bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A057: Therapeutic modality, antitumor efficacy and immune safety for targeting innate immune checkpoint TREX1 as cancer immunotherapy
Authors: Xing Cong , Tu Xintao , Huai Wanwan , Tang Zhen , Song Kun , Knox Kennady , Dobbs Nicole , Yang Kun , Yan Nan
Published: October 2024

Three-prime repair exonuclease 1 (TREX1) is the major DNase in mammalian cells that degrades cytosolic DNA to prevent activation of the cGAS-STING pathway. Genotoxic stress, DNA damage, and radiotherapy induce TREX1 expression in cancer cells, allowing them to evade innate immune activation of type I interferon (IFN-I)-mediated antitumor response. How TREX1 can be targeted for cancer immunotherapy remains elusive. Here, we report a high-throughput small-molecule inhibitor (SMI) screen of TREX1 using a cell-free DNase assay. We identify two lead compounds that inhibit TREX1 DNase activity at low micromolar concentrations, induce IFN-I signaling in cancer cells, and inhibit tumor growth in mice in an IFNAR-dependent manner. We further show that Trex1 knockout cancer cells elicit robust systemic antitumor immunity through tumor-intrinsic cGAS-STING activation and can be used as autologous cancer vaccines to protect against future tumor challenge. We also establish an inducible whole-body Trex1 knockout mouse model to simulate “on-demand” systemic TREX1 inactivation in adult mice. Sustained TREX1 loss in adult mice suppresses a broad range of solid tumors and metastatic tumors without incurring immune toxicity, demonstrating feasibility of an immune-safe therapeutic window. Together, our data present multiple therapeutic modalities for targeting TREX1 using SMIs and as an autologous cancer vaccine, as well as antitumor efficacy and immune safety, which should pave the way for developing TREX1-targeted cancer immunotherapy.

Citation Format: Cong Xing, Xintao Tu, Wanwan Huai, Zhen Tang1, Kun Song, Kennady Knox, Nicole Dobbs, Kun Yang, Nan Yan. Therapeutic modality, antitumor efficacy and immune safety for targeting innate immune checkpoint TREX1 as cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A057.
Abstract A058: Oncolytic adenovirus induces potent anti-tumor efficacy via robust activation of immune cells in bladder cancer
Authors: Kim Yunlim , Lim Bum Jin , Yoon A-Rum , Yun Chae-Ok , Kim Choung-Soo
Published: October 2024

Bladder cancer (BC) is one of the most prevalent malignancies globally. Despite recent advancements, resistance to conventional treatments such as surgery, chemotherapy, and immunotherapy remains common among BC patients. Thus, developing novel therapeutic agents or enhancing the efficacy of current treatments is essential for better management of BC. Oncolytic adenoviruses represent a promising new approach, capable of inflaming the tumor microenvironment and eliciting tumor-specific T cell responses. In this study, we aimed to understand the immune mechanisms involved in the antitumor therapeutic efficacy of oAd/IL-12/shVEGF—an oncolytic adenovirus co-expressing interleukin-12 (IL-12) and short hairpin RNA targeting vascular endothelial growth factor (shVEGF)—both in vitro and in vivo against BC. To investigate the therapeutic potential of oAd/IL-12/shVEGF in a syngeneic MB49 BC model, tumor-bearing mice were intratumorally injected with the oncolytic virus when tumors reached 70-100 mm³. Tumor volume and body weight were monitored until the end of the experiment. Mice were sacrificed when tumors reached 2000 mm³, and both tumor and spleen tissues were disaggregated for analysis. Tumor tissues were examined for proliferation marker (PCNA), adenovirus injection marker (E1A), and antitumor immune marker (CD8) using H&E and immunohistochemical analysis. To evaluate immune modulation, levels of IFN-γ, TNF-α, and IL-12 in tumor tissues and splenocytes were measured using ELISA kits. Tumor-specific immune responses were assessed by evaluating the number of IFN-γ-secreting immune cells in splenocytes via ELISPOT assay. Statistical analysis was performed using one-way ANOVA. Treatment with oAd/IL-12/shVEGF significantly suppressed tumor growth compared to PBS-treated controls. The oncolytic virus increased levels of IFN-γ, TNF-α, and IL-12 in both tumor tissues and splenocytes compared to PBS. Additionally, oAd/IL-12/shVEGF enhanced CD8+ T cell infiltration into tumor tissues and significantly reduced PCNA expression, indicating decreased tumor cell proliferation. Consistent with these findings, the number of IFN-γ-secreting immune cells was significantly higher in mice treated with oAd/IL-12/shVEGF compared to those treated with PBS. These results suggest that oAd/IL-12/shVEGF is a promising clinical cancer immunotherapeutic agent for inducing antitumor immunity in bladder cancer.

Citation Format: Yunlim Kim, Bum Jin Lim, A-Rum Yoon, Chae-Ok Yun, Choung-Soo Kim. Oncolytic adenovirus induces potent anti-tumor efficacy via robust activation of immune cells in bladder cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A058.
Abstract A059: Uncovering Bystander Killing Mechanisms of Trastuzumab Deruxtecan (T-DXd): Effective Extracellular Payload Release via Cathepsin L in HER2-low Breast Cancer.
Authors: Tsao Li-Chung , Wang John S. , Ragusa Joey , Liu Bushangqing , McBane Jason , Spasojevic Ivan , Fan Ping , Trotter Timothy N. , Lyerly Herbert Kim , Hartman Zachary C
Published: October 2024

Trastuzumab deruxtecan (T-DXd), or fam-trastuzumab-deruxtecan-nxki, is a novel antibody-drug-conjugate (ADC) targeting HER2 that has demonstrated profound clinical efficacy across HER2-positive breast cancer (BC), including in HER2-low and HER2 “ultra-low” BC. However, the precise mechanism underlying its efficacy in HER2-low BC is still poorly understood. To determine the mechanism of DXd release and cytotoxicity, we compared in vivo T-DXd treatment of human BC xenografts with varying HER2 expression profiles, coupled with in vitro bystander killing analysis of co-cultured HER2-negative cells, and liquid chromatography–mass spectrometry of DXd payload levels in the tumor microenvironment. Our findings revealed that the efficacy of T-DXd in HER2-low and HER2-negative BC is mediated by extracellular proteases, specifically cathepsin L (CTSL), but not cathepsin B, within the tumor microenvironment (TME). Unlike traditional ADCs such as trastuzumab emtansine (T-DM1), which contain a non-cleavable linker and require efficient intracellular endocytosis for payload release and cytotoxicity, HER2-low and HER2 “ultra-low” BC demonstrated limited ADC uptake. Despite this, these cancer types exhibited strong sensitivity to T-DXd in vivo, but not to T-DM1. Critically, using CTSL overexpression and knockout strategies on HER2 “ultra-low” MDA-MB-231 cells, we found that extracellular CTSL released by tumor cells mediates the proteolytic cleavage of T-DXd’s linker. This enables broader DXd payload release and cytotoxicity, bypassing traditional ADC-resistance mechanisms, including HER2 downregulation and resistance to ADC internalization. Our studies reveal a crucial payload release mechanism of T-DXd within the TME, mediated by extracellular CTSL cleavage of T-DXd’s tetrapeptide linker. This mechanism likely contributes to the broad efficacy of T-DXd in HER2-low and even HER2 “ultra-low” BC over T-DM1. Collectively, our findings suggest that CTSL and other extracellular proteases in the TME may serve as important biomarkers for predicting T-DXd efficacy.

Citation Format: Li-Chung Tsao, John S. Wang, Joey Ragusa, Bushangqing Liu, Jason McBane, Ivan Spasojevic, Ping Fan, Timothy N. Trotter, Herbert Kim Lyerly, Zachary C Hartman. Uncovering Bystander Killing Mechanisms of Trastuzumab Deruxtecan (T-DXd): Effective Extracellular Payload Release via Cathepsin L in HER2-low Breast Cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A059.
Abstract B002: HIF-2A inhibition in adaptive immunity against cancer growth
Authors: Frazier Katya , Muise Eric , Stolz Joshua , Fischer Lukas , Buchanan Mark , Schneider Charlie , Ho Chan Brian Pak , Carr Richard , Perini Rodolfo , Long Brian , Linn Douglas
Published: October 2024

Hypoxia Inducible Factors (HIFs) are transcription factors implicated in many cellular processes key to survival, proliferation, and function, particularly for cancer cells. HIF2A has been identified as an oncogene in the context of renal cell carcinoma (RCC), and belzutifan (MK-6482) is a HIF2A inhibitor that is FDA-approved for VHL-associated and advanced RCC. HIF1A and HIF2A are expressed by all cells in the hypoxic tumor microenvironment, including anti-tumor immune cells, and have been shown to drive T cell effector function. Several ongoing clinical trials are evaluating MK-6482 in combination with immune checkpoint blockade therapy for advanced RCC, however the potential impact that MK-6482 may directly have on the adaptive immune response remains poorly understood. Considering the functional link between HIF signaling and T cell function, we explored whether HIF-2A inhibition by MK-6482 could impact activation and/or anti-tumor action of T cells supported by anti-PD-1 and anti-CTLA-4 immune checkpoint blockade. Interrogation of primary T cell activation by mixed lymphocyte reaction revealed that MK-6482 did not induce significant changes in cytokine secretion or cell proliferation with or without immune checkpoint blockade, despite evidence of HIF2A protein reduction. MK-6482 in combination with immune checkpoint blockade increased antitumor efficacy compared to either alone in an RCC humanized mouse model, resulting in almost complete tumor regression. IHC analysis of tumors revealed a trend of increased T cell infiltration and a significant reduction in HIF2A protein following combined treatment, potentially contributing to the tumor regression. mRNA sequencing of tumors also revealed increased expression of T cell activation pathways, suggesting that the combination treatment induced greater anti-tumor activity of infiltrating T cells. Together, our data support continued clinical evaluation of belzutifan and checkpoint blockade combination treatment for RCC, and we continue to explore the potential mechanistic effects by both in vivo and in vitro follow-up studies.

Citation Format: Katya Frazier, Eric Muise, Joshua Stolz, Lukas Fischer, Mark Buchanan, Charlie Schneider, Brian Pak Ho Chan, Richard Carr, Rodolfo Perini, Brian Long, Douglas Linn. HIF-2A inhibition in adaptive immunity against cancer growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B002.
Abstract B025: A T cell engager targeting cancer associated fibroblasts inhibits tumor growth and modulates the tumor microenvironment
Authors: Tagore Joshua , Norgard Robert , Penikalapati Sia , Bachmayr-Heyda Anna , Budhani Pratha , Corrales-Pecino Leticia , Kashyap Abhishek , Xia Youli , O'Brien Sarah
Published: October 2024

Fibroblast activating protein (FAP) is an attractive target for therapeutic intervention being mainly expressed in malignant tissues. Previous studies have targeted FAP using a variety of methods yet failed in clinics. Here, we utilize FAP-targeted T cell engager (TcE) in KPCY tumor models to recapitulate a pre-clinical environment. The use of FAP- TcE efficiently depleted FAP+ fibroblasts in vitro and in vivo from tumors. This resulted in bystander killing of tumor cells and tumor growth control in vivo. This therapeutic effect was not dependent on priming via lymph node activation as shown in other publications. To understand the complex interactions with FAP expression, we perform comprehensive single cell RNA-sequencing profiling before and after FAP-TcE depletion to understand the pivotal genetic roles of FAP depletion in all cell types. This analysis initially revealed a T cell exhaustion phenotype with upregulated of PD-1 on T cells after FAP-TcE treatment. However, while addition of anti-PD-1 therapy significantly enhanced tumor efficacy, complete control was absent. RNA sequencing of the fibroblasts identified depletion of a myCAF-like fibroblast and an outgrowth of a mixed CAF population with phenotypes of both myCAF and iCAF. This population correlated with tumor growth, and cell cycle gene signatures. Future work will investigate the implications of this fibroblast population’s role in subverting immune suppression.

Citation Format: Joshua Tagore, Robert Norgard, Sia Penikalapati, Anna Bachmayr-Heyda, Pratha Budhani, Leticia Corrales-Pecino, Abhishek Kashyap, Youli Xia, Sarah O'Brien. A T cell engager targeting cancer associated fibroblasts inhibits tumor growth and modulates the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B025.
Abstract B031: TCR signal strength drives tumor-specific CD8 T cell differentiation
Authors: Carson Sandra , Schietinger Andrea
Published: October 2024

Immunotherapies, such as immune checkpoint blockade, demonstrate the potential power of CD8 T cells to eliminate cancer cells, however these strategies only work in a subset of patients and tumor types. To design predictably effective immunotherapies, we must elucidate the mechanisms controlling tumor-specific T cell dysfunction and therapeutic reprogramming. TOX is a key transcription factor driving T cell differentiation in progressing tumors and required for T cell persistence. T cell receptor (TCR) signal strength (determined by the affinity of TCR for peptide-bound major histocompatibility complex (pMHC)) is known to regulate T cell differentiation during infections. However, how TCR signal strength impacts TOX expression and differentiation in tumors is less clear. Here, we developed a novel autochthonous mouse cancer model in which we can vary TCR signal strength to span the range observed for human tumor-infiltrating T cells and track tumor-specific CD8 T cells over several months from tumor initiation until end-stage cancer progression: we cloned a Sleeping Beauty transposon/transposase-based vector (SB-Cre) encoding Cre-recombinase and a fluorescent reporter protein fused to a tumor model antigen (OVA) under the control of the liver-specific albumin promoter. Through single amino acid substitutions of the native OVA sequence, we generated altered peptide ligands that are recognized by OVA-specific CD8 T cells with varying TCR signal strength. SB-vectors were delivered via hydrodynamic tail vein injection into mice with inducible activating oncogenes and silencing of tumor suppressor genes, a highly-efficient method to induce liver tumors. Over the course of tumor development we phenotypically and functionally characterized tumor-specific CD8 T cells in tumor draining lymph nodes (tdLN) and progressing liver tumors. Our data reveal how TCR signal strength determines TOX-driven differentiation and dysfunction of tumor-specific T cells starting at the earliest stages of tumorigenesis in tdLN. Ongoing efforts aim to investigate the functional impact of TCR signal strength on T cell differentiation and anti-tumor responses, including responsiveness to immunotherapeutic interventions.

Citation Format: Sandra Carson, Andrea Schietinger. TCR signal strength drives tumor-specific CD8 T cell differentiation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B031.
Abstract B033: Excessive Chimeric Antigen Receptor signaling correlates with poor clinical outcomes
Authors: Draper Isabella , Bueter Eric , Annesley Colleen , Summers Corinne , Gardner Rebecca , Smith Stephen
Published: October 2024

While CAR-T clinical trials have seen promising results in B-acute lymphoblastic leukemia (B-ALL), unpredictable side effects, such as Cytokine Release Syndrome (CRS) and Immune Effector Cell Associated Neurotoxicity (ICANS), limit CAR-T cells from becoming a first line treatment. Different CAR designs produce different in-human responses, but extant preclinical assays largely fail to predict clinical responses and toxicity. Here, we present data from two independent studies in which we compared the molecular signal transduction profiles of well-performing vs poorly-performing CARs in the clinic. We identified a consistent set of protein-protein interactions that correlate with both poor response and toxicity in CAR trials. In study #1, healthy donor T cells expressing either the poorly performing anti-CD22 (IgG4 Hinge-CD28TM-41BB-CD3z) PLAT-04 CAR, or the better performing anti-CD22 (CD8 Hinge-CD8TM-41BB-CD3z) PLAT-07 CAR were stimulated for five minutes with CD22. Signal transduction was analyzed using Quantitative Multiplex Immunoprecipitation (QMI), an ELISA-like immunoassay, to quantify 400+ protein-protein interactions in CAR signal transduction. In study #2, patient-matched samples expressing murine scFv anti-CD19 (IgG4 Hinge-CD28TM-41BB-CD3z) PLAT-02 CAR or the more neurotoxic fully human scFv anti-CD19 (IgG4 Hinge-CD28-41BB-CD3z) PLAT-06 CAR were stimulated with CD19 for five minutes and signal transduction was analyzed by QMI. Despite reported poor expansion and clinical responses in patients, the PLAT-04 CAR signaled more strongly through ZAP70, TRAFs, and the LAT signalosome relative to the PLAT-07 CAR. The PLAT-06 CAR, which induced high rates of neurotoxicity in patients, also signaled more strongly through ZAP70, GRAP2, and TRAFs than the clinically successful and less toxic PLAT-02 CAR. LAT signalosome formation was similar in both the PLAT-06 and PLAT-02 CARs. These data suggest that poor CAR performance may stem from hyper-activated signaling. Both poorly-performing CARs, despite representing distinct outcomes (poor tumor killing or severe toxicity), signaled more strongly through T cell activating pathways than the optimal-performing CARs. These studies also suggest that variation in non-costimulatory CAR domains (scFv, hinge, TM) contribute to differential CAR signaling. Further studies correlating CAR design with signal transduction and clinical outcomes will allow for the design of safer and more effective CARs.

Citation Format: Isabella Draper, Eric Bueter, Colleen Annesley, Corinne Summers, Rebecca Gardner, Stephen Smith. Excessive Chimeric Antigen Receptor signaling correlates with poor clinical outcomes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B033.
Abstract B060: Enhanced therapeutic efficacy of a bioflavonoid loaded lipid nanoparticles via remodeling tumor microenvironment (TME) and KEAP1-NRF2 signaling in a murine breast tumor model
Authors: Sunita Priyashree , Sahu Rosa , Pattanayak Shakti P
Published: October 2024

Investigations on bioactive phytoconstituents, especially bioflavonoids and their role in the mitigation of breast cancer have directed our interest to 2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one or taxifolin (TX) which possesses potent chemotherapeutic potential in murine breast cancer model. However, it has been observed to possess poor aqueous solubility and thus truncated bioavailability which limit its pharmacological efficacy. The current study focuses on engineering a stable lipid nano-cargo with sufficient entrapment efficiency for hydrophobic TX to produce significantly improved anti-breast cancer activity. The TX-nanoliposomes were exhaustively characterized through various physico-chemical parameters (hydrodynamic particle size and zeta potential, FT-IR, XRD, TGA, DSC, FESEM etc.) and subjected to various in vitro, in vivo and molecular biology studies for efficacy. While the nano-cargo formulation showed enhanced cytotoxicity than raw bioflavonoid against breast cancer, its cytocompatibility as well as hemocompatibility evinced further preclinical investigations. This non-leaky, lipid nano-shuttle, owing to its optimal release kinetics and passive targeted delivery of TX augmented the chemotherapeutic potential against breast cancer through modulating the tumor microenvironment (TME) with infiltration of dominant CD3+/CD8+T-cells along with iNOS+M1-macrophages and Keap1-Nrf2 antioxidant signaling (within the cells). The current study proves that TX-nano cargo enhanced the chemotherapeutic efficacy against breast cancer by improving bioavailability and targeting delivery, leading to TME-remodeling.

Citation Format: Priyashree Sunita, Rosa Sahu, Shakti P Pattanayak. Enhanced therapeutic efficacy of a bioflavonoid loaded lipid nanoparticles via remodeling tumor microenvironment (TME) and KEAP1-NRF2 signaling in a murine breast tumor model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B060.
Tissue and Imaging Biomarkers of Response to Neoadjuvant Nivolumab or Nivolumab plus Ipilimumab in Patients with Resectable Hepatocellular Carcinoma
Authors: LaPelusa Michael , Chamseddine Shadi , Tran Cao Hop Sanderson , Xiao Lianchun , Hasanov Elshad , Bhosale Priya , Amin Hesham M. , Mohamed Yehia I. , Gok Yavuz Betul , Sakr Yara , Xu Li , Hu Ian , Lee Sunyoung S. , Sakamuri Divya , Jindal Sonali , Nguyen Van , Curran Michael A. , Sun Ryan , Rashid Asif , Duda Dan Gabriel , Sharma Padmanee , Qayyum Aliya , Kaseb Ahmed Omar
Published: October 2024

Introduction: Perioperative immunotherapy has shown promise in some patients with early-stage hepatocellular carcinoma (HCC). This study examined tissue and imaging biomarkers associated with pathologic response in a phase II clinical trial in patients with resectable HCC. Methods: Analysis included 18 patients with biopsy-proven resectable HCC treated with neoadjuvant nivolumab plus ipilimumab or nivolumab alone in a phase II clinical trial at MD Anderson Cancer Center (NCT03222076). Liver MRE (to measure tissue fibrosis) and biopsies (to evaluate immune activation markers) were obtained serially pretreatment and after completing neoadjuvant immunotherapy. A major pathologic response (MPR) was defined as tumor necrosis of more than 70%. Data comparing patients with MPR versus those without were summarized using descriptive statistics and compared using the Wilcoxon rank-sum test. Results: Patients with MPR after neoadjuvant immunotherapy tended to have larger tumors (mean 9.52 vs. 4.99 centimeters; p = 0.050). They had a significant reduction in tumor size posttreatment (14.67% reduction vs. 9.15% increase in size; p = 0.042) and a nonsignificant decrease in serum AFP (−24.20% vs. −14.00%; p = 0.085). Further, patients with MPR had a greater increase in intratumoral expression levels of CD8 (26.92% vs. −0.04%; p = 0.026), granzyme B (15.56% vs. −2.24%; p = 0.011), and PD-1 (20.17% vs. 0.40%; p = 0.048) but not PD-L1 (7.69% vs. 0.57%; p = 0.26). For imaging biomarkers, tumor and liver fibrosis were comparable before and after neoadjuvant therapy in patients with MPR versus nonresponders. Conclusion: Changes in tumor size, immune cell infiltration, and immune cell activation are candidate predictive markers of pathologic response to neoadjuvant immunotherapy in patients with resectable HCC.
Personality Traits and Drug Use: A Longitudinal Study Using Data from the British Cohort Study
Authors: Martínez-Gabaldón Eduardo , Martínez-Pérez Jorge Eduardo
Published: October 2024

Introduction: Drug use is a significant health, economic and social concern globally. Research indicates that personality traits are crucial in explaining drug use. This paper contributes to the expanding literature by exploring how personality traits at age 10 affect the likelihood of having used any drug at age 30. Methods: Data were extracted from the British Cohort Study 1970. The Big Five dimensions were derived by aggregating items related to distinct traits. Furthermore, probit regression analysis was conducted to ascertain the relationship between personality traits at age 10 and drug use by age 30. Results: Children with low levels of conscientiousness, or agreeableness; or high levels of extraversion, or internal locus of control at the age of 10 are more likely to use any drug in adulthood. In addition, significant differences were observed across gender and types of drugs. Conclusions: These findings suggest that early personality traits play a pivotal role in predicting the likelihood of drug use in adulthood. The results interest policymakers, as they could guide the implementation of personality-targeted interventions to mitigate the adverse effects of specific personality traits. For instance, emotional regulation training could benefit children with low conscientiousness; while stimulating activities such as sports, creative arts, or music could engage children with high extraversion.
A Successful Case of Intervention for Traumatic Central Retinal Artery Occlusion
Authors: Pourazizi Mohsen , Dehghani Alireza , Karbasi Sepehr , Rahmanipour Elham
Published: October 2024

Introduction: Central retinal artery occlusion (CRAO) is a serious ophthalmic disease predominantly affecting older individuals with cardiovascular risk factors. While most cases are attributed to thrombus formation from atheromatous plaques or cardioembolic events, trauma-related CRAO, though rare, presents unique diagnostic and therapeutic challenges. Case Presentation: A 47-year-old woman with multiple controlled comorbidities presented to the emergency department with right eye pain and erythema following a traumatic injury involving a knitting needle. Initial examinations revealed hand motion visual acuity in the right eye, a partial thickness scleral laceration, and conjunctival laceration, which were surgically repaired. Postoperatively, she developed blurred vision, hyphema, and signs of CRAO, prompting anterior chamber paracentesis. OCT imaging revealed marked hyperreflectivity and thickening of the inner retinal layers, indicating significant ischemic damage. Despite normal inflammatory markers, the patient’s visual acuity gradually improved from 2/10 to 5/10 with intervention and eventually reached 10/10 with myopic correction after the hyphema resolved. Conclusion: The case emphasizes the necessity of early recognition and intervention in managing traumatic CRAO to mitigate irreversible retinal damage. It underscores the need for enhanced diagnostic and therapeutic strategies as understanding the condition’s pathophysiology advances.
Long-Term Follow-Up of a Child with EWSR1-BEND2 Fused Spinal Astroblastoma
Authors: Fernandes Arroteia Isabel , Licci Maria , Hench Jürgen , Bartoli Andrea , Ansari Marc , Plavsky Pavlo , Terrier Axel , von Bueren Andre Oscar , Frank Stephan , Soleman Jehuda , Guzman Raphael
Published: October 2024

Introduction: Spinal astroblastoma is a rare highly malignant tumor that mainly affects children. We review the few cases described in the literature and highlight the challenges of managing this neoplasm by illustrating a case recently treated at our institutions. To our knowledge, this is the first published case of EWSR1-BEND2 fused spinal astroblastoma with long-term follow-up. Case Presentation: An 8-year-old girl was transferred from her home country to Switzerland for treatment of a recurrent intramedullary tumor of the cervical spine extending from C2-C7. The tumor was primarily diagnosed as an ependymoma of the spinal cord. Prior to her transfer to our department, the patient had undergone subtotal resection of the lesion, radiation therapy, multiple chemotherapy regimens, and biopsy of the recurrent tumor. Clinically, the patient presented with tetraparesis and had recently experienced worsening upper extremity weakness with complete loss of hand function. We performed a near total resection of the recurrent tumor. Ultra-fast Nanopore seq® based DNA methylome profiling allowed confirmation of the molecular diagnosis of a high-grade neuroepithelial tumor (HGNET-MN1) consistent with astroblastoma in less than 2 h, with subsequent molecular workup revealing a EWSR1-BEND2 fusion. After surgery, the patient gradually regained function in her hands. She was sent to a specialized pediatric rehabilitation center, and while the tumor was being followed radiologically with no adjuvant treatment planned, the patient presented with a relapse of the tumor in only 3 months. Given the acute worsening of radiating pain and sudden respiratory failure, a cervical decompression was performed. MRI of the cervical spine showed infiltration of the lower aspects of the brainstem. The patient was offered palliative comfort care. Conclusion: Spinal astroblastoma is a rare and highly aggressive tumor affecting children and young adults with a high recurrence rate and thus far not well-defined prognosis. The molecular signature of astroblastoma needs to be further characterized to establish a treatment-relevant classification and to allow a better prognostication. Currently, gross-total resection combined with radiotherapy remains the mainstay of treatment for spinal astroblastoma.
Characterising the contribution of auditory and somatosensory inputs to TMS-evoked potentials following stimulation of prefrontal, premotor, and parietal cortex
Authors: Biabani Mana , Fornito Alex , Goldsworthy Mitchell , Thompson Sarah , Graetz Lynton , Semmler John G. , Opie George M. , Bellgrove Mark A. , Rogasch Nigel C.
Published: October 2024

Transcranial magnetic stimulation (TMS) results in a series of deflections in electroencephalography (EEG) recordings known as a TMS-evoked potential (TEP). However, it remains unclear whether these responses reflect neural activity resulting from transcranial stimulation of the cortex, the sensory experiences of TMS, or a combination of the two. Across three experiments (total n = 135), we recorded EEG activity following TMS to the dorsolateral prefrontal cortex, premotor cortex, and parietal cortex as well as a sensory control condition (stimulation of the shoulder or electrical stimulation of the scalp with a click sound). We found that TEPs showed a stereotypical frontocentral N100/P200 complex following TMS of all cortical sites and control conditions, regardless of TMS intensity or the type of sensory control. In contrast, earlier TEPs (<60 ms) showed site-specific characteristics which were largest at the site of stimulation, although TEP topographies were distorted in a subgroup of individuals due to residual TMS-evoked muscle artefact despite cleaning with independent component analysis. Self-reported sensory experiences differed across sites, with prefrontal stimulation resulting in stronger auditory (click sound perception) and somatosensory input (scalp muscle twitch, discomfort) than premotor or parietal stimulation, a pattern that was reflected in the amplitude of later (N100/P200), but not earlier (<60 ms), TEP peak amplitudes. Later TEPs were also larger in individuals who experienced stronger click sound perception and, to a lesser extent, TMS-evoked scalp muscle twitches. Increasing click sound perception by removing auditory masking increased N100/P200 amplitudes without altering earlier peaks, an effect which was more prominent at sites with more successful masking. Together, these findings suggest that the frontocentral N100/P200 complex primarily represents a generalised sensory response resulting from TMS-related auditory and somatosensory input when present. In contrast, early TEP peaks likely primarily reflect activity resulting from transcranial stimulation of the cortex when artefacts were adequately accounted for. The results have important implications for designing and interpreting TEP studies, especially when comparing TEPs between stimulation sites and participant groups showing differences in sensory experiences following TMS.
Arbitrary methodological decisions skew inter-brain synchronization estimates in hyperscanning-EEG studies
Authors: Zimmermann Marius , Schultz-Nielsen Kathrine , Dumas Guillaume , Konvalinka Ivana
Published: October 2024

Over the past decade, hyperscanning has emerged as an important methodology to study neural processes underlying human interaction using fMRI, EEG, fNIRS, and MEG. However, many methodological decisions regarding preprocessing and analysis of hyperscanning data have not yet been standardized in the hyperscanning community, yet may affect inter-brain estimates. Here, we systematically investigate the effects common methodological choices can have on estimates of phase-based inter-brain synchronization (IBS) measures, using real and simulated hyperscanning (dual) EEG data. Notably, we introduce a new method to compute circular correlation coefficients in IBS studies, which performs more reliably in comparison to the standard approach, showing that the conventional circular correlation implementation leads to large fluctuations in IBS estimates due to fluctuations in circular mean directions. Furthermore, we demonstrate how short epoch durations (of 1 s or less) can lead to inflated IBS estimates in scenarios with no strong underlying interaction. Finally, we show how signal-to-noise ratios and temporal factors may confound IBS estimates, particularly when comparing, for example, resting states with conditions involving motor actions. For each of these investigated effects, we provide recommendations for future research employing hyperscanning-EEG techniques, aimed at increasing validity and replicability of inter-brain synchronization studies.
Mind-Body Dualism, Health, and Well-being in University Students
Authors: McGhee C. M. , Gelman Susan A. , Stewart Abigail J.
Published: October 2024

Mind-body dualism conceptualizes mind and body as distinct, but there are different ways that dualism may be instantiated. In this study, we examined how Hierarchical Dualism (the belief that mind and body are distinct, and the mind is superior) and Mutual-Influence Dualism (the belief that mind and body are separate but interrelate) related to health behaviors and mental health in three student samples: exclusively queer, exclusively straight, and a mixed university subject pool (N = 535). Participants in each sample endorsed Mutual-Influence Dualism at a higher rate than Hierarchical Dualism. Mutual-Influence dualism was consistently associated with greater engagement in health-promoting behaviors and greater well-being, whereas Hierarchical Dualism differed by sample. These results suggest that dualist beliefs do not uniformly shape the lives of those who hold them: rather, the relation between dualist beliefs and health differs as a function of the type of dualism and the identities we hold.
Are There Any True Formal Models of Success- and Prestige-Biased Social Learning?
Authors: Cruz y Celis Peniche Patricio
Published: October 2024

Cultural transmission theorists have proposed there is an inherent tradeoff between social learning strategies [SLS s] that rely on direct observation of a cultural variant’s payoffs (i.e., direct bias) and those that rely on a model’s cues of success or prestige (i.e., indirect bias). While the former relies on higher-quality informational goods, a model’s success or prestige cues may be easier to access. This paper reviews mathematical models that have purported to capture indirect bias, and shows they fail to capture this tradeoff, instead making assumptions that reduce their transmission dynamics to those of a direct bias. I include a simple agent-based model to illustrate that their formal equivalence, and therefore our ability to conclude that success and prestige bias are adaptive SLS s, depends on a high correlation between success/prestige cues and a model’s payoffs. This suggests the importance of empirically ascertaining how learners evaluate a model’s fitness, and how they mitigate the risks of biasing their learning on payoff-correlates rather than payoffs themselves. Exploring the cognition underlying these decisions may shed light on maladaptive social learning.
Unveiling the acoustic repertoire of true boas: hisses resemble white noise and indicate individual identity
Authors: Citeli Nathalie K. , Silva-Jr Edvaldo F. , Meneses Afonso S.O. , Santos Maria Laura S. , Gonzalez Rodrigo C. , Rodrigues Anna C.V.S. , de-Carvalho Mariana , Maranhão Ednilza , Brandão Reuber A. , Diniz Pedro
Published: October 2024

Although hissing is a common strategy of defence used by snakes, especially of the Phytonidae and Boidae families, few studies have described in detail the acoustics components of this behaviour. Here we gathered eight recordings from six different boas from Brazil and extracted acoustic measurements from their hissing sounds. We also examined the potential of our measurements to encode individual identity using discriminant function analyses (DFAs) and to correlate with body length using linear mixed models (LMMs). Boas produce from four to 12 hisses per minute (7.13 ± 3.04) evoked by a negative stimulus, a visual looming stimulus generated by researcher’s approach. Each hiss usually has two parts (the first louder part and the second softer part) that are basically broadband white noises split by a short silent interval. The first hiss part also has more frequency modulations and narrower bandwidth than the second hiss part. The DFAs correctly assigned all hisses to their correspondent individuals in the testing data. The first discriminant function explained most of the variance (⩾84%) in the discrimination between groups for the entire hiss and for both hiss parts in the training data subset. Frequency parameters and spectral entropy (for entire hiss and hiss part 1) and the mean frequency and duration (for hiss part 2) were the strongest absolute loadings in the DFAs. Intraspecific morphological traits (e.g. sexual dimorphism and ontogenetic variations) may influence the sound parameters, as detected by individual variations and the tendency for larger individuals to produce lower frequency hisses. Further studies may investigate these aspects in detail, including anatomy of the snake’s larynx and experiments with different types of predators.
Towards a New Reconstruction of the Proto-Yeniseian Sound System. Part II: Word-Final Consonants
Authors: Hill Eugen , Fries Simon , Korobzow Natalie , Günther Laura , Bonmann Svenja
Published: October 2024

We present correspondence sets involving word-final consonants and including all known members of the Yeniseian language family. A systematic application of the Comparative Method to these data yields the following results: (I) three different correspondence sets and, accordingly, three different Proto-Yeniseian phonemes each must be assumed for both Southern Ket word-final -t and -l’, (II) two different correspondence sets and, accordingly, two different Proto-Yeniseian phonemes must be assumed for Southern Ket word-final -s’, (III) the data indicate that one of the two Proto-Yeniseian liquids/rhotics developed in a similar way in Kott, Arin and Pumpokol. We do not see evidence for the postulation of lateral affricates, retroflex sounds or labialised velars as assumed for Proto-Yeniseian by S. Starostin or E. J. Vajda on macro-comparative grounds. The Proto-Yeniseian phonological system that can be reconstructed using Yeniseian data alone is simpler than previously published reconstructions of the Proto-Yeniseian phoneme inventory.
The Multiplicity of Abortion Pills: Considering the Public Constructions of ru486 in Sweden
Authors: Ramsey Morag
Published: October 2024

To this day, abortion pills are a contentious technology – used freely and legally in some countries while prohibited in others. Previous scholarship has shown abortion pills to be difficult to integrate into medical systems. Available since the early 1990s, little has been written on the early adoption of abortion pills in Sweden, one of the first countries to register the compound ru486 for use. This is remarkable if we consider what is at stake when introducing new abortion technologies – namely, the conditions for gender equality and the very tangible implications for maternal health. This article examines the Swedish process of acquiring ru486: mapping the varied actors invested in its use, and analysing the different constructions of abortion pills that were made in these networks. It argues that earlier reproductive research initiatives and their extensive press coverage helped to make registration possible for ru486 in the early 1990s. Comparisons between the constructions of ru486 in Canada and the U.S. illustrate a few key differences between the countries and show why, despite many similarities, Sweden was the first to officially acquire the drug.
Household heroines
Authors: Noorman Judith
Published: October 2024

This essay is about the discovery of Maria van Van Nesse’s ledger, which was hidden in a Belgian family archive. With 123 mentions of paintings and drawings, listed among over 3,500 household expenses, Van Nesse instantly became the best documented art buyer of the seventeenth-century Republic, regardless of gender. This essay compares her impact on the art market with that of her sister, Adriana. Furthermore, by applying household consumption theory to art history, and by adding a gender dimension to socio-economic studies, this essay studies the behavioral patterns and decision-making process underlying the purchase of paintings for the household. In so doing, it sheds new light on the market for luxury goods, including artworks, and the retail landscape.
The images and interventions of Adriana Perez in the Rockox Collection
Authors: Grimmett Kendra
Published: October 2024

Adriana Perez (1568–1619), an affluent woman from Antwerp, who belonged to a prosperous family of Spanish merchants, was the wife of burgomaster Nicolaas Rockox for 30 years. While her husband is celebrated for his patronage of Peter Paul Rubens and for his enviable collection of paintings, sculptures, coins, and books, evidence of Perez’s interventions can be found throughout the Rockox Collection. This article analyzes Perez’s marriage contract, will, two portraits, and the inscription that she contributed to Rockox’s friendship book to bring the elite lady out from her husband’s shadow and to place her at his side as a companion and partner. By reexamining her biography and the married couple’s shared commissions and collection, this paper investigates Adriana Perez’s roles as a co-patron of and audience for the artworks that she and her husband purchased and displayed in their household and over their tomb.
Cultivating a female presence in the early eighteenth-century learned community
Authors: van Deinsen Lieke
Published: October 2024

During the early modern period, printed portraiture became increasingly crucial for shaping the public image of scholars. But what if your appearance didn’t fit the ideal image of a scholar, yet you still sought to be recognized in scholarly circles? This article examines the case of Maria de Wilde, daughter of the renowned Amsterdam collector of antiquities Jacob de Wilde, to reveal the strategies learned women and their advocates employed to navigate this challenge. By analyzing how her portraits were crafted and contributed to her perceived credibility within the learned community, I argue that these portraits could play a crucial role in women’s pursuit of acceptance in the male-dominated scholarly world of the late seventeenth and early eighteenth centuries. By blending women’s inherent femininity with their desired intellectual authority in a single visual representation, these portraits served as powerful tools in women’s ongoing quest for intellectual recognition.
Two new species of the genus Maaserphus Lin, 1988 (Hymenoptera: Proctotrupidae) from Japan and Taiwan
Authors: ABE JUNTA
Published: October 2024

Maaserphus bunun Abe, sp. nov. and M. yamagishii Abe, sp. nov. are described from Japan and Taiwan. Two known species of this genus, M. flavitarsis He & Xu, 2015 and M. striatus Lin, 1988, are newly recorded from Japan.
Small-Scale Wind Fluctuations within Melting Layers of Winter Storms: Results from WINTRE-MIX
Authors: Zaremba Troy J. , Minder Justin R. , Friedrich Katja
Published: October 2024

Investigations into the melting layer (ML) of winter storms have revealed small-scale fluctuations in the horizontal wind that could significantly affect the surface precipitation type (p-type) and the evolution of the ML. Despite previous evidence of such fluctuations, essential questions remain concerning their characteristics and the forces driving them. Therefore, this study characterizes small-scale horizontal wind fluctuations (<1 km in length with perturbation magnitudes < 3 m s−1) and their environments within the ML of winter storms. This analysis uses data from a scanning X-band Doppler radar collected during the Winter Precipitation Type Research Multiscale Experiment (WINTRE-MIX), conducted during February and March 2022. We present three case studies where small-scale horizontal wind fluctuations are identified using along-radial and along-azimuthal radial velocity perturbations. These cases cover the range of environmental conditions observed during WINTRE-MIX, including (i) a descending ML with change in surface p-type from snow to rain, (ii) a steady ML with a surface p-type transition from freezing rain to rain due to surface cold air erosion, and (iii) a steady ML with a surface p-type transition from freezing rain to ice pellets due to surface cold air advection. Forcing mechanisms for small-scale wind fluctuations during each case are attributed to static instability, vertically trapped gravity waves, and/or shear instability inferred from rawinsonde data, HRRR analysis, and radar data. Our findings suggest that static instability, gravity waves, and shear instability drive the ML’s small-scale wind fluctuations and may influence surface precipitation-type transitions.

Significance Statement

This research aims to enhance our understanding of horizontal motions (<1 km in length) within melting layers (MLs) of winter storms and their underlying causes. This study uses radar data to detect differences in horizontal motion within the ML of three different winter storms. Weather balloon observations and output from computer weather forecasts are then used to distinguish between horizontal motions generated by convection, vertically trapped gravity waves, or shear. Our findings reveal that horizontal motions within the ML are generated by different forcing mechanisms within different storms and that horizontal motions may influence the surface p-type.
Factors Associated With Repeat Pediatric Influenza Vaccination Among Inconsistent Vaccinators
Authors: Abraham Claire , Gilkey Melissa B. , Walsh Kathleen E. , Hickingbotham Madison R. , Galbraith Alison A.
Published: October 2024

Promoting consistent vaccination practices may help improve suboptimal influenza vaccination rates. This study evaluated the prevalence and correlates of repeat influenza (flu) vaccination among children who had previously received the vaccine inconsistently. An online survey study was conducted in 2022 among parents of commercially insured children ages 3 to 19 years who were previously inconsistently vaccinated. Of 317 respondents, 85% reported that their child received a flu vaccine in the 2021 to 2022 flu season. Among these parents, 61% reported concern that their child would get sick from flu as the most important reason for vaccinating. Repeat vaccination was less likely among parents who reported that school/daycare requirements were a reason for vaccinating in the prior season (odd ratio [OR] = 0.17, 95% confidence interval [CI] = 0.05-0.55). Our findings suggest that school policies may improve vaccination rates among inconsistent vaccinators.