bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 7640: Prognostic significance of S100A16 expression in patients with resected lung adenocarcinoma
Authors: Hung Jung-Jyh
Published: March 2024

Background: Lung cancer is the leading cause of cancer death worldwide. Tumor recurrence is the most common cause of treatment failure after surgical resection. The S100 protein family is a multigenic group of cytoplasmic calcium-binding proteins. S100A16 has to be reported to be an independent prognostic indicator of poor overall survival in lung adenocarcinoma recently. However, the prognostic value of S100A16 in recurrence-free survival (RFS) in patients with resected lung adenocarcinoma has not been well demonstrated. The relationship between S100A16 expression and the histological subtypes of lung adenocarcinoma remained unknown.

Methods: A total of 79 patients with resected lung adenocarcinoma were included in the study. S100A16 expression was determined by immunohistochemistry in tumor specimens. The prognostic value of S100A16 overexpression and its relationship with clinicopathological variables, including histology subtypes, were investigated.

Results: S100A16 overexpression tended to be significantly associated with order age (P = 0.074). There was no significant association between S100A16 overexpression and predominant pattern group (lepidic/acinar/papillary vs. micropapillary/solid) (P = 0.447). Univariate analysis indicated that pathologic stage (II or III vs. I) (P = 0.001) and S100A16 overexpression (P = 0.005) were significant prognostic factors for worse recurrence-free survival (RFS). Predominant pattern group (lepidic/acinar/papillary vs. micropapillary/solid) (P = 0.064) tended to be a significant prognostic factor for worse RFS. In multivariate analysis, pathologic stage (II or III vs. I) (HR, 27.847; 95% CI, 4.173 to 185.831; P = 0.001), and S100A16 overexpression (HR, 21.740; 95% CI, 2.516 to 187.870; P = 0.005) were still significant prognostic factors for worse RFS.

Conclusions: S100A16 overexpression was a significant prognostic factor for worse RFS in patients with resected lung adenocarcinoma. This information is useful to stratify high-risk patients of recurrence after resection of lung adenocarcinoma.

Citation Format: Jung-Jyh Hung. Prognostic significance of S100A16 expression in patients with resected lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7640.
Abstract 80: Toward best practices for B-cell receptor repertoire profiling
Authors: Xiao Wenming ,   BCR-SEQC consortium
Published: March 2024

FDA anticipates that immune cell receptor profiling will become crucial to the Agency’s evaluation of the efficacy and safety of emerging cancer immunotherapies and immunomodulatory drugs by advancing precision medicine and providing orthogonal, functional evidence. High-throughput sequencing of B-cell receptor sequencing (BCR) gene rearrangements and downstream analysis empowers researchers to define the B-cell clonal landscape, as well as identify biomarkers for minimal residual disease (MRD). Although this field has made vast strides over the last decade, it lacks standardized assay controls, adequate sensitivity and specificity in gene mapping/alignment, and appropriately qualified reference data sets, materials, and validation methods. Moreover, detailed comparisons of wet-bench analytical methods or bioinformatic procedures have not appeared. The FDA led B-cell receptor sequencing quality control (BCR-SEQC) consortium is establishing protocols for the development of reference materials and data sets for the evaluation of NGS-based BCR repertoire reconstruction. The consortium is also developing materials for performance bench-marking studies. To this end, we performed whole-genome sequencing, RNAseq, and BCR-seq on 50 B-cell lines to determine the clonotype, full-length transcripts, and expression abundance of BCR genes in each cell line. Two batches of reference materials (DNA, RNA, and cells) were generated from each of nine cell lines that were determined unambiguously to be monoclonal in BCR expression of both heavy and light chains. These materials were distributed to ten companies to test up to 15 BCR-seq products. Our benchmarking studies include six widely-used sequencing technologies. The overarching objectives of this research were to elucidate current capabilities and limitations, address fundamental technical needs, provide reference materials and data sets, and establish actionable best practices for reconstructing B cell receptor repertoires from NGS data.

Citation Format: Wenming Xiao, BCR-SEQC consortium. Toward best practices for B-cell receptor repertoire profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 80.
Abstract 835: Occupational-related exposure to benzene and risk of female genital cancers: Systematic review and meta-analysis
Authors: Shah Darshi , DeStefano Vincent , Shah Veer , Seyyedsalehi Monireh Sadat , Bonetti Mattia , Boffetta Paolo
Published: March 2024

Purpose: The IARC monograph has classified benzene as a class I carcinogen, as evidenced by its association with hematological malignancies. However, its association with female genital cancers (ovarian, uterine, cervical) has not been characterized. Therefore, a meta-analysis of cohort studies was performed to determine the possible correlation between occupational benzene exposure and the risk of female genital cancers.

Methods: A systematic literature review was conducted that identified 7221 relevant publications. A total of 9 cohort studies detailing occupational exposure to benzene and correlated risk of ovarian, uterine, and cervical cancers were retained, and a meta-analysis (using fixed effects model) was performed. PECOS criteria and STROBE guidelines were followed, and the study protocol was registered in the PROSPERO database (Reg. No. 379720). Study quality was assessed using a modified Newcastle-Ottawa scale (NOS).

Results: The summary relative risk (RR) for ever-benzene exposure was 1.22 (95% CI=1.03-1.44, I2<0.001%, n=19); corresponding RR results for female genital cancers incidence and mortality were 1.09 (95% CI=0.92-1.29, I2=5.0%, n=17) and 1.69 (95% CI=1.18-2.4, I2<0.001%, n=9), respectively. These findings were confirmed in sub-analyses by geographical area, industry type, publication year, and levels of benzene exposure. Heterogeneity was detected amongst industries of employment (p-het=0.012) which included petroleum, chemical, printing, and mixed industries categories. Notably, the printing industry (compositors, press operators, and bookbinders) had a summary RR of 2.56 (95% CI=1.45-4.52, I2=35.0%, n=2). However, no heterogeneity was observed for geographical regions (p-het=0.77), duration of benzene exposure (p-het=0.73), publication year (p-het=0.89), or among varying study quality (< or ≥ median NOS score; p-het=0.14). No publication bias was detected (p=0.43).

Conclusions: Our meta-analysis identified an association between occupational benzene exposure and the risk of female genital cancers. The association was restricted to the industry of employment. Effects of residual confounding variables cannot be excluded, however, given the present association, there is a potential for causality, especially in workers employed in the printing industry.

Citation Format: Darshi Shah, Vincent DeStefano, Veer Shah, Monireh Sadat Seyyedsalehi, Mattia Bonetti, Paolo Boffetta. Occupational-related exposure to benzene and risk of female genital cancers: Systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 835.
Abstract 876: spatialGE: Empowering researchers to study the tumor microenvironment leveraging spatial transcriptomics
Authors: Ospina Oscar , Manjarres-Betancur Roberto , Gonzalez-Calderon Guillermo , Soupir Alex C. , Smalley Inna , Tsai Kenneth , Markowitz Joseph , Berglund Anders , Yu Xiaoqing , Fridley Brooke L.
Published: March 2024

The use of single-cell RNA-seq (scRNA-seq) to understand the complexity of the tumor microenvironment (TME) has been pivotal in advancing cancer research and treatment strategies. Nevertheless, locating the individual TME components in their spatial contexts is essential to understanding the complexity of the TME, tumorigenesis, metastasis, and drug response. The recent popularity of spatially resolved transcriptomics (SRT) allows researchers to describe the TME and their spatial neighborhoods; however, SRT data analysis can be challenging for non-data scientists. Thus, we have developed spatialGE, a point-and-click web application designed to empower researchers in the analysis of SRT data. Our application offers a suite of functionalities, including the visualization of spatial gene expression activity maps, quantification of the spatial heterogeneity, testing of pathway-level spatial aggregation, tissue domain/niche detection, detection of spatial gradients in expression patterns, and differential expression analysis. Furthermore, spatialGE allows direct comparative analysis of gene expression with the morphology in tissue images, as well as methods for cell/domain phenotyping. Data input has been streamlined and made flexible to receive outputs from multiple SRT platforms. Analyses and results are stored within user-defined projects to facilitate accessibility at any time. We demonstrate the usefulness of spatialGE through its application to leptomeningeal metastatic melanoma (LMM) tissues assayed with the Visium platform. The gene expression tissue domain detection and gradient analysis in spatialGE indicated that SERPINA3 expression is higher in tumor regions closer to stroma. This finding led to cell culture experiments indicating that knocking down SERPINA3 results in the sensitization of tumors to MAPK-targeting therapy. These results highlight the utility of spatialGE for exploring SRT data and the empowerment of cancer researchers to explore the spatial architecture of the TME.

Citation Format: Oscar Ospina, Roberto Manjarres-Betancur, Guillermo Gonzalez-Calderon, Alex C. Soupir, Inna Smalley, Kenneth Tsai, Joseph Markowitz, Anders Berglund, Xiaoqing Yu, Brooke L. Fridley. spatialGE: Empowering researchers to study the tumor microenvironment leveraging spatial transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 876.
Abstract 899: Development of a deep learning model for cell type mapping in colorectal cancer using H&E images leveraging image-based spatial transcriptomics data
Authors: Cook Seungho , Lee Dongjoo , Lim Myunghyun , Lee Jae Eun , Lee Daeseung , Im Hyung-Jun , Pyo Jung-Soo , Na Kwon Joong , Choi Hongyoon
Published: March 2024

Purpose The tumor microenvironment (TME) is crucial in colorectal cancer as it influences disease progression, treatment response, and patient outcomes, providing valuable insights for personalized therapies and prognostic assessments. Here, we have developed a deep learning model by integrating hematoxylin and eosin (H&E) stained images of colorectal cancer and image-based spatial transcriptomics (Xenium) to infer spatial mapping of cell types in TME only using H&E images.

Methods A total of 30 H&E images of colorectal cancer obtained by tissue microarray were registered with image-based spatial transcriptomics data (Xenium). Utilizing a Variational Autoencoder (VAE) based model and leveraging reference single-cell data enables the acquisition of cell types for individual cells in image-based spatial transcriptomics. A convolutional neural network (CNN) model was developed using H&E image as inputs to predict cell types in H&E-stained tissue image patches of colorectal cancer collected from various patients. The model also estimated the cell types from H&E-stained whole slide tissue image of colorectal cancer of The Cancer Genome Atlas (TCGA-COAD).

Results The accuracy of the model's predictions for cell types using H&E image patches was notably high and exhibited a significant concordance with the results obtained through the validation. The Intersection over Union (IoU) metric for image segmentation indicated a value of 0.66 for epithelial cells and 0.44 for TNK cells. The output of deep learning model for epithelial cells and T/NK cells from TCGA-COAD tissue images showed a correlation with human-labeled regions of cancer epithelium and immune cells.

Conclusions Leveraging image-based spatial transcriptomics, we developed a deep learning model capable of discerning various cell types within the tumor microenvironment solely from H&E images. This clinically translatable approach is valuable for investigating tumor microenvironment to develop biomarkers associated with various cancer therapeutics particularly immuno-oncology drugs. This approach can yield objective deep learning-based models without human labels for characterizing the tumor microenvironment in single-cell resolution, particularly regarding spatial immune distribution.

Citation Format: Seungho Cook, Dongjoo Lee, Myunghyun Lim, Jae Eun Lee, Daeseung Lee, Hyung-Jun Im, Jung-Soo Pyo, Kwon Joong Na, Hongyoon Choi. Development of a deep learning model for cell type mapping in colorectal cancer using H&E images leveraging image-based spatial transcriptomics data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 899.
Abstract 910: Clinical inference and biological dissection of tumor ploidy and heterogeneity in cutaneous melanoma for immunotherapy response using deep learning
Authors: Glettig Marc , Tarantino Giuseppe , Aprati Tyler , Elmarakeby Haitham , Liu David
Published: March 2024

Background: Tumor ploidy and heterogeneity demonstrated to be pivotal in predicting immunotherapy response in cutaneous melanoma in several independent cohorts (Liu NatMed2019, Tarantino BioRXiv2022). Their estimation can guide more personalized and rational utilization of these immunotherapies. However, 1) the biology underpinning ploidy and heterogeneity is unknown; and 2) these findings were derived in patients using retrospective research tumor-normal paired whole exome sequencing which is not performed for clinical management.

Methods: This study addresses this gap by employing deep learning models to predict these crucial markers using routinely available clinical assays, including H&E images. Attention-based computer vision models enable the identification of key morphological features in H&E slides. Segmentation of tumor tissue to perform automated masking, enhances ploidy inference.Moreover, biologically informed neural networks (P-Net, Elmarakeby Nature2021) uncover transcriptional and genomic features linked to ploidy and tumor heterogeneity. Our models are trained on publicly available data (e.g., Liu et al Nature Medicine 2019; TCGA SKCM) from melanoma cohorts and further validated in independent cohorts to ensure robustness.

Results: We developed and validated automated tumor tissue masking, enabling the prediction of Whole Genome Doubling (WGD) from H&E Slides with an AUC > 0.75. Attention-based models identify distinct Tumor Microenvironment (TME) structures predictive of high tumor heterogeneity. P-Net application revealed the Calmodulin pathway, previously associated with regulating proliferation in cancer and targeted with chemotherapy, as intricately linked to high tumor heterogeneity, providing valuable insights into underlying mechanisms.

Conclusion: In conclusion, our study strategically harnesses and integrates existing datasets to rigorously test, refine, and validate hypotheses concerning the biological and therapeutic implications of genomic heterogeneity and ploidy. Notably, our predictive models with automated tumor masking demonstrate a remarkable AUC >0.75 for biomarkers traditionally challenging to derive from clinical assays. This breakthrough opens avenues for novel therapeutic strategies targeting genomic heterogeneity and ploidy, providing a transformative potential to enhance patient care and outcomes.

Citation Format: Marc Glettig, Giuseppe Tarantino, Tyler Aprati, Haitham Elmarakeby, David Liu. Clinical inference and biological dissection of tumor ploidy and heterogeneity in cutaneous melanoma for immunotherapy response using deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 910.
Abstract 925: Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection
Authors: Hsieh Yao-Yu , Tsai Chin-Wen ,   T-CARE Group, Liang Yi-Hsieh
Published: March 2024

Introduction: Anti-EGFR monoclonal antibody plus doublet chemotherapy is the mainstay of first-line treatment of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Some of these patients might undergo secondary resection. However, there is no standardized suggestion on whether colorectal cancer liver metastasis patients should keep target therapy after secondary resection. NCCN guidelines suggest chemotherapy only in patients receiving primary liver resection. Whether we could spare the use of target therapy after secondary resection is the main aim of our study.

Methods: Using Taiwan's National Health Insurance Research Database, we established a cohort of KRAS wild-type mCRC patients treated with first-line anti-EGFR therapy plus doublet chemotherapy between 2013 and 2018. Secondary surgery was defined as either resection of liver metastases or radiofrequency ablation.

Results: 5694 stage IV mCRC patients received anti-EGFR MAb plus doublet chemotherapy as a first-line treatment between 2013 and 2018. 174 patients were enrolled in the final analysis, with 153 continuing anti-EGFR MAb after secondary resection and 21 patients without anti-EGFR MAb. Compared with those who without anti-EGFR therapy after secondary resection, patients who continued anti-EGFR MAb exhibited significantly longer overall survival (OS; median, 43.8 vs. 31.9 months, p = 0.031) but not in time to treatment failure (TTF; median, 22.2 vs. 26.6 months, p = 0.841). The OS benefits of continuing anti-EGFR MAb remained regardless of left-sided or right-sided primary tumors (40.9 vs. 43.0 months, p = 0.980). The patient cohort from 2016 to 2018 showed more prolonged survival than from 2012 to 2015 (not reached vs. 40.450, p = 0.0305). TTF has no statistical difference when considering patient cohort or primary tumor location. In multivariate analyses, continuing first-line anti-EGFR MAb therapy after secondary resection remained an independent predictor of longer OS.

Conclusion: For mCRC patients who received secondary resection after first-line anti-EGFR and doublet chemotherapy, continuing anti-EGFR MAb after resection was associated with significantly longer OS regardless of primary tumor sidedness.

Citation Format: Yao-Yu Hsieh, Chin-Wen Tsai, T-CARE Group, Yi-Hsieh Liang. Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 925.
Abstract 942: Response to systemic therapies in patient-derived cell lines from primary and recurrent adult granulosa cell tumors
Authors: Brink Geertruid , Hami Nizar , Mertens Sander , Hofhuis Ward , Piek Jurgen , de Kroon Cor , Lok Christianne , Roes Eva Maria , van Lonkhuijzen Luc , Nijman Hans , Snippert Hugo , Groeneweg Jolijn , Witteveen Petronella , Zweemer Ronald
Published: March 2024

Introduction: In patients with adult-type granulosa cell tumor (aGCT), a rare subtype of ovarian cancer, surgery is the preferred treatment for both primary and recurrent disease. However, the probability of complete resection decreases after multiple recurrences, in which case systemic treatment is an alternative option. Response rates of systemic therapy are variable, resistance is a problem and it is difficult to predict which therapy will work in which patient. Drug screen testing on patient-derived aGCT cell lines may offer a solution.

Methods: In a national prospective study on aGCT, fresh tissue was collected immediately after surgery. Tumor tissue was cultured and developed into 2D cell lines. Both clinically applicable and experimental drugs were tested on the patient-derived cell lines and two control cell lines. Dose-response curves and synergy were calculated using GraphPad Prism and Compusyn software.

Results: We cultured 34 patient-derived cell lines from tissue of seven patients with primary aGCT and from 13 patients with recurrence. In eight patients multiple sites were cultured. A total of 27 drugs were tested, including 10 monotherapies and 17 combinations. Carboplatin/gemcitabine showed efficacy and synergy 33 of 34 patient-derived cell lines (97%), in contrast to the regular carboplatin/paclitaxel and carboplatin/etoposide combinations (50% and 74%, respectively). The experimental combinations alpelisib/fulvestrant and alpelisib/gemcitabine showed efficacy of more than 75%. Testing of anti-hormonal therapy was not sufficiently reliable with this technique.

Conclusion: Drug screening on patient-derived tumor cell lines adequately reflects the reality of the variable response to systemic therapy in aGCT. In future research, this technique could be used to personalize the systemic treatment of aGCT patients. The response to carboplatin/gemcitabine in our patient-derived cell lines is striking.

Citation Format: Geertruid Brink, Nizar Hami, Sander Mertens, Ward Hofhuis, Jurgen Piek, Cor de Kroon, Christianne Lok, Eva Maria Roes, Luc van Lonkhuijzen, Hans Nijman, Hugo Snippert, Jolijn Groeneweg, Petronella Witteveen, Ronald Zweemer. Response to systemic therapies in patient-derived cell lines from primary and recurrent adult granulosa cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 942.
Abstract 948: A novel combinatorial therapy for lethal neuroendocrine prostate cancer
Authors: Wang Mu-En , Tu Wei-Ling , Lu Yi , Wu Jinjin , Bawcom Alyssa , Armstrong Andrew J. , Wang Qianben , Wang Yuzhuo , Huang Jiaoti , Chen Ming
Published: March 2024

Background: Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer that can arise de novo, but more commonly develops after hormone therapies for advanced prostate adenocarcinoma. Current treatment options for NEPC are only palliative, and most patients die within several months. Additionally, single-agent clinical trials targeting NEPC so far have only produced disappointing results, highlighting the clear need to develop effective combinatorial therapies for NEPC. RB1 loss, a pivotal event in the development of NEPC, can sensitize cancer cells to ferroptosis in multiple cancer cell types, including prostate cancer. Here, we aim to identify an optimal combinatorial therapy for NEPC based on targeting ferroptosis.

Methods: We determined the cell-killing efficacy of ferroptosis inducers and several current and emerging treatment regimens for NEPC as single agents, then performed drug synergism analyses of the above two potent treatments. Lastly, we investigated the molecular mechanisms of drug synergism by examining the major types of cell death induced by combinatorial treatment through molecular and biochemical assays.

Results: Our results demonstrated that both ferroptosis inducers and BCL2 inhibitors as single agents led to robust cell death in NEPC cell lines tested. In contrast, cisplatin, the standard of care for NEPC, and Aurora kinase A inhibitor showed modest to no cell-killing effect. Furthermore, suboptimal doses of ferroptosis inducers and BCL-2 inhibitors synergistically induced cell death in NEPC cell lines. Unexpectedly, we found that low-dose ferroptosis inducer led to increased production of mitochondria ROS, which in turn exacerbated BCL-2 suppression-induced apoptosis.

Conclusions: Our findings reveal a novel combinatorial therapy for NEPC. Based on our in vitro data, we will further test the in vivo therapeutic efficacy of ferroptosis inducers combined with BCL-2 inhibitors against NEPC growth.

Citation Format: Mu-En Wang, Wei-Ling Tu, Yi Lu, Jinjin Wu, Alyssa Bawcom, Andrew J. Armstrong, Qianben Wang, Yuzhuo Wang, Jiaoti Huang, Ming Chen. A novel combinatorial therapy for lethal neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 948.
Supplementary Methods and Materials from D-2-HG Inhibits IDH1mut Glioma Growth via FTO Inhibition and Resultant m6A Hypermethylation
Authors: Pianka Sean T. , Li Tie , Prins Terry J. , Eldred Blaine S.C. , Kevan Bryan M. , Liang Haowen , Zapanta Rinonos Serendipity , Kornblum Harley I. , Nathanson David A. , Pellegrini Matteo , Liau Linda M. , Nghiemphu Phioanh Leia , Cloughesy Timothy F. , Lai Albert
Published: March 2024

Supplementary Methods and Materials for detailed information on Immunoblotting, Intracellular D-2-HG Quantification, Gene-specific m6A RT-qPCR, TCGA Gene Expression Analyses, Gliomasphere Microarray Analyses, Animal Procedures, Gaussia Luciferase Tumor Burden Estimation, and Survival Analysis.
Figure S4 from D-2-HG Inhibits IDH1mut Glioma Growth via FTO Inhibition and Resultant m6A Hypermethylation
Authors: Pianka Sean T. , Li Tie , Prins Terry J. , Eldred Blaine S.C. , Kevan Bryan M. , Liang Haowen , Zapanta Rinonos Serendipity , Kornblum Harley I. , Nathanson David A. , Pellegrini Matteo , Liau Linda M. , Nghiemphu Phioanh Leia , Cloughesy Timothy F. , Lai Albert
Published: March 2024

Pharmacologic Inhibition of FTO Results in Growth Inhibition of IDH1wt Gliomaspheres In Vitro.
Figure S1 from D-2-HG Inhibits IDH1mut Glioma Growth via FTO Inhibition and Resultant m6A Hypermethylation
Authors: Pianka Sean T. , Li Tie , Prins Terry J. , Eldred Blaine S.C. , Kevan Bryan M. , Liang Haowen , Zapanta Rinonos Serendipity , Kornblum Harley I. , Nathanson David A. , Pellegrini Matteo , Liau Linda M. , Nghiemphu Phioanh Leia , Cloughesy Timothy F. , Lai Albert
Published: March 2024

IDH1mut Production of D-2-HG Induces RNA m6A Hypermethylation.
FIGURE 5 from D-2-HG Inhibits IDH1mut Glioma Growth via FTO Inhibition and Resultant m6A Hypermethylation
Authors: Pianka Sean T. , Li Tie , Prins Terry J. , Eldred Blaine S.C. , Kevan Bryan M. , Liang Haowen , Zapanta Rinonos Serendipity , Kornblum Harley I. , Nathanson David A. , Pellegrini Matteo , Liau Linda M. , Nghiemphu Phioanh Leia , Cloughesy Timothy F. , Lai Albert
Published: March 2024

Pharmacologic inhibition of FTO using FB23-2 reduces tumor growth rates in intracranial IDH1wt gliomasphere xenografts. A, Pharmacokinetic analysis of FB23-2 permeability through the BBB showing drug elimination dynamics in plasma and brain (2 mice/timepoint). B, Schematic of in vivo experiments whereby intracranial gliomasphere xenografts were established before undergoing randomization to daily intraperitoneal injections of either FB23-2 treatment or DMSO control, with injection volumes based on individual weights (20 mg/kg). In vivo monitoring of tumor growth measured via plasma Gaussia Luciferase activity (tail vein) revealed differences at 7–8 weeks (GS187) and 6–7 weeks (XDS4130; at week 8, only 1 mouse remained in DMSO group), respectively [ANOVA, (C) treatment: F(1,16) = 4.7, P ≤ 0.05; time: F(7,106) = 79.1, P ≤ 0.0001; interaction: F(7,106) = 4.3, P ≤ 0.0003; (D) treatment: F(1,18) = 16.7, P ≤ 0.0007; time: F(1.6,23.6) = 41.7, P ≤ 0.0001; interaction: F(7,104) = 5.3, P ≤ 0.0001; asterisks indicate post hoc Newman–Keuls on day 7 and 8]. Kaplan–Meier curves showing overall survival differences in xenograft mice treated with FB23-2 (3 µmol/L) or DMSO control, evaluated via a log-rank (Mantel–Cox) test for GS187 (E, P < 0.005) and XDS4130 (F, P ≤ 0.05). G, Activated Cas3 immunostaining (G, 10X magnification) of representative XDS4130 xenografts (surgically extracted and flash-frozen post-mortem). “MS” refers to the mouse identification number. H, Increase in number of Cas3 positive cells in tumors from mice treated with FB23-2 relative to DMSO controls (P ≤ 0.005). *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; and ****, P ≤ 0.0001 compared with relevant controls. Unless otherwise stated, P values indicate unpaired Student t test comparisons with the control, or between two groups as indicated by the horizontal line.
Data from D-2-HG Inhibits IDH1mut Glioma Growth via FTO Inhibition and Resultant m6A Hypermethylation
Authors: Pianka Sean T. , Li Tie , Prins Terry J. , Eldred Blaine S.C. , Kevan Bryan M. , Liang Haowen , Zapanta Rinonos Serendipity , Kornblum Harley I. , Nathanson David A. , Pellegrini Matteo , Liau Linda M. , Nghiemphu Phioanh Leia , Cloughesy Timothy F. , Lai Albert
Published: March 2024

Abstract
IDH1mut gliomas produce high levels of D-2-hydroxyglutarate (D-2-HG), an oncometabolite capable of inhibiting α-ketoglutarate–dependent dioxygenases critical to a range of cellular functions involved in gliomagenesis. IDH1mut gliomas also exhibit slower growth rates and improved treatment sensitivity compared with their IDH1wt counterparts. This study explores the mechanism driving apparent reduced growth in IDH1mut gliomas. Specifically, we investigated the relationship between IDH1mut and the RNA N6-methyladenosine (m6A) demethylases FTO and ALKBH5, and their potential for therapeutic targeting. We investigated the role of D-2-HG and m6A in tumor proliferation/viability using glioma patient tumor samples, patient-derived gliomaspheres, and U87 cells, as well as with mouse intracranial IDH1wt gliomasphere xenografts. Methylation RNA immunoprecipitation sequencing (MeRIP-seq) RNA sequencing was used to identify m6A-enriched transcripts in IDH1mut glioma. We show that IDH1mut production of D-2-HG is capable of reducing glioma cell growth via inhibition of the m6A epitranscriptomic regulator, FTO, with resultant m6A hypermethylation of a set of mRNA transcripts. On the basis of unbiased MeRIP-seq epitranscriptomic profiling, we identify ATF5 as a hypermethylated, downregulated transcript that potentially contributes to increased apoptosis. We further demonstrate how targeting this pathway genetically and pharmacologically reduces the proliferative potential of malignant IDH1wt gliomas, both in vitro and in vivo. Our work provides evidence that selective inhibition of the m6A epitranscriptomic regulator FTO attenuates growth in IDH1wt glioma, recapitulating the clinically favorable growth phenotype seen in the IDH1mut subtype.
Significance:
We show that IDH1mut-generated D-2-HG can reduce glioma growth via inhibition of the m6A demethylase, FTO. FTO inhibition represents a potential therapeutic target for IDH1wt gliomas and possibly in conjunction with IDH1mut inhibitors for the treatment of IDH1mut glioma. Future studies are necessary to demonstrate the role of ATF5 downregulation in the indolent phenotype of IDH1mut gliomas, as well as to identify other involved gene transcripts deregulated by m6A hypermethylation.
European Training Requirements in Neonatology 2021: The ESPR, EAP, and UEMS Accredited European Syllabus for Neonatal Training
Authors: Roehr Charles Christoph , Szczapa Tomasz , Stiris Tom , Hadjipanayis Adamos , Koletzko Berthold , Ross-Russell Rob , Hüppi Petra , Wellmann Sven , Vento Maximo ,   European Board of Neonatal & Child Health Research (EBNCHR),   European Society for Paediatric Research (ESPR),   European Academy of Paediatrics (EAP),   European Board of Paediatrics (EBP)/Union of European Medical Specialists (UEMS)
Published: March 2024

Introduction: The European Union stipulates transnational recognition of professional qualifications for several sectoral professions, including medical doctors. The Union of European Medical Specialists (UEMS), in its “Charter on Training of Medical Specialists,” defines the principles for high-level medical training. These principles are manifested in the framework for European Training Requirements (ETR), ensuring medical training reflects modern medical practice and current scientific findings. In 1998, the European Society for Paediatric Research developed the first ETR for Neonatology. We present the ETR Neonatology in its third iteration (ETR III), ratified by the European Academy of Paediatrics (EAP), and approved by UEMS in 2021. Methods: In generating the ETR III, existing European policy documents on training requirements, including national syllabi and the European Standards of Care for Newborn Health were considered. To ensure the ETR III meets a pan-European standard of expertise in Neonatology, input from representatives from 27 European national paediatric/neonatal societies, and a European parent organisation, was sought. Results: The ETR III summarises the requirements of contemporary training programs in Neonatology and offers a system for accrediting trainers and training centres. We describe the content of the ETR III training syllabus and means of gaining and assessing competency as a medical care provider in Neonatology. Conclusion: Graduates of courses following the ETR III Neonatology will obtain a certificate of satisfactory training completion which should be accepted by all European member states as a baseline qualification to practice as a specialist in neonatal medicine, enabling mutual recognition of status throughout Europe.
Recent Developments in the Role of Histone Acetylation in Asthma
Authors: Potaczek Daniel P. , Bazan-Socha Stanisława , Wypasek Ewa , Wygrecka Małgorzata , Garn Holger
Published: March 2024

Background: Epigenetic modifications are known to mediate both beneficial and unfavorable effects of environmental exposures on the development and clinical course of asthma. On the molecular level, epigenetic mechanisms participate in multiple aspects of the emerging and ongoing asthma pathology. Summary: Studies performed in the last several years expand our knowledge on the role of histone acetylation, a classical epigenetic mark, in the regulation of (patho)physiological processes of diverse cells playing a central role in asthma, including those belonging to the immune system (e.g., CD4+ T cells, macrophages) and lung structure (e.g., airway epithelial cells, pulmonary fibroblasts). Those studies demonstrate a number of specific histone acetylation-associated mechanisms and pathways underlying pathological processes characteristic for asthma, as well as report their modification modalities. Key Messages: Dietary modulation of histone acetylation levels in the immune system might protect against the development of asthma and other allergies. Interfering with the enzymes controlling the histone acetylation status of structural lung and (local) immune cells might provide future therapeutic options for asthmatics. Despite some methodological obstacles, analysis of the histone acetylation levels might improve asthma diagnostics.
Overlap Syndrome of Diffuse Systemic Sclerosis, Sjögren Syndrome, and ANCA-Associated Renal-Limited Vasculitis: Three Entities in One Patient – Case Report
Authors: Cordoba-Hurtado Angela  Maria , Fuentes-Mendez Laura , Perez-Navarro Lucia Monserrat , Soto-Abraham Virgilia , Valdez-Ortiz Rafael
Published: March 2024

Introduction: The presence of three different entities in a single patient is usually of clinical interest and mostly anecdotal. The overlap of systemic sclerosis (SSc), Sjögren syndrome (SS), and ANCA-associated renal-limited vasculitis has been reported only once previously. Case Presentation: A 61-year-old female was evaluated at consultation with 2 years of symptomatology, presenting cardboard-like skin, sclerodactyly, limited oral opening, and dry skin and eyes. She was admitted for progressive renal failure (serum creatinine, 5.5 mg/dL). Her serology work-up showed positive anti-SCL-70, anti-Ro, anti-La, anti-MPO, and antinuclear antibodies. Renal biopsy was performed and confirmed histological findings for SSc, SS, and ANCA-associated vasculitis with active extracapillary glomerulonephritis with fibrous predominance (EUVAS-Berden sclerotic class), active tubulointerstitial nephritis, focal tubular injury, and moderate chronic arteriolopathy. Treatment with 6 monthly doses of methylprednisolone and cyclophosphamide was established. At the last follow-up, the patient maintained a stable serum creatinine level of 2.6 mg/dL and had decreased proteinuria, no erythrocyturia, and no requirement for renal replacement therapy. Conclusion: Systemic sclerosis is a rare autoimmune disease; nevertheless, overlap with Sjögren syndrome is relatively common, although its association with ANCA vasculitis is anecdotal. Diagnostic integration presents a challenge for nephrologists to define the prognosis and a specific treatment.
Telitacicept Treatment Refractory Lupus Nephritis: A Case Report
Authors: Li Sijia , Deng Shuting , Wen Sichun , Peng Siqi , Jiang Nan , Li Bohou , Chen Boxi , Yuan Ye , Wu Qiong , Tao Yiming , Ma Jianchao , Lin Ting , Wen Feng , Li Zhuo , Dai Hao , Huang Renwei , Feng Zhonglin , Li Zhilian , Liu Shuangxin , Xu Lixia
Published: March 2024

Introduction: Refractory lupus nephritis (LN) causes kidney disease progression and increases the risk of loss of renal function. Due to the high specificity and few side effects of biological agents, they are recommended for the treatment of systemic lupus erythematosus. There are few data on telitacicept for the treatment of refractory LN. Case Presentation: Here, we report the efficacy and safety of telitacicept in the treatment of refractory LN in a 25-year-old female patient. This patient with refractory lupus developed Pneumocystis jirovecii pneumonia while using multitargeted therapy, and the patient’s urine protein was rapidly relieved after telitacicept combination with low-dose mycophenolate mofetil (MMF). Conclusion: This result suggests that telitacicept has a positive effect on refractory LN with no significant side effects. Further reports and a registry are necessary to confirm that telitacicept with low-dose MMF should be preferred in refractory LN.
Incremental Value of a Metabolic Risk Score for Heart Failure Mortality: A Population-Based Study
Authors: Joo Jungnam , Shearer Joseph J. , Wolska Anna , Remaley Alan T. , Otvos James D. , Connelly Margery A. , Sampson Maureen , Bielinski Suzette J. , Larson Nicholas B. , Park Hoyoung , Conners Katherine M. , Turecamo Sarah , Roger Véronique L.
Published: March 2024

BACKGROUND:

Heart failure is heterogeneous syndrome with persistently high mortality. Nuclear magnetic resonance spectroscopy enables high-throughput metabolomics, suitable for precision phenotyping. We aimed to use targeted metabolomics to derive a metabolic risk score (MRS) that improved mortality risk stratification in heart failure.

METHODS:

Nuclear magnetic resonance was used to measure 21 metabolites (lipoprotein subspecies, branched-chain amino acids, alanine, GlycA (glycoprotein acetylation), ketone bodies, glucose, and citrate) in plasma collected from a heart failure community cohort. The MRS was derived using least absolute shrinkage and selection operator penalized Cox regression and temporal validation. The association between the MRS and mortality and whether risk stratification was improved over the Meta-Analysis Global Group in Chronic Heart Failure clinical risk score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels were assessed.

RESULTS:

The study included 1382 patients (median age, 78 years, 52% men, 43% reduced ejection fraction) with a 5-year survival rate of 48% (95% CI, 46%–51%). The MRS included 9 metabolites measured. In the validation data set, a 1 standard deviation increase in the MRS was associated with a large increased rate of death (hazard ratio, 2.2 [95% CI, 1.9–2.5]) that remained after adjustment for Meta-Analysis Global Group in Chronic Heart Failure score and NT-proBNP (hazard ratio, 1.6 [95% CI, 1.3–1.9]). These associations did not differ by ejection fraction. The integrated discrimination and net reclassification indices, and Uno’s C statistic, indicated that the addition of the MRS improved discrimination over Meta-Analysis Global Group in Chronic Heart Failure and NT-proBNP.

CONCLUSIONS:

This MRS developed in a heart failure community cohort was associated with a large excess risk of death and improved risk stratification beyond an established risk score and clinical markers.
Game Engines for Immersive Visualization: Using Unreal Engine Beyond Entertainment
Authors: Krüger Marcel , Gilbert David , Kuhlen Torsten W. , Gerrits Tim
Published: March 2024

One core aspect of immersive visualization labs is to develop and provide powerful tools and applications that allow for efficient analysis and exploration of scientific data. As the requirements for such applications are often diverse and complex, the same applies to the development process. This has led to a myriad of different tools, frameworks, and approaches that grew and developed over time. The steady advance of commercial off-the-shelf game engines such as Unreal Engine has made them a valuable option for development in immersive visualization labs. In this work, we share our experience of migrating to Unreal Engine as a primary developing environment for immersive visualization applications. We share our considerations on requirements, present use cases developed in our lab to communicate advantages and challenges experienced, discuss implications on our research and development environments, and aim to provide guidance for others within our community facing similar challenges.
The Common Good According to Whom?
Authors: Howard Dana
Published: March 2024

Alex John London’s new book, For the Common Good: Philosophical Foundations of Research Ethics highlights the fact that establishing just social arrangements is not only a matter of incentivizing popular will to act for the common good; it also requires filling in informational gaps about which policies, arrangements, and interventions will advance the basic interests of members in an equitable, effective and efficient manner. Promoting justice requires, in part, acquiring the knowledge for how to do so. In developing this point, London carefully traces these missteps in the main philosophical debates and then resuscitates the importance of questions of justice at the heart of research ethics. In doing so, it provides a transformative corrective for the field. This review critically examines one of the central pillars of London’s egalitarian research imperative approach: the way in which the social value of research is closely linked with minimizing uncertainty among reasonable experts.
The Legal Status and Targeting of Hacker Groups in the Russia-Ukraine Cyber Conflict
Authors: Biggio Giacomo
Published: March 2024

The armed conflict between Russia and Ukraine has been characterized by a considerable number of cyber operations by States and non-State actors in support to either party to the conflict. One year since the Russian invasion of Ukraine, the ‘Russia-Ukraine cyber conflict’ offers valuable insights for estimating the effectiveness of International Humanitarian Law in regulating the status and the conduct of individuals engaging in cyberspace operations during wartime. By discussing the status of hackers groups and individuals who have conducted cyber operations in support of Ukraine, this Article claims that the relevance of the concept of combatancy is diminished in the cyber domain, and that the notion of direct participation in hostilities must be adapted to the specific features of cyberspace. Furthermore, the article focuses on the issues relating to the targeting of individual who directly participate in hostilities by conducting cyber operations in support of Ukraine. By doing so, the Article argues that cyber direct participants place themselves at an increased risk of being attacked, even though the Russian armed forces are limited in their targeting decisions by the principles of proportionality and precaution.
Hebrew Loanwords in Two Rural Dialects of Arabic in Israel
Authors: Abu Elhija Duaa
Published: March 2024

This study examines loanwords from Hebrew into Arabic in the spoken language of people from Iksal village, in the lower Galilee and Um Al-Fahm city, in the Triangle region in Israel. The current study specifically examines borrowing in spoken language, with a comparison of the current findings with a previous research by Abu Elhija (2017), where the data was taken from online writings on Facebook. The research questions the frequency of loanword items from Hebrew into two rural dialects, the domains that appear with Hebrew loanwords, the phonological representations of the loanwords, and the reasons for these words to be borrowed. The main findings show that more loanwords were found in the spoken corpus than in the social media corpus in Abu Elhija (2017). There are more loanwords in synchronous communication compared to asynchronous. The findings also show that topics like education, employment, and technology had the most extensive loanwords. Moreover, in the case of loanwords used by Arabs in Israel, a word can be considered a loanword regardless of its phonology.
The Relationship Between Adverse Childhood Experiences and Postpartum Depression: A Systematic Review and Meta-Analysis
Authors: Fu Congrui , Li Cong , Wan Xin , Yang Yu , Zhang Shuxin , Hu Jie
Published: March 2024

Although numerous factors have been found to influence postpartum depression (PPD), no previous meta-analysis have systematically explored whether it is affected by adverse childhood experiences (ACEs). This study aimed to explore the influence of ACEs and their subtypes on PPD. A systematic literature search was conducted using Web of Science, PubMed, Embase, Wan Fang, China Science and Technology Journal Database, Chinese Biomedical Database, and China National Knowledge Infrastructure, and literature was screened according to inclusion and exclusion criteria. Methodological quality assessment and data extraction were performed on the included studies. A random-effects model was used to pool the effects. In total, 24 studies were included, and 73 independent effects were extracted from them. The meta-analysis revealed that ACE was a risk factor for PPD (odds ratio [OR] = 2.31, 95% confidence interval [CI] [2.04, 2.63]). The subgroup analysis results showed that emotional abuse was the ACE subtype most strongly related to the occurrence of PPD (OR = 2.95, 95% CI [2.08, 4.20]), followed by emotional neglect (OR = 2.87, 95% CI [1.89, 4.36]) and sexual abuse (OR = 2.81, 95% CI [1.93, 4.09]). In addition, family member incarceration (OR = 2.62, 95% CI [1.51, 4.54]), physical abuse (OR = 2.31, 95% CI [1.67, 3.19]), and physical neglect (OR = 2.15, 95% CI [1.36, 3.39]) also have strong effects on PPD. ACE is a risk factor for PPD. Early screening of ACE plays an important role in the prevention and intervention of PPD.