bluuebunny/crossref_metadata_2025 huggingface dataset:
Defending Against Data Poisoning Attacks: From Distributed Learning to Federated Learning
Authors: Tian Yuchen , Zhang Weizhe , Simpson Andrew , Liu Yang , Jiang Zoe Lin
Published: November 2021

Federated learning (FL), a variant of distributed learning (DL), supports the training of a shared model without accessing private data from different sources. Despite its benefits with regard to privacy preservation, FL’s distributed nature and privacy constraints make it vulnerable to data poisoning attacks. Existing defenses, primarily designed for DL, are typically not well adapted to FL. In this paper, we study such attacks and defenses. In doing so, we start from the perspective of DL and then give consideration to a real-world FL scenario, with the aim being to explore the requisites of a desirable defense in FL. Our study shows that (i) the batch size used in each training round affects the effectiveness of defenses in DL, (ii) the defenses investigated are somewhat effective and moderately influenced by batch size in FL settings and (iii) the non-IID data makes it more difficult to defend against data poisoning attacks in FL. Based on the findings, we discuss the key challenges and possible directions in defending against such attacks in FL. In addition, we propose detect and suppress the potential outliers(DSPO), a defense against data poisoning attacks in FL scenarios. Our results show that DSPO outperforms other defenses in several cases.
Dynamic changes in chromatin accessibility are associated with the atherogenic transitioning of vascular smooth muscle cells
Authors: Wang Ying , Gao Hua , Wang Fudi , Ye Zhongde , Mokry Michal , Turner Adam W , Ye Jianqin , Koplev Simon , Luo Lingfeng , Alsaigh Tom , Adkar Shaunak S , Elishaev Maria , Gao Xiangyu , Maegdefessel Lars , Björkegren Johan L M , Pasterkamp Gerard , Miller Clint L , Ross Elsie G , Leeper Nicholas J
Published: November 2021

Aims

De-differentiation and activation of pro-inflammatory pathways are key transitions vascular smooth muscle cells (SMCs) make during atherogenesis. Here, we explored the upstream regulators of this ‘atherogenic transition’.

Methods and results

Genome-wide sequencing studies, including Assay for Transposase-Accessible Chromatin using sequencing and RNA-seq, were performed on cells isolated from both murine SMC-lineage-tracing models of atherosclerosis and human atherosclerotic lesions. At the bulk level, alterations in chromatin accessibility were associated with the atherogenic transitioning of lesional SMCs, especially in relation to genes that govern differentiation status and complement-dependent inflammation. Using computational biology, we observed that a transcription factor previously related to coronary artery disease, Activating transcription factor 3 (ATF3), was predicted to be an upstream regulator of genes altered during the transition. At the single-cell level, our results indicated that ATF3 is a key repressor of SMC transitioning towards the subset of cells that promote vascular inflammation by activating the complement cascade. The expression of ATF3 and complement component C3 was negatively correlated in SMCs from human atherosclerotic lesions, suggesting translational relevance. Phenome-wide association studies indicated that genetic variation that results in reduced expression of ATF3 is correlated with an increased risk for atherosclerosis, and the expression of ATF3 was significantly down-regulated in humans with advanced vascular disease.

Conclusion

Our study indicates that the plasticity of atherosclerotic SMCs may in part be explained by dynamic changes in their chromatin architecture, which in turn may contribute to their maladaptive response to inflammation-induced stress.
Transcatheter mitral valve repair for the treatment of severe mitral regurgitation and exertional pre-syncope in a patient with non-obstructive hypertrophic cardiomyopathy: a case report
Authors: Lucarelli Katya , Troisi Federica , Scarcia Maria , Grimaldi Massimo
Published: November 2021

Background

Hypertrophic cardiomyopathy (HCM) has a complex pathophysiology and heterogeneous phenotypic expression. In obstructive HCM with significant mitral regurgitation (MR), MitraClip device implantation reduces MR severity and symptoms. There are no data regarding MitraClip implantation in patients with non-obstructive HCM and significant MR.

Case summary

A 78-year-old woman with non-obstructive HCM and significant functional MR (3+) was admitted to our centre for dyspnoea and episodes of pre-syncope under light stress. Transthoracic and transoesophageal echocardiography showed a normal left ventricular ejection fraction and normal right heart pressures, an inverted mitral filling pattern, and a central prevalent jet (A2-P2 origin) of MR. Exercise echocardiography performed to verify exercise tolerance was interrupted at the 50-W stage due to severe hypotension and pre-syncope. After transcatheter edge-to-edge repair using the MitraClip system, the patient exhibited a reduction in MR Grade from 3+ to 1+. Follow-up up to 1-year post-procedure revealed noticeable improvements in exercise tolerance and symptoms. There were no further episodes of pre-syncope.

Discussion

In non-obstructive HCM, the pathophysiological role of MR in symptom generation is unknown. In this patient, we speculated that significant MR contributed to the mechanisms responsible for severe hypotension and pre-syncope during exercise. A reduction in MR after MitraClip implantation was associated with symptomatic improvements. Our findings further highlight the potential utility of the exercise stress test in therapeutic decision-making for patients with non-obstructive HCM and MR.
High-resolution in situ analysis of Cas9 germline transcript distributions in gene-drive Anopheles mosquitoes
Authors: Terradas Gerard , Hermann Anita , James Anthony A , McGinnis William , Bier Ethan
Published: November 2021

Gene drives are programmable genetic elements that can spread beneficial traits into wild populations to aid in vector-borne pathogen control. Two different drives have been developed for population modification of mosquito vectors. The Reckh drive (vasa-Cas9) in Anopheles stephensi displays efficient allelic conversion through males but generates frequent drive-resistant mutant alleles when passed through females. In contrast, the AgNosCd-1 drive (nos-Cas9) in Anopheles gambiae achieves almost complete allelic conversion through both genders. Here, we examined the subcellular localization of RNA transcripts in the mosquito germline. In both transgenic lines, Cas9 is strictly coexpressed with endogenous genes in stem and premeiotic cells of the testes, where both drives display highly efficient conversion. However, we observed distinct colocalization patterns for the two drives in female reproductive tissues. These studies suggest potential determinants underlying efficient drive through the female germline. We also evaluated expression patterns of alternative germline genes for future gene-drive designs.
Diet-induced changes in titer support a discrete response of Wolbachia-associated plastic recombination in Drosophila melanogaster
Authors: Mostoufi Sabrina L , Singh Nadia D
Published: November 2021

Plastic recombination in Drosophila melanogaster has been associated with a variety of extrinsic and intrinsic factors such as temperature, starvation, and parasite infection. The bacterial endosymbiont Wolbachia pipientis has also been associated with plastic recombination in D. melanogaster. Wolbachia infection is pervasive in arthropods and this infection induces a variety of phenotypes in its hosts, the strength of which can depend on bacterial titer. Here, we test the hypothesis that the magnitude of Wolbachia-associated plastic recombination in D. melanogaster depends on titer. To manipulate titer, we raised Wolbachia-infected and uninfected flies on diets that have previously been shown to increase or decrease Wolbachia titer relative to controls. We measured recombination in treated and control individuals using a standard backcrossing scheme with two X-linked visible markers. Our results recapitulate previous findings that Wolbachia infection is associated with increased recombination rate across the yellow-vermillion interval of the X chromosome. Our data show no significant effect of diet or diet by Wolbachia interactions on recombination, suggesting that diet-induced changes in Wolbachia titer have no effect on the magnitude of plastic recombination. These findings represent one of the first steps toward investigating Wolbachia-associated plastic recombination and demonstrate that the phenotype is a discrete response rather than a continuous one.
Identification of condition-specific biomarker systems in uterine cancer
Authors: Hickman Allison R , Hang Yuqing , Pauly Rini , Feltus Frank A
Published: November 2021

Uterine cancer is the fourth most common cancer among women, projected to affect 66,000 US women in 2021. Uterine cancer often arises in the inner lining of the uterus, known as the endometrium, but can present as several different types of cancer, including endometrioid cancer, serous adenocarcinoma, and uterine carcinosarcoma. Previous studies have analyzed the genetic changes between normal and cancerous uterine tissue to identify specific genes of interest, including TP53 and PTEN. Here we used Gaussian Mixture Models to build condition-specific gene coexpression networks for endometrial cancer, uterine carcinosarcoma, and normal uterine tissue. We then incorporated uterine regulatory edges and investigated potential coregulation relationships. These networks were further validated using differential expression analysis, functional enrichment, and a statistical analysis comparing the expression of transcription factors and their target genes across cancerous and normal uterine samples. These networks allow for a more comprehensive look into the biological networks and pathways affected in uterine cancer compared with previous singular gene analyses. We hope this study can be incorporated into existing knowledge surrounding the genetics of uterine cancer and soon become clinical biomarkers as a tool for better prognosis and treatment.
ABHD5 frameshift deletion in Golden Retrievers with ichthyosis
Authors: Kiener Sarah , Wiener Dominique J , Hopke Kaitlin , Diesel Alison B , Jagannathan Vidhya , Mauldin Elizabeth A , Casal Margret L , Leeb Tosso
Published: November 2021

Ichthyoses are hereditary skin disorders characterized by the formation of scales and defects in the outermost layer of the epidermis. In dogs, at least six different breed-specific ichthyoses including a relatively common PNPLA1-related autosomal recessive ichthyosis in Golden Retrievers are known. In this study, we investigated 14 Golden Retrievers with scales that were not homozygous for the mutant PNPLA1 allele suggesting a genetically distinct new form of ichthyosis. Histopathological examinations showed lamellar, orthokeratotic hyperkeratosis, and mildly hyperplastic epidermis that led to the diagnosis of a nonepidermolytic ichthyosis. Combined linkage and homozygosity mapping in 14 cases and 30 nonaffected family members delimited a critical interval of ∼12.7 Mb on chromosome 23. Whole-genome sequencing of an affected dog revealed a single protein-changing variant within this region that was not present in 795 control genomes. The identified variant is a 14 bp deletion in the ABHD5 gene (c.1006_1019del), leading to a frameshift and altering the last 14 codons p.(Asp336Serfs*6). The genotypes at this variant showed perfect cosegregation with the ichthyosis phenotype in a large family comprising 14 cases and 72 controls. ABHD5 encodes an acyltransferase required for lipid metabolism. In humans, variants in ABHD5 cause Chanarin-Dorfman syndrome, a neutral lipid storage disease with ichthyosis. Our data in dogs together with the knowledge on the effects of ABHD5 variants in humans strongly suggest ABHD5:c.1006_1019del as candidate causative genetic variant for a new canine form of ichthyosis, which we propose to designate as Golden Retriever ichthyosis type 2 (ICH2).
Monitoring the changing seismic site response of a fast-moving rockslide (Brienz/Brinzauls, Switzerland)
Authors: Häusler Mauro , Gischig Valentin , Thöny Reto , Glueer Franziska , Donat Fäh
Published: November 2021

Seismic measurements on unstable rock slopes are a complementary tool to surface displacement surveys to characterize and monitor landslides. A key parameter is seismic amplification, which tends to scale with the degree of rock mass degradation. Amplification also provides a direct measure of how the wavefield is intensified during seismic loading, eventually leading to coseismic failure. Here we present the dynamic response of the fast-moving Brienz/Brinzauls rock slope instability in Switzerland (10 $ \times $ 106 to 25 $ \times $ 106 m3), which threatens settlements and infrastructure in the area. The rockslide shows strong seismic amplification at two resonant frequencies with factors of up to 11 and wavefield polarization influenced by the local fracture network orientation. We monitored the dynamic response over a period of 30 months using ambient vibrations and regional earthquake recordings. We observed a change in wavefield polarization of up to 50°, coinciding with a rotation of the relative surface displacement vector field measured by geodetic systems, highlighting the linkage between wavefield polarization and stress field (i.e. rock mass kinematics). For the analysis of secondary, relative surface displacements, we propose a singular value filtering of the displacement field to remove the principal component of landslide motion. In addition, we found increased seismic amplification values after periods of strong precipitation, providing empirical field evidence that the local precipitation history is a key parameter for assessing the hazard of earthquake-induced slope failure.
AIM against survey fraud
Authors: Habib Daniel , Jha Nishant
Published: November 2021

Objectives

Although there exists a variety of anonymous survey software, this study aimed to develop an improved system that incentivizes responses and proactively detects fraud attempts while maintaining anonymity.

Materials and Methods

The Anonymous Incentive Method (AIM) was designed to utilize a Secure Hash Algorithm, which deterministically assigned anonymous identifiers to respondents. An anonymous raffle system was established to randomly select participants for a reward. Since the system provided participants with their unique identifiers and passwords upon survey completion, participants were able to return to the survey website, input their passwords, and receive their rewards at a later date. As a case study, the validity of this novel approach was assessed in an ongoing study on vaping in high school friendship networks.

Results

AIM successfully assigned irreversible, deterministic identifiers to survey respondents. Additionally, the particular case study used to assess the efficacy of AIM verified the deterministic aspect of the identifiers.

Discussion

Potential limitations, such as scammers changing the entry used to create the identifier, are acknowledged and given practical mitigation protocols. Although AIM exhibits particular usefulness for network studies, it is compatible with a wide range of applications to help preempt survey fraud and expedite study approval.

Conclusion

The improvements introduced by AIM are 2-fold: (1) duplicate responses can be filtered out while maintaining anonymity and (2) the requirement for the participant to keep their identifier and password for some time before returning to the survey website to claim a reward ensures that rewards only go to actual respondents.
Impact of forage diversity on forage productivity, nutritive value, beef cattle performance, and enteric methane emissions
Authors: Thompson Logan R , Maciel Isabella C F , Rodrigues Patricia D R , Cassida Kim A , Rowntree Jason E
Published: November 2021

Greenhouse gas emissions from the beef industry are largely attributed to the grazing sector, specifically from beef cattle enteric methane emissions. Therefore, the study objective was to examine how forage diversity impacts forage productivity, nutritive value, animal performance, and enteric methane emissions. This study occurred over three consecutive grazing seasons (2018 to 2020) and compared two common Midwest grazing mixtures: 1) a simple, 50:50 alfalfa:orchardgrass mixture (SIMP) and 2) a botanically diverse, cool-season species mixture (COMP). Fifty-six steers and heifers were adapted to an Automated Head Chamber System (AHCS) each year (C-Lock Inc., Rapid City, SD) and stratified into treatment groups based on acclimation visitation. Each treatment consisted of four pastures, three 3.2-ha and one 1.6-ha, with eight and four animals each, respectively. Forage production was measured biweekly in pre- and postgrazed paddocks, and forage nutritive value was analyzed using near-infrared reflectance spectroscopy. Shrunk body weights were taken monthly to determine animal performance. Forage availability did not differ between treatments (P = 0.69) but tended lower in 2018 (P = 0.06; 2.40 t dry matter ha−1) than 2019 (2.92 t dry matter ha−1) and 2020 (P = 0.10; 2.81 t dry matter ha−1). Crude protein was significantly lower for COMP in 2018 compared with SIMP. Forage acid detergent fiber content was significantly lower for the COMP mixture (P = 0.02). The COMP treatment resulted higher dry matter digestibility (IVDMD48) in 2018 and 2019 compared with the SIMP treatment (P < 0.01). Animal performance did not differ between treatments (P > 0.50). There was a tendency for the COMP treatment to have lower enteric CH4 production on a g d−1 basis (P = 0.06), but no difference was observed on an emission intensity basis (g CH4 kg−1 gain; P = 0.56). These results would indicate that adoption of the complex forage mixture would not result in improved forage productivity, animal performance, or reduced emission intensity compared with the simple forage mixture.
Evaluation for Arts-Based Research Performance: Audience Perceptions ofRising from the Ashes
Authors: Viega Michael
Published: November 2021

The purpose of the study is to understand how audiences evaluated an arts-based research performance called Rising from the Ashes. Audience evaluation promises egalitarian and pluralistic perspectives that may assist artist-as-researchers with gaining new insight into out of performative arts-based research results. Rising from the Ashes was performed several times between 2015 and 2019. Evaluations were provided to six different audiences and consisted of rating-scale and open-ended questions based on general criteria for judging arts-based research: incisiveness, concision, generativity, social significance, evocation and illumination, and coherence. Descriptive rating scores and thematic analysis of open-ended questions aided in the artist-as-researcher’s understanding of how audiences responded to the performances. Descriptive scores showed that audiences strongly agreed that the performance was concise, incisive, and evocative and illuminating. The performance was less likely to support audiences’ understanding of the social issues addressed in the study, which implied decreased generativity and social significance. Open-ended questions enhanced and supported rating-scale responses as well as revealed specific elements of the performance that addressed its coherence. The results deepened the artists-as-researcher’s understanding of potential strengths and limitations of Rising from the Ashes based on the audience evaluations. Implications for arts-based research evaluation in music therapy, particularly related to music performance, are discussed.
Critical Appraisal of Paralyzed Veterans of America Guidelines in Spinal Cord Injury: An International Collaborative Study Using the Appraisal of Guidelines for Research and Evaluation II Instrument (AGREE II)
Authors: Liang Ning , Wu Sizhan , Roberts Simon , Makaram Navnit , Ngwayi James Reeves Mbori , Porter Daniel Edward
Published: November 2021

Introduction

Spinal cord injuries (SCI) in military personnel, veterans, and others require an evidence-based, multidisciplinary approach to their care. This appraisal used the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument to evaluate the methodological quality of clinical guidelines for the management of SCI published by the Paralyzed Veterans of America (PVA) organization.

Materials and Methods

We searched clinical guidelines on SCI published by PVA until December 2019. Four appraisers across three international centers independently evaluated the quality of eligible clinical guidelines using AGREE II. Mean AGREE II scores for each domain were calculated. In higher quality domains, scores for individual items were analyzed.

Results

A total of 12 guidelines published by PVA on SCI were assessed. Mean scores for all six domains were as follows: Scope and Purpose (78.8%), Stakeholder Involvement (63.7%), Rigor of Development (68.4%), Clarity of Presentation (80.1%), Applicability (53.0%), and Editorial Independence (28.5%). The mean score for the overall quality of all PVA guidelines was 71.9% (95% CI: 69.7–74.1). No guideline was assessed as “not recommended” by any appraiser. Overall quality was significantly associated with year of publication (rs = 0.754, P = 0.0046). Overall agreement among appraisers was excellent (intraclass correlation coefficients for each guideline ranged from 0.96 to 0.99).

Conclusions

PVA guidelines for the management of SCI demonstrated acceptable or good quality across most domains. We recommend the use of PVA guidelines for the assessment and treatment of SCI and related disorders. The quality of PVA guidelines for the management of SCI have improved over time.
Sex-Specific Physical Performance Adaptive Responses Are Elicited After 10 Weeks of Load Carriage Conditioning
Authors: Wills Jodie A , Saxby David J , Glassbrook Daniel J , Doyle Timothy L A
Published: November 2021

Introduction

The purpose of this study was to identify and characterize sex-specific physical and psychophysical performance adaptations in response to a novel 10-week training program.

Materials and Methods

Fifteen males and thirteen females completed a standardized load carriage task (5 km at 5.5 km.h−1, wearing a 23 kg torso-borne vest) before and after 10 weeks of resistance and load carriage training. Psychophysical responses (i.e., heart rate and ratings of perceived exertion) were measured throughout the load carriage task. Physical performance (i.e., countermovement and squat jumps, push-ups, sit-ups, and beep test) was measured at before, mid-way, and after the training program (weeks 0, 6, and 11, respectively).

Results

Training elicited significant improvements in squat jump maximal force, push-ups, and beep test performance (P < .05). Males outperformed females in all performance measures, with interactions (time, sex) for push-ups, sit-ups, and beep test performance. After training, aerobic capacity improved by 5.4% (42.9 mL· kg−1· min−1 to 45.2 mL· kg−1· min−1) in males but did not improve in females. Psychophysical responses decreased for both sexes (P < .05) during the load carriage task post-training.

Conclusion

While 10 weeks of standardized training elicited positive adaptations in both physical and psychophysical performance, sex-specific differences were still evident. To lessen these differences, sex-specific training should be considered to optimize load carriage performance.
The physics of non-ideal general relativistic magnetohydrodynamics
Authors: Andersson N , Hawke I , Celora T , Comer G L
Published: November 2021

We consider a framework for non-ideal magnetohydrodynamics in general relativity, paying particular attention to the physics involved. The discussion highlights the connection between the microphysics (associated with a given equation of state) and the global dynamics (from the point of view of numerical simulations), and includes a careful consideration of the assumptions that lead to ideal and resistive magnetohydrodynamics. We pay particular attention to the issue of local charge neutrality, which tends to be assumed but appears to be more involved than is generally appreciated. While we do not resolve all the involved issues, we highlight how some of the assumptions and simplifications may be tested by simulations. The final formulation prepares the ground for a new generation of models of relevant astrophysical scenarios.
GRB 191016A: a highly collimated gamma-ray burst jet with magnetized energy injection
Authors: Shrestha M , Steele I A , Kobayashi S , Jordana-Mitjans N , Smith R J , Jermak H , Arnold D , Mundell C G , Gomboc A , Guidorzi C
Published: November 2021

Long gamma-ray burst GRB 191016A was a bright and slow rising burst that was detected by the Swift satellite and followed up by ground based Liverpool Telescope (LT). LT follow up started 2411 s after the Swift Burst Alert Telescope (BAT) trigger using imager IO:O around the time of the late optical peak. From 3987–7687 s, we used the LT polarimeter RINGO3 to make polarimetric and photometric observations of the GRB simultaneously in the V, R, and I bands. The combined optical light curve shows an initial late peak followed by a decline until 6147 s, 6087 s, and 5247 s for I, R, and V filters respectively followed by a flattening phase. There is evidence of polarization at all phases including polarization ($P = 14.6 \pm 7.2 {{\ \rm per\ cent}}$) which is coincident with the start of the flattening phase. The combination of the light curve morphology and polarization measurement favours an energy injection scenario where slower magnetized ejecta from the central engine catches up with the decelerating blast wave. We calculate the minimum energy injection to be ΔE/E > 0.36. At a later time, combining the optical light curve from Burst Observer and Optical Transient Exploring System (BOOTES) (reported via GCN) and IO:O we see evidence of a jet break with jet opening angle 2°.
Patterns of piRNA Regulation in Drosophila Revealed through Transposable Element Clade Inference
Authors: Said Iskander , McGurk Michael P , Clark Andrew G , Barbash Daniel A
Published: November 2021

Transposable elements (TEs) are self-replicating “genetic parasites” ubiquitous to eukaryotic genomes. In addition to conflict between TEs and their host genomes, TEs of the same family are in competition with each other. They compete for the same genomic niches while experiencing the same regime of copy-number selection. This suggests that competition among TEs may favor the emergence of new variants that can outcompete their ancestral forms. To investigate the sequence evolution of TEs, we developed a method to infer clades: collections of TEs that share SNP variants and represent distinct TE family lineages. We applied this method to a panel of 85 Drosophila melanogaster genomes and found that the genetic variation of several TE families shows significant population structure that arises from the population-specific expansions of single clades. We used population genetic theory to classify these clades into younger versus older clades and found that younger clades are associated with a greater abundance of sense and antisense piRNAs per copy than older ones. Further, we find that the abundance of younger, but not older clades, is positively correlated with antisense piRNA production, suggesting a general pattern where hosts preferentially produce antisense piRNAs from recently active TE variants. Together these findings suggest a pattern whereby new TE variants arise by mutation and then increase in copy number, followed by the host producing antisense piRNAs that may be used to silence these emerging variants.
Treatment strategies for elderly-onset rheumatoid arthritis in the new era
Authors: Sugihara Takahiko
Published: November 2021

Elderly-onset rheumatoid arthritis (EORA) is characterized by acute onset and clinical features of high disease activity. Anti-cyclic citrullinated peptide antibody (ACPA) positivity or the presence of bone erosions predicts a radiological joint destruction of EORA, but ACPA-negative EORA with a polymyalgia rheumatica (PMR) phenotype may also present. Biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors were beneficial both in older and in younger patients in terms of risk–benefit balance. Implementation of a treat-to-target strategy could improve EORA outcomes, but older patients have more age-related comorbidities and interstitial lung disease than younger patients. Baseline comorbidities, more frequent methotrexate dose-dependent adverse events, serious infections, cardiovascular disease events, and malignancy all influence the choice of treatment and the treatment goals for older patients. Based on articles reviewed here, it is suggested that current treatment strategies for younger patients are also useful for ACPA-positive EORA and for ACPA-negative EORA with bone erosion. Differential diagnosis of ACPA-negative EORA without erosive arthritis and PMR with peripheral manifestations is challenging, and the treatment strategy of patients presenting with this overlap phenotype remained unclear. An appropriate treatment strategy for all patients with EORA still needs to be developed.
Bone microstructure changes due to once-/twice-weekly teriparatide administration: A report of five cases using high-resolution peripheral quantitative computed tomography
Authors: Tsukamoto Manabu , Okimoto Nobukazu , Mori Miyuki , Yoshioka Toru , Asano Kei , Ikejiri Yoshiaki , Uzawa Toyonobu , Yoshimura Takeshi , Suzuki Hiroaki , Yamanaka Yoshiaki , Kawasaki Makoto , Sakai Akinori
Published: November 2021

This study was conducted with the aim of presenting cases in which high-resolution peripheral quantitative computed tomography (HR-pQCT) was used to investigate changes in the bone microstructure due to once-weekly/twice-weekly administration of teriparatide (TPTD). Of osteoporosis patients who participated in a non-inferiority trial (TWICE study: once-weekly vs twice-weekly TPTD) with lumbar bone mineral density as the primary endpoint, five cases scanned by HR-pQCT before TPTD administration were analysed. Two cases were given once-weekly TPTD, three were given twice-weekly TPD, and HR-pQCT was repeated after 48 weeks. A sufficient anabolic effect of once-weekly/twice-weekly TPTD on the trabecular and cortical bone at the tibia was obtained. In addition, the average change in cortical porosity (Ct.Po) was only 0.3% in the tibia and 0.2% in the radius. These findings indicate that once-weekly and twice-weekly TPTD can be expected to improve the bone microstructure, and the increase in Ct.Po may be suppressed.
The Effect of Music Therapy on Perceived Parental Stress in Perinatal Care: An Exploratory Study
Authors: Bollard-Marcovitz Jenna , Tachdjian Raffi , Roa Esteban , Flores Luisa , Brown Scott , Gill Amira , Brown Chelsea , Wicks Eiress , Danelyan Hranush , Tan Mint , Pak Grace , Pincus Bethany , Petrey-Juarez Julia
Published: November 2021

The perinatal experience contains many stressors that can impact parental mental health. We examined the integration of music therapy (MT), an evidence-based health profession, and its stress reduction role in parents during their inpatient maternity and neonatal intensive care unit (NICU) experience. The Perceived Stress Scale (PSS) and Stress Numeric Rating Scale (SNRS-11) were used to measure stress reduction in 34 maternity and NICU parents (17 maternity patients and 17 NICU parents). Participants included parents on the antepartum unit (expecting parents on bedrest), laboring parents, pre-operation parents before cesarean delivery, parents of full-term healthy infants on the postpartum unit, and parents of premature infants on the NICU. Results were calculated based upon number of sessions rather than total number of participants and indicated that after one MT session, a 50% reduction in the SNRS-11 was measured in NICU and antepartum parents. The PSS score demonstrated a more modest stress reduction in the NICU parents but failed to achieve a statistically significant decrease in the maternity group. Findings were in line with existing literature in MT-associated stress reduction levels and may be integrated as part of an ongoing continuity of care during pregnancy, delivery, and NICU hospitalization. Earlier screening for stress may benefit parents during their perinatal hospital stay. Further research exploring the benefits of MT, as part of continuum of care and stress management for the inpatient perinatal parent population, may encourage the inclusion of MT services and improve quality of care.
EPCO-03. GLIOMA ONCOGENESIS IN THE CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY (CMMRD) SYNDROME
Authors: Guerrini-Rousseau Léa , Merlevede Jane , Denizeau Philippe , Andreiuolo Felipe , Varlet Pascale , Puget Stéphanie , Beccaria Kevin , Blauwblomme Thomas , Cabaret Odile , Hamzaoui Nadim , Bourdeaut Franck , Faure-Conter Cécile , Muleris Martine , Colas Chrystelle , de Beaumais Tiphaine Adam , Castel David , Rouleau Etienne , Brugières Laurence , Grill Jacques , Debily Marie-Anne
Published: November 2021

PURPOSE

Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context.

METHODS

A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas).

RESULTS

Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40NS SNV/Mb, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden.

CONCLUSION

CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.
EPCO-08. ATRX DEFICIENCY INDUCES DYSFUNCTIONAL HETEROCHROMATIN ARCHITECTURE IN GLIOMAS AND ESTABLISHES DISEASE-DEFINING TRANSCRIPTIONAL NETWORKS
Authors: Malgulwar Prit Benny , Danussi Carla , Singh Anand , Kannan Kasthuri , Rai Kunal , Huse Jason
Published: November 2021

Loss of ATRX (Alpha Thalassemia/Mental Retardation Syndrome X, a member of SWI/SNF family chromatin regulator is altered in diffuse gliomas and defines molecular subtypes with aggressive behavior. Mechanistically, ATRX regulates incorporation of histone H3.3 into chromatin sites across the genome, maintains alternative lengthening of telomeres and establishes genomic distribution of polycomb responsive genes. We have recently reported Atrx deficiency induces glioma oncogenic features via widespread alterations in chromatin accessibility using mouse Neural Progenitor Cells (mNPCs- Tp53 -/-,Atrx -/-). Surprisingly, Atrx was found to be associated with transcription start site and enhancer regions, suggesting their strong association with epigenome architecture. In this background, we have recently performed ChIP-seq for histone marks that define active transcription, enhancers, repressors and gene bodies and Cohesion molecules on Atrx intact and deficient mNPCs. Our integrated analysis reports depletion of H3K9me3 loci’s with enrichment of H3K27me3 marks that coincidently enriched with Atrx binding sites and Lamina-Associated Domains (LADs). GSEA confirmed that the genes corresponding to “newly formed LADs” in mNPC-to-astrocyte differentiation are significantly enriched for genes down-regulated in Atrx deficient mNPCs and belongs to Gene Ontology categories such as cell cycle, chromosome organization and DNA damage. Alternatively, genes corresponding to decreased LAD association are enriched for up-regulated genes in Atrx deficient mNPCs and for regulation of differentiation, adhesion and cell death. Additionally, whole-genome bisulphite sequencing further demonstrated loss of methylation marks at H3K9me3 sites in Atrx deficient mNPCs, suggesting perturbations of heterochromatin regions leading to activation of canonical signals that define glioma phenotype and disease-state. To summarize, our data establishes tangible links between Atrx deficiency and dysregulated chromatin and heterochromatin architecture in gliomas and suggests the role of Atrx in establishing global chromatin features and transcriptional networks. Further, our data unravel novel therapeutic molecules/pathways for engineering potential.
EPCO-11. SINGLE-NUCLEI TRANSCRIPTOMICS RELATES GLIOBLASTOMA INFILTRATION TO DISTINCT GLIAL PROGENITOR STATES
Authors: Mussa Zarmeen , Ramos Susana , Beaumont Kristin , Sebra Robert , Tsankov Alexander , Tsankova Nadejda
Published: November 2021

Our understanding of glioblastoma (GBM) intratumoral heterogeneity, particularly in the context of neurodevelopment, has thus far been primarily focused on the more surgically accessible tumor core niche. In contrast, the biology of GBM cells at the infiltrative edge, which evade surgical resection and drive tumor recurrence, remains poorly characterized. To this end, we microdissected and performed single-nuclei RNA sequencing (snRNA-seq) on approximately 62,000 nuclei taken from the tumor core and from the infiltrative edge of six GBM tumors with diverse genomic drivers, including IDH1, EGFR, PDGFRA, FGFR3, and NF1. Unbiased clustering reveals distinct neoplastic and non-neoplastic populations, further distinguished using copy number variation analysis. After projecting previously defined signatures taken from snRNA-seq analysis of human adult neocortex/subventricular zone and prenatal germinal matrix, we find that approximately 90% of tumor cells recapitulate a neurodevelopment-like molecular phenotype, reprising gene expression signatures of prenatal astrocytes and of a distinct glial intermediate progenitor cell population (g-IPC) that precedes both astrocyte and oligodendrocyte lineage differentiation. Examining the infiltrative edge of samples with the most confident microdissection (n=4), we see that while distinct populations of tumor cells in this niche express proneural and classical signatures, these cells are overall enriched for a g-IPC-like phenotype, relative to the tumor core, irrespective of the tumors’ genomic alterations. A subset of cells at the infiltrative edge, in particular, recapitulates the signature of an uncommitted g-IPC subtype, expressing both astroglial and oligodendroglial markers. Trajectory analyses also reveal distinct branches of core and edge tumor cells, which are predominantly astrocyte- and g-IPC-like, respectively. Differential gene expression analysis of GBM cells at the infiltrative edge vs. tumor core reveals a migration signature, dominated by EGFR, ERBB4, PCDH9, and PCDH15. Ultimately, this high resolution analysis of heterogeneity at the infiltrative edge allows us to uncover potentially targetable drivers of invasion in GBM.
EPCO-18. A MESENCHYMAL CELL POPULATION MEDIATES RESISTANCE TO AURORA KINASE INHIBITORS IN GLIOBLASTOMA
Authors: Suter Robert , Stathias Vasileios , Jermakowicz Anna , Pradhyumnan Hari , Affer Maurizio , Guglielmetti Florence , Ivan Michael , Komotar Ricardo , de la Fuente Macarena , Sarkaria Jann , Schürer Stephan , Ayad Nagi
Published: November 2021

Glioblastoma (GBM) remains the most common adult brain cancer, with a dismal average patient survival of less than two years. No new treatments have been approved for GBM since the introduction of the alkylating agent temozolomide in 2005. Even then, temozolomide treatment only increases the average survival of GBM patients by a few months. Thus, novel therapeutic options are direly needed. The aurora kinases A and B are targetable and overexpressed in GBM, and their expression is highly correlated with patient survival outcomes. Our lab has found that small molecule aurora kinase inhibition reduces GBM tumor growth in vitro and in vivo, however, eventually tumors still grow. Computational analysis integrating compound transcriptional response signatures from the LINCS L1000 dataset with the single-cell RNA-sequencing data of patient GBM tumors resected at the University of Miami predicts that aurora inhibition targets a subset of cells present within any GBM tumor. Results of in vivo single-cell perturbation experiments with the aurora kinase inhibitor alisertib coincide with our predictions and reveal a cellular transcriptional phenotype resistant to aurora kinase inhibition, characterized by a mesenchymal expression program. We find that small molecules that are predicted to target different cell populations from alisertib, including this resistant mesenchymal population, synergize with alisertib to kill GBM cells. As a whole, we have identified the cellular population resistant to aurora kinase inhibition and have developed an analytical framework that identifies synergistic small molecule combinations by identifying compounds that target transcriptionally distinct cellular populations within GBM tumors.
EPCO-21. CORE REGULATORY CIRCUIT TRANSCRIPTION FACTORS DRIVE EXPRESSION FROM HIGH LEVEL AMPLICONS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Deng Davy , Dubois Frank , Crane Alexander , Harutyunyan Ashot , Beroukhim Rameen , Bandopadhayay Pratiti
Published: November 2021

BACKGROUND

Pediatric High-Grade Gliomas (pHGGs) show recurrent high-level amplifications around the oncogenes MET, MYCN and EGFR. However what drives expression of the oncogenes from these amplicons remains unclear. We aim to discover enhancers on these amplicons that are responsible for oncogene expressions and the core regulatory transcription factors (TFs) they bind.

METHOD

Using RNA-seq from 12 pHGG cell lines, we identified groups of high and low-expressing pHGG lines for MET, MYCN and EGFR. We then compared the H3K27Ac ChIP-seq between the two groups using diffbind. This allowed us to identify statistically significant peaks that are differentially activated in the oncogene-high v.s. oncogene-low expressing groups. Additionally, we overlapped the positions of these candidate oncogene enhancers with the regions that are recurrently incorporated into high-level amplicons based on published whole genome sequencing data. Using a previously defined set of core regulatory TFs we determined which TF binds the amplified oncogene enhancers and could be driving oncogenic expressions of MET, MYCN and EGFR in pHGGs.

RESULTS

We identify 3 cell lines for both the high- and low-expressing groups for each oncogene. Cell lines with high expression of the oncogene showed distinct enhancers with significant enrichment in H3K27Ac compared to the cell lines with low expression for each oncogene. Of all enhancers with enrichment high oncogene expression groups those with binding sites for known pHGG core regulatory circuit TF were preferentially incorporated into the high-level amplicons of the oncogene. We also identified core TFs that bind enhancers for MYCN, EGFR and MET as well as core TFs that are unique to a single oncogene.

CONCLUSION

We identified candidate core transcription factor that drives expression of multiple oncogenes in pHGG. These could serve as a potential novel therapeutic target for pHGGs with addiction to MYCN or RTK signaling.
EPCO-24. MACHINE LEARNING ALGORITHMS UTILIZING TRANSCRIPTIONAL SIGNATURES PREDICT SURVIVAL OUTCOMES IN GLIOMA
Authors: Zhou zhaoming , Lai Mingyao , Li Juan , Hu Qingjun , Shan Changguo , Zhou Cheng , Cai Linbo
Published: November 2021

BACKGROUND

Glioblastomas (GBM) is a common primary malignant brain tumor. This study performed RNA-seq with 227 glioma samples with the aim to identify the immune-related gene markers for glioma prognosis prediction.

METHODS

Differentially expressed genes (DEGs) were identified between glioma and healthy samples in the TCGA dataset. Differentially expressed immune-related genes (DE-IRGs) were determined by intersecting DEGs to the immune-related genes in the ImmProt database. Independent survival associated DE-IRGs were selected by univariate and multivariate cox-regression analysis in TCGA dataset and validated in the CGGA databases and our RNA-seq data. Further enrichment analysis demonstrated the hub-genes among those prognosis-associated DE-IRGs. After the expression of hub-genes were confirmed by immunohistochemistry (IHC), the hub-genes protein levels on slides were further utilized to establishing the prognosis prediction models by several machine learning methods, including least absolute shrinkage and selection operator (LASSO), generalized linear model (GLM) and linear discriminant analysis (LDA).

RESULTS

There were 404 DE-IRGs determined in glioma in comparison with healthy tissue samples in TCGA. After evaluated by univariate and multivariate cox-regression, 55 DE-IRGs remaining significant. Thirty-four DE-IRGs were verified to be survival associated in both CGGA and our sequencing cohort, among which, 4 hub-genes (LIF and MDK, LAMB1, and CALU) were determined by enrichment analysis. All of the 4 hub-genes were expression confirmed on the protein level by IHC staining. Based on the staining results, a survival risk score (SRS) was established by machine learning methods (GLM, LDA, and LASSO). Based on SRS, glioma patients were divided into high- and low-risk groups, the overall survivals were significantly different between those two groups, regardless of the tumor grades or pathology types.

CONCLUSIONS

This study identified a potential immune prognostic signature (LIF and MDK, LAMB1, and CALU) of glioma that would be helpful for OS predicting and for potential therapeutics development.