A randomised multicentre phase II study with cisplatin/docetaxel vs oxaliplatin/docetaxel as first-line therapy in patients with advanced or metastatic non-small cell lung cancer.

BACKGROUND: This study was designed to compare cisplatin/docetaxel with oxaliplatin/docetaxel in patients with advanced and metastatic non-small lung cancer as a first-line treatment. METHODS: Patients were randomly assigned to receive either cisplatin 75 mg m(-2) and docetaxel 75 mg m(-2) every 3 weeks or oxaliplatin 85 mg m(-2) and docetaxel 50 mg m(-2) every 2 weeks. The primary end point was response rate, and secondary end points were toxicity, time to progression and overall survival. RESULTS: A total of 88 patients (median age: 65 (39-86) years; stage IV: 93%) were randomly assigned. Response rate (complete and partial response) was 47% (95% CI: 33-61%) in the cisplatin/docetaxel arm and 28% (95% CI: 17-43%) in the oxaliplatin/docetaxel arm (P=0.118). There was no significant difference in time to progression (6.3 vs 4.9 months, P=0.111) and median overall survival (11.6 vs 7.0 months, P=0.102) with cisplatin/docetaxel vs oxaliplatin/docetaxel, although slight trends favouring cisplatin were seen. Oxaliplatin/docetaxel was associated with significantly less (any grade) renal toxicity (56% vs 11%), any grade fatigue (81% vs 59%), complete alopecia (76% vs 27%), any grade leukopenia (84% vs 61%) and grade 3/4 leukopenia (44% vs 14%) and neutropenia (56% vs 27%). CONCLUSION: Oxaliplatin/docetaxel has activity in metastatic non-small cell lung cancer, but it seems to be inferior to cisplatin/docetaxel.

Apoptosis and JNK activation are differentially regulated by Fas expression level in renal tubular epithelial cells.

BACKGROUND: In chronic renal disease, renal tubular epithelial cell (RTC) Fas expression is up-regulated, leading to apoptotic RTC deletion and tubular atrophy. In vitro, cytokine- or hypoxia-induced up-regulation of Fas expression is associated with RTC apoptosis. In contrast, constitutively expressed, low level RTC Fas does not mediate apoptosis, suggesting that Fas may be coupled to expression level-dependent RTC signaling pathways. Fas is known to signal through JNK in many systems, but the requirement of JNK activation for apoptosis remains controversial. METHODS: To determine if RTC Fas regulates JNK activity and apoptosis, human RTC were transfected with graded concentrations of a eukaryotic expression vector for murine Fas. Apoptosis was measured by annexin V, TUNEL and PARP cleavage assays. JNK activity was determined by immune complex kinase assay and/or immunoblots with phospho-specific JNK antibodies, in the presence or absence of co-expressed dominant negative JNK constructs. RESULTS: Fas antibody stimulation of RTC with high Fas expression levels (to model RTC phenotype in renal disease) caused a tenfold increase in apoptosis, while RTC with low level Fas expression (to model normal RTC phenotype) were apoptosis-resistant. Fas ligation activated JNK in RTC expressing low levels of Fas, but not in apoptosis-sensitive RTC with increased Fas expression. Dominant negative JNK co-expression failed to inhibit apoptosis in RTC expressing high levels of Fas, suggesting that JNK is neither necessary, nor sufficient, for Fas-dependent apoptosis. CONCLUSIONS: At high levels of expression, RTC Fas promotes apoptosis in a JNK-independent manner. At low basal expression, Fas induces JNK activation, but not apoptosis, consistent with novel roles for RTC Fas as a mediator of cell stress or chronic inflammation.

Influence of active site and tyrosine modification on the secretion and activity of the Aeromonas hydrophila lipase/acyltransferase.

Aeromonas sp. secrete a lipase/acyltransferase that shares several properties with the mammalian plasma enzyme lecithin:cholesterol acyltransferase. Reaction of the enzyme with tetranitromethane led to modification of 2 tyrosines and a nearly 80% decline in enzyme activity. Replacing Tyr230 with Phe altered the activity of the enzyme in the same way as did treatment with tetranitromethane. Unlike the wild type enzyme, which preferentially hydrolyzes the 2-position acyl chain of phosphatidylcholine, the Y230F mutant enzyme did not discriminate between the 1- and 2-positions of the phospholipid. Tyr230 may be necessary to correctly position phospholipid substrates at the active site. Several amino acids around the active site Ser16 of the lipase were also changed. Replacing Ser18 with Gly, bringing the enzyme's sequence into line with the "lipase consensus sequence," resulted in reduced secretion of the protein and complete loss of activity. Changing this serine to Val led to an inactive protein that was not secreted at all. Substituting Phe13 in the hydrophobic region of the consensus sequence with Ser also prevented secretion, although the mutant protein appeared to be active. The Aeromonas lipase may represent a distinct group of lipolytic enzymes which have a novel active site structure.

[Coccidioidomycosis--differential diagnosis of lung infiltrates with peripheral eosinophilia]. / Coccidioidomykose--eine Differentialdiagnose bei Lungeninfiltrat mit peripherer Eosinophilie.

A 20-year-old man developed pulmonary coccidioidomycosis after travelling in Mexico and California. Cardinal clinical symptoms were fever, pulmonary infiltrate with ipsilateral hilar adenopathy on the chest X-ray, and a 14% eosinophilia in the peripheral blood. In addition he experienced erythema nodosum, arthralgias and night sweats. After a five-week febrile course the symptoms disappeared spontaneously without specific treatment. Coccidioidomycosis was diagnosed by serology, and Coccidioides immitis grew in the sputum culture. With ever more travellers to other parts of the globe coccidioidomycosis must be considered in the differential diagnosis of pulmonary infiltrates with peripheral eosinophilia.