Disruption of TGF-β Signaling Improves Ocular Surface Epithelial Disease in Experimental Autoimmune Keratoconjunctivitis Sicca

TGF-β is a pleiotropic cytokine that can have pro- or anti-inflammatory effects depending on the context. Elevated levels of bioactive TGF-β1 in tears and elevated TGF-β1mRNA transcripts in conjunctiva and minor salivary glands of human Sjögren's Syndrome patients has also been reported. The purpose of this study was to evaluate the response to desiccating stress (DS), an experimental model of dry eye, in dominant-negative TGF-β type II receptor (CD4-DNTGFβRII) mice. These mice have a truncated TGF-β receptor in CD4(+) T cells, rendering them unresponsive to TGF-β.DS was induced by subcutaneous injection of scopolamine and exposure to a drafty low humidity environment in CD4-DNTGFβRII and wild-type (WT) mice, aged 14 weeks, for 5 days. Nonstressed (NS) mice served as controls. Parameters of ocular surface disease included corneal smoothness, corneal barrier function and conjunctival goblet cell density. NS CD4-DNTGFβRII at 14 weeks of age mice exhibited a spontaneous dry eye phenotype; however, DS improved their corneal barrier function and corneal surface irregularity, increased their number of PAS+ GC, and lowered CD4(+) T cell infiltration in conjunctiva. In contrast to WT, CD4-DNTGFβRII mice did not generate a Th-17 and Th-1 response, and they failed to upregulate MMP-9, IL-23, IL-17A, RORγT, IFN-γ and T-bet mRNA transcripts in conjunctiva. RAG1KO recipients of adoptively transferred CD4+T cells isolated from DS5 CD4-DNTGFβRII showed milder dry eye phenotype and less conjunctival inflammation than recipients of WT control.Our results showed that disruption of TGF-β signaling in CD4(+) T cells causes paradoxical improvement of dry eye disease in mice subjected to desiccating stress

Successful treatment of mucosa-associated lymphoid tissue lymphoma in a patient with gastric and rectal lesions with metachronous and ectopic development

A 75-year-old female, who had an abnormal stomach x-ray finding, was admitted to the hospital for further examination and therapy. Upper GI endoscopy showed reddish and swollen folds on the greater curvature of the gastric body and a biopsy was of this lesion revealed malignant lymphoma (small cell type or mucosa-associated lymphoid tissue (MALT) lymphoma suspected). The patient was infected with Helicobacter pylori (H. pylori), however, in response to the patient's wishes, a total gastrectomy, omentectomy and splenectomy were performed and the histological diagnosis was gastric MALT lymphoma. Two courses of CHOP therapy (cyclophosphamide (CPM) 750 mg/m2/day, day 1, adriamycin (ADM) 50 mg/m2/day, day 1, vincristine sulfate (VCR) 1.4 mg/m2/day, day 1, prednisolone 100 mg/body, day 1–5) were administered as adjuvant chemotherapy. A colonoscopic examination performed about 4.5 yr after the operation revealed rectal submucosal tumors and the biopsied specimens were diagnosed as malignant lymphoma. A transanal focal resection was performed and the histological diagnosis was metachronous and ectopic development of MALT lymphoma. The histological finding was similar to the gastric lesion. About 4 and 7 yr after the first development of rectal MALT lymphoma, MALT lymphomas developed repeatedly in the rectal lesion, however, these were resected repeatedly and no developmenthas occurred during the past two years. This report presents a very rare case of metachronous and ectopic MALT lymphoma development in the gastric and rectal lesions

Keratinocyte Growth Factor Induces Gene Expression Signature Associated with Suppression of Malignant Phenotype of Cutaneous Squamous Carcinoma Cells

Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n = 6) than in normal skin samples (n = 6). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal keratinocytes

The International HapMap Project

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62838/1/nature02168.pd