Global methylome scores correlate with histological subtypes of colorectal carcinoma and show different associations with common clinical and molecular features

Background. The typical methylation patterns associated with cancer are hypermethylation at gene promoters and global genome hypomethylation. Aberrant CpG island hypermethylation at promoter regions and global genome hypomethylation have not been associated with histological colorectal carcinomas (CRC) subsets. Using Illumina’s 450 k Infinium Human Methylation beadchip, the methylome of 82 CRCs were analyzed, comprising different histological subtypes: 40 serrated adenocarcinomas (SAC), 32 conventional carcinomas (CC) and 10 CRCs showing histological and molecular features of microsatellite instability (hmMSI‐H), and, additionally, 35 normal adjacent mucosae. Scores reflecting the overall methylation at 250 bp, 1 kb and 2 kb from the transcription starting site (TSS) were studied. Results. SAC has an intermediate methylation pattern between CC and hmMSI‐H for the three genome locations. In addition, the shift from promoter hypermethylation to genomic hypomethylation occurs at a small sequence between 250 bp and 1 Kb from the gene TSS, and an asymmetric distribution of methylation was observed between both sides of the CpG islands (N vs. S shores). Conclusion. These findings show that different histological subtypes of CRC have a particular global methylation pattern depending on sequence distance to TSS and highlight the so far underestimated importance of CpGs aberrantly hypomethylated in the clinical phenotype of CRCs.This work was supported by two grants from Instituto de Salud Carlos III, Ministerio de Sanidad, Spain and FEDER funds (refs: PI12-1232, PI18-0144) and another from the European Union’s Horizon 2020 research and innovation program (ref. 848098

Comparative antibacterial potential of selected aldehyde-based biocides and surfactants against planktonic Pseudomonas fluorescens

The antimicrobial efficacy of two aldehydebased biocides (glutaraldehyde, GTA, and orthophthalaldehyde, OPA) and two surfactants (cetyltrimethyl ammonium bromide, CTAB, and sodium dodecyl sulphate, SDS) was tested against planktonic Pseudomonas fluorescens. The antimicrobial effects were evaluated by respiratory activity as a measure of the oxygen uptake rate, adenosine triphosphate (ATP) release, outer membrane proteins (OMP) expression and cellular colour changes. The results were compared with the bacterial characteristics without chemical treatment. Tests in the presence of bovine serum albumin (BSA), in order to mimic a disinfection process in the real situation under dirty conditions, were performed according to the European Standard EN-1276. P. fluorescens was completely inactivated with OPA (minimum bactericidal concentration, MBC = 0.5 mM) and CTAB (MBC = 5 mM) and was resistant to GTA and SDS. Only CTAB promoted cellular disruption and consequent ATP release. The antimicrobial action of the chemicals tested was significantly reduced when BSA was introduced into the bacterial cultures, increasing markedly the MBC values. Additionally, the presence of BSA acted as a disruption protective agent when CTAB was applied and stimulated the bacterial respiratory activity when lower concentrations of SDS were tested. The OMP of the bacterial cells was affected by the application of both surfactants. OMP expression remained unaltered after biocide treatment. Bacterial colour change was noticed after treatment with biocides and surfactants. In summary, P. fluorescens was extremely resistant to GTA and SDS, with antimicrobial action being quenched markedly by the reaction with BSA.Instituto de Biotecnologia e Química Fina (IBQF).Fundação para a Ciência e a Tecnologia (FCT) - (Project CHEMBIO - POCI/BIO/61872/2004

Bone mineral density and cytokine levels during interferon therapy in children with chronic hepatitis B: does interferon therapy prevent from osteoporosis?

BACKGROUND: Our aim was to determinate bone mineral density (BMD), levels of biochemical markers and cytokines in children with chronic hepatitis B treated with interferon (IFN)-alpha and to investigate effect of IFN-alpha therapy on these variables. To the best of our knowledge, this is first study carried out about BMD and cytokine levels in pediatric patients with chronic hepatitis B treated with IFN-alpha. METHODS: BMD, levels of parathyroid hormone (PTH), osteocalcin, C-terminal cross-linking telopeptide of type I collagen (CTX), calcium, alkaline phosphates (ALP), cytokines as TNF-alpha, interleukin (IL)-1(β), IL-2r, IL-6, and IL-8 were studied in 54 children with chronic hepatitis B (4–15 years old) treated with interferon alone (n = 19) or in combination with lamivudine (n = 35) for six months and as controls in 50 age-matched healthy children. RESULTS: There was no significant difference in respect to serum IL-1(β), TNF-α and osteocalcin levels while serum IL-2r (p = 0.002), IL-6 (p = 0.001), IL-8 (p = 0.013), PTH (p = 0.029), and CTX (p = 0.021) levels were higher in children with chronic hepatitis B than in healthy controls. BMD of femur neck (p = 0.012) and trochanter (p = 0.046) in patients were higher than in healthy controls. There was a statistically significant correlation between serum IL-1(β )and osteocalcin (r = -0.355, p < 0.01); between serum IL-8 and CTX levels (r = 0.372, p = 0.01), and ALP (r = 0.361, p = 0.01); between serum ALP and femur neck BMD (r = 0.303, p = 0.05), and trochanter BMD (r = 0.365, p = 0.01); between spine BMD and IL-2R (r = -0.330, p < 0.05). CONCLUSION: In conclusion, our study suggest that BMD of femur, serum IL-2r, IL-6, IL-8, PTH, and CTX levels were higher in children with chronic hepatitis B treated with IFN-alpha alone or combination with lamivudine than in healthy children. High femur BMD measurements found in patients may suggest that IFN-alpha therapy in children with chronic hepatitis B could contribute indirectly to prevent from hip osteoporosis. Additionally, further investigations on effects of IFN-alpha for bone structure in children should be performed in the future

Burden of community-acquired and nosocomial rotavirus gastroenteritis in the pediatric population of Western Europe: a scoping review

<p>Abstract</p> <p>Background</p> <p>Rotavirus affects 95% of children worldwide by age 5 years and is the leading cause of severe dehydrating diarrhea. The objective of this review was to estimate the burden of rotavirus gastroenteritis (RVGE) in the Western European pediatric population.</p> <p>Methods</p> <p>A comprehensive literature search (1999-2010) was conducted in PubMed and other sources (CDC; WHO, others). Data on the epidemiology and burden of RVGE among children < 5 years-old in Western Europe --including hospital-acquired disease--were extracted.</p> <p>Results</p> <p>76 studies from 16 countries were identified. The mean percentage of acute gastroenteritis (AGE) cases caused by rotavirus ranged from 25.3%-63.5% in children < 5 years of age, peaking during winter. Incidence rates of RVGE ranged from 1.33-4.96 cases/100 person- years. Hospitalization rates for RVGE ranged from 7% to 81% among infected children, depending on the country. Nosocomial RVGE accounted for 47%-69% of all hospital-acquired AGE and prolonged hospital stays by 4-12 days. Each year, RVGE incurred $0.54-$53.6 million in direct medical costs and $1.7-$22.4 million in indirect costs in the 16 countries studied. Full serotyping data was available for 8 countries. G1P[8], G2P[4], G9P[8], and G3P[8] were the most prevalent serotypes (cumulative frequency: 57.2%- 98.7%). Serotype distribution in nosocomial RVGE was similar.</p> <p>Conclusions</p> <p>This review confirms that RVGE is a common disease associated with significant morbidity and costs across Western Europe. A vaccine protecting against multiple serotypes may decrease the epidemiological and cost burden of RVGE in Western Europe.</p

In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis

Abstract The peptide hormone human relaxin-2 (H2-RLX) has emerged as a potential therapy for cardiovascular and fibrotic diseases, but its short in vivo half-life is an obstacle to long-term administration. The discovery of ML290 demonstrated that it is possible to identify small molecule agonists of the cognate G-protein coupled receptor for H2-RLX (relaxin family peptide receptor-1 (RXFP1)). In our efforts to generate a new medicine for liver fibrosis, we sought to identify improved small molecule functional mimetics of H2-RLX with selective, full agonist or positive allosteric modulator activity against RXFP1. First, we confirmed expression of RXFP1 in human diseased liver. We developed a robust cellular cAMP reporter assay of RXFP1 signaling in HEK293 cells transiently expressing RXFP1. A high-throughput screen did not identify further specific agonists or positive allosteric modulators of RXFP1, affirming the low druggability of this receptor. As an alternative approach, we generated novel ML290 analogues and tested their activity in the HEK293-RXFP1 cAMP assay and the human hepatic cell line LX-2. Differences in activity of compounds on cAMP activation compared with changes in expression of fibrotic markers indicate the need to better understand cell- and tissue-specific signaling mechanisms and their disease-relevant phenotypes in order to enable drug discovery