Radioiodide is an effective therapy for thyroid cancer. This treatment modality exploits the thyroid -specific expression of the sodium iodide symporter ( NIS ) gene, which allows rapid internalization of iodide into thyroid cells. To test whether a similar treatment strategy could be exploited in nonthyroid malignancies, we transfected non -small cell lung cancer ( NSCLC ) cell lines with the NIS gene. Although the expression of NIS allowed significant radioiodide uptake in the transfected NSCLC cell lines, rapid radioiodide efflux limited tumor cell killing. Because thyroperoxidase ( TPO ) catalyzes iodination of proteins and subsequently causes iodide retention within thyroid cells, we hypothesized that coexpression of both NIS and TPO genes would overcome this deficiency. Our results show that transfection of NSCLC cells with both human NIS and TPO genes resulted in an increase in radioiodide uptake and retention and enhanced tumor cell apoptosis. These findings suggest that single gene therapy with only the NIS gene may have limited efficacy because of rapid efflux of radioiodide. In contrast, the combination of NIS and TPO gene transfer, with resulting TPO -mediated organification and intracellular retention of radioiodide, may lead to more effective tumor cell death. Thus, TPO could be used as a therapeutic strategy to enhance the NIS -based radioiodide concentrator gene therapy for locally advanced lung cancer. Cancer Gene Therapy ( 2001 ) 8, 612 -618

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Idiopathic pulmonary fibrosis (IPF) is a devastating disease with less than a 50% five-year survival (1, 2). While steroids and other immunosuppressive agents serve as the standard treatment for IPF, these agents have proved inadequate (3). In most instances immunosuppressive agents do little to affect the course of the disease and have serious adverse side effects. Thus, novel therapeutic strategies are clearly needed. Recent published findings suggest novel treatment paradigms based on a more complete understanding of the pathogenesis of pulmonary fibrosis (3, 4). IL-7 is a 25-kDa glycoprotein originally isolated from bone marrow stroma cells (5). IL-7 was originally defined as a pre-B lymphocyte growth factor and was subsequently found to augment the growth of T lymphocytes (6-8). We (9) and others (10-13) have documented that IL-7 can potently enhance T cell function and IFN-γ production. IL-7 synergizes with IL-12 in the induction of T cell proliferation, cytotoxicity, and IFN-γ release (11). In agreement with these findings are studies indicating that IL-7 plays a role in cell-mediated immune responses characteristic of type 1 cytokines (10). We have found that IL-7 downregulates macrophage (14), fibrosarcoma, and melanoma (15, 16) production of TGF-β. IL-7 has the capacity to downregulate the transcriptional rate of the TGF-β gene in murine macrophages in an IFN-γindependent manner (14). TGF-β is a critical fibrogenic factor in the development of pulmonary fibrosis. Based on the importance of TGF-β in the pathogenesis of pulmonary fibrosis, we speculated that the most effective therapies would be those that decrease both the production and the cellular effects of TGF-β. In the current study we investigate the role of IL-7 in TGF-β production and signaling and the potential for IL-7 as a new antifibrotic agent in the treatment of interstitial pulmonary fibrosis. Methods Cell culture. Pulmonary fibrosis fibroblasts (PFFs) were isolated from lung resection specimens obtained from patients with IPF. Normal fibroblasts (NFs) were isolated from patients with nonfibrotic diseases. U4A, U3A, and U4A/JAK1 cell lines were generously provided by George R. Stark (Cleveland Clinic Foundation, Cleveland, Ohio, USA). The cells were maintained in 5% CO 2 in air as monolayers at 37°C in 75-cm 2 tissue culture flasks containing 20 ml of DMEM supplemented with 10% FBS, 100 units/ml penicillin, 0.1 mg/ml streptomycin, and 2 mM glutamine (JRH Biosciences, Lenexa, Kansas, USA). Cytokines and antibodies. Human activated recombinant TGF-β1 (3.2 × 10 4 units/µg), recombinant human IL-7

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rhGH showed beneficial effects on rat septic shock. The possible mechanisms may involve the attenuation of bacteria/endotoxin translocation and decreased systemic endotoxin level; inhibition of the production and release of TNFalpha; improved circulatory function; improved systemic host defenses and maintenance of intestinal mucosa barrier.

Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated, including in non-small cell lung cancer (NSCLC). Here, we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth and primary tumor growth and metastatic behavior Snail-mediated transformation relied upon silencing of the tumor-suppressive RNA splicing regulatory protein ESRP1. In clinical specimens of NSCLC, ESRP1 loss was documented in Snail-expressing premalignant pulmonary lesions. Mechanistic investigations showed that Snail drives malignant progression in an ALDHCD44CD24 pulmonary stem cell subset in which ESRP1 and stemness-repressing microRNAs are inhibited. Collectively, our results show how ESRP1 loss is a critical event in lung carcinogenesis, and they identify new candidate directions for targeted therapy of NSCLC. This study defines a Snail-ESRP1 cancer axis that is crucial for human lung carcinogenesis, with implications for new intervention strategies and translational opportunities. .

BackgroundThere has been a dramatic increase in T cell receptor (TCR) sequencing spurred, in part, by the widespread adoption of this technology across academic medical centers and by the rapid commercialization of TCR sequencing. While the raw TCR sequencing data has increased, there has been little in the way of approaches to parse the data in a biologically meaningful fashion. The ability to parse this new type of 'big data' quickly and efficiently to understand the T cell repertoire in a structurally relevant manner has the potential to open the way to new discoveries about how the immune system is able to respond to insults such as cancer and infectious diseases.