Early anteroposterior regionalisation of human neural crest is shaped by a pro-mesodermal factor

The neural crest (NC) is an important multipotent embryonic cell population and its impaired specification leads to various developmental defects, often in an anteroposterior (A-P) axial level-specific manner. The mechanisms underlying the correct A-P regionalisation of human NC cells remain elusive. Recent studies have indicated that trunk NC cells, the presumed precursors of childhood tumour neuroblastoma, are derived from neuromesodermal-potent progenitors of the postcranial body. Here we employ human embryonic stem cell differentiation to define how neuromesodermal progenitor (NMP)-derived NC cells acquire a posterior axial identity. We show that TBXT, a pro-mesodermal transcription factor, mediates early posterior NC/spinal cord regionalisation together with WNT signalling effectors. This occurs by TBXT-driven chromatin remodelling via its binding in key enhancers within HOX gene clusters and other posterior regulator-associated loci. This initial posteriorisation event is succeeded by a second phase of trunk HOX gene control that marks the differentiation of NMPs toward their TBXT-negative NC/spinal cord derivatives and relies predominantly on FGF signalling. Our work reveals a previously unknown role of TBXT in influencing posterior NC fate and points to the existence of temporally discrete, cell type-dependent modes of posterior axial identity control

CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS: THE REAL LIFE EXPERIENCE OF RETE EMATOLOGICA PUGLIESE (REP)

Background: Carfilzomib, lenalidomide and dexamethasone (KRd) has been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. However, its effectiveness and safety profile in real clinical practice should be further assessed. Aims: We retrospectively evaluated 120 consecutive RRMM patients treated with KRd, in 9 hematology departments of Rete Ematologica Pugliese (REP), with the aim to evaluate the efficacy and safety with KRd treatment in a real world setting. Methods: Between December of 2015 and August 2018,120 RRMM patients were analyzed.The patients’ baseline characteristics are presented in Table 1. Median patient’s age was 66 years and 41 patients(34%) were older than 70 years. The median number of previous treatment lines was 1 (range 1–11). The 94% of the patients had been already treated with bortezomib-based regimens and 33% with both lenalidomide- and bortezomib-based regimens. Moreover, half of the patients (52%) had a previous autologous stem cell transplant. The median time from the diagnosis to start of treatment with KRd was 40 months (range 5–295) and 30 patients were treated with KRd early (≤18 months from diagnosis).Disease status at the start of treatment with KRd was refractory in 33 patients(29%) and 13 patients(12%) were refractory to lenalidomide. Twenty-four patients(21%) were refractory at last therapy before KRd enrollment. Results: The overall response rate (ORR) was 84%(n = 93),with 23%(25) complete response (CR) and 50%(55) very good partial response(VGPR).The median duration of response was 12,9 months (range, 3,33– 27,7). ORR was higher in patients relapsed after a previous autologous transplant (ASCT;56% vs 37% in those relapsed without prior ASCT;p 0,05).Patients treated in late relapse had a better ORR (44%) vs those in early relapse (19%; p 0,02). After a median follow-up of 13,4 months, median PFS was not reached (NR) and 2y-PFS was 61%, Figure 1. PFS was longer in responding patients (achieving at least PR) to those with less than PR (median PFS NR vs 4,9 months;p 0,0001).Median PFS in patients relapsed after a prior ASCT was NR vs 20 months in those without prior ASCT, (p 0,002).Patients achieving ASCT after KRD had a better PFS in confront to those without ASCT (median NR vs 9 months, p 0,001).Several baseline patient characteristics, such as the III ISS scoring, older age, prior exposure to lenalidomide and early relapse were found to negatively impact PFS.Twenty-eight patients(24%) performed 4 KRd cycles as bridge treatment to ASCT. The 64% of patients reached a VGPR and 67% received ASCT, with 9 upgraded from VGPR to complete response (CR) after ASCT.The treatment discontinuation rate due to adverse events (AEs) was 13%, most commonly related to lenalidomide(8%). KRd dose reduction was necessary in 11% of patients (2,5% for carfilzomib and 8% for lenalidomide).The most frequent AE was neutropenia(43%) and anemia (41%). Infections occurred in 10% of patients.Adverse Cardiovascular toxicity (Atrial fibrillation and pulmonary hypertension)occurred in 8% of patients. Summary/Conclusion: Our analysis confirmed that KRd is effective in RRMM patients. It is well tolerated and applicable to the majority of patients outside clinical trials. A longer PFS was shown in patients 24th Congress of the European Hematology Association 276 | 2019;3:S1 achieving at least a partial response (PR), relapsing after previous ASCT and in those with the possibility to perform ASCT after KRd treatment. Accordingly,KRd should be used as an optimal bridge regimen to ASCT. Previous ASCT should not hamper the option for KRd therap

The Financial Feasibility Analysis of Urban Transformation Projects: An Application of a Quick Assessment Model

In the field of urban planning processes, the territorial redevelopment initiatives are important for the sustainable development of the cities. With reference to a real case study in the city of Pontedera (Italy), the aim of the present work is to highlight the usefulness of the Cost-Volume Profit Analysis (CVPA) as a tool to support the decisions of the public and private operators involved in three urban redevelopment initiatives. Specifically, for each identified transformation plots, two scenarios have been analyzed, by considering for each one all the building rights allowed by the General Regulatory Plan (GRP) of the city, and the requests of public and private subjects involved. The results achieved prove the inadequacy and rigidity of the forecasts of the GRP which, therefore, need to be checked in advance to avoid the expenditure of public money. In this way, the proposed model allows the public subject to correctly calibrate the extent and type of requests to be made to the private entrepreneur, who will be able to verify its own financial balance sheet and its expected amount of revenues and costs. The implemented methodology can be a useful support for the municipal administration in order to favor a quick financial assessment and to activate a negotiation on the building parameters of the different analyzed interventions

Ecosystem Services and Land Take. A Composite Indicator for the Assessment of Sustainable Urban Projects

The worrying levels of land take and insufficient ecosystem services related to phenomena of uncontrolled urban expansion in the cities force many countries far away from achieving Sustainable Development Goals of Agenda 2030. It is necessary to promote strategies which lead to effective and efficient measures in the perspective of sustainable development.The work aim is to propose an evaluation protocol useful to support public and private subjects for sustainable practices in urban contexts. Depending on the types of use and land cover envisaged, the implementation of the proposed methodological framework allows for the definition of a Composite Indicator (CI) to measure the urban environmental and economic sustainability level. The proposed CI expresses qualitatively and quantitatively the socio-economic and environmental impact (trade-off) that single initiative generates in the reference context in terms of ecosystem services as a function of the land use change between ex-ante and ex-post phases of the urban transformation process.Multi-parameter methodological approach by a sequence of logicaloperational phases that lead to the definition of the CI is proposed. Steps of the proposed method are characterized by the algebraic structures typical of the Benefit of Doubt Approach (BDA) and Goal programming principles. Testing of the proposed protocol for CI construction is in progress

Public-Private Negotiation of the Increase in Land or Property Value by Urban Variant: An Analytical Approach Tested on a Case of Real Estate Development

The insufficiency of public resources in Europe, which increased due to the debt crisis of 2010, has raised the need for combined financing forms to activate urban settlement transformation processes. Among these is the partial recapture of surplus value generated by interventions that derogate from urban planning tools as a regulation form of the differential rent phenomenon. This form of financing recalls the concept of land value recapture; it consists of an extraordinary charge of urbanisation (ECU) paid to policymakers. In Italy, the national law (2014) assigns responsibility for ECU determination to local decision-makers. Their plurality of operational guidelines are generally inspired by the transformation value criterion, and are sometimes methodologically incoherent and dispersive in their modus operandi. To support policymakers in the programming of public works within the limits of their available financial resources, the aim of the present work is to test a coherent, rational and applicable procedure in the field of estimation in order to analytically determine the "surplus value " generated by the intervention ante and post urban variant. The proposed procedural model is based on the structural characterisation of multiple methodologies used in practice and in the literature. The procedure was tested on a case study in the Italian context of Rome City. The results deduced from its implementation clarify that the ECU evaluation must also appropriately weigh the mutual benefits according to the "timing " and "riskiness " of the investment

A Methodological Approach Based on the Choquet Integral for Sustainable Valuations

Several methods and operational tools for assessing the sustainability and corresponding aspects can be identified in the current literature. At international level, the use of synthetic indices is clearly established through analytical indicators capable of expressing multiple aspects from an economic, social and environmental perspective. By a literature review, the construction of indices through a multi-criteria approach can be placed in the weights assignment and in construction processes based on the geometric and arithmetic average of values. The allocation of appropriate weights to performance indicators lacks, in particular, an objectivemethodology and subjective elements linked, e.g., to the decision-makers involved and corresponding interests. This research aims to describe a methodological frame for indices constructing through the multi-criteria approach of the Choquet Integral. The use of Choquet's integral supports the evaluations of multiple aspects of sustainability as monitoring of the relative unbalanced values, and the weights assignment occurs through analytical functions well-established, as the Shapley function

The Effects of Covid-19 Pandemic on the Housing Market: A Case Study in Rome (Italy)

The present study is part of a wider research line focused on the analysis of the effects caused by the pandemic of the Coronavirus disease (Covid-19) on the Italian residential property market. The paper aims to propose a methodology for the assessment of the effects of this abnormal event on the housing price mechanisms. The research could be an operational support for the Public Administration and private investors in their decision making processes. In particular, with reference to the city of Rome (Italy), two datasets of residential properties have been collected and processed through an econometric technique, in order to identify the variations occurred in terms of market appreciation for specific housing factors. The outputs highlight changes in market demand concerning a preference for outdoor spaces, both condominiums and private (terraces and balconies) and for properties located in peripheral areas of the city

Testing a dual isotope model to track carbon and water gas exchanges in a Mediterranean forest

Due to climate change, drier summers have been observed over the last ten years in Mediterranean areas. Increasing drought levels may have a different weight in influencing the stomatal versus photosynthetic activity of forests, altering the water-use efficiency (i.e.i.e. i.e., WUE, the amount of carbon gain per water lost) and, consequently, the global carbon balance. By combining leaf gas exchanges and leaf carbon/oxygen isotope measurements, we tested under Mediterranean conditions a semi-quantitative dual isotope model to track adjustments in stomatal conductance (gs) and maximum CO2 assimilation at saturating light (Amaxmaxmax) in response to changes in air and soil water availability. The experiment was established at Allumiere site (Rome, Italy) over the course of two consecutive years. There, we modified the amount of precipitation reaching the soil on water depleted (D) and watered (W) replicate plots (~100 m2) of an Arbutus unedoArbutus unedoArbutus unedoArbutus unedoArbutus unedoArbutus unedoArbutus unedoArbutus unedoArbutus unedoArbutus unedoArbutus unedoArbutus unedoArbutus unedo L. forest using a system of rain gutters and sprinklers, respectively. Changes in soil water availability affected gs and Amaxmaxmax in parallel. As an application of the model, we found that, in response to reduced air and soil water availability, constant carbon (δ1313C) and increasing oxygen (δ1818O) isotope values were consistent with a parallel decline of either gs and Amaxmaxmax. As a result of parallel decline, WUE did not differ or only slightly differed between treatments, in contrast with most of the studies that found a wide-spread increase of WUE in response to enhanced drought. This study highlights the potentiality of the dual isotope model to provide insights of forest ecosystem functioning in Mediterranean environments