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BACKGROUND: Diesel exhaust particles (DEP), which contain hazardous compounds, are emitted during the combustion of diesel. As approximately one-third of the vehicles worldwide use diesel, there are growing concerns about the risks posed by DEP to human health. Long-term exposure to DEP is associated with airway hyperresponsiveness, pulmonary fibrosis, and inflammation; however, the molecular mechanisms behind the effects of DEP on the respiratory tract are poorly understood. Such mechanisms can be addressed by examining transcriptional and DNA methylation changes. Although several studies have focused on the effects of short-term DEP exposure on gene expression, research on the transcriptional effects and genome-wide DNA methylation changes caused by long-term DEP exposure is lacking. Hence, in this study, we investigated transcriptional and DNA methylation changes in human adenocarcinoma alveolar basal epithelial A549 cells caused by prolonged exposure to DEP and determined whether these changes are concordant. RESULTS: DNA methylation analysis using the Illumina Infinium MethylationEPIC BeadChips showed that the methylation levels of DEP-affected CpG sites in A549 cells changed in a dose-dependent manner; the extent of change increased with increasing dose reaching the statistical significance only in samples exposed to 30 µg/ml DEP. Four-week exposure to 30 µg/ml of DEP significantly induced DNA hypomethylation at 24,464 CpG sites, which were significantly enriched for DNase hypersensitive sites, genomic regions marked by H3K4me1 and H3K27ac, and several transcription factor binding sites. In contrast, 9,436 CpG sites with increased DNA methylation levels were significantly overrepresented in genomic regions marked by H3K27me3 as well as H3K4me1 and H3K27ac. In parallel, gene expression profiling by RNA sequencing demonstrated that long-term exposure to DEP altered the expression levels of 2,410 genes, enriching 16 gene sets including Xenobiotic metabolism, Inflammatory response, and Senescence. In silico analysis revealed that the expression levels of 854 genes correlated with the methylation levels of the DEP-affected cis-CpG sites. CONCLUSIONS: To our knowledge, this is the first report of genome-wide transcriptional and DNA methylation changes and their associations in A549 cells following long-term exposure to DEP.
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Metilación de ADN , Transcriptoma , Emisiones de Vehículos , Humanos , Metilación de ADN/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Células A549 , Transcriptoma/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/efectos de los fármacos , Islas de CpG , Material Particulado/toxicidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/metabolismoRESUMEN
Developing novel therapies that outperform the existing chemotherapeutic treatments is required for treatment-resistant ovarian clear cell carcinoma. We investigated the antitumor effect of metformin on ovarian clear cell carcinoma, enhancement of the antitumor effect by its combination with chemotherapy, and its molecular regulatory mechanism. First, we evaluated the viability of ovarian clear cell carcinoma lines using the water-soluble tetrazolium-1 assay and found that metformin suppressed cell viability. Cell viability was significantly suppressed by co-treatment with cisplatin and metformin. In contrast, co-treatment with paclitaxel and metformin showed no significant difference in viability compared with the group without metformin. Western blot analysis showed increased phosphorylation of AMP-activated protein kinase in some cell lines and suppressed phosphorylation of the mammalian target of rapamycin in a particular cell line. Flow cytometry analysis revealed a significant increase in the rate of apoptosis in the metformin-treated group and rate of cell cycle arrest at the G2/M phase in a particular cell line. These results indicated that metformin may be effective against cultured ovarian clear cell carcinoma cells, particularly in combination with cisplatin.
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Adenocarcinoma de Células Claras , Antineoplásicos , Apoptosis , Supervivencia Celular , Cisplatino , Metformina , Neoplasias Ováricas , Metformina/farmacología , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Femenino , Cisplatino/farmacología , Apoptosis/efectos de los fármacos , Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Paclitaxel/farmacología , Fosforilación/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacosRESUMEN
Metabolic abnormalities play a pivotal role in various pathological conditions, necessitating the quantification of specific metabolites for diagnosis. While mass spectrometry remains the primary method for metabolite measurement, its limited throughput underscores the need for biosensors capable of rapid detection. Previously, we reported that pillar[6]arene with 12 carboxylate groups (P6AC) forms host-guest complexes with 1-methylnicotinamide (1-MNA), which is produced in vivo by nicotinamide N-methyltransferase (NNMT). P6AC acts as a biosensor by measuring the fluorescence quenching caused by photoinduced electron transfer upon 1-MNA binding. However, the low sensitivity of P6AC makes it impractical for detecting 1-MNA in unpurified biological samples. In this study, we found that P6A with 12 sulfonate groups (P6AS) is a specific and potent supramolecular host for 1-MNA interactions even in biological samples. The 1-MNA binding affinity of P6AS in water was found to be (5.68 ± 1.02) × 106 M-1, which is approximately 700-fold higher than that of P6AC. Moreover, the 1-MNA detection limit of P6AS was determined to be 2.84 × 10-7 M, which is substantially lower than that of P6AC. Direct addition of P6AS to culture medium was sufficient to quantify 1-MNA produced by cancer cells. Furthermore, this sensor was able to specifically detect 1-MNA even in unpurified human urine. P6AS therefore enables rapid and high-throughput quantification of 1-MNA, and further improvement of our strategy will contribute to the establishment of high-throughput screening of NNMT inhibitors, diagnosis of liver diseases, and imaging of human cancer cells in vivo.
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OBJECTIVES: This study aimed to validate the diagnostic accuracy of the International Ovarian Tumor Analysis (IOTA) Assessment of Different NEoplasias in the adneXa (ADNEX) model in Japanese women, population with a distinct adnexal mass distribution compared with European women, and to evaluate the model's utility by gynecology trainees and ultrasound specialists. METHODS: This single-center, retrospective study analyzed ultrasound data from January 2017 to March 2020 of 206 women with adnexal masses. Patients who underwent ultrasonography and serum CA-125 measurement and received postsurgery histological diagnosis were included. The ADNEX model's diagnostic performance was evaluated by two trainees and two specialists using the area under the receiver operating characteristic curve (AUC) and measures of accuracy, sensitivity, specificity, and predictive values for overall performance and each examiner. RESULTS: Of the 206 included Japanese women, the prevalence of malignancy was 30.1%, including borderline cases. The overall AUC for distinguishing malignancy was 0.848 (95% confidence interval [CI]: 0.817-0.880). The AUC for each examiner ranged from 0.791 to 0.898, with Specialist 2 showing the highest accuracy and sensitivity varying between 0.677 and 0.839. A moderate degree of agreement was noted among the four examiners (Fleiss' kappa was 0.586). The performance of trainees and specialists differed significantly in evaluating the solid tissue and the papillary projections in both malignant and benign groups (P < .001). CONCLUSIONS: The IOTA ADNEX model effectively differentiates benign and malignant adnexal masses in Japanese women. Although the accuracy matched up moderately among the four examiners, better accuracy is expected with training in evaluating solid tissue and papillary projections.
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This study investigated the association between air pollutants and asthma prevalence in male and female Japanese adults. In this retrospective cross-sectional analysis, annual mean exposure levels of air pollutants, specifically nitrogen dioxide (NO2) and particulate matter with a median aerodynamic diameter ≤2.5 µm (PM2.5), were assessed at a local monitoring site. Multivariable logistic regression models, adjusted for genetic and/or lifestyle factors, were used to explore the association between air pollutants and asthma, with stratification by sex. A total of 1,497 participants aged ≥40 years were included. Their mean age was 65.9 ± 12.4 years, with 847 being women. Overall, 91 participants were diagnosed with asthma. In the multivariable model, ambient exposure levels of NO2 and PM2.5 were significantly associated with asthma in women but not in men. This study highlights sex as a significant determinant of the link between air pollutants and asthma exacerbation, particularly among female Japanese adults.
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Leukocyte immunoglobulin (Ig)-like receptors (LILRs) on human chromosome 19q13.4 encode 11 immunoglobulin superfamily receptors, exhibiting genetic diversity within and between human populations. Among the LILR genes, the genomic region surrounding LILRB3 and LILRA6 has yet to be fully characterized due to their significant sequence homology, which makes it difficult to differentiate between them. To examine the LILRB3 and LILRA6 genomic region, a tool named JoGo-LILR CN Caller, which can call copy number from short-read whole genome sequencing (srWGS) data, was applied to an extensive international srWGS dataset comprising 2,504 samples. During this process, a previously unreported loss of both LILRB3 and LILRA6 was detected in three samples. Using long-read sequencing of these samples, we have discovered a novel large deletion (33,692 bp) in the LILRB3 and LILRA6 genomic regions in the Japanese population. This deletion spanned three genes, LILRB3, LILRA6, and LILRB5, resulting in LILRB3 exons 12-13 being located immediately downstream of LILRB5 exons 1-12 with the loss of LILRA6, suggesting the potential expression of a hybrid gene between LILRB5 and LILRB3 (LILRB5-3). Transcription and subsequent translation of the LILRB5-3 hybrid gene were also verified. The hybrid junction was located within the intracellular domain, resulting in an LILRB5 extracellular domain fused to a partial LILRB3 intracellular domain with three immunoreceptor tyrosine-based inhibitory motifs (ITIMs), suggesting that LILRB5-3 acquired a novel signaling function. Further application of the JoGo-LILR tool to srWGS samples suggested the presence of the LILRB5-3 hybrid gene in the CEU population. Our findings provide insight into the genetic and functional diversity of the LILR family.
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Receptores Inmunológicos , Transducción de Señal , Humanos , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Transducción de Señal/genética , Secuenciación Completa del Genoma , Variaciones en el Número de Copia de ADN , Antígenos CDRESUMEN
We report a case of a pregnant patient with Gitelman syndrome (GS) who conceived by in vitro fertilization-embryo transfer (IVF-ET). A 39-year-old woman was referred for hypokalemia, with a serum potassium level of 2.2 mEq/L. She had difficulty conceiving spontaneously. Because of her age, her hypokalemia could be exacerbated by pregnancy. We provided preconception care and managed her pregnancy by frozen-thawed embryo transfer with careful monitoring of the K levels. However, her serum K level dropped to 2.5 mEq/L at 8 weeks of gestation. It was expected that her K demand would increase with pregnancy; hence, she required hospitalization and a 1.5-fold increase in replacement dose to maintain her K levels. At 11 weeks of gestation, her serum K level rose to 3.0 mEq/L. The baby was born adequately sized after 38 weeks of gestation via vaginal delivery. The patient's K levels were stable during the postpartum period. Genetic testing revealed three heterozygous missense variants in SLC12A3 that were consistent with GS. In conclusion, preconception care and cooperation between internal medicine and obstetrics led to an excellent and successful delivery of an IVF fetus in an older patient with GS. There are no guidelines for electrolyte disorders in pregnancy, and only a few studies have reported on GS during pregnancy, including detailed postpartum assessments.
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OBJECTIVE: To investigate the relationship between oral frailty (OF), nutrient intake and calf circumference (CC) in middle-aged and older adults. DESIGN: Cross-sectional study. SETTING: Residents of four model districts of Shika town, Ishikawa Prefecture, Japan, using data from November 2017 to February 2018. PARTICIPANTS: One hundred and ninety-four residents aged ≥50 years in four model districts of Shika town. The OF total score ≥3 was defined as OF. Participants were divided into OF and non-OF groups and divided into the low-CC/kg and the high-CC/kg groups. OUTCOME MEASURES: The primary outcome is to use a two-way analysis of covariance to analyse the interaction between the two CC/kg groups and the two OF groups on nutrition intake. The secondary outcome is to use multiple regression analysis to investigate the nutrients significantly related to CC/kg when stratified by OF, with age, sex, body mass index, drinking status, smoking status and regular exercise as input covariates. RESULTS: A two-way analysis of covariance revealed a significant interaction between the two CC/kg groups and the two OF groups on animal protein intake (p=0.039). Multiple comparisons using the Bonferroni analysis revealed a significantly lower animal protein intake in the OF group than in the non-OF group with a low CC/kg (p=0.033) but not in the group with a high CC/kg. The multiple regression analysis stratified by OF revealed a positive correlation between animal protein intake and CC/kg (p=0.002). CONCLUSIONS: The present results revealed a significantly lower animal protein intake in the OF group than in the non-OF group in the low-CC/kg group, but no such difference was observed in the high-CC/kg group. Further longitudinal studies are needed to elucidate this relationship.
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Fragilidad , Persona de Mediana Edad , Animales , Humanos , Anciano , Fragilidad/epidemiología , Estudios Transversales , Índice de Masa Corporal , Estudios Longitudinales , Ingestión de EnergíaRESUMEN
Master transcription factors such as TP63 establish super-enhancers (SEs) to drive core transcriptional networks in cancer cells, yet the spatiotemporal regulation of SEs within the nucleus remains unknown. The nuclear pore complex (NPC) may tether SEs to the nuclear pore where RNA export rates are maximal. Here, we report that NUP153, a component of the NPC, anchors SEs to the NPC and enhances TP63 expression by maximizing mRNA export. This anchoring is mediated through protein-protein interaction between the intrinsically disordered regions (IDRs) of NUP153 and the coactivator BRD4. Silencing of NUP153 excludes SEs from the nuclear periphery, decreases TP63 expression, impairs cellular growth, and induces epidermal differentiation of squamous cell carcinoma. Overall, this work reveals the critical roles of NUP153 IDRs in the regulation of SE localization, thus providing insights into a new layer of gene regulation at the epigenomic and spatial level.
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Many questions remain regarding the genetics of idiopathic generalized epilepsy (IGE), a subset of genetic generalized epilepsy (GGE). We aimed to identify the candidate coding variants of epilepsy panel genes in a cohort of affected individuals, using variant frequency information from a control cohort of the same region. We performed whole-exome sequencing analysis of 121 individuals and 10 affected relatives, focusing on variants of 950 candidate genes associated with epilepsy according to the Genes4Epilepsy curated panel. We identified 168 candidate variants (CVs) in 137 of 950 candidate genes in 88 of 121 affected individuals with IGE, of which 61 were novel variants. Notably, we identified five CVs in known GGE-associated genes (CHD2, GABRA1, RORB, SCN1A, and SCN1B) in five individuals and CVs shared by affected individuals in each of four family cases for other epilepsy candidate genes. The results of this study demonstrate that IGE is a disease with high heterogeneity and provide IGE-associated CVs whose pathogenicity should be proven by future studies, including advanced functional analysis. The low detection rate of CVs in the GGE-associated genes (4.1%) in this study suggests the current incompleteness of the Genes4Epilepsy panel for the diagnosis of IGE in clinical practice.
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Epilepsia Generalizada , Epilepsia , Humanos , Epilepsia Generalizada/genética , Epilepsia/genética , Inmunoglobulina ERESUMEN
A germline chimera is a useful model for developing and differentiating germ cells in vivo. Gonadal germ cells (GGCs) collected from chicken embryonic gonads may be used to produce germline chimeras as donor cells. However, the migratory and proliferative abilities of GGCs after transfer into recipient embryos are unclear. Here, the migratory and proliferative abilities of GGCs collected from 7-day-old White Leghorn embryos and fluorescently labeled were analyzed following transfer into the dorsal aorta of 2.5-day-old Rhode Island Red (RIR) embryos. Five days after transfer, the numbers of male and female GGCs were significantly higher in the RIR gonads than those in non-gonadal RIR organs when 50 GGCs were transferred per embryo. To analyze the temporal migration of GGCs in intermediate mesoderm, 50 GGCs were again transferred. The numbers of male and female GGCs in RIR gonads increased significantly from days 3 to 6 after transfer. To analyze GGC migration and proliferation in the gonads, a single GGC was transferred into 100 male and 100 female embryos. Five days after transfer, the frequencies of settled and proliferated GGCs were 37% (37/100) and 24% (24/100) in males, and 23% (23/100) and 8% (8/100) in females, respectively. Thus, GGCs are a heterogeneous cell population that may or may not have migratory and proliferative abilities. The heterogeneity of GGCs may be greater in females than that in males. When 50 GGCs were transplanted, almost all those present in embryos had settled and proliferated in the gonads and mesonephros. The migratory and proliferative abilities of GGCs in recipient gonads were considerably diverse in individual GGCs or between donor sexes.
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BACKGROUND: The prevalence of salvage surgeries after drug therapy for non-small cell lung cancer (NSCLC) has risen, mainly due to recent progress in molecular-targeted drugs and immune checkpoint inhibitors for NSCLC. While the safety and effectiveness of salvage surgery after drug therapy for NSCLC have been studied, its indications remain unclear. We aimed to identify the prognostic factors affecting survival in patients with advanced-stage (stages III-IV) NSCLC treated with salvage surgery after drug therapy. METHODS: A retrospective investigation was conducted on patients who received salvage surgery after drug therapy at four hospitals between 2007 and 2020. Salvage surgery was defined as surgery after drug therapy for local progression, tumor conversion to resectable status, and discontinuation of prior drug therapy owing to serious complications. RESULTS: Thirty-two patients received cytotoxic agents alone (n = 12 [38%]), tyrosine kinase inhibitors (TKIs; n = 16 [50%]), or immune checkpoint inhibitors (n = 4 [13%]) as prior drug therapy. In 11 (34%) and 21 (66%) patients, the clinical stage before treatment was III or IV, respectively. The median initial and preoperative serum carcinoembryonic antigen (CEA) levels were 10.2 (range, 0.5-1024) ng/mL and 4.2 (range, 0.6-92.5) ng/mL, respectively. Among the patients, 28 (88%) underwent lobectomy, 2 (6%) underwent segmentectomy, and 2 (6%) underwent wedge resection. Complete resection of the primary lesion was accomplished in 28 (88%) patients. Postoperative complications were documented in six (19%) patients. Mortality rates were 0% at 30 days and 3% at 90 days post-operation. The 5-year overall survival rate stood at 66%, while the 5-year progression-free survival rate was 21%. Multivariate analyses showed that prior TKI therapy and preoperative serum CEA level < 5 ng/mL were prognostic factors influencing overall survival (hazard ratio [95% confidence interval]: 0.06 [0.006-0.68] and 0.03 [0.002-0.41], respectively). The 5-year overall survival in the 11 patients with both favorable prognosticators was 100%. CONCLUSIONS: In this study, prior TKI therapy and preoperative serum CEA level < 5 ng/mL were favorable prognostic factors for overall survival in patients with NSCLC treated with salvage surgery. Patients with these prognostic factors are considered good candidates for salvage surgery after drug therapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Estudios Retrospectivos , Antígeno Carcinoembrionario , Inhibidores de Puntos de Control Inmunológico , Pronóstico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugíaRESUMEN
Differentiation therapy has been proposed as a promising therapeutic strategy for acute myeloid leukemia (AML); thus, the development of more versatile methodologies that are applicable to a wide range of AML subtypes is desired. Although the FOXOs transcription factor represents a promising drug target for differentiation therapy, the efficacy of FOXO inhibitors is limited in vivo. Here, we show that pharmacological inhibition of a common cis-regulatory element of forkhead box O (FOXO) family members successfully induced cell differentiation in various AML cell lines. Through gene expression profiling and differentiation marker-based CRISPR/Cas9 screening, we identified TRIB1, a complement of the COP1 ubiquitin ligase complex, as a functional FOXO downstream gene maintaining an undifferentiated status. TRIB1 is direct target of FOXO3 and the FOXO-binding cis-regulatory element in the TRIB1 promoter, referred to as the FOXO-responsive element in the TRIB1 promoter (FRE-T), played a critical role in differentiation blockade. Thus, we designed a DNA-binding pharmacological inhibitor of the FOXO-FRE-T interface using pyrrole-imidazole polyamides (PIPs) that specifically bind to FRE-T (FRE-PIPs). The FRE-PIPs conjugated to chlorambucil (FRE-chb) inhibited transcription of TRIB1, causing differentiation in various AML cell lines. FRE-chb suppressed the formation of colonies derived from AML cell lines but not from normal counterparts. Administration of FRE-chb inhibited tumor progression in vivo without remarkable adverse effects. In conclusion, targeting cis-regulatory elements of the FOXO family is a promising therapeutic strategy that induces AML cell differentiation.
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BACKGROUND: The 15-valent pneumococcal conjugate vaccine (PCV15 or V114) has recently been approved for pediatric vaccination against pneumococcal diseases (PDs) in Japan. The study aims to evaluate the cost-effectiveness of pediatric vaccination with V114 versus 13-valent PCV (PCV13) in Japan. METHODS: The study used a decision analytical Markov model to estimate the cost and effectiveness outcomes for a birth cohort in Japan over a 10-year time horizon. The model tracked the occurrences of acute PD events, including invasive PD (IPD), non-bacteremic pneumococcal pneumonia (NBPP) and pneumococcal acute otitis media (AOM) and the long-term impact of post-meningitis sequalae. Vaccine effectiveness was estimated based on literature and assumptions, and accounted for indirect effects and vaccine waning. The base case took the societal perspective, including both direct and indirect costs, while a healthcare payer perspective was modeled in a scenario analysis. Additional scenario analyses and sensitivity analyses were conducted. RESULTS: In the base case, V114 was associated with an incremental gain of 24 quality-adjusted life years and a reduction of ¥365,610,955 in total costs compared to PCV13. It was expected to reduce the number of pneumococcal AOM, NBPP, and IPD cases by 1,832, 1,333 and 25, respectively. All scenario analyses and most sensitivity analyses showed that V114 was a dominant strategy compared to PCV13. CONCLUSIONS: Pediatric vaccination with V114 is expected to lead to cost savings and more health benefits compared to PCV13 in Japan from both societal and healthcare payer perspectives. The findings are robust under plausible assumptions and inputs.
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Otitis Media , Infecciones Neumocócicas , Neumonía , Niño , Humanos , Análisis de Costo-Efectividad , Vacunas Conjugadas/uso terapéutico , Japón , Análisis Costo-Beneficio , Infecciones Neumocócicas/prevención & control , Programas de Inmunización , Vacunas Neumococicas , Otitis Media/prevención & controlRESUMEN
OBJECTIVE: We explored the relationship of dietary intake of fatty acids with chronic kidney disease (CKD) according to glycemic status in Japanese people. METHODS: A total of 1031 participants aged ≥40 y were included in this population-based, cross-sectional study. A validated self-administered diet history questionnaire was used to measure the dietary intakes of fat and fatty acids, including omega-3 and omega-6 polyunsaturated fatty acids. CKD was defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2 and diabetes as the use of antidiabetic medication, fasting plasma glucose ≥ 126 mg/dL, or hemoglobin A1c of ≥6.5%. Urine biomarkers of kidney injury (liver-type fatty acid-binding protein, ß2-microglobulin, and albumin) were also examined. RESULTS: The mean age of the participants was 62.5 ± 11.2 y, and 482 (46.8%) of them were men. Overall, 177 (17.2%) participants had CKD. In the multivariable model, low omega-3 intake (odds ratio = 0.109; 95% CI, 0.019-0.645) and high omega-6-to-omega-3 ratio (odds ratio = 2.112; 95% CI, 1.167-3.822) were associated with CKD in participants with diabetes but not in those without. In selected participants with diabetes, a substantial trend of urinary liver-type fatty acid-binding protein and ß2-microglobulin level elevation along with an increase in the dietary ratio of omega-6 to omega-3 was observed. CONCLUSIONS: Low dietary omega-3 intake and high omega-6-to-omega-3 ratio were associated with CKD in middle-aged and older Japanese people with diabetes but not in those without diabetes. These results may provide insight into the more tailored approaches for dietary polyunsaturated fatty acids to prevent CKD.
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We studied the pathophysiology of aplastic anaemia (AA) in six different pairs of relatives without a family history of hematologic disorders or congenital AA. Five and four of the six pairs shared the HLA-DRB1*15:01 and B*40:02 alleles, respectively. Glycosylphosphatidylinositol-anchored protein-deficient blood cells were detected in eight of the 10 patients evaluated. In a mother-daughter pair from one family, flow cytometry detected leukocytes lacking HLA-A2 due to loss of heterogeneity in chromosome 6p. Whole-exome sequencing of the family pair revealed a missense mutation in MYSM1. These results suggest that genetic inheritance of immune traits might underlie familial AA in some patients.
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Association rule is a transparent machine learning method expected to share information about risks for chronic kidney disease (CKD) among diabetic patients, but its findings in clinical data are limited. We used the association rule to evaluate the risk for kidney disease in General and Worker diabetic cohorts. The absence of risk factors was examined for association with stable kidney function and worsening kidney function. A confidence value was used as an index of association, and a lift of > 1 was considered significant. Analyses were applied for individuals stratified by KDIGO's (Kidney Disease: Improving Global Outcomes) CKD risk categories. A General cohort of 4935 with a mean age of 66.7 years and a Worker cohort of 2153 with a mean age of 47.8 years were included in the analysis. Good glycemic control was significantly related to stable kidney function in low-risk categories among the General cohort, and in very-high risk categories among the Worker cohort; confidences were 0.82 and 0.77, respectively. Similar results were found with poor glycemic control and worsening kidney function; confidences of HbA1c were 0.41 and 0.27, respectively. Similarly, anemia, obesity, and hypertension showed significant relationships in the low-risk General and very-high risk Worker cohorts. Stratified risk assessment using association rules revealed the importance of the presence or absence of risk factors.
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Diabetes Mellitus , Nefropatías Diabéticas , Hipertensión , Insuficiencia Renal Crónica , Humanos , Anciano , Persona de Mediana Edad , Factores de Riesgo , Insuficiencia Renal Crónica/complicaciones , Medición de Riesgo , Hipertensión/complicacionesRESUMEN
Background: Recent genome-wide association studies have revealed that nonalcoholic fatty liver disease (NAFLD) is correlated with genetic polymorphisms. However, the effects of genetic variation on nutritional metabolism and NAFLD are complex and further studies are still needed. Objectives: This study aimed to assess the nutritional characteristics interacting with the correlation between genetic predisposition and NAFLD. Methods: We assessed the 2013-2017 health examination data of 1191 adults aged ≥40 y living in Shika town, Ishikawa Prefecture, Japan. Adults with moderate or heavy alcohol consumption and hepatitis were excluded, and 464 participants who underwent genetic analyses were included in the study. Abdominal echography was performed to diagnose fatty liver condition, and dietary intake and nutritional balance were evaluated using the brief self-administered diet history questionnaire. NAFLD-related gene polymorphisms were identified using Japonica Array v2 (Toshiba). Results: Among the 31 single nucleotide polymorphisms, only the polymorphism T-455C in the apolipoprotein C3 (APOC3) gene (rs2854116) was significantly associated with fatty liver condition. The condition was more common in participants with heterozygotes of the APOC3 gene (rs2854116) than in those with the TT and CC genotypes. Significant interactions were observed between NAFLD and the intake of fat, vegetable fat, MUFAs, PUFAs, cholesterol, n-3 FAs, and n-6 FAs. Moreover, participants with NAFLD who presented with the TT genotype had a significantly higher fat intake than those without NAFLD. Conclusions: The polymorphism T-455C in the APOC3 gene (rs2854116) and fat intake are associated with the NAFLD risk in Japanese adults. Participants with a fatty liver who presented with the TT genotype of rs2854116 had a higher fat intake. Such nutrigenetic interaction can deepen our understanding of the NAFLD pathology. Moreover, in clinical settings, the correlation between genetic factors and nutrition intake should be considered in personalized nutritional interventions against NAFLD. Curr Dev Nutr 2023;xx:xx.The study was registered in the University Hospital Medical Information Network Clinical Trials Registry as UMIN 000024915.
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Social behavior is essential for health, survival, and reproduction of animals; however, the role of astrocytes in social behavior remains largely unknown. The transmembrane protein CD38, which acts both as a receptor and ADP-ribosyl cyclase to produce cyclic ADP-ribose (cADPR) regulates social behaviors by promoting oxytocin release from hypothalamic neurons. CD38 is also abundantly expressed in astrocytes in the postnatal brain and is important for astroglial development. Here, we demonstrate that the astroglial-expressed CD38 plays an important role in social behavior during development. Selective deletion of CD38 in postnatal astrocytes, but not in adult astrocytes, impairs social memory without any other behavioral abnormalities. Morphological analysis shows that depletion of astroglial CD38 in the postnatal brain interferes with synapse formation in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, astroglial CD38 expression promotes synaptogenesis of excitatory neurons by increasing the level of extracellular SPARCL1 (also known as Hevin), a synaptogenic protein. The release of SPARCL1 from astrocytes is regulated by CD38/cADPR/calcium signaling. These data demonstrate a novel developmental role of astrocytes in neural circuit formation and regulation of social behavior in adults.