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AIMS: The variant p.Arg149Cys in ACTA2, which encodes smooth muscle cell (SMC)-specific α-actin, predisposes to thoracic aortic disease and early onset coronary artery disease in individuals without cardiovascular risk factors. This study investigated how this variant drives increased atherosclerosis. METHODS AND RESULTS: Apoe-/- mice with and without the variant were fed a high-fat diet for 12 weeks, followed by evaluation of atherosclerotic plaque formation and single-cell transcriptomics analysis. SMCs explanted from Acta2R149C/+ and wildtype (WT) ascending aortas were used to investigate atherosclerosis-associated SMC phenotypic modulation. Hyperlipidemic Acta2R149C/+Apoe-/- mice have a 2.5-fold increase in atherosclerotic plaque burden compared to Apoe-/- mice with no differences in serum lipid levels. At the cellular level, misfolding of the R149C α-actin activates heat shock factor 1, which increases endogenous cholesterol biosynthesis and intracellular cholesterol levels through increased HMG-CoA reductase (HMG-CoAR) expression and activity. The increased cellular cholesterol in Acta2R149C/+ SMCs induces endoplasmic reticulum stress and activates PERK-ATF4-KLF4 signaling to drive atherosclerosis-associated phenotypic modulation in the absence of exogenous cholesterol, while WT cells require higher levels of exogenous cholesterol to drive phenotypic modulation. Treatment with the HMG-CoAR inhibitor pravastatin successfully reverses the increased atherosclerotic plaque burden in Acta2R149C/+Apoe-/- mice. CONCLUSION: These data establish a novel mechanism by which a pathogenic missense variant in a smooth muscle-specific contractile protein predisposes to atherosclerosis in individuals without hypercholesterolemia or other risk factors. The results emphasize the role of increased intracellular cholesterol levels in driving SMC phenotypic modulation and atherosclerotic plaque burden.
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Aterosclerosis , Hiperlipidemias , Placa Aterosclerótica , Ratones , Animales , Placa Aterosclerótica/complicaciones , Actinas/metabolismo , Ratones Noqueados para ApoE , Aterosclerosis/etiología , Colesterol/metabolismo , Hiperlipidemias/complicaciones , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Músculo Liso/metabolismo , Músculo Liso/patología , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
BACKGROUND: Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling. METHODS: We generated an SMC-specific Perk knockout mouse model, induced hyperlipidemia in the mice by AAV-PCSK9DY injection, and subjected them to a high-fat diet. We then assessed atherosclerotic plaque formation and performed single-cell transcriptomic studies using aortic tissue from these mice. RESULTS: SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 clusters of modulated SMCs in hyperlipidemic mice, one of which is absent when Perk is deleted in SMCs. The 2 modulated SMC clusters have significant overlap of transcriptional changes, but the Perk-dependent cluster uniquely shows a global decrease in the number of transcripts. SMC-specific Perk deletion also prevents migration of both contractile and modulated SMCs from the medial layer of the aorta. CONCLUSIONS: Our results indicate that hypercholesterolemia drives both Perk-dependent and Perk-independent SMC modulation and that deficiency of Perk significantly blocks atherosclerotic plaque formation.
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Aterosclerosis , Miocitos del Músculo Liso , Placa Aterosclerótica , eIF-2 Quinasa , Animales , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Células Cultivadas , Colesterol/metabolismo , Retículo Endoplásmico/metabolismo , Masculino , Ratones , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/metabolismo , Placa Aterosclerótica/metabolismo , eIF-2 Quinasa/metabolismoRESUMEN
OBJECTIVE: Prognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop a prognostic model by profiling the genomic features of patients with mEGAC with widely varying outcomes. DESIGN: We profiled 40 untreated mEGACs (20 shorter survivors <13 months and 20 longer survivors >36 months) with whole-exome sequencing (WES) and RNA sequencing and performed an integrated analysis of exome, transcriptome, immune profile and pathological phenotypes to identify the molecular determinants, developing an integrated model for prognosis and comparison with The Cancer Genome Atlas (TCGA) cohorts. RESULTS: KMT2C alterations were exclusively observed in shorter survivors together with high level of intratumour heterogeneity and complex clonal architectures, whereas the APOBEC mutational signatures were significantly enriched in longer survivors. Notably, the loss of heterozygosity in chromosome 4 (Chr4) was associated with shorter survival and 'cold' immune phenotype characterised by decreased B, CD8, natural killer cells and interferon-gamma responses. Unsupervised transcriptomic clustering revealed a shorter survivor subtype with distinct expression features (eg, upregulated druggable targets JAK2, MAP3K13 and MECOM). An integrated model was then built based on clinical variables and the identified molecular determinants, which significantly segregated shorter and longer survivors. All the above features and the integrated model have been validated independently in multiple TCGA cohorts. CONCLUSION: This study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.
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Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Perfil Genético , Neoplasias Gástricas/genética , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Masculino , Pronóstico , Medición de Riesgo , Análisis de Secuencia de ARN , Secuenciación del ExomaRESUMEN
BACKGROUND: We describe the first reported case of myelofibrosis as an extremely rare complication of gastric cancer during pregnancy; the clinical diagnosis and treatment of which is highly challenging due to nonspecific symptoms coupled with the conflicting needs of immediate disease control and continuation of pregnancy. CASE PRESENTATION: We report a 36-year-old pregnant woman who presented with cytopenia, fatigue, vomiting, and diarrhea for 20 days on the background of newly diagnosed myelofibrosis secondary to gastric signet ring adenocarcinoma. She accepted palliative care and died several months after the delivery of a healthy newborn. CONCLUSION: Signet ring gastric adenocarcinoma is an unusual cause of myelofibrosis during pregnancy. Treatment remains a great challenge as clinicians have to consider the needs of immediate treatment against fetal well-being while taking into account patient preference and fetus rights.
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Adenocarcinoma/diagnóstico , Carcinoma de Células en Anillo de Sello/diagnóstico , Mielofibrosis Primaria/diagnóstico , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/complicaciones , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adulto , Carcinoma de Células en Anillo de Sello/complicaciones , Carcinoma de Células en Anillo de Sello/patología , Carcinoma de Células en Anillo de Sello/terapia , Femenino , Humanos , Cuidados Paliativos , Embarazo , Mielofibrosis Primaria/etiología , Mielofibrosis Primaria/patología , Mielofibrosis Primaria/terapia , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapiaRESUMEN
Endometrial cancer (EC) stands as one of the most prevalent malignancies affecting the female genital tract, witnessing a rapid surge in incidence globally. Despite the well-established association of histone methyltransferase SMYD3 with the development and progression of various cancers, its specific oncogenic role in endometrial cancer remains unexplored. In the present study, we report that the expression level of SMYD3 is significantly upregulated in EC samples and associated with EC progression. Through meticulous in vivo and in vitro experiments, we reveal that depletion of SMYD3 curtails cell proliferation, migration, and invasion capabilities, leading to compromised non-homologous end joining repair (NHEJ) and heightened sensitivity of EC cells to radiation. Furthermore, our pathway enrichment analysis underscores the pivotal involvement of the DNA damage repair pathway in regulating EC progression. Mechanistically, in response to DNA damage, SMYD3 is recruited to these sites in a PARP1-dependent manner, specifically methylating LIG4. This methylation sets off a sequential assembly of the LIG4/XRCC4/XLF complex, actively participating in the NHEJ pathway and thereby fostering EC progression. Notably, our findings highlight the promise of SMYD3 as a crucial player in NHEJ repair and its direct correlation with EC progression. Intriguingly, pharmacological intervention targeting SMYD3 with its specific inhibitor, BCI-121, emerges as a potent strategy, markedly suppressing the tumorigenicity of EC cells and significantly enhancing the efficacy of radiotherapy. Collectively, our comprehensive data position SMYD3 as a central factor in NHEJ repair and underscore its potential as a promising pharmacological target for endometrial cancer therapy, validated through both in vitro and in vivo systems.
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Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is caused by biallelic loss-of-function variants in pericentrin (PCNT), and premature coronary artery disease (CAD) is a complication of the syndrome. Histopathology of coronary arteries from patients with MOPDII who died of CAD in their 20s showed extensive atherosclerosis. Hyperlipidemic mice with smooth muscle cell-specific (SMC-specific) Pcnt deficiency (PcntSMC-/-) exhibited significantly greater atherosclerotic plaque burden compared with similarly treated littermate controls despite similar serum lipid levels. Loss of PCNT in SMCs induced activation of heat shock factor 1 (HSF1) and consequently upregulated the expression and activity of HMG-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis. The increased cholesterol biosynthesis in PcntSMC-/- SMCs augmented PERK signaling and phenotypic modulation compared with control SMCs. Treatment with the HMGCR inhibitor, pravastatin, blocked the augmented SMC modulation and reduced plaque burden in hyperlipidemic PcntSMC-/- mice to that of control mice. These data support the notion that Pcnt deficiency activates cellular stress to increase SMC modulation and plaque burden, and targeting this pathway with statins in patients with MOPDII has the potential to reduce CAD in these individuals. The molecular mechanism uncovered further emphasizes SMC cytosolic stress and HSF1 activation as a pathway driving atherosclerotic plaque formation independently of cholesterol levels.
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Aterosclerosis , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Placa Aterosclerótica , Animales , Humanos , Ratones , Aterosclerosis/patología , Colesterol/metabolismo , Miocitos del Músculo Liso/metabolismo , Placa Aterosclerótica/patologíaRESUMEN
Missense variants throughout ACTA2, encoding smooth muscle α-actin (αSMA), predispose to adult onset thoracic aortic disease, but variants disrupting arginine 179 (R179) lead to Smooth Muscle Dysfunction Syndrome (SMDS) characterized by childhood-onset diverse vascular diseases. Our data indicate that αSMA localizes to the nucleus in wildtype (WT) smooth muscle cells (SMCs), enriches in the nucleus with SMC differentiation, and associates with chromatin remodeling complexes and SMC contractile gene promotors, and the ACTA2 p.R179 variant decreases nuclear localization of αSMA. SMCs explanted from a SMC-specific conditional knockin mouse model, Acta2SMC-R179/+, are less differentiated than WT SMCs, both in vitro and in vivo, and have global changes in chromatin accessibility. Induced pluripotent stem cells from patients with ACTA2 p.R179 variants fail to fully differentiate from neural crest cells to SMCs, and single cell transcriptomic analyses of an ACTA2 p.R179H patient's aortic tissue shows increased SMC plasticity. Thus, nuclear αSMA participates in SMC differentiation and loss of this nuclear activity occurs with ACTA2 p.R179 pathogenic variants.
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Missense variants throughout ACTA2, encoding smooth muscle α-actin (αSMA), predispose to adult-onset thoracic aortic disease, but variants disrupting arginine 179 (R179) lead to Smooth Muscle Dysfunction Syndrome (SMDS) characterized by diverse childhood-onset vascular diseases. Here we show that αSMA localizes to the nucleus in wildtype (WT) smooth muscle cells (SMCs), enriches in the nucleus with SMC differentiation, and associates with chromatin remodeling complexes and SMC contractile gene promotors. The ACTA2 p.R179 αSMA variant shows decreased nuclear localization. Primary SMCs from Acta2 SMC-R179C/+ mice are less differentiated than WT SMCs in vitro and in vivo and have global changes in chromatin accessibility. Induced pluripotent stem cells from patients with ACTA2 p.R179 variants fail to fully differentiate from neuroectodermal progenitor cells to SMCs, and single-cell transcriptomic analyses of an ACTA2 p.R179H patient's aortic tissue show increased SMC plasticity. Thus, nuclear αSMA participates in SMC differentiation, and loss of this nuclear activity occurs with ACTA2 p.R179 pathogenic variants.
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Systemic Epstein-Barr virus-positive T-cell and natural killer (NK)-cell lymphoproliferative diseases of childhood are a group of lethal diseases mostly affecting children and young adults. The Ohshima Grading System and the 2017 World Health Organization (WHO) classification have been used for classifying this spectrum, but these systems have not been validated externally and compared. Therefore, we examined 36 cases of systemic Epstein-Barr virus-positive T-cell and NK-cell lymphoproliferative diseases of childhood with long-term follow-up, from Southwest China, to systematically summarize the clinicopathologic features and to validate and compare the Ohshima Grading System and the 2017 WHO classification in discrimination ability, predictive accuracy, concordance indices, and explained variation. Clinically, our cohort showed severe manifestations and poor prognoses. Morphologically, the hematopoietic and lymphoid specimens showed proliferation of small-sized to medium-sized bland-looking lymphocytes that might mask disease severity, whereas other extranodal lesions showed a disorganized to obliterated architecture infiltrated by medium-sized to large-sized, subtle to obvious atypical cells, which may mimic extranodal NK/T-cell lymphoma. Immunophenotypically, our cases mainly originate from CD8 αß T cells. Therefore, clinical and pathologic features should be equally considered to avoid missed diagnosis or misdiagnosis. In addition, the 2017 WHO classification shows a flexible grasp of pathologic features, thus classifying some cases (polymorphic and monoclonal cases with fulminant course) more reasonably; thereby, it showed statistically improved results compared with the Ohshima Grading System. However, underestimating the risk of some polyclonal cases and imprecisely discriminating monoclonal cases at diagnosis are common dilemmas in both systems. Therefore, the construction of a comprehensive grading algorithm for improved prognostic value and precise diagnosis requires additional studies.
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Infecciones por Virus de Epstein-Barr/clasificación , Herpesvirus Humano 4/genética , Células Asesinas Naturales/inmunología , Trastornos Linfoproliferativos/clasificación , Linfocitos T/inmunología , Adolescente , Adulto , Edad de Inicio , Proliferación Celular , Niño , Preescolar , China , Bases de Datos Factuales , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/virología , Femenino , Genes Codificadores de la Cadena alfa de los Receptores de Linfocito T , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Humanos , Lactante , Células Asesinas Naturales/patología , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/virología , Masculino , Persona de Mediana Edad , Pronóstico , ARN Viral/genética , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Linfocitos T/patología , Factores de Tiempo , Adulto JovenRESUMEN
OBJECTIVE: Although methadone for addiction treatment (MAT) has been widely used in China, the low adherence rate in MAT clinics poses a great challenge. We aimed to investigate the factors related to the adherence of heroin-dependent patients to MAT based on the Health Belief Model (HBM) in Sichuan, China. METHODS: A cross-sectional structured interview was conducted between August and November 2018. Stratified multi-stage sampling was carried out. A total of 581 participants were enrolled from 5 clinics and completed the face-to-face structured interview. Univariate, adjusted logistic regression, multivariate logistic regression analysis and the structural equation modeling (SEM) were employed to explore the association between constructs of HBM and adherence to MAT among heroin-dependent patients. RESULTS: The adherence rate of MAT was 79.3% in the past 6 months. Among all constructs of HBM, self-efficacy (AOR: 1.16, 95% CI: 1.10, 1.22), perceived benefits (AOR: 1.05, 95% CI: 1.00, 1.10) and perceived barriers (AOR: 0.87, 95% CI: 0.77, 0.98) were associated with adherence to MAT. Self-efficacy was directly associated with adherence to MAT (ß = 0.347, P < 0.05). Perceive benefits (ß = 0.276, P < 0.01) and perceived barriers (ß = -0.241, P < 0.05) were directly associated with self-efficacy. However, perceived benefits (ß = 0.096, P < 0.01) and perceived barriers (ß = -0.084, P < 0.01) were only indirectly associated with adherence to MAT. CONCLUSION: The adherence of heroin-dependent patients to MAT can be explained by self-efficacy, perceived benefits and barriers. Self-efficacy plays a significant role as a mediating variable. Future interventions should be considered to improve patients' self-efficacy to MAT.
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Metadona , Autoeficacia , China , Estudios Transversales , Modelo de Creencias sobre la Salud , Heroína , Humanos , Metadona/uso terapéuticoRESUMEN
Primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) is a rare subtype of extranodal DLBCL. Because of the rarity of this disease, its morphologic and genetic features are not comprehensively studied. Here, we systematically reviewed the clinicopathologic features of 42 cases of PA-DLBCL from our institution and investigated the frequency of MYD88 L265P and CD79B (exon 5) mutation in 29 eligible cases using Sanger sequencing. Clinically, PA-DLBCL was predominant in elderly male patients with advanced clinical stage and poor outcomes. Morphologically, the tumors often showed a sinusoidal and/or cohesive pattern with condensed chromatin and inconspicuous nucleolus which mimicked neuroendocrine carcinoma. Moreover, increased Reed-Sternberg-like cells were observed frequently. These confounding morphologic manifestations may lead to misdiagnosis. Genetically, PA-DLBCL harbored a high prevalence of MYD88 L265P (24%) and CD79B mutations (52%) which may be involved in lymphomagenesis. The CD79B mutation was significantly associated with a worse prognosis. A novel Histo-Molecular Classification system (4 categories) was proposed based on correlation with genetic changes. Generally, the neuroendocrine carcinoma-like type was associated with CD79B mutation, whereas the RS-like cell type indicated MYD88 L265P. The biphasic type was correlated with coexisting mutations of MYD88 and CD79B, whereas the common type implied no mutation. Furthermore, the common type showed significantly better survival. In conclusion, the proposed new category system could indicate the genetic changes as well as facilitate risk stratification to guide treatment and predict prognosis. Although this study augmented our understanding of PA-DLBCL, further analysis is required to validate our results and extend them to extranodal DLBCL at other sites.
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Neoplasias de las Glándulas Suprarrenales/genética , Antígenos CD79/genética , Linfoma de Células B Grandes Difuso/genética , Mutación , Factor 88 de Diferenciación Mieloide/genética , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Neoplasias de las Glándulas Suprarrenales/mortalidad , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Predisposición Genética a la Enfermedad , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Tasa de Mutación , Estadificación de Neoplasias , Fenotipo , Células de Reed-Sternberg/patologíaRESUMEN
Chronic active Epstein-Barr virus (EBV) infection of T-cell and NK-cell type, systemic form (CAEBV-T/NK-S) is characterized by EBV T-cell and/or NK-cell proliferation with no changes suggesting malignancy. Therefore, when Hodgkin/Reed-Sternberg (HRS)-like cells are scattered in CAEBV-T/NK-S, it is more likely to be misdiagnosed as classic Hodgkin lymphoma. We encountered a case wherein the patient showed HRS-like cells with typical NK phenotype. Therefore, we further investigated 8 similar cases to provide clinicopathologic and genetic features and discuss their distinction from other related diseases. Clinically, all cases met the diagnostic criteria of CAEBV. Moreover, 4/8 patients had hemophagocytic lymphohistiocytosis. The median survival was 16 months (range, 5 to 35 mo). Pathologically, all lymph node samples had a remarkably similar morphology with scattered HRS-like cells surrounded by a mixture of small-sized lymphocytes, plasma cells, and macrophages that masqueraded classic Hodgkin lymphoma. Besides, erythrophagocytosis was detected in 4/11 samples. The HRS-like cells were positive for CD2, CD3p, CD30, CD56, GrB, and EBER-ISH, but negative for CD20, CD5, PAX-5, and LMP-1. The surrounding lymphocytes were mainly CD8 cytotoxic T cells, without obvious aberrant expression. In addition, all patients were polyclonal in the T-cell receptor γ rearrangement test. The harbored mutations were mainly in epigenetic modifiers, JAK-STAT signaling pathway, and apoptosis/cell cycle pathway, including SOCS1, DDX3X, and KMT2D, similar to other EBV-associated T/NK-cell lymphoproliferative disorders. Therefore, the evidence indicates that "HRS-like cells of NK phenotype" is a variant of CAEBV-T/NK-S. This study may raise awareness of such confounding CAEBV-T/N-S cases in clinical practice to avoid misdiagnosis and treatment delay.
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Infecciones por Virus de Epstein-Barr/diagnóstico , Reordenamiento Génico de la Cadena gamma de los Receptores de Antígenos de los Linfocitos T , Enfermedad de Hodgkin/diagnóstico , Células Asesinas Naturales/patología , Trastornos Linfoproliferativos/diagnóstico , Mutación , Células de Reed-Sternberg/patología , Linfocitos T/patología , Adolescente , Adulto , Anciano , Diagnóstico Diferencial , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/virología , Femenino , Predisposición Genética a la Enfermedad , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/virología , Humanos , Células Asesinas Naturales/virología , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/virología , Masculino , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Células de Reed-Sternberg/virología , Linfocitos T/virologíaRESUMEN
OBJECTIVES: Extranodal NK/T-cell lymphoma is reportedly a rare but emerging type of lymphoma in adolescents. The present study was performed to specify its imaging characteristics. METHODS: Our hospital's picture archiving and communication systems were searched from January 2009 to December 2016. We identified 13 patients aged <18 years with pathologically confirmed extranodal NK/T-cell lymphoma in the head and neck region. The computed tomography and magnetic resonance images were reviewed to summarize the imaging characteristics of extranodal NK/T-cell lymphoma in adolescents. RESULTS: The mean age at onset was 15.2 ± 1.46 years (range, 12-17 years) with a male:female ratio of 1.17:1.00. Most of the patients (n = 10) displayed nasal cavity and/or paranasal involvement. The tumor was homogeneous in both computed tomography and magnetic resonance images and showed slight enhancement. No calcification or liquefactive necrosis was observed. Adjacent structures were usually involved. CONCLUSION: Suggestive imaging characteristics could acquaint specialists with extranodal NK/T-cell lymphoma in adolescents, facilitating improved early recognition of the diagnosis and helping to improve the patient's outcome.
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Linfoma Extranodal de Células NK-T/diagnóstico por imagen , Linfoma Extranodal de Células NK-T/patología , Imagen por Resonancia Magnética/métodos , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Tomografía Computarizada por Rayos X/métodos , Adolescente , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , PronósticoRESUMEN
The nature of hippocampal changes in schizophrenia before first treatment, and whether hippocampal subfields are affected by antipsychotic treatment are important questions for schizophrenia research. Forty-one first-episode antipsychotic-naïve acutely ill schizophrenia inpatients had MRI scans before and six weeks after antipsychotic treatment. Thirty-nine matched healthy controls were also scanned, twenty-two of which were scanned a second time six weeks later. Volumes of hippocampal subfields were measured via FreeSurfer v6.0 using a longitudinal analysis pipeline. Before treatment, schizophrenia patients had no significant changes in total hippocampal volume but exhibited significantly greater subfield volumes than controls in bilateral molecular layers of the hippocampus (ML), bilateral granular cell layers of the dentate gyrus (GC-DG), and bilateral cornu ammonis area 4 (CA4). After six weeks of antipsychotic treatment, patients showed volume reductions compared with pretreatment scans in total hippocampus bilaterally, with subfield volume reduction noted in previously enlarged subfields (i.e., bilateral ML, GC-DG and CA4) and in bilateral hippocampal tails, left CA1, CA3, and fimbria. Subfields with volume increases before treatment were reduced to the level of healthy controls (bilateral ML and GC-DG) or near to it (bilateral CA4) after treatment. These results indicate subfield-specific hippocampal hypertrophy prior to treatment, and that these abnormalities were reduced after acute antipsychotic therapy in a dose-related manner together with volume reductions in other areas that were not hypertrophic before treatment.
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Antipsicóticos/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/tratamiento farmacológico , Adolescente , Adulto , Antipsicóticos/farmacología , Región CA1 Hipocampal/diagnóstico por imagen , Región CA1 Hipocampal/efectos de los fármacos , Región CA3 Hipocampal/diagnóstico por imagen , Región CA3 Hipocampal/efectos de los fármacos , Giro Dentado/diagnóstico por imagen , Giro Dentado/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Fórnix/diagnóstico por imagen , Fórnix/efectos de los fármacos , Humanos , Masculino , Tamaño de los Órganos , Adulto JovenRESUMEN
BACKGROUND: The paradoxical reports about the prognostic value of the CD30 expression in extranodal NK/T-cell lymphoma (ENKTL) have restricted its further applications in clinical practice. To identify the common effects and the variation, we conducted this systematic review and meta-analysis. METHODS: PubMed, MEDLINE, Embase, and Web of Science were searched between January 1975 and 31 January 2017. The pooled hazard ratio was used to estimate the effect of the CD30 expression on overall survival. Bias was assessed by prespecified criteria referring to Reporting Recommendations for Tumor Marker Prognostic Studies and Newcastle-Ottawa Scale. RESULTS: Ten retrospective cohort studies with 310 patients are included. CD30 is associated with better overall survival significantly (HR 0.71, 95% CI 0.51 to 0.99, I2 = 0%). A greater effect is observed among studies including participants predominant in regional involvement (HR 0.31, 95%CI 0.13 to 0.76, I2 = 0%) compared with those in systemic involvement. CONCLUSIONS: This study indicates that the CD30 expression is significantly associated with better prognosis in ENKTL, especially for patients with regional lymphoma involvement.
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Spontaneous intramural haematoma of the oesophagus (SIHO) is a relatively rare event with benign courses. Most of the patients with SIHO may experience spontaneous healing without complications. We report a case of SIHO with clotted haemothorax. Uniportal video-assisted thoracic surgery (VATS) was successfully applied as a diagnostic and therapeutic method. Although conservative treatment is adequate for the majority of patients with SIHO, uniportal VATS may be a suitable option if there was clotted haemothorax.
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The efficacy and biocompatibility of nanoscale magnetic resonance imaging (MRI) contrast agents depend on optimal molecular structures and compositions. Gadolinium [Gd(III)] based dendritic macromolecules with well-defined and tunable nanoscale sizes are excellent candidates as multivalent MRI contrast agents. Here, we propose a novel alternate preparation of biodegradable hyperbranched polymer-gadolinium conjugates via a simple strategy and report potentially efficient and biocompatible nanoscale MRI contrast agents for cancer diagnosis. The enzyme-responsive hyperbranched poly(oligo-(ethylene glycol) methacrylate)-gadolinium conjugate (HB-POEGMA-Gd) was prepared via one-step reversible addition-fragmentation chain transfer (RAFT) polymerization and Gd(III) chelating, and the cRGDyK functionalized polymer (HB-POEGMA-cRGD-Gd) was obtained via click chemistry. By using an enzyme similar to lysosomal cathepsin B, hyperbranched conjugates of high molecular weights (MW) (180 and 210 kDa) and nanoscale sizes (38 and 42 nm) were degraded into low MW (25 and 30 kDa) and smaller products (4.8 and 5.2 nm) below the renal threshold. Conjugate-based nanoscale systems had three-fold more T1 relaxivity compared to clinical agent diethylenediaminepentaacetic acid (DTPA)-Gd. Animal studies with the nanoscale system offered greater tumor accumulation and enhanced signal intensity (SI) in mouse U87 tumors of which the greatest activity was conferred by the cRGDyK moiety functionalized hyperbranched conjugate. In vitro cytotoxicity, hemocompatibility and in vivo toxicity studies confirmed no adverse events. This design strategy for multifunctional Gd(III)-labeled biodegradable dendritic macromolecules may have significant potential as future efficient, biocompatible polymeric nanoscale MRI diagnostic contrast agents for cancer.
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Nanoestructuras , Animales , Materiales Biocompatibles , Medios de Contraste , Gadolinio , Sustancias Macromoleculares , Imagen por Resonancia Magnética , Ratones , PolímerosRESUMEN
Owing to their dendritic architectural features, branched copolymers have been investigated as drug delivery systems. In this paper, an enzyme- and pH-sensitive branched poly[N-(2-hydroxypropyl)methacrylamide] (polyHPMA) copolymer-doxorubicin (DOX) conjugate possessing a molecular weight (MW) of 165 kDa was designed and prepared via a one-pot reaction and drug conjugation. This conjugate's potential as a smart, nanoscale drug delivery system (NDDS) is also investigated. The branched conjugate was capable of forming nanoparticles with a negative surface charge. The self-assembled nanoparticles were 102 nm in diameter as measured by dynamic light scattering (DLS) and 95 nm in diameter via scanning electron microscopy, respectively. The nanoparticles were degraded to low-MW products (23â¼25 kDa) in the presence of papain or cathepsin B, and the degradation was monitored via DLS and size-exclusion chromatography. The nanoparticles demonstrated pH-sensitive drug release, as the DOX was attached to the branched copolymer via a hydrazone bond. In comparison to free DOX, the conjugate-based nanoparticles exhibited greater accumulation in breast tumors, resulting in enhanced antitumor therapeutic indexes. Furthermore, widespread dissemination of the conjugate among breast tumor cells was confirmed by immunohistochemical assay. Finally, no obvious systemic toxicities were observed in vivo in normal mice. Thus, the branched HPMA copolymer-DOX conjugate may be employed as a safe and efficient pH- and enzyme-responsive NDDS for cancer therapy.
Asunto(s)
Neoplasias , Acrilamidas , Animales , Doxorrubicina , Sistemas de Liberación de Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Ratones , PolímerosRESUMEN
Multiple myeloma (MM) is the second most common hematologic neoplasms and an appropriate in vivo environment for myeloma cells has potential implications for initiation, progression, and metastasis of MM. Exosomes, entities carrying microRNAs (miRNAs) to target locations, participate in the cross-talk between myeloma cells and nonmalignant components of the in vivo environment. This study disclosed the emerging roles of circulating exosome-associated miRNAs in drug resistance (DR) of MM. To this end, the medical records of consecutively hospitalized MM patients, who received novel agents-based therapies, were analyzed. Then, an optimized procedure was established for exosome isolation and exosomal RNA analysis. The exosome-associated miRNA expression patterns for predicting bortezomib (Bz) resistance of MM were further examined using a microarray. In total, 204 patients were enrolled with DR rates of 36.5%, 73.1% and 81.8% in the bortezomib (Bz), thalidomide and lenalidomide containing groups. The serum total light chain ratio ≥ 100, CRP ≥ 20 mg/L, and the second-line usage increased risks of acquired Bz-resistance. Among 68 cases having genetic tests, a high risk factor for predicting de novo DR was 1q21 amplification, which also correlated with lower levels of cholesterol and LDL-C. Moreover, nano-sized exosomes were isolated with significantly increasing internal RNAs and down-regulation of exosomal miR-16-5p, miR-15a-5p and miR-20a-5p, miR-17-5p was revealed in the patients resistant to Bz. The routine workup of MM hardly suggested a value for DR prediction. The circulating exosomes carrying miRNAs provided a window that permits a better understanding of the in vivo intercellular crosstalk in MM patients.