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© 2017 by the authors. The interdisciplinary research field of microfluidics has the potential to revolutionize current technologies that require the handling of a small amount of fluid, a fast response, low costs and automation. Microfluidic platforms that handle small amounts of liquid have been categorised as continuous-flow microfluidics and digital microfluidics. The first part of this paper discusses the recent advances of the two main and opposing applications of liquid handling in continuous-flow microfluidics: mixing and separation. Mixing and separation are essential steps in most lab-on-a-chip platforms, as sample preparation and detection are required for a variety of biological and chemical assays. The second part discusses the various digital microfluidic strategies, based on droplets and liquid marbles, for the manipulation of discrete microdroplets. More advanced digital microfluidic devices combining electrowetting with other techniques are also introduced. The applications of the emerging field of liquid-marble-based digital microfluidics are also highlighted. Finally, future perspectives on microfluidic liquid handling are discussed.

© 2017 by the authors. The interdisciplinary research field of microfluidics has the potential to revolutionize current technologies that require the handling of a small amount of fluid, a fast response, low costs and automation. Microfluidic platforms that handle small amounts of liquid have been categorised as continuous-flow microfluidics and digital microfluidics. The first part of this paper discusses the recent advances of the two main and opposing applications of liquid handling in continuous-flow microfluidics: mixing and separation. Mixing and separation are essential steps in most lab-on-a-chip platforms, as sample preparation and detection are required for a variety of biological and chemical assays. The second part discusses the various digital microfluidic strategies, based on droplets and liquid marbles, for the manipulation of discrete microdroplets. More advanced digital microfluidic devices combining electrowetting with other techniques are also introduced. The applications of the emerging field of liquid-marble-based digital microfluidics are also highlighted. Finally, future perspectives on microfluidic liquid handling are discussed.

C/EPB alpha proteins, encoded by the CCAAT-enhancer-binding protein a gene, play a crucial role in granulocytic development, and defects in this transcription factor have been reported in acute myeloid leukemia. Here, we defined the C/EPB alpha signature characterized by a set of genes up-regulated upon C/EPB alpha activation. We analyzed expression of the C/EPB alpha signature in a cohort of 525 patients with acute myeloid leukemia and identified a subset characterized by low expression of this signature. We referred to this group of patients as the C/EPB alpha dysfunctional subset. Remarkably, a large percentage of samples harboring C/EPB alpha biallelic mutations clustered within this subset. We hypothesize that re-activation of the C/EPB alpha signature in the C/EPB alpha dysfunctional subset could have therapeutic potential. In search for small molecules able to reverse the low expression of the C/EPB alpha signature we applied the connectivity map. This analysis predicted positive connectivity between the C/EPB alpha activation signature and histone deacetylase inhibitors. We showed that these inhibitors reactivate expression of the C/EPB alpha signature and promote granulocytic differentiation of primary samples from the C/EPB alpha dysfunctional subset harboring biallelic C/EPB alpha mutations. Altogether, our study identifies histone deacetylase inhibitors as potential candidates for the treatment of certain leukemias characterized by down-regulation of the C/EPB alpha signature.

BACKGROUND & AIMS: Almost all gastric cancers are adenocarcinomas, which have considerable heterogeneity among patients. We sought to identify subtypes of gastric adenocarcinomas with particular biological properties and responses to chemotherapy and targeted agents. METHODS: We compared gene expression patterns among 248 gastric tumors; using a robust method of unsupervised clustering, consensus hierarchical clustering with iterative feature selection, we identified 3 major subtypes. We developed a classifier for these subtypes and validated it in 70 tumors from a different population. We identified distinct genomic and epigenomic properties of the subtypes. We determined drug sensitivities of the subtypes in primary tumors using clinical survival data, and in cell lines through high-throughput drug screening. RESULTS: We identified 3 subtypes of gastric adenocarcinoma: proliferative, metabolic, and mesenchymal. Tumors of the proliferative subtype had high levels of genomic instability, TP53 mutations, and DNA hypomethylation. Cancer cells of the metabolic subtype were more sensitive to 5-fluorouracil than the other subtypes. Furthermore, in 2 independent groups of patients, those with tumors of the metabolic subtype appeared to have greater benefits with 5-fluorouracil treatment. Tumors of the mesenchymal subtype contain cells with features of cancer stem cells, and cell lines of this subtype are particularly sensitive to phosphatidylinositol 3-kinase-AKT-mTOR inhibitors in vitro. CONCLUSIONS: Based on gene expression patterns, we classified gastric cancers into 3 subtypes, and validated these in an independent set of tumors. The subgroups have differences in molecular and genetic features and response to therapy; this information might be used to select specific treatment approaches for patients with gastric cancer.

Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-kappaB, and Wnt/beta-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms.