bluuebunny/crossref_metadata_2025_split huggingface dataset:
(128) ABORTION AND THE MYTH OF THE HARM-FREE PREGNANCY
Authors: Creatura C 
Published: June 2024

Abstract

Introduction
A comprehensive description of the impact of pregnancy and childbirth on the human body has never been published. All pregnancies pose an unquantifiable threat to one's health and childbirth has permanent, irreversible effects that are cumulative and often late-manifesting. This reality refutes the anti-abortion, pro-natalist claim that there is any such thing as an elective abortion.

Objective
Abortion access supports the fundamental human right to bodily autonomy and sexual self-determination, hence every abortion is performed in the service of the pregnant person's health. The neglect of these principles has allowed politically-motivated legislatures to introduce imprecise health exception language that does not acknowledge the actual impact of pregnancy and childbirth. Affirming that abortion is life-saving healthcare refutes the health exception fallacy.

Methods
Maternal mortality and morbidity statistics are flawed and incomplete. None of the standard measures adequately captures the effects of pregnancy, whether voluntary or forced, upon the health of the parturient or her community. This report elucidates the unpredictable and often unattributed morbidity associated with pregnancy and childbirth, and argues for a human rights approach to abortion policy.

Results
Abortion bans have downstream effects that negatively impact the care of all pregnancy-capable people and their communities. Allowing non-experts to legislate against evidence-based care creates confusion and leads to mistrust of the healthcare system. Gendered disinformation, gag rules, and criminalization of pregnancy all result in stigma and harm.

Conclusions
The cultural reluctance to seriously study the effects of pregnancy on health is linked to gender inequality and is correlated with restrictive abortion laws that violate ethical principles of beneficence and patient autonomy. Involuntary pregnancy is a major and preventable cause of human suffering that can be relieved with permissive abortion policies based on ethical and scientific standards of care.

Disclosure
No.
Phytic acid-based nanomedicine against mTOR represses lipogenesis and immune response for metabolic dysfunction-associated steatohepatitis therapy
Authors: Xu Fenghua , Zhao Shoujie , Zhu Yejing , Zhu Jun , Kong Lingyang , Li Huichen , Ma Shouzheng , Wang Bo , Qu Yongquan , Tian Zhimin , Zhao Junlong , Liu Lei 
Published: June 2024

Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common chronic liver diseases and is mainly caused by metabolic disorders and systemic inflammatory responses. Recent studies have indicated that the activation of the mammalian (or mechanistic) target of rapamycin (mTOR) signaling participates in MASH progression by facilitating lipogenesis and regulating the immune microenvironment. Although several molecular medicines have been demonstrated to inhibit the phosphorylation or activation of mTOR, their poor specificity and side effects limit their clinical application in MASH treatment. Phytic acid (PA), as an endogenous and natural antioxidant in the liver, presents significant anti-inflammatory and lipid metabolism-inhibiting functions to alleviate MASH. In this study, considering the unique phosphate-rich structure of PA, we developed a cerium-PA (CePA) nanocomplex by combining PA with cerium ions possessing phosphodiesterase activity. CePA intervened in the S2448 phosphorylation of mTOR through the occupation effect of phosphate groups, thereby inhibiting the inflammatory response and mTOR-sterol regulatory element-binding protein 1 (SREBP1) regulation axis. The in vivo experiments suggested that CePA alleviated MASH progression and fat accumulation in high-fat diet-fed mice. Mechanistic studies validated that CePA exerts a liver-targeted mTOR repressive function, making it a promising candidate for MASH and other mTOR-related disease treatments.
A Relational Theory of Dignity and Human Rights: An Alternative to Autonomy
Authors: Metz Thaddeus 
Published: June 2024

Abstract
In this article I draw on resources from the Global South, and particularly the African philosophical tradition, to construct a theory of human rights grounded on dignity that presents a challenge to globally dominant, autonomy-based approaches. Whereas the latter conceive of human rights violations as degradations of our rational nature, the former does so in terms of degradations of our capacity to be party to harmonious or friendly relationships. Although I have in the past presented the basics of this relational approach, in this article I present new argumentation in support of it. I defend it from criticism and also go on the offensive by arguing that understanding the human rights violations of torture and rape to be (roughly) behavior that treats innocent parties in an extremely discordant or unfriendly way is, if not more plausible than standard Kantian understandings, at least a promising alternative to them.
A Plasmodium apicoplast-targeted unique exonuclease/FEN exhibits interspecies functional differences attributable to an insertion that alters DNA-binding
Authors: Chatterjee Tribeni , Tiwari Anupama , Gupta Ritika , Shukla Himadri , Varshney Aastha , Mishra Satish , Habib Saman 
Published: June 2024

Abstract
The human malaria parasite Plasmodium falciparum genome is among the most A + T rich, with low complexity regions (LCRs) inserted in coding sequences including those for proteins targeted to its essential relict plastid (apicoplast). Replication of the apicoplast genome (plDNA), mediated by the atypical multifunctional DNA polymerase PfPrex, would require additional enzymatic functions for lagging strand processing. We identified an apicoplast-targeted, [4Fe–4S]-containing, FEN/Exo (PfExo) with a long LCR insertion and detected its interaction with PfPrex. Distinct from other known exonucleases across organisms, PfExo recognized a wide substrate range; it hydrolyzed 5′-flaps, processed dsDNA as a 5′-3′ exonuclease, and was a bipolar nuclease on ssDNA and RNA–DNA hybrids. Comparison with the rodent P. berghei ortholog PbExo, which lacked the insertion and [4Fe–4S], revealed interspecies functional differences. The insertion-deleted PfExoΔins behaved like PbExo with a limited substrate repertoire because of compromised DNA binding. Introduction of the PfExo insertion into PbExo led to gain of activities that the latter initially lacked. Knockout of PbExo indicated essentiality of the enzyme for survival. Our results demonstrate the presence of a novel apicoplast exonuclease with a functional LCR that diversifies substrate recognition, and identify it as the candidate flap-endonuclease and RNaseH required for plDNA replication and maintenance.
ATRT-01. MODELLING ATYPICAL TERATOID/ RHABDOID TUMOUR AND HEALTHY BRAIN CROSSTALK
Authors: Porter Harry Dean , McCrorie Phoebe , Diksin Mohammed , Moloney Cara , Grundy Richard , Rahman Ruman 
Published: June 2024

Abstract

BACKGROUND
Atypical Teratoid/Rhabdoid Tumours (ATRT) are aggressive paediatric brain tumours which mostly occur in the first three years of life and which rapidly recur after surgical resection. There has been debate over the use of cytotoxic consolidation therapy due to the severity of off target effects associated with chemo/radiotherapy use in young patients. Astrocytes have previously been shown to support progression and therapy resistance of other brain tumours; however, their role in ATRT pathophysiology is yet to be elucidated.

METHODS
To better understand how adjacent “healthy” brain tissue may be complicit in ATRT recurrence, we have developed a 3D in vitro model in which ATRT cells are co-cultured with astrocytes within a bespoke decellularized human cerebellum extracellular matrix (ECM) hydrogel.

RESULTS
Immunofluorescence confirmed that human cerebellar ECM hydrogels retain human brain ECM components (hyaluronic acid, laminin, and fibronectin). ATRT-astrocyte co-culture spheroids were formed within the ECM hydrogel and observed to display a distinctive morphology relative to monoculture controls, with no difference in overall viability. Co-cultured tumour cells were successfully harvested from the model and isolated from astrocyte populations using fluorescence activated cell sorting. In both 2D and 3D culture, we have shown that astrocytes labelled with CM-DiI transfer this cell tracker dye to ATRT-MYC (BT12, BT16) and ATRT-TYR (BT37) cells, potentially indicating intercellular trafficking. Furthermore, in 2D culture ATRT-MYC (BT12 and BT16) cells form actin rich cell-cell processes with astrocytes when co-cultured in vitro.

CONCLUSIONS
This work represents a comprehensively characterised model of ATRT interaction with the healthy brain. Future work will analyse changes in ATRT cell transcriptomes when astrocytes are present in the model. By understanding how the presence of astrocytes in the tumour microenvironment may promote tumour survival and progression, we aim to use this data to identify candidate therapeutics to inhibit crosstalk and improve patient outcomes.
ATRT-03. PRIMARY DIFFUSE LEPTOMENINGEAL ATYPICAL TERATOID/RHABDOID TUMOR (ATRT) OF CHILDHOOD DEMONSTRATING UNEXPECTED IMPROVEMENT UPON CESSATION OF CONVENTIONAL THERAPY FOR PRESUMED PROGRESSION; A MOLECULARLY CHARACTERIZED CASE REPORT
Authors: Stivaros Stavros , Parkes Laura , Bedir Rania , Cheesman Edmund , Ram Dipak , Leung Lydia , Huang Annie , Kilday John-Paul 
Published: June 2024

Abstract

BACKGROUND
Atypical teratoid/rhabdoid tumors (ATRTs) are malignant tumors of the central nervous system, typically presenting in the posterior fossa of very young children. Prognosis remains poor despite current therapy, while tumorigenesis implicates both genomic and epigenetic dysregulation. Primary diffuse leptomeningeal disease (PDL ATRT), without a defined intraparenchymal lesion, is an extremely rare ATRT variant with only seven cases reported. None of these preceding cases had undergone molecular characterization. We compared our case, who demonstrated an atypical clinical and radiological trajectory, against these seven cases.

CASE PRESENTATION
We describe a PDL ATRT, with hitherto novel molecular and imaging characteristics, in a pediatric patient who subsequently demonstrated radiological and clinical recovery from radiologically diagnosed metastatic relapse in the absence of conventional ATRT salvage treatment. Our case is the first to utilize Magnetic Resonance Imaging Arterial Spin Labelling perfusion imaging to suggest an underlying malignancy as the responsible etiology for this patient’s complex presentation, and the first to use methylation profiling to establish a tumor molecular subgroup for a PDL ATRT patient (identifying a MYC-subgroup in this case).

CONCLUSIONS
For this reported case of pediatric MYC-subgroup PDL ATRT, MR perfusional imaging aided in establishing the diagnosis and predicting potential relapse as part of a multi-parametric imaging assessment. We administered upfront intensive multimodal therapy, including high-dose CSRT to the patient, resulting in the longest overall survival for any patient reported with this extremely challenging ATRT variant. His unanticipated clinical and radiological improvement following a subsequent radiological diagnosis of tumor relapse highlights the importance of confirming recurrence by tissue extraction where feasible, but suggests that further evaluation of histone deacetylase inhibition as a potential future therapy in ATRT is warranted.
ATRT-07. PRC1/BMI1 ACTIVITY ALTERS CHROMATIN ACCESSIBILITY TO REGULATE DIFFERENTIATION IN ATYPICAL TERATOID RHABDOID TUMORS
Authors: Alimova Irina , Murdock Gillian , Pierce Angela M , Danis Etienne , Wang Dong , Serkova Natalie , Foreman Nicholas , Dahl Nathan , Venkataranman Sujatha , Vibhakar Rajeev 
Published: June 2024

Abstract

BACKGROUND
SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. Atypical Teratoid Rhabdoid Tumor (ATRT) is a highly aggressive pediatric brain tumor and characterized by SMARCB1 deletion.

METHODS
Genome wide RNAi screen, RNA-seq and ChIP-Seq analysis, colony formation assay, cell cycle, western blotting, immunoprecipitation, mass spectrometry analysis, mouse xenograft model, IVIS and MRI imaging.

RESULTS
We performed an RNAi-based functional genomic screen to identify key epigenetic regulators that co-operate with SMARCB1 loss and contribute to tumorigenesis in ATRT. 406 genes associated with epigenetic regulation in patient-derived ATRT cell lines were targeted. This screen identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as one of the top targets essential for ATRT cell growth. Using RNA-seq and ChIP-Seq analysis we demonstrated that BMI1 co-operates with SMARCB1 deletion to suppress transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. In SMARCB1 deficient cells BMI1 forms a partial PRC1 complex devoid of DNA binding components. We found that genetic inactivation of BMI1 suppresses ATRT cell clonogenicity and neurosphere formation, leads to S-phase arrest and induces ATRT cell differentiation in vitro. In vivo BMI1 inhibition induces apoptosis, leading to significantly increasing survival of treated mice. By Doxycycline-inducible SMARCB1 re-expression system we revealed activation of proapoptotic proteins p16 and p21. With immunoprecipitation for BMI1, followed by mass spectrometry analysis we demonstrated that re-expression of SMARCB1 activates two PRC1 chromatin localizing components CBX4 and CBX8. Moreover, SMARCB1 re-expression significantly prolongs mice survival and decreases tumor size as evaluated by IVIS imaging system and T2-MRI.

CONCLUSION
Thus, we demonstrated that SMARCB1 deletion results in reprograming of BMI1 chromatin occupancy away from lineage specification by altering the components of the PRC1 complex and that PRC1/BMI1 inhibition is a novel therapeutic approach in ATRT.
ATRT-20. ATYPICAL TERATOID RHABDOID TUMOR: ASSOCIATION OF CLINICAL, HISTOLOGICAL, RADIOLOGICAL, MOLECULAR, AND THERAPEUTIC DATA WITH THE SURVIVAL OF PATIENTS ATTENDED AT IOP/GRAACC/UNIFESP
Authors: Rodrigues Jéssica Benigno , Cappellano Andrea Maria , da Silva Frederico Adolfo Benevides , Cavalheiro Sergio , Dastoli Patricia , da Costa Marcos Devanir Silva , de Alves Maria Teresa Seixas , de Toledo Silvia Regina Caminada , Tesser-Gamba Francine , da da Silva Nasjla Saba Silva Saba 
Published: June 2024

Abstract

BACKGROUND
In childhood, Atypical Rhabdoid Teratoid Tumor accounts for 2% of cases of brain tumors. There is no consensus for the treatment, resulting in multiple protocols.

METHODS
Retrospective study at the Institute of Pediatric Oncology-IOP/GRAACC/UNIFESP, from January 2000 to December 2022. There were 31 patients admitted during this period. The classification of the histological type into rhabdoid/classic, small round and blue cells, epithelial, and mesenchymal was carried out by the same pathologist, and a 50% cutoff characterized the predominant pattern. A neuro-radiologist reviewed the radiological data. Molecular analysis was performed using NGS.

RESULTS
In patients &lt;3yo, 74.9% of patients died. Overall survival (OS) at 3 years was 24.5%, and progression-free survival (PFS) at 3 years was 13.8%. In patients &lt;3yo, the absence of metastases was associated with a higher OS and PFS (3y-OS 35.6% and 3y-PFS 23.7%, vs 3y-OS 10% and 3y-PFS 0% in patients with M+). The OS was higher in patients who received radiotherapy at the first treatment (3y-OS of 66.6% vs 7.8% in the non-irradiated group). The classic histological pattern had a lower PFS than the epithelial and small cell groups (p=0.021). In patients&gt;3 yo, 57.1% of patients died. The 3y-OS was 38.1% and the 3y-PFS was 53.5%. In this age group, there was no difference in OS and PFS considering metastases, location, histological pattern, and tumor volume. For post-surgical status, only PFS was significantly higher in patients with complete resection (3y-PFS of 75%, p=0.008). The mean survival time in patients &lt;3 yo was 1.9 years, and the mean survival time in patients &gt;3 yo was 2.5 years. The genetic alterations found were SMARCB1, NOTCH1, and KMT2D.

CONCLUSION
Patients &gt;3yo seem to have a higher OS and PFS than those &lt;3 yo. Early diagnosis of ATRT may corroborate to a better outcome. The radiotherapy in the first treatment can improve the outcome of patients under 3 years of age. The classic histological pattern was associated with worse PFS.
BIOM-11. TUMOUR SUPPRESSIVE ROLES OF MIR-206 AND MIR-383 VIACORO1C ANDSV2B IN AGGRESSIVE PAEDIATRIC AND ADULT BRAIN MALIGNANCIES
Authors: Mustafov Denis , Lambrou George I , Siddiqui Shoib S , Braoudaki Maria 
Published: June 2024

Abstract
Medulloblastoma (MB), the most prevalent brain malignancy in children, poses challenges in paediatric oncology due to its aggressiveness and potential for metastasis. Tailored treatment strategies are essential due to the impact of treatment-related toxicities and long-term side effects on children’s developing brains. This study aimed to identify therapeutic targets for paediatric MB and explore common biosignatures with glioblastoma multiforme (GBM), the most aggressive adult brain tumour. Total RNA and microRNAs (miRNAs) were extracted from eleven paediatric brain tissues (normal brain tissues, n=2; MB tumour tissue, n=8; pilocytic astrocytoma, n=1). High-throughput small-RNA sequencing (sRNA-seq) and transcriptomics were performed to identify the most deregulated miRNAs in paediatric MB tissue samples. Selected miRNAs, gene targets and encoded proteins were evaluated in vitro and ex vivo via real-time polymerase chain reaction (RT-qPCR), western blotting and immunohistochemistry (IHC). The sRNA-seq demonstrated that miR-383 and miR-206 were highly down regulated in MB samples suggesting their tumour suppressor properties. Bioinformatics analysis using miRSystem and TargetScan identified SV2B and CORO1C as their direct targets, respectively. Transcriptomics showed significant upregulation of SV2B and CORO1C in MB tissue samples. RT-qPCR analysis confirmed overexpression of SV2B and CORO1C within GBM cell lines and IHC depicted significant overexpression of SV2B and CORO1C proteins in paediatric MB and GBM patient cohorts (n=28) compared to their normal brain counterparts (n=32). Elevated CORO1C expression was also detected in adult MB (n=23) and GBM (n=73) tissue samples, when compared to normal brain tissue. Western blotting further verified the significant overexpression of CORO1C and SV2B within GBM cells, suggesting their role as potential oncoproteins. Collectively, our preliminary study proposes the clinical significance of miR-206 and miR-383 when overexpressed in the therapy of aggressive paediatric and adult brain malignancies.
CP-01. FATIGUE IN PATIENTS WITH HYPOTHALAMIC SYNDROME – A CROSS-SECTIONAL ANALYSIS IN THE GERMAN CHILDHOOD-ONSET CRANIOPHARYNGIOMA COHORT
Authors: Beckhaus Julia , Özyurt Jale , Mehren Aylin , Friedrich Carsten , Müller Hermann L 
Published: June 2024

Abstract

BACKGROUND
Patients with tumors of the sellar region are at risk of developing hypothalamic syndrome. Survivors experience fatigue and excessive daytime sleepiness even years after tumor treatment. The aim of this cross-sectional study was to determine the severity of fatigue in patients with and without hypothalamic syndrome.

METHODS
Patients diagnosed with CP or pilocytic astrocytoma were recruited from the KRANIOPHARYNGEOM 2000/2007/Registry 2019 studies and included in this analysis. Eligibility criteria were regular participation in outpatient after-care, one completed Multidimensional Fatigue Inventory-20 (MFI-20) questionnaire and complete medical records on criteria for hypothalamic syndrome. With univariable and multivariable linear regression, the relation of hypothalamic syndrome and levels of fatigue symptoms (MFI-20 sum score) were assessed. MFI-20 scores were compared to sex- and age-matched reference values from a German normative population using paired t-test.

RESULTS
Data on 46 patients, with a median age of 20 years, was available for this analysis of which 28 (61%) patients presented with hypothalamic syndrome. After adjustment for age and sex, patients with hypothalamic syndrome reported higher scores in the physical (= 3.61 [95% CI: 1.38–5.85]), mental (= 2.80 [95% CI: 0.28–5.32]) and sum MFI-20 (= 12.02 [95% CI: 2.93–21.10]) domain than patients without hypothalamic syndrome. Compared to reference values from a general German population, all patients reported higher mean scores in each fatigue domain. Regardless of the level of daytime sleepiness in patients with hypothalamic syndrome, the reported fatigue scores were high. Daytime sleepiness did not correlate with fatigue.

CONCLUSIONS
Fatigue symptoms are present in patients with CP. However, patients with hypothalamic syndrome are more affected in mental, physical and overall fatigue. It is crucial in clinical practice, to distinguish between sleep disorders and fatigue and to target patients with hypothalamic syndrome.
CP-05. MAPK PATHWAY ACTIVATION, CLONAL EVOLUTION, INCLUDING RARE TP53 LOSS, AND THE IMMUNE ENVIRONMENT OF RECURRENT CRANIOPHARYNGIOMA
Authors: Apps John R , Gonzalez-Meljem Mario , Guiho Romain , Pickles Jessica C , Prince Eric , Schwalbe Edward , Joshi Nikhil , Stone Thomas J , Ogunbiyi Olumide , Chalker Jane , Bassey Akang , Otto Georg , Davies Rosalind , Hughes Debbie , Tan Enrica , Brandner Sebastian , Lee Victoria , Hayhurst Caroline , Kline Cassie , Castellano Sergi , Hankinson Todd C , Deutschbein Timo , Jacques Thomas S , Martinez-Barbera Juan Pedro 
Published: June 2024

Abstract

BACKGROUND
Craniopharyngiomas are rare challenging tumours, with around 25% of cases recurring despite surgery and/or radiotherapy. Relatively little is known about the biology of recurrence and there is an urgent need to develop new therapies. Our previous studies have suggested preclinical efficacy of MEKinhition with trametinib in human and murine adamantinomatous craniopharyngoioma (ACP) tissue. At ISPNO2022 we reported methylation and expression profiling results from a cohort of relapsed craniopharyngioma, identifying acquisition of chromosomal abnormalities across recurrence, the persistent activation of MAPK pathway at recurrence, the presence of myeloid cells and a rare case of malignant transformation associated with TP53 loss.

METHODS
Here we present an update from this study through exploring additional datasets, preclinical drug testing, and genetic manipulation of genetic engineered mouse models of ACP

RESULTS
Exploration of whole genome sequencing data from 67 cases of ACP from Children’s Brain Tumour Network has confirmed the presence of chromosomal arm changes in 7 (10%) of cases, including at diagnosis, confirming that the genomic landscape of ACP is more complex than previously thought. To further explore the potential of MAPK pathway inhibiton we have demonstrated efficacy of a further two clinically available MEK inbhiibtors, Selumetinib and Binimetinib, in reducing proliferation and inducing cell death in ex vivo explants of murine ACP. To explore the role of TP53 loss in aggressive craniopharyngioma, we show that Trp53 loss in a murine ACP model results in very aggressive tumours and reduced mouse survival. Finally, we have further characterised the tumour immune infiltrate showing differences in the cellular composition between ACP and Papillary CP, and revealing a diverse phenotype of macrophages in ACP.

CONCLUSIONS
Together, this research provides further preclinical support for the ongoing evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in patients with craniopharyngioma.