bluuebunny/crossref_metadata_2025_split huggingface dataset:
Porcine-derived pancreatic enzyme replacement therapy may be linked to chronic hepatitis E virus infection in cystic fibrosis lung transplant recipients
Authors: Thornton Christina S , Waddell Barbara J , Congly Stephen E , Svishchuk Julianna , Somayaji Ranjani , Fatovich Linda , Isaac Debra , Doucette Karen , Fonseca Kevin , Drews Steven J , Borlang Jamie , Osiowy Carla , Parkins Michael D 
Published: April 2024

ObjectivesIn high-income countries hepatitis E virus (HEV) is an uncommonly diagnosed porcine-derived zoonoses. After identifying disproportionate chronic HEV infections in persons with cystic fibrosis (pwCF) postlung transplant, we sought to understand its epidemiology and potential drivers.DesignAll pwCF post-transplant attending our regional CF centre were screened for HEV. HEV prevalence was compared against non-transplanted pwCF and with all persons screened for suspected HEV infection from 2016 to 2022 in Alberta, Canada. Those with chronic HEV infection underwent genomic sequencing and phylogenetic analysis. Owing to their swine derivation, independently sourced pancreatic enzyme replacement therapy (PERT) capsules were screened for HEV.ResultsHEV seropositivity was similar between transplanted and non-transplanted pwCF (6/29 (21%) vs 16/83 (19%); p=0.89). Relative to all other Albertans investigated for HEV as a cause of hepatitis (n=115/1079, 10.7%), pwCF had a twofold higher seropositivity relative risk and this was four times higher than the Canadian average. Only three chronic HEV infection cases were identified in all of Alberta, all in CF lung transplant recipients (n=3/29, 10.3%). Phylogenetics confirmed cases were unrelated porcine-derived HEV genotype 3a. Ninety-one per cent of pwCF were taking PERT (median 8760 capsules/person/year). HEV RNA was detected by RT-qPCR in 44% (47/107) of PERT capsules, and sequences clustered with chronic HEV cases.ConclusionPwCF had disproportionate rates of HEV seropositivity, regardless of transplant status. Chronic HEV infection was evident only in CF transplant recipients. HEV may represent a significant risk for pwCF, particularly post-transplant. Studies to assess HEV incidence and prevalence in pwCF, and potential role of PERT are required.
Tetracyclines enhance antitumor T-cell immunity via the Zap70 signaling pathway
Authors: Tone Mari , Iwahori Kota , Hirata Michinari , Ueyama Azumi , Tani Akiyoshi , Haruta Jun-Ichi , Takeda Yoshito , Shintani Yasushi , Kumanogoh Atsushi , Wada Hisashi 
Published: April 2024

BackgroundCancer immunotherapy including immune checkpoint inhibitors is only effective for a limited population of patients with cancer. Therefore, the development of novel cancer immunotherapy is anticipated. In preliminary studies, we demonstrated that tetracyclines enhanced T-cell responses. Therefore, we herein investigated the efficacy of tetracyclines on antitumor T-cell responses by human peripheral T cells, murine models, and the lung tumor tissues of patients with non-small cell lung cancer (NSCLC), with a focus on signaling pathways in T cells.MethodsThe cytotoxicity of peripheral and lung tumor-infiltrated human T cells against tumor cells was assessed by using bispecific T-cell engager (BiTE) technology (BiTE-assay system). The effects of tetracyclines on T cells in the peripheral blood of healthy donors and the tumor tissues of patients with NSCLC were examined using the BiTE-assay system in comparison with anti-programmed cell death-1 (PD-1) antibody, nivolumab. T-cell signaling molecules were analyzed by flow cytometry, ELISA, and qRT-PCR. To investigate the in vivo antitumor effects of tetracyclines, tetracyclines were administered orally to BALB/c mice engrafted with murine tumor cell lines, either in the presence or absence of anti-mouse CD8 inhibitors.ResultsThe results obtained revealed that tetracyclines enhanced antitumor T-cell cytotoxicity with the upregulation of granzyme B and increased secretion of interferon-γ in human peripheral T cells and the lung tumor tissues of patients with NSCLC. The analysis of T-cell signaling showed that CD69 in both CD4+and CD8+T cells was upregulated by minocycline. Downstream of T-cell receptor signaling, Zap70 phosphorylation and Nur77 were also upregulated by minocycline in the early phase after T-cell activation. These changes were not observed in T cells treated with anti-PD-1 antibodies under the same conditions. The administration of tetracyclines exhibited antitumor efficacy with the upregulation of CD69 and increases in tumor antigen-specific T cells in murine tumor models. These changes were canceled by the administration of anti-mouse CD8 inhibitors.ConclusionsIn conclusion, tetracyclines enhanced antitumor T-cell immunity via Zap70 signaling. These results will contribute to the development of novel cancer immunotherapy.
Weak cosmic censorship conjecture and black hole shadow for black hole with generalized uncertainty principle
Authors: Tang Meirong 
Published: April 2024

AbstractBased on string theory, loop quantum gravity, black hole physics, and other theories of quantum gravity, physicists have proposed generalized uncertainty principle (GUP) modifications. In this work, within the framework of GUP gravity theory, we successfully derive an exact solution to Einstein’s field equation, and discuss the possibility of using EHT to test GUP and how GUP changes the weak cosmic censorship conjecture for black holes. We analyze two different ways of constructing GUP rotating black holes (model I and model II). Model I takes into account the modification of mass by GUP, i.e., the change in mass by quantization of space, and the resulting GUP rotating black hole metric (18) is similar in form to the Kerr black hole metric. Model II takes into account the modification of the rotating black hole when GUP is an external field, where GUP acts like an electric charge, and the resulting GUP rotating black hole metric (19) is similar in form to the Kerr–Newman black hole metric. The difference between (18) and (19) in the spacetime linear structure provides a basis for us to examine the physical nature of GUP rotating black holes from observation. By analyzing the shadow shape of the GUP rotating black hole, we discover intriguing characteristics regarding the impact of first-order and second-order momentum correction coefficients on the black hole’s shadow shape. These findings will be instrumental in future GUP testing using EHT. Additionally, by incident test particle and scalar field with a rotating GUP black hole, the weak cosmic censorship conjecture is not violated in either extreme black holes or near-extreme black holes.
A Path to Persistence after EGFR Inhibition
Authors: Rumde Purva H. , Burns Timothy F. 
Published: April 2024

Abstract
Residual cancer cells persist even after targeted therapies, serving as a reservoir for the subsequent acquisition of genetic alterations that lead to acquired drug resistance and tumor relapse. These initial drug-tolerant persisters (DTP) are phenotypically heterogenous with transient phenotypes attributed to epigenetic, metabolic, and cell-cycle changes. DTPs are responsible for the inevitable relapse seen in EGFR-mutant non–small cell lung cancer (NSCLC) despite high initial response to tyrosine kinase inhibitor (TKI) treatment. While past in vitro studies identified diverse drivers of drug-tolerant persistence to EGFR TKIs in NSCLC, the resultant phenotypic plasticity is not well understood and in vivo models of persistence are lacking. In this issue of Cancer Research, Hu and colleagues used patient-derived xenograft models of EGFR-mutant lung cancer treated with the third-generation TKI osimertinib to investigate mechanisms of persistence at the time of maximal response. Using bulk and single-cell RNA sequencing, the authors identified a DTP transcriptional cluster mediated by the key neuroendocrine lineage transcription factor ASCL1, which triggers an epithelial-to-mesenchymal transition transcriptional program. ASCL1 overexpression increased osimertinib tolerance in vitro as well, apparently independent of its role in neuroendocrine differentiation. Interestingly, the ability of ASCL1 to induce persistence was context dependent as this occurred only in epigenetically permissive cells. Overall, these findings contribute to our understanding of DTP heterogeneity seen after osimertinib treatment and provide insights into potential therapeutic targets.
See related article by Hu et al., p. 1303
Supplementary Figure S2 from Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma
Authors: Habashy Karl J. , Dmello Crismita , Chen Li , Arrieta Victor A. , Kim Kwang-Soo , Gould Andrew , Youngblood Mark W. , Bouchoux Guillaume , Burdett Kirsten B. , Zhang Hui , Canney Michael , Stupp Roger , Sonabend Adam M. 
Published: April 2024

<p>Supplementary Figure 2. Human glioma cell lines exhibit variable responses to paclitaxel and carboplatin.
(A) Dose-response curves showing the response to PTX (blue) and CBDCA (red) in human cell lines. (B) Bar chart showing the maximal efficacy (Emax) of PTX and CBDCA against human glioma cell lines. </p>
Abstract P29: GSTT2 AND THE RESPONSE TO BCG IMMUNOTHERAPY
Authors: Patwardhan Mugdha , Toh Kane , Chiong Edmund , Mahendran Ratha 
Published: April 2024

Abstract
Whilst M. bovis Bacillus Calmette-Guérin (BCG) therapy remains the gold-standard for treatment of high-risk non-muscle invasive bladder cancer (BC), 30-40% of patients fail therapy, resulting in disease recurrence and progression. A better understanding of the underlying mechanisms of BCG therapy can aid in revealing key response pathways, which may lead to the discovery of new targets, and in turn new approaches to treat BC. The glutathione-S-transferase theta 2 (GSTT2) gene is a member of the GST family. Loss of GSTT2 expression has been associated with modulation of intracellular ROS and BCG survival in BC cell lines. Retrospective analysis of BC patients revealed that patients with the GSTT2B deletion responded better to fewer instillations of BCG.
To understand these responses, wild-type (WT) and GSTT2-knockout (KO) mice were implanted with MB49-PSA BC cells, in subcutaneous and orthotopic settings. Once tumors were established, the mice were treated with four weekly BCG instillations, after which the subcutaneous tumors and bladders were harvested for downstream analysis.
Single-cell RNA sequencing of whole-bladders was used to identify specific cell clusters within the bladder, and to analyze differential gene expression. Hmga2, Ahnak and Peak1 were found to be differentially expressed in bladders from WT and GSTT2-KO mice. These genes are known to be involved in pro- and anti-tumorigenic pathways such as epithelial-mesenchymal transition and inflammation. Additionally, quantitative real-time PCR analysis in the subcutaneous and orthotopic tumors revealed differences in the expression of immune-related genes, especially markers of immune exhaustion such as PD-L1 and CTLA-4. Flow cytometry analysis of subcutaneous tumors also revealed differences in T-cell infiltration.
Thus, loss of GSTT2 may influence the response to BCG therapy, through modulating downstream signaling pathways and immune responses. Elucidating such pathways can lead to a better understanding of the mechanism of BCG and its role as a therapy for BC.
Citation Format: Mugdha Patwardhan, Kane Toh, Edmund Chiong, Ratha Mahendran. GSTT2 AND THE RESPONSE TO BCG IMMUNOTHERAPY [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P29.
Abstract P41: Ex vivo Drug Testing Identifies a Novel Drug Pair in Targeting STS
Authors: Chan Sharon Pei Yi , Wong Wai Yee , Ismail Nur Nadiah , Luo Baiwen , Chen Benjamin Jieming , Phua Brandon Xuan Ming , Woo Xing Yi , Toh Tan Boon , Chow Edward Kai-Hua , Yang Valerie Shiwen 
Published: April 2024

Abstract
Soft tissue sarcomas (STS) are a highly heterogeneous collection of tumors that arise from primitive mesenchymal cells. Due to a reliance on cytotoxic chemotherapy as standard of care, survival outcomes for advanced STS patients remain poor. While efforts to understand sarcomagenesis have revealed potential biomarkers, the diversity of STS subtypes and interpatient tumour heterogeneity has led to the lack of effective molecular targeted therapies available. Given the uniquely individualized nature of STS, we hypothesize that the application of an experimental-analytics method, Quadratic Phenotypic Optimization Platform (QPOP), towards primary STS patient samples can improve identification of patient-specific drug combinations. Across a total of 45 patient samples collected, QPOP identified a novel drug pair as most frequently top-ranked, outperforming standard of care ifosfamide and doxorubicin. Interestingly, analysis of QPOP ranking trends revealed this combination to be broadly effective, implying common targetable pathways independent of STS subtype. Single-drug and combination dose-response assays performed in a panel of established patient lines supported its synergistic interaction, accompanied by increased PARP and caspase-3 cleavage with immunoblotting, and increased apoptotic response with Annexin V assay. Mechanistically, this synergy results in cell cycle arrest and induction of programmed cell death pathways, as revealed by molecular profiling on representative patient and cell lines. We further showed that co-treatment synergistically repressed oncogenic MYC and activated the p27kip1 tumor suppressor. Finally, this combination was more effective at impairing tumor progression than single agents alone in an STS xenograft mouse model. Overall, work here provides preliminary clinical evidence for the prioritization of a novel drug pair in addressing STS beyond known clinicopathologic parameters.
Citation Format: Sharon Pei Yi Chan, Wai Yee Wong, Nur Nadiah Ismail, Baiwen Luo, Benjamin Jieming Chen, Brandon Xuan Ming Phua, Xing Yi Woo, Tan Boon Toh, Edward Kai-Hua Chow, Valerie Shiwen Yang. Ex vivo Drug Testing Identifies a Novel Drug Pair in Targeting STS [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P41.
Abstract P53: Inhibition of STING/Galectin-9 Axis Sensitize Anthracyclines Treatment And Induce Anti-tumor Immunity
Authors: Sun Xian , Wang Wei-Jan , Lang Jilu , Yang Riyao , Shen Wan-Jou , Sun Linlin , Hung Mien-Chie 
Published: April 2024

Abstract
Anthracyclines, are a class of conventional and routinely used firstline chemotherapy drugs to treat breast cancer. Immunogenic cell death (ICD) is characterized by the exposure of danger signals that promote dendritic cell maturation and antigen presentation and is often associated with the induction of cancer cell-intrinsic IFN-I signaling pathway. In addition, among multiple chemotherapeutic drugs such as doxorubicin (Dox) is well-known to promote tumor immunogenicity by interfering with DNA synthesis. Galectin-9 (Gal-9), as a member of β-galactoside-binding protein family, has been demonstrated to induce T cell death and promote immunosuppression in the tumor microenvironment. In addition, it has been shown that some interferon (IFN) and interleukin (IL) factors can induce Gal-9 expression. However, the mechanism cross-talk between anthracyclines and Gal-9 immunecheckpoint inhibitor remains unknown. Here we show that doxorubicin induces PD-L1 expression in human breast cancer cell lines and animal models. Mechanistically, doxorubicin promoted IFNβ expression, which in turn enhanced doxorubicin-induced Gal-9. Furthermore, we discovered that doxorubicin induces tumor Gal-9 via STING upregulation. The combination of doxorubicin and anti-Gal-9 therapy compared with each agent alone significantly increased the therapeutic efficacy in vivo. Clinically, a higher Gal-9 and p-STING level in the tumor region of after-treatment anthracyclines as compared to before treatment is indicated in breast cancer tumor tissue. Taken together, our study demonstrates crosstalk between anthracyclines-induced ICD and tumor-associated immunosuppression and provides a novel therapeutic strategy by combining anthracyclines and Gal-9 antibody in breast cancer.
Citation Format: Xian Sun, Wei-Jan Wang, Jilu Lang, Riyao Yang, Wan-Jou Shen, Linlin Sun, Mien-Chie Hung. Inhibition of STING/Galectin-9 Axis Sensitize Anthracyclines Treatment And Induce Anti-tumor Immunity [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P53.
Abstract P70: HIGH-THROUGHPUT IMAGING-BASED PHENOTYPIC PROFILING OF IMMUNE CELLS FROM BRCA2 VARIANT CARRIERS AND NON-CARRIERS
Authors: Zhong Guorui , Fu Oscar , Yeo Claresta , Chong Siao Ting , Chan Sock Hoai , Ngeow Joanne , Loo Lit-Hsin 
Published: April 2024

Abstract
Mutated germline alleles in the DNA damage repair (DDR) genes BRCA1/2 are major risk factors for breast and ovarian cancers. Recent studies have found that BRCA1-mutant tumors tend to have higher abundance of immune cells within the tumor microenvironment, but much better response was observed from the BRCA2-mutant tumors when given immune-checkpoint inhibitors, suggesting possible functional and phenotypic effects of germline BRCA2 mutations on the immune cells. However, most existing studies focus on investigating the genomic instability and phenotypes of hereditary mutations in breast and ovarian cancer cells. Thus, the impact of these mutations on immune cells’ phenotypes and functions remains largely unknown. Here, we report a study of immune cells with and without BRCA2 mutations using High-throughput Imaging-based Phenotypic Profiling (HIPP), which can identify changes in cellular morphology and protein subcellular localization patterns that are not obvious from other traditional functional assays. We performed HIPP on immune cells from nine BRCA2 pathogenic variant carriers and eight non-carriers. Automatic quantification of ~200 phenotypic features from each single cell revealed that CD8+ T cells from BRCA2 variant carriers have distinct and quantifiable changes in their morphological features (such as cytoskeleton structures) and immunological features (such as Granzyme B expressions). Moreover, we found that BRCA2-mutant CD8+ T cells proliferate faster than normal CD8+ T cells. Our results suggest that BRCA2 mutations affect the functions and phenotypes of immune cells. Some of these phenotypic features and markers may be used to classify BRCA2 variants and predict the pathogenicity of variants of uncertain significance (VUS). Our study provides new insight into the immune phenotyping of cancer patients at individual level and may help to stratify patients, leading to the development of more effective therapeutic strategies. This method can potentially extend to other germline variants and overcome the challenge of VUS interpretation in clinical management.
Citation Format: Guorui Zhong, Oscar Fu, Claresta Yeo, Siao Ting Chong, Sock Hoai Chan, Joanne Ngeow, Lit-Hsin Loo. HIGH-THROUGHPUT IMAGING-BASED PHENOTYPIC PROFILING OF IMMUNE CELLS FROM BRCA2 VARIANT CARRIERS AND NON-CARRIERS [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P70.
Observed Global Mean State Changes Modulating the Collective Influence of the Tropical Atlantic and Indian Oceans on ENSO
Authors: Martín-Gómez Verónica , Rodríguez-Fonseca Belén , Polo Irene , Martín-Rey Marta 
Published: April 2024

Abstract
In the last decades, many efforts have been made to understand how different tropical oceanic basins are able to impact El Niño–Southern Oscillation (ENSO). However, the collective connectivity among the tropical oceans and their associated influence on ENSO are less understood. Using a complex network methodology, the degree of collective connectivity among the tropical oceans is analyzed focusing on the detection of periods when the tropical basins collectively interact and the Atlantic and Indian basins influence the equatorial Pacific sea surface temperatures (SSTs). The background state for the periods of strong collective connectivity is also investigated. Our results show a marked multidecadal variability in the tropical interbasin connection, with periods of stronger and weaker collective connectivity. These changes seem to be modulated by changes in the North Atlantic Ocean mean state a decade in advance. In particular, strong connectivity occurs in periods with colder than average tropical North Atlantic surface ocean. Associated with this cooling, an anomalous convergence of the vertical integral of total energy flux (VIEF) takes place over the tropical north–west Atlantic, associated with anomalous divergence of VIEF over the equatorial eastern Pacific. In turn, an anomalous zonal surface pressure gradient over the tropical Pacific weakens the trades over the western equatorial Pacific. Consequently, a shallower thermocline emerges over the western equatorial Pacific, which can enhance thermocline feedbacks, the triggering of ENSO events, and therefore, ENSO variability. By construction, our results put forward opposite conditions for periods of weak tropical basin connectivity. These results have important implications for seasonal to decadal predictions.
Comparison of Contralateral vs Ipsilateral Vein Graft for Traumatic Vascular Injury Repair: A Cohort From PROOVIT
Authors: Siddiqi Noreen , Lammers Daniel , Hu Parker , Stonko David , DuBose Joseph , Hurst Stuart , Hashmi Zain , Morrison Jonathan , Betzold Richard 
Published: April 2024

Traumatic injury leading to arterial damage has traditionally been repaired using autologous vein graft from the contralateral limb. This often requires a secondary surgical site and the potential of prolonged operative time for patients. We sought to assess the use of ipsilateral vs contralateral vein grafts in patients who experienced traumatic extremity vascular injury. A multicenter database was queried to identify arterial injuries requiring operative intervention with vein grafting. The primary outcome of interest was need for operative reintervention. Secondary outcomes included risk of thrombosis, infection, and intensive care unit length of stay. 358 patients (320 contralateral and 38 ipsilateral) were included in the analysis. The ipsilateral vein cohort did not display a statistically significant decrease in need for reoperation when compared to the contralateral group (11% vs 23%; OR 0.41, 95% CI −0.07-1.3; P = .14). Contralateral repair was associated with longer median intensive care unit (ICU) LOS (4.3 vs 3.1 days; P < .01).