Daniel C. Jupiter

STARNET 2: a web-based tool for accelerating discovery of gene regulatory networks using microarray co-expression data

BackgroundAlthough expression microarrays have become a standard tool used by biologists, analysis of data produced by microarray experiments may still present challenges. Comparison of data from different platforms, organisms, and labs may involve complicated data processing, and inferring relationships between genes remains difficult.ResultsSTARNET2 is a new web-based tool that allows post hoc visual analysis of correlations that are derived from expression microarray data. STARNET2 facilitates user discovery of putative gene regulatory networks in a variety of species (human, rat, mouse, chicken, zebrafish, Drosophila, C. elegans, S. cerevisiae, Arabidopsis and rice) by graphing networks of genes that are closely co-expressed across a large heterogeneous set of preselected microarray experiments. For each of the represented organisms, raw microarray data were retrieved from NCBIs Gene Expression Omnibus for a selected Affymetrix platform. All pairwise Pearson correlation coefficients were computed for expression profiles measured on each platform, respectively. These precompiled results were stored in a MySQL database, and supplemented by additional data retrieved from NCBI. A web-based tool allows user-specified queries of the database, centered at a gene of interest. The result of a query includes graphs of correlation networks, graphs of known interactions involving genes and gene products that are present in the correlation networks, and initial statistical analyses. Two analyses may be performed in parallel to compare networks, which is facilitated by the new HEATSEEKER module.ConclusionSTARNET2 is a useful tool for developing new hypotheses about regulatory relationships between genes and gene products, and has coverage for 10 species. Interpretation of the correlation networks is supported with a database of previously documented interactions, a test for enrichment of Gene Ontology terms, and heat maps of correlation distances that may be used to compare two networks. The list of genes in a STARNET network may be useful in developing a list of candidate genes to use for the inference of causal networks. The tool is freely available at http://vanburenlab.medicine.tamhsc.edu/starnet2.html, and does not require user registration.

A visual data mining tool that facilitates reconstruction of transcription regulatory networks.

Background Although the use of microarray technology has seen exponential growth, analysis of microarray data remains a challenge to many investigators. One difficulty lies in the interpretation of a list of differentially expressed genes, or in how to plan new experiments given that knowledge. Clustering methods can be used to identify groups of genes with similar expression patterns, and genes with unknown function can be provisionally annotated based on the concept of “guilt by association”, where function is tentatively inferred from the known functions of genes with similar expression patterns. These methods frequently suffer from two limitations: (1) visualization usually only gives access to group membership, rather than specific information about nearest neighbors, and (2) the resolution or quality of the relationships are not easily inferred. Methodology/Principal Findings We have addressed these issues by improving the precision of similarity detection over that of a single experiment and by creating a tool to visualize tractable association networks: we (1) performed meta-analysis computation of correlation coefficients for all gene pairs in a heterogeneous data set collected from 2,145 publicly available micorarray samples in mouse, (2) filtered the resulting distribution of over 130 million correlation coefficients to build new, more tractable distributions from the strongest correlations, and (3) designed and implemented a new Web based tool (StarNet, http://vanburenlab.medicine.tamhsc.edu/starnet.html) for visualization of sub-networks of the correlation coefficients built according to user specified parameters. Conclusions/Significance Correlations were calculated across a heterogeneous collection of publicly available microarray data. Users can access this analysis using a new freely available Web-based application for visualizing tractable correlation networks that are flexibly specified by the user. This new resource enables rapid hypothesis development for transcription regulatory relationships.

The long-term impact of routine intraoperative nerve monitoring during thyroid and parathyroid surgery

BACKGROUNDnDespite widespread use of intraoperative nerve monitoring (IONM) as an adjunct to visual identification of the recurrent laryngeal nerve (RLN), published studies have shown little or no benefit. No long-term studies exist detailing the effect of experience gained from IONM on the rate of RLN injury. The aim of this study was to evaluate the impact of IONM feedback on surgical outcomes over time at a single institution.nnnMETHODSnWe conducted retrospective analysis of prospectively gathered data for 1,936 patients including 3,435 nerves at risk between March 2004 and September 2011. Each RLN was analyzed for the specific, unilateral operative procedure that placed the nerve at risk of injury. The primary outcome measures included temporary vocal cord palsy and permanent vocal cord paralysis or paresis as determined by intraoperative loss of RLN function and postoperative laryngoscopy. Additional measures included instances where IONM assisted the surgeons localization of the RLN.nnnRESULTSnOf the 3,435 nerves at risk, 105 (3.06%) were injured, 4 had permanent paralysis (0.12%), and 7 had paresis (0.20%). Over time, a decrease in RLN injury was seen per successive operative year for thyroid lobectomy with paratracheal lymph node dissection with or without parathyroidectomy (odds ratio, 0.98; 95% confidence interval, 0.97-1.00; P = .04); the rate of nerve injury stabilized after 20 months of continued use of nerve monitoring. IONM particularly assisted the surgeon with identification of 108 nerves at risk (3.14%) with aberrant anatomy, and with identification of 236 nerves at risk (6.87%) during difficult dissections.nnnCONCLUSIONnWith experience, routine use of IONM during thyroid and parathyroid operations significantly decreased the incidence of injury to the RLN for thyroid lobectomy with paratracheal lymph node dissection and provided useful assistance with RLN identification for 10% of nerves at risk.

Molecular pathogenesis of malignant mesothelioma.

Malignant mesothelioma is a rare, highly aggressive cancer arising from mesothelial cells that line the pleural cavities. Approximately 80% of mesothelioma cases can be directly attributed to asbestos exposure. Additional suspected causes or co-carcinogens include other mineral fibres, simian virus 40 (SV40) and radiation. A mesothelioma epidemic in Turkey has demonstrated a probable genetic predisposition to mineral fibre carcinogenesis and studies of human tissues and animal models of mesothelioma have demonstrated genetic and epigenetic events that contribute to the multistep process of mineral fibre carcinogenesis. Several growth factors and their receptors have a significant role in the oncogenesis, progression and resistance to therapy of mesothelioma. Epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF) have been shown as targets for therapy based on promising preclinical data. However, clinical trials of tyrosine kinase inhibitors in mesothelioma have been disappointing. Bcl-XL is an important antiapoptotic member of the Bcl-2 family and is overexpressed in several solid tumours, including mesothelioma. Reduction of Bcl-XL expression in mesothelioma induces apoptosis and engenders sensitisation to cytotoxic chemotherapeutic agents. Pharmacological inhibitors of antiapoptotic Bcl-2 family members continue to undergo refinement and have shown promise in mesothelioma.

Are Commercial Negative Pressure Systems Worth the Cost in Open Abdomen Management

BACKGROUNDnA commercial negative pressure product is compared with the Barker technique (sterile x-ray cassette cover, lap pads, adhesive drape with negative pressure) for temporary abdominal closure in open abdomen management.nnnSTUDY DESIGNnWe performed a retrospective review of 37 open abdomen patients who had temporary abdominal closure with a commercial negative pressure device (ABThera, KCI) from 2010 to 2011. These patients were compared with the most recent 37 patients having open abdomen management using the Barker technique from 2009 to 2010. Patient demographics, body mass index (BMI), preoperative albumin, indication for open abdomen management, number of operations, use of sequential closure, and success with closure were analyzed. Patients were compared using chi square, t-test, and logistic regression analysis with significance of p < 0.05.nnnRESULTSnMean age and BMI were significantly higher in the ABThera patients. No statistically significant differences were seen in male:female ratio, indication for open abdomen management, preoperative albumin, number of operations, and use of sequential closure. In 33 patients (89%) ultimate midline fascial closure was achieved with the ABThera vs in 22 patients (59%) using the Barker technique (p < 0.05). Logistic regression analysis was performed on the 3 significant variables identified on bivariate analysis. Only the type of temporary abdominal closure proved significant, with an odds ratio of 7.97 favoring ABThera (95% CI 1.98 to 32.00).nnnCONCLUSIONSnA commercially available negative pressure device for temporary abdominal closure had significantly greater success with ultimate closure after open abdomen management compared with the Barker technique. The added cost of the device is offset by improved patient results and savings from successful closure.

Anything You Can Do I Can Do Better

Newly introduced drugs or treatments may not be substantively more effective than current therapies, but these drugs or treatments may have distinct advantages in terms of lower costs or fewer or less severe side effects. Demonstrating the utility of a novel treatment is thus unlike usual hypothesis testing, in which researchers seek to prove that treatments differ (i.e., that one treatment is better than another). Instead, researchers must prove that the treatments are equivalent in effectiveness (i.e., that the treatments do not differ). I discuss here how to execute this type of study: the non-inferiority study.

Goal directed fluid resuscitation decreases time for lactate clearance and facilitates early fascial closure in damage control surgery

BACKGROUNDnDamage-control surgery frequently results in open abdomen. The objective of this study was to determine whether resuscitation with goal-directed fluid therapy (GDT) using dynamic hemodynamic indices via modern pulse contour analysis devices such as the FloTrac Vigileo monitor leads to lower fluid requirements, subsequent quicker abdominal closure, and overall improved outcomes in these patients.nnnMETHODSnPatients admitted to the surgical intensive care unit with open abdomen were retrospectively reviewed. Those resuscitated with Vigileo-guided GDT were matched to those resuscitated by static clinical parameters.nnnRESULTSnTotal fluid intake and vasopressor requirements were similar in both groups. GDT with the Vigileo allowed earlier lactate clearance and reduced the number of days until abdominal wall closure by an average of .99 days.nnnCONCLUSIONSnVigileo-mediated GDT did not affect fluid volume or vasopressor use in open abdomen patients, but facilitated more effective resuscitation and decreased the number of days to fascial closure, leading to shorter hospital stays. Vigileo-mediated GDT, therefore, may improve overall outcomes in open abdomen patients.

A comparison of postoperative effects of bariatric surgery on medical markers of morbidity

BACKGROUNDnBariatric surgery reduces the prevalence of diabetes and improves lipid profiles. Low-density lipoprotein particle (LDL-P) is a more accurate predictor of cardiovascular events than high-density lipoprotein (HDL) and LDL cholesterol. The effects of bariatric procedures on LDL-P have not been previously reported.nnnMETHODSnTwo hundred thirty patients undergoing bariatric surgery, including gastric bypass, sleeve gastrectomy, and laparoscopic adjustable gastric band placement at a single institution were included. HDL, LDL, hemoglobin A1c, and LDL-P were measured preoperatively and at 3, 6, and 12 months postoperatively. Weight was recorded at baseline and after 1 year.nnnRESULTSnThere was a decrease in serum LDL-P levels, averaging 472.58 (P < .0001) over 1 year. HDL levels increased. Hemoglobin A1c and LDL levels declined. On average, patients lost 58% of excess weight.nnnCONCLUSIONnLDL-P significantly decreased after bariatric surgery in relation to weight loss. It may be inferred that bariatric surgery decreases the risk of cardiovascular events.

Is calcaneal inclination higher in patients with insertional Achilles tendinosis? A case-controlled, cross-sectional study.

Insertional Achilles tendinosis is a condition where a patient complains of isolated pain at the Achilles tendon insertion site due to intratendinous degeneration. It has been suggested that this condition is associated with cavus foot deformity. However, to our knowledge, there is no study that has confirmed this observation. We carried out a cross-sectional, case-controlled study to explore the association of increased calcaneal inclination-a surgically important characteristic of cavus foot deformity-with insertional Achilles tendinosis. Patients with Achilles tendinosis and matched controls without the pathology were compared. Although a statistically significant difference was detected in calcaneal inclination angle between these 2 groups (p = .038), we felt that the difference was not clinically significant (calcaneal inclination angle = 20.9 vs. 18.9, respectively). Within the limitations of the study, we conclude that there is no clinically significant difference in calcaneal inclination between those with or without insertional Achilles tendinosis.

Logistic Models—An Odd(s) Kind of Regression

The logistic regression model bears some similarity to the multivariable linear regression with which we are familiar. However, the differences are great enough to warrant a discussion of the need for and interpretation of logistic regression.