Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow-Turnover Airway Epithelium.

Epithelial lineages have been studied at cellular resolution in multiple organs that turn over rapidly. However, many epithelia, including those of the lung, liver, pancreas, and prostate, turn over slowly and may be regulated differently. We investigated the mouse tracheal epithelial lineage at homeostasis by using long-term clonal analysis and mathematical modeling. This pseudostratified epithelium contains basal cells and secretory and multiciliated luminal cells. Our analysis revealed that basal cells are heterogeneous, comprising approximately equal numbers of multipotent stem cells and committed precursors, which persist in the basal layer for 11 days before differentiating to luminal fate. We confirmed the molecular and functional differences within the basal population by using single-cell qRT-PCR and further lineage labeling. Additionally, we show that self-renewal of short-lived secretory cells is a feature of homeostasis. We have thus revealed early luminal commitment of cells that are morphologically indistinguishable from stem cells.This study was supported by the Medical Research Council (G0900424 to E.R.), European Union grant EuroSyStem (200720; FP7/2008), the Newton Trust (to E.R.), the Wellcome Trust (098357/Z/12/Z to B.D.S.). Core grants from the Wellcome Trust (092096) and Cancer Research UK (C6946/A14492).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.celrep.2015.06.01

Graves Hyperthyroidism After Stopping Immunosuppressive Therapy in Type 1 Diabetic Islet Cell Recipients With Pretransplant TPO Autoantibodies

OBJECTIVE — After an initially successful islet cell transplantation, a number of patients return to C-peptide negativity, and therefore immunosuppressive therapy is discontinued. Some are then found to have developed Graves disease. We examined the risk of Graves disease after immunosuppression. RESEARCHDESIGNANDMETHODS — Immunosuppressive therapy was stopped in 13 type 1 diabetic islet cell recipients who had received one course of antithymocyte globulin and maintenance doses of mycophenolate mofetil and a calcineurin inhibitor. None had a history of thyroid disease. RESULTS — In four patients, clinical Graves hyperthyroidism was observed within 21 months after discontinuation and 30–71 months after the start of immunosuppressive therapy. All four patients exhibited a pretransplant positivity for thyroid peroxidase (TPO) autoantibod-ies, while the nine others were TPO negative pre- and posttransplantation. CONCLUSIONS — Type 1 diabetic recipients of islet cell grafts with pretransplant TPO autoantibody positivity exhibit a high risk for developing Graves hyperthyroidism after immu-nosuppressive therapy is discontinued for a failing graft. Diabetes Care 32:1817–1819, 2009 I slet cell transplantation has beenshown to reproducibly achieve meta-bolic correction in nonuremic type 1 diabetic patients (1,2). However, in the years following transplantation, several of them return to C-peptide negativity and thus to a discontinuation of their immu-nosuppressive therapy (2)

Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland.

Recent lineage tracing studies have revealed that mammary gland homeostasis relies on unipotent stem cells. However, whether and when lineage restriction occurs during embryonic mammary development, and which signals orchestrate cell fate specification, remain unknown. Using a combination of in vivo clonal analysis with whole mount immunofluorescence and mathematical modelling of clonal dynamics, we found that embryonic multipotent mammary cells become lineage-restricted surprisingly early in development, with evidence for unipotency as early as E12.5 and no statistically discernable bipotency after E15.5. To gain insights into the mechanisms governing the switch from multipotency to unipotency, we used gain-of-function Notch1 mice and demonstrated that Notch activation cell autonomously dictates luminal cell fate specification to both embryonic and basally committed mammary cells. These functional studies have important implications for understanding the signals underlying cell plasticity and serve to clarify how reactivation of embryonic programs in adult cells can lead to cancer.Wellcome Trus

Les bulles « robustes »:Pourquoi il faut construire des logements en région parisienne

« Bulle » ou « pas bulle » ? La question taraude les observateurs et les acteurs du marché immobilier français. Nous examinons dans cet article les éléments empiriques et théoriques qui expliquent la hausse des prix récente et sa résistance aux retournements conjoncturels. En combinant la notion de bulle économique, les arguments de l’économie spatiale et une analyse d’économie politique, nous suggérons que la valorisation importante de l’immobilier en France est le résultat d’une logique rationnelle et conforte les intérêts des acteurs locaux. Dès lors, la forte valorisation peut être considérée comme une « bulle robuste », à même de résister à des chocs importants. Cette bulle organise un transfert intergénérationnel et peut avoir des effets positifs. Elle peut également renforcer la ségrégation spatiale, alimenter les inégalités territoriales et empêcher d’exploiter les économies d’agglomération possibles. L’analyse est détaillée sur la région Ile-de-France où ces phénomènes sont particulièrement marqués

Avelumab for advanced Merkel cell carcinoma in the Netherlands: a real-world cohort

Background Merkel cell carcinoma (MCC) is associated with high recurrence rates and poor survival when metastatic disease is present. The immune checkpoint inhibitor avelumab has shown high response rates (RRs) and durable responses in patients with advanced MCC (aMCC) in clinical trials. To date, only results from clinical trials, patients treated in an expanded access program and very small numbers of patients have been reported. In this study, detailed real-world efficacy and toxicity data of avelumab in patients with aMCC are reported. Methods Patients with aMCC treated in four dedicated referral centers in the Netherlands were analyzed from February 2017 until December 2019. Patients were included if they had received at least one administration of avelumab, regardless of previous lines of therapy. Patient data were collected retrospectively from patient records. Primary endpoints were response rate (RR) and duration of response (DOR). Secondary endpoints were progressionfree survival (PFS), overall survival (OS), and toxicity. Results Fifty-four patients received avelumab. Eight (15%) patients had locally advanced disease (laMCC). In 40 (74%) patients, avelumab was first-line treatment, these included all patients with laMCC. The median follow-up was 8.9 (range 0.5–35.9) months. RR was 57% (n=31) with 24% (n=13) of patients achieving a complete response. The median DOR was 8.4 (range 1.3–22.1) months and 23 (43%) patients had an ongoing response at the end of the study. The median PFS was 8.6 (95% CI 1.6–15.5) months, and the median OS was 25.8 (95% CI 9.1–42.4) months. Six (11%) patients experienced grade 3 toxicity. No grade 4–5 toxicity was seen. Conclusions In this real-world cohort, clinical efficacy and toxicity outcomes in clinical practice were in line with results from clinical trials and showed relatively high RRs and durable responses in patients with aMCC

HLA-A2–Matched Peripheral Blood Mononuclear Cells From Type 1 Diabetic Patients, but Not Nondiabetic Donors, Transfer Insulitis to NOD-scid/γcnull/HLA-A2 Transgenic Mice Concurrent With the Expansion of Islet-Specific CD8+ T cells

OBJECTIVE: Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing beta-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes. RESEARCH DESIGN AND METHODS: We adoptively transferred HLA-A2-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/gammac(null)/HLA-A*0201 (NOD-scid/gammac(null)/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/gammac(null)/A2 mice after transfer. RESULTS: Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/gammac(null)/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/gammac(null)/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2-matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8(+) T cells among the islet infiltrates. CONCLUSIONS: We show that insulitis is transferred to NOD-scid/gammac(null)/A2 mice that received HLA-A2-matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8(+) T cells are epitope-specific and produce interferon-gamma after in vitro peptide stimulation. This indicates that NOD-scid/gammac(null)/A2 mice transferred with HLA-A2-matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell-mediated responses in patients with type 1 diabetes