Interleukin 20 regulates dendritic cell migration and expression of co-stimulatory molecules

BACKGROUND: Psoriasis is an inflammatory disease characterized by leukocyte skin infiltration. Interestingly, recent works suggest that the migration of dendritic cells (DCs) is abnormal in psoriatic skin. DCs have significant role in regulating the function of T lymphocytes, at least in part influenced by the local environment of cytokines. In psoriatic skin lesions the expression of IL-20 is highly up-regulated. It is unclear if this cytokine has any influence on DCs. METHODS: Here, we investigated the influence of IL-20 in monocyte-derived dendritic cell (MDDCs) in vitro. This work addressed IL-20 effects on DC maturation, receptor expression and signaling. By use of extra cellular matrix components mimicking the skin environment, we also studied the functional effects of IL-20 on the chemotactic migration of DCs. Based on the recent finding that CD18 integrin are shed during migration of myeloid leukocytes, the concentration of these adhesion molecules was measured in MDDCs culture supernatants post migration. RESULTS: Following stimulation with IL-20, immature human MDDCs enhanced the expression of the co-stimulatory molecule CD86, further enabling activation of the p38 MAPK, but not the STAT3, pathway. IL-20 increased the migration of MDDCs in a biphasic response narrowly controlled by the interleukin concentration. A concomitant change in the shedding of CD18 integrins suggested that these adhesion molecules play a role in the migration of the MDDCs through the extracellular matrix layer. CONCLUSION: Taken together, our findings points to a possible, yet subtle, role of IL-20 in DCs migration. The biphasic response suggests that the aberrant IL-20 expression in psoriasis impedes DC migration, which could be a part of the processes that precipitates the dysregulated inflammatory response associated with this disease

Biosensors of inorganic lead exposure and effect in an adult amphibian

Lead (Pb) is a ubiquitous environmental pollutant, widely distributed, representing a high toxicological and ecotoxicological risk. Several morphological, functional, and biochemical parameters have been proposed as biomarkers of effect and exposure to Pb. The information related to adverse effects of Pb is not abundant for adult amphibians. These animals are of interest, because during their development they move from aquatic to terrestrial habitats, which may be polluted by the metal since they are receptors of products generated by anthropogenic activities. Previous studies carried out on the adult South American toad Bufo arenarum (Amphibia, Anura) showed that it has a high tolerance to lead and studied the effect of sublethal doses of the metal on the erythrocyte osmotic fragility and δ-ALAD activity. It was also shown that after a single injection of Pb, a significant increase in the number of reticulocytes was produced, suggesting the suitability of those cell counts as a biomarker of exposure to the metal; its impact on the immune system of the toads was also studied. In this work we extend our early studies on the same species evaluating the chronic effect of sublethal Pb (equivalent to 5.6% of the 120-h LD-50) on free erythrocyte protoporphyrin (FEP) and blood Pb and δ-ALAD activity; blood lead was positively associated with a significant decrease in the enzyme activity and to an increase in the FEP level. Pb concentration in target organs (liver, spleen, femur, and kidney) and the total cumulated amount as well as its impact over the mass of those organs were also determined. In addition, the magnitude of the possible depuration through urine and intestine was evaluated. Our results showed that FEP, δ-ALAD, and blood Pb are reliable biosensors of chronic metal intoxication, the former being the marker with the highest sensitivity.Facultad de Ciencias Exacta

Fermentation of deproteinized cheese whey powder solutions to ethanol by engineered Saccharomyces cerevisiae : effect of supplementation with corn steep liquor and repeated-batch operation with biomass recycling by flocculation

The lactose in cheese whey is an interesting substrate for the production of bulk commodities such as bio-ethanol, due to the large amounts of whey surplus generated globally. In this work, we studied the performance of a recombinant Saccharomyces cerevisiae strain expressing the lactose permease and intracellular ß-galactosidase from Kluyveromyces lactis in fermentations of deproteinized concentrated cheese whey powder solutions. Supplementation with 10 g/l of corn steep liquor significantly enhanced whey fermentation, resulting in the production of 7.4% (v/v) ethanol from 150 g/l initial lactose in shake-flask fermentations, with a corresponding productivity of 1.2 g/l/h. The flocculation capacity of the yeast strain enabled stable operation of a repeated-batch process in a 5.5-l air-lift bioreactor, with simple biomass recycling by sedimentation of the yeast flocs. During five consecutive batches, the average ethanol productivity was 0.65 g/l/h and ethanol accumulated up to 8% (v/v) with lactose-toethanol conversion yields over 80% of theoretical. Yeast viability (>97%) and plasmid retention (>84%) remained high throughout the operation, demonstrating the stability and robustness of the strain. In addition, the easy and inexpensive recycle of the yeast biomass for repeated utilization makes this process economically attractive for industrial implementation.Fundação para a Ciência e a Tecnologia (FCT)LACTOGAL-Produtos Alimentares S.A.Companhia Portuguesa de Amidos, S.A

Age of the Association between Helicobacter pylori and Man

When modern humans left Africa ca. 60,000 years ago (60 kya), they were already infected with Helicobacter pylori, and these bacteria have subsequently diversified in parallel with their human hosts. But how long were humans infected by H. pylori prior to the out-of-Africa event? Did this co-evolution predate the emergence of modern humans, spanning the species divide? To answer these questions, we investigated the diversity of H. pylori in Africa, where both humans and H. pylori originated. Three distinct H. pylori populations are native to Africa: hpNEAfrica in Afro-Asiatic and Nilo-Saharan speakers, hpAfrica1 in Niger-Congo speakers and hpAfrica2 in South Africa. Rather than representing a sustained co-evolution over millions of years, we find that the coalescent for all H. pylori plus its closest relative H. acinonychis dates to 88–116 kya. At that time the phylogeny split into two primary super-lineages, one of which is associated with the former hunter-gatherers in southern Africa known as the San. H. acinonychis, which infects large felines, resulted from a later host jump from the San, 43–56 kya. These dating estimates, together with striking phylogenetic and quantitative human-bacterial similarities show that H. pylori is approximately as old as are anatomically modern humans. They also suggest that H. pylori may have been acquired via a single host jump from an unknown, non-human host. We also find evidence for a second Out of Africa migration in the last 52,000 years, because hpEurope is a hybrid population between hpAsia2 and hpNEAfrica, the latter of which arose in northeast Africa 36–52 kya, after the Out of Africa migrations around 60 kya

Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909

T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T cell responses, our data caution that a vaccination with leukemia-associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Rhabdomyosarcoma Arising in Inflammatory Rhabdomyoblastic Tumor: A Genetically Distinctive Subtype of Rhabdomyosarcoma

“Inflammatory rhabdomyoblastic tumor” (IRMT) is a recently coined name for a distinctive soft tissue neoplasm characterized by slow growth, a dense histiocytic infiltrate, scattered, bizarre-appearing tumor cells with morphologic and immunohistochemical evidence of skeletal muscle differentiation, a near-haploid karyotype with retained biparental disomy of chromosomes 5 and 22, and usually indolent behavior. There are 2 reports of rhabdomyosarcoma (RMS) arising in IRMT. We studied the clinicopathologic and cytogenomic features of 6 cases of IRMT with progression to RMS. Tumors occurred in the extremities of 5 men and 1 woman (median patient age, 50 years; median tumor size, 6.5 cm). Clinical follow-up (6 patients: median, 11 months; range 4-163 months) documented local recurrence and distant metastases in 1 and 5 of 6 patients, respectively. Therapy included complete surgical resection (4 patients) and adjuvant/neoadjuvant chemo/radiotherapy (6 patients). One patient died of disease, 4 were alive with metastatic disease, and one was without evidence of disease. All primary tumors contained conventional IRMT. Progression to RMS appeared as follows: (1) overgrowth of monomorphic rhabdomyoblasts with diminished histiocytes, (2) monomorphic spindle cell morphology with variably pleomorphic rhabdomyoblasts and low mitotic activity, or (3) morphologically undifferentiated spindle cell and epithelioid sarcoma. All but one were diffusely desmin-positive, with more limited MyoD1/myogenin expression. All RMS arising in IRMT, either primary or metastatic, demonstrated widespread loss of heterozygosity with retained heterozygosity of chromosomes 5 and 20, and all but one displayed additional gains and losses involving loci containing oncogenes/ tumor suppressor genes, most often CDKN2A and CDKN2B. RMS arising in IRMT have unique clinicopathologic and cytogenomic features, warranting classification as a distinct, potentially aggressive RMS subtype. It should be distinguished from other RMSs, particularly fusion-driven spindle cell RMS and pleomorphic RMS