bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical evaluation of two phylogenetically distant arenavirus vectors for the development of novel immunotherapeutic combination strategies for cancer treatment
Authors: Raguz Josipa , Pinto Catarina , Pölzlbauer Theresa , Habbeddine Mohamed , Rosskopf Sandra , Strauß Judith , Just Valentin , Schmidt Sarah , Bidet Huang Katell , Stemeseder Felix , Schippers Timo , Stewart Ethan , Jez Jakub , Berraondo Pedro , Orlinger Klaus K. , Lauterbach Henning 
Published: April 2024

BackgroundEngineered arenavirus vectors have recently been developed to leverage the body’s immune system in the fight against chronic viral infections and cancer. Vectors based on Pichinde virus (artPICV) and lymphocytic choriomeningitis virus (artLCMV) encoding a non-oncogenic fusion protein of human papillomavirus (HPV)16 E6 and E7 are currently being tested in patients with HPV16+ cancer, showing a favorable safety and tolerability profile and unprecedented expansion of tumor-specific CD8+T cells. Although the strong antigen-specific immune response elicited by artLCMV vectors has been demonstrated in several preclinical models, PICV-based vectors are much less characterized.MethodsTo advance our understanding of the immunobiology of these two vectors, we analyzed and compared their individual properties in preclinical in vivo and in vitro systems. Immunogenicity and antitumor effect of intratumoral or intravenous administration of both vectors, as well as combination with NKG2A blockade, were evaluated in naïve or TC-1 mouse tumor models. Flow cytometry, Nanostring, and histology analysis were performed to characterize the tumor microenvironment (TME) and T-cell infiltrate following treatment.ResultsDespite being phylogenetically distant, both vectors shared many properties, including preferential infection and activation of professional antigen-presenting cells, and induction of potent tumor-specific CD8+T-cell responses. Systemic as well as localized treatment induced a proinflammatory shift in the TME, promoting the infiltration of inducible T cell costimulator (ICOS)+CD8+T cells capable of mediating tumor regression and prolonging survival in a TC-1 mouse tumor model. Still, there was evidence of immunosuppression built-up over time, and increased expression of H2-T23 (ligand for NKG2A T cell inhibitory receptor) following treatment was identified as a potential contributing factor. NKG2A blockade improved the antitumor efficacy of artARENA vectors, suggesting a promising new combination approach. This demonstrates how detailed characterization of arenavirus vector-induced immune responses and TME modulation can inform novel combination therapies.ConclusionsThe artARENA platform represents a strong therapeutic vaccine approach for the treatment of cancer. The induced antitumor immune response builds the backbone for novel combination therapies, which warrant further investigation.
Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C
Authors: Gomar Celia , Di Trani Claudia Augusta , Bella Angela , Arrizabalaga Leire , Gonzalez-Gomariz Jose , Fernandez-Sendin Myriam , Alvarez Maite , Russo-Cabrera Joan Salvador , Ardaiz Nuria , Aranda Fernando , Schippers Timo , Quintero Marisol , Melero Ignacio , Orlinger Klaus K , Lauterbach Henning , Berraondo Pedro 
Published: April 2024

BackgroundLymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored.MethodsWe assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination’s efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials.ResultsIntratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8+T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8+T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included.ConclusionIntratumoral injection of poly(I:C) sensitizes MHClowtumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy.
Tumor-targeted therapy with BRAF-inhibitor recruits activated dendritic cells to promote tumor immunity in melanoma
Authors: Hornsteiner Florian , Vierthaler Janine , Strandt Helen , Resag Antonia , Fu Zhe , Ausserhofer Markus , Tripp Christoph H , Dieckmann Sophie , Kanduth Markus , Farrand Kathryn , Bregar Sarah , Nemati Niloofar , Hermann-Kleiter Natascha , Seretis Athanasios , Morla Sudhir , Mullins David , Finotello Francesca , Trajanoski Zlatko , Wollmann Guido , Ronchese Franca , Schmitz Marc , Hermans Ian F , Stoitzner Patrizia 
Published: April 2024

BackgroundTumor-targeted therapy causes impressive tumor regression, but the emergence of resistance limits long-term survival benefits in patients. Little information is available on the role of the myeloid cell network, especially dendritic cells (DC) during tumor-targeted therapy.MethodsHere, we investigated therapy-mediated immunological alterations in the tumor microenvironment (TME) and tumor-draining lymph nodes (LN) in the D4M.3A preclinical melanoma mouse model (harboring the V-Raf murine sarcoma viral oncogene homolog B (BRAF)V600Emutation) by using high-dimensional multicolor flow cytometry in combination with multiplex immunohistochemistry. This was complemented with RNA sequencing and cytokine quantification to characterize the immune status of the tumors. The importance of T cells during tumor-targeted therapy was investigated by depleting CD4+or CD8+T cells in tumor-bearing mice. Tumor antigen-specific T-cell responses were characterized by performing in vivo T-cell proliferation assays and the contribution of conventional type 1 DC (cDC1) to T-cell immunity during tumor-targeted therapy was assessed using Batf3−/−mice lacking cDC1.ResultsOur findings reveal that BRAF-inhibitor therapy increased tumor immunogenicity, reflected by an upregulation of genes associated with immune activation. The T cell-inflamed TME contained higher numbers of activated cDC1 and cDC2 but also inflammatory CCR2-expressing monocytes. At the same time, tumor-targeted therapy enhanced the frequency of migratory, activated DC subsets in tumor-draining LN. Even more, we identified a cDC2 population expressing the Fc gamma receptor I (FcγRI)/CD64 in tumors and LN that displayed high levels of CD40 and CCR7 indicating involvement in T cell-mediated tumor immunity. The importance of cDC2 is underlined by just a partial loss of therapy response in a cDC1-deficient mouse model. Both CD4+and CD8+T cells were essential for therapy response as their respective depletion impaired therapy success. On resistance development, the tumors reverted to an immunologically inert state with a loss of DC and inflammatory monocytes together with the accumulation of regulatory T cells. Moreover, tumor antigen-specific CD8+T cells were compromised in proliferation and interferon-γ-production.ConclusionOur results give novel insights into the remodeling of the myeloid landscape by tumor-targeted therapy. We demonstrate that the transient immunogenic tumor milieu contains more activated DC. This knowledge has important implications for the development of future combinatorial therapies.
Use of risk chart algorithms for the identification of psoriatic arthritis patients at high risk for cardiovascular disease: findings derived from the project CARMA cohort after a 7.5-year follow-up period
Authors: Polo y La Borda Jessica , Castañeda Santos , Heras-Recuero Elena , Sánchez-Alonso Fernando , Plaza Zulema , García Gómez Carmen , Ferraz-Amaro Ivan , Sanchez-Costa Jesús Tomás , Sánchez-González Olga Carmen , Turrión-Nieves Ana Isabel , Perez-Alcalá Ana , Pérez-García Carolina , González-Juanatey Carlos , Llorca Javier , Gonzalez-Gay Miguel Angel 
Published: April 2024

ObjectiveTo assess the predictive value of four cardiovascular (CV) risk algorithms for identifying high-risk psoriatic arthritis (PsA) patients.MethodsEvaluation of patients with PsA enrolled in the Spanish prospective project CARdiovascular in RheuMAtology. Baseline data of 669 PsA patients with no history of CV events at the baseline visit, who were followed in rheumatology outpatient clinics at tertiary centres for 7.5 years, were retrospectively analysed to test the performance of the Systematic Coronary Risk Assessment (SCORE), the modified version (mSCORE) European Alliance of Rheumatology Associations (EULAR) 2015/2016, the SCORE2 algorithm (the updated and improved version of SCORE) and the QRESEARCH risk estimator version 3 (QRISK3).ResultsOver 4790 years of follow-up, there were 34 CV events, resulting in a linearised rate of 7.10 per 1000 person-years (95% CI 4.92 to 9.92). The four CV risk scales showed strong correlations and all showed significant associations with CV events (p<0.001). SCORE, mSCORE EULAR 2015/2016 and QRISK3 effectively differentiated between low and high CV risk patients, although the cumulative rate of CV events observed over 7.5 years was lower than expected based on the frequency predicted by these risk scales. Additionally, model improvement was observed when combining QRISK3 with any other scale, particularly the combination of QRISK3 and SCORE2, which yielded the lowest Akaike information criterion (411.15) and Bayesian information criterion (420.10), making it the best predictive model.ConclusionsRisk chart algorithms are very useful for discriminating PsA at low and high CV risk. An integrated model featuring QRISK3 and SCORE2 yielded the optimal synergy of QRISK3’s discrimination ability and SCORE2’s calibration accuracy.
Early prehabilitation reduces admissions and time in hospital in patients with newly diagnosed lung cancer
Authors: Phillips Iain , Deans Maria , Walton Abi , Vallet Mahéva , Mencnarowksi Julie , McMillan Debbie , Peacock Catriona , Hall Peter , O’Brien Fiona , Stares Mark , Mackean Melanie , Plant Tracie , Grecian Robert , Allan Lindsey , Petrie Rebecca , Blues Duncan , Haddad Suraiya , Barrie Colin 
Published: April 2024

ObjectivesLung cancer is the leading cause of cancer death in the UK. Prehabilitation aims to maximise patient fitness and minimise the negative impact of anticancer treatment. What constitutes prehabilitation before non-surgical anticancer treatment is not well established. We present data from a pilot project of Early prehabilitation In lung Cancer.MethodsAll new patients with likely advanced lung cancer were offered prehabilitation at respiratory clinic, if fit for further investigation. Prehabilitation included assessment and appropriate intervention from a consultant in palliative medicine, registered dietitian and rehabilitation physiotherapist. Four objective endpoints were identified, namely admissions to hospital, time spent in the hospital, treatment rates and overall survival. Outcomes were to be compared with 178 prehab eligible historical controls diagnosed from 2019 to 2021.ResultsFrom July 2021 to June 2023, 65 patients underwent prehabilitation and 72% of patients underwent all 3 interventions. 54 patients had a stage 3 or 4 lung cancer. In the prehab group, fewer patients attended Accident and Emergency (31.5 vs 37.4 attendances per 100 patients) and fewer were admitted (51.9 vs 67.9) when compared with historical controls. Those receiving prehab spent a lot less time in the hospital (129.7 vs 543.5 days per 100 patients) with shorter admissions (2.5 vs 8 days). Systemic anticancer treatment rates increased in the short term but were broadly similar overall. Median survival was higher in the prehabilitation group (0.73 vs 0.41 years, p=0.046).ConclusionsEarly prehabilitation appears to reduce time spent in the hospital. It may improve survival. Further work is required to understand its full effect on treatment rates.
Angioembolization for splenic injuries: does it help? Retrospective evaluation of grade III–V splenic injuries at two level I trauma centers
Authors: Ahmad M Usman , Lee David , Tennakoon Lakshika , Chao Tiffany Erin , Spain David , Staudenmayer Kristan 
Published: April 2024

BackgroundSplenic angioembolization (SAE) has increased in utilization for blunt splenic injuries. We hypothesized lower SAE usage would not correlate with higher rates of additional intervention or mortality when choosing initial non-operative management (NOM) or surgery.Study designTrauma registries from two level I trauma centers from 2010 to 2020 were used to identify patients aged >18 years with grade III–V blunt splenic injuries. Results were compared with the National Trauma Data Bank (NTDB) for 2018 for level I and II centers. Additional intervention or failure was defined as any subsequent SAE or surgery. Mortality was defined as death during admission.ResultsThere were 266 vs 5943 patients who met inclusion/exclusion criteria at Stanford/Santa Clara Valley Medical Center (SCVMC) versus the NTDB. Initial intervention differed significantly between cohorts with the use of SAE (6% vs 17%, p=0.000). Failure differed significantly between cohorts (1.5% vs 6.5%, p=0.005). On multivariate analysis, failure in NOM was significantly associated with NTDB cohort status, age 65+ years, more than one comorbidity, mechanism of injury, grade V spleen injury, and Injury Severity Score (ISS) 25+. On multivariate analysis, failure in SAE was significantly associated with Shock Index >0.9 and 10+ units blood in 24 hours. On multivariate analysis, a higher risk of mortality was significantly associated with NTDB cohort status, age 65+ years, no private insurance, more than one comorbidity, mechanism of injury, ISS 25+, 10+ units blood in 24 hours, NOM, more than one hospital complications, anticoagulant use, other Abbreviated Injury Scale ≥3 abdominal injuries.ConclusionsCompared with national data, our cohort had less SAE, lower rates of additional intervention, and had lower risk-adjusted mortality. Shock Index >0.9, grade V splenic injuries, and increased transfusion requirements in the first 24 hours may signal a need for surgical intervention rather than SAE or NOM and may reduce mortality in appropriately selected patients.Level of evidenceLevel II/III.
Comparative study of quarkonium transport in hot QCD matter
Authors: Andronic A. , Gossiaux P. B. , Petreczky P. , Rapp R. , Strickland M. , Blaizot J. P. , Brambilla N. , Braun-Munzinger P. , Chen B. , Delorme S. , Du X. , Escobedo M. A. , Ferreiro E. G. , Jaiswal A. , Rothkopf A. , Song T. , Stachel J. , Vander Griend P. , Vogt R. , Wu B. , Zhao J. , Yao X. 
Published: April 2024

AbstractThis document summarizes the efforts of the EMMI Rapid Reaction Task Force on “Suppression and (re)generation of quarkonium in heavy-ion collisions at the LHC”, centered around their 2019 and 2022 meetings. It provides a review of existing experimental results and theoretical approaches, including lattice QCD calculations and semiclassical and quantum approaches for the dynamical evolution of quarkonia in the quark-gluon plasma as probed in high-energy heavy-ion collisions. The key ingredients of the transport models are itemized to facilitate comparisons of calculated quantities such as reaction rates, binding energies, and nuclear modification factors. A diagnostic assessment of the various results is attempted and coupled with an outlook for the future.
SIRT3 Negatively Regulates TFH-Cell Differentiation in Cancer
Authors: Hou Yueru , Cao Yejin , He Ying , Dong Lin , Zhao Longhao , Dong Yingjie , Niu Ruiying , Bi Yujing , Liu Guangwei 
Published: April 2024

Abstract
Follicular helper T (TFH) cells are essential for inducing germinal center (GC) reactions to mediate humoral adaptive immunity in tumors; however, the mechanisms underlying TFH-cell differentiation remain unclear. In this study, we found that the metabolism sensor sirtuin 3 (SIRT3) is critical for TFH-cell differentiation and GC formation during tumor development and viral infection. SIRT3 deficiency in CD4+ T cells intrinsically enhanced TFH-cell differentiation and GC reactions during tumor development and viral infection. Mechanistically, damaged oxidative phosphorylation (OXPHOS) compensatively triggered the NAD+–glycolysis pathway to provide a cellular energy supply, which was necessary for SIRT3 deficiency–induced TFH-cell differentiation. Blocking NAD+ synthesis–glycolysis signaling or recovering OXPHOS activities reversed the TFH-cell differentiation induced by SIRT3 deficiency. Moreover, the mTOR and hypoxia-inducible factor 1α (HIF1α) signaling axis was found to be responsible for TFH-cell differentiation induced by SIRT3 deficiency. HIF1α directly interacted with and regulated the activity of the transcription factor Bcl6. Thus, our findings identify a cellular energy compensatory mechanism, regulated by the mitochondrial sensor SIRT3, that triggers NAD+-dependent glycolysis during mitochondrial OXPHOS injuries and an mTOR–HIF1α–Bcl6 pathway to reprogram TFH-cell differentiation. These data have implications for future cancer immunotherapy research targeting SIRT3 in T cells.
Reformadores de classe média no Império brasileiro: a sociedade central de imigração
Authors: Hall Michael M. 
Published: April 2024

(1º parágrafo do artigo)
O termo “classe média” tem uma acepçäo bastante ambigua, e o seu uso tem sido täo controvertido no Brasil como em outros paises do mundo. Diversos estudiosos já notaram que as mudangas económicas que ocorreram no final do século passado, em particular a expansão da economia de exportação, criaram certas condições no Brasil que causaram o crescimento de camadas sociais intermediárias compostas nem de trabalhadores manuais, nem de membros da elite latifundiária. A essa nova classe média, embora seja uma categoria quase residual na estrutura social, tem-se, não obstante, dado um papel importante em quase todas as principais mudanças sociais e políticas que aconteceram nos últimos anos do Império, inclusive na abolição da escravatura e na queda da monarquia. No entretanto, até agora são poucas as pesquisas que resultaram em informações detalhadas e precisas sobre as características desses novos grupos; daí ser util examinar aqui um caso particular de reformadores de classe média — o da Sociedade Central de Imigração .
Arrhythmia Burden Among Adult Patients With Congenital Heart Disease: A Population‐Based Study
Authors: Schamroth Pravda Nili , Kalter‐Leibovici Ofra , Nir Amiram , Lorber Avraham , Dadashev Alexander , Hirsch Rafael , Benderly Michal ,   for the Israeli Congenital Heart Disease Research Group
Published: April 2024

Background
A significant percentage of patients with congenital heart disease surviving into adulthood will develop arrhythmias. These arrhythmias are associated with an increased risk of adverse events and death. We aimed to assess arrhythmia prevalence, risk factors, and associated health care usage in a large national cohort of patients with adult congenital heart disease.

Methods and Results
Adults with a documented diagnosis of congenital heart disease, insured by Clalit and Maccabi health services between January 2007 and December 2011, were included. We assessed the associations between arrhythmia and subsequent hospitalization rates and death with mixed negative binomial and Cox proportional hazard models, respectively. Among 11 653 patients with adult congenital heart disease (median age, 47 years [interquartile range, 31–62]), 8.7% had a tachyarrhythmia at baseline, 1.5% had a conduction disturbance, and 0.5% had both. Among those without a baseline arrhythmia, 9.2% developed tachyarrhythmias, 0.9% developed a conduction disturbance, and 0.3% developed both during the study period. Compared with no arrhythmia (reference group), arrhythmia in the previous 6 months was associated with a higher multivariable adjusted hospitalization rate, 1.33‐fold higher than the rate of the reference group (95% CI, 1.00–1.76) for ventricular arrhythmia, 1.27‐fold higher (95% CI, 1.17–1.38) for atrial arrhythmias, and 1.33‐fold higher (95% CI, 1.04–1.71) for atrioventricular block. Atrial tachyarrhythmias were associated with an adjusted mortality hazard ratio (HR) of 1.65 (95% CI, 1.44–2.94), and ventricular tachyarrhythmias with a >2‐fold increase in mortality risk (HR, 2.06 [95% CI, 1.44–2.94]).

Conclusions
Arrhythmias are significant comorbidities in the adult congenital heart disease population and have a significant impact on health care usage and survival.
The juvenile hormone analogue, pyriproxifen, alters protein and fat composition of Tenebrio molitor larvae
Authors: Hill V. , Lopez-Viso C. , Brameld J. , Salter A. , Parr T. 
Published: April 2024

Abstract
Maximising the yield of product from livestock is common practice in the agriculture industry and there is potential to extend this practice to the emerging insect industry, to produce high-quality, sustainable protein. Tenebrio molitor larvae, commonly called yellow mealworms, were fed for 28 days on wheat bran containing the juvenile hormone analogue, pyriproxifen at either 2 mg pyriproxifen/kg wheat bran (JH-PL) or 15 mg pyriproxifen/kg wheat bran (JH-PH). As expected, pupation was inhibited in both pyriproxifen treated groups and significant changes in nutritional composition were observed. Pyriproxifen treated mealworms had a higher protein content per 100 grams of dried material, while fat content was reduced 68% in JH-PH compared to control. These changes were associated with an increase in moisture content and reduction in energy content. The fatty acid profile of extracted fat also displayed significant alterations, with pyriproxifen treated mealworms showing an increase in proportions of saturated fatty acids, reduction in oleic acid but no effect on linoleic acid. The amino acid composition also exhibited a change in composition as a result of pyriproxifen treatment, including an increase in the essential amino acid, lysine, in JH-PH treated mealworms. This change in amino acid profile was associated with a change in the protein composition as observed on SDS-PAGE, with the appearance of a new band identified as the egg-yolk protein, vitellogenin, which has lipid-transporter activity. Hence, pyriproxifen treatment of mealworms has a repartitioning effect, resulting in an increase in the proportion of protein and a decrease in fat on a dry matter basis, demonstrating that mealworm nutrient composition can be manipulated to provide a higher value feed ingredient.