Potential drivers of changing ecological conditions in English and Welsh rivers since 1990.

River invertebrate communities across Europe have been changing in response to variations in water quality over recent decades, but the underlying drivers are difficult to identify because of the complex stressors and environmental heterogeneity involved. Here, using data from ∼4000 locations across England and Wales, collected over 29 years, we use three approaches to help resolve the drivers of spatiotemporal variation in the face of this complexity: i) mapping changes in invertebrate richness and community composition; ii) structural equation modelling (SEM) to distinguish land cover, water quality and climatic influences; and iii) geographically weighted regression (GWR) to identify how the apparent relationships between invertebrate communities and abiotic variables change across the area. Mapping confirmed widespread increases in richness and the proportion of pollution-sensitive taxa across much of England and Wales. It also revealed regions where pollution-sensitive taxa or overall richness declined, the former primarily in the uplands. SEMs confirmed strong increases in average biochemical oxygen demand and nutrient concentrations related to urban and agricultural land cover, but only a minority of land cover's effect upon invertebrate communities was explained by average water chemistry, highlighting potential factors such as episodic extremes or emerging contaminants. GWR identified strong geographical variation in estimated relationships between macroinvertebrate communities and environmental variables, with evidence that the estimated negative impacts of nutrients and water temperature were increasing through time. Overall the results are consistent with widespread biological recovery of Britain's rivers from past gross organic pollution, whilst highlighting declines in some of the most diverse and least impacted streams. Modelling points to a complex and changing set of drivers, highlighting the multifaceted impacts of catchment land cover and the evolving role of different stressors, with the relationship to gross organic pollution weakening, whilst estimated nutrient and warming effects strengthened.

Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma.

Acquired resistance to immunotherapy remains a critical yet incompletely understood biological mechanism. Here, using a mouse model of pancreatic ductal adenocarcinoma (PDAC) to study tumor relapse following immunotherapy-induced responses, we find that resistance is reproducibly associated with an epithelial-to-mesenchymal transition (EMT), with EMT-transcription factors ZEB1 and SNAIL functioning as master genetic and epigenetic regulators of this effect. Acquired resistance in this model is not due to immunosuppression in the tumor immune microenvironment, disruptions in the antigen presentation machinery, or altered expression of immune checkpoints. Rather, resistance is due to a tumor cell-intrinsic defect in T-cell killing. Molecularly, EMT leads to the epigenetic and transcriptional silencing of interferon regulatory factor 6 (Irf6), rendering tumor cells less sensitive to the pro-apoptotic effects of TNF-α. These findings indicate that acquired resistance to immunotherapy may be mediated by programs distinct from those governing primary resistance, including plasticity programs that render tumor cells impervious to T-cell killing.

Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy.

Acquired resistance to immune checkpoint immunotherapy remains a critical yet incompletely understood biological mechanism. Here, using a mouse model of pancreatic ductal adenocarcinoma (PDAC) to study tumor relapse following immunotherapy-induced responses, we found that tumors underwent an epithelial-to-mesenchymal transition (EMT) that resulted in reduced sensitivity to T cell-mediated killing. EMT-transcription factors (EMT-TFs) ZEB1 and SNAIL function as master genetic and epigenetic regulators of this tumor-intrinsic effect. Acquired resistance was not due to immunosuppression in the tumor immune microenvironment, disruptions in the antigen presentation machinery, or altered expression of immune checkpoints. Rather, EMT was associated with epigenetic and transcriptional silencing of interferon regulatory factor 6 (Irf6), which renders tumor cells less sensitive to the pro-apoptotic effects of TNF-α. These findings show how resistance to immunotherapy in PDAC can be acquired through plasticity programs that render tumor cells impervious to T cell killing.

Evidence of biological recovery from gross pollution in English and Welsh rivers over three decades.

Uncertainty around the changing ecological status of European rivers reflects an evolving array of anthropogenic stressors, including climate change. Although previous studies have revealed some recovery from historical pollution in the 1990s and early-2000s, there are contrasting trends among pollutants across Europe and recovery may have stalled or been reversed. To provide more contemporary evidence on trends and status, here we investigate changes in English and Welsh river macroinvertebrate communities over almost 30 years (1991-2019) using a network of nearly 4000 survey locations. Analysis comprised: i) trends in taxonomic and functional richness, community composition and ecological traits, ii) gains, losses and turnover of taxa, and the overall homogeneity of macroinvertebrate communities nationally, and iii) an exploration of how temporal trends varied with catchment characteristics. Taxonomic richness increased, primarily in the 1990s, whilst a shift towards pollution-sensitive taxa continued throughout the study period, accompanied by a growing prevalence in traits such as preferences for fast-flowing conditions, coarser substrata, and 'shredding' or 'scraping' feeding strategies. Changes consistent with improvement occurred in both urbanised and agricultural catchments, but were more pronounced in urban rivers as they gained pollution sensitive taxa that were otherwise more prevalent in rural rivers. Overall, these results indicate continuing biological recovery from organic pollution, consistent with national scale trends in water quality. Results reemphasise the importance of looking at multiple facets of diversity, with periods of near-constant richness disguising changes in taxonomic and functional composition. Whilst this national-scale picture is broadly positive, we highlight the need to investigate more local variations or pollutants that depart from this aggregate picture.

Site-Dependent Immune Escape Due to Impaired Dendritic Cell Cross-Priming.

T-cell recognition of tumor neoantigens is critical for cancer immune surveillance and the efficacy of immunotherapy. Tumors can evade host immunity by altering their antigenicity or orchestrating an immunosuppressive microenvironment, leading to outgrowth of poorly immunogenic tumors through the well-established process of cancer immunoediting. Whether cancer immune surveillance and immunoediting depend on the tissue site of origin, however, is poorly understood. Herein, we studied T-cell-mediated surveillance of antigenic, clonal murine pancreatic adenocarcinoma cells expressing neoantigen. Whereas such tumors are robustly eliminated after subcutaneous or intravenous challenge, we observed selective immune escape within the pancreas and peritoneum. Tumor outgrowth occurred in the absence of immunoediting, and antitumor immunity could not be rescued by PD-1 or CTLA-4 checkpoint blockade. Instead, tumor escape was associated with diminished CD8+ T-cell priming by type I conventional dendritic cells (cDC1). Enhancing cDC1 cross-presentation by CD40 agonist treatment restored immunologic control by promoting T-cell priming and broadening T-cell responses through epitope spread. These findings demonstrate that immune escape of highly antigenic tumors can occur without immunoediting in a tissue-restricted manner and highlight barriers to cDC1-mediated T-cell priming imposed by certain microenvironments that must be addressed for successful combination immunotherapies.

Adult Pleomorphic Rhabdomyosarcomas: Assessing Outcomes Associated with Radiotherapy and Chemotherapy Use in the National Cancer Database.

PURPOSE: Practice patterns for treatment of localized adult pleomorphic rhabdomyosarcoma (PRMS) remain quite variable given its rarity. Current national guidelines recommend management similar to that of other high-grade soft tissue sarcomas (STS), which include surgery with perioperative radiation (RT) with or without chemotherapy. Using the National Cancer Database (NCDB), we assessed practice patterns and overall outcomes of patients with localized PRMS. Patients and Methods. Patients with stage II/III PRMS treated with surgical resection from 2004 to 2015 were identified from the NCDB. Predictors of RT and chemotherapy use were assessed using multivariable logistic regression analysis. The association of radiation and chemotherapy status on overall survival was assessed using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Of 243 total patients, RT and chemotherapy were not uniformly utilized, with 44% receiving chemotherapy and in those who did not undergo amputation 62% receiving RT. In those who did not undergo amputation, RT was associated with improved survival on both univariate (HR: 0.49, 95% CI 0.32-0.73, P < 0.001) and multivariate analysis (HR: 0.40, 95% CI 0.26-0.62, P < 0.001), corresponding to greater 5-year overall survival (59% vs. 38%, P < 0.001). Chemotherapy was associated with a higher rate of 5-year overall survival (63% vs. 39%, P < 0.001). However, the survival benefit of chemotherapy did not reach statistical significance on multivariate analysis (HR: 0.65, 95% CI 0.41-1.03, P=0.064). Notable predictors of omission of RT included female gender (OR: 0.40, 95% CI 0.22-0.74, P < 0.01) and age ≥ 70 (OR: 0.55, 95% CI 0.30-1.00, P=0.05). Correspondingly, factors associated with omission of chemotherapy included age ≥70 (OR: 0.17, 95% CI 0.08-0.39, P < 0.001). CONCLUSIONS: A significant proportion of patients with localized adult PRMS are not receiving RT. Likewise, use of chemotherapy was heterogeneous. Our findings note potential benefits and underutilization of RT, for which further investigation is warranted.

Sufficiency of CD40 activation and immune checkpoint blockade for T cell priming and tumor immunity.

Innate immune receptors such as toll-like receptors (TLRs) provide critical molecular links between innate cells and adaptive immune responses. Here, we studied the CD40 pathway as an alternative bridge between dendritic cells (DCs) and adaptive immunity in cancer. Using an experimental design free of chemo- or radiotherapy, we found CD40 activation with agonistic antibodies (⍺CD40) produced complete tumor regressions in a therapy-resistant pancreas cancer model, but only when combined with immune checkpoint blockade (ICB). This effect, unachievable with ICB alone, was independent of TLR, STING, or IFNAR pathways. Mechanistically, αCD40/ICB primed durable T cell responses, and efficacy required DCs and host expression of CD40. Moreover, ICB drove optimal generation of polyfunctional T cells in this "cold" tumor model, instead of rescuing T cell exhaustion. Thus, immunostimulation via αCD40 is sufficient to synergize with ICB for priming. Clinically, combination αCD40/ICB may extend efficacy in patients with "cold" and checkpoint-refractory tumors.

CQI approaches for evaluating management development programs: A case study with health service managers from geographically remote settings.

Health systems are known for being complex. Yet, there is a paucity of evidence about programs that successfully develop competent frontline managers to navigate these complex systems. There is even less evidence about developing frontline managers in areas of contextual complexity such as geographically remote and isolated health services. This study used a customised management development program containing continuous quality improvement (CQI) approaches to determine whether additional levels of evaluation could provide evidence for program impact. Generalisability is limited by the small sample size; however, the findings suggest that continuous improvement approaches, such as action learning workplace-based CQI projects not only provide for real-world application of the manager's learning; they can potentially produce the type of data needed to conduct evaluations for organisational impact and cost-benefits. The case study contributes to the literature in an area where there is a scarcity of empirical research. Further, this study proposes a pragmatic method for using CQI approaches with existing management development programs to generate the type of data needed for multi-level evaluation.

The retraction of the protoplast during PCD is an active, and interruptible, calcium-flux driven process.

The protoplast retracts during apoptosis-like programmed cell death (AL-PCD) and, if this retraction is an active component of AL-PCD, it should be used as a defining feature for this type of programmed cell death. We used an array of pharmacological and genetic tools to test if the rates of protoplast retraction in cells undergoing AL-PCD can be modulated. Disturbing calcium flux signalling, ATP synthesis and mitochondrial permeability transition all inhibited protoplast retraction and often also the execution of the death programme. Protoplast retraction can precede loss of plasma membrane integrity and cell death can be interrupted after the protoplast retraction had already occurred. Blocking calcium influx inhibited the protoplast retraction, reduced DNA fragmentation and delayed death induced by AL-PCD associated stresses. At higher levels of stress, where cell death occurs without protoplast retraction, blocking calcium flux had no effect on the death process. The results therefore strongly suggest that retraction of the protoplast is an active biological process dependent on an early Ca2+-mediated trigger rather than cellular disintegration due to plasma membrane damage. Therefore this morphologically distinct cell type is a quantifiable feature, and consequently, reporter of AL-PCD.

Web-Based Positive Psychology Interventions: A Reexamination of Effectiveness.

OBJECTIVE: Seligman, Steen, Park, and Peterson (2005) suggested that positive psychology interventions (PPIs) contain specific, powerful, therapeutic ingredients that effect greater increases in happiness and reductions in depression than a placebo control. This study reexamined the three PPIs that Seligman et al. found to be most effective when delivered over the internet. METHOD: Three PPIs and a placebo control, identical with the interventions used by Seligman et al., were examined in a web-based, randomized assignment design. RESULTS: Mixed-design analysis of variance and multilevel modeling showed that all interventions, including the placebo, led to significant increases in happiness and reductions in depression. The effects of PPIs were indistinguishable from those of the placebo control. CONCLUSION: Using web-based delivery, both PPIs and theoretically neutral placebos can increase happiness and reduce depression in self-selected populations. Possible explanations include that non-specific factors common to most therapeutic treatments are responsible for the observed changes, or that cultural or other context-related variables operate to account for the divergent findings.

Lack of immunoediting in murine pancreatic cancer reversed with neoantigen.

In carcinogen-driven cancers, a high mutational burden results in neoepitopes that can be recognized immunologically. Such carcinogen-induced tumors may evade this immune response through "immunoediting," whereby tumors adapt to immune pressure and escape T cell-mediated killing. Many tumors lack a high neoepitope burden, and it remains unclear whether immunoediting occurs in such cases. Here, we evaluated T cell immunity in an autochthonous mouse model of pancreatic cancer and found a low mutational burden, absence of predicted neoepitopes derived from tumor mutations, and resistance to checkpoint immunotherapy. Spontaneous tumor progression was identical in the presence or absence of T cells. Moreover, tumors arising in T cell-depleted mice grew unchecked in immune-competent hosts. However, introduction of the neoantigen ovalbumin (OVA) led to tumor rejection and T cell memory, but this did not occur in OVA immune-tolerant mice. Thus, immunoediting does not occur in this mouse model - a likely consequence, not a cause, of absent neoepitopes. Because many human tumors also have a low missense mutational load and minimal neoepitope burden, our findings have clinical implications for the design of immunotherapy for patients with such tumors.

Happy Days: Positive Psychology interventions effects on affect in an N-of-1 trial.

Positive Psychology Interventions (PPIs) have been suggested as self-help tools to increase subjective well-being and happiness. However, most previous studies have been based on between-group comparisons, which are not informative with regard to trajectories of individual change over time. This study is a first attempt at examining whether completing frequently used PPIs - 'Three Good Things in Life', 'Using Signature Strengths in a New Way' and 'Gratitude Visit' -results in consistent changes in affect at the level of the individual. In an N-of-1-study design, participants were randomly allocated to one of six counterbalanced patterns of the PPIs over a 9-10 week period. The affective aspect of subjective well-being was measured daily using the Positive and Negative Affect Scale (PANAS). Hierarchical linear modelling showed significant changes in PANAS scores, but no statistically significant differential impact on positive affect of the PPIs, apart from a marginally significant time × intervention interaction for 'Using Signature Strengths in a New Way'. This suggests that frequently used PPIs do not result in changes in affect over time. This finding questions recommending the use of PPIs as self-help tools.

Las intervenciones de la Psicología Positiva (IPP) se han sugerido como herramientas de autoayuda para aumentar el bienestar subjetivo y la felicidad. Sin embargo, la mayoría de los estudios previos se ha basado en comparaciones entre grupos que no informan del cambio individual en el tiempo. Este estudio es un primer intento de examinar si las IPP habitualmente empleadas "Tres cosas buenas de la vida", "Uso de las fortalezas características de un modo distinto" y "Visita de gratitud" provocan cambios en el afecto a nivel individual. En un diseño N = 1, los participantes fueron asignados al azar a uno de los seis patrones contrabalanceados de las IPP durante 9-10 semanas. El aspecto afectivo del bienestar subjetivo se midió diariamente usando la Escala de Afecto Positivo y Afecto Negativo (PANAS). El modelo jerárquico lineal mostró cambios estadísticamente significativos en las puntuaciones PANAS, pero ningún efecto diferencial estadísticamente significativo en el afecto positivo, excepto la interacción tiempo x intervención para "fortalezas características". Los resultados sugieren que las IPP empleadas habitualmente no provocan cambios en el afecto a lo largo del tiempo. Este hallazgo cuestiona el uso de las IPP como herramientas de autoayuda.

Preventing mental illness: closing the evidence-practice gap through workforce and services planning.

BACKGROUND: Mental illness is prevalent across the globe and affects multiple aspects of life. Despite advances in treatment, there is little evidence that prevalence rates of mental illness are falling. While the prevention of cardiovascular disease and cancers are common in the policy dialogue and in service delivery, the prevention of mental illness remains a neglected area. There is accumulating evidence that mental illness is at least partially preventable, with increasing recognition that its antecedents are often found in infancy, childhood, adolescence and youth, creating multiple opportunities into young adulthood for prevention. Developing valid and reproducible methods for translating the evidence base in mental illness prevention into actionable policy recommendations is a crucial step in taking the prevention agenda forward. METHOD: Building on an aetiological model of adult mental illness that emphasizes the importance of intervening during infancy, childhood, adolescence and youth, we adapted a workforce and service planning framework, originally applied to diabetes care, to the analysis of the workforce and service structures required for best-practice prevention of mental illness. RESULTS: The resulting framework consists of 6 steps that include identifying priority risk factors, profiling the population in terms of these risk factors to identify at-risk groups, matching these at-risk groups to best-practice interventions, translation of these interventions to competencies, translation of competencies to workforce and service estimates, and finally, exploring the policy implications of these workforce and services estimates. The framework outlines the specific tasks involved in translating the evidence-base in prevention, to clearly actionable workforce, service delivery and funding recommendations. CONCLUSIONS: The framework describes the means to deliver mental illness prevention that the literature indicates is achievable, and is the basis of an ongoing project to model the workforce and service structures required for mental illness prevention.

CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS.

OBJECTIVE: This study evaluated the efficacy and safety of ATL1102, an antisense oligonucleotide that selectively targets the RNA for human CD49d, the α subunit of very late antigen 4, in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: In a multicenter, double-blind, placebo-controlled randomized phase II trial, 77 patients with RRMS were treated with 200 mg of ATL1102 subcutaneously injected 3 times in the first week and twice weekly for 7 weeks or placebo and monitored for a further 8 weeks. MRI scans were taken at baseline and weeks 4, 8, 12, and 16. The primary endpoint was the cumulative number of new active lesions (either new gadolinium-enhancing T1 lesions or nonenhancing new or enlarging T2 lesions) at weeks 4, 8, and 12. RESULTS: A total of 72 patients completed the study and 74 intention-to-treat patients were assessed. ATL1102 significantly reduced the cumulative number of new active lesions by 54.4% compared to placebo (mean 3.0 [SD 6.12] vs 6.2 [9.89], p = 0.01). The cumulative number of new gadolinium-enhancing T1 lesions was reduced by 67.9% compared to placebo (p = 0.002). Treatment-emergent adverse events included mild to moderate injection site erythema and decrease in platelet counts that returned to within the normal range after dosing. CONCLUSIONS: In patients with RRMS, ATL1102 significantly reduced disease activity after 8 weeks of treatment and was generally well-tolerated. This trial provides evidence for the first time that antisense oligonucleotides may be used as a therapeutic approach in neuroimmunologic disorders. CLASSIFICATION: This study provides Class I evidence that for patients with RRMS, the antisense oligonucleotide ATL1102 reduces the number of new active head MRI lesions.

The fusarium mycotoxin deoxynivalenol can inhibit plant apoptosis-like programmed cell death.

The Fusarium genus of fungi is responsible for commercially devastating crop diseases and the contamination of cereals with harmful mycotoxins. Fusarium mycotoxins aid infection, establishment, and spread of the fungus within the host plant. We investigated the effects of the Fusarium mycotoxin deoxynivalenol (DON) on the viability of Arabidopsis cells. Although it is known to trigger apoptosis in animal cells, DON treatment at low concentrations surprisingly did not kill these cells. On the contrary, we found that DON inhibited apoptosis-like programmed cell death (PCD) in Arabidopsis cells subjected to abiotic stress treatment in a manner independent of mitochondrial cytochrome c release. This suggested that Fusarium may utilise mycotoxins to suppress plant apoptosis-like PCD. To test this, we infected Arabidopsis cells with a wild type and a DON-minus mutant strain of F. graminearum and found that only the DON producing strain could inhibit death induced by heat treatment. These results indicate that mycotoxins may be capable of disarming plant apoptosis-like PCD and thereby suggest a novel way that some fungi can influence plant cell fate.

Type I interferon is selectively required by dendritic cells for immune rejection of tumors.

Cancer immunoediting is the process whereby the immune system suppresses neoplastic growth and shapes tumor immunogenicity. We previously reported that type I interferon (IFN-α/ß) plays a central role in this process and that hematopoietic cells represent critical targets of type I IFN's actions. However, the specific cells affected by IFN-α/ß and the functional processes that type I IFN induces remain undefined. Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN-γ during cancer immunoediting. Using mixed bone marrow chimeric mice, we demonstrate that type I IFN sensitivity selectively within the innate immune compartment is essential for tumor-specific T cell priming and tumor elimination. We further show that mice lacking IFNAR1 (IFN-α/ß receptor 1) in dendritic cells (DCs; Itgax-Cre(+)Ifnar1(f/f) mice) cannot reject highly immunogenic tumor cells and that CD8α(+) DCs from these mice display defects in antigen cross-presentation to CD8(+) T cells. In contrast, mice depleted of NK cells or mice that lack IFNAR1 in granulocytes and macrophage populations reject these tumors normally. Thus, DCs and specifically CD8α(+) DCs are functionally relevant targets of endogenous type I IFN during lymphocyte-mediated tumor rejection.