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1.
Rev. venez. oncol ; 33(1): 2-10, mar. 2021. ilus, tab
Artículo en Español | LILACS, LIVECS | ID: biblio-1147430

RESUMEN

Presentar nuestra experiencia de 18 años en el tratamiento con radioterapia y evaluar cifras de control tumoral local en pacientes con diagnóstico de tumor de células gigantes tenosinovial difuso sinovitis villonodular pigmentada difusa. 33 pacientes, tratados durante el período 2000-2018. En 19 (57,6 %) se practicó sinovectomía parcial, 10 (30,3 %) fueron tratados con artroplastia y sinovectomía, 4 (12,2 %) con sinovectomía total. 32 pacientes recibieron radioterapia posoperatoria, 1 paciente preoperatoria. Técnica más empleada fue planificación 2D 51,5 % seguida de conformada con planificación 3D (RTC3D) 48,5 %. La dosis total promedio administrada 44 Gy (rango 10,5 - 50). Tiempo promedio de tratamiento radiante 28 días (8-35). Tiempo de seguimiento entre 0,7 - 240,8 meses, mediana 12 meses, promedio 52,1 meses. 26 pacientes (79 %) presentaron mejoría de la sintomatología inicial y 6 (18 %) refirieron estabilidad de los síntomas. La respuesta clínica al tratamiento en relación al tiempo de seguimiento, 12 pacientes (36,4 %) estaban asintomáticos, 10 con un seguimiento mayor a 60 meses; 14 (42,4 %) refieren respuesta clínica satisfactoria, (2 con un seguimiento mayor a 60 meses) 6 pacientes presentaban enfermedad estable, para un control local del 97 %. El 87,9 % presentaron dermatitis grado I, 1 desarrolló dermatitis grado II, 3 no presentaron efectos adversos. La radioterapia es una modalidad de tratamiento muy efectiva como adyuvante a la sinovectomía, observándose altas tasas de control local de la enfermedad con una baja morbilidad(AU)


To report our eighteen-year experience with radiation therapy in the treatment of diffuse tenosinovial giant cell tumor / diffuse pigmented villonodular synovitis and to assess local control of the disease. A review of 33 patients with treated with radiation therapy during the period 2000-2018 was done. 19 (57.6 %) partial synovectomy was performed, 10 (30.3 %) underwent arthroplasty plus synovectomy, 4 (12.2 %) total synovectomy. 32 patients received radiotherapy postoperative and 1 pre-operative. Most common technique employed was conventional (2D) in 51.5 % and 3D conformal (3DCRT) in 48.5 %. The average total dose was 44 Gy (range 10.5-50), with a mean treatment time of 28 days (8-35). Follow-up time ranged from 0.7- 240.8 months, median time and mean time of 12 and 52.1 months respectively After RT 26 (79 %) of the patients obtained improvement of the initial symptoms and 6 (18 %) were stable. 12 patients (36.4 %) were asymptomatic with follow-up time longer than 36 months (10 of 12 had follow-up time >60 months), 14 (42.4 %) had significant clinical improvement (2 of 14 had follow-up time >60 months), and 6 had stable disease, local control of 97 %. Complications were few, acute skin toxicity was grade I in 29 (87.9%) and grade II in 1 patient. There was no significant chronic toxicity. Radiation therapy is an effective adjuvant treatment modality after synovectomy in patients with high local control rates and low morbidity(AU)


Asunto(s)
Humanos , Masculino , Femenino , Trisomía/genética , Tumor de Células Gigantes de las Vainas Tendinosas/etiología , Tumor de Células Gigantes de las Vainas Tendinosas/radioterapia , Artroscopía , Fenómenos Fisiológicos Musculoesqueléticos , Metástasis de la Neoplasia
2.
Am J Epidemiol ; 190(2): 230-238, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33524116

RESUMEN

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.


Asunto(s)
Estatura , Neoplasias Colorrectales/epidemiología , Neoplasias Endometriales/epidemiología , Adulto , Factores de Edad , Neoplasias Colorrectales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN , Neoplasias Endometriales/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores Sexuales
3.
Int J Med Microbiol ; 311(2): 151477, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33524636

RESUMEN

OBJECTIVE: We aim to describe the epidemiological, clinical and microbiological characteristics of the linezolid- and vancomycin- resistant Enterococcus faecium (LVRE) in a tertiary care hospital in Germany. METHODS: We conducted a retrospective analysis of 196 LVRE cases observed from 1st January 2012 to 31th December 2018. Patients' medical charts were reviewed and available LVRE (n = 102) were subjected to whole-genome-sequencing. Antibiotic consumption was measured in defined daily dose (DDD)/100 bed-days (BD). RESULTS: The prevalence of LVRE isolates among VRE was 6.3 % in 2018. Most patients had an onco-hematological disease (134/196, 68.4 %). From 2012-2018 an increase of +356.7 % of linezolid defined daily dose/100 bed-days was observed. In 71.4 % (90/126, 70 missing values) of the patients, linezolid was prescribed in the previous 6 months. The median exposure to linezolid was 15 days (Interquartile, IQR 9-23). 42/196 (21.4 %) patients had an LVRE-related infection with an overall 30-day mortality rate of 33 %. In 121/196 (61.7 %) patients, linezolid-susceptible VREfm were isolated before LVRE, suggesting secondary acquisition of linezolid resistance. Genetic analysis revealed that most isolates belonged to ST117 (64/102 available isolates, 62.7 %). The G2576T 23S rDNA mutation was identified as the most common resistance mechanism (96/102, 94.1 %). poxtA was identified in two isolates, while cfr, and optrA were not detected. CONCLUSIONS: Incidence of LVRE related to 23S rDNA mutations is rising and probably associated with antibiotic consumption. Restrictions in the use of linezolid may be needed in order to retain therapeutic options in VRE.


Asunto(s)
Farmacorresistencia Bacteriana , Enterococcus faecium/efectos de los fármacos , Infecciones por Bacterias Grampositivas , Linezolid/farmacología , Resistencia a la Vancomicina , Antibacterianos/farmacología , Enterococcus faecium/genética , Alemania/epidemiología , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/epidemiología , Humanos , Pruebas de Sensibilidad Microbiana , ARN Ribosómico 23S/genética , Estudios Retrospectivos , Vancomicina
4.
Mol Cell ; 81(3): 426-441.e8, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33545059

RESUMEN

Eukaryotic genomes replicate via spatially and temporally regulated origin firing. Cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK) promote origin firing, whereas the S phase checkpoint limits firing to prevent nucleotide and RPA exhaustion. We used chemical genetics to interrogate human DDK with maximum precision, dissect its relationship with the S phase checkpoint, and identify DDK substrates. We show that DDK inhibition (DDKi) leads to graded suppression of origin firing and fork arrest. S phase checkpoint inhibition rescued origin firing in DDKi cells and DDK-depleted Xenopus egg extracts. DDKi also impairs RPA loading, nascent-strand protection, and fork restart. Via quantitative phosphoproteomics, we identify the BRCA1-associated (BRCA1-A) complex subunit MERIT40 and the cohesin accessory subunit PDS5B as DDK effectors in fork protection and restart. Phosphorylation neutralizes autoinhibition mediated by intrinsically disordered regions in both substrates. Our results reveal mechanisms through which DDK controls the duplication of large vertebrate genomes.


Asunto(s)
Replicación del ADN , Origen de Réplica , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Replicación del ADN/efectos de los fármacos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Puntos de Control de la Fase S del Ciclo Celular , Especificidad por Sustrato , Factores de Tiempo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Xenopus laevis
5.
Nat Commun ; 12(1): 888, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563962

RESUMEN

The design principle of establishing an intracellular protein gradient for asymmetric cell division is a long-standing fundamental question. While the major molecular players and their interactions have been elucidated via genetic approaches, the diversity and redundancy of natural systems complicate the extraction of critical underlying features. Here, we take a synthetic cell biology approach to construct intracellular asymmetry and asymmetric division in Escherichia coli, in which division is normally symmetric. We demonstrate that the oligomeric PopZ from Caulobacter crescentus can serve as a robust polarized scaffold to functionalize RNA polymerase. Furthermore, by using another oligomeric pole-targeting DivIVA from Bacillus subtilis, the newly synthesized protein can be constrained to further establish intracellular asymmetry, leading to asymmetric division and differentiation. Our findings suggest that the coupled oligomerization and restriction in diffusion may be a strategy for generating a spatial gradient for asymmetric cell division.


Asunto(s)
División Celular Asimétrica , Escherichia coli/citología , Escherichia coli/metabolismo , Espacio Intracelular/metabolismo , Bacillus subtilis/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Caulobacter crescentus/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular , Polaridad Celular , Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica
6.
Nat Commun ; 12(1): 880, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563981

RESUMEN

L1 retrotransposons can pose a threat to genome integrity. The host has evolved to restrict L1 replication. However, mechanisms underlying L1 propagation out of the host surveillance remains unclear. Here, we propose an evolutionary survival strategy of L1, which exploits RNA m6A modification. We discover that m6A 'writer' METTL3 facilitates L1 retrotransposition, whereas m6A 'eraser' ALKBH5 suppresses it. The essential m6A cluster that is located on L1 5' UTR serves as a docking site for eukaryotic initiation factor 3 (eIF3), enhances translational efficiency and promotes the formation of L1 ribonucleoprotein. Furthermore, through the comparative analysis of human- and primate-specific L1 lineages, we find that the most functional m6A motif-containing L1s have been positively selected and became a distinctive feature of evolutionarily young L1s. Thus, our findings demonstrate that L1 retrotransposons hijack the RNA m6A modification system for their successful replication.


Asunto(s)
Adenosina/análogos & derivados , Evolución Molecular , Elementos de Nucleótido Esparcido Largo/genética , ARN/metabolismo , Regiones no Traducidas 5' , Adenosina/genética , Adenosina/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Animales , Células HeLa , Humanos , Metilación , Metiltransferasas/metabolismo , Primates/clasificación , Primates/genética , Biosíntesis de Proteínas , ARN/química , Ribonucleoproteínas/metabolismo
7.
Nat Commun ; 12(1): 896, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563994

RESUMEN

Histone phosphorylation is a ubiquitous post-translational modification that allows eukaryotic cells to rapidly respond to environmental stimuli. Despite correlative evidence linking histone phosphorylation to changes in gene expression, establishing the causal role of this key epigenomic modification at diverse loci within native chromatin has been hampered by a lack of technologies enabling robust, locus-specific deposition of endogenous histone phosphorylation. To address this technological gap, here we build a programmable chromatin kinase, called dCas9-dMSK1, by directly fusing nuclease-null CRISPR/Cas9 to a hyperactive, truncated variant of the human MSK1 histone kinase. Targeting dCas9-dMSK1 to human promoters results in increased target histone phosphorylation and gene activation and demonstrates that hyperphosphorylation of histone H3 serine 28 (H3S28ph) in particular plays a causal role in the transactivation of human promoters. In addition, we uncover mediators of resistance to the BRAF V600E inhibitor PLX-4720 in human melanoma cells using genome-scale screening with dCas9-dMSK1. Collectively, our findings enable a facile way to reshape human chromatin using CRISPR/Cas9-based epigenome editing and further define the causal link between histone phosphorylation and human gene activation.


Asunto(s)
Sistemas CRISPR-Cas , Epigenómica/métodos , Histonas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Acetilación , Proteína 9 Asociada a CRISPR/genética , Proteína 9 Asociada a CRISPR/metabolismo , Línea Celular Tumoral , Cromatina/genética , Resistencia a Antineoplásicos/genética , Humanos , Indoles/farmacología , Fosforilación , Regiones Promotoras Genéticas/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Sulfonamidas/farmacología , Activación Transcripcional
8.
Nat Commun ; 12(1): 944, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33574228

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits high levels of mortality and morbidity and has dramatic consequences on human life, sociality and global economy. Neutralizing antibodies constitute a highly promising approach for treating and preventing infection by this novel pathogen. In the present study, we characterize and further evaluate the recently identified human monoclonal MD65 antibody for its ability to provide protection against a lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice. Eighty percent of the untreated mice succumbed 6-9 days post-infection, while administration of the MD65 antibody as late as 3 days after exposure rescued all infected animals. In addition, the efficiency of the treatment is supported by prevention of morbidity and ablation of the load of infective virions in the lungs of treated animals. The data demonstrate the therapeutic value of human monoclonal antibodies as a life-saving treatment for severe COVID-19 infection.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Antivirales/administración & dosificación , /inmunología , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/genética , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/genética , Anticuerpos Antivirales/inmunología , Chlorocebus aethiops , Femenino , Inmunoglobulina G/administración & dosificación , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Pulmón/patología , Pulmón/virología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , /fisiología , Seroconversión , Células Vero , Carga Viral
9.
Medicine (Baltimore) ; 100(6): e24355, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578531

RESUMEN

BACKGROUND: Genetic polymorphisms in the 15q25 region have been associated with the risk of lung cancer (LC). However, studies have yielded conflicting results. METHODS: Searches were conducted in databases, including PubMed, EMbase, Web of Science, CNKI, and Wanfang, for case-control studies up to August 1, 2019. After retrieving eligible studies and data extraction, we calculated pooled odds ratios with 95% confidence intervals. In the meta-analysis, we included 32 publications with a total of 52,795 patients with LC and 97,493 control cases to evaluate the polymorphisms in the CHRNA5/A3/B4 gene cluster in the 15q25 region. RESULTS: Data of the meta-analysis showed a significantly increased risk of LC in the presence of genetic polymorphisms (rs1051730, rs16969968, rs8034191). In the smoking subgroup, the CHRNA3 rs1051730 polymorphism was found to contribute to LC risk using following 5 models: the allelic model, the homozygous model, the heterozygous model, the dominant model, and the recessive model. Thus, the rs1051730 polymorphism may modify LC susceptibility under the condition of smoking. Stratification studies for CHRNA5-rs8034191 showed that Caucasian groups with the wild-type genotype (C/C) may be susceptible to LC in all 5 models. No significant relationship between CHRNA3 rs6495309 or rs3743073 and LC susceptibility was found. However, Asians with the rs3743037 B-allele showed an obviously higher risk of LC susceptibility than the Caucasian population, observed via allelic, heterozygous, and dominant models. CONCLUSIONS: The 3 polymorphisms of rs1051730, rs16969968 and rs8034191 in the CHRNA5/A3/B4 gene cluster in the 15q25 region were associated with LC risk, which might be influenced by ethnicity and smoking status.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Neoplasias Pulmonares/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple/genética , Receptores Nicotínicos/genética , Humanos , Neoplasias Pulmonares/etiología , Familia de Multigenes/genética , Factores de Riesgo
10.
Medicine (Baltimore) ; 100(6): e24458, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578538

RESUMEN

RATIONALE: The rare BRAF L597Q (c.T1790A) point mutation has been previously reported in childhood acute lymphoblastic leukemia. We present the first rare case of occult papillary thyroid carcinoma with BRAF L597Q mutation in a Tibetan patient. PATIENT CONCERNS: A 57-year-old male patient presented with a protruding mass on the left forehead for 2 years and numbness in the right limb for 3 weeks. DIAGNOSES: The patient had a double mutation of BRAF L597Q and V600E in 2 separate lesions at thyroid and brain, the immunohistochemical staining showed that the cytokeratin (CK), thyroglobulin (Tg) and thyroid transforming factor-1 (TTF-1) were immunoreactive. All the findings supported the diagnosis of solitary brain metastasis of occult papillary thyroid carcinoma. INTERVENTIONS: The patient underwent left frontal lobe metastasis (thyroid cancer) resection that involved craniectomy and artificial skull repair. OUTCOMES: During the 24-month follow-up, no postoperative complications or recurrence and metastasis were found. LESSONS: This is the first case of solitary brain metastasis of occult papillary thyroid carcinoma with double mutation of BRAF L597Q and V600E in 2 separate lesions reported in the literature. Our study extends the disease spectrum of occult papillary thyroid carcinoma and suggests that the BRAF L597Q mutation might play a specific role in inducing the solitary brain metastasis of occult papillary thyroid carcinoma in a Chinese Tibetan patient, but the detailed molecular mechanism remains to be confirmed by a large number of functional experiments and clinical research.


Asunto(s)
Neoplasias Encefálicas/secundario , Mutación Puntual/genética , Proteínas Proto-Oncogénicas B-raf/genética , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Tomografía Computarizada por Rayos X
11.
Medicine (Baltimore) ; 100(6): e24464, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578539

RESUMEN

BACKGROUND: Recently, the relationships between uncoupling protein-2 (UCP2) -866G/A (rs659366) and Ala55Val (rs660339) polymorphisms and the risk of type 2 diabetes mellitus (T2DM) have been explored considerably, but the results are greatly inconsistent. This meta-analysis was performed to further identify the association of UCP2 rs659366 and rs660339 with the risk of T2DM. METHODS: Eligible studies were searched from PubMed, Embase, Cochrane Library, VIP database, Chinese National Knowledge Infrastructure, and Chinese WanFang database until March 8, 2020. The odds ratios with corresponding 95% confidence intervals (CIs), and P-values were used to assess the strength of the association. RESULTS: A total of 26 studies were included in this study. UCP2 rs659366 was associated with the risk of T2DM in allele model (OR: 1.112, 95%CI: 1.009-1.224, P = 0.032), dominant model (OR: 1.189, 95%CI: 1.035-1.366, P = 0.014), and heterozygous model (OR: 1.177, 95%CI: 1.032-1.342, P = .015). A significantly increased risk of T2DM was detected in Asians by UCP2 rs659366 allele (OR: 1.132, 95%CI: 1.016-1.262, P = .025), dominant (OR: 1.218, 95%CI: 1.046-1.418, P = .011), homozygous (OR: 1.254, 95%CI: 1.022-1.540, P = .031) or heterozygous (OR: 1.198, 95%CI: 1.047-1.371, P = .009) models. There was no significant correlation between UCP2 rs660339 and the risk of T2DM (P>.05). CONCLUSIONS: The UCP2 rs65366 is significantly associated with the risk of T2DM, especially in Asian population, while no evidence is found between the UCP2 rs660339 and the susceptibility to T2DM.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Proteína Desacopladora 2/genética , Humanos
12.
Medicine (Baltimore) ; 100(6): e24471, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578541

RESUMEN

BACKGROUND: In osteosarcoma, the lung is the most common metastatic organ. Intensive work has been made to illuminate the pathogeny, but the specific metastatic mechanism remains unclear. Thus, we conducted the study to seek to find the key genes and critical functional pathways associated with progression and treatment in lung metastasis originating from osteosarcoma. METHODS: Two independent datasets (GSE14359 and GSE85537) were screened out from the Gene Expression Omnibus (GEO) database and the overlapping differentially expressed genes (DEGs) were identified using GEO2R online platform. Subsequently, the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis of DEGs were conducted using DAVID. Meanwhile, the protein-protein interaction (PPI) network constructed by STRING was visualized using Cytoscape. Afterwards, the key module and hub genes were extracted from the PPI network using the MCODE and cytoHubba plugin. Moreover, the raw data obtained from GSE73166 and GSE21257 were applied to verify the expression differences and conduct the survival analyses of hub genes, respectively. Finally, the interaction network of miRNAs and hub genes constructed by ENCORI was visualized using Cytoscape. RESULTS: A total of 364 DEGs were identified, comprising 96 downregulated genes and 268 upregulated genes, which were mainly involved in cancer-associated pathways, adherens junction, ECM-receptor interaction, focal adhesion, MAPK signaling pathway. Subsequently, 10 hub genes were obtained and survival analysis demonstrated SKP2 and ASPM were closely related to poor prognosis of patients with osteosarcoma. Finally, hsa-miR-340-5p, has-miR-495-3p, and hsa-miR-96-5p were found to be most closely associated with these hub genes according to the interaction network of miRNAs and hub genes. CONCLUSION: The key genes and functional pathways identified in the study may contribute to understanding the molecular mechanisms involved in the carcinogenesis and progression of lung metastasis originating from osteosarcoma, and provide potential diagnostic and therapeutic targets.


Asunto(s)
Neoplasias Óseas/patología , Neoplasias Pulmonares/secundario , Osteosarcoma/patología , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/genética , Biología Computacional , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Genes Relacionados con las Neoplasias/genética , Marcadores Genéticos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteosarcoma/diagnóstico , Osteosarcoma/genética , Transducción de Señal/genética
13.
Medicine (Baltimore) ; 100(6): e24481, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578542

RESUMEN

ABSTRACT: This study conducts a correlation exploration of CYP2C19 gene polymorphism and clopidogrel resistance in Han Chinese patients with cerebral infarction in Guizhou Region.A total of 270 Han Chinese patients with cerebral infarction, who were hospitalized in our hospital from January 2016 to January 2018, are selected. These patients were divided into 2 groups, clopidogrel resistance group (n = 60) and clopidogrel sensitive group (n = 210). According to the TEG results, the CYP2C19 gene polymorphism detection was carried out by using the PCR-RFLP method, while IL-6 level in the patient's blood was measured by using the ELISA method.The resistance group occupies 22.22%. The platelet inhibition ratio of the resistance group was 23 ±â€Š7%, which was significantly lower than that of the sensitive group (65 ±â€Š13%), and the difference was statistically significant (P < .05). The Logisitic regression analysis revealed that the history of diabetes, history of high blood pressure, increase in low density lipoprotein and CYP2C19 mutant gene were independent risk factors of clopidogrel resistance. After treatment, the serum IL-6 level of patients in the resistance group was 17.21 ±â€Š0.98 ng/L, which was significant higher than that of patients in the sensitive group (11.21 ±â€Š0.68 ng/L), and the difference was statistically significant (P < .05).Patients with cerebral infarction in Guizhou region have a higher occurrence rate of clopidogrel resistance. Clopidogrel resistance not only will weaken the anti-inflammatory action of the drug, but also correlates with the patient's CYP2C19 mutant gene and blood lipid level.


Asunto(s)
Infarto Cerebral/tratamiento farmacológico , Clopidogrel/uso terapéutico , Citocromo P-450 CYP2C19/genética , Polimorfismo Genético/genética , Grupo de Ascendencia Continental Asiática/genética , China , Clopidogrel/farmacocinética , Resistencia a Medicamentos/genética , Femenino , Frecuencia de los Genes/genética , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa
14.
BMC Pulm Med ; 21(1): 58, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33588817

RESUMEN

BACKGROUND: Hyperoxia downregulates the tight junction (TJ) proteins of the alveolar epithelium and leads to barrier dysfunction. Previous study has showed that STE20/SPS1-related proline/alanine-rich kinase (SPAK) interferes with the intestinal barrier function in mice. The aim of the present study is to explore the association between SPAK and barrier function in the alveolar epithelium after hyperoxic exposure. METHODS: Hyperoxic acute lung injury (HALI) was induced by exposing mice to > 99% oxygen for 64 h. The mice were randomly allotted into four groups comprising two control groups and two hyperoxic groups with and without SPAK knockout. Mouse alveolar MLE-12 cells were cultured in control and hyperoxic conditions with or without SPAK knockdown. Transepithelial electric resistance and transwell monolayer permeability were measured for each group. In-cell western assay was used to screen the possible mechanism of p-SPAK being induced by hyperoxia. RESULTS: Compared with the control group, SPAK knockout mice had a lower protein level in the bronchoalveolar lavage fluid in HALI, which was correlated with a lower extent of TJ disruption according to transmission electron microscopy. Hyperoxia down-regulated claudin-18 in the alveolar epithelium, which was alleviated in SPAK knockout mice. In MLE-12 cells, hyperoxia up-regulated phosphorylated-SPAK by reactive oxygen species (ROS), which was inhibited by indomethacin. Compared with the control group, SPAK knockdown MLE-12 cells had higher transepithelial electrical resistance and lower transwell monolayer permeability after hyperoxic exposure. The expression of claudin-18 was suppressed by hyperoxia, and down-regulation of SPAK restored the expression of claudin-18. The process of SPAK suppressing the expression of claudin-18 and impairing the barrier function was mediated by p38 mitogen-activated protein kinase (MAPK). CONCLUSIONS: Hyperoxia up-regulates the SPAK-p38 MAPK signal pathway by ROS, which disrupts the TJ of the alveolar epithelium by suppressing the expression of claudin-18. The down-regulation of SPAK attenuates this process and protects the alveolar epithelium against the barrier dysfunction induced by hyperoxia.


Asunto(s)
Lesión Pulmonar Aguda/metabolismo , Células Epiteliales Alveolares/metabolismo , Claudinas/genética , Hiperoxia/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Alveolos Pulmonares/metabolismo , Uniones Estrechas/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Lesión Pulmonar Aguda/patología , Células Epiteliales Alveolares/ultraestructura , Animales , Líquido del Lavado Bronquioalveolar/química , Claudinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Hiperoxia/patología , Ratones , Ratones Noqueados , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Permeabilidad , Proteínas Serina-Treonina Quinasas/metabolismo , Alveolos Pulmonares/ultraestructura , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Uniones Estrechas/ultraestructura
15.
BMJ ; 372: n214, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589468

RESUMEN

OBJECTIVE: To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population. DESIGN: Retrospective, population based diagnostic evaluation. PARTICIPANTS: 49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project. MAIN OUTCOME MEASURES: Genotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in the BRCA1 and BRCA2 genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data. RESULTS: Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03). CONCLUSIONS: SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Neoplasias de la Próstata/diagnóstico , Adulto , Anciano , Neoplasias de la Mama/genética , Reacciones Falso Negativas , Reacciones Falso Positivas , Femenino , Genes BRCA1 , Genes BRCA2 , Pruebas Genéticas/métodos , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Ováricas/genética , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Neoplasias de la Próstata/genética , Sistema de Registros , Estudios Retrospectivos , Análisis de Secuencia de ADN
16.
Medicine (Baltimore) ; 100(5): e23787, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33592836

RESUMEN

ABSTRACT: Soft tissue sarcomas (STSs) are heterogeneous at the clinical with a variable tendency of aggressive behavior. In this study, we constructed a specific DNA methylation-based classification to identify the distinct prognosis-subtypes of STSs based on the DNA methylation spectrum from the TCGA database. Eventually, samples were clustered into 4 subgroups, and their survival curves were distinct from each other. Meanwhile, the samples in each subgroup reflected differentially in several clinical features. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was also conducted on the genes of the corresponding promoter regions of the above-described specific methylation sites, revealing that these genes were mainly concentrated in certain cancer-associated biological functions and pathways. In addition, we calculated the differences among clustered methylation sites and performed the specific methylation sites with LASSO algorithm. The selection operator algorithm was employed to derive a risk signature model, and a prognostic signature based on these methylation sites performed well for risk stratification in STSs patients. At last, a nomogram consisted of clinical features and risk score was developed for the survival prediction. This study declares that DNA methylation-based STSs subtype classification is highly relevant for future development of personalized therapy as it identifies the prediction value of patient prognosis.


Asunto(s)
Metilación de ADN/genética , Nomogramas , Sarcoma/clasificación , Neoplasias de los Tejidos Blandos/clasificación , Algoritmos , Biomarcadores de Tumor/genética , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica/genética , Ontología de Genes , Humanos , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Medición de Riesgo , Sarcoma/genética , Sarcoma/mortalidad , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/mortalidad
17.
Medicine (Baltimore) ; 100(5): e24007, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33592857

RESUMEN

RATIONALE: This study aimed to investigate the genetic mutation characteristics of congenital idiopathic hypogonadotropic hypogonadism (IHH) through the clinical features and genetic analysis of 2 patients with IHH in 1 pedigree. PATIENT CONCERNS: A 23-year-old girl presented with primary amenorrhea, sparse pubic hair, lack of breast development, and delayed sexual development. DIAGNOSES: Combined with the clinical characteristics, auxiliary examinations, and molecular genetic analysis, the patient was diagnosed as IHH. INTERVENTIONS: Whole exome and Sanger sequencing were performed to validate the mutation in family members. OUTCOMES: A novel homozygous missense mutation c.521A > G (p.Q174R) in the GNRHR gene was identified in the 2 affected sisters. Familial segregation showed that the homozygous variant was inherited from their parents respectively and the eldest sister was the carrier without correlative symptom. LESSONS: We reported a novel GNRHR mutation in a pedigree with congenital idiopathic hypogonadotropic hypogonadism. Glutamine at amino acid position 174 was highly conserved among various species. The molecular structure of GNRHR protein showed that p.Q174R mutation brought in a new stable hydrogen bond between position 174 and 215, may impede conformational mobility of the TMD4 and TMD5. It suggests that the missense mutation c.521A > G related to congenital idiopathic hypogonadotropic hypogonadism was probably a causative factor for both sisters. Through high-throughput sequencing and experimental verification, we had basically determined the patient's pathogenic mutation and inheritance, which could better guide doctors for treatment.


Asunto(s)
Hipogonadismo , Receptores LHRH/genética , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Homocigoto , Humanos , Hipogonadismo/congénito , Hipogonadismo/genética , Hipogonadismo/fisiopatología , Mutación Missense , Linaje , Hermanos , Adulto Joven
18.
Medicine (Baltimore) ; 100(5): e24194, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33592864

RESUMEN

BACKGROUND: The relationship between p53 expression and chemosensitivity of non-small cell lung cancer (NSCLC) is unclear. This study aims to explore the correlation between p53 expression and sensitivity to platinum-based chemotherapy in patients with NSCLC. METHODS: Pubmed, Web of Science, EMBASE, CNKI, China Wanfang databases were searched for studies on the relationship between the p53 expression and the chemosensitivity to platinum drugs in patients with NSCLC. The last search time was May 2020. Stata 15.0 software was used for statistical analysis. RESULTS: A total of 21 studies were included, covering 1387 patients in total. The results showed that the pooled OR = 1.55 (95%CI: 1.05∼2.29, P < .05), for Asian population, the pooled OR = 1.67 (95%CI: 0.95∼3.09, P > .05), for Caucasian population, the pooled OR = 1.34 (95%CI: 0.74∼2.43), there was no significant difference between Asian and Caucasian. The results of subgroup analysis of publication year showed that, the pooled OR = 2.07 (95%CI: 1.39∼3.07, P < .01), the heterogeneity among the studies decreased remarkably after 2005. The subgroup analysis of advanced patients showed that the pooled OR = 1.93 (95%CI: 1.27∼2.93), the difference was statistically significant. CONCLUSION: Patients with p53 negative expression is more sensitive to platinum-based chemotherapy than those with p53 positive expression in NSCLC, especially in advanced NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Compuestos de Platino/farmacología , Proteína p53 Supresora de Tumor/genética , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Pruebas de Farmacogenómica , Resultado del Tratamiento
19.
Medicine (Baltimore) ; 100(5): e24292, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33592873

RESUMEN

RATIONALE: Gefitinib is a first-line palliative chemotherapy drug used to treat advanced non-small-cell lung cancer (NSCLC) in patients who have an epidermal growth factor receptor (EGFR) mutation. However, approximately two-thirds of NSCLC patients with EGFR-tyrosine kinase inhibitor experience dermatological toxicity. Cutaneous toxicity is usually not life threatening but can necessitate modification or discontinuation of medication in severe cases. In this case, despite a reduction in the dose of gefitinib due to side effects, combined treatment with modified Bojungikki-tang (BJKIT) increased progression-free survival (PFS) in an advanced NSCLC patient. PATIENT CONCERNS: An 83-year-old Asian woman presented with chief complaints of chronic cough, dyspnea, weight loss, and anorexia. DIAGNOSES: The patient was diagnosed with stage IV NSCLC (T2aN3M1), adenocarcinoma with metastasis to the lymph node, brain, and bone based on image scan and biopsy. An EGFR deletion was detected in exon 19. INTERVENTIONS: The patient was treated with gefitinib (250 mg/d) and traditional herbal medicine, modified Bojungikki-tang (BJIKT). However, after 1 year of combination therapy, gefitinib was tapered down to once per week while modified BJIKT was maintained. OUTCOMES: A partial response was achieved, but after 3 months severe papulopustular skin rashes developed and became aggravated with time. Thus, the gefitinib dose was reduced. However, the PFS has been maintained for approximately 78 months. LESSONS: Despite the reduction in gefitinib dose due to side effects, the combined treatment of gefitinib and the modified BJIKT has maintained a PFS of over 78 months, indicating that modified BJIKT enhanced the anti-cancer effect of gefitinib in a patient with advanced NSCLC harboring the EFGR mutation, and may have delayed acquired resistance, the main limitation on the efficacy of gefitinib. Further investigations including clinical trials are needed to confirm these effects.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB/genética , Gefitinib , Neoplasias Pulmonares , Fitoterapia/métodos , Enfermedades de la Piel , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Femenino , Gefitinib/administración & dosificación , Gefitinib/efectos adversos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/fisiopatología , Neoplasias Pulmonares/terapia , Mutación , Estadificación de Neoplasias , Supervivencia sin Progresión , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/prevención & control
20.
Medicine (Baltimore) ; 100(5): e24385, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33592885

RESUMEN

INTRODUCTION: The transformation of acute promyelocytic leukemia (APL) to acute mononuclear leukemia during treatment is a rare clinical phenomenon, and no CCAAT/enhancer-binding protein alpha (CEBPA) double mutations have been reported. PATIENT CONCERNS: A 42-year-old male was hospitalized for ecchymosis of the left lower limb for more than 1 month, gingival bleeding, and fatigue for 10 days, with aggravation of symptoms for 2 days. DIAGNOSIS: A diagnosis of APL was based on bone marrow (BM) morphology, immunophenotyping, fusion gene analysis, and fluorescence in situ hybridization. At a 1-year follow-up of maintenance treatment, he developed thrombocytopenia and was diagnosed with acute myeloid leukemia (AML) with a CEBPA double mutation by BM morphology, immunotyping, chromosomal analysis, polymerase chain reaction, and next generation sequencing. INTERVENTIONS: Complete remission of APL was achieved after all-trans retinoic acid and arsenic trioxide double induction therapy, followed by 2 cycles of mitoxantrone and cytarabine, and 1 cycle of idarubicin and cytarabine. Thereafter, sequential maintenance therapy of arsenic trioxide + all-trans retinoic acid + methotrexate was started. In the fourth cycle of maintenance therapy, APL was transformed into AML with a CEBPA double mutation. After 1 cycle of idarubicin and cytarabine, the patient achieved complete remission and received 3 cycles of idarubicin and cytarabine and three cycles of high-dose cytarabine as consolidation therapy. OUTCOMES: At present, the patient is in continuous remission with minimal residual disease negative for both of APL and AML. CONCLUSION: AML with a CEBPA double mutation after APL treatment is very rare, thus the prognosis of this event will require further observation.


Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT/genética , Transformación Celular Neoplásica/genética , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/genética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Masculino , Mutación
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