Abstract P363: Evaluation of Health and Economic Impact of the Current Policy to Eliminate Industrial Trans Fats from Processed Foods in Argentina by 2014

Objectives: Industrial trans fatty acids (TFA) increase CHD risk, but use remains high in developing nations. From 2004-2014, Argentina initiated policies to reduce industrial TFA: voluntary agreements with industry in 2004, mandatory labeling in 2006, and elimination by Food Code by 2014. We aimed to evaluate the policy’s impact on CHD, DALYs and costs. Methods: A review of diet trials, local studies, and consultations with experts was performed to estimate baseline TFA intake in 2004 and types of replacements used by industry from 2004-2014. We built an epidemiological simulation model calculating 3 scenarios to estimate effects of isocaloric replacement of TFA with alternative fats/oils, based on (1) changes in the total:HDL-C ratio (Δ TC/HDL) and (2) changes in other risk biomarkers, and the predicted effects of these biomarker changes on CHD; and (3) observed associations of TFA which CHD events in prospective studies, which may better account for pleiotrophic effects. We used Framingham risk equations to estimate first CHD events with vs. without the policy according to individual age-sex-risk factor distributions (including ΔTC/HDL), utilizing an Argentine population-based sample of 4,000 adults weighted to the full population. Results: After 2014, this policy would prevent each year from 1.3% (based on Δ TC/HDL only; to 7.4% (based on pleiotrophic effects) of all CHD events in Argentina (Table). Accounting for intervention costs and averted events, the policy is actually cost-saving. Conclusions: This is the first model evaluating the impact of an actual policy for eliminating TFA in a developing country. Given the 165,000 annual CHD events in Argentina, at an annual incidence rate of almost 1% in adults, near elimination of industrial TFA might avert under the most conservative assumptions, 1.3% of CHD and saved $36 million. In other low-resource settings, where TFA intake is higher, these effects could be larger. Our findings inform policy makers in Argentina and other developing countries on the huge impact of this policy

SWOG S0354: A phase II trial of CNTO328, a monoclonal antibody against interleukin-6 (IL-6), in chemotherapy pretreated patients (pts) with castration- resistant prostate cancer (CRPC)

5143 Background: IL-6 facilitates cancer cell survival via pleiotrophic effects on proliferation, apoptosis, angiogenesis, differentiation, and chemo-resistance. A multicenter phase II study of CNTO328 in chemo pretreated CRPC pts was conducted. Methods: Eligible pts had one prior chemotherapy, Zubrod performance status 0–2, and adequate end-organ function. Regimen: CNTO328 6 mg/kg IV q2 weeks x 12 cycles. Response assessment was q6 weeks. Primary endpoint was PSA response rate (RR) defined as ≥50% reduction. Accrual was completed in 2 stages, with planned accrual of 20 eligible pts in the first stage and 40 overall. Plasma cytokines were measured by Luminex in 44 pts. Results: Of 62 pts, 54 were eligible; all had received prior taxane therapy. Two (3.7%; 95% CI: 0.5%, 12.8%) had PSA response. Of 47 pts evaluable by RECIST, none had a response and 10 (21%) had stable disease (SD). With median follow-up of 6.6 months, median progression-free survival is 1.6 months (95% CI: 1.6, 1.7). Grade 4 toxicity included 1 case of DIC and 1 CNS ischemia; grade 3 toxicities included elevated AST (1), gastritis/esophagitis (2), thrombocytopenia (2), pain (2), leucopenia (1), and neuropathy (2). Median baseline IL-6 levels were 12.5 pg/mL (IQR: 2.5, 41.5). Pts with levels >12.5 pg/mL had worse 6-month survival vs. < 12.5 pg/mL (53% vs 94%, p = 0.02). Post-cycle 1, IL-6 levels were > 250-fold higher, indicating antibody-target complex formation. 33/39 pts had a decline in C-reactive protein (CRP) plasma levels at 6 weeks. Conclusions: CNTO328 was well-tolerated and resulted in a PSA RR of 3.7% and RECIST SD rate of 21%. Declining CRP levels during treatment reflect biologic activity. Elevated baseline IL-6 levels portend a poor prognosis. Additional translational studies will be presented. Additional study of CNTO328 in combination may be warranted. [Table: see text]

Functional Analysis of the Streptomyces coelicolor NrdR ATP-Cone Domain: Role in Nucleotide Binding, Oligomerization, and DNA Interactions

ABSTRACT Ribonucleotide reductases (RNRs) are essential enzymes in all living cells, providing the only known de novo pathway for the biosynthesis of deoxyribonucleotides (dNTPs), the immediate precursors of DNA synthesis and repair. RNRs catalyze the controlled reduction of all four ribonucleotides to maintain a balanced pool of dNTPs during the cell cycle. Streptomyces species contain genes, nrdAB and nrdJ, coding for oxygen-dependent class I and oxygen-independent class II RNRs, either of which is sufficient for vegetative growth. Both sets of genes are transcriptionally repressed by NrdR. NrdR contains a zinc ribbon DNA-binding domain and an ATP-cone domain similar to that present in the allosteric activity site of many class I and class III RNRs. Purified NrdR contains up to 1 mol of tightly bound ATP or dATP per mol of protein and binds to tandem 16-bp sequences, termed NrdR-boxes, present in the upstream regulatory regions of bacterial RNR operons. Previously, we showed that the ATP-cone domain alone determines nucleotide binding and that an NrdR mutant defective in nucleotide binding was unable to bind to DNA probes containing NrdR-boxes. These observations led us to propose that when NrdR binds ATP/dATP it undergoes a conformational change that affects DNA binding and hence RNR gene expression. In this study, we analyzed a collection of ATP-cone mutant proteins containing changes in residues inferred to be implicated in nucleotide binding and show that they result in pleiotrophic effects on ATP/dATP binding, on protein oligomerization, and on DNA binding. A model is proposed to integrate these observations.

Characterization of Streptomyces scabies mutants deficient in melanin biosynthesis

Streptomyces scabies, a causal agent of common scab, produces both melanin and a secondary metabolite called thaxtomin A. To establish a possible relation between melanin and thaxtomin A production in S. scabies, we carried out N-methyl-N′-nitro-N-nitrosoguanidine (NTG) mutagenesis and isolated 11 melanin-negative mutants of S. scabies EF-35. These mutants were characterized for thaxtomin A production, pathogenicity, sporulation, and stress resistance. Nine of these mutants showed a significant reduction in thaxtomin A production when compared with the wild strain. However, only a few mutants exhibited a reduced level of virulence or a loss in their ability to induce common scab symptoms on potato tubers. Other pleiotrophic effects, such as higher sensitivity to heavy metals and incapacity to sporulate under certain stress conditions, were also associated with a deficiency in melanin production.Key words: common scab, potato, secondary metabolism, stress, thaxtomin.