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Bilateral salpingo-oophorectomy (BSO; removal of ovaries and fallopian tubes) prior to age 48 is associated with elevated risk for both Alzheimer's disease (AD) and sleep disorders such as insomnia and sleep apnea. In early midlife, individuals with BSO show reduced hippocampal volume, function, and hippocampal-dependent verbal episodic memory performance associated with changes in sleep. It is unknown whether BSO affects fine-grained sleep measurements (sleep microarchitecture) and how these changes might relate to hippocampal-dependent memory. We recruited thirty-six early midlife participants with BSO. Seventeen of these participants were taking 17ß-estradiol therapy (BSO+ET) and 19 had never taken ET (BSO). Twenty age-matched control participants with intact ovaries (AMC) were also included. Overnight at-home polysomnography recordings were collected, along with subjective sleep quality and hot flash frequency. Multivariate Partial Least Squares (PLS) analysis was used to assess how sleep varied between groups. Compared to AMC, BSO without ET was associated with significantly decreased time spent in non-rapid eye movement (NREM) stage 2 sleep as well as increased NREM stage 2 and 3 beta power, NREM stage 2 delta power, and spindle power and maximum amplitude. Increased spindle maximum amplitude was negatively correlated with verbal episodic memory performance. Decreased sleep latency, increased sleep efficiency, and increased time spent in rapid eye movement sleep were observed for BSO+ET. Findings suggest there is an association between ovarian hormone loss and sleep microarchitecture, which may contribute to poorer cognitive outcomes and be ameliorated by ET.
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INTRODUCTION: This study aimed to evaluate associations between frailty and outcomes in patients with intrahepatic cholangiocarcinoma (ICC) undergoing hepatic lobectomy using a large, nationally representative sample. METHODS: This population-based, retrospective observational study extracted the data of adults ≥20 years old with ICC undergoing hepatic lobectomy from the US Nationwide Inpatient Sample database between 2005 and 2018. Frailty was assessed by the validated Hospital Frailty Risk Score (HFRS). Associations between frailty and surgical outcomes were analyzed using logistic regression analyses. RESULTS: After exclusions, 777 patients were enrolled, including 427 frail and 350 non-frail. Patients' mean age was 64.5 (±0.4) years and the majority were males (51.1%) and whites (76.5%). Frailty was significantly associated with increased odds of in-hospital mortality (aOR: 18.51, 95% CI: 6.70, 51.18), non-home discharge (aOR: 3.58, 95% CI: 2.26, 5.66), prolonged LOS (aOR: 5.56, 95% CI: 3.87, 7.99), perioperative cardiac arrest/stroke (aOR: 5.44, 95% CI: 1.62, 18.24), acute respiratory distress syndrome (ARDS)/respiratory failure (aOR: 3.88, 95% CI: 2.40, 6.28), tracheostomy/ventilation (aOR: 3.83, 95% CI: 2.23, 6.58), bleeding/transfusion (aOR: 1.67, 95% CI: 1.24, 2.26), acute kidney injury (AKI) (aOR: 14.37, 95% CI: 7.13, 28.99), postoperative shock (aOR: 4.44, 95% CI: 2.54, 7.74), and sepsis (aOR: 11.94, 95% CI: 6.90, 20.67). DISCUSSION/CONCLUSION: Among patients with ICC undergoing hepatic lobectomy, HFRS-defined frailty is a strong predictor of worse in-patient outcomes, including in-hospital death, prolonged LOS, unfavorable discharge, and complications (perioperative cardiac arrest/stroke, ARDS/respiratory failure, tracheostomy/ventilation, bleeding/transfusion, AKI, postoperative shock, and sepsis). Study results may help stratify risk in frail patients undergoing hepatic resection for ICC.
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Lesión Renal Aguda , Colangiocarcinoma , Fragilidad , Paro Cardíaco , Síndrome de Dificultad Respiratoria , Insuficiencia Respiratoria , Sepsis , Accidente Cerebrovascular , Adulto , Masculino , Humanos , Persona de Mediana Edad , Adulto Joven , Femenino , Pacientes Internos , Fragilidad/complicaciones , Fragilidad/epidemiología , Mortalidad Hospitalaria , Estudios Retrospectivos , Colangiocarcinoma/cirugía , Factores de Riesgo , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Tiempo de InternaciónRESUMEN
We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods, including analysis of novel candidate genes, identified candidates in 21% (61/287). Of these, 24 families have additional evidence through data sharing to support likely diagnoses (8% of cohort). This study indicates few diagnoses are missed by clinical laboratories, the incremental gain from reanalysis of clinically-relevant genes is modest, and the highest yield comes from validation of novel disease-gene associations. Future implementation of translational research methods, including continued reporting of compelling genes of uncertain significance by clinical laboratories, should be considered to maximize diagnoses.
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Pruebas Genéticas , Humanos , Pruebas Genéticas/métodos , Ontario/epidemiología , Secuenciación del ExomaRESUMEN
Cancer immunotherapy has achieved impressive therapeutic effects in many cancers, while only a small subset of patients benefit from it and some patients even have experienced severe toxicity. It is urgent to develop a feasible large-cohort humanized mouse model to evaluate the pre-clinical efficacy and safety of cancer immunotherapy. Furthermore, developing potentially effective combination therapy between cancer immunotherapy and other therapies also needs humanized mouse model to adequately mimic clinical actual setting. Herein, we established a humanized mouse model engrafted with less human CD34+ HSCs than ever before and then evaluated reconstitution efficiency and the profiles of human immune cells in this humanized mouse model. Also, this humanized mouse model was used to evaluate the preclinical efficacy and safety of cancer immunotherapy. For each batch of CD34+ HSCs humanized mouse model, a relatively-large cohort with over 25% human CD45+ cells in peripheral blood was established. This humanized mouse model could efficiently reconstitute human innate and adaptive immune cells. This humanized mouse model supported patient-derived xenograft tumor growth and tumor infiltration of PD-1+ human T cells. Furthermore, therapeutic efficacy, re-activation of tumor-infiltrated T cells, and side effects of checkpoint blockade therapy could be monitored in this humanized mouse model. Human T cells from this humanized mouse model were successfully engineered with CD19-CAR. CD19 CAR-T cells could effectively deplete B cells and suppress tumor growth of acute lymphoblastic leukemia in vivo in this humanized mouse model. This humanized mouse model also could be used to demonstrate the efficacy of bispecific antibodies, such as anti-CD19/CD3. Overall, our work provides a feasible large-cohort humanized mouse model for evaluating a variety of cancer immunotherapy approaches including checkpoint inhibitors, adoptive cell therapy, and bispecific antibody therapy, and demonstrates that human T cells from this humanized mouse model possess anti-tumor activities in vitro and in vivo.
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Anticuerpos Biespecíficos , Neoplasias , Animales , Anticuerpos Biespecíficos/farmacología , Antígenos CD34 , Modelos Animales de Enfermedad , Células Madre Hematopoyéticas , Humanos , Inmunoterapia , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Despite a multitude of investigations assessing the impact of green coffee extract supplementation on obesity indices, there is still a great deal of heated debate regarding the benefits of this intervention in obesity management. Therefore, in order to clarify the effect of green coffee extract on waist circumference (WC), body mass index (BMI) and body weight (BW), we conducted an umbrella review of interventional meta-analyses. The Web of Science, Scopus, PubMed/Medline, and Embase databases were searched using specific keywords and word combinations. The umbrella meta-analysis was performed using the Stata software version 17 (Stata Corp. College Station, Texas, USA). We pooled effect sizes (ES) and confidence intervals (CI) for the outcomes using the random effects model (the DerSimonian and Laird method). In total, 5 eligible meta-analyses were included in the final quantitative assessment. Data pooled from 5 eligible papers revealed that green coffee extract can reduce BW (WMD: -1.22 kg, 95% CI: -1.53 to -0.92, p < 0.001), BMI (WMD: -0.48 kg/m2, 95% CI: -0.67 to -0.29, p < 0.001) and WC (WMD: -0.55 cm, 95% CI: -0.80 to -0.31, p < 0.001). Subgroup analyses highlighted that green coffee extract supplementation in dosages ≤600 mg/day and interventions lasting >7 wk are more likely to decrease BW. The present umbrella meta-analysis confirms the beneficial effects of green coffee extract in reducing WC, BMI, and BW. Thus, we may infer that green coffee extract can be used as a complementary therapy in the management of obesity.
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PURPOSE: Demonstrating the clinical utility of genetic testing is fundamental to clinical adoption and reimbursement, but standardized definitions and measurement strategies for this construct do not exist. The Clinician-reported Genetic testing Utility InDEx (C-GUIDE) offers a novel measure to fill this gap. This study assessed its validity and inter-rater reliability. METHODS: Genetics professionals completed C-GUIDE after disclosure of test results to patients. Construct validity was assessed using regression analysis to measure associations between C-GUIDE and global item scores as well as potentially explanatory variables. Inter-rater reliability was assessed by administering a vignette-based survey to genetics professionals and calculating Krippendorff's α. RESULTS: On average, a 1-point increase in the global item score was associated with an increase of 3.0 in the C-GUIDE score (P < .001). Compared with diagnostic results, partially/potentially diagnostic and nondiagnostic results were associated with a reduction in C-GUIDE score of 9.5 (P < .001) and 10.2 (P < .001), respectively. Across 19 vignettes, Krippendorff's α was 0.68 (95% CI: 0.63-0.72). CONCLUSION: C-GUIDE showed acceptable validity and inter-rater reliability. Although further evaluation is required, C-GUIDE version 1.2 can be useful as a standardized approach to assess the clinical utility of genetic testing.
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Pruebas Genéticas , Humanos , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
BACKGROUND: About 25-37% of resectable pancreatic ductal adenocarcinoma (PDAC) had a great chance of early recurrence after radical resection, which is mainly due to preoperative micrometastasis. We herein demonstrated the profiles of ctDNA in resectable PDAC and use of ctDNA to identify patients with potential micrometastasis. METHODS: A total of 113 and 44 resectable PDACs were enrolled in discovery and validation cohorts, separately. A panel containing 50 genes was used to screen ctDNA by an NGS-based assessment with high specificity. RESULTS: In the discovery cohort, the overall detection rate was 38.05% (43/113). Among positive ctDNA, KRAS mutation had the highest detection rate (23.01%, 26/113), while the others were <5%. Survival analysis showed that plasma KRAS mutations, especially KRAS G12D mutation, had significant association with OS and RFS of resectable PDAC. Plasma KRAS G12D mutation showed a strong correlation with early distant metastasis. In the validation cohort, survival analysis showed similar association between plasma KRAS G12D mutation and poor outcomes. CONCLUSIONS: This study demonstrated that plasma KRAS mutations, especially KRAS G12D mutation, served as a useful predictive biomarker for prognosis of resectable PDAC. More importantly, due to high correlation with micrometastasis, preoperative detection of plasma KRAS G12D mutation helps in optimising surgical selection of resectable PDAC.
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Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , ADN Tumoral Circulante/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia , Periodo Preoperatorio , Pronóstico , Estudios ProspectivosRESUMEN
A patient-derived xenograft (PDX) approach, which relies on direct transplantation of tumor specimens into an immunocompromised animal, is a commonly used method for investigating tumor therapy predictions in vivo. This study evaluated influencing factors, including clinical, oncological, and genetic variables, for a pancreatic PDX model in mice. Tumor specimens were obtained from 121 patients with pancreatic ductal adenocarcinoma who underwent surgical resection at the Changhai Pancreatic Surgery Medical Center (Shanghai, China) between April 2016 and February 2017. Pancreatic cancer (PC) samples <3 mm3 were subcutaneously implanted into the NOD/Shi-scid/IL-2Rγnull (NSG) mice. Once the xenograft reached 300-500 mm3 or reached 180 d after cell inoculation, the tumor was excised. Part of the tumor was subsequently transplanted to next-generation mice, and another part was analyzed by using immunohistochemistry. Among the 121 patients with PC, tumor xenograft was successfully generated in 86 patients (71.1%). Primary tumor >3.5 cm in size was independently associated with xenograft formation rate. In addition, several enriched mutated genes within the VEGF pathway and higher microvessel density were found in the positive group (with xenograft) compared with the negative group (without xenograft). We concluded that tumor size and mutated VEGF pathway in PC are important factors affecting PDX model construction with NSG mice.-Guo, S., Gao, S., Liu, R., Shen, J., Shi, X., Bai, S., Wang, H., Zheng, K., Shao, Z., Liang, C., Peng, S., Jin, G. Oncological and genetic factors impacting PDX model construction with NSG mice in pancreatic cancer.
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Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Animales , Carcinoma Ductal Pancreático/irrigación sanguínea , Femenino , Xenoinjertos , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Mutación , Neovascularización Patológica , Neoplasias Pancreáticas/irrigación sanguínea , Pronóstico , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: To report a unique retinal signaling defect in GNB5-related disease. METHODS: A 3-year-old female child underwent detailed systemic and ophthalmological evaluation. The eye examination included fundus photography, spectral domain optical coherence tomography and an extended protocol full-field electroretinography (ERG) including the ISCEV recommended standard steps. The dark-adapted (DA) ERGs were performed to a series of white flashes (range 0.006-30.0 cd s m-2) and two red flashes. The DA ERGs to higher stimulus intensities (3.0, 10.0 and 30.0 cd s m-2) were tested using a range of inter-stimulus intervals (ISI) of up to 60 s. In addition to standard light-adapted (LA) ERGs, a short-duration (0.5 s) LA 3.0 30-Hz flicker ERG and a long-duration LA ON-OFF ERG were also performed. Genetic testing included microarray, mitochondrial genome testing and whole exome sequencing. RESULTS: The child was diagnosed to have status epilepticus and bradycardia at 6 months of age. Subsequently, she was diagnosed to have global developmental delay and hypotonia. On ophthalmological evaluation, the child fixes and follows light. Fundus evaluation showed mild optic disk pallor; macular SD-OCT was normal. The dim flash DA ERGs (DA 0.006 and DA 0.01 cd s m-2) were non-detectable. DA red flash ERGs showed the presence of an x-wave (cone component) and no rod component. The DA 3.0, 10.0 and 30.0 ERGs showed electronegative configuration regardless of the ISI; the averaged a-wave amplitude (4 flashes) was smaller at shorter ISI but became normal at a prolonged ISI (60 s). The LA 30-Hz flicker ERG was severely reduced but detectable for the initial 0.5 s; this became non-detectable after 5 s of averaging. The LA 3.0 2-Hz ERG showed markedly reduced a- and b-wave amplitudes and a reduced b:a ratio; the LA ON-OFF ERGs were non-detectable. WES identified a homozygous null mutation in G protein subunit beta 5 (GNB5; c.1032C>A/p.Tyr344*). CONCLUSION: This report identifies for the first time a unique retinopathy associated with biallelic mutations in GNB5. The observed phenotype is consistent with a dual retinal signaling defect reminiscent of features of bradyopsia and rod ON-bipolar dysfunction.
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Subunidades beta de la Proteína de Unión al GTP/genética , Mutación , Enfermedades de la Retina/genética , Preescolar , Adaptación a la Oscuridad/fisiología , Electrorretinografía/métodos , Enfermedades Hereditarias del Ojo , Femenino , Humanos , Fenotipo , Estimulación Luminosa , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/fisiopatología , Tomografía de Coherencia Óptica , Visión Ocular/genética , Secuenciación del ExomaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplastic disease, characterized with poor outcomes and a 5-year survival rate less than 5%. Dysregulation or dysfunction of immune response factors contribute to cancer development. In this study, we found that OCIAD1 is high expressed in pancreatic cancer gene chip, and verified OCIAD1 associating with cancer malignancy in specimens from patients with PDAC. OCIAD1 down-regulation inhibited PDAC cell lines migration and vice versa. Further analysis of pancreatic cancer gene chip found OCIAD1 high expression was associating with low ATM expression. Then we proved that OCIAD1 regulated ATM to affect the migration of PDAC. Thus we concluded that high OCIAD1 levels in PDAC promoted tumor cells migration. OCIAD1 exerted its effects by regulating ATM.
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Proteínas de la Ataxia Telangiectasia Mutada/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Anciano , Línea Celular Tumoral , Movimiento Celular/genética , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Pathogenic variants in GNB5 cause an autosomal recessive neurodevelopmental disorder with neonatal sinus bradycardia. Seizures or epilepsy occurred in 10 of 22 previously reported cases, including 6 children from one family. We delineate the epileptology of GNB5 encephalopathy. Our nine patients, including five new patients, were from seven families. Epileptic spasms were the most frequent seizure type, occurring in eight of nine patients, and began at a median age of 3 months (2 months to 3 years). Focal seizures preceded spasms in three children, with onset at 7 days, 11 days, and 4 months. One child presented with convulsive status epilepticus at 6 months. Three children had burst suppression on electroencephalography (EEG), three had hypsarrhythmia, and one evolved from burst suppression to hypsarrhythmia. Background slowing was present in all after age 3 years. Magnetic resonance imaging (MRI) showed cerebral atrophy in one child and cerebellar atrophy in another. All nine had abnormal development prior to seizure onset and ultimately had profound impairment without regression. Hypotonia was present in all, with contractures developing in two older patients. All individuals had biallelic pathogenic variants in GNB5, predicted by in silico tools to result in protein truncation and loss-of-function. GNB5 developmental and epileptic encephalopathy is characterized by epileptic spasms, focal seizures, and profound impairment.
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Encefalopatías/diagnóstico , Encefalopatías/genética , Epilepsia/diagnóstico , Epilepsia/genética , Subunidades beta de la Proteína de Unión al GTP/genética , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Linaje , Adulto JovenRESUMEN
Statin exposure has been reported to improve survival in several cancers. However, studies evaluating the association between statins and prognostic outcomes in patients with lung cancer are conflicting and heterogeneous. Pubmed, EMBASE and reference lists of included studies were searched to identify studies investigating the association between statin exposure and lung cancer prognosis. The primary outcome measure was overall survival (OS) and secondary ones included cancer-specific survival (CSS) and recurrence-free survival (RFS). Hazard ratios (HRs) with 95% confidence intervals (95% CIs) of these outcomes were pooled using random-effects models. Thirteen studies with data from 99,297 individuals satisfying the inclusion criteria were identified. Studies were ranked to be at low to moderate risk of bias. Meta-analysis showed that statin exposure was significantly associated with improved OS (pooled HR 0.79, 95% CI 0.72-0.86), CSS (pooled HR 0.83, 95% CI 0.77-0.89) and RFS (pooled HR 0.85, 95% CI 0.81-0.89). Subgroup analyses showed that statin users after diagnosis of lung cancer had more survival benefit for OS (HR 0.68, 95% CI 0.51-0.92) than those before diagnosis (HR 0.86, 95% CI 0.81-0.90) and current users (HR 0.79, 95% CI 0.62-1.02) (P for interaction <0.001). Besides, statin users were likely to have more survival benefits in stage IV lung cancer patients (HR 0.77, 95% CI 0.74-0.79) than in mixed stage (I-IV or I-III) patients (P for interaction = 0.004). Statin exposure is associated with significantly improved survival in patients with lung cancer. Future studies are warranted to further demonstrate the therapeutic role of statins in specific lung cancer patients.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Neoplasias Pulmonares/epidemiología , Supervivencia sin Enfermedad , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Estudios Observacionales como Asunto , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND AND AIM: The thiopurines are effective in the management of patients with inflammatory bowel disease (IBD), but the association between thiopurines use and the risk of skin cancer (including nonmelanoma skin cancer [NMSC] and melanoma skin cancer) has already been sufficiently reported. However, the results of these studies are inconsistent, and thus, the objective of our analysis was to explore whether thiopurines can lead to an excess risk of skin cancer in IBD patients. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched to identify relevant studies that evaluated the risk of skin cancer in IBD patients treated with thiopurines. A random effects meta-analysis was conducted to calculate the pooled incidence rate ratios as well as risk ratios (RRs). Subgroup analysis was performed to explore the potential source of heterogeneity. RESULTS: Thirteen studies comprising 149 198 participants were included. The result suggested that thiopurines significantly increased the risk of overall skin cancer in IBD patients (random effects: RR = 1.80, 95% confidence interval [CI] 1.14-2.87, P = 0.013), among which NMSC showed an excess risk associated with thiopurines use (random effects: RR = 1.88, 95% CI 1.48-2.38, P < 0.001) while no increased risk was observed with respect to melanoma skin cancer (random effects: RR = 1.22, 95% CI 0.90-1.65, P = 0.206). Subgroup analysis regarding sample size and geographic distribution in skin cancer and follow-up duration in NMSC reached statistical significance, while other subgroups showed no significance. CONCLUSION: Exposition of thiopurines in patients with IBD is associated with a higher risk of skin cancer. Routine skin screening and daily skin protective practice are recommended for these patients.
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Azatioprina/efectos adversos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Melanoma/etiología , Mercaptopurina/efectos adversos , Neoplasias Cutáneas/etiología , Azatioprina/uso terapéutico , Bases de Datos Bibliográficas , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Melanoma/prevención & control , Mercaptopurina/uso terapéutico , Riesgo , Neoplasias Cutáneas/prevención & controlRESUMEN
BACKGROUND/AIMS: Colonoscopy screening has been accepted broadly to evaluate the risk and incidence of colorectal cancer (CRC) during health examination in outpatients. However, the intrusiveness, complexity and discomfort of colonoscopy may limit its application and the compliance of patients. Thus, more reliable and convenient diagnostic methods are necessary for CRC screening. Genome instability, especially copy-number variation (CNV), is a hallmark of cancer and has been proved to have potential in clinical application. METHODS: We determined the diagnostic potential of chromosomal CNV at the arm level by whole-genome sequencing of CRC plasma samples (n = 32) and healthy controls (n = 38). Arm level CNV was determined and the consistence of arm-level CNV between plasma and tissue was further analyzed. Two methods including regular z score and trained Support Vector Machine (SVM) classifier were applied for detection of colorectal cancer. RESULTS: In plasma samples of CRC patients, the most frequent deletions were detected on chromosomes 6, 8p, 14q and 1p, and the most frequent amplifications occurred on chromosome 19, 5, 2, 9p and 20p. These arm-level alterations detected in plasma were also observed in tumor tissues. We showed that the specificity of regular z score analysis for the detection of colorectal cancer was 86.8% (33/38), whereas its sensitivity was only 56.3% (18/32). Applying a trained SVM classifier (n = 40 in trained group) as the standard to detect colorectal cancer relevance ratio in the test samples (n = 30), a sensitivity of 91.7% (11/12) and a specificity 88.9% (16/18) were finally reached. Furthermore, all five early CRC patients in stages I and II were successfully detected. CONCLUSION: Trained SVM classifier based on arm-level CNVs can be used as a promising method to screen early-stage CRC.
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Cromosomas/metabolismo , Neoplasias Colorrectales/diagnóstico , ADN/sangre , Adulto , Anciano , Anciano de 80 o más Años , Aneuploidia , Área Bajo la Curva , Estudios de Casos y Controles , Cromosomas/genética , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , ADN/genética , ADN/metabolismo , Variaciones en el Número de Copia de ADN , Detección Precoz del Cáncer , Endoscopía Gastrointestinal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Curva ROC , Sensibilidad y Especificidad , Análisis de Secuencia de ADN , Máquina de Vectores de Soporte , Adulto JovenRESUMEN
Retinopathy of prematurity (ROP), the most common cause of blindness in premature infants, has long been associated with inner retinal alterations. However, recent studies reveal outer retinal dysfunctions in patients formerly afflicted with ROP. We have recently demonstrated that choroidal involution occurs early in retinopathy. Herein, we investigated the mechanisms underlying the choroidal involution and its long-term impact on retinal function. An oxygen-induced retinopathy (OIR) model was used. In vitro and ex vivo assays were applied to evaluate cytotoxic effects of IL-1ß on choroidal endothelium. Electroretinogram was used to evaluate visual function. We found that proinflammatory IL-1ß was markedly increased in retinal pigment epithelium (RPE)/choroid and positively correlated with choroidal degeneration in the early stages of retinopathy. IL-1ß was found to be cytotoxic to choroid in vitro, ex vivo, and in vivo. Long-term effects on choroidal involution included a hypoxic outer neuroretina, associated with a progressive loss of RPE and photoreceptors, and visual deterioration. Early inhibition of IL-1ß receptor preserved choroid, decreased subretinal hypoxia, and prevented RPE/photoreceptor death, resulting in life-long improved visual function in IL-1 receptor antagonist-treated OIR animals. Together, these findings suggest a critical role for IL-1ß-induced choroidal degeneration in outer retinal dysfunction. Neonatal therapy using IL-1 receptor antagonist preserves choroid and prevents protracted outer neuroretinal anomalies in OIR, suggesting IL-1ß as a potential therapeutic target in ROP.
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Enfermedades de la Coroides/fisiopatología , Interleucina-1beta/metabolismo , Retinopatía de la Prematuridad/fisiopatología , Animales , Animales Recién Nacidos , Coroides/metabolismo , Coroides/fisiopatología , Enfermedades de la Coroides/etiología , Enfermedades de la Coroides/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Electrorretinografía , Endotelio/metabolismo , Humanos , Recién Nacido , Oxígeno/efectos adversos , Células Fotorreceptoras/metabolismo , Ratas , Ratas Sprague-Dawley , Retina/metabolismo , Retina/fisiopatología , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/fisiopatología , Retinopatía de la Prematuridad/inducido químicamente , Retinopatía de la Prematuridad/etiología , Retinopatía de la Prematuridad/metabolismoRESUMEN
OBJECTIVE: Pathological ocular neovascularization is a major cause of blindness. Increased dietary intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but ω-3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of ω-3 LCPUFA on neovascular eye diseases. APPROACH AND RESULTS: The mouse models of oxygen-induced retinopathy and laser-induced CNV were used to investigate pathological angiogenesis in the retina and choroid, respectively. The plasma levels of ω-3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and ω-3 LCPUFA-derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of ω-3 LCPUFA on retinal neovascularization and CNV by 30% and 20%, respectively. In CYP2C8-overexpressing mice fed a ω-3 LCPUFA diet, montelukast suppressed retinal neovascularization and CNV by 36% and 39% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C ω-3 LCPUFA-derived active metabolites, increased oxygen-induced retinopathy and CNV in vivo. Exposure to selected ω-3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast. CONCLUSIONS: Inhibition of CYP2C activity adds to the protective effects of ω-3 LCPUFA on pathological retinal neovascularization and CNV.
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Acetatos/farmacología , Inhibidores de la Angiogénesis/farmacología , Neovascularización Coroidal/prevención & control , Inhibidores del Citocromo P-450 CYP2C8/farmacología , Citocromo P-450 CYP2C8/metabolismo , Ácidos Grasos Omega-3/farmacología , Quinolinas/farmacología , Neovascularización Retiniana/prevención & control , Retinopatía de la Prematuridad/prevención & control , Animales , Aorta/efectos de los fármacos , Aorta/enzimología , Células Cultivadas , Neovascularización Coroidal/enzimología , Neovascularización Coroidal/genética , Neovascularización Coroidal/fisiopatología , Ciclopropanos , Citocromo P-450 CYP2C8/genética , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Ácidos Grasos Omega-3/metabolismo , Genotipo , Humanos , Hiperoxia/complicaciones , Rayos Láser , Ratones Endogámicos C57BL , Ratones Transgénicos , Neovascularización Fisiológica/efectos de los fármacos , Fenotipo , Neovascularización Retiniana/enzimología , Neovascularización Retiniana/genética , Neovascularización Retiniana/fisiopatología , Retinopatía de la Prematuridad/enzimología , Retinopatía de la Prematuridad/genética , Retinopatía de la Prematuridad/fisiopatología , Sulfuros , Técnicas de Cultivo de TejidosRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) presents as an aggressive malignancy caused by environmental and genetic factors. In order to identify causal genes for PDAC, we performed whole exome sequencing (WES) to detect gene mutations in seven pairs of PDAC tissue and adjacent non-tumor tissue samples. Finally, we found a new nonsynonymous single nucleotide variant (nsSNV) in solute carrier 24 family member 2 (SLC24A2) gene resulting in the substitution of native glutamic acid (E) into aspartic acid (D) at position of 287 amino acid (E287D) in SLC24A2 protein, and confirmed this variant by Sanger gene sequencing. SLC24A2 is a potassium-dependent sodium-calcium exchanger and can transport metal ion across cell membrane. Multiple in silico variants' effects analyses methods including SIFT, PolyPhen, PROVEAN, and PANTHER demonstrated this variant had probably damaging effects, which was consistent with the results obtained from Mutation Taster software analysis with a probability of 0.99999997 to be "disease causing." The three dimension (3D) structure analysis results suggested this variant had little effects on the solubility and hydrophobicity of the protein; but it could decrease the protein stability by increasing the total protein structure energy (-8874.33 kJ/mol for the mutant and -8963.54 kJ/mol for the native) and by causing the mutant protein decreasing three stabilizing residues. Less stability of the mutant 287D protein than the native E287 protein was also supported by I-Mutant and Western-blotting analysis results. Overall, a new mutation in SLC24A2 gene was identified to decrease the stability of SLC24A2, which may have potential clinical usages.
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Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Intercambiador de Sodio-Calcio/genética , Sustitución de Aminoácidos , Simulación por Computador , Análisis Mutacional de ADN , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Mutación , Polimorfismo Genético/genética , Polimorfismo de Nucleótido Simple , Estructura Terciaria de Proteína , Secuenciación del ExomaRESUMEN
OBJECTIVE: Regulation of angiogenesis is critical for many diseases. Specifically, pathological retinal neovascularization, a major cause of blindness, is suppressed with dietary ω3-long-chain polyunsaturated fatty acids (ω3LCPUFAs) through antiangiogenic metabolites of cyclooxygenase and lipoxygenase. Cytochrome P450 epoxygenases (CYP2C8) also metabolize LCPUFAs, producing bioactive epoxides, which are inactivated by soluble epoxide hydrolase (sEH) to transdihydrodiols. The effect of these enzymes and their metabolites on neovascularization is unknown. APPROACH AND RESULTS: The mouse model of oxygen-induced retinopathy was used to investigate retinal neovascularization. We found that CYP2C (localized in wild-type monocytes/macrophages) is upregulated in oxygen-induced retinopathy, whereas sEH is suppressed, resulting in an increased retinal epoxide:diol ratio. With a ω3LCPUFA-enriched diet, retinal neovascularization increases in Tie2-driven human-CYP2C8-overexpressing mice (Tie2-CYP2C8-Tg), associated with increased plasma 19,20-epoxydocosapentaenoic acid and retinal epoxide:diol ratio. 19,20-Epoxydocosapentaenoic acids and the epoxide:diol ratio are decreased with overexpression of sEH (Tie2-sEH-Tg). Overexpression of CYP2C8 or sEH in mice does not change normal retinal vascular development compared with their wild-type littermate controls. The proangiogenic role in retina of CYP2C8 with both ω3LCPUFA and ω6LCPUFA and antiangiogenic role of sEH in ω3LCPUFA metabolism were corroborated in aortic ring assays. CONCLUSIONS: Our results suggest that CYP2C ω3LCPUFA metabolites promote retinal pathological angiogenesis. CYP2C8 is part of a novel lipid metabolic pathway influencing retinal neovascularization.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/metabolismo , Ácidos Grasos Omega-3/toxicidad , Macrófagos/enzimología , Monocitos/enzimología , Neovascularización Retiniana/inducido químicamente , Animales , Ácido Araquidónico/metabolismo , Hidrocarburo de Aril Hidroxilasas/genética , Biotransformación , Hipoxia de la Célula , Citocromo P-450 CYP2C8 , Grasas de la Dieta/farmacocinética , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Epóxido Hidrolasas/deficiencia , Epóxido Hidrolasas/genética , Epóxido Hidrolasas/fisiología , Proteínas del Ojo/metabolismo , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/clasificación , Ácidos Grasos Omega-3/farmacocinética , Ácidos Grasos Insaturados/administración & dosificación , Ácidos Grasos Insaturados/farmacocinética , Humanos , Lipooxigenasa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oxígeno/toxicidad , Prostaglandina-Endoperóxido Sintasas/metabolismo , ARN Mensajero/biosíntesis , Receptor TIE-2/genética , Proteínas Recombinantes de Fusión/metabolismo , Neovascularización Retiniana/prevención & controlRESUMEN
BACKGROUND: The tumor susceptibility gene 101 (TSG101) was originally identified as a tumor-suppressor gene that mediates many molecular and biological processes, such as ubiquitination, endosomal trafficking, cell survival, and virus budding, but its role in hepatocellular carcinoma (HCC) is currently unknown. MATERIAL AND METHODS: We assessed the expression of TSG101 in HCC and paracancerous tissues using qPCR. Then, we used the TSG101-specific siRNA mix to disrupt the expression of TSG101 to investigate the subsequent effect on human hepatoma-7 (Huh7) cells. Western blot was used to detect the protein expression of TSG101 and other molecules. Cell growth assay was performed using CCK8. Transwell assay was used to investigate the migration and invasion ability of Huh7 cells after transfection with of TSG101 siRNA. Flow cytometry was used to estimate the effect of TSG101 knockdown on cell cycle and apoptosis. Confocal laser scanning microscopy was used to observe the actin filaments change and the formation of autophagy. RESULTS: TSG101 was over-expressed in HCC tissues. TSG101 silence was able to suppress Huh7 cell proliferation, migration, and invasion. Furthermore, silencing of TSG101 could induce cell cycle arrest at G1 phase and inhibit the expression of cyclin A and cyclin D, while up-regulating the expression of CDK2. The mechanism might be induction of autophagic cell death and inactivation of Akt and ERK1/2. CONCLUSIONS: TSG101 plays an important role in the development of HCC and may be a target for molecular therapy.