Showing papers by "University College Cork published in 2017"

Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

Abstract: Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Abstract: Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Tumour-associated and non-tumour-associated microbiota in colorectal cancer

Abstract: Objective A signature that unifies the colorectal cancer (CRC) microbiota across multiple studies has not been identified. In addition to methodological variance, heterogeneity may be caused by both microbial and host response differences, which was addressed in this study. Design We prospectively studied the colonic microbiota and the expression of specific host response genes using faecal and mucosal samples (‘ON’ and ‘OFF’ the tumour, proximal and distal) from 59 patients undergoing surgery for CRC, 21 individuals with polyps and 56 healthy controls. Microbiota composition was determined by 16S rRNA amplicon sequencing; expression of host genes involved in CRC progression and immune response was quantified by real-time quantitative PCR. Results The microbiota of patients with CRC differed from that of controls, but alterations were not restricted to the cancerous tissue. Differences between distal and proximal cancers were detected and faecal microbiota only partially reflected mucosal microbiota in CRC. Patients with CRC can be stratified based on higher level structures of mucosal-associated bacterial co-abundance groups (CAGs) that resemble the previously formulated concept of enterotypes. Of these, Bacteroidetes Cluster 1 and Firmicutes Cluster 1 were in decreased abundance in CRC mucosa, whereas Bacteroidetes Cluster 2, Firmicutes Cluster 2, Pathogen Cluster and Prevotella Cluster showed increased abundance in CRC mucosa. CRC-associated CAGs were differentially correlated with the expression of host immunoinflammatory response genes. Conclusions CRC-associated microbiota profiles differ from those in healthy subjects and are linked with distinct mucosal gene-expression profiles. Compositional alterations in the microbiota are not restricted to cancerous tissue and differ between distal and proximal cancers.

Towards standards for human fecal sample processing in metagenomic studies

Abstract: Technical variation in metagenomic analysis must be minimized to confidently assess the contributions of microbiota to human health. Here we tested 21 representative DNA extraction protocols on the same fecal samples and quantified differences in observed microbial community composition. We compared them with differences due to library preparation and sample storage, which we contrasted with observed biological variation within the same specimen or within an individual over time. We found that DNA extraction had the largest effect on the outcome of metagenomic analysis. To rank DNA extraction protocols, we considered resulting DNA quantity and quality, and we ascertained biases in estimates of community diversity and the ratio between Gram-positive and Gram-negative bacteria. We recommend a standardized DNA extraction method for human fecal samples, for which transferability across labs was established and which was further benchmarked using a mock community of known composition. Its adoption will improve comparability of human gut microbiome studies and facilitate meta-analyses.

Next-generation probiotics: the spectrum from probiotics to live biotherapeutics

Abstract: The leading probiotics currently available to consumers are generally drawn from a narrow range of organisms. Knowledge of the gut microbiota and its constituent actors is changing this paradigm, particularly given the phylogenetic range and relatively unknown characteristics of the organisms under investigation as novel therapeutics. For this reason, and because their development is likely to be more amenable to a pharmaceutical than a food delivery route, these organisms are often operationally referred to as next-generation probiotics, a concept that overlaps with the emerging concept of live biotherapeutic products. The latter is a class of organisms developed exclusively for pharmaceutical application. In this Perspective, we discuss what lessons have been learned from working with traditional probiotics, explore the kinds of organisms that are likely to be used as novel microbial therapeutics, discuss the regulatory framework required, and propose how scientists may meet this challenge.

Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration

Abstract: There is a growing realisation that the gut-brain axis and its regulation by the microbiota may play a key role in the biological and physiological basis of neurodevelopmental, age-related and neurodegenerative disorders. The routes of communication between the microbiota and brain are being unravelled and include the vagus nerve, gut hormone signalling, the immune system, tryptophan metabolism or by way of microbial metabolites such as short chain fatty acids. The importance of early life gut microbiota in shaping future health outcomes is also emerging. Disturbances of this composition by way of antibiotic exposure, lack of breastfeeding, infection, stress and the environmental influences coupled with the influence of host genetics can result in long-term effects on physiology and behaviour, at least in animal models. It is also worth noting that mode of delivery at birth influences microbiota composition with those born by Caesarean section having a distinctly different microbiota in early life to those born per vaginum. At the other extreme of life, ageing is associated with a narrowing in microbial diversity and healthy ageing correlates with a diverse microbiome. Recently, the gut microbiota has been implicated in a variety of conditions including depression, autism, schizophrenia and Parkinson's disease. There is still considerable debate as to whether or not the gut microbiota changes are core to the pathophysiology of such conditions or are merely epiphenomenal. It is plausible that such neuropsychiatric disorders might be treated in the future by targeting the microbiota either by microbiota transplantation, antibiotics or psychobiotics.

Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET Cohort.

Abstract: The gut is the most extensively studied niche of the human microbiome. The aim of this study was to characterise the initial gut microbiota development of a cohort of breastfed infants (n = 192 ) from 1 to 24 weeks of age. V4-V5 region 16S rRNA amplicon Illumina sequencing and, in parallel, bacteriological culture. The metabolomic profile of infant urine at 4 weeks of age was also examined by LC-MS. Full-term (FT), spontaneous vaginally delivered (SVD) infants’ microbiota remained stable at both phylum and genus levels during the 24-week period examined. FT Caesarean section (CS) infants displayed an increased faecal abundance of Firmicutes (p < 0.01) and lower abundance of Actinobacteria (p < 0.001) after the first week of life compared to FT-SVD infants. FT-CS infants gradually progressed to harbouring a microbiota closely resembling FT-SVD (which remained stable) by week 8 of life, which was maintained at week 24. The gut microbiota of preterm (PT) infants displayed a significantly greater abundance of Proteobacteria compared to FT infants (p < 0.001) at week 1. Metabolomic analysis of urine at week 4 indicated PT-CS infants have a functionally different metabolite profile than FT (both CS and SVD) infants. Co-inertia analysis showed co-variation between the urine metabolome and the faecal microbiota of the infants. Tryptophan and tyrosine metabolic pathways, as well as fatty acid and bile acid metabolism, were found to be affected by delivery mode and gestational age. These findings confirm that mode of delivery and gestational age both have significant effects on early neonatal microbiota composition. There is also a significant difference between the metabolite profile of FT and PT infants. Prolonged breastfeeding was shown to have a significant effect on the microbiota composition of FT-CS infants at 24 weeks of age, but interestingly not on that of FT-SVD infants. Twins had more similar microbiota to one another than between two random infants, reflecting the influence of similarities in both host genetics and the environment on the microbiota.

Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

Abstract: Objective: To determine the incidence rates of sudden unexpected death in epilepsy (SUDEP) in different epilepsy populations and address the question of whether risk factors for SUDEP have been identified. Methods: Systematic review of evidence; modified Grading Recommendations Assessment, Development, and Evaluation process for developing conclusions; recommendations developed by consensus. Results: Findings for incidence rates based on 12 Class I studies include the following: SUDEP risk in children with epilepsy (aged 0–17 years) is 0.22/1,000 patient-years (95% confidence interval [CI] 0.16–0.31) (moderate confidence in evidence). SUDEP risk increases in adults to 1.2/1,000 patient-years (95% CI 0.64–2.32) (low confidence in evidence). The major risk factor for SUDEP is the occurrence of generalized tonic-clonic seizures (GTCS); the SUDEP risk increases in association with increasing frequency of GTCS occurrence (high confidence in evidence). Recommendations: Level B: Clinicians caring for young children with epilepsy should inform parents/guardians that in 1 year, SUDEP typically affects 1 in 4,500 children; therefore, 4,499 of 4,500 children will not be affected. Clinicians should inform adult patients with epilepsy that SUDEP typically affects 1 in 1,000 adults with epilepsy per year; therefore, annually 999 of 1,000 adults will not be affected. For persons with epilepsy who continue to experience GTCS, clinicians should continue to actively manage epilepsy therapies to reduce seizures and SUDEP risk while incorporating patient preferences and weighing the risks and benefits of any new approach. Clinicians should inform persons with epilepsy that seizure freedom, particularly freedom from GTCS, is strongly associated with decreased SUDEP risk.

Physical activity in European adolescents and associations with anxiety, depression and well-being

Abstract: In this cross-sectional study, physical activity, sport participation and associations with well-being, anxiety and depressive symptoms were examined in a large representative sample of European adolescents. A school-based survey was completed by 11,110 adolescents from ten European countries who took part in the SEYLE (Saving and Empowering Young Lives in Europe) study. The questionnaire included items assessing physical activity, sport participation and validated instruments assessing well-being (WHO-5), depressive symptoms (BDI-II) and anxiety (SAS). Multi-level mixed effects linear regression was used to examine associations between physical activity/sport participation and mental health measures. A minority of the sample (17.9 % of boys and 10.7 % of girls; p < 0.0005) reported sufficient activity based on WHO guidelines (60 min + daily). The mean number of days of at least 60 min of moderate-to-vigorous activity in the past 2 weeks was 7.5 ± 4.4 among boys and 5.9 days ± 4.3 among girls. Frequency of activity was positively correlated with well-being and negatively correlated with both anxiety and depressive symptoms, up to a threshold of moderate frequency of activity. In a multi-level mixed effects model more frequent physical activity and participation in sport were both found to independently contribute to greater well-being and lower levels of anxiety and depressive symptoms in both sexes. Increasing activity levels and sports participation among the least active young people should be a target of community and school-based interventions to promote well-being. There does not appear to be an additional benefit to mental health associated with meeting the WHO-recommended levels of activity.

Systematic review of systematic reviews of non-pharmacological interventions to treat behavioural disturbances in older patients with dementia. The SENATOR-OnTop series.

Abstract: Objective To provide an overview of non-pharmacological interventions for behavioural and psychological symptoms in dementia (BPSD). Design Systematic overview of reviews. Data sources PubMed, EMBASE, Cochrane Database of Systematic Reviews, CINAHL and PsycINFO (2009–March 2015). Eligibility criteria Systematic reviews (SRs) that included at least one comparative study evaluating any non-pharmacological intervention, to treat BPSD. Data extraction Eligible studies were selected and data extracted independently by 2 reviewers. The AMSTAR checklist was used to assess the quality of the SRs. Data analysis Extracted data were synthesised using a narrative approach. Results 38 SRs and 142 primary studies were identified, comprising the following categories of non-pharmacological interventions: (1) sensory stimulation interventions (12 SRs, 27 primary studies) that encompassed: acupressure, aromatherapy, massage/touch therapy, light therapy and sensory garden; (2) cognitive/emotion-oriented interventions (33 SRs; 70 primary studies) that included cognitive stimulation, music/dance therapy, dance therapy, snoezelen, transcutaneous electrical nerve stimulation, reminiscence therapy, validation therapy, simulated presence therapy; (3) behaviour management techniques (6 SRs; 32 primary studies) and (4) other therapies (5 SRs, 12 primary studies) comprising exercise therapy, animal-assisted therapy, special care unit and dining room environment-based interventions. Music therapy was effective in reducing agitation (SMD, −0.49; 95% CI −0.82 to −0.17; p=0.003), and anxiety (SMD, −0.64; 95% CI −1.05 to −0.24; p=0.002). Home-based behavioural management techniques, caregiver-based interventions or staff training in communication skills, person-centred care or dementia care mapping with supervision during implementation were found to be effective for symptomatic and severe agitation. Conclusions A large number of non-pharmacological interventions for BPSD were identified. The majority of the studies had great variation in how the same type of intervention was defined and applied, the follow-up duration, the type of outcome measured, usually with modest sample size. Overall, music therapy and behavioural management techniques were effective for reducing BPSD.

The composition, extraction, functionality and applications of rice proteins: A review

Abstract: Background Rice is a staple food and an important source of proteins in many regions worldwide. Its protein component is generally regarded as hypoallergenic, and a number of studies have highlighted the nutritional and health benefits associated with consumption of rice proteins. In recent years, the processing of plant proteins has drawn scientific and industrial interest, and rice protein-enriched ingredients have become commercially available. Scope and Approach The aim of this study was to provide a critical review of the state of the art regarding the composition, extraction methods, functional properties and applications of rice proteins. Key Findings and Conclusions Rice is composed of four protein fractions, namely albumin (water-soluble), globulin (salt-soluble), glutelin (alkali-soluble), which represents the dominant protein in brown and milled rice, and prolamin (alcohol-soluble), a minor protein in all rice milling fractions. Different methods to extract proteins from rice, including alkaline, enzymatic and physical methods, have been, and continue to be, evaluated for their efficacy, and some have been applied industrially. However, only a limited amount of studies have described the functional properties of rice proteins and how these can be improved by means of enzymatic hydrolysis. Applications of intact rice proteins are limited due to their poor solubility in water. However, hydrolysed rice proteins are used in the formulation of hypoallergenic infant formulas and may potentially be used in a variety of food systems due to their improved functionality. Despite the advances in the characterisation of rice proteins, a greater understanding of their physicochemical properties and how to modify their functionality is required in order to expand their range of food applications.

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism.

Abstract: BackgroundThe use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. MethodsWe conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicati...

The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces

Abstract: Recent findings point towards diet having a major impact on human health. Diets can either affect the gut microbiota resulting in alterations in the host’s physiological responses or by directly targeting the host response. The microbial community in the mammalian gut is a complex and dynamic system crucial for the development and maturation of both systemic and mucosal immune responses. Therefore, the complex interaction between available nutrients, the microbiota and the immune system are central regulators in maintaining homeostasis and fighting against invading pathogens at mucosal sites. Westernized diet, defined as high dietary intake of saturated fats and sucrose and low intake of fibre, represent a growing health risk contributing to the increased occurrence of metabolic diseases e.g. diabetes and obesity in countries adapting a westernized lifestyle. Inflammatory Bowel Diseases (IBD) and asthma are chronic mucosal inflammatory conditions of unknown aetiology with increasing prevalence worldwide. These conditions have a multifactorial aetiology including genetic factors, environmental factors and dysregulated immune responses. Their increased prevalence cannot solely be attributed to genetic considerations implying that other factors such as diet can be a major contributor. Recent reports indicate that the gut microbiota and modifications thereof, due to a consumption of a diet high in saturated fats and low in fibres, can trigger factors regulating the development and/or progression of both conditions. While asthma is a disease of the airways, increasing evidence indicates a link between the gut and airways in disease development. Herein, we provide a comprehensive review on the impact of westernized diet and associated nutrients on immune cell responses and the microbiota and how these can influence the pathology of IBD and asthma.

Salt reduction strategies in processed meat products – A review

Abstract: Background Sodium chloride is one of the most widely used additives in the food processing sector. Currently, the daily sodium intake is approximately three times the recommended daily allowance for an adult (in Ireland and UK) and processed meat products contribute to about 20% of the total sodium dietary intake. The dietary concern about salt consumption has encouraged food industries to consider methods for lowering salt use. However, due to the essential functions (flavour, texture and shelf-life ) provided by salt in meat products, the effects of using reduced amounts of salt must be carefully considered. Scope and approach In this review the numerous approaches for sodium reduction in processed foods are presented, highlighting: the reduction of salt level over time, the use of salt substitutes such as other metallic salts and the use of flavour enhancers such as monosodium glutamate or yeast extract. Novel technologies to assist the development of low sodium products, such as high pressure processing and power ultrasound are also introduced. Limitations for each method are discussed, with emphasis on the microbiological implications for the shelf-life stability of low-sodium products. Key findings and conclusions Multiple challenges need to be addressed in order to improve the flavour perception and safety of sodium-reduced products. A combination of multiple tools could give the desired effect; in particular, novel technological treatments such as high hydrostatic pressure and ultrasound technology , seem to be promising to ensure microbiological safety in low-sodium meat products.

Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium

Abstract: Background Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. Methods In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. Findings We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00–1.29), 1.33 (1.16–1.51), and 1.67 (1.44–1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. Interpretation In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.

Bacteriophages and Bacterial Plant Diseases.

Abstract: Losses in crop yields due to disease need to be reduced in order to meet increasing global food demands associated with growth in the human population. There is a well recognised need to develop new environmentally-friendly control strategies to combat bacterial crop disease. Current control measures involving the use of traditional chemicals or antibiotics are losing their efficacy due to the natural development of bacterial resistance to these agents. In addition, there is an increasing awareness that their use is environmentally unfriendly. Bacteriophages, the viruses of bacteria, have received increased research interest in recent years as a realistic environmentally friendly means of controlling bacterial diseases. Their use presents a viable control measure for a number of destructive bacterial crop diseases, with some phage-based products already becoming available on the market. Phage biocontrol possesses advantages over chemical controls in that tailor-made phage cocktails can be adapted to target specific disease-causing bacteria. Unlike chemical control measures, phage mixtures can be easily adapted for bacterial resistance which may develop over time. In this review, we will examine the progress and challenges for phage-based disease biocontrol in food crops.

"What can i help you with?": infrequent users' experiences of intelligent personal assistants

Abstract: Intelligent Personal Assistants (IPAs) are widely available on devices such as smartphones. However, most people do not use them regularly. Previous research has studied the experiences of frequent IPA users. Using qualitative methods we explore the experience of infrequent users: people who have tried IPAs, but choose not to use them regularly. Unsurprisingly infrequent users share some of the experiences of frequent users, e.g. frustration at limitations on fully hands-free interaction. Significant points of contrast and previously unidentified concerns also emerge. Cultural norms and social embarrassment take on added significance for infrequent users. Humanness of IPAs sparked comparisons with human assistants, juxtaposing their limitations. Most importantly, significant concerns emerged around privacy, monetization, data permanency and transparency. Drawing on these findings we discuss key challenges, including: designing for interruptability; reconsideration of the human metaphor; issues of trust and data ownership. Addressing these challenges may lead to more widespread IPA use.