bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A051 Genome-wide CRISPR/Cas9 library screening identified TP53 as a critical driver for resistance to EZH2 inhibitor in rhabdoid tumors
Authors: Chauvin Céline , Hery Tiphaine , Bouarich Rachida , Nemati Fariba , Teyssonneau Diego , Fouassier Camille , Giudiceandrea Chiara , Han Zhi-Yan , Zaidi Sakina , Surdez Didier , Roman-Roman Sergio , Decaudin Didier , Margueron Raphaël , Bourdeaut Franck 
Published: September 2024

Abstract
Rhabdoid tumors (RTs) are rare, highly aggressive pediatric malignancies which occur in kidney, soft-parts and brain. They are characterized by a complete inactivation of the SMARCB1 tumor suppressor gene encoding a core subunit of the chromatin remodeling SWI/SNF complex. Prognosis for children with RTs is poor as, in many instances, these tumors are resistant to conventional type chemotherapy. Pharmacological inhibition of EZH2 is a promising strategy to treat some tumors with loss of function in SMARCB1. However, the clinical response rate remains low, and both primary and secondary resistance have been reported. Understanding the mechanisms of resistance to EZH2 inhibition may allow new therapeutic hypothesis. For this purpose, we realized a genome-wide CRISPR-Cas9 knockout screening on two rhabdoid cell lines treated with EZH2 inhibitor. We identified TP53 loss as the sole consistent gene knock-out able to confer some resistance to EZH2 inhibition in both cell lines. Conversely, we demonstrated that MDM2/MDM4 inhibition, in a TP53-dependant manner, strongly synergized with EZH2 inhibition to control cell lines viability in vitro. We further treated 4 rhabdoid patient-derived xenografts with UNC1999, Idasanutlin and the combination of both and observed a potent tumor growth control upon combined EZH2 and MDM2/MDM4 inhibitions. To conclude, our results strongly encourage to assess the actual efficacy of combined MDM2/MDM4 and EZH2 inhibitors in the treatment of patients with SMARCB1-deficient rhabdoid tumors.
Citation Format: Céline Chauvin, Tiphaine Hery, Rachida Bouarich, Fariba Nemati, Diego Teyssonneau, Camille Fouassier, Chiara Giudiceandrea, Zhi-Yan Han, Sakina Zaidi, Didier Surdez, Sergio Roman-Roman, Didier Decaudin, Raphaël Margueron, Franck Bourdeaut. Genome-wide CRISPR/Cas9 library screening identified TP53 as a critical driver for resistance to EZH2 inhibitor in rhabdoid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A051.
Abstract A052 Project HOPE: A spatiotemporal single-cell landscape of high-grade gliomas in children, adolescents and young adults
Authors: Danielli Sara G. , Neyazi Sina , Hack Olivia A. , Jiang Li , Lo Cascio Costanza , Nascimento Andrezza , Nguyen Cuong , Rozowsky Jacob , Liu Ilon , Hoare Owen , Shamardani Karin , Cunliffe-Koehler Kennedy , Gojo Johannes , Ligon Keith L. , Baird Lissa , Alexandrescu Sanda , Cotter Jennifer , Prados Michael , Resnick Adam , Wang Lin , Monje Michelle , Diaz Aaron , Filbin Mariella G. 
Published: September 2024

Abstract
Despite the growing insights into the cellular heterogeneity of pediatric brain tumors, the transcriptional changes and spatial reorganization during disease progression remain largely unexplored. Here, we present an in-depth single-cell and 10X Xenium spatial transcriptomic characterization of 24 matched pediatric high-grade gliomas (pHGGs) in children, adolescents and young adults (AYA) profiled at both diagnosis and recurrence - constituting a total of 55 tissue samples. By stratifying the transcriptional programs activated at recurrence, we identify two distinct global response sets. Hemispheric AYA tumors predominantly exhibit upregulation of extracellular matrix pathways at recurrence, whereas midline tumors preferentially activate generic stress response programs. On a cellular level, we find that heterogeneity within the malignant tumor compartment remains largely unchanged at recurrence. However, a subset of AYA patients with hemispheric pHGG shows enrichment of the neural-progenitor-like (NPC-like) tumor cell state, and compositional changes in the immune and normal cell landscape, characterized by a global decrease in myeloid cells and an increase in oligodendrocyte fractions. Those changes lead, in turn, to enhanced NPC-like tumor cell-to-oligodendrocyte interactions. Spatial analysis of our extensive cohort at unprecedented subcellular resolution further reveals distinct cellular and spatial features associated with tumor progression, particularly in the remodeling of cell-cell interactions and tumor cell neighborhoods. Overall, this study provides a comprehensive longitudinal single-cell and spatial atlas of pHGG, uncovering the extensive cellular heterogeneity associated with tumor progression. Our findings highlight the role of intrinsic and extrinsic tumor adaptations in shaping disease progression in pHGG, offering potential novel therapeutic targets.
Citation Format: Sara G. Danielli, Sina Neyazi, Olivia A. Hack, Li Jiang, Costanza Lo Cascio, Andrezza Nascimento, Cuong Nguyen, Jacob Rozowsky, Ilon Liu, Owen Hoare, Karin Shamardani, Kennedy Cunliffe-Koehler, Johannes Gojo, Keith L. Ligon, Lissa Baird, Sanda Alexandrescu, Jennifer Cotter, Michael Prados, Adam Resnick, Lin Wang, Michelle Monje, Aaron Diaz, Mariella G. Filbin. Project HOPE: A spatiotemporal single-cell landscape of high-grade gliomas in children, adolescents and young adults [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A052.
Abstract B004: Putting function back into paediatric cancer genomics – modelling the therapeutic implications of novel genomic features
Authors: Sadras Teresa , Brown Lauren M. , Salib Alice , Liu Pei Y. , Mayoh Chelsea , Tyrrell Vanessa , Cowley Mark J. , Ekert Paul G. 
Published: September 2024

Abstract
One of the great promises of precision oncology programs lies in linking the specific genomic features of a tumour to therapies that directly or indirectly target these features.The ZERO Childhood Cancer Program (ZERO) is Australia’s national precision medicine program for childhood cancer. ZERO has demonstrated that precision guided therapy is associated with improved survival of children diagnosed with high-risk cancers, by identifying therapeutic options that would otherwise go unrecognised. However, there are many roadblocks preventing use of these therapies. One is the situation where a genomic feature is suspected of being a cancer driver and targetable, but has not been previously described. Another is encountering more familiar oncogenic lesions in atypical tumour contexts. This lack of direct clinical experience or preclinical data about the biological and therapeutic significance of the lesions means, the targeted therapies are often not used even when potential for clinical benefit. We are attempting to address this through an experimental program that generates models of individual genomic lesions to establish, at the bench, whether a genomic aberration is oncogenic and how it can be therapeutically targeted. Our focus has been on to novel variants predicted to activate receptor tyrosine kinase signalling found in the ZERO program.We will show we use a variety of approaches, including CRISPR/Cas9 engineering of novelkinase activating lesions in cytokine dependent cell lines to measure whether they are sufficient to transform these cells from cytokine dependence to independence. Further, we compare how driver fusions engineered in the endogenous genome compare, with respect to transforming capacity and responses to targeted therapies, to exogenous over-expression of the same fusions By studying rare or unique variants, we have identified novel mechanisms of tyrosine kinase activation, and identified therapeutic options for individual cancers, so meeting a definition of precision medicine. Further, we contend that understanding the biology of rare or unique variants does more than recover lost therapeutic opportunities for clinicians and families, it also provides important new knowledge about the biology of childhood cancer.
Citation Format: Teresa Sadras, Lauren M. Brown, Alice Salib, Pei Y. Liu, Chelsea Mayoh, Vanessa Tyrrell, Mark J. Cowley, Paul G. Ekert. Putting function back into paediatric cancer genomics – modelling the therapeutic implications of novel genomic features [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B004.
Abstract IA003: Genetic predisposition to pediatric cancer: the long way from discovery to surveillance guidelines
Authors: Bourdeaut Franck 
Published: September 2024

Abstract
Pediatric cancers are estimated to be related to a genetic predisposition in about 8 to 10% of cases. This estimation mostly relies on already discovered cancer predisposing genes. However, the numerous new cancer predisposing genes that have been discovered in the past decade thanks to high throughput sequencing in vast cohort of pediatric patients illustrate that new genes may still be unravelled. Moreover, the frequency of early post-zygotic mosaicism is being readdressed thanks to more dedicated sequencing and research. The actual clinical impact of all those discoveries is the main challenge for the community: defining the penetrance, delineating the cancer spectrum and therefore the appropriate surveillance, and setting up innovative follow-up techniques are necessary. Here, we’ll describe recent findings on brain tumor predisposing genes (ELP1 and SMARCB1, among others) to illustrate the increasing recognition of genetic predisposition in pediatric cancers and how the clinical translation of these laboratory findings remain challenging at clinical and ethical levels.
Citation Format: Franck Bourdeaut. Genetic predisposition to pediatric cancer: the long way from discovery to surveillance guidelines [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr IA003.
The Marriage Ceremony in Early Medieval Ashkenaz
Authors: Yahalom Shalem 
Published: September 2024

Abstract
This article examined the marriage procedures prevalent in Mainz and other places in eleventh century Ashkenaz. Marriages took place on the Sabbath, as in Christian society, where weddings were held on holidays and days of rest. The ketubah was written on Friday in order to prepare for the wedding. Marriage during this period was not a symbolic ritual but a tangible act of sexual intercourse. Accordingly, a festive meal was held during which the couple consummated the marriage. Since the betrothal took place in a limited social circle, the betrothal blessing was recited toward the end of the Sabbath in the framework of a public, festive ceremony. After verification of the bride’s virginity, which meant she was eligible to receive the ketubah, the marriage blessings were recited on Saturday night and the ketubah became legally binding.
The Early Work of Paul Fraisse: The Timing of ‘Spontaneous’ Rhythms
Authors: Wearden John H. 
Published: September 2024

Abstract
The article discusses Paul Fraisse’s early study of the timing of what he called ‘spontaneous’ rhythms, where people were required to perform a specified sequence of spaced taps on a response key without the times between the responses being controlled. Results come from his doctoral thesis, carried out under the supervision of Albert Michotte in Louvain/Leuven in Belgium between 1935 and 1937. In spite of the lack of timing instructions, responses were divided into ‘short times’ (around 200 ms), ‘long times’ (usually around 450 ms), and ‘pauses’ (the times between execution of consecutive rhythmic sequences). This division held over changes in the tap sequence, when different patterns of three, four, and five responses were produced. A later experiment varied total sequence duration, including the pauses, and the ratio of long to short times was approximately preserved even with marked changes in sequence duration, except at the slowest speed. Fraisse regarded the pause as having a different function from the short and long times. It changed only slightly when the pattern changed, but marked changes in the duration of the pause did not affect the pattern. Fraisse suggested it was a kind of separator, needed to maintain the rhythmic structure of the patterns, and used the idea of a temporal ‘Gestalt’ where the pause represented the ‘ground’ or ‘framework’ and the rhythmic sequence the ‘Figure ’.
Mobility trajectories in multiple sclerosis: A comparative study of timed 25-foot walk and a patient-reported outcome measure
Authors: Briggs Farren BS , Gunzler Douglas D , Miller Deborah M , Ontaneda Daniel , De Nadai Alessandro S 
Published: September 2024

Background: Loss of mobility is common in persons with multiple sclerosis (PwMS), but little is known about this impairment from the patient’s perspective. Objective: The aim is to model longitudinal variation in a mobility patient-reported outcome (PRO) and compare trajectories to those observed for Timed 25-Foot Walk (T25FW) in a retrospective cohort. Methods: Latent-class growth analysis was applied to 47,508 measures of Performance Scales© Mobility PRO (PS-Mobility) over ~4 years for 8524 PwMS. For 7347 PwMS, there were 41,988 T25FW measures during this period. Repeated measures correlation and concordance of trajectory assignment were evaluated. Results: At the group level, PS-Mobility and T25FW linearly worsened and repeated-measures correlation was moderate. Eight latent classes with varying shapes that worsened described PS-Mobility variation, compared to six latent classes for T25FW that differed by intercept. The agreement between PS-Mobility and T25FW cluster assignment was modest. A higher proportion of individuals who were Black/African American, older, Medicaid beneficiaries, living in deprived neighborhoods, had longer disease duration, had progressive disease, and ever smokers were assigned to more impaired clusters. Discussion: Cross-sectionally, PS-Mobility and T25FW were highly correlated, but longitudinally correlation was modest to moderate, underscoring the importance of considering both objective and subjective perspectives in evaluating mobility changes in PwMS.
Randomized open-label study of second-generation antipsychotics for the treatment of schizophrenia: 104-week final results of the JUMPs study assessing treatment discontinuation, remission, and social functioning
Authors: Ishigooka Jun , Nakagome Kazuyuki , Ohmori Tetsuro , Iwata Nakao , Inada Ken , Iga Jun-ichi , Kishi Taro , Fujita Kiyoshi , Kikuchi Yuka , Shichijo Toshiaki , Tabuse Hideaki , Koretsune Shotatsu , Terada Hiroshi , Terada Haruko , Kishimoto Toshifumi , Tsutsumi Yuichiro , Ohi Kazutaka 
Published: September 2024

Abstract
Background
We report the final results of treatment with aripiprazole, blonanserin, and paliperidone from the Japan Useful Medication Program for Schizophrenia (JUMPs), a 104-week naturalistic study.

Methods
JUMPs was an open-label, three-arm, randomized, parallel-group, 104-week study. Patients aged ≥ 20 years with schizophrenia requiring antipsychotic treatment or a switch from previous therapy were enrolled. The primary endpoint was treatment discontinuation rate over 104 weeks. Secondary endpoints included remission rate, Personal and Social Performance (PSP), safety, Positive and Negative Syndrome Scale (PANSS), and quality of life (QOL; EuroQol-5 dimension).

Results
In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). Treatment discontinuation rates (aripiprazole, 80.5%; blonanserin, 81.2%; paliperidone, 71.4%) were not significantly different (p = 0.2385) among the treatment groups at 104 weeks; comparable outcomes were observed for endpoints, including remission (42.9%, 46.7%, and 45.8%), PANSS, and safety. In the overall cohort, while the improvement in the PSP total score at Week 104 was not significantly different from baseline, a significant improvement (p < 0.05) in QOL and total PANSS scores (including all subscales) was observed at Week 104 compared with baseline. Multivariable analysis identified a shorter disease duration and a higher chlorpromazine-equivalent antipsychotic dosage level (≥ 1000 mg) before switching to monotherapy as predictors of treatment discontinuation.

Conclusions
The 104-week treatment outcomes were comparable between groups; the overall trend of improvement in remission rate, safety, and QOL suggests the importance of continued treatment.

Clinical trial registration
UMIN-Clinical Trials Registry UMIN000007942 (public release date: 14/05/2012).
Competencies required by sonographers teaching ultrasound interprofessionally: a Delphi consensus study
Authors: Cormack Carolynne J. , Childs Jessie , Kent Fiona 
Published: September 2024

Abstract
Background
Clinicians from multiple professional backgrounds are increasingly using point-of-care ultrasound in clinical practice. Performing ultrasound is a complex skill, and training is required to ensure competency and patient safety. There is a lack of skilled trainers within health professions to meet this increasing educational demand. The role of sonographers in educating other health professionals in point-of-care ultrasound has not yet been well defined. Sonographers can provide ultrasound education interprofessionally, if equipped with appropriate clinical knowledge and educational skills.

Methods
A Delphi consensus study was conducted to define the knowledge, skills and attributes required of sonographers teaching point-of-care ultrasound to other health professionals in Australia and New Zealand. Health professionals with subject matter expertise in the leadership, facilitation, and delivery of ultrasound education by sonographers were invited to participate.

Results
There were 72 expert participants in survey round one, and 49 in round two. Participants included physicians, sonographers, and other health professionals. Consensus was reached on 31 competency items for sonographers teaching ultrasound interprofessionally, with agreement of greater than 94% reached by participants.

Conclusions
This consensus study has defined the knowledge, skills and attitudes required for sonographer competence in point-of-care ultrasound education. This is an important step to developing a training pathway for sonographers engaging in this emerging area.
AAV-DJ is superior to AAV9 for targeting brain and spinal cord, and de-targeting liver across multiple delivery routes in mice
Authors: Chauhan Monika , Daugherty Audrey L. , Khadir Fatemeh , Duzenli Ozgun F. , Hoffman Alexandra , Tinklenberg Jennifer A. , Kang Peter B. , Aslanidi George , Pacak Christina A. 
Published: September 2024

AbstractHighly efficient adeno associated viruses (AAVs) targeting the central nervous system (CNS) are needed to deliver safe and effective therapies for inherited neurological disorders. The goal of this study was to compare the organ-specific transduction efficiencies of two AAV capsids across three different delivery routes. We compared AAV9-CBA-fLucYFP to AAV-DJ-CBA-fLucYFP using the following delivery routes in mice: intracerebroventricular (ICV) 1 × 1012 vg/kg, intrathecal (IT) 1 × 1012 vg/kg, and intravenous (IV) 1 × 1013 vg/kg body weight. Our evaluations revealed that following ICV and IT administrations, AAV-DJ demonstrated significantly increased vector genome (vg) uptake throughout the CNS as compared to AAV9. Through the IV route, AAV9 demonstrated significantly increased vg uptake in the CNS. However, significantly fewer vgs were detected in the off-target organs (kidney and liver) following administration of AAV-DJ using the IT and IV delivery routes as compared to AAV9. Distributions of vgs correlate well with transgene transcript levels, luciferase enzyme activities, and immunofluorescence detection of YFP. Overall, between the two vectors, AAV-DJ resulted in better targeting and expression in CNS tissues paired with de-targeting and reduced expression in liver and kidneys. Our findings support further examination of AAV-DJ as a gene therapy capsid for the treatment of neurological disorders.
Identification of HDAC10 as a candidate oncogene in clear cell renal carcinoma that facilitates tumor proliferation and metastasis
Authors: Yang Luojia , Wei Qin , Chen Xinran , Yang Yang , Huang Qingbo , Wang Baojun , Ma Xin 
Published: September 2024

Abstract
Background
Clear cell renal cell carcinoma (ccRCC) remains one of the most lethal urological malignancies even though a great number of improvements in diagnosis and management have achieved over the past few decades. Accumulated evidence revealed that histone deacetylases (HDACs) play vital role in cell proliferation, differentiation and apoptosis. Nevertheless, the biological functions of histone deacetylation modification related genes in ccRCC remains poorly understood.

Method
Bulk transcriptomic data and clinical information of ccRCC patients were obtained from the TCGA database and collected from the Chinese PLA General Hospital. A total of 36 histone deacetylation genes were selected and studied in our research. Univariate cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression, random forest (RF) analysis, and protein-protein interaction (PPI) network analysis were applied to identify key genes affecting the prognosis of ccRCC. The ‘oncoPredict’ algorithm was utilized for drug-sensitive analysis. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore the potential biological function. The ssGSEA algorithm was used for tumor immune microenvironment analysis. The expression levels of HDAC10 were validated by RT-PCR and immunohistochemistry (IHC). 5-ethynyl-2′-deoxyuridine (EdU assay), CCK-8 assay, cell transwell migration and invasion assay and colony formation assay were performed to detect the proliferation and invasion ability of ccRCC cells. A nomogram incorporating HDAC10 and clinicopathological characteristics was established to predict the prognosis of ccRCC patients.

Result
Two machine learning algorithms and PPI analysis identified four histone deacetylation genes that have a significant association with the prognosis of ccRCC, with HDAC10 being the key gene among them. HDAC10 is highly expressed in ccRCC and its high expression is associated with poor prognosis for ccRCC patients. Pathway enrichment and the experiments of EdU staining, CCK-8 assay, cell transwell migration and invasion assay and colony formation assay demonstrated that HDAC10 mediated the proliferation and metastasis of ccRCC cells and involved in reshaping the tumor microenvironment (TME) of ccRCC. A clinically reliable prognostic predictive model was established by incorporating HDAC10 and other clinicopathological characteristics ( https://nomogramhdac10.shinyapps.io/HDAC10_Nomogram/ ).

Conclusion
Our study found the increased expression of HDAC10 was closely associated with poor prognosis of ccRCC patients. HDAC10 showed a pro-tumorigenic effect on ccRCC and promote the proliferation and metastasis of ccRCC, which may provide new light on targeted therapy for ccRCC.