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Anemia in β-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired α-globin chains impose substantial oxidative stress on β-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbbth3/+ mouse model for β-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbbth3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in β-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2α axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing β-thalassemia-related liver iron overload. In ex vivo studies on erythroid precursors from patients with β-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for β-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials.

Introduction: Despite considerable therapeutic advances in the last 20 years, metastatic cancers remain a major cause of death. We previously identified prominin‐2 (PROM2) as a biomarker predictive of distant metastases and decreased survival, thus providing a promising bio‐target. In this translational study, we set out to decipher the biological roles of PROM2 during the metastatic process and resistance to cell death, in particular for metastatic melanoma. Methods and results: Methods and results: We demonstrated that PROM2 overexpression was closely linked to an increased metastatic potential through the increase of epithelial‐to‐mesenchymal transition (EMT) marker expression and ferroptosis resistance. This was also found in renal cell carcinoma and triple negative breast cancer patient‐derived xenograft models. Using an oligonucleotide anti‐sense anti‐PROM2, we efficaciously decreased PROM2 expression and prevented metastases in melanoma xenografts. We also demonstrated that PROM2 was implicated in an aggravation loop, contributing to increase the metastatic burden both in murine metastatic models and in patients with metastatic melanoma. The metastatic burden is closely linked to PROM2 expression through the expression of EMT markers and ferroptosis cell death resistance in a deterioration loop. Conclusion: Our results open the way for further studies using PROM2 as a bio‐target in resort situations in human metastatic melanoma and also in other cancer types. [ABSTRACT FROM AUTHOR]

Anemia in [beta]-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired [alpha]-globin chains impose substantial oxidative stress on [beta]-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the [Hbb.sup.th3/+] mouse model for [beta]-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in [Hbb.sup.th3/+] mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in [beta]-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2[alpha] axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing [beta]-thalassemia-related liver iron overload. In ex vivo studies on erythroid precursors from patients with [beta]-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for [beta]-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials., Introduction Ineffective erythropoiesis and reduced red cell survival are key determinants of the anemia and other comorbidities in [beta]-thalassemia (1-3). Reduced [beta]-chain production leads to a decoupling from heme production, [...]

Large-sized gold nanoparticles, promising imaging and therapeutic tools in human cancer, need long-term studies evaluating tissue bio-distribution in blood, organs and tumor. In a preclinical model of mouse xenografted with human renal cancer, we analysed the bio-distribution of a single dose (160 µg/kg) intravenously injected of poly-ethylene glycol (PEG)ylated gold nanoshells (~150 nm), in blood, normal and tumoral tissues. Using inductively coupled plasma mass spectrometry (ICP-MS), dark field and electron microscopy, we performed a sequential study of nanoshell uptake and distribution in the tumor. We also studied microscopically the organs most sensitive to efficient anticancer drugs to detect a possible long-term toxicity. Gold quantities significantly decreased in blood between early and late time points, whereas they significantly increased in liver and spleen. In addition, gold nanoshells did not induce any tissue damage, such as necrosis, inflammatory infiltrate or fibrosis in mouse liver, spleen, kidney or bone marrow after 6 months. In human renal cancer xenografts, ICP-MS showed an early decrease of gold, with 1-week stability before decrease at Day 15. Dark field microscopy showed gold particles within the vessel lumen 5 to 30 min after nanoshell injection, while 24 h later, gold particle distribution was mainly intracellular. Electron microscopy identified nanoshells within blood vessels at 5 and 30 min, within endothelial cells at 3 and 6 h and within cytoplasms of macrophages in the tumoral tissue after 24 h. In conclusion, no toxicity was observed in mice 6 months after administration of PEGylated gold nanoshells and the distribution kinetics progressed from intravascular flow at 30 min to intratumoral cells 24 h later. Keywords Gold nanoshells . Mouse xenograft Human renal cancer . Sequential study . Tissue biodistribution . Long-term tolerance, Introduction Gold nanoparticles are now synthesised into a large variety of forms. Only some of them are suitable for in vivo hyperthermia. A recent comparative study of small-sized gold nanoparticles [...]

Tumor cells with donor genotype have been identified in human skin cancer after allogeneic transplantation; however, the donor contribution to the malignant epithelium has not been established. Kidney transplant recipients have an increased risk of invasive skin squamous cell carcinoma (SCC), which is associated with accumulation of the tumor suppressor p53 and TP53 mutations. In 21 skin SCCs from kidney transplant recipients, we systematically assessed p53 expression and donor/recipient origin in laser-microdissected [p53.sup.+] tumor cells. In one patient, molecular analyses demonstrated that skin tumor cells had the donor genotype and harbored a TP53 mutation in codon 175. In a kidney graft biopsy performed 7 years before the skin SCC diagnosis, we found [p53.sup.+] cells in the renal tubules. We identified the same TP53 mutation in these [p53.sup.+] epithelial cells from the kidney transplant. These findings provide evidence for a donor epithelial cell contribution to the malignant skin epithelium in the recipient in the setting of allogeneic kidney transplantation. This finding has theoretical implications for cancer initiation and progression and clinical implications in the context of prolonged immunosuppression and longer survival of kidney transplant patients., Introduction The concept of adult stem cell plasticity (1), (2) has opened new fields for scientific and clinical developments. Allogeneic transplantations offer a rare clinical opportunity to study homing and [...]

Patients with sickle-cell disease (SCD) suffer from tissue damage and life-threatening complications caused by vasoocclusive crisis (VOC). Endothelin receptors (ETRs) are mediators of one of the most potent vasoconstrictor pathways in mammals, but the relationship between vasoconstriction and VOC is not well understood. We report here that pharmacological inhibition of ETRs prevented hypoxia-induced acute VOC and organ damage in a mouse model of SCD. An in vivo ultrasonographic study of renal hemodynamics showed a substantial increase in endothelin-mediated vascular resistance during hypoxia/reoxygenation-induced VOC. This increase was reversed by administration of the dual ETR antagonist (ETRA) bosentan, which had pleiotropic beneficial effects in vivo. It prevented renal and pulmonary microvascular congestion, systemic inflammation, dense rbc formation, and infiltration of activated neutrophils into tissues with subsequent nitrative stress. Bosentan also prevented death of sickle-cell mice exposed to a severe hypoxic challenge. These findings in mice suggest that ETRA could be a potential new therapy for SCD, as it may prevent acute VOC and limit organ damage in sickle-cell patients., Introduction Painful vasoocclusive crisis (VOC) is one of the major and specific manifestations of sickle-cell disease (SCD). VOC is a complex process involving hemoglobin S polymer formation and poorly deformable [...]