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BACKGROUND: Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level. METHODS: Here we establish a patient-derived explant culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+T cell cytotoxic activity. RESULTS: We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax+metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+T cells and thus facilitating antitumor immunity. CONCLUSIONS: Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.

The use of indicator species in forest conservation and management planning can facilitate enhanced preservation of biodiversity from the negative effects of forestry and other uses of land. However, this requires detailed and spatially comprehensive knowledge of the habitat preferences and distributions of selected focal indicator species. Unfortunately, due to limited resources for field surveys, only a small proportion of the occurrences of focal species is usually known. This shortcoming can be circumvented by using modeling techniques to predict the spatial distribution of suitable sites for the target species. Airborne laser scanning (ALS) and other remote sensing (RS) techniques have the potential to provide useful environmental data covering systematically large areas for these purposes. Here, we focused on six bird of prey and woodpecker species known to be good indicators of boreal forest biodiversity values. We used known nest sites of the six indicator species based on nestling ringing records. Thus, the most suitable nesting sites of these species provide important information for biodiversity‐friendly forest management and conservation planning. We developed fine‐grained, that is, 96 × 96 m grid cell resolution, predictive maps across the whole of Finland of the suitable nesting habitats based on ALS and other RS data and spatial information on the distribution of important forest stands for the six studied biodiversity indicator bird species based on nesting‐habitat suitability modeling, that is, the MaxEnt model. Habitat preferences of the study species, as determined by MaxEnt, were in line with the previous knowledge of species‐habitat relations. The proportion of suitable habitats of these species in protected areas (PAs) was considerable, but our analysis also revealed many potentially high‐quality forest stands outside PAs. However, many of these sites are increasingly threatened by logging because of increased pressures for using forests for bioeconomy and forest industry based on National Forest Strategy. Predicting habitat suitability based on information on the nest sites of indicator species provides a new tool for systematic conservation planning over large areas in boreal forests in Europe, and a corresponding approach would also be feasible and recommendable elsewhere where similar data are available. [ABSTRACT FROM AUTHOR]

• We compiled an ecosystem extent, supply and use accounts of runoff retention service. • The InVEST Urban Flood Mitigation Model was used to calculate the amount of on-site runoff retention. • The potential supply of the on-site runoff retention service during the considered rain events decreased between 2012 and 2018. • New buildings increased the demand, use and value of the service, but also enhanced the potential damage cost. • Data availability was the main limitation in compiling the ecosystem accounts. Urban ecosystem accounting can provide the structure for systematically integrating the value of urban green spaces into management and decision making to support urban resilience and sustainability. However, there are very few instructive examples of urban ecosystem accounting, particularly those created collaboratively with a municipality. Therefore, the aim of this study was to develop co-created urban ecosystem accounts using Tampere, Finland, as a case study. By discussing concrete political and planning-related needs, priorities, and data availability, this study identified urban flooding and the role of green spaces in alleviating this challenge as critical issues. An ecosystem extent account was compiled for accounting years 2012 and 2018 to quantify changes in the extent of ecosystem types. Additionally, an ecosystem service account (physical and monetary), for runoff retention, was compiled for the same years. The runoff retention service was quantified using the InVEST Urban Flood Risk Mitigation model, considering two precipitation events representative of rainstorms that trigger urban flooding. The runoff retention service was translated into service providing areas, which were used in conjunction with service demanding areas to estimate the physical terms of actual flows of retention service for accounting. The monetary value of the service was estimated using the avoided damage cost method. Between 2012 and 2018, the value of runoff mitigation service provided by green spaces increased by 7 % under the 24 mm scenario and by more than 40 % under the 50 mm scenario. The accounts showed concretely how important urban green spaces are in the City of Tampere, and provide an argument to preserve and even increase them in the urban structure. Our experiential ecosystem accounts for urban runoff retention service by green spaces also offer insights to other municipalities, encouraging them to take steps forward in ecosystem accounting. [ABSTRACT FROM AUTHOR]

Objectives: Four isoforms originating from alternative splicing of PGF gene have been reported for placental growth factor (PlGF). Main PlGF isoforms 1 and 2 have been associated with screening and diagnosis of pre-eclampsia (PE). Despite of the vast amount of research around PlGF in PE, protein levels of isoforms PlGF-3 and -4 have not been reported in human serum samples.Study Design: In this study a PlGF-3 specific DELFIA research immunoassay based on a custom recombinant Fab binder was developed and characterized. Serum levels of a third PlGF isoform during pregnancy were determined and screening performance of PlGF-3 for PE and small for gestational age (SGA) was investigated.Main Outcome Measures: Levels of serum and placental tissue PlGF 3 and predictive power of PlGF-3 for Pre-eclampsia and SGA.Results: PlGF-3 was below the detection limit of 1.6 pg/mL in most of the serum samples collected during pregnancy. Detected protein levels of PlGF-3 were not associated to be predictive for PE or SGA. However, measurable, and relatively higher amounts of PlGF-3 was extracted from placental tissue samples.Conclusion: Data obtained indicates that very low amounts of PlGF-3 is present in blood but significantly higher amounts of protein is present in placental tissue where it is prominently associated with cellular membranes. [ABSTRACT FROM AUTHOR]

Introduction: Evidence from many areas of healthcare suggests that skills learned during simulation transfer to clinical settings; however, this has not yet been investigated in hyperbaric medicine. This systematic review aimed to identify, summarize, and assess the impact of simulation-based education in hyperbaric medicine. Methods: Eligible studies investigated the effect of simulation-based education for learning in hyperbaric medicine, used any design, and were published in English in a peer-reviewed journal. Learning outcomes across all Kirkpatrick levels were included. MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched. Pairs of independent reviewers assessed references for study eligibility. Results: We found no article assessing the impact of simulation-based education in hyperbaric medicine published in English. Only one potentially relevant paper published in German was found. Conclusions: More research is needed to determine how the hyperbaric medicine community and their patients may benefit from simulation-based education to optimize both practice and patient care. [ABSTRACT FROM AUTHOR]

The predicted long lag time between a decrease in atmospheric deposition and a measured response in vegetation has generally excluded the investigation of vegetation recovery from the impacts of atmospheric deposition. However, policy-makers require such evidence to assess whether policy decisions to reduce emissions will have a positive impact on habitats. Here we have shown that 40 years after the peak of SO x emissions, decreases in SO x are related to significant changes in species richness and cover in Scottish Calcareous, Mestrophic, Nardus and Wet grasslands. Using a survey of vegetation plots across Scotland, first carried out between 1958 and 1987 and resurveyed between 2012 and 2014, we test whether temporal changes in species richness and cover of bryophytes, Cyperaceae, forbs, Poaceae, and Juncaceae can be explained by changes in sulphur and nitrogen deposition, climate and/or grazing intensity, and whether these patterns differ between six grassland habitats: Acid, Calcareous, Lolium , Nardus , Mesotrophic and Wet grasslands. The results indicate that Calcareous, Mesotrophic, Nardus and Wet grasslands in Scotland are starting to recover from the UK peak of SO x deposition in the 1970's. A decline in the cover of grasses, an increase in cover of bryophytes and forbs and the development of a more diverse sward (a reversal of the impacts of increased SO x ) was related to decreased SO x deposition. However there was no evidence of a recovery from SO x deposition in the Acid or Lolium grasslands. Despite a decline in NO x deposition between the two surveys we found no evidence of a reversal of the impacts of increased N deposition. The climate also changed significantly between the two surveys, becoming warmer and wetter. This change in climate was related to significant changes in both the cover and species richness of bryophytes, Cyperaceae, forbs, Poaceae and Juncaceae but the changes differed between habitats. [ABSTRACT FROM AUTHOR]

In boreal herb-rich forests, the dominance of Norway spruce ( Picea abies ) decreases light availability for understory species, many of which depend on canopy gaps for reproduction. Here, we explored the response of a rare clonal understory herb, the lady’s slipper orchid ( Cypripedium calceolus ), to tree removal. We used demographic data spanning 16 years from ten unharvested control sites and ten harvest sites which were divided into three treatments with differing harvest intensity: (1) dense spruce forests, where half of the total tree basal area (TBA) was cut, (2) sparse spruce forests, where one-fourth of the spruce TBA was cut and (3) sparse broadleaf forests, where one-fourth of the total TBA was cut. The effects of harvesting on different demographic rates (ramet density, reproduction, survival, and dormancy) were studied with generalized linear mixed models with harvest intensity, time since harvest and the starting level of the response variable as explanatory variables. Tree removal sites had 2.2 times higher orchid ramet density, 2.4 times higher odds of survival, and 2.1–3.1 times higher odds of flowering and fruiting than the control sites, but these effects were not seen at all treatment levels at all times. Tree removal had no effect on dormancy or seedling or flower density. Orchid flowering and fruiting probabilities increased only at the most intensively harvested sites (both spruce forest sites, and dense spruce forest with 50% TBA removal, respectively), while survival and ramet density increased at the moderately harvested broadleaf forest sites. The effects on flowering and fruiting probabilities and survival disappeared quickly (after three years) when the canopy gaps closed, whereas ramet density responded only with a lag of over three years and was maintained to the end of the study. Our results thus demonstrate that for the lady’s slipper orchid, selective tree harvest might be a suitable management method that increases population size at the ramet level. [ABSTRACT FROM AUTHOR]

Objectives: Stroke is a known complication after myocardial infarction (MI) and it is associated with increased mortality. We aimed to establish the true cumulative incidence of stroke and its subtypes and the associated mortality in a contemporary setting among patients treated for acute coronary syndrome (ACS).Materials and Methods: A retrospective registry study based on the data of 8,049 consecutive patients treated for ACS in a sole provider of specialized cardiac and neurologic care for a catchment area of over 0.5 million residents between 2007 and 2018. Incident strokes and their subtypes were identified by in-depth review of written hospital records, hospital discharge registry data and causes of death registry data maintained by Statistics Finland up until December 31st 2020.Results: During a median follow-up of 5.8 years (IQR 3.2-9.0) 570 ACS patients suffered a stroke. The cumulative incidences of stroke for first week, first month, first year and at thirteen years were: 0.8 %, 1.1 %, 2.2 % and 10.3 %. In long-term, patients with different ACS subtypes had similar cumulative incidence of strokes, although the incidence of in-hospital strokes was highest among myocardial infarction patients. Stroke mortality rate was 32.5 % (n=185/570). The majority (88.8 %) of strokes were ischemic with the proportion being most substantial for in-hospital strokes (95.6 %).Conclusions: The risk of stroke among patients treated for ACS and the related mortality are still notable in a contemporary setting. A distinctive majority of strokes following ACS were ischemic especially early on after ACS. [ABSTRACT FROM AUTHOR]

Although the lung has extensive regenerative capacity, some diseases affecting the distal lung result in irreversible loss of pulmonary alveoli. Hitherto, treatments are supportive and do not specifically target tissue repair. Regenerative medicine offers prospects to promote lung repair and regeneration. The neonatal lung may be particularly receptive, because of its growth potential, compared to the adult lung. Based on our current understanding of neonatal lung injury, the ideal therapeutic approach includes mitigation of inflammation and fibrosis, and induction of regenerative signals. Cell-based therapies have shown potential to prevent and reverse impaired lung development. Their mechanisms of action suggest effects on both, mitigating the pathophysiological processes and promoting lung growth. Here, we review our current understanding of normal and impaired alveolarization, provide some rationale for the use of cell-based therapies and summarize current evidence for the therapeutic potential of cell-based therapies for pulmonary regeneration in preterm infants. [ABSTRACT FROM AUTHOR]

The herpes virus entry mediator (HVEM) receptor and its ligand, HVEM-L, are involved in both herpes simplex virus type-1 (HSV-1) herpes simplex virus type-2 (HSV-2) infection, and in T-cell activation such that antagonists of this interaction are expected to have utility in viral and inflammatory diseases. In this report we describe the configuration of a homogeneous 384-well assay based on time-resolved energy transfer from a europium chelate on the HVEM receptor to an allophycocyanin (APC) acceptor on the ligand. Specific time resolved emission from the acceptor is observed on receptor:ligand complex formation. The results of various direct and indirect labeling strategies are described. Several assay optimization experiments were necessary to obtain an assay that was robust to automation and file compound interference while sensitive to the effect of potential inhibitors. The signal was stable for more than 24 h at room temperature using the Eu3+ chelates, suggesting no dissociation of the lanthanide ion. The 384-well assay was readily automated and was able to identify more than 99.5% of known positive controls in the validation studies successfully. Screening identified both a series of known potent inhibitors and several structural classes of hits that readily deconvoluted to yield single compound inhibitors with the desired functional activity in secondary biological assays. The equivalence of the data in 384- and 1536-well formats indicates that routine implementation of 1536-well chelate-based energy transfer screening appears to be primarily limited by liquid handling rather than detection issues. [ABSTRACT FROM PUBLISHER]