Evidence-based management guidelines for noncystic fibrosis bronchiectasis in children and adolescents.

Noncystic fibrosis bronchiectasis is a chronic respiratory disease that carries high socioeconomic and medical burdens and is caused by diverse respiratory illnesses. To improve clinical outcomes, early recognition, active treatment of exacerbations, and prevention of further exacerbations are essential. However, evidence for the treatment and prevention of acute exacerbation of noncystic fibrosis bronchiectasis, especially in children, is lacking. Therefore, the evidence- and consensus-based guidelines for medical and nonmedical treatment strategies for noncystic fibrosis bronchiectasis in children and adolescents were developed by the Korean Academy of Pediatric Allergy and Respiratory Disease using the methods recommended by the Grading of Recommendations Assessment, Development, and Evaluation working group with evidence published through July 2, 2020. This guideline encompasses evidence-based treatment recommendations as well as expert opinions, addressing crucial aspects of the treatment and management of noncystic fibrosis bronchiectasis in children. This includes considerations for antibiotics and airway clearance strategies, particularly in areas where evidence may be limited. Large, well-designed, and controlled studies are required to accumulate further evidence of management strategies for noncystic fibrosis bronchiectasis in children and adolescents.

Exosome Precipitation by Ionic Strength Modulation: ExoPRISM.

Extracellular vesicles (EVs) are emerging as crucial materials for precision theragnostic applications. However, current separation methods are time-consuming, costly, and not scalable and deliver limited yields or purity. Here, we present EV precipitation by ionic strength modulation (ExoPRISM), a simple, low-cost, user-friendly, and readily adaptable approach for separating EVs in high yields without compromising their biological functions. Adding an electrolyte solution to blood plasma in small increments generates the sequential precipitation of proteins and EVs, allowing for fractional separation of EVs using low-speed centrifugation. The coprecipitated electrolytes are easily washed away, and the entire EV separation and washing process takes less than an hour. This approach successfully separates EVs from a broad range of volumes and types of biological fluids, including culture medium, urine, plasma, and serum, showing promise as a robust tool for next-generation liquid biopsies and regenerative medicine.

CD5 Expression Dynamically Changes During the Differentiation of Human CD8+ T Cells Predicting Clinical Response to Immunotherapy.

Defining the molecular dynamics associated with T cell differentiation enhances our understanding of T cell biology and opens up new possibilities for clinical implications. In this study, we investigated the dynamics of CD5 expression in CD8+ T cell differentiation and explored its potential clinical uses. Using PBMCs from 29 healthy donors, we observed a stepwise decrease in CD5 expression as CD8+ T cells progressed through the differentiation stages. Interestingly, we found that CD5 expression was initially upregulated in response to T cell receptor stimulation, but diminished as the cells underwent proliferation, potentially explaining the differentiation-associated CD5 downregulation. Based on the proliferation-dependent downregulation of CD5, we hypothesized that relative CD5 expression could serve as a marker to distinguish the heterogeneous CD8+ T cell population based on their proliferation history. In support of this, we demonstrated that effector memory CD8+ T cells with higher CD5 expression exhibited phenotypic and functional characteristics resembling less differentiated cells compared to those with lower CD5 expression. Furthermore, in the retrospective analysis of PBMCs from 30 non-small cell lung cancer patients, we found that patients with higher CD5 expression in effector memory T cells displayed CD8+ T cells with a phenotype closer to the less differentiated cells, leading to favorable clinical outcomes in response to immune checkpoint inhibitor (ICI) therapy. These findings highlight the dynamics of CD5 expression as an indicator of CD8+ T cell differentiation status, and have implications for the development of predictive biomarker for ICI therapy.

POU6F2 mutation in humans with pubertal failure alters GnRH transcript expression.

Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by the absence of pubertal development and subsequent impaired fertility often due to gonadotropin-releasing hormone (GnRH) deficits. Exome sequencing of two independent cohorts of IHH patients identified 12 rare missense variants in POU6F2 in 15 patients. POU6F2 encodes two distinct isoforms. In the adult mouse, expression of both isoform1 and isoform2 was detected in the brain, pituitary, and gonads. However, only isoform1 was detected in mouse primary GnRH cells and three immortalized GnRH cell lines, two mouse and one human. To date, the function of isoform2 has been verified as a transcription factor, while the function of isoform1 has been unknown. In the present report, bioinformatics and cell assays on a human-derived GnRH cell line reveal a novel function for isoform1, demonstrating it can act as a transcriptional regulator, decreasing GNRH1 expression. In addition, the impact of the two most prevalent POU6F2 variants, identified in five IHH patients, that were located at/or close to the DNA-binding domain was examined. Notably, one of these mutations prevented the repression of GnRH transcripts by isoform1. Normally, GnRH transcription increases as GnRH cells mature as they near migrate into the brain. Augmentation earlier during development can disrupt normal GnRH cell migration, consistent with some POU6F2 variants contributing to the IHH pathogenesis.

UBAP2 plays a role in bone homeostasis through the regulation of osteoblastogenesis and osteoclastogenesis.

Osteoporosis is a condition characterized by decreased bone mineral density (BMD) and reduced bone strength, leading to an increased risk of fractures. Here, to identify novel risk variants for susceptibility to osteoporosis-related traits, an exome-wide association study is performed with 6,485 exonic single nucleotide polymorphisms (SNPs) in 2,666 women of two Korean study cohorts. The rs2781 SNP in UBAP2 gene is suggestively associated with osteoporosis and BMD with p-values of 6.1 × 10-7 (odds ratio = 1.72) and 1.1 × 10-7 in the case-control and quantitative analyzes, respectively. Knockdown of Ubap2 in mouse cells decreases osteoblastogenesis and increases osteoclastogenesis, and knockdown of ubap2 in zebrafish reveals abnormal bone formation. Ubap2 expression is associated with E-cadherin (Cdh1) and Fra1 (Fosl1) expression in the osteclastogenesis-induced monocytes. UBAP2 mRNA levels are significantly reduced in bone marrow, but increased in peripheral blood, from women with osteoporosis compared to controls. UBAP2 protein level is correlated with the blood plasma level of the representative osteoporosis biomarker osteocalcin. These results suggest that UBAP2 has a critical role in bone homeostasis through the regulation of bone remodeling.

Evaluation of Blood Tumor Mutation Burden for the Efficacy of Second-Line Atezolizumab Treatment in Non-Small Cell Lung Cancer: BUDDY Trial.

This study aimed to investigate the feasibility of blood-based biomarkers, including blood tumor mutation burden (bTMB), to predict atezolizumab efficacy in relapsed and advanced non-small cell lung cancer (NSCLC). Stage IV NSCLC patients who had previously received platinum-doublet chemotherapy were recruited and received 1200 mg of atezolizumab every three weeks. Blood was collected to obtain plasma cell-free DNA (cfDNA) before the first cycle (C0) and at the fourth cycle (C4). bTMB was measured by CT-ULTRA in patients with cfDNA over 10 ng. The objective response rate (ORR) of the enrolled 100 patients was 10%, and there was no difference in ORR according to bTMB (cutoff: 11.5 muts/Mb) at C0 (high bTMB: 8.1% vs. low bTMB: 11.1%). However, the C4/C0 bTMB ratio was significantly lower in the durable clinical benefit (DCB) patients. The cfDNA concentration at C0, the C4/C0 ratio of the cfDNA concentration, the highest variant allele frequency (hVAF), and the VAF standard deviation (VAFSD) were significantly lower in the DCB patients. In the multivariate analysis, a high cfDNA concentration at C0 (cutoff: 8.6 ng/mL) and a C4/C0 bTMB ratio greater than 1 were significantly associated with progression-free survival. These results suggest that baseline levels and dynamic changes of blood-based biomarkers (bTMB, cfDNA concentration, and VAFSD) could predict atezolizumab efficacy in previously treated NSCLC patients.

Combined effects of microplastics and benz[a]anthracene on cardiotoxicity in zebrafish (Danio rerio) larvae: Size matters.

The size of microplastics (MPs) plays an important role in combined toxic effects including synergistic or antagonistic effects. However, the influence of the size of MPs on the combined toxicity of contaminants remains unclear. In this study, we employed a zebrafish model to investigate the effects of MP size on the combined toxicity of benz[a]anthracene (BaA), a representative polyaromatic hydrocarbon, using three different sizes of polystyrene MPs (PSMPs) (0.2, 1.0, and 10 µm). Treatment of all groups did not result in any mortality of the zebrafish larvae. However, small-sized PSMPs (0.2 µm) enhanced the toxic effect of BaA in larvae such as cardiac defect and disruption of vessel formation. Medium-sized PSMPs (1.0 µm) were boundary in terms of the combined toxic effect; however, large-sized PSMPs (10 µm) alleviated the cardiotoxicity of BaA, including cardiac defect, ROS levels, and cell death. The combined effects showed a correlation with the body burden of MPs and BaA in larvae according to particle size (in the order of 0.2 µm > 1.0 µm > 10 µm). The synergistic effects occurred likely because the small PSMPs facilitated the body burden of BaA, induced excessive ROS by Ahr-mediated activity, and caused cell death in the heart, resulting in increased heart defects in the larvae. In contrast, large PSMPs abated the combined toxic effect through decreased body burden, whereas medium PSMPs form a boundary in combined effects. Therefore, the combined toxic effects of MPs are dependent on their size, which plays an important role in the transport and accumulation of environmental pollutants.

Blood-Based Biomarker Analysis for Predicting Efficacy of Chemoradiotherapy and Durvalumab in Patients with Unresectable Stage III Non-Small Cell Lung Cancer.

We recruited 50 patients with unresectable stage III NSCLC who received CCRT between March 2020 and March 2021. Durvalumab consolidation (DC) was administered to patients (n = 23) without progression after CCRT and programmed death-ligand 1 (PD-L1) ≥ 1%. Blood samples were collected before (C0) and after CCRT (C1) to calculate PBC counts and analyze CTCs. CTCs, isolated by the CD-PRIMETM system, exhibited EpCAM/CK+/CD45- phenotype in BioViewCCBSTM. At median follow-up of 27.4 months, patients with residual CTC clusters at C1 had worse median PFS than those without a detectable CTC cluster (11.0 vs. 27.8 months, p = 0.032), and this trend was noted only in the DC group (p = 0.034). Patients with high platelets at C1 (PLThi, >252 × 103/µL) had worse median PFS than those with low platelets (PLTlo) (5.9 vs. 17.1 months, p < 0.001). In multivariable analysis, PLThi and residual CTC clusters at C1 were independent risk factors for PFS, and DC group with PLThi and residual CTC clusters at C1 showed the worst median PFS (2.6 months, HR 45.16, p = 0.001), even worse than that of the CCRT alone group with PLThi (5.9 months, HR 15.39, p = 0.001). The comprehensive analysis of CTCs and PBCs before and after CCRT revealed that the clearance of CTC clusters and platelet counts at C1 might be potential biomarkers for predicting survival.

The association between MTHFR polymorphism, dietary methyl donors, and childhood asthma and atopy.

BACKGROUND: Studies investigating the genetic association of the C677T methylenetetrahydrofolate reductase (MTHFR) genotype and dietary methyl donors with asthma and atopy are limited, and have variable results. OBJECTIVE: To investigate the effect of dietary methyl donor intake on the risk of childhood asthma and atopy, based on the C677T polymorphism in the MTHFR gene. METHODS: This cross-sectional study included 2,333 elementary school children aged 6-8 years across Korea during 2005 and 2006, as part of the first Children's Health and Environmental Research survey. Genotyping for the MTHFR (rs1801133) polymorphism was performed using the TaqMan assay. Multivariable-adjusted logistic regression analysis was performed to determine a descriptive association between the dietary methyl donor intake, MTHFR polymorphism, and childhood asthma and atopy. RESULTS: Intake of dietary methyl donors like folates was significantly associated with a decreased risk of the wheezing symptom, in the past 12 months, and "ever asthma" diagnosis, respectively. Vitamin B6 intake was also associated with a decreased atopy risk. The T allele of the MTHFR (rs1801133) gene was significantly associated with a decreased risk of atopy. Increased intakes of folate, vitamin B2, and vitamin B6 were protective factors against atopy, especially in children with the T allele on the MTHFR gene, compared to those with lower intakes and the CC genotype. CONCLUSIONS: High intakes of dietary methyl donors were associated with reduced risk of atopy and asthma symptoms. These may have additive effects related to the susceptibility alleles of the MTHFR gene. The clinical implications require evaluation.

Particulate matter exposure during pregnancy increases risk of childhood asthma: modified by gender and NRF2 genotype.

BACKGROUND: Exposure to particulate matter (PM) has been known to develop asthma in children and the oxidative stress-related mechanisms are suggested. For the development of asthma, not only the exposure dose but also the critical window and the risk modifying factors should be evaluated. OBJECTIVE: We investigated whether prenatal exposure to PM10 increases the risk of childhood asthma and evaluated the modifying factors, such as gender and reactive oxidative stress-related gene. METHODS: A general population-based birth cohort, the Panel Study of Korean Children (PSKC), including 1572 mother-baby dyads was analyzed. Children were defined to have asthma at age 7 when a parent reported physician-diagnosed asthma. Exposure to PM10 during pregnancy was estimated by land-use regression models based on national monitoring system. TaqMan method was used for genotyping nuclear factor, erythroid 2-related factor, NRF2 (rs6726395). A logistic Bayesian distributed lag interaction model (BDLIM) was used to evaluate the associations between prenatal PM10 exposure and childhood asthma by gender and NRF2. RESULTS: Exposure to PM10 during pregnancy was associated with the development of asthma (aOR 1.03, 95% CI 1.001.06). Stratifying by gender and NRF2 genotype, exposure to PM10 during 26-28 weeks gestation increased the risk of childhood asthma, especially in boys with NRF2 GG genotype. CONCLUSIONS: A critical window for PM10 exposure on the development of childhood asthma was during 26-28 weeks of gestation, and this was modified by gender and NRF2 genotype.

A method for early diagnosis of lung cancer from tumor originated DNA fragments using plasma cfDNA methylome and fragmentome profiles.

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients.

Simply structured polarization-independent high efficiency multilayer dielectric gratings.

A polarization-independent multilayer dielectric diffraction grating with a low aspect ratio and high diffraction efficiency was designed and fabricated. The diffraction grating designed with a grating density of 1200 lines/mm had an aspect ratio of 0.59, mean polarization-independent diffraction efficiency in the Littrow angle of ±2.5∘, and 1030-1080 nm wavelength range of 97.2%. The designed grating was fabricated using ion assisted deposition and reactive ion etching techniques. The mean polarization-independent diffraction efficiency of the fabricated grating was 96.1%, and its standard deviation was 0.68%. The fabricated diffraction grating was irradiated with a 1064 nm cw laser, with a power density of 30kW/cm2, for 1 min to measure the temperature change before and after the laser application. It was verified that the temperature variation of the diffraction grating without heat treatment was 8.8°C, and the temperature variation after heat treatment at 400°C decreased to 2.3°C.

Atopic Dermatitis With Coexisting Food Allergy in Early Life Is Associated With Childhood Asthma.

PURPOSE: Atopic dermatitis (AD) and food allergy (FA) are associated with respiratory comorbidities, in the concept of 'atopic march.' However, children with AD and a coexisting FA have various disease courses, and the mechanism of atopic march remains unclear. In this study, we investigated whether the phenotype of AD with coexisting FA in early life affected asthma or allergic rhinitis (AR) in school children. METHODS: A total of 1,579 children from the Panel Study on Korean Children (PSKC) cohort were followed-up in 2013. The participants diagnosed with AD in this cohort were classified by the age of AD onset and persistence as well as FA history. We compared the presence of comorbidities-asthma and rhinitis-among different AD phenotypes. RESULTS: Asthma and AR with current symptoms within 12 months at age 6-8 years were associated with early-onset persistent AD phenotype, regardless of coexisting FA. AD with FA conferred a higher risk of recent wheezing at 8 years of age than AD without FA (adjusted odds ratio, 8.09; 95% confidence interval, 2.54-25.76). Children with early-onset persistent AD with FA manifested a distinctive trajectory with a higher prevalence of wheezing and AR at age 5-8 years than those without AD. CONCLUSIONS: AD with FA in early life is strongly associated with asthma and AR in school children, and the early-onset persistent AD with FA had a strong additive effect on the risk of asthma at school age. Classifying AD phenotypes regarding FA in early life will help predict and prevent asthma and AR in school children.

Transplantation of PSA-NCAM-Positive Neural Precursors from Human Embryonic Stem Cells Promotes Functional Recovery in an Animal Model of Spinal Cord Injury.

BACKGROUND: Spinal cord injury (SCI) results in permanent impairment of motor and sensory functions at and below the lesion site. There is no therapeutic option to the functional recovery of SCI involving diverse injury responses of different cell types in the lesion that limit endogenous nerve regeneration. In this regard, cell replacement therapy utilizing stem cells or their derivatives has become a highly promising approach to promote locomotor recovery. For this reason, the demand for a safe and efficient multipotent cell source that can differentiate into various neural cells is increasing. In this study, we evaluated the efficacy and safety of human polysialylated-neural cell adhesion molecule (PSA-NCAM)-positive neural precursor cells (hNPCsPSA-NCAM+) as a treatment for SCI. METHODS: One hundred thousand hNPCsPSA-NCAM+ isolated from human embryonic stem cell-derived NPCs were transplanted into the lesion site by microinjection 7 days after contusive SCI at the thoracic level. We examined the histological characteristics of the graft and behavioral improvement in the SCI rats 10 weeks after transplantation. RESULTS: Locomotor activity improvement was estimated by the Basso-Beattie-Bresnahan locomotor rating scale. Behavioral tests revealed that the transplantation of the hNPCsPSA-NCAM+ into the injured spinal cords of rats significantly improved locomotor function. Histological examination showed that hNPCsPSA-NCAM+ had differentiated into neural cells and successfully integrated into the host tissue with no evidence of tumor formation. We investigated cytokine expressions, which led to the early therapeutic effect of hNPCsPSA-NCAM+, and found that some undifferentiated NPCs still expressed midkine, a well-known neurotrophic factor involved in neural development and inflammatory responses, 10 weeks after transplantation. CONCLUSION: Our results demonstrate that hNPCsPSA-NCAM+ serve as a safe and efficient cell source which has the potential to improve impaired motor function following SCI.

A review on the impacts of nanomaterials on neuromodulation and neurological dysfunction using a zebrafish animal model.

Nanomaterials have been widely employed from industrial to medical fields due to their small sizes and versatile characteristics. However, nanomaterials can also induce unexpected adverse effects on health. In particular, exposure of the nervous system to nanomaterials can cause serious neurological dysfunctions and neurodegenerative diseases. A number of studies have adopted various animal models to evaluate the neurotoxic effects of nanomaterials. Among them, zebrafish has become an attractive animal model for neurotoxicological studies due to several advantages, including the well-characterized nervous system, efficient genome editing, convenient generation of transgenic lines, high-resolution in vivo imaging, and an array of behavioral assays. In this review, we summarize recent studies on the neurotoxicological effects of nanomaterials, particularly engineered nanomaterials and nanoplastics, using zebrafish and discuss key findings with advantages and limitations of the zebrafish model in neurotoxicological studies.

NOS2 and S-nitrosothiol signaling induces DNA hypomethylation and LINE-1 retrotransposon expression.

Inducible nitric oxide synthase (NOS2) produces high local concentrations of nitric oxide (NO), and its expression is associated with inflammation, cellular stress signals, and cellular transformation. Additionally, NOS2 expression results in aggressive cancer cell phenotypes and is correlated with poor outcomes in patients with breast cancer. DNA hypomethylation, especially of noncoding repeat elements, is an early event in carcinogenesis and is a common feature of cancer cells. In addition to altered gene expression, DNA hypomethylation results in genomic instability via retrotransposon activation. Here, we show that NOS2 expression and associated NO signaling results in substantial DNA hypomethylation in human cell lines by inducing the degradation of DNA (cytosine-5)­methyltransferase 1 (DNMT1) protein. Similarly, NOS2 expression levels were correlated with decreased DNA methylation in human breast tumors. NOS2 expression and NO signaling also resulted in long interspersed noncoding element 1 (LINE-1) retrotransposon hypomethylation, expression, and DNA damage. DNMT1 degradation was mediated by an NO/p38-MAPK/lysine acetyltransferase 5­dependent mechanism. Furthermore, we show that this mechanism is required for NO-mediated epithelial transformation. Therefore, we conclude that NOS2 and NO signaling results in DNA damage and malignant cellular transformation via an epigenetic mechanism.

Food allergy in early childhood increases the risk of oral allergy syndrome in schoolchildren: A birth cohort study.

BACKGROUND: The level of pollen in Korea has increased over recent decades. Research suggests that oral allergy syndrome (OAS) may be more frequent in childhood than previously recognized. We aimed to investigate the prevalence and characteristics of OAS in children aged 6-10 years from a general-population-based birth cohort. METHODS: We analyzed 930 children from the cohort for childhood origin of asthma and allergic diseases (COCOA). Allergic diseases were diagnosed annually by pediatric allergists. The skin prick tests were performed with 14 common inhalant allergens and four food allergens for the general population of children aged 3 and 7 years. RESULTS: Of the 930 eligible children, 44 (4.7%) aged 6-10 years were diagnosed with OAS. The mean age at onset was 6.74 years. OAS prevalence was 7.2% among children with allergic rhinitis (AR) and 19.1% among those with pollinosis, depending on comorbidity. OAS was more prevalent in schoolchildren with atopic dermatitis, food allergy, and sensitization to food allergens and grass pollen in early childhood. In schoolchildren with AR, only a history of food allergy until the age of 3 years increased the risk of OAS (aOR 2.971, 95% CI: 1.159-7.615). CONCLUSION: Food allergy and food sensitization in early childhood were associated with OAS in schoolchildren with AR. Further study is required to elucidate the mechanism by which food allergy in early childhood affects the development of OAS.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase IIb Clinical Study to Evaluate the Safety and Efficacy of DHP1401 in Patients with Mild to Moderate Alzheimer's Disease Treated with Donepezil: DHP1401 Randomized Trial in Mild to Moderate Alzheimer's Disease (DRAMA).

BACKGROUND: Preclinical studies in transgenic models of Alzheimer's disease (AD) suggest that DHP1401 has neuroprotective and memory-enhancing effects. OBJECTIVE: To evaluate the efficacy and safety of DHP1401 in AD patients treated with donepezilMethods:Methods: In a double-blind study, patients with mild-to-moderate AD were randomized (1:1:1) to receive a twice daily total dose of 500 mg or 1000 mg DHP1401 or placebo for 24 weeks. Tolerability and safety were monitored at baseline and weeks 12 and 24. RESULTS: total of 180 patients were randomized to Active 1 (500 mg: n = 62), Active 2 (1000 mg: n = 53), and control groups (n = 65) in 16 sites in Korea. There was no significant difference in the Alzheimer's Disease Assessment Scale (ADAS-cog) score, the primary efficacy endpoint, from baseline. However, in the subgroup with mild AD patients (MMSE, 20-26) who received the high dose of DHP1401 and the group that received donepezil 5 mg, the ADAS-cog scores improved. MMSE and K-TMT-e type B were significant in both active groups at week 24. The most frequently observed symptom was dizziness (2.78%), and the most commonly observed reactions were related to metabolism and nutrition disorders (5.00%). No remarkable adverse events were observed for 24 weeks. CONCLUSION: Although the effectiveness of DHP1401 was not proved to be superior as the primary efficacy endpoint, the secondary endpoints, MMSE and K-TMT-e type B, showed significant beneficial effects. Also, the subgroups showed that ADAS-cog scores significantly were improved. DHP1401 could be proven beneficial for the AD treatment by further clinical trials.

PLXNB1 mutations in the etiology of idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) comprises a group of rare genetic disorders characterized by pubertal failure caused by gonadotropin-releasing hormone (GnRH) deficiency. Genetic factors involved in semaphorin/plexin signaling have been identified in patients with IHH. PlexinB1, a member of the plexin family receptors, serves as the receptor for semaphorin 4D (Sema4D). In mice, perturbations in Sema4D/PlexinB1 signaling leads to improper GnRH development, highlighting the importance of investigating PlexinB1 mutations in IHH families. In total, 336 IHH patients (normosmic IHH, n = 293 and Kallmann syndrome, n = 43) from 290 independent families were included in the present study. Six PLXNB1 rare sequence variants (p.N361S, p.V608A, p.R636C, p.V672A, p.R1031H, and p.C1318R) are described in eight normosmic IHH patients from seven independent families. These variants were examined using bioinformatic modeling and compared to mutants reported in PLXNA1. Based on these analyses, the variant p.R1031H was assayed for alterations in cell morphology, PlexinB1 expression, and migration using a GnRH cell line and Boyden chambers. Experiments showed reduced membrane expression and impaired migration in cells expressing this variant compared to the wild-type. Our results provide clinical, genetic, molecular/cellular, and modeling evidence to implicate variants in PLXNB1 in the etiology of IHH.