Regulatory and Policy-Related Aspects of Calcium Fortification of Foods. Implications for Implementing National Strategies of Calcium Fortification

Daily calcium intake is well below current recommendations in most low- and middle-income countries (LMICs). Calcium intake is usually related to bone health, however an adequate calcium intake has also been shown to reduce hypertensive disorders of pregnancy, lower blood pressure and cholesterol values, and to prevent recurrent colorectal adenomas. Food fortification of foods has been identified as a cost-effective strategy to overcome micronutrient gaps in public health. This review summarizes regulatory aspects of fortification of commonly consumed foods with micronutrients, with an emphasis on calcium. We selected a convenient sample of 15 countries from differentWHOregions and described the regulatory framework related to calcium fortification of staple foods. We assessed the relevant policies in electronic databases including the WHO Global database on the Implementation of Nutrition Action (GINA) for fortification policies and the Global Fortification Data Exchange Database, a fortification database developed and maintained by Food Fortification Initiative (FFI), Global Alliance for Improved Nutrition (GAIN), Iodine Global Network (IGN), and Micronutrient Forum. Food fortification with micronutrients is widely used in many of the selected countries. Most countries had national legislation for the addition of micronutrients to staple foods, especially wheat flour. These national legislations, that includes regulations and standards, can provide the framework to consider the implementation of adding calcium to the fortification strategies, including the selection of the adequate food vehicle to reach the targeted population at risk safely. The strategy to include calcium in the fortification mix in fortified staple foods seems promising in these countries. However, potential undesired changes on the organoleptic characteristics of fortified foods and products thereof, and operational feasibility at the manufacturing site should be evaluated by the stakeholders during the planning stage. Codex Alimentarius standards should be considered by regulators in order to assure adherence to international standards. While the selected countries already have established national regulations and/or standards for fortification of key staple food vehicles, and there are experiences in the implementation of fortification of some staple foods, national food intake surveys can help plan, design, and modify existing fortification programs as well as monitor food and nutrient consumption to assess risk and benefits.Fil: Cormick, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. Universidad Nacional de La Matanza; ArgentinaFil: Betrán, Ana Pilar. Organizacion Mundial de la Salud; ArgentinaFil: Metz, Fletcher. Carleton College; Estados UnidosFil: Palacios, Cristina. Florida International University; Estados UnidosFil: Beltrán Velazquez, Filiberto. Organizacion Mundial de la Salud; ArgentinaFil: de las Nieves García-Casal, María. Organizacion Mundial de la Salud; ArgentinaFil: Peña Rosas, Juan Pablo. Organizacion Mundial de la Salud; ArgentinaFil: Hofmeyr, G. Justus. University Of Fort Hare; SudáfricaFil: Belizan, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentin

Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors

[Background] Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients.[Methods] We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR).[Results] We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib.[Conclusions] ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.This research is supported by a Fero Fellowship Award (C.S.), Asociación Española Contra el Cáncer (J.P. Barcelona) (C.S.), and ISCIII PI16/01371 (C.S.). C.S. and A.V. acknowledge to the Cellex Foundation for providing facilities and equipment

Biomass-modulated fire dynamics during the last glacial-interglacial transition at the central pyrenees (Spain)

Understanding long-term fire ecology is essential for current day interpretation of ecosystem fire responses. However palaeoecology of fire is still poorly understood, especially at high-altitude mountain environments, despite the fact that these are fire-sensitive ecosystems and their resilience might be affected by changing fire regimes. We reconstruct wildfire occurrence since the Lateglacial (14.7. cal. ka BP) to the Mid-Holocene (6. cal. ka BP) and investigate the climate-fuel-fire relationships in a sedimentary sequence located at the treeline in the Central Spanish Pyrenees. Pollen, macro- and micro-charcoal were analysed for the identification of fire events (FE) in order to detect vegetation post-fire response and to define biomass-fire interactions. mean fire intervals (mfi) reduced since the Lateglacial, peaking at 9-7.7. cal. ka BP while from 7.7 to 6. cal. ka BP no fire is recorded. We hypothesise that Early Holocene maximum summer insolation, as climate forcing, and mesophyte forest expansion, as a fuel-creating factor, were responsible for accelerating fire occurrence in the Central Pyrenees treeline. We also found that fire had long-lasting negative effects on most of the treeline plant communities and that forest contraction from 7.7. cal. ka BP is likely linked to the ecosystem's threshold response to high fire frequencies.This research has been funded by the projects DINAMO (CGL2009-07992) (funding EGPF — grant ref. BES-2010-038593 and MSC), DINAMO2 (CGL2012-33063), ARAFIRE (2012 GA LC 064), GRACCIE-CONSOLIDER (CSD2007-00067). GGR was funded by the Juan de la Cierva Program (grant ref. JCI2009-04345) and JAE-Doc CSIC Program, LLM was supported by a postdoctoral MINT fellowship funded by the Institute for the Environment (Brunel University), AMC is a Ramón y Cajal fellow (ref: RYC-2008-02431), APS holds a grant funded by the Aragon Government (ref. 17030G/5423/480072/14003) and JAE holds a grant funded by the Basque Country Government (BFI-2010-5)

Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients. We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR). We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib. ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics

Revealing the last 13,500 years of environmental history from the multiproxy record of a mountain lake (Lago Enol, northern Iberian Peninsula)

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s10933-009-9387-7.We present the Holocene sequence from Lago Enol (43°16′N, 4°59′W, 1,070 m a.s.l.), Cantabrian Mountains, northern Spain. A multiproxy analysis provided comprehensive information about regional humidity and temperature changes. The analysis included sedimentological descriptions, physical properties, organic carbon and carbonate content, mineralogy and geochemical composition together with biological proxies including diatom and ostracod assemblages. A detailed pollen study enabled reconstruction of variations in vegetation cover, which were interpreted in the context of climate changes and human impact. Four distinct stages were recognized for the last 13,500 years: (1) a cold and dry episode that includes the Younger Dryas event (13,500–11,600 cal. year BP); (2) a humid and warmer period characterizing the onset of the Holocene (11,600–8,700 cal. year BP); (3) a tendency toward a drier climate during the middle Holocene (8,700–4,650 cal. year BP); and (4) a return to humid conditions following landscape modification by human activity (pastoral activities, deforestation) in the late Holocene (4,650–2,200 cal. year BP). Superimposed on relatively stable landscape conditions (e.g. maintenance of well established forests), the typical environmental variability of the southern European region is observed at this site.The Spanish Inter-Ministry Commission of Science and Technology (CICYT), the Spanish National Parks agency, the European Commission, the Spanish Ministry of Science, and the European Social Fund

Revealing the last 13,500 years of environmental history from the multiproxy record of a mountain lake (Lago Enol, northern Iberian Peninsula)

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s10933-009-9387-7.We present the Holocene sequence from Lago Enol (43°16′N, 4°59′W, 1,070 m a.s.l.), Cantabrian Mountains, northern Spain. A multiproxy analysis provided comprehensive information about regional humidity and temperature changes. The analysis included sedimentological descriptions, physical properties, organic carbon and carbonate content, mineralogy and geochemical composition together with biological proxies including diatom and ostracod assemblages. A detailed pollen study enabled reconstruction of variations in vegetation cover, which were interpreted in the context of climate changes and human impact. Four distinct stages were recognized for the last 13,500 years: (1) a cold and dry episode that includes the Younger Dryas event (13,500–11,600 cal. year BP); (2) a humid and warmer period characterizing the onset of the Holocene (11,600–8,700 cal. year BP); (3) a tendency toward a drier climate during the middle Holocene (8,700–4,650 cal. year BP); and (4) a return to humid conditions following landscape modification by human activity (pastoral activities, deforestation) in the late Holocene (4,650–2,200 cal. year BP). Superimposed on relatively stable landscape conditions (e.g. maintenance of well established forests), the typical environmental variability of the southern European region is observed at this site.The Spanish Inter-Ministry Commission of Science and Technology (CICYT), the Spanish National Parks agency, the European Commission, the Spanish Ministry of Science, and the European Social Fund

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Spermatozoa capture HIV-1 through heparan sulfate and efficiently transmit the virus to dendritic cells

Semen is the main vector for HIV-1 dissemination worldwide. It contains three major sources of infectious virus: free virions, infected leukocytes, and spermatozoa-associated virions. We focused on the interaction of HIV-1 with human spermatozoa and dendritic cells (DCs). We report that heparan sulfate is expressed in spermatozoa and plays an important role in the capture of HIV-1. Spermatozoa-attached virus is efficiently transmitted to DCs, macrophages, and T cells. Interaction of spermatozoa with DCs not only leads to the transmission of HIV-1 and the internalization of the spermatozoa but also results in the phenotypic maturation of DCs and the production of IL-10 but not IL-12p70. At low values of extracellular pH (∼6.5 pH units), similar to those found in the vaginal mucosa after sexual intercourse, the binding of HIV-1 to the spermatozoa and the consequent transmission of HIV-1 to DCs were strongly enhanced. Our observations support the notion that far from being a passive carrier, spermatozoa acting in concert with DCs might affect the early course of sexual transmission of HIV-1 infection