A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS.

In the present study, we report a human-inherited, impaired, adaptive immunity disorder, which predominantly manifested as a B cell differentiation defect, caused by a heterozygous IKZF3 missense variant, resulting in a glycine-to-arginine replacement within the DNA-binding domain of the encoded AIOLOS protein. Using mice that bear the corresponding variant and recapitulate the B and T cell phenotypes, we show that the mutant AIOLOS homodimers and AIOLOS-IKAROS heterodimers did not bind the canonical AIOLOS-IKAROS DNA sequence. In addition, homodimers and heterodimers containing one mutant AIOLOS bound to genomic regions lacking both canonical motifs. However, the removal of the dimerization capacity from mutant AIOLOS restored B cell development. Hence, the adaptive immunity defect is caused by the AIOLOS variant hijacking IKAROS function. Heterodimeric interference is a new mechanism of autosomal dominance that causes inborn errors of immunity by impairing protein function via the mutation of its heterodimeric partner.

Factors contributing to the diagnosis and onset prediction of perennial allergic rhinitis in high-risk children: A sub-analysis of the CHIBA study.

BACKGROUND: This study aimed to clarify the diagnostic and predictive factors for perennial allergic rhinitis (PAR) onset in children by analyzing the results of the Chiba High-risk Birth Cohort for Allergy study, which examined newborns with a family history of allergies. METHODS: Overall, 306 pregnant women were recruited. Their newborns were examined by otolaryngologists and pediatric allergists at 1, 2, and 5 years of age. Participants with clinical and laboratory data available at all consultation points were considered eligible. RESULTS: Among 187 eligible participants, the prevalence rates of PAR were 2.1%, 4.3%, and 24.1% at 1, 2, and 5 years of age, respectively. AR-specific nasal local findings and eosinophils in nasal smear were observed in a substantial number of patients with PAR at 1 and 2 years of age. Factors present up to 2 years of age that were associated with PAR onset at 5 years of age, in descending order, were as follows: sensitization to house dust mites (HDM), nasal eosinophilia, and sensitization to cat dander. In 44 cases with HDM sensitization, nasal eosinophilia up to 2 years of age achieved a sensitivity of 76.0% and a specificity of 73.7% for predicting PAR onset at 5 years. CONCLUSIONS: Rhinitis findings and nasal eosinophilia are useful auxiliary diagnostic items for pediatric PAR. Sensitization to HDM and nasal eosinophilia were the most influential factors associated with future PAR onset. A combination of these factors may facilitate the prediction of PAR onset.

Gut microbiota and fecal metabolites in sustained unresponsiveness by oral immunotherapy in school-age children with cow's milk allergy.

BACKGROUND: Oral immunotherapy (OIT) can ameliorate cow's milk allergy (CMA); however, the achievement of sustained unresponsiveness (SU) is challenging. Regarding the pathogenesis of CMA, recent studies have shown the importance of gut microbiota (Mb) and fecal water-soluble metabolites (WSMs), which prompted us to determine the change in clinical and gut environmental factors important for acquiring SU after OIT for CMA. METHODS: We conducted an ancillary cohort study of a multicenter randomized, parallel-group, delayed-start design study on 32 school-age children with IgE-mediated CMA who underwent OIT for 13 months. We defined SU as the ability to consume cow's milk exceeding the target dose in a double-blind placebo-controlled food challenge after OIT followed by a 2-week-avoidance. We longitudinally collected 175 fecal specimens and clustered the microbiome and metabolome data into 29 Mb- and 12 WSM-modules. RESULTS: During OIT, immunological factors improved in all participants. However, of the 32 participants, 4 withdrew because of adverse events, and only 7 were judged SU. Gut environmental factors shifted during OIT, but only in the beginning, and returned to the baseline at the end. Of these factors, milk- and casein-specific IgE and the Bifidobacterium-dominant module were associated with SU (milk- and casein-specific IgE; OR for 10 kUA/L increments, 0.67 and 0.66; 95%CI, 0.41-0.93 and 0.42-0.90; Bifidobacterium-dominant module; OR for 0.01 increments, 1.40; 95%CI, 1.10-2.03), and these associations were observed until the end of OIT. CONCLUSIONS: In this study, we identified the clinical and gut environmental factors associated with SU acquisition in CM-OIT.

Association of umbilical cord serum TARC/CCL17 with childhood allergies: A birth cohort study.

BACKGROUND: Early identification of infants at high risk of allergies can improve the efficacy of preventive interventions. However, an established quantifiable risk assessment method in the early postnatal period does not exist. TARC (or CCL17) is a Th2 chemokine used as an activity marker for atopic dermatitis (AD). Therefore, we evaluated the association between cord blood TARC (cTARC) and the development of allergic diseases in childhood. METHODS: This is a high-risk birth cohort for allergy, consisting of children with a family history of allergy. We collected 263 pairs of maternal and child cord blood samples perinatally and child blood samples at ages 1, 2, and 5 years. TARC and allergen-specific immunoglobulin E levels were measured, and the relationship between allergic diseases was analyzed. RESULTS: The median cTARC was 989 pg/mL (interquartile range [IQR]: 667-1430 pg/mL). The cTARC levels in children who developed AD were higher than those in children who did not develop AD, and the association strengthened with younger age (median [IQR] at 1 year: 1285 [816-1965] vs. 933 [662-1330] pg/mL, p < 0.01; at 2 years: 1114 [787-1753] vs. 950 [660-1373] pg/mL, p = 0.02). In the multivariate analysis, cTARC was associated with AD, egg white sensitization, food allergy, allergic rhinitis, and Japanese cedar pollen sensitization. CONCLUSIONS: cTARC was associated with the development of allergic diseases and allergen sensitization in early childhood. These results suggest that, infantile AD-mediated atopic march starts during fetal life, and this immune status is reflected in the cTARC at birth.

Severe neuroglycopenic symptoms due to nonketotic hypoglycemia in children with cardio-facio-cutaneous syndrome.

Cardio-facio-cutaneous syndrome (CFC) (OMIM 115150) is a congenital disease caused by constitutive activation of the Raf/MEK/ERK signaling cascade. Unlike aspects of morphological anomalies, metabolic functions related to the disease have garnered little attention. We present severe neuroglycopenic symptoms due to nonketotic hypoglycemia in two children with CFC (Case 1, a 4-year-old male with c.389A > G heterozygous variant in MAP2K1; Case 2, a 3-year-old male with c.770A > G heterozygous variant in BRAF). Case 1 exhibited a nonketotic hypoglycemic coma and clustered left-hemispheric convulsions despite receiving infusion therapy, leading to severe sequelae with choreoathetosis. Brain magnetic resonance imaging of Case 1 showed T2-elongation with restricted diffusion on the bilateral basal ganglia and thalamus, with the dominance of the right putamen. Case 2 presented a prolonged generalized seizure as an initial clinical symptom but fully recovered. The presence of growth hormone and cortisol deficiency was ruled out in both cases. Blood spots acylcarnitine profiles excluded the co-occurrence of mitochondrial HMG-CoA synthase deficiency and HMG-CoA lyase deficiency. These cases demonstrate the potential vulnerability to nonketotic hypoglycemia, especially during lipid shortages. As children with CFC frequently have difficulties feeding, we suggest great attention should be paid to the potential risk of severe nonketotic hypoglycemia.

Skin care interventions in infants for preventing eczema and food allergy.

BACKGROUND: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective for preventing eczema or food allergy. OBJECTIVES: Primary objective To assess the effects of skin care interventions such as emollients for primary prevention of eczema and food allergy in infants. Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy. SEARCH METHODS: We performed an updated search of the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase in September 2021. We searched two trials registers in July 2021. We checked the reference lists of included studies and relevant systematic reviews, and scanned conference proceedings to identify further references to relevant randomised controlled trials (RCTs).  SELECTION CRITERIA: We included RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (≤ 12 months) without pre-existing eczema, food allergy, or other skin condition. Eligible comparisons were standard care in the locality or no treatment. Types of skin care interventions could include moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required. DATA COLLECTION AND ANALYSIS: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured at the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen. MAIN RESULTS: We identified 33 RCTs comprising 25,827 participants. Of these, 17 studies randomising 5823 participants reported information on one or more outcomes specified in this review.  We included 11 studies, randomising 5217 participants, in one or more meta-analyses (range 2 to 9 studies per individual meta-analysis), with 10 of these studies providing IPD; the remaining 6 studies were included in the narrative results only.   Most studies were conducted at children's hospitals. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although the definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to three years. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported information on our prespecified outcomes, 13 assessed emollients. We assessed most of the evidence in the review as low certainty and had some concerns about risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. We assessed the evidence for the primary food allergy outcome as high risk of bias due to the inclusion of only one trial, where findings varied based on different assumptions about missing data. Skin care interventions during infancy probably do not change the risk of eczema by one to three years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; risk difference 5 more cases per 1000 infants, 95% CI 28 less to 47 more; moderate-certainty evidence; 3075 participants, 7 trials) or time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). Skin care interventions during infancy may increase the risk of IgE-mediated food allergy by one to three years of age (RR 2.53, 95% CI 0.99 to 6.49; low-certainty evidence; 976 participants, 1 trial) but may not change risk of allergic sensitisation to a food allergen by age one to three years (RR 1.05, 95% CI 0.64 to 1.71; low-certainty evidence; 1794 participants, 3 trials). Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial); however, this was only seen for cow's milk, and may be unreliable due to over-reporting of milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.33, 95% CI 1.01 to 1.75; risk difference 17 more cases per 1000 infants, 95% CI one more to 38 more; moderate-certainty evidence; 2728 participants, 6 trials) and may increase the risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) and stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although CIs for slippages and stinging/allergic reactions were wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses showed that the effects of interventions were not influenced by age, duration of intervention, hereditary risk, filaggrin (FLG) mutation, chromosome 11 intergenic variant rs2212434, or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and eczema or food allergy development. AUTHORS' CONCLUSIONS: Based on low- to moderate-certainty evidence, skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema; may increase risk of food allergy; and probably increase risk of skin infection. Further study is needed to understand whether different approaches to infant skin care might prevent eczema or food allergy.

Skincare interventions in infants for preventing eczema and food allergy: A cochrane systematic review and individual participant data meta-analysis.

OBJECTIVE: Eczema and food allergy start in infancy and have shared genetic risk factors that affect skin barrier. We aimed to evaluate whether skincare interventions can prevent eczema or food allergy. DESIGN: A prospectively planned individual participant data meta-analysis was carried out within a Cochrane systematic review to determine whether skincare interventions in term infants prevent eczema or food allergy. DATA SOURCES: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to July 2020. ELIGIBILITY CRITERIA FOR SELECTED STUDIES: Included studies were randomized controlled trials of infants <1 year with healthy skin comparing a skin intervention with a control, for prevention of eczema and food allergy outcomes between 1 and 3 years. RESULTS: Of the 33 identified trials, 17 trials (5823 participants) had relevant outcome data and 10 (5154 participants) contributed to IPD meta-analysis. Three of seven trials contributing to primary eczema analysis were at low risk of bias, and the single trial contributing to primary food allergy analysis was at high risk of bias. Interventions were mainly emollients, applied for the first 3-12 months. Skincare interventions probably do not change risk of eczema by age 1-3 years (RR 1.03, 95% CI 0.81, 1.31; I2 =41%; moderate certainty; 3075 participants, 7 trials). Sensitivity analysis found heterogeneity was explained by increased eczema in a trial of daily bathing as part of the intervention. It is unclear whether skincare interventions increase risk of food allergy by age 1-3 years (RR 2.53, 95% CI 0.99 to 6.47; very low certainty; 996 participants, 1 trial), but they probably increase risk of local skin infections (RR 1.34, 95% CI 1.02, 1.77; I2 =0%; moderate certainty; 2728 participants, 6 trials). CONCLUSION: Regular emollients during infancy probably do not prevent eczema and probably increase local skin infections.

Skin care interventions in infants for preventing eczema and food allergy.

BACKGROUND: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective in preventing eczema or food allergy. OBJECTIVES: Primary objective To assess effects of skin care interventions, such as emollients, for primary prevention of eczema and food allergy in infants Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy. SEARCH METHODS: We searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials. SELECTION CRITERIA: RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required. DATA COLLECTION AND ANALYSIS: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured by the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen. MAIN RESULTS: This review identified 33 RCTs, comprising 25,827 participants. A total of 17 studies, randomising 5823 participants, reported information on one or more outcomes specified in this review. Eleven studies randomising 5217 participants, with 10 of these studies providing IPD, were included in one or more meta-analysis (range 2 to 9 studies per individual meta-analysis). Most studies were conducted at children's hospitals. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported our outcomes, 13 assessed emollients. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to two years. We assessed most of this review's evidence as low certainty or had some concerns of risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. Evidence for the primary food allergy outcome was rated as high risk of bias due to inclusion of only one trial where findings varied when different assumptions were made about missing data. Skin care interventions during infancy probably do not change risk of eczema by one to two years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; moderate-certainty evidence; 3075 participants, 7 trials) nor time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). It is unclear whether skin care interventions during infancy change risk of IgE-mediated food allergy by one to two years of age (RR 2.53, 95% CI 0.99 to 6.47; 996 participants, 1 trial) or allergic sensitisation to a food allergen at age one to two years (RR 0.86, 95% CI 0.28 to 2.69; 1055 participants, 2 trials) due to very low-certainty evidence for these outcomes. Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial). However, this was only seen for cow's milk, and may be unreliable due to significant over-reporting of cow's milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.34, 95% CI 1.02 to 1.77; moderate-certainty evidence; 2728 participants, 6 trials) and may increase risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) or stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although confidence intervals for slippages and stinging/allergic reactions are wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses show that effects of interventions were not influenced by age, duration of intervention, hereditary risk, FLG mutation,  or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and risk of developing eczema or food allergy. AUTHORS' CONCLUSIONS: Skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema, and probably increase risk of skin infection. Effects of skin care interventions on risk of food allergy are uncertain. Further work is needed to understand whether different approaches to infant skin care might promote or prevent eczema and to evaluate effects on food allergy based on robust outcome assessments.

Specific temperament in patients with nevoid basal cell carcinoma syndrome.

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is a neurocutaneous disease, characterized by tumorigenesis and developmental anomalies due to aberrant sonic hedgehog (Shh) signaling. Patients with NBCCS typically appear calm and carefree, suggesting that a specific personality in these patients may be associated with an enhanced hedgehog pathway. Our study aimed to determine the personality type in these patients. METHODS: We enrolled 14 mentally normal patients with genetically confirmed NBCCS (seven males and seven females; mean age = 25.2 years) and 20 controls (10 males and 10 females; mean age = 27.9 years). The patients were assessed with the Japanese version of the Temperament and Character Inventory, based on the seven-dimensional model of temperament and character, and their clinical symptoms were evaluated. The amygdala volumes of six patients with NBCCS were measured using magnetic resonance imaging with image-processing software. RESULTS: Patients with NBCCS scored significantly lower on harm avoidance (0.89) than controls (1.00; P = 0.0084). Moreover, patients with NBCCS and developmental malformations such as rib anomalies, who may have experienced Shh signaling enhancement from the prenatal period, scored significantly lower on harm avoidance (0.80 [P = 0.0031]). The left amygdala volume was also significantly reduced in patients with NBCCS (P = 0.0426). CONCLUSIONS: Patients with NBCCS who experienced increased Shh signaling from the prenatal period showed significantly lower harm avoidance related to serotonin. The left amygdala volume was significantly reduced in these patients. Our results indicate that Shh signaling may influence the human personality.

Establishment of a Gorlin syndrome model from induced neural progenitor cells exhibiting constitutive GLI1 expression and high sensitivity to inhibition by smoothened (SMO).

The hedgehog signaling pathway is a vital factor for embryonic development and stem cell maintenance. Dysregulation of its function results in tumor initiation and progression. The aim of this research was to establish a disease model of hedgehog-related tumorigenesis with Gorlin syndrome-derived induced pluripotent stem cells (GS-iPSCs). Induced neural progenitor cells from GS-iPSCs (GS-NPCs) show constitutive high GLI1 expression and higher sensitivity to smoothened (SMO) inhibition compared with wild-type induced neural progenitor cells (WT-NPCs). The differentiation process from iPSCs to NPCs may have similarity in gene expression to Hedgehog signal-related carcinogenesis. Therefore, GS-NPCs may be useful for screening compounds to find effective drugs to control Hedgehog signaling activity.

Activated invariant natural killer T cells directly recognize leukemia cells in a CD1d-independent manner.

Invariant natural killer T (iNKT) cells are innate-like CD1d-restricted T cells that express the invariant T cell receptor (TCR) composed of Vα24 and Vß11 in humans. iNKT cells specifically recognize glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d. iNKT cells show direct cytotoxicity toward CD1d-positive tumor cells, especially when CD1d presents glycolipid antigens. However, iNKT cell recognition of CD1d-negative tumor cells is unknown, and direct cytotoxicity of iNKT cells toward CD1d-negative tumor cells remains controversial. Here, we demonstrate that activated iNKT cells recognize leukemia cells in a CD1d-independent manner, however still in a TCR-mediated way. iNKT cells degranulated and released Th1 cytokines toward CD1d-negative leukemia cells (K562, HL-60, REH) as well as αGalCer-loaded CD1d-positive Jurkat cells. The CD1d-independent cytotoxicity was enhanced by natural killer cell-activating receptors such as NKG2D, 2B4, DNAM-1, LFA-1 and CD2, but iNKT cells did not depend on these receptors for the recognition of CD1d-negative leukemia cells. In contrast, TCR was essential for CD1d-independent recognition and cytotoxicity. iNKT cells degranulated toward patient-derived leukemia cells independently of CD1d expression. iNKT cells targeted myeloid malignancies more than acute lymphoblastic leukemia. These findings reveal a novel anti-tumor mechanism of iNKT cells in targeting CD1d-negative tumor cells and indicate the potential of iNKT cells for clinical application to treat leukemia independently of CD1d.

Fulminant myocarditis following recurrent generalized erythrokeratoderma in a child with a heterozygous GJA1 variant.

Pathogenic germline variants in the gap junction protein alpha 1 (GJA1) gene have been identified in several congenital disorders affecting cutaneous, skeletal, and cardiac tissues. Here, we describe a 12-year-old patient with a GJA1 c.113G>A, p.(Gly38Glu) variant, who presented with fulminant myocarditis following recurrent generalized erythrokeratoderma. His mother and younger sister had the same clinical manifestations with the same GJA1 variant, but did not have cardiac dysfunction. GJA1 variants have been reported in patients with congenital cardiac malformations, while acute myocarditis in GJA1-related disorders has not been reported so far.

JPH203, a newly developed anti-cancer drug, shows a preincubation inhibitory effect on L-type amino acid transporter 1 function.

JPH203 is a novel anti-cancer drug targeting L-type amino acid transporter 1 (LAT1), which plays a primary role in the uptake of essential amino acids in tumor cells. Although a co-incubation inhibitory effect of JPH203 has been shown in a conventional uptake assay, its preincubation inhibitory effects have remained undetermined. Therefore, we aimed to characterize the preincubation inhibitory effects of JPH203 on LAT1 function using leucine uptake assays in LAT1-positive human colon cancer HT-29 cells. Preincubation of the cells with JPH203 (0.3 µM for 120 min) decreased the activity level to 30% of that in dimethylsulfoxide-treated cells. Similarly, in time-dependency analysis, preincubation of HT-29 cells with 10 µM JPH203 for 30, 60, and 120 min decreased the leucine uptake activity (42%, 32%, and 28% of that in control cells, respectively). Furthermore, the IC50 value of the combination of preincubation and co-incubation effects was lower than that of co-incubation inhibition alone (34.2 ± 3.6 nM vs. 99.2 ± 11.0 nM). In conclusion, we revealed that JPH203 has the capability to inhibit LAT1 function through preincubation effects. Moreover, preincubation synergistically enhances the co-incubation inhibitory effects. These findings provide a novel insight into the anti-cancer effects of JPH203 in cancer therapy.

Haemophilus influenzae type b capsular polysaccharide antibody levels in Japanese young patients with hematological malignancies and asplenia.

Individuals with immunosuppressive condition have a high risk of invasive Haemophilus influenzae type b (Hib) infection. In Japan, routine Hib vaccination program for children under 5 years old was introduced in December 2008. However, the national policy does not make provision for individuals aged ≥5 years who have medical conditions associated with a high risk of invasive Hib disease to receive Hib vaccine. We measured serum anti-polyribosylribitol phosphate specific (anti-PRP) antibodies to Hib in patients aged ≥5 years with hematological malignancies and asplenia and evaluated their levels of anti-PRP antibodies in post administration of Hib vaccine era. A total of 65 patients (48 with hematological malignancies, and 17 with asplenia) were included in this study, of which 84% had not received Hib vaccine. In addition, 95.4% had short-term protective levels of anti-PRP antibodies (defined as ≥0.15 µg/mL) and 41.5% had long-term protective levels of anti-PRP antibodies (defined as ≥1.0 µg/mL). Five patients had low anti-PRP antibody levels despite a history of Hib vaccination. Our results suggest that young patients with underlying diseases such as hematological malignancies and asplenia may be at risk of invasive Hib disease. Hence, we recommend they should receive Hib vaccines even if they are over the age limit for routine Hib vaccination program.

Consensus statements on pediatric atopic dermatitis from dermatology and pediatrics practitioners in Japan: Goals of treatment and topical therapy.

BACKGROUND: Pediatric atopic dermatitis (PAD) is a pluricausal disease and is frequently seen in dermatological and pediatric practice. Therefore, it is important to find common views in clinical practice and to promote consensus among practitioners. Aiming to obtain common views among dermatologists and pediatricians and to disseminate them widely in clinical practice, we held the PAD Consensus Forums described herein. METHODS: Questionnaire surveys of treatment goals and drug therapy were conducted to prepare topics for discussion at the PAD Consensus Forums. Reaching consensus was defined as agreement among at least 70% of the participants. RESULTS: As a result of discussion among 24 dermatologists and 25 pediatricians, consensus was obtained on 7 topics. These topics configure 3 consensus of treatment goals (Attainment targets were divided into the short/medium term and the long term. Attainment targets were associated with the primary evaluation domains of the Harmonising Outcome Measures for Eczema (HOME) roadmap, etc.) and 4 consensus of drug therapy (The number of applications of topical anti-inflammatory drugs in the acute phase and selection and ideal intervals between applications of topical anti-inflammatory drugs in proactive therapy, etc.). CONCLUSIONS: The consensus is expected to help practitioners set appropriate treatment goals in clinical practice and facilitate the choice of drugs for treatment.

Japanese guidelines for atopic dermatitis 2020.

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion, which is frequently encountered in clinical practice. Skin barrier dysfunction leads to enhanced skin irritability to non-specific stimuli and epicutaneous sensitization. In the lesion site, a further inflammation-related reduction in skin barrier function, enhanced irritability and scratching-related stimuli deteriorate eczema, leading to vicious cycle of inflammation. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

MicroRNAs profiling in fibroblasts derived from patients with Gorlin syndrome.

Gorlin syndrome (GS) is a hereditary disorder with tumorigenicity, caused by constitutive hyperactivity of hedgehog signaling. Smoothened (SMO) antagonists have been effectively used in the clinical treatment of hedgehog signaling-related cancer. However, these treatments have led to problematic side effects, including severe adverse reactions and drug resistance from additional somatic mutations. We profiled microRNAs in GS fibroblasts to explore a novel therapeutic target for controlling hyper-activated hedgehog signaling. To identify GS-related microRNAs, we analyzed dermal fibroblasts from five patients with GS and three normal controls. We used microarray comparative genomic hybridization to screen 632 human microRNAs in GS fibroblasts. We identified 16 down- and 19 upregulated microRNAs with over twofold change in expression. We validated the increased expression of four microRNAs, confirming hsa-miR-196a-5p downregulation and hsa-miR-4485 upregulation using real-time PCR. Moreover, hsa-miR-196a-5p is complementary to sites in the 3' UTR of MAP3K1, which exhibits upregulated expression at mRNA and protein levels in GS fibroblasts. In addition, hedgehog signal induction with exogenous components decreased miR-196a-5p expression and increased map3k1 expression in a mouse mesenchymal cell line. Given that MAP3K1 has been reported to activate hedgehog signaling, hsa-miR-196a-5p may contribute to the positive feedback loop in this pathway.

Skin Care and Synbiotics for Prevention of Atopic Dermatitis or Food Allergy in Newborn Infants: A 2 × 2 Factorial, Randomized, Non-Treatment Controlled Trial.

BACKGROUND: Atopic dermatitis (AD) and food allergy (FA) are common childhood diseases, which may either be interrelated or be the result of skin barrier disruption and gut mucosal dysbiosis. Although some evidence suggests the efficacy of emollients and synbiotics, there is no conclusive evidence on the use of these interventions alone or in combination. OBJECTIVES: This study is aimed at identifying the efficacy of emollients and synbiotics in preventing AD and FA in children during the first year of life. METHODS: The babies of mothers recruited prenatally received either an emollient, synbiotic, both or neither. The intervention was carried out from birth up to 6 months of age. The age of occurrence of AD and FA were reported in multiple questionnaires at 1, 6, and 9 months and at 1 year of age. AD was diagnosed by a pediatrician at 9 months of age. RESULTS: A -total of 459 babies qualified for the outcome assessment at 1 year of age. Neither the emollient nor the synbiotic showed any effect on reducing the development of AD and FA at 1 year of age. CONCLUSIONS: This study did not provide any evidence to show that emollients and synbiotics, alone or in combination are sufficient to prevent the occurrence of AD or FA in children up to 1 year of age.