RESUMEN
Germline missense mutations in GJB2 encoding connexin (Cx) 26 have been found in keratitis, ichthyosis and deafness (KID) syndrome. We explored the effects of three mouse Cx26 mutants (Cx26-G12R, -G45E and -D50N) corresponding to KID syndrome-causative human mutants on hemichannel activities leading to cell death and the expression of immune response-associated genes. We analyzed the 3D images of cells expressing wild-type (WT) or mutant Cx26 molecules to demonstrate clearly the intracellular localization of Cx26 mutants and hemichannel formation. High extracellular Ca2+ conditions lead to the closure of gap junction hemichannels in Cx26-G12R or Cx26-G45E expressing cells, resulting in prohibition of the Cx26 mutant-induced cell death. Fluorescent dye uptake assays revealed that cells with Cx26-D50N had aberrantly high hemichannel activities, which were abolished by a hemichannel blocker, carbenoxolone and 18α-Glycyrrhetinic acid. These results further support the idea that abnormal hemichannel activities play important roles in the pathogenesis of KID syndrome. Furthermore, we revealed that the expressions of IL15, CCL5, IL1A, IL23R and TLR5 are down-regulated in keratinocytes expressing Cx26-D50N, suggesting that immune deficiency in KID syndrome expressing Cx26-D50N might be associated not only with skin barrier defects, but also with the down-regulated expression of immune response-related genes.
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Conexina 26/genética , Conexina 26/metabolismo , Sordera/etiología , Sordera/metabolismo , Ictiosis/etiología , Ictiosis/metabolismo , Queratitis/etiología , Queratitis/metabolismo , Mutación , Biomarcadores , Supervivencia Celular/genética , Técnica del Anticuerpo Fluorescente , Expresión Génica , Células HeLa , Humanos , Espacio Intracelular/metabolismo , Queratinocitos/metabolismo , Unión Proteica , Transporte de Proteínas , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Introduction Radiotherapy is not commonly used for the treatment of gastric cancer in Japan, where surgery is the standard local treatment. We report the results of chemoradiotherapy in patients with advanced or recurrent gastric cancer which was deemed difficult to treat surgically. Methods Twenty-one patients with gastric cancer (including sixteen with advanced/recurrent gastric cancer and five with poor general condition) underwent chemo-radiotherapy, for whom the therapeutic efficacy, toxicity and survival period were analysed. Results The tumour response to chemoradiotherapy was categorised as complete, partial, stable or progressive in 5, 9, 3, and 4 patients, respectively, with an overall response rate of 67%. No serious complications such as gastrointestinal perforation or bleeding occurred, and no cardiac, hepatic or renal dysfunction developed during the follow-up period. The mean survival time was 19.8 months (range, 3-51 months). One patient died of another disease, 18 died of primary cancer and the cause of death was unknown in 2 patients. Conclusions Chemoradiotherapy appears to be an effective treatment for localised gastric cancer without distant metastases, but further studies are needed to determine the indications for chemoradiotherapy and late adverse effects, as well as the chemotherapy regimens to be used.
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Adenocarcinoma/terapia , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia , Recurrencia Local de Neoplasia/terapia , Ácido Oxónico/uso terapéutico , Radioterapia Conformacional/métodos , Neoplasias Gástricas/terapia , Tegafur/uso terapéutico , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Cisplatino/administración & dosificación , Combinación de Medicamentos , Femenino , Fluorouracilo/administración & dosificación , Humanos , Japón , Masculino , Estudios Retrospectivos , Neoplasias Gástricas/patología , Tasa de SupervivenciaRESUMEN
In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at 1 year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information that had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear. Disease-free survival (DFS) at 10 years from the end of therapy was 66.0±2.8%. Females (n=138) had better DFS (74.6±3.7%) than males (n=142, 57.5±4.2%, P=0.002). Patients with TCF3-PBX1 (n=11) and ETV6-RUNX1 (n=16) had excellent DFS (90.9±8.7% and 93.8±6.1%, respectively), whereas high hyperdiploidy (n=23) was the most unfavorable subgroup, with 56.6±10.3% of DFS. Short duration of therapy can cure more than half of pediatric ALL, especially females, TCF3-PBX1 and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Adolescente , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Quimioterapia de Mantención , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Recurrencia , Factores de Riesgo , Análisis de Supervivencia , Factores de Tiempo , Translocación Genética , Resultado del TratamientoAsunto(s)
Enfermedades del Cabello/genética , Cabello/anomalías , Hipotricosis/genética , Lipasa/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Efecto Fundador , Humanos , Lactante , Japón , Masculino , Adulto JovenRESUMEN
Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase-PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/µl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined.
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Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Dominios y Motivos de Interacción de Proteínas/genética , Proteínas Tirosina Quinasas/genética , Adolescente , Biomarcadores de Tumor , Niño , Preescolar , Estudios de Cohortes , Terapia Combinada , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad , Humanos , Factor de Transcripción Ikaros/genética , Lactante , Janus Quinasa 2/genética , Japón , Masculino , Mutación , Proteínas de Fusión Oncogénica/química , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del TratamientoRESUMEN
CCAAT/enhancer-binding protein alpha (CEBPA) mutations are a favorable prognostic factor in adult acute myeloid leukemia (AML) patients; however, few studies have examined their significance in pediatric AML patients. Here we examined the CEBPA mutation status and clinical outcomes of pediatric AML patients treated in the AML-05 study. We found that 47 (14.9%) of the 315 evaluable patients harbored mutations in CEBPA; 26 cases (8.3%) harbored a single mutation (CEBPA-single) and 21 (6.7%) harbored double or triple mutations (CEBPA-double). After excluding core-binding factor-AML cases, patients harboring CEBPA mutations showed better overall survival (OS; P=0.048), but not event-free survival (EFS; P=0.051), than wild-type patients. Multivariate analysis identified CEBPA-single and CEBPA-double as independent favorable prognostic factors for EFS in the total cohort (hazard ratio (HR): 0.47 and 0.33; P=0.02 and 0.01, respectively). CEBPA-double was also an independent favorable prognostic factor for OS (HR: 0.30; P=0.04). CEBPA-double remained an independent favorable factor for EFS (HR: 0.28; P=0.04) in the normal karyotype cohort. These results suggest that CEBPA mutations, particularly CEBPA-double, are an independent favorable prognostic factor in pediatric AML patients, which will have important implications for risk-stratified therapy.
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Proteínas Potenciadoras de Unión a CCAAT/genética , Leucemia Mieloide Aguda/genética , Mutación , Adolescente , Niño , Preescolar , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Polimorfismo Genético , PronósticoAsunto(s)
Leucemia Mieloide Aguda/genética , Mutación , Neoplasias Primarias Secundarias/genética , Proteínas Proto-Oncogénicas c-cbl/genética , Adolescente , Niño , Preescolar , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Masculino , Síndromes Mielodisplásicos/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Translocación GenéticaAsunto(s)
Cromosomas Humanos Par 11/genética , Neoplasias Hematológicas/genética , Leucemia/genética , Mutación , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas WT1/genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Anciano , Diferenciación Celular , Niño , Femenino , Frecuencia de los Genes , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Leucemia/mortalidad , Leucemia/patología , Masculino , Persona de Mediana Edad , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Pronóstico , Proteínas Recombinantes de Fusión/genética , Tasa de SupervivenciaRESUMEN
Mixed-lineage-leukemia (MLL) fusion oncogenes are closely involved in infant acute leukemia, which is frequently accompanied by mutations or overexpression of FMS-like receptor tyrosine kinase 3 (FLT3). Earlier studies have shown that MLL fusion proteins induced acute leukemia together with another mutation, such as an FLT3 mutant, in mouse models. However, little has hitherto been elucidated regarding the molecular mechanism of the cooperativity in leukemogenesis. Using murine model systems of the MLL-fusion-mediated leukemogenesis leading to oncogenic transformation in vitro and acute leukemia in vivo, this study characterized the molecular network in the cooperative leukemogenesis. This research revealed that MLL fusion proteins cooperated with activation of Ras in vivo, which was substitutable for Raf in vitro, synergistically, but not with activation of signal transducer and activator of transcription 5 (STAT5), to induce acute leukemia in vivo as well as oncogenic transformation in vitro. Furthermore, Hoxa9, one of the MLL-targeted critical molecules, and activation of Ras in vivo, which was replaceable with Raf in vitro, were identified as fundamental components sufficient for mimicking MLL-fusion-mediated leukemogenesis. These findings suggest that the molecular crosstalk between aberrant expression of Hox molecule(s) and activated Raf may have a key role in the MLL-fusion-mediated-leukemogenesis, and may thus help develop the novel molecularly targeted therapy against MLL-related leukemia.
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Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Leucemia/etiología , Proteína de la Leucemia Mieloide-Linfoide/fisiología , Quinasas raf/metabolismo , Proteínas ras/fisiología , Enfermedad Aguda , Animales , Ratones , Proteínas de Fusión Oncogénica , Receptor Cross-TalkAsunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Translocación Genética , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 4 , Humanos , Lactante , Estructura Terciaria de Proteína , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/químicaRESUMEN
The AML1 gene is frequently rearranged by chromosomal translocations in acute leukemia. We identified that the LAF4 gene on 2q11.2-12 was fused to the AML1 gene on 21q22 in a pediatric patient having T-cell acute lymphoblastic leukemia (T-ALL) with t(2;21)(q11;q22) using the bubble PCR method for cDNA. The genomic break points were within intron 7 of AML1 and of LAF4, resulting in the in-frame fusion of exon 7 of AML1 and exon 8 of LAF4. The LAF4 gene is a member of the AF4/FMR2 family and was previously identified as a fusion partner of MLL in B-precursor ALL with t(2;11)(q11;q23), although AML1-LAF4 was in T-ALL. LAF4 is the first gene fused with both AML1 and MLL in acute leukemia. Almost all AML1 translocations except for TEL-AML1 are associated with myeloid leukemia; however, AML1-LAF4 was associated with T-ALL as well as AML1-FGA7 in t(4;21)(q28;q22). These findings provide new insight into the common mechanism of AML1 and MLL fusion proteins in the pathogenesis of ALL. Furthermore, we successfully applied bubble PCR to clone the novel AML1-LAF4 fusion transcript. Bubble PCR is a powerful tool for detecting unknown fusion transcripts as well as genomic fusion points.
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Cromosomas Humanos Par 21 , Cromosomas Humanos Par 2 , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Reacción en Cadena de la Polimerasa/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Translocación Genética , Enfermedad Aguda , Secuencia de Bases , Niño , Análisis Mutacional de ADN/métodos , ADN Complementario/análisis , Humanos , Masculino , Modelos Biológicos , Datos de Secuencia MolecularRESUMEN
A quadrigeminal cistern arachnoid cyst is a very rare cause of typical trigeminal neuralgia. A 62-year-old woman presented with right facial pain of 8 years duration. Neuroradiological findings revealed a cystic mass in the quadrigeminal region that compressed the cerebellum downward and the brainstem anteriorly and was associated with hydrocephalus. She had neuroendoscopically-assisted cyst-cisternal shunting via a small craniotomy. Postoperatively, the trigeminal neuralgia disappeared. The origin of the trigeminal neuralgia may have either been a marked distortion of the pons that caused stretching of the trigeminal nerve and irregular demyelination within the root entry zone, or there was contact between the root entry zone and a vascular structure. Neuroendoscopy is useful for treating arachnoid cysts; however, in order to safely relieve symptoms, the procedure needs to be appropriately adapted depending on the pathogenesis. In this paper, we review the literature and discuss the pathophysiology and treatment of our case.
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Quistes Aracnoideos/patología , Quistes Aracnoideos/cirugía , Derivaciones del Líquido Cefalorraquídeo/métodos , Endoscopía/métodos , Procedimientos Neuroquirúrgicos/métodos , Espacio Subaracnoideo/cirugía , Neuralgia del Trigémino/etiología , Neuralgia del Trigémino/cirugía , Quistes Aracnoideos/etiología , Derivaciones del Líquido Cefalorraquídeo/tendencias , Descompresión Quirúrgica/instrumentación , Descompresión Quirúrgica/métodos , Femenino , Humanos , Hidrocefalia/etiología , Hidrocefalia/prevención & control , Hidrocefalia/cirugía , Imagen por Resonancia Magnética , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/instrumentación , Puente/patología , Puente/cirugía , Espacio Subaracnoideo/patología , Espacio Subaracnoideo/fisiopatología , Techo del Mesencéfalo/patología , Techo del Mesencéfalo/cirugía , Resultado del Tratamiento , Nervio Trigémino/patología , Nervio Trigémino/fisiopatología , Neuralgia del Trigémino/patologíaAsunto(s)
Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/fisiología , Translocación Genética , Células de la Médula Ósea/metabolismo , Niño , Exones , Humanos , Japón , Leucemia Mieloide Aguda/etnología , Oncogenes , Estructura Terciaria de Proteína , Inducción de RemisiónRESUMEN
BACKGROUND: To establish multiple bypass flow in an adult Moyamoya disease patient, the distal stump of the parietal superficial temporal artery (dsPSTA) was used as an additional donor. METHODS: Its potential as the donor was first evaluated by measuring the arterial pressure directly in three patients, revealing about 80% in mean arterial pressure of those measured at the proximal stump and radial artery. The anastomosis was performed just as conventionally except an additional anastomosis between the dsPSTA and frontal branch of the middle cerebral artery in 10 hemispheres of 7 patients. RESULTS: The patency of the dsPSTA bypass was confirmed on postoperative angiography in 5 patients. The comparison of pre- and post-operative single photon emission computed tomography was feasible in 8 hemispheres of 6 patients of which 7 demonstrated improvement of the cerebral blood flow. CONCLUSION; This technique provides a novel source of donor artery in the treatment of Moyamoya disease, in which multiple anastomoses are desirable.
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Revascularización Cerebral/métodos , Circulación Cerebrovascular/fisiología , Enfermedad de Moyamoya/cirugía , Arterias Temporales/cirugía , Adulto , Anciano , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Angiografía Cerebral , Femenino , Humanos , Masculino , Persona de Mediana Edad , Arteria Cerebral Media/anatomía & histología , Arteria Cerebral Media/fisiología , Arteria Cerebral Media/cirugía , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/patología , Tomografía de Emisión de Positrones , Arterias Temporales/anatomía & histología , Arterias Temporales/fisiología , Resultado del TratamientoAsunto(s)
Leucemia Mieloide/genética , Proteínas Nucleares/genética , Enfermedad Aguda , Adolescente , Niño , Preescolar , Análisis Mutacional de ADN , Humanos , Lactante , Recién Nacido , Japón , Cariotipificación , Mutación , NucleofosminaRESUMEN
We evaluated the therapeutic usefulness of adjuvant chemotherapy in patients with completely resected non-small cell lung cancer (NSCLC). We also examined the relation between DNA ploidy pattern and the response to chemotherapy. A total of 267 patients with NSCLC (pathologically documented stage I, II, or IIIA) underwent complete resection, and DNA ploidy pattern was analysed. Patients with stage I disease (n=172) were randomly assigned to receive surgery alone (group A) or surgery followed by adjuvant chemotherapy (UFT (oral anti-cancer drug, a combination of Uracil and Tegaful) 400 mg day-1 for 1 year after surgery; group B). Stage II or IIIA disease patients (n=95) were randomly assigned to surgery alone (group C) or surgery followed by chemotherapy (two 28-day courses of cisplatin 80 mg m-2 on day 1 plus vindesine 3 mg m-2 on days 1 and 8, followed by UFT 400 mg day-1 for at least 1 year; group D). Eight-year overall survival rate in patients with stage I disease was 74.2% (95% confidence interval (CI): 64.4-84.0%) in group B and 57.6% (95% CI: 46.4-68.8%) in group A (P=0.045 by log-rank test). In patients with stage II and IIIA disease, no difference was found between groups C and D. Analysis according to DNA ploidy pattern revealed no difference between the groups. Postoperative chemotherapy with UFT was suggested to be useful in patients with completely resected stage I NSCLC. No difference was seen in relation to DNA pattern in any treatment group.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Factores de Edad , Carcinoma de Pulmón de Células no Pequeñas/genética , Quimioterapia Adyuvante , Terapia Combinada , Femenino , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Ploidias , Factores de Riesgo , Factores Sexuales , Tasa de Supervivencia , Tegafur/administración & dosificación , Resultado del Tratamiento , Uracilo/administración & dosificaciónRESUMEN
Anti-neovascular therapy, one of the effective anti-angiogenic chemotherapy, damages new blood vessels by cytotoxic agents delivered to angiogenic endothelial cells and results in indirect eradication of tumor cells. We previously reported that liposomes-modified with a pentapeptide, Ala-Pro-Arg-Pro-Gly (APRPG-Lip) homing to angiogenic site, highly accumulated in tumor tissue, and APRPG-Lip encapsulating adriamycin (APRPG-LipADM) effectively suppressed tumor growth in tumor-bearing mice. In the present study, we examined the topological distribution of fluorescence-labeled APRPG-LipADM as well as TUNEL-stained cells in an actual tumor specimen obtained from Colon 26 NL-17 carcinoma-bearing mice. The fluorescence-labeled APRPG-Lip dominantly localized to vessel-like structure: a part of which was also stained with anti-CD31 antibody. Furthermore, TUNEL-stained cells were co-localized to the same structure. These data indicated that APRPG-LipADM bound to angiogenic endothelial cells and induced apoptosis of them. We also investigated the applicability of anti-neovascular therapy using APRPG-LipADM to ADM-resistant P388 solid tumor. As a result, APRPG-LipADM significantly suppressed tumor growth in mice bearing the ADM-resistant tumor. These data suggest that APRPG-LipADM is applicable to various kinds of tumor including drug-resistant tumor since it targets angiogenic endothelial cells instead of tumor cells, and eradicates tumor cells through damaging the neovessels.