A critical evaluation of network and pathway based classifiers for outcome prediction in breast cancer

Recently, several classifiers that combine primary tumor data, like gene expression data, and secondary data sources, such as protein-protein interaction networks, have been proposed for predicting outcome in breast cancer. In these approaches, new composite features are typically constructed by aggregating the expression levels of several genes. The secondary data sources are employed to guide this aggregation. Although many studies claim that these approaches improve classification performance over single gene classifiers, the gain in performance is difficult to assess. This stems mainly from the fact that different breast cancer data sets and validation procedures are employed to assess the performance. Here we address these issues by employing a large cohort of six breast cancer data sets as benchmark set and by performing an unbiased evaluation of the classification accuracies of the different approaches. Contrary to previous claims, we find that composite feature classifiers do not outperform simple single gene classifiers. We investigate the effect of (1) the number of selected features; (2) the specific gene set from which features are selected; (3) the size of the training set and (4) the heterogeneity of the data set on the performance of composite feature and single gene classifiers. Strikingly, we find that randomization of secondary data sources, which destroys all biological information in these sources, does not result in a deterioration in performance of composite feature classifiers. Finally, we show that when a proper correction for gene set size is performed, the stability of single gene sets is similar to the stability of composite feature sets. Based on these results there is currently no reason to prefer prognostic classifiers based on composite features over single gene classifiers for predicting outcome in breast cancer

Trends and variation in the management of oesophagogastric cancer patients: a population-based survey

<p>Abstract</p> <p>Background</p> <p>Previous evidence indicates potential variation in the quality of care of cancer patients. We aimed to examine whether recent changes in the treatment of oesophagogastric cancers have been distributed equally among different patient subgroups.</p> <p>Methods</p> <p>We analysed population-based cancer registry data about the treatment patterning of oesophagogastric cancer (other than oesophageal squamous cell carcinoma) during 1995-2006.</p> <p>Results</p> <p>There were 14,077 patients aged ≥40 years (69% men). There was only limited information on stage, and no information on co-morbidity status. During successive triennia, curative surgery use decreased from 28% to 20% (p < 0.001) whilst chemotherapy use increased from 9% to 30% (p < 0.001). Use of palliative surgery and of radiotherapy increased significantly but modestly (7% to 10%, and 9% to 11%, respectively). In multivariable logistic regression adjusting for age group, gender, diagnosis period and tumour type, curative surgery and chemotherapy were used less frequently in more deprived patients [per increasing deprivation group Odds Ratio (OR) = 0.96, 95% Confidence Interval (CI) 0.93-0.99, and OR = 0.90, 95%CI 0.87-0.93, respectively, p < 0.001 for both)]. Chemotherapy was also used less frequently in women (OR = 0.76, p < 0.001).</p> <p>Conclusions</p> <p>During the study period, curative surgery decreased by a third and chemotherapy use increased by more than three-fold, reflecting improvements in the appropriateness and quality of management, but chemotherapy use, in particular, was unequal, both by socioeconomic status and gender.</p

Built Shallow to Maintain Homeostasis and Persistent Infection: Insight into the Transcriptional Regulatory Network of the Gastric Human Pathogen Helicobacter pylori

Transcriptional regulatory networks (TRNs) transduce environmental signals into coordinated output expression of the genome. Accordingly, they are central for the adaptation of bacteria to their living environments and in host–pathogen interactions. Few attempts have been made to describe a TRN for a human pathogen, because even in model organisms, such as Escherichia coli, the analysis is hindered by the large number of transcription factors involved. In light of the paucity of regulators, the gastric human pathogen Helicobacter pylori represents a very appealing system for understanding how bacterial TRNs are wired up to support infection in the host. Herein, we review and analyze the available molecular and “-omic” data in a coherent ensemble, including protein–DNA and protein–protein interactions relevant for transcriptional control of pathogenic responses. The analysis covers ∼80% of the annotated H. pylori regulators, and provides to our knowledge the first in-depth description of a TRN for an important pathogen. The emerging picture indicates a shallow TRN, made of four main modules (origons) that process the physiological responses needed to colonize the gastric niche. Specific network motifs confer distinct transcriptional response dynamics to the TRN, while long regulatory cascades are absent. Rather than having a plethora of specialized regulators, the TRN of H. pylori appears to transduce separate environmental inputs by using different combinations of a small set of regulators

A Novel System of Cytoskeletal Elements in the Human Pathogen Helicobacter pylori

Pathogenicity of the human pathogen Helicobacter pylori relies upon its capacity to adapt to a hostile environment and to escape from the host response. Therefore, cell shape, motility, and pH homeostasis of these bacteria are specifically adapted to the gastric mucus. We have found that the helical shape of H. pylori depends on coiled coil rich proteins (Ccrp), which form extended filamentous structures in vitro and in vivo, and are differentially required for the maintenance of cell morphology. We have developed an in vivo localization system for this pathogen. Consistent with a cytoskeleton-like structure, Ccrp proteins localized in a regular punctuate and static pattern within H. pylori cells. Ccrp genes show a high degree of sequence variation, which could be the reason for the morphological diversity between H. pylori strains. In contrast to other bacteria, the actin-like MreB protein is dispensable for viability in H. pylori, and does not affect cell shape, but cell length and chromosome segregation. In addition, mreB mutant cells displayed significantly reduced urease activity, and thus compromise a major pathogenicity factor of H. pylori. Our findings reveal that Ccrp proteins, but not MreB, affect cell morphology, while both cytoskeletal components affect the development of pathogenicity factors and/or cell cycle progression

Use of a total traffic count metric to investigate the impact of roadways on asthma severity: a case-control study

<p>Abstract</p> <p>Background</p> <p>This study had two principal objectives: (i) to investigate the relationship between asthma severity and proximity to major roadways in Perth, Western Australia; (ii) to demonstrate a more accurate method of exposure assessment for traffic pollutants using an innovative GIS-based measure that fully integrates all traffic densities around subject residences.</p> <p>Methods</p> <p>We conducted a spatial case-control study, in which 'cases' were defined as individuals aged under 19 years of age with more severe asthma (defined here as two or more emergency department contacts with asthma in a defined 5-year period) versus age- and gender-matched 'controls' with less severe asthma (defined here as one emergency department contact for asthma). Traffic exposures were measured using a GIS-based approach to determine the lengths of the roads falling within a buffer area, and then multiplying them by their respective traffic counts.</p> <p>Results</p> <p>We examined the spatial relationship between emergency department contacts for asthma at three different buffer sizes: 50 metres, 100 metres and 150 metres. No effect was noted for the 50 metre buffer (OR = 1.07; 95% CI: 0.91-1.26), but elevated odds ratios were observed with for crude (unadjusted) estimates OR = 1.21 (95% CI: 1.00-1.46) for 100 metre buffers and OR = 1.25 (95% CI: 1.02-1.54) for 150 metre buffers. For adjusted risk estimates, only the 150 metre buffer yielded a statistically significant finding (OR = 1.24; 95% CI:1.00-1.52).</p> <p>Conclusions</p> <p>Our study revealed a significant 24% increase in the risk of experiencing multiple emergency department contacts for asthma for every log-unit of traffic exposure. This study provides support for the hypothesis that traffic related air pollution increases the frequency of health service contacts for asthma. This study used advanced GIS techniques to establish traffic-weighted buffer zones around the geocoded residential location of subjects to provide an accurate assessment of exposure to traffic emissions, thereby providing a quantification of the ranges over which pollutants may exert a health effect.</p

Bright light therapy in pregnant women with major depressive disorder: Study protocol for a randomized, double-blind, controlled clinical trial

Background: Depression during pregnancy is a common and high impact disease. Generally, 5-10 % of pregnant women suffer from depression. Children who have been exposed to maternal depression during pregnancy have a higher risk of adverse birth outcomes and more often show cognitive, emotional and behavioural problems. Therefore, early detection and treatment of antepartum depression is necessary. Both psychotherapy and antidepressant medication, first choice treatments in a non-pregnant population, have limitations in treating depression during pregnancy. Therefore, it is urgent and relevant to investigate alternative treatments for antepartum depression. Bright light therapy (BLT) is a promising treatment for pregnant women with depressive disorder, for it combines direct availability, sufficient efficacy, low costs and high safety, taking the safety for the unborn child into account as well. Methods: In this study, 150 pregnant women (12-18 weeks pregnant) with a DSM-V diagnosis of depressive disorder will be randomly allocated in a 1:1 ratio to one of the two treatment arms: treatment with BLT (9.000 lux) or treatment with dim red light therapy (100 lux). Both groups will be treated for 6 weeks at home on a daily basis for 30 min, within 30 min of habitual wake-up time. Follow-up will take place after 6 weeks of therapy, 3 and 10 weeks after end of therapy, at birth and 2, 6 and 18 months postpartum. Primary outcome will be the average change in depressive symptoms between the two groups, as measured by the Structured Interview Guide for the Hamilton Depression Scale - Seasonal Affective Disorder version and the Edinburg Postnatal Depression Scale. Changes in rating scale scores of these questionnaires over time will be analysed using generalized linear mixed models. Secondary outcomes will be the changes in maternal cortisol and melatonin levels, in maternal sleep quality and gestational age, birth weight, infant behaviour, infant cortisol exposure and infant cortisol stress response. Discussion: If BLT reduces depressive symptoms in pregnant women, it will provide a safe, cheap, non-pharmacological and efficacious alternative treatment for psychotherapy and antidepressant medication in treating antepartum depression, without any expected adverse reactions for the unborn child. Trial registration: Netherlands Trial Register NTR5476. Registered 5 November 2015

Combinatorial Development of Biomaterials for Clonal Growth of Human Pluripotent Stem Cells

July 3, 2012Both human embryonic stem cells and induced pluripotent stem cells can self-renew indefinitely in culture; however, present methods to clonally grow them are inefficient and poorly defined for genetic manipulation and therapeutic purposes. Here we develop the first chemically defined, xeno-free, feeder-free synthetic substrates to support robust self-renewal of fully dissociated human embryonic stem and induced pluripotent stem cells. Material properties including wettability, surface topography, surface chemistry and indentation elastic modulus of all polymeric substrates were quantified using high-throughput methods to develop structure–function relationships between material properties and biological performance. These analyses show that optimal human embryonic stem cell substrates are generated from monomers with high acrylate content, have a moderate wettability and employ integrin α[subscript v]β[subscript 3] and α[subscript v]β[subscript 5] engagement with adsorbed vitronectin to promote colony formation. The structure–function methodology employed herein provides a general framework for the combinatorial development of synthetic substrates for stem cell culture.National Institutes of Health (U.S.) (Grant R37-CA084198)National Institutes of Health (U.S.) (Grant RO1-CA087869)National Institutes of Health (U.S.) (Grant RO1-HD045022)National Institutes of Health (U.S.) (Grant DE016516)Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (Contract W911NF-07-D-0004

Novel essential amino acid supplements enriched with L-leucine facilitate increased protein and energy intakes in older women: a randomised controlled trial

Background: Inadequate protein intake (PI), containing a sub-optimal source of essential amino acids (EAAs), and reduced appetite are contributing factors to age-related sarcopenia. The satiating effects of dietary protein per se may negatively affect energy intake (EI), thus there is a need to explore alternative strategies to facilitate PI without compromising appetite and subsequent EI. Methods: Older women completed two experiments (EXP1 and EXP2) where they consumed either a Bar (565 kJ), a Gel (477 kJ), both rich in EAAs (7.5 g, 40% L-leucine), or nothing (Control). In EXP1, participants (n=10, 68±5 years, mean±SD) consumed Bar, Gel or Control with appetite sensations and appetite-related hormonal responses monitored for one hour, followed by consumption of an ad libitum breakfast (ALB). In EXP2, participants (n=11, 69±5 years) ingested Bar, Gel or Control alongside an ALB. Results: In EXP1, EI at ALB was not different (P=0.674) between conditions (1179±566, 1254±511, 1206±550 kJ for the Control, Bar, and Gel respectively). However, total EI was significantly higher in the Bar and Gel compared to the Control after accounting for the energy content of the supplements (P<0.0005). Analysis revealed significantly higher appetite Area under the Curve (AUC) (P<0.007), a tendency for higher acylated ghrelin AUC (P=0.087), and significantly lower pancreatic polypeptide AUC (P=0.02) in the Control compared with the Bar and Gel. In EXP2, EI at ALB was significantly higher (P=0.028) in the Control (1282±513 kJ) compared to the Bar (1026±565 kJ) and Gel (1064±495 kJ). However, total EI was significantly higher in the Bar and Gel after accounting for the energy content of the supplements (P<0.007). Conclusions: Supplementation with either the Bar or Gel increased total energy intake whether consumed one hour before or during breakfast. This may represent an effective nutritional means for addressing protein and total energy deficiencies in older women

The Role of Intestinal Microbiota in the Development and Severity of Chemotherapy-Induced Mucositis

Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients. According to the model introduced by Sonis, both inflammation and apoptosis of the mucosal barrier result in its discontinuity, thereby promoting bacterial translocation. According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a prominent role for the commensal intestinal microbiota in the development of several inflammatory diseases like inflammatory bowel disease, pouchitis, and radiotherapy-induced diarrhea. Furthermore, chemotherapeutics have a detrimental effect on the intestinal microbial composition (strongly decreasing the numbers of anaerobic bacteria), coinciding in time with the development of chemotherapy-induced mucositis. We hypothesize that the commensal intestinal microbiota might play a pivotal role in chemotherapy-induced mucositis. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance to harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules. Via these pathways, the commensal intestinal microbiota might influence all phases in the Sonis model of the pathogenesis of mucositis. Further research is needed to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis