RESUMO
Cholangiocarcinoma (CCA) is one of the most difficult malignancies to treat as the therapeutic options are limited. Although several driver genes have been identified, most remain unknown. In this study, we identified a failed axon connection homolog (FAXC), whose function is unknown in mammals, by analyzing serially passaged CCA xenograft models. Knockdown of FAXC reduced subcutaneous tumorigenicity in mice. FAXC was bound to annexin A2 (ANXA2) and c-SRC, which are tumor-promoting genes. The FAXC/ANXA2/c-SRC complex forms in the mitochondria. FAXC enhances SRC-dependent ANXA2 phosphorylation at tyrosine-24, and the C-terminal amino acid residues (351-375) of FAXC are required for ANXA2 phosphorylation. Transcriptome data from a xenografted CCA cell line revealed that FAXC correlated with epithelial-mesenchymal transition, hypoxia, and KRAS signaling genes. Collectively, these findings advance our understanding of CCA tumorigenesis and provide candidate therapeutic targets.
Assuntos
Anexina A2 , Neoplasias dos Ductos Biliares , Carcinogênese , Colangiocarcinoma , Mitocôndrias , Quinases da Família src , Animais , Humanos , Masculino , Camundongos , Anexina A2/metabolismo , Anexina A2/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Mitocôndrias/metabolismo , Fosforilação , Transdução de Sinais , Quinases da Família src/metabolismo , Quinases da Família src/genéticaRESUMO
Cholangiocarcinoma is a fatal disease with limited therapeutic options. We screened genes required for cholangiocarcinoma tumorigenicity and identified FADS2, a delta-6 desaturase. FADS2 depletion reduced in vivo tumorigenicity and cell proliferation. In clinical samples, FADS2 was expressed in cancer cells but not in stromal cells. FADS2 inhibition also reduced the migration and sphere-forming ability of cells and increased apoptotic cell death and ferroptosis markers. Lipidome assay revealed that triglyceride and cholesterol ester levels were decreased in FADS2-knockdown cells. The oxygen consumption ratio was also decreased in FADS2-depleted cells. These data indicate that FADS2 depletion causes a reduction in lipid levels, resulting in decrease of energy production and attenuation of cancer cell malignancy.
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BACKGROUND AND AIM: We previously identified that ever-smoking and severe gastric atrophy in pepsinogen are risk factors for synchronous gastric cancers (SGCs). This study aimed to determine the association of alcohol drinking status or alcohol-related genetic polymorphism with SGCs and also stratify their risk. METHODS: This multi-center prospective cohort study included patients who underwent endoscopic submucosal dissection for the initial early gastric cancers at 22 institutions in Japan. We evaluated the association of alcohol drinking status or alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) genotypes with SGCs. We then stratified the risk of SGCs by combining prespecified two factors and risk factors identified in this study. RESULTS: Among 802 patients, 130 had SGCs. Both the ADH1B Arg and ALDH2 Lys alleles demonstrated a significant association with SGCs on multivariate analysis (odds ratio, 1.77), although alcohol drinking status showed no association. The rates of SGCs in 0-3 risk factors in the combined evaluation of three risk factors (ever-smoking, severe gastric atrophy in pepsinogen, and both the ADH1B Arg and ALDH2 Lys alleles) were 7.6%, 15.0%, 22.0%, and 32.1%, respectively. The risk significantly increased from 0 to 3 risk factors on multivariate analysis (P for trend <0.001). CONCLUSIONS: Both the ADH1B Arg and ALDH2 Lys alleles were at high risk for SGCs. The risk stratification by these three factors may be a less invasive and promising tool for predicting their risk.
Assuntos
Álcool Desidrogenase , Consumo de Bebidas Alcoólicas , Aldeído-Desidrogenase Mitocondrial , Polimorfismo Genético , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Álcool Desidrogenase/genética , Aldeído-Desidrogenase Mitocondrial/genética , Masculino , Feminino , Consumo de Bebidas Alcoólicas/efeitos adversos , Idoso , Pessoa de Meia-Idade , Fatores de Risco , Estudos Prospectivos , Medição de Risco , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Estudos de Coortes , Fumar/efeitos adversos , Japão/epidemiologia , Risco , GenótipoRESUMO
Although esophageal cancers invading the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic resection (ER) are associated with a risk of lymph node metastasis, details of metastatic recurrence after additional treatment remain unknown. We aimed to identify the risk factors for metastatic recurrence and recurrence patterns in patients receiving additional treatment after ER for esophageal cancer. Between 2006 and 2017, patients with pT1a-MM/pT1b-SM esophageal cancer who underwent ER with additional treatment (esophagectomy, chemoradiotherapy [CRT], and radiation therapy) at 21 institutions in Japan were enrolled. We evaluated the risk factors for metastatic recurrence after ER with additional treatment. Subsequently, the rate and pattern (locoregional or distant) of metastatic recurrence were investigated for each additional treatment. Of the 220 patients who received additional treatment, 57, 125, and 38 underwent esophagectomy, CRT, and radiation therapy, respectively. In the multivariate analysis, lymphatic invasion was the sole risk factor for metastatic recurrence after additional treatment (hazard ratio, 3.50; P = 0.029). Although the risk of metastatic recurrence with additional esophagectomy was similar to that with CRT (hazard ratio, 1.01; P = 0.986), the rate of locoregional recurrence tended to be higher with additional esophagectomy (80.0% (4/5) vs. 36.4% (4/11)), leading to a better prognosis in patients with metastatic recurrence after additional esophagectomy than CRT (survival rate, 80.0% (4/5) vs. 9.1% (1/11)). Patients with lymphatic invasion have a high risk of metastatic recurrence after ER with additional treatment for pT1a-MM/pT1b-SM esophageal cancer. Additional esophagectomy may result in a better prognosis after metastatic recurrence.
RESUMO
Gastric cancer is the fifth most common malignancy worldwide. However, targeted therapy for advanced gastric cancer is still limited. Here, we report BEX2 (Brain expressed X-linked 2) as a poor prognostic factor in two gastric cancer cohorts. BEX2 expression was increased in spheroid cells, and its knockdown decreased aldefluor activity and cisplatin resistance. BEX2 was found to upregulate CHRNB2 (Cholinergic Receptor Nicotinic Beta 2 Subunit) expression, a cancer stemness-related gene, in a transcriptional manner, and the knockdown of which also decreases aldefluor activity. Collectively, these data are suggestive of the role of BEX2 in the malignant process of gastric cancer, and as a promising therapeutic target.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Prognóstico , Linhagem Celular Tumoral , Oncogenes , Proteínas do Tecido Nervoso/metabolismoRESUMO
BACKGROUND: Although additional treatment is considered for patients with esophageal squamous cell carcinoma (ESCC) invading into the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic submucosal dissection (ESD), the actual benefits of this method remain to be elucidated. AIMS: We aimed to evaluate the prognostic benefits of additional treatment in such patients. METHODS: Between 2006 and 2017, we enrolled patients with pT1a-MM/pT1b-SM ESCC after ESD at 21 institutions in Japan. Overall survival (OS) and disease-specific survival (DSS) were compared between the additional treatment and follow-up groups after propensity score matching, to reduce the bias of baseline characteristics. A subgroup analysis was performed according to the pathological findings: category A, pT1a-MM but negative for lymphovascular invasion (LVI) and vertical margin (VM); category B, tumor invasion into the submucosa ≤ 200 µm but negative for LVI and VM; category C, others. RESULTS: Of 593 patients with pT1a-MM/pT1b-SM ESCC after ESD, 101 matched pairs were extracted after propensity score matching. The OSs were similar between the additional treatment and follow-up groups (80.6% vs. 78.6% in 5 years; P = 0.972). In a subgroup analysis, the OS in the additional treatment group was significantly lower than that in the follow-up group (65.7% vs. 95.2% in 5 years; P = 0.037) in category A, whereas OS did not significantly differ in category C (76.8% vs. 69.5% in 5 years; P = 0.360). CONCLUSIONS: Additional treatment after ESD in patients with pT1a-MM/pT1b-SM ESCC was not associated with an improved prognosis.
Assuntos
Ressecção Endoscópica de Mucosa , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/cirurgia , Carcinoma de Células Escamosas do Esôfago/patologia , Prognóstico , Neoplasias Esofágicas/patologia , Ressecção Endoscópica de Mucosa/métodos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVES: We aimed to clarify the prognostic factors for patients with esophageal squamous cell carcinoma (ESCC) invading into the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic submucosal dissection (ESD). METHODS: This retrospective study enrolled such patients at 21 institutions in Japan between 2006 and 2017. We evaluated 15 factors, including pathological risk categories for ESCC-specific mortality, six non-cancer-related indices, and treatment strategies. RESULTS: In the analysis of 593 patients, the 5-year overall and disease-specific survival rates were 83.0% and 97.6%, respectively. In a multivariate Cox analysis, male sex (hazard ratio [HR] 3.56), Charlson comorbidity index (CCI) ≥3 (HR 2.53), ages of 75-79 (HR 1.61) and ≥80 years (HR 2.04), prognostic nutrition index (PNI) <45 (HR 1.69), and pathological intermediate-risk (HR 1.63) and high-risk (HR 1.89) were prognostic factors. Subsequently, we developed a clinical risk classification for non-ESCC-related mortality based on the number of prognostic factors (age ≥75 years, male sex, CCI ≥3, PNI <45): low-risk, 0; intermediate-risk, 1-2; and high-risk, 3-4. The 5-year non-ESCC-related mortality rates for patients without additional treatment were 0.0%, 10.2%, and 45.8% in the low-, intermediate-, and high-risk groups, respectively. Meanwhile, the 5-year ESCC-specific mortality rates for the pathological low-, intermediate-, and high-risk groups were 0.3%, 5.3%, and 18.2%, respectively. CONCLUSIONS: We clarified prognostic factors for patients with pT1a-MM/pT1b-SM ESCC after ESD. The combined assessment of non-ESCC- and ESCC-related mortalities by the two risk classifications might help clinicians in deciding treatment strategies for such patients.
Assuntos
Ressecção Endoscópica de Mucosa , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Masculino , Idoso de 80 Anos ou mais , Idoso , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/patologia , Estudos Retrospectivos , Prognóstico , Mucosa/cirurgia , Mucosa/patologia , Resultado do TratamentoRESUMO
Cancer stem cells (CSCs) are responsible for therapy resistance and share several properties with normal stem cells. Here, we show that brain-expressed X-linked gene 2 (BEX2), which is essential for dormant CSCs in cholangiocarcinoma, is highly expressed in human hepatocellular carcinoma (HCC) lesions compared with the adjacent normal lesions and that in 41 HCC cases the BEX2high expression group is correlated with a poor prognosis. BEX2 localizes to Ki67-negative (nonproliferative) cancer cells in HCC tissues and is highly expressed in the dormant fraction of HCC cell lines. Knockdown of BEX2 attenuates CSC phenotypes, including sphere formation ability and aldefluor activity, and BEX2 overexpression enhances these phenotypes. Moreover, BEX2 knockdown increases cisplatin sensitivity, and BEX2 expression is induced by cisplatin treatment. Taken together, these data suggest that BEX2 induces dormant CSC properties and affects the prognosis of patients with HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Idoso , Aldeído Desidrogenase/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Cisplatino/farmacologia , Feminino , Inativação Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Organoides , Prognóstico , Esferoides CelularesRESUMO
R3HDM1 (R3H domain containing 1) is an uncharacterized RNA-binding protein that is highly expressed in the human cerebral cortex. We report the first case of a 12-year-old Japanese male with haploinsufficiency of R3HDM1. He presented with mild intellectual disability (ID) and developmental delay. He had a pericentric inversion of 46,XY,inv(2)(p16.1q21.3)dn with breakpoints in intron 19 of R3HDM1 (2q21.3) and the intergenic region (2p16.1). The R3HDM1 levels in his lymphoblastoid cells were reduced to approximately half that of the healthy controls. However, the expression of MIR128-1, in intron 18 of R3HDM1, was not affected via the pericentric inversion. Knockdown of R3HDM1 in mouse embryonic hippocampal neurons suppressed dendritic growth and branching. Notably, the Database of Genomic Variants reported the case of a healthy control with a 488-kb deletion that included both R3HDM1 and MIR128-1. miR-128 has been reported to inhibit dendritic growth and branching in mouse brain neurons, which directly opposes the novel functions of R3HDM1. These findings suggest that deleting both R3HDM1 and MIR128-1 alleviates the symptoms of the disease caused by loss-of-function mutations in R3HDM1 only. Thus, haploinsufficiency of R3HDM1 in the patient may be the cause of the mild ID due to the genetic imbalance between R3HDM1 and MIR128-1.
Assuntos
Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Haploinsuficiência/genética , Deficiência Intelectual/genética , Criança , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/patologia , Humanos , Deficiência Intelectual/patologia , MasculinoRESUMO
A heterozygous deletion at Xq27.3q28 including FMR1, AFF2, and IDS causing intellectual disability and characteristic facial features is very rare in females, with only 10 patients having been reported. Here, we examined two female patients with different clinical features harboring the Xq27.3q28 deletion and determined the chromosomal breakpoints. Moreover, we assessed the X chromosome inactivation (XCI) in peripheral blood from both patients. Both patients had an almost overlapping deletion at Xq27.3q28, however, the more severe patient (Patient 1) showed skewed XCI of the normal X chromosome (79:21) whereas the milder patient (Patient 2) showed random XCI. Therefore, deletion at Xq27.3q28 critically affected brain development, and the ratio of XCI of the normal X chromosome greatly affected the clinical characteristics of patients with deletion at Xq27.3q28. As the chromosomal breakpoints were determined, we analyzed a change in chromatin domains termed topologically associated domains (TADs) using published Hi-C data on the Xq27.3q28 region, and found that only patient 1 had a possibility of a drastic change in TADs. The altered chromatin topologies on the Xq27.3q28 region might affect the clinical features of patient 1 by changing the expression of genes just outside the deletion and/or the XCI establishment during embryogenesis resulting in skewed XCI.
Assuntos
Deleção Cromossômica , Deficiência Intelectual/genética , Inativação do Cromossomo X , Pré-Escolar , Cromossomos Humanos X , Análise Citogenética , Feminino , Humanos , Lactente , Japão , Proteína Nuclear Ligada ao X/genéticaRESUMO
Inherited GPI (glycosylphosphatidylinositol) deficiencies (IGDs), a recently defined group of diseases, show a broad spectrum of symptoms. Hyperphosphatasia mental retardation syndrome, also known as Mabry syndrome, is a type of IGDs. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins; however, IGDs constitute a rare group of diseases, and correlations between the spectrum of symptoms and affected genes or the type of mutations have not been shown. Here, we report four newly identified and five previously described Japanese families with PIGO (phosphatidylinositol glycan anchor biosynthesis class O) deficiency. We show how the clinical severity of IGDs correlates with flow cytometric analysis of blood, functional analysis using a PIGO-deficient cell line, and the degree of hyperphosphatasia. The flow cytometric analysis and hyperphosphatasia are useful for IGD diagnosis, but the expression level of GPI-anchored proteins and the degree of hyperphosphatasia do not correlate, although functional studies do, with clinical severity. Compared with PIGA (phosphatidylinositol glycan anchor biosynthesis class A) deficiency, PIGO deficiency shows characteristic features, such as Hirschsprung disease, brachytelephalangy, and hyperphosphatasia. This report shows the precise spectrum of symptoms according to the severity of mutations and compares symptoms between different types of IGD.
Assuntos
Estudos de Associação Genética , Deficiência Intelectual/genética , Deficiências da Aprendizagem/genética , Proteínas de Membrana/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Exoma , Feminino , Genótipo , Células HEK293 , Humanos , Lactente , Deficiência Intelectual/patologia , Japão , Deficiências da Aprendizagem/patologia , Masculino , Proteínas de Membrana/deficiência , Mutação , Linhagem , Fenótipo , SíndromeRESUMO
Partial trisomy 2p syndrome is occasionally associated with neural tube defects (NTDs), such as anencephaly, encephalocele, and spina bifida, in addition to common features of intellectual disability, developmental delay, and characteristic facial appearance. The 2p24 region has been reported to be associated with NTDs. Here, we report the cases of 2 siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter caused by the paternal translocation t(2;5)(p24.3;p14.3). Of the two siblings, the elder sister had spina bifida. We determined the nucleotide sequences of the chromosomal breakpoints and found that the sizes of trisomy 2p and monosomy 5p segments were 18.77 and 17.89 Mb, respectively. NTDs were present in four of seven previously reported patients with trisomy 2p and monosomy 5p as well as in one of the two patients examined in the present study. Although the monosomy 5p of the nine patients were similar in size, the two patients reported here had the smallest size of trisomy 2p. When the clinical features of the nine patients were compared to the present two patients, the elder sister had postaxial polydactyly of the left foot in addition to the characteristic facial appearance and spina bifida, indicating that these features were associated with trisomy 2p24.3-pter. To our knowledge, this is the first study on spina bifida to determine the nucleotide sequences of breakpoints for trisomy 2p24.3-pter and monosomy 5p14.3-pter. Increased gene dosages of dosage-sensitive genes or genes at the trisomy segment (2p24.3) of the presented patients could be associated with NTDs of patients with trisomy 2p.
Assuntos
Síndrome de Cri-du-Chat/genética , Defeitos do Tubo Neural/genética , Disrafismo Espinal/genética , Trissomia/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 5/genética , Síndrome de Cri-du-Chat/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Defeitos do Tubo Neural/diagnóstico por imagem , Defeitos do Tubo Neural/fisiopatologia , Irmãos , Disrafismo Espinal/diagnóstico por imagem , Disrafismo Espinal/fisiopatologia , Translocação Genética/genética , Trissomia/diagnóstico , Trissomia/fisiopatologiaRESUMO
BACKGROUND: Short-chain enoyl-CoA hydratase-ECHS1-catalyses many metabolic pathways, including mitochondrial short-chain fatty acid ß-oxidation and branched-chain amino acid catabolic pathways; however, the metabolic products essential for the diagnosis of ECHS1 deficiency have not yet been determined. The objective of this report is to characterise ECHS1 and a mild form of its deficiency biochemically, and to determine the candidate metabolic product that can be efficiently used for neonatal diagnosis. METHODS: We conducted a detailed clinical, molecular genetics, biochemical and metabolic analysis of sibling patients with ECHS1 deficiency. Moreover, we purified human ECHS1, and determined the substrate specificity of ECHS1 for five substrates via different metabolic pathways. RESULTS: Human ECHS1 catalyses the hydration of five substrates via different metabolic pathways, with the highest specificity for crotonyl-CoA and the lowest specificity for tiglyl-CoA. The patients had relatively high (â¼7%) residual ECHS1 enzyme activity for crotonyl-CoA and methacrylyl-CoA caused by the compound heterozygous mutations (c.176A>G, (p.N59S) and c.413C>T, (p.A138V)) with normal mitochondrial complex I-IV activities. Affected patients excrete large amounts of N-acetyl-S-(2-carboxypropyl)cysteine, a metabolite of methacrylyl-CoA. CONCLUSIONS: Laboratory data and clinical features demonstrated that the patients have a mild form of ECHS1 deficiency harbouring defective valine catabolic and ß-oxidation pathways. N-Acetyl-S-(2-carboxypropyl) cysteine level was markedly high in the urine of the patients, and therefore, N-acetyl-S-(2-carboxypropyl)cysteine was regarded as a candidate metabolite for the diagnosis of ECHS1 deficiency. This metabolite is not part of current routine metabolic screening protocols, and its inclusion, therefore, holds immense potential in accurate diagnosis.
Assuntos
Acetilcisteína/análogos & derivados , Enoil-CoA Hidratase/deficiência , Redes e Vias Metabólicas , Erros Inatos do Metabolismo/enzimologia , Acetilcisteína/metabolismo , Acetilcisteína/urina , Acil Coenzima A/metabolismo , Criança , Pré-Escolar , Enoil-CoA Hidratase/metabolismo , Feminino , Humanos , Japão , Masculino , Erros Inatos do Metabolismo/fisiopatologia , Mutação , Valina/metabolismoRESUMO
Xq28 duplication syndrome including MECP2 is a neurodevelopmental disorder characterized by axial hypotonia at infancy, severe intellectual disability, developmental delay, mild characteristic facial appearance, epilepsy, regression, and recurrent infections in males. We identified a Japanese family of Xq28 duplications, in which the patients presented with cerebellar ataxia, severe constipation, and small feet, in addition to the common clinical features. The 488-kb duplication spanned from L1CAM to EMD and contained 17 genes, two pseudo genes, and three microRNA-coding genes. FISH and nucleotide sequence analyses demonstrated that the duplication was tandem and in a forward orientation, and the duplication breakpoints were located in AluSc at the EMD side, with a 32-bp deletion, and LTR50 at the L1CAM side, with "tc" and "gc" microhomologies at the duplication breakpoints, respectively. The duplicated segment was completely segregated from the grandmother to the patients. These results suggest that the duplication was generated by fork-stalling and template-switching at the AluSc and LTR50 sites. This is the first report to determine the size and nucleotide sequences of the duplicated segments at Xq28 of three generations of a family and provides the genotype-phenotype correlation of the patients harboring the specific duplicated segment.
Assuntos
Povo Asiático/genética , Cromossomos Humanos X , Duplicação Gênica , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Adolescente , Adulto , Sequência de Bases , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Linhagem , Adulto JovemRESUMO
Mitochondrial trifunctional protein (MTP) is a hetero-octamer composed of four α- and four ß-subunits that catalyzes the final three steps of mitochondrial ß-oxidation of long chain fatty acids. HADHA and HADHB encode the α-subunit and the ß-subunit of MTP, respectively. To date, only two cases with MTP deficiency have been reported to be associated with hypoparathyroidism and peripheral polyneuropathy. Here, we report on two siblings with autosomal recessive infantile onset hypoparathyroidism, peripheral polyneuropathy, and rhabdomyolysis. Sequence analysis of HADHA and HADHB in both siblings shows that they were homozygous for a mutation in exon 14 of HADHB (c.1175C>T, [p.A392V]) and the parents were heterozygous for the mutation. Biochemical analysis revealed that the patients had MTP deficiency. Structural analysis indicated that the A392V mutation identified in this study and the N389D mutation previously reported to be associated with hypoparathyroidism are both located near the active site of MTP and affect the conformation of the ß-subunit. Thus, the present patients are the second and third cases of MTP deficiency associated with missense HADHB mutation and infantile onset hypoparathyroidism. Since MTP deficiency is a treatable disease, MTP deficiency should be considered when patients have hypoparathyroidism as the initial presenting feature in infancy.
Assuntos
Hipoparatireoidismo/congênito , Subunidade beta da Proteína Mitocondrial Trifuncional/genética , Mutação , Polineuropatias/diagnóstico , Polineuropatias/genética , Adolescente , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Humanos , Hipoparatireoidismo/diagnóstico , Hipoparatireoidismo/genética , Lactente , Masculino , Subunidade beta da Proteína Mitocondrial Trifuncional/química , Modelos Moleculares , Linhagem , Fenótipo , Conformação Proteica , Irmãos , Gêmeos DizigóticosRESUMO
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.
Assuntos
Estudos de Associação Genética , Doença de Hirschsprung/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Microcefalia/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Alelos , Linhagem Celular , Criança , Pré-Escolar , Códon sem Sentido , Fácies , Feminino , Mutação da Fase de Leitura , Expressão Gênica , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/epidemiologia , Proteínas de Homeodomínio/metabolismo , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Japão , Masculino , Microcefalia/diagnóstico , Microcefalia/epidemiologia , Fenótipo , Prevalência , Estabilidade Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Adulto Jovem , Homeobox 2 de Ligação a E-box com Dedos de ZincoRESUMO
Introduction: Detecting non-cavitary epithelioid cell granuloma by gastrointestinal biopsy is important in the initial diagnosis of Crohn's disease (CD). In the present study, we aimed to determine the rate of granuloma detection by gastrointestinal biopsy according to the number of biopsies performed. Methods: The present study included patients newly diagnosed with CD at our hospital between April 2017 and March 2023. During endoscopic examinations, biopsy specimens were taken from affected lesions. Initially, one section per biopsy was examined to detect granuloma. In cases where no granulomas were detected, step sections were additionally prepared and examined. The rate of granuloma detection by gastrointestinal biopsy was retrospectively examined. Results: A total of 30 patients with a new diagnosis of CD were included in this study. In total, 284 gastrointestinal biopsies were performed in 29 cases. The rate of granuloma detection by gastrointestinal biopsy per case was 58.6% (17 out of 29 cases). The rate of granuloma detection by gastrointestinal biopsy per biopsy was 6.0% (17 out of 284 biopsies) on initial histological examination and 11.6% (33 out of 284 biopsies) following examination of step sections. The rate of granuloma detection was significantly improved by performing histological examination of step sections compared with initial examinations (p < 0.05). Conclusion: The rate of granuloma detection per biopsy was 11.6%, even after histological examination of step sections. These results indicate that performing multiple intestinal biopsies and assessing for the presence of granuloma using multiple section examinations are required in the initial diagnosis of CD.
RESUMO
BACKGROUND: No studies have evaluated the relationship between lifestyle and synchronous gastric cancers (SGCs) in patients with endoscopic submucosal dissection (ESD) for early gastric cancers (EGCs). Using data from the Tohoku gastrointestinal (GI) study, we aimed to identify factors associated with SGCs. METHODS: Tohoku GI study is a multicenter prospective cohort study investigating the relationship between lifestyle and metachronous gastric cancers. Patients who had a schedule to undergo ESD for primary EGCs were enrolled. We used logistic regression analysis to examine the relationship of 15 candidate factors, including lifestyle, with the prevalence of SGCs in this study. RESULTS: Of 850 patients between 2016 and 2019, 16.0% (136 patients) had SGCs. In multivariate analysis, smoking history (odds ratio [OR], 1.93; p = 0.048) and severe atrophic gastritis assessed by pepsinogen (OR, 1.92; p = 0.004) were risk factors for the prevalence of SGCs. Regarding smoking, current smoking (OR, 2.33; p = 0.021), but not former smoking (OR, 1.76; p = 0.098), was a significant risk factor for its prevalence. In the stratified analysis, severe atrophic gastritis assessed by pepsinogen was a risk factor in patients without Helicobacter pylori (H. pylori) eradication (OR, 2.10; p = 0.002), but not a risk factor in those with H. pylori eradication (OR, 0.75; p = 0.737). CONCLUSION: Smoking history was a risk factor for the prevalence of SGCs in patients with ESD for EGCs, and severe atrophic gastritis assessed by pepsinogen was also a risk factor when H. pylori was not eradicated.
Assuntos
Ressecção Endoscópica de Mucosa , Gastrite Atrófica , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Gastrite Atrófica/epidemiologia , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/cirurgia , Pepsinogênio A , Ressecção Endoscópica de Mucosa/efeitos adversos , Prevalência , Estudos Prospectivos , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/epidemiologiaRESUMO
PURPOSE: Little is known about the prognostic factors for survival after endoscopic submucosal dissection (ESD) in elderly patients with early gastric cancer (EGC). The aim of this study is to determine prognostic factors and a prediction model of 3-year survival after ESD for EGC in patients aged ≥ 85 years. METHODS: We retrospectively evaluated the clinical outcomes of 740 patients with EGC aged ≥ 85 years, who were treated by ESD at 30 institutions in Japan. Overall survival (OS) and disease-specific survival (DSS) were calculated with the Kaplan-Meier method. Prediction models for 3-year OS after ESD were estimated using the Cox proportional hazards model based on Uno's C-statistics. RESULTS: During the follow-up period, 309 patients died of any cause and 10 patients died of gastric cancer. OS and DSS after 3 years were 82.7% and 99.2%, respectively. No significant differences in OS were found among curability categories. The Cox proportional hazards model revealed the geriatric nutritional risk index (GNRI) and the Charlson comorbidity index (CCI) to be predictors of 3-year survival. We established a final model (EGC-2 model) expressed by GNRI - (2.2×CCI) with a cutoff value of 96. The overall survival rate was significantly lower in the model value < 96 group than in the model value ≥ 96 group (P < 0.001). CONCLUSIONS: The prediction model using GNRI and CCI will be useful to support decision-making for the treatment of EGC in elderly patients aged ≥ 85 years.
Assuntos
Ressecção Endoscópica de Mucosa , Neoplasias Gástricas , Idoso , Humanos , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia , Ressecção Endoscópica de Mucosa/métodos , Gastrectomia , Detecção Precoce de Câncer , Resultado do Tratamento , Mucosa GástricaRESUMO
BACKGROUND: The guidelines recommend additional gastrectomy after noncurative endoscopic resection for early gastric cancers (EGCs). However, no additional treatment might be acceptable in some patients aged ≥ 85 years. We aimed to identify this patient group using the data in a highly aged area. METHODS: We enrolled patients aged ≥ 85 years after noncurative endoscopic resection for EGCs at 30 institutions of the Tohoku district in Japan between 2002 and 2017. Treatment selection and prognosis after noncurative endoscopic resection were investigated. Fourteen candidates were evaluated using the Cox model to identify risk factors for poor overall survival (OS) in patients with no additional treatment. RESULTS: Of 1065 patients aged ≥ 85 years, 143 underwent noncurative endoscopic resection. Despite the guidelines' recommendation, 88.8% of them underwent no additional treatment. The 5-year OS rates in those with additional gastrectomy and those with no additional treatment were 63.1 and 65.2%, respectively. Multivariate analysis showed independent risk factors for poor OS in patients with no additional treatment were the high-risk category in the eCura system (hazard ratio [HR], 2.91), Charlson comorbidity index (CCI) ≥ 3 (HR, 2.78), and male (HR, 2.04). In patients with no additional treatment, nongastric cancer-specific survival was low (69.0% in 5 years), whereas disease-specific survival rates were very high in the low- and intermediate-risk categories of the eCura system (100.0 and 97.1%, respectively, in 5 years). CONCLUSIONS: No additional treatment may be acceptable in the low- and intermediate-risk categories of the eCura system in patients aged ≥ 85 years with noncurative endoscopic resection for EGCs.