Rearranged jatrophane-type diterpenes from euphorbia species. Evaluation of their effects on the reversal of multidrug resistance

The rearranged jatrophane-type diterpenes ( 1 - 3), isolated from the Me (2)CO extracts of Euphorbia portlandica and Euphorbia segetalis, were examined for their effects on multidrug resistance (MDR) in mouse lymphoma cells. Compounds 2 and 3 revealed to be active with the latter being more active than the positive control verapamil, a known resistance modifier. The new compound 1, named portlandicine, was isolated from Euphorbia portlandica and its structure characterised by high-field NMR spectroscopic methods including 2D NMR techniques: COSY, HMQC, HMBC and NOESY. The known diterpene 2, together with aleuritolic acid ( 4), oleanolic acid ( 5), and betulin diacetate ( 6), were also isolated from the same species.     

Three new jatrophane polyesters and antiproliferative constituents from Euphorbia tuckeyana

Three new jatrophane diterpene polyesters named tuckeyanols A and B and euphotuckeyanol, as well as ten known compounds, helioscopinolides A, B, D and E, naringenin, aromadendrin, coniferaldehyde, 4,20-dideoxy-5-hydroxyphorbol 12,13-diisobutyrate, 4,20-dideoxy-5-hydroxyphorbol 12-benzoate-13-isobutyrate and dehydrodiconiferyl diacetate, were isolated from the methanolic extract of Euphorbia tuckeyana. Their structures were elucidated by physical and spectroscopic methods including 1 D and 2 D homo- and heteronuclear NMR techniques (COSY, HMQC, HMBC and NOESY), and HR-mass spectrometry. Four of the isolated compounds were investigated for their antiproliferative activity in three human gastrointestinal cancer cell lines: gastric (EPG85-257), pancreatic (EPP85-181) and colon (HT-29) carcinomas. Three of them have showed to be moderate inhibitors of the growth of gastric and pancreatic tumor cell lines.     

Bioavailability of phenols from a phenol-enriched olive oil

Phenolic compounds are one of the main reasons behind the healthy properties of virgin olive oil (VOO). However, their daily intake from VOO is low compared with that obtained from other phenolic sources. Therefore, the intake of VOO enriched with its own phenolic compounds could be of interest to increase the daily dose of these beneficial compounds. To evaluate the effectiveness of enrichment on their bioavailability, the concentration of phenolic compounds and their metabolites in human plasma (0, 60, 120, 240 and 300 min) from thirteen healthy volunteers (seven men and six women, aged 25 and 69 years) was determined after the ingestion of a single dose (30 ml) of either enriched virgin olive oil (EVOO) (961·17 mg/kg oil) or control VOO (288·89 mg/kg oil) in a cross-over study. Compared with VOO, EVOO increased plasma concentration of the phenol metabolites, particularly hydroxytyrosol sulphate and vanillin sulphate (P < 0·05). After the consumption of VOO, the maximum concentration of these peaks was reached at 60 min, while EVOO shifted this maximum to 120 min. Despite these differences, the wide variability of results indicates that the absorption and metabolism of olive oil phenols are highly dependent on the individual.     

Single-nucleotide polymorphisms (5p15.33, 15q25.1, 6p22.1, 6q27 and 7p15.3) and lung cancer survival in the European Prospective Investigation into Cancer and Nutrition (EPIC)

The single-nucleotide polymorphisms (SNPs) rs402710 (5p15.33), rs16969968 and rs8034191 (15q25.1) have been consistently identified by genome-wide association studies (GWAS) as significant predictors of lung cancer risk, while rs4324798 (6p22.1) was previously found to influence survival time in small-cell lung cancer (SCLC) patients. Using the same population of one of the original GWAS, we investigated whether the selected SNPs and 31 others (also identified in GWAS) influence survival time, assuming an additive model. The effect of each polymorphism on all cause survival was estimated in 1094 lung cancer patients, and lung cancer-specific survival in 763 patients, using Cox regression adjusted for a priori confounders and competing causes of death where appropriate. Overall, after 1558 person-years of post-diagnostic follow-up, 874 deaths occurred from all causes, including 690 from lung cancer. In the lung cancer-specific survival analysis (1102 person-years), only rs7452888 (6q27) and rs2710994 (7p15.3) modified survival, with adjusted hazard ratios of 1.19 (P = 0.009) and 1.32 (P = 0.011) respectively, taking competing risks into account. Some weak associations were identified in subgroup analysis for rs16969968 and rs8034191 (15q25.1) and rs4324798 (6p22.1) and survival in never-smokers, as well as for rs402710 in current smokers and SCLC patients. In conclusion, rs402710 (5p15.33), rs16969968 and rs8034191 (both 15q25.1) and rs4324798 (6p22.1) were found to be unrelated to survival times in this large cohort of lung cancer patients, regardless of whether the cause of death was from lung cancer or not. However, rs7452888 (6q27) was identified as a possible candidate SNP to influence lung cancer survival, while stratified analysis hinted at a possible role for rs8034191, rs16969968 (15q25.1) and rs4324798 (6p22.1) in influencing survival time in lung cancer patients who were never-smokers, based on a small sample.     

Common variable immunodeficiency: association between memory B cells and lung diseases

BACKGROUND: Malabsorption syndrome often develops in patients with common variable immunodeficiency (CVID). Why structural damages appear in some CVID patients and not in others is not fully understood. Memory B cells (MBs) are responsible for the production of specific antibodies, and their defects have previously been related to autoimmune, granulomatous, and lymphoproliferative complications of CVID. The objective of this study was to ascertain whether a relationship exists between MB defects and the clinical outcome of respiratory and intestinal involvement in these patients. METHODS: Forty-one CVID patients were grouped as follows, according to the quantification of peripheral MBs: the MB2 group (n = 7) included patients with normal MBs; the MB1 group (n = 16) included patients with low switched MBs; and the MB0 group (n = 18) included patients with absent/low MBs. The clinical outcome of respiratory and intestinal involvement of patients was then compared among the three groups. RESULTS: In the MB0 group, chronic lung disease (ie, bronchiectasis and diminished FVC and/or FEV1) developed in 50% of patients vs 13% in the MB1 group and 0% in the MB2 group (p < 0.05). In the MB0 group, malabsorption syndrome or chronic noninfectious diarrhea developed in 50% of patients vs 19% in the MB1 group and 0% in the MB2 group (p < 0.05). No differences were found among the three groups for age at onset of symptoms, delay in diagnosis/treatment, months of follow-up/treatment, and prediagnostic serum IgG concentration. CONCLUSIONS: Alterations in MB count appear to be associated with a severe clinical outcome of respiratory and intestinal involvement in CVID. The MB count could be a useful laboratory parameter for orienting the prognosis and management of CVID patients.     

Effectiveness of drug-eluting stents in patients with bare-metal in-stent restenosis: meta-analysis of randomized trials.

OBJECTIVES: We sought to synthesize the available evidence on the effectiveness of drug-eluting stents for bare-metal in-stent restenosis. BACKGROUND: Although there is clinical evidence that drug-eluting stents are associated with better results than other treatments for in-stent restenosis, they are not yet approved for this indication. Meta-analysis of randomized trials may yield more precise estimates of treatment effects and enable a rapid adoption of effective treatments in clinical practice. METHODS: Data sources included PubMed and conference proceedings. Prespecified criteria were met by 4 randomized studies comparing sirolimus- or paclitaxel-eluting stents versus balloon angioplasty or vascular brachytherapy in 1,230 patients with bare-metal in-stent restenosis. Studies reported the clinical outcomes of efficacy and safety during a minimum of 9 months. The primary outcome was target lesion revascularization. RESULTS: No significant heterogeneity was found across trials, thus showing a similar effect size regardless of the use of balloon angioplasty or vascular brachytherapy as comparators. The risk of target lesion revascularization (odds ratio 0.35, 95% confidence interval [CI] 0.25 to 0.49; p < 0.001) and that of angiographic restenosis (odds ratio 0.36, 95% CI 0.27 to 0.49; p = 0.001) were markedly lower in patients treated with drug-eluting stents. There were no differences between patients treated with drug-eluting stents and those treated with other techniques with respect to the composite of death or myocardial infarction (odds ratio 1.04, 95% CI 0.54 to 2.03; p = 0.55). CONCLUSIONS: Drug-eluting stents are markedly superior to conventional techniques (balloon angioplasty and vascular brachytherapy) and should be considered as first-line treatment for patients with bare-metal in-stent restenosis.     

A randomized comparison of sirolimus-eluting stent with balloon angioplasty in patients with in-stent restenosis: results of the Restenosis Intrastent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting (RIBS-II) trial.

OBJECTIVES: We sought to assess the effectiveness of sirolimus-eluting stents (SES) in patients with in-stent restenosis (ISR). BACKGROUND: Treatment of patients with ISR remains a challenge. METHODS: The Restenosis Intrastent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting (RIBS-II) study is a multicenter randomized trial conducted in 150 patients with ISR (76 allocated to SES and 74 to balloon angioplasty [BA]). The primary end point was recurrent restenosis rate at nine months. Secondary end points included prespecified subgroup analysis, lumen volume on intravascular ultrasound (IVUS), and a composite of major clinical events at one year. RESULTS: Angiographic success was obtained in all patients. At 9-month angiographic follow-up (96% of eligible patients) minimal lumen diameter was larger (2.52 mm [interquartile range (IQR) 2.09 to 2.81] vs. 1.54 mm [IQR 0.91 to 2.05]; p < 0.001) and recurrent restenosis rate was lower (11% vs. 39%; p < 0.001) in the SES group. Prespecified subgroup analyses were consistent with the main outcome measure. Lumen volume on IVUS at 9 months was also larger (279 mm3 [IQR 227 to 300] vs. 197 mm3 [IQR 177 to 230]; p < 0.001) in the SES group. At one-year clinical follow-up (100% of patients), the event-free survival (freedom from death, myocardial infarction, and target vessel revascularization) was significantly improved in the SES group (88% vs. 69%; p < 0.004) as the result of a lower requirement for target vessel revascularization (11% vs. 30%; p < 0.003). CONCLUSIONS: In patients with ISR, the use of SES provides superior long-term clinical, angiographic, and IVUS outcome than BA treatment.     

USPIO-enhanced magnetic resonance imaging for nodal staging in patients with head and neck cancer

PURPOSE: To determine the accuracy of ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) for nodal staging in patients with head and neck cancer. MATERIALS AND METHODS: Twenty patients with carcinomas of the upper aerodigestive tract were prospectively enrolled. MRI was performed before and 24-36 hours after intravenous infusion of an USPIO agent, ferumoxtran-10 (Sinerem; Guerbet, France; and Combidex; Advanced Magnetics) at a dose of 2.6 mg Fe/kg using T2-weighted spin-echo and gradient-echo sequences. Surgery was performed the same day or the day after the ferumoxtran-10-enhanced MR examination. Based on MRI, selected nodes were surgically removed and directly correlated with pathology using hematoxylin-eosin (H&E) and Perls stainings. RESULTS: A total of 63 nodes were studied; 36 were nonmetastatic, 25 metastatic, and two inflammatory. Ferumoxtran-10-enhanced MRI allowed diagnosis of 24 metastatic and 30 nonmetastatic nodes, yielding a sensitivity of 96%, a specificity of 78.9%, a positive predictive value of 75%, and a negative predictive value of 96.8%, compared to 64%, 78.9%, 66.6%, and 76.9%, respectively, for nonenhanced MRI. Accuracy of ferumoxtran-10-enhanced MRI was 85.7%. The gradient-echo T2-weighted sequence was the most accurate to detect signal loss in nonmetastatic nodes. CONCLUSION: USPIO-enhanced MRI is useful for nodal staging of patients with head and neck cancers.