Nearest Template Prediction: A Single-Sample-Based Flexible Class Prediction with Confidence Assessment

Gene-expression signature-based disease classification and clinical outcome prediction has not been widely introduced in clinical medicine as initially expected, mainly due to the lack of extensive validation needed for its clinical deployment. Obstacles include variable measurement in microarray assay, inconsistent assay platform, analytical requirement for comparable pair of training and test datasets, etc. Furthermore, as medical device helping clinical decision making, the prediction needs to be made for each single patient with a measure of its reliability. To address these issues, there is a need for flexible prediction method less sensitive to difference in experimental and analytical conditions, applicable to each single patient, and providing measure of prediction confidence. The nearest template prediction (NTP) method provides a convenient way to make class prediction with assessment of prediction confidence computed in each single patient's gene-expression data using only a list of signature genes and a test dataset. We demonstrate that the method can be flexibly applied to cross-platform, cross-species, and multiclass predictions without any optimization of analysis parameters

The yeast P5 type ATPase, Spf1, regulates manganese transport into the endoplasmic reticulum

The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn2+ homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn2+ in ∆spf1 cells and an increase following it’s overexpression. In agreement with the observed loss of luminal Mn2+ we could observe concurrent reduction in many Mn2+-related process in the ER lumen. Conversely, cytosolic Mn2+-dependent processes were increased. Together, these data support a role for Spf1p in Mn2+ transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn2+-dependent neurological disorders

Survival prediction from clinico-genomic models - a comparative study

<p>Abstract</p> <p>Background</p> <p>Survival prediction from high-dimensional genomic data is an active field in today's medical research. Most of the proposed prediction methods make use of genomic data alone without considering established clinical covariates that often are available and known to have predictive value. Recent studies suggest that combining clinical and genomic information may improve predictions, but there is a lack of systematic studies on the topic. Also, for the widely used Cox regression model, it is not obvious how to handle such combined models.</p> <p>Results</p> <p>We propose a way to combine classical clinical covariates with genomic data in a clinico-genomic prediction model based on the Cox regression model. The prediction model is obtained by a simultaneous use of both types of covariates, but applying dimension reduction only to the high-dimensional genomic variables. We describe how this can be done for seven well-known prediction methods: variable selection, unsupervised and supervised principal components regression and partial least squares regression, ridge regression, and the lasso. We further perform a systematic comparison of the performance of prediction models using clinical covariates only, genomic data only, or a combination of the two. The comparison is done using three survival data sets containing both clinical information and microarray gene expression data. Matlab code for the clinico-genomic prediction methods is available at <url>http://www.med.uio.no/imb/stat/bmms/software/clinico-genomic/</url>.</p> <p>Conclusions</p> <p>Based on our three data sets, the comparison shows that established clinical covariates will often lead to better predictions than what can be obtained from genomic data alone. In the cases where the genomic models are better than the clinical, ridge regression is used for dimension reduction. We also find that the clinico-genomic models tend to outperform the models based on only genomic data. Further, clinico-genomic models and the use of ridge regression gives for all three data sets better predictions than models based on the clinical covariates alone.</p

Improving spatial prioritisation for remote marine regions: optimising biodiversity conservation and sustainable development trade-offs

Creating large conservation zones in remote areas, with less intense stakeholder overlap and limited environmental information, requires periodic review to ensure zonation mitigates primary threats and fill gaps in representation, while achieving conservation targets. Follow-up reviews can utilise improved methods and data, potentially identifying new planning options yielding a desirable balance between stakeholder interests. This research explored a marine zoning system in north-west Australia–abiodiverse area with poorly documented biota. Although remote, it is economically significant (i.e. petroleum extraction and fishing). Stakeholder engagement was used to source the best available biodiversity and socio-economic data and advanced spatial analyses produced 765 high resolution data layers, including 674 species distributions representing 119 families. Gap analysis revealed the current proposed zoning system as inadequate, with 98.2% of species below the Convention on Biological Diversity 10% representation targets. A systematic conservation planning algorithm Maxan provided zoning options to meet representation targets while balancing this with industry interests. Resulting scenarios revealed that conservation targets could be met with minimal impacts on petroleum and fishing industries, with estimated losses of 4.9% and 7.2% respectively. The approach addressed important knowledge gaps and provided a powerful and transparent method to reconcile industry interests with marine conservation

Differential Expression of Alpha 4 Integrins on Effector Memory T Helper Cells during Bordetella Infections. Delayed Responses in Bordetella pertussis

Bordetella pertussis (B. pertussis) is the causative agent of whooping cough, a respiratory disease that is reemerging worldwide. Mechanisms of selective lymphocyte trafficking to the airways are likely to be critical in the immune response to this pathogen. We compared murine infection by B. pertussis, B. parapertussis, and a pertussis toxin-deleted B. pertussis mutant (BpΔPTX) to test the hypothesis that effector memory T-helper cells (emTh) display an altered pattern of trafficking receptor expression in B. pertussis infection due to a defect in imprinting. Increased cell recruitment to the lungs at 5 days post infection (p.i.) with B. parapertussis, and to a lesser extent with BpΔPTX, coincided with an increased frequency of circulating emTh cells expressing the mucosal-associated trafficking receptors α4β7 and α4β1 while a reduced population of these cells was observed in B. pertussis infection. These cells were highly evident in the blood and lungs in B. pertussis infection only at 25 days p.i. when B. parapertussis and BpΔPTX infections were resolved. Although at 5 days p.i., an equally high percentage of lung dendritic cells (DCs) from all infections expressed maturation markers, this expression persisted only in B. pertussis infection at 25 days p.i. Furthermore, at 5 days p.i with B. pertussis, lung DCs migration to draining lymph nodes may be compromised as evidenced by decreased frequency of CCR7+ DCs, inhibited CCR7-mediated in vitro migration, and fewer DCs in lung draining lymph nodes. Lastly, a reduced frequency of allogeneic CD4+ cells expressing α4β1 was detected following co-culture with lung DCs from B. pertussis-infected mice, suggesting a defect in DC imprinting in comparison to the other infection groups. The findings in this study suggest that B. pertussis may interfere with imprinting of lung-associated trafficking receptors on T lymphocytes leading to extended survival in the host and a prolonged course of disease

Spirituality as an Essential Determinant for the Good Life, its Importance Relative to Self-Determinant Psychological Needs

This study focuses on the relevance of spirituality as an essential element for the Good Life. Despite spirituality’s prominence in people’s lives and cultures, it has been mostly neglected in psychological needs theories. This paper investigates the value of spirituality compared to that of the three basic psychological needs of self-determination theory: relatedness, competence and autonomy. In a scenario study design, participants in two samples (students and train passengers) were asked to judge a survey on the personal well-being of an imaginary person. The results show that spirituality positively contributes to the qualification of a good life, in terms of desirability and moral goodness. In addition, the crucial role of relatedness was confirmed

Complications related to deep venous thrombosis prophylaxis in trauma: a systematic review of the literature

Deep venous thrombosis prophylaxis is essential to the appropriate management of multisystem trauma patients. Without thromboprophylaxis, the rate of venous thrombosis and subsequent pulmonary embolism is substantial. Three prophylactic modalities are common: pharmacologic anticoagulation, mechanical compression devices, and inferior vena cava filtration. A systematic review was completed using PRISMA guidelines to evaluate the potential complications of DVT prophylactic options. Level one evidence currently supports the use of low molecular weight heparins for thromboprophylaxis in the trauma patient. Unfortunately, multiple techniques are not infrequently required for complex multisystem trauma patients. Each modality has potential complications. The risks of heparin include bleeding and heparin induced thrombocytopenia. Mechanical compression devices can result in local soft tissue injury, bleeding and patient non-compliance. Inferior vena cava filters migrate, cause inferior vena cava occlusion, and penetrate the vessel wall. While the use of these techniques can be life saving, they must be appropriately utilized

A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients

INTRODUCTION: The Oncotype DX assay was recently reported to predict risk for distant recurrence among a clinical trial population of tamoxifen-treated patients with lymph node-negative, estrogen receptor (ER)-positive breast cancer. To confirm and extend these findings, we evaluated the performance of this 21-gene assay among node-negative patients from a community hospital setting. METHODS: A case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 and not treated with adjuvant chemotherapy. Cases (n = 220) were patients who died from breast cancer. Controls (n = 570) were breast cancer patients who were individually matched to cases with respect to age, race, adjuvant tamoxifen, medical facility and diagnosis year, and were alive at the date of death of their matched case. Using an RT-PCR assay, archived tumor tissues were analyzed for expression levels of 16 cancer-related and five reference genes, and a summary risk score (the Recurrence Score) was calculated for each patient. Conditional logistic regression methods were used to estimate the association between risk of breast cancer death and Recurrence Score. RESULTS: After adjusting for tumor size and grade, the Recurrence Score was associated with risk of breast cancer death in ER-positive, tamoxifen-treated and -untreated patients (P = 0.003 and P = 0.03, respectively). At 10 years, the risks for breast cancer death in ER-positive, tamoxifen-treated patients were 2.8% (95% confidence interval [CI] 1.7–3.9%), 10.7% (95% CI 6.3–14.9%), and 15.5% (95% CI 7.6–22.8%) for those in the low, intermediate and high risk Recurrence Score groups, respectively. They were 6.2% (95% CI 4.5–7.9%), 17.8% (95% CI 11.8–23.3%), and 19.9% (95% CI 14.2–25.2%) for ER-positive patients not treated with tamoxifen. In both the tamoxifen-treated and -untreated groups, approximately 50% of patients had low risk Recurrence Score values. CONCLUSION: In this large, population-based study of lymph node-negative patients not treated with chemotherapy, the Recurrence Score was strongly associated with risk of breast cancer death among ER-positive, tamoxifen-treated and -untreated patients

Integrative approach for differentially overexpressed genes in gastric cancer by combining large-scale gene expression profiling and network analysis

Gene expression profiling is a valuable tool for identifying differentially expressed genes in studies of disease subtype and patient outcome for various cancers. However, it remains difficult to assign biological significance to the vast number of genes. There is an increasing awareness of gene expression profile as an important part of the contextual molecular network at play in complex biological processes such as cancer initiation and progression. This study analysed the transcriptional profiles commonly activated at different stages of gastric cancers using an integrated approach combining gene expression profiling of 222 human tissues and gene regulatory dynamic mapping. We focused on an inferred core network with CDKN1A (p21WAF1/CIP1) as the hub, and extracted seven candidates for gastric carcinogenesis (MMP7, SPARC, SOD2, INHBA, IGFBP7, NEK6, LUM). They were classified into two groups based on the correlation between expression level and stage. The seven genes were commonly activated and their expression levels tended to increase as disease progressed. NEK6 and INHBA are particularly promising candidate genes overexpressed at the protein level, as confirmed by immunohistochemistry and western blotting. This integrated approach could help to identify candidate players in gastric carcinogenesis and progression. These genes are potential markers of gastric cancer regardless of stage

Divergent Pro-Inflammatory Profile of Human Dendritic Cells in Response to Commensal and Pathogenic Bacteria Associated with the Airway Microbiota

Recent studies using culture-independent methods have characterized the human airway microbiota and report microbial communities distinct from other body sites. Changes in these airway bacterial communities appear to be associated with inflammatory lung disease, yet the pro-inflammatory properties of individual bacterial species are unknown. In this study, we compared the immune stimulatory capacity on human monocyte-derived dendritic cells (DCs) of selected airway commensal and pathogenic bacteria predominantly associated with lungs of asthma or COPD patients (pathogenic Haemophillus spp. and Moraxella spp.), healthy lungs (commensal Prevotella spp.) or both (commensal Veillonella spp. and Actinomyces spp.). All bacteria were found to induce activation of DCs as demonstrated by similar induction of CD83, CD40 and CD86 surface expression. However, asthma and COPD-associated pathogenic bacteria provoked a 3–5 fold higher production of IL-23, IL-12p70 and IL-10 cytokines compared to the commensal bacteria. Based on the differential cytokine production profiles, the studied airway bacteria could be segregated into three groups (Haemophilus spp. and Moraxella spp. vs. Prevotella spp. and Veillonella spp. vs. Actinomyces spp.) reflecting their pro-inflammatory effects on DCs. Co-culture experiments found that Prevotella spp. were able to reduce Haemophillus influenzae-induced IL-12p70 in DCs, whereas no effect was observed on IL-23 and IL-10 production. This study demonstrates intrinsic differences in DC stimulating properties of bacteria associated with the airway microbiota