bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A017: Multiple intratumoral sources of kit ligand promote oncogenic kit signaling in gastrointestinal stomal tumor
Authors: Tieniber Andrew D. , Rossi Ferdinando , Hanna Andrew , Liu Mengyuan , Etherington Mark , Do Kevin , Wang Laura , DeMatteo Ronald P. 
Published: September 2022

Abstract
Introduction: Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kit receptor. While highly effective, tyrosine kinase inhibitors like imatinib are not curative. The natural ligand for the Kit receptor is Kit Ligand (KitL), which exists in both soluble and membrane-bound forms. We sought to determine the role of KitL in the oncogenic Kit signaling of GIST. Methods: KitV558Δ/+ mice, which spontaneously develop an intestinal GIST, were treated with imatinib or vehicle for 1 week, and sorted non-immune (CD45-) cells from tumors were submitted for single-cell RNA sequencing (n=3/group). GIST T1 cells were treated with KitL with or without imatinib and oncogenic Kit signaling was evaluated. KitV558Δ/+ mice were crossed with various KitL mutant and inducible models and tumor weights were measured (n=3-4/group). Human GISTs were stained for KitL expression by IHC, and an existing bulk RNA sequencing human GIST dataset with matched human serum was analyzed. Results: Unsupervised clustering revealed endothelial, smooth muscle, and tumor cells had high expression of KitL RNA in untreated tumors from KitV558Δ/+ mice. Imatinib therapy increased KitL RNA in all 3 cell types, suggesting that extra-tumoral KitL expression is dependent on oncogenic signaling (p&lt;0.05). In GIST T1 cells, exogenous KitL increased Kit activation and reduced imatinib’s efficacy. Tumors from mice with homozygous KitL deletion (KitV558Δ/+;Etv1Cre-ERT2/+;KitLflox/flox) were smaller than tumors from littermates with heterozygous KitL deletion (KitV558Δ /+;Etv1Cre-ERT2/+;KitLflox/+), providing evidence that KitL contributes to GIST development in vivo despite the presence of mutated Kit (p&lt;0.05). Furthermore, tumors from KitV558Δ/+;KitLKitL1Δ/KitL1Δ mice, which lack the proteolytic cleavage site for soluble KitL, were smaller than matched KitV558Δ/+ mice, indicating that soluble KitL is important for maximal tumor growth in vivo (p&lt;0.05). Heterogeneous KitL expression was confirmed in human GISTs by IHC. Human serum contained more KitL in patients with tumors resistant to imatinib and in those with tumors expressing more KitL RNA(p&lt;0.05). Conclusions: KitL is produced by multiple cell types within GIST and contributes to oncogenesis. Targeting KitL may be important for optimal tumor therapy.
Citation Format: Andrew D. Tieniber, Ferdinando Rossi, Andrew Hanna, Mengyuan Liu, Mark Etherington, Kevin Do, Laura Wang, Ronald P. DeMatteo. Multiple intratumoral sources of kit ligand promote oncogenic kit signaling in gastrointestinal stomal tumor [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A017.
Abstract B020: Multimodal single-cell analyses reveal identification of unique transcriptional subgroups in ewing sarcoma
Authors: Apfelbaum April A. , Waltner Olivia , Bhise Shruti S. , Kanaan Sami , Sarthy Jay F. , Furlan Scott N. , Lawlor Elizabeth R. 
Published: September 2022

Abstract
Ewing sarcoma (EwS) tumors are driven by pathognomonic fusions between FET proteins and ETS family transcription factors (most frequently EWS::FLI1). EWS::FLI1 drives tumorigenesis through massive transcriptomic and epigenomic rewiring. Despite mutational homogeneity, EwS are highly transcriptionally heterogeneous suggesting that cell context is a key determinant of EWS::FLI1-driven gene signatures. Fusion protein activity has been revealed as a core source of EwS heterogeneity. However, deep investigation into the transcriptomic and epigenomic heterogeneity of EwS cells has yet to be described. Molecular subtyping of EwS has thus far proven to be difficult to achieve with bulk RNA-sequencing approaches. We hypothesized that single-cell characterization of EwS cells would provide the necessary resolution to allow identification and characterization of transcriptionally distinct tumor subgroups. We subjected eight established EwS cell lines, one PDX-derived EwS line, and five non-EwS cell lines to single-cell multiomic (ATAC + RNA) sequencing. A range of 1300-3800 live cells were captured per sample, with an average of 25,000 transcript and accessible reads per cell. Initial analysis of transcriptomes confirmed the EwS-specific, EWS::FLI1-dependent signature gene sets in EwS samples. Integrated analysis of the multiome data from the 9 EwS samples identified inter-tumor heterogeneity and unsupervised k-means clustering revealed three molecular subgroups that were not evident from expression data alone. Subgroup 1 comprised only the A673 cell line, while the remaining 8 EwS samples were split between subgroups 2 and 3. Gene ontology analysis defined enrichment of distinct gene sets across the 3 subgroups. Interestingly, expression of subgroup 2-defining genes was reduced following knockdown of EWSR1::FLI1, while expression of subgroup 3-defining genes increased. Thus, these data show that transcriptionally distinct subgroups of EwS exist and these are defined, in part, by whether EWS::FLI1-dependent gene activation or gene repression dominates transcriptional rewiring. Our ongoing studies suggest that these molecular subgroups are defined by cooperation between the fusion and cell context-dependent transcription factors. Future analyses will determine if these distinct multiomic programs exist in primary patients tumors and test the pathobiologic and clinical significance of these novel molecular subgroups.
Citation Format: April A. Apfelbaum, Olivia Waltner, Shruti S. Bhise, Sami Kanaan, Jay F. Sarthy, Scott N. Furlan, Elizabeth R. Lawlor. Multimodal single-cell analyses reveal identification of unique transcriptional subgroups in ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B020.
Abstract IA017: Impact of oxygen and nutrient availability on sarcoma tumor neighborhood
Authors: Simon M. Celeste 
Published: September 2022

Abstract
Molecular oxygen (O2) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP- consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best- studied mechanism of response to hypoxia involves hypoxia inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a multitude of genes, including those involved in cell survival, angiogenesis, glycolysis and invasion/metastasis. Importantly, changes in oxygen can also be sensed via other stress pathways as well as changes in metabolite levels and the generation of reactive oxygen species by mitochondria. Collectively, this leads to cellular adaptations of protein synthesis, energy metabolism, mitochondrial respiration, lipid and carbon metabolism as well as nutrient acquisition. These mechanisms are integral inputs into fine- tuning the responses to hypoxic stress.
Citation Format: M. Celeste Simon. Impact of oxygen and nutrient availability on sarcoma tumor neighborhood [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA017.
Abstract IA030: A population-based, whole genome sequencing approach to mapping the genetic basis of mesenchymal malignancies
Authors: Thomas David M. 
Published: September 2022

Abstract
Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify novel pathways specific to mesenchymal cancers, whole genome germline sequencing was performed on 1,644 sporadic cases, and 3,205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare variant burden and ontologic analysis identified two new sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, while heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.
Citation Format: David M. Thomas. A population-based, whole genome sequencing approach to mapping the genetic basis of mesenchymal malignancies [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA030.
Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Authors: Langille Ellen , Al-Zahrani Khalid N. , Ma Zhibo , Liang Minggao , Uuskula-Reimand Liis , Espin Roderic , Teng Katie , Malik Ahmad , Bergholtz Helga , Ghamrasni Samah El , Afiuni-Zadeh Somaieh , Tsai Ricky , Alvi Sana , Elia Andrew , Lü YiQing , Oh Robin H. , Kozma Katelyn J. , Trcka Daniel , Narimatsu Masahiro , Liu Jeff C. , Nguyen Thomas , Barutcu Seda , Loganathan Sampath K. , Bremner Rod , Bader Gary D. , Egan Sean E. , Cescon David W. , Sørlie Therese , Wrana Jeffrey L. , Jackson Hartland W. , Wilson Michael D. , Witkiewicz Agnieszka K. , Knudsen Erik S. , Pujana Miguel Angel , Wahl Geoffrey M. , Schramek Daniel 
Published: September 2022

Abstract

Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for precision medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent “long-tail” breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 (“EpiDrivers”), cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of PIK3CAH1047R and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDriver mutations are found in ∼39% of human breast cancers, and ∼50% of ductal carcinoma in situ express casein, suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology.

Significance:
Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. In vivo CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis.
This article is highlighted in the In This Issue feature, p. 2711
Serial Profiling of Circulating Tumor DNA Identifies Dynamic Evolution of Clinically Actionable Genomic Alterations in High-Risk Neuroblastoma
Authors: Bosse Kristopher R. , Giudice Anna Maria , Lane Maria V. , McIntyre Brendan , Schürch Patrick M. , Pascual-Pasto Guillem , Buongervino Samantha N. , Suresh Sriyaa , Fitzsimmons Alana , Hyman Adam , Gemino-Borromeo Maria , Saggio Jennifer , Berko Esther R. , Daniels Alexander A. , Stundon Jennifer , Friedrichsen Megan , Liu Xin , Margolis Matthew L. , Li Marilyn M. , Tierno Marni Brisson , Oxnard Geoffrey R. , Maris John M. , Mossé Yael P. 
Published: September 2022

Abstract

Neuroblastoma evolution, heterogeneity, and resistance remain inadequately defined, suggesting a role for circulating tumor DNA (ctDNA) sequencing. To define the utility of ctDNA profiling in neuroblastoma, 167 blood samples from 48 high-risk patients were evaluated for ctDNA using comprehensive genomic profiling. At least one pathogenic genomic alteration was identified in 56% of samples and 73% of evaluable patients, including clinically actionable ALK and RAS–MAPK pathway variants. Fifteen patients received ALK inhibition (ALKi), and ctDNA data revealed dynamic genomic evolution under ALKi therapeutic pressure. Serial ctDNA profiling detected disease evolution in 15 of 16 patients with a recurrently identified variant—in some cases confirming disease progression prior to standard surveillance methods. Finally, ctDNA-defined ERRFI1 loss-of-function variants were validated in neuroblastoma cellular models, with the mutant proteins exhibiting loss of wild-type ERRFI1's tumor-suppressive functions. Taken together, ctDNA is prevalent in children with high-risk neuroblastoma and should be followed throughout neuroblastoma treatment.

Significance:
ctDNA is prevalent in children with neuroblastoma. Serial ctDNA profiling in patients with neuroblastoma improves the detection of potentially clinically actionable and functionally relevant variants in cancer driver genes and delineates dynamic tumor evolution and disease progression beyond that of standard tumor sequencing and clinical surveillance practices.
See related commentary by Deubzer et al., p. 2727.
This article is highlighted in the In This Issue feature, p. 2711
Accurate and Clear Quantitative Precipitation Nowcasting Based on a Deep Learning Model with Consecutive Attention and Rain-Map Discrimination
Authors: Ashesh Ashesh , Chang Chia-Tung , Chen Buo-Fu , Lin Hsuan-Tien , Chen Boyo , Huang Treng-Shi 
Published: September 2022

Abstract
Deep learning models are developed for high-resolution quantitative precipitation nowcasting (QPN) in Taiwan up to 3 h ahead. Many recent works aim to accurately predict relatively rare high-rainfall events with the help of deep learning. This rarity is often addressed by formulations that reweight the rare events. However, these formulations often carry a side effect of producing blurry rain-map nowcasts that overpredict in low-rainfall regions. Such nowcasts are visually less trustworthy and practically less useful for forecasters. We fix the trust issue by introducing a discriminator that encourages the model to generate realistic rain maps without sacrificing the predictive accuracy of rainfall extremes. Moreover, with consecutive attention across different hours, we extend the nowcasting time frame from typically 1 to 3 h to further address the needs for socioeconomic weather-dependent decision-making. By combining the discriminator and the attention techniques, the proposed model based on the convolutional recurrent neural network is trained with a dataset containing radar reflectivity and rain rates at a granularity of 10 min and predicts the hourly accumulated rainfall in the next three hours. Model performance is evaluated from both statistical and case-study perspectives. Statistical verification shows that the new model outperforms the current operational QPN techniques. Case studies further show that the model can capture the motion of rainbands in a frontal case and also provide an effective warning of urban-area torrential rainfall in an afternoon-thunderstorm case, implying that deep learning has great potential and is useful in 0–3-h nowcasting.
Comparison of Intraseasonal Variation of the Meridional Displacement of the Western North Pacific Subtropical High in Early and Late Summer
Authors: Zhou Peihao , Li Xiuzhen 
Published: September 2022

Abstract
The meridional displacement of the western North Pacific subtropical high (WNPSH) on an intraseasonal time scale is investigated, with emphasis on differences between early (May–June) and late (July–August) summer. The intraseasonal variation (ISV) of the meridional displacement of the WNPSH is dominated by the 10–30-day period, and the variation amplitude is larger in late summer. The ISV of the WNPSH is attributed mainly to the evolution of an anomalous cyclone/anticyclone north of the WNPSH in early summer, whereas it is due to a south-to-north dipole of an anomalous anticyclone and cyclone over East Asia in late summer. Moreover, the WNPSH tends to shift westward when it moves northward, and vice versa, especially in early summer. Both tropical convection and mid- to high-latitude teleconnection across Eurasia are responsible for the ISV of the meridional displacement of the WNPSH in early and late summer. The role of mid- to high-latitude teleconnection is more important in early summer, whereas tropical convection over the South China Sea is more crucial in late summer, through triggering a Pacific–Japan (PJ) pattern. In early summer, as the WNPSH shifts northward, rainfall increases over the Yangtze River valley and decreases over Southeast China, and vice versa. In late summer, deficient rainfall over North China persists when the WNPSH is at its southernmost location and during its northward shift, and vice versa. The characteristics, underlying processes, and impacts of the 10–30-day meridional displacement of the WNPSH are significantly different in early and late summer.
Mechanical and thermal behaviors of Ti36-Al16-V16-Fe16-Cr16 high entropy alloys fabricated by spark plasma sintering: An advanced material for high temperature/strength applications
Authors: Ujah Chika O , Popoola Patricia A , Popoola Olawale , Uyor Uwa O 
Published: September 2022

Conventional superalloys possess high strength, high oxidation resistance and high creep resistance. Nonetheless, some lose strength at elevated temperatures, while others suffer high temperature oxidation and creep. This work was aimed at developing high entropy alloy (HEA) of Ti36-Al16-V16-Fe16-Cr16 at near equi molar configuration using spark plasma sintering technique which would be able to address the challenges of conventional superalloys. The powders were mixed with Turbular mixer at 69 rpm for 10 h. The sintering was carried out with the same sintering pressure of 40 MPa, time of 10 min, heating rate of 100°C/mins on all the samples. Only the sintering temperature was varied. The temperatures used included 700°C, 800°C, 900°C, 1000°C and 1100°C, respectively. The powders and sintered samples were characterized with Scanning electron microscopy connected to Energy Dispersive Spectroscopy and X-ray diffractometer. The mechanical properties were tested with Nano indenter using ASTM D785 standard; while the thermal stability was investigated with thermogravimetric analyzer. Results showed that HEA sintered at 1000°C possessed the best nanomechanical, thermal and microstructural properties while that sintered at 700°C had the weakest properties. The best developed alloy had an improved elastic modulus of 671.17 ± 50 GPa and 930.12 ± 38 GPa at darker flakey phase and white phase, respectively. It had creep resistance of 1.82%, densification of 98.96% and porosity of 1.04%. It was concluded that the developed alloy can perform much better than most superalloys in high temperature and high strength and applications.
A new finding for the obesity paradox? Evaluation of the relationship between muscle and adipose tissue in nuclear grade prediction in patients with clear cell renal cell carcinoma
Authors: Demirel Emin , Dilek Okan 
Published: September 2022

BackgroundObesity is associated with an increased risk of developing clear cell renal cell carcinoma (ccRCC), but paradoxically there is a positive association between obesity and surveillance.PurposeTo investigate the relationship between nucleus grade classification and body composition in patients with matched co-morbid conditions with non-metastatic ccRCC.Materials and MethodsA total of 253 patients with non-metastatic ccRCC were included in the study. Body composition was assessed with abdominal computed tomography (CT) using an automated artificial intelligence software. Both adipose and muscle tissue parameters of the patients were calculated. In order to investigate the net effect of body composition, propensity score matching (PSM) procedure was applied over age, sex, and T stage parameters. In this way, selection bias and imbalance between groups were minimized. Univariate and multivariate logistic regression analyses were performed to identify the association between body composition and WHO/ISUP grade (I–IV).ResultWhen the body composition of the patients was examined without matching the conditions, it was found that the subcutaneous adipose tissue (SAT) values were higher in patients with low grades ( P = 0.001). Normal attenuation muscle area (NAMA) was higher in high-grade patients than low-grade patients ( P < 0.05). In the post-matching evaluation, only SAT/NAMA was found to be associated with high-grade ccRCC (univariate analysis: odds ratio [OR]=0.899, 95% confidence interval [CI]=0.817−0.988, P = 0.028; multivariate analysis: OR=0.922, 95% CI=0.901−0.974, P = 0.042).ConclusionCT-based body composition parameters can be used as a prognostic marker in predicting nuclear grade when age, sex, and T stage match conditions. This finding offers a new perspective on the obesity paradox.
Bronchial artery embolization for hemoptysis in adult patients with cystic fibrosis: a single-center retrospective study
Authors: Roussel Alexandre , Sage Edouard , Roux Antoine , Guth Axel , Mellot François , Gravel Guillaume 
Published: September 2022

Background Hemoptysis is a severe complication of cystic fibrosis (CF) for which bronchial artery embolization (BAE) is an efficient primary therapeutic option. However, recurrence is more frequent than for other etiologies of hemoptysis. Purpose To assess the safety and efficacy of BAE in patients with CF and hemoptysis and predictive factors for recurrent hemoptysis Material and Methods This retrospective study reviewed all adult patients with CF treated by BAE for hemoptysis in our center from 2004 to 2021. The primary endpoint was the recurrence of hemoptysis after bronchial artery embolization. Secondary endpoints were overall survival and complications. We introduced the vascular burden (VB) defined as the sum of all bronchial artery diameters measured on pre-procedural enhanced computed tomography (CT) scans. Results A total of 48 BAE were performed in 31 patients. A total of 19 recurrences occurred with a median recurrence-free survival of 3.9 years. In univariate analyzes, percentage of unembolized VB (%UVB) (hazard ratio [HR] = 1.034, 95% confidence interval [CI=1.016–1.052; P < 0.001) and %UVB vascularizing the suspected bleeding lung (%UVB-lat) (HR = 1.024, 95% CI=1.012–1.037; P < 0.001) were associated with recurrence. In multivariate analyzes, only %UVB-lat remained significantly associated with recurrence (HR = 1.020, 95% CI=1.002–1.038; P = 0.030). One patient died during follow-up. No complication of grade 3 or higher was reported according to the CIRSE classification system for complications. Conclusion When possible, unilateral BAE seems sufficient in patients with CF with hemoptysis even in such a diffuse disease involving both lungs. The efficiency of BAE could be improved by thoroughly targeting all arteries vascularizing the bleeding lung.