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Ethylene response factors (ERFs) comprise one of the largest transcription factor families in many plant species. Tobacco (Nicotiana tabacum) ERF3 (NtERF3) and other ERF-associated amphiphilic repression (EAR) motif-containing ERFs are known to function as transcriptional repressors. NtERF3 and several repressor-type ERFs induce cell death in tobacco leaves and are also associated with a defence response against tobacco mosaic virus (TMV). We investigated whether transcriptional activator-type NtERFs function together with NtERF3 in the defence response against TMV infection by performing transient ectopic expression, together with gene expression, chromatin immunoprecipitation (ChIP) and promoter analyses. Transient overexpression of NtERF2 and NtERF4 induced cell death in tobacco leaves, albeit later than that induced by NtERF3. Fusion of the EAR motif to the C-terminal end of NtERF2 and NtERF4 abolished their cell death-inducing ability. The expression of NtERF2 and NtERF4 was upregulated at the early phase of N gene-triggered hypersensitive response (HR) against TMV infection. The cell death phenotype induced by overexpression of wild-type NtERF2 and NtERF4 was suppressed by co-expression of an EAR motif-deficient form of NtERF3. Furthermore, ChIP and promoter analyses suggested that NtERF2, NtERF3 and NtERF4 positively or negatively regulate the expression of NtERF3 by binding to its promoter region. Overall, our results revealed the cell death-inducing abilities of genes encoding activator-type NtERFs, including NtERF2 and NtERF4, suggesting that the HR-cell death signalling via the repressor-type NtERF3 is competitively but coordinately regulated by these NtERFs.
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Nicotiana , Proteínas de Plantas , Muerte Celular , Etilenos/metabolismo , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/metabolismo , Nicotiana/genética , Nicotiana/metabolismo , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Complete mesocolic excision (CME) with central vascular ligation (CVL) requires the surgeon to sharply dissect the mesocolon and approach the superior mesenteric artery (SMA) and superior mesenteric vein (SMV) for ligation of the supplying vessels relating to right-sided colon cancer at their origin. Even with preoperative images, it can still be challenging to identify these structures during laparoscopic surgery because of various intraoperative conditions. The aim of this study was to assess the efficacy of intraoperative ultrasound (IOUS) for identification of blood vessels during right-sided colon cancer surgery. METHODS: We performed IOUS on 19 patients diagnosed with right-sided colon cancer at our institution, in January-October 2020. Preoperatively, a three-dimensional computed tomography (3D-CT) angiogram was obtained for the majority of patients to visualize the SMA, SMV, and their respective branches. The running position of the ileocolic artery (ICA) and right colic artery (RCA) related to the SMV and the presence of the middle colic artery were identified and compared using preoperative 3D-CT, IOUS, and intraoperative findings. RESULTS: Nineteen patients [seven men and 12 women with a mean age of 73.9 ± 8.4 years (range 58-82 years)] were studied, including some with a body mass index of > 30 kg/m2, locally advanced cancer, and severe adhesion. There were IOUSs that detected the SMA, SMV, and their tributaries in all patients. The positional relationships between the SMV and the ICA and RCA revealed by IOUS were consistent with the preoperative and intraoperative findings. CONCLUSION: IOUS is a safe, feasible, and reproducible technique that can assist in detecting the branching of the SMA and SMV during CME with CVL in laparoscopic right-sided colon cancer surgery, regardless of individual conditions.
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Neoplasias del Colon , Laparoscopía , Mesocolon , Anciano , Anciano de 80 o más Años , Colectomía , Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/cirugía , Femenino , Humanos , Ligadura , Masculino , Mesocolon/diagnóstico por imagen , Mesocolon/cirugía , Persona de Mediana EdadRESUMEN
AIM: To clarify the prevalence and degree of maternal microchimerism in Japanese children with type 1 diabetes, as well as its effect on phenotypic variation. METHODS: We studied 153 Japanese children with type 1 diabetes, including 124 children positive for ß-cell autoantibodies, and their 71 unaffected siblings. The number of circulating microchimeric cells per 105 host cells was estimated by the use of quantitative-polymerase chain reaction targeting non-transmitted maternal human leukocyte antigen alleles. The results were compared to previous data from white European people. Phenotypic comparison was performed between maternal microchimerism carriers and non-carriers with diabetes. RESULTS: Maternal microchimerism was detected in 15% of children with autoantibody-positive type 1 diabetes, 28% of children with autoantibody-negative type 1 diabetes, and 16% of unaffected siblings. There were no differences in the prevalence or levels of maternal microchimerism among the three groups or between the children with type 1 diabetes and their unaffected siblings. Furthermore, maternal microchimerism carriers and non-carriers exhibited similar phenotypes. CONCLUSIONS: Maternal microchimerism appears to be less common in Japanese children with type 1 diabetes than in white European people. Our data indicate that maternal microchimerism is unlikely to be a major trigger or a phenotypic determinant of type 1 diabetes in Japanese children and that the biological significance of maternal microchimerism in type 1 diabetes may differ among ethnic groups.
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Pueblo Asiatico , Autoanticuerpos/inmunología , Quimerismo , Diabetes Mellitus Tipo 1/sangre , Intercambio Materno-Fetal/inmunología , Adolescente , Estudios de Casos y Controles , Niño , Diabetes Mellitus Tipo 1/inmunología , Femenino , Antígenos HLA , Humanos , Japón , Masculino , Madres , Embarazo , Hermanos , Transportador 8 de Zinc/inmunologíaRESUMEN
Mechanical loading plays an important role in bone homeostasis. However, molecular mechanisms behind the mechanical regulation of bone homeostasis are poorly understood. We previously reported p130Cas (Cas) as a key molecule in cellular mechanosensing at focal adhesions. Here, we demonstrate that Cas is distributed in the nucleus and supports mechanical loading-mediated bone homeostasis by alleviating NF-κB activity, which would otherwise prompt inflammatory processes. Mechanical unloading modulates Cas distribution and NF-κB activity in osteocytes, the mechanosensory cells in bones. Cas deficiency in osteocytes increases osteoclastic bone resorption associated with NF-κB-mediated RANKL expression, leading to osteopenia. Upon shear stress application on cultured osteocytes, Cas translocates into the nucleus and down-regulates NF-κB activity. Collectively, fluid shear stress-dependent Cas-mediated alleviation of NF-κB activity supports bone homeostasis. Given the ubiquitous expression of Cas and NF-κB together with systemic distribution of interstitial fluid, the Cas-NF-κB interplay may also underpin regulatory mechanisms in other tissues and organs.
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Huesos/metabolismo , Proteína Sustrato Asociada a CrK/metabolismo , Homeostasis , FN-kappa B/metabolismo , Transducción de Señal , Estrés Mecánico , Animales , Biomarcadores , Resorción Ósea , Huesos/diagnóstico por imagen , Proteína Sustrato Asociada a CrK/genética , Expresión Génica , Ratones , Ratones Noqueados , Osteoclastos/metabolismo , Osteocitos/metabolismo , Ligando RANK/genética , Ligando RANK/metabolismo , Microtomografía por Rayos XRESUMEN
STUDY QUESTION: Do monosomy rescue (MR) and trisomy rescue (TR) in preimplantation human embryos affect other developmental processes, such as X-chromosome inactivation (XCI)? SUMMARY ANSWER: Aneuploid rescue precedes XCI and increases the incidence of XCI skewness by reducing the size of the embryonic progenitor cell pools. WHAT IS KNOWN ALREADY: More than half of preimplantation human embryos harbor aneuploid cells, some of which can be spontaneously corrected through MR or TR. XCI in females is an indispensable process, which is predicted to start at the early-blastocyst phase. STUDY DESIGN, SIZE, DURATION: We examined the frequency of XCI skewness in young females who carried full uniparental disomy (UPD) resulting from MR or TR/gamete complementation (GC). The results were statistically analyzed using a theoretical model in which XCI involves various numbers of embryonic progenitor cells. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 39 children and young adults ascertained by imprinting disorders. XCI ratios were determined by DNA methylation analysis of a polymorphic locus in the androgen receptor gene. We used Bayesian approach to assess the probability of the occurrence of extreme XCI skewness in the MR and TR/GC groups using a theoretical model of 1-12 cell pools. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 12 of 39 individuals (31%) showed skewed XCI. Extreme skewness was observed in 3 of 15 MR cases (20%) and 1 of 24 TR/GC cases (4.2%). Statistical analysis indicated that XCI in the MR group was likely to have occurred when the blastocyst contained three or four euploid embryonic progenitor cells. The estimated size of the embryonic progenitor cell pools was approximately one-third or one-fourth of the predicted size of normal embryos. The TR/GC group likely had a larger pool size at the onset of XCI, although the results remained inconclusive. LIMITATIONS, REASONS FOR CAUTION: This is an observational study and needs to be validated by experimental analyses. WIDER IMPLICATIONS OF THE FINDINGS: This study provides evidence that the onset of XCI is determined by an intrinsic clock, irrespectively of the number of embryonic progenitor cells. Our findings can also be applied to individuals without UPD or imprinting disorders. This study provides a clue to understand chromosomal and cellular dynamics in the first few days of human development, their effects on XCI skewing and the possible implications for the expression of X-linked diseases in females. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Grants-in-aid for Scientific Research on Innovative Areas (17H06428) and for Scientific Research (B) (17H03616) from Japan Society for the Promotion of Science (JSPS), and grants from Japan Agency for Medical Research and Development (AMED) (18ek0109266h0002 and 18ek0109278h0002), National Center for Child Health and Development and Takeda Science Foundation. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.
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Aneuploidia , Tamaño de la Célula , Cromosomas Humanos X/genética , Células Madre Embrionarias/patología , Inactivación del Cromosoma X/genética , Adolescente , Teorema de Bayes , Blastocisto , Niño , Preescolar , Estudios de Cohortes , Desarrollo Embrionario/genética , Femenino , Impresión Genómica , Humanos , Incidencia , Lactante , Embarazo , Diagnóstico Preimplantación/métodos , Adulto JovenRESUMEN
BACKGROUND: Some literature has reported on endovascular treatment for very early hepatic artery stenosis (HAS; within 2 weeks after liver transplantation, and has deemed endovascular treatment to be a contraindication because out of serious complications associated with the procedure. We report on 2 cases of very early HAS successfully treated with endovascular treatment after living-donor liver transplantation (LDLT). CASE 1: A 54-year-old woman underwent LDLT with a left liver graft. The native right gastric artery and left hepatic artery (LHA) of the donor were anastomosed. On postoperative day (POD) 13, HAS was suspected and multidetector computerized tomographic angiography (MDCTA) was performed, which revealed 90% stenosis of the arterial anastomosis and 50% stenosis of the LHA in the graft. We performed percutaneous balloon arterioplasty (PBA) without any complications. The artery was patent with a postoperative follow-up of 60 months without the need for repeat intervention. CASE 2: A 67-year-old woman with a history of repeated transarterial chemoembolization for hepatocellular carcinoma underwent LDLT with a left liver graft. The native A4 and LHA of the donor were anastomosed. We performed MDCTA on POD 11, which revealed 70% stenosis of the native hepatic artery. We performed PBA followed by stent placement on POD 11 without complication. The artery was patent with a postoperative follow-up of 40 months without the need for repeated intervention. CONCLUSIONS: Endovascular treatment has the potential to avoid the need for repeated surgical interventions or retransplantation, and it can be safely performed in carefully selected patients.
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Procedimientos Endovasculares/métodos , Arteria Hepática/patología , Arteria Hepática/cirugía , Trasplante de Hígado/efectos adversos , Complicaciones Posoperatorias/cirugía , Anciano , Constricción Patológica/cirugía , Femenino , Humanos , Trasplante de Hígado/métodos , Donadores Vivos , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Genetic abnormalities in mitochondrial complex assembling factors are associated with leukoencephalopathy. We present a 1-year-old girl with consciousness disturbance after a respiratory infection. Brain MRI revealed leukoencephalopathy with bilaterally symmetrical hyperintensity in the substantia nigra, medial thalamic nuclei, and basal nuclei, as well as cavities in the cerebral white matter and corpus callosum. Lactate levels in the spinal fluid were high, while magnetic resonance spectroscopy of the cerebral white matter and basal nuclei showed high peak lactate levels, suggesting mitochondrial dysfunction. The respiratory enzyme activity of complex I was reduced to 17% to 21% in skeletal muscle. Whole exome sequencing identified compound heterozygous variations in NDUFAF3, involved in the assembly of mitochondrial complex I (c.342_343insGTG:p.117Valdup, c.505C > A:p.Pro169Thr). Two-dimensional, blue-native polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate-PAGE revealed reductions in Q-module (NDUFS2, NDUFS3, and NDUFA9) and P-module (NDUFB10 and NDUFB11) subunits, indicating disruption of mitochondrial complex I assembly. Our report expands the spectrum of clinical phenotypes associated with pathogenic variants of NDUFAF3.
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Predisposición Genética a la Enfermedad , Leucoencefalopatías/genética , Mitocondrias/genética , Proteínas Mitocondriales/genética , Complejo I de Transporte de Electrón/genética , Femenino , Humanos , Lactante , Leucoencefalopatías/patología , Mitocondrias/patología , Mutación , Secuenciación del ExomaRESUMEN
AIM: To examine the contribution of PTPN2 coding variants to the risk of childhood-onset Type 1A diabetes. METHODS: PTPN2 mutation analysis was carried out for 169 unrelated Japanese people with childhood-onset Type 1A diabetes. We searched for coding variants that were absent or extremely rare in the general population and were scored as damaging by multiple in silico programs. We performed mRNA analysis and three-dimensional structural prediction of the detected variants, when possible. We also examined possible physical links between these variants and previously reported risk SNPs as well as clinical information from variant-positive children. RESULTS: One frameshift variant (p.Q286Yfs*24) and two probably damaging missense substitutions (p.C232W and p.R350Q) were identified in one child each. Of these, p.Q286Yfs*24 and p.C232W were hitherto unreported, while p.R350Q accounted for 2/121,122 alleles of the exome datasets. The p.Q286Yfs*24 variant did not encode stable mRNA, and p.C232W appeared to affect the structure of the tyrosine-protein phosphatase domain. The three variants were physically unrelated to known risk SNPs. The variant-positive children manifested Type 1A diabetes without additional clinical features and invariably carried risk human leukocyte antigen alleles. CONCLUSIONS: The results provide the first indication that PTPN2 variants contribute to the risk of Type 1A diabetes, independently of known risk SNPs. PTPN2 coding variants possibly induce non-specific Type 1A diabetes phenotypes in individuals with human leukocyte antigen-mediated disease susceptibility. Our findings warrant further validation.
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Diabetes Mellitus Tipo 1/genética , Mutación del Sistema de Lectura/genética , Mutación Missense/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Adolescente , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad/genética , Antígenos HLA/genética , Humanos , Lactante , Masculino , Sistemas de Lectura Abierta/genética , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero/genéticaRESUMEN
Azoospermia affects up to 1% of adult men. Non-obstructive azoospermia is a multifactorial disorder whose molecular basis remains largely unknown. To date, mutations in several genes and multiple submicroscopic copy-number variations (CNVs) have been identified in patients with non-obstructive azoospermia. The aim of this study was to clarify the contribution of nucleotide substitutions in known causative genes and submicroscopic CNVs in the genome to the development of non-obstructive azoospermia. To this end, we conducted sequence analysis of 25 known disease-associated genes using next-generation sequencing and genome-wide copy-number analysis using array-based comparative genomic hybridization. We studied 40 Japanese patients with idiopathic non-obstructive azoospermia. Functional significance of molecular alterations was assessed by in silico analyses. As a result, we identified four putative pathogenic mutations, four rare polymorphisms possibly associated with disease risk, and four probable neutral variants in 10 patients. These sequence alterations included a heterozygous splice site mutation in SOHLH1 and a hemizygous missense substitution in TEX11, which have been reported as causes of non-obstructive azoospermia. Copy-number analysis detected five X chromosomal or autosomal CNVs of unknown clinical significance, in addition to one known pathogenic Y chromosomal microduplication. Five patients carried multiple molecular alterations. The results indicate that monogenic and oligogenic mutations, including those in SOHLH1 and TEX11, account for more than 10% of cases of idiopathic non-obstructive azoospermia. Furthermore, this study suggests possible contributions of substitutions in various genes as well as submicroscopic CNVs on the X chromosome and autosomes to non-obstructive azoospermia, which require further validation.
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Azoospermia/genética , Hibridación Genómica Comparativa , Análisis Mutacional de ADN/métodos , Fertilidad/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Herencia Multifactorial , Mutación , Polimorfismo Genético , Azoospermia/diagnóstico , Azoospermia/fisiopatología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Ciclo Celular , Proteínas Cromosómicas no Histona/genética , Cromosomas Humanos X , Cromosomas Humanos Y , Variaciones en el Número de Copia de ADN , Dosificación de Gen , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Japón , Masculino , Fenotipo , Valor Predictivo de las PruebasRESUMEN
AIMS: A majority of children with Type 1 diabetes in Japan are registered with the government-subsidized Specified Pediatric Chronic Disease Treatment Research Projects (SPCDTRP). In this study, the incidence and prevalence of childhood-onset (< 15 years) Type 1 diabetes in Japan were estimated by drawing on SPCDTRP data. METHODS: Data available for 2005-2012 from the SPCDTRP and Statistics Bureau, Ministry of Internal Affairs and Communications were used to estimate the incidence of Type 1 diabetes for 2005-2010, adjusted to cover those registered within 3 years of disease onset and stratified by sex, age at onset and period of onset. RESULTS: The incidence of Type 1 diabetes for 2005-2010 was 2.25/100,000 persons [95% confidence intervals (95% CI), 2.14-2.36] (boys: 1.91, 95% CI, 1.83-1.98; girls: 2.52, 95% CI, 2.34-2.69), with that for the age brackets 0-4, 5-9 and 10-14 years being 1.48 (95% CI, 1.29-1.66), 2.27 (95% CI, 2.08-2.47) and 3.00 (95% CI, 2.74-3.25), respectively. The onset of disease was shown to peak at age 13 among boys (3.28, 95% CI, 3.02-3.55) and at age 10 among girls (3.28, 95% CI, 3.02-3.55). The peak periods of disease onset were April/May and December. The number of children aged < 15 years with Type 1 diabetes for 2005-2012 was estimated to be 2326 (95% CI, 2202-2450) with the prevalence estimated as 13.53/100,000 persons (95% CI, 12.63-14.43). CONCLUSIONS: Study findings demonstrated no increase in the incidence of Type 1 diabetes, although suggesting, in agreement with earlier reports, that the onset of disease peaks in adolescence with a female predominance. In addition, the incidence of childhood-onset diabetes exhibited an annual bimodal pattern in this study.
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Diabetes Mellitus Tipo 1/epidemiología , Transición de la Salud , Adolescente , Edad de Inicio , Niño , Preescolar , Diabetes Mellitus Tipo 1/etnología , Femenino , Humanos , Incidencia , Japón/epidemiología , Masculino , Prevalencia , Sistema de Registros , Estaciones del Año , Factores Sexuales , Medicina EstatalRESUMEN
This study analyzes the Thermoluminescence (TL) emissions for five emission bands, trace element concentrations and defects in quartz grains extracted from metamorphic rocks and quartz veins in the Sambagawa metamorphic belt, central Shikoku. An emission of 500nm with 195, 245, and 320-325°C glow peaks are observed through the lowest to highest grade samples. A 450nm emission band with intense 195 and 245°C glow peaks and a 320-325°C shoulder peak is found in the higher grade samples. A 570nm emission band with a 170°C glow peak is observed in the samples derived from the lower grade zones. These characteristics of TL emissions of quartz suggest that they can be an indicator for the identification of rock derived from different metamorphic grades. The higher metamorphic grade samples with 450nm emission bands in particular show higher intensities of the E1' center. This relation indicates that the activation of the E1' center in higher metamorphic conditions possibly contributed to the 450nm emission band. Also, the 500nm emission band is generally observed in the samples with the signal intensities of the Aluminum hole center, suggesting that the center is the source of this emission band. We also observed that the lower metamorphic grade samples contain lower signal intensities of the Aluminum hole center, despite higher aluminum concentrations. This inconsistency indicates that the formation of interstitial aluminum ions cause local lattice distortion regions, where self-trapped excitons can be formed and presumably provide the 570nm emissions.
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Although complex chromosomal rearrangements were thought to reflect the accumulation of DNA damage over time, recent studies have shown that such rearrangements frequently arise from 'all-at-once' catastrophic cellular events. These events, designated chromothripsis, chromoanasynthesis, and chromoanagenesis, were first documented in the cancer genome and subsequently observed in the germline. These events likely result from micronucleus-mediated chromosomal shattering and subsequent random reassembly of DNA fragments, although several other mechanisms have also been proposed. Typically, only one or a few chromosomes of paternal origin are affected per event. These events can produce intrachromosomal deletions, duplications, inversions, and translocations, as well as interchromosomal translocations. Germline complex rearrangements of autosomes often result in developmental delay and dysmorphic features, whereas X chromosomal rearrangements are usually associated with relatively mild clinical manifestations. The concept of these catastrophic events provides novel insights into the etiology of human genomic disorders. This review introduces the molecular characteristics and phenotypic outcomes of catastrophic cellular events in the germline.
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Aberraciones Cromosómicas , Cromotripsis , Células Germinativas , Roturas del ADN de Doble Cadena , Femenino , Reordenamiento Génico , Genoma Humano , Mutación de Línea Germinal , Humanos , Masculino , EmbarazoRESUMEN
AIM: To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children. METHODS: We analysed FUT2 variants and ABO genotypes in a total of 531 Japanese children diagnosed with Type 1 diabetes and 448 control subjects. The possible association of FUT2 variants and ABO genotypes with the onset of Type 1 diabetes was statistically examined. RESULTS: The se2 genotype (c.385A>T) of the FUT2 gene was found to confer susceptibility to Type 1A diabetes in a recessive effects model [odds ratio for se2/se2, 1.68 (95% CI 1.20-2.35); corrected P value = 0.0075]. CONCLUSIONS: The FUT2 gene contributed to the development of Type 1 diabetes in the present cohort of Japanese children.
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Diabetes Mellitus Tipo 1/genética , Fucosiltransferasas/genética , Sistema del Grupo Sanguíneo ABO/genética , Pueblo Asiatico/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Humanos , Japón , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
The increasing elderly population has a great impact on public health, and it is important to understand the progression of musculoskeletal disorders seen in this population. To establish useful preventative methods for such locomotive disorders, we must detect early changes in these individuals and identify those at risk in order to implement early interventions. The purpose of this review was: (1) to introduce an operational definition of locomotion dysfunction to prevent a care-need condition, and to verify its validity through a prospective cohort study, and (2) to review the indication of exercise intervention for multiple musculoskeletal involvements from the preceding literature. We developed a measurement scale called the Geriatric Locomotive Function Scale (GLFS)-25, which clearly reflects the degree of functional deterioration. We used it in a prospective cohort study of 314 patients recruited from 5 clinics or nursing care facilities and investigated the relationship of the GLFS-25 with 46 variables covering various clinical manifestations. The results clearly revealed that the change in the GLFS-25 classification reflected a common pattern seen in those with locomotive dysfunction. Recently, several important movements regarding physical activity and its public promotion have been advocated by international health organizations and journal publishers. Though it has not been confirmed yet that complex musculoskeletal diseases can be treated using therapeutic exercise, the promotion of physical activity appears promising. The degree of activity limitation in aged individuals with locomotive disorders can be evaluated using this scale, which may be useful in predicting the effectiveness of future interventions.
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Pancreatic cancer exhibits the worst prognostic outcome among human cancers. Recently, we have described that depletion of RUNX2 enhances gemcitabine (GEM) sensitivity of p53-deficient pancreatic cancer AsPC-1 cells through the activation of TAp63-mediated cell death pathway. These findings raised a question whether RUNX2 silencing could also improve GEM efficacy on pancreatic cancer cells bearing p53 mutation. In the present study, we have extended our study to p53-mutated pancreatic cancer MiaPaCa-2 cells. Based on our current results, MiaPaCa-2 cells were much more resistant to GEM as compared with p53-proficient pancreatic cancer SW1990 cells, and there existed a clear inverse relationship between the expression levels of TAp73 and RUNX2 in response to GEM. Forced expression of TAp73α in MiaPaCa-2 cells significantly promoted cell cycle arrest and/or cell death, indicating that a large amount of TAp73 might induce cell death even in the presence of mutant p53. Consistent with this notion, overexpression of TAp73α stimulated luciferase activity driven by p53/TAp73-target gene promoters in MiaPaCa-2 cells. Similar to AsPC-1 cells, small interfering RNA-mediated knockdown of RUNX2 remarkably enhanced GEM sensitivity of MiPaCa-2 cells. Under our experimental conditions, TAp73 further accumulated in RUNX2-depleted MiaPaCa-2 cells exposed to GEM relative to GEM-treated non-silencing control cells. As expected, silencing of p73 reduced GEM sensitivity of MiPaCa-2 cells. Moreover, GEM-mediated Tyr phosphorylation level of TAp73 was much more elevated in RUNX2-depleted MiaPaCa-2 cells. Collectively, our present findings strongly suggest that knockdown of RUNX2 contributes to a prominent enhancement of GEM sensitivity of p53-mutated pancreatic cancer cells through the activation of TAp73-mediated cell death pathway, and also provides a promising strategy for the treatment of patients with pancreatic cancer bearing p53 mutation.
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AIMS: The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. METHODS: We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. RESULTS: Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10-5 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. CONCLUSIONS: The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.
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Cromosomas Humanos Par 17/genética , Diabetes Mellitus Tipo 1/genética , Haplotipos/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Alelos , Niño , Preescolar , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Lactante , Japón/etnología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Recent studies have suggested that disomic oocyte-mediated uniparental disomy 15 (UPD(15)mat) is increased in patients with Prader-Willi syndrome (PWS) born after medically assisted reproduction (MAR). However, it remains unknown whether the increase is primarily due to MAR procedure itself or advanced maternal childbearing ages as a predisposing factor for the disomic oocyte production. To examine this matter, we studied 122 naturally conceived PWS patients (PWS-NC group) and 13 MAR-conceived patients (PWS-MAR group). The relative frequency of disomic oocyte-mediated UPD(15)mat was significantly higher in PWS-MAR group than in PWS-NC group (7/13 vs 20/122, p = 0.0045), and the maternal childbearing ages were significantly higher in PWS-MAR group than in PWS-NC group [median (range), 38 (26-45) vs 30 (19-42), p = 0.0015]. However, the logistic regression analysis revealed no significant association between the occurrence of disomic oocyte-mediated UPD(15)mat and MAR, after adjusting for childbearing age (p = 0.25). Consistent with this, while the frequency of assisted reproductive technology (ART)-conceived livebirths was higher in the PWS patients than in the Japanese general population (6.4% vs 1.1%, p = 0.00018), the distribution of childbearing ages was significantly skewed to the increased ages in the PWS patients (p < 2.2 × 10(-16) ). These results argue against a positive association of MAR procedure itself with the development of UPD(15)mat.
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Cromosomas Humanos Par 15/genética , Síndrome de Prader-Willi/genética , Técnicas Reproductivas Asistidas/estadística & datos numéricos , Disomía Uniparental , Adulto , Factores de Edad , Femenino , Humanos , Modelos Logísticos , Masculino , Edad Materna , Persona de Mediana Edad , Oocitos/metabolismo , Edad Paterna , Síndrome de Prader-Willi/etiología , Técnicas Reproductivas Asistidas/efectos adversos , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Adulto JovenRESUMEN
We previously reported that one of the ethylene response factors (ERFs), NtERF3, and other members of the subgroup VIII-a ERFs of the AP2/ERF family exhibit cell death-inducing ability in tobacco leaves. In this study, we focused on the involvement of NtERF3 in a cell death signalling pathway in tobacco plants, particularly downstream of NtSIPK/NtWIPK and NtWRKY1, which are mitogen-activated protein kinases and a phosphorylation substrate of NtSIPK, respectively. An ERF-associated amphiphilic repression (EAR) motif-deficient NtERF3b mutant (NtERF3bΔEAR) that lacked cell death-inducing ability suppressed the induction of cell death caused by NtERF3a. The transient co-expression of NtERF3bΔEAR suppressed the hypersensitive reaction (HR)-like cell death induced by NtSIPK and NtWRKY1. The induction of cell death by NtSIPK and NtWRKY1 was also inhibited in transgenic plants expressing NtERF3bΔEAR. Analysis of gene expression, ethylene production and cell death symptoms in salicylic acid-deficient tobacco plants suggested the existence of some feedback regulation in the HR cell death signalling pathway mediated by SIPK/WIPK and WRKY1. Overall, these results suggest that NtERF3 functions downstream of NtSIPK/NtWIPK and NtWRKY1 in a cell death signalling pathway, with some feedback regulation.
Asunto(s)
Etilenos/metabolismo , Regulación de la Expresión Génica de las Plantas , Nicotiana/fisiología , Reguladores del Crecimiento de las Plantas/metabolismo , Proteínas de Plantas/metabolismo , Transducción de Señal , Secuencia de Bases , Muerte Celular , Retroalimentación Fisiológica , Genes Reporteros , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Datos de Secuencia Molecular , Fosforilación , Hojas de la Planta/genética , Hojas de la Planta/fisiología , Proteínas de Plantas/genética , Plantas Modificadas Genéticamente , Ácido Salicílico/metabolismo , Análisis de Secuencia de ADN , Nicotiana/citología , Nicotiana/genéticaRESUMEN
BACKGROUND: Clinical T1 gastric cancer has low metastatic potential to lymph nodes and is generally curable by local treatment. Endoscopic resection can preserve the whole stomach and does not impair the patient's quality of life; however, its indication is strictly limited to the subset of patients without nodal metastasis. The study was designed to predict reliably the patients without nodal metastasis based only on the clinical information. METHODS: We examined patients with clinical T1 disease who were treated with surgery. The clinically available information was evaluated for its ability to predict nodal metastasis by logistic regression model. Then, the predictive ability of the logistic regression model using the risk factors for nodal metastasis was evaluated by a receiver operating characteristic curve. RESULTS: A total of 511 patients were entered into this study. The clinical depth (cT1a or cT1b), maximal tumor diameter, and pathological type were confirmed to be significantly different between patients with and without nodal metastasis. The cutoff value of the tumor diameter differed depending on the histology and clinical depth: 79 mm for differentiated type and 48 mm for undifferentiated type in cT1a tumors, and 43 mm for differentiated type and 11 mm for undifferentiated type in cT1b tumors. According to these criteria, 348 of the 511 patients (68.1 %) were classified to have predictive N0 status. The negative predictive value was 95.7 % (95 % confidence interval 94.0-97.5 %). CONCLUSIONS: The predictive criteria based on the multivariate logistic model identified that almost two-thirds of the patients with clinical T1 gastric cancer were possible candidates for endoscopic treatment.
Asunto(s)
Adenocarcinoma/cirugía , Endoscopía , Gastrectomía , Modelos Estadísticos , Calidad de Vida , Neoplasias Gástricas/cirugía , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Curva ROC , Factores de Riesgo , Neoplasias Gástricas/patologíaRESUMEN
STUDY DESIGN: Cross-sectional study. OBJECTIVES: To determine the effect of injury duration on plantar-flexor elastic properties in individuals with chronic spinal cord injury (SCI) and spasticity. SETTING: National Rehabilitation Center for Persons with Disabilities, Japan. METHODS: A total of 16 chronic SCI patients (age, 33±9.3 years; injury localization, C6-T12; injury duration, 11-371 months) participated. Spasticity of the ankle plantar-flexors was assessed using the Modified Ashworth Scale (MAS). The calf circumference and muscle thickness of the medial gastrocnemius (MG), lateral gastrocnemius and soleus were assessed using tape measure and ultrasonography. In addition, the ankle was rotated from 10° plantar-flexion to 20° dorsiflexion at 5 deg s(-1) with a dynamometer, and the ankle angle and torque were recorded. After normalizing the data (the initial points of angle and torque were set to zero), we calculated the peak torque and energy. Furthermore, angle-torque data (before and after normalization) were fitted with a second- and fourth-order polynomial, and exponential (Sten-Knudsen) models, and stiffness indices (SISOP, SIFOP, SISK) and AngleSLACK (the angle at which plantar-flexor passive torque equals zero) were calculated. The stretch reflex gain and offset were determined from 0-10° dorsiflexion at 50, 90, 120 and 150 deg s(-1). After logarithmic transformation, Pearson's correlation coefficients were calculated. RESULTS: MAS, calf circumference, MG thickness, peak torque and SIFOP significantly decreased with injury duration (r log-log=-0.63, -0.69, -0.63, -0.53 and -0.55, respectively, P<0.05). The peak torque and SIFOP maintained significant relationships even after excluding impacts from muscle morphology. CONCLUSION: Plantar-flexor elasticity in chronic SCI patients decreased with increased injury duration.