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1.
Cell ; 155(2): 462-77, 2013 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-24120142

RESUMEN

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.


Asunto(s)
Neoplasias Encefálicas/genética , Glioblastoma/genética , Neoplasias Encefálicas/metabolismo , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Glioblastoma/metabolismo , Humanos , Masculino , Mutación , Proteoma/análisis , Transducción de Señal
2.
Int J Mol Sci ; 25(14)2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39063002

RESUMEN

Arbutin and 6'-O-caffeoylarbutin (CA) from Vaccinium dunalianum Wight are known for their ability to inhibit melanin synthesis. To boost the production of arbutin and CA, precursor feeding with hydroquinone (HQ) was studied in V. dunalianum suspension cells. The effect of HQ on the biosynthesis of arbutin and CA in the suspension cells was investigated using high-performance liquid chromatography (HPLC), and possible molecular mechanisms were analyzed using metabolomics and transcriptomics analyses. HPLC analysis only showed that the addition of HQ significantly enhanced arbutin synthesis in cells, peaking at 15.52 ± 0.28 mg·g-1 after 0.5 mmol·L-1 HQ treatment for 12 h. Subsequently, metabolomics identified 78 differential expression metabolites (DEMs), of which arbutin and CA were significantly up-regulated metabolites. Moreover, transcriptomics found a total of 10,628 differential expression genes (DEGs). The integrated transcriptomics and metabolomics revealed that HQ significantly enhanced the expression of two arbutin synthase (AS) genes (Unigene0063512 and Unigene0063513), boosting arbutin synthesis. Additionally, it is speculated that CA was generated from arbutin and 3,4,5-tricaffeoylquinic acid catalyzed by caffeoyl transferase, with Unigene0044545, Unigene0043539, and Unigene0017356 as potentially associated genes with CA synthesis. These findings indicate that the precursor feeding strategy offers a promising approach for the mass production of arbutin and CA in V. dunalianum suspension cells and provides new insights for CA biosynthesis in V. dunalianum.


Asunto(s)
Arbutina , Perfilación de la Expresión Génica , Hidroquinonas , Metabolómica , Arbutina/farmacología , Arbutina/análogos & derivados , Arbutina/metabolismo , Arbutina/biosíntesis , Hidroquinonas/metabolismo , Metabolómica/métodos , Transcriptoma , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Metaboloma , Cromatografía Líquida de Alta Presión , Células Cultivadas
3.
Molecules ; 29(7)2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38611834

RESUMEN

Alongside fermentable sugars, weak acids, and furan derivatives, lignocellulosic hydrolysates contain non-negligible amounts of lignin-derived aromatic compounds. The biological funnel of lignin offers a new strategy for the "natural" production of protocatechuic acid (PCA). Herein, Pseudomonas putida KT2440 was engineered to produce PCA from lignin-derived monomers in hydrolysates by knocking out protocatechuate 3,4-dioxygenase and overexpressing vanillate-O-demethylase endogenously, while acetic acid was used for cell growth. The sugar catabolism was further blocked to prevent the loss of fermentable sugar. Using the engineered strain, a total of 253.88 mg/L of PCA was obtained with a yield of 70.85% from corncob hydrolysate 1. The highest titer of 433.72 mg/L of PCA was achieved using corncob hydrolysate 2 without any additional nutrients. This study highlights the potential ability of engineered strains to address the challenges of PCA production from lignocellulosic hydrolysate, providing novel insights into the utilization of hydrolysates.


Asunto(s)
Hidroxibenzoatos , Lignina , Pseudomonas putida , Pseudomonas putida/genética , Ácido Acético , Azúcares
4.
Small ; 19(17): e2208134, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36710251

RESUMEN

Electronic textiles (e-textiles) hold great promise for serving as next-generation wearable electronics owing to their inherent flexible, air-permeable, and lightweight characteristics. However, these e-textiles are of limited performance mainly because of lacking powerful materials combination. Herein, a versatile e-textile through a simple, high-efficiency mixed-dimensional assembly of 2D MXene nanosheets and 1D silver nanowires (AgNWs) are presented. The effective complementary actions of MXene and AgNWs endow the e-textiles with superior integrated performances including self-powered pressure sensing, ultrafast joule heating, and highly efficient electromagnetic interference (EMI) shielding. The textile-based self-powered smart sensor systems obtained through the screen-printed assembly of MXene-based supercapacitor and pressure sensor are flexible and lightweight, showing ultrahigh specific capacitance (2390 mF cm-2 ), robust areal energy density (119.5 µWh cm-2 ), excellent sensitivity (474.8 kPa-1 ), and low detection limit (1 Pa). Furthermore, the interconnected conductive MXene/AgNWs network enables the e-textile with ultrafast temperature response (10.4 °C s-1 ) and outstanding EMI shielding effectiveness of ≈66.4 dB. Therefore, the proposed mixed-dimensional assembly design creates a multifunctional e-textile that offers a practical paradigm for next-generation smart flexible electronics.

5.
J Am Acad Dermatol ; 88(5): 1051-1059, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-31306728

RESUMEN

BACKGROUND: Compared with sun-exposed melanomas, less is known regarding the pathogenesis of sun-protected melanomas. Sun-protected melanomas share many epidemiologic factors, but their genetic heterogeneity is not well studied. OBJECTIVE: We investigated the genomic profile of acral, mucosal, and vulvovaginal melanomas. We hypothesize that mucosal melanomas, recognized for their uniquely aggressive clinical behavior, have distinct genomic features. METHODS: We performed whole transcriptome messenger RNA and DNA (1711 genes) sequencing, messenger RNA expression profiling, tumor mutational burden, ultraviolet signature, and copy number variants analysis on 29 volar/digital acral, 7 mucosal, and 6 vulvovaginal melanomas. RESULTS: There was significant genetic heterogeneity, particularly in acral melanomas, with 36% having BRAF alterations, whereas other melanomas had none (P = .0159). Nonzero ultraviolet signatures were more frequent in acral melanomas, suggesting greater ultraviolet involvement. Mucosal melanomas formed a distinct group with increased expression of cell cycle and proliferation genes. Various targetable aberrations were identified, such as AURKA and ERBB2, in mucosal and acral melanomas, respectively. LIMITATIONS: The sample size was a small. CONCLUSION: There is significant genetic heterogeneity among sun-protected melanomas. Mucosal melanomas have upregulation in cell cycle and proliferation genes, which may explain their aggressive behavior. Ultraviolet radiation plays some role in a subset of acral but not other melanomas.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Rayos Ultravioleta/efectos adversos , Estudios Retrospectivos , Mutación , Melanoma/patología , Neoplasias Cutáneas/patología , Genómica , Melanoma Cutáneo Maligno
6.
Semin Dial ; 36(2): 178-182, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36597266

RESUMEN

Factor XI (FXI) deficiency is a rare bleeding disorder of unpredictable severity that correlates poorly with FXI coagulation activity and that poses great challenges for perioperative hemostatic management and the dialysis methods potentially available to new end-stage renal disease (ESRD) patients. We describe an individual with both ESRD and severe FXI deficiency, who successfully underwent peritoneal dialysis (PD) after emergency abdominal surgery. In the traditional concept, recent abdominal surgery is a contraindication to PD, especially for patients with bleeding risk. However, this case report highlights that PD can still be an possible option for patients with FXI deficiency who have just undergone abdominal surgery; laparoscopic PD catheter placement offers a chance to establish PD access in patients traditionally viewed as noncandidates for this method. Careful perioperative management and fresh frozen plasma transfusion ensure successful surgery. This case should be of help to clinicians and patients considering PD in similar situations.


Asunto(s)
Deficiencia del Factor XI , Fallo Renal Crónico , Diálisis Peritoneal , Humanos , Factor XI , Transfusión de Componentes Sanguíneos , Diálisis Renal , Plasma
7.
Proc Natl Acad Sci U S A ; 117(44): 27365-27373, 2020 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-33077595

RESUMEN

Actively transcribed genes in mammals are decorated by H3K79 methylation, which is correlated with transcription levels and is catalyzed by the histone methyltransferase DOT1L. DOT1L is required for mammalian development, and the inhibition of its catalytic activity has been extensively studied for cancer therapy; however, the mechanisms underlying DOT1L's functions in normal development and cancer pathogenesis remain elusive. To dissect the relationship between H3K79 methylation, cellular differentiation, and transcription regulation, we systematically examined the role of DOT1L and its catalytic activity in embryonic stem cells (ESCs). DOT1L is dispensable for ESC self-renewal but is required for establishing the proper expression signature of neural progenitor cells, while catalytic inactivation of DOT1L has a lesser effect. Furthermore, DOT1L loss, rather than its catalytic inactivation, causes defects in glial cell specification. Although DOT1L loss by itself has no major defect in transcription elongation, transcription elongation defects seen with the super elongation complex inhibitor KL-2 are exacerbated in DOT1L knockout cells, but not in catalytically dead DOT1L cells, revealing a role of DOT1L in promoting productive transcription elongation that is independent of H3K79 methylation. Taken together, our study reveals a catalytic-independent role of DOT1L in modulating cell-fate determination and in transcriptional elongation control.


Asunto(s)
Diferenciación Celular/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Elongación de la Transcripción Genética/fisiología , Proliferación Celular/efectos de los fármacos , Metilación de ADN/fisiología , Células Madre Embrionarias/metabolismo , Epigénesis Genética/genética , Epigenómica , Regulación de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metilación , Metiltransferasas/metabolismo , Células-Madre Neurales/metabolismo , Procesamiento Proteico-Postraduccional , Factores de Elongación Transcripcional/metabolismo
8.
Molecules ; 28(16)2023 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-37630274

RESUMEN

Composites with excellent thermomechanical and thermochemical properties are urgently needed in the aerospace field, especially for structural applications under high-temperature conditions. Carbon fiber-reinforced Si-based composites are considered the most promising potential high-temperature materials due to their excellent oxidation resistance and ablative behaviors, good structural designability, and excellent mechanical properties. The reinforcement of the relevant composites mainly involves carbon fiber, which possesses good mechanical and temperature resistance abilities. In this paper, the ablation behaviors and mechanisms of related composites are reviewed. For carbon fiber-reinforced pure Si-based composites (C/SiM composites), the anti-ablation mechanism is mainly attributed to the continuous glassy SiO2, which inhibits the damage of the substrate. For C/SiM composite doping with refractory metal compounds, the oxides of Si and refractory metal together protect the main substrate from ablation and oxidation. Moreover, in addition to thermochemical damage, thermophysical and thermomechanical behavior severely destroy the surface coating of the substrate.

9.
Blood ; 134(19): 1619-1631, 2019 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-31409672

RESUMEN

Mutations in GATA1, which lead to expression of the GATA1s isoform that lacks the GATA1 N terminus, are seen in patients with Diamond-Blackfan anemia (DBA). In our efforts to better understand the connection between GATA1s and DBA, we comprehensively studied erythropoiesis in Gata1s mice. Defects in yolks sac and fetal liver hematopoiesis included impaired terminal maturation and reduced numbers of erythroid progenitors. RNA-sequencing revealed that both erythroid and megakaryocytic gene expression patterns were altered by the loss of the N terminus, including aberrant upregulation of Gata2 and Runx1. Dysregulation of global H3K27 methylation was found in the erythroid progenitors upon loss of N terminus of GATA1. Chromatin-binding assays revealed that, despite similar occupancy of GATA1 and GATA1s, there was a striking reduction of H3K27me3 at regulatory elements of the Gata2 and Runx1 genes. Consistent with the observation that overexpression of GATA2 has been reported to impair erythropoiesis, we found that haploinsufficiency of Gata2 rescued the erythroid defects of Gata1s fetuses. Together, our integrated genomic analysis of transcriptomic and epigenetic signatures reveals that, Gata1 mice provide novel insights into the role of the N terminus of GATA1 in transcriptional regulation and red blood cell maturation which may potentially be useful for DBA patients.


Asunto(s)
Eritropoyesis/genética , Factor de Transcripción GATA1/genética , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/fisiopatología , Animales , Cromatina/genética , Epigénesis Genética/genética , Ratones , Ratones Mutantes , Isoformas de Proteínas
10.
Angew Chem Int Ed Engl ; 60(46): 24526-24533, 2021 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-34418248

RESUMEN

Molecular imprinting represents one of the most promising strategies to design artificial enzyme inhibitors. However, the study of molecularly imprinted enzyme inhibitors (MIEIs) remains at a primary stage. Advanced applications of MIEIs for cell regulation have rarely been explored. Using a solid-phase oriented imprinting strategy so as to leave the active site of the enzymes accessible, we synthesized two MIEIs that exhibit high specificity and potent inhibitory effects (inhibition constant at low nM range) towards trypsin and angiogenin. The trypsin MIEI inhibits trypsin activity, tryptic digestion-induced extracellular matrix lysis and cell membrane destruction, indicating its utility in the treatment of active trypsin-dependent cell injury. The angiogenin MIEI blocks cancer cell proliferation by suppressing the ribonuclease activity of angiogenin and decreasing the angiogenin level inside and outside HeLa cells. Our work demonstrates the versatility of MIEIs for both enzyme inhibition and cell fate manipulation, showing their great potential as therapeutic drugs in biomedicine.


Asunto(s)
Inhibidores Enzimáticos/química , Impresión Molecular/métodos , Polímeros/química , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Matriz Extracelular/metabolismo , Células HeLa , Humanos , Cinética , Nanopartículas/química , Polímeros/síntesis química , Polímeros/metabolismo , Ribonucleasa Pancreática/antagonistas & inhibidores , Ribonucleasa Pancreática/metabolismo , Tripsina/química , Tripsina/metabolismo
11.
J Biol Chem ; 294(49): 18674-18684, 2019 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-31659118

RESUMEN

Tumor cells adapt to nutrient-limited environments by inducing gene expression that ensures adequate nutrients to sustain metabolic demands. For example, during amino acid limitations, ATF4 in the amino acid response induces expression of asparagine synthetase (ASNS), which provides for asparagine biosynthesis. Acute lymphoblastic leukemia (ALL) cells are sensitive to asparagine depletion, and administration of the asparagine depletion enzyme l-asparaginase is an important therapy option. ASNS expression can counterbalance l-asparaginase treatment by mitigating nutrient stress. Therefore, understanding the mechanisms regulating ASNS expression is important to define the adaptive processes underlying tumor progression and treatment. Here we show that DNA hypermethylation at the ASNS promoter prevents its transcriptional expression following asparagine depletion. Insufficient expression of ASNS leads to asparagine deficiency, which facilitates ATF4-independent induction of CCAAT-enhancer-binding protein homologous protein (CHOP), which triggers apoptosis. We conclude that chromatin accessibility is critical for ATF4 activity at the ASNS promoter, which can switch ALL cells from an ATF4-dependent adaptive response to ATF4-independent apoptosis during asparagine depletion. This work may also help explain why ALL cells are most sensitive to l-asparaginase treatment compared with other cancers.


Asunto(s)
Factor de Transcripción Activador 4/metabolismo , Asparagina/metabolismo , Aspartatoamoníaco Ligasa/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Factor de Transcripción Activador 4/genética , Aspartatoamoníaco Ligasa/genética , Proteínas Potenciadoras de Unión a CCAAT/genética , Regiones Promotoras Genéticas/genética , ARN de Transferencia/genética , ARN de Transferencia/metabolismo
12.
Microb Cell Fact ; 19(1): 104, 2020 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-32410635

RESUMEN

BACKGROUND: Marine macroalgae Gelidium amansii is a promising feedstock for production of sustainable biochemicals to replace petroleum and edible biomass. Different from terrestrial lignocellulosic biomass, G. amansii is comprised of high carbohydrate content and has no lignin. In previous studies, G. amansii biomass has been exploited to obtain fermentable sugars along with suppressing 5-hydroxymethylfurfural (HMF) formation for bioethanol production. In this study, a different strategy was addressed and verified for dual production of D-galactose and HMF, which were subsequently oxidized to D-galactonic acid and 5-hydroxymethyl-2-furancarboxylic acid (HMFCA) respectively via Pseudomonas putida. RESULTS: G. amansii biomass was hydrolyzed by dilute acid to form D-galactose and HMF. The best result was attained after pretreatment with 2% (w/w) HCl at 120 °C for 40 min. Five different Pseudomonas sp. strains including P. putida ATCC 47054, P. fragi ATCC 4973, P. stutzeri CICC 10402, P. rhodesiae CICC 21960, and P. aeruginosa CGMCC 1.10712, were screened for highly selective oxidation of D-galactose and HMF. Among them, P. putida ATCC 47054 was the outstanding suitable biocatalyst converting D-galactose and HMF to the corresponding acids without reduced or over-oxidized products. It was plausible that the pyrroloquinoline quinone-dependent glucose dehydrogenase and undiscovered molybdate-dependent enzyme(s) in P. putida ATCC 47054 individually played pivotal role for D-galactose and HMF oxidation. Taking advantage of its excellent efficiency and high selectivity, a maximum of 55.30 g/L D-galactonic acid and 11.09 g/L HMFCA were obtained with yields of 91.1% and 98.7% using G. amansii hydrolysates as substrate. CONCLUSIONS: Valorization of G. amansii biomass for dual production of D-galactonic acid and HMFCA can enrich the product varieties and improve the economic benefits. This study also demonstrates the perspective of making full use of marine feedstocks to produce other value-added products.


Asunto(s)
Biomasa , Furaldehído/análogos & derivados , Rhodophyta/química , Azúcares Ácidos/metabolismo , Ácidos/metabolismo , Fermentación , Furaldehído/metabolismo , Galactosa/metabolismo , Hidrólisis , Oxidación-Reducción , Pseudomonas putida/metabolismo
13.
Nanotechnology ; 31(37): 375707, 2020 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-32464616

RESUMEN

Antibacterial fibers have great potential in many applications including wound dressings, surgical gowns, and surgical sutures, and play an important role in our daily life. However, the traditional fabrication method for the antibacterial fibers shows high cost, complexity, and inferior antibacterial durability. Herein, we report a facile and scalable fabrication of highly effective antibacterial alginate (SA) composite fibers through blend spinning of zeolitic imidazolate framework-67 (ZIF-67) particles and SA. The fabricated ZIF-67@SA composite fibers show high tensile strength and initial modulus. More importantly, the ZIF-67@SA composite fibers demonstrate excellent antibacterial properties, and the antibacterial efficiency reaches over 99% at ultralow ZIF-67 loading (0.05 wt%). In addition, the ZIF-67@SA fibers show good antibacterial durability even after five laundering cycles. The excellent antibacterial performance of the ZIF-67@SA fibers is attributed to the synergistic effects of the highly effective antibacterial ZIF-67 particles, swelling of alginate, and immobilization of ZIF-67 particles both inside and outside the fiber surface. This work may shed light on the antibacterial mechanism of metal organic frameworks and pave the way for the development of high-performance antibacterial textiles.


Asunto(s)
Alginatos/química , Antibacterianos/química , Estructuras Metalorgánicas/química , Zeolitas/química , Antibacterianos/farmacología , Escherichia coli/efectos de los fármacos , Imidazoles/química
14.
Bioprocess Biosyst Eng ; 43(1): 67-73, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31535223

RESUMEN

Currently, biotransformation of 5-hydroxymethylfurfural (HMF) into a series of high-value bio-based platform chemicals is massively studied. In this study, selective biooxidation of HMF to 5-hydroxymethyl-2-furancarboxylic acid (HMFCA) by Pseudomonas putida KT2440 with superior titer, yield, and productivity was reported. The biocatalytic performances of P. putida KT2440 were optimized separately. Under optimal conditions, 100% yield of HMFCA was obtained when HMF concentration was less than 150 mM, while the maximum concentration of 155 mM was achieved from 160 mM HMF in 12 h. P. putida KT2440 was highly tolerate to HMF, up to 190 mM. Besides, it was capable of selective oxidation of other furan aldehydes to the corresponding carboxylic acids with good yield of 100%. This study further demonstrates the potential of P. putida KT2440 as a biocatalyst for biomass conversion, as this strain has been proved the capacity to convert and utilize many kinds of biomass-derived sugars and ligin-derived aromatic compounds.


Asunto(s)
Biocatálisis , Furaldehído/análogos & derivados , Furanos/metabolismo , Pseudomonas putida/metabolismo , Furaldehído/metabolismo , Oxidación-Reducción
15.
Nature ; 499(7457): 214-218, 2013 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-23770567

RESUMEN

Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.


Asunto(s)
Heterogeneidad Genética , Mutación/genética , Neoplasias/genética , Oncogenes/genética , Artefactos , Momento de Replicación del ADN , Exoma/genética , Reacciones Falso Positivas , Expresión Génica , Genoma Humano/genética , Humanos , Neoplasias Pulmonares/genética , Tasa de Mutación , Neoplasias/clasificación , Neoplasias/patología , Neoplasias de Células Escamosas/genética , Reproducibilidad de los Resultados , Tamaño de la Muestra
16.
Nature ; 486(7403): 405-9, 2012 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-22722202

RESUMEN

Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.


Asunto(s)
Neoplasias de la Mama/clasificación , Neoplasias de la Mama/genética , Mutación/genética , Translocación Genética/genética , Algoritmos , Neoplasias de la Mama/patología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad beta del Factor de Unión al Sitio Principal/genética , Análisis Mutacional de ADN , Exoma/genética , Femenino , Fusión Génica/genética , Humanos , Proteínas de la Membrana/genética , México , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Vietnam
17.
Paediatr Anaesth ; 28(10): 914-923, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30207420

RESUMEN

BACKGROUND: In many centers, fresh frozen plasma is generally used as the main component of pump prime in pediatric cardiopulmonary bypass. However, many factors have resulted in stringent control of plasma transfusion and prompted the study of safe and efficient substitutes. AIMS: The aim of this study was to investigate the feasibility of a priming strategy with gelatin during cardiopulmonary bypass in pediatric patients undergoing cardiac surgery and identify the factors associated with postoperative chest-tube drainage. METHODS: We reviewed 1164 pediatric patients who underwent cardiac surgery with cardiopulmonary bypass between January 2012 and April 2013 in Fuwai hospital. Infants and children were primed with different types of solution: plasma or gelatin. Clinical data included postoperative coagulation function (pharmacological agents, chest-tube drainage, and transfusion requirements), recovery indicators (mechanical ventilator time, ICU stay and hospital stay), incidence of in-hospital mortality, and morbidity. Multivariate linear regression analysis was used to identify factors correlated with postoperative chest-tube drainage. RESULTS: No difference in mortality or morbidity was found between the plasma and gelatin groups. In infants, increased chest-tube drainage (postoperation 12 hours, median difference -0.046 ml/kg/hr, 95%CI: -0.105 to -0.007, P = 0.001; postoperation 24 hours, median difference -0.047 ml/kg/hr, 95%CI: -0.081 to -0.025, P < 0.001), and decreased transfusion (red blood cell, median difference 0.00 ml/kg/hr, 95%CI: 0.000-100, P < 0.001; fresh frozen plasma, median difference 5.556 ml/kg/hr, 95%CI: 2.30-8.333, P = 0.001), and recovery time (mechanical ventilator time, median difference 3.00 hours, 95%CI: 1.00-5.500, P < 0.001; ICU stay, median difference 17.00 hours, 95%CI: 1.00-22.000, P = 0.001; hospital stay, median difference 1.00 day, 95%CI: 0.00-2.000, P = 0.038) were demonstrated in the gelatin group. In children, the transfusion requirements (red blood cell, median difference 100 ml, P < 0.001;fresh frozen plasma, median difference 1.11 ml/kg, 95%CI: 0.000-2.42, P = 0.001) were decreased in the gelatin group. Multivariate linear regression analysis revealed that the type of priming solution (ß = 1.940,95%CI: 1.057-2.823,P < 0.001), bypass time (ß = 0.024, 95%CI: 0.013-0.036, P < 0.001), and age (ß = -0.257, 95%CI: -0.422 to -0.09, P = 0.002) were independent variables correlating with chest-tube drainage in infants. CONCLUSION: In the general pediatric patients undergoing elective cardiac surgery, substitution of gelatin for fresh frozen plasma in cardiopulmonary bypass is feasible.


Asunto(s)
Transfusión Sanguínea/métodos , Puente Cardiopulmonar/métodos , Coloides/administración & dosificación , Puente de Arteria Coronaria/métodos , Gelatina/administración & dosificación , Plasma , Coagulación Sanguínea , Tubos Torácicos , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Recuperación de la Función , Estudios Retrospectivos
18.
Proc Natl Acad Sci U S A ; 111(3): 1102-7, 2014 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-24385586

RESUMEN

High-grade serous ovarian cancers are characterized by widespread recurrent copy number alterations. Although some regions of copy number change harbor known oncogenes and tumor suppressor genes, the genes targeted by the majority of amplified or deleted regions in ovarian cancer remain undefined. Here we systematically tested amplified genes for their ability to promote tumor formation using an in vivo multiplexed transformation assay. We identified the GRB2-associated binding protein 2 (GAB2) as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells. Cancer cell lines overexpressing GAB2 require GAB2 for survival and show evidence of phosphatidylinositol 3-kinase (PI3K) pathway activation, which was required for GAB2-induced transformation. Cell lines overexpressing GAB2 were as sensitive to PI3K inhibition as cell lines harboring mutant PIK3CA. Together, these observations nominate GAB2 as an ovarian cancer oncogene, identify an alternative mechanism to activate PI3K signaling, and underscore the importance of PI3K signaling in this cancer.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Neoplasias Ováricas/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica , Femenino , Genómica , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Sistemas de Lectura Abierta , Neoplasias Ováricas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal
19.
EMBO J ; 30(16): 3242-58, 2011 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-21804531

RESUMEN

Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is an important, highly conserved, regulator of cell growth. Ancient among the signals that regulate mTORC1 are nutrients. Amino acids direct mTORC1 to the surface of the late endosome/lysosome, where mTORC1 becomes receptive to other inputs. However, the interplay between endosomes and mTORC1 is poorly understood. Here, we report the discovery of a network that links mTORC1 to a critical component of the late endosome/lysosome, the V-ATPase. In an unbiased screen, we found that mTORC1 regulated the expression of, among other lysosomal genes, the V-ATPases. mTORC1 regulates V-ATPase expression both in cells and in mice. V-ATPase regulation by mTORC1 involves a transcription factor translocated in renal cancer, TFEB. TFEB is required for the expression of a large subset of mTORC1 responsive genes. mTORC1 coordinately regulates TFEB phosphorylation and nuclear localization and in a manner dependent on both TFEB and V-ATPases, mTORC1 promotes endocytosis. These data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/fisiología , Endocitosis/fisiología , Procesamiento Proteico-Postraduccional , Proteínas/fisiología , ATPasas de Translocación de Protón Vacuolares/fisiología , Secuencias de Aminoácidos , Animales , Línea Celular Transformada/efectos de los fármacos , Línea Celular Transformada/metabolismo , Dactinomicina/farmacología , Endocitosis/efectos de los fármacos , Inducción Enzimática/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Lisosomas/enzimología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Complejos Multiproteicos , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/fisiología , Transducción de Señal/fisiología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/fisiología , ATPasas de Translocación de Protón Vacuolares/biosíntesis , ATPasas de Translocación de Protón Vacuolares/genética
20.
J Cutan Pathol ; 42(5): 308-17, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25754356

RESUMEN

BACKGROUND: SMARCB1 (INI1/BAF47/SNF5) encodes a part of a multiprotein complex that regulates gene expression through chromatin remodeling. SMARCB1 expression is lost or downregulated in multiple human tumors, including epithelioid sarcoma, meningioma and rhabdoid tumors of the brain, soft tissue and kidney. METHODS: A 46-gene or 50-gene next-generation sequencing AmpliSeq Cancer Panel (Life Technologies; San Francisco, CA, USA) was applied to ∼1400 primary or metastatic melanoma tissues. RESULTS: We identified eight cases of melanoma harboring mutations in SMARCB1. Immunohistochemistry demonstrated preservation of SMARCB1 protein expression in all cases. SMARCB1 mutations occurred together with TP53 mutations in five of the eight cases, suggesting a functional relationship between these tumor suppressors in melanoma. CONCLUSIONS: Because single-base substitutions in SMARCB1 occur in a small subset of melanomas and do not affect SMARCB1 protein expression, such mutations would only be discovered by sequencing approaches. Our findings highlight the potential for next-generation sequencing platforms to identify mutations unexpected for melanoma that may contribute to its oncogenic potential. Though rare, the identification of SMARCB1 mutations adds to the growing literature regarding the role of epigenetic control mechanisms in melanoma progression and therapeutic resistance and provide a rationale for strategies targeting such alterations (via chromatin remodeling agents) in clinical trials.


Asunto(s)
Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Melanoma/genética , Mutación , Análisis de Secuencia de ADN/métodos , Factores de Transcripción/genética , Adulto , Anciano , Anciano de 80 o más Años , Regulación hacia Abajo , Epigénesis Genética , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Proteína SMARCB1 , Proteína p53 Supresora de Tumor/genética
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