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Innate and adaptive resistance to cancer therapies, such as chemotherapies, molecularly targeted therapies, and immune-modulating therapies, is a major issue in clinical practice. Subpopulations of tumor cells expressing the receptor tyrosine kinase AXL become enriched after treatment with antimitotic drugs, causing tumor relapse. Elevated AXL expression is closely associated with drug resistance in clinical samples, suggesting that AXL plays a pivotal role in drug resistance. Although several molecules with AXL inhibitory activity have been developed, none have sufficient activity and selectivity to be clinically effective when administered in combination with a cancer therapy. Here, we report a novel small molecule, ER-851, which is a potent and highly selective AXL inhibitor. To investigate resistance mechanisms and identify driving molecules, we conducted a comprehensive gene expression analysis of chemoresistant tumor cells in mouse xenograft models of genetically engineered human lung cancer and human triple-negative breast cancer. Consistent with the effect of AXL knockdown, cotreatment of ER-851 and antimitotic drugs produced an antitumor effect and prolonged relapse-free survival in the mouse xenograft model of human triple-negative breast cancer. Importantly, when orally administered to BALB/c mice, this compound did not induce retinal toxicity, a known side effect of chronic MER inhibition. Together, these data strongly suggest that AXL is a therapeutic target for overcoming drug resistance and that ER-851 is a promising candidate therapeutic agent for use against AXL-expressing antimitotic-resistant tumors.

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Hypertrophic cardiomyopathy (HCM) is the primary cause of sudden cardiac death in children and adolescents. Patients with HCM frequently have ventricular tachycardia and ventricular fibrillation, although complete atrioventricular block (CAVB) is very rare. We report a case of HCM with CAVB in an 8-year-old girl who underwent transvenous implantable cardioverter-defibrillator placement after resuscitation. In this patient, we identified a de novo heterozygous missense variant, Arg406Trp (c.1216C > T), in the desmin (DES) gene. Pathogenic variants in the DES gene result in cardiomyopathy, conduction disorders, and skeletal muscle weakness. This recently identified variant may cause HCM with CAVB. Résumé: La cardiomyopathie hypertrophique (CMH) est la première cause de mort subite d'origine cardiaque chez les enfants et les adolescents. Les patients atteints de CMH présentent fréquemment une tachycardie ventriculaire et une fibrillation ventriculaire, bien que le bloc auriculo-ventriculaire complet (BAVC) soit très rare. Nous rapportons un cas de CMH avec BAVC chez une fillette de 8 ans qui a reçu un défibrillateur cardioverteur implantable par voie transveineuse après réanimation. Chez cette patiente, nous avons isolé un variant faux sens hétérozygote de novo, Arg406Trp (c.1216C > T), dans le gène de la desmine (DES). Les variants pathogènes du gène DES entraînent une cardiomyopathie, des troubles de la conduction et une faiblesse des muscles squelettiques. Ce variant récemment identifié peut causer une CMH avec BAVC.

Innate and adaptive resistance to cancer therapies, such as chemotherapies, molecularly targeted therapies, and immune-modulating therapies, is a major issue in clinical practice. Subpopulations of tumor cells expressing the receptor tyrosine kinase AXL become enriched after treatment with anti-mitotic drugs, causing tumor relapse. Elevated AXL expression is closely associated with drug resistance in clinical samples, suggesting that AXL plays a pivotal role in drug resistance. Although several molecules with AXL inhibitory activity have been developed, none have sufficient activity and selectivity to be clinically effective when administered in combination with a cancer therapy. Here, we report a novel small molecule, ER-001259851-000, which is a potent and highly selective AXL inhibitor. To investigate resistance mechanisms and identify driving molecules, we conducted a comprehensive gene expression analysis of chemo-resistant tumor cells in mouse xenograft models of genetically engineered human lung cancer and human triple-negative breast cancer. Consistent with the effect of AXL knockdown, co-treatment of ER-001259851-000 and antimitotic drugs produced an anti-tumor effect and prolonged relapse-free survival in the mouse xenograft model of human triple-negative breast cancer. Importantly, when orally administered to BALB/c mice, this compound did not induce retinal toxicity, a known side effect of chronic MER inhibition. Together, these data strongly suggest that AXL is a therapeutic target for overcoming drug resistance and that ER-001259851-000 is a promising candidate therapeutic agent for use against AXL-expressing anti-mitotic-resistant tumors.

Background:T1 mapping is a recently developed imaging analysis method that allows quantitative assessment of myocardial T1 values obtained using MRI. In children, MRI is performed under free-breathing. Thus, it is important to know the changes in T1 values between free-breathing and breath-holding. This study aimed to compare the myocardial T1 mapping during breath-holding and free-breathing.Methods:Thirteen patients and eight healthy volunteers underwent cardiac MRI, and T1 values obtained during breath-holding and free-breathing were examined and compared. Statistical differences were determined using the paired t-test.Results:The mean T1 values during breath-holding were 1211.1 ± 39.0 ms, 1209.7 ± 37.4 ms, and 1228.9 ± 52.5 ms in the basal, mid, and apical regions, respectively, while the mean T1 values during free-breathing were 1165.1 ± 69.0 ms, 1103.7 ± 55.8 ms, and 1112.0 ± 81.5 ms in the basal, mid, and apical regions, respectively. The T1 values were lower during free-breathing than during breath-holding in almost all segments (basal: p = 0.008, mid: p < 0.001, apical: p < 0.001). The mean T1 values in each cross section were 3.1, 7.8, and 7.7% lower during free-breathing than during breath-holding in the basal, mid, and apical regions, respectively.Conclusions:We found that myocardial T1 values during free-breathing were about 3–8% lower in all cross sections than those during breath-holding. In free-breathing, it may be difficult to assess myocardial T1 values, except in the basal region, because of underestimation; thus, the findings should be interpreted with caution, especially in children.

Background POU1F1 encodes both PIT-1α, which plays pivotal roles in pituitary development and GH, PRL and TSHB expression, and the alternatively spliced isoform PIT-1β, which contains an insertion of 26-amino acids (β-domain) in the transactivation domain of PIT-1α due to the use of an alternative splice acceptor at the end of the first intron. PIT-1β is expressed at much lower levels than PIT-1α and represses endogenous PIT-1α transcriptional activity. Although POU1F1 mutations lead to combined pituitary hormone deficiency (CPHD), no patients with β-domain mutations have been reported. Results Here, we report that a three-generation family exhibited different degrees of CPHD, including growth hormone deficiency with intrafamilial variability of prolactin/TSH insufficiency and unexpected prolactinoma occurrence. The CPHD was due to a novel POU1F1 heterozygous variant (c.143-69T>G) in intron 1 of PIT-1α (RefSeq number NM_000306) or as c.152T>G (p.Ile51Ser) in exon 2 of PIT-1β (NM_001122757). Gene splicing experiments showed that this mutation yielded the PIT-1β transcript without other transcripts. The lymphocyte PIT-1β mRNA expression was significantly higher in the patients with the heterozygous mutation than a control. A luciferase reporter assay revealed that the PIT-1β-Ile51Ser mutant repressed PIT-1α and abolished transactivation capacity for the rat prolactin promoter in GH3 pituitary cells. Conclusions We describe, for the first time, that the PIT-1β mutation can cause CPHD through a novel genetic mechanism, such as PIT-1β overexpression, and that POU1F1 mutation might be associated with a prolactinoma. Analysis of new patients and long-term follow-up are needed to clarify the characteristics of PIT-1β mutations.

BACKGROUND A heterozygous mutation of STAT3 causes autosomal dominant hyper immunoglobulin E (IgE) syndrome; however, there are still many unclear points regarding the clinical spectrum of this syndrome. METHODS In addition to a clinical description of patients in terms of pedigree, a genetic analysis, quantitation of peripheral blood Th17 and ex vivo IL-17 production were carried out. RESULTS The proband, a 2-year-old boy (Patient 1) with early onset atopic dermatitis-like eczema and recurrent bacterial infections, was suspected of autosomal dominant hyper immunoglobulin E syndrome on the basis of his symptoms and family history. His mother (Patient 2) also had skin eczema and recurrent bacterial infections, and his sister (Patient 3) had skin eczema. A novel STAT3 mutation (p.S476F) was detected in all three patients, but not in the father, who had no such symptoms. A significant decrease in peripheral blood Th17 subsets and IL-17 production was found in all the patients. Curiously, all three patients carrying the p.S476F mutation in STAT3 lacked connective tissue signs such as distinctive facial features, retention of primary teeth, and joint hyperextensibility. CONCLUSIONS Autosomal dominant hyper IgE syndrome should, perhaps, be considered even if patients lack connective tissue signs, as long as hypersensitivity to infection and skin manifestations with hyper IgE are present.

BACKGROUND Because of the overabundance of vaccination information on the internet, in the media, and on social media, providing clear and correct information on immunization is critical for parental decision-making. In 2018, the Japan Pediatric Society created and distributed a Vaccine Information Statement (VIS) to provide appropriate immunization information to caregivers. The objectives of the present study were to evaluate the effect of the VIS on immunization rates, adherence to schedule, and parental understanding of immunization in Japan. METHODS This cross-sectional study was conducted at 18 centers in 2 prefectures in Japan. Caregivers were assigned to an intervention group, which received the VIS and a questionnaire when their child reached the age of 1 month, and a control group, which received only the questionnaire. Using the self-reported questionnaires, we evaluated vaccination rates and schedule adherence at age 2 months, and parental knowledge, attitudes, and beliefs regarding immunization. Three months later, the questionnaires were returned, and the findings were compared between the 2 groups. RESULTS We contacted 422 and 428 persons in the intervention and control groups, respectively, and 111/422 (26.3%) and 119/428 (27.8%) returned the surveys. Vaccination rates and adherence rates for the first dose of 4 recommended vaccines did not differ significantly (P > 0.25); however, there were some positive effects on items related to vaccine knowledge (P = 0.03), perceived benefits (P = 0.02), perceived barriers (P

There are no recommended diagnostic criteria for transient congenital hypothyroidism (CH) during early childhood. In this study, we aimed to identify the factors that distinguish permanent (P)- and transient (T)-CH. We retrospectively analyzed the clinical, biochemical, and imaging data of 42 children with a definitive diagnosis of P- or T-CH by re-evaluation tests at our institution from November 1986 to October 2019. Patients who continued levothyroxine (L-T4) treatment after the re-evaluation tests were classified as group P (n = 19), while patients who were diagnosed with T-CH and discontinued L-T4 treatment were classified as group T (n = 23). Initial testing performed during infancy showed that the mean serum TSH and free T4 (FT4) levels did not differ significantly between groups P and T. None of the patients in group T required an increased dosage of L-T4 at the age of 3 yr and above while 85% of the patients in group P required increased dosages of L-T4. Hence, T-CH was suspected in patients who did not require an increase in L-T4 dosage at the age of 3 yr and above.

Objective: This study examined psychological status trajectories of mothers of infants with nonsyndromic orofacial clefts in Japan. Design: Prospective cohort study. Setting: Data from the Japan Environment and Children’s Study. Participants: Infants with a nonsyndromic cleft (N = 148) including cleft lip and palate (CLP; n = 72), cleft lip (CL; n = 46), and cleft palate (CP; n = 30). The control group included unaffected infants (N = 84 454). Main Outcome Measures: At 15 weeks and 27 weeks of pregnancy and 12 months after birth, the Kessler Psychological Distress Scale (clinical cutoff ≥5) was used. At 1 month and 6 months after birth, the Edinburgh Postnatal Depression Scale (clinical cutoff ≥9) was used. Results: Prenatal diagnosis rates were unavailable. Mothers of infants with CLP had higher psychological distress than controls at 27 weeks of pregnancy (prevalence ratio [PR] = 1.36, 95% CI: 1.06-1.74) and postnatal depression at 1 month after birth (PR = 2.21, 95% CI: 1.53-3.19). Mothers of infants with CP showed heightened psychological distress at 27 weeks of pregnancy (PR = 1.62, 95% CI: 1.21-2.17) and postnatal depression 6 months after birth (PR = 1.86, 95% CI: 1.01-3.43). There was no significant association between CL and maternal psychological status. At 12 months after birth, no differences in distress were found between mothers of infants with a cleft and controls. Conclusions: Mothers of infants with orofacial clefts may need psychosocial support, particularly during pregnancy and the first year after birth.

This prospective cohort study aimed to examine the associations between mold growth, type of stoves, and fragrance materials and early childhood wheezing and asthma, using data from the Japan Environment and Children's Study. Mold growth at home, usage of kerosene/gas stove, wood stove/fireplace, and air freshener/deodorizer were surveyed using a questionnaire at 1.5-year-old, and childhood wheezing and doctor-diagnosed asthma during the previous year were obtained using a 3-year-old questionnaire. Multilevel logistic regression analysis was performed to evaluate the association between exposure to childhood wheezing and asthma. A total of 60 529 children were included in the analysis. In multivariate analyses, mold growth and wood stove/fireplace had significantly higher odds ratios (ORs) for wheezing (mold growth: 1.13; 95% CI, 1.06-1.22; wood stove/fireplace: 1.23; 95% CI, 1.03-1.46). All four exposures had no significant ORs for childhood doctor-diagnosed asthma; however, in the supplemental analysis of northern regions, wood stove/fireplace had a significantly higher OR for asthma. Mold growth and wood stove/fireplace had significant associations with childhood wheezing in the northern regions. Mold elimination in the dwellings and use of clean heating (no air pollution emissions) should be taken into consideration to prevent and improve childhood wheezing and asthma.

Background Coronavirus disease 2019 (COVID‐19) pandemic has affected the lives of young and old people. Most reports on pediatric cases suggest that children experience fewer and milder symptoms than adults do. This is the first nationwide study that focused on pediatric cases reported by pediatricians, including those with no or mild symptoms, in Japan. Methods We analyzed the epidemiological and clinical characteristics, and transmission patterns of 840 pediatric (

Axl and Mer are members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases. Previously, we reported that enzyme-mediated inhibition of Mer by an Axl/Mer dual inhibitor led to retinal toxicity in mice, whereas selective Axl inhibition by compound 1 did not. On the other hand, compound 1 showed low membrane permeability. Here, we designed and synthesized a novel series of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives and evaluated their Axl and Mer inhibitory activities, leading to identification of ER-001259851-000 as a potent and selective Axl inhibitor with drug-likeness and a promising pharmacokinetic profile in mice.

Background: The influence of maternal psychological distress on infant congenital heart defects (CHDs) has not been thoroughly investigated. Furthermore, there have been no reports on the combined effect of maternal psychological distress and socioeconomic status on infant CHDs. This study aimed to examine whether maternal psychological distress, socioeconomic status, and their combinations were associated with CHD.Methods: We conducted a prospective cohort study using data from the Japan Environment and Children’s Study, which recruited pregnant women between 2011 and 2014. Maternal psychological distress was evaluated using the Kessler Psychological Distress Scale in the first trimester, while maternal education and household income were evaluated in the second and third trimesters. The outcome of infant CHD was determined using the medical records at 1 month of age and/or at birth. Crude and adjusted logistic regression analyses were performed to evaluate the association between maternal psychological distress and education and household income on infant CHD.Results: A total of 93,643 pairs of mothers and infants were analyzed, with 1.1% of infants having CHDs. Maternal psychological distress had a significantly higher odds ratio in the crude analysis but not in the adjusted analysis, while maternal education and household income were statistically insignificant. In the analysis of the combination variable of lowest education and psychological distress, the trend for p was statistically significant in the crude and adjusted analyses.Conclusions: The combination of maternal psychological distress and lower education may be a possible indicator of infant CHD.

Lower respiratory tract infections due to respiratory syncytial virus are associated with morbidity and mortality in infants and children. Thus precise elucidation of respiratory syncytial virus lower respiratory tract infection pathophysiology is important.Medical records of hospitalized patients were reviewed. Patients were divided into three groups. Group I: patients who improved without oxygen supply. Group II: patients who received oxygen supply, but not nasal high-flow cannula therapy. Group III: patients who received nasal high-flow cannula. Patients were also divided by age group into the6 months and ≥6 months groups. Parameters for differentiating the severity among groups were then evaluated. Further, serum concentration of high-mobility group box-1 and several cytokines (Inerleukin-6, soluble tumor necrosis factor receptor-1/2, Interleukin-18, Interferon-gamma responsive protein-100) were evaluated.One hundred eighty-nine were enrolled. An analysis of variance for those6 months showed overall differences including younger age, lower pH, and increased partial pressure of carbon dioxide (pCO2), bicarbonate (HCO3-), and base excess at the time of admission. On the other hand, analysis of variance for ≥6 months revealed that, in addition to a lower pH and increased pCO2, patients showed differences including decreased serum total protein and albumin, and increased aspartate aminotransferase (AST), alanin aminotransferase (ALT), lactate dehydrogenase (LDH), Ferritin and C-reactive protein (CRP) levels. Further, evaluation of serum cytokines showed that IL-6, s tumor necrotizing factor receptor-1/2, and high-mobility group box-1 were higher in Group II/III among the ≥6 months age group, but not for those in the6 months group.The pathophysiology of severe respiratory syncytial virus lower respiratory tract infection varies according to the age at onset. In late infancy and childhood, a certain proportion of patients show a hyperinflammatory status.

Background Lower respiratory tract infections (LRTIs) are a cause of inpatient and outpatient care among children. Although orofacial clefts seem to be associated with LRTIs, epidemiological studies are scarce on this topic. This study aimed to examine whether infants with orofacial clefts were associated with LRTIs. Methods This prospective cohort study used data from the Japan Environment and Children's Study, whose baseline recruitment was conducted during 2011-2014. This study included 81,535 participants. The number of infants with cleft lip and palate (CLP), cleft lip (CL), and cleft palate only (CP) was 67, 49, and 36, respectively. We defined history of LRTIs until 12 months' age reported by their mothers as the dependent variable. Accumulated breastfeeding duration was used as potential mediators. Results The incidence proportion of LRTIs among the control group was 6.0%. The incidence proportion among infants with CLP, CL, and CP were 11.9%, 14.3%, and 5.6%, respectively. After adjusting for covariates, compared with the control group, infants with CLP and CL were associated with risk of LRTIs (incidence risk ratio [IRR] of CLP = 2.38 [95% confidence interval = 1.30, 4.36] and of CL = 2.73 [1.40, 5.33]) , but not ones with CP (1.08 [0.28, 4.15]). Accumulated breastfeeding duration decreased the IRR of CLP only (IRR of CLP = 2.16 [1.19, 3.93]). Conclusions Infants with orofacial clefts aged 1 year have a potentially high incidence proportion of LRTIs. Accumulated breastfeeding duration might mediate the associations of CLP.

Axl and Mer are a members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases, which, when activated, can promote tumor cell survival, proliferation, migration, invasion, angiogenesis, and tumor-host interactions. Chronic inhibition of Mer leads to retinal toxicity in mice. Therefore, successful development of an Axl targeting agent requires ensuring that it is safe for prolonged treatment. Here, to clarify whether enzyme inhibition of Mer by a small molecule leads to retinal toxicity in mice, we designed and synthesized Axl/Mer inhibitors and Axl-selective inhibitors. We identified an Axl/Mer dual inhibitor 28a, which showed retinal toxicity at a dose of 100 mg/kg in mice. Subsequent derivatization of a pyridine derivative led to the discovery of a pyrimidine derivative, 33g, which selectively inhibited the activity of Axl over Mer without retinal toxicity at a dose of 100 mg/kg in mice. Additionally, the compound displayed in vivo anti-tumor effects without influencing body weight in a Ba/F3-Axl isogenic subcutaneous model.

Clinical diagnosis of transient abnormal myelopoiesis (TAM) relies on the detection of characteristic blasts and leukocytosis in peripheral blood. We report two patients of trisomy 21 with TAM with hypereosinophilia, who had neither circulating blasts nor leukocytosis. Genetic testing of polymorphonuclear leukocytes isolated from whole blood revealed heterozygous mutations in GATA1, suggesting that the mutations were harbored in increased eosinophils. Both patients had direct hyperbilirubinemia and one died of liver fibrosis. Our findings emphasize the importance of screening for GATA1 mutations in neonatal infants with Down syndrome and hypereosinophilia even if blasts are not detected in peripheral blood smears.

Introduction Although imatinib is the first-line of therapy for Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML), in Japan, it is recommended by the manufacturer that lactating women treated with imatinib mesylate for CML should discontinue breastfeeding their infants. Case A 32-year-old pregnant patient was diagnosed with Ph-positive CML at 13 weeks of gestation. She received imatinib (400 mg/day) after 28 weeks of gestation. A female infant was delivered at a gestational age of 35 weeks and 3/7 days after preterm premature rupture of membranes. It was decided to feed only colostrum to the infant and formula feeding was done subsequently because of the risk of the transfer of imatinib to breast milk. The milk/plasma (M/P) ratio and the relative infant dose (RID) for imatinib were calculated to be 0.35 and 1.4%, respectively at 5 days of life. Moreover, the serum level of imatinib in the child of age 5 days was 27 ng/mL, which was much lower than the target trough value for CML (1000 ng/mL). Conclusion The M/P ratio and RID values for maternally administered imatinib were within the safe range for breastfeeding, as reported in previous studies. In addition, it was found that the serum concentration of imatinib in the child was relatively low during short-term breastfeeding.

Biallelic neuroblastoma amplified sequence (NBAS) gene mutations have recently been identified to cause a reduction in its protein expression and a broad phenotypic spectrum, from isolated short stature, optic nerve atrophy, and Pelger-Huet anomaly (SOPH) syndrome or infantile liver failure syndrome 2 to a combined, multi-systemic disease including skeletal dysplasia and immunological and neurological abnormalities. Herein, we report a 34-year-old patient with a range of phenotypes for NBAS deficiency due to compound heterozygous variants; one is a SOPH-specific variant, p.Arg1914His, and the other is a novel splice site variant, c.6433-2A>G. The patient experienced recurrent acute liver failure until early childhood. Hypogammaglobulinemia, a decrease in natural killer cells, and optic nerve atrophy were evident from infancy to childhood. In adulthood, the patient exhibited novel phenotypic features such as hepatic cirrhosis complicated by portal hypertension and autoimmune hemolytic anemia. The patient also suffered from childhood-onset insulin-requiring diabetes with progressive beta cell dysfunction. The patient had severe short stature and exhibited dysmorphic features compatible with SOPH, intellectual disability, and epilepsy. NBAS protein expression in the patient's fibroblasts was severely low. RNA expression analysis for the c.6433-2A>G variant showed that this variant activated two cryptic splice sites in intron 49 and exon 50, for which the predicted consequences at the protein level were an in-frame deletion/insertion, p.(Ile2199_Asn2202delins16), and a premature termination codon, p.(Ile2199Tyrfs*17), respectively. These findings indicate that NBAS deficiency is a multi-systemic progressive disease. The results of this study extend the spectrum of clinical and genetic findings related to NBAS deficiency.

A 9-year-old girl was diagnosed with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL). Although she entered remission after induction therapy, she relapsed 15 months after maintenance therapy cessation. Since further investigation revealed EBF1-PDGFRB fusion, her condition was treated as BCR-ABL1-like acute lymphoblastic leukemia. She was started on a tyrosine kinase inhibitor, imatinib, and chemotherapy and underwent umbilical cord blood transplantation following reduced intensity conditioning. She has remained in complete remission for 36 months after cord blood transplantation. This case demonstrates the successful use of a tyrosine kinase inhibitor to treat BCP-ALL with a fusion transcript and highlights the need for a standardized treatment protocol.