Safety, tolerability, pharmacokinetics, and antimalarial activity of MMV533: a phase 1a first-in-human, randomised, ascending dose and food effect study, and a phase 1b Plasmodium falciparum volunteer infection study.

Background: Novel antimalarials are needed to address emerging resistance to artemisinin and partner drugs. We did two trials to evaluate safety, tolerability, pharmacokinetics, and activity against blood stage Plasmodium falciparum for the drug candidate MMV533.

Methods: A phase 1a first-in-human (FIH) trial was conducted at Nucleus Network (Melbourne, VIC, Australia).

Investigating the Role of Soybean Genetic Resistance on the Production of Sclerotia.

Sclerotia serve as survival structures for many plant pathogens, including Sclerotinia sclerotiorum, which causes Sclerotinia stem rot (SSR) in soybeans and leads to significant yield losses. While partially resistant soybean varieties are effective in reducing SSR incidence, the relationship between resistance and sclerotial production remains unclear. This study investigated the sclerotial production of two soybean recombinant inbred lines (RILs) with differential levels of SSR resistance under both greenhouse and field conditions.

High Extracellular K Skews T-Cell Differentiation Towards Tumour Promoting Th2 and T Subsets.

Potassium ions (K) released from dying necrotic tumour cells accumulate in the tumour microenvironment (TME) and increase the local K concentration to 50 mM (high-[K]). Here, we demonstrate that high-[K] decreases expression of the T-cell receptor subunits CD3ε and CD3ζ and co-stimulatory receptor CD28 and thereby dysregulates intracellular signal transduction cascades. High-[K] also alters the metabolic profiles of T-cells, limiting the metabolism of glucose and glutamine, consistent with functional exhaustion.

The novel quinoline derivative SKA-346 as a K3.1 channel selective activator.

The calcium-activated K3.1 channel plays a crucial role in T-cell immune response. Genetic manipulation of T-cells to upregulate the expression of K channels has been shown to boost T-cell cytotoxicity in cancer.

Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria.

Background: The combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results.

Methods: Twenty-four healthy adults enrolled over three consecutive cohorts were inoculated with Plasmodium falciparum-infected erythrocytes on day 0.