Retinoblastoma gene product (pRB) plays critical roles in regulation of the cell cycle and tumor suppression. It is known that downregulation of pRB can stimulate carcinogenesis via abrogation of the pRB pathway, although the mechanism has not been elucidated. In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB. pRB was efficiently ubiquitinated by wild-type Mdm2 in vivo as well as in vitro, but other RB family proteins were not. Mutant Mdm2 with a substitution in the RING finger domain showed dominant-negative stabilization of pRB. Both knockout and knockdown of Mdm2 caused accumulation of pRB. Moreover, Mdm2 inhibited pRB-mediated flat formation of Saos-2 cells. Downregulation of pRB expression was correlated with a high level of expression of Mdm2 in human lung cancers. These results suggest that Mdm2 regulates function of pRB via ubiquitin-dependent degradation of pRB.

d Tuberculosis (TB) continues to be a major health problem, and there are few biomarkers for predicting prognosis. Indoleamine 2,3-dioxygenase (IDO), a potent immunoregulatory molecule, catalyzes the rate-limiting step of tryptophan (Trp) degradation in the kynurenine (Kyn) pathway. An increase in IDO activity determined by the serum Trp/Kyn ratio has been shown to be associated with poor prognosis in cancers and bacteremia. In TB, however, there are no studies measuring serum IDO activity to determine its clinical significance. We evaluated serum IDO activity with 174 pulmonary TB (PTB) patients and 85 controls, using liquid chromatography/electrospray ionization tandem mass spectrometry. IDO activity was estimated by calculating the serum Kyn-to-Trp ratio. PTB patients had significantly higher Kyn concentrations and IDO activity and significantly lower Trp concentrations (P < 0.0001, P < 0.0001, and P < 0.0001, respectively) than the controls. Of 174 PTB patients, 39 (22.4%) died. The patients who died had significantly higher concentrations of Kyn and significantly lower Trp concentrations, resulting in significantly higher IDO activity (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). In a receiver operating characteristic (ROC) analysis, serum IDO activity had the highest area under the curve (0.850), and this activity was an independent prognostic factor in multivariate analysis. These results suggest that serum IDO activity can be used as a novel prognostic marker in PTB.T uberculosis (TB) remains a worldwide health problem, with 8.8 million new cases per year (21, 24). Advanced diagnosis technique, such as PCR for TB DNA and gamma interferon (IFN-␥) release assays (IGRAs), have improved detection of TB, and progress in multidrug combination therapy and expansion of directly observed therapy (DOTS) has increased the treatment completion rate and reduced the relapse rate. However, TB still causes over 1.6 million deaths per year (21,24). To assess the disease activity, therapeutic response, or risk for relapse, a large number of candidate biomarkers, such as sputum microbiologic examinations, serum neopterin, IGRAs, and urine tuberculous DNA, have been vigorously investigated (18, 21). However, there are few useful markers for predicting mortality in pulmonary TB (PTB).Indoleamine 2, 3-dioxygenase (IDO) is the rate-limiting enzyme that catalyzes tryptophan (Trp) degradation along the kynurenine (Kyn) pathway (9,11,12,19,25). In infectious diseases, IDO was initially considered an antimicrobial molecule acting through local starvation of Trp, which is an essential amino acid for bacterial growth. Interestingly, recent studies have unveiled a novel immunoregulatory role of IDO. By reducing the local Trp concentration and producing immunomodulatory Trp metabolites, such as Kyn, IDO potently inhibits T-cell functions and generates regulatory T cells (Treg), leading to immune suppression or tolerance. More interestingly, this immunoregulatory role of IDO has been shown to be associated with the immune esc...

CPA is a disease with a poor prognosis, which shows distinct clinical characteristics from colonization.

These data suggest that YKL-40 is increased in the circulation and lungs of IPF patients, suggesting that this glycoprotein is associated with the pathophysiology of IPF.

Interstitial lung disease (ILD) associated with polymyositis/dermatomyositis (ILD-PM/DM), including amyopathic dermatomyositis (ADM), is recognized as an important condition because it frequently causes death, despite intensive therapy with high-dose corticosteroid and immunosuppressive agents, such as cyclosporine A and cyclophosphamide. Intravenous immunoglobulin therapy (IVIG) has shown efficacy for myopathy associated with PM/DM, but its usefulness for ILD-PM/DM is unclear. This study was designed to investigate the efficacy of IVIG for refractory ILD-PM/DM. A review was made of medical charts of five patients (2 men and 3 women) who were treated with IVIG for refractory ILD-PM/DM resistant to high-dose corticosteroid and cyclosporine A and/or cyclophosphamide. One patient had acute ILD-PM and four patients had acute ILD-ADM. Of the five patients, one patient with ILD-PM and one patient with ILD-ADM survived. No adverse reactions were seen due to IVIG treatment. There were no critical differences in the clinical parameters and clinical courses between survivors and nonsurvivors. IVIG treatment is safe and could be an effective salvage therapy for refractory ILD-PM/DM in certain cases, suggesting that further controlled trials are worthwhile.