bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B015: RNA N6-methyladenosine (m6A) as a therapeutic target in Diffuse Midline Glioma (DMG)
Authors: Ross Samuel E. , Holliday Holly , Tsoli Maria , Ziegler David S. , Dinger Marcel E.
Published: March 2024

Diffuse Midline Glioma (DMG) is an incurable pediatric brain tumor thought to originate from oligodendrocyte precursor cells in midline brain structures. The RNA modification N6-methyladenosine (m6A) plays an important role in RNA stability and is critical to neuronal stem-cell self-renewal and differentiation. We therefore sought to investigate m6A as a therapeutic target in DMG. Moreover, targeting the epitranscriptome has shown promise in the treatment of other cancers, and several small-molecule inhibitors of m6A writers and erasers have been recently developed. To that end, we tested the sensitivity of a panel of patient-derived DMG cell lines to FB23-2, an inhibitor of the m6A eraser FTO, and STM2457, an inhibitor of the mRNA m6A writer METTL3. In order to interrogate the therapeutic mechanisms and identify predictive biomarkers for response, we then performed RNA-seq to measure gene expression changes, and native RNA-seq to measure RNA m6A levels. We found that DMG cell lines were more sensitive to FB23-2 (IC50 ~10μM) than STM2457 (IC50 ~100μM), indicating that m6A gain rather than loss may be a potential therapeutic strategy. Furthermore, we observed variation in FB23-2 sensitivity between cell lines with RNA-sequencing identifying marked changes in the expression of cell cycle, cell stress response, and differentiation associated genes in the cell lines which responded best to FB23-2. Additionally, these analyses also identified several potential biomarkers for response to FB23-2. Finally, we generated the first m6A transcriptome maps for DMG using native RNA sequencing and demonstrated that m6A is abundant in DMG cell lines and is particularly enriched on cell cycle, cell stress response, and metabolic pathway transcripts. Overall, our work identified the FTO m6A demethylase as a potential therapeutic target in DMG, whereby its inhibition with FB23-2 increases m6A abundance, altering the stability of critical transcripts and pathways.

Citation Format: Samuel E. Ross, Holly Holliday, Maria Tsoli, David S. Ziegler, Marcel E. Dinger. RNA N6-methyladenosine (m6A) as a therapeutic target in Diffuse Midline Glioma (DMG) [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B015.
Abstract PR-007: H3.3K27M diffuse midline gliomas are sensitive to SWI/SNF chromatin remodeler degradation
Authors: Mota Mateus , Sweha Stefan , Pun Matt , Natarajan Siva Kumar , Ding Yujie , Chung Chan , Hawes Debra , Yang Fusheng , Judkins Alexander , Samajdar Susanta , Cao Xuhong , Xiao Lanbo , Parolia Abhijit , Chinnaiyan Arul , Venneti Sriram
Published: March 2024

Diffuse Midline Gliomas (DMG) including Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain tumor. The lysine 27 (K27)-to-methionine (M) point mutation in histone H3.1 or H3.3 (H3.1K27M or H3.3K27M, respectively) affects about 80% of patients establishing H3K27M mutation as a tumor hallmark. Mutated H3 histones inhibit the function of Polycomb repressive complex 2 resulting in global reduction of repressive H3K27me3. In addition, increased acetylation of H3K27 is observed, further contributing to an aberrant chromatin state. Considering the impact of epigenetic alterations in DIPG, we investigated the role of Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodelers in shaping the oncogenic chromatin state in DIPG cells. DIPG cells harboring H3.3K27M mutation were sensitive to combined SMARCA4/SMARCA2/PBRM1 degradation by the proteolysis targeting chimera (PROTAC) AU-15330 degrader. Our premise is based on the SWI/SNF complex altering chromatin states of tumor cells to regulate the tumor immune microenvironment. We hypothesized that the SWI/SNF complex in tumor cells modulates immune responses in DIPG. Cytokine profiler arrays in AU-15330 versus vehicle treated H3.3K27M cells showed a marked decrease of Intercellular Cell Adhesion Molecule-1 (ICAM-1) glycoprotein levels. In addition to its well-known role in leukocyte endothelial transmigration, ICAM-1 contributes to malignant potential of tumor cells. We validated downregulation of ICAM-1 mRNA and protein levels by AU-15330 by immunoblotting, proteomics, and transcriptomics, suggesting an epigenetic regulation of ICAM-1 gene transcription by the SWI/SNF complex. Moreover, silencing of mutant H3.3-encoding gene decreased ICAM-1 protein levels, suggesting ICAM-1 expression is promoted by H3.3K27M mutation-induced SWI/SNF chromatin remodeling in DIPG. In conclusion, our work suggests the H3.3K27M mutation renders DIPG cells dependent on chromatin remodeling by SWI/SNF complexes that can in turn alters the expression of immune system-associated components, such as ICAM-1. Our future work is geared to understanding the role of the SWI/SNF complex in regulating the immune tumor microenvironment in H3K27M DMGs.

Citation Format: Mateus Mota, Stefan Sweha, Matt Pun, Siva Kumar Natarajan, Yujie Ding, Chan Chung, Debra Hawes, Fusheng Yang, Alexander Judkins, Susanta Samajdar, Xuhong Cao, Lanbo Xiao, Abhijit Parolia, Arul Chinnaiyan, Sriram Venneti. H3.3K27M diffuse midline gliomas are sensitive to SWI/SNF chromatin remodeler degradation [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-007.
Abstract A019: Development of adaptive anoikis resistance promotes ovarian cancer metastasis that can be prevented by CDK8/19 Mediator kinase inhibition
Authors: Monavarian Mehri , Rajkarnikar Resha , Page Emily Faith , Kumari Asha , Quintero Liz Macias , Ianov Lara , Sahoo sarthak , Jolly Mohit Kumar , Worthey Elizabeth , Hempel Nadine , Singh Abhyudai , Broude Eugenia , Mythreye Karthikeyan
Published: March 2024

Anoikis resistance or evasion of cell death triggered by cell detachment is a hallmark of cancer that is concurrent with cell survival and metastasis. Phenotypes of intrinsically anoikis resistant cancer cells have been extensively investigated but the mechanism of how exposure to suspension stress may lead to the acquisition of an anoikis resistance phenotype has not been previously described. Here we show that cycles of suspension stress followed by attached growth, mimicking an in vivo scenario, lead to adaptation to anoikis and acquisition of resistance to cell death, concomitant with increased chemoresistance and metastasis in vivo. Based on mutational and clonal population behavior analysis and modeling using a modified Luria-Delbrück’s fluctuation analysis we find that such acquired anoikis resistance is not genetic. Transcriptional reprogramming is, however,essential for the acquisition of adaptive anoikis resistance in vitro and in vivo, since these processes are exquisitely sensitive to selective inhibition of the CDK8/19 Mediator kinase, a broad-spectrum regulator of transcriptional reprogramming. Longitudinal analysis of the acquisition of anoikis resistance indicates strong repression programs along with a hybrid epithelial/mesenchymal phenotype and an enhanced need for oxidative phosphorylation, resulting in the emergence of anoikis-adapted cells that also efficiently evade T cell-mediated immune surveillance. Our data demonstrate that recovery from the brink of anoikis is a direct contributor to metastasis in ovarian cancer and can be therapeutically prevented using inhibitors of CDK8/19 Mediator kinase

Citation Format: Mehri Monavarian, Resha Rajkarnikar, Emily Faith Page, Asha Kumari, Liz Macias Quintero, Lara Ianov, sarthak Sahoo, Mohit Kumar Jolly, Elizabeth Worthey, Nadine Hempel, Abhyudai Singh, Eugenia Broude, Karthikeyan Mythreye. Development of adaptive anoikis resistance promotes ovarian cancer metastasis that can be prevented by CDK8/19 Mediator kinase inhibition [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A019.
Abstract A030: Regulation of SIRT3 overexpression in anchorage independent ovarian cancer
Authors: Srinivasan Sneha , Tang Priscilla , Mythreye Karthikeyan , Hempel Nadine
Published: March 2024

Ovarian cancer remains the most lethal gynecological malignancy, and late-stage diagnosis and significant metastatic spread are prominent contributors to its lethality. To achieve optimal metastasis, ovarian tumor cells must modify their response to heightened oxidative stress to ensure their survival. One crucial mechanism of this modification involves the scavenging of mitochondrial superoxide anions by superoxide dismutase (SOD2). Mitochondrial Sirtuin Deacetylase 3 (SIRT3) deacetylates SOD2 to enhance its antioxidant capacity, facilitating the conversion of superoxide (O2−) to H2O2. We have shown that this antioxidant mechanism helps to preserve mitochondrial function of high grade serous ovarian cancer cell lines, enhances cellular survival in anchorage-independence, and is necessary for in vivo metastatic spread to the omentum. Expression of both SOD2 and SIRT3 increase in ovarian cancer cells following matrix detachment, and we found that SOD2 is regulated by both transcription and translation, resulting in rapid and sustained increases in this mitochondrial antioxidant in response to matrix detachment. Presently, we are exploring the mechanisms of SIRT3 regulation, as this deacetylase is necessary for the maintenance of SOD2 activity in anchorage independent conditions. We find that active transcription is required for the increased SIRT3 expression observed in anchorage independence and are currently investigating the role NF-kB plays as a critical transcription factor of SIRT3 in this context. Understanding the regulation of SIRT3 will shed light on ovarian cancer cell survival adaptations during metastasis and provide potential insights into new targets for therapeutic interventions.

Citation Format: Sneha Srinivasan, Priscilla Tang, Karthikeyan Mythreye, Nadine Hempel. Regulation of SIRT3 overexpression in anchorage independent ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A030.
Abstract A035: Genome-wide CRISPRi screening reveals determinants of platinum sensitivity and resistance in high-grade serous ovarian cancer
Authors: Kong Yi Wen , Handly Erika D. , Lu Robin A. , Bird Molly A. , Schilling Hannah-Lou , Yaffe Samkyu P. , Yaffe Michael B. , Koch David H.
Published: March 2024

Platinum-based chemotherapeutic drugs induce intra- and interstrand crosslinks between purine residues, resulting in DNA damage and tumor cell death. Although these drugs are widely used as front-line treatment for multiple human cancers, particularly high-grade serous ovarian cancer (HGSOC), the development of platinum resistance and tumor recurrence remains a common clinical problem due to an incomplete understanding of what governs the cellular response to platinum-induced DNA damage. Here we report the results from genome-wide CRISPRi-screens for modulators of sensitivity and resistance to two widely used platinum agents, cisplatin and oxaliplatin, using a cell-based approach that mimics clinical treatment protocols. Using this unbiased genomic approach, we demonstrate that lethality after cisplatin or oxaliplatin treatment in p53-defective ovarian cancer cells is markedly enhanced by suppressing genes in the Fanconi anemia (FA) and homologous recombination (HR) pathways, but considerably less enhanced by suppressing genes in the nucleotide excision repair (NER) pathway, despite the well-established importance of NER in reversing platinum-induced intrastrand crosslinks. Loss of NER activity, however, can markedly increase tumor cell death from cisplatin-induced DNA damage, if the cell cycle checkpoint kinase MK2 is co-targeted, indicating an augmented synthetic lethal relationship between XPA, MK2, and mutant p53 in the presence of DNA crosslinks. A second targeted CRISPRi screen implicated several known and novel RNA-binding proteins (RBPs) as potent sensitizers of HGSOC to both platinum agents and taxanes, including the RNA-modifying enzyme ADAR1. Together, these findings indicate that (1) platinum-induced interstrand DNA crosslinks, which require repair by FA and HR, rather than intrastrand crosslinks repaired by NER, are the primary determinants of tumor cell survival following treatment, (2) loss of NER function alone, which only modestly sensitizes cells to platinum-induced DNA crosslinks, results in a markedly enhanced dependence of the DNA-damaged tumor cells on sustained cell cycle checkpoint arrest mediated by MK2 for tumor cell survival, and that (3) a small subset of RBPs control the sensitivity of ovarian cancer cells to both platinum-based agents and anti-microtubule drugs that form the current clinical standard of care for HGSOC.

Citation Format: Yi Wen Kong, Erika D. Handly, Robin A. Lu, Molly A. Bird, Hannah-Lou Schilling, Samkyu P. Yaffe, Michael B. Yaffe, David H. Koch. Genome-wide CRISPRi screening reveals determinants of platinum sensitivity and resistance in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A035.
Abstract A072: Altering the ovarian cancer tumor microenvironment using car t cell therapy
Authors: McMellen Alexandra N. , Leibowitz Michael S.
Published: March 2024

Ovarian cancer accounts for 12,810 deaths per year in the USA, making it the deadliest gynecologic malignancy. Unfortunately, patients who are resistant to standard of care treatments have very limited effective therapeutic options. Immunotherapies are an emerging class of treatments that utilize a patient’s immune system to recognize and destroy tumor cells and have resulted in dramatic responses in many hematologic malignancies. In particular, reprograming patient T cells to recognize specific surface antigen(s) known as chimeric antigen receptor (CAR) T cell therapy, has provided both pediatric and adult patients with relapsed or treatment-unresponsive hematologic malignancies novel and potentially curative treatment options. CAR T cell therapy received FDA approval in 2018 for the treatment of B cell leukemia, however despite significant efforts, has been largely ineffective in solid malignancies. This is due in part to the complex solid tumor immune microenvironment (TME) and how it may change in response to therapies. For example, there is evidence that an FDA approved treatment for ovarian cancer called poly(ADP) ribose polymerase inhibitors (PARP; PARPi) leads to increased immune cell infiltration and cancer sensitivity to immunotherapies. This proposal will delineate the immune composition of the ovarian cancer TME using mouse models that closely recapitulate ovarian cancer progression and examine the impact of CAR T cells on the TME. We will utilize mouse ovarian cancer models that are sensitive and resistant to PARP inhibition. The information derived from these studies will provide a better understanding of the evolution of ovarian cancer TME and provide insight on how CAR T cells may alter the TME. Ultimately, we hope this work will lead to the development of safer and more effective therapeutic options for ovarian cancer patients.

Citation Format: Alexandra N. McMellen, Michael S. Leibowitz. Altering the ovarian cancer tumor microenvironment using car t cell therapy [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A072.
Abstract B014: Charting ovarian cancer dependencies with patient-derived organoids
Authors: Anderson Ashley , Bertea Tate , Neiswender James , Brenan Lisa , Wong Megan , Simerzin Alina , Wie Sarah , Boyle Isabella , Golden Lauren , De Kegel Barbara , Dempster Josh , Tseng Yuen-Yi , Root David , Hill Sarah , Aguirre Andrew , Vazquez Francisca
Published: March 2024

The Cancer Dependency Map aims to accelerate precision cancer medicine by identifying the landscape of cancer vulnerabilities across all tumors. To address underrepresented cancer types, we have optimized a genome-wide CRISPR KO screening pipeline, utilizing a condensed Cas12a library, for patient-derived 3D models. Here, we present characterization of a cohort of ovarian models which consist of underrepresented cancer subtypes along with treatment-resistant cancers. In particular, our organoid dataset includes low-grade serous carcinoma models, an ovarian cancer subtype that is understudied and not previously characterized in 2D DepMap screens. The increased representation of ovarian models will improve the potential of DepMap to uncover genetic drivers of ovarian cancers. Through genomic perturbation we showed that these 3D models achieved screen quality comparable to historically derived 2D models. Our methods provide a framework for screening future cancer models and discovering vulnerabilities in select patient populations.

Citation Format: Ashley Anderson, Tate Bertea, James Neiswender, Lisa Brenan, Megan Wong, Alina Simerzin, Sarah Wie, Isabella Boyle, Lauren Golden, Barbara De Kegel, Josh Dempster, Yuen-Yi Tseng, David Root, Sarah Hill, Andrew Aguirre, Francisca Vazquez. Charting ovarian cancer dependencies with patient-derived organoids [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B014.
Abstract IA018: Epigenome targeting in ovarian cancer: preclinical models to clinic
Authors: Matei Daniela
Published: March 2024

DNA methylation causes silencing of tumor suppressor (TSGs) and differentiation-associated genes, being linked to chemoresistance. Ovarian cancer (OC) is uniquely suited for epigenome targeting as a disease driven by loss of TSGs, rather than oncogenes. Hypomethylating agents (HMA) have been shown to re-sensitize OC to chemotherapy and immunotherapy. A novel HMA (4-thio-decitabine) effectively depleted DNMTs, induced global hypomethylation and transcriptional reprogramming leading to inhibition of OC cell proliferation and tumor growth. Mechanistically, among other gene sets, NTX-301 significantly altered the fatty acid metabolism pathway. A key enzyme in this pathway, the stearoyl co-A desaturase which regulates the last step in lipogenesis, converting saturated fatty acids into unsaturated fatty acids (UFAs) was potently inhibited by NTX-301. This led to depletion of UFAs in cells and tumors treated with the HMA and cell death through ferroptosis. In a clinical trial for women with recurrent, platinum resistant OC, epigenetic priming was used to enhance response to immune checkpoint inhibitors. Among 35 evaluable patients, the clinical benefit rate was 31.4% (95% CI: 16.9 – 49.3%). Methylomic and transcriptomic analyses revealed activation of pathways related to anti-tumor immunity in post-treatment biopsies. High dimensional immune profiling of PBMCs showed higher frequency of peripheral naive and/or central memory CD4+ T cells subsets and of classical monocytes in patients deriving clinical benefit. Multiplex immunohistochemistry indicated that baseline higher density of CD8+ T cells and CD20+ B cells in tumor tissue and presence of putative tertiary lymphoid structures were associated with clinical benefit. These results propose novel mechanisms by which HMAs exert anti-tumor activity in preclinical and clinical models.

Citation Format: Daniela Matei. Epigenome targeting in ovarian cancer: preclinical models to clinic [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA018.
Supplementary Figure S3 from Engaging Communities in Cancer Prevention and Control Activity Prioritization through a Statewide Needs Assessment: A Case Study from Nebraska
Authors: Watanabe-Galloway Shinobu , Napit Krishtee , McCullough Jordan , Luma Lady Beverly , Kabayundo Josiane , Carritt Nicole L. , Schabloske Laura , Robinson Tamara , Rohde Jolene , Champion Victoria , LoConte Noelle K. , Ratnapradipa Kendra L.
Published: March 2024

Supplementary Figure S3: Infographic on cancer burden tailored toward Hispanics
Supplementary Figure S2 from Engaging Communities in Cancer Prevention and Control Activity Prioritization through a Statewide Needs Assessment: A Case Study from Nebraska
Authors: Watanabe-Galloway Shinobu , Napit Krishtee , McCullough Jordan , Luma Lady Beverly , Kabayundo Josiane , Carritt Nicole L. , Schabloske Laura , Robinson Tamara , Rohde Jolene , Champion Victoria , LoConte Noelle K. , Ratnapradipa Kendra L.
Published: March 2024

Supplementary Figure S2: Infographic on cancer burden tailored toward American Indian/Alaska Native population
Data from Engaging Communities in Cancer Prevention and Control Activity Prioritization through a Statewide Needs Assessment: A Case Study from Nebraska
Authors: Watanabe-Galloway Shinobu , Napit Krishtee , McCullough Jordan , Luma Lady Beverly , Kabayundo Josiane , Carritt Nicole L. , Schabloske Laura , Robinson Tamara , Rohde Jolene , Champion Victoria , LoConte Noelle K. , Ratnapradipa Kendra L.
Published: March 2024

Abstract
Community outreach and engagement (COE) activities are important in identifying catchment area needs, communicating these needs, and facilitating activities relevant to the population. The National Cancer Institute–designated cancer centers are required to conduct catchment-wide cancer needs assessments as part of their COE activities. The University of Nebraska Medical Center Buffett Cancer Center undertook a three-year-long process to conduct a needs assessment, identify priorities, and develop workgroups to implement cancer prevention and control activities. Activities were conducted through collaborations with internal and external partners. The needs assessment focused on prevention, early detection, and treatment of cancer and involved secondary data analysis and focus groups with identified underrepresented priority populations (rural, African American, Hispanic, Native American, and LGBTQ+ populations). Results were tailored and disseminated to specific audiences via internal and external reports, infographics, and presentations. Several workgroups were developed through meetings with the internal and external partners to address identified priorities. COE-specific initiatives and metrics have been incorporated into University of Nebraska Medical Center and Buffett Cancer Center strategic plans. True community engagement takes a focused effort and significant resources. A systemic and long-term approach is needed to develop trusted relationships between the COE team and its local communities.
Engaging Communities in Cancer Prevention and Control Activity Prioritization through a Statewide Needs Assessment: A Case Study from Nebraska
Authors: Watanabe-Galloway Shinobu , Napit Krishtee , McCullough Jordan , Luma Lady Beverly , Kabayundo Josiane , Carritt Nicole L. , Schabloske Laura , Robinson Tamara , Rohde Jolene , Champion Victoria , LoConte Noelle K. , Ratnapradipa Kendra L.
Published: March 2024

Community outreach and engagement (COE) activities are important in identifying catchment area needs, communicating these needs, and facilitating activities relevant to the population. The National Cancer Institute–designated cancer centers are required to conduct catchment-wide cancer needs assessments as part of their COE activities. The University of Nebraska Medical Center Buffett Cancer Center undertook a three-year-long process to conduct a needs assessment, identify priorities, and develop workgroups to implement cancer prevention and control activities. Activities were conducted through collaborations with internal and external partners. The needs assessment focused on prevention, early detection, and treatment of cancer and involved secondary data analysis and focus groups with identified underrepresented priority populations (rural, African American, Hispanic, Native American, and LGBTQ+ populations). Results were tailored and disseminated to specific audiences via internal and external reports, infographics, and presentations. Several workgroups were developed through meetings with the internal and external partners to address identified priorities. COE-specific initiatives and metrics have been incorporated into University of Nebraska Medical Center and Buffett Cancer Center strategic plans. True community engagement takes a focused effort and significant resources. A systemic and long-term approach is needed to develop trusted relationships between the COE team and its local communities.
Next-Generation Screening for Colorectal Cancer, an Incremental Approach to a Global Disease
Authors: Bresalier Robert S.
Published: March 2024

New screening tests for early detection of colorectal cancer and its precursors are rapidly emerging with the focus on noninvasive tests which can be used in both structured opportunistic and population-based organized screening programs. Novel technologies are identifying new combinations of promising markers. Conducting large prospective clinical trials of efficacy requires very large numbers of subjects constituting intended-use populations. These trials are often preceded by studies using smaller numbers of “convenience” samples to derive panels of relevant markers and algorithms to combine them and define what constitutes a positive test. The article by Gagrat and colleagues in this issue reports results from one such study designed to yield a “next-generation” multitargeted (mt-sDNA) stool test. This report exemplifies the advantages and limitations of this approach.

See related article by Gagrat et al., p. 119
Figure S8 from Neutralizing Antibodies Impair the Oncolytic Efficacy of Reovirus but Permit Effective Combination with T cell–Based Immunotherapies
Authors: Groeneveldt Christianne , Kinderman Priscilla , Griffioen Lisa , Rensing Olivia , Labrie Camilla , van den Wollenberg Diana J.M. , Hoeben Rob C. , Coffey Matt , Loghmani Houra , Verdegaal Els M.E. , Welters Marij J.P. , van der Burg Sjoerd H. , van Hall Thorbald , van Montfoort Nadine
Published: March 2024

Figure S8. Neutralization capacity of plasma used for the transfer to NSG mice.
Figure S7 from Neutralizing Antibodies Impair the Oncolytic Efficacy of Reovirus but Permit Effective Combination with T cell–Based Immunotherapies
Authors: Groeneveldt Christianne , Kinderman Priscilla , Griffioen Lisa , Rensing Olivia , Labrie Camilla , van den Wollenberg Diana J.M. , Hoeben Rob C. , Coffey Matt , Loghmani Houra , Verdegaal Els M.E. , Welters Marij J.P. , van der Burg Sjoerd H. , van Hall Thorbald , van Montfoort Nadine
Published: March 2024

Figure S7. Reo-specific neutralizing antibodies are present 5 days after intratumoral Reo administration.
Figure S2 from Neutralizing Antibodies Impair the Oncolytic Efficacy of Reovirus but Permit Effective Combination with T cell–Based Immunotherapies
Authors: Groeneveldt Christianne , Kinderman Priscilla , Griffioen Lisa , Rensing Olivia , Labrie Camilla , van den Wollenberg Diana J.M. , Hoeben Rob C. , Coffey Matt , Loghmani Houra , Verdegaal Els M.E. , Welters Marij J.P. , van der Burg Sjoerd H. , van Hall Thorbald , van Montfoort Nadine
Published: March 2024

Figure S2. Gating strategy used for flow cytometric analysis of immune cell composition.
Supplementary table 5 from An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype
Authors: Zhang Yaochuan , Song Yifu , Wang Xiaoliang , Shi Mengwu , Lin Yibin , Tao Dongxia , Han Sheng
Published: March 2024

ChIP PCR Primers
Supplementary Figure 8 from An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype
Authors: Zhang Yaochuan , Song Yifu , Wang Xiaoliang , Shi Mengwu , Lin Yibin , Tao Dongxia , Han Sheng
Published: March 2024

C3a/C3aR pathway played an important role in the positive regulation of TIM-3 expression by NFAT1.
Supplementary Figure 1 from An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype
Authors: Zhang Yaochuan , Song Yifu , Wang Xiaoliang , Shi Mengwu , Lin Yibin , Tao Dongxia , Han Sheng
Published: March 2024

Generation of Nfat1 knockout mice using CRISPR/Cas9-mediated genome editing and the correlation between NFAT1 and tumor-associated macrophages.
Supplementary Table 2 from FcγRIIB Is an Immune Checkpoint Limiting the Activity of Treg-Targeting Antibodies in the Tumor Microenvironment
Authors: Knorr David A. , Blanchard Lucas , Leidner Rom S. , Jensen Shawn M. , Meng Ryan , Jones Andrew , Ballesteros-Merino Carmen , Bell Richard B. , Baez Maria , Marino Alessandra , Sprott David , Bifulco Carlo B. , Piening Brian , Dahan Rony , Osorio Juan C. , Fox Bernard A. , Ravetch Jeffrey V.
Published: March 2024

Primers for site-directed mutagenesis
Supplementary Table 1 from FcγRIIB Is an Immune Checkpoint Limiting the Activity of Treg-Targeting Antibodies in the Tumor Microenvironment
Authors: Knorr David A. , Blanchard Lucas , Leidner Rom S. , Jensen Shawn M. , Meng Ryan , Jones Andrew , Ballesteros-Merino Carmen , Bell Richard B. , Baez Maria , Marino Alessandra , Sprott David , Bifulco Carlo B. , Piening Brian , Dahan Rony , Osorio Juan C. , Fox Bernard A. , Ravetch Jeffrey V.
Published: March 2024

Antibody sequences
Supplementary Figure 4 from FcγRIIB Is an Immune Checkpoint Limiting the Activity of Treg-Targeting Antibodies in the Tumor Microenvironment
Authors: Knorr David A. , Blanchard Lucas , Leidner Rom S. , Jensen Shawn M. , Meng Ryan , Jones Andrew , Ballesteros-Merino Carmen , Bell Richard B. , Baez Maria , Marino Alessandra , Sprott David , Bifulco Carlo B. , Piening Brian , Dahan Rony , Osorio Juan C. , Fox Bernard A. , Ravetch Jeffrey V.
Published: March 2024

Antitumor activity of Fc-engineered murine anti-CCR8 antibodies
Figure S4 from Intragenic Rearrangement Burden Associates with Immune Cell Infiltration and Response to Immune Checkpoint Blockade in Cancer
Authors: Zhang Han , Lee Sanghoon , Muthakana Renee R. , Lu Binfeng , Boone David N. , Lee Daniel , Wang Xiao-Song
Published: March 2024

Figure S4. Contributions of different types of genetic markers to T-inflamed signature in ICGC simple mutation-dominant cancers (a) and IGR-dominant cancers (b) after regressing out tumor types. The ICGC patient cohorts shown in Figure S4a and S4b correspond to the same patient cohorts shown in Figure 1f and 1g respectively. TMB and IGR remained the most significant regressors among all genetic markers in simple mutation-dominant and IGR-dominant cancers, respectively.
Figure S2 from Intragenic Rearrangement Burden Associates with Immune Cell Infiltration and Response to Immune Checkpoint Blockade in Cancer
Authors: Zhang Han , Lee Sanghoon , Muthakana Renee R. , Lu Binfeng , Boone David N. , Lee Daniel , Wang Xiao-Song
Published: March 2024

Figure S2. Correlations between IGR burden, TMB and Indels in the ICGC Pan-cancer dataset. (a) Scatter plot of Indel burden (x-axis) and TMB (y-axis), colored by T-inflamed signature. (b) Scatter plot of Indel burden (x-axis) and IGR burden (y-axis). (c) Median Indel burden vs tumor mutation burden for each cancer type. (d) Median Indel burden vs IGR burden for each cancer type. Dotted lines in (c, d) indicate mean plus one standard deviation cutoffs of the corresponding biomarkers.
Supplementary Fig. 2 from LILRB3 Supports Immunosuppressive Activity of Myeloid Cells and Tumor Development
Authors: Huang Ryan , Liu Xiaoye , Kim Jaehyup , Deng Hui , Deng Mi , Gui Xun , Chen Heyu , Wu Guojin , Xiong Wei , Xie Jingjing , Lewis Cheryl , Homsi Jade , Yang Xing , Zhang Chengcheng , He Yubo , Lou Qi , Smith Caroline , John Samuel , Zhang Ningyan , An Zhiqiang , Zhang Cheng Cheng
Published: March 2024

Supplementary Fig. 2 with figure legend
Figure S5 from T-cell States, Repertoire, and Function in Classical Hodgkin Lymphoma Revealed through Single-Cell Analyses
Authors: Chen Xiufen , Yu Jovian , Venkataraman Girish , Smith Sonali M. , Chen Mengjie , Cooper Alan , Tumuluru Sravya , Brody Joshua D. , Godfrey James , Kline Justin
Published: March 2024

Supplemental Figure S5. Proportions and expanded clonotypes in exhausted/effector CD8+ T cells by EBER and HLA-I expression status
Figure S1 from T-cell States, Repertoire, and Function in Classical Hodgkin Lymphoma Revealed through Single-Cell Analyses
Authors: Chen Xiufen , Yu Jovian , Venkataraman Girish , Smith Sonali M. , Chen Mengjie , Cooper Alan , Tumuluru Sravya , Brody Joshua D. , Godfrey James , Kline Justin
Published: March 2024

Supplemental Figure S1. Cell types and states in the cHL environment
Data from An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype
Authors: Zhang Yaochuan , Song Yifu , Wang Xiaoliang , Shi Mengwu , Lin Yibin , Tao Dongxia , Han Sheng
Published: March 2024

Abstract
Extensive infiltration by tumor-associated macrophages (TAM) in combination with myeloid-derived suppressor cells constitute the immunosuppressive microenvironment and promote the malignant phenotype of gliomas. The aggressive mesenchymal (MES)-subtype glioma stem cells (GSC) are prominent in the immunosuppressive microenvironment of gliomas. However, the underlying immune-suppressive mechanisms are still unknown. The current study showed that the antitumor immune microenvironment was activated in glioma in Nfat1−/− mice, suggesting induction of the immune-suppressive microenvironment by nuclear factor of activated T cells-1 (NFAT1). In TAMs, NFAT1 could upregulate the transcriptional activity of complement 3 (C3) and increase the secretion of C3a, which could then bind to C3aR and promote M2-like macrophage polarization by activating TIM-3. Simultaneously, C3a/C3aR activated the Ca2+-NFAT1 pathway, forming a positive feedback loop for the M2-like polarization of TAMs, which further promoted the MES transition of GSCs. Finally, disruption of this feedback loop using a C3aR inhibitor significantly inhibited glioma growth both in vitro and in vivo. The current study demonstrated that a NFAT1-C3a-C3aR positive feedback loop induces M2-like TAMs and further promotes the malignant phenotype of GSCs, which might be the potential therapeutic target for glioma.
Data from FcγRIIB Is an Immune Checkpoint Limiting the Activity of Treg-Targeting Antibodies in the Tumor Microenvironment
Authors: Knorr David A. , Blanchard Lucas , Leidner Rom S. , Jensen Shawn M. , Meng Ryan , Jones Andrew , Ballesteros-Merino Carmen , Bell Richard B. , Baez Maria , Marino Alessandra , Sprott David , Bifulco Carlo B. , Piening Brian , Dahan Rony , Osorio Juan C. , Fox Bernard A. , Ravetch Jeffrey V.
Published: March 2024

Abstract
Preclinical murine data indicate that fragment crystallizable (Fc)-dependent depletion of intratumoral regulatory T cells (Treg) is a major mechanism of action of anti–CTLA-4. However, the two main antibodies administered to patients (ipilimumab and tremelimumab) do not recapitulate these effects. Here, we investigate the underlying mechanisms responsible for the limited Treg depletion observed with these therapies. Using an immunocompetent murine model humanized for CTLA-4 and Fcγ receptors (FcγR), we show that ipilimumab and tremelimumab exhibit limited Treg depletion in tumors. Immune profiling of the tumor microenvironment (TME) in both humanized mice and humans revealed high expression of the inhibitory Fc receptor, FcγRIIB, which limits antibody-dependent cellular cytotoxicity/phagocytosis. Blocking FcγRIIB in humanized mice rescued the Treg-depleting capacity and antitumor activity of ipilimumab. Furthermore, Fc engineering of antibodies targeting Treg-associated targets (CTLA-4 or CCR8) to minimize FcγRIIB binding significantly enhanced Treg depletion, resulting in increased antitumor activity across various tumor models. Our results define the inhibitory FcγRIIB as an immune checkpoint limiting antibody-mediated Treg depletion in the TME, and demonstrate Fc engineering as an effective strategy to overcome this limitation and improve the efficacy of Treg-targeting antibodies.
Supplemental Figure 1 from Identification and Characterization of a Small Molecule Bcl-2 Functional Converter
Authors: Kopparapu Prasad R. , Pearce Martin C. , Löhr Christiane V. , Duong Cathy , Jang Hyo Sang , Tyavanagimatt Shanthakumar , O'Donnell Edmond F. , Nakshatri Harikrishna , Kolluri Siva K.
Published: March 2024

Bcl-2 dependent apoptotic effects of BFC1108. Independent experimental replicates of data in Figure 2C are shown.
Supplementary Table 3 from Establishment and Characterization of an Epstein-Barr Virus–positive Cell Line from a Non-keratinizing Differentiated Primary Nasopharyngeal Carcinoma
Authors: Chai Annie Wai Yeeng , Yee Shi Mun , Lee Hui Mei , Abdul Aziz Norazlin , Yee Pei San , Marzuki Marini , Wong Ka Wo , Chiang Alan K.S. , Chow Larry Ka-Yue , Dai Wei , Liu Teng Fei , Tan Lu Ping , Khoo Alan Soo Beng , Lo Kwok Wai , Lim Paul V.H. , Rajadurai Pathmanathan , Lightfoot Howard , Barthorpe Syd , Garnett Mathew J. , Cheong Sok Ching
Published: March 2024

Short Tandem Repeats (STR) profiling of NPC268 cell lines at early and late passages confirmed authenticity with patient's buffy coat DNA
Empathy from dissimilarity: Multivariate pattern analysis of neural activity during observation of somatosensory experience
Authors: Lulla Roshni , Christov-Moore Leonardo , Vaccaro Anthony , Reggente Nicco , Iacoboni Marco , Kaplan Jonas T.
Published: March 2024

Empathy seems to rely on our ability to faithfully simulate multiple aspects of others’ inferred experiences, often using brain structures we would use during a similar experience. Much neuroimaging work in this vein has related empathic tendencies to univariate correlates of simulation strength or salience. However, novel evidence suggests that empathy may rely on the multivariate distinctiveness of these simulations. Someone whose representations of painful and non-painful stimulation are more distinct from each other may more accurately simulate that experience upon seeing somebody else experience it. We sought to predict empathic tendencies from the dissimilarity between neural activity patterns evoked by observing other people experience pain and touch and compared those findings to traditional univariate analyses. In support of a simulationist perspective, diverse observed somatosensory experiences were best classified by activation patterns in contralateral somatosensory and insular cortices, the same areas that would be active were the subject experiencing the stimuli themselves. In support of our specific hypothesis, the degree of dissimilarity between patterns for pain and touch in distinct areas was each associated with different aspects of trait empathy. Furthermore, the pattern dissimilarity analysis proved more informative regarding individual differences than analogous univariate analyses. These results suggest that multiple facets of empathy are associated with an ability to robustly distinguish between the simulated states of others at corresponding levels of the processing hierarchy, observable via the distinguishability of neural patterns arising with those states. Activation pattern dissimilarity may be a useful tool for parsing the neuroimaging correlates of complex cognitive functions like empathy.
Demystifying the likelihood of reidentification in neuroimaging data: A technical and regulatory analysis
Authors: Jwa Anita S. , Koyejo Oluwasanmi , Poldrack Russell A.
Published: March 2024

Sharing research data has been widely promoted in the field of neuroimaging and has enhanced the rigor and reproducibility of neuroimaging studies. Yet the emergence of novel software tools and algorithms, such as face recognition, has raised concerns due to their potential to reidentify defaced neuroimaging data that are thought to have been deidentified. Despite the surge of privacy concerns, however, the risk of reidentification via these tools and algorithms has not yet been examined outside the limited settings for demonstration purposes. There is also a pressing need to carefully analyze regulatory implications of this new reidentification attack because concerns about the anonymity of data are the main reason that researchers think they are legally constrained from sharing their data. This study aims to tackle these gaps through rigorous technical and regulatory analyses. Using a simulation analysis, we first tested the generalizability of the matching accuracies in defaced neuroimaging data reported in a recent face recognition study (Schwarz et al., 2021). The results showed that the real-world likelihood of reidentification in defaced neuroimaging data via face recognition would be substantially lower than that reported in the previous studies. Next, by taking a US jurisdiction as a case study, we analyzed whether the novel reidentification threat posed by face recognition would place defaced neuroimaging data out of compliance under the current regulatory regime. Our analysis suggests that defaced neuroimaging data using existing tools would still meet the regulatory requirements for data deidentification. A brief comparison with the EU’s General Data Protection Regulation (GDPR) was also provided. Then, we examined the implication of NIH’s new Data Management and Sharing Policy on the current practice of neuroimaging data sharing based on the results of our simulation and regulatory analyses. Finally, we discussed future directions of open data sharing in neuroimaging.
Electroencephalography Spectral-power Volatility Predicts Problem-solving Outcomes
Authors: Yu Yuhua , Oh Yongtaek , Kounios John , Beeman Mark
Published: March 2024

Temporal variability is a fundamental property of brain processes and is functionally important to human cognition. This study examined how fluctuations in neural oscillatory activity are related to problem-solving performance as one example of how temporal variability affects high-level cognition. We used volatility to assess step-by-step fluctuations of EEG spectral power while individuals attempted to solve word-association puzzles. Inspired by recent results with hidden-state modeling, we tested the hypothesis that spectral-power volatility is directly associated with problem-solving outcomes. As predicted, volatility was lower during trials solved with insight compared with those solved analytically. Moreover, volatility during prestimulus preparation for problem-solving predicted solving outcomes, including solving success and solving time. These novel findings were replicated in a separate data set from an anagram-solving task, suggesting that less-rapid transitions between neural oscillatory synchronization and desynchronization predict better solving performance and are conducive to solving with insight for these types of problems. Thus, volatility can be a valuable index of cognition-related brain dynamics.
Modest building blocks
Authors: Vandermeulen Wout
Published: March 2024

This article seeks to contribute to the growing current of legal historical literature on early modern commercial law. It examines the topic of monopolies and their prohibition in the Codex of Justinian (C. 4,59,2). Its purpose is to explore one aspect of the renewed interest in the topic among lawyers and theologians in the early 16th century, when trading corporations and authorities worldly and ecclesial caused a proliferation of monopolies. The aspect in question is the source material from the legal and theological tradition that early modern authors had at their disposal. Through analysing the printed editions of medieval works from Roman and canon law and from theology, this contribution sketches an image of scattered attention and a strong focus on guilds until the very last years of the Middle Ages. Only after 1450 do the roots of the notions that would dominate later debates come to the fore, and near exclusively in the works of moral theologians such as Konrad Summenhart.
Origen de la teoría sobre la Paráfrasis del Pseudo-Teófilo
Authors: Reinoso-Barbero Fernando
Published: March 2024

Origin of the theory about the Pseudo-Theophilus’ Paraphrase. – The sudden and abrupt change in Contardo Ferrini’s stance towards Theophilus, is attributed here to the misinterpretation of a letter sent to him by Zachariä von Lingenthal on January 31, 1884, just as his magnificent edition of the Paraphrase was on the brink of publication. This circumstance compels him to hastily modify and adapt its Prolegomena to his new theory, leading to significant unforeseen consequences. Furthermore, due to the rush, he also overlooks making modifications in other sections of his edition where, for this reason, Theophilus is still acknowledged as the author of the Paraphrase.
Zur Entmündigung wegen Wahnsinn und Verschwendung im römischen Recht
Authors: Lehne-Gstreinthaler Christine
Published: March 2024

This article is devoted to the incapacitation procedure for insane and profligate persons in Roman law. On the basis of literary and legal sources, an attempt is made to explain the incapacitation procedure in more detail. Special attention is given to the concept of interdiction and the question of involvement of physicians in such proceedings.
Testamentary practices and village courts in the Bailiwick of ’s-Hertogenbosch (c. 1470-1550)
Authors: Vermeer Mark
Published: March 2024

This paper discusses the origin, function and uses of schepentestamenten, acts of last will registered before municipal courts of aldermen. From the second half of the fifteenth century, peasants and townsmen found recourse to these courts for the registration of acts of last will. At first these acts were primarily contracts among spouses mutually conveying to each other the property upon death, but especially after the secularisation of the notarial profession in 1531 the number of pious bequests and religious beneficiaries greatly increased. In general, three strategies prevail in the employment of the last will: overruling the customary dispensation to the surviving spouse and providing this person with additional resources, specifying the position of each of the children (especially when some were illegitimate or had received by life), and preventing loss of wealth from the family. For the legal instruments, the aldermen resorted to their standard formulary, although attuned to the peculiarities of the last will. The trust and authority the courts of aldermen enjoyed, in combination with their executive clout in enforcing compliance, allowed them to discard various formal elements required in notarial instruments, while also making them popular institutions for the registration of last wills.
Clarifying the status of Caribbean Pinguicula (Lentibulariaceae) type specimens
Authors: DOMÍNGUEZ YOANNIS
Published: March 2024

After the most recent taxonomic treatment of the genus Pinguicula in the Caribbean, several names have been found to need typification or correction of the cited type specimens. Analyses of original material and literature related to each name led to the designation of five lectotypes, one epitype and the correction of one previous inadvertent typification. Additionally, corrections to the citation of type specimens were made when necessary, including notes for each treated name. The nomenclatural status of each name for the Caribbean taxa of Pinguicula is provided.