Targeting a lineage-specific PI3KÉ£-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule.

Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.

Hto, Tritiated Amino Acid Exposure and External Exposure Induce Differential Effects on Hematopoiesis and Iron Metabolism.

The increased potential for tritium releases from either nuclear reactors or from new facilities raises questions about the appropriateness of the current ICRP and WHO recommendations for tritium exposures to human populations. To study the potential toxicity of tritium as a function of dose, including at a regulatory level, mice were chronically exposed to tritium in drinking water at one of three concentrations, 10 kBq.l-1, 1 MBq.l-1 or 20 MBq.l-1. Tritium was administered as either HTO or as tritiated non-essential amino acids (TAA). After one month's exposure, a dose-dependent decrease in red blood cells (RBC) and iron deprivation was seen in all TAA exposed groups, but not in the HTO exposed groups. After eight months of exposure this RBC decrease was compensated by an increase in mean globular volume - suggesting the occurrence of an iron deficit-associated anemia. The analysis of hematopoiesis, of red blood cell retention in the spleen and of iron metabolism in the liver, the kidneys and the intestine suggested that the iron deficit was due to a decrease in iron absorption from the intestine. In contrast, mice exposed to external gamma irradiation at equivalent dose rates did not show any change in red blood cell numbers, white blood cell numbers or in the plasma iron concentration. These results showed that health effects only appeared following chronic exposure to concentrations of tritium above regulatory levels and the effects seen were dependent upon the speciation of tritium.

Chronic Exposure to Uranium from Gestation: Effects on Behavior and Neurogenesis in Adulthood.

Uranium exposure leads to cerebral dysfunction involving for instance biochemical, neurochemical and neurobehavioral effects. Most studies have focused on mechanisms in uranium-exposed adult animals. However, recent data on developing animals have shown that the developing brain is also sensitive to uranium. Models of uranium exposure during brain development highlight the need to improve our understanding of the effects of uranium. In a model in which uranium exposure began from the first day of gestation, we studied the neurobehavioral consequences as well as the progression of hippocampal neurogenesis in animals from dams exposed to uranium. Our results show that 2-month-old rats exposed to uranium from gestational day 1 displayed deficits in special memory and a prominent depressive-like phenotype. Cell proliferation was not disturbed in these animals, as shown by 5-bromo-2'deoxyuridine (BrdU)/neuronal specific nuclear protein (NeuN) immunostaining in the dentate gyrus. However, in some animals, the pyramidal cell layer was dispersed in the CA3 region. From our previous results with the same model, the hypothesis of alterations of neurogenesis at prior stages of development is worth considering, but is probably not the only one. Therefore, further investigations are needed to correlate cerebral dysfunction and its underlying mechanistic pathways.

Molecular epidemiology of drug-resistant Plasmodium falciparum in Benguela province, Angola.

BACKGROUND: The malaria situation has been worsening in Angola, partly due to armed conflict until the recent past and drug-resistant Plasmodium falciparum. Malaria transmission is heterogeneous within the country, and data on drug-resistant malaria in different parts of the country are incomplete. The aim of the present study was to evaluate resistance to 4-aminoquinolines and antifolate drugs in P. falciparum isolates collected in Benguela province, central Angola, using molecular markers. METHODS: Fingerprick capillary blood was collected from asymptomatic children aged less than 15 years old during a household survey in and around Balombo town in 2010-2011. Samples were screened for P. falciparum by nested PCR. Molecular markers (P. falciparum dihydrofolate reductase [pfdhfr], P. falciparum dihydropteroate synthase [pfdhps], P. falciparum chloroquine resistance transporter [pfcrt], and P. falciparum multidrug-resistance gene 1 [pfmdr1]) were sequenced to determine the key codons associated with drug resistance. RESULTS: A total of 60 blood samples were positive for P. falciparum. Most isolates with successful PCR amplification had mutant pfdhfr alleles, with either double mutant AICNI (69%) or triple mutant AIRNI (21%) haplotypes. A16V, S108T, and I164L substitutions were not found. Many of the isolates were carriers of either SGKAA (60%) or AGKAA (27%) pfdhps haplotype. K540E substitution was absent. There were only two pfcrt haplotypes: wild-type CVMNK (11%) and mutant CVIET (89%). Wild-type pfmdr1 NYSND haplotype was found in 19% of the isolates, whereas single mutant pfmdr1 YYSND and NFSND haplotypes occurred in 48% and 11%, respectively. Double mutant pfmdr1 haplotypes (YFSND and YYSNY) occurred rarely. CONCLUSIONS: The results suggest that the high prevalence of mutant pfcrt CVIET haplotype is in agreement with low clinical efficacy of chloroquine observed in earlier studies and that the double pfdhfr mutant AICNI and single pfdhps mutant SGKAA are currently the predominant haplotypes associated with antifolate resistance in Benguela province. The hallmark of clinical resistance observed in East Africa, i.e. triple pfdhfr mutant haplotype (AIRNI) and double pfdhps mutant haplotype (SGEAA), was absent. These molecular findings need to be further evaluated in parallel with clinical studies, in particular with the efficacy of intermittent preventive treatment using sulphadoxine-pyrimethamine in pregnant women and artesunate-amodiaquine for uncomplicated malaria.