bluuebunny/crossref_metadata_2025_split huggingface dataset:
YBX1 mediates translation of oncogenic transcripts to control cell competition in AML
Authors: Perner Florian , Schnoeder Tina M. , Xiong Yijun , Jayavelu Ashok Kumar , Mashamba Nomusa , Santamaria Nuria Tubio , Huber Nicolas , Todorova Kristina , Hatton Charles , Perner Birgit , Eifert Theresa , Murphy Ciara , Hartmann Maximilian , Hoell Jessica I. , Schröder Nicolas , Brandt Sabine , Hochhaus Andreas , Mertens Peter R. , Mann Matthias , Armstrong Scott A. , Mandinova Anna , Heidel Florian H. 
Published: August 2021

AbstractPersistence of malignant clones is a major determinant of adverse outcome in patients with hematologic malignancies. Despite the fact that the majority of patients with acute myeloid leukemia (AML) achieve complete remission after chemotherapy, a large proportion of them relapse as a result of residual malignant cells. These persistent clones have a competitive advantage and can re-establish disease. Therefore, targeting strategies that specifically diminish cell competition of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified YBX1 as a mediator of disease persistence in JAK2-mutated myeloproliferative neoplasms. The role of YBX1 in AML, however, remained so far elusive. Here, inactivation of YBX1 confirms its role as an essential driver of leukemia development and maintenance. We identify its ability to amplify the translation of oncogenic transcripts, including MYC, by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupts this regulatory circuit and displaces oncogenic drivers from polysomes, with subsequent depletion of protein levels. As a consequence, leukemia cells show reduced proliferation and are out-competed in vitro and in vivo, while normal cells remain largely unaffected. Collectively, these data establish YBX1 as a specific dependency and therapeutic target in AML that is essential for oncogenic protein expression.
The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia
Authors: Niederkorn Madeline , Ishikawa Chiharu , M. Hueneman Kathleen , Bartram James , Stepanchick Emily , R. Bennett Joshua , E. Culver-Cochran Ashley , Bolanos Lyndsey C. , Uible Emma , Choi Kwangmin , Wunderlich Mark , Perentesis John P. , M. Chlon Timothy , Filippi Marie-Dominique , Starczynowski Daniel T. 
Published: August 2021

AbstractUbiquitin-specific peptidase 15 (USP15) is a deubiquitinating enzyme implicated in critical cellular and oncogenic processes. We report that USP15 mRNA and protein are overexpressed in human acute myeloid leukemia (AML) as compared to normal hematopoietic progenitor cells. This high expression of USP15 in AML correlates with KEAP1 protein and suppression of NRF2. Knockdown or deletion of USP15 in human and mouse AML models significantly impairs leukemic progenitor function and viability and de-represses an antioxidant response through the KEAP1-NRF2 axis. Inhibition of USP15 and subsequent activation of NRF2 leads to redox perturbations in AML cells, coincident with impaired leukemic cell function. In contrast, USP15 is dispensable for human and mouse normal hematopoietic cells in vitro and in vivo. A preclinical small-molecule inhibitor of USP15 induced the KEAP1-NRF2 axis and impaired AML cell function, suggesting that targeting USP15 catalytic function can suppress AML. Based on these findings, we report that USP15 drives AML cell function, in part, by suppressing a critical oxidative stress sensor mechanism and permitting an aberrant redox state. Furthermore, we postulate that inhibition of USP15 activity with small molecule inhibitors will selectively impair leukemic progenitor cells by re-engaging homeostatic redox responses while sparing normal hematopoiesis.
Verification of immunology-related genetic associations in BPD supports ABCA3 and five other genes
Authors: Blume Felix , Kirsten Holger , Ahnert Peter , Chakraborty Trinad , Gross Arnd , Horn Katrin , Toliat Mohammad Reza , Nürnberg Peter , Westenfelder Eva-Maria , Goepel Wolfgang , Scholz Markus 
Published: August 2021

Abstract
Background
Inflammatory processes are key drivers of bronchopulmonary dysplasia (BPD), a chronic lung disease in preterm infants. In a large sample, we verify previously reported associations of genetic variants of immunology-related genes with BPD.

Methods
Preterm infants with a gestational age ≤32 weeks from PROGRESS and the German Neonatal Network (GNN) were included. Through a consensus case/control definition, 278 BPD cases and 670 controls were identified. We identified 49 immunity-related genes and 55 single-nucleotide polymorphisms (SNPs) previously associated with BPD through a comprehensive literature survey. Additionally, a quantitative genetic association analysis regarding oxygen supplements, mechanical ventilation, and continuous positive air pressure (CPAP) was performed.

Results
Five candidate SNPs were nominally associated with BPD-related phenotypes with effect directions not conflicting the original studies: rs11265269-CRP, rs1427793-NUAK1, rs2229569-SELL, rs1883617-VNN2, and rs4148913-CHST3. Four of these genes are involved in cell adhesion. Extending our analysis to all well-imputed SNPs of all candidate genes, the strongest association was rs45538638-ABCA3 with CPAP (p = 4.9 × 10−7, FDR = 0.004), an ABC transporter involved in surfactant formation.

Conclusions
Most of the previously reported associations could not be replicated. We found additional support for SNPs in CRP, NUAK1, SELL, VNN2, and ABCA3. Larger studies and meta-analyses are required to corroborate these findings.

Impact

Larger cohort for improved statistical power to detect genetic associations with bronchopulmonary dysplasia (BPD).

Most of the previously reported genetic associations with BPD could not be replicated in this larger study.

Among investigated immunological relevant candidate genes, additional support was found for variants in genes CRP, NUAK1, SELL, VNN2, and CHST3, four of them related to cell adhesion.

rs45538638 is a novel candidate SNP in reported candidate gene ABC-transporter ABCA3.

Results help to prioritize molecular candidate pathomechanisms in follow-up studies.
Review of patient-reported outcomes in multiple myeloma registrational trials: highlighting areas for improvement
Authors: Fernandes Laura L. , Zhou Jiaxi , Kanapuru Bindu , Horodniceanu Erica , Gwise Thomas , Kluetz Paul G. , Bhatnagar Vishal 
Published: August 2021

AbstractOver the past 13 years, there have been advances in characterizing the patient experience in oncology trials, primarily using patient-reported outcomes (PROs). This review aims to provide details on the PRO measures and analyses used in multiple myeloma (MM) registrational trials. We identified registrational trials supporting MM indications from 2007 to 2020 from FDA databases. Trial protocols, statistical analysis plans, and clinical study reports were reviewed for PRO measures used, collection methods, statistical analyses, baseline and instrument completion definitions, and thresholds for clinical meaningfulness. Twenty-five trials supporting 20 MM indications were identified; 17 (68%) contained submitted PRO data. Of the 17 trials, 14 were randomized controlled trials and the remainder were single-arm trials. All but one trial were open label trials. Seven trials collected data electronically and five in paper format. The majority of trials evaluated at least two PRO measures (82%) with two trials (12%) utilizing four measures. Nine unique PRO measures were used, most commonly the EORTC QLQ-30 (87%), EQ-5D (65%), and QLQ-MY20 (47%). All 17 (100%) trials provided descriptive summaries, 10 (59%) carried out longitudinal mixed model analysis, 9 (53%) conducted responder analysis, and 2 (12%) did a basic inferential test. We noted substantial heterogeneity in terms of PRO collection methods, measures, definitions, and analyses, which may hinder the ability to effectively capture and interpret patient experience in future MM clinical trials. Further research is needed to determine the most appropriate approaches for statistical and analytical methodologies for PRO data in MM trials.
Combined effects of hyperthermia and chemotherapy on the regulate autophagy of oral squamous cell carcinoma cells under a hypoxic microenvironment
Authors: Shi Fan , Luo Dan , Zhou Xuexiao , Sun Qiaozhen , Shen Pei , Wang Shengzhi 
Published: August 2021

AbstractAutophagy has a complex dual role in tumor survival or cell death owning to that is an evolutionarily conserved catabolic mechanism and provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Hyperthermia is a rapidly growing field in cancer therapy and many advances have been made in understanding and applying the mechanisms of hyperthermia. The shallow oral and maxillofacial position and its abundant blood supply are favorable for the use of hyperthermia. However, the relationship between hyperthermia and autophagy has not been examined of oral squamous cell carcinoma (OSCC) in the tumor hypoxia microenvironment. Here, the expression level of autophagy relative genes is examined to explore autophagy effect on the responses of hyperthermia, hypoxia, and innutrition tumor microenvironment. It is founded that hyperthermia and hypoxia cause autophagy in starvation conditions; further, in hypoxia and innutrition tumor microenvironment, hyperthermia combines YC-1 and 3-MA could inhibit HIF-1α/BNIP3/Beclin1 signal pathway and decrease the secretion of HMGB1; moreover, the cell apoptosis rate increases with an inhibited of cell migration capacity. Thus, the present study demonstrated that combined use of YC-1 and 3-MA might increase the death of tumor cells in physiological and hyperthermic conditions, which could be relevant with the inhibition of autophagy in OSCC tumor cells under hypoxia microenvironment in vitro, which offers new insight into the therapy of OSCC and its application in treating others study carcinomas.
Autologous transplantation of thecal stem cells restores ovarian function in nonhuman primates
Authors: Chen Hong , Xia Kai , Huang Weijun , Li Huijian , Wang Chao , Ma Yuanchen , Chen Jianhui , Luo Peng , Zheng Shuwei , Wang Jiancheng , Wang Yi , Dong Lin , Tan Zhipeng , Lai Xingqiang , Mao Frank Fuxiang , Li Weiqiang , Liang Xiaoyan , Wang Tao , Xiang Andy Peng , Ke Qiong 
Published: August 2021

AbstractPremature ovarian insufficiency (POI) is defined as the loss of ovarian activity under the age of 40. Theca cells (TCs) play a vital role during folliculogenesis and TCs dysfunction participate in the pathogenesis of POI. Therefore, transplantation of thecal stem cells (TSCs), which are capable of self-renewal and differentiation into mature TCs, may provide a new strategy for treating POI. To investigate the feasibility, safety, and efficacy of TSCs transplantation in clinically relevant non-human primate (NHP) models, we isolate TSCs from cynomolgus monkeys, and these cells are confirmed to expand continuously and show potential to differentiate into mature TCs. In addition, engraftment of autologous TSCs into POI monkeys significantly improves hormone levels, rescues the follicle development, promotes the quality of oocytes and boosts oocyte maturation/fertilization rate. Taken together, these results for the first time suggest that autologous TSCs can ameliorate POI symptoms in primate models and shed new light on developing stem cell therapy for POI.
Acquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes
Authors: Redman-Rivera Lindsay N. , Shaver Timothy M. , Jin Hailing , Marshall Clayton B. , Schafer Johanna M. , Sheng Quanhu , Hongo Rachel A. , Beckermann Kathryn E. , Wheeler Ferrin C. , Lehmann Brian D. , Pietenpol Jennifer A. 
Published: August 2021

Abstractp53 is mutated in over half of human cancers. In addition to losing wild-type (WT) tumor-suppressive function, mutant p53 proteins are proposed to acquire gain-of-function (GOF) activity, leading to novel oncogenic phenotypes. To study mutant p53 GOF mechanisms and phenotypes, we genetically engineered non-transformed and tumor-derived WT p53 cell line models to express endogenous missense mutant p53 (R175H and R273H) or to be deficient for p53 protein (null). Characterization of the models, which initially differed only by TP53 genotype, revealed that aneuploidy frequently occurred in mutant p53-expressing cells. GOF phenotypes occurred clonally in vitro and in vivo, were independent of p53 alteration and correlated with increased aneuploidy. Further, analysis of outcome data revealed that individuals with aneuploid-high tumors displayed unfavorable prognoses, regardless of the TP53 genotype. Our results indicate that genetic variation resulting from aneuploidy accounts for the diversity of previously reported mutant p53 GOF phenotypes.
Neural signatures of hyperdirect pathway activity in Parkinson’s disease
Authors: Oswal Ashwini , Cao Chunyan , Yeh Chien-Hung , Neumann Wolf-Julian , Gratwicke James , Akram Harith , Horn Andreas , Li Dianyou , Zhan Shikun , Zhang Chao , Wang Qiang , Zrinzo Ludvic , Foltynie Tom , Limousin Patricia , Bogacz Rafal , Sun Bomin , Husain Masud , Brown Peter , Litvak Vladimir 
Published: August 2021

AbstractParkinson’s disease (PD) is characterised by the emergence of beta frequency oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between the anatomy of this circuit and oscillatory synchronisation within it remains unclear. We address this by combining recordings from human subthalamic nucleus (STN) and internal globus pallidus (GPi) with magnetoencephalography, tractography and computational modelling. Coherence between supplementary motor area and STN within the high (21–30 Hz) but not low (13-21 Hz) beta frequency range correlated with ‘hyperdirect pathway’ fibre densities between these structures. Furthermore, supplementary motor area activity drove STN activity selectively at high beta frequencies suggesting that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway. Computational modelling revealed that exaggerated high beta hyperdirect pathway activity can provoke the generation of widespread pathological synchrony at lower beta frequencies. These findings suggest a spectral signature and a pathophysiological role for the hyperdirect pathway in PD.
Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma
Authors: Frontzek Fabian , Staiger Annette M. , Zapukhlyak Myroslav , Xu Wendan , Bonzheim Irina , Borgmann Vanessa , Sander Philip , Baptista Maria Joao , Heming Jan-Niklas , Berning Philipp , Wullenkord Ramona , Erdmann Tabea , Lutz Mathias , Veratti Pia , Ehrenfeld Sophia , Wienand Kirsty , Horn Heike , Goodlad John R. , Wilson Matthew R. , Anagnostopoulos Ioannis , Lamping Mario , Gonzalez-Barca Eva , Climent Fina , Salar Antonio , Castellvi Josep , Abrisqueta Pau , Menarguez Javier , Aldamiz Teresa , Richter Julia , Klapper Wolfram , Tzankov Alexandar , Dirnhofer Stefan , Rosenwald Andreas , Mate José Luis , Tapia Gustavo , Lenz Peter , Miething Cornelius , Hartmann Wolfgang , Chapuy Björn , Fend Falko , Ott German , Navarro José-Tomas , Grau Michael , Lenz Georg 
Published: August 2021

AbstractPlasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor aMYCtranslocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications inMCL1andIRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.
B-SOiD, an open-source unsupervised algorithm for identification and fast prediction of behaviors
Authors: Hsu Alexander I. , Yttri Eric A. 
Published: August 2021

AbstractStudying naturalistic animal behavior remains a difficult objective. Recent machine learning advances have enabled limb localization; however, extracting behaviors requires ascertaining the spatiotemporal patterns of these positions. To provide a link from poses to actions and their kinematics, we developed B-SOiD - an open-source, unsupervised algorithm that identifies behavior without user bias. By training a machine classifier on pose pattern statistics clustered using new methods, our approach achieves greatly improved processing speed and the ability to generalize across subjects or labs. Using a frameshift alignment paradigm, B-SOiD overcomes previous temporal resolution barriers. Using only a single, off-the-shelf camera, B-SOiD provides categories of sub-action for trained behaviors and kinematic measures of individual limb trajectories in any animal model. These behavioral and kinematic measures are difficult but critical to obtain, particularly in the study of rodent and other models of pain, OCD, and movement disorders.
Predicting post-operative right ventricular failure using video-based deep learning
Authors: Shad Rohan , Quach Nicolas , Fong Robyn , Kasinpila Patpilai , Bowles Cayley , Castro Miguel , Guha Ashrith , Suarez Erik E. , Jovinge Stefan , Lee Sangjin , Boeve Theodore , Amsallem Myriam , Tang Xiu , Haddad Francois , Shudo Yasuhiro , Woo Y. Joseph , Teuteberg Jeffrey , Cunningham John P. , Langlotz Curtis P. , Hiesinger William 
Published: August 2021

AbstractDespite progressive improvements over the decades, the rich temporally resolved data in an echocardiogram remain underutilized. Human assessments reduce the complex patterns of cardiac wall motion, to a small list of measurements of heart function. All modern echocardiography artificial intelligence (AI) systems are similarly limited by design – automating measurements of the same reductionist metrics rather than utilizing the embedded wealth of data. This underutilization is most evident where clinical decision making is guided by subjective assessments of disease acuity. Predicting the likelihood of developing post-operative right ventricular failure (RV failure) in the setting of mechanical circulatory support is one such example. Here we describe a video AI system trained to predict post-operative RV failure using the full spatiotemporal density of information in pre-operative echocardiography. We achieve an AUC of 0.729, and show that this ML system significantly outperforms a team of human experts at the same task on independent evaluation.
Large uncertainties in trends of energy demand for heating and cooling under climate change
Authors: Deroubaix Adrien , Labuhn Inga , Camredon Marie , Gaubert Benjamin , Monerie Paul-Arthur , Popp Max , Ramarohetra Johanna , Ruprich-Robert Yohan , Silvers Levi G. , Siour Guillaume 
Published: August 2021

AbstractThe energy demand for heating and cooling buildings is changing with global warming. Using proxies of climate-driven energy demand based on the heating and cooling Degree-Days methodology applied to thirty global climate model simulations, we show that, over all continental areas, the climate-driven energy demand trends for heating and cooling were weak, changing by less than 10% from 1950 to 1990, but become stronger from 1990 to 2030, changing by more than 10%. With the multi-model mean, the increasing trends in cooling energy demand are more pronounced than the decreasing trends in heating. The changes in cooling, however, are highly variable depending on individual simulations, ranging from a few to several hundred percent in most of the densely populated mid-latitude areas. This work presents an example of the challenges that accompany future energy demand quantification as a result of the uncertainty in the projected climate.
Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition
Authors: Aziz Diar , Portman Neil , Fernandez Kristine J. , Lee Christine , Alexandrou Sarah , Llop-Guevara Alba , Phan Zoe , Yong Aliza , Wilkinson Ashleigh , Sergio C. Marcelo , Ferraro Danielle , Etemadmoghadam Dariush , Bowtell David D. ,   kConFab Investigators, Serra Violeta , Waring Paul , Lim Elgene , Caldon C. Elizabeth 
Published: August 2021

AbstractBasal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.
Superpixel image segmentation of VISTA expression in colorectal cancer and its relationship to the tumoral microenvironment
Authors: Wu Dongling , Hacking Sean , Vitkovski Taisia , Nasim Mansoor 
Published: August 2021

AbstractColorectal cancer (CRC) is the third most common cause of cancer related death in the United States (Jasperson et al. in Gastroenterology 138:2044–2058, https://doi.org/10.1053/j.gastro.2010.01.054, 2010). Many studies have explored prognostic factors in CRC. Today, much focus has been placed on the tumor microenvironment, including different immune cells and the extracellular matrix (ECM). The present study aims to evaluate the role of V-domain immunoglobulin suppressor of T cell activation (VISTA). We utilized QuPath for whole slides image analysis, performing superpixel image segmentation (SIS) on a 226 patient-cohort. High VISTA expression correlated with better disease-free survival (DFS), high tumor infiltrative lymphocyte, microsatellite instability, BRAF mutational status as well as lower tumor stage. High VISTA expression was also associated with mature stromal differentiation (SD). When cohorts were separated based on SD and MMR, only patients with immature SD and microsatellite stability were found to correlate VISTA expression with DFS. Considering raised VISTA expression is associated with improved survival, TILs, mature SD, and MMR in CRC; careful, well-designed clinical trials should be pursued which incorporate the underlying tumoral microenvironment.