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The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.

Haploidentical donors are now increasingly considered for transplantation in the absence of HLA-matched donors or when an urgent transplant is needed. Donor-specific anti-HLA antibodies (DSA) have been recently recognized as an important barrier against successful engraftment of donor cells, which can affect transplant survival. DSA appear more prevalent in this type of transplant due to higher likelihood of alloimmunization of multiparous females against offspring’s HLA antigens, and the degree of mismatch. Here we summarize the evidence for the role of DSA in the development of primary graft failure in haploidentical transplantation and provide consensus recommendations from the European Society for Blood and Marrow Transplant Group on testing, monitoring, and treatment of patients with DSA receiving haploidentical hematopoietic progenitor cell transplantation.

The number of HLA-haploidentical hematopoietic cell transplants continues to increase worldwide due to recent improvements in outcomes, allowing more patients with hematological malignancies and non-malignant disorders to benefit from this procedure and have a chance to cure their disease. Despite these encouraging results, questions remain as multiple donors are usually available for transplantation, and choosing the best HLA-haploidentical donor for transplantation remains a challenge. Several approaches to haploidentical transplantation have been developed over time and, based on the graft received, can be grouped as follows: T-cell depleted haploidentical transplants, either complete or partial, or with T-cell replete grafts, performed with post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, or G-CSF-primed bone marrow graft and enhanced GVHD prophylaxis. Carefully selecting the donor can help optimize transplant outcomes for recipients of haploidentical donor transplants. Variables usually considered in the donor selection include presence of donor-specific antibodies in the recipient, donor age, donor/recipient gender and ABO combinations, and immunogenic variables, such as natural killer cell alloreactivity or KIR haplotype. Here we provide a comprehensive review of available evidence for selecting haploidentical donors for transplantation, and summarize the recommendations from the European Society for Blood and Marrow Transplantation (EBMT) on donor selection for different transplant platforms.

Background Interest in value-based healthcare, generally defined as providing better care at lower cost, has grown worldwide, and learning health systems (LHSs) have been proposed as a key strategy for improving value in healthcare. LHSs are emerging around the world and aim to leverage advancements in science, technology and practice to improve health system performance at lower cost. However, there remains much uncertainty around the implementation of LHSs and the distinctive features of these systems. This paper presents a conceptual framework that has been developed in Canada to support the implementation of value-creating LHSs. Methods The framework was developed by an interdisciplinary team at the Institut national d’excellence en santé et en services sociaux (INESSS). It was informed by a scoping review of the scientific and grey literature on LHSs, regular team discussions over a 14-month period, and consultations with Canadian and international experts. Results The framework describes four elements that characterise LHSs, namely (1) core values, (2) pillars and accelerators, (3) processes and (4) outcomes. LHSs embody certain core values, including an emphasis on participatory leadership, inclusiveness, scientific rigour and person-centredness. In addition, values such as equity and solidarity should also guide LHSs and are particularly relevant in countries like Canada. LHS pillars are the infrastructure and resources supporting the LHS, whereas accelerators are those specific structures that enable more rapid learning and improvement. For LHSs to create value, such infrastructures must not only exist within the ecosystem but also be connected and aligned with the LHSs’ strategic goals. These pillars support the execution, routinisation and acceleration of learning cycles, which are the fundamental processes of LHSs. The main outcome sought by executing learning cycles is the creation of value, which we define as the striking of a more optimal balance of impacts on patient and provider experience, population health and health system costs. Conclusions Our framework illustrates how the distinctive structures, processes and outcomes of LHSs tie together with the aim of optimising health system performance and delivering greater value in health systems.

Delivery of recombinant proteins to therapeutic cells is limited by a lack of efficient methods. This hinders the use of transcription factors or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) ribonucleoproteins to develop cell therapies. Here, we report a soluble peptide designed for the direct delivery of proteins to mammalian cells including human stem cells, hard-to-modify primary natural killer (NK) cells, and cancer cell models. This peptide is composed of a 6x histidine-rich domain fused to the endosomolytic peptide CM18 and the cell penetrating peptide PTD4. A less than two-minute co-incubation of 6His-CM18-PTD4 peptide with spCas9 and/or asCpf1 CRISPR ribonucleoproteins achieves robust gene editing. The same procedure, co-incubating with the transcription factor HoxB4, achieves transcriptional regulation. The broad applicability and flexibility of this DNA- and chemical-free method across different cell types, particularly hard-to-transfect cells, opens the way for a direct use of proteins for biomedical research and cell therapy manufacturing.

Lck and Zap70, two non-receptor tyrosine kinases, play a crucial role in the regulation of membrane proximal TCR signaling critical for thymic selection, CD4/CD8 lineage choice and mature T cell function. Signal initiation upon TCR/CD3 and peptide/MHC interaction induces Lck-mediated phosphorylation of CD3 ITAMs. This is necessary for Zap70 recruitment and its phosphorylation by Lck leading to full Zap70 activation. In its native state Zap70 maintains a closed conformation creating an auto-inhibitory loop, which is relieved by Lck-mediated phosphorylation of Y315/Y319. Zap70 is differentially expressed in thymic subsets and mature T cells with CD8 T cells expressing the highest amount compared to CD4 T cells. However, the mechanistic basis of differential Zap70 expression in thymic subsets and mature T cells is not well understood. Here, we show that Zap70 is degraded relatively faster in DP and mature CD4 T cells compared to CD8 T cells, and inversely correlated with relative level of activated Zap70. Importantly, we found that Zap70 expression is negatively regulated by Lck activity: augmented Lck activity resulting in severe diminution in total Zap70. Moreover, Lck-mediated phosphorylation of Y315/Y319 was essential for Zap70 degradation. Together, these data shed light on the underlying mechanism of Lck-mediated differential modulation of Zap70 expression in thymic subsets and mature T cells.

Blueberries are a rich source of polyphenols, widely studied for the prevention or attenuation of metabolic diseases. However, the health contribution and mechanisms of action of polyphenols depend on their type and structure. Here, we evaluated the effects of a wild blueberry polyphenolic extract (WBE) ( Vaccinium angustifolium Aiton) on cardiometabolic parameters, gut microbiota composition and gut epithelium histology of high-fat high-sucrose (HFHS) diet-induced obese mice and determined which constitutive polyphenolic fractions (BPF) was responsible for the observed effects. To do so, the whole extract was separated in three fractions, F1) Anthocyanins and phenolic acids, F2) oligomeric proanthocyanidins (PACs), phenolic acids and flavonols (PACs degree of polymerization DP < 4), and F3) PACs polymers (PACs DP > 4) and supplied at their respective concentration in the whole extract. After 8 weeks, WBE reduced OGTT AUC by 18.3% compared to the HFHS treated rodents and the F3 fraction  contributed the most to this effect. The anthocyanin rich F1 fraction did not reproduce this response. WBE and the BPF restored the colonic mucus layer. Particularly, the polymeric PACs-rich F3 fraction increased the mucin-secreting goblet cells number. WBE caused a significant 2-fold higher proportion of Adlercreutzia equolifaciens whereas oligomeric PACs-rich F2 fraction increased by 2.5-fold the proportion of Akkermansia muciniphila . This study reveals the key role of WBE PACs in modulating the gut microbiota and restoring colonic epithelial mucus layer, providing a suitable ecological niche for mucosa-associated symbiotic bacteria, which may be crucial in triggering health effects of blueberry polyphenols.

Extracellular tannase Lactiplantibacillus plantarum -producing strains (TanA+) release bioactive metabolites from dietary tannins. However, there is a paucity of knowledge of TanA+ strains and their hydrolyzing capacities. This study aimed to shed light on the metabolic and genomic features of TanA+  L. plantarum strains and to develop a screening technique. The established spectrophotometric was validated by UPLC-UV-QToF. Eight of 115 screened strains harbored the tanA gene, and six presented TanA activity (PROBI S126, PROBI S204, RKG 1-473, RKG 1-500, RKG 2-219, and RKG 2-690). When cultured with tannic acid (a gallotannin), TanA+ strains released 3.2−11 times more gallic acid than a lacking strain (WCFS1) ( p  < 0.05). TanA+ strains with gallate decarboxylase (n = 5) transformed this latter metabolite, producing 2.2–4.8 times more pyrogallol than the TanA lacking strain ( p  < 0.05). However, TanA+ strains could not transform punicalagin (an ellagitannin). Genomic analysis revealed high similarity between TanA+ strains, as only two variable regions of phage and polysaccharide synthesis were distinguished. A phylogenetic analysis of 149 additional genome sequences showed that tanA  harboring strains form a cluster and present two bacteriocin coding sequences profile. In conclusion, TanA+  L. plantarum strains are closely related and possess the ability to resist and transform gallotannins. TanA can be screened by the method proposed herein.

The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase-independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression--but not activity--of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/β-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase-independent and PP2A-mediated inhibition of JAK2 and β-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1-positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/β-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and relieve lifelong patient dependence on TKIs.

The consumption of plant-based bioactive compounds modulates the gut microbiota and interacts with the innate and adaptive immune responses associated with metabolic disorders. The present study aimed to evaluate the effect of cranberry polyphenols (CP), rich in flavonoids, and agavins (AG), a highly branched agave-derived neo-fructans, on cardiometabolic response, gut microbiota composition, metabolic endotoxemia, and mucosal immunomodulation of C57BL6 male mice fed an obesogenic high-fat and high-sucrose (HFHS) diet for 9 weeks. Interestingly, CP+AG-fed mice had improved glucose homeostasis. Oral supplementation with CP selectively and robustly (five-fold) increases the relative abundance of Akkermansia muciniphila , a beneficial bacteria associated with metabolic health. AG, either alone or combined with CP (CP+AG), mainly stimulated the glycan-degrading bacteria Muribaculum intestinale , Faecalibaculum rodentium , Bacteroides uniformis , and Bacteroides acidifaciens. This increase of glycan-degrading bacteria was consistent with a significantly increased level of butyrate in obese mice receiving AG, as compared to untreated counterparts. CP+AG-supplemented HFHS-fed mice had significantly lower levels of plasma LBP than HFHS-fed controls, suggesting blunted metabolic endotoxemia and improved intestinal barrier function. Gut microbiota and derived metabolites interact with the immunological factors to improve intestinal epithelium barrier function. Oral administration of CP and AG to obese mice contributed to dampen the pro-inflammatory immune response through different signaling pathways. CP and AG, alone or combined, increased toll-like receptor (TLR)-2 ( Tlr2 ) expression, while decreasing the expression of interleukin 1ß (ILß1) in obese mice. Moreover, AG selectively promoted the anti-inflammatory marker Foxp3 , while CP increased the expression of NOD-like receptor family pyrin domain containing 6 ( Nlrp6 ) inflammasome. The intestinal immune system was also shaped by dietary factor recognition. Indeed, the combination of CP+AG significantly increased the expression of aryl hydrocarbon receptors ( Ahr ). Altogether, both CP and AG can shape gut microbiota composition and regulate key mucosal markers involved in the repair of epithelial barrier integrity, thereby attenuating obesity-associated gut dysbiosis and metabolic inflammation and improving glucose homeostasis.