bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex and population differences underlie variation in reproductive success in a warming environment
Authors: Santos Marta A , Grandela Afonso , Antunes Marta A , Quina Ana S , Santos Mauro , Matos Margarida , Simões Pedro 
Published: June 2023

Abstract
Current rising temperatures are threatening biodiversity. It is therefore crucial to understand how climate change impacts male and female fertility and whether evolutionary responses can help in coping with heat stress. We use experimental evolution to study male and female fertility during the real-time evolution of two historically differentiated populations of Drosophila subobscura under different thermal selection regimes for 23 generations. We aim to (a) tease apart sex-specific differences in fertility after exposure to warming conditions during development, (b) test whether thermal selection can enhance fertility under thermal stress, and (c) address the role of historically distinct genetic backgrounds. Contrary to expectations, heat stress during development had a higher negative impact on female fertility than on male fertility. We did not find clear evidence for enhanced fertility in males or females evolving under warming conditions. Population history had a clear impact on fertility response under thermal stress, particularly in males with those from lower latitude presenting better performance than their higher latitude counterparts. We show that the impact of thermal stress on fertility varies between traits, sexes, and genetic backgrounds. Incorporating these several levels of variation is crucial for a deeper understanding of how fertility evolves under climate change.
In utero choline exposure alters growth, metabolism, feed efficiency, and carcass characteristics of Holstein × Angus cattle from weaning to slaughter
Authors: Brown William E , Holdorf Henry T , Johnson Sara J , Kendall Sophia J , Green Sophia E , White Heather M 
Published: June 2023

Abstract
Feeding rumen-protected choline (RPC) to late gestation dairy cows has potential to affect growth in offspring. The objective of this study was to evaluate the effects of in utero choline exposure on the growth, feed efficiency (FE), metabolism, and carcass quality of Angus × Holstein cattle. Multiparous Holstein cows pregnant with male (N = 17) or female (N = 30) Angus-sired calves were enrolled 21 d prepartum and randomly assigned to one of four dietary treatments varying in quantity and formulation of RPC. The treatments included a control with 0 g/d supplemental RPC (CTL), supplemental RPC fed at the recommended dose (RD) of 15 g/d from either an established RPC product (RPC1RD; ReaShure; Balchem Corp.) or choline ion from a concentrated RPC prototype (RPC2RD; Balchem Corp.), or a high dose (HD) of RPC2 fed at 22 g/d (RPC2HD). From 2 to 6 mo of age, calves were group housed and offered 2.3 kg grain/hd/d (42% CP) with ad libitum grass hay, and stepped up to a complete finishing diet by 7 mo (12.0% CP; 1.34 Mcal/kg NEg). Weight and height were measured monthly. Animal FE was measured in individual pens for 35 d at 8 mo. Feed intake was measured daily, and blood was obtained on day 18 during the FE period. Afterwards, cattle were group housed and offered a free-choice finishing diet until slaughter, where carcass yield and quality characteristics were measured. Mixed models were used in PROC MIXED (SAS, 9.4) with the fixed effects of treatment, sex, time, their interactions, and the random effect of calf. Month was the repeated measure, and preplanned contrasts were used. Blood and FE data were analyzed with the fixed effect of dam choline treatment, calf sex, and the interaction. Increasing dose of RPC tended to increase weight over the entire study period. Feeding any RPC increased hip and wither height compared with CTL, and increasing RPC dose linearly increased hip and wither height. Treatment and sex interacted on DMI whereby increasing RPC intake linearly increased DMI for males but not females. Compared with control, feeding any RPC decreased plasma insulin, glucose, and an insulin sensitivity index (RQUICKI). In utero choline exposure increased kidney–pelvic–heart fat and marbling score. Mechanisms of action for intrauterine choline exposure on offspring growth, metabolism, and carcass characteristics should be explored as they have direct implications for profitability for cattle growers and feeders.
The effects of disagreement and unfriending on political polarization: a moderated-mediation model of cross-cutting discussion on affective polarization via unfriending contingent upon exposure to incivility
Authors: Lin Han , Wang Yi , Lee Janggeun , Kim Yonghwan 
Published: June 2023

Abstract
Cross-cutting discussion is the foundation of deliberative democracy. However, previous research has reported inconsistent results regarding the effects of exposure to dissimilar perspectives on political polarization. This study aims to extend the literature by exploring how cross-cutting discussion influences affective polarization through unfriending and how this indirect effect is contingent upon exposure to incivility. The study analyzes panel data from a two-wave online survey conducted in South Korea (N = 890). The results show a significantly positive indirect effect of unfriending, suggesting that cross-cutting discussion further reinforces affective polarization via unfriending. Furthermore, the study identifies the boundary conditions for this mediating mechanism, showing that the mediated relationship of cross-cutting discussion on affective polarization via unfriending is stronger for those who are more exposed to incivility on social media.
‘A slashing review is a thing that they like’: Vivisection and Victorian Literary Criticism
Authors: Hornsby Asha 
Published: June 2023

Abstract
In nineteenth-century Britain, the antivivisection movement attracted a striking number of authors, poets, and playwrights, who attended meetings, signed petitions, contributed funds, and lent their pens to the cause. However, the language of vivisection extended far beyond literature with a purpose, seeping into the heart of late-Victorian literary debates. This article explores analogies of writing as vivisection in literary-critical discourse. Surveying the newspapers and periodicals of the period demonstrates that such terminology was remarkably sprawling in terms of the genres and authors it was applied to and the meanings it conveyed. Essayists and reviewers also used metaphors relating to experimental physiology’s modus operandi to shape and articulate key methodological and ideological principles that were emerging in late-Victorian literary-critical theory and practice. These included discussions of how to analyse living authors and contemporary works, conceptualizations of whether critical operations should produce social benefits, and considerations of the aesthetic and technical opportunities that literary or critical vivisection offered or, indeed, prevented.
Breakthrough candidemia with hematological disease: Results from a single-center retrospective study in Japan, 2009–2020
Authors: Nishida Ruriko , Eriguchi Yoshihiro , Miyake Noriko , Nagasaki Yoji , Yonekawa Akiko , Mori Yasuo , Kato Koji , Akashi Koichi , Shimono Nobuyuki 
Published: June 2023

Abstract
Breakthrough candidemia (BrC) is a significant problem in immunocompromised patients, particularly those with hematological disorders. To assess the characteristics of BrC in patients with hematologic disease treated with novel antifungal agents, we collected clinical and microbiological information on said patients from 2009 to 2020 in our institution. Forty cases were identified, of which 29 (72.5%) received hematopoietic stem cell transplant (HSCT)-related therapy. At BrC onset, the most administered class of antifungal agents were echinocandins, administered to 70% of patients. Candida guilliermondii complex was the most frequently isolated species (32.5%), followed by C. parapsilosis (30%). These two isolates were echinocandin-susceptible in vitro but had naturally occurring FKS gene polymorphisms that reduced echinocandin susceptibility. Frequent isolation of these echinocandin-reduced-susceptible strains in BrC may be associated with the widespread use of echinocandins. In this study, the 30-day crude mortality rate in the group receiving HSCT-related therapy was significantly higher than in the group not receiving it (55.2% versus 18.2%, P = .0297). Most patients affected by C. guilliermondii complex BrC (92.3%) received HSCT-related therapy and had a 30-day mortality rate of 53.8%; despite treatment administration, 3 of 13 patients had persistent candidemia. Based on our results, C. guilliermondii complex BrC is a potentially fatal condition in patients receiving HSCT-related therapy with echinocandin administration.
ATRT-01. PARP INHIBITION AS A THERAPEUTIC TARGET IN ATRT
Authors: Alimova Irina , Mardok Gillian , Pierce Angela , Wang Dong , Madhavan Krishna , Brunt Breauna , Vibhakar Rajeev 
Published: June 2023

Abstract
Atypical teratoid rhabdoid tumors (ATRTs) are highly aggressive pediatric brain tumors with poor survival. The available treatments rely on toxic chemotherapy and radiotherapy, which alone can cause poor outcomes for young patients. Poly (ADP-ribose) polymerases (PARP), multifunctional enzymes which play an important role in DNA damage repair and genome stability have emerged as a new target in cancer therapy. An FDA approved drug screen revealed that Rucaparib, a PARP inhibitor, is important for ATRT cell growth.In this study we investigated the effect of Rucaparib treatment in ATRT. Using MTS and colony formation assays we found that Rucaparib treatment decreased ATRT cell growth and inhibited clonogenic potential of ATRT cells. Flow cytometry and Western blot analysis showed that Rucaparib treatment led to cell cycle arrest and apoptosis. Moreover, Rucaparib treatment led to DNA damage accumulation as seen by increased expression of yH2AX by immunofluorescence. In vivo, Rucaparib treatment significantly decreased tumor growth and prolonged survival in orthotopic mouse models. Furthermore, Immunohistochemistry revealed an increased number of P53 and Caspase3positive cells in the Rucaparib treatment group, confirming the induction of apoptosis in vivo. Furthermore, Rucaparib pretreatment sensitizes ATRT cells to radiation and significantly increased survival of xenograft-bearing mice. Thus, we demonstrated that Rucaparib has potential to be a new therapeutic strategy for ATRT as shown by its ability to decrease ATRT tumor growth both in vitro and in vivo.
BIOL-12. ENHANCING IMMUNE-MEDIATED TUMOR CONTROL IN MURINE MODELS OF GROUP 3 MEDULLOBLASTOMA
Authors: Abbas Zahra , Hii Hilary , Buck Jessica , Johnson Iley , Byrne Jacob , Elaskalani Omar , Kuchibhotla Mani , George Courtney , Arias Clara Andradas , Howlett Meegan , Lesterhuis Joost , Johns Terrance , Gottardo Nicholas , Endersby Raelene 
Published: June 2023

Abstract
Stagnation in clinical outcomes as well as severe side-effects of current treatment approaches for Group 3 medulloblastoma have prompted the search for novel therapies. To date, immunotherapies have not demonstrated success in medulloblastoma. Due to the highly aggressive nature of relapsed medulloblastoma, we suggest that it would be advantageous to introduce new immunotherapies first-line, alongside conventional therapies. To design immunotherapeutic strategies that are compatible in combination with standard therapies, we first determined the effect of standard-of-care craniospinal irradiation (CSI) and chemotherapy on the immunology of these tumours in immune competent and deficient murine models. We show that standard treatment approaches deplete adaptive immune cells, while macrophage and brain-resident microglia are not depleted. Furthermore, medulloblastomas are myeloid dominant tumors, and blocking the anti-phagocytic CD47-SIRPa interaction has shown preclinical efficacy. Therefore, we tested the combination of anti-CD47 immunotherapy with radiotherapy in a patient-derived xenograft model of Group 3 medulloblastoma. We found that anti-CD47 monotherapy had limited efficacy, while CSI results in only a temporary reduction in tumor size. In the cerebellum of relapsed tumors post-CSI, flow cytometry revealed increased peripheral myeloid populations. Remarkably, the combination of anti-CD47 and CSI was effective in clearing tumors and maintaining long-term tumor-free survival. Using RNA sequencing and immunohistochemistry, we found that the combination therapy results in enhanced cytokine signalling and phagocytic myeloid cell infiltration into the tumors compared to the monotherapies. We have also developed and characterized novel age-appropriate preclinical models for medulloblastoma and have observed altered myeloid cell phenotypes in these age-appropriate models. We are now testing this novel combination therapy in our new neonatal murine models to determine efficacy in age-appropriate hosts.
BIOL-18. NEWLY DEVELOPED REPLICATION REPAIR DEFICIENT (RRD) MOUSE MODELS PROVIDE INSIGHTS INTO MEDULLOBLASTOMA/GLIOMAGENESIS AND RESPONSE TO IMMUNOTHERAPY
Authors: Aamir Zoya , Galati Melissa , Gattoni Emma , Crump Owen , Nunes Nuno M , Das Anirban , Fernandez Nicholas R , Wong Angel K Q , Fortin Jerome , Stengs Lucie , Bianchi Vanessa , Edwards Melissa , Negm Logine , Chung Jiil , Malkin David , Egan Sean , Hawkins Cynthia , Tabori Uri 
Published: June 2023

Abstract
Replication Repair Deficiency (RRD), caused by germline monoallelic (Lynch Syndrome) or biallelic (Constitutional Mismatch Repair Deficiency, CMMRD) mutations in MMR genes, is present in 5-10% of glioblastomas in children, adolescents, and young adults. RRD glioblastomas are chemoradiation-resistant, but respond favorably to immune checkpoint inhibition (ICI). Representative immunocompetent animal models are urgently needed for 3 recently identified subgroups based on specific somatically-acquired mutations, survival, and immunotherapy response (RRD1: MMRD with POLE mutations, RRD2: MMRD associated with TP53 mutations, and RRD3: MMRD harboring IDH1 mutations). Using germline mutations and brain-specific Cre-drivers, we genetically engineered mouse models that recapitulate each human RRD-subgroup. RRD1 (Nestin- and Olig2-Cre+/ Msh2LoxP/LoxP/PoleS459F/+ and LSL-PoleP286R/+): CMMRD-like Nestin-Cre-driven mice develop posterior-fossa glioma-like or medulloblastoma (MB)-like tumors at ~2.7 months. Olig2-Cre-driven mice display hemispheric gliomas at ~10 months, suggesting distinct cell-of-origin. RRD2 (Nestin-Cre+/Trp53LoxP/LoxP and Msh2LoxP/LoxP or Mlh1-/-): CMMRD-like tumors develop in heterogenous locations at ~4.5 months (p&lt;0.0001), classifying primarily as MB-like in hindbrain, and glioma-like in other brain regions. Strikingly, germline Mlh1 tumors occur earlier than Nestin-Cre-driven RRD2 tumors, indicating early developmental mutation accumulation in CMMRD-patients. Lynch-like RRD1/2 mice succumb exclusively to gliomas &gt;13 months (p&lt;0.0001). RRD3 (Olig2-Cre+/Msh2LoxP/LoxP/Trp53LoxP/LoxP/LSL-Idh1R132H/+): brain tumors occur later and are hemispheric. These observations recapitulate human data, where CMMRD-patients develop glioblastoma/MB earlier than Lynch-patients (8.6 vs. 14-years; p&lt;0.0001), and posterior-fossa glioblastoma/MB presents earlier than hemispheric gliomas (p=0.04). Additionally, tumor onset and location vary (RRD1: 7.6-years, RRD2: 8.3-years, hemispheric/posterior-fossa; RRD3: 12-years, hemispheric; p=0.005). In both mice and humans, RRD1 exhibits ultra-hypermutation, high immune infiltration, and response to ICI, whereas RRD2 harbors lower mutational burden, are immune-cold, and ICI-monotherapy resistant. Temporal dynamics of RRD tumor development is currently being tracked by serial MRI to define biologically relevant time points. Our models accurately mimic the human condition and provide unique insights into RRD tumorigenesis, allowing optimization of subgroup-tailored therapeutic approaches.
DIPG-02. A NOVEL STRATEGY TO RADIOSENSITISE DIFFUSE MIDLINE GLIOMAS VIA DUAL-TARGETING OF GLUCOSE METABOLISM
Authors: Shen Han , Chang Cecilia , Ing Prunella , Nguyen Sandy , Mudassar Faiqa , Cook Kristina , Lai Joey , Gloss Brian , O’Neill Geraldine , Gee Harriet , Hau Eric 
Published: June 2023

Abstract
Diffuse Midline Gliomas (DMG) is the leading cause of brain tumor-related death in children. Currently, radiation is the only treatment that offers transient benefit but almost all DMG relapse due to radioresistance. Compared to normal brain tissue, DMG are hypo-perfused with tumor cells being exposed to hypoxia, a low oxygen microenvironment serves as a potent barrier to effective radiotherapy. Biguanides are hypoglycemic agents that can reduce the oxygen consumption rate (OCR) in mitochondria, thereby sparing more oxygen and alleviating hypoxia. Our previous study has shown that metformin significantly improves the radiosensitivity of DMG and extends survival in a patient-derived xenograft (PDX) model. In comparison with metformin, phenformin demonstrated greater efficacies in anti-proliferation, OCR and hypoxia inhibition, and radiosensitization in a panel of DMG cultures. These effects were possibly induced by phenformin through inhibition of mitochondrial complex I in DMG cells. The anti-tumor effect of phenformin was further enhanced by combining a second drug dichloroacetate that simultaneously attenuated phenformin-induced acidification. Specifically, the combination treatment induced higher levels of reactive oxygen species and DNA damage, which subsequently resulted in a much stronger effect in cell-cycle and proliferation arrest, apoptosis, and hypoxia inhibition. Metabolically, the co-treatment simultaneously targeted multiple pathways, which significantly reduced ATP production and further triggered metabolic catastrophe. RNA sequencing demonstrated significant alterations induced by the combination in cell-cycle, DNA repair, unfolded protein response and alternative energetic pathways. Furthermore, the combination treatment significantly improved the radiosensitivity of DMG cells, evidenced by higher levels of DNA damage, apoptosis, and clonogenic inhibition. Our preliminary in vivo data demonstrated a possible reduction in tumor burden following 4 weeks of combination treatment, with no elevation of serum L-lactate level in phenformin-treated groups. This therapeutic efficacy is currently being validated in multiple orthotopic DMG models with optimized treatment schedules.
DIPG-05. EVALUATION OF TELOMERE-MODIFYING COMPOUND THIO AS A RADIOSENSITIZER AND IMMUNOMODULATOR TO TREAT DIPG
Authors: Mishra Deepak , Umaru Banlanjo , Kumar Shiva Senthil , Gryaznov Sergei , Drissi Rachid 
Published: June 2023

Abstract
Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive tumors of the central nervous system in children. Radiotherapy remains the only standard treatment but is rarely curative. In recent years, several immunotherapy strategies have emerged as an option to treat DIPG. However, the low mutational burden and rare infiltration of T lymphocytes, render these tumors immunologically “cold” and therefore pose challenges for general immunotherapy. We have previously reported in pediatric brain tumors the preclinical validation of THIO (6-thio-2’-deoxyguanosine), a telomerase substrate precursor analog. Treatment of cancer cells with THIO caused both telomeric and genomic DNA damage and rapid cell death. In vivo treatment delayed tumor growth in mouse models of high-risk medulloblastoma and DIPG. Importantly, THIO crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. The cGAS-STING pathway is a cellular mechanism that senses cytosolic double stranded DNA, stimulating type I interferons (IFNs) and IFN-stimulated genes, thereby activating the innate and adaptive anti-tumor immune responses. Micronuclei resulting from cell division in the presence of unresolved DNA damage, has been shown to be recognized by the cGAS-STING pathway. THIO was shown to induce anti-tumor immunity through micronuclei formation in colon and lung tumor models. We hypothesized that THIO treatment will activate anti-tumor immunity in DIPG. Our results indicate that THIO treatment sensitized DIPG cells to ionizing radiation (IR) leading to a significant decrease in DIPG cell proliferation. We are currently testing this combination in vivo in an orthotopic mouse model of DIPG. We will present results on the potential of THIO to activate anti-tumor immunity through the activation of Sting pathway in a syngeneic mouse model of DIPG. These preclinical studies will support potential use of THIO in combination with IR to treat children with high-risk pediatric brain tumors.
DIPG-07. ROBUST CGAS-STING PATHWAY MEDIATED-INDUCTION OF ANTITUMOR ADAPTIVE IMMUNE RESPONSE: A POTENTIAL FOR DMG IMMUNOTHERAPY
Authors: Umaru Banlanjo , Mishra Deepak , Kumar Shiva Senthil , Devine Brendan , Drissi Rachid 
Published: June 2023

Abstract
Immunotherapy has emerged as groundbreaking in cancer treatment showing improved overall survival of patients with advanced cancers. However, its application for diffuse midline glioma (DMG) is still challenging due to the non-inflammatory immune environment with lack of T lymphocyte infiltration, low mutation burden associated with low or absence of neo-antigen expression and suppressive immune microenvironment in DMG. Therefore, determination of novel factors that not only trigger the immune response but also evading the tumor immunosuppression is imperative. The cGAS-STING pathway was shown to elicit the maturation and activation of dendritic cells (DCs) in response to the release of double stranded DNA (dsDNA) from tumor cells leading to effective cytotoxic T-cell infiltration and activity. Here, we aimed to determine the effects of a small molecule PTC596 (BMI-1 modulator and tubulin biding molecule) in cGAS-STING pathway activation and induction of antitumor immunity. We have previously reported the single agent efficacy for PTC596 in controlling tumor growth and improving survival compared to vehicle-treated mice. Our preliminary results using PTC596, indicate the presence of multinucleated cells and the formation of micronuclei, colocalizing with cGAS and induction of STAT1 activation (marker of inflammation through type 1 IFN). We are currently evaluating purified DCs post-PTC596 treatment for the activation of the cGAS-STING pathway and interferon-stimulated genes (ISGs) and determining their cross-priming capacity. In vivo, using our established syngeneic orthotopic DIPG models, we are evaluating the T cell infiltration (CD3, CD4 and CD8), and characterizing the tumor microenvironment in response to PTC596. Data collected from the above experiments will be presented and discussed.