Protein interactome of muscle invasive bladder cancer

Muscle invasive bladder carcinoma is a complex, multifactorial disease caused by disruptions and alterations of several molecular pathways that result in heterogeneous phenotypes and variable disease outcome. Combining this disparate knowledge may offer insights for deciphering relevant molecular processes regarding targeted therapeutic approaches guided by molecular signatures allowing improved phenotype profiling. The aim of the study is to characterize muscle invasive bladder carcinoma on a molecular level by incorporating scientific literature screening and signatures from omics profiling. Public domain omics signatures together with molecular features associated with muscle invasive bladder cancer were derived from literature mining to provide 286 unique protein-coding genes. These were integrated in a protein-interaction network to obtain a molecular functional map of the phenotype. This feature map educated on three novel disease-associated pathways with plausible involvement in bladder cancer, namely Regulation of actin cytoskeleton, Neurotrophin signalling pathway and Endocytosis. Systematic integration approaches allow to study the molecular context of individual features reported as associated with a clinical phenotype and could potentially help to improve the molecular mechanistic description of the disorder

Causal analyses with target trial emulation for real-world evidence removed large self-inflicted biases: systematic bias assessment of ovarian cancer treatment effectiveness

Background and Objectives: Drawing causal conclusions from real-world data (RWD) poses methodological challenges and risk of bias. We aimed to systematically assess the type and impact of potential biases that may occur when analyzing RWD using the case of progressive ovarian cancer. Methods: We retrospectively compared overall survival with and without second-line chemotherapy (LOT2) using electronic medical records. Potential biases were determined using directed acyclic graphs. We followed a stepwise analytic approach ranging from crude analysis and multivariable-adjusted Cox model up to a full causal analysis using a marginal structural Cox model with replicates emulating a reference randomized controlled trial (RCT). To assess biases, we compared effect estimates (hazard ratios [HRs]) of each approach to the HR of the reference trial. Results: The reference trial showed an HR for second line vs. delayed therapy of 1.01 (95% confidence interval [95% CI]: 0.82e1.25). The corresponding HRs from the RWD analysis ranged from 0.51 for simple baseline adjustments to 1.41 (95% CI: 1.22e1.64) accounting for immortal time bias with time-varying covariates. Causal trial emulation yielded an HR of 1.12 (95% CI: 0.96e1.28). Conclusion: Our study, using ovarian cancer as an example, shows the importance of a thorough causal design and analysis if one is expecting RWD to emulate clinical trial results

Muscle Invasive Bladder carcinoma pathway enrichment, set of 72 protein coding genes.

<p>Nodes in orange denote pathways identified as relevant in both literature and enrichment analysis; nodes in blue depict pathways of relevance according to enrichment analysis. The size of each node size scales with the number of gene symbols encoded in each pathway term.</p

KEGG pathways significantly associated with muscle invasive bladder carcinoma utilizing the gene set embedded in the induced subgraph.

<p>Pathway terms, total number of MIBC features associated with the term, Bonferroni corrected p-value and specific gene symbols found overlapping amongst the 4 pathway terms.</p><p>KEGG pathways significantly associated with muscle invasive bladder carcinoma utilizing the gene set embedded in the induced subgraph.</p

Data assembly workflow.

<p>PubMed, Google Scholar and Web of Science literature analysis and Omics data source screening with focus on transcriptomics. From the 4263 abstracts screened 3979 articles were excluded not specifically focusing on muscle-invasive bladder cancer phenotype (stages T2–T4). 188 studies out of 285 articles were discarded, as these did not meet required study designs and 2-fold change in magnitude of differential abundance of identified features. This restriction resulted in 1,279 protein-coding genes and was further used in the systems based analysis for MIBC.</p

Muscle Invasive Bladder carcinoma interactome, set of 286 protein coding genes.

<p>Nodes in orange denote pathways identified as relevant in both literature and enrichment analysis, nodes in blue depicts pathways of relevance according to enrichment analysis. Node size scales with the number of gene symbols encoded in each pathway term.</p

Feature set Overlap.

<p>A. Redundant features were discarded from 1,279 protein coding genes resulting in 1,054 unique features.The overlap between individual omics studies and literature were calculated. B. The 1,054 protein coding genes were further reduced to 592 by discarding enzymes linked to metabolites as well as miRNA targeted gene symbols, further included for deriving the induced MIBC subgraph resting on BioGRID, IntAct and Reactome protein interaction information.</p

KEGG pathways significantly associated with MIBC according to gene symbols found in more than one omics study type.

<p>Pathway terms, number of molecules associated with the term, Bonferroni corrected p-value and specific gene symbols found overlapping amongst the 7 pathway terms.</p><p>KEGG pathways significantly associated with MIBC according to gene symbols found in more than one omics study type.</p

Intravenous Artesunate for Severe Malaria in Travelers, Europe

Multicenter trials in Southeast Asia have shown better survival rates among patients with severe malaria, particularly those with high parasitemia levels, treated with intravenous (IV) artesunate than among those treated with quinine. In Europe, quinine is still the primary treatment for severe malaria. We conducted a retrospective analysis for 25 travelers with severe malaria who returned from malaria-endemic regions and were treated at 7 centers in Europe. All patients survived. Treatment with IV artesunate rapidly reduced parasitemia levels. In 6 patients at 5 treatment centers, a self-limiting episode of unexplained hemolysis occurred after reduction of parasitemia levels. Five patients required a blood transfusion. Patients with posttreatment hemolysis had received higher doses of IV artesunate than patients without hemolysis. IV artesunate was an effective alternative to quinine for treatment of malaria patients in Europe. Patients should be monitored for signs of hemolysis, especially after parasitologic cure