bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 922: Body composition and metabolic dysfunction really matter for the achievement of better outcomes in high-grade serous ovarian cancer
Authors: Cuello-Fredes Mauricio A. , Gomez Fernan , Wichmann Ignacio , Suarez Felipe , Kato Sumie , Brañes Jorge , Orlandini Elisa , Ibañez Carolina 
Published: April 2023

Abstract
Our objective was to evaluate the impact of body composition (BC), beyond body mass index (BMI), and lipid metabolism disorders on therapeutic responses and outcomes in high-grade serous ovarian cancer (HGSOC).Methods: 123 and 415 patients with advanced HGSOC from two cohorts (PUC and TCGA) were analyzed. Databases containing clinical/genomic variables were built-up. BC was estimated using the measurement of adiposity (e.g., Whole body Adipose Tissue [WBAT]) and muscle mass (Lumbar muscle area to vertebral body at L4-level, [PLVI]) by CT-scan. A list of 425 genes linked to obesity and lipid metabolism was used to identify clusters using non-negative matrix factorization. GSEA, Gene Ontology, KEGG pathways enrichment, and Ecotyper analyzes were also made. Survival curves and Cox-regression models were also built-up. Results: We identified four BC types and two clusters that, unlike BMI, effectively correlate with survival regardless of achieving optimal debulking or complete response. Mention deserves central sarcopenia, which was associated with worse survival in any condition. So also, that recovering a normal BC and adding medications to correct metabolism disorders (e.g., statins) could have a positive impact on outcomes. Along with this, we showed that micro-environments depleted of immune cells predominate in HGSOC, something more evident in the BC type (High WBAT/Low PLVI) and cluster (Obesity/Lipid Metabolism Type I) with worse prognosis. Conclusions: Here, we demonstrate the relevance of BC and lipid metabolism disorders in determining therapeutic responses and long-term outcomes. Also, the importance of incorporating corrective measures addressing these disorders to obtain better results. (Research supported by Fondecyt 1201083)
Citation Format: Mauricio A. Cuello-Fredes, Fernan Gomez, Ignacio Wichmann, Felipe Suarez, Sumie Kato, Jorge Brañes, Elisa Orlandini, Carolina Ibañez. Body composition and metabolic dysfunction really matter for the achievement of better outcomes in high-grade serous ovarian 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 922.
Abstract 940: Comprehensive characterization of MET exon 14 skipping mutations in non-small cell lung cancer
Authors: Wu Xue , Zhang Yaru , Pang Jiaohui , Lin Li , Yin Jiani C. , Tang Haimeng , Shao Yang 
Published: April 2023

Abstract
Background: MET exon 14 skipping mutation (METΔex14) is a key driver event in non-small cell lung cancer (NSCLC), and can be acquired following drug resistance to MET, EGFR or ALK inhibitors. Clinical and genomic features of METΔex14 in NSCLC remain to be further characterized.
Methods: A total of 556 baseline samples, 54 MET inhibitor-resistant samples and 16 EGFR/ALK inhibitor-resistant samples from 586 METΔex14 NSCLC patients were included in the analysis. Tissue and/or plasma samples were subjected to targeted next-generation sequencing (NGS) using Geneseeq’s 139/425 cancer-relevant gene panels.
Results: The overall frequency of METΔex14 was 1.1%, with a total of 266 distinct variants detected. Of these, 40.2% were base substitutions in the intronic non-coding region immediately adjacent to the splice acceptor site, followed by indels (25.6%) and base substitutions (4.5%) in the splice donor site, and indels (21.4%) and base substitutions (2.3%) in the splice acceptor site, etc. No associations with clinical features were found among different variants. At baseline, METΔex14 commonly co-occurred with TP53 mutations (40.8%), and CDK4 (15.8%) and MET (7.9%) amplifications. In 42 (7.6%) patients, concurrent oncogenic mutations in EGFR, KRAS, ALK, RET, BRAF, and ERBB2 were also detected. Such patients displayed a different spectrum of METΔex14 variants compared with those without concurrent oncogenic mutations (P=0.08). In patients treated with MET inhibitors, no difference in survival was seen among different METΔex14 variants (P=0.38). Notably, activation of EGFR or MET (kinase domain mutations/amplification) conferred primary resistance to savolitinib and crizotinib. In addition, patients with high chromosomal instability or low intratumoral heterogeneity had unfavorable PFS. Secondary resistance to MET-TKI included MET activation (D1228N/H, Y1230C/S, amplification), EGFR activating mutations/amplification, KRAS G12V, as well as FGFR2/4 amplification. Surprisingly, we identified a FGFR3-TACC3 fusion as a previously unreported secondary resistance mechanism to savolitinib in the second line setting. Finally, we found that MET exon 14 skipping mutation might be a rare secondary resistance mechanism to EGFR/ALK inhibitors.
Conclusion: In this study, we characterized METΔex14 in a large cohort of NSCLC patients and explored potential primary and secondary resistance mechanisms to savolitinib and crizotinib, which may facilitate drug development and help inform clinical actions.
Citation Format: Xue Wu, Yaru Zhang, Jiaohui Pang, Li Lin, Jiani C. Yin, Haimeng Tang, Yang Shao. Comprehensive characterization of MET exon 14 skipping mutations in non-small cell lung 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 940.
Abstract 952: Prioritizing mutations associated with smoking as a variable in lung cancer precision medicine with immunotherapies
Authors: Smith Margaret Rose , Wang Yuezhu , D’Agostino Ralph , Lin Yin , Ruiz Jimmy , Lycan Thomas , Topaloglu Umit , Abdulhaleem Mohammed , Chan Michael , Xing Fei 
Published: April 2023

Abstract
Background: In 2022, 230,000 new lung cancer cases will be diagnosed in the United States. The treatment regimen for non-small cell lung cancer (NSCLC) has drastically changed owing to the superior anti-cancer effects of immunotherapies. Immune checkpoint inhibitors (ICI) and chemo-immunotherapy (chemo-ICI) are the first-line treatments for NSCLC. Tumor Mutation Burden (TMB) and PD-L1 expression in tumor cells are potential biomarkers in predicting a patient’s survival and response to ICI. However, emerging data have shown that TMB and PD-L1 may no longer be an adequate biomarkers in predicting a patient’s response to ICI or chemo-ICI. We hypothesize that by using tumor-sequencing data and taking into effect a patient’s smoking status, we can identify biomarkers that predict survival to either ICI or chemo-ICI.
Methods: To identify biomarkers, we collected genomic sequencing data and comprehensive clinical characteristics on 424 NSCLC patients who received ICI or chemo-ICI treatment at Atrium Health Wake Forest Baptist. Cox-proportional hazard regression models were fit to identify mutations that were “beneficial” (HR &lt; 1) or “detrimental” (HR &gt; 1) for patients on different treatment regimens, followed by the generation of mutation composite scores (MCS) for each treatment. Co-occurrence analysis was performed to identify novel co-occurring and mutually exclusive mutations in each treatment and smoking group by mutation interaction analysis.
Results: We identify beneficial and harmful mutations in patients that received ICI or chemo-ICI treatment. We also identified unique biomarkers based on smoking statues. We then created an MCS for each smoking statues group and treatment type to assist personalize treatment.
Future directions: We will validate these results in other institute cohorts and add other clinical characteristics to personalize treatment based on MCS for an individual patient.
Citation Format: Margaret Rose Smith, Yuezhu Wang, Ralph D’Agostino, Yin Lin, Jimmy Ruiz, Thomas Lycan, Umit Topaloglu, Mohammed Abdulhaleem, Michael Chan, Fei Xing. Prioritizing mutations associated with smoking as a variable in lung cancer precision medicine with immunotherapies [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 952.
Abstract 970: Clinical analysis of patients (pts) with lung cancer treated with anti-PD1/PDL1 therapy
Authors: Zhao Xin , Liu Siyao , Su Junyan 
Published: April 2023

Abstract
Background: Characterization of Lung cancer treated with anti-PD1/PDL1 therapy was approach to predict the clinical benefit. This research is a prospective and observational study of long-term immunization therapy safety in routine clinical practice in lung cancer.
Methods: This study obtained 395 Chinese patients lung cancer patients who underwent surgical resection or biopsies from January 2020 to January 2022. It is aimed to evaluated the value of TMB, MSI, and PD-1 expression in the pts subset that was therapy at anti-PD1/PDL1 therapy(n=47), other anticancer therapies (n=348) included chemoradiation therapy(55%), docetaxel(18%), EGFR-TKIs (16%), pemetrexed (5%) etc.
Results: In this cohort, lung cancer pts treated with anti-PD1/PDL1 therapy had a higher proportion of MSI-H than others (7.7% vs 3.4%). PD-L1 High expression in two groups (anti-PD1/PDL1 therapy vs others) about in 19.1%(n=9) vs 10.6% (n=37), and low expression in 8.9% (n =31) vs 10.6% (n=5) pts. Median TMB was 13 mut/Mb from anti-PD1/PDL1 therapy and 9.6 mut/Mb from other therapy.
Conclusions: Lung cancer pts were integrated after to immunotherapy vs other therapy, most pts received multiple subsequent anticancer therapies. In this study, immune-related biomarker analysis of lung cancer populations with multiple treatment methods may help improve the efficacy of precise treatment in lung cancer.
Table Other therapy(n = 348) Anti-PD1/PDL1 therapy(n = 47) PD-L1 IHC High 10.6% 19.1% PD-L1 IHC Low 8.9% 10.6% TMB Median (mut/Mb) 9.6 13.0 MSS Status 76.0% 74.4% MSI Low Status 20.7% 17.9% MSI High Status 3.4% 7.7%
Citation Format: Xin Zhao, Siyao Liu, Junyan Su. Clinical analysis of patients (pts) with lung cancer treated with anti-PD1/PDL1 therapy [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 970.
Abstract SY31-02: Determinants of hypoxia in pancreatic cancer and identification of ULK1 as a potential therapeutic target
Authors: Zhang Ji , Cojocari Dan , Cairns Rob , Koritzinsky Marianne , Wouters Bradly G. 
Published: April 2023

Abstract
The effectiveness of radiation treatment is impacted by spatially defined features of the tumor microenvironment including areas of tumor hypoxia. This is due in part to direct protection against radiation damage by hypoxia, as well as through the influence of hypoxia on tumor, stroma and immune cell phenotypes. Despite this understanding, our progress in advancing therapies to address tumor hypoxia in patients have been largely unsuccessful. This is driven in part to the incredible variability in tumor hypoxia across patients as well as to a limited understanding of the underlying causes and consequences of hypoxia on an individual patient basis. As a step towards more precision approaches for hypoxia directed therapies we are characterizing hypoxia and its causes in individual patients and in matched patient derived xenografts. Our data reveal a striking variation in hypoxia across patients, and a corresponding variation in both oxygen consumption and hypoxia tolerance in patient derived organoids. We hypothesize that levels of hypoxia within individual tumors are determined through separate processes that drive changes in oxygen demand coupled with those that influence adaptation and survival to hypoxic stress. We have also identified ULK1 as a key contributor to both of these processes. Loss or inhibition of ULK1, a gene activated downstream of the unfolded protein response during hypoxia, results in defects in both mitochondrial and ER turnover leading to increases in both oxygen consumption and ER stress. Consequently, knockdown of ULK1 in established pancreatic cancer xenografts results in development of more hypoxia, while at the same time promotes the death of cells that become hypoxic. This has a dramatic impact on tumor growth, leading to complete remission in some models and suggesting that ULK1 should be pursued as a tumor microenvironment therapeutic target.
Citation Format: Ji Zhang, Dan Cojocari, Rob Cairns, Marianne Koritzinsky, Bradly G. Wouters. Determinants of hypoxia in pancreatic cancer and identification of ULK1 as a potential therapeutic target. [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 SY31-02.
Supplementary Figure S2 from A PSCA/PGRN–NF-κB–Integrin–α4 Axis Promotes Prostate Cancer Cell Adhesion to Bone Marrow Endothelium and Enhances Metastatic Potential
Authors: Zhao Zhigang , Li Ermao , Luo Lianmin , Zhao Shankun , Liu Luhao , Wang Jiamin , Kang Ran , Luo Jintai 
Published: April 2023

<p>PSCA had no effect on the expression levels of integrin αv (ITGAV), integrin β1 (ITGB1) and integrin β3 (ITGB3) in PCa cells. A.	Western blot analyses. B. qRT-PCR analyses.</p>
Data from Inhibiting WEE1 and IKK-RELA Crosstalk Overcomes TNFα Resistance in Head and Neck Cancers
Authors: Hu Zhengbo , Viswanathan Ramya , Cheng Hui , Chen Jianghong , Yang Xinping , Huynh Angel , Clavijo Paul , An Yi , Robbins Yvette , Silvin Christopher , Allen Clint , Ormanoglu Pinar , Martin Scott , Cornelius Shaleeka , Saleh Anthony , Chen Zhong , Van Waes Carter , Morgan Ethan L. 
Published: April 2023

<div>Abstract<p>TNFα is a key mediator of immune and radiotherapy-induced cytotoxicity, but many cancers, including head and neck squamous cell carcinomas (HNSCC), display TNF resistance due to activation of the canonical IKK–NF-κB/RELA pro-survival pathway. However, toxicities associated with direct targeting of the canonical pathway point to the need to identify mechanism(s) contributing to TNFα resistance and synthetic lethal targets to overcome such resistance in cancer cells. Here, RNAi screening for modulators of TNFα–NF-κB reporter activity and cell survival unexpectedly implicated the WEE1 and CDC2 G<sub>2</sub>–M checkpoint kinases. The IKKα/β-RELA and WEE1-CDC2 signaling pathways are activated by TNFα and form a complex in cell lines derived from both human papillomavirus (−) and (+) subtypes of HNSCC. WEE1 inhibitor AZD1775 reduced IKK/RELA phosphorylation and the expression of NF-κB–dependent pro-survival proteins Cyclin D1 and BCL2. Combination of TNFα and AZD1775 enhanced caspase-mediated apoptosis <i>in vitro</i>, and combination treatment with radiotherapy and AZD1775 potentiated inhibition of HNSCC tumor xenograft growth <i>in vivo</i>, which could be significantly attenuated by TNFα depletion. These data offer new insight into the interplay between NF-κB signaling and WEE1-mediated regulation of the G<sub>2</sub>–M cell-cycle checkpoint in HNSCC.</p>Implications:<p>Inhibiting WEE1 and IKK-RELA crosstalk could potentially enhance the effects of therapies mediated by TNFα with less systemic immune suppression and toxicity than observed with direct interruption of IKK-NF-κB/RELA signaling.</p></div>
C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis inFLT3-Mutant Leukemia
Authors: Sabatier Marie , Birsen Rudy , Lauture Laura , Mouche Sarah , Angelino Paolo , Dehairs Jonas , Goupille Léa , Boussaid Ismael , Heiblig Maël , Boet Emeline , Sahal Ambrine , Saland Estelle , Santos Juliana C. , Armengol Marc , Fernández-Serrano Miranda , Farge Thomas , Cognet Guillaume , Simonetta Federico , Pignon Corentin , Graffeuil Antoine , Mazzotti Céline , Avet-Loiseau Hervé , Delos Océane , Bertrand-Michel Justine , Chedru Amélie , Dembitz Vilma , Gallipoli Paolo , Anstee Natasha S. , Loo Sun , Wei Andrew H. , Carroll Martin , Goubard Armelle , Castellano Rémy , Collette Yves , Vergez François , Mansat-De Mas Véronique , Bertoli Sarah , Tavitian Suzanne , Picard Muriel , Récher Christian , Bourges-Abella Nathalie , Granat Fanny , Kosmider Olivier , Sujobert Pierre , Colsch Benoit , Joffre Carine , Stuani Lucille , Swinnen Johannes V. , Guillou Hervé , Roué Gael , Hakim Nawad , Dejean Anne S. , Tsantoulis Petros , Larrue Clément , Bouscary Didier , Tamburini Jerome , Sarry Jean-Emmanuel 
Published: April 2023

AbstractAlthough transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.Significance:FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML.This article is highlighted in the In This Issue feature, p. 1501
Figure S5 from Excessive Costimulation Leads to Dysfunction of Adoptively Transferred T Cells
Authors: Wijewarnasuriya Dinali , Bebernitz Christina , Lopez Andrea V. , Rafiq Sarwish , Brentjens Renier J. 
Published: April 2023

<p>(A)	CAR T cells, day 0 before infusion, were characterized by flow cytometry. Data shown is mean +/- s.e.m. of three independent experiments. "ns" (not significant) by unpaired t test. (B)	Representative flow cytometry plots of CAR T cell CD8+ and CD4+ ratios day 5 after infusion referenced in Figure 2D. (C)	Representative flow cytometry plots of PD-1, LAG-3, and TIM-3 inhibitory receptor expression of CD8+ CAR T cells referenced in Figure 2E. (D)	CAR T cells, day 5 after infusion, were characterized by flow cytometry. m1928ï�ºIL-12 CAR T cells, gated on CD8+ T cells, expressed higher levels of double positive inhibitory receptors, LAG-3;TIM-3 (*p=0.0397) and LAG-3;PD-1 (*p=0.001), and showed a trend toward higher levels of TIM-3;PD-1 (*p=0.0563). Data obtained is mean +/- s.e.m. of three independent experiments analyzed by unpaired t test.</p>
Figure S4 from Excessive Costimulation Leads to Dysfunction of Adoptively Transferred T Cells
Authors: Wijewarnasuriya Dinali , Bebernitz Christina , Lopez Andrea V. , Rafiq Sarwish , Brentjens Renier J. 
Published: April 2023

<p>(A)	CAR T cells, day 5 after infusion, were characterized by flow cytometry in terms of percentage and representative plots. m1928ï�ºIL-12 CAR T cells expressed higher levels of inhibitory receptors, PD-1 (*p=0.0015) and LAG-3 (*p=0.0491) and showed a trend toward higher levels of TIM-3 (*p=0.1715). Data obtained is mean +/- s.e.m. of three independent experiments analyzed by unpaired t test. (B)	Representative flow cytometry plots of PD-1, LAG-3, and TIM-3 inhibitory receptor expression of CAR T cells referenced in Figure 2B.</p>
Figure S3 from Excessive Costimulation Leads to Dysfunction of Adoptively Transferred T Cells
Authors: Wijewarnasuriya Dinali , Bebernitz Christina , Lopez Andrea V. , Rafiq Sarwish , Brentjens Renier J. 
Published: April 2023

<p>(A)	CAR T cells were co-cultured with EL4mCD19 tumor cells and then assessed for cytotoxicity 4 hours later, using a luciferase killing assay. There was no difference in tumor lysis between CAR T cells and vex-GFP tagged CAR T cells (two-way ANOVA). Data shown is representative of two independent experiments. (B)	Flow cytometry gating strategy to determine CD8+ and CD4+ ratio and PD-1, TIM-3, and LAG-3 inhibitory receptor expression.</p>
The Effect of Teacher’s Teaching Style in Araling Panlipunan on Student’s Motivation of Grade 8 Students in Sta. Cruz South High School
Authors: Ofiaza Evangeline S. 
Published: April 2023

The study shows that shows, out of ninety (90) respondents, there is an equal number of respondents when grouped according to gender. The study revealed that 80% of the respondents acknowledge the importance effective teaching styles to motivate the students. The stiudy further confirm that 3.7% of the respondents, considered Araling Panlipunan fun and interesting. It was also confirmed in the study that 3.8% of the respondents participated actively in Araling Panlipunan. The study revealed that majority of the respondents had the view that having effective teaching-styles in motivating students had a high impact on the academic performance. Based on the findings of the study, the following recommendations are made:Faculty staffs are encouraged to adapt new trends of teaching in order to inspire our students embracing Araling Panlipunan subject. It is further recommended that Araling Panlipunan teachers should not only using a pen and paper materials in teaching, instead think of an effective materials were in students become more motivated in exploring ideas like projectors and more. Conduct future studies to develop more teaching styles to motivate students to study Araling Panlipunan.
A Blanket That Leaves the Feet Cold: Exploring the AI Act Safety Framework for Medical AI
Authors: Palmieri Sofia , Goffin Tom 
Published: April 2023

Abstract
The AI Act is based on, and at the same time aims to protect fundamental rights, implying their protection, while fulfilling the safety requirement prescribed by the AI Act within the whole lifecycle of AI systems. Based on a risk classification, the AI Act provides a set of requirements that each risk class must meet in order for AI to be legitimately offered on the EU market and be considered safe. However, despite their classification, some minimal risk AI systems may still be prone to cause risks to fundamental rights and user safety, and therefore require attention. In this paper we explore the assumption that despite the fact that the AI Act can find broad ex litteris coverage, the significance of this applicability is limited.