Papillary renal cell carcinoma (pRCC) is the second most common type of renal cell carcinoma. The only curative treatment available for pRCC is radical surgery. If the disease becomes widespread, neither chemo- nor radiotherapy will have therapeutic effect, hence further research on pRCC is of utmost importance. Histologically, pRCC is characterized by a papillary growth pattern with focal aggregation of macrophages of the foam cell phenotype. In other forms of cancer, a clear role for tumor-associated macrophages during cancer growth and progression has been shown. Although the presence of foamy macrophages is a histological hallmark of pRCC tumors, little is known regarding their role in pRCC biology. In order to study the interaction between pRCC tumor and myeloid cells, we established primary cultures from pRCC tissue. We show that human pRCC cells secrete the chemokines IL-8, CXCL16, and chemerin, and that these factors attract primary human monocytes in vitro. RNAseq data from The Cancer Genome Atlas confirmed a high expression of these factors in pRCC tissue. Conditioned medium from pRCC cultures induced a shift in human monocytes toward the M2 macrophage phenotype. In extended cultures, these macrophages became enlarged and loaded with lipids, adopting the foam cell morphology found in pRCC tissue. These results show for the first time that pRCC primary tumor cells secrete factors that attract and differentiate monocytes into anti-inflammatory tumor-associated macrophages with foam cell histology.

Bank voles are known reservoirs for Puumala hantavirus and probably also for Ljungan virus (LV), a suggested candidate parechovirus in type 1 diabetes etiology and pathogenesis. The aim of this study was to determine whether wild bank voles had been exposed to LV and if exposure associated to autoantibodies against insulin (IAA), glutamic acid decarboxylase 65 (GADA), or islet autoantigen-2 (IA-2A). Serum samples from bank voles (Myodes glareolus) captured in early summer or early winter of 1997 and 1998, respectively, were analyzed in radio binding assays for antibodies against Ljungan virus (LVA) and Puumala virus (PUUVA) as well as for IAA, GADA, and IA-2A. LVA was found in 25% (189/752), IAA in 2.5% (18/723), GADA in 2.6% (15/615), and IA-2A in 2.5% (11/461) of available bank vole samples. LVA correlated with both IAA (P = 0.007) and GADA (P < 0.001), but not with IA-2A (P = 0.999). There were no correlations with PUUVA, detected in 17% of the bank voles. Compared to LVA negative bank voles, LVA positive animals had higher levels of both IAA (P = 0.002) and GADA (P < 0.001), but not of IA-2A (P = 0.205). Levels of LVA as well as IAA and GADA were higher in samples from bank voles captured in early summer. In conclusion, LVA was detected in bank voles and correlated with both IAA and GADA but not with IA-2A. These observations suggest that exposure to LV may be associated with islet autoimmunity. It remains to be determined if islet autoantibody positive bank voles may develop diabetes in the wild. J. Med. Virol. 89:24-31, 2017. © 2016 Wiley Periodicals, Inc.

Mechanical ventilation is often required in patients with pulmonary disease to maintain adequate gas exchange. Despite improved knowledge regarding the risks of over ventilating the lung, ventilator induced lung injury (VILI) remains a major clinical problem due to inhomogeneities within the diseased lung itself as well as the need to increase pressure or volume of oxygen to the lung as a life-saving measure. VILI is characterized by increased physical forces exerted within the lung, which results in cell death, inflammation and long-term fibrotic remodeling. Animal models can be used to study VILI, but it is challenging to distinguish the contributions of individual cell types in such a setup. In vitro models, which allow for controlled stretching of specific lung cell types have emerged as a potential option, but these models and the membranes used in them are unable to recapitulate some key features of the lung such as the 3D nanofibrous structure of the alveolar basement membrane while also allowing for cells to be cultured at an air liquid interface (ALI) and undergo increased mechanical stretch that mimics VILI. Here we develop a lung on a chip device with a nanofibrous synthetic membrane to provide ALI conditions and controllable stretching, including injurious stretching mimicking VILI. The lung on a chip device consists of a thin (i.e. ~20 μm) stretchable poly(caprolactone) (PCL) nanofibrous membrane placed between two channels fabricated in polydimethylsiloxane (PDMS) using 3D printed molds. We demonstrate that this lung on a chip device can be used to induce mechanotrauma in lung epithelial cells due to cyclic pathophysiologic stretch (~25%) that mimics clinical VILI. Pathophysiologic stretch induces cell injury and subsequently cell death, which results in loss of the epithelial monolayer, a feature mimicking the early stages of VILI. We also validate the potential of our lung on a chip device to be used to explore cellular pathways known to be altered with mechanical stretch and show that pathophysiologic stretch of lung epithelial cells causes nuclear translocation of the mechanotransducers YAP/TAZ. In conclusion, we show that a breathable lung on a chip device with a nanofibrous membrane can be easily fabricated using 3D printing of the lung on a chip molds and that this model can be used to explore pathomechanisms in mechanically induced lung injury.

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