Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection

Malignant mesothelioma (MM) is associated with asbestos exposure and the presence of SV40 viral sequences. Recently, we reported that SV40 infection of human mesothelial cells (HM) causes aberrant methylation of the tumor suppressor gene (TSG) RASSF1A. We investigated methylation of 12 genes by methylation-specific PCR in 63 MMs, six MM cell lines, and two foci of SV40-infected HM. Methylation percentages of the tested genes ranged from 3 to 65%. The frequencies of HPP1, RASSF1A, Cyclin D2, and RRAD methylation, and the value of the methylation index, were significantly higher in SV40 sequence-positive MMs than in SV40-negative MMs. Methylation of TMS1 and HIC-1 was associated with shortened survival. SV40-infected HM showed progressive aberrant methylation of seven genes (RASSF1A, HPP1, DcR1, TMS1, CRBP1, HIC-1, and RRAD) during serial passage. Our results demonstrate a relationship between SV40 and methylation of multiple genes in MM, indicating that the virus plays a role in the pathogenesis of MM.     

Pituitary tumour transforming gene (PTTG) induces genetic instability in thyroid cells

Cancer reflects the progressive accumulation of genetic alterations and subsequent genetic instability of cells. Cytogenetic studies have demonstrated the importance of aneuploidy in differentiated thyroid cancer development. The pituitary tumour transforming gene (PTTG), also known as securin, is a mitotic checkpoint protein which inhibits sister chromatid separation during mitosis. PTTG is highly expressed in many cancers and overexpression of PTTG induces aneuploidy in vitro. Using fluorescent intersimple sequence repeat PCR (FISSR-PCR), we investigated the relationship between PTTG expression and the degree of genetic instability in normal and tumorous thyroid samples. The genomic instability index (GI index) was 6.7-72.7% higher in cancers than normal thyroid tissues. Follicular thyroid tumours exhibited greater genetic instability than papillary tumours (27.6% (n=9) versus 14.5% (n=10), P=0.03). We also demonstrated a strong relationship between PTTG expression and the degree of genetic instability in thyroid cancers (R2=0.80, P=0.007). To further investigate PTTG's role in genetic instability, we transfected FTC133 thyroid follicular cells and observed increased genetic instability in cells overexpressing PTTG compared with vector-only-transfected controls (n=3, GI Index VO=29.7+/-5.2 versus PTTG=63.7+/-6.4, P=0.013). Further, we observed a dose response in genetic instability and PTTG expression (GI Index low dose (0.5 microg DNA/ six-well plate) PTTG=15.3%+/-1.7 versus high dose (3 microg DNA) PTTG=50.8%+/-3.3, P=0.006). Overall, we describe the first use of FISSR-PCR in human cancers, and demonstrate that PTTG expression correlates with genetic instability in vivo, and induces genetic instability in vitro. We conclude that PTTG may be an important gene in the mutator phenotype development in thyroid cancer.     

The Functional Assessment of Anorexia/Cachexia Therapy (FAACT) Appetite Scale in veteran cancer patients

Anorexia and appetite assessment is an important priority in supportive oncology. A series of 156 veterans participating in a hematology oncology service completed the Functional Assessment of Anorexia/Cachexia Therapy (FAACT), the Functional Assessment of Cancer Therapy-General scale, the Memorial Symptom Assessment Scale Short Form (MSAS-SF), and the Zung Self-Rating Depression Scale and were followed for survival. The FAACT score correlated well with Karnofsky performance status, quality of life, and symptom distress subscales. A single appetite distress item from the MSAS-SF correlated well with these measures. Both appetite measures correlated with the presence of other symptoms and with concurrently measured hemoglobin, serum sodium, albumin, and cholesterol levels. These self-reported appetite measures were univariate predictors of survival and contributed additional prognostic information to data related to weight-loss distress. In a smaller study, the FAACT score correlated with a visual analogue measure of appetite and with the North Center Cancer Treatment Group appetite instrument.These data support use of these tools for the evaluation of appetite concerns among patients with advanced cancer.     

Emerging drugs for idiopathic pulmonary fibrosis

Pulmonary fibrosis is often the end stage of chronic, persistent, low-level lung injury, either of known or unknown cause. The most severe form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF), a disease process of unknown aetiology and one that often leads to respiratory failure and death. At present there are no proven or effective drug therapies for IPF. Recent advances in understanding of disease pathogenesis have focused attention on drug targeting of fibrogenic pathways, as opposed to traditional anti-inflammatory approaches. In this report, the present status of drug development of a number of emerging antifibrotic strategies and agents that may prove more effective in the therapy of this progressive, debilitating and fatal disease are reviewed.