Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer

Development and application of statistical models for medical scientific researc

Whole genome analysis of a schistosomiasis-transmitting freshwater snail

Biomphalaria snails are instrumental in transmission of the human blood fluke Schistosoma mansoni. With the World Health Organization's goal to eliminate schistosomiasis as a global health problem by 2025, there is now renewed emphasis on snail control. Here, we characterize the genome of Biomphalaria glabrata, a lophotrochozoan protostome, and provide timely and important information on snail biology. We describe aspects of phero-perception, stress responses, immune function and regulation of gene expression that support the persistence of B. glabrata in the field and may define this species as a suitable snail host for S. mansoni. We identify several potential targets for developing novel control measures aimed at reducing snail-mediated transmission of schistosomiasis

Mapping geographical inequalities in childhood diarrhoeal morbidity and mortality in low-income and middle-income countries, 2000–17 : analysis for the Global Burden of Disease Study 2017

Background Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood diarrhoea. Methods We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor estimates. Findings The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1–65·8), 17·4% (7·7–28·4), and 59·5% (34·2–86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy coverage. Interpretation By co-analysing geospatial trends in diarrhoeal burden and its key risk factors, we could assess candidate drivers of subnational death reduction. Further, by doing a counterfactual analysis of the remaining disease burden using key risk factors, we identified potential intervention strategies for vulnerable populations. In view of the demands for limited resources in LMICs, accurately quantifying the burden of diarrhoea and its drivers is important for precision public health

Evidence of an inflammatory-like response in non-normally pigmented tissues of two scleractinian corals

Increasing evidence of links between climate change, anthropogenic stress and coral disease underscores the importance of understanding the mechanisms by which reef-building corals resist infection and recover from injury. Cellular inflammation and melanin-producing signalling pathway are two mechanisms employed by invertebrates to remove foreign organisms such as pathogens, but they have not been recorded previously in scleractinian corals. This study demonstrates the presence of the phenoloxidase (PO) activating melanin pathway in two species of coral, Acropora millepora and a massive species of Porites, which both develop local pigmentation in response to interactions with a variety of organisms. l-DOPA (3-(3,4-dihydroxyphenyl)-l-alanine) substrate-based enzyme activation assays demonstrated PO activity in healthy tissues of both species and upregulation in pigmented tissues of A. millepora. Histological staining conclusively identified the presence of melanin in Porites tissues. These results demonstrate that the PO pathway is active in both coral species. Moreover, the upregulation of PO activity in areas of non-normal pigmentation in A. millepora and increased melanin production in pigmented Porites tissues suggest the presence of a generalized defence response to localized stress. Interspecific differences in the usage of pathways involved in innate immunity may underlie the comparative success of massive Porites sp. as long-lived stress tolerators

Effect of administration of apoptotic blebs on disease development in lupus mice.

Item does not contain fulltextINTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the formation of autoantibodies against nuclear components. Disturbed apoptosis and reduced clearance of apoptotic material have been assigned a role in the pathogenesis of SLE. During apoptosis, apoptotic blebs are formed, in which SLE autoantigens are clustered. In vitro, apoptotic blebs can induce maturation of dendritic cells (DC), which in turn can stimulate IL-17 production by T cells. Here, we investigated the effects of administration of apoptotic blebs, separate or in combination with dendritic cells, on disease progression and autoantibody production in lupus and normal mice. METHODS: A preparation of apoptotic blebs, with or without DC, was intravenously administered to MRL/lpr and CBA mice at weeks 7, 9, and 11 of age. T-cell responses against autoantigens present in blebs were examined by delayed type hypersensitivity reactions. Disease progression of the mice was evaluated by determining proteinuria and the titers of anti-DNA, anti-histone, and anti-nucleosome autoantibodies in plasma. RESULTS: Repeated administration of apoptotic blebs, with or without DC, had no effect on the course of proteinuria or on anti-DNA, anti-histone and anti-nucleosome autoantibody levels in MRL/lpr mice. Intravenous injections of apoptotic blebs resulted in a decrease in the DTH response towards s.c. administered blebs in MRL/lpr mice and in reduced anti-nucleosome antibody titers in CBA mice. These tolerizing effects were lost when apoptotic blebs were administered together with syngeneic DC after 2 hours of co-incubation. DISCUSSION AND CONCLUSIONS: In contrast to previous studies with apoptotic cells, and deviating from our in vitro findings with apoptotic blebs, we observed no stimulating effect of the administration of apoptotic blebs on disease progression in MRL/lpr lupus mice. The tolerogenic effects that were observed may be associated with rapid removal of i.v. administered blebs by phagocytes in an immune-silencing way.1 juni 201

Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients

PURPOSE: We have investigated the capacity of immature and mature monocyte-derived DCs pulsed with melanoma-associated peptides (gp100 and tyrosinase) to induce a primary cytotoxic T-lymphocyte response in vivo. EXPERIMENTAL DESIGN: Advanced HLA-A2.1(+) melanoma patients were vaccinated with peptide- and keyhole limpet hemocyanin (KLH)-pulsed DCs, either immature (9 patients) or matured by monocyte-conditioned medium/tumor necrosis factor alpha/prostaglandin E(2) (10 patients). Results : All patients vaccinated with mature DCs showed a pronounced proliferative T-cell and humoral response against KLH. By contrast, KLH responses were absent in most of the patients vaccinated with immature DCs. Delayed-type hypersensitivity (DTH) reactions against antigen-pulsed DCs were only observed in patients vaccinated with mature DCs and not in patients vaccinated with immature DCs. MHC-peptide tetramer staining of DTH-derived T cells revealed the presence of specific T cells recognizing the melanoma-associated peptides in 1 patient. In a second patient, DTH-derived T cells showed specific lysis of tumor cells expressing the antigens used for DC pulsing. Only patients vaccinated with mature DCs showed objective clinical responses. Interestingly, both patients with long-term progression-free survival (22 and >40 months) were both vaccinated with mature DCs and demonstrated antigen-specific T-cell reactivity of DTH-derived T cells. CONCLUSIONS: We conclude that mature DC are superior to immature DC in the induction of immunological responses in melanoma patients, which may translate into improved clinical results

Point mutation in the stalk of angiotensin-converting enzyme causes a dramatic increase in serum angiotensin-converting enzyme but no cardiovascular disease.

Item does not contain fulltextBACKGROUND: Angiotensin-converting enzyme (ACE) metabolizes many small peptides and plays a key role in blood pressure regulation. Elevated serum ACE is claimed to be associated with an increased risk for cardiovascular disease. Previously, two families with dramatically increased serum ACE were described, but no systematic survey of affected individuals was performed, and the molecular background of this trait is unknown. METHODS AND RESULTS: Eight families were identified with autosomal dominant inheritance of a dramatic (5-fold) increase of serum ACE activity. Strikingly, no clinical abnormalities were apparent in the affected subjects. Isolated blood cells were used for genetic and biochemical analysis. The level of ACE expression on the blood leukocytes and dendritic cells and total cell-associated ACE of the affected individuals was similar to that in nonaffected relatives; however membrane-bound mutant ACE was much more efficiently clipped from the cell surface compared with its wild-type counterpart. A point mutation causing Pro1199Leu in the stalk region of the ACE molecule cosegregates with the increase in serum ACE (LOD score, 6.63). CONCLUSIONS: A point mutation in the stalk region of the ACE protein causes increased shedding, leading to increased serum ACE, whereas cell-bound ACE is unaltered, and affected individuals exhibit no clinical abnormalities. These findings qualify the importance of serum ACE and establish a new determinant of ACE solubilization

Probing the binding specificities of human Siglecs by cell-based glycan arrays

Siglecs are a family of sialic acid-binding receptors expressed by cells of the immune system and a few other cell types capable of modulating immune cell functions upon recognition of sialoglycan ligands. While human Siglecs primarily bind to sialic acid residues on diverse types of glycoproteins and glycolipids that constitute the sialome, their fine binding specificities for elaborated complex glycan structures and the contribution of the glycoconjugate and protein context for recognition of sialoglycans at the cell surface are not fully elucidated. Here, we generated a library of isogenic human HEK293 cells with combinatorial loss/gain of individual sialyltransferase genes and the introduction of sulfotransferases for display of the human sialome and to dissect Siglec interactions in the natural context of glycoconjugates at the cell surface. We found that Siglec-4/7/15 all have distinct binding preferences for sialylated GalNAc-type O-glycans but exhibit selectivity for patterns of O-glycans as presented on distinct protein sequences. We discovered that the sulfotransferase CHST1 drives sialoglycan binding of Siglec-3/8/7/15 and that sulfation can impact the preferences for binding to O-glycan patterns. In particular, the branched Neu5Acα2-3(6-O-sulfo)Galβ1-4GlcNAc (6'-Su-SLacNAc) epitope was discovered as the binding epitope for Siglec-3 (CD33) implicated in late-onset Alzheimer's disease. The cell-based display of the human sialome provides a versatile discovery platform that enables dissection of the genetic and biosynthetic basis for the Siglec glycan interactome and other sialic acid-binding proteins