Gram-Negative Bacterial Sensors for Eukaryotic Signal Molecules

Ample evidence exists showing that eukaryotic signal molecules synthesized and released by the host can activate the virulence of opportunistic pathogens. The sensitivity of prokaryotes to host signal molecules requires the presence of bacterial sensors. These prokaryotic sensors, or receptors, have a double function: stereospecific recognition in a complex environment and transduction of the message in order to initiate bacterial physiological modifications. As messengers are generally unable to freely cross the bacterial membrane, they require either the presence of sensors anchored in the membrane or transporters allowing direct recognition inside the bacterial cytoplasm. Since the discovery of quorum sensing, it was established that the production of virulence factors by bacteria is tightly growth-phase regulated. It is now obvious that expression of bacterial virulence is also controlled by detection of the eukaryotic messengers released in the micro-environment as endocrine or neuro-endocrine modulators. In the presence of host physiological stress many eukaryotic factors are released and detected by Gram-negative bacteria which in return rapidly adapt their physiology. For instance, Pseudomonas aeruginosa can bind elements of the host immune system such as interferon-γ and dynorphin and then through quorum sensing circuitry enhance its virulence. Escherichia coli sensitivity to the neurohormones of the catecholamines family appears relayed by a recently identified bacterial adrenergic receptor. In the present review, we will describe the mechanisms by which various eukaryotic signal molecules produced by host may activate Gram-negative bacteria virulence. Particular attention will be paid to Pseudomonas, a genus whose representative species, P. aeruginosa, is a common opportunistic pathogen. The discussion will be particularly focused on the pivotal role played by these new types of pathogen sensors from the sensing to the transduction mechanism involved in virulence factors regulation. Finally, we will discuss the consequence of the impact of host signal molecules on commensally or opportunistic pathogens associated with different human tissue

Papillome mammaire : comment je fais… une pyramidectomie guidée par un fil de crin

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Hystérectomie : évolution des pratiques entre 2009 et 2019 en France

International audienceObjective: Hysterectomy is the most common procedure in women. We wanted to make an assessment of the hysterectomy in France in 2019. We also assessed the variations over time in the indications and the surgical approch for hysterectomy, this with regard to the various events that may have been at the origin of the modification practices. Methods: We used the Medical Information Systems Program in Medicine, Surgery, Obstetrics and Dentistry to extract all acts relating to a hysterectomy regardless of its route of approach from 2009 to 2019. Results: Hysterectomy is a frequent procedure which was performed in nearly 60,000 women in France in 2019. The most frequently used surgical approach is now laparoscopy, performed in 30% of hysterectomies, followed by laparotomic (29%), then vaginal approaches (26%) and coelio-vaginal (15%). Laparoscopic procedures are performed more often in public than private hospitals. Adnexectomy is associated with 41% of hysterectomies. A decrease in the number of hysterectomies was observed between 2008 and 2019, from approximately 72,000 in 2008 to approximately 60,000 in 2019. This decrease occurs during a period in which new therapies have emerged as well as new recommendations. Conclusion: The evolution of the number of hysterectomies is correlated with the development of therapeutic alternatives for pathologies for which a hysterectomy has traditionally been performed

Validation externe de 2 scores prédictifs de récidive de tumeurs mucineuses et séreuses borderline de l'ovaire : le nomogramme de Bendifallah et le score d'Ouldamer

International audienceBackground Borderline ovarian tumors are rare and can occur in young women. For these patients, a fertility sparing surgery should be discussed. Two predicting borderline ovarian tumor relapse risk models were developed in 2014 (Nomogram of Bendifallah) and 2017 (Score of Ouldamer). This study aimed to valid in an external population, these two scores using a multi-institutional BOT database. Methods In this bicentric and retrospective study, all consecutive patients comprising the variable nomogram documented treated between January 2006 and December 2012 for BOT in centre hospitalier de Poissy-Saint-Germain and hôpital René-Huguenin were included. A ROC model was established for each predicting scores. Results Sixty-five patients were included in the study. Twelve patients showed a recurrence (19%), three of them experienced an infiltrative cancer (5%). The median time of recurrence was 25 months (range: 8–115). The concordance index for the Nomogram of Bendifallah and the Score of Ouldamer were 0.88 (IC 95% [0.78–0.98]) and 0.87 (IC 95% [0.77–0.96]) respectively. Conclusion This study from an independent population valids the Bendifallah nomogram and Ouldamer score for clinical use in predicting borderline ovarian recurrence

CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer

International audienceBackground. Minimal residual disease is the main issue of advanced ovarian cancer treatment. According to the literature and previous results, we hypothesized that Mesenchymal Stromal Cells (MSC) could support this minimal residual disease by protecting ovarian cancer cells (OCC) from chemotherapy. In vitro study confirmed that MSC could induce OCC chemoresistance without contact using transwell setting. Further experiments showed that this induced chemoresistance was dependent on IL-6 OCC stimulation.Methods. We combined meticulous in vitro profiling and tumor xenograft models to study the role of IL-6 in MSC/OCC intereactions.Results. We demonstrated that Tocilizumab® (anti-IL-6R therapy) in association with chemotherapy significantly reduced the peritoneal carcinosis index (PCI) than chemotherapy alone in mice xenografted with OCCs+MSCs. Further experiments showed that CCL2 and CCL5 are released by MSC in transwell co-culture and induce OCCs IL-6 secretion and chemoresistance. Finally, we found that IL-6 induced chemoresistance was dependent on PYK2 phosphorylation.Conclusions. These findings highlight the potential key role of the stroma in protecting minimal residual disease from chemotherapy, thus favoring recurrences. Future clinical trials targeting stroma could use anti-IL-6 therapy in association with chemotherapy

a section of the journal Frontiers in Psychology Sex Differences in Language Across Early Childhood: Family Socioeconomic Status does not Impact Boys and Girls Equally

Child sex and family socioeconomic status (SES) have been repeatedly identified as a source of inter-individual variation in language development; yet their interactions have rarely been explored. While sex differences are the focus of a renewed interest concerning emerging language skills, data remain scarce and are not consistent across preschool years. The questions of whether family SES impacts boys and girls equally, as well as of the consistency of these differences throughout early childhood, remain open. We evaluated consistency of sex differences across SES and age by focusing on how children (N = 262), from 2;6 to 6;4 years old, from two contrasting social backgrounds, acquire a frequent phonological alternation in French -the liaison. By using a picture naming task eliciting the production of obligatory liaisons, we found evidence of sex differences over the preschool years in low-SES children, but not between high-SES boys and girls whose performances were very similar. Low-SES boys' performances were the poorest whereas low-SES girls' performances were intermediate, that is, lower than those of high-SES children of both sexes but higher than those of low-SES boys. Although all children's mastery of obligatory liaisons progressed with age, our findings showed a significant impeding effect of low-SES, especially for boys

Additional file 1: Figure S1. of CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer

A. EOC in situ surrounded by ascites. Cells Epcam− (red gate) were cell sorted and cultured. B. Phase contrast pictures of cells sorted in A. Scale bar: 50 μm C. Flow cytometry for every MSC markers on cells sorted in A. D. Cell sorted in fig. 1a were cultured for few days and stained with CD29 (green), CD105 (green), CD90 (red), CD73 (red) antibodies. Scale: 10 μm. Figure S2. OCCs were treated for 48 h with a blocking antibody against IL-6 (20 μg/mL). The percentage of live cells (green gate), apoptotic cells (red gate) and dead cells (black gate) are represented on the plot. Figure S3. A. Paraffin-embedded vimentin immunohistochemistry for the mouse group Control + MSC and Chemo + MSC. B. Confocal images for Epcam on 10μm sections of snap-frozen tumors. Scale: 100 μm. Figure S4. A. Relative quantification of IL-6 gene in RT-PCR on Ovcar3 (orange) and APOCC (purple) treated with SH IL-6 (SH) or scrambled (Scr), and MSC (grey) before (No cocu) or after co-incubation with OCCs scr or SH for 48 h. The histogram represents ratios between the transwell and the control condition of their 2–ΔΔCp real-time PCR values. B. Acquisition of the membrane in chemiluminescence. C. Hierarchical representation of the pixel density of each dot of the cytokine array. Figure S5. Phase contrast of OCCs after treatment with IL-8 (50 ng/ml), Dkk1 (20 ng/ml), IL-6 (50 ng/ml), MCP-1 (10 nM), CCL5 (100 ng/ml), CXCL12 (100 ng/ml), bFGF (10 ng/ml) for 48 h prior treatment with Carboplatin (200 μM) and Taxol (0.1 μM) for 24 h. Figure S6. A. Proteome profiler human phosphokinase array. B. Proteome profiler human phosphokinase array. C. Fold increase of pixel density of each condition compared to APOCC control (blue part) or to APOCC SH-IL6 (purple part). (PDF 1100 kb

Additional file 2: Table S1. of CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer

Primers list. (DOCX 14 kb

Long-Term Results with Everolimus in Advanced Hormone Receptor Positive Breast Cancer in a Multicenter National Real-World Observational Study

Everolimus is the first oral targeted therapy widely used in advanced HR+/HER2− breast cancer. We sought to evaluate the impact of everolimus-based therapy on overall survival in the ESME-MBC database, a national metastatic breast cancer cohort that collects retrospective data using clinical trial-like methodology including quality assessments. We compared 1693 patients having received everolimus to 5928 patients not exposed to everolimus in the same period. Overall survival was evaluated according to treatment line, and a propensity score with the inverse probability of treatment weighting method was built to adjust for differences between groups. Crude and landmark overall survival analyses were all compatible with a benefit from everolimus-based therapy. Adjusted hazard ratios for overall survival were 0.34 (95% CI: 0.16–0.72, p = 0.0054), 0.34 (95% CI: 0.22–0.52, p < 0.0001), and 0.23 (95% CI: 0.14–0.36, p < 0.0001) for patients treated with everolimus in line 1, 2, and 3 and beyond, respectively. No clinically relevant benefit on progression-free survival was observed. Causes for everolimus discontinuation were progressive disease (56.2%), adverse events (27.7%), and other miscellaneous reasons. Despite the limitations inherent to such retrospective studies, these results suggest that adding everolimus-based therapy to the therapeutic sequences in patients with advanced HR+/HER2− breast cancer may favorably affect overall survival

Real-world clinical and survival outcomes of patients with early relapsed triple-negative breast cancer from the ESME national cohort

International audienceBackgroundEarly metastatic relapse of triple-negative breast cancer (mTNBC) after anthracyclins and/or taxanes based (A/T) primary treatment represents a highly aggressive cancer situation requiring urgent characterisation and handling. Epidemio-Strategy-Medico-Economical-Metastatic Breast Cancer (ESME-MBC) database, a multicenter, national, observational cohort (NCT03275311) provides recent data on this entity.MethodsAll ESME patients diagnosed between 2008 and 2020 with mTNBC occurring as a relapse after a systemic neoadjuvant/adjuvant taxane and/or anthracycline-based chemotherapy were included. Early relapses were defined by a metastatic diagnosis up to 12 months of the end of neo/adjuvant A/T chemotherapy. We assessed overall survival (OS) and progression-free-survival under first-line treatment (PFS1) by early versus late relapse (≥12 months).ResultsPatients with early relapse (N = 881, 46%) were younger and had a larger tumour burden at primary diagnosis than those with late relapses (N = 1045). Early relapse rates appeared stable over time. Median OS was 10.1 months (95% CI 9.3–10.9) in patients with early relapse versus 17.1 months (95% CI 15.7–18.2) in those with late relapse (adjusted hazard-ratio (aHR): 1.92 (95% CI 1.73–2.13); p < 0.001). The median PFS1 was respectively 3.1 months (95% CI 2.9–3.4) and 5.3 months (95% CI 5.1–5.8); (aHR: 1.66; [95% CI 1.50–1.83]; p < 0.001). Among early relapsed patients, a higher number of metastatic sites, visceral disease but not treatment types, were independently associated with a poorer OS.ConclusionThese real-world data provide strong evidence on the dismal prognosis, higher treatment resistance and major unmet medical need associated with early relapsed mTNBC.Database registration: clinicaltrials.gov Identifier NCT03275