Omega-3 polyunsaturated fatty acids and depression: a review of the evidence.

Brain lipids contain a high proportion of polyunsaturated fatty acids (PUFA), which are a main component of cell membranes. Omega-3 (omega-3) PUFA eicosapentaeoic acid (EPA) and docosahexaenoic acid (DHA) are the most common PUFA in the brain. The physiological roles of omega-3 PUFA in the brain include regulation of cell membrane fluidity, dopaminergic and serotoninergic transmission, membrane-bound enzymes and cellular signal transduction. They are also thought to play a role in brain glucose metabolism, eicosanoid synthesis, gene expression, cell growth and protection from apoptosis. Increasing evidence from animal and human research shows omega-3 PUFA depletion may play an etiological role in several inflammatory, autoimmune and neuropsychiatric disorders. In particular, an association between omega-3 PUFA and depression was repeatedly suggested in observational and experimental studies on populations affected by major depression, depressed mood or post-partum depression. Consistently, the potential therapeutic role of omega-3 PUFA dietary supplementation was tested in clinical trials on depression. The current review identifies and evaluates available epidemiological evidence of a negative relationship between omega-3 PUFA and depression and examines its biological plausibility. Although current evidence increasingly supports an inverse association between omega-3 PUFA and depression, the validity of findings from observational and experimental research is limited by several methodological issues. Further studies with larger sample sizes and more sophisticated design are required to provide convincing evidence of a causal relationship between omega-3 PUFA and depression.

Mitochondrial 16S DNA variation in populations of Triatoma infestans from Argentina.

Variation in the mtDNA 16S ribosomal RNA gene in populations of Triatoma infestans (Klug) was surveyed. DNA sequence comparisons yielded 18 haplotypes among 130 individuals from 16 localities that represent a large proportion of the range of T. infestans in Argentina. The most common genotype in all populations was found in 76.9% of individuals and two other haplotypes were shared among different populations. The remaining 15 haplotypes were present exclusively in one of the populations, suggesting currently low levels of genetic exchange. Analysis of mtDNA 16S sequences uncovered substantial genetic variation among T. infestans populations. Haplotype and nucleotide diversities varied among populations, from 0% to 0.84% and 0% to 0.29%, respectively. It appears that this locus has a low mutation rate. Uncorrected pairwise differences of T. infestans haplotypes ranged from 0% to 1.2%. The molecular phylogeny supported the monophyly of T. infestans haplotypes and clustered two different pairs of haplotypes with a moderate degree of bootstrap support (approximately 60%). Mitochondrial DNA phylogeographic differentiation was not evident, suggesting a recent rapid spread of the species. Analysis of molecular variance showed hierarchical structure in the data. Considerably less variation was found among T. infestans populations from the northwest and northeast regions than among those belonging to the central area. Such a lack of variation may be indicative of one or more past population bottlenecks.

Second line therapy with weekly low-dose docetaxel for pretreated non-small-cell lung carcinoma patients: a multicenter Italian phase II study.

Docetaxel is one of the most active drugs in second-line therapy for non-small-cell-lung-carcinoma (NSCLC). The aim of this multicenter study was to evaluate the safety and efficacy of weekly low-dose docetaxel. Forty-two patients with advanced NSCLC pretreated with cisplatinum-based chemotherapy were enrolled. Docetaxel was administered at a dose of 25 mg/m(2) weekly for 12 consecutive weeks. A total of 386 doses were given with a median number of 10 doses per patient (range: 3-12). Treatment showed low incidence of hematologic toxicity and modest non-hematologic toxicity. An episode of grade 4 thrombocytopenia was reported but no episodes of grade 3 or 4 neutropenia. Most frequent non-hematologic toxicities were asthenia and alopecia. Response rate was 10.5% and median survival time (MST) was 12.8 weeks. Weekly treatment with 25 mg/m(2) docetaxel for 12 consecutive weeks appears to be a feasible and active regimen with mild toxicity in heavily pretreated NSCLC patients.

Acute cardiotoxicity during capecitabine treatment: a case report.

Capecitabine (Xeloda, Roche, Monza), a fluoropyrimidine carbamate, is an orally administered drug that delivers fluorouracil (5-FU) selectively to the tumor. The drug has demonstrated activity in metastatic breast cancer, pancreatic cancer and colorectal cancer. In this case report the authors describe an unusually and reversible cardiac side effect which occurs to 39-year-old patient treated with capecitabine 2000 mg/m2/day for advanced gastric cancer. It is important to note that the safety data from clinical trials indicate that capecitabine has a toxicity profile typical of infused fluoropyrimidines. However, none of the studies described cardiac side effects.

Galectin-3 overexpression protects from apoptosis by improving cell adhesion properties.

Galectin-3 is a carbohydrate-binding protein endowed with affinity for beta-galactosides. It plays a role in cell-cell and cell-matrix interactions. Furthermore, it has been hypothesized to be involved in tumor progression and metastasis. To address the role of galectin-3 in the invasive and metastatic processes, we stably overexpressed galectin-3 in human breast carcinoma cell lines, and we evaluated the influence of elevated galectin-3 expression on several cell features, including cellular homotypic and heterotypic interactions and cell survival. No differences in various parameters related with cell growth features and proliferation were detected. By contrast, we found that galectin-3 overexpressing cells, with respect to low galectin-3 expressing cells, exerted: (1) a significantly enhanced adhesion to laminin, fibronectin and vitronectin exerted both directly or via increased expression of specific integrins, e.g., alpha-4 and beta-7; (2) a remodeling of those cytoskeletal elements associated with cell spreading, i.e., microfilaments; (3) an enhanced survival upon exposure to different apoptotic stimuli, such as cytokine and radiation. Collectively, our results indicate that overexpression of galectin-3 may play a role in tumor cell invasion and metastasis by specifically influencing cell adhesion to the extracellular matrix. This may confer selective survival advantage and resistance to the particular homeless-induced apoptosis called anoikia.

Isolation and functional characterization of the human 90K promoter.

90K is a secreted protein thought to be involved in the body's defense against pathogens and cancer. To elucidate its transcriptional regulation, the promoter of human 90K (HGMW-approved symbol LGAL S3BP) was isolated and characterized. Analysis of the 3. 3-kb 5'-flanking region revealed that it is a TATA-less promoter, but neither GC-rich nor dependent on SP1 sites. RNase protection assays detected one major transcription start site (+1) and several minor transcription start sites upstream and downstream. Deletion studies defined a minimal promoter (-103 --> -49) and indirectly suggested positive synergism between different elements within it. Consistent with the proposed function of 90K, its promoter activity could be stimulated by poly(I). poly(C), mimicking viral infection. Two regions mediating induction by poly(I). poly(C) (-171 --> -112, -32 --> 46) were identified by deletion mutants. A small region around the minimal promoter (-99 --> -12) was highly homologous between human and mouse. While both human and mouse minimal promoters contained an interferon-responsive element (IRF-E), the human minimal promoter was not inducible by poly(I). poly(C) in contrast to that of the mouse. Point mutations 30 bp upstream of the IRF-E, however, conferred inducibility to the human minimal promoter, suggesting interaction between different promoter elements.

Cyclooxygenase-independent induction of p21WAF-1/cip1, apoptosis and differentiation by L-745,337, a selective PGH synthase-2 inhibitor, and salicylate in HT-29 cells.

In order to dissect out cyclooxygenase-dependent from cyclooxygenase-independent mechanisms in the antiproliferative effects of selective prostaglandin H synthase (PGHS)-2 inhibitors, we compared the effects of L-745,337 (a highly selective PGHS-2 inhibitor) with sodium salicylate (a weak PGHS inhibitor) on prostanoid production, induction of the cyclin-dependent kinase inhibitor p21WAF-1/cip1, mutant p53 (m273-p53) levels, apoptosis and differentiation in human colon adenocarcinoma HT-29 cells. L-745,337 dose-dependently suppressed the cyclooxygenase activity of HT-29 cells (IC50: 0.24 microM). Four-day treatment with L-745,337 caused a concentration-dependent inhibition of cell growth (IC50: 0.9 mM) associated with the induction of p21WAF-1/cip1 and an increase in the proportion of apoptotic nuclei (EC50: 0.1 and 0.34 mM, respectively) while reducing the levels of m273-p53 (IC50: 0.2 mM). Sodium salicylate, at the concentration of 10 mM that did not affect prostanoid formation, caused a 60% reduction of cell growth associated with a 3-fold induction of p21WAF-1/cip1 and a 60% increase in the proportion of apoptotic nuclei. Ultrastructural analysis showed that L-745,337 (0.5 mM) and sodium salicylate (10 mM) caused the induction of a differentiated phenotype. We conclude that high concentrations of L-745,337 and sodium salicylate inhibit colon cancer cell growth by a mechanism unrelated to cyclooxygenase inhibition that may involve p53-independent induction of the tumor suppressor p21WAF-1/cip1.

A phase II study of neoadjuvant chemotherapy with cisplatin epirubicin and VP-16 for stage III unresectable non-small cell lung cancer.

BACKGROUND: The survival rate for surgically resected stage III N2 non-small cell lung cancer (NSCLC) patients is less than 10%. METHODS: A phase II study of cisplatin, epirubicin, and VP-16 (PEV) was undertaken in an attempt to improve the curative potential of surgery. Forty-one patients with stage III N2 NSCLC received 3 cycles of pEV. Patients with either complete response (CR) or partial response (PR) underwent surgery and 3 additional courses of PEV. RESULTS: The response rate in the whole patient population was 58%. Eighteen patients were resected; twelve resections were complete and 6 were incomplete. Toxicity was mild and consisted mainly of myelosuppression. Twenty-six patients have died, and the median survival of all 41 patients was 18.1 months, with a 3-year survival of 23%. The median survival for those patients who were resected was 27 months with a 3-year survival of 42%. CONCLUSIONS: PEV is an effective low toxic drug combination for limited NSCLC.

90K (MAC-2 BP) gene expression in breast cancer and evidence for the production of 90K by peripheral-blood mononuclear cells.

The tumor-derived antigen 90K (Mac-2 BP) is a widely expressed, secreted glycoprotein found in the serum of healthy individuals and at elevated levels in the serum of patients with breast cancer and other types of cancer. The precise function of 90K, particularly in the context of tumor-host relationships, has not yet been established. In this study, the clinical significance of 90K mRNA expression was studied in relation to other established prognostic parameters in 86 patients with primary breast carcinoma. The 2.2-kb 90K message was detected in all tumor samples, but there was marked variation in expression levels from tumor to tumor. Patients were classified into 2 groups on the basis of 90K expression: group 1 (n = 62) included patients with low expression, and group 2 (n = 24) consisted of patients with high expression. An inverse significant correlation was found between the levels of 90K mRNA expression and overexpression of c-erbB2/Neu receptor kinase, a marker of poor prognosis for patients with breast cancer. There was no significant difference between the groups with respect to tumor size, number of involved axillary lymph nodes, hormone-receptor status, p53 expression or proliferation activity as estimated by Ki-67 count. Similarly, no association was found between the level of 90K expression and the risk of death from breast cancer. These data are at variance with published findings showing that high serum 90K levels are associated with poor survival. Significantly, investigation of 90K-gene expression in peripheral-blood mononuclear cells (PBMC) revealed higher levels of 90K message in PBMC of breast-cancer patients than in healthy individuals. This new finding suggests that PBMC activated in response to tumor growth and progression may be an important source of serum 90K in breast cancer.

Expression of the 90K immunostimulator gene is controlled by a promoter with unique features.

90K is a secreted glycoprotein with tumor suppressive functions, which is up-regulated in various types of cancer and in AIDS. In order to understand the regulation of its expression, the mouse 90K gene was isolated and analyzed. The gene spans about 8.8-kilobase pairs and consists of 6 exons and was localized on chromosome 11, region E. RNase protection identified one major transcription start site (+1) and three minor ones (-3, +32, +34). The mouse 90K gene was found to have a TATA-less promoter of unusual structure. The 2. 3-kilobase pair 5'-flanking region exhibited strong promoter activity in NIH 3T3 cells; however, it contained neither a TATA-box nor a SP1 site and was not GC-rich. No known initiator motif was found around the transcription start site. 5'- and 3'-deletions defined a minimal promoter of 51 base pairs (-66 --> -16), not including the start site, essential and sufficient for promoter activity. This minimal promoter showed increased activity after stimulation with interferon-gamma or poly(I.C), a substance mimicking viral infection. Essential for both inductions was the integrity of an interferon regulatory factor element within this sequence, a potential binding site for the anti-oncogenic transcription factor interferon regulatory factor-1.

Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases.

The aim of our study was to characterize a model of human prostaglandin endoperoxide synthase-2 (PGHS-2) expression allowing the assessment of pharmacological inhibition in vitro and ex vivo. Heparinized human whole blood samples were incubated with lipopolysaccharide (LPS, 0.1-50 micrograms/ml) for 0 to 24 hr at 37 degrees C. The contribution of platelet PGHS-1 was suppressed by either pretreating the subjects with aspirin (300 mg 48 hr before sampling) or adding aspirin (10 micrograms/ml) in vitro at time 0. PGE2 was measured by radioimmunoassay. LPS induced expression of cyclooxygenase activity in a time- and concentration-dependent fashion. After 24 hr at 10 micrograms/ml LPS, PGE2 production averaged 12.1 +/- 6.2 ng/ml (mean +/- S.D., n = 7). Cyclooxygenase activity increased in parallel with the mass of a monocyte protein doublet analyzed by Western blot using antibodies directed against the carboxyl-terminal portion of human PGHS-2. Dexamethasone (2 microM) inhibited LPS-induced PGE2 production by 96 +/- 4% (mean +/- S.D., n = 3). Four different inhibitors were tested in vitro on the cyclooxygenase activity of LPS-induced monocyte PGH-2 and thrombin-stimulated platelet PGHS-1. IC50 values (microM) for inhibition of PGHS-1 and PGHS-2 were: indomethacin, 0.70 +/- 0.20 vs 0.36 +/- 0.10 (P < .05); S-indobufen, 0.64 +/- 0.22 vs. 14.9 +/- 8 (P < .05), R-indobufen, 38 +/- 18 vs. 230 +/- 68 (P < .01), 6-methoxy-2-naphthyl acetic acid (the active metabolite of nabumetone), 278 +/- 96 vs. 187 +/- 96.(ABSTRACT TRUNCATED AT 250 WORDS)