A Feed-Forward Circuit Linking Wingless, Fat-Dachsous Signaling, and the Warts-Hippo Pathway to Drosophila Wing Growth

The secreted morphogen Wingless promotes Drosophila wing growth by fueling a wave front of Fat-Dachsous signaling that recruits new cells into the wing primordium

Incidence of Syndromes Associated With Frontotemporal Lobar Degeneration in 9 European Countries

Importance Diagnostic incidence data for syndromes associated with frontotemporal lobar degeneration (FTLD) in multinational studies are urgent in light of upcoming therapeutic approaches.Objective To assess the incidence of FTLD across Europe.Design, Setting, and Participants The Frontotemporal Dementia Incidence European Research Study (FRONTIERS) was a retrospective cohort study conducted from June 1, 2018, to May 31, 2019, using a population-based registry from 13 tertiary FTLD research clinics from the UK, the Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy and including all new FTLD-associated cases during the study period, with a combined catchment population of 11 023 643 person-years. Included patients fulfilled criteria for the behavioral variant of frontotemporal dementia (BVFTD), the nonfluent variant or semantic variant of primary progressive aphasia (PPA), unspecified PPA, progressive supranuclear palsy, corticobasal syndrome, or frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Data were analyzed from July 19 to December 7, 2021.Main Outcomes and Measures Random-intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity.Results Based on 267 identified cases (mean [SD] patient age, 66.70 [9.02] years; 156 males [58.43%]), the estimated annual incidence rate for FTLD in Europe was 2.36 cases per 100 000 person-years (95% CI, 1.59-3.51 cases per 100 000 person-years). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71 years, with 13.09 cases per 100 000 person-years (95% CI, 8.46-18.93 cases per 100 000 person-years) among men and 7.88 cases per 100 000 person-years (95% CI, 5.39-11.60 cases per 100 000 person-years) among women. Overall, the incidence was higher among men (2.84 cases per 100 000 person-years; 95% CI, 1.88-4.27 cases per 100 000 person-years) than among women (1.91 cases per 100 000 person-years; 95% CI, 1.26-2.91 cases per 100 000 person-years). BVFTD was the most common phenotype (107 cases [40.07%]), followed by PPA (76 [28.46%]) and extrapyramidal phenotypes (69 [25.84%]). FTD-ALS was the rarest phenotype (15 cases [5.62%]). A total of 95 patients with FTLD (35.58%) had a family history of dementia. The estimated number of new FTLD cases per year in Europe was 12 057.Conclusions and Relevance The findings suggest that FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD incidence may contribute to appropriate health and social care planning and in the design of future clinical trials.Peer reviewe

Predictors of Care Home Admission and Survival Rate in Patients With Syndromes Associated With Frontotemporal Lobar Degeneration in Europe

Background and Objectives Data on care home admission and survival rates of patients with syndromes associated with frontotemporal lobar degeneration (FTLD) are limited. However, their estimation is essential to plan trials and assess the efficacy of intervention. Population-based registers provide unique samples for this estimate. The aim of this study was to assess care home admission rate, survival rate, and their predictors in incident patients with FTLD-associated syndromes from the European FRONTIERS register-based study. Methods We conducted a prospective longitudinal multinational observational registry study, considering incident patients with FTLD-associated syndromes diagnosed between June 1, 2018, and May 31, 2019, and followed for up to 5 years till May 31, 2023. We enrolled patients fulfilling diagnosis of the behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS), and FTD with motor neuron disease (FTD-MND). Kaplan-Meier analysis and Cox multivariable regression models were used to assess care home admission and survival rates. The survival probability score (SPS) was computed based on independent predictors of survivorship. Results A total of 266 incident patients with FTLD were included (mean age ± SD = 66.7 ± 9.0; female = 41.4%). The median care home admission rate was 97 months (95% CIs 86–98) from disease onset and 57 months (95% CIs 56–58) from diagnosis. The median survival was 90 months (95% CIs 77–97) from disease onset and 49 months (95% CIs 44–58) from diagnosis. Survival from diagnosis was shorter in FTD-MND (hazard ratio [HR] 4.59, 95% CIs 2.49–8.76, p &lt; 0.001) and PSP/CBS (HR 1.56, 95% CIs 1.01–2.42, p = 0.044) compared with bvFTD; no differences between PPA and bvFTD were found. The SPS proved high accuracy in predicting 1-year survival probability (area under the receiver operating characteristic curve = 0.789, 95% CIs 0.69–0.87), when defined by age, European area of residency, extrapyramidal symptoms, and MND at diagnosis. Discussion In FTLD-associated syndromes, survival rates differ according to clinical features and geography. The SPS was able to predict prognosis at individual patient level with an accuracy of;80% and may help to improve patient stratification in clinical trials. Future confirmatory studies considering different populations are needed.</p

A unified mechanism for the control of Drosophila wing growth by the morphogens Decapentaplegic and Wingless.

Development of the Drosophila wing-a paradigm of organ development-is governed by 2 morphogens, Decapentaplegic (Dpp, a BMP) and Wingless (Wg, a Wnt). Both proteins are produced by defined subpopulations of cells and spread outwards, forming gradients that control gene expression and cell pattern as a function of concentration. They also control growth, but how is unknown. Most studies have focused on Dpp and yielded disparate models in which cells throughout the wing grow at similar rates in response to the grade or temporal change in Dpp concentration or to the different amounts of Dpp "equalized" by molecular or mechanical feedbacks. In contrast, a model for Wg posits that growth is governed by a progressive expansion in morphogen range, via a mechanism in which a minimum threshold of Wg sustains the growth of cells within the wing and recruits surrounding "pre-wing" cells to grow and enter the wing. This mechanism depends on the capacity of Wg to fuel the autoregulation of vestigial (vg)-the selector gene that specifies the wing state-both to sustain vg expression in wing cells and by a feed-forward (FF) circuit of Fat (Ft)/Dachsous (Ds) protocadherin signaling to induce vg expression in neighboring pre-wing cells. Here, we have subjected Dpp to the same experimental tests used to elucidate the Wg model and find that it behaves indistinguishably. Hence, we posit that both morphogens act together, via a common mechanism, to control wing growth as a function of morphogen range

Allogeneic hematopoietic stem cell transplantation may restore gluten tolerance in patients with celiac disease

We report on 2 patients affected by both celiac disease (CD) and \u3b2-thalassemia major who underwent successful myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for the latter condition. After HSCT, the introduction of a gluten-containing diet did not cause the reappearance of clinical, serological, and histological markers of CD in up to 5 years of follow-up. After transplantation, in both patients, dendritic cells and regulatory FoxP3T cells showed a recovery of normal values and no proliferative T-cell response upon gliadin stimulation was found. These data suggest that allogeneic HSCT may lead to induction of gluten tolerance in patients with CD

A multicentre, multinational, prospective, observational registry study of defibrotide in patients diagnosed with veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation: an EBMT study

International audienc

A multicenter, multinational, prospective observational registry study of defibrotide in patients diagnosed with severe veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after hematopoietic cell transplantation (HCT)

Severe hepatic VOD/SOS is a potentially life-threatening complication of HCT conditioning that may also develop after high-dose chemotherapy. The most severe form of VOD/SOS is often accompanied by multi-organ failure (MOF) and is associated with a mortality rate of &gt;80% when managed with supportive care alone. As part of the marketing authorization in Europe, there was an obligation to set up a disease registry of patients with severe VOD/SOS post-HCT who were treated with defibrotide. The goal of this registry was to collect safety and outcome data and assess patterns of defibrotide utilization in the post-approval setting. This multicenter, multinational, prospective observational study (NCT03032016) was performed by the European Society for Blood and Marrow Transplantation (EBMT). The study included patients with severe VOD/SOS post-HCT who were treated with defibrotide and enrolled from April 2015 to July 2018. Participating centers were members of the EBMT. Physicians registered patients diagnosed with severe VOD/SOS, as assessed by the investigator using classical/standard criteria (including but not limited to hyperbilirubinemia, hepatomegaly, ascites, and weight gain &gt;5%), who consented to participate in the study. In addition, patients who were prescribed defibrotide for purposes other than the approved indication (eg, VOD/SOS prophylaxis, treatment of non-severe VOD/SOS or thrombotic microangiopathy) and consented to participate were registered and information collected. There were no specific exclusion criteria; however, treating physicians were alerted to contraindications, special warnings, and precautions detailed in the defibrotide summary of product characteristics. After inclusion, patient information was collected from participating centers at 100 days, 6 months, and 12 months post-HCT. The primary objective was to assess the incidence of specific serious adverse events (SAEs) of interest, which were hemorrhage and site of bleeding, hypotension, coagulopathy, allergic or hypersensitivity reactions, injection-site reaction, infection and septicemia, and thromboembolic events. Secondary endpoints included Day 100 survival, and overall rate of VOD/SOS (and MOF, if present) resolution (based on standard criteria). Summary statistics were calculated for baseline data and safety variables; outcome analyses are descriptive. Here we report an analysis of data with a cutoff of June 18, 2019. Database lock is planned for October 2019, and the presentation will be updated to include the final data. A total of 61 patients with severe VOD/SOS were included; MOF was diagnosed at registration in 34 (56%) patients. The median age of patients with severe VOD/SOS was 14.4 (range: 0-68) years, 34 (56%) aged &lt;18 years and 27 (44%) aged 6518 years. A total of 54 (89%) patients received allogeneic HCT. Primary diseases included acute myeloid leukemia (26%), acute lymphoid leukemia (13%), solid tumor (12%), and myelodysplastic syndrome (8%). The median length of defibrotide exposure was 17 (IQR: 11-25) days. An SAE of interest occurred in 19 (31%; 95% confidence interval [CI]: 20%-43%) patients with severe VOD/SOS. The most common SAEs of interest by category were infection (n = 13 [21%; 95% CI: 11%-32%]) and bleeding events (n = 8 [13%; 95% CI: 5%-22%]). The most common individual SAEs of interest ( 655% of patients) were pneumonia (8%), gastrointestinal bleeding (8%), and sepsis (5%). Death occurred in 30 (49%) patients within 1 year, with VOD/SOS indicated as a cause of death in 13/30 (43%) patients. The Kaplan-Meier-estimated survival rate at Day 100 for patients diagnosed with severe VOD/SOS post-HCT who were treated with defibrotide was 74% (95% CI: 61%-83%). At latest follow-up, the survival rate was 51%, with median Kaplan-Meier-estimated survival post-HCT not yet reached. VOD/SOS resolved in 46 (75%) patients; the cumulative rate of VOD/SOS resolution at Day 100 was 87% (95% CI: 72%-94%). Resolution of MOF was achieved in 19/34 (56%) patients who had MOF at VOD/SOS diagnosis. In conclusion, among patients with severe VOD/SOS post-HCT (with/without MOF), the incidence of SAEs of interest was consistent with that observed in previous defibrotide clinical trials. Treatment with defibrotide resulted in high rates of Day 100 survival and VOD/SOS resolution

Significance of Degree of HLA Disparity Using T-cell Replete Peripheral Blood Stem Cells From Haploidentical Donors With Posttransplantation Cyclophosphamide in AML in First Complete Hematologic Remission: A Study of the Acute Leukemia Working Party of the EBMT

Availability of haploidentical donors has broadened utilization of allogeneic hematopoietic cell transplantation (allo-HCT). Peripheral blood stem cells (PBSC) are being used with increased frequency in haploidentical allo-HCT. We evaluated extent of HLA disparity (2–3/8 versus 4/8 HLA antigen mismatches) on post-allograft outcomes when using T-cell replete PBSC from haploidentical donors for acute myeloid leukemia in first complete remission. Primary objectives entailed assessing cumulative incidence of grade 2–4 acute graft-versus-host disease (GVHD) and chronic GVHD (any grade). A total of 645 patients received a haploidentical allo-HCT from a donor with either 2–3 of 8 HLA antigen mismatches (n = 180) or with 4 of 8 HLA antigen mismatches (n = 465). Presence of 2–3 of 8 versus 4 of 8 HLA mismatches did not affect the incidence of acute GVHD (grade 2–4) and chronic GVHD (any grade). Overall survival (OS), leukemia-free survival (LFS) relapse incidence (RI), nonrelapse mortality and the composite endpoint of GVHD-free relapse-free survival were also similar among the groups. Pertaining to HLA-B leader matching effect, our analysis did not discern any difference in aforementioned post-allograft outcomes for this variable. However, in univariate analysis, absence of an antigen mismatch in HLA-DPB1 showed a trend for better OS. Notwithstanding inherent limitations associated with registry data, our results did not show an advantage of selecting a haploidentical donor with 2–3 of 8 HLA antigen mismatches over one with 4 of 8 HLA antigen mismatches when using PBSC as the cell source. Adverse cytogenetics remains a major adverse determinant of inferior OS and LFS and a higher RI. Using reduced-intensity conditioning yielded worse OS and LFS

Risk factors and outcomes according to age at transplantation with an HLA-identical sibling for sickle cell disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for sickle cell disease (SCD).41 Several barriers prevent its widespread application, including the lack of a suitable donor, risk of early and late onset of regimen-related toxicities, rejection and mortality. Despite these limitations, the number of transplants for hemoglobinopathies has been increasing in the last decade. The overall probability of survival (OS) for patients with SCD transplanted with a human lymphocyte antigen (HLA)- identical sibling graft ranges between 91 and 100% with an event-free survival (EFS) of 73-100%.3 A controversial issue is the ideal age to perform HSCT in SCD patients. In fact, whilst early age HSCT could prevent SCD-related organ damage, resulting in better patient outcomes, the emergence of new available SCD supportive care, promising curative therapies could justify not proceeding with HSCT in certain cases [...