Clinical and genomic analysis of a randomised phase II study evaluating anastrozole and fulvestrant in postmenopausal patients treated for large operable or locally-advanced hormone-receptor-positive breast cancer

Background: The aim of this study was to assess the efficacy of neoadjuvant anastrozole and fulvestrant treatment of large operable or locally-advanced hormone- receptor-positive breast cancer not eligible for initial breast-conserving surgery, and to identify genomic changes occurring after treatment. Methods: 120 post-menopausal patients were randomised to receive 1 mg anastrozole (61 patients) or 500 mg fulvestrant (59 patients) for 6 months. Genomic DNA copy number profiles were generated for a subgroup of 20 patients before and after treatment. Results: 108 patients were evaluable for efficacy and 118 for toxicity. The objective response rate determined by clinical palpation was 58.9% (95% CI 45.0-71.9) in the anastrozole arm and 53.8% (95% CI 39.5-67.8) in the fulvestrant arm. The breast- conserving surgery rate was 58.9% (95% CI 45.0-71.9) in the anastrozole arm and 50.0% (95% CI 35.8-64.2) in the fulvestrant arm. Pathological responses >50% occurred in 24 patients (42.9%) in the anastrozole arm and 13 (25.0%) in the fulvestrant arm. The Ki-67 score fell after treatment but there was no significant difference between the reduction in the two arms (anastrozole 16.7% [95%CI 13.3-21.0] before, 3.2% [95%CI 1.9-5.5] after, n=43; fulvestrant 17.1% [95%CI 13.1-22.5] before, 3.2% [95%CI 1.8-5.7] after, n=38) or between the reduction in Ki-67 in clinical responders and non- responders. Genomic analysis appeared to show a reduction of clonal diversity following treatment with selection of some clones with simpler copy number profiles. Conclusion: Both anastrozole and fulvestrant were effective and well-tolerated, enabling breast-conserving surgery in over 50% of patients. Clonal changes consistent with clonal selection by the treatment were seen in a subgroup of patients

The Complete Genome of Propionibacterium freudenreichii CIRM-BIA1T, a Hardy Actinobacterium with Food and Probiotic Applications

Background: Propionibacterium freudenreichii is essential as a ripening culture in Swiss-type cheeses and is also considered for its probiotic use [1]. This species exhibits slow growth, low nutritional requirements, and hardiness in many habitats. It belongs to the taxonomic group of dairy propionibacteria, in contrast to the cutaneous species P. acnes. The genome of the type strain, P. freudenreichii subsp. shermanii CIRM-BIA1 (CIP 103027T), was sequenced with an 11-fold coverage. Methodology/Principal Findings: The circular chromosome of 2.7 Mb of the CIRM-BIA1 strain has a GC-content of 67% and contains 22 different insertion sequences (3.5% of the genome in base pairs). Using a proteomic approach, 490 of the 2439 predicted proteins were confirmed. The annotation revealed the genetic basis for the hardiness of P. freudenreichii, as the bacterium possesses a complete enzymatic arsenal for de novo biosynthesis of aminoacids and vitamins (except panthotenate and biotin) as well as sequences involved in metabolism of various carbon sources, immunity against phages, duplicated chaperone genes and, interestingly, genes involved in the management of polyphosphate, glycogen and trehalose storage. The complete biosynthesis pathway for a bifidogenic compound is described, as well as a high number of surface proteins involved in interactions with the host and present in other probiotic bacteria. By comparative genomics, no pathogenicity factors found in P. acnes or in other pathogenic microbial species were identified in P. freudenreichii, which is consistent with the Generally Recognized As Safe and Qualified Presumption of Safety status of P. freudenreichii. Various pathways for formation of cheese flavor compounds were identified: the Wood-Werkman cycle for propionic acid formation, amino acid degradation pathways resulting in the formation of volatile branched chain fatty acids, and esterases involved in the formation of free fatty acids and esters. Conclusions/Significance: With the exception of its ability to degrade lactose, P. freudenreichii seems poorly adapted to dairy niches. This genome annotation opens up new prospects for the understanding of the P. freudenreichii probiotic activity

New insight on cheese ripening thanks to untargeted metabolomics approach

Untargeted metabolomics approaches are being developed and appear as a must in the modern food science and microbiology research to investigate food quality and safety. Our objective was to assess the relevance of untargeted metabolomics to explore for the first time Camembert cheese ripening, by using liquid chromatography coupled on-line with high resolution mass spectrometry. Metabolic fingerprints were found to differ significantly depending on the ripening time, pointing out the capacity of this approach to study microbial metabolism within cheese and its influence on the ripening process of Camembert cheese. Nearly a hundred metabolites were identified thanks to in-house and public databases. The results highlighted variations over the ripening process of a large diversity of well-known cheese metabolites such as 13 amino acids and 25 volatile compounds, but also less studied ones such as two vitamins and creatinine. As a consequence, untargeted metabolomics approach appears as a technology-driven opportunity to further deepen the characterization of the overall mechanisms of cheese ripening

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Bridging the divide: older learners and new technologies ICT and older learners: strategies and case studie

Promising immunomodulatory effects of selected strains of dairy propionibacteria as evidenced[i] in vitro[/i] and[i] in vivo.[/i]

Selected immunomodulatory probiotic bacteria can counteract inflammation of the intestine through multiple regulatory activities and may be either complementary or an alternative to conventional treatments toward inflammatory bowel disease (IBD), a growing health concern in developed countries. Probiotic strains such as lactobacilli and bifidobacteria are able to induce anti-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs) in vitro and were shown to exert efficient anti-inflammatory effects on colitis in vivo (9, 26). However, little is known about the immunomodulatory potential of highly consumed starter bacteria such as dairy propionibacteria. Consumption of fermented products has an impact on immune system function (25), and the bacterial content of these products is responsible for immunomodulation (6, 10). Dairy propionibacteria display various probiotic properties either similar to or distinct from those reported for probiotic bifidobacteria and lactic acid bacteria (3). Although an anti-inflammatory potential of a few dairy propionibacterium strains was occasionally suggested in vitro (15) or in animals (22, 24, 31), no reliable observation was established in terms of strain variability and of specific mechanisms involved. In addition, supplementation with dairy propionibacteria in human randomized, placebo-controlled, double-blind trials has mainly concerned mixtures comprising probiotic bacteria assigned to genera other than Propionibacterium but rarely with propionibacteria alone (16). Thus, because of synergistic effects, it is not possible to attribute observed health benefits to a specific bacterium per se within the mixtures

Untargeted metabolomics approach: toward new understanding of cheese ripening

Metabolomics approaches, particularly those based on mass spectrometry (MS) techniques,are being developed and appear as a must in the modern food science and microbiologyresearch to investigate food quality and safety. Cheese ripening mechanisms has always beeninvestigated with targeted approaches. Our objective was to assess the relevance ofuntargeted metabolomics to explore cheese ripening. MS metabolic fingerprints were foundto differ significantly depending on the incubation time, pointing out the capacity of thisapproach to study the evolution of bacterial metabolism within cheese. Forty-five metaboliteswere identified on the basis of an internal data bank. Variations over time of a large diversityof well-known cheese metabolites such as 12 amino acids and 25 volatile compounds, butalso less studied ones such as 4 vitamins and L-carnitine were highlighted. From now on,untargeted metabolomics offer new perspectives for the understanding of cheese ripeningmechanisms

First mass spectrometry metabolic fingerprinting of bacterial metabolism in a model cheese

Metabolic fingerprinting is an untargeted approach which has not yet been undertaken to investigate cheese. This study is a proof of concept, concerning the ability of mass spectrometry (MS) metabolic fingerprinting to investigate modifications induced by bacterial metabolism in cheese over time. An ultrafiltrated milk concentrate was used to manufacture model cheeses inoculated with Lactococcus lactis LD61. Metabolic fingerprints were acquired after 0, 8 and 48 h from two different fractions of the metabolome: the water-soluble fraction using liquid chromatography–high resolution-MS and a volatile fraction using gas chromatography–MS. Metabolic fingerprints differed significantly over time. Forty-five metabolites were identified, including well-known cheese metabolites, such as 12 amino acids and 25 volatile metabolites, and less studied ones, such as four vitamins, uric acid, creatine and L-carnitine. These results showed the relevance of cheese MS fingerprinting to generate new findings and to detect even slight differences between two conditions

Promising immunomodulatory properties of select strains of dairy propionibacteria

Promising immunomodulatory properties of select strains of dairy[i] propionibacteria[/i]. 4 .Congress of European Microbiologists FEMS 201