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Tissue-resident memory T (TRM) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and whether TRM cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a TRM-like phenotype in ES lungs. In preclinical models, tumor-specific or bystander TRM-like cells present prior to tumor onset boosted immune cell recruitment, causing tumor immune evasion through loss of MHC class I protein expression and resistance to immune checkpoint inhibitors. In humans, only tumors arising in ES patients underwent clonal immune evasion, unrelated to tobacco-associated mutagenic signatures or oncogenic drivers. These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes.

The tumor microenvironment (TME) contains a rich source of nutrients that sustains cell growth and facilitate tumor development. Glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert antitumor function. Immunotherapy unleashes T cell antitumor function, and although many solid tumors respond well, a significant proportion of patients do not benefit. In patients with KRAS-mutant lung adenocarcinoma, KEAP1 and STK11/Lkb1 co-mutations are associated with impaired response to immunotherapy. To investigate the metabolic and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape in these patients. Here, we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and activation of CD8 T cells. Thus, glutaminase inhibition negatively impacts CD8 T cells activated by anti-PD1 immunotherapy.

This work examined the chiral inversion of 2-arylpropionic acids (2-APAs) under anaerobic conditions and the associated microbial community. The anaerobic condition was simulated by two identical anaerobic digesters. Each digester was fed with the substrate containing 11 either pure (R)- or pure (S)-2-APA enantiomers. Chiral inversion was evidenced by the concentration increase of the other enantiomer in the digestate and the changes in the enantiomeric fraction between the two enantiomers. Both digesters showed similar and poor removal of 2-APAs (≤30%, except for naproxen) and diverse chiral inversion behaviors under anaerobic conditions. Four compounds exhibited (S → R) unidirectional inversion [flurbiprofen, ketoprofen, naproxen, and 2-(4-tert-butylphenyl)propionic acid], and the remaining seven compounds showed bidirectional inversion. Several aerobic and facultative anaerobic bacterial genera (Candidatus Microthrix, Rhodococcus, Mycobacterium, Gordonia, and Sphingobium) were identified in both digesters and predicted to harbor the 2-arylpropionyl-CoA epimerase (enzyme involved in chiral inversion) encoding gene. These genera presented at low abundances, <0.5% in the digester dosed with (R)-2-APAs and <0.2% in the digester dosed with (S)-2-APAs. The low abundances of these genera explain the limited extent of chiral inversion observed in this study.

© 2020 Elsevier B.V. Adsorption pre-treatment to enhance the nanofiltration (NF) removal of inorganic ions, dissolved organic carbon (DOC) and organic micropollutants (OMP) from microfiltered (MF) wastewater was investigated using NF 90 membrane (contact angle 79% and molecular weight cut off value of 90–200 Da). The NF showed greater rejection for divalent cations (Ca2+, Mg2+) and anions (SO42−) compared to monovalent cations (Na+, K+) and anions (Cl−, NO3−). The degree of total DOC removal was: GAC adsorption + NF (86%) > an ion exchange resin (Purolite) adsorption + NF (81%) > NF operation alone (72%). GAC + NF removed biopolymers and hydrophobic substances almost completely and the highest percentage of LMW neutral substances. In contrast, Purolite + NF almost completely removed humic substances. The degree of membrane fouling order was: LMW neutrals > building blocks > biopolymers > hydrophobics > humics. Adsorption pre-treatment reduced membrane fouling and increased solution flux, the outcome being better with GAC compared to Purolite. Of the 10 MOPs in the MF water, seven were rejected > 90% by NF without any pre-treatment. Conversely, Purolite and GAC pre-treatments rejected > 90% of all OMPs.

We report a biocatalytic, buoyancy-propelled metal-organic framework (MOF) nanomotor system with boosted removal efficiency for both inorganic heavy metal ions and organic per- and poly-fluoroalkyl substances (PFAS). With the motion-induced convection and increased mass transfer of the target pollutants, the nano system exhibits excellent contaminants remediation capacity in both fresh water and sea water environments. This journal is

The mutational landscape of human cancers is highly complex. While next generation sequencing aims to comprehensively catalogue somatic alterations in tumor cells, it fails to delineate driver from passenger mutations. Functional genomic approaches, particularly CRISPR/Cas9, enable both gene discovery, and annotation of gene function. Indeed, recent CRISPR/Cas9 technologies have flourished with the development of more sophisticated and versatile platforms capable of gene knockouts to high throughput genome wide editing of a single nucleotide base. With new platforms constantly emerging, it can be challenging to navigate what CRISPR tools are available and how they can be effectively applied to understand cancer biology. This review provides an overview of current and emerging CRISPR technologies and their power to model cancer and identify novel treatments. Specifically, how CRISPR screening approaches have been exploited to enhance immunotherapies through the identification of tumor intrinsic and extrinsic mechanisms to escape immune recognition will be discussed.

Reverse osmosis concentrate (ROC) generated as a waste stream during reverse osmosis treatment of reclaimed wastewater, presents significant disposal challenges. This is because it causes environmental pollution when it is disposed to lands and natural water bodies. A long-term dynamic adsorption experiment was conducted by passing ROC from a wastewater reclamation plant, firstly through a granular activated carbon (GAC) column, and subsequently through an anion exchange resin (Purolite) column, for the removal of two major ROC pollutants, namely dissolved organic carbon (DOC) and microorganic pollutants (MOP). GAC removed most of the smaller-sized low molecular weight neutrals and building block fractions as well as the hydrophobic fraction of DOC with much less removal by the subsequent Purolite column. In contrast, the humics fraction was less well removed by the GAC column; however, Purolite column removed all that was remaining of this fraction. This study demonstrated that combining adsorbents having different affinities towards a variety of DOC fractions constitute an effective method of taking advantage of their different properties and achieving larger DOC removals. Almost 100% of all 17 MOPs were removed by the GAC column, even after 2880 bed volumes of continuous use. This contrasted with the DOC fractions' removal which was much lower.

Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. Results: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] ¼ 0.99, 95% confidence interval [CI] ¼ 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc¼ 0.79, 95% CI ¼ 0.69 to 0.91; HRc¼ 0.70, 95% CI ¼ 0.59 to 0.82; HRc¼ 0.50, 95% CI ¼ 0.40 to 0.63, for 2, 3, and 4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend ¼ .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] ¼ 1.69, 95% CI ¼ 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc ¼ 1.33, 95% CI ¼ 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc¼ 0.72, 95% CI ¼ 0.54 to 0.98). Conclusions: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers.

© 2018 This study examined the occurrence of 49 micropollutants in reclaimed water and Silver Perch (Bidyanus bidyanus) living in a reclaimed water reservoir. The numbers of micropollutants detected in reclaimed water, Silver Perch liver, and Silver Perch flesh were 20, 23, and 19, respectively. Concentrations of all micropollutants in reclaimed water, except benzotriazole, were well below the Australian Guideline for Recycled Water (AGRW) values for potable purposes. The concentration of benzotriazole in reclaimed water was 675 ± 130 ng/L while the AGRW value for this compound was 7 ng/L. Not all micropollutants detected in the water phase were identified in the Silver Perch flesh and liver tissues. Likewise, not all micropollutants detected in the Silver Perch flesh and liver were identified in the reclaimed water. In general, micropollutant concentrations in the liver were higher than in the flesh. Perfluorooctane sulfonate (PFOS) was detected at a trace level in reclaimed water well below the AGRW guideline value for potable purposes, but showed a high and medium bioconcentration factor in Silver Perch liver and flesh, respectively. In addition, the risk quotient for PFOS was medium and high when considering its concentration in Silver Perch liver and flesh, respectively. Results reported here highlight the need to evaluate multiple parameters for a comprehensive risk assessment. The results also single out PFOS as a notable contaminant of concern for further investigation.

BACKGROUND: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. METHODS: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. RESULTS: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98). CONCLUSIONS: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers.

© 2017 Elsevier B.V. There are over 40,000 chemical compounds registered for use in Australia, and only a handful are monitored in the aquatic receiving environments. Their effects on fish species in Australia are largely unknown. Mosquitofish (Gambusia holbrooki) were sampled from six river sites in Southeast Queensland identified as at risk from a range of pollutants. The sites selected were downstream of a wastewater treatment plant discharge, a landfill, two agricultural areas, and two sites in undeveloped reaches within or downstream of protected lands (national parks). Vitellogenin analysis, histopathology of liver, kidney and gonads, morphology of the gonopodium, and chemical body burden were measured to characterize fish health. Concentrations of trace organic contaminants (TrOCs) in water were analyzed by in vitro bioassays and chemical analysis. Estrogenic, anti-estrogenic, anti-androgenic, progestagenic and anti-progestagenic activities and TrOCs were detected in multiple water samples. Several active pharmaceutical ingredients (APIs), industrial compounds, pesticides and other endocrine active compounds were detected in fish carcasses at all sites, ranging from < 4–4700 ng/g wet weight, including the two undeveloped sites. While vitellogenin protein was slightly increased in fish from two of the six sites, the presence of micropollutants did not cause overt sexual endocrine disruption in mosquitofish (i.e., no abnormal gonads or gonopodia). A correlation between lipid accumulation in the liver with total body burden warrants further investigation to determine if exposure to low concentrations of TrOCs can affect fish health and increase stress on organs such as the liver and kidneys via other mechanisms, including disruption of non-sexual endocrine axes involved in lipid regulation and metabolism.

© 2018 A pilot-scale study was conducted to investigate the fate of trace organic contaminants (TrOCs) during anaerobic digestion of primary sludge. Of the 44 TrOCs monitored, 24 were detected in all primary sludge samples. Phase distribution of TrOCs was correlated well with their hydrophobicity (>67% mass in the solid phase when LogD > 1.5). The pilot-scale anaerobic digester achieved a steady performance with a specific methane yield of 0.39–0.92 L/gVSremoved and methane composition of 63–65% despite considerable variation in the primary sludge. The fate of TrOCs in the aqueous and solid phases was governed by their physicochemical properties. Biotransformation was significant (>83%) for five TrOCs with logD < 1.5 and electron donating functional groups in molecular structure. The remaining TrOCs with logD < 1.5 were persistent and thus accumulated in the aqueous phase. Most TrOCs with logD > 1.5 were poorly removed under anaerobic conditions. Sorption onto the solid phase appears to impede the biodegradation of these TrOCs.

© 2017 Elsevier B.V. In Australia, trace organic contaminants (TrOCs) and endocrine active compounds (EACs) have been detected in rivers impacted by sewage effluent, urban stormwater, agricultural and industrial inputs. It is unclear whether these chemicals are at concentrations that can elicit endocrine disruption in Australian fish species. In this study, native rainbowfish (Melanotaenia fluviatilis) and introduced invasive (but prevalent) mosquitofish (Gambusia holbrooki) were exposed to the individual compounds atrazine, estrone, bisphenol A, propylparaben and pyrimethanil, and mixtures of compounds including hormones and personal care products, industrial compounds, and pesticides at environmentally relevant concentrations. Vitellogenin (Vtg) protein and liver Vtg mRNA induction were used to assess the estrogenic potential of these compounds. Vtg expression was significantly affected in both species exposed to estrone at concentrations that leave little margin for safety (p < 0.001). Propylparaben caused a small but statistically significant 3× increase in Vtg protein levels (p = 0.035) in rainbowfish but at a concentration 40× higher than that measured in the environment, therefore propylparaben poses a low risk of inducing endocrine disruption in fish. Mixtures of pesticides and a mixture of hormones, pharmaceuticals, industrial compounds and pesticides induced a small but statistically significant increase in plasma Vtg in rainbowfish, but did not affect mosquitofish Vtg protein or mRNA expression. These results suggest that estrogenic activity represents a low risk to fish in most Australian rivers monitored to-date except for some species of fish at the most polluted sites.

It has been proposed that in slow-growing vertebrate populations survival generally has a greater influence on population growth than reproduction. Despite many studies cautioning against such generalizations for conservation, wildlife management for slow-growing populations still often focuses on perturbing survival without careful evaluation as to whether those changes are likely or feasible.Here, we evaluate the relative importance of reproduction and survival for the conservation of two bottlenose dolphin (Tursiops cf aduncus) populations: a large, apparently stable population and a smaller one that is forecast to decline. We also assessed the feasibility and effectiveness of wildlife management objectives aimed at boosting either reproduction or survival. Consistent with other analytically based elasticity studies, survival had the greatest effect on population trajectories when altering vital rates by equal proportions. However, the findings of our alternative analytical approaches are in stark contrast to commonly used proportional sensitivity analyses and suggest that reproduction is considerably more important. We show that1.) in the stable population reproductive output is higher, and adult survival is lower;2.) the difference in viability between the two populations is due to the difference in reproduction;3.) reproductive rates are variable, whereas survival rates are relatively constant over time;4.) perturbations on the basis of observed, temporal variation indicate that population dynamics are much more influenced by reproduction than by adult survival;5.) for the apparently declining population, raising reproductive rates would be an effective and feasible tool to reverse the forecast population decline; increasing survival would be ineffective.Our findings highlight the importance of reproduction – even in slow-growing populations – and the need to assess the effect of natural variation in vital rates on population viability. We echo others in cauti

This study evaluated the performance of a side-stream ceramic nanofiltration membrane bioreactor (NF-MBR) system with respect to basic water quality parameters as well as trace organic contaminant (TrOC) removal efficiency. The results show a stable biological performance of the continuous NF-MBR system with high effluent quality (total organic carbon < 4 mg L−1 and NH4+–N below the detection limit). Significantly higher performance by this NF-MBR in comparison to the conventional microfiltration/ultrafiltration MBR regarding the removal of a large number of TrOCs was observed. TrOC removal efficiency depended on their hydrophobicity and molecular features. All hydrophobic compounds (LogD pH=6 > 3) were well removed (>85%), except diazinon (59 ± 7%). Hydrophilic compounds containing electron donating groups were also well removed (>90%). By contrast, hydrophilic compounds containing electron withdrawing groups were poorly removed (8–54%). Most of the 40 TrOCs investigated in this study did not accumulate in the sludge. Only three hydrophobic compounds, namely amitriptyline, triclosan and triclocarban showed considerable accumulation in sludge (>500 ng g−1). Mass balance indicated biodegradation/transformation as the most significant TrOC removal mechanism by this NF-MBR.

© American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America. Trace organic contaminant (TrOC) studies in Australia have, to date, focused on wastewater effluents, leaving a knowledge gap of their occurrence and risk in freshwater environments. This study measured 42 TrOCs including industrial compounds, pesticides, and pharmaceuticals and personal care products by liquid chromatography tandem mass spectrometry at 73 river sites across Australia quarterly for 1 yr. Trace organic contaminants were found in 92% of samples, with a median of three compounds detected per sample (maximum 18). The five most commonly detected TrOCs were the pharmaceuticals salicylic acid (82%, maximum = 1530 ng/L), paracetamol (also known as acetaminophen; 45%, maximum = 7150 ng/L), and carbamazepine (27%, maximum = 682 ng/L), caffeine (65%, maximum = 3770 ng/L), and the flame retardant tris(2- chloroethyl) phosphate (44%, maximum = 184 ng/L). Pesticides were detected in 28% of the samples. To determine the risk posed by the detected TrOCs to the aquatic environment, hazard quotients were calculated by dividing the maximum concentration detected for each compound by the predicted noeffect concentrations. Three of the 42 compounds monitored (the pharmaceuticals carbamazepine and sulfamethoxazole and the herbicide simazine) had a hazard quotient >1, suggesting that they may be causing adverse effects at the most polluted sites. A further 10 compounds had hazard quotients >0.1, indicating a potential risk; these included four pharmaceuticals, three personal care products, and three pesticides. Most compounds had hazard quotients significantly <0.1. The number of TrOCs measured in this study was limited and further investigations are required to fully assess the risk posed by complex mixtures of TrOCs on exposed biota.

Given limited resources and time for conservation actions, it is crucial to focus wildlife management recommendations on vital rates that have the greatest impact on population viability. It has been proposed that in slow-growing animal populations, including most marine mammals, adult survival has a greater influence on population growth than reproduction. The implication of this principle is that adult survival is more important for population viability than reproduction. Here we evaluate the relative importance of reproduction and survival for the viability of two bottlenose dolphin (Tursiops cf. aduncus) populations in Western Australia: a large, apparently stable population (Shark Bay) and a smaller one (Bunbury) that was forecast to decline. Consistent with previous studies, adult survival had the greatest effect on population trajectories when altering vital rates by equal proportions (+/− 4%). However, our alternative analytical approaches suggest that reproduction may be considerably more important. We show that (1) reproductive output is higher, and adult survival is lower in the stable population; (2) the difference in viability between the two population is best explained by the difference in reproductive rates; (3) reproductive rates are variable, whereas survival rates are relatively constant over time (12-year time period for Shark Bay); (4) perturbations based on this observed natural variation (+/− 1 SD) indicate that population dynamics are much more influenced by reproduction than by adult survival. Our findings highlight the importance of reproduction—even in slow-growing populations—and the need to assess the effect of natural variation in vital rates on population viability