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Abstract: Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CART-19) represents a significant advance in the treatment of patients with relapsed or refractory CD19+ B-cell lymphomas. However, a significant portion of patients either relapse or fail to respond. Moreover, many patients have symptomatic disease, requiring bridging radiation therapy (RT) during the period of CAR T-cell manufacturing. To investigate the impact of 1 to 2 fractions of low-dose RT on CART-19 treatment response, we developed a mouse model using A20 lymphoma cells for CART-19 therapy. We found that low-dose fractionated RT had a positive effect on generating abscopal systemic antitumor responses beyond the irradiated site. The combination of RT with CART-19 therapy resulted in additive effects on tumor growth in irradiated masses. Notably, a significant additional increase in antitumor effect was observed in nonirradiated tumors. Mechanistically, our results validate activation of the cyclic guanosine adenosine synthetase/stimulator of interferon genes pathway, tumor-associated antigen crosspriming, and elicitation of epitope spreading. Collectively, our findings suggest that RT may serve as an optimal priming and bridging modality for CAR T-cell therapy, overcoming treatment resistance and improving clinical outcomes in patients with CD19+ hematologic malignancies., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Carbonaceous aerosols (CA), composed of black carbon (BC) and organic matter (OM), significantly impact the climate. Light absorption properties of CA, particularly of BC and brown carbon (BrC), are crucial due to their contribution to global and regional warming. We present the absorption properties of BC (b Abs,BC ) and BrC (b Abs,BrC ) inferred using Aethalometer data from 44 European sites covering different environments (traffic (TR), urban (UB), suburban (SUB), regional background (RB) and mountain (M)). Absorption coefficients showed a clear relationship with station setting decreasing as follows: TR > UB > SUB > RB > M, with exceptions. The contribution of b Abs,BrC to total absorption (b Abs ), i.e. %Abs BrC , was lower at traffic sites (11-20 %), exceeding 30 % at some SUB and RB sites. Low AAE values were observed at TR sites, due to the dominance of internal combustion emissions, and at some remote RB/M sites, likely due to the lack of proximity to BrC sources, insufficient secondary processes generating BrC or the effect of photobleaching during transport. Higher b Abs and AAE were observed in Central/Eastern Europe compared to Western/Northern Europe, due to higher coal and biomass burning emissions in the east. Seasonal analysis showed increased b Abs , b Abs,BC , b Abs,BrC in winter, with stronger %Abs BrC , leading to higher AAE. Diel cycles of b Abs,BC peaked during morning and evening rush hours, whereas b Abs,BrC , %Abs BrC , AAE, and AAE BrC peaked at night when emissions from household activities accumulated. Decade-long trends analyses demonstrated a decrease in b Abs , due to reduction of BC emissions, while b Abs,BrC and AAE increased, suggesting a shift in CA composition, with a relative increase in BrC over BC. This study provides a unique dataset to assess the BrC effects on climate and confirms that BrC can contribute significantly to UV-VIS radiation presenting highly variable absorption properties in Europe., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Griša Močnik, Asta Gregorič, Matic Ivančič and Martin Rigler were or are employed by the manufacturer of the instruments used in this study., (Copyright © 2024. Published by Elsevier Ltd.)

Associations between indoor air pollution from fine particulate matter (PM with aerodynamic diameter d p  < 2.5 μm) and human health are poorly understood. Here, we analyse the concentration-response curves for fine and ultrafine PM, the gene expression, and the methylation patterns in human bronchial epithelial cells (BEAS-2B) exposed at the air-liquid interface (ALI) within a classroom in downtown Rome. Our results document the upregulation of aryl hydrocarbon receptor (AhR) and genes associated with xenobiotic metabolism (CYP1A1 and CYP1B1) in response to single exposure of cells to fresh urban aerosols at low fine PM mass concentrations within the classroom. This is evidenced by concentrations of ultrafine particles (UFPs, dp < 0.1 μm), polycyclic aromatic hydrocarbons (PAH), and ratios of black carbon (BC) to organic aerosol (OA). Additionally, an interleukin 18 (IL-18) down-regulation was found during periods of high human occupancy. Despite the observed gene expression dysregulation, no changes were detected in the methylation levels of the promoter regions of these genes, indicating that the altered gene expression is not linked to changes in DNA methylation and suggesting the involvement of another epigenetic mechanism in the gene regulation. Gene expression changes at low exposure doses have been previously reported. Here, we add the possibility that lung epithelial cells, when singly exposed to real environmental concentrations of fine PM that translate into ultra-low doses of treatment, may undergo epigenetic alteration in the expression of genes related to xenobiotic metabolism. Our findings provide a perspective for future indoor air quality regulations. We underscore the potential role of indoor UFPs as carriers of toxic molecules with low-pressure weather conditions, when rainfall and strong winds may favour low levels of fine PM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 National reserch Council of Italy - CNR. Published by Elsevier Ltd.. All rights reserved.)

Background: Oxidative stress has emerged as a key contributor to numerous NCDs (non-communicable diseases), including cardiovascular diseases, cancer, and diabetes. This study aims to explore the potential of targeted interventions to mitigate oxidative stress as part of a primary prevention strategy., Methods: The study included 32 healthy participants (11 men, 21 women) aged 45-65 who completed both the initial and follow-up assessments of the Healthy Days Initiative, a community-based wellness program organized by the non-profit Associazione O.R.A. ETS. Through blood analysis, vital sign assessment, lifestyle questionnaires, and individualized recommendations, participants received guidance on improving their health and reducing disease risk. The initiative also offered the opportunity for participants to consume a flavonoid supplement containing quercitrin, rutin, and hesperidin, with the goal of reducing oxidative stress. Participants who opted for supplementation were instructed to take 1-2 tablets daily for two weeks. Data collected included demographic information, anthropometric measurements, vital signs, dietary and lifestyle habits, medical history, WHO-5 Well-Being Index scores, and blood parameters., Results: Significant reductions were observed in glucose levels (from 82 to 74.5 mg/dL), reactive oxygen metabolites (d-ROMs) (from 394.5 to 365.5 U.CARR), and systolic blood pressure (from 133 to 122 mmHg) after the two-week flavonoid intervention. Most participants (26/31) reported no side effects, and the majority (30/31) expressed a willingness to continue using a product combination of quercitrin, rutin, and hesperidin or a similar product long-term., Conclusions: While limited in scope and duration, the PREVES-FLAVON study contributes valuable insights to the growing body of evidence suggesting that flavonoid supplementation may play a significant role in reducing risk factors associated with NCDs in primary prevention settings. By targeting novel risk factors such as oxidative stress, this intervention holds promise for mitigating the global burden of NCDs and promoting healthy aging.

Particulate Matter (PM) is a complex and heterogeneous mixture of atmospheric particles recognized as a threat to human health. Oxidative Potential (OP) measurement is a promising and integrative method for estimating PM-induced health impacts since it is recognized as more closely associated with adverse health effects than ordinarily used PM mass concentrations. OP measurements could be introduced in the air quality monitoring, along with the parameters currently evaluated. PM deposition in the lungs induces oxidative stress, inflammation, and DNA damage. The study aimed to compare the OP measurements with toxicological effects on BEAS-2B and THP-1 cells of winter and summer PM 1 collected in the Po Valley (Italy) during 2021. PM 1 was extracted in deionized water by mechanical agitation and tested for OP and, in parallel, used to treat cells. Cytotoxicity, genotoxicity, oxidative stress, and inflammatory responses were assessed by MTT test, DCFH-DA assay, micronucleus, γ-H2AX, comet assay modified with endonucleases, ELISA, and Real-Time PCR. The evaluation of OP was performed by applying three different assays: dithiothreitol (OP DTT ), ascorbic acid (OP AA ), and 2',7'-dichlorofluorescein (OP DCFH ), in addition, the reducing potential was also analysed (RP DPPH ). Seasonal differences were detected in all the parameters investigated. The amount of DNA damage detected with the Comet assay and ROS formation highlights the presence of oxidative damage both in winter and in summer samples, while DNA damage (micronucleus) and genes regulation were mainly detected in winter samples. A positive correlation with OP DCFH (Spearman's analysis, p < 0.05) was detected for IL-8 secretion and γ-H2AX. These results provide a biological support to the implementation in air quality monitoring of OP measurements as a useful proxy to estimate PM-induced cellular toxicological responses. In addition, these results provide new insights for the assessment of the ability of secondary aerosol in the background atmosphere to induce oxidative stress and health effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: This retrospective study investigates the efficacy of cemiplimab, a monoclonal antibody targeting the PD-1 receptor, in treating squamous cell carcinoma (SCC) of the skin., Methods: The study analyzes data from 50 patients with SCC, focusing on various clinical parameters, including patient demographics, tumor characteristics, treatment history, disease status at the beginning of therapy, and survival outcomes., Results: Of the patients who received at least one cycle of cemiplimab, 42% showed a clinical response. Adverse reactions were generally low, with the safety profile deemed excellent. During a median follow-up of 9.6 months, 17 patients experienced progression or death. Among these, 15 patients had died at the time of the analysis. The median progression-free survival (PFS) for the entire cohort was approximately 20.8 months, while median overall survival (OS) was not reached. Univariate Cox regression analysis for PFS showed that tumors in the arms and legs were associated with higher progression risk, while age above 65 years was not statistically significant. Distant metastasis exhibited a trend towards improved PFS. In terms of OS, distant metastasis was a significant predictor of reduced survival, while age above 65 years was not statistically significant. In a multivariate model, only the absence of distant metastasis remained significant, with an adjusted odds ratio (OR) of 12.3 (95% confidence interval 1.3-112.1)., Conclusion: These findings provide valuable insights into the real-world effectiveness of cemiplimab in SCC management., (© 2023. The Author(s).)

A reliable determination of equivalent black carbon (eBC) mass concentrations derived from filter absorption photometers (FAPs) measurements depends on the appropriate quantification of the mass absorption cross-section (MAC) for converting the absorption coefficient (b abs ) to eBC. This study investigates the spatial-temporal variability of the MAC obtained from simultaneous elemental carbon (EC) and b abs measurements performed at 22 sites. We compared different methodologies for retrieving eBC integrating different options for calculating MAC including: locally derived, median value calculated from 22 sites, and site-specific rolling MAC. The eBC concentrations that underwent correction using these methods were identified as LeBC (local MAC), MeBC (median MAC), and ReBC (Rolling MAC) respectively. Pronounced differences (up to more than 50 %) were observed between eBC as directly provided by FAPs (NeBC; Nominal instrumental MAC) and ReBC due to the differences observed between the experimental and nominal MAC values. The median MAC was 7.8 ± 3.4 m 2 g -1 from 12 aethalometers at 880 nm, and 10.6 ± 4.7 m 2 g -1 from 10 MAAPs at 637 nm. The experimental MAC showed significant site and seasonal dependencies, with heterogeneous patterns between summer and winter in different regions. In addition, long-term trend analysis revealed statistically significant (s.s.) decreasing trends in EC. Interestingly, we showed that the corresponding corrected eBC trends are not independent of the way eBC is calculated due to the variability of MAC. NeBC and EC decreasing trends were consistent at sites with no significant trend in experimental MAC. Conversely, where MAC showed s.s. trend, the NeBC and EC trends were not consistent while ReBC concentration followed the same pattern as EC. These results underscore the importance of accounting for MAC variations when deriving eBC measurements from FAPs and emphasize the necessity of incorporating EC observations to constrain the uncertainty associated with eBC., Competing Interests: Declaration of competing interest Griša Močnik is employed by Haze Instruments d.o.o., the manufacturer of the aerosol instrumentation., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Parkin is an E3 ubiquitin ligase, which plays a key role in the development of Parkinson disease. Parkin defects also occur in numerous cancers, and a growing body of evidence indicates that Parkin functions as a tumor suppressor that impedes a number of cellular processes involved in tumorigenesis. Here, we generated murine and human models that closely mimic the advanced-stage tumors where Parkin deficiencies are found to provide deeper insights into the tumor suppressive functions of Parkin. Loss of Parkin expression led to aggressive tumor growth, which was associated with poor tumor antigen presentation and limited antitumor CD8+ T-cell infiltration and activation. The effect of Parkin deficiency on tumor growth was lost following depletion of CD8+ T cells. In line with previous findings, Parkin deficiency was linked with mitochondria-associated metabolic stress, PTEN degradation, and enhanced Akt activation. Increased Akt signaling led to dysregulation of antigen presentation, and treatment with the Akt inhibitor MK2206-2HCl restored antigen presentation in Parkin-deficient tumors. Analysis of data from patients with clear cell renal cell carcinoma indicated that Parkin expression was downregulated in tumors and that low expression correlated with reduced overall survival. Furthermore, low Parkin expression correlated with reduced patient response to immunotherapy. Overall, these results identify a role for Parkin deficiency in promoting tumor immune evasion that may explain the poor prognosis associated with loss of Parkin across multiple types of cancer., Significance: Parkin prevents immune evasion by regulating tumor antigen processing and presentation through the PTEN/Akt network, which has important implications for immunotherapy treatments in patients with Parkin-deficient tumors., (©2023 The Authors; Published by the American Association for Cancer Research.)

Exposures to fine particulate matter (PM[Formula: see text]) have been associated with health impacts, but the understanding of the PM[Formula: see text] concentration-response (PM[Formula: see text]-CR) relationships, especially at low PM[Formula: see text], remains incomplete. Here, we present novel data using a methodology to mimic lung exposure to ambient air (2[Formula: see text] 60 [Formula: see text]g m[Formula: see text]), with minimized sampling artifacts for nanoparticles. A reference model (Air Liquid Interface cultures of human bronchial epithelial cells, BEAS-2B) was used for aerosol exposure. Non-linearities observed in PM[Formula: see text]-CR curves are interpreted as a result of the interplay between the aerosol total oxidative potential (OP[Formula: see text]) and its distribution across particle size (d[Formula: see text]). A d[Formula: see text]-dependent condensation sink (CS) is assessed together with the distribution with d[Formula: see text] of reactive species . Urban ambient aerosol high in OP[Formula: see text], as indicated by the DTT assay, with (possibly copper-containing) nanoparticles, shows higher pro-inflammatory and oxidative responses, this occurring at lower PM[Formula: see text] concentrations (< 5 [Formula: see text]g m[Formula: see text]). Among the implications of this work, there are recommendations for global efforts to go toward the refinement of actual air quality standards with metrics considering the distribution of OP[Formula: see text] with d[Formula: see text] also at relatively low PM[Formula: see text]., (© 2023. The Author(s).)

This study analyzed the variability of equivalent black carbon (eBC) mass concentrations and their sources in urban Europe to provide insights into the use of eBC as an advanced air quality (AQ) parameter for AQ standards. This study compiled eBC mass concentration datasets covering the period between 2006 and 2022 from 50 measurement stations, including 23 urban background (UB), 18 traffic (TR), 7 suburban (SUB), and 2 regional background (RB) sites. The results highlighted the need for the harmonization of eBC measurements to allow for direct comparisons between eBC mass concentrations measured across urban Europe. The eBC mass concentrations exhibited a decreasing trend as follows: TR > UB > SUB > RB. Furthermore, a clear decreasing trend in eBC concentrations was observed in the UB sites moving from Southern to Northern Europe. The eBC mass concentrations exhibited significant spatiotemporal heterogeneity, including marked differences in eBC mass concentration and variable contributions of pollution sources to bulk eBC between different cities. Seasonal patterns in eBC concentrations were also evident, with higher winter concentrations observed in a large proportion of cities, especially at UB and SUB sites. The contribution of eBC from fossil fuel combustion, mostly traffic (eBC T ) was higher than that of residential and commercial sources (eBC RC ) in all European sites studied. Nevertheless, eBC RC still had a substantial contribution to total eBC mass concentrations at a majority of the sites. eBC trend analysis revealed decreasing trends for eBC T over the last decade, while eBC RC remained relatively constant or even increased slightly in some cities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Several studies have shown the influence of commensal microbes on T cell function, specifically in the setting of checkpoint immunotherapy for cancer. In this study, we investigated how vancomycin-induced gut microbiota dysbiosis affects chimeric antigen receptor (CAR) T immunotherapy using multiple preclinical models as well as clinical correlates. In two murine tumor models, hematopoietic CD19 + -A20 lymphoma and CD19 + -B16 melanoma, mice receiving vancomycin in combination with CD19-directed CAR T cell (CART-19) therapy displayed increased tumor control and tumor-associated antigens (TAAs) cross-presentation compared with CART-19 alone. Fecal microbiota transplant from human healthy donors to pre-conditioned mice recapitulated the results obtained in naive gut microbiota mice. Last, B cell acute lymphoblastic leukemia patients treated with CART-19 and exposed to oral vancomycin showed higher CART-19 peak expansion compared with unexposed patients. These results substantiate the role of the gut microbiota on CAR T cell therapy and suggest that modulation of the gut microbiota using vancomycin may improve outcomes after CAR T cell therapy across tumor types., Competing Interests: Declaration of interests M.R.: BMS, BAYER, GSK, consultancy; Novartis, patents and royalties; AbClon, consultancy, research funding; Tmunity, patents and royalties; viTToria Biotherapeutics, research funding. N.F.: Sana Biotechnology, consultancy; Novartis, research funding; Kite Pharma, consultancy; Syndax Pharmaceuticals, consultancy. C.H.J.: Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, and Ziopharm, current equity holder in publicly traded company; AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm, consultancy; Novartis, patents and royalties. D.L.P.: American Society for Transplantation and Cellular Therapy, honoraria; ASH and DeCart, membership on the Board of Directors or advisory committee; Genentech, current employment, current equity holder in publicly traded company; Incyte and Janssen, Kite/Gilead, and National Marrow Donor Program, membership on an entity’s board of directors or advisory committee; Novartis, membership on an entity’s board of directors or advisory committee, patents and royalties, and research funding; Unity, patents and royalties; and Wiley and Sons Publishing, honoraria. S.J.S.: TG Therapeutics, research funding; Incyte, research funding; Adaptive Biotechnologies, research funding; Pharmacyclics, research funding; Merck, research funding; Genentech/Roche, consultancy, research funding; Tessa Therapeutics, consultancy; Loxo Oncology, consultancy; Juno Therapeutics, consultancy, research funding; BeiGene, consultancy; Alimera Sciences, consultancy; Acerta Pharma/AstraZeneca, consultancy; Novartis, consultancy, honoraria, patents and royalties, research funding; AbbVie, consultancy, research funding; Nordic Nanovector, consultancy; Celgene, consultancy, honoraria, research funding., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Approximately a third of cancer-related deaths are attributable to modifiable factors., Methods: As a pilot experience, a cross-sectional survey was conducted in 8,000 citizens residing in four different municipalities of the Salerno province (Sarno, Pagani, San Valentino Torio, and San Marzano sul Sarno) to investigate key lifestyle and dietary habits., Results: A total of 703 of participants (8.7%) reported a history of malignancy. Alarmingly, 30.5% declared to be a current smoker, while 78.8% did not report any kind of physical activity. Encouragingly, 64.5% declared to be abstemious, and 83.0% declared to consume fruit and vegetables every day, while 4.7% and 31.9% declared not to consume meat and fried food, respectively, at any time. Never-consumers of fruit and vegetables had higher odds of having a history of colorectal cancer (OR = 5.01; 95% CI = 1.46-17.15; p = 0.01)., Conclusions: The PREVES study has served to prove the validity of an operational model allowing to integrate hospital and territorial healthcare services, which we expect to be applied at a larger scale. Key information regarding dietary and lifestyle habits of the investigated population was obtained. Larger studies conducted using more accurate approaches to investigate diet, such as 24-h recalls and food frequency questionnaires, are warranted., (© 2023 S. Karger AG, Basel.)

Introduction: Cancer aggravates COVID-19 prognosis. Nosocomial transmission of SARS-CoV-2 is particularly frequent in cancer patients, who need to attend hospitals regularly. Since March 2020, all cancer patients having access to the Oncology Unit at the "Andrea Tortora" Hospital (Pagani, Salerno - referred to as "the Hospital") as inpatients or outpatients receiving intravenous therapy have been screened for SARS-CoV-2 using RT-PCR nasal swab. The ongoing COICA (COVID-19 infection in cancer patients) study is an ambispective, multicenter, observational study designed to assess the prognosis of SARS-CoV-2 infection in cancer patients. The aim of the study presented here was to explore potential differences in COVID-19-related outcomes among screening-detected versus nonscreening-detected SARS-CoV-2-infected patients. Methods: The COICA study enrolled cancer patients who had received any anticancer systemic therapy within 3 months since the day they tested positive for SARS-CoV-2 on RT-PCR. The target accrual is 128 patients, and the study was approved by the competent Ethics Committee. Only the subgroup of patients enrolled at the Hospital was considered in this unplanned interim analysis. Logistic regression analysis was used to evaluate the association of screening-based versus nonscreening-based diagnosis. Results: Since March 15, 2020, until August 15, 2021, a total of 931 outpatients and 230 inpatients were repeatedly screened for SARS-CoV-2 using RT-PCR nasal swab at the Hospital. Among these, 71 asymptomatic patients were positive on routine screening and 5 patients were positive for SARS-CoV-2 outside the institutional screening. Seven patients died because of COVID-19. At univariate analysis, nonscreening- versus screening-detected SARS-CoV-2 infection was associated with significantly higher odds of O 2 therapy (OR = 16.2; 95% CI = 2.2-117.1; p = 0.006), hospital admission (OR = 31.5; 95% CI = 3.1-317.8; p = 0.003), admission to ICU (OR = 23.0; 95% CI = 2.4-223.8; p = 0.007), and death (OR = 8.8; 95% CI = 1.2-65.5; p = 0.034). Conclusion: Routine screening with RT-PCR may represent a feasible and effective strategy in reducing viral circulation and possibly COVID-19 mortality in patients with active cancer having repeated access to hospital facilities., (© 2021 S. Karger AG, Basel.)