Sniffing out atherosclerosis: Olfactory receptors are best known for their presence in the nose and their role in detecting smells, but they are also present in other tissues and perform additional biological functions. For example, vascular macrophages involved in the pathogenesis of atherosclerosis express multiple subtypes of olfactory receptors. Orecchioni et al . focused on olfactory receptor 2, a receptor for the compound octanal, and identified its contribution to atherosclerosis pathogenesis and the formation of atherosclerotic plaques (see the Perspective by Rayner and Rasheed). The authors show that most of the octanal was not directly derived from the diet, but rather was generated as a by-product of lipid peroxidation, suggesting a potential pathway for intervention. —YN

We report on the fabrication of nanofluidic channels directly buried in silicate glass with transverse widths down to less than 50 nm using three-dimensional (3D) femtosecond laser direct writing. Using this technique, integrated micro-nanofluidic systems have been produced by simultaneously writing micro- and nanofluidic channels arranged into various 3D configurations in glass substrates. The fabricated micro- and nanofluidic systems have been used to demonstrate DNA analysis, e.g. stretching of DNA molecules. Our technique offers new opportunities to develop novel 3D micro-nanofluidic systems for a variety of lab-on-a-chip applications.

The fate of circulating tumor cells (CTC) is an important determinant of metastasis and recurrence, which leads to most deaths in hepatocellular carcinoma (HCC). Therefore, quantification of CTCs proves to be an emerging tool for diagnosing, stratifying, and monitoring patients with metastatic diseases. In vivo flow cytometry has the capability to monitor the dynamics of fluorescently labeled CTCs continuously and noninvasively. Here, we combine in vivo flow cytometry technique and a GFP-transfected HCC orthotopic metastatic tumor model to monitor CTC dynamics. Our in vivo flow cytometry has approximately 1.8-fold higher sensitivity than whole blood analysis by conventional flow cytometry. We found a significant difference in CTC dynamics between orthotopic and subcutaneous tumor models. We also investigated whether liver resection promotes or restricts hematogenous metastasis in advanced HCC. Our results show that the number of CTCs and early metastases decreases significantly after the resection. The resection prominently restricts hematogenous metastasis and distant metastases. CTC dynamics is correlated with tumor growth in our orthotopic tumor model. The number and size of distant metastases correspond to CTC dynamics. The novel in vivo flow cytometry technique combined with orthotopic tumor models might provide insights to tumor hematogenous metastasis and guidance to cancer therapy. Cancer Res; 72(10); 2683–91. ©2012 AACR.

Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions.

Neutrophils are essential for innate immunity and inflammation and many neutrophil functions are β₂ integrin-dependent. Integrins can extend (E⁺) and acquire a high-affinity conformation with an ‘open’ headpiece (H⁺). The canonical switchblade model of integrin activation proposes that the E⁺ conformation precedes H⁺, and the two are believed to be structurally linked. Here we show, using high-resolution quantitative dynamic footprinting (qDF) microscopy combined with a homogenous conformation-reporter binding assay in a microfluidic device, that a substantial fraction of β₂ integrins on human neutrophils acquire an unexpected E⁻H⁺ conformation. E⁻H⁺ β₂ integrins bind intercellular adhesion molecules (ICAMs) in cis, which inhibits leukocyte adhesion in vitro and in vivo. This endogenous anti-inflammatory mechanism inhibits neutrophil aggregation, accumulation and inflammation.

Neutrophils are the most abundant leukocyte in human blood. They are critical for fighting infections and are involved in inflammatory diseases. Mitochondria are indispensable for eukaryotic cells, as they control the biochemical processes of respiration and energy production. Mitochondria in neutrophils have been underestimated since glycolysis is a major metabolic pathway for fuel production in neutrophils. However, several studies have shown that mitochondria are greatly involved in multiple neutrophil functions as well as neutrophil-related diseases. In this review, we focus on how mitochondrial components, metabolism, and related genes regulate neutrophil functions and relevant diseases.