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.
Donor lymphocyte infusion has been used in the management of relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. It can eradicate minimal residual disease or be ...used to rescue a hematologic relapse, being able to induce durable remissions in a subset of patients. With the increased use of haploidentical hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emptive and prophylactic use in clinical practice.
MicroRNAs and heterogeneous ribonucleoproteins (hnRNPs) are posttranscriptional gene regulators that bind mRNA in a sequence-specific manner. Here, we report that loss of miR-328 occurs in blast ...crisis chronic myelogenous leukemia (CML-BC) in a BCR/ABL dose- and kinase-dependent manner through the MAPK-hnRNP E2 pathway. Restoration of miR-328 expression rescues differentiation and impairs survival of leukemic blasts by simultaneously interacting with the translational regulator poly(rC)-binding protein hnRNP E2 and with the mRNA encoding the survival factor PIM1, respectively. The interaction with hnRNP E2 is independent of the microRNA's seed sequence and it leads to release of
CEBPA mRNA from hnRNP E2-mediated translational inhibition. Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins.
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► Expression of miR-328 is reduced in CD34
+ CML blast crisis (CML-BC) progenitors ► miR-328 directly binds hnRNP E2 and rescues
CEBPA mRNA translation ► miR-328 restores C/EBPα-dependent maturation of myeloid CML-BC progenitors ► miR-328 pairs with
PIM1 3′UTR and impairs survival of CML-BC progenitors
Allogeneic hematopoietic cell transplantation led to the discovery of the allogeneic GVL effect, which remains the most convincing evidence that immune cells can cure cancer in humans. However, ...despite its great paradigmatic and clinical relevance, induction of GVL by conventional allogeneic hematopoietic cell transplantation remains a quite rudimentary form of leukemia immunotherapy. It is toxic and its efficacy is far from optimal. It is therefore sobering that since the discovery of the GVL effect 3 decades ago, the way GVL is induced and manipulated has practically not changed. Preclinical and clinical studies suggest that injection of T cells primed against a single Ag present on neoplastic cells could enhance the GVL effect without causing any GVHD. We therefore contend that Ag-targeted adoptive T-cell immunotherapy represents the future of leukemia immunotherapy, and we discuss the specific strategies that ought to be evaluated to reach this goal. Differences between these strategies hinge on 2 key elements: the nature of the target Ag and the type of Ag receptor expressed on T cells.
Berries are rich in polyphenols and plant cell wall polysaccharides (fibers), including cellulose, hemicellulose, arabinans and arabino-xyloglucans rich pectin. Most of polyphenols and fibers are ...known to be poorly absorbed in the small intestine and reach the colon where they interact with the gut microbiota, conferring health benefits to the host. This study assessed the contribution of polyphenol-rich whole cranberry and blueberry fruit powders (CP and BP), and that of their fibrous fractions (CF and BF) on modulating the gut microbiota, the microbial functional profile and influencing metabolic disorders induced by high-fat high-sucrose (HFHS) diet for 8 weeks. Lean mice-associated taxa, including
,
, and
, were selectively induced by diet supplementation with polyphenol-rich CP and BP. Fiber-rich CF also triggered polyphenols-degrading families
and
. Diet supplementation with polyphenol-rich CP, but not with its fiber-rich CF, reduced fat mass depots, body weight and energy efficiency in HFHS-fed mice. However, CF reduced liver triglycerides in HFHS-fed mice. Importantly, polyphenol-rich CP-diet normalized microbial functions to a level comparable to that of Chow-fed controls. Using multivariate association modeling, taxa and predicted functions distinguishing an obese phenotype from healthy controls and berry-treated mice were identified. The enterotype-like clustering analysis underlined the link between a long-term diet intake and the functional stratification of the gut microbiota. The supplementation of a HFHS-diet with polyphenol-rich CP drove mice gut microbiota from
enterotype into an enterotype linked to healthier host status, which is
. This study highlights the prebiotic role of polyphenols, and their contribution to the compositional and functional modulation of the gut microbiota, counteracting obesity.
Sustained TCR signaling is critical for ThPOK induction in MHC class II (MHCII)-signaled thymocytes leading to the CD4 helper lineage commitment. ThPOK suppresses the cytotoxic program in the ...signaled thymocytes and is shown to be necessary and sufficient for the CD4 helper lineage choice. Accordingly, loss and gain of ThPOK function redirects MHCII- and MHC class I (MHCI)-signaled thymocytes into the CD8 cytotoxic and CD4 helper lineage, respectively. However, the impact of a defined ThPOK level on the CD4 helper lineage choice of MHCII- and MHCI-specific thymocytes and the role of TCR signaling in this process is not evaluated. Equally, it is not clear if suppression of the cytotoxic program by ThPOK is sufficient in redirecting MHCI-restricted thymocytes into the CD4 helper lineage. In this study, we have investigated CD8 to CD4 helper lineage redirection in three independent ThPOK overexpressing transgenic mouse lines. Our analysis shows that one of the transgenic lines, despite overexpressing ThPOK compared with wild-type CD4 mature T cells and compromising cytotoxic program, failed to redirect all MHCI-signaled thymocytes into the CD4 helper lineage, resulting in the continued presence of CD8
mature T cells and the generation of a large number of double negative mature T cells. Critically, the same ThPOK transgene completely restored the CD4 helper lineage commitment of MHCII-specific
thymocytes. Importantly, augmenting TCR signaling significantly enhanced the ThPOK-mediated CD4 helper lineage choice of MHCI-specific thymocytes but was still substantially less efficient than that of MHCII-specific thymocytes expressing the same amount of ThPOK. Together, these data suggest that the ThPOK-induced CD4 helper lineage commitment is strongly influenced by TCR signal strength and MHC specificity of developing thymocytes.
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.
Atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) is associated with PV to left atrium reconduction. Effective lesion creation necessitates adequate contact force between the ...ablation catheter and myocardium.
The purpose of this study was to study the utility of contact force-guided ablation on immediate and long-term outcomes.
Seventy-five patients with highly symptomatic paroxysmal AF underwent wide circumferential PVI using an irrigated-tip radiofrequency catheter. In 25 patients, ablation was guided by real-time contact force measurements (CF group; SmartTouch, Biosense Webster). A control group of 50 patients underwent PVI using a standard nonforce sensing catheter (standard group; ThermoCool, Biosense Webster). After PVI, all patients underwent adenosine testing to unmask dormant conduction. Patients were followed up at 3, 6, and 12 months and by transtelephonic monitoring as well.
Dormant conduction was unmasked and subsequently eliminated in 4 PV pairs (8%; 16% of patients) in the CF group and 35 PV pairs (35%; 52% of patients) in the standard group (P = .0004 per PV pair; P = .0029 per patient). The single-procedure, off-antiarrhythmic drug freedom from recurrent atrial arrhythmias at 1 year was 88% in the CF group vs 66% in the standard group (P = .047). Procedure duration and fluoroscopy time were significantly longer in the CF group (P = .0038 and P = .0001, respectively).
The use of real-time contact force guidance results in a significant reduction in the prevalence of dormant conduction with improved long-term freedom from recurrent arrhythmias. The utility of a contact force-guided approach requires evaluation in a long-term prospective randomized study.
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.
Environmental and herd-associated factors such as geographical location, climatic conditions, forage types, bedding, soil, animal genetics, herd size, housing, lactation stage, and udder health are ...exploited by farmers to dictate specific management strategies that ensure dairy operation profitability and enhance the sustainability of milk production. Along with milking routines, milking systems, and storage conditions, these farming practices greatly influence the microbiota of raw milk, as evidenced by several recent studies. During the past few years, the increased interest in high-throughput sequencing technologies combined with culture-dependent methods to investigate dairy microbial ecology has improved our understanding of raw milk community dynamics throughout storage and processing. However, knowledge is still lacking on the niche-specific communities in the farm environment, and on the factors that determine bacteria transfer to the raw milk. This review summarizes findings from the past 2 decades regarding the effects of farm management practices on the diversity of bacterial species that determine the microbiological quality of raw cow milk.
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