Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity.

Heterozygous mutations in the ATP1A3 gene, coding for an alpha subunit isoform (α3) of Na/K-ATPase, are the primary genetic cause for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS), early infantile epileptic encephalopathy (EIEE), childhood rapid onset ataxia (CROA) and relapsing encephalopathy with rapid onset ataxia (RECA) extend the clinical spectrum of ATP1A3 related disorders. AHC and RDP demonstrate distinct clinical features, with AHC symptoms being generally more severe compared to RDP.

An axon initial segment is required for temporal precision in action potential encoding by neuronal populations.

Central neurons initiate action potentials (APs) in the axon initial segment (AIS), a compartment characterized by a high concentration of voltage-dependent ion channels and specialized cytoskeletal anchoring proteins arranged in a regular nanoscale pattern. Although the AIS was a key evolutionary innovation in neurons, the functional benefits it confers are not clear. Using a mutation of the AIS cytoskeletal protein βIV-spectrin, we here establish an in vitro model of neurons with a perturbed AIS architecture that retains nanoscale order but loses the ability to maintain a high Na density.

Intratumoral 224Ra-loaded wires spread alpha-emitters inside solid human tumors in athymic mice achieving tumor control.

Background: We developed a new method of brachytherapy, termed diffusing alpha-emitters radiation therapy (DaRT), based on the use of intratumoral (224)Ra-loaded wires, which release short-lived alpha-emitting atoms by recoil. Here, we examined their ability to destroy and control the development of several human-derived tumors implanted in athymic mice.

Materials And Methods: The experiments were performed on athymic mice bearing malignant human-derived tumors including prostate (PC-3), glioblastoma (GBM, U87-MG), colon (HCT15), squamous cell carcinoma (FaDu) and melanoma (C32).

Local control of experimental malignant pancreatic tumors by treatment with a combination of chemotherapy and intratumoral 224radium-loaded wires releasing alpha-emitting atoms.

We developed (224)Ra-loaded wires that when inserted into solid tumors, release radioactive atoms that spread in the tumor and irradiate it effectively with alpha particles (diffusing alpha-emitters radiation therapy [DaRT]). In this study, we tested the ability of intratumoral (224)Ra-loaded wires to control the local growth of pancreatic tumors and the enhancement of this effect by chemotherapy. Pancreatic mouse tumors (Panc02) were treated with (224)Ra-loaded wire(s) with or without gemcitabine.

Comparative in vitro microdosimetric study of murine- and human-derived cancer cells exposed to alpha particles.

Diffusing alpha-emitter radiation therapy (DaRT) is a proposed new form of brachytherapy using α particles to treat solid tumors. The method relies on implantable ²²⁴Ra-loaded sources that continually release short-lived α-particle-emitting atoms that spread inside the tumor over a few millimeters. This treatment was demonstrated to have a significant effect on tumor growth in murine and human-derived models, but the degree of tumor response varied across cell lines.