Epidemiologic studies suggest a strong genetic component for susceptibility to systemic lupus erythematosus (SLE). To investigate the genetic mechanism of pathogenesis of SLE, we studied the difference in gene expression of peripheral blood cells between 10 SLE patients and 18 healthy controls using oligonucleotide microarray. When gene expression for patients was compared to the mean of normal controls, among the 3002 target genes, 61 genes were identified with greater than a twofold change difference in expression level. Of these genes, 24 were upregulated and 37 downregulated in at least half of the patients. By the Welch's ANOVA/Welch's t-test, all these 61 genes were significantly different (Po0.05) between SLE patients and normal controls. Among these genes with differential expression, IFN-o and Ly6E (TSA-1/Sca-2) may play an important role in the mechanism of SLE pathogenesis. TSA-1 antigens may represent an important alternative pathway for T-cell activation that may be involved in IFN-mediated immunomodulation. Hierarchical clustering showed that patient samples were clearly separated from controls based on their gene expression profile. These results demonstrate that high-density oligonucleotide microarray has the potential to explore the mechanism of pathogenesis of systemic lupus erythematosus.

Gastric cancer is the second most common cancer in the world and the fifth leading cause of cancer-related death in Taiwan. To improve the survival of gastric cancer patients, biomarkers for early detection and effective anticancer therapy are required. An essential first step is to profile gene expression in gastric cancer and identify genes that are aberrantly expressed, and to do this cDNA microarrays were performed. The clinic -pathologic correlation and prognostic significance of the aberrantly expressed genes were evaluated to identify novel biomarkers of gastric cancer. Fresh surgical samples of tumour tissue and matching noncancerous mucosa were obtained immediately after gastric resection in 43 patients. Secreted Protein, Acidic and Rich in Cysteine (SPARC) (Osteonectins), one of the most highly expressed genes in both intestinal and diffuse gastric cancers in our microarray results, was selected for further study. The overexpression of SPARC was verified using real-time quantitative-reverse transcription -polymerase chain reaction (Q-RT -PCR), Northern blot and immunohistochemical staining. The expression of SPARC in tumour tissues was, on average, 4.27-fold increased (95% CI 2.68 -5.85) compared to adjacent noncancerous mucosa (Po0.001). The expression of SPARC was higher in advanced (T2, T3 and T4) cancer compared to the early (T1) cancer (P ¼ 0.048) with regard to depth of wall invasion. Higher expression of SPARC was significantly associated with lymph node metastasis (Po0.001), lymphatic invasion (P ¼ 0.004) and perineural invasion (P ¼ 0.047). Expression of SPARC in patients in stage II and above was significantly higher than those in stage I (P ¼ 0.017). The 3-year survival of patients with lower expression of SPARC was significantly better than those with a higher expression (log rank P ¼ 0.047). These data indicate the potential of SPARC as a prognostic marker for gastric cancer.

Primary spontaneous pneumothorax (PSP) is a common manifestation of Birt-Hogg-Dubé syndrome caused by folliculin gene (FLCN) mutation, which is also found in isolated familial PSP cases. A complete genetic analysis of FLCN was performed in 102 unrelated Chinese patients with isolated PSP and 21 of their family members. Three novel mutations (c.924_926del, c.1611_1631del and c.1740C>T) and a previously reported mutation (c.1733insC) were identified in five familial and five sporadic PSP patients. Of the 21 family members of patients with PSP including 3 previous considered as sporadic, 4 (19%) had history of at least one episode of PSP and 9 (43%) were FLCN mutant carriers without PSP. Seven of the nine (78%) mutant carriers had pulmonary cysts detected by high-resolution computed tomography (HRCT). Although c.924_926del and c.1611_1631del were found in eight patients from the same geographic district, haplotype analysis demonstrated that they did not share the same affected haplotype, thus excluding common ancestry. This study first demonstrates that FLCN mutation contributes to not only familial but also 'apparently sporadic' patients with isolated PSP. It suggests that mutation analysis and HRCT scan may be recommended for first-degree family members of PSP patients with FLCN mutations, irrespective of their family history status of PSP.

Thyroid hormones (THs) regulate growth, development, differentiation and metabolic processes by interacting and activating thyroid hormone receptors (TRs). Although much progress has been made in our understanding of the transcriptional regulation of many TR target genes, little is known of the regulation of plasma protein gene expression by TRs. To investigate the role of TRs in plasma protein expression we used human hepatocellular carcinoma cell lines and carried out cDNA microarray analysis. Our results indicate that several plasma proteins including transferrin, prothrombin, angiotensinogen, haptoglobin, -2-HS-glycoprotein and chain, complement, lipoproteins and fibrinogen are up-regulated by THs. Furthermore, clusterin, -2-macroglobulin precursor, prothymosin and -fetoprotein were found to be down-regulated by THs.Transferrin, an iron-binding protein expressed in all mammals, and mainly synthesized in the liver, was investigated further. Immunoblot and Northern blot analyses revealed that exposure of HepG2-TR 1 sub-lines and HepG2-Neo cells to tri-iodothyronine (T 3 ) induced time-and dose-dependent increases in the abundance of transferrin mRNA and protein, with the extent of these effects correlating with the level of expression of TR 1. Nuclear run-on experiments indicate that this induction is functioning at the transcriptional level. Moreover, cyclohexamide treatment did not eliminate the induction of transferrin by TH. Thus, our results suggest that the induction of transferrin by TH is direct and may in fact be mediated by an as yet unidentified response element in the promoter region.

BACKGROUND AND PURPOSE Prevention or disease‐modifying therapies are critical for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. However, no such intervention is currently available. Growing evidence has demonstrated that administration of histone deacetylase (HDAC) inhibitors ameliorates a wide range of neurologic and psychiatric disorders in experimental models. Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinson's disease models. EXPERIMENTAL APPROACH Mesencephalic neuron–glia cultures and reconstituted cultures were used to investigate neurotrophic and neuroprotective effects of SAHA. We measured toxicity in dopaminergic neurons, using dopamine uptake assay and morphological analysis and expression of neurotrophic substances by enzyme‐linked immunosorbent assay and real‐time RT PCR. KEY RESULTS In mesencephalic neuron–glia cultures, SAHA displayed dose‐ and time‐dependent prolongation of the survival and protection against neurotoxin‐induced neuronal death of dopaminergic neurons. Mechanistic studies revealed that the neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation. CONCLUSION AND IMPLICATIONS The novel neurotrophic and neuroprotective effects of SAHA demonstrated in this study suggest that further study of this HDAC inhibitor could provide a new therapeutic approach to the treatment of neurodegenerative diseases.