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In silico proteolysis using 27 proteases theoretically released numerous ACE-inhibitory peptides from collagen alpha-1(I) and alpha-2(I) sequences. Papain was the most effective protease to release ACE-inhibitory peptides. Two quantitative structure–activity relationship (QSAR) models for ACE-inhibitory peptides were established and employed to predict the activities of in silico-derived collagen peptides. Furthermore, two promising in silico peptides (Tyr-Trp and Leu-Arg-Tyr) derived from papain and bromelain digestion were synthesised and experimentally confirmed as novel ACE inhibitors. In vitro digestion of collagen by papain generated ACE-inhibitory peptides and the most active one was identified as a pentapeptide (Gly-Pro-Arg-Gly-Phe). However, Gly-Pro-Arg-Gly-Phe remained unidentified as the ACE-inhibitory peptide during the in silico digestion by papain mainly due to complete hydrolysis, which was not the case during in vitro digestion affected by external factors. Overall, the present study highlights bovine collagen as a promising precursor of ACE-inhibitory peptides by in silico and in vitro protein digestions.

Abstract Between 1 September and 15 November 2017, 48 A(H5N8) highly pathogenic avian influenza (HPAI) outbreaks in poultry holdings and 9 H5 HPAI wild bird events were reported within Europe. A second epidemic HPAI A(H5N8) wave started in Italy on the third week of July and is still ongoing on 15 November 2017. The Italian epidemiological investigations indicated that sharing of vehicles, sharing of personnel and close proximity to infected holdings are the more likely sources of secondary spread in a densely populated poultry area. Despite the ongoing human exposures to infected poultry during the outbreaks, no transmission to humans has been identified in the EU. The report includes an update of the list of wild bird target species for passive surveillance activities that is based on reported AI‐infected wild birds since 2006. The purpose of this list is to provide information on which bird species to focus in order to achieve the most effective testing of dead birds for detection of H5 HPAI viruses. Monitoring the avian influenza situation in other continents revealed the same risks as in the previous report (October 2016‐August 2017): the recent human case of HPAI A(H5N6) in China underlines the continuing threat of this avian influenza virus to human health and possible introduction via migratory wild birds into Europe. Close monitoring is required of the situation in Africa with regards to HPAI of the subtypes A(H5N1) and A(H5N8), given the rapidity of the evolution and the uncertainty on the geographical distribution of these viruses. Interactions between EFSA and member states have taken place to initiate discussions on improving the quality of data collections and to find a step‐wise approach to exchange relevant (denominator) data without causing an additional resource burden.

Oral squamous cell carcinoma (OSCC) patients have a high mortality rate; thus, new clinical biomarkers and therapeutic options are needed. MicroRNAs (miRNAs) are short noncoding RNAs that regulate posttranscriptional gene expression and are commonly deregulated in OSCC and other cancers. MicroRNA-21 (miR-21) is the most consistently overexpressed miRNA in several types of cancer, and it might be a useful clinical biomarker and therapeutic target. To better understand the role of miR-21 in OSCC, paraffin-embedded tumor tissue samples from 86 patients with primary OSCC were analyzed by in situ hybridization. We found that miR-21 was primarily expressed in the tumor stroma and in some tumor-associated blood vessels with no expression in the adjacent normal epithelia or stroma. Using image analysis, we quantitatively estimated miR-21 expression levels specifically in the stroma of a cohort of OSCC samples. These miR-21 levels significantly correlated with disease free survival with the highest levels being located in the stroma. Stromal miR-21 expression was independently associated with a poorer prognosis, even after adjusting for clinical parameters (perineural invasion and N-stage) in a multivariate analysis. In summary, we have shown that miR-21 is located in the carcinoma cells, stroma and blood vessels of tumors, and its expression specifically in the stromal compartment has a negative prognostic value in OSCC.

BackgroundThe purpose of this study was to examine the prevalence of human papillomavirus (HPV) in patients with head and neck squamous cell carcinoma of unknown primary (CUP).MethodsAll patients diagnosed with and treated for CUP between January 1, 2000, and June 1, 2011, at two Danish medical centers were included. All patients received a thorough diagnostic work-up, including FDG-PET, before being diagnosed as CUP. We determined the HPV status in all patients using a combination of HPV DNA PCR and p16 stain. In addition, clinical information on the study patients was retrieved from clinical records.ResultsOf the identified 60 patients with CUP, 13 were shown to be positive for HPV DNA, amounting to 22% of the study population. In addition, we were able to show a clear disease-free and overall-survival benefit in the HPV-positive group, with a hazard ratio of 0.16 (95% CI: 0.038-0.67) for over-all survival. This survival benefit was also apparent when adjusted for advanced age in a multivariate Cox regression analysis.ConclusionA fairly large percentage of CUP cases are HPV-related, and because this is related to both the location and prognosis, we recommend HPV testing as part of the diagnostic work-up.

Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects.We addressed the gene expression signatures in colorectal cancer linked to Lynch syndrome and FCCTX with the aim to identify candidate genes and to map signaling pathways relevant in hereditary colorectal carcinogenesis.The 18 k whole-genome c-DNA-mediated annealing, selection, extension, and ligation (WG-DASL) assay was applied to 123 colorectal cancers, including 39 Lynch syndrome tumors and 37 FCCTX tumors. Target genes were technically validated using real-time quantitative RT-PCR (qRT-PCR) and the expression signature was validated in independent datasets.Colorectal cancers linked to Lynch syndrome and FCCTX showed distinct gene expression profiles, which by significance analysis of microarrays (SAM) differed by 2188 genes. Functional pathways involved were related to G-protein coupled receptor signaling, oxidative phosphorylation, and cell cycle function and mitosis. qRT-PCR verified altered expression of the selected genes NDUFA9, AXIN2, MYC, DNA2 and H2AFZ. Application of the 2188-gene signature to independent datasets showed strong correlation to MMR status.Distinct genetic profiles and deregulation of different canonical pathways apply to Lynch syndrome and FCCTX and key targets herein may be relevant to pursue for refined diagnostic and therapeutic strategies in hereditary colorectal cancer.

Equine Assisted Physiotherapy (EAPT) offers children with cerebral palsy (CP) opportunities for new movement experiences, and may influence movement qualities. Descriptions of how, and to what extent EAPT affects trunk control is missing. The aim of this study was to explore if, and how changes in trunk control and changes in other movement aspects were observable in children with CP during EAPT, and if potential changes in trunk control could be measured. A multiple case study with a mixed methods design was completed. Two children with CP, GMFCS grade 1, were observed using video during a period of six months, and tested with Trunk Impairment Scale modified Norwegian Version. Skilled physiotherapists analyzed the videos qualitatively, and triangulated recurring changes in movement with the results from the test. Riding bareback, improvements in trunk control were observed and measured. However, riding in a saddle led to reduced trunk control. Other observable movement changes were: from asymmetry to symmetry, adaptation to rhythm, mastery of riding skills, and reduced loss of postural control. Increased instances of adapting own movements in spontaneous dialogue with the horse, were observed. Instructions and feedback from the therapist influenced the dialogue with the horse both positively and negatively. This study describes in detail how balance and symmetry can be stimulated during EAPT in a body characterized by imbalance and asymmetry. During EAPT, the children gained the possibility to explore new movement qualities. Equipment and feedback influenced movement qualities. [ABSTRACT FROM AUTHOR]

The study investigated the development over time of the incidence, diagnostic imaging, and treatment of giant cell arteritis (GCA). This nationwide, population-based cohort study was conducted in Denmark using medical and administrative registries. Incident GCA cases from 1996–2018 were defined as patients aged ≥50 years registered with a first-time GCA diagnosis and ≥3 prescriptions for glucocorticoids (GCs) within 6 months after diagnosis. We determined incidence rates of GCA, the proportion of patients still receiving GCs >2 years after diagnosis, the proportion of patients receiving temporal artery biopsies (TAB) and diagnostic imaging including ultrasound, positron emission tomography, magnetic resonance, and/or computed tomography angiography at the time of diagnosis. We identified 9908 incident GCA cases. The incidence rates of GCA remained stable at 19–25 per 100,000 people aged >50 years from 1996–2018. The proportion of GCA patients receiving a TAB remained constant until 2016, after which it promptly declined from 70–80% to 29–39%. In contrast, the proportion of patients receiving diagnostic imaging increased from 2% to 66% from 2000–2018. The proportion of GCA patients remaining in GC treatment has steadily decreased from 1996–2016, but remains high at 64%, 40%, and 34% after 2, 5, and 10 years following the diagnosis, respectively. The cumulative GC dose has remained relatively stable. Incidence rates of GCA have remained stable since 1996 despite increasing use of diagnostic imaging. There is a clear discrepancy between current international GCA treatment guidelines and the clinical practice up to 2018. [ABSTRACT FROM AUTHOR]

Purpose : Osteoporosis is under-diagnosed and often co-exists with other diseases. Very low bone mineral density (BMD) indicates risk of osteoporosis and opportunistic screening for low BMD in CT-scans has been suggested. In a non-contrast enhanced thoracic CT scan, the scan-field-of-view includes vertebrae enabling BMD estimation. However, many CT scans are obtained by administration of contrast material. If the impact of contrast enhancement on BMD measurements could be quantified, considerably more patients are eligible for screening. Methods : This study investigated the impact of intravenous contrast on thoracic BMD measurements in cardiac CT scans pre- and post-contrast, including different contrast trigger levels of 130 and 180 Hounsfield units (HU). BMD was measured using quantitative CT with asynchronous calibration. Results : In 195 participants undergoing cardiac CT (mean age 57±9 years, 37 % females) contrast increased mean thoracic BMD from 116±33 mg/cm3 (non-enhanced CT) to 130±38 mg/cm3 (contrast-enhanced CT) (p<0.001). Using clinical cut-off values for very low (<80 mg/cm3) and low BMD (<120 mg/cm3) showed that 24 % (47/195 participants) were misclassified when BMD was measured on contrast-enhanced CT-scans. Of the misclassified patients, 6 % (12/195 participants) were categorized as having low BMD despite having very low BMD on the non-enhanced images. Contrast-CT using a higher contrast trigger level showed a significant increase in BMD compared to the lower trigger level (119±32 vs. 135±40 mg/cm3, p<0.01). Conclusion : For patients undergoing cardiac CT, using contrast-enhanced images to assess BMD entails substantial overestimation. Contrast protocol trigger levels also affect BMD measurements. Adjusting for these factors is needed before contrast-enhanced images can be used clinically. Mini abstract : Osteoporosis is under-diagnosed. Contrast-enhanced CT made to examine other diseases might be utilized simultaneously for bone mineral density (BMD) screening. These scans, however, likely entails overestimation of BMD due to the effect of contrast. Adjusting for this effect is needed before contrast-enhanced images can be implemented clinically for BMD screening. [ABSTRACT FROM AUTHOR]

Atherosclerosis and osteoporosis are both common and preventable diseases. Evidence supports a link between coronary artery disease (CAD) and low bone mineral density (BMD). This study aimed to assess the association between thoracic spine BMD and CAD in men and women with symptoms suggestive of CAD. This cross-sectional study included 1487 (mean age 57 years (range 40-80), 47% men) patients referred for cardiac computed tomography (CT). Agatston coronary artery calcium score (CACS), CAD severity (no, mild, moderate, and severe), vessel involvement (no, 1-, 2-, and 3/left main disease), and invasive measurements were evaluated. BMD of three thoracic vertebrae was measured using quantitative CT. We used the American college of radiology cut-off values for lumbar spine BMD to categorize patients into very low (<80 mg/cm3), low (80-120 mg/cm3), or normal BMD (>120 mg/cm3). BMD as a continuous variable was included in the linear regression analyses to assess associations between CACS (CACS=0, CACS 1- 399, and CACS ≥ 400) and BMD, and CAD severity and BMD. Significant lower BMD was present with increasing CACS and stenosis degree unadjusted. Multivariate linear regression analyses in women revealed a significant correlation between BMD and CACS groups (β = −4.06, p<0.05), but no correlation between BMD and CAD severity (β = −1.59, p = 0.14). No association was found between BMD and CACS (β = −1.50, p = 0.36) and CAD severity (β = 0.07, p = 0.94) in men. BMD is significantly correlated to CACS after adjusting for confounders in women, but not in men, suggesting a possible sex difference in pathophysiology. [ABSTRACT FROM AUTHOR]

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Despite being a frequent and treatable disease, osteoporosis remains under-diagnosed worldwide. Our study aim was to characterize the bone mineral density (BMD) status in a group of patients with symptoms suggestive of coronary artery disease (CAD) with low/intermediate risk profile undergoing routine cardiac computed tomography (CT) to rule out CAD. This cross-sectional study used prospectively acquired data from a large consecutively included cohort. Participants were referred for cardiac CT based on symptoms of CAD. Quantitative CT (QCT) dedicated software was used to obtain BMD measurements in 3 vertebrae starting from the level of the left main coronary artery. We used the American College of Radiology cut-off values for lumbar spine QCT to categorize patients into very low (<80 mg/cm3), low (80-120 mg/cm3), or normal BMD (>120 mg/cm3). Analyses included 1487 patients. Mean age was 57 years (range 40-80), and 52% were women. The number of patients with very low BMD was 105 women (14%, 105/773) and 74 men (10%, 74/714). The majority of patients with very low BMD was not previously diagnosed with osteoporosis (87%) and received no anti-osteoporotic treatment (90%). Opportunistic screening in patients referred for cardiac CT revealed a substantial number of patients with very low BMD. The majority of these patients was not previously diagnosed with osteoporosis and received no anti-osteoporotic treatment. Identification of these patients could facilitate initiation of anti-osteoporotic treatment and reduce the occurrence of osteoporosis-related complications [ABSTRACT FROM AUTHOR]