bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 956: FBXW7 regulates imatinib chemoresistance through targeting MCL1 for apoptotic regulation in gastrointestinal stromal tumors
Authors: Wu Xiyu , Iwatsuki Masaaki , Lou Meiyue , Ishimoto Takatsugu , Baba Yoshifumi , Miyamoto Yuji , Baba Hideo 
Published: April 2023

Abstract
Introduction: Imatinib definitively contribute to improve prognosis for high-risk or unresectable GISTs. Due to therapeutic efficacy is limited by imatinib chemoresistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that early enable patients to utilize more effective therapeutic strategies remains urgent. Here, we evaluate that the ability of FBXW7 acts as a predictor of imatinib therapeutic effect in preclinical models, and the potential of FBXW7-MCL1 axis promote imatinib-induced apoptosis response.
Methods: The cellular and in vivo correlation between FBXW7 and imatinib chemoresistance via FBXW7-MCL1 axis were evaluated by detecting IC50 value, apoptosis assay, and GIST xenograft studies. The clinical significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs by immunohistochemical staining and multivariate analyses.
Results: FBXW7 affects imatinib chemoresistance through regulating cellular apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate cellular apoptosis. MCL1 involves in the regulation of imatinib chemoresistance through inhibiting apoptosis of GIST-T1 cells. FBXW7 regulates imatinib chemoresistance via down-regulating MCL1 for enhancing imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells via targeting MCL1 to predict therapeutic efficacy of imatinib treatment in vivo. Through 5-year RFS rates analysis and multivariate analysis, the ability of FBXW7 predicting therapeutic efficacy of high-risk GIST patients with adjuvant imatinib was proved.
Conclusions: FBXW7 regulates imatinib chemoresistance through inhibiting MCL1 for enhancing imatinib-induced apoptosis in GIST and acted as a reliable predictor of imatinib treatment efficacy in high-risk GIST patients treated imatinib.
Citation Format: Xiyu Wu, Masaaki Iwatsuki, Meiyue Lou, Takatsugu Ishimoto, Yoshifumi Baba, Yuji Miyamoto, Hideo Baba. FBXW7 regulates imatinib chemoresistance through targeting MCL1 for apoptotic regulation in gastrointestinal stromal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 956.
Abstract 96: Integrated molecular analysis of human dedifferentiated liposarcoma identifies a population of liposarcoma progenitors vulnerable to TGF beta inhibition
Authors: Gruel Nadège , Quignot Chloé , Vibert Julien , Bonvalot Sylvie , Zein Sophie El , Tzanis Dimitri , Baulande Sylvain , Mariani Odette , Waterfall Joshua , Delattre Olivier , Watson Sarah 
Published: April 2023

Abstract
Introduction: Dedifferentiated liposarcomas (DDLPS) are the most frequent high-grade soft tissue sarcoma in adults. From a pathological point of view, these tumors are composed of high-grade undifferentiated tumor cells (DD), often showing an abrupt transition from a compartment of well-differentiated adipocytic tumor cells (WD). Tumor cells from both WD and DD compartments are characterized by recurrent MDM2 amplification, but their cellular origin and the molecular mechanisms associated with dedifferentiation are poorly understood.
Methods: We performed an integrated molecular analysis of tumors collected from 11 patients undergoing surgery for primary untreated DDLPS. DDLPS tumors were analyzed by single-cell RNA sequencing (scRNAseq) and bulk RNA sequencing on paired WD and DD samples from the same tumors. Results were validated in vitro and in vivo in an additional cohort of human tumors, patient-derived xenografts and DDLPS cell lines.
Results: Through RNA-sequencing of 102,753 individual cells from 11 primary DDLPS lesions, major cell clusters were identified based on unsupervised clustering of gene expression profiles and canonical markers. They include 31 tumor microenvironment clusters and 11 tumor cell clusters. A cluster of tumor cells from the WD compartment is characterized by signatures of early adipocytic progenitors, previously identified as TGFβ-dependent, DPP4-positive stromal progenitors. We show that these cells harbor specifically the truncal genomic alterations of the cancer, with further subclonal mutations identifiable in both WD and DD compartments of DDLPS. Furthermore, these cells have multipotent properties and their differentiation towards the adipocytic lineage is inhibited by TGFβ. Treatment of DD tumor cells with TGFβ inhibitors restores their adipocytic phenotype in vitro and in vivo.
Conclusion: We provide the first single-cell atlas of human DDLPS tumor and microenvironment and identify a population of adipocytic tumor progenitors at the origin of both WD and DD compartments. This study provides rationale for the development of therapeutic strategies based on TGFβ inhibition in advanced DDLPS.
Citation Format: Nadège Gruel, Chloé Quignot, Julien Vibert, Sylvie Bonvalot, Sophie El Zein, Dimitri Tzanis, Sylvain Baulande, Odette Mariani, Joshua Waterfall, Olivier Delattre, Sarah Watson. Integrated molecular analysis of human dedifferentiated liposarcoma identifies a population of liposarcoma progenitors vulnerable to TGF beta inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 96.
Abstract 967: Real-world transcriptomic biomarkers as replacement for immunohistochemistry and FISH studies in breast cancer
Authors: Albitar Maher , Goy Andre , Pecora Andrew , Graham Deena , McNamara Donna Donna , Charifa Ahmad Ahmad , IP Andrew , Ma Wanlong , Waintraub Stanley 
Published: April 2023

Abstract
Background: Human epidermal growth factor receptor-2 (HER2) and hormone receptors are typically used as binary biomarkers for selecting breast cancer therapy. There is a need to explore the clinical relevance of these biomarkers as continuous variables. This is particularly relevant for the new class of antibody-drug conjugates (ADC), in which a relatively low HER2 expression level is adequate for targeting tumor cells. We explored the potential of RNA profiling, determined by next generation sequencing (NGS), to provide more flexible clinical biomarkers as compared with immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH).
Methods: Clinical and laboratory data from 57 breast cancers collected by the COTA real-world data company were used to study biomarker levels as detected by routine clinical transcriptomic tests. HER2 (ERBB2), estrogen receptor alpha (ESR1), and androgen receptor (AR) mRNA levels were compared with reported HER2 and estrogen receptor (ER) IHC and FISH results.
Results: RNA levels accurately reflected and predicted HER2 amplification (see table below). Importantly, RNA data showed significant variation and overlap in the levels of ERBB2 mRNA between cases scored by IHC as zero, 1+, and 2+. This variation correlated with progression-free survival (PFS). Similarly, the ESR1 RNA levels accurately reflected ER status and demonstrated significant variation between positive cases. RNA data also showed significant variations in the AR levels. Patients wssith high AR mRNA levels had significantly better PFS (P=0.05). Patients expressing high ER and AR levels had significantly better PFS than those expressing low ESR1 and AR levels (P=0.03).
Conclusions: These findings suggest that RNA analysis using NGS is an alternative to IHC and FISH. RNA provides continuous data that can determine cut-off points predicting response to therapy and should be explored in predicting ADC response.
ERBB2 mRNA levels (FPKM) in various HER2 IHC groupss IHC Score Valid N Mean Median Minimum Maximum Quartile Range Std.Dev. Zero 19 231 243 63 537 170 110 Zero vs one 3 151 155 45 253 208 104 Zero to one vs one 18 397 302 172 845 365 222 One Vs two 13 495 423 159 1094 273 284 Two vs three 4 7523 7649 937 13859 7183 5310
Citation Format: Maher Albitar, Andre Goy, Andrew Pecora, Deena Graham, Donna Donna McNamara, Ahmad Ahmad Charifa, Andrew IP, Wanlong Ma, Stanley Waintraub. Real-world transcriptomic biomarkers as replacement for immunohistochemistry and FISH studies in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 967.
Abstract SY30-03: Composing each patient’s equation: Unraveling brain tumor complexity by integrating multi-regional image-localized biopsies
Authors: Swanson Kristin R. 
Published: April 2023

Abstract
Glioblastoma is a uniquely challenging and aggressive cancer that is practically considered uniformly fatal. This aggressiveness is driven by heterogeneity between and within patients and the diffuse invasion of tumor cells deep into the normal appearing brain tissue surrounding the frank tumor abnormality. Mathematical neuro-oncology (MNO) is a burgeoning field that seeks to bring together individual patient data (like patient imaging, tissue biopsies etc) to tune mathematical models that accurately predict and quantify response to treatments for each patient. These mathematical models use both mechanistic “weather forecasting” methods and artificial intelligence pattern recognition methods. Ultimately, these models form the basis of modern "precision medicine" approaches to tailor therapy in a patient-specific manner. These models can be used to overcome the limited ability of imaging to accurately detect tumor cells, improve prognostic predictions, stratify patients, and assess treatment response in silico in the construction of effective clinical trials and treatment protocols, thus accelerating the pace of clinical research.
This presentation will focus on the growing translation of MNO to clinical neuro-oncology highlighting burgeoning insights into sex differences in tumor incidence, outcomes, and response to therapy. Specifically, I will discuss 1) use of our 4,500+ patient cohorts of 100,000+ annotated serial MR imaging data to develop digital twins accurately predict response and outcomes in patients and 2) our unique collection of 1000+ image-localized biopsies across nearly 200 patients to detect sex-distinct patterns of mapping between regional imaging features and underlying regional tumor biology. We will demonstrate the value of these novel combined resources in predicting response to treatment for EGFR-targeted therapies in 3 clinical trials and differentiating response to novel dendritic cells vaccines and CAR T-cell therapies in 2 additional clinical trials.
Taken together, these complimentary approaches provide a platform to incorporate inter- and intra- tumoral heterogeneity into accurate predictive models that advance precision oncology for glioblastoma patients.
Citation Format: Kristin R. Swanson. Composing each patient’s equation: Unraveling brain tumor complexity by integrating multi-regional image-localized biopsies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY30-03.
Abstract SY33-02: Novel molecular mechanisms of lung cancer plasticity and targeting lung squamous cell carcinoma
Authors: Han Cecil 
Published: April 2023

Abstract
Lung cancer is marked by a high degree of genetic and histopathological heterogeneity. Lineage plasticity, the ability of cells to transform from one cell type to another, has been associated with intratumoral heterogeneity and therapeutic resistance. The molecular drivers and mechanisms of cancer cell plasticity and histological transdifferentiation of lung cancer are largely unknown. A deubiquitinating enzyme, Ubiquitin-Specific Peptidase 13 (USP13), is frequently amplified at chromosome 3q.26 amplicon in lung squamous cell carcinoma. USP13 knock-in overexpressing mouse model was crossed with KrasLSL-G12D; Trp53fl/fl (KP) mouse to generate KrasLSL-G12D; Trp53fl/fl; Usp13LSL (KPU) mouse model. Intratracheal administration of adenovirus expressing Cre recombinase to the lung of the KPU mouse developed aggressive lung tumors and a shortened survival compared to the KP mouse model. Importantly, while the KP mice developed lung adenocarcinoma, 100% of KPU mice developed lung squamous cell carcinoma. The squamous cell carcinoma of the KPU mice faithfully mimicked the molecular signatures, cellular pathways, and tumor microenvironments of human lung squamous cell carcinoma. Delivery of cell type-restricted viruses to the lungs further identified bronchiolar secretory club cells as the predominant cell-of-origin of KPU-induced lung squamous cell carcinoma. USP13 altered the levels of TTF-1 and c-Myc in club cells of the airway and reinforced the fate of CC10+ club cells to squamous carcinoma development instead of adenocarcinoma. USP13 directly acted on the K48-linked ubiquitination of c-Myc and increased the protein stability of c-Myc in human lung cancer cells. Overexpression of USP13 increased the half-life of c-Myc while inhibiting USP13 deubiquitinase activity decreased the c-Myc protein level. USP13 upregulated the expression of squamous lineage markers (Sox2, CK5, P40) in the primary mouse and advanced human lung cancer cells. Our findings revealed that USP13 promotes the lineage plasticity of origin-of-cells of the lung and drives transdifferentiation to squamous cell carcinoma. Finally, our study suggests the critical role of USP13 in unlocking the phenotypic plasticity of lung cancer, which may lead to novel therapeutics targeting lung cancer.
Citation Format: Cecil Han. Novel molecular mechanisms of lung cancer plasticity and targeting lung squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY33-02.
Data from Test Performance of Immunologic Fecal Occult Blood Testing and Sigmoidoscopy Compared with Primary Colonoscopy Screening for Colorectal Advanced Adenomas
Authors: Khalid-de Bakker Carolina A.J. , Jonkers Daisy M.A.E. , Sanduleanu Silvia , de Bruïne Adriaan P. , Meijer Gerrit A. , Janssen Jan B.M.J. , van Engeland Manon , Stockbrügger Reinhold W. , Masclee Ad A.M. 
Published: April 2023

<div>Abstract<p>Given the current increase in colorectal cancer screening, information on performance of screening tests is needed, especially in groups with a presumed lower test performance. We compared test performance of immunologic fecal occult blood testing (FIT) and pseudosigmoidoscopy with colonoscopy for detection of advanced adenomas in an average risk screening population. In addition, we explored the influence of gender, age, and location on test performance. FIT was collected prior to colonoscopy with a 50 ng/mL cutoff point. FIT results and complete colonoscopy findings were available from 329 subjects (mean age: 54.6 ± 3.7 years, 58.4% women). Advanced adenomas were detected in 38 (11.6%) of 329 subjects. Sensitivity for advanced adenomas of FIT and sigmoidoscopy were 15.8% (95% CI: 6.0–31.3) and 73.7% (95% CI: 56.9–86.6), respectively. No sensitivity improvement was obtained using the combination of sigmoidoscopy and FIT. Mean fecal hemoglobin in FIT positives was significantly lower for participants with only proximal adenomas versus those with distal ones (<i>P</i> = 0.008), for women versus men (<i>P</i> = 0.023), and for younger (<55 years) versus older (≥55 years) subjects (<i>P</i> = 0.029). Sensitivities of FIT were 0.0% (95% CI: 0.0–30.9) in subjects with only proximal versus 21.4% (95% CI: 8.3–41.0) in those with distal nonadvanced adenomas; 5.3% (95% CI: 0.0–26.0) in women versus 26.3% (95% CI: 9.2–51.2) in men; 9.5% (95% CI: 1.2–30.4) in younger versus 23.5% (95% CI: 6.8–49.9) in older subjects. Sigmoidoscopy had a significantly higher sensitivity for advanced adenomas than FIT. A single FIT showed very low sensitivity, especially in subjects with only proximal nonadvanced adenomas, in women, and in younger subjects. This points to the existence of “low” FIT performance in subgroups and the need for more tailored screening strategies. <i>Cancer Prev Res; 4(10); 1563–71. ©2011 AACR</i>.</p></div>
Data from Elevated Dietary Carbohydrate and Glycemic Intake Associate with an Altered Oral Microbial Ecosystem in Two Large U.S. Cohorts
Authors: Monson Kelsey R. , Peters Brandilyn A. , Usyk Mykhaylo , Um Caroline Y. , Oberstein Paul E. , McCullough Marjorie L. , Purdue Mark P. , Freedman Neal D. , Hayes Richard B. , Ahn Jiyoung 
Published: April 2023

<div><p>The human oral microbiome is associated with chronic diseases including cancer. However, our understanding of its relationship with diet is limited. We assessed the associations between carbohydrate and glycemic index (GI) with oral microbiome composition in 834 nondiabetic subjects from the NCI Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the American Cancer Society Cancer Prevention Study II cohorts. The oral microbiome was characterized using 16Sv3-4 rRNA sequencing from oral mouthwash samples. Daily carbohydrate and GI were assessed from food frequency questionnaires. We used linear regression, permutational multivariate ANOVA, and negative binomial Generalized Linear Models (GLM) to test associations of diet with α- and β-diversity and taxon abundance (adjusting for age, sex, cohort, body mass index, smoking, caloric intake, and alcohol). A <i>q</i>-value (FDR-adjusted <i>P</i> value) of <0.05 was considered significant. Oral bacterial α-diversity trended higher in participants in the highest quintiles of carbohydrate intake, with marginally increased richness and Shannon diversity (<i>P</i><sub>trend</sub> = 0.06 and 0.07). Greater carbohydrate intake was associated with greater abundance of class Fusobacteriia (<i>q</i> = 0.02) and genus <i>Leptotrichia</i> (<i>q</i> = 0.01) and with lesser abundance of an Actinomyces operational taxonomic unit (<i>q</i> = 4.7E-04). Higher GI was significantly related to greater abundance of genus Gemella (<i>q</i> = 0.001). This large, nationwide study provides evidence that diets high in carbohydrates and GI may influence the oral microbiome.</p>Significance:<p>Taxonomic differences at the highest intake quintiles may reflect diet-induced increases in carcinogenic bacteria and decreases in protective bacteria. Genus <i>Leptotrichia</i> has been implicated in cancer and inflammatory disease, while immunostimulatory genus <i>Gemella</i> may increase inflammatory disease risk. These differences further our understanding of possible mechanisms leading to oral and systemic disease.</p></div>
Searching for a Semantic Parallel to the Concept of Depression
Authors: Cerroni Enrico 
Published: April 2023

Abstract
This paper examines whether a semantic parallel to the modern use of the word depression can be identified in ancient Greek. To that end, it retraces the development of the lexical family of the verb θλίβω, ‘to press’, and the abstract noun θλῖψις to gain the emotional and psychological meaning of ‘pressure’ or ‘affliction’. An analysis of the collected data suggests that a similar valence may be found in Hellenistic and Imperial Greek. However, this development is disregarded by authors with greater stylistic ambitions. Even physicians such as Galen continue to use θλῖψις solely in a physical, concrete sense. Conversely, the conceptualization in the singular of the word de-pression is lacking in ancient Greek. An antecedent may be identified in the formation of the prefixed verb καταθλίβω and the derived noun κατάθλιψις, found only from Late Antiquity onward, but this retains a concrete valence.
Middepth Recipes
Authors: Rogers Mason , Ferrari Raffaele , Nadeau Louis-Philippe 
Published: April 2023

Abstract
The Indo-Pacific Ocean appears exponentially stratified between 1- and 3-km depth with a decay scale on the order of 1 km. In his celebrated paper “Abyssal recipes,” W. Munk proposed a theoretical explanation of these observations by suggesting a pointwise buoyancy balance between the upwelling of cold water and the downward diffusion of heat. Assuming a constant upwelling velocity w and turbulent diffusivity κ, the model yields an exponential stratification whose decay scale is consistent with observations if κ ∼ 10−4 m2 s−1. Over time, much effort has been made to reconcile Munk’s ideas with evidence of vertical variability in κ, but comparably little emphasis has been placed on the even stronger evidence that w decays toward the surface. In particular, the basin-averaged w nearly vanishes at 1-km depth in the Indo-Pacific. In light of this evidence, we consider a variable-coefficient, basin-averaged analog of Munk’s budget, which we verify against a hierarchy of numerical models ranging from an idealized basin-and-channel configuration to a coarse global ocean simulation. Study of the budget reveals that the decay of basin-averaged w requires a concurrent decay in basin-averaged κ to produce an exponential-like stratification. As such, the frequently cited value of 10−4 m2 s−1 is representative only of the bottom of the middepths, whereas κ must be much smaller above. The decay of mixing in the vertical is as important to the stratification as its magnitude.

Significance Statement
Using a combination of theory and numerical simulations, it is argued that the observed magnitude and shape of the global ocean stratification and overturning circulation appear to demand that turbulent mixing increases quasi-exponentially toward the ocean bottom. Climate models must therefore prescribe such a vertical profile of turbulent mixing in order to properly represent the heat and carbon uptake accomplished by the global overturning circulation on centennial and longer time scales.