bluuebunny/crossref_metadata_2025_split huggingface dataset:
TBIO-10. NGS molecular profile of paediatric brain tumours: results from 92 consecutive patients treated at Centro Hospitalar Universitário de São João
Authors: Lima Jorge , Pinheiro Jorge , Nunes Susana , Fernandes Ana Paula , Soares Paula , Machado Jose Carlos , Pereira Josue , da Costa Maria Joao Gil 
Published: June 2022

Abstract
AIM: Our aim was to progress in bringing molecular medicine to routine clinical practice in the setting of paediatric neuro-oncology. We have implemented a protocol between Ipatimup and Centro Hospitalar Universitário de São João for the rapid and efficient delivery of the molecular portrait of paediatric brain tumours. MATERIAL AND METHODS: We have enrolled 92 patients with the following inclusion criteria: Age 0-18 years; newly diagnosed brain tumour; previously diagnosed brain tumour, whenever it presented as rare, aggressive or refractory disease; availability of tumour material; signed informed consent. Tumour samples were centrally reviewed by expert pathologists and profiled using the Oncomine Childhood Cancer Research Assay. RESULTS: In the 92 tumours that were molecularly profiled, BRAF was the most frequently altered gene, especially in pilocytic astrocytomas, being also detected in other LGG and HGG. Other commonly mutated genes were PIK3CA and FGFR, the former in HGG and the latter in LGG. MYB and RAF1 rearrangements were also found in low grade glial/glioneuronal tumours, while HGG showed a more complex profile, with many cases harbouring multiple alterations in EGFR, PDGFRA, ATRX, H3F3A, HIST1H3B, TP53, among others. A 16-year old patient with CMMR (homozygous mutation in PMS2) developed a glioblastoma that carried nearly 5x the average number of mutations. Among the 8 medulloblastomas, 2 showed mutations in the SHH pathway (1 in PTCH1 and one in SUFU) and 2 in the WNT pathway (1 in CTNNB1 and one in APC). In the remaining cases, one ependymoma presented MYCN amplification, while no alterations were detected in 3 patients. CONCLUSIONS: This study enabled the detailed molecular study of 92 paediatric brain patients, allowing a more robust tumour classification and the identification of actionable alterations. A subset of the patients are already undergoing targeted therapy, mainly using BRAF or MEK inhibitors with generally good improvement.
THER-01. Precision brain tumor therapy by AAV-mediated oncogene editing
Authors: von Soosten Laura , Haar Janina , Frehtman Veronika , Holderbach Stefan , Belzen Julius Upmeier zu , Jendrusch Michael , Okonechnikov Konstantin , Pfister Stefan M , Grimm Dirk , Leuchs Barbara , Jones David , Kutscher Lena M , Zuckermann Marc 
Published: June 2022

Abstract
Pediatric high-grade glioma is a heterogeneous group of highly malignant tumors of the central nervous system, with a median overall survival of less than two years after diagnosis, demanding novel treatment options. One innovative approach is gene therapy, which has so far been hampered for cancer treatment owing to the lack of a system targeting tumor cells specifically. To overcome this limitation, we established a novel strategy for gene therapy, combining tumor cell-specific adeno-associated virus (AAV) variants with oncogene-specific CRISPR-Cas nucleases. We screened 177 different Cas9/gRNA combinations targeting the genes encoding H3K27M or BRAFV600E, and identified highly specific nucleases that edited the oncogenic allele but left the respective WT loci intact, which we validated by PCR amplicon sequencing. Next, we intravenously injected an AAV library engineered to encode its own capsid DNA into mice harboring patient-derived xenograft tumors driven by H3K27M or BRAFV600E. After 21 days, we resected neoplasms and separated mCherry-labeled tumor cells from normal surrounding cells by fluorescence-activated cell sorting. Using the DNA from tumor cells as template, we generated a second AAV library, which was utilized in another round of in vivo selection. At the end of each screen, DNA from tumor cells, surrounding cells, and control tissues (liver and spleen) was analyzed by amplicon sequencing. Strikingly, we identified multiple AAV variants that were highly and recurrently enriched in the analyzed tumor tissues. We are currently validating these variants by intravenously injecting selected, GFP-encoding AAVs to tumor-bearing mice and by subsequently analyzing their distribution throughout the aforementioned tissues. We will combine oncogene-specific nucleases with these validated AAV variants and analyze their anti-tumoral efficacy in a preclinical setting. Furthermore, we plan to adapt this approach to allografted mice, evaluating its feasibility and efficacy in syngeneic models.
THER-02. Pediatric brain tumor cultures reveal differential susceptibility to four oncolytic viruses
Authors: Vazaios Konstantinos , Stavrakaki Eftychia , Vogelezang Lisette , van den Hoogen Bernadette , Hoeben Rob C , Chiocca Antonio E , Goins William F , Hulleman Esther , Straetemans Trudy , Calkoen Friso G J , van der Lugt Jasper , Lamfers Martine L M 
Published: June 2022

Abstract
INTRODUCTION: New therapeutic modalities such as Oncolytic viruses (OVs) are considered possible treatment options for pediatric brain tumors (PBTs) either as monotherapy or as adjuvants to immunotherapies. OVs specifically lyse tumor cells and can induce anti-tumor immune responses. Here, we evaluate the oncolytic potency of different clinically relevant OVs against various PBT entities. METHODS: The effect of four different OVs, Reovirus (R124), Newcastle Disease virus (NDV), Adenovirus (DNX-2401) and Herpes simplex virus-1 (rQNestin 34.5v.1), was assessed on patient-derived cell cultures belonging to four different PBT entities. Cell viability 5 days after virus treatment of diffuse midline gliomas (DMG n=6), atypical teratoid rhabdoid tumors (n=4), glioblastomas (n=1) and ependymomas (n=2) was measured using Cell Titer Glo assay to demonstrate the cytotoxic potency of each virus. RESULTS: Our screenings revealed that DNX-2401, rQNestin and NDV could infect and kill the majority of cell cultures (12 out of 13, 11 out of 13 and 11 out of 13, respectively). rQNestin34.5v.1 required lower amounts of infectious particles per cell (MedianEC50: 0.65±2.7) compared to NDV (3.5±1.7) and DNX-2401 (7.5±14.5), with DMGs being more sensitive for rQNestin34.5v.1 than non-DMGs. R124 was effective in only 6 out of 13 cultures, with DMGs being more resistant with EC50 &gt; 100 (5 out of 6) compared to non-DMG cell lines with EC50 &lt; 8 (5 out of 7). CONCLUSION: All cell lines revealed differential susceptibility to the 4 different OVs with at least one effective OV per cell line. Further analysis of transcriptome and methylome data might uncover genes and pathways which correlate with specific OV susceptibility and provide biomarkers for response prediction. Further investigation is ongoing to interpret how differential susceptibility affects OV-induced anti-tumor immunity.
INSP-08. Cerebellar mutism syndrome: incidence, symptoms, risk factors, prognosis. Results and future perspectives from the Nordic-European study of the cerebellar mutism syndrome
Authors: Sehested Astrid , Grønbæk Jonathan , Laustsen Aske , Juhler Marianne 
Published: June 2022

Abstract
Cerebellar mutism syndrome (CMS) can be a devastating consequence of paediatric fossa posterior tumour surgery. This prospective observational multi-centre study was designed to investigate incidence, symptoms, risk factors and prognosis of CMS. It has been running since 2014 and is currently involving 28 centres in 10 countries. So far 600 patients have been included as of 1.2.22, and with the aim of including a total of 1000 the study is still ongoing. Analysis of the first 500 patients has described the incidence, course and associated risk factors of postoperative speech impairment (POSI). Midline location, histological diagnosis of medulloblastoma and ATRT and younger age are associated with increased risk of POSI in our cohort. Route of surgical access specifically comparing telovelar to transvermian approach does not seem to influence the risk of POSI. Second surgery is associated with a lower risk of POSI than primary surgery, whereas we found no difference in risk of cranial nerve dysfunction. Left-handedness is not associated with an increased risk of POSI. Further and ongoing analysis include language analyses of recorded patient speech samples, detailed imaging analysis and description of associations between POSI and other neurological symptoms. The results aim to facilitate pre-operative risk assessment and postoperative robust scoring methods for use in clinical trials. Presented on behalf of the CMS study group, clinicaltrials.gov: Nordic study of the cerebellar mutism syndrome.
LGG-28. Rapid symptomatic improvement for a patient treated with BRAF inhibition for BRAFV600E mutated ganglioglioma
Authors: Cantor Evan , Cochrane Anne , Morris Stephanie , Meyer Ashley , Ogle Andrea , Shatara Margaret , Cluster Andrew , Deng Mai , Abdelbaki Mohamed S , Brossier Nicole M 
Published: June 2022

Abstract
BACKGROUND: Biologically targeted agents such as the BRAF inhibitor dabrafenib are now used to treat progressive low-grade glioma (LGG), but the effect of these agents on the neurologic symptoms that accompany LGGs is poorly understood. CASE: A 21-year-old male was diagnosed with medullary ganglioglioma (GG) after presenting with persistent vertigo and positional headaches. Immunohistochemistry was consistent with BRAF V600E mutation and dabrafenib was started. The patient had resolution of his neurologic symptoms within 3 weeks of treatment initiation; surveillance MRI several months later demonstrated interval decrease in tumor size. The patient remained on therapy for 2 years. Several days after planned drug discontinuation the patient had re-emergence of persistent vertigo that impaired his ability to work. Repeat imaging two months later demonstrated an increase in tumor size and solid enhancement along tumor margins. He was restarted on dabrafenib. Within one week, he again had complete resolution of his vertigo. DISCUSSION: Gangliogliomas are comprised of mixed neuronal and glial components and associated with epilepsy, headache and other localizing neurologic symptoms. In this report, we describe clinical and radiographic response from single-therapy dabrafenib in a patient with BRAF V600E+ GG, along with a very rapid resolution of neurologic symptoms upon initiation of the drug and recrudescence shortly following cessation of therapy. The symptoms subsided within a week of restarting dabrafenib, suggesting a separate, more rapid mechanism of symptom reversal than decline in tumor size. BRAF mutations have been identified in both the neuronal and glial components of ganglioglioma, suggesting that dabrafenib may provide symptomatic relief via inhibition of abberant neuronal processes. CONCLUSION: BRAF inhibitors can rapidly improve neurological symptoms via a rapid, not yet fully elucidated mechanism. Kinetics of this response suggest it is independent of effects on tumor volume and the degree of compression to tissue surrounding the tumor.
The psychosocial work environment among educators during the COVID-19 pandemic
Authors: Smith P , Oudyk J , Cedillo L , Inouye K , Potter G , Mustard C 
Published: June 2022

Abstract

Background
The education sector has been heavily impacted by COVID-19. While the impact on school-aged children has received much attention, less attention has focused on the experiences of educators.

Aims
To compare various dimensions of the psychosocial work environment and health outcomes between educators engaged in online learning to those engaged in in-person learning in the Canadian province of Ontario.

Methods
Responses from 5438 educators engaged in either online or in-person learning were collected between 23 November and 21 December 2020; three months after the start of the 2020/21 academic year in September 2020. Psychosocial outcomes included quantitative demands, work pace, predictability, role conflicts, and social support from supervisors and co-workers; assessed using an abbreviated version of the Copenhagen Psychosocial Questionnaire. Secondary outcomes included burnout and sleep troubles. Ordinary Least-Squares regression models examined adjusted mean differences in the levels of outcomes for respondents in in-person versus online learning, after adjustment for a variety of covariates.

Results
Compared to respondents engaged in in-person learning, respondents engaged in online learning reported less predictability, higher role conflicts and less support from supervisors and co-workers. Statistically significant differences in work pace, burnout and sleep troubles were also observed across learning modes, although these differences did not exceed previously suggested thresholds for minimum important differences.

Conclusions
Important differences in the psychosocial work environment were observed between respondents engaged in in-person learning versus online learning. Addressing these differences is required, given the potential continued importance of online learning within the context of the COVID-19 pandemic and beyond.
Association of Polymorphisms at the SIX1/SIX6 Locus With Normal Tension Glaucoma in a Korean Population
Authors: Shin Hye-Young , Lee Young Chun , Lee Mee Yon 
Published: June 2022

Précis:
We demonstrated that SIX1/SIX6 locus polymorphism (rs10483727 and rs33912345) was significantly associated with a genetic susceptibility to NTG in a Korean population. More studies are needed to investigate whether the SIX1/SIX6 locus is associated with NTG among various ethnic populations.

Purpose:
Several previous studies have reported that the relevance of the SIX1/SIX6 locus to open angle glaucoma (OAG) in various ethnic populations. However, definitions of OAG patients were different among those studies. The relevance of the SIX1/SIX6 locus to normal tension glaucoma (NTG) in a Korean population remains uncertain. Therefore, the purpose of this study was to investigate the relationship of the SIX1/SIX6 locus with NTG in a Korean cohort.

Method:
Patients with NTG and ethnically matched healthy controls were recruited from eye clinics in Korea (210 cases and 117 controls). Four polymorphisms (rs33912345, rs12436579, rs2179970, and rs10483727) of the SIX1/SIX6 locus were genotyped for 327 subjects using a TaqMan single nucleotide polymorphism genotyping assay.

Results:
The rs33912345 polymorphism was significantly correlated with NTG in the recessive model [odds ratio (OR): 0.265; 95% confidence interval (CI): 0.078–0.898, P=0.033], but not in the allelic and dominant models (both P>0.05). The SNP rs10483727 was significantly associated with NTG in the allelic model (OR: 0.674; 95% CI: 0.464–0.979, P=0.038) and the recessive model (OR: 0.187; 95% CI: 0.058–0.602, P=0.005). Genetic association analysis of SNP rs12436579 and rs2179970 revealed no significant difference in genotype distribution between NTG cases and controls in the allelic, dominant, or recessive models (all P>0.05).

Conclusion:
The current study found that SIX1-SIX6 locus rs10483727 and rs33912345 polymorphisms were significantly associated with NTG risk in the Korean population.
Noninvasive prenatal screening using cell-free DNA
Authors: Mladenka Christine 
Published: June 2022

ABSTRACT
Noninvasive prenatal screening using cell-free DNA involves analysis of a sample of maternal blood for DNA fragments of fetal chromosomes from the fetal–placental unit to detect common chromosome abnormalities, trisomy 21, trisomy 13, trisomy 18, and sex chromosomes as early as 10 weeks' gestation when the fetal fraction is usually more than 4%. It is the most sensitive and specific prenatal screening option for these conditions. Because it is a screening test, false-positive and false-negative results can occur. Positive screen results necessitate further evaluation for diagnosis to confirm a medical condition, before critical decisions regarding pregnancy are made. Professional organizations provide clinical recommendations to providers regarding prescreen and postscreen counseling and management of results.
The Selective Estrogen Receptor Modulator, Raloxifene, Is Protective Against Renal Ischemia–reperfusion Injury
Authors: Hernandez Paul , O’Brien Ciaran , Concors Seth J. , Wang Zhonglin , Ge Guanghui , Hancock Wayne W. , Levine Matthew H. 
Published: June 2022

Background.There is increasing evidence that estrogen is responsible for improved outcomes in female kidney transplant recipients. Although the exact mechanism is not yet known, estrogen appears to exert its protective effects by ameliorating ischemia–reperfusion injury (IRI). In this study, we have examined whether the beneficial effects of exogenous estrogen in renal IRI are replicated by therapy with any one of several selective estrogen receptor modulators.Methods.C57BL/6 adult mice underwent standardized warm renal ischemia for 28 min after being injected with the selective estrogen receptor modulators, raloxifene, lasofoxifene, tamoxifen, bazedoxifene, or control vehicle (dimethyl sulfoxide), at 16 and 1 h before IRI. Plasma concentrations of blood urea nitrogen and creatinine were assessed 24, 48, 72, and 96 h post-IRI. Tissue was collected 30 d postischemia for fibrosis analysis using Sirius Red staining.Results.Raloxifene treatment in female mice resulted in significantly lower blood urea nitrogen and creatinine after IRI and significantly lower fibrosis 30 d following IRI.Conclusions.Raloxifene is protective against both acute kidney injury and fibrosis resulting from renal IRI in a mouse model.
Pleural macrophages translocate to the lung during infection to promote improved influenza outcomes
Authors: Stumpff James P , Kim Sang Yong , Forero Adriana , Nishida Andrew , Steuerman Yael , Gat-Viks Irit , Nair Meera G , Morrison Juliet 
Published: June 2022

ABSTRACTSeasonal influenza results in 3 to 5 million cases of severe disease and 250,000 to 500,000 deaths annually. Macrophages have been implicated in both the resolution and progression of the disease, but the drivers of these outcomes are poorly understood. We probed mouse lung transcriptomic datasets using the Digital Cell Quantifier algorithm to predict immune cell subsets that correlated with mild or severe influenza A virus (IAV) infection outcomes. We identified a novel lung macrophage population that transcriptionally resembled small serosal cavity macrophages and correlated with mild disease. Until now, the study of serosal macrophage translocation in the context of infections has been neglected. Here, we show that pleural macrophages (PMs) migrate from the pleural cavity to the lung after infection with pH1N1 A/California/04/2009 IAV. We found that the depletion of PMs increased morbidity and pulmonary inflammation. There were increased proinflammatory cytokines in the pleural cavity and an influx of neutrophils within the lung. Our results show PMs are recruited to the lung during IAV infection and contribute to recovery from influenza. This study expands our knowledge of PM plasticity and provides a new source of lung macrophages independent of monocyte recruitment and local proliferation.GRAPHICAL ABSTRACT
Intraindividual variability in cognitive function in older people in the English Longitudinal Study of Ageing: modelling risk factors using a mixed-effects beta-binomial model
Authors: Parker Richard M.A. , Tilling Kate , Terrera Graciela Muniz , Barrett Jessica K. 
Published: June 2022

ABSTRACTCognitive functioning in older age has a huge impact on quality of life and physical and mental health. Whilst most research in cognition in older age has focussed on mean levels, there is some evidence that individuals with cognitive functioning that varies a lot around this may have different risk factors and outcomes to those with less variable functioning. Existing approaches to investigate such intraindividual variability (IIV) typically involve deriving a summary statistic for each person from residual error around a fitted mean. However, such methods ignore sampling variability, prohibit the exploration of associations with time-varying factors, and are biased by floor and ceiling effects. To address this, we fitted a mixed-effects location scale beta-binomial model to estimate average per-trial probability and IIV in a word recall test with the English Longitudinal Study of Aging (ELSA). After adjusting for mean performance, in an analysis of 9,873 individuals observed across 7 (mean: 3.4) waves we found IIV to be greater: at older ages; with lower education; in females; with more difficulties with activities of daily living; in later cohorts; and when interviewers recorded issues which may have affected the tests. Our study identifies groups with more varying cognitive performance, which has implications for their daily functioning and care. Further work is needed to identify the impact of this for future health outcomes.
A Spatial Whole-Cell Model for Hepatitis B Viral Infection and Drug Interactions
Authors: Ghaemi Zhaleh , Nafiu Oluwadara , Tajkhorshid Emad , Gruebele Martin , Hu Jianming 
Published: June 2022

AbstractDespite a vaccine, hepatitis B virus (HBV) remains a world-wide source of infections and deaths, and tackling the infection requires a multimodal approach against the virus. We develop a whole-cell computational platform combining spatial and kinetic models for the infection cycle of a virus host cell (hepatocyte) by HBV. We simulate a near complete viral infection cycle with this whole-cell platform stochastically for 10 minutes of biological time, to predict viral infection, map out virus-host as well as virus-drug interactions. We find that with an established infection, decreasing the copy number of the viral envelope proteins can shift the dominant infection pathways from secreting the capsids from the cell to re-importing the capsids back to the nucleus, resulting in higher viral DNA referred to as covalently closed circular DNA (cccDNA) copy number. This scenario can mimic the consequence of drugs designed to manipulate viral gene expression (such as siRNAs). Viral capsid mutants lead to their destabilization such that they disassemble at nuclear pore complexes, result in an increase in cccDNA copy number. However, excessive destabilization leading to cytoplasmic disassembly does not increase the cccDNA copy number. Finally, our simulations can predict the best drug dosage and timing of its administration to reduce the cccDNA copy number which is the hallmark of infection. Our adaptable computational platform can be utilized to study other viruses, more complex host-virus interactions, and identify the most central viral pathways that can be targeted by drugs or a combination of them.