Occurrence of Salmonella in the Cattle Production in France.

Salmonella is among the most common foodborne pathogens worldwide, and can lead to acute gastroenteritis. Along with poultry, cattle production is recognized as an important source of human infection. Salmonella transmission from cattle to humans can occur through the environment, or through close contact with sick animals or their derived products. This study aimed to investigate the intestinal carriage of Salmonella spp. within French cattle production. A total of 959 cattle intestinal samples, from one of the largest French slaughterhouses, were analyzed. Isolated strains were genotyped by pulsed field gel electrophoresis (PFGE), and a sub-selection was taken by whole genome sequencing (WGS). Twenty-nine samples were positive for Salmonella spp., yielding an estimated prevalence of 3% in cattle production. Eight different Salmonella serotypes were found: Montevideo was the most prevalent (34%), followed by Mbandaka (24%) and Anatum (14%). PFGE genotyping allowed the clustering of Salmonella isolates according to their serotype. Within the clusters, some isolates presented 100% similarity. To investigate potential epidemiological links between them, WGS and core genome multilocus sequence typing (cgMLST) were used, revealing identical profiles between isolates originating from different areas and/or different animal breeds. This investigation provides new insights on Salmonella serotype epidemiology in cattle production in France.

Translational strategy using multiple nuclear imaging biomarkers to evaluate target engagement and early therapeutic efficacy of SAR439859, a novel selective estrogen receptor degrader.

PURPOSE: Preclinical in vivo nuclear imaging of mice offers an enabling perspective to evaluate drug efficacy at optimal dose and schedule. In this study, we interrogated sufficient estrogen receptor occupancy and degradation for the selective estrogen receptor degrader (SERD) compound SAR439859 using molecular imaging and histological techniques. MATERIAL AND METHODS: [18F]FluoroEstradiol positron emission tomography (FES-PET), [18F]FluoroDeoxyGlucose (FDG) PET, and [18F]FluoroThymidine (FLT) PET were investigated as early pharmacodynamic, tumor metabolism, and tumor proliferation imaging biomarkers, respectively, in mice bearing subcutaneous MCF7-Y537S mutant ERα+ breast cancer model treated with the SERD agent SAR439859. ER expression and proliferation index Ki-67 were assessed by immunohistochemistry (IHC). The combination of palbociclib CDK 4/6 inhibitor with SAR439859 was tested for its potential synergistic effect on anti-tumor activity. RESULTS: After repeated SAR439859 oral administration over 4 days, FES tumoral uptake (SUVmean) decreases compared to baseline by 35, 57, and 55% for the 25 mg/kg qd, 12.5 mg/kg bid and 5 mg/kg bid treatment groups, respectively. FES tumor uptake following SAR439859 treatment at different doses correlates with immunohistochemical scoring for ERα expression. No significant difference in FDG uptake is observed after SAR439859 treatments over 3 days. FLT accumulation in tumor is significantly decreased when palbociclib is combined to SAR439859 (- 64%) but not different from the group dosed with palbociclib alone (- 46%). The impact on proliferation is corroborated by Ki-67 IHC data for both groups of treatment. CONCLUSIONS: In our preclinical studies, dose-dependent inhibition of FES tumoral uptake confirmed target engagement of SAR439859 to ERα. FES-PET thus appears as a relevant imaging biomarker for measuring non-invasively the impact of SAR439859 on tumor estrogen receptor occupancy. This study further validates the use of FLT-PET to directly visualize the anti-proliferative tumor effect of the palbociclib CDK 4/6 inhibitor alone and in combination with SAR439859.

Effective clearance of GL-3 in a human iPSC-derived cardiomyocyte model of Fabry disease.

Fabry disease, a rare X-linked α-galactosidase A deficiency, causes progressive lysosomal accumulation of globotriaosylceramide (GL-3) in a variety of cell types. As the disease progresses, renal failure, left ventricular hypertrophy, and strokes may occur. Enzyme replacement therapy (ERT), with recombinant α-galactosidase A, is currently available for use to reduce GL-3 deposits. However, although it improves cardiac function and decreases left ventricular mass, GL-3 clearance upon ERT has been demonstrated in cardiac capillary endothelium but not in cardiomyocytes of patients. Relevant models are needed to understand the pathogenesis of cardiac disease and explore new therapeutic approaches. We generated induced pluripotent stem cells (iPSC) from Fabry patients and differentiated them into cardiomyocytes. In these cells, GL-3 accumulates in the lysosomes over time, resulting in phenotypic changes similar to those found in cardiac tissue from Fabry patients. Using this human in vitro model, we demonstrated that substrate reduction therapy via glucosylceramide synthase inhibition was able to prevent accumulation and to clear lysosomal GL-3 in cardiomyocytes. This new in vitro model recapitulates essential features of cardiomyocytes from patients with Fabry disease and therefore provides a useful and relevant tool for further investigations of new therapy.

European validation of Real-Time PCR method for detection of Salmonella spp. in pork meat.

The classical microbiological method for detection of Salmonella spp. requires more than five days for final confirmation, and consequently there is a need for an alternative methodology for detection of this pathogen particularly in those food categories with a short shelf-life. This study presents an international (at European level) ISO 16140-based validation study of a non-proprietary Real-Time PCR-based method that can generate final results the day following sample analysis. It is based on an ISO compatible enrichment coupled to an easy and inexpensive DNA extraction and a consolidated Real-Time PCR assay. Thirteen laboratories from seven European Countries participated to this trial, and pork meat was selected as food model. The limit of detection observed was down to 10 CFU per 25 g of sample, showing excellent concordance and accordance values between samples and laboratories (100%). In addition, excellent values were obtained for relative accuracy, specificity and sensitivity (100%) when the results obtained for the Real-Time PCR-based methods were compared to those of the ISO 6579:2002 standard method. The results of this international trial demonstrate that the evaluated Real-Time PCR-based method represents an excellent alternative to the ISO standard. In fact, it shows an equal and solid performance as well as it reduces dramatically the extent of the analytical process, and can be easily implemented routinely by the Competent Authorities and Food Industry laboratories.