Historic distribution of Polycyclic Aromatic Compounds (PAC) in a Skagerrak fjord, Swedish west coast as reflected in a high-resolution sediment record and compared to the Environmental Quality Standards (EQS).

We present the historic distribution of Polycyclic Aromatic Compounds (PAC) in a Skagerrak fjord, a relatively unexploited area, on the Swedish west coast. PACs encompass various compounds, including PAHs, alkyl-PAHs, nitro-PAHs, and oxy-PAHs. These compounds, have environmental implications due to their harmful properties. Using a high-resolution sediment record, PAC variations including standard PAHs, nitro-PAHs and oxy-PAHs were investigated over the last approximately 170 years, comparing them with other European records. The sediment record reveals a significant increase in PAC levels during the 1940s-1950s, followed by peaks in the 1960s and 1970s, and a subsequent decrease in the 1980s. These trends align with industrial growth and evolving stronger environmental regulations in the region. The highest recorded concentration of PACs (1950-1970) reached levels comparable to present-day polluted urban environments. The study also compared PAH levels with EQS values. Results indicated that PAH levels exceeded EQS standards, potentially posing risks to sediment-dwelling organisms.

Diversity of intratumoral regulatory T cells in B-cell non-Hodgkin lymphoma.

Tumor-infiltrating regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment. Despite extensive studies, the prognostic impact of tumor-infiltrating Tregs in B-cell non-Hodgkin lymphomas (B-NHLs) remains unclear. Emerging studies suggest substantial heterogeneity in the phenotypes and suppressive capacities of Tregs, emphasizing the importance of understanding Treg diversity and the need for additional markers to identify highly suppressive Tregs. Here, we applied single-cell RNA sequencing and T-cell receptor sequencing combined with high-dimensional cytometry to decipher the heterogeneity of intratumoral Tregs in diffuse large B-cell lymphoma and follicular lymphoma (FL), compared with that in nonmalignant tonsillar tissue. We identified 3 distinct transcriptional states of Tregs: resting, activated, and unconventional LAG3+FOXP3- Tregs. Activated Tregs were enriched in B-NHL tumors, coexpressed several checkpoint receptors, and had stronger immunosuppressive activity compared with resting Tregs. In FL, activated Tregs were found in closer proximity to CD4+ and CD8+ T cells than other cell types. Furthermore, we used a computational approach to develop unique gene signature matrices, which were used to enumerate each Treg subset in cohorts with bulk gene expression data. In 2 independent FL cohorts, activated Tregs was the major subset, and high abundance was associated with adverse outcome. This study demonstrates that Tregs infiltrating B-NHL tumors are transcriptionally and functionally diverse. Highly immunosuppressive activated Tregs were enriched in tumor tissue but absent in the peripheral blood. Our data suggest that a deeper understanding of Treg heterogeneity in B-NHL could open new paths for rational drug design, facilitating selective targeting to improve antitumor immunity.

Efficient chimeric antigen receptor targeting of a central epitope of CD22.

Chimeric antigen receptor (CAR) T-cell therapy has had considerable success in the treatment of B-cell malignancies. Targeting the B-lineage marker CD19 has brought great advances to the treatment of acute lymphoblastic leukemia and B-cell lymphomas. However, relapse remains an issue in many cases. Such relapse can result from downregulation or loss of CD19 from the malignant cell population or expression of alternate isoforms. Consequently, there remains a need to target alternative B-cell antigens and diversify the spectrum of epitopes targeted within the same antigen. CD22 has been identified as a substitute target in cases of CD19-negative relapse. One anti-CD22 antibody-clone m971-targets a membrane-proximal epitope of CD22 and has been widely validated and used in the clinic. Here, we have compared m971-CAR with a novel CAR derived from IS7, an antibody that targets a central epitope on CD22. The IS7-CAR has superior avidity and is active and specific against CD22-positive targets, including B-acute lymphoblastic leukemia patient-derived xenograft samples. Side-by-side comparisons indicated that while IS7-CAR killed less rapidly than m971-CAR in vitro, it remains efficient in controlling lymphoma xenograft models in vivo. Thus, IS7-CAR presents a potential alternative candidate for the treatment of refractory B-cell malignancies.

Seasonal trends and retention of polycyclic aromatic compounds (PACs) in a remote sub-Arctic catchment.

Atmospheric deposition is the most dominant source of polycyclic aromatic hydrocarbons (PAHs) in remote and pristine areas. Despite low bioaccumulation potential, PAHs and their persistent transformation products (PAH-derivatives) are chemicals of concern as they can harm human and animal health through chronic low dose exposure. In this study, atmospheric deposition fluxes of polycyclic aromatic compounds (PACs) were measured on a seasonal basis (3-month periods) from 2012 to 2016 in a remote subarctic forest catchment in northern Europe. The target PACs included 19 PAHs and 15 PAH-derivatives (oxygenated, nitrogenated, and methylated PAHs). The deposition fluxes of Æ©PAHs and Æ©PAH-derivatives were in the same range and averaged 530 and 500 ng m2 day-1, respectively. The fluxes were found to be higher with a factor of 2.5 for Æ©PAHs and a factor of 3 for Æ©PAH-derivatives during cold (<0 °C) in comparison to warm (>10 °C) periods. PAHs and PAH-derivatives showed similar seasonal patterns, which suggests that these two compound classes have similar sources and deposition mechanisms, and that the source strength of the PAH-derivatives in air follows that of the PAHs. The terrestrial export of PACs via the outlet of the catchment stream was estimated to be 1.1% for Æ©PAHs and 1.7% for Æ©PAH-derivatives in relation to the annual amounts deposited to the catchment, which suggests that boreal forests are sinks for PACs derived from the atmosphere. Some individual PACs showed higher export than others (i.e. chrysene, cyclopenta(c,d)pyrene, carbazole, quinoline, and benzo(f)quinoline), with high export PACs mostly characterized by low molecular weight and low hydrophobicity (2-3 benzene rings; log Kow<6.0).

Seasonal trends of per- and polyfluoroalkyl substances in river water affected by fire training sites and wastewater treatment plants.

Fire-fighting training areas and wastewater treatment plants (WWTPs) are potential sources of per- and polyfluoroalkyl substances (PFASs) to the nearby aquatic environment. This study investigated seasonal variations of PFAS levels in two river catchments in Sweden; one impacted by Stockholm Arlanda Airport (Sites 1 and 2), and the other by WWTPs and a military airport (Uppsala) (Sites 3 and 4). Æ©PFAS concentrations were up to 61 (Sites 1 and 2) and 4 (Sites 3 and 4) times higher compared to the reference site. Distinct different seasonal trends were observed in the two catchments with higher ∑PFAS concentrations during the high water flow season at Site 1 compared to the low water flow season, whereas Sites 3 and 4 showed an inverse seasonal trend. This demonstrates that the pollution is mobilized during periods of high flow in the first catchment (Stockholm Arlanda Airport), while it is diluted during high flow in the second catchment (Uppsala). Average annual loads for ∑PFASs were estimated at ∼5.2 and ∼3.7 kg yr-1 for the catchment in Uppsala and Stockholm Arlanda Airport, respectively. Thus, both catchments add PFASs to Lake Mälaren, which is Sweden's most important source area for drinking water production.

The response of metal mobilization and redistribution to reoxygenation in Baltic Sea anoxic sediments.

To bring life back to anoxic coastal and sea basins, reoxygenation of anoxic/hypoxic zones has been proposed. This research focuses on the metals released during the oxidization of sediments from two locations in the anoxic Eastern Gotland Basin under a laboratory-scale study. Triplicate experimental cores and reference cores were collected from the North and South Eastern Gotland Basins. The oxygenation of the water column took place over a 96-hour experiment in a dark and 5 °C environment. In 12 and 24 hour intervals, the surface waters were exchanged and, over time, analyzed for pH, electroconductivity (EC), total organic carbon (TOC), soluble metal concentrations, and the top samples (0-10 cm) were analyzed with 3-step (E1: water-soluble, E2: exchangeable, and E3: organic-bound) sequential chemical extraction (SCE). Results show stable pH and decreasing EC in the column waters. The EC indicates that metals are released in the initial phases (12 h) of reoxygenation for both sites. Arsenic, Ba, Co, Mn, Rb, U, K, Sr, and Mo are released into the water column during the 96 hour experiment, and based on the calculations for the entire East Gotland Basin, would mean 8, 50, 0.55, 734, 53, 27, 347,178, 3468, and 156 µg L-1 are released, respectively. Elements Mn, Mo, U, and As are released in higher concentrations during the experiment than previously measured in the Eastern Gotland Basin, which provides vital information for future proposed remediation and natural geochemical processes with their known environmental impacts. The SCE results show that redox-sensitive metals (Mn, U, and Mo) are released in the highest concentrations into the solution. The relationship between the highest released metals (beside redox-sensitive) into solution over the oxygenation and their initial abundant phase is noticed, where the smallest released concentrations belong to K < Rb < Sr in E2, and As

Breast cancer metastasis: immune profiling of lymph nodes reveals exhaustion of effector T cells and immunosuppression.

Sentinel lymph nodes are the first nodes draining the lymph from a breast and could reveal early changes in the host immune system upon dissemination of breast cancer cells. To investigate this, we performed single-cell immune profiling of lymph nodes with and without metastatic cells. Whereas no significant changes were observed for B-cell and natural killer (NK)-cell subsets, metastatic lymph nodes had a significantly increased frequency of CD8 T cells and a skewing toward an effector/memory phenotype of CD4 and CD8 T cells, suggesting an ongoing immune response. Additionally, metastatic lymph nodes had an increased frequency of TIGIT (T-cell immunoreceptor with Ig and ITIM domains)-positive T cells with suppressed TCR signaling compared with non-metastatic nodes, indicating exhaustion of effector T cells, and an increased frequency of regulatory T cells (Tregs) with an activated phenotype. T-cell alterations correlated with the percentage of metastatic tumor cells, reflecting the presence of metastatic tumor cells driving T effector cells toward exhaustion and promoting immunosuppression by recruitment or increased differentiation toward Tregs. These results show that immune suppression occurs already in early stages of tumor progression.

Baltic Sea sediments record anthropogenic loads of Cd, Pb, and Zn.

The unsustainable settlement and high industrialization around the catchment of the Baltic Sea has left records of anthropogenic heavy metal contamination in Baltic Sea sediments. Here, we show that sediments record post-industrial and anthropogenic loads of Cd, Zn, and Pb over a large spatial scale in the Baltic Sea. We also demonstrate that there is a control on the accumulation of these metals in relation to oxic/anoxic conditions of bottom waters. The total concentrations of Cd, Zn, and Pb were obtained with the near-total digestion method in thirteen cores collected from the Bothnian Bay, the Bothnian Sea, and the west and central Baltic Proper. The lowest average concentrations of Cd, Zn, and Pb were observed in Bothnian Bay (0.4, 125, 40.2 mg kg-1 DW, respectively). In contrast, the highest concentrations were observed in the west Baltic Proper (5.5, 435, and 56.6 mg kg-1 DW, respectively). The results indicate an increasing trend for Cd, Zn, and Pb from the early nineteenth century until the 1970s, followed by a decrease until 2000-2008. However, surface sediments still have concentrations above the pre-industrial values suggested by the Swedish EPA (Cd is 0.2, Zn is 85, and Pb is 31 mg kg-1 DW). The results also show that the pre-industrial Cd, Zn, and Pb concentrations obtained from 3 cores with ages < 1500 B.C. were 1.8, 1.7, and 1.2 times higher, respectively, than the pre-industrial values suggested by the Swedish EPA. To conclude, accumulations of metals in the Baltic Sea are governed by anthropogenic load and the redox conditions of the environment. The significance of correct environmental governance (measures) can be illustrated with the reduction in the pollution of Pb, Zn, and Cd within the Baltic Sea since the 1980s.

Dispersal of cellulose fibers and metals from contaminated sediments of industrial origin in an estuary.

The boreal forest's pulp and paper industry plays a major role in economic prosperity but, historically, caused an environmental burden. Remnants of discharges of contaminated suspended solids (fiberbanks) are continuously being discovered on the beds of shallow seas, rivers and lakes in the northern hemisphere. We investigated the dispersion of Cd, Cr, Cu, Hg, Ni, Pb and Zn from deeper to surficial layers in fiberbanks in a Swedish estuary and the larger-scale transport of the same metals to distal areas of sediment accumulation. We also tested the C:N ratio as a common denominator for these anthropogenic, cellulose-rich deposits. Sampling and analyses of three fiberbanks located in the inner part of the estuary and from sediment accumulation sites outside and along the estuary reveals that metal concentrations are regressing to background levels towards the surface at the accumulation sites. The fiberbanks show a higher degree of contamination and C:N ratios demonstrate inclusion of cellulose fibers. C:N ratios also indicate that there is currently no significant transport of fiberbank material into the distal areas. A ∼10 cm natural cap of recently settled fine-grained sediment covering one of the fiberbanks seems to prevent metals dispersing into overlying water whereas the other two fiberbanks show signs of metal enrichment and potential mercury methylation in surficial layers. Although the estuarine system seems to recover from the impact of industrial waste, there is no evidence that the fiberbanks will be remediated naturally but instead will continue to threaten the aquatic environment.

Seasonal trends of legacy and alternative flame retardants in river water in a boreal catchment.

Boreal forests store large amounts of atmospherically deposited (semi-)persistent organic pollutants (POPs). The terrestrial POPs may be exported to streams and rivers through processes that are heavily impacted by seasonality. In this screening study, concentrations of 4 legacy and 45 alternative flame retardants (FRs) were determined in the dissolved and particulate phase in streams within a relatively pristine boreal catchment in northern Europe (Krycklan Catchment Study; 3 sites) and in rivers more impacted by human activities further downstream towards the Baltic Sea (3 sites). The sampling included the main hydrological seasons (snow-free, snow-covered, and spring flood) and was conducted during two consecutive years (2014-2016). Of the 49 analyzed FRs, 11 alternative halogenated FRs (HFRs), 13 alternative organophosphorus FRs (OPFRs), and 4 legacy polybrominated diphenyl ethers (PBDEs) were detected in at least one sample. The average bulk (dissolved + particulate) concentrations of ∑FRs (including all sites) were highest for ∑HFRs (38 ±â€¯70 ng L-1), followed by the ∑OPFRs (3.9 ±â€¯4.9 ng L-1) and the ∑PBDEs (0.0040 ±â€¯0.016 ng L-1). Bulk concentrations of HFRs, OPFRs, and PBDEs were highly variable with season and sampling location, e.g., during spring flood, bulk concentrations were up to 600 times, 3.7 times, and 4.9 times higher for HFRs, OPFRs and PBDEs, respectively, than during periods of lower flow. Bulk concentrations of ∑OPFRs, were elevated at all sites ~6 days before the actual start of the spring flood in 2015, suggesting that hydrophobicity fractionation had occurred within the snowpack. Similar to previous studies of other POPs in the same headwater catchment, there was a general trend that levels of ∑FRs were higher at the mire site than at the forested site. Annual fluxes of FRs were found to be ~15 times higher downstream the city of Umeå compared to at the outlet of the pristine catchment. This study should be regarded as a screening study considering the large number of diverse FRs analyzed and variability in the results.

Comparison of boreal acid sulfate soil microbial communities in oxidative and reductive environments.

Due to land uplift after the last ice age, previously stable Baltic Sea sulfidic sediments are becoming dry land. When these sediments are drained, the sulfide minerals are exposed to air and can release large amounts of metals and acid into the environment. This can cause severe ecological damage such as fish kills in rivers feeding the northern Baltic Sea. In this study, five sites were investigated for the occurrence of acid sulfate soils and their geochemistry and microbiology was identified. The pH and soil chemistry identified three of the areas as having classical acid sulfate soil characteristics and culture independent identification of 16S rRNA genes identified populations related to acidophilic bacteria capable of catalyzing sulfidic mineral dissolution, including species likely adapted to low temperature. These results were compared to an acid sulfate soil area that had been flooded for ten years and showed that the previously oxidized sulfidic materials had an increased pH compared to the unremediated oxidized layers. In addition, the microbiology of the flooded soil had changed such that alkalinity producing ferric and sulfate reducing reactions had likely occurred. This suggested that flooding of acid sulfate soils mitigates their environmental impact.

Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma.

T cells modified to express chimeric antigen receptor (CAR) targeting CD19 (CD19CAR) have produced remarkable clinical responses in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. CD19CAR T-cell therapy has also demonstrated prominent effects in B-cell non-Hodgkin lymphoma (B-NHL) patients. However, a subset of patients who relapse after CD19CAR T-cell therapy have outgrowth of CD19- tumor cells. Hence, development of alternative CARs targeting other B-cell markers represents an unmet medical need for B-cell acute lymphoblastic leukemia and B-NHL. Here, we confirmed previous data by showing that, overall, B-NHL has high expression of CD37. A second-generation CD37CAR was designed, and its efficacy in T cells was compared with that of CD19CAR. In vitro assessment of cytotoxicity and T-cell function upon coculture of the CAR T cells with different target B-cell lymphoma cell lines demonstrated comparable efficacy between the 2 CARs. In an aggressive B-cell lymphoma xenograft model, CD37CAR T cells were as potent as CD19CAR T cells in controlling tumor growth. In a second xenograft model, using U2932 lymphoma cells containing a CD19- subpopulation, CD37CAR T cells efficiently controlled tumor growth and prolonged survival, whereas CD19CAR T cells had limited effect. We further show that, unlike CD19CAR, CD37CAR was not sensitive to antigen masking. Finally, CD37CAR reactivity was restricted to B-lineage cells. Collectively, our results demonstrated that CD37CAR T cells also can effectively eradicate B-cell lymphoma tumors when CD19 antigen expression is lost and support further clinical testing for patients with relapsed/refractory B-NHL.

TIGIT and PD-1 Mark Intratumoral T Cells with Reduced Effector Function in B-cell Non-Hodgkin Lymphoma.

Checkpoint blockade can reverse T-cell exhaustion and promote antitumor responses. Although blocking the PD-1 pathway has been successful in Hodgkin lymphoma, response rates have been modest in B-cell non-Hodgkin lymphoma (NHL). Coblockade of checkpoint receptors may therefore be necessary to optimize antitumor T-cell responses. Here, characterization of coinhibitory receptor expression in intratumoral T cells from different NHL types identified TIGIT and PD-1 as frequently expressed coinhibitory receptors. Tumors from NHL patients were enriched in CD8+ and CD4+ T effector memory cells that displayed high coexpression of TIGIT and PD-1, and coexpression of these checkpoint receptors identified T cells with reduced production of IFNγ, TNFα, and IL2. The suppressed cytokine production could be improved upon in vitro culture in the absence of ligands. Whereas PD-L1 was expressed by macrophages, the TIGIT ligands CD155 and CD112 were expressed by lymphoma cells in 39% and 50% of DLBCL cases and in some mantle cell lymphoma cases, as well as by endothelium and follicular dendritic cells in all NHLs investigated. Collectively, our results show that TIGIT and PD-1 mark dysfunctional T cells and suggest that TIGIT and PD-1 coblockade should be further explored to elicit potent antitumor responses in patients with NHL.

Sources of polychlorinated dibenzo-p-dioxins and dibenzofurans to Baltic Sea herring.

Levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in herring (Clupea harengus) remain high in several parts of the Baltic Sea, despite declines in PCDD/F emissions since the 1980s. The reasons behind this are not well understood. This study applied a statistical modeling approach where sources of PCDD/Fs that contaminate Baltic biota were quantitatively assessed by analyzing existing datasets. PCDD/F patterns were extracted from a herring dataset using positive matrix factorization (PMF). The extracted biota patterns were transformed into sediment patterns using fish-to-sediment transformation factors, and the resulting patterns were compared with known source PCDD/F patterns. The model distinguished three model patterns, which explained 85% of the data. These patterns were matched to tetra-chlorophenol (TCP), penta-chlorophenol/atmospheric background (PCP/AB), and thermal source patterns, respectively. The thermal source was the largest contributor to toxic equivalents (TEQ) in herring, but the level decreased from 42 ±â€¯9.0 pg TEQ g-1 lipid weight (lw) before year 2000 (pre-2000) to 15 ±â€¯2.4 pg TEQ g-1 lw post-2000, i.e., a decline of around one-third in the original TEQ concentration. The contribution of TCP more than doubled, from 2.1 ±â€¯0.62 pg TEQ g-1 lw to 5.6 ±â€¯1.1 pg TEQ g-1 lw, and the relative contribution of PCP/AB also increased. These increasing trends suggest that, as primary air emissions of PCDD/Fs are managed and levels decline, the impact of TCP and PCP/AB sources on Baltic Sea biota will become more important over time and that PCDD/F-contaminated sites in coastal areas and marine environments require more attention.

Distribution and dispersal of metals in contaminated fibrous sediments of industrial origin.

Industrial emissions can impact aquatic environments and unregulated discharges from pulp and paper factories have resulted in deposits of cellulose fiber along the Swedish coast. These deposits are contaminated by metals, but due to their unique fibrous character the extent of sorption and dispersal of the metals is unclear. Fibrous sediments were sampled at two sites in the Ångermanälven river estuary, Sweden. The partitioning of metals between the sediment, pore water and bottom water was investigated and the degree of bioavailability was evaluated. The levels of metals in the sediment were high in fibrous or offshore samples, depending on the metal, whereas the levels of dissolved metals in pore water were low or below the limit of quantification. Partition coefficients (KD) showed that sorption to the sediment was stronger at one of the fibrous sites, possibly related to the type and size of organic matter. Undisturbed bottom water samples contained low levels of both dissolved and particle bound metals, but when comparing measured metal concentrations to threshold values of ecological status and ecotoxicological assessment criteria, both sediments and bottom water may be detrimental to living organisms. In-situ re-suspension experiments showed that the concentrations of particle bound metals increased whereas the dissolved concentrations decreased. The analyzed metals are probably retained by the solid phases of the fibrous sediment or adsorbed to particles in the water, reducing their bioavailability.

Screening of organic flame retardants in Swedish river water.

Alternative flame retardants (FRs) have now replaced legacy FRs (such as polybrominated diphenyl ethers, PBDEs), but little is known about their fate in the aquatic environment. In this study, a range of legacy FRs (n=10) and alternative FRs, including halogenated FRs (HFRs, n=32) and organophosphorus FRs (OPFRs, n=19), were screened in water samples collected from 23 rivers covering the whole latitudinal range of Sweden. Of the 61 targeted FRs, 26 were detected in at least one of the river samples, with ΣFR concentrations ranging up to 170ngL-1 (mean 31±45ngL-1). In general, higher concentrations and a larger variety of FRs were detected in southern Sweden (ΣFR=60±56ngL-1) compared with the north (ΣFR=9.0±16ngL-1). In the south, HFRs were dominant, constituting on average 59% of ∑FRs, whereas in the north, OPFRs were dominant, constituting on average 82% of ∑FRs. This difference was best explained by higher population density in the south. The total daily flux of FRs into the Baltic Sea was estimated to be ~31kg and comprised mainly tetrabromobisphenol-A (TBBPA), 3,4,5,6-tetrabromophthalic anhydride (TEBP-Anh), and 2,4,6-tribromophenol (TBP). To the best of our knowledge, this is the first report of environmental occurrence of TEBP-Anh, which was detected in two rivers and is suggested to originate from airports located near the sampling sites.

The Role of Spring Flood and Landscape Type in the Terrestrial Export of Polycyclic Aromatic Compounds to Streamwater.

Concentrations of polycyclic aromatic compounds (PACs), including 19 polycyclic aromatic hydrocarbons (PAHs) and 15 PAH-derivatives (oxygenated and nitrogen heterocyclic PAHs), were measured in streams in a remote headwater catchment in northern Europe and in more urbanized, downstream areas. Sampling was conducted during 2014 to 2016 and included the main hydrological seasons (snow-free, snow-covered, and spring flood) at six sampling sites. Levels of the targeted PACs varied substantially over time and space and were up to 110-fold (on average 17-fold) and 7000-fold (on average 670-fold) higher for PAHs and PAH-derivatives, respectively, during spring flood compared with preceding snow-covered and snow-free seasons. Higher levels of ∑PACs were generally found in a headwater stream draining a mire than at an adjacent forested site, with up to 20 times and 150 times higher levels for ∑PAH and ∑PAH-derivatives, respectively. The particle-bound PAC levels were positively correlated to surface runoff in the mire stream (∑PAHs: p = 0.032; ∑PAH-derivatives: p = 0.040) but not in the corresponding forest stream, during snowmelt and winter base flow. In more urbanized downstream areas, particle-bound PACs were instead strongly associated with suspended particulate matter ( p < 0.05; ∑PAHs and ∑PAH-derivatives except one site). Levels of ∑PACs in the streamwater were on average 3-fold higher downstream of the most densely populated area than at the outlet of the headwater catchment. The higher PAC levels in the downstream water compared to the remote headwater were clearer when normalized to SPM amounts (instead of water volume), with a gradual downstream trend between the sites.

T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling.

Purpose: T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing coinhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets.Experimental Design: Surface expression of 9 coinhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of T-cell immunoglobulin and ITIM domain (TIGIT) ligands was detected by immunohistochemistry.Results: TIGIT was a frequently expressed coinhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly coexpressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFNγ, while TCR proximal signaling (p-CD3ζ, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored upon in vitro culture. The costimulatory receptor CD226 was downregulated in TIGIT+ compared with TIGIT- CD8 FL T cells, further skewing the balance toward immunosuppression.Conclusions: TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between coinhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients. Clin Cancer Res; 24(4); 870-81. ©2017 AACR.

Influence of natural organic matter on the extraction efficiency of flame retardants from surface waters.

The influence of natural organic matter (NOM) on the solid-phase extraction (SPE) efficiency was investigated for legacy and emerging flame retardants (FRs; n=26) in surface water. Three different groups of FRs were analyzed: polybrominated diphenyl ethers (PBDEs), halogenated flame retardants (HFRs), and organophosphorus flame retardants (OPFRs). In addition, five sorbents (Amberlite XAD-2, Amberlite IRA-743, Oasis HLB, Chromabond HR-P, and Chromabond HR-X) were evaluated for the extraction of FRs (n=33) in water, of which Oasis HLB eluted with dichloromethane and acetone:n-hexane (1:1, v/v) provided the highest overall recoveries. In subsequent NOM experiments, where FRs were extracted from water containing different NOM concentrations, both increased and decreased extraction efficiency with increasing NOM level were observed. Physicochemical and semi-empirical quantum chemistry properties were calculated for the FRs and used for analyzing relations between FRs. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) showed that the FRs separated into four different groups based on their properties. The FRs within each group responded similarly to increasing NOM, while differences in behavior were observed between the groups. This suggests that the structural properties of micropollutants highly influence NOM-FR interaction mechanisms. For instance, at high NOM levels, recoveries decreased substantially for FRs containing a moiety that can form strong hydrogen bonds (such as the double-bonded oxygen in e.g., OPFRs). Many of the compounds showed maximum extraction efficiency at higher levels of NOM. This suggests that binding of NOM to the sorbent and subsequent interaction between sorbent-bound NOM and FRs is an important mechanism for extraction of micropollutants from surface waters.

Spatial distribution and source tracing of per- and polyfluoroalkyl substances (PFASs) in surface water in Northern Europe.

The impact of point and diffuse sources for 26 per- and polyfluoroalkyl substances (PFASs) in northern Europe were investigated by studying Swedish rivers (n = 40) and recipient seawater (Baltic Sea and Kattegat; n = 18). Different composition profiles were observed in the rivers, with ten rivers having a remarkably high fraction of perfluoroalkane sulfonic acids (PFSAs; 65% of the Æ©PFASs) as compared to other rivers (19%) suggesting major impact of one or several source types dominated by PFSAs. Population density and low latitude (south) were strongly correlated to the widely used perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA) as well as to perfluorohexanesulfonic acid (PFHxS). Significant relationships between several PFCAs and PFSAs (i.e. perfluorobutanoic acid (PFBA), perfluoroheptanoic acid (PFHpA), PFOA, perfluorobutanesulfonic acid (PFBS), and PFHxS) and dissolved organic carbon (DOC) were detected (p < 0.05), indicating chemical binding and co-transport with DOC in fresh water and seawater. Partial least squares regression analysis showed that perfluoroalkyl carboxylic acids (PFCAs) were related to latitude according to their perfluorocarbon chain length (C3, C7, C8, C9, C10 and C11), with longer chains associated with higher latitudes. This suggests the presence of mechanisms promoting higher prevalence of longer chained PFCAs in the north, e.g. precursor degradation, and/or aerosol associated stabilization of PFCAs and their precursors.