Breast cancer is the most common type of cancer worldwide and one of the major causes of cancer death in women. Epidemiological studies have established a link between night-shift work and increased ...cancer risk, suggesting that circadian disruption may play a role in carcinogenesis. Here, we aim to shed light on the effect of chronic jetlag (JL) on mammary tumour development. To do this, we use a mouse model of spontaneous mammary tumourigenesis and subject it to chronic circadian disruption. We observe that circadian disruption significantly increases cancer-cell dissemination and lung metastasis. It also enhances the stemness and tumour-initiating potential of tumour cells and creates an immunosuppressive shift in the tumour microenvironment. Finally, our results suggest that the use of a CXCR2 inhibitor could correct the effect of JL on cancer-cell dissemination and metastasis. Altogether, our data provide a conceptual framework to better understand and manage the effects of chronic circadian disruption on breast cancer progression.
Bovine tuberculosis (bTB) is a common disease in cattle and wildlife, with health, zoonotic and economic implications. Infected wild animals, and particularly reservoirs, could hinder eradication of ...bTB from cattle populations, which could have an important impact on international cattle trade. Therefore, surveillance of bTB in wildlife is of particular importance to better understand the epidemiological role of wild species and to adapt the control measures. In France, a bTB surveillance system for free-ranging wildlife, the Sylvatub system, has been implemented since 2011. It relies on three surveillance components (SSCs) (passive surveillance on hunted animals (EC-SSC), passive surveillance on dead or dying animals (SAGIR-SSC) and active surveillance (PSURV-SSC)). The effectiveness of the Sylvatub system was previously assessed, through the estimation of its sensitivity (i.e. the probability of detecting at least one case of bTB infection by each SSC, specie and risk-level area). However, to globally assess the performance of a surveillance system, the measure of its sensitivity is not sufficient, as other factors such as economic or socio-economic factors could influence the effectiveness. We report here an estimation of the costs of the surveillance activities of the Sylvatub system, and of the cost-effectiveness of each surveillance component, by specie and risk-level, based on scenario tree modelling with the same tree structure as used for the sensitivity evaluation. The cost-effectiveness of the Sylvatub surveillance is better in higher-risk departments, due in particular to the higher probability of detecting the infection (sensitivity). Moreover, EC-SSC, which has the highest unit cost, is more efficient than the surveillance enhanced by the SAGIR-SSC, due to its better sensitivity. The calculation of the cost-effectiveness ratio shows that PSURV-SSC remains the most cost-effective surveillance component of the Sylvatub system, despite its high cost in terms of coordination, sample collection and laboratory analysis.
Lung transplantation is the only curative option for end-stage chronic respiratory diseases. However the survival rate is only about 50% at 5 years. Although experimental evidences have shown that ...innate allo-responses impact on the clinical outcome, the knowledge of the involved mechanisms involved is limited. We established a cross-circulatory platform to monitor the early recruitment and activation of immune cells in an extracorporeal donor lung by coupling blood perfusion to cell mapping with a fluorescent marker in the pig, a commonly-used species for lung transplantation. The perfusing pig cells were easily detectable in lung cell suspensions, in broncho-alveolar lavages and in different areas of lung sections, indicating infiltration of the organ. Myeloid cells (granulocytes and monocytic cells) were the dominant recruited subsets. Between 6 and 10 h of perfusion, recruited monocytic cells presented a strong upregulation of MHC class II and CD80/86 expression, whereas alveolar macrophages and donor monocytic cells showed no significant modulation of expression. This cross-circulation model allowed us to monitor the initial encounter between perfusing cells and the lung graft, in an easy, rapid, and controllable manner, to generate robust information on innate response and test targeted therapies for improvement of lung transplantation outcome.
Bovine tuberculosis (bTB) is a common disease of cattle and wildlife, with economic repercussions and implications for animal and human health. The surveillance of bTB in wildlife is particularly ...important, to shed light on the epidemiological role of wild species and for the adaptation of control measures. In France, a bTB surveillance system for free-ranging wildlife, the Sylvatub system, was launched in 2011 on wild boars, red deer, roe deer and badgers. It relies on active and passive surveillance activities, constrained by practical difficulties, such as the accessibility of wild animals, and regulatory rules for the trapping of badgers, for example. We report here the first assessment of stakeholders' perceptions of the Sylvatub system and its acceptability, based on 20 individual semi-structured interviews with three types of stakeholder (collectors, coordinators, officers) in areas with different rates of bTB infection. With the caveat that these findings cannot be assumed to be representative of the national situation, we found that the Sylvatub system was considered useful by all the stakeholders interviewed. Those from the world of hunting participate in surveillance mostly to help livestock farmers, who are not systematically involved in bTB surveillance in wildlife. Many practical and regulatory constraints were raised, which could be offset by recognition of the work done by the "hunting community", to maintain the willingness of these individuals to participate. We also identified a need for improvements in communication and information. Qualitative information, such as that collected here, is essential to improve our understanding of the reasons favoring and disfavoring participation in surveillance, and should be taken into account in the evaluation process. These results are relevant to hunters and to veterinary authorities wishing to identify the determinants of participation in the Sylvatub system. They could provide support for decision-making processes to improve surveillance strategies.
The fetal development of organs and functions is vulnerable to perturbation by maternal inflammation which may increase susceptibility to disorders after birth. Because it is not well understood how ...the placenta and fetus respond to acute lung- inflammation, we characterize the response to maternal pulmonary lipopolysaccharide exposure across 24 h in maternal and fetal organs using multi-omics, imaging and integrative analyses. Unlike maternal organs, which mount strong inflammatory immune responses, the placenta upregulates immuno-modulatory genes, in particular the IL-6 signaling suppressor Socs3. Similarly, we observe no immune response in the fetal liver, which instead displays metabolic changes, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. The maternal liver and plasma display similar metabolic alterations, potentially increasing bioavailability of docosahexaenoic acid for the mother and fetus. Thus, our integrated temporal analysis shows that systemic inflammation in the mother leads to a metabolic perturbation in the fetus.Maternal immune activation during pregnancy can negatively impact the developing fetus. Here, applying multi-omics (RNA-seq, phosphoproteomics and lipidomics) and imaging, the authors show that while maternal immune activation induces strong innate response in maternal organs it does not extend through the placenta but leads to fetal metabolic changes.
In MeLiM minipigs, melanomas develop around birth, can metastasize, and have histopathologic characteristics similar to humans. Interestingly, MeLiM melanomas eventually regress. This favorable ...outcome raises the question of their malignancy, which we investigated. We clinically followed tens of tumors from onset to first signs of regression. Transcriptome analysis revealed an enrichment of all cancer hallmarks in melanomas, although no activating or suppressing somatic mutation were found in common driver genes. Analysis of tumor cell genomes revealed high mutation rates without UV signature. Canonical proliferative, survival and angiogenic pathways were detected in MeLiM tumor cells all along progression stages. Functionally, we show that MeLiM melanoma cells are capable to grow in immunocompromised mice, with serial passages and for a longer time than in MeLiM pigs. Pigs set in place an immune response during progression with dense infiltration by myeloid cells while melanoma cells are deficient in B2M expression. To conclude, our data on MeLiM melanomas reveal several malignancy characteristics. The combination of these features with the successful spontaneous regression of these tumors make it an outstanding model to study an efficient anti-tumor immune response.
To answer to patients' medical wandering, often due to "unexplained symptoms" of "unexplained diseases" and to misinformation, multidisciplinary care centers for suspected Lyme borreliosis (LB), such ...as the 5 Tick-Borne Diseases (TBDs) Reference Centers (TBD-RC), were created a few years ago in France, the Netherlands and Denmark. Our study consisted of a comprehensive analysis of the satisfaction of the patients managed at a TBD-RC for suspected LB in the context of scientific and social controversy.
We included all adults who were admitted to one of the TBD-RC from 2017 to 2020. A telephone satisfaction survey was conducted 12 months after their first consultation. It consisted of 5 domains, including 2 free-text items: "What points did you enjoy?" and "What would you like us to change or to improve?". In the current study, the 2 free-items were analyzed with a qualitative method called reflexive thematic analysis within a semantic and latent approach.
The answer rate was 61.3% (349/569) and 97 distinctive codes from the 2-free-text items were identified and classified into five themes: (1) multidisciplinarity makes it possible to set up quality time dedicated to patients; (2) multidisciplinarity enables seamless carepaths despite the public hospital crisis compounded by the COVID-19 pandemic; (3) multidisciplinarity is defined as trust in the team's competences; (4) an ambivalent opinion and uncertainty are barriers to acceptance of the diagnosis, reflecting the strong influence of the controversy around LB; and (5) a lack of adapted communication about TBDs, their management, and ongoing research is present.
The multidisciplinary management for suspected LB seemed an answer to medical wandering for the majority of patients and helped avoid misinformation, enabling better patient-centered shared information and satisfaction, despite the context of controversy.
Non-classical monocyte subsets may derive from classical monocyte differentiation and the proportion of each subset is tightly controlled. Deregulation of this repartition is observed in diverse ...human diseases, including chronic myelomonocytic leukemia (CMML) in which non-classical monocyte numbers are significantly decreased relative to healthy controls. Here, we identify a down-regulation of hsa-miR-150 through methylation of a lineage-specific promoter in CMML monocytes. Mir150 knock-out mice demonstrate a cell-autonomous defect in non-classical monocytes. Our pulldown experiments point to Ten-Eleven-Translocation-3 (TET3) mRNA as a hsa-miR-150 target in classical human monocytes. We show that Tet3 knockout mice generate an increased number of non-classical monocytes. Our results identify the miR-150/TET3 axis as being involved in the generation of non-classical monocytes.
Nine male and eight female calves born to a Normande artificial insemination bull named "Ly" were referred to the French National Observatory of Bovine Abnormalities for multiple fractures, shortened ...gestation, and stillbirth or perinatal mortality.
Using Illumina BovineSNP50 array genotypes from affected calves and 84 half-sib controls, the associated locus was mapped to a 6.5-Mb interval on chromosome 19, assuming autosomal inheritance with germline mosaicism. Subsequent comparison of the whole-genome sequences of one case and 5116 control genomes, followed by genotyping in the affected pedigree, identified a de novo missense substitution within the NC1 domain of the COL1A1 gene (Chr19 g.36,473,965G > A; p.D1412N) as unique candidate variant. Interestingly, the affected residue was completely conserved among 243 vertebrate orthologs, and the same substitution in humans has been reported to cause type II osteogenesis imperfecta (OI), a connective tissue disorder that is characterized primarily by bone deformity and fragility. Moreover, three COL1A1 mutations have been described to cause the same syndrome in cattle. Necropsy, computed tomography, radiology, and histology confirmed the diagnosis of type II OI, further supporting the causality of this variant. In addition, a detailed analysis of gestation length and perinatal mortality in 1387 offspring of Ly and more than 160,000 progeny of 63 control bulls allowed us to statistically confirm in a large pedigree the association between type II OI and preterm delivery, which is probably due to premature rupture of fetal membranes and has been reported in several isolated cases of type II OI in humans and cattle. Finally, analysis of perinatal mortality rates and segregation distortion supported a low level of germ cell mosaicism in Ly, with an estimate of 4.5% to 7.7% of mutant sperm and thus 63 to 107 affected calves born. These numbers contrast with the 17 cases reported and raise concerns about the underreporting of congenital defects to heredo-surveillance platforms, even for textbook genetic syndromes.
In conclusion, we describe a large animal model for a recurrent substitution in COL1A1 that is responsible for type II OI in humans. More generally, this study highlights the utility of such datasets and large half-sib families available in livestock species to characterize sporadic genetic defects.
Weaning has been described as one of the most stressful events in the life of horses. Given the importance of the interaction between the gut-brain axis and gut microbiota under stress, we evaluated ...(i) the effect of two different weaning methods on the composition of gut microbiota across time and (ii) how the shifts of gut microbiota composition after weaning affect the host. A total of 34 foals were randomly subjected to a progressive (P) or an abrupt (A) weaning method. In the P method, mares were separated from foals at progressively increasing intervals every day, starting from five min during the fourth week prior to weaning and ending with 6 h during the last week before weaning. In the A method, mares and foals were never separated prior to weaning (0 d). Different host phenotypes and gut microbiota composition were studied across 6 age strata (days -30, 0, 3, 5, 7, and 30 after weaning) by 16S rRNA gene sequencing. Results revealed that the beneficial species belonging to
, and
were more abundant in the A group prior to weaning compared to the P group, suggesting that the gut microbiota in the A cohort was better adapted to weaning.
, on the other hand, showed the opposite pattern after weaning. Fungal loads, which are thought to increase the capacity for fermenting the complex polysaccharides from diet, were higher in P relative to A. Beyond the effects of weaning methods, maternal separation at weaning markedly shifted the composition of the gut microbiota in all foals, which fell into three distinct community types at 3 days post-weaning. Most genera in community type 2 (i.e.,
XI, and
spp.) were negatively correlated with salivary cortisol levels, but positively correlated with telomere length and N-butyrate production. Average daily gain was also greater in the foals harboring a community type 2 microbiota. Therefore, community type 2 is likely to confer better stress response adaptation following weaning. This study identified potential microbial biomarkers that could predict the likelihood for physiological adaptations to weaning in horses, although causality remains to be addressed.
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