NETs) has been demonstrated to be a pathogenic mechanism of idiopathic inflammatory myopathy (IIM)-associated interstitial lung disease (ILD). This study aimed to answer whether an experimental autoimmune myositis (EAM) model can be used to study IIM-ILD and whether NETs participate in the development of EAM-ILD. An EAM mouse model was established using skeletal muscle homogenate and pertussis toxin (PTX). The relationship between NETs and the ILD phenotype was determined via histopathological analysis. As NETs markers, serum cell-free DNA (cfDNA) and serum citrullinated histone 3 (Cit-H3)-DNA were tested. The healthy mouse was injected with PTX intraperitoneally to determine whether PTX intervention could induce NETs formation in vivo. Neutrophils isolated from the peripheral blood of healthy individuals were given different interventions to determine whether PTX and skeletal muscle homogenate can induce neutrophils to form NETs in vitro. EAM-ILD had three pathological phenotypes similar to IIM-ILD. Cit-H3, neutrophil myeloperoxidase, and neutrophil elastase were overexpressed in the lungs of EAM model mice. The serum cfDNA level and Cit-H3-DNA complex level were significantly increased in EAM model mice. Serum cfDNA levels were increased significantly in vivo intervention with PTX in mice. Both PTX and skeletal muscle homogenate-induced neutrophils to form NETs in vitro. EAM-ILD pathological phenotypes are similar to IIM-ILD, and NETs are involved in the development of ILD in a murine model of EAM. Thus, the EAM mouse model can be used as an ideal model targeting NETs to prevent and treat IIM-ILD.
Bailout clipping of a leaflet perforation during mitral transcatheter edge-to-edge repair using a larger clip size: a case report
Authors: Nishiura Naoki , Kubo Shunsuke , Maruo Takeshi , Kadota Kazushige
Published: September 2023

Background

Leaflet tear and perforation are serious complications of transcatheter edge-to-edge repair (TEER) using the MitraClip system for severe mitral regurgitation (MR). However, no optimal bailout strategy has been established.

Case summary

An 80-year-old woman developed heart failure due to acute ischaemic severe MR after primary percutaneous coronary intervention. Given the requirement for inotropic drugs and an intra-aortic balloon pump to stabilize her heart failure, we decided to perform TEER using the MitraClip G4 system. The NTW clip was selected considering the limited posterior leaflet, wide central MR, and delivery to the central A2/P2. The leaflet was successfully grasped, and the MR jet dramatically decreased while the clip was closed. However, the MR jet suddenly appeared after completely closing the clip arm. A new eccentric jet was detected coming from the mid-portion of the posterior leaflet, indicating leaflet perforation. We decided to manage the leaflet perforation by covering the perforated portion with a longer type of clip. An XTW clip was then carefully delivered to the previously grasped portion, after which we confirmed that the tip of the clip arm was positioned more posteriorly to the leaflet perforation. After slowly closing the clip, MR decreased to mild, with transoesophageal echocardiography showing no eccentric MR. After her haemodynamics stabilized, she was discharged 28 days after the procedure.

Discussion

This case details a successful bailout clipping of a leaflet perforation using an XTW clip. Leaflet anatomy evaluation is important to ensure that the injured portion is covered by the longer clip arm.
Can’t Buy Me Love (with Foreign Aid)
Authors: Constantelos John , Diven Polly J , Kilburn H Whitt
Published: September 2023

Does foreign aid improve the image of donors in recipient countries? Studies have found weak overall effects, but also positive correlations that are highly conditional on donor and recipient factors, like program characteristics and regime type. Our statistical and case study analysis of US foreign aid leads to a more skeptical perspective. We assess the impact of foreign aid on public opinion of the United States in twenty recipient countries during the Obama and Trump presidencies, using Pew Research Center survey data. A multi-level longitudinal analysis of individual and country-level variables finds that correlations between aid disbursements and foreign public opinion disappear when controlling for attitudes about the US president. These results are corroborated in crucial case studies of Kenya and Turkey. The findings are important for governments that use aid to influence foreign opinion and for scholarship that considers aid to be a source of soft power.
Forward genetic screen of Caenorhabditis elegans mutants with impaired sleep reveals a crucial role of neuronal diacylglycerol kinase DGK-1 in regulating sleep
Authors: Chen Chung-Kuan , Kawano Taizo , Yanagisawa Masashi , Hayashi Yu
Published: September 2023

The sleep state is widely observed in animals. The molecular mechanisms underlying sleep regulation, however, remain largely unclear. In the nematode Caenorhabditis elegans, developmentally timed sleep (DTS) and stress-induced sleep (SIS) are 2 types of quiescent behaviors that fulfill the definition of sleep and share conserved sleep-regulating molecules with mammals. To identify novel sleep-regulating molecules, we conducted an unbiased forward genetic screen based on DTS phenotypes. We isolated 2 mutants, rem8 and rem10, that exhibited significantly disrupted DTS and SIS. The causal gene of the abnormal sleep phenotypes in both mutants was mapped to dgk-1, which encodes diacylglycerol kinase. Perhaps due to the diminished SIS, dgk-1 mutant worms exhibited decreased survival following exposure to a noxious stimulus. Pan-neuronal and/or cholinergic expression of dgk-1 partly rescued the dgk-1 mutant defects in DTS, SIS, and post-stress survival. Moreover, we revealed that pkc-1/nPKC participates in sleep regulation and counteracts the effect of dgk-1; the reduced DTS, SIS, and post-stress survival rate were partly suppressed in the pkc-1; dgk-1 double mutant compared with the dgk-1 single mutant. Excessive sleep observed in the pkc-1 mutant was also suppressed in the pkc-1; dgk-1 double mutant, implying that dgk-1 has a complicated mode of action. Our findings indicate that neuronal DGK-1 is essential for normal sleep and that the counterbalance between DGK-1 and PKC-1 is crucial for regulating sleep and mitigating post-stress damage.
Mpox-Related Ophthalmic Disease: A Retrospective Observational Study in a Single Center in Mexico
Authors: Rodríguez-Badillo Paulina , Rodríguez-Aldama Juan Carlos , Gabián-Fortes Lucía del Carmen , Sifuentes-Rentería Sergio , Valdez-González María Teresa , Pérez-Flores Brian Eduardo , Velasco-Ramos Regina , Fernández-Vizcaya Oscar , Crabtree-Ramírez Brenda , Pérez-Barragán Edgar
Published: September 2023

Mpox-related ophthalmic disease has been reported as infrequent. We retrospectively describe the ocular manifestations present in 11 of 100 patients with confirmed mpox; 9 were people with HIV. We suggest that an ophthalmological evaluation should be performed in all patients with ocular symptoms or moderate and severe mpox disease.
Prolonged use of linezolid in bone and joint infections: a retrospective analysis of adverse effects
Authors: Veerman Karin , Goosen Jon , Spijkers Karin , Jager Nynke , Heesterbeek Petra , Telgt Denise
Published: September 2023

Objectives

Antibiotic treatment for bone and joint infections generally lasts for 6 weeks or longer. Linezolid may be a good option for treating bone and joint infections, but there is an increased risk of potential serious adverse drug events (ADEs) when used for more than 28 days. The aim of this study was to obtain detailed information on the type and time to occurrence of the patient-reported ADEs, the dynamics of haematopoiesis over time, and the reasons for early discontinuation of linezolid when used for an intended maximum duration of 12 weeks.

Methods

This single-centre retrospective study was conducted at the Sint Maartenskliniek in The Netherlands. Patients were included if they were planned to use linezolid for more than 28 days. The main reason for discontinuation of linezolid, the ADE according to the Naranjo score, and the time to occurrence of ADEs were analysed.

Results

Among 78 patients, drug toxicity led to early discontinuation of linezolid in 11 (14%) patients before and nine (12%) after 28 days of therapy. The median treatment duration was 42 days. Gastrointestinal intolerance (42%) and malaise (32%) were the most common ADEs. In 75% of the cases the ADE occurred within 28 days of therapy. Sixty-seven patients were able to continue linezolid beyond 28 days, 87% of whom completed therapy as scheduled. Severe cytopenia, according to the Common Terminology Criteria for Adverse events (CTCA), was observed in four patients and was reversible after discontinuation of linezolid. One patient suffered optic neuropathy related to linezolid use.

Conclusions

Linezolid could be considered an alternative option to the current standard of IV glycopeptides for the treatment of bone and joint infection for up to 12 weeks. If patients pass the first 28 days of therapy, the likelihood of successful completion of therapy is high with a low risk of serious ADEs.
Whole-genome resequencing reveals the genomic diversity and signatures of selection in Romanov sheep
Authors: Cao Chunna , Kang Yuxin , Zhou Qian , Nanaei Hojjat Asadollahpour , Bo Didi , Liu Peiyao , Bai Yangyang , Li Ran , Jiang Yu , Lan Xianyong , Pan Chuanying
Published: September 2023

Romanov sheep are adapted to the extremely cold and harsh environment and display a distinctive grey color. Herein, we analyzed the population structure, genetic diversity, and selection signatures of Romanov sheep based on whole-genome sequencing data of 17 Romanov sheep, 114 individuals from other 10 European breeds. The results of PCA, ADMIXTURE, and NJ-tree showed that the Romanov sheep was closely related to other northern European breeds. A relative high level of genetic diversity, low inbreeding coefficient, and large effective population size was observed in Romanov sheep when compared with other European breeds. We then screened the genomic selection signatures of Romanov sheep using FST, XP-XLP, and XP-EHH methods. The most significant region under selection (CHR14:14.2 to 14.3 Mb) harbored a haplotype that contained MC1R gene. Furthermore, this haplotype was also found in other grey-body breeds including Gotland sheep, Grey Tronder Sheep, and German grey heath sheep, suggesting that it was associated with the unique coat color of these breeds. We also found one region (CHR10:40.8Mb- 41.0Mb) harboring PCDH9 gene which was potentially associated with cold environmental adaptation. In summary, this study identified candidate genes that were associated with the unique grey color and environmental adaptation in Romanov sheep, which provided a basis for understanding the genetic background and utilization of this breed.
Influence of handling in corrals on the temperament of different breeds of beef cattle raised in Brazil
Authors: Freitas Anielly de P , Lima Maria Lúcia P , Simili Flávia F , Negrão João A , Schenkel Flavio S , de Paz Claudia Cristina P
Published: September 2023

The objective of the present study was to verify the effect of handling in corrals on the stress of beef cattle of Nelore, Caracu, and Guzerá breeds through the analysis of the relationship between behavioral traits, growth, and blood parameters. A total of 778 records of entry scores, chute scores, exit scores, flight speed, cortisol, glucose, lactate, live weight, and body condition scores were collected on steers and heifers of the three breeds, born between September and December. The animals came from the Advanced Beef Cattle Research Center of the Animal Science Institute. The variance analyses were performed using the GENMOD procedure. The PROC CORR estimated Spearman correlation coefficients for all traits studied, and the principal components analysis was performed according to the procedure PRINCOMP. Heifers had higher reactivity than steers, with higher behavioral scores and blood parameters. Overall, Caracu individuals demonstrated lower reactivity in comparison to Nelore and Guzerá. However, they presented high stress when they were restrained. The principal component analysis highlighted that behavioral traits and blood parameters were contrasted with growth traits; thus, this analysis can help selectors (livestock farmers) understand the importance of selecting less reactive animals and more easily choose the animals they want to select for breeding. Our results indicate that handling in corrals could be considered a stressful event for bovines. For this reason, measuring blood parameters and behavioral traits can compose necessary decision-making tools regarding changes and adequacies while handling events to reduce stress and consequently improve the herd’s reactivity.
Heat shock protein 27 regulates myogenic and self-renewal potential of bovine satellite cells under heat stress
Authors: Kim Won Seob , Daddam Jayasimha R , Keng Boon Hong , Kim Jaehwan , Kim Jongkyoo
Published: September 2023

While satellite cells play a key role in the hypertrophy, repair, and regeneration of skeletal muscles, their response to heat exposure remains poorly understood, particularly in beef cattle. This study aimed to investigate the changes in the transcriptome, proteome, and proliferation capability of bovine satellite cells in response to different levels of heat stress (HS) and exposure times. Satellite cells were isolated from 3-mo-old Holstein bulls (body weight: 77.10 ± 2.02 kg) and subjected to incubation under various temperature conditions: 1) control (38 °C; CON), 2) moderate (39.5 °C; MHS), and extreme (41 °C; EHS) for different durations ranging from 0 to 48 h. Following 3 h of exposure to extreme heat (EHS), satellite cells exhibited significantly increased gene expression and protein abundance of heat shock proteins (HSPs; HSP70, HSP90, HSP20) and paired box gene 7 (Pax7; P < 0.05). HSP27 expression peaked at 3 h of EHS and remained elevated until 24 h of exposure (P < 0.05). In contrast, the expression of myogenic factor 5 (Myf5) and paired box gene 3 (Pax3) was decreased by EHS compared to the control at 3 h of exposure (P < 0.05). Notably, the introduction of HSP27 small interference RNA (siRNA) transfection restored Myf5 expression to control levels, suggesting an association between HSP27 and Myf5 in regulating the self-renewal properties of satellite cells upon heat exposure. Immunoprecipitation experiments further confirmed the direct binding of HSP27 to Myf5, supporting its role as a molecular chaperone for Myf5. Protein–protein docking algorithms predicted a high probability of HSP27–Myf5 interaction as well. These findings indicate that extreme heat exposure intrinsically promotes the accumulation of HSPs and modulates the early myogenic regulatory factors in satellite cells. Moreover, HSP27 acts as a molecular chaperone by binding to Myf5, thereby regulating the division or differentiation of satellite cells in response to HS. The results of this study provide a better understanding of muscle physiology in heat-stressed cells, while unraveling the intricate molecular mechanisms that underlie the HS response in satellite cells.
Risk stratification of invasive cervical cancer diagnosed after cervical conization
Authors: Shiga Tomoka , Taguchi Ayumi , Mori Mayuyo , Yamaguchi Shogo , Honjoh Harunori , Nishijima Akira , Eguchi Satoko , Miyamoto Yuichiro , Sone Kenbun , Kawana Kei , Osuga Yutaka
Published: September 2023

Background

Cervical intraepithelial neoplasia (CIN) diagnosis is based on colposcopy-aided histological examination. However, its accuracy in CIN diagnosis is limited. Some invasive cervical cancers (ICCs) are diagnosed after cervical conization. Therefore, risk stratification of undetected ICC is particularly important for the management of patients with CIN. This study aimed to identify the risk factors for undetected ICC. We especially focused on the association of human papillomavirus (HPV) genotypes.

Methods

We retrospectively reviewed the clinicopathological characteristics (including age, parity, and preoperative diagnosis) and HPV genotypes of 348 patients diagnosed with CIN or adenocarcinoma in situ (AIS) who underwent cervical conization at our hospital between 2008 and 2016. The relationship between preoperative factors, including HPV genotypes and post-conization ICC, was evaluated.

Results

Among the 348 patients, 322, 7, and 19 had preoperative CIN3, CIN2, and AIS, respectively; 181 were nulliparous. The median patient age was 41 (23–83) years. HPV genotyping was performed on 237 patients. Overall, post-conization ICC was detected in 16 patients (4.6%). Multivariate analysis showed that nulliparity and HPV16 positivity were the independent risk factors for post-conization ICC (OR: 6.01, P = 0.0302; OR: 5.26, P = 0.0347, respectively). The combination of HPV16 status and parity improved diagnostic accuracy. Seven of 53 HPV16-positive cases (13%) without childbirth history were diagnosed with post-conization ICC. In contrast, none of the HPV16-negative cases with childbirth history was diagnosed with post-conization ICC.

Conclusion

HPV16 positivity and nulliparity were identified as risk factors for undetected ICC. Careful treatment selection and preoperative scrupulous examination are especially important in these cases.
Israel, an Anatomy of the World: Microcosmic Contours Between Romans 9–11 and 1–8
Authors: Dixon Thomas P
Published: September 2023

While a near consensus now deems Romans 9–11 integral to the letter rather than peripheral, explanations of how these chapters integrate remain disparate. Apparent links between Rom. 9–11 and 1–8 abound, but no one has yet exposed the underlying congruence between the two sections’ argumentative trajectories. Coordinating divine activity in these letter segments reveals the interpretive value of ‘microcosm’ imagery, an ancient and versatile metaphor that will prove more illuminating than ‘climax’ inter alia for understanding Paul’s presentation of Israel. In Romans, the κόσμος itself is an actor in the text, with Israel serving as its microcosm. Romans 9–11 then portrays God’s actions toward Israel in a microcosmic relation to God’s actions toward the κόσμος in Rom. 1–8. In its disobedience, judgement, and salvation, Israel embodies the anatomy of the world, a layered harmony that may help reconcile warring camps in recent Pauline scholarship.
Drought survival in conifer species is related to the time required to cross the stomatal safety margin
Authors: Petek-Petrik Anja , Petrík Peter , Lamarque Laurent J , Cochard Hervé , Burlett Régis , Delzon Sylvain
Published: September 2023

The regulation of water loss and the spread of xylem embolism have mostly been considered separately. The development of an integrated approach taking into account the temporal dynamics and relative contributions of these mechanisms to plant drought responses is urgently needed. Do conifer species native to mesic and xeric environments display different hydraulic strategies and temporal sequences under drought? A dry-down experiment was performed on seedlings of four conifer species differing in embolism resistance, from drought-sensitive to extremely drought-resistant species. A set of traits related to drought survival was measured, including turgor loss point, stomatal closure, minimum leaf conductance, and xylem embolism resistance. All species reached full stomatal closure before the onset of embolism, with all but the most drought-sensitive species presenting large stomatal safety margins, demonstrating that highly drought-resistant species do not keep their stomata open under drought conditions. Plant dry-down time to death was significantly influenced by the xylem embolism threshold, stomatal safety margin, and minimum leaf conductance, and was best explained by the newly introduced stomatal margin retention index (SMRIΨ50) which reflects the time required to cross the stomatal safety margin. The SMRIΨ50 may become a key tool for the characterization of interspecific drought survival variability in trees.
On the fundamentality of the radial acceleration relation for late-type galaxy dynamics
Authors: Stiskalek Richard , Desmond Harry
Published: September 2023

Galaxies have been observed to exhibit a level of simplicity unexpected in the complex galaxy formation scenario posited by standard cosmology. This is particularly apparent in their dynamics, where scaling relations display much regularity and little intrinsic scatter. However, the parameters responsible for this simplicity have not been identified. Using the Spitzer Photometry & Accurate Rotation Curves galaxy catalogue, we argue that the radial acceleration relation (RAR) between galaxies’ baryonic and total dynamical accelerations is the fundamental 1D correlation governing the radial (in-disc) dynamics of late-type galaxies. In particular, we show that the RAR cannot be tightened by the inclusion of any other available galaxy property, that it is the strongest projection of galaxies’ radial dynamical parameter space, and that all other statistical radial dynamical correlations stem from the RAR plus the non-dynamical correlations present in our sample. We further provide evidence that the RAR’s fundamentality is unique in that the second most significant dynamical relation does not possess any of these features. Our analysis reveals the root cause of the correlations present in galaxies’ radial dynamics: they are nothing but facets of the RAR. These results have important ramifications for galaxy formation theory because they imply that to explain statistically late-type galaxy dynamics within the disc it is necessary and sufficient to explain the RAR and lack of any significant, partially independent correlation. While simple in some modified dynamics models, this poses a challenge to standard cosmology.
Probing the Galactic halo with RR Lyrae stars – IV. On the Oosterhoff dichotomy of RR Lyrae stars
Authors: Zhang Shan , Liu Gaochao , Huang Yang , Lv Zongfei , Bird Sarah Ann , Chen Bingqiu , Zhang Huawei , Beers Timothy C , Li Xinyi , Tian Haijun , Zhang Peng
Published: September 2023

We use 3653 (2661 RRab, 992 RRc) RR Lyrae stars (RRLs) with 7D (3D position, 3D velocity, and metallicity) information selected from Sloan Digital Sky Survey, Large Sky Area Multi-Object Fiber Spectroscopic Telescope, and Gaia EDR3, and divide the sample into two Oosterhoff groups (Oo I and Oo II) according to their amplitude–period behaviour in the Bailey diagram. We present a comparative study of these two groups based on chemistry, kinematics, and dynamics. We find that Oo I RRLs are relatively more metal-rich, with predominately radially dominated orbits and large eccentricities, while Oo II RRLs are relatively more metal-poor, and have mildly radially dominated orbits. The Oosterhoff dichotomy of the Milky Way’s halo is more apparent for the inner-halo region than for the outer-halo region. Additionally, we also search for this phenomenon in the haloes of the two largest satellite galaxies, the Large and Small Magellanic clouds, and compare over different bins in metallicity. We find that the Oosterhoff dichotomy is not immutable, and varies based on position in the Galaxy and from galaxy to galaxy. We conclude that the Oosterhoff dichotomy is the result of a combination of stellar and galactic evolution, and that it is much more complex than the dichotomy originally identified in Galactic globular clusters.
The MillenniumTNG Project: semi-analytic galaxy formation models on the past lightcone
Authors: Barrera Monica , Springel Volker , White Simon D M , Hernández-Aguayo César , Hernquist Lars , Frenk Carlos , Pakmor Rüdiger , Ferlito Fulvio , Hadzhiyska Boryana , Delgado Ana Maria , Kannan Rahul , Bose Sownak
Published: September 2023

Upcoming large galaxy surveys will subject the standard cosmological model, Lambda Cold Dark Matter, to new precision tests. These can be tightened considerably if theoretical models of galaxy formation are available that can predict galaxy clustering and galaxy–galaxy lensing on the full range of measurable scales, throughout volumes as large as those of the surveys, and with sufficient flexibility that uncertain aspects of the underlying astrophysics can be marginalized over. This, in particular, requires mock galaxy catalogues in large cosmological volumes that can be directly compared to observation, and can be optimized empirically by Monte Carlo Markov Chains or other similar schemes, thus eliminating or estimating parameters related to galaxy formation when constraining cosmology. Semi-analytic galaxy formation methods implemented on top of cosmological dark matter simulations offer a computationally efficient approach to construct physically based and flexibly parametrized galaxy formation models, and as such they are more potent than still faster, but purely empirical models. Here, we introduce an updated methodology for the semi-analytic L-Galaxies code, allowing it to be applied to simulations of the new MillenniumTNG project, producing galaxies directly on fully continuous past lightcones, potentially over the full sky, out to high redshift, and for all galaxies more massive than $\sim 10^8\, {\rm M}_\odot$. We investigate the numerical convergence of the resulting predictions, and study the projected galaxy clustering signals of different samples. The new methodology can be viewed as an important step towards more faithful forward-modelling of observational data, helping to reduce systematic distortions in the comparison of theory to observations.
H i-rich but low star formation galaxies in MaNGA: physical properties and comparison to control samples
Authors: Sharma Anubhav , Masters Karen L , Stark David V , Garland James , Drory Niv , Fraser-McKelvie Amelia , Weijmans Anne-Marie
Published: September 2023

Gas-rich galaxies are typically star forming. We make use of H i-MaNGA, a programme of H i follow-up for the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey of the Sloan Digital Sky Surveys, to construct a sample of unusual neutral hydrogen (H i, 21 cm)-rich galaxies that have low star formation rates (SFRs), using infrared colour from the Wide-field Infrared Survey Explorer as a proxy for specific SFR. Out of a set of 1575 MaNGA galaxies with H i-MaNGA detections, we find that 83 (5 per cent) meet our selection criteria to be H i rich with low SFR. We construct two stellar mass-matched control samples: H i-rich galaxies with typical SFR (high SF control) and H i-poor galaxies with low SFR (low H i control). We investigate the properties of each of these samples, comparing physical parameters such as ionization state maps, stellar and ionized gas velocity and dispersion, environment measures, metallicity, and morphology to search for the reasons why these unusual H i-rich galaxies are not forming stars. We find evidence for recent external accretion of gas in some galaxies (via high counter-rotating fractions), along with some evidence for active galactic nucleus (AGN) feedback (from a high central low-ionization emission-line region and/or red geyser fraction), and bar quenching (via an enhanced strong bar fraction). Some galaxies in the sample are consistent with simply having their H i in a high angular momentum, large-radius, low-density disc. We conclude that no single physical process can explain all H i-rich, low-SFR galaxies.
Relative baryon-dark matter velocities in cosmological zoom simulations
Authors: Conaboy Luke , Iliev Ilian T , Fialkov Anastasia , Dixon Keri L , Sullivan David
Published: September 2023

Supersonic relative motion between baryons and dark matter due to the decoupling of baryons from the primordial plasma after recombination affects the growth of the first small-scale structures. Large box sizes (greater than a few hundred Mpc) are required to sample the full range of scales pertinent to the relative velocity, while the effect of the relative velocity is strongest on small scales (less than a few hundred kpc). This separation of scales naturally lends itself to the use of ‘zoom’ simulations, and here we present our methodology to self-consistently incorporate the relative velocity in zoom simulations, including its cumulative effect from recombination through to the start time of the simulation. We apply our methodology to a large-scale cosmological zoom simulation, finding that the inclusion of relative velocities suppresses the halo baryon fraction by 46–23 per cent between z = 13.6 and 11.2, in qualitative agreement with previous works. In addition, we find that including the relative velocity delays the formation of star particles by ∼20 Myr on average (of the order of the lifetime of a ∼9 M⊙ Population III star) and suppresses the final stellar mass by as much as 79 per cent at z = 11.2.
Commensal transient searches in eight short gamma-ray burst fields
Authors: Chastain S I , van der Horst A J , Rowlinson A , Rhodes L , Andersson A , Diretse R , Fender R P , Woudt P A
Published: September 2023

A new generation of radio telescopes with excellent sensitivity, instantaneous uv coverage, and large fields of view, are providing unprecedented opportunities for performing commensal transient searches. Here, we present such a commensal search in deep observations of short gamma-ray burst fields carried out with the MeerKAT radio telescope in South Africa at 1.3 GHz. These four hour observations of eight different fields span survey lengths of weeks to months. We also carry out transient searches in time slices of the full observations, at time-scales of 15 min and 8 s. We find 122 variable sources on the long time-scales, of which 52 are likely active galactic nuclei, but there are likely also some radio flaring stars. While the variability is intrinsic in at least two cases, most of it is consistent with interstellar scintillation. In this study, we also place constraints on transient rates based on state-of-the-art transient simulations codes. We place an upper limit of 2 × 10−4 transients per day per square degree for transients with peak flux of 5 mJy, and an upper limit of 2.5 × 10−2 transients per day per square degree for transients with a fluence of 10 Jy ms, the minimum detectable fluence of our survey.
PL01.5.A NEOADJUVANT CAMRELIZUMAB AND APATINIB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMAS:PRIMARY REPORT OF AN OPEN LABEL PHASE II STUDY
Authors: Chen Z , Guo C , Yang Q , Hu W , Cao X , Liao Y , Zhang J , Jiang X , Li D , Chen Y
Published: September 2023

BACKGROUND

Recurrent high-grade gliomas (HGG) is a challenge with a poor prognosis and limited treatment options. A study has reported that neoadjuvant immunotherapy upregulates PD-L1 expression and CD8+T cell infiltration, which is expected to improve the survival of HGG. Our study (NCT04588987) aimed to assess the efficacy and safety of perioperative camrelizumab (anti-PD-1 antibody) and apatinib (antiangiogenic agent) in patients with recurrent HGG.

METHODS

Patients with recurrent HGG received 14 days of neoadjuvant treatment with camrelizumab (intravenous injection 200 mg on day 1) and apatinib (oral 250 mg per day on days 1-7), followed by surgery for recurrent tumor. Sequential therapy began 2 weeks after surgery with the biweekly camrelizumab (200mg) and 4 weeks after surgery with the daily apatinib (250mg) until investigator-assessed progressive disease or unable to tolerate toxicity. The primary endpoint was overall survival (OS).

RESULTS

Between Oct 9, 2020 and Feb 14, 2023, 18 patients have been enrolled (14 for recurrent glioblastomas, 3 for anaplastic astrocytoma and 1 for anaplastic oligodendroglioma). At the data cut-off (Mar 31, 2023), 16 patients discontinued study treatment (12 cases of disease progression, 1 case of liver function injury, 1 case of COVID-19 infection, 1 case refused treatment and 1 case died before progression). The median treatment time for camrelizumab and apatinib were 4.8 (95% CI: 3.8-5.9) months and 5.2 (95% CI: 3.9-6.4) months, respectively. The median OS was 12.9 months (95% CI: 9.3-16.4) with a median follow-up time of 17.5 (95%CI:9.0-26.1) months. The median PFS was 4.8 months (95% CI: 4.4-5.2). Nine (50%) patients occurred grade 3 treatment-related adverse events (TRAEs). Decreased lymphocyte count (22.2%, 4/18), hypertension (16.7%,3/18) and Increased aspartate aminotransferase (11.1%,2/18) were the most common grade 3 TRAEs, and there were no grade 4 or 5 TRAEs.

CONCLUSION

This combination therapy in recurrent HGG demonstrated encouraging efficacy, and TRAEs are manageable.Keywords: Apatinib, Camrelizumab, Neoadjuvant therapy, Recurrent high-grade gliomas.
KS03.6.A HIGH RATE OF MULTIFOCAL RELAPSE AND SUBSEQUENT POOR PROGRESSION-FREE SURVIVAL POST SALVAGE RADIATION THERAPY FOR WHO GRADE 2-3 MENINGIOMA MANAGED WITH INITIAL SURGERY ALONE
Authors: Back M , Horsley P , Yim J , Drummond J
Published: September 2023

BACKGROUND

Optimal initial management for patients with localised high risk meningioma remains uncertain with long natural history disease promoting the option of delaying adjuvant radiation therapy until relapse. This study assessed patterns of relapse and survival in a cohort of patients with high-risk meningioma managed with initial surgical therapy alone.

MATERIAL AND METHODS

Consecutive patients with meningioma referred for radiation therapy (IMRT) between January 2008-December 2021 were entered into an ethics approved database managed by the Neuro-oncology MDT. Categorisation and subsequent management plans were based by grade on WHO2007-2016 classification. Immediate or delayed referral pathway for IMRT was individualised by neurosurgical team. At time of subsequent referral for IMRT at relapse patients had tumour site / volume determined by MRI and Dotatate PET. Tumour volume, site of relapse in relation to initial cavity and number of recurrent foci of disease were recorded. For patients subsequently receiving IMRT an integrated-boost, generally 60Gy/54Gy, was used. Primary endpoints were site of relapse in relation to initial surgical cavity, number of foci, and median time from initial surgery. Secondary endpoints were median progression-free(mRFS)/overall survival(mOS) calculated from start salvage IMRT compared to cohort of intercurrent patients managed at initial diagnosis.

RESULTS

One hundred and five patients with meningioma were referred, with median follow-up for survivors of 3.6yrs (q1-3:1.5-7.7yrs). Median age was 59.2yrs; 59% had convexity meningioma; WHO2016 grade was G3 in 21%; Atypical(G2) in 66% and G1/no biopsy in 9% of patients. Twenty-two patients have subsequently relapsed post IMRT; with sixteen deceased for 8yrPFS and 8yrOS of 63.5% and 73.5% respectively. Forty-nine(46%) of patients were referred for IMRT at relapse, of which 39% had repeat resection prior to IMRT referral; and 14% were WHO2016 G3 at most recent resection. Based on MRI/Dotatate 61% had more than one focus of tumour around initial surgical cavity. Subsequent to salvage IMRT, fifteen of the 49 patients have had further relapse and eleven are deceased. Patients managed at relapse had worse PFS with 55.1% 8yrPFS vs 78.0% 8yrPFS (p=0.03); however equivalent OS with 68.8% 8yrOS vs 79.4% 8yrOS (p=0.62).

CONCLUSION

Patients with G2/3 meningioma managed with surgery alone upfront more often had relapses that were multifocal that were not managed with further salvage surgery. The subsequent progression-free survival was poor with a high rate of subsequent relapse post salvage IMRT, especially when compared to patients managed with IMRT at time of initial diagnosis.
JS06.4.A MULTI-OMIC CHARACTERIZATION OF LUNG CANCER BRAIN METASTASIS REVEALS THE METABOLIC VULNERABILITY AS A NOVEL THERAPEUTIC TARGET
Authors: Duan H , Wei S , Liu Y , Zhang G , Mou Y
Published: September 2023

Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A better understanding of the molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Here, we performed integrated analyses of both bulk and single cell genomic transcriptomic and proteomic data derived from five published and two newly generated patient cohorts, totaling 141 patients with paired and unpaired primary lung cancer and LC-BrM. This was subsequently validated by immunohistochemistry (IHC) and multiplexed immunofluorescence (mIF) staining. LC-BrMs exhibited significantly lower tumor mutational burden but higher intra-tumor heterogeneity. We observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TP53, MUC16, LRP1B, KRAS, FAT3, and NF1. In addition, the genome-wide landscape of somatic copy number alterations (SCNAs) was found to be similar between primary lung cancers and LC-BrM lesions. Nevertheless, three regions of focal amplification were significantly enriched in LC-BrMs, including 11q13.1, 14q11.2, and 12p13.31. Integrated analyses of transcriptional and proteomic data revealed mitochondrial-specific metabolism was activated in LC-BrMs and accompanied by a suppressed tumor immune microenvironment, which was further corroborated by IHC and mIF data. Importantly, targeting oxidative phosphorylation with gamitrinib in combination with anti-PD1 immune checkpoint blockade (ICB) therapy significantly improved the survival of mice with LC-BrMs. In conclusion, our findings not only provide comprehensive and multi-omic perspectives of the molecular mechanisms of LC-BrMs but also contribute to the development of potential therapeutic strategies with the goal of translating it into clinical trials for patients with LC-BrMs.
JS07.5.A PROGNOSTIC FACTORS ASSOCIATED WITH POOR OUTCOME IN ADULT PATIENTS WITH MEDULLOBLASTOMA
Authors: GARCILAZO-REYES Y J , Dal-Col P , Bielle F , Mokhtari K , Feuvret L , Jacob J , Duran-Pena A , Capelle L , Savatovsky J , Bourdeaut F , Masliah-Planchon J , Cacho-Díaz B , Hoang-Xuan K , Idbaih A , Laigle-Donadey F
Published: September 2023

BACKGROUND

Medulloblastoma (MB) is a rare tumor in adults. Current recommendations are based on scarce data available in adults, and mostly derived from pediatric series. Prognostic factors have not been uniformly defined in adults to date.

MATERIAL AND METHODS

We retrospectively collected all cases of adult patients diagnosed and treated between 1995 and 2019 in our institution for histopathological proven MB. We described patient´s characteristics, disease features, treatment modalities and studied the prognostic factors for survival outcomes using univariate and multivariate analysis.

RESULTS

We identified a total of 89 cases. Male gender (66%), lateral cerebellar location (48%), desmoplastic/nodular histology (43%), Sonic Hedgehog molecular group (76%) and Chang´s M0 (72%) were the most frequent patient´s and disease characteristics. Patients mostly achieved complete resection/near total resection (62%); surgery followed by chemotherapy/radiotherapy (CT/RT) was the most frequent initial strategy (76%), favoring carboplatin-based regimens (70%), posterior fossa RT ≥50 Gy (71%) and craniospinal RT ≥ 30 Gy (59%) as the most frequently regimen used. According to the Association of French Speaking Neuro-oncologists and the European Reference Network on Rare Adult Cancers risk scales (ANOCEF and EURACAN), we found 44 and 48% of intermediate-risk patients and 49 and 45% of high-risk patients, respectively. Both cerebral and spinal presentation at diagnosis was documented in 16 (18%) patients. Complete response was achieved in 71(80%) patients. Nine was the maximal number of progressions documented, 35(39%) patients relapsed, CT was the preferred strategy at relapses, privileging carboplatin-based regimens at first relapse. The median overall survival (mOS) was 124.42 months (95%CI 68.53 - 180.11) and the median progression free survival (mPFS) was 30.48 months (95%CI 13.46 - 47.51), the 5-year OS was 53% and the 5-year PFS was 51%. In multivariate analysis, Chang´s ≥ M2 metastatic classification (p=0.001), no CT in association to RT (p=0.005), and lower doses on craniospinal RT <30 Gy (p=0.015) were associated with poor prognosis for OS; Chang´s ≥ M2 (p=0.009) was also a prognostic factor for poor PFS.

CONCLUSION

This study dedicated specifically to adult MB patients suggests relevant prognostic factors for adult MB patients. We identify Chang´s ≥ M2 as poor prognostic factor of OS and PFS, and we confirm that the use of CT/RT at diagnosis and RT doses ≥ 30 Gy are associated with better survival in adults MB.
OS02.4.A IMPACT OF SURGERY ON SURVIVAL IN PATIENTS WITH MULTIPLE BRAIN METASTASES
Authors: Sagerer A , Buszello C , Lucas M , Eyüpoglu I , Hennig S , Schackert G , Juratli T
Published: September 2023

BACKGROUND

Surgical resection of brain metastases (BM) alleviates symptoms and can improve patients’ survival. However, the benefit of resection in multiple BM is controversial due to patients’ limited life expectancy. Therefore, we investigated the impact of resection of multiple BM on patients’ survival.

MATERIAL AND METHODS

We reviewed clinical data from 544 patients (216 female, 328 male) who underwent surgery for BM in our hospital between 2010 and 2022. Overall survival (OS) was estimated using the Kaplan-Meier estimator. In addition, follow-up data, adjuvant treatment and tumor recurrence data were collected.

RESULTS

We identified 280 patients (51.5%) with one and 264 patients (48.5%) with two or more BM. Bronchial carcinoma represented the most common primary tumor entity (n= 185, 88 one and 97 multiple BM), followed by melanoma (n= 109, 44 one and 65 multiple BM), breast cancer (n= 54, 31 one and 23 multiple BM), gastro-intestinal tumor (n= 64, 39 one and 25 multiple BM) and lastly cancer of unknown primary (CUP) (n= 29, 11 one and 18 multiple BM). We then compared the survival between patients with a single with those with multiple BM. The median OS of all patients with one BM was with 11.6 months significantly longer than those with two or more BM (7.3 months, p< 0.001, 95% CI one vs. multiple BM: 8.6-14.5 vs. 6.2-8.4 months, respectively). Notably, 29.3% of patients with one BM and 16.5% with multiple BM lived longer than 24 months after resection (long-term survivor, p= 0.001). Regarding primary tumor histology, patients with breast cancer with a single BM had a significant longer OS with 19.7 compared to patients with multiple BM (5.0 months, p= 0.031). Remarkably, 33.3% of all long-term survivors with breast cancer had multiple BM. Patients with a single BM originating from other cancers showed a superior but yet not significant OS in comparison with their counterparts with multiple BM after resection. This included: gastro-intestinal cancer 12.2 vs. 6.5 months (p= 0.160), melanoma 11.6 vs. 7.3 months (p= 0.236) and CUP 3.0 vs. 2.7 months (p= 0.258). The long-term survivor rate of patients with resected multiple BM varied between 20.6% in melanoma and 7.4% in patients with CUP.

CONCLUSION

Despite limited prognosis in patients with multiple BM, surgical resection should be considered as an effective treatment option. Our study shows that a substantial subset of patients with multiple BM who underwent resection survive longer than 24 months after resection.