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The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.
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Carcinogénesis/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Regulación Neoplásica de la Expresión Génica , Adulto , Anciano , Anciano de 80 o más Años , Animales , Proteínas Portadoras/genética , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Variaciones en el Número de Copia de ADN , Carcinoma de Células Escamosas de Esófago , Exoma , Proteína de Dominio de Muerte Asociada a Fas/genética , Femenino , Perfilación de la Expresión Génica , Estudios de Asociación Genética , Humanos , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , MicroARNs/genética , Persona de Mediana Edad , Mutación , Proteínas del Tejido Nervioso/genética , Pronóstico , Selección Genética , Transactivadores/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Trauma surgical dogma teaches that patients should have intraoperative angiography (IA) if the surgeon cannot identify a pulse in the injured extremity following a vascular repair. This study was undertaken to assess the utility of IA in trauma patients who underwent open brachial or femoral artery revascularization. METHODS: Retrospective analysis of the Prospective Observational Vascular Injury Trial (PROOVIT) database from 2013 to 2021 evaluated patients >15 years with penetrating or blunt injuries requiring operative intervention of the brachial, superficial femoral, or common femoral arteries. Prospective Observational Vascular Injury Trial data evaluated included documented pulse in the injured extremity at revascularization completion, adjunctive IA, immediate revision, and vascular reintervention during the hospitalization. RESULTS: Of the 5057 patients with vascular injury, 185 patients met our inclusion criteria. The majority were male (86.5%) with a median age, injury severity score, and systolic blood pressure of 29, 12, and 117, respectively. Of the study patients, 39% underwent IA, 14% had immediate revision, and 8% required vascular reoperation during their admission. Patients who underwent IA and with no documented palpable pulse after repair were significantly more likely to require immediate revision before leaving the operating room (22% vs 9%, P = .013) and were not more likely to require reoperation, than those who did not undergo IA (7% vs 9%, P = .613). CONCLUSIONS: Intraoperative angiography is a valuable tool for surgeons for vascular extremity trauma and is associated with a greater rate of immediate revision. Familiarity with angiographic technique is essential for vascular trauma and should be a focal point of training.
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Lesiones del Sistema Vascular , Humanos , Masculino , Femenino , Lesiones del Sistema Vascular/diagnóstico por imagen , Lesiones del Sistema Vascular/cirugía , Estudios Retrospectivos , Angiografía , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/cirugía , Extremidad Inferior/irrigación sanguínea , Resultado del TratamientoRESUMEN
INTRODUCTION: Historically, a zone II hematoma mandated exploration after penetrating trauma, but this has been challenged given potentially higher nephrectomy rates and the advent of therapeutic endovascular and endoscopic interventions. We hypothesized penetrating mechanism was not a predictor for delayed intervention in the modern era. METHODS: This single-center, retrospective study included renal trauma patients from 3/2019 to 6/2022. Our institutional practice is selective exploration of zone II hematomas for active bleeding and expanding hematoma only, regardless of mechanism. Descriptive statistics and multivariable logistic regression (MLR) were performed. RESULTS: One-hundred and forty-four patients were identified, with median age 32 years (IQR:23,49), 66% blunt mechanism, and injury severity score 17(IQR:11,26). Forty-three (30%) required operative intervention, and of the 20 that had a zone II exploration, 3 (15%) underwent renorrhaphy and 17 (85%) underwent nephrectomy. Penetrating patients more frequently underwent immediate operative intervention (67%vs10%,P < .0001), required nephrectomy (27%vs5%,P = .0003), and were less likely to undergo pre-intervention CT (51%vs96%,P < .0001) compared to blunt patients. Delayed renal interventions were higher in penetrating (33%vs13%,P = .004) with no difference in mortality or length of stay compared to blunt mechanism. Ureteral stent placement and renal embolization were the most common delayed interventions. On MLR, the only independent predictor for delayed intervention was need for initial operative intervention (OR 3.803;95%CI:1.612-8.975,P = .0023). Four (3%) required delayed nephrectomy, of which only one underwent initial operative intervention without zone 2 exploration. CONCLUSIONS: The most common delayed interventions after renal trauma were renal embolization and ureteral stent. Penetrating mechanism was not a predictor of delayed renal intervention in a trauma center that manages zone II retroperitoneal hematomas similarly regardless of mechanism.
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Hematoma , Riñón , Nefrectomía , Tiempo de Tratamiento , Heridas no Penetrantes , Heridas Penetrantes , Humanos , Estudios Retrospectivos , Masculino , Femenino , Adulto , Riñón/lesiones , Persona de Mediana Edad , Nefrectomía/métodos , Heridas no Penetrantes/cirugía , Heridas no Penetrantes/terapia , Heridas no Penetrantes/mortalidad , Heridas Penetrantes/cirugía , Heridas Penetrantes/mortalidad , Heridas Penetrantes/terapia , Hematoma/cirugía , Hematoma/terapia , Hematoma/etiología , Puntaje de Gravedad del Traumatismo , Adulto Joven , Traumatismos Abdominales/cirugía , Traumatismos Abdominales/mortalidad , Traumatismos Abdominales/diagnóstico , Embolización Terapéutica/métodosRESUMEN
BACKGROUND: Although many genes have been implicated as hypertension candidates, to date, few studies have integrated different types of genomic data for the purpose of biomarker selection. METHODS: Applying a newly proposed sparse representation based variable selection (SRVS) method to the Genetic Analysis Workshop19 data, we analyzed a combined data set consisting of 11522 gene expressions and 354893 single-nucleotide polymorphisms (SNPs) from 397 subjects (case/control: 151/246), with the aim to identify potential biomarkers for blood pressure using both gene expression measures and SNP data. RESULTS: Among the top 1000 variables (SNPs/gene expressions = 575/425) selected, the bioinformatics analysis showed that 302 were plausibly associated with blood pressure. In addition, we identified 173 variables that were associated with body weight and 84 associated with left ventricular contractility. Together, 55.9 % of the top 1000 variables showed associations with blood pressure related phenotypes(SNP/gene expression =348/211). CONCLUSIONS: Our results support the feasibility of the SRVS algorithm in integrating multiple data sets of different structure for comprehensive analysis.
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OBJECTIVE: Accumulating evidence implicates inflammatory cytokines in the development of psychiatric disorders, including schizophrenia (SZ). IL-18 is one of cytokines that plays a crucial role in immune response and neurodevelopment. We aimed to investigate potential genetic alterations of the cytokine system underpinning SZ. METHODS: We tested the association of genetic variants within the cytokine-cytokine receptor interaction (CCRI) pathway with SZ, using GWAS-derived data involving 768 adult SZ patients and 1348 controls, and replicated the association of IL18R1 rs1035130 with SZ in an independent sample of 1957 adult patients and 1509 controls. We compared expression levels of IL18, IL18R1 and IL18RAP in peripheral blood of a cohort of adolescent participants (<18 years), including 14 early-onset SZ patients and 13 healthy controls. Furthermore, we carried out a cis-eQTL (expression Quantitative Trait Loci) and a cis-mQTL (Methylation Quantitative Trait Loci) analysis for IL18R1 rs1035130. RESULTS: In the discovery stage, we detected association signals within two IL18 pathway genes, IL18R1 and IL18RAP, with the most significant marker being IL18R1 rs1035130 (P = 1.84E-7, OR = 0.70). In the validation stage, we found rs1035130 was associated with SZ (P = 0.028, OR = 0.89). Expressions of IL18 and IL18R1 were altered in blood of SZ patients compared with 13 controls. Furthermore, cis-QTL analyses indicated that rs1035130 was associated with an eQTL and 5 mQTLs. CONCLUSION: Our findings suggest the alteration of IL18 pathway may contribute to the psychopathology of SZ.