Les atteintes dermatologiques infectieuses et réflexes liées à un foyer bucco-dentaire chronique (mise au point illustrée)

Le chirurgien-dentiste peut être consulté par un patient à la demande d un dermatologue dans le cadre d une recherche de foyers infectieux dentaires qui seraient à l origine d une pathologie cutanée. Les foyers infectieux bucco-dentaires chroniques peuvent être à l origine de manifestations à distance cutanées s ils ne sont pas diagnostiqués et/ou négligés, le plus souvent sur terrain affaibli mais, parfois aussi, chez des individus immunocompétents. Les processus d action à distance des foyers dentaires sont la dissémination microbienne par pyophagie, inhalation-aspiration, bactériémie, septicémie. Mais, l accent est porté aussi sur le rôle des toxines et le mécanisme neuro-végétatif. La preuve du lien entre infection dentaire et manifestation cutanée seconde est difficile à établir. Elle repose sur un examen odonto-stomatologique clinique et radiographique et sur la positivité de résultats d examens biologique et bactériologique. Bien souvent, seule la preuve thérapeutique (disparition totale de la maladie suite à une thérapeutique dentaire) viendra sanctionner l hypothèse étiologique dentaire, en l absence d autre étiologie. Un suivi bucco-dentaire restera indispensable pour prévenir la réapparition de la maladie. Une mise au point sera effectuée à partir d une discussion sur les données de la littérature récente et de deux cas cliniques rapportés au sein du service de dermatologie du Centre Hospitalier de Valenciennes.LILLE2-UFR Odontologie (593502202) / SudocLILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Successful treatment with yttrium-90 microspheres in a metastatic breast cancer patient and sclerosing cholangitis.

Breast cancer is the most common malignancy occurring in women worldwide. More than 90% of patients present with localized disease are treated with curative intent; however, recurrence can occur with development of metastatic lesions. Frequently associated with extra-hepatic lesions, localized treatments (surgery or stereotaxic body radiotherapy) are rarely proposed in liver lesions. Y radioembolization has extensively been evaluated in colorectal cancer, but its role in breast cancer with isolated liver metastases remains largely unknown. Pre-existing liver diseases are known risk factors for Y induced liver toxicity. Not considered as an excluding factor for this treatment, data are limited regarding its safe use with cholangitis. We report a successful control of liver metastases by Y radioembolization in a breast cancer patient

Generation of a Double KO Mouse by Simultaneous Targeting of the Neighboring Genes Tmem176a and Tmem176b Using CRISPR/Cas9: Key Steps from Design to Genotyping

International audienceThe CRISPR/Cas9 system has been tailored to a revolutionary genetic tool because of its remarkable simplicity and efficacy. While complex genome editing in the mouse since the 1990s has been dominated by the use of embryonic stem (ES) cells, CRISPR/Cas9 now offers a versatile and fast approach to precisely modify virtually any DNA regions directly in mouse zygotes. Yet, this relative simplicity does not preclude a conscientious preparatory work that is often neglected when initiating a project. Here, we describe the key steps leading to successful generation of a double knockout (KO) mouse by simultaneously targeting two homolog genes, Tmem176a and Tmem176b, which are located in the same genomic locus. Additionally, we show that similar efficiency can be obtained in a mixed genetic background or directly in the C57BL/6 inbred strain. Thus, presented as a detailed case study that should be helpful to the non-specialists, we focus on the genotyping strategy to anticipate the various possibilities

Long-lasting benefit on multimodal treatment combining osimertinib and stereotaxic radiotherapy for metastatic non-small cell lung cancer with the EGFR exon 20 insertion 773-774 HVdelinsLM: a case report.

A non-small-cell-lung-cancer patient with cerebral metastasis presenting an atypical exon 20 mutation in the EGFR gene had a long-lasting tumor cotrol on mulimodal treatment with osimertinib and stereotaxic radiotherapy on oligoprogressing lesions. Most exon-20 mutations are resistant to first, second and third generation EGFR-directed TKI. This case was discussed on our molecular tumour board. As the more specific exon-20 targeted therapies were not yet available and as sporadic short responses on the third generation EGFR-directed TKI, osimertinib had been described, the patient started osimertinib. She had a prolonged tumoral response on Osimertinib. The patient is still asymptomatic up to 32 months after initiating the medication. This case confirms that not all exon20 EGFR mutations are equal to osimertinib and that the localization of the exon 20 insertion mutation is probably important to consider when treating EGFR mutated NSCLC. The long-term clinical benefit can be maintained through stereotactic radiotherapy on focal progressive lesions

The Intracellular Ion flux mediated by TMEM176A and TMEM176B is involved in the regulation of Dendritic Cell Functions

International audienceThe regulation of immune cells by intracellular ion channels remains poorly explored. Here we investigated the role of two cation channels encoded by Tmem176a and Tmem176b that are highly expressed in myeloid cells in the immune system. To avoid any functional compensation, we generated double knock-out (DKO) mice, allowing simultaneous deletion of these two highly redundant and coregulated genes using the CRISPR-Cas9 system. The absence of Tmem176a/b significantly impacted antigen processing and presentation to CD4+ T cells in vivo and selectively altered cytokine production by dendritic cells (DCs). Using a novel real-time fluorescence-based system to analyze intracellular trafficking we found that both channels co-localized in highly dynamic post-Golgi vesicles preferentially interacting with, but not accumulating in, acidic organelles. Thus, these results highlight the importance of TMEM176A/B-mediated cation flux for the fine regulation of DC biology

The Intracellular Ion flux mediated by TMEM176A and TMEM176B is involved in the regulation of Dendritic Cell Functions

International audienceThe regulation of immune cells by intracellular ion channels remains poorly explored. Here we investigated the role of two cation channels encoded by Tmem176a and Tmem176b that are highly expressed in myeloid cells in the immune system. To avoid any functional compensation, we generated double knock-out (DKO) mice, allowing simultaneous deletion of these two highly redundant and coregulated genes using the CRISPR-Cas9 system. The absence of Tmem176a/b significantly impacted antigen processing and presentation to CD4+ T cells in vivo and selectively altered cytokine production by dendritic cells (DCs). Using a novel real-time fluorescence-based system to analyze intracellular trafficking we found that both channels co-localized in highly dynamic post-Golgi vesicles preferentially interacting with, but not accumulating in, acidic organelles. Thus, these results highlight the importance of TMEM176A/B-mediated cation flux for the fine regulation of DC biology

Role of the intracellular ion channels TMEM176A and TMEM176B in the immune system

International audienceIon channels represent attractive targets for the development of new therapies but still remain poorly studied in the immune system, in particular intracellular ion channels. In this work, we explored the role of two highly redundant ion channels named TMEM176A and TMEM176B that are intriguingly strongly expressed both in RORγt+ cells (ILC3, Th17) and immature dendritic cells. To investigate the role of these homologs and avoid any compensation effect, we generated a double KO (DKO) mouse using CRISPR-Cas9. Surprisingly, Tmem176a/b appeared dispensable for the function of RORγt+ cells and in the protective function of type 17 immunity during chemically-induced or infectious colitis. In contrast, antigen presentation by dendritic cells to CD4+ T cells through MHC II was selectively impaired in DKO mice. Using a real-time fluorescence-based system to analyze intracellular trafficking we found that both channels co-localized in highly dynamic post-Golgi vesicles preferentially interacting with, but not accumulating in, acidic organelles. These results indicate that TMEM176A/B ion channels play a predominant role in adaptive immunity as new intracellular components of the intracellular MHC II machinery

Teaching NeuroImages: Cytotoxic lesions of the corpus callosum in encephalopathic patients with COVID-19

International audienc

RORγt+ cells selectively express redundant cation channels linked to the Golgi apparatus

International audienceRetinoid-related orphan receptor gamma t (RORγt) is a master transcription factor central to type 17 immunity involving cells such as T helper 17, group 3 innate lymphoid cells or IL-17-producing γδ T cells. Here we show that the intracellular ion channel TMEM176B and its homologue TMEM176A are strongly expressed in these RORγt + cells. We demonstrate that TMEM176A and B exhibit a similar cation channel activity and mainly colocalise in close proximity to the trans-Golgi network. Strikingly, in the mouse, the loss of Tmem176b is systematically associated with a strong upregulation of Tmem176a. While Tmem176b single-deficiency has no effect on the course of experimental autoimmune encephalomyelitis, T cell or DSS-induced colitis, it significantly reduces imiquimod-induced psoriasis-like skin inflammation. These findings shed light on a potentially novel specific process linked to post-Golgi trafficking for modulating the function of RORγt + cells and indicate that both homologues should be simultaneously targeted to clearly elucidate the role of this intracellular ion flow

N-methyl-2-pyridone-5-carboxamide (2PY)—Major Metabolite of Nicotinamide: An Update on an Old Uremic Toxin

N-methyl-2-pyridone-5-carboxamide (2PY, a major metabolite of nicotinamide, NAM) was recently identified as a uremic toxin. Recent interventional trials using NAM to treat high levels of phosphorus in end-stage renal disease have highlighted new potential uremic toxicities of 2PY. In the context of uremia, the accumulation of 2PY could be harmful—perhaps by inhibiting poly (ADP-ribose) polymerase-1 activity. Here, we review recently published data on 2PY’s metabolism and toxicological profile