A phase II study of single-agent gemcitabine as a second-line treatment in advanced non-small cell lung cancer

OBJECTIVE: To evaluate the efficacy and safety of the single-agent gemcitabine in advanced non-small cell lung cancer (NSCLC) as second-line chemotherapy. METHODS: Between February 2002 and November 2004, a total of 27 patients, who had previously been treated with paclitaxel and platinum as first line chemotherapy, were enrolled in the study. Patients were treated with gemcitabine (1000 mg/m(2)) on days 1, 8 and 15 in a 28 day cycle. The response was assessed every two cycles. Toxicities were evaluated according to common toxicity criteria (CTC). RESULTS: The median age was 62 (range, 46-79) years old. Among the 27 patients, 26 were male. Twenty-three patients had an ECOG performance status of 0 or 1 and four patients had a status of 2. Pathologically, 24 patients had squamous cell carcinoma and 3 had adenocarcinoma. Partial responses were observed in 15 patients. All patients were evaluated for response and toxicity. The overall response rate was 18.5% (95% confidence interval, 5-33%) and the median response duration was 17 (range, 7.4 to 49+) weeks. The median time to progression was 10 (range, 7 to 34+) weeks. The median overall survival for all patients was 38 (range, 10 to 122+) weeks. During a total of 87 cycles, granulocytopenia greater than CTC grade 2 occurred in 7%, thrombocytopenia in 1% and anemia in 24% of case. Non-hematologic toxicities were minor and easily controlled. CONCLUSION: This study confirms the activity and safety of the single-agent gemcitabine as a second-line therapy in pretreated patients with advanced NSCLC.     

A novel homozygous missense ADAMTS13 mutation Y658C in a patient with recurrent thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a devastating systemic disorder that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, neurological dysfunction, and renal failure. In the hereditary form of TTP, severe deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor, is associated with the development of this disorder. A 34-year-old woman was diagnosed with TTP due to severely reduced ADAMTS13 activity; clinical manifestations resolved only by repeated total plasma exchanges or transfusion. Homozygous and heterozygous Y658C (c.1973A>G) alleles were detected in the patient and her child with severe and mild ADAMTS13 deficiencies, respectively. Herein, we report a novel missense mutation Y658C (c.1973A>G) on exon 17 of ADAMTS13 and discuss its clinical implications.     

The role of Janus kinase 2 (JAK2) activation in pneumococcal EstA protein-induced inflammatory response in RAW 264.7 macrophages

In a previous study, we demonstrated pneumococcal EstA-induced inflammatory response through NF-κB and MAPK-dependent pathways. Herein, we tested the hypothesis that the Janus kinase 2 (JAK2) activation and associated signaling cascades may also be involved in EstA-induced inflammatory process in RAW 264.7 macrophages. Our immunoblot analysis indicated EstA-induced activation of JAK2, with the phosphorylated protein detected from 1 to 24 h post-stimulation. As type I interferon (IFN) signaling requires the JAK/STAT pathway, we investigated EstA-induced expression of INF-α4 and INF-β by semi-quantitative and quantitative RT PCR. Our results indicated both concentration- and time-dependent increases in both IFN-α4 and IFN-β mRNA expression after EstA challenge, with the highest fold-increases observed at 4 h and 6 h post-stimulation for IFN-α4 and IFN-β mRNA, respectively. Furthermore, we applied a pharmacological approach to demonstrate the effect of JAK2 inhibition on EstA-induced nitric oxide (NO) and pro-inflammatory cytokine production. The JAK2 inhibitor AG-490 reduced significantly (P < 0.05) EstA-induced NO production and the expression of iNOS mRNA in a concentration-dependent manner. Similarly, EstA-induced IL-1β and IL-6 production and their respective mRNA expression were markedly suppressed by AG-490. However, AG-490 had no inhibitory effect on both mRNA and protein levels of TNF-α. Taken together, we demonstrate that JAK2 activation and IFN I signaling are integral parts of EstA-induced inflammatory process. Further studies will elucidate the interaction of the different signaling pathways, the specific downstream targets of JAK2, the kinetics of cytokine release, and if EstA could induce the pro-inflammatory mediators to the same extent in alveolar macrophages.     

Enhancement of anti-inflammatory and antinociceptive actions of red ginseng extract by fermentation

Objectives This work aimed to compare some pharmacological properties of red ginseng extract (RG) and fermented red ginseng extract (FRG). Methods Antinociceptive activity was analysed using the acetic acid‐induced abdominal constriction response. Anti‐inflammatory activity was evaluated using acetic acid‐induced vascular permeability and carrageenan‐induced inflammation in the air pouch, and analysed through the measurement of nitrite content in the lipopolysaccharide (LPS)‐stimulated macrophage cells. Anti‐angiogenic activity was determined using the chick chorioallantoic membrane assay. Key findings In‐vivo anti‐inflammatory activity of FRG was stronger than that of RG in two animal models, vascular permeability and air‐pouch models. In the vascular permeability model, the doses of RG and FRG required for half‐maximal inhibition (IC50) were 181 and 59 mg/kg, respectively. FRG exhibited significantly stronger antinociceptive activity than RG. In the acetic acid‐induced abdominal constriction response, the IC50 values of RG and FRG were 153 and 27 mg/kg, respectively. Although both RG and FRG were able to suppress production of nitric oxide in the LPS‐stimulated RAW264.7 macrophage cells, the suppressive activity of FRG appeared to be stronger than that of RG. However, RG and FRG showed similar anti‐angiogenic activity. Conclusions FRG possesses enhanced anti‐inflammatory and antinociceptive activity but similar anti‐angiogenic activity than RG.     

Psychosocial work stress during pregnancy and birthweight

Although there is a growing interest in the health effects of psychosocial work stress, studies on the relationships between job stress and adverse reproductive outcome are limited. We, therefore, investigated the associations between prenatal maternal occupational stress and birthweight using 310 mother-infant pairs included in the Mothers and Children's Environmental Health (MOCEH) study. Information on job stress was collected by interviewing women at enrollment during the first trimester of pregnancy using standardised questionnaires, namely, the Job Content Questionnaire (JCQ) of job strain and effort-reward imbalance (ERI) questionnaires. Regression analyses were carried out. Decision latitude scores of the JCQ were found to be positively related to birthweight, while ERI ratios determined using the ERI model were found to be inversely related to gestational age. In addition, a passive job as defined by the job strain model was found to be associated with a lower birthweight, compared with a relaxed job. These results suggest that work-related psychosocial stress in pregnant women appears to affect birth outcomes, such as birthweight and gestational age.     

Pharmacological induction of heat shock protein exerts neuroprotective effects in experimental intracerebral hemorrhage

Heat shock proteins (HSPs) are reported to reduce inflammation and apoptosis in a variety of brain insults. Geranylgeranylacetone (GGA), developed as an antiulcer in Japan, has been known to induce HSP70 and to exert cytoprotective effects. In this study, we investigated whether GGA, as a specific HSP inducer, exerts therapeutic effects in experimentally induced intracerebral hemorrhage (ICH). ICH was induced with male Sprague-Dawley rats via the collagenase infusion. GGA (800 mg/kg) was administered via oral tube according to various schedules of treatment. The treatment with GGA, beginning before the induction of ICH and continuing until day 3, showed the reduction of brain water content and the increased level of HSP70 protein, as compared to the treatment with vehicle, although GGA started after the induction of ICH or administered as a single dose before ICH failed to up-regulate HSP70 and to reduce brain edema. The rats treated with GGA exhibited better functional recovery than those treated with vehicle. In the pre- and post- treatment group, inflammatory cells and cell death in the perihematomal regions were found to have been decreased. The treatment of GGA inhibited the mRNA expression of MMP-9, uPA, IL-6 and MIP-1, with concomitant increment of eNOS and phosphorylated STAT3 and Akt after ICH. We demonstrated that GGA induced a reduction in the brain edema along with marked inhibitory effects on inflammation and cell death after ICH.