Endothelial damage and dysfunction in acute graft-versus-host disease

Clinical studies suggested that endothelial dysfunction and damage could be involved in the development and severity of acute graft-versus-host disease (aGVHD). Accordingly, we found increased percentage of apoptotic Casp3+ blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGVHD. In murine experimental aGVHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGVHD target organs. During intestinal aGVHD, colonic vasculature structurally changed, reflected by increased vessel branching and vessel diameter. Because recent data demonstrated an association of endothelium-related factors and steroid refractory aGVHD (SR-aGVHD), we analyzed human biopsies and murine tissues from SR-aGVHD. We found extensive tissue damage but low levels of alloreactive T cell infiltration in target organs, providing the rationale for T-cell independent SR-aGVHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental SR-aGVHD. Our results demonstrate extensive damage, structural changes, and dysfunction of the vasculature during aGVHD. Therapeutic intervention by endothelium-protecting agents is an attractive approach for SR-aGVHD complementing current anti-inflammatory treatment options

The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy

Basal-like tumours account for 15% of invasive breast carcinomas and are associated with a poorer prognosis and resistance to therapy. We hypothesised that this aggressive phenotype is because of an intrinsically elevated hypoxic response. Microarrayed tumours from 188 patients were stained for hypoxia-inducible factor (HIF)-1α, prolyl hydroxylase (PHD)1, PHD2, PHD3 and factor inhibiting HIF (FIH)-1, and carbonic anhydrase (CA) IX stained in 456 breast tumours. Tumour subtypes were correlated with standard clincopathological parameters as well as hypoxic markers. Out of 456 tumours 62 (14%) tumours were basal-like. These tumours were positively correlated with high tumour grade (P<0.001) and were associated with a significantly worse disease-free survival compared with luminal tumours (P<0.001). Fifty percent of basal-like tumours expressed HIF-1α, and more than half expressed at least one of the PHD enzymes and FIH-1. Basal-like tumours were nine times more likely to be associated with CAIX expression (P<0.001) in a multivariate analysis. Carbonic anhydrase IX expression was positively correlated with tumour size (P=0.005), tumour grade (P<0.001) and oestrogen receptor (ER) negativity (P<0.001). Patients with any CAIX-positive breast tumour phenotype and in the basal tumour group had a significantly worse prognosis than CAIX-negative tumours when treated with chemotherapy (P<0.001 and P=0.03, respectively). The association between basal phenotype and CAIX suggests that the more aggressive behaviour of these tumours is partly due to an enhanced hypoxic response. Further, the association with chemoresistance in CAIX-positive breast tumours and basal-like tumours in particular raises the possibility that targeted therapy against HIF pathway or downstream genes such as CAs may be an approach to investigate for these patients

Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast

INTRODUCTION: Hypoxia-inducible factor 1 (HIF-1) alpha and its downstream targets carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) are key factors in the survival of proliferating tumor cells in a hypoxic microenvironment. We studied the expression and prognostic relevance of HIF-1α and its downstream targets in phyllodes tumors and fibroadenomas of the breast. METHODS: The expression of HIF-1α, CAIX, VEGF and p53 was investigated by immunohistochemistry in a group of 37 primary phyllodes tumors and 30 fibroadenomas with known clinical follow-up. The tumor microvasculature was visualized by immunohistochemistry for CD31. Proliferation was assessed by Ki67 immunostaining and mitotic counts. Being biphasic tumors, immunoquantification was performed in the stroma and epithelium. RESULTS: Only two fibroadenomas displayed low-level stromal HIF-1α reactivity in the absence of CAIX expression. Stromal HIF-1α expression was positively correlated with phyllodes tumor grade (P = 0.001), with proliferation as measured by Ki67 expression (P < 0.001) and number of mitoses (P < 0.001), with p53 accumulation (P = 0.003), and with global (P = 0.015) and hot-spot (P = 0.031) microvessel counts, but not with CAIX expression. Interestingly, concerted CAIX and HIF-1α expression was frequently found in morphologically normal epithelium of phyllodes tumors. The distance from the epithelium to the nearest microvessels was higher in phyllodes tumors as compared with in fibroadenomas. Microvessel counts as such did not differ between fibroadenomas and phyllodes tumors, however. High expression of VEGF was regularly found in both tumors, with only a positive relation between stromal VEGF and grade in phyllodes tumors (P = 0.016). Stromal HIF-1α overexpression in phyllodes tumors was predictive of disease-free survival (P = 0.032). CONCLUSION: These results indicate that HIF-1α expression is associated with diminished disease-free survival and may play an important role in stromal progression of breast phyllodes tumors. In view of the absence of stromal CAIX expression in phyllodes tumors, stromal upregulation of HIF-1α most probably arises from hypoxia-independent pathways, with p53 inactivation as one possible cause. In contrast, coexpression of HIF-1α and CAIX in the epithelium in phyllodes tumors points to epithelial hypoxia, most probably caused by relatively distant blood vessels. On the other hand, HIF-1α and CAIX seem to be of minor relevance in breast fibroadenomas

Reduced microvascular density in omental biopsies of children with chronic kidney disease

Endothelial dysfunction is an early manifestation of cardiovascular disease (CVD) and consistently observed in patients with chronic kidney disease (CKD). We hypothesized that CKD is associated with systemic damage to the microcirculation, preceding macrovascular pathology. To assess the degree of "uremic microangiopathy", we have measured microvascular density in biopsies of the omentum of children with CKD.Omental tissue was collected from 32 healthy children (0-18 years) undergoing elective abdominal surgery and from 23 age-matched cases with stage 5 CKD at the time of catheter insertion for initiation of peritoneal dialysis. Biopsies were analyzed by independent observers using either a manual or an automated imaging system for the assessment of microvascular density. Quantitative immunohistochemistry was performed for markers of autophagy and apoptosis, and for the abundance of the angiogenesis-regulating proteins VEGF-A, VEGF-R2, Angpt1 and Angpt2.Microvascular density was significantly reduced in uremic children compared to healthy controls, both by manual imaging with a digital microscope (median surface area 0.61% vs. 0.95%, p<0.0021 and by automated quantification (total microvascular surface area 0.89% vs. 1.17% p = 0.01). Density measured by manual imaging was significantly associated with age, height, weight and body surface area in CKD patients and healthy controls. In multivariate analysis, age and serum creatinine level were the only independent, significant predictors of microvascular density (r2 = 0.73). There was no immunohistochemical evidence for apoptosis or autophagy. Quantitative staining showed similar expression levels of the angiogenesis regulators VEGF-A, VEGF-receptor 2 and Angpt1 (p = 0.11), but Angpt2 was significantly lower in CKD children (p = 0.01).Microvascular density is profoundly reduced in omental biopsies of children with stage 5 CKD and associated with diminished Angpt2 signaling. Microvascular rarefaction could be an early systemic manifestation of CKD-induced cardiovascular disease

IMPROVE-PD Finder: A Web-Based Platform to Search and Share Peritoneal Dialysis Biobank, Registry, and Clinical Trial Metadata

Peritoneal dialysis (PD) is a life-sustaining kidney replacement therapy for the increasing number of people with permanent kidney failure across all age groups worldwide. Although PD potentially offers socioeconomic and performance benefits over hemodialysis, both treatments severely accelerate complications of chronic kidney disease, in particular atherosclerotic disease progression that worsens outcomes when compared with non-dialysis patients.1 Improved understanding of the underlying molecular pathogenic mechanisms should help in the design of interventions that improve outcomes.2 Current state of the art in PD research, however, faces major limitations. Although there are numerous in vitro and ex vivo studies on complex cellular and molecular networks active in PD3, 4, 5 and in vivo animal models of PD6, 7, 8 that provide in-depth pathomechanistic insights and allow identification of promising therapeutic targets,9,S1,S2 translation into clinical studies is a major challenge.S3 Patient studies that aim to substantiate experimental findings with definitive clinical outcome data are mostly small. As a result, they have not provided sufficient power to derive meaningful or clinically implementable conclusions.2 Basic PD technique has hardly changed over decades, despite high PD-related complication rates. Randomized prospective trials with hard clinical end points studied with adequate power are difficult to realize in a multifactorial setting with low patient numbers (360,000 worldwide) and are associated with high costs. To overcome these barriers intermediate end points such as PD effluent biomarkers associated (but not necessarily causally related) with hard clinical end points and composite end points are often studied.S4,S5 Equally, combining analyses of existing cohort studies and trial data through collaborative sharing might be of considerable benefit

Twenty-three unsolved problems in hydrology (UPH) – a community perspective

This paper is the outcome of a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts. The procedure involved a public consultation through on-line media, followed by two workshops through which a large number of potential science questions were collated, prioritised, and synthesised. In spite of the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work. Questions remain focussed on process-based understanding of hydrological variability and causality at all space and time scales. Increased attention to environmental change drives a new emphasis on understanding how change propagates across interfaces within the hydrological system and across disciplinary boundaries. In particular, the expansion of the human footprint raises a new set of questions related to human interactions with nature and water cycle feedbacks in the context of complex water management problems. We hope that this reflection and synthesis of the 23 unsolved problems in hydrology will help guide research efforts for some years to come

Climate Change in the Baltic Sea Region: A Summary

Based on the Baltic Earth Assessment Reports of this thematic issue in Earth System Dynamics and recent peer-reviewed literature, current knowledge about the effects of global warming on past and future changes in climate of the Baltic Sea region is summarized and assessed. The study is an update of the Second Assessment of Climate Change (BACC II) published in 2015 and focusses on the atmosphere, land, cryosphere, ocean, sediments and the terrestrial and marine biosphere. Based on the summaries of the recent knowledge gained in paleo-, historical and future regional climate research, we find that the main conclusions from earlier assessments remain still valid. However, new long-term, homogenous observational records, e.g. for Scandinavian glacier inventories, sea-level driven saltwater inflows, so-called Major Baltic Inflows, and phytoplankton species distribution and new scenario simulations with improved models, e.g. for glaciers, lake ice and marine food web, have become available. In many cases, uncertainties can now be better estimated than before, because more models can be included in the ensembles, especially for the Baltic Sea. With the help of coupled models, feedbacks between several components of the Earth System have been studied and multiple driver studies were performed, e.g. projections of the food web that include fisheries, eutrophication and climate change. New data sets and projections have led to a revised understanding of changes in some variables such as salinity. Furthermore, it has become evident that natural variability, in particular for the ocean on multidecadal time scales, is greater than previously estimated, challenging our ability to detect observed and projected changes in climate. In this context, the first paleoclimate simulations regionalized for the Baltic Sea region are instructive. Hence, estimated uncertainties for the projections of many variables increased. In addition to the well-known influence of the North Atlantic Oscillation, it was found that also other low-frequency modes of internal variability, such as the Atlantic Multidecadal Variability, have profound effects on the climate of the Baltic Sea region. Challenges were also identified, such as the systematic discrepancy between future cloudiness trends in global and regional models and the difficulty of confidently attributing large observed changes in marine ecosystems to climate change. Finally, we compare our results with other coastal sea assessments, such as the North Sea Region Climate Change Assessment (NOSCCA) and find that the effects of climate change on the Baltic Sea differ from those on the North Sea, since Baltic Sea oceanography and ecosystems are very different from other coastal seas such as the North Sea. While the North Sea dynamics is dominated by tides, the Baltic Sea is characterized by brackish water, a perennial vertical stratification in the southern sub-basins and a seasonal sea ice cover in the northern sub-basins</p

Climate change in the Baltic Sea region: a summary

Based on the Baltic Earth Assessment Reports of this thematic issue in Earth System Dynamics and recent peer-reviewed literature, current knowledge of the effects of global warming on past and future changes in climate of the Baltic Sea region is summarised and assessed. The study is an update of the Second Assessment of Climate Change (BACC II) published in 2015 and focuses on the atmosphere, land, cryosphere, ocean, sediments, and the terrestrial and marine biosphere. Based on the summaries of the recent knowledge gained in palaeo-, historical, and future regional climate research, we find that the main conclusions from earlier assessments still remain valid. However, new long-term, homogenous observational records, for example, for Scandinavian glacier inventories, sea-level-driven saltwater inflows, so-called Major Baltic Inflows, and phytoplankton species distribution, and new scenario simulations with improved models, for example, for glaciers, lake ice, and marine food web, have become available. In many cases, uncertainties can now be better estimated than before because more models were included in the ensembles, especially for the Baltic Sea. With the help of coupled models, feedbacks between several components of the Earth system have been studied, and multiple driver studies were performed, e.g. projections of the food web that include fisheries, eutrophication, and climate change. New datasets and projections have led to a revised understanding of changes in some variables such as salinity. Furthermore, it has become evident that natural variability, in particular for the ocean on multidecadal timescales, is greater than previously estimated, challenging our ability to detect observed and projected changes in climate. In this context, the first palaeoclimate simulations regionalised for the Baltic Sea region are instructive. Hence, estimated uncertainties for the projections of many variables increased. In addition to the well-known influence of the North Atlantic Oscillation, it was found that also other low-frequency modes of internal variability, such as the Atlantic Multidecadal Variability, have profound effects on the climate of the Baltic Sea region. Challenges were also identified, such as the systematic discrepancy between future cloudiness trends in global and regional models and the difficulty of confidently attributing large observed changes in marine ecosystems to climate change. Finally, we compare our results with other coastal sea assessments, such as the North Sea Region Climate Change Assessment (NOSCCA), and find that the effects of climate change on the Baltic Sea differ from those on the North Sea, since Baltic Sea oceanography and ecosystems are very different from other coastal seas such as the North Sea. While the North Sea dynamics are dominated by tides, the Baltic Sea is characterised by brackish water, a perennial vertical stratification in the southern subbasins, and a seasonal sea ice cover in the northern subbasins