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IntroductionThe decisive key to disease-free survival in B-cell precursor acute lymphoblastic leukemia in children, is the combination of diagnostic timeliness and treatment efficacy, guided by accurate patient risk stratification. Implementation of standardized and high-precision diagnostic/prognostic systems is particularly important in the most marginalized geographic areas in Mexico, where high numbers of the pediatric population resides and the highest relapse and early death rates due to acute leukemias are recorded even in those cases diagnosed as standard risk.MethodsBy using a multidimensional and integrated analysis of the immunophenotype of leukemic cells, the immunological context and the tumor microenvironment, this study aim to capture the snapshot of acute leukemia at disease debut of a cohort of Mexican children from vulnerable regions in Puebla, Oaxaca and Tlaxcala and its potential use in risk stratification.Results and discussionOur findings highlight the existence of a distinct profile of ProB-ALL in children older than 10 years, which is associated with a six-fold increase in the risk of developing measurable residual disease (MRD). Along with the absence of CD34+ seminal cells for normal hematopoiesis, this ProB-ALL subtype exhibited several characteristics related to poor prognosis, including the high expression level of myeloid lineage markers such as MPO and CD33, as well as upregulation of CD19, CD34, CD24, CD20 and nuTdT. In contrast, it showed a trend towards decreased expression of CD9, CD81, CD123, CD13, CD15 and CD21. Of note, the mesenchymal stromal cell compartment constituting their leukemic niche in the bone marrow, displayed characteristics of potential suppressive microenvironment, such as the expression of Gal9 and IDO1, and the absence of the chemokine CXCL11. Accordingly, adaptive immunity components were poorly represented. Taken together, our results suggest, for the first time, that a biologically distinct subtype of ProB-ALL emerges in vulnerable adolescents, with a high risk of developing MRD. Rigorous research on potential enhancing factors, environmental or lifestyle, is crucial for its detection and prevention. The use of the reported profile for early risk stratification is suggested.

Objectives: Nothing is known about the interest of the combination of exercise tests to diagnose Lower-extremity Peripheral Artery Disease (LEPAD). The aim of this study was to assess if combining exercise testing criteria [post-exercise Ankle-Brachial Index (ABI) + exercise-oximetry (exercise-TcPO2)] improves the detection of lower limbs arterial stenoses as compared with post-exercise ABI using American Heart Association (AHA) criteria, or exercise-TcPO2 alone.Material and Methods: In a prospective monocentric study, consecutive patients with exertional-limb pain and normal resting-ABI referred to our vascular center (Rennes, France) were assessed from May 2016 to February 2018. All included patients had a computed tomography angiography (CTA), a resting-ABI, a post-exercise ABI and an exercise-TcPO2. AHA post-exercise criteria, new validated post-exercise criteria (post-exercise ABI decrease ≥18.5%, post-exercise ABI decrease

B-cell acute lymphoblastic leukemia (B-ALL) results from the expansion of malignant lymphoid precursors within the bone marrow (BM), where hematopoietic niches and microenvironmental signals provide leukemia-initiating cells (LICs) the conditions to survive, proliferate, initiate disease, and relapse. Normal and malignant lymphopoiesis are highly dependent on the BM microenvironment, particularly on CXCL12-abundant Reticular (CAR) cells, which provide a niche for maintenance of primitive cells. During B-ALL, leukemic cells hijack BM niches, creating a proinflammatory milieu incompetent to support normal hematopoiesis but favoring leukemic proliferation. Although the lack of a phenotypic stem cell hierarchy is apparent in B-ALL, LICs are a rare and quiescent population potentially responsible for chemoresistance and relapse. Here, we developed novel patient-derived leukemia spheroids (PDLS), an ex vivo avatar model, from mesenchymal stromal cells (MSCs) and primary B-ALL cells, to mimic specialized niche structures and cell-to-cell intercommunication promoting normal and malignant hematopoiesis in pediatric B-ALL. 3D MSC spheroids can recapitulate CAR niche-like hypoxic structures that produce high levels of CXCL10 and CXCL11. We found that PDLS were preferentially enriched with leukemia cells displaying functional properties of LICs, such as quiescence, low reactive oxygen species, drug resistance, high engraftment in immunodeficient mice, and long-term leukemogenesis. Moreover, the combination of PDLS and patient-derived xenografts confirmed a microenvironment-driven hierarchy in their leukemic potential. Importantly, transcriptional profiles of MSC derived from primary patient samples revealed two unique signatures (1), a CXCL12low inflammatory and leukemia expansion (ILE)-like niche, that likely supports leukemic burden, and (2) a CXCL11hi immune-suppressive and leukemia-initiating cell (SLIC)-like niche, where LICs are likely sustained. Interestingly, the CXCL11+ hypoxic zones were recapitulated within the PDLS that are capable of supporting LIC functions. Taken together, we have implemented a novel PDLS system that enriches and supports leukemia cells with stem cell features driven by CXCL11+ MSCs within hypoxic microenvironments capable of recapitulating key features, such as tumor reemergence after exposure to chemotherapy and tumor initiation. This system represents a unique opportunity for designing ex vivo personalized avatars for B-ALL patients to evaluate their own LIC pathobiology and drug sensitivity in the context of the tumor microenvironment.

BACKGROUND:The sensitivity and specificity of exercise testing have never been studied simultaneously against an objective quantification of arterial stenosis. Aims were to define the sensitivity and specificity of several exercise tests to detect peripheral artery disease (PAD), and to assess whether or not defined criteria defined in patients suspected of having a PAD show a difference dependent on the resting ABI. METHODS:In this prospective study, consecutive patients with exertional limb pain referred to our vascular center were included. All patients had an ABI, a treadmill exercise-oximetry test, a second treadmill test (both 10% slope; 3.2km/h speed) with post-exercise pressures, and a computed-tomography-angiography (CTA). The receiver-operating-characteristic curve was used to define a cut-off point corresponding to the best area under the curve (AUC; [CI95%]) to detect arterial stenosis ≥50% as determined by the CTA. RESULTS:Sixty-three patients (61+/-11 years-old) were included. Similar AUCs from 0.72[0.63-0.79] to 0.83[0.75-0.89] were found for the different tests in the overall population. To detect arterial stenosis ≥50%, cut-off values of ABI, post-exercise ABI, post-exercise ABI decrease, post-exercise ankle pressure decrease, and distal delta from rest oxygen pressure (DROP) index were ≤0.91, ≤0.52, ≥43%, ≥20mmHg and ≤-15mmHg, respectively (p0.91, cut-off values of post-exercise ABI decrease (AUC = 0.67[0.53-0.78]), and DROP (AUC = 0.67[0.53-0.78]) were ≥18.5%, and ≤-15mmHg respectively (p