A Three-Year Analysis of Toxic Benzene Levels and Associated Impact in Ploieşti City, Romania

This study examines the levels of benzene and the potential health impact during three years of continuous monitoring (2019–2021), including the COVID-lockdown period from 2020 in a city that is an important Romanian center for petroleum refining and associated product manufacturing. The dataset contains benzene, toluene, NOx, PM10 concentrations, and meteorological factors monitored by six automatic stations from the national network of which four are in the city and two outside. Special attention was given to the benzene dynamics to establish patterns related to the health impact and leukemia. An assessment of the exposure was performed using EPA’s ExpoFIRST v. 2.0 for computing the inhalation Average Daily Dose (ADD) and Lifetime Average Daily Dose (LADD). The health impact was estimated based on several indicators such as lifetime cancer risk (LCR), Hazard Quotient (HQ), Disability-Adjusted Life Years (DALY), and Environmental burden of disease (EBD). Overall, the annual average of all stations was almost similar between years i.e., 3.46 in 2019, 3.41 in 2020, and 3.63 µg/m3 in 2021, respectively. The average of all stations during the lockdown period was 2.67 µg/m3, which was lower than the multiannual average of the 2019–2021 period, i.e., 3.5 µg/m3. Significant correlations were present between benzene and other pollutants such as NOx (r = 0.57), PM10 fraction (r = 0.70), and toluene (r = 0.69), and benzene and temperature (r = −0.46), humidity (r = 0.28), and wind speed (r = −0.34). Regarding the ADD, in all scenarios, the most affected age categories are small children, despite a lower outdoor exposure time. From birth to −4, 5.6 × 10−4, and 4.04 × 104 mg/kg-day, and 3.95 × 10−4, 10.6 × 10−4, and 6.76 × 10−4 mg/kg-day for the LADD, respectively. The Integrated Lifetime Cancer Risk (ILTCR) values were 14.1 × 10−5 in winter, 9.04 × 10−5 in spring, 8.74 × 10−5 in summer, and 10.6 × 10−4 in autumn. The ILTCR annual averages were 1.08 × 10−4 (2019), 1.07 × 10−4 (2020), 1.04 × 10−4 (2021), and 1.06 × 10−4 for the entire period. The resulting ILTCR values point out very risky conditions, with the annual averages reaching the definite cancer risk category. The corresponding burden based on the DALY’s loss due to leukemia in Ploieşti was estimated at 0.291 (2 μg/m3 benzene), 0.509 (3.5 μg/m3 benzene), 0.582 (4 μg/m3 benzene), and 0.873 DALYs per 100,000 inhabitants (6 μg/m3 benzene), respectively. The current study provides useful insights for a better understanding of the exposure levels to benzene and associated health impact in Ploieşti despite the limitations determined by the data hiatus and incomplete or missing information regarding the health impact

Mesenchymal stromal cells protect mantle cell lymphoma cells from sponta- neous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor κB pathways

The online version of this article has a Supplementary Appendix. Background There is increasing evidence that stromal cell interactions are required for the survival and drug resistance of several types of B-cell malignancies. There is relatively little information regarding the role of the bone marrow/lymphoid microenvironment in the pathogenesis of mantle cell lymphoma. In this study we investigated the interaction of primary mantle cell lymphoma cells with stromal cells in an ex vivo co-culture system. Design and Methods The murine stromal cell line MS-5 and human bone marrow mesenchymal stromal cells were each co-cultured with primary mantle cell lymphoma cells for up to 7 months. Mantle cell lymphoma cultures alone or combined with human stromal cells were analyzed for cell number, cell migration, nuclear factor-κB activation and drug resistance. Results Co-culture of mantle cell lymphoma cells and human stromal cells results in the survival and proliferation of primary mantle cell lymphoma cells for at least 7 months compared to mantle cell lymphoma cells cultured alone. Mantle cell lymphoma-human stromal cell interactions resulted in activation of the B-cell activating factor/nuclear factor-κB signaling axis resulting in reduced apoptosis, increased mantle cell lymphoma migration and increased drug resistance. Conclusions Direct mantle cell lymphoma-human stromal cell interactions support long-term expansion and increase the drug-resistance of primary mantle cell lymphoma cells. This is due in part to activation of the canonical and non-canonical nuclear factor κB pathways. We also demonstrated the ability of B-cell activating factor to augment CXCL12-and CXCL13-induced cell migration. Collectively, these findings demonstrate that human stromal cell-mantle cell lymphoma interactions play a pivotal role in the pathogenesis of mantle cell lymphoma and that analysis of mantle cell lymphoma-human stromal cell interactions may help in the identification of novel targets for therapeutic use. Key words: mantle cell lymphoma, mesenchymal cell, drug resistance, BAFF, NF-κB. Haematologica 2012;97(8):1255-1263. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Medina DJ, Goodell L, Glod J, Gélinas C, Rabson AB, and Strair RK. Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor κB pathways. Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor κB pathways ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o

Monocytes form a vascular barrier and participate in vessel repair after brain injury

Subpopulations of bone marrow-derived cells can be induced to assume a number of endothelial properties in vitro. However, their ability to form a functional vascular barrier has not been demonstrated. We report that human CD14+ peripheral blood monocytes cultured under angiogenic conditions develop a number of phenotypic and functional properties similar to brain microvascular endothelial cells. These cells express the tight junction proteins zonula occludens 1 (ZO-1) and occludin and form a barrier with a transcellular electrical resistance (TCER) greater than 100 ohm cm2 and low permeability to 4 kDa and 20 kDa dextrans. The TCER of the cellular barrier is decreased by bradykinin and histamine. We also demonstrate that these cells associate with repairing vasculature in areas of brain and skin injury. Our data suggest that CD14+ peripheral blood monocytes participate in the repair of the vascular barrier after brain injury

Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma.

BackgroundGene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells.MethodsFour cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay.ResultsResponses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients.ConclusionsOur studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy.Trial registrationClinicalTrials.gov, NCT01343043 , Registered 27 April 2011

Do we need a threshold conception of competence?

On the standard view we assess a person’s competence by considering her relevant abilities without reference to the actual decision she is about to make. If she is deemed to satisfy certain threshold conditions of competence, it is still an open question whether her decision could ever be overruled on account of its harmful consequences for her (‘hard paternalism’). In practice, however, one normally uses a variable, risk dependent conception of competence, which really means that in considering whether or not to respect a person’s decision-making authority we weigh her decision on several relevant dimensions at the same time: its harmful consequences, its importance in terms of the person’s own relevant values, the infringement of her autonomy involved in overruling it, and her decision-making abilities. I argue that we should openly recognize the multi-dimensional nature of this judgment. This implies rejecting both the threshold conception of competence and the categorical distinction between hard and soft paternalism