Redox-activity and in vitro effects of regional atmospheric aerosol pollution: Seasonal differences and correlation between oxidative potential and in vitro toxicity of PM1.

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 PM1 collected in the Po Valley (Italy) during 2021. PM1 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 (OPDTT), ascorbic acid (OPAA), and 2',7'-dichlorofluorescein (OPDCFH), in addition, the reducing potential was also analysed (RPDPPH). 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 OPDCFH (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.

Modulation of the gut microbiota engages antigen cross-presentation to enhance antitumor effects of CAR T cell immunotherapy.

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.

Direct observation of aqueous secondary organic aerosol from biomass-burning emissions.

The mechanisms leading to the formation of secondary organic aerosol (SOA) are an important subject of ongoing research for both air quality and climate. Recent laboratory experiments suggest that reactions taking place in the atmospheric liquid phase represent a potentially significant source of SOA mass. Here, we report direct ambient observations of SOA mass formation from processing of biomass-burning emissions in the aqueous phase. Aqueous SOA (aqSOA) formation is observed both in fog water and in wet aerosol. The aqSOA from biomass burning contributes to the "brown" carbon (BrC) budget and exhibits light absorption wavelength dependence close to the upper bound of the values observed in laboratory experiments for fresh and processed biomass-burning emissions. We estimate that the aqSOA from residential wood combustion can account for up to 0.1-0.5 Tg of organic aerosol (OA) per y in Europe, equivalent to 4-20% of the total OA emissions. Our findings highlight the importance of aqSOA from anthropogenic emissions on air quality and climate.

Evidence of aerosols as a media for rapid daytime HONO production over China.

Current knowledge of daytime HONO sources remains incomplete. A large missing daytime HONO source has been found in many places around the world, including polluted regions in China. Conventional understanding and recent studies attributed this missing source mainly to ground surface processes or gas-phase chemistry, while assuming aerosols to be an insignificant media for HONO production. We analyze in situ observations of HONO and its precursors at an urban site in Beijing, China, and report an apparent dependence of the missing HONO source strength on aerosol surface area and solar ultraviolet radiation. Based on extensive correlation analysis and process-modeling, we propose that the rapid daytime HONO production in Beijing can be explained by enhanced hydrolytic disproportionation of NO2 on aqueous aerosol surfaces due to catalysis by dicarboxylic acid anions. The combination of high abundance of NO2, aromatic hydrocarbons, and aerosols over broad regions in China likely leads to elevated HONO levels, rapid OH production, and enhanced oxidizing capacity on a regional basis. Our findings call for attention to aerosols as a media for daytime heterogeneous HONO production in polluted regions like Beijing. This study also highlights the complex and uncertain heterogeneous chemistry in China, which merits future efforts of reconciling regional modeling and laboratory experiments, in order to understand and mitigate the regional particulate and O3 pollutions over China.

[Air pollution in an urban area nearby the Rome-Ciampino city airport]. / Inquinamento atmosferico in un'area urbana limitrofa all'aeroporto di Roma-Ciampino.

OBJECTIVES: to assess air pollution spatial and temporal variability in the urban area nearby the Ciampino International Airport (Rome) and to investigate the airport-related emissions contribute. DESIGN AND SETTING: the study domain was a 64 km2 area around the airport. Two fifteen-day monitoring campaigns (late spring, winter) were carried out. Results were evaluated using several runs outputs of an airport-related sources Lagrangian particle model and a photochemical model (the Flexible Air quality Regional Model, FARM). MAIN OUTCOME MEASURES: both standard and high time resolution air pollutant concentrations measurements: CO, NO, NO2, C6H6, mass and number concentration of several PM fractions. 46 fixed points (spread over the study area) of NO2 and volatile organic compounds concentrations (fifteen days averages); deterministic models outputs. RESULTS: standard time resolution measurements, as well as model outputs, showed the airport contribution to air pollution levels being little compared to the main source in the area (i.e. vehicular traffic). However, using high time resolution measurements, peaks of particles associated with aircraft takeoff (total number concentration and soot mass concentration), and landing (coarse mass concentration) were observed, when the site measurement was downwind to the runway. CONCLUSIONS: the frequently observed transient spikes associated with aircraft movements could lead to a not negligible contribute to ultrafine, soot and coarse particles exposure of people living around the airport. Such contribute and its spatial and temporal variability should be investigated when assessing the airports air quality impact.

Local Radiation Enhances Systemic CAR T Cell Efficacy by Augmenting Antigen Cross-Presentation and T-cell Infiltration.

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-positive 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 cells manufacturing. To investigate the impact of 1-2 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 non-irradiated tumors. Mechanistically, our results validate activation of the cGAS/STING pathway, tumor-associated antigen (TAA) cross-priming, 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-positive hematologic malignancies.

Associations between fine particulate matter, gene expression, and promoter methylation in human bronchial epithelial cells exposed within a classroom under air-liquid interface.

Associations between indoor air pollution from fine particulate matter (PM with aerodynamic diameter dp < 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.

Recommendations for reporting equivalent black carbon (eBC) mass concentrations based on long-term pan-European in-situ observations.

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 (babs) to eBC. This study investigates the spatial-temporal variability of the MAC obtained from simultaneous elemental carbon (EC) and babs 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 m2 g-1 from 12 aethalometers at 880 nm, and 10.6 ± 4.7 m2 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.

Exposure to urban nanoparticles at low PM[Formula: see text] concentrations as a source of oxidative stress and inflammation.

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].

Parkin Deficiency Suppresses Antigen Presentation to Promote Tumor Immune Evasion and Immunotherapy Resistance.

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.

The variability of mass concentrations and source apportionment analysis of equivalent black carbon across urban Europe.

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 (eBCT) was higher than that of residential and commercial sources (eBCRC) in all European sites studied. Nevertheless, eBCRC still had a substantial contribution to total eBC mass concentrations at a majority of the sites. eBC trend analysis revealed decreasing trends for eBCT over the last decade, while eBCRC remained relatively constant or even increased slightly in some cities.

Combination of vasculature targeting, hypofractionated radiotherapy, and immune checkpoint inhibitor elicits potent antitumor immune response and blocks tumor progression.

BACKGROUND: Tumor endothelial marker 1 (TEM1) is a protein expressed in the tumor-associated endothelium and/or stroma of various types of cancer. We previously demonstrated that immunization with a plasmid-DNA vaccine targeting TEM1 reduced tumor progression in three murine cancer models. Radiation therapy (RT) is an established cancer modality used in more than 50% of patients with solid tumors. RT can induce tumor-associated vasculature injury, triggering immunogenic cell death and inhibition of the irradiated tumor and distant non-irradiated tumor growth (abscopal effect). Combination treatment of RT with TEM1 immunotherapy may complement and augment established immune checkpoint blockade. METHODS: Mice bearing bilateral subcutaneous CT26 colorectal or TC1 lung tumors were treated with a novel heterologous TEM1-based vaccine, in combination with RT, and anti-programmed death-ligand 1 (PD-L1) antibody or combinations of these therapies, tumor growth of irradiated and abscopal tumors was subsequently assessed. Analysis of tumor blood perfusion was evaluated by CD31 staining and Doppler ultrasound imaging. Immunophenotyping of peripheral and tumor-infiltrating immune cells as well as functional analysis was analyzed by flow cytometry, ELISpot assay and adoptive cell transfer (ACT) experiments. RESULTS: We demonstrate that addition of RT to heterologous TEM1 vaccination reduces progression of CT26 and TC1 irradiated and abscopal distant tumors as compared with either single treatment. Mechanistically, RT increased major histocompatibility complex class I molecule (MHCI) expression on endothelial cells and improved immune recognition of the endothelium by anti-TEM1 T cells with subsequent severe vascular damage as measured by reduced microvascular density and tumor blood perfusion. Heterologous TEM1 vaccine and RT combination therapy boosted tumor-associated antigen (TAA) cross-priming (ie, anti-gp70) and augmented programmed cell death protein 1 (PD-1)/PD-L1 signaling within CT26 tumor. Blocking the PD-1/PD-L1 axis in combination with dual therapy further increased the antitumor effect and gp70-specific immune responses. ACT experiments show that anti-gp70 T cells are required for the antitumor effects of the combination therapy. CONCLUSION: Our findings describe novel cooperative mechanisms between heterologous TEM1 vaccination and RT, highlighting the pivotal role that TAA cross-priming plays for an effective antitumor strategy. Furthermore, we provide rationale for using heterologous TEM1 vaccination and RT as an add-on to immune checkpoint blockade as triple combination therapy into early-phase clinical trials.

Development of Exhaustion and Acquisition of Regulatory Function by Infiltrating CD8+CD28- T Lymphocytes Dictate Clinical Outcome in Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) has a poor clinical outcome despite the presence of a rich CD8+ T cell tumor infiltrate in the majority of patients. This may be due to alterations of tumor infiltrating CD8+ T cells. Here, we performed a characterization of HNSCC infiltrating CD8+ T cells in a cohort of 30 patients. The results showed that differential intratumoral frequency of CD8+CD28+ T cells, CD8+CD28- T cells, and CD8+CD28-CD127-CD39+ Treg distinguished between HNSCC patients who did or did not respond to treatment. Moreover, high PD1 expression identified a CD8+CD28- T cell subpopulation, phenotypically/functionally corresponding to CD8+CD28-CD127-CD39+ Treg, which showed a high expression of markers of exhaustion. This observation suggests that development of exhaustion and acquisition of regulatory properties may configure the late differentiation stage for intratumoral effector T cells, a phenomenon we define as effector-to-regulatory T cell transition.

Evidence of reactive aromatics as a major source of peroxy acetyl nitrate over China.

We analyze the observations of near-surface peroxy acetyl nitrate (PAN) and its precursors in Beijing, China in August of 2007. The levels of PAN are remarkably high (up to 14 ppbv), surpassing those measured over other urban regions in recent years. Analyses employing a 1-D version of a chemical transport model (Regional chEmical and trAnsport Model, REAM) indicate that aromatic non-methane hydrocarbons (NMHCs) are the dominant (55-75%) PAN source. The major oxidation product of aromatics that produces acetyl peroxy radicals is methylglyoxal (MGLY). PAN and O(3) in the observations are correlated at daytime; aromatic NMHCs appear to play an important role in O(3) photochemistry. Previous NMHC measurements indicate the presence of reactive aromatics at high levels over broad polluted regions of China. Aromatics are often ignored in global and (to a lesser degree) regional 3D photochemical transport models; their emissions over China as well as photochemistry are quite uncertain. Our findings suggest that critical assessments of aromatics emissions and chemistry (such as the yields of MGLY) are necessary to understand and assess ozone photochemistry and regional pollution export in China.

Ambient BTX measurements in Suzhou, China.

Within the Sino-Italian environmental protection cooperation framework established in 2002, a comprehensive air quality monitoring network has been developed in urban Suzhou, a medium-sized Chinese city, in compliance with European standards (Directive 96/62/EC). This paper is among the first attempts to present a systematic and scientific analysis of benzene, toluene, and xylenes (BTX) pollution in China. It presents our analysis of BTX space-related and time-related measurement results. Background BTX concentrations were investigated by passive sampler Analyst(R) in 2003. We depicted the spatial distribution of average BTX concentrations collected from three 15-day campaigns on isoconcentration maps. This is the first time such detailed BTX concentration maps have been developed in China in a city scale. Continuous measurement of BTX by automatic gas chromatography was carried out at two fixed monitoring stations, one in an urban residential zone and one in a heavy traffic zone, from April to December 2005. The results show similar seasonal trends at both sites, the similarities reaching their greatest level in December and their lowest level in August. The average daily profile of BTX shows greater fluctuation in spring and winter with clear morning and evening peaks. Daily average benzene, toluene, and m,p-xylenes concentrations for the study period were 2.64, 11.52, and 3.52 microg m(-3), respectively. The benzene/toluene ratio we found was lower in Suzhou than those published in studies of other worldwide cities, which indicates serious levels of toluene pollution from local stationary sources. The similarities in seasonal trend and spatial distribution in these manual and automatic measurement results were compared with each other, though the concentration values differed.

Preventing Airborne Transmission of SARS-CoV-2 in Hospitals and Nursing Homes.

The first case of the coronavirus disease 2019 (COVID-19), the novel contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was reported in Wuhan, China in December 2019 [...].

Size resolved aerosol respiratory doses in a Mediterranean urban area: From PM10 to ultrafine particles.

In the framework of the 2017 "carbonaceous aerosol in Rome and Environs" (CARE) experiment, particle number size distributions have been continuously measured on February 2017 in downtown Rome. These data have been used to estimate, through MPPD model, size and time resolved particle mass, surface area and number doses deposited into the respiratory system. Dosimetry estimates are presented for PM10, PM2.5, PM1 and Ultrafine Particles (UFPs), in relation to the aerosol sources peculiar to the Mediterranean basin and to the atmospheric conditions. Particular emphasis is focused on UFPs and their fraction deposited on the olfactory bulb, in view of their possible translocation to the brain. The site of PM10 deposition within the respiratory system considerably changes, depending on the aerosol sources and then on its different size distributions. On making associations between health endpoints and aerosol mass concentrations, the relevant coarse and fine fractions would be more properly adopted, because they have different sources, different capability of penetrating deep into the respiratory system and different toxicological implications. The separation between them should be set at 1 µm, rather than at 2.5 µm, because the fine fraction is considerably less affected by the contribution of the natural sources. Mass dose is a suitable metric to describe coarse aerosol events but gives a poor representation of combustion aerosol. This fraction of particles, made of UFPs and of accumulation mode particles (mainly with size below 0.2 µm), is of high health relevance. It elicited the highest oxidative activity in the CARE experiment and is properly described by the particle surface area and by the number metrics. Such metrics are even more relevant for the UFP doses deposited on the olfactory bulb, in consideration of the role recognized to oxidative stress in the progression of neurodegenerative diseases. Such metrics would be more appropriate, rather than PMx mass concentrations, to correlate neurodegenerative pathologies with aerosol pollution.

Levels of Urinary Biomarkers of Oxidatively Generated Damage to DNA and RNA in Different Groups of Workers Compared to General Population.

(1) Background: The products of guanine oxidation in DNA and RNA excreted in urine are 8-oxo-7,8-dihydroguanine (8-oxoGua), 8-oxo-7,8-dihydroguanosine (8-oxoGuo), and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo). Despite intra and inter-individual variability, it is possible to identify situations that significantly increase the levels of these compounds when comparing urinary concentrations of some workers to those of the general population. (2) Methods: urines from gasoline pump attendants (58 from Saudi Arabia and 102 from Italy), 24 workers of a fiberglass reinforced plastics plant, 17 painters and 6 divers were analyzed by HPLC/MS-MS. To test the individual variability, two subjects provided daily samples for one month, and 132 urine samples from the general population were analyzed. (3) Results: We summarized the results for each biomarker, and found the following were statistically higher than in the general population: 8-oxoGua in fiberglass and Italian gasoline workers; 8-oxodGuo in fiberglass and both Saudi Arabian and Italian gasoline workers; 8-oxoGuo in fiberglass workers, both Saudi Arabian and Italian gasoline workers, and painters after the working shift. (4) Conclusions: these results confirm that both 8-oxodGuo and 8-oxoGuo are valuable biomarkers for occupational exposures to dangerous chemicals and seem to suggest that 8-oxoGuo, related to RNA oxidation, is a suitable biomarker to evaluate short term, reversible effects of occupational exposures even within the health-based limit values.

Targeting mitochondria in cancer: current concepts and immunotherapy approaches.

An essential advantage during eukaryotic cell evolution was the acquisition of a network of mitochondria as a source of energy for cell metabolism and contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation including mitochondrial biogenesis, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. In cancer, the metabolism of cells is reprogrammed for energy generation from oxidative phosphorylation to aerobic glycolysis and impacts cancer mitochondrial function. Furthermore cancer cells can also modulate energy metabolism within the cancer microenvironment including immune cells and induce "metabolic anergy" of antitumor immune response. Classical approaches targeting the mitochondria of cancer cells usually aim at inducing changing energy metabolism or directly affecting functions of mitochondrial antiapoptotic proteins but most of such approaches miss the required specificity of action and carry important side effects. Several types of cancers harbor somatic mitochondrial DNA mutations and specific immune response to mutated mitochondrial proteins has been observed. An attractive alternative way to target the mitochondria in cancer cells is the induction of an adaptive immune response against mutated mitochondrial proteins. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial DNA mutations or Tumor Associated Mitochondria Antigens using the immune system.

Sphingosine Kinases promote IL-17 expression in human T lymphocytes.

Sphingosine 1-phosphate (S1P) has a role in many cellular processes. S1P is involved in cell growth and apoptosis, regulation of cell trafficking, production of cytokines and chemokines. The kinases SphK1 and SphK2 (SphKs) phosphorilate Sphingosine (Sph) to S1P and several phosphatases revert S1P to sphingosine, thus assuring a balanced pool that can be depleted by a Sphingosine lyase in hexadecenal compounds and aldehydes. There are evidences that SphK1 and 2 may per se control cellular processes. Here, we report that Sph kinases regulate IL-17 expression in human T cells. SphKs inhibition impairs the production of IL-17, while their overexpression up-regulates expression of the cytokine through acetylation of IL-17 promoter. SphKs were up-regulated also in PBMCs of patients affected by IL-17 related diseases. Thus, S1P/S1P kinases axis is a mechanism likely to promote IL-17 expression in human T cells, representing a possible therapeutic target in human inflammatory diseases.