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\"Black French Women and the Struggle for Equality, 1848-2016 explores how Black women--in France, the French Caribbean, Réunion Island, Gorée, Dakar, Rufisque, and Saint-Louis--experienced and reacted to French colonialism\"-- Provided by publisher.

Background Metaplastic breast cancer (MBC) is a rare form of breast cancer characterized by an aggressive clinical presentation, with a poor response to standard chemotherapy. MBCs are typically triple-negative breast cancers (TNBCs), frequently with alterations to genes of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. The objective of this study was to determine the response to PI3K and MAPK pathway inhibitors in patient-derived xenografts (PDXs) of MBCs with targetable alterations. Methods We compared survival between triple-negative MBCs and other histological subtypes, in a clinical cohort of 323 TNBC patients. PDX models were established from primary breast tumors classified as MBC. PI3K-AKT-mTOR and RTK-MAPK pathway alterations were detected by targeted next-generation sequencing (NGS) and analyses of copy number alterations. Activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways was analyzed with reverse-phase protein arrays (RPPA). PDXs carrying an activating mutation of PIK3CA and genomic changes to the RTK-MAPK signaling pathways were treated with a combination consisting of a PI3K inhibitor and a MEK inhibitor. Results In our clinical cohort, the patients with MBC had a worse prognosis than those with other histological subtypes. We established nine metaplastic TNBC PDXs. Three had a pathogenic mutation of PIK3CA and additional alterations to genes associated with RTK-MAPK signaling. The MBC PDXs expressed typical EMT and stem cell genes and were of the mesenchymal or mesenchymal stem-like TNBC subtypes. On histological analysis, MBC PDXs presented squamous or chondroid differentiation. RPPA analysis showed activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. In vivo, the combination of PI3K and MAPK inhibitors displayed marked antitumor activity in PDXs carrying genomic alterations of PIK3CA , AKT1 , BRAF , and FGFR4 . Conclusion The treatment of metaplastic breast cancer PDXs by activation of the PI3K-AKT-mTOR and RTK-MAPK pathways at the genomic and protein levels with a combination of PI3K and MEK inhibitors resulted in tumor regression in mutated models and may therefore be of interest for therapeutic purposes.

Background:CD45RC is an isoform of CD45, a transmembrane tyrosine phosphatase, essential regulator of T and B cells antigen receptor signaling. CD45RC is expressed by most blood B cells while in T cells its high expression is restricted to Th1 precursor and Th1 cells, as well as TEMRA. We demonstrated that administration of an anti-CD45RC mAb in preclinical models of transplant rejection, graft versus host disease (GvHD), Duchene dystrophy or Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED) leads to prevention or control of the disease. RA is a chronic relapsing/remitting disease characterized by synovitis, joint deformity, loss of function and increased mortality. While T-cells are a major component in the pathogenesis, B-cells are also pathogenic.Objectives:In this study, we deciphered the mechanism of action of the anti-human CD45RC mAb and assessed its effect in vitro and in vivo on human immune cell populations. We then assessed the potential of the anti-CD45RC mAb in an experimental model of rheumatoid arthritis.Methods:Cells were isolated from peripheral blood. Apoptosis, antibody-Dependent Cellular Cytotoxicity (ADCC), antibody-Dependent Cellular Phagocytosis (ADCP) and Complement-Dependent Cytotoxicity (CDC) were assessed by Annexin V/DAPI staining. In vivo studies were performed in CD34+ immune-humanized NSG mice, in a model of xenogeneic GVHD in human PBMC-reconstituted immunodeficient NSG mice or in a model of collagen-induced arthritis (CIA) in rat.Results:We demonstrated that the humanized anti-human CD45RC mAb induced CD45RChigh T and B cell death mainly by direct apoptosis of CD45RChigh cells expressing around 105 molecules per µm2 of membrane, inducing signaling but not cytokine release. We demonstrated contribution of ADCC and ADCP-mediated death of CD45RChigh cells. Using in vivo studies in CD34+ immune-humanized NSG mice, we showed that a single iv administration of anti-CD45RC mAb induced an efficient killing of CD45RChigh T and B cells as soon as day 1, this effect was dose and time-dependent and targeted cells recovered by day 24. We also showed a dose dependent efficacy in a model of xenogeneic GVHD in human PBMC-reconstituted immunodeficient NSG mice. Treatment with an anti-rat CD45RC mAb in a rat model of CIA efficiently prevented weight loss, mean arthritis severity, maximum score and AUC,in contrast to the isotype control mAb. Anti-CD45RC mAb completely inhibited anti-collagen antibody production, inflammation of the paws and GM-CSF secretion in the sera in contrast to controls. Efficacy of the anti-CD45RC mAb correlated with depletion of CD45RChigh T and B cells by d3 (>94%) and until sacrifice with conserved Treg numbers. Analysis of RA patients showed in the blood presence of CD45RChigh cells and a strong infiltration by CD45RChigh cells of synovial tissues using IHC. Analysis of the potency of the anti-human CD45RC mAb demonstrated efficient apoptosis in vitro of CD45RChigh T and B from blood cells from RA patients and HC.Conclusion:Altogether our study demonstrates the mechanisms by which anti-human CD45RC mAb mediates CD45RChigh T and B cell death to control immune responses. Our study demonstrates that anti-CD45RC mAb treatment is a potent immunomodulatory agent rebalancing the Treg/teff ratio to reduce joint inflammation and disease activity in RA and a potential alternative for first line DMARD. This highly specific targeting of cells involved in transplant rejection and autoimmune diseases could substantially improve the management of patients across a wide range of affections.REFERENCES:[1] Besnard M. et al. Anti-CD45RC antibody immunotherapy prevents and treats experimental Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy syndrome. J Clin Invest. 2022. doi: 10.1172/JCI156507.[2] Boucault L. et al.. Transient Antibody Targeting of CD45RC Inhibits the Development of Graft-versus-Host Disease. Blood Advances. 2020. doi: 10.1182/bloodadvances.2020001688.[3] Picarda E. et al.. Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells. JCI Insights. 2017 Feb 9;2(3):e90088.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Cecile Bergua: None declared, Marine Besnard: None declared, Ghenima Ahmil: None declared, Laure-Helene Ouisse: None declared, Nadege Vimond: None declared, Apolline Salama: None declared, Berangere Evrard: None declared, Elise Brisebard: None declared, Alexis Collette AbolerIS Pharma, Frederic Blanchard: None declared, Thibaut Larcher: None declared, Ronald Van Brempt AbolerIS Pharma, Benoit Le Goff: None declared, Ignacio Anegon AbolerIS Pharma, AbolerIS Pharma, Carole Guillonneau AbolerIS Pharma, AbolerIS Pharma, AbolerIS Pharma.

This study was carried out to evaluate the relationships of cellular changes in the abomasal mucosa and parasitological parameters, by comparing resistant and susceptible young Creole goats (kids) after experimental infection with Haemonchus contortus. The kids were infected over 2 periods (challenges 1 and 2) of 7 and 6 weeks, respectively. Fecal egg count (FEC), blood eosinophilia, packed cell volume (PCV), and body weight were weekly monitored. At the end of both challenges a subgroup of kids was slaughtered for nematode burden measurements and analysis of inflammatory cell infiltration in the abomasal mucosa. The average daily gain was higher in resistant kids after both challenges. Blood eosinophilia and FEC were higher in susceptible kids after both challenges. The number of immature worms and the means of female length were lower after challenge 2 whatever the genetic status. No differences were observed in the eosinophil and mononuclear cell infiltration between challenges 1 and 2 and resistant and susceptible kids. Globule leukocyte infiltration was found higher after the challenge 1 in resistant kids. This effect of the genetic status on globule leukocytes counts but not on the other inflammatory cell highlights the need for further study on the functional activity of these cell populations.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants that can be present at high levels as mixtures in polluted aquatic environments. Many PAHs are potent mutagens and several are well-known carcinogens. Despite numerous studies on individual compounds, little is known about the toxicity of PAHs mixtures that are encountered in environmental situations. In the present work, zebrafish were continuously fed from 5 days post-fertilisation to 14 months post-fertilisation (mpf) with a diet spiked with fractions of either pyrolytic (PY), petrogenic light oil (LO), or petrogenic heavy oil (HO) origin at three concentrations. A decrease in survival was identified after 3 mpf in fish fed with the highest concentration of HO or LO, but not for PY. All PAH fractions caused preneoplastic and neoplastic disorders in long-term-exposed animals. Target tissues were almost exclusively of epithelial origin, with the bile duct epithelium being the most susceptible to chronic exposure to all PAH fractions, and with germ cells being the second most responsive cells. Significantly higher incidences of neoplasms were observed with increasing PAH concentration and exposure duration. The most severe carcinogenic effects were induced by dietary exposure to HO compared to exposure to LO or PY (45, 30 and 7 %, respectively, after 9 to 10 months of exposure to an intermediate concentration of PAHs). In contrast, earliest carcinogenic effects were detected as soon as 3 mpf after exposure to LO, including the lowest concentration, or to PY. PAH bioactivation and genotoxicity in blood was assessed by ethoxyresorufin-O-deethylase activity quantification and comet and micronuclei assays, respectively, but none of these were positive. Chronic dietary exposure of zebrafish to PAH mixtures results in carcinogenotoxic events that impair survival and physiology of exposed fish.

The GeoFlow experiment focus on convective flows in rotating spherical shells influenced by a central force field. To eliminate the unidirectional acceleration due to gravity on earth, these long-time experiments require microgravity environment on the International Space Station. While recent results of accompanying numerics are presented in [1, 2], here we present the actual status of experiment preparation.

BackgroundRecent evolution in the understanding of rheumatoid arthritis (RA) mechanisms is the role of antibodies directed against citrullinated (cit) proteins (ACPAs). The shared epitope (SE) on the MHC class II is the main genetic risk factor of RA and favors presence of ACPAs. Mouse models dependent on cit peptides immunization require transgenic expression of the SE and are controversial. Non-human primates are ideal to study the interaction between ACPA and RA since 8% carry, similarly to humans, the SE called the H6 haplotype.ObjectivesThe goal of this study was to develop a new animal model of RA based on immunization of genetically predisposed macaques against cit peptides to generate an ACPA-mediated model of arthritis.MethodsSix macaques were intra dermally (ID) immunized with 4 peptides: vimentin (59–71) and (66–78), α fibrinogen (79–91) and aggrecan (89–103). H6 animals were immunized with either cit (n=2) or arginine (arg) (n=2) containing peptides. Two non H6 animals were immunized with cit peptides. These peptides are known to induce a T cell response in RA patients carrying the SE. T-cell response was assessed with Interferon γ ELISPOT and B-cell response by ELISA. An intra articular (IA) boost was done 30 weeks after initial immunization with either incomplete Freud's adjuvant (IFA) alone, IFA and cit peptides and IFA plus non relevant peptides.ResultsIn the macaques, the T-cell response was specific to cit or arg peptides (depending on the peptides used for immunization). Surprisingly, the presence of the H6 epitope did not influence the response. Conversely the antibodies generated in response to the peptides were cross-reactive between the cit and arg peptides. Since no clinical response was observed, an IA boost was performed with the same 4 cit peptides and IFA adjuvant. This led to a prolonged neutrophil-rich mono-arthritis preferentially in H6 animals (Figure). Conversely, animals boosted with IFA alone only or with IFA plus myelin oligodendrocyte glycoprotein (MOG) peptides and previously immunized with MOG peptides presented with a transient mono-arthritis. Histological analysis revealed a local mononuclear infiltrate in one of the two animals that had prolonged knee monoarthritis. There was no clinical polyarthritis but 2 animals displayed synovial proliferation in 1 MCP and 1 MTP, respectively.ConclusionsImmunization of macaques with cit peptides, then IA boost with the same cit peptides plus IFA, induced a prolonged monoarthritis. Shared epitope bearing did not restrict the T-cell response but seemed to favor the prolonged swelling after the IA boost. Neutrophil infiltration of the joint occurred similarly to what is seen in RA. Further use of neutrophil chemo-attractant might lead to a poly-articular disease. This macaque model of RA appears unique to study the events occurring during the pre-clinical phase of RA.Disclosure of InterestNone declared

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that induces in humans a disease characterized by fever, rash, and pain in muscles and joints. The recent emergence or reemergence of CHIKV in the Indian Ocean Islands and India has stressed the need to better understand the pathogenesis of this disease. Previous CHIKV disease models have used young or immunodeficient mice, but these do not recapitulate human disease patterns and are unsuitable for testing immune-based therapies. Herein, we describe what we believe to be a new model for CHIKV infection in adult, immunocompetent cynomolgus macaques. CHIKV infection in these animals recapitulated the viral, clinical, and pathological features observed in human disease. In the macaques, long-term CHIKV infection was observed in joints, muscles, lymphoid organs, and liver, which could explain the long-lasting CHIKV disease symptoms observed in humans. In addition, the study identified macrophages as the main cellular reservoirs during the late stages of CHIKV infection in vivo. This model of CHIKV physiopathology should allow the development of new therapeutic and/or prophylactic strategies.

Chikungunya virus (CHIKV) is a mosquito transmitted alphavirus associated with a robust systemic infection and an acute inflammatory rheumatic disease. A high fiber diet has been widely promoted for its ability to ameliorate inflammatory diseases. Fiber is fermented in the gut into short chain fatty acids such as acetate, propionate, and butyrate, which enter the circulation providing systemic anti-inflammatory activities. Herein we show that mice fed a high fiber diet show a clear exacerbation of CHIKV arthropathy, with increased edema and neutrophil infiltrates. RNA-Seq analyses illustrated that a high fiber diet, in this setting, promoted a range of pro-neutrophil responses including Th17/IL-17. Gene Set Enrichment Analyses demonstrated significant similarities with mouse models of inflammatory psoriasis and significant depression of macrophage resolution phase signatures in the CHIKV arthritic lesions from mice fed a high fiber diet. Supplementation of the drinking water with butyrate also increased edema after CHIKV infection. However, the mechanisms involved were different, with modulation of AP-1 and NF-κB responses identified, potentially implicating deoptimization of endothelial barrier repair. Thus, neither fiber nor short chain fatty acids provided benefits in this acute infectious disease setting, which is characterized by widespread viral cytopathic effects and a need for tissue repair.