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The majority of low-grade isocitrate dehydrogenase-mutant (IDHmt) gliomas undergo malignant progression (MP), but their underlying mechanism remains unclear. IDHmt gliomas exhibit global DNA methylation, and our previous report suggested that MP could be partly attributed to passive demethylation caused by accelerated cell cycles. However, during MP, there is also active demethylation mediated by ten-eleven translocation, such as DNA hydroxymethylation. Hydroxymethylation is reported to potentially contribute to gene expression regulation, but its role in MP remains under investigation. Therefore, we conducted a comprehensive analysis of hydroxymethylation during MP of IDHmt astrocytoma. Five primary/malignantly progressed IDHmt astrocytoma pairs were analyzed with oxidative bisulfite and the Infinium EPIC methylation array, detecting 5-hydroxymethyl cytosine at over 850,000 locations for region-specific hydroxymethylation assessment. Notably, we observed significant sharing of hydroxymethylated genomic regions during MP across the samples. Hydroxymethylated CpGs were enriched in open sea and intergenic regions (p < 0.001), and genes undergoing hydroxymethylation were significantly associated with cancer-related signaling pathways. RNA sequencing data integration identified 91 genes with significant positive/negative hydroxymethylation-expression correlations. Functional analysis suggested that positively correlated genes are involved in cell-cycle promotion, while negatively correlated ones are associated with antineoplastic functions. Analyses of The Cancer Genome Atlas clinical data on glioma were in line with these findings. Motif-enrichment analysis suggested the potential involvement of the transcription factor KLF4 in hydroxymethylation-based gene regulation. Our findings shed light on the significance of region-specific DNA hydroxymethylation in glioma MP and suggest its potential role in cancer-related gene expression and IDHmt glioma malignancy.
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Neoplasias Encefálicas , Metilación de ADN , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Glioma , Isocitrato Deshidrogenasa , Factor 4 Similar a Kruppel , Mutación , Humanos , Isocitrato Deshidrogenasa/genética , Glioma/genética , Glioma/patología , Glioma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Islas de CpG/genética , Femenino , Masculino , Astrocitoma/genética , Astrocitoma/patología , Astrocitoma/metabolismo , Persona de Mediana Edad , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , AdultoRESUMEN
While patients with cancer show a higher prevalence of psychiatric disorders than the general population, the mechanism underlying this interaction remains unclear. The present study examined whether tumor-bearing (TB) mice show psychological changes using the conditioned fear paradigm and the role of cytokines in these changes. TB mice were established by transplantation with mouse osteosarcoma AXT cells. These TB mice were then found to exhibit disruption in extinction of conditioned fear memory. Eighteen cytokines in serum were increased in TB mice, among which i.c.v. injection of interleukin (IL)-1ß and IL-6 strengthened fear memory in normal mice. Contents of IL-17 and keratinocyte-derived cytokine (KC) in the amygdala and KC in the hippocampus were increased in TB mice. KC mRNA in both the amygdala and hippocampus was also increased in TB mice, and i.c.v. injection of KC dose-dependently strengthened fear memory in normal mice. In addition, injection of IL-1ß, but not IL-6, increased KC mRNA in the amygdala and hippocampus. In TB mice KC mRNA was increased in both astrocytes and microglia of the amygdala and hippocampus. The microglia inhibitor minocycline, but not the astrocyte inhibitor fluorocitrate, alleviated disruption in extinction of conditioned fear memory in TB mice. Microinjection of KC into the hippocampus, but not into the amygdala, increased fear memory in normal mice. These findings indicate that TB mice show an increase in serum cytokines, including IL-1ß, that increases KC production in microglia of the hippocampus, which then disrupts extinction of fear memory.
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Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we treat male STAM (STelic Animal Model) mice, which develop diabetes, NASH and HCC associated with dysbiosis upon low-dose streptozotocin and high-fat diet (HFD), with insulin or phlorizin. Although both treatments ameliorate hyperglycemia and NASH, insulin treatment alone lead to suppression of HCC accompanied by improvement of dysbiosis and restoration of antimicrobial peptide production. There are some similarities in changes of microflora from insulin-treated patients comorbid with diabetes and NASH. Insulin treatment, however, fails to suppress HCC in the male STAM mice lacking insulin receptor specifically in intestinal epithelial cells (ieIRKO), which show dysbiosis and impaired gut barrier function. Furthermore, male ieIRKO mice are prone to develop HCC merely on HFD. These data suggest that impaired gut insulin signaling increases the risk of HCC, which can be countered by restoration of insulin action in diabetes.
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Carcinoma Hepatocelular , Diabetes Mellitus Experimental , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Masculino , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/patología , Hígado/patología , Carcinoma Hepatocelular/patología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Disbiosis/complicaciones , Disbiosis/patología , Neoplasias Hepáticas/patología , Insulina , Ratones Endogámicos C57BL , Dieta Alta en Grasa/efectos adversos , Modelos Animales de EnfermedadRESUMEN
Gastric cancer is among the most common malignancies worldwide, characterized by geographical, epidemiological and histological heterogeneity. Here, we report an extensive, multiancestral landscape of driver events in gastric cancer, involving 1,335 cases. Seventy-seven significantly mutated genes (SMGs) were identified, including ARHGAP5 and TRIM49C. We also identified subtype-specific drivers, including PIGR and SOX9, which were enriched in the diffuse subtype of the disease. SMGs also varied according to Epstein-Barr virus infection status and ancestry. Non-protein-truncating CDH1 mutations, which are characterized by in-frame splicing alterations, targeted localized extracellular domains and uniquely occurred in sporadic diffuse-type cases. In patients with gastric cancer with East Asian ancestry, our data suggested a link between alcohol consumption or metabolism and the development of RHOA mutations. Moreover, mutations with potential roles in immune evasion were identified. Overall, these data provide comprehensive insights into the molecular landscape of gastric cancer across various subtypes and ancestries.
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Infecciones por Virus de Epstein-Barr , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Transcriptoma , Herpesvirus Humano 4/genética , GenómicaRESUMEN
PURPOSE: To investigate the long-term outcomes of cataract surgery for glaucoma management in patients with primary angle-closure disease (PACD). STUDY DESIGN: Retrospective case series. METHODS: We reviewed the medical records of 87 eyes of 87 patients with PACD who underwent uncomplicated cataract surgery alone at the Kobe City Medical Center General Hospital. Only patients with a minimum follow-up of 10 years were included. The patients were divided into PACD spectrum categories: primary angle-closure glaucoma (PACG), primary-angle closure (PAC), and primary angle-closure suspect (PACS). The treatment outcomes were compared among the 3 groups. Intraocular pressure (IOP), number of glaucoma eye drops, requirement of additional glaucoma treatment, visual field progression, and progression to glaucoma during the follow-up period were evaluated. RESULTS: Among the 87 patients, 39 had PACG; 26, PAC; and 22, PACS. Ten years after surgery, the IOP had significantly decreased from baseline in all 3 groups. The rate of requirement of additional glaucoma treatment during the follow-up period was significantly higher in the PACG group than in the other groups. Almost half of the patients with PACG required additional glaucoma treatment; of those patients, six (15.4%) underwent glaucoma surgery. Three patients (11.5%) with PAC required additional glaucoma medication. Visual field progression was observed in 28.1% of the patients with PACG. In 1 patient with PAC, the condition progressed to PACG, but there was no such progression in any of the patients with PACS. CONCLUSIONS: We confirmed that cataract surgery had a long-term (> 10 years) effect on IOP reduction in eyes with PACD. Early intervention with cataract surgery may be preferable for glaucoma management in patients with PACD.
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Extracción de Catarata , Catarata , Glaucoma de Ángulo Cerrado , Glaucoma , Humanos , Catarata/complicaciones , Glaucoma/complicaciones , Glaucoma de Ángulo Cerrado/complicaciones , Glaucoma de Ángulo Cerrado/cirugía , Presión Intraocular , Estudios RetrospectivosRESUMEN
Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated "primed" state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis.
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Adipogénesis/genética , Proteínas Potenciadoras de Unión a CCAAT/genética , Histona Desacetilasas/genética , Metiltransferasas/genética , Co-Represor 1 de Receptor Nuclear/genética , PPAR gamma/genética , Células 3T3-L1 , Acetilación , Ciclosoma-Complejo Promotor de la Anafase/genética , Ciclosoma-Complejo Promotor de la Anafase/metabolismo , Animales , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Proteínas Cdc20/genética , Proteínas Cdc20/metabolismo , Elementos de Facilitación Genéticos , Regulación de la Expresión Génica , Células HEK293 , Histona Desacetilasas/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Metiltransferasas/metabolismo , Ratones , Ratones Desnudos , Co-Represor 1 de Receptor Nuclear/metabolismo , PPAR gamma/metabolismo , Unión Proteica , Proteolisis , Células Sf9 , Transducción de SeñalRESUMEN
Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. Here, we perform an integrative genomic profiling of 163 pediatric liver tumors (154 HBs and nine hepatocellular carcinomas) based on the data acquired from a cohort study (JPLT-2). The total number of somatic mutations is precious low (0.52/Mb on exonic regions) but correlated with age at diagnosis. Telomerase reverse transcriptase (TERT) promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling reveals that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of IGF2 promoters, suggests their "cell of origin" derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach for understanding the epigenetic drivers of hepatoblast carcinogenesis and deriving clues for risk stratification.
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Metilación de ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Preescolar , Secuenciación de Inmunoprecipitación de Cromatina/métodos , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Mutación , Regiones Promotoras Genéticas/genética , Telomerasa/genética , Secuenciación del Exoma/métodos , beta Catenina/genéticaRESUMEN
Previous reports suggest that diabetes mellitus is associated with psychiatric disorders, including depression and anxiety, but the mechanisms involved are unknown. We have reported that streptozotocin (STZ)-induced diabetic mice show enhancement of conditioned fear memory. To clarify the mechanisms through which diabetes affects conditioned fear memory, the present study investigated the role of l-lactate and glutamatergic function in enhancement of conditioned fear memory in diabetes. l-lactate levels in the amygdala and hippocampus, which are known to play important roles in fear memory, were significantly increased in STZ-induced diabetic mice. The glucose transporter (GLUT) 1 was significantly increased both in the amygdala and in the hippocampus. In contrast, GLUT3, the monocarboxylic acid transporter (MCT) 1 and MCT2 in the amygdala and hippocampus were not altered in STZ-induced diabetic mice. I.c.v. injection of l-lactate to non-diabetic mice significantly increased duration of freezing, whereas the MCT inhibitor 4-CIN significantly inhibited duration of freezing in STZ-induced diabetic mice. Injection of l-lactate significantly increased glutamate levels in the amygdala and hippocampus. Duration of freezing induced by l-lactate was significantly inhibited by the AMPA receptor antagonist NBQX. In addition, injection of NBQX into the amygdala and hippocampus significantly inhibited duration of freezing in STZ-induced diabetic mice. These results suggest that l-lactate levels are increased in the amygdala and hippocampus in diabetic mice, which may enhance fear memory though activation of glutamatergic function in the amygdala and hippocampus.
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Miedo/psicología , Memoria/fisiología , Amígdala del Cerebelo/efectos de los fármacos , Animales , Ansiedad , Encéfalo/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Miedo/fisiología , Ácido Glutámico/metabolismo , Hipocampo/efectos de los fármacos , Ácido Láctico/metabolismo , Masculino , Ratones , Neuronas/metabolismo , Estreptozocina/farmacologíaRESUMEN
Ten-eleven translocation 1 (TET1) is an essential methylcytosine dioxygenase of the DNA demethylation pathway. Despite its dysregulation being known to occur in human cancer, the role of TET1 remains poorly understood. In this study, we report that TET1 promotes cell growth in human liver cancer. The transcriptome analysis of 68 clinical liver samples revealed a subgroup of TET1-upregulated hepatocellular carcinoma (HCC), demonstrating hepatoblast-like gene expression signatures. We performed comprehensive cytosine methylation and hydroxymethylation (5-hmC) profiling and found that 5-hmC was aberrantly deposited preferentially in active enhancers. TET1 knockdown in hepatoma cell lines decreased hmC deposition with cell growth suppression. HMGA2 was highly expressed in a TET1high subgroup of HCC, associated with the hyperhydroxymethylation of its intronic region, marked as histone H3K4-monomethylated, where the H3K27-acetylated active enhancer chromatin state induced interactions with its promoter. Collectively, our findings point to a novel type of epigenetic dysregulation, methylcytosine dioxygenase TET1, which promotes cell proliferation via the ectopic enhancer of its oncogenic targets, HMGA2, in hepatoblast-like HCC.
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Proteína HMGA2/genética , Neoplasias Hepáticas/genética , Oxigenasas de Función Mixta/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , Cromatina/genética , Citosina/metabolismo , Metilación de ADN , Dioxigenasas/metabolismo , Epigénesis Genética , Expresión Génica , Técnicas de Silenciamiento del Gen , Proteína HMGA2/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Oxigenasas de Función Mixta/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: The diagnosis of chronic pancreatitis (CP) using endoscopic ultrasound (EUS) criteria, referred to as the Rosemont classification (RC), has been widely performed. However, the validity of the RC, which was based on expert opinion, is still controversial. If EUS findings are associated with CP, then they should be associated with risk factors for CP. In this study, to verify the appropriateness of the RC and each EUS finding, we performed a retrospective analysis from the viewpoint of risk factors for CP. SUMMARY: Three hundred and forty-four patients were enrolled in this study. Clinical background characteristics that associate with CP were alcohol intake, smoking, history of acute pancreatitis (AP), and age. The correlation between EUS criteria for CP and clinical background was investigated. All EUS findings except the presence of cysts showed significant correlations with one or 2 of the 3 following factors: ethanol (EtOH) intake, smoking status, and history of AP. Results of the univariate and multivariate analyses showed that 3 factors (EtOH intake, smoking, and history of AP) other than age were positively correlated with the RC. Moreover, the risk of progression from normal to consistent CP to indeterminate and suggestive CP was found to increase with increasing EtOH intake. Key Messages: The RC and each EUS finding was validated from the viewpoint of risk factors for CP.
Asunto(s)
Pancreatitis Crónica , Enfermedad Aguda , Endosonografía , Humanos , Pancreatitis Crónica/diagnóstico por imagen , Estudios Retrospectivos , Factores de RiesgoRESUMEN
PURPOSE: The purpose of this study was to improve the accuracy of dose-distribution calculations by understanding how the calculated dose varies with the change in the relative electron density replacing polymethyl methacrylate (PMMA) in patient-specific quality assurance. METHOD: We calculated the relative electron density at which dose attenuation in each dose calculation algorithm coincides with the measured value of the dose attenuation of single-field irradiation. Next, the dose change was calculated by changing the relative electron density or physical electron density for substituting PMMA for each X-ray energy and calculation algorithm. Furthermore, using clinical plans, changes in point-dose verification and dose-distribution verification that occurred when the relative electron density or physical electron density was varied were investigated. RESULTS: The dose attenuation varies depending on the dose-calculation algorithm, and the optimum value of the electron density is different for each. After the electron density optimization, the point dose verification using the 97.1% to 98.3% (3%/3 mm), 90.0% to 94.3% (2%/3 mm) and gained a dominant improvement tendency (P<0.001). CONCLUSIONS: We clarified dose change accompanying relative electron density or physical electron density change. We concluded that the accuracy of dose-distribution calculation for verification improves by replacing PMMA with optimal relative electron density or physical electron density.
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Electrones , Polimetil Metacrilato , Algoritmos , Humanos , Fantasmas de Imagen , Radiometría , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por ComputadorRESUMEN
Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLL protein family, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC, as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC regardless of CTNNB1 mutation status because ß-catenin did not translocate into the nucleus due to the E-cadherin/ß-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC, with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in target genes. Similarly, cell-cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC, with TP53 or RB1 gene mutations associated with chromosomal deletion of 4q or 16q. HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Collectively, these data show that as HCC progresses, additional molecular events exclusive of driver gene mutations cooperatively contribute to transcriptional activation of downstream targets according to methylation status. SIGNIFICANCE: In addition to driver gene mutations in the WNT and p53 pathways, further molecular events are required for aberrant transcriptional activation of these pathways as HCC progresses.
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Carcinoma Hepatocelular/genética , Genes p53 , Neoplasias Hepáticas/genética , Proteínas Wnt/genética , Carcinoma Hepatocelular/patología , Metilación de ADN , ADN de Neoplasias/aislamiento & purificación , Progresión de la Enfermedad , Epigénesis Genética , Dosificación de Gen , Tecnología de Genética Dirigida , Expresión Génica , Genes cdc , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Neoplasias Hepáticas/patología , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína Oncogénica v-akt/genética , Fosfatidilinositol 3-Quinasas/genética , Probabilidad , ARN Neoplásico/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Telomerasa/genética , Activación Transcripcional , Regulación hacia Arriba , beta Catenina/genéticaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
We describe base editors that combine both cytosine and adenine base-editing functions. A codon-optimized fusion of the cytosine deaminase PmCDA1, the adenosine deaminase TadA and a Cas9 nickase (Target-ACEmax) showed a high median simultaneous C-to-T and A-to-G editing activity at 47 genomic targets. On-target as well as DNA and RNA off-target activities of Target-ACEmax were similar to those of existing single-function base editors.
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Proteína 9 Asociada a CRISPR/genética , Sistemas CRISPR-Cas/genética , ADN/genética , Edición Génica , Adenina/metabolismo , Adenosina Desaminasa/genética , Citosina/metabolismo , Desoxirribonucleasa I/genética , Genoma Humano/genética , Glicoproteínas/genética , Guanina/metabolismo , Células HEK293 , Humanos , Mutación/genética , Proteínas Nucleares/genética , ARN/genéticaRESUMEN
Non-alcoholic steatohepatitis (NASH) is characterized by macrovesicular steatosis with ballooning degeneration of hepatocytes, diffused lobular inflammation, and fibrosis. PPAR ligands are promising therapeutic agents in NASH; accordingly, we evaluated the effects of the first clinically available selective PPARα modulator, pemafibrate. We found that pemafibrate improves F4/80-positive macrophage accumulation, ballooning degeneration of hepatocytes, and the non-alcoholic fatty liver disease (NAFLD) activity score without affecting triglyceride (TG) accumulation in the liver of a mouse model of NASH (STAM). A global gene expression analysis indicated that pemafibrate enhances TG hydrolysis and fatty acid ß-oxidation as well as re-esterification from dihydroxyacetone 3-phosphate and monoacylglycerol to TG. These changes are accompanied by the induction of genes involved in lipolysis and lipid droplet formation, along with an increased number and reduced size of lipid droplets in pemafibrate-treated livers. Pemafibrate reduced the expression of the cell adhesion molecule Vcam-1, myeloid cell markers, and inflammation- and fibrosis-related genes in STAM mice. Furthermore, pemafibrate significantly reduced VCAM-1 expression induced by high glucose in cultured human umbilical vein endothelial cells. These results suggest that pemafibrate prevents NASH development by reducing myeloid cell recruitment via interactions with liver sinusoidal endothelial cells, without altering hepatic TG accumulation.
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Benzoxazoles/farmacología , Butiratos/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , PPAR alfa/genética , Molécula 1 de Adhesión Celular Vascular/genética , Animales , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Oxidación-Reducción , Triglicéridos/metabolismoRESUMEN
Germline and environmental effects on the development of gastric cancers (GC) and their ethnic differences have been poorly understood. Here, we performed genomic-scale trans-ethnic analysis of 531 GCs (319 Asian and 212 non-Asians). There was one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, almost all of which were attributable to alcohol intake behavior, smoking habit, and Asian-specific defective ALDH2 allele. Alcohol-related GCs have low mutation burden and characteristic immunological profiles. In addition, we found frequent (7.4%) germline CDH1 variants among Japanese GCs, most of which were attributed to a few recurrent single-nucleotide variants shared by Japanese and Koreans, suggesting the existence of common ancestral events among East Asians. Specifically, approximately one-fifth of diffuse-type GCs were attributable to the combination of alcohol intake and defective ALDH2 allele or to CDH1 variants. These results revealed uncharacterized impacts of germline variants and lifestyles in the high incidence areas.
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Neoplasias Gástricas , Aldehído Deshidrogenasa Mitocondrial/genética , Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Células Germinativas , Humanos , Estilo de Vida , Neoplasias Gástricas/etiología , Neoplasias Gástricas/genéticaRESUMEN
An 83-year-old man was referred to our hospital for a detailed evaluation for vomiting. Esophagogastroduodenoscopy and abdominal computed tomography showed duodenal stenosis with wall thickness. Biopsy including endoscopic ultrasound-guided fine-needle aspiration of the thickened wall showed inflammation without malignancy. During the clinical course, wall thickening of the distal bile duct appeared. Biopsy under endoscopic retrograde cholangiography showed papillary adenocarcinoma. Surgery revealed that the tumor had widely invaded the duodenal wall from the outside; therefore, only gastrojejunostomy was performed. It was hypothesized that the cholangiocarcinoma had progressed to the serosal side, disseminated in the peritoneum, infiltrated the duodenal serosa, and caused duodenal stenosis.
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BACKGROUND: There is increasing evidence for the benefit of poly ADP ribose polymerase (PARP) inhibitors in a subset of high-grade serous ovarian carcinoma (HGSC) patients, especially those with homologous recombination (HR)-deficient tumors. However, new treatment strategies, such as immune checkpoint inhibition, are required for patients with HR-proficient tumors. METHODS: A total of 80 cases of HGSC were analyzed in this study. Whole exome and RNA sequencing was performed for these tumors. Methylation arrays were also carried out to examine BRCA1 and RAD51C promoter methylation status. Mutations, neoantigen load, antigen presentation machinery, and local immune profile were investigated, and the relationships of these factors with clinical outcome were also analyzed. RESULTS: As expected, the numbers of predicted neoAgs were lower in HR-proficient (n=46) than HR-deficient tumors (n=34). However, 40% of the patients with HR-proficient tumors still had higher than median numbers of neoAgs and better survival than patients with lower numbers of neoAgs. Incorporation of human leukocyte antigen (HLA)-class I expression status into the survival analysis revealed that patients with both high neoAg numbers and high HLA-class I expression (neoAghiHLAhi) had the best progression-free survival (PFS) in HR-proficient HGSC (p=0.0087). Gene set enrichment analysis demonstrated that the genes for effector memory CD8 T cells, TH1 T cells, the interferon-γ response, and other immune-related genes, were enriched in these patients. Interestingly, this subset of patients also had better PFS (p=0.0015) and a more T-cell-inflamed tumor phenotype than patients with the same phenotype (neoAghiHLAhi) in HR-deficient HGSC. CONCLUSIONS: Our results suggest that immune checkpoint inhibitors might be an alternative to explore in HR-proficient cases which currently do not benefit from PARP inhibition.
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Antígenos de Neoplasias/inmunología , Cistadenocarcinoma Seroso/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Recombinación Homóloga , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Ováricas/inmunología , Linfocitos T/inmunología , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/genética , Femenino , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Fenotipo , Pronóstico , Tasa de SupervivenciaRESUMEN
The purpose of the present study is to report our experience of endoscopic ultrasound-guided coil deployment with sclerotherapy (EUS-CS) for isolated gastric varices (IGV) through a case series. Eight consecutive patients who had risky IGV were prospectively enrolled. EUS-CS was performed according to the following procedures: (i) several coils were first deployed in the IGV under EUS guidance; (ii) contrast medium was subsequently injected without removing the needle; (iii) if the infused contrast medium stayed in the IGV and feeding vein, sclerosant was then injected to obliterate the IGV and feeders. Coil deployment in the IGV was successfully performed in all cases. Sclerosant was injected both into the IGV and feeders in seven patients (87.5%). There was no adverse event during the procedure. During a median follow-up of 57 months, one patient who could not inject the sclerosant into IGV and feeders had an early hemorrhagic recurrence. Our case series showed that EUS-CS could be a feasible and safe procedure for the treatment of IGV.
Asunto(s)
Várices Esofágicas y Gástricas , Várices Esofágicas y Gástricas/diagnóstico por imagen , Várices Esofágicas y Gástricas/terapia , Estudios de Factibilidad , Estudios de Seguimiento , Hemorragia Gastrointestinal/diagnóstico por imagen , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/terapia , Humanos , Escleroterapia/efectos adversos , Resultado del Tratamiento , Ultrasonografía IntervencionalRESUMEN
Objective To prolong the health expectancy, it is important to prevent age-related diseases, such as osteoporosis and cerebrovascular disease, which are major causes of a bedridden state. Early predictable biomarkers for these diseases are urgently required in the clinical setting. Three members of the fibroblast growth factor (FGF) family - FGF19, FGF21, and FGF23 - are designated as endocrine FGFs and play crucial roles in various metabolic processes. We tried to clarify the clinical utility of endocrine FGFs as biomarkers for age-related diseases in elderly patients. Methods We examined the serum endocrine FGF levels and analyzed their association with various clinical parameters in 73 outpatients >60 years old as a single-center cross-sectional study. Results In a multivariable linear regression analysis, FGF19 was associated with ALT, a history of cardiovascular disease, and medication with active vitamin D3. FGF21 was associated with the estimated glomerular filtration rate (eGFR), triglyceride level, and hypertension. FGF23 was associated with the eGFR and the serum levels of 1,25-dihydroxy vitamin D3 and TRACP5b. In addition, a receiver operating characteristics analysis revealed that the measurement of FGF21 and FGF23 was useful for detecting chronic kidney disease (CKD) and its complications, including cardiovascular disease and metabolic bone disorder. Conclusion The measurement of FGF21 and FGF23 may be useful for evaluating CKD and its complications. Using serum endocrine FGFs as biomarkers for age-related conditions may help prevent elderly patients from entering a bedridden state.