Population pharmacokinetic and pharmacodynamic model guided weight-tiered dose of AST-001 in pediatric patients with autism spectrum disorder.

AST-001, a novel syrup formulation of L-serine, was developed for the treatment of autism spectrum disorders (ASD) in pediatric patients. This study aimed to establish a pharmacokinetic (PK)-pharmacodynamic (PD) model to elucidate the effect of AST-001 on adaptive behavior in children with ASD. Due to the absence of PK samples in pediatric patients, a previously published population PK model was used to link the PD model by applying an allometric scale to body weight.

AST-001 versus placebo for social communication in children with autism spectrum disorder: A randomized clinical trial.

Aim: This study examined the efficacy of AST-001 for the core symptoms of autism spectrum disorder (ASD) in children.

Methods: This phase 2 clinical trial consisted of a 12-week placebo-controlled main study, a 12-week extension, and a 12-week follow-up in children aged 2 to 11 years with ASD. The participants were randomized in a 1:1:1 ratio to a high-dose, low-dose, or placebo-to-high-dose control group during the main study.

l-Serine Protects Murine Retinal Ganglion Cells from Oxidative Stress via Modulation of Mitochondrial Dysfunction.

Purpose: This study aimed to investigate the effects of l-serine on mitochondrial dysfunction in retinal ganglion cells after exposure to HO-induced oxidative stress.

Methods: Retinal ganglion cells obtained from C57BL6 mice (postnatal days 1-4) were purified and cultured. A cell viability assay was performed following exposure to HO-induced oxidative stress to assess the cytoprotective effects of l-serine on retinal ganglion cells.

Sirtuin 3 mutation- induced mitochondrial dysfunction and optic neuropathy: a case report.

Background: Mitochondrial optic neuropathy is characterized by painless, progressive, symmetrical central vision loss, and dyschromatopsia owing to mitochondrial dysfunction. This report documents a rare case of mitochondrial optic neuropathy due to the SIRT3 gene mutation.

Case Presentation: This report describes a case of a 17-year-old boy who presented with symptoms of bilateral painless, progressive vision decline over several years.

Changes of lysosome by L-serine in rotenone-treated hippocampal neurons.

Oxidative stress destroys cellular organelles and damages DNA, eventually leading to degenerative brain disorders. Persistent mitochondrial damage by oxidative stress eventually causes cells to inhibit the function of lysosomes. Rotenone used in this study inhibits complex 1 of the mitochondrial electron transport chain.

Restoration of Cathepsin D Level via L-Serine Attenuates PPA-Induced Lysosomal Dysfunction in Neuronal Cells.

L-serine is a non-essential amino acid endogenously produced by astrocytes and is abundant in human diets. Beneficial roles of the metabolic products from L-serine in various conditions in the brain including neuronal development have been reported. Through several preclinical studies, L-serine treatment was also shown to offer beneficial therapeutic effects for brain damage such as ischemic stroke, amyotrophic lateral sclerosis, and Parkinson's disease.

Population Pharmacokinetic Model of AST-001, L-Isomer of Serine, Combining Endogenous Production and Exogenous Administration in Healthy Subjects.

AST-001 is an L-isomer of serine that has protective effects on neurological disorders. This study aimed to establish a population pharmacokinetic (PK) model of AST-001 in healthy Korean to further propose a fixed-dose regimen in pediatrics. The model was constructed using 648 plasma concentrations from 24 healthy subjects, including baseline endogenous levels during 24 h and concentrations after a single dose of 10, 20, and 30 g of AST-001.

Atypical Presentation of Enlarged Vestibular Aqueducts Caused by Variants.

Enlarged vestibular aqueduct is the most common inner ear malformation in pediatric patients with sensorineural hearing loss. Here, we report a new presentation of enlarged vestibular aqueduct in a Korean family. The family consists of two parents and five daughters, and the first and second daughters were diagnosed with bilateral enlarged vestibular aqueducts.

Case report of compound variants in Korean siblings with cystic fibrosis: importance of differentiating cystic fibrosis from inflammatory bowel disease.

The prevalence of cystic fibrosis (CF) is considerably lower in Asian populations compared with that of Caucasians. Cases of CF are typically due to mutations in the CF transmembrane conductance regulator gene with autosomal recessive inheritance. Here, we report two cases of newly diagnosed CF in Korea-a 13-year-old boy and his 5-year-old brother.

Case report of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome: first report in Korea with a novel mutation in the gene.

Juvenile polyposis/hereditary hemorrhagic telangiectasia (JPS/HHT) syndrome is a rare, autosomal dominant disorder caused by mutations in the gene, presenting with features of both juvenile polyposis syndrome (JPS) and HHT. Reports and studies of JPS/HHT syndrome are mostly from Western countries, while there are scarce reports from East Asian countries. We report a case of a Korean boy who had been previously diagnosed with JPS at 7 years and had first visited to our center at 15 years of age.

Clinical Experience of Nusinersen in a Broad Spectrum of Spinal Muscular Atrophy: A Retrospective Study.

Background: Nusinersen has recently been approved and more widely used as first-line treatment of spinal muscular atrophy (SMA). This study aimed to evaluate the real-world experience of nusinersen use for patients with a broad spectrum of SMA.

Methods: We reviewed consecutive patients with SMA treated with nusinersen from April 2018 to April 2020.

G Cell Cycle Arrest and Extrinsic Apoptotic Mechanisms Underlying the Anti-Leukemic Activity of CDK7 Inhibitor BS-181.

In vitro antitumor activity of the CDK7 inhibitor BS-181 against human T-ALL Jurkat cells was determined. Treatment of Jurkat clones (JT/Neo) with BS-181 caused cytotoxicity and several apoptotic events, including TRAIL/DR4/DR5 upregulation, c-FLIP down-regulation, BID cleavage, BAK activation, ΔΨ loss, caspase-8/9/3 activation, and PARP cleavage. However, the BCL-2-overexpressing Jurkat clone (JT/BCL-2) abrogated these apoptotic responses.

Congenital abnormalities of the retinal vasculature in neurofibromatosis type I.

The aim of this cross-sectional study was to investigate congenital abnormalities of the retinal vasculature (CARVs) in patients with neurofibromatosis type I (NF-1). Forty-eight patients (96 eyes) with NF-1 diagnosed according to the National Institutes of Health (NIH) criteria and 48 healthy controls were included in this study. Standard fundus photographs were obtained for each subject to evaluate the presence and frequency of CARVs.

Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes.

Cohen syndrome (CS), a rare autosomal recessive disorder, has been associated with genetic mutations in the gene, which regulates vesicle-mediated protein sorting and transport. However, the cellular mechanism underlying CS pathogenesis in patient-derived human neurons remains unknown. We identified a novel compound heterozygous mutation, due to homozygous variation of biparental origin and heterozygous variation inherited from the father, in the gene in a 20-month-old female patient.

The molecular pathophysiology of vascular anomalies: Genomic research.

Vascular anomalies are congenital localized abnormalities that result from improper development and maintenance of the vasculature. The lesions of vascular anomalies vary in location, type, and clinical severity of the phenotype, and the current treatment options are often unsatisfactory. Most vascular anomalies are sporadic, but patterns of inheritance have been noted in some cases, making genetic analysis relevant.

Variation in clinical usefulness of biomarkers of acute kidney injury in young children undergoing cardiac surgery.

Background: Acute kidney injury (AKI) is one of the most significant postoperative complications of pediatric cardiac surgery. Because serum creatinine has limitations as a diagnostic marker of AKI, new biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) are being evaluated to overcome these limitations and detect AKI at an early stage after cardiac surgery.

Purpose: This study aimed to investigate the clinical usefulness of these biomarkers in young children.

Real-Life Effectiveness and Tolerability of Perampanel in Pediatric Patients Aged 4 Years or Older with Epilepsy: A Korean National Multicenter Study.

Background And Purpose: The US Food and Drug Administration approval for perampanel has only recently been expanded to patients as young as 4 years, and so there have been few real-life studies of the effects of perampanel in pediatric patients. The aim of this study was to determine the long-term efficacy, factors affecting treatment response, and tolerability of perampanel as an add-on therapy in pediatric patients aged 4 years or older with epilepsy.

Methods: This multicenter retrospective observational study collected data from pediatric epilepsy centers of four Korean national universities.

Spatial Learning and Motor Deficits in () Mutant Mouse.

Vacuolar protein sorting-associated protein 13B (VPS13B), also known as COH1, is one of the VPS13 family members which is involved in transmembrane transport, Golgi integrity, and neuritogenesis. Mutations in the gene are associated with Cohen syndrome and other cognitive disorders such as intellectual disabilities and autism spectrum disorder (ASD). However, the pathophysiology of VPS13B-associated cognitive deficits is unclear, in part, due to the lack of animal models.

l-Serine protects mouse hippocampal neuronal HT22 cells against oxidative stress-mediated mitochondrial damage and apoptotic cell death.

The cytoprotective mechanism of l-serine against oxidative stress-mediated neuronal apoptosis was investigated in mouse hippocampal neuronal HT22 cells. Treatment with the reactive oxygen species (ROS) inducer 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) increased cytosolic and mitochondrial ROS and apoptosis, without necrosis, in HT22 cells. ROS-mediated apoptosis was accompanied by the induction of the endoplasmic reticulum (ER) stress-mediated apoptotic pathway, involving CHOP/GADD153 upregulation, JNK and p38 MAPK activation, and caspase-12 and caspase-8 activation, and subsequent induction of the mitochondrial apoptotic pathway through BAK and BAX activation, mitochondrial membrane potential (Δψm) loss, caspase-9 and caspase-3 activation, PARP cleavage, and nucleosomal DNA fragmentation.