bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ectopic expression of cGAS inSalmonella typhimuriumenhances STING-mediated IFN-β response in human macrophages and dendritic cells
Authors: Waanders Lisette , van der Donk Lieve E H , Ates Louis S , Maaskant Janneke , van Hamme John L , Eldering Eric , van Bruggen Jaco A C , Rietveld Joanne M , Bitter Wilbert , Geijtenbeek Teunis B H , Kuijl Coenraad P 
Published: April 2023

BackgroundInterferon (IFN)-β induction via activation of the stimulator of interferon genes (STING) pathway has shown promising results in tumor models. STING is activated by cyclic dinucleotides such as cyclic GMP–AMP dinucleotides with phosphodiester linkages 2′–5′ and 3′–5′ (cGAMPs), that are produced by cyclic GMP–AMP synthetase (cGAS). However, delivery of STING pathway agonists to the tumor site is a challenge. Bacterial vaccine strains have the ability to specifically colonize hypoxic tumor tissues and could therefore be modified to overcome this challenge. Combining high STING-mediated IFN-β levels with the immunostimulatory properties ofSalmonella typhimuriumcould have potential to overcome the immune suppressive tumor microenvironment.MethodsWe have engineeredS. typhimuriumto produce cGAMP by expression of cGAS. The ability of cGAMP to induce IFN-β and its IFN-stimulating genes was addressed in infection assays of THP-I macrophages and human primary dendritic cells (DCs). Expression of catalytically inactive cGAS is used as a control. DC maturation and cytotoxic T-cell cytokine and cytotoxicity assays were conducted to assess the potential antitumor response in vitro. Finally, by making use of differentS. typhimuriumtype III secretion (T3S) mutants, the mode of cGAMP transport was elucidated.ResultsExpression of cGAS inS. typhimuriumresults in a 87-fold stronger IFN-β response in THP-I macrophages. This effect was mediated by cGAMP production and is STING dependent. Interestingly, the needle-like structure of the T3S system was necessary for IFN-β induction in epithelial cells. DC activation included upregulation of maturation markers and induction of type I IFN response. Coculture of challenged DCs with cytotoxic T cells revealed an improved cGAMP-mediated IFN-γ response. In addition, coculture of cytotoxic T cells with challenged DCs led to improved immune-mediated tumor B-cell killing.ConclusionS. typhimuriumcan be engineered to produce cGAMPs that activate the STING pathway in vitro. Furthermore, they enhanced the cytotoxic T-cell response by improving IFN-γ release and tumor cell killing. Thus, the immune response triggered byS. typhimuriumcan be enhanced by ectopic cGAS expression. These data show the potential ofS. typhimurium–cGAS in vitro and provides rationale for further research in vivo.
BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors
Authors: Fu Yu , Yang Bin , Cui Yaoyuan , Hu Xingyuan , Li Xi , Lu Funian , Qin Tianyu , Zhang Li , Hu Zhe , Guo Ensong , Fan Junpeng , Xiao Rourou , Li Wenting , Qin Xu , Hu Dianxing , Peng Wenju , Liu Jingbo , Wang Beibei , Mills Gordon B , Chen Gang , Sun Chaoyang 
Published: April 2023

BackgroundMismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect. However, the mechanisms underlying remain unknown. Here, we identify that BRD4 inhibition induces a persistent dMMR phenotype in cancers.MethodsWe confirmed the correlation between BRD4 and mismatch repair (MMR) by the bioinformatic analysis on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium data, and the statistical analysis on immunohistochemistry (IHC) scores of ovarian cancer specimens. The MMR genes (MLH1,MSH2,MSH6,PMS2) were measured by quantitative reverse transcription PCR, western blot, and IHC. The MMR status was confirmed by whole exome sequencing, RNA sequencing, MMR assay and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay. The BRD4i AZD5153 resistant models were induced both in vitro and in vivo. The transcriptional effects of BRD4 on MMR genes were investigated by chromatin immunoprecipitation among cell lines and data from the Cistrome Data Browser. The therapeutic response to ICB was testified in vivo. The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry.ResultsWe identified the positive correlation betweenBRD4and MMR genes in transcriptional and translational aspects. Also, the inhibition of BRD4 transcriptionally reduced MMR genes expression, resulting in dMMR status and elevated mutation loads. Furthermore, prolonged exposure to AZD5153 promoted a persistent dMMR signature both in vitro and in vivo, enhancing tumor immunogenicity, and increased sensitivity to α-programmed death ligand-1 therapy despite the acquired drug resistance.ConclusionsWe demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy.
Irreversible electroporation augments β-glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma
Authors: Woeste Matthew R , Shrestha Rejeena , Geller Anne E , Li Shu , Montoya-Durango Diego , Ding Chuanlin , Hu Xiaoling , Li Hong , Puckett Aaron , Mitchell Robert A , Hayat Traci , Tan Min , Li Yan , McMasters Kelly M , Martin Robert C G , Yan Jun 
Published: April 2023

BackgroundPancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan induced trained immunity in the treatment of PC.Methodsβ-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. β-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag−/−mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral β-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral β-glucan after IRE was evaluated by mass cytometry.ResultsIRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, β-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered β-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. β-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered β-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE.ConclusionsThese data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.
Naive T cells inhibit the outgrowth of intractable antigen-activated memory T cells: implications for T-cell immunotherapy
Authors: Sharma Sandhya , Woods Mae , Mehta Naren U , Sauer Tim , Parikh Kathan S , Schmueck-Henneresse Michael , Zhang Huimin , Mehta Birju , Brenner Malcolm K , Heslop Helen E , Rooney Cliona M 
Published: April 2023

BackgroundThe wider application of T cells targeting viral tumor-antigens via their native receptors is hampered by the failure to expand potent tumor-specific T cells from patients. Here, we examine reasons for and solutions to this failure, taking as our model the preparation of Epstein-Barr virus (EBV)-specific T cells (EBVSTs) for the treatment of EBV-positive lymphoma. EBVSTs could not be manufactured from almost one-third of patients, either because they failed to expand, or they expanded, but lacked EBV specificity. We identified an underlying cause of this problem and established a clinically feasible approach to overcome it.MethodsCD45RO+CD45RA− memory compartment residing antigen-specific T cells were enriched by depleting CD45RA positive (+) peripheral blood mononuclear cells (PBMCs) that include naïve T cells, among other subsets, prior to EBV antigen stimulation. We then compared the phenotype, specificity, function and T-cell receptor (TCR) Vβ repertoire of EBVSTs expanded from unfractionated whole (W)-PBMCs and CD45RA-depleted (RAD)-PBMCs on day 16. To identify the CD45RA component that inhibited EBVST outgrowth, isolated CD45RA+ subsets were added back to RAD-PBMCs followed by expansion and characterization. The in vivo potency of W-EBVSTs and RAD-EBVSTs was compared in a murine xenograft model of autologous EBV+ lymphoma.ResultsDepletion of CD45RA+ PBMCs before antigen stimulation increased EBVST expansion, antigen-specificity and potency in vitro and in vivo. TCR sequencing revealed a selective outgrowth in RAD-EBVSTs of clonotypes that expanded poorly in W-EBVSTs. Inhibition of antigen-stimulated T cells by CD45RA+ PBMCs could be reproduced only by the naïve T-cell fraction, while CD45RA+ regulatory T cells, natural killer cells, stem cell memory and effector memory subsets lacked inhibitory activity. Crucially, CD45RA depletion of PBMCs from patients with lymphoma enabled the outgrowth of EBVSTs that failed to expand from W-PBMCs. This enhanced specificity extended to T cells specific for other viruses.ConclusionOur findings suggest that naïve T cells inhibit the outgrowth of antigen-stimulated memory T cells, highlighting the profound effects of intra-T-cell subset interactions. Having overcome our inability to generate EBVSTs from many patients with lymphoma, we have introduced CD45RA depletion into three clinical trials:NCT01555892andNCT04288726using autologous and allogeneic EBVSTs to treat lymphoma andNCT04013802using multivirus-specific T cells to treat viral infections after hematopoietic stem cell transplantation.
Severe cytopenia after CD19 CAR T-cell therapy: a retrospective study from the EBMT Transplant Complications Working Party
Authors: Penack Olaf , Peczynski Christophe , Koenecke Christian , Polge Emmanuelle , Kuhnl Andrea , Fegueux Nathalie , Daskalakis Michael , Kröger Nicolaus , Dreger Peter , Besley Caroline , Schanz Urs , Bloor Adrian , Ganser Arnold , Forcade Edouard , Corral Lucia López , Passweg Jakob R , Novak Urban , Moiseev Ivan , Schoemans Hélène , Basak Grzegorz W , Chabannon Christian , Sureda Anna , Averbuch Dina , Glass Bertram , de la Camara Rafael , Peric Zinaida 
Published: April 2023

We investigated the incidence and outcome of anti-CD19 chimeric antigen receptor (CAR) T-cells-associated Common Terminology Criteria for Adverse Events (CTCAE) ≥grade 3 cytopenia. In the EBMT CAR-T registry, we identified 398 adult patients with large B-cell lymphoma who had been treated with CAR-T-cells with axicel (62%) or tisacel (38%) before August 2021 and had cytopenia status documented for the first 100 days. Most patients had received two or three previous lines of therapy, however, 22.3% had received four or more. Disease status was progressive in 80.4%, stable in 5.0% and partial/complete remission in 14.6%. 25.9% of the patients had received a transplantation before. Median age was 61.4 years (min–max; IQR=18.7–81; (52.9–69.5)).The cumulative incidence of ≥grade 3 cytopenia was 9.0% at 30 days (95% CI (6.5 to 12.1)) and 12.1% at 100 days after CAR T-cell infusion (95% CI (9.1 to 15.5)). The median time from CAR-T infusion to cytopenia onset was 16.5 days (min–max; IQR=1–90; (4–29.8)). Grade 3 and grade 4 CTCAE cytopenia occurred in 15.2% and 84.8%, respectively. In 47.6% there was no resolution.Severe cytopenia had no significant impact on overall survival (OS) (HR 1.13 (95% CI 0.74 to 1.73), p=0.57). However, patients with severe cytopenia had a poorer progression-free survival (PFS) (HR 1.54 (95% CI 1.07 to 2.22), p=0.02) and a higher relapse incidence (HR 1.52 (95% CI 1.04 to 2.23), p=0.03). In those patients who developed severe cytopenia during the first 100 days (n=47), OS, PFS, relapse incidence and non-relapse mortality at 12 months after diagnosis of severe cytopenia were 53.6% (95% CI (40.3 to 71.2)), 20% (95% CI (10.4 to 38.6)), 73.5% (95% CI (55.2 to 85.2)) and 6.5% (95% CI (1.7 to 16.2)), respectively.In multivariate analysis of severe cytopenia risk factors, only year of CAR-T infusion (HR=0.61, 95% CI (0.39 to 0.95), p=0.028) and total number of treatment lines before CAR-T infusion (one or two lines vs three or more, HR=0.41, 95% CI (0.21 to 0.83), p=0.013) had a significant positive association with the incidence of cytopenia. Other factors, such as previous transplantation, disease status at time of CAR-T, patient age and patient sex, had no significant association.Our data provide insight on frequency and clinical relevance of severe cytopenia after CAR T-cell therapy in the European real-world setting.
TP53c.455C>T p.(Pro152Leu) pathogenic variant is a lower risk allele with attenuated risks of breast cancer and sarcoma
Authors: Evans D Gareth , Harkness Elaine F , Woodward Emma R 
Published: April 2023

Germline (likely) pathogenicTP53variants cause Li-Fraumeni syndrome (LFS), typically associated with sarcoma, brain, breast and adrenal tumours. Although classical LFS is highly penetrant, the p.R337H variant, common in Brazil, is typically associated with childhood adrenal tumours and an older onset age of other LFS tumours. Previously, we reported the finding of p.P152L in 6 children from 5 families with adrenal tumours. We have now assessed cancer risks over the subsequent 23 years, and in one further family with p.P152L. Cancer risks were compared with those in the 11 families known to our service with classical dominant negative mutations affecting neighbouring codons 245 and 248 (codon 245/248).Compared with codon 245/248 families, we found lower age-related risks for all non-adrenal tumours in codon 152 families (p<0.0001) with an absence of breast cancer as compared with 100% penetrance by age 36 years in codon 245/248 families (p<0.0001), and lower rates of sarcoma in non-irradiated individuals (p=0.0001). Although there were more adrenal tumours in codon 152 families (6/26 individuals, 1/27 for codon 245/248), this was not significant (p=0.05).Understanding codon-specific cancer risks in LFS is important for accurate personalised cancer risk assessment, and subsequent prevention and early detection strategies.
A propensity score-matched comparative study of balloon guide catheters versus conventional guide catheters for concurrent mechanical thrombectomy with carotid stenting in tandem strokes: comparison of first pass effect, symptomatic intracranial hemorrhage, and 90-day functional outcomes
Authors: Baig Ammad A , Waqas Muhammad , Turner Ryan C , Kuo Cathleen C , Donnelly Brianna M , Lai Pui Man Rosalind , Raygor Kunal P , Bouslama Mehdi , Lim Jaims , Neumaier BS Jenna , Cappuzzo Justin M , Davies Jason M , Snyder Kenneth V , Siddiqui Adnan H , Levy Elad I 
Published: April 2023

BackgroundExtensive clot burden in tandem strokes accounts for poor mechanical thrombectomy (MT) outcomes. Several studies have shown the benefit of balloon guide catheters (BGCs) in MT and carotid artery stenting.ObjectiveIn view of this potential benefit, to investigate the safety and effectiveness of proximal flow arrest using a BGC during concurrent MT and carotid revascularization for tandem stroke treatment in a comparative, propensity score-matched (PSM) study.MethodsPatients with a tandem stroke identified from our endovascular database were dichotomized into groups treated with BGCs versus conventional guide catheters. One-to-one PSM adjustment for baseline demographics and treatment selection bias using nearest-neighbor matching was performed. Patient demographics, presentation characteristics, and procedural details were recorded. Outcomes assessed were final modified Thrombolysis in Cerebral Infarction (mTICI) grade, periprocedural symptomatic intracranial hemorrhage (sICH) rate, in-hospital mortality, and 90-day modified Rankin Scale (mRS) score. Mann-Whitney U test and multivariate logistic regression were performed to compare procedural parameters and clinical outcomes.ResultsConcurrent carotid revascularization (stenting with/without angioplasty) and MT was performed in 125 cases (BGC: 85; no BGC: 40). After PSM (40 patients/group), the BGC group had a significantly shorter procedure duration (77.9 vs 61.5 min; OR=0.996; P=0.006), lower discharge National Institutes of Health Stroke Scale score (8.0 vs 11.0; OR=0.987; P=0.042), and higher odds of 90-day mRS 0–2 score (52.3% vs 27.5%; OR=0.34; P=0.040). On multivariate regression, the BGC group had a significantly higher first pass effect rate (mTICI 2b or 3)(OR=1.115, 95% CI 1.015 to 1.432; P=0.013) and lower periprocedural sICH rate (OR=0.615, 95% CI 0.406 to 0.932; P=0.025). No difference in in-hospital mortality was observed (OR=1.591, 95% CI 0.976 to 2.593; P=0.067).ConclusionBGCs used for concurrent MT–carotid revascularization with flow arrest were safe and resulted in superior clinical and angiographic outcomes in patients with a tandem stroke.
E-cigarette use among early adolescent tobacco cigarette smokers: testing the disruption and entrenchment hypotheses in two longitudinal cohorts
Authors: Kelly Brian C , Vuolo Mike , Maggs Jennifer , Staff Jeremy 
Published: April 2023

Objective
Using longitudinal data from two large-scale cohorts in the UK and USA, we examine whether e-cigarette use steers adolescent early smokers away from tobacco cigarettes (disruption hypothesis) or deepens early patterns of tobacco smoking (entrenchment hypothesis) in comparison with early smokers who do not use e-cigarettes.

Methods
Youth who smoked tobacco cigarettes by early adolescence (before age 15) were selected from the ongoing UK Millennium Cohort Study (n=1090) and the US Population Assessment of Tobacco and Health (n=803) study. In regression models, the focal predictor was lifetime use of an e-cigarette by early adolescence and the primary outcome was current tobacco use by late adolescence (before age 18). Logistic and multinomial models controlled for early adolescent risk factors and sociodemographic background, and were weighted for attrition and adjusted for complex survey designs.

Results

Among youth who were early cigarette smokers, 57% of UK and 58% of US youth also used e-cigarettes. The odds of later adolescent smoking among early smoking youth were significantly higher among e-cigarette users relative to those who had not used e-cigarettes (adjusted OR (AOR
UK
)=1.45; AOR
USA
=2.19). In both samples, multinomial models indicated that early smoking youth who used e-cigarettes were more likely to be frequent smokers relative to not smoking (AOR
UK
=2.01; AOR
USA
=5.11) and infrequent smoking (AOR
UK
=1.67; AOR
USA
=2.11).

Conclusions
Despite national differences in e-cigarette regulation and marketing, there is evidence e-cigarette use among early adolescent smokers in the UK and USA leads to higher odds of any smoking and more frequent tobacco cigarette use later in adolescence.
Low-energy nuclear reactions with stored ions: a new era of astrophysical experiments at heavy ion storage rings
Authors: Glorius Jan , Bruno Carlo Giulio 
Published: April 2023

AbstractHeavy ion storage rings are powerful tools to store and observe key nuclear properties of rare radioactive isotopes. Recent developments in ring physics and enhanced beam intensities have now opened up the possibility to carry out low-energy investigations of nuclear reactions at rings. Pure, intense, exotic beams of isotopes that are otherwise challenging to access can be impinged on pure, ultra-thin targets, allowing the study of long-standing nuclear astrophysical puzzles in a variety of stellar sites that have so far resisted traditional approaches. In this review paper, we will describe pioneering studies with decelerated beams at the ESR storage ring at GSI (Germany), as well as future exciting prospects at the ESR and CRYRING at GSI/FAIR.
Revealing the determinants of gender inequality in urban cycling with large-scale data
Authors: Battiston Alice , Napoli Ludovico , Bajardi Paolo , Panisson André , Perotti Alan , Szell Michael , Schifanella Rossano 
Published: April 2023

AbstractCycling is an outdoor activity with massive health benefits, and an effective solution for sustainable urban transport. Despite these benefits and the recent rising popularity of cycling, most countries still have a negligible uptake. This uptake is especially low for women: there is a largely unexplained, persistent gender gap in cycling. To understand the determinants of this gender gap in cycling at scale, here we use massive, automatically-collected data from the tracking application Strava on outdoor cycling for 61 cities across the United States, the United Kingdom, Italy and the Benelux area. While Strava data is particularly well-suited to describe the behavior of regular cyclists and its generalizability to occasional cyclists requires further investigation, the size of these data and their characteristics represent an unprecedented opportunity for the literature on cycling. Leveraging the associated gender and usage information, we first quantify the emerging gender gap in recreational cycling at city-level. A comparison of cycling rates of women across cities within similar geographical areas—where the penetration of Strava is assumed to be comparable—unveils a broad range of gender gaps. On a macroscopic level, we link this heterogeneity to a variety of urban indicators and provide evidence for traditional hypotheses on the determinants of the gender-cycling-gap. We find a positive association between female cycling rate and urban road safety. On a microscopic level, we identify female preferences for street-specific features in the city of New York. Assuming that the determinants of the gender-cycling-gap are similar across regular and occasional cyclists, our study suggests that enhancing the quality of the dedicated cycling infrastructure may be a way to make urban environments more accessible for women, thereby making urban transport more sustainable for everyone.