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The importance of biogenic silver/silver chloride nanoparticles has become increasing day by day. In the present study, silver/silver chloride nanoparticles (Ag/AgCl-NPs) were synthesized from Kaempferia rotunda tuberous rhizome extract to evaluate the antiproliferative activity against human glioblastoma stem cells (GSCs) in vitro and Ehrlich ascites carcinoma (EAC) cells in vivo in mice. Synthesis of nanoparticles was confirmed by colour change and UV-visible spectrum and characterized by TEM, XRD, TGA, AFM and FTIR. K rotunda and recently synthesized Zizyphus mauritiana fruit extract-mediated Ag/AgCl-NPs inhibited 77.2% and 71% of GSCs growth at 32 µg/mL concentration with the IC50 values of 6.8 and 10.4 µg/mL, respectively. Cell morphological studies and caspase-3 immunofluorescence assay revealed that both biogenic nanoparticles induced apoptosis in GSCs. Expression levels of several genes were checked by real-time PCR after treatment with K rotunda tuberous rhizome-mediated Ag/AgCl-NPs. PARP, EGFR, NOTCH2 and STAT3 gene expression were decreased with the increase of NFκB, TLR9, IL1, TNFα, IKK and p21 gene that would be the cause of induction of apoptosis in GSCs. The cell cycle arrest at G2 /M phase was confirmed by flow cytometric assay. Both nanoparticles were injected intraperitoneally to rapidly growing EAC cells for 5 consecutive days. Approximately, 32.3% and 55% EAC cells growth were inhibited by K rotunda tuberous rhizome-mediated Ag/AgCl-NPs at 6 and 12 mg/kg/day doses, respectively while only 20% cell growth inhibition was monitored at 12 mg/kg/day dose of Z mauritiana-mediated Ag/AgCl-NPs. From the above results, it can be concluded that presently synthesized nanoparticles would be a potent anticancer agent.
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Neoplasias Encefálicas/metabolismo , Carcinoma de Ehrlich/metabolismo , Glioblastoma/metabolismo , Nanopartículas del Metal/química , Células Madre Neoplásicas/efectos de los fármacos , Compuestos de Plata/química , Plata/química , Animales , Antineoplásicos/farmacología , Apoptosis , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Ehrlich/tratamiento farmacológico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Citometría de Flujo , Regulación de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Humanos , Concentración 50 Inhibidora , Ratones , Microscopía Electrónica de Transmisión , Trasplante de Neoplasias , Propiedades de Superficie , Rayos Ultravioleta , Difracción de Rayos X , ZingiberaceaeRESUMEN
BACKGROUND: Recent studies have suggested that the gut microbiota is altered in children with juvenile idiopathic arthritis (JIA). However, age, sex, and body mass index (BMI) were not matched in the previous studies, and the results are inconsistent. We conducted an age-, sex-, and BMI-matched cross-sectional study to characterize the gut microbiota in children with JIA, and evaluate its potential in clinical prediction. METHODS: A total of 40 patients with JIA and 42 healthy controls, ranging from 1 to 16 years, were enrolled in this study. Fecal samples were collected for 16S rDNA sequencing. The data were analyzed using QIIME software and R packages. Specifically, the random forest model was used to identify biomarkers, and the receiver operating characteristic curve and the decision curve analysis were used to evaluate model performance. RESULTS: A total of 39 fecal samples from patients with JIA, and 42 fecal samples from healthy controls were sequenced successfully. The Chao 1 and Shannon-Wiener index in the JIA group were significantly lower than those in the control group, and the Bray-Curtis dissimilarity also differed significantly between the two groups. The relative abundance of 4 genera, Anaerostipes, Dialister, Lachnospira, and Roseburia, decreased significantly in the JIA group compared to those in the control group. The 4 genera included microbes that produce short-chain fatty acids (SCFAs) and were negatively correlated with some rheumatic indices. Moreover, 12 genera were identified as potential biomarkers by using the nested cross-validation function of the random forest. A random forest model constructed using these genera was able to differentiate the patients with JIA from the healthy controls, and the area under the receiver operating characteristic curve was 0.7975. The decision curve analysis indicated that the model had usefulness in clinical practice. CONCLUSIONS: The gut microbiota in patients with JIA is altered and characterized by a decreased abundance of 4 SCFA-producing genera. The decreases in the 4 genera correlated with more serious clinical indices. Twelve genera could be used as biomarkers and predictors in clinical practice. TRIAL REGISTRATION: The study is registered online at the Chinese Clinical Trial Registry on 11 May 2018 (registration number: ChiCTR1800016110).
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Artritis Juvenil/microbiología , Bacterias/clasificación , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN/métodos , Adolescente , Bacterias/genética , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , ADN Bacteriano/genética , ADN Ribosómico/genética , Heces/microbiología , Femenino , Microbioma Gastrointestinal , Humanos , Lactante , Masculino , FilogeniaRESUMEN
BACKGROUND: Rearranged during transfection (RET) proto-oncogene encodes a receptor tyrosine kinase for glial cell line-derived neurotrophic factor (GDNF) signaling, and high RET expression is closely related to the tumorigenesis and malignancy of neuroblastoma(NB). METHODS: We have investigated whether RET signals through hedgehog (HH) pathway in NB cell proliferation and tumor growth by in vitro cell culture and in vivo xenograft approaches. RESULTS: The key members of both GDNF/RET and HH/GLI pathways are expressed in NB cell lines to different extents. Knockdown of RET in NB cells significantly attenuates the activity of HH signaling, whereas overexpression of RET robustly enhances the output of transcriptional activation by HH. Likewise, activation of RET by GDNF induces HH signaling, whereas knockdown of RET attenuates both basal and GDNF-induced activities of HH signaling. Moreover, protein kinase B lies on the downstream of GDNF/RET signaling module to inhibit the GSK3ß, resulting in activation of HH signaling. Furthermore, either knockdown of RET by shRNA or inhibition of HH pathway by cyclopamine attenuates not only basal but also GDNF-induced proliferation of SH-SY5Y cells, and knockdown of either RET or smoothened in SH-SY5Y cell xenografts significantly attenuated the tumor growth. Finally, inhibition of HH signaling by GLI1 and GLI2 inhibitor, Gant61, reduces not only basal but also RET-induced proliferation of SH-SY5Y cells and outgrowth of xenografts. CONCLUSION: GDNF/RET/AKT/GSK3ß signaling module activates HH pathway to stimulate NB cells proliferation and tumor outgrowth. GENERAL SIGNIFICANCE: Targeting HH pathway is a rational approach for therapeutic intervention of NB with high RET expression.
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Proliferación Celular/efectos de los fármacos , Proteínas Hedgehog/metabolismo , Neuroblastoma/metabolismo , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Factores de Transcripción de Tipo Kruppel/antagonistas & inhibidores , Proteínas Nucleares/antagonistas & inhibidores , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-ret/metabolismo , Piridinas/farmacología , Pirimidinas/farmacología , ARN Interferente Pequeño/metabolismo , Transfección/métodos , Alcaloides de Veratrum/farmacología , Proteína con Dedos de Zinc GLI1/antagonistas & inhibidores , Proteína Gli2 con Dedos de ZincRESUMEN
p205, an interferon-inducible protein, is induced in the course of osteogenesis in mouse bone marrow stromal cells (BMSCs). Knocking down p205 markedly impairs whereas overexpressing p205 enhances the osteoblast differentiation of BMSCs, as revealed by the altered expression of osteogenic genes, the change of ALP activity and the ARS-stained mineral nodules. The positive role of p205 in BMSC osteogenesis is probably due, at least in part, to the association of it with Id proteins. Further investigation indicated that p205 may disturb the formation of Runx2/Ids complex and free more Runx2 to induce the differentiation process. Taken together, our findings demonstrated for the first time that p205 functions as an activator in osteoblast differentiation.
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Diferenciación Celular/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Células Madre Mesenquimatosas/citología , Neuropéptidos/genética , Osteogénesis/genética , Animales , Interferones/administración & dosificación , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Receptores de Cinasa C ActivadaRESUMEN
In this work, three hybrid vertical down-flow constructed wetland (HVDF-CW) systems with different compound substrates were fed with domestic sewage and their pollutants removal performance under different hydraulic loading and step-feeding ratio was investigated. The results showed that the hydraulic loading and step-feeding ratio were two crucial factors determining the removal efficiency of most pollutants, while substrate types only significantly affected the removal of COD and NH4(+)-N. Generally, the lower the hydraulic loading, the better removal efficiency of all contaminants, except for TN. By contrast, the increase of step-feeding ratio would slightly reduce the removal rate of ammonium and TP but obviously promoted the TN removal. Therefore, the optimal operation of this CWs could be achieved with low hydraulic loading combined with 50% of step-feeding ratio when TN removal is the priority, whereas medium or low hydraulic loading without step-feeding would be suitable when TN removal is not taken into consideration. The obtained results in this study can provide us with a guideline for design and optimization of hybrid vertical flow constructed wetland systems to improve the pollutants removal from domestic sewage.
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Restauración y Remediación Ambiental/métodos , Aguas del Alcantarillado/química , Eliminación de Residuos Líquidos/métodos , Purificación del Agua/métodos , Humedales , Nitrógeno/análisisRESUMEN
BACKGROUND: Approximately 30% of breast cancer does not express the estrogen receptor (ER), which is necessary for endocrine-based therapy approaches. Many studies demonstrated that eukaryotic translation initiation factor 5A2 (eIF5A2) serves as a proliferation-related oncogene in tumorigenic processes. METHODS: The present study used cell viability assays, EdU incorporation assays, western blot, and immunofluorescence to explore whether N1-guanyl-1,7-diaminoheptane (GC7), which inhibits eIF5A2 activation, exerts synergistic cytotoxicity with doxorubicin in breast cancer. RESULTS: We found that GC7 enhanced doxorubicin cytotoxicity in ER-negative HCC1937 cells but had little effect in ER-positive MCF-7 and Bcap-37 cells. Administration of GC7 reversed the doxorubicin-induced epithelial-mesenchymal transition (EMT) in ER-negative breast cancer cells. Knockdown of eIF5A2 by siRNA inhibited the doxorubicin-induced EMT in ER-negative HCC1937 cells. CONCLUSION: These data demonstrated that GC7 combination therapy may enhance the therapeutic efficacy of doxorubicin in estrogen negative breast cancer cells by preventing EMT through inhibition of eIF5A2 activation.
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Neoplasias de la Mama/metabolismo , Diaminas/farmacología , Doxorrubicina/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Factores de Iniciación de Péptidos/metabolismo , Proteínas de Unión al ARN/metabolismo , Receptores de Estrógenos/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Factor 5A Eucariótico de Iniciación de TraducciónRESUMEN
BACKGROUND: Epithelial-mesenchymal transition (EMT) has been believed to be related with chemotherapy resistance in non-small cell lung cancer (NSCLC). Recent studies have suggested eIF5A-2 may function as a proliferation-related oncogene in tumorigenic processes. METHODS: We used cell viability assays, western blotting, immunofluorescence, transwell-matrigel invasion assay, wound-healing assay combined with GC7 (a novel eIF5A-2 inhibitor) treatment or siRNA interference to investigate the role of eIF5A-2 playing in NSCLC chemotherapy. RESULTS: We found low concentrations of GC7 have little effect on NSCLC viability, but could enhance cisplatin cytotoxicity in NSCLC cells. GC7 also could reverse mesenchymal phenotype in NCI-H1299 and prevented A549 cells undergoing EMT after TGF-ß1 inducement. eIF5A-2 knockdown resulted in EMT inhibition. CONCLUSION: Our data indicated GC7 enhances cisplatin cytotoxicity and prevents the EMT in NSCLC cells by inhibiting eIF5A-2.
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/farmacología , Inhibidores Enzimáticos/farmacología , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , Factores de Iniciación de Péptidos/antagonistas & inhibidores , Proteínas de Unión al ARN/antagonistas & inhibidores , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Silenciador del Gen , Guanina/farmacología , Humanos , Concentración 50 Inhibidora , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/antagonistas & inhibidores , Factores de Iniciación de Péptidos/genética , ARN Interferente Pequeño , Proteínas de Unión al ARN/genética , Vimentina/metabolismo , Factor 5A Eucariótico de Iniciación de TraducciónRESUMEN
OBJECTIVE: To explore the clinical characteristics and significance of RET proto-oncogene screening in multiple endocrine neoplasia type 2A (MEN2A). METHODS: Comprehensive medical history was obtained for 5 members from a 3-generation family from southern China. Clinical investigations have included biochemical testing, imaging, and screening of germline RET proto-oncogene mutations. RESULTS: Genetic screening has revealed a missense mutation at codon 618(TGC>CGC) of exon 10 in 3 patients(p.C618R), which was consistent with their clinical manifestations. For the 3 individuals, the age at diagnosis was 21, 26 and 36 yr, and the maximum diameter of medullary thyroid carcinoma was 22, 25 and 39 cm, respectively. The 36-year-old female patient initially underwent right total thyroidectomy plus right neck lymph node dissection. Four years later, she again underwent left adrenal tumorectomy and left total thyroidectomy plus left neck lymph node dissection. The 21-year-old male patient underwent right total thyroidectomy plus right modified neck dissection. The follow-up was respectively 146 and 26 months following the initial operation. Two patients still presented elevated calcitonin and had bilateral neck lymph node masses and/or left thyroid masses on imaging examination. The 26-year-old female patient, who presented bilateral thyroid masses and elevated calcitonin, has refused thyroidectomy. CONCLUSION: Combined family survey and RET gene screening can facilitate early diagnosis and surgical treatment to improve the prognosis.
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Pueblo Asiatico/genética , Neoplasia Endocrina Múltiple Tipo 2a/enzimología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Mutación Missense , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/genética , Adulto , Secuencia de Bases , Carcinoma Neuroendocrino , Exones , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Proto-Oncogenes Mas , Adulto JovenRESUMEN
Dirac semimetals have demonstrated significant attraction in the field of optoelectronics due to their unique bandgap structure and high carrier mobility. Combining them with classical semiconductor materials to form heterojunctions enables broadband optoelectronic conversion at room temperature. However, the low light absorption of layered Dirac semimetals substantially limits the device's responsivity in the infrared band. Herein, a three-dimensional (3D) heterostructure, composed of silicon nanopillars (SiNPs) and a conformal PtTe2 film, is proposed and demonstrated to enhance the photoresponsivity for uncooled broadband detection. The light trapping effect in the 3D heterostructure efficiently promotes the interaction between light and PtTe2, while also enhancing the light absorption efficiency of silicon, which enables the enhancement of the device responsivity across a broadband spectrum. Experimentally, the PtTe2-SiNPs heterojunction device demonstrates excellent photoelectric conversion behavior across the visible, near-infrared, and long-wave infrared (LWIR) bands, with its responsivity demonstrating an order-of-magnitude improvement compared to the counterparts with planar silicon heterojunctions. Under 11 µm laser irradiation, the noise equivalent power (NEP) can reach 1.76 nW·Hz-1/2 (@1 kHz). These findings offer a strategic approach to the design and fabrication of high-performance broadband photodetectors based on Dirac semimetals.
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OBJECTIVE: To systematically screen and identify long noncoding RNA (lncRNA) associated with bone marrow adiposity changes in aplastic anemia (AA). METHODS: The PPARγ and C/EBPα ChIP-Seq data in ChIPBase was analyzed by bioinformatics and the potential lncRNA co-transcriptionally regulated by PPARγ and C/EBPα was screened. The expression of candidate lncRNA was verified by qRT-PCR in the in vitro adipogenic differentiation model of BM-MSC, BM-MSC infected with lenti-shPPARγ and lenti-shC/EBPα as well as clinical BM-MSC samples derived from AA and controls. RESULTS: PPARγ and C/EBPα were significantly highly expressed in AA BM-MSC, and knock-down of PPARγ and C/EBPα impaired the adipogenic capacity of AA BM-MSC. PPARγ and C/EBPα cotranscriptionally activate LINC01230 promoter activity in binding sites dependant manner. The LINC01230 was also aberrantly highly expressed in AA BM-MSC compared with controls. CONCLUSION: PPARγ and C/EBPα are aberrantly expressed in AA BM-MSC and may promote the adipogenic differentiation of AA BM-MSC, and to a certain extent mediate the bone marrow adiposity alteration by transcriptionally activating LINC01230 expression.
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Anemia Aplásica , Médula Ósea , PPAR gamma , ARN Largo no Codificante , ARN Largo no Codificante/genética , Humanos , Anemia Aplásica/genética , PPAR gamma/genética , PPAR gamma/metabolismo , Médula Ósea/metabolismo , Proteína alfa Potenciadora de Unión a CCAAT/genética , Diferenciación Celular , Células Madre Mesenquimatosas/metabolismo , Adipogénesis , Adiposidad , Células de la Médula ÓseaRESUMEN
BACKGROUND: Increasing evidence indicate that enhanced adipogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) could contribute to the adiposity alteration in marrow microenvironment of aplastic anemia (AA). Identifying small molecule drugs with role in inhibiting adipogenesis of BM-MSCs may represent a novel direction in AA therapy by improving BM-MSCs mediated marrow microenvironment. METHODS: For the purpose, we isolated AA BM-MSCs through whole bone marrow cell culture, evaluated a series of small molecule drugs using the in vitro adipogenic differentiation model of BM-MSCs, and finally focused on emodin, a natural anthraquinone derivative. Subsequently, we systematically investigated the molecular mechanism of emodin in attenuating adipogenic process by means of microarray profiling, bioinformatics analysis and lentivirus-mediated functional studies and rescue assay. RESULTS: We found that emodin presented significantly suppressive effect on the in vitro adipogenic differentiation of AA BM-MSCs. Further mechanistic investigation revealed that emodin could increase the expression of Tribbles homolog 3 (TRIB3) which exhibited remarkably decreased expression in AA BM-MSCs compared with the normal counterparts and was subsequently demonstrated as a negative regulator in adipogenesis of AA BM-MSCs. Besides, TRIB3 depletion alleviated the suppressive effect of emodin on the adipogenic differentiation of AA BM-MSCs. CONCLUSION: Our findings propose that emodin mediated TRIB3 up-regulation alleviates the adipogenic capacity of AA BM-MSCs, and emodin could serve as a potential therapeutic regimen for AA therapy.
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Anemia Aplásica , Emodina , Células Madre Mesenquimatosas , Humanos , Adipogénesis/genética , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/metabolismo , Médula Ósea , Emodina/farmacología , Células de la Médula Ósea , Diferenciación Celular , Células Cultivadas , Proteínas Represoras/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMEN
Xeroderma pigmentosum-variant (XPV) is one type of XP, a rare autosomal recessive disorder, and caused by defects in the post replication repair machinery while nucleotide-excision repair (NER) is not impaired. In the present study, we reported a Chinese family with XPV phenotype, which was confirmed by histopathological results. Genetic variants were detected by polymerase chain reaction and exon sequencing. Furthermore, the reported molecular defects in XPV patients from previous literatures were reviewed. A homozygous c.67C>T mutation in the exon 2 of DNA polymerase eta (POLH), a novel non-sense mutation in POLH, was discovered.
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Codón sin Sentido , ADN Polimerasa Dirigida por ADN/genética , Neoplasias Cutáneas/genética , Xerodermia Pigmentosa/genética , Adulto , China , Femenino , Humanos , Masculino , Linaje , Neoplasias Cutáneas/patología , Xerodermia Pigmentosa/patologíaRESUMEN
OBJECTIVE: To explore the clinical patterns and clinical significance for RET screening in adrenal pheochromocytoma (PHEO) associated with multiple endocrine neoplasia type 2A (MEN2A). METHODS: The clinical data of 32 PHEO patients with MEN2A from 13 unrelated MEN2A pedigrees from August 1989 to January 2013 were analyzed. The comprehensive medical data included systemic examinations and germline RET gene screening. RESULTS: Among 68 patients belonging to 13 MEN2A families, 32 (47.1%) presented with PHEO. There were 19 males and 13 females with a mean age of (41 ± 12) years. And the mean maximum diameter of PHEO was (4.6 ± 2.2) cm. The diagnosis of PHEO was made after medullary thyroid carcinoma (n = 12, 37.5%), simultaneously (n = 12, 37.5%), initially (n = 7, 21.9%) and death during appendectomy for PHEO-induced hypertensive crisis (n = 1, 3.1%). The diagnosis of PHEO was made before (n = 22) or after (n = 10) clinical screening. The former had 12 symptomatic cases while the latter only 1 case (12/22 vs 1/10, P = 0.024).Except for 5 asymtomatic fatal cases during non-PHEO operations, bilateral PHEO was found in 17 cases including 3 unilaterally treated cases developing another PHEO in contralateral adrenal with a lag period of 5, 10 and 17 years. There were 7 symptomatic patients in bilateral cases versus 6 in unilateral cases (7/17 vs 6/10, P = 0.440). Twenty-five patients underwent PHEO surgery: laparascopic approach in 14 cases (8 with bilateral simultaneous adrenalectomy) and open approach in 11 (2 with bilateral simultaneous adrenalectomy). And 10 patients undergoing bilateral adrenal-sparing operations or adrenalectomy required hormonal replacement therapy. During a mean observation period of 72 (1-282) months, no local recurrence, distant metastasis or Addisonian crisis were noted in 25 cases (contralateral relapse in 3 cases). Among them, 2 cases developed adrenocortical insufficiency unresponsive to an adjustment of hormonal doses.RET screening showed 4 recurrent missense substitutions in 32 MEN2A-PHEO patients: p. C634Y exon 11 (n = 27, 84.4%), p. C634R exon 11 (n = 3, 9.4%), p. C634F exon 11 (n = 1, 3.1%) and p. C618R exon 10 (n = 1, 3.1%). CONCLUSIONS: The mutations of RET proto-oncognene of PHEO in MEN2A are frequently located at codon 634. A combination of pedigree examination and RET gene screening may facilitate an early diagnosis and early treatment of asymptomatic PHEO patients in MEN2A.Laparoscopic cortical-sparing adrenalectomy for preserving adrenocortical function is a preferred surgical approach.
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Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasia Endocrina Múltiple Tipo 2a/metabolismo , Proteínas Proto-Oncogénicas c-ret/metabolismo , Adrenalectomía , Exones , Femenino , Humanos , Masculino , Mutación , Feocromocitoma , Proto-Oncogenes MasRESUMEN
OBJECTIVE: To explore the clinical characteristics, therapeutic and clinical significance for RET proto-oncogene screening in a pedigree with familial medullary thyroid carcinoma. METHODS: Comprehensive medical history was obtained from 19 members in a 4-generate southern Chinese family. Systemic clinical investigations including biochemical testing, imaging examinations and germline RET screening. RESULTS: RET screening showed heterozygous missense mutations of TGC to TAC at codon 618 on exon 10 in 8 cases (p.C618Y) completely consistent with the clinical manifestations. The clinical data of 7 patients with medullary thyroid carcinoma (MTC) and 2 carriers of asymptomatic RET mutation from were analyzed. Single/bilateral multi-centric MTC with lymph node metastases was confirmed in 6 cases by histopathology and 1 case by clinical examination. There were 1 male and 6 females with an initial mean diagnostic age was 49.6 years (range: 24 - 78). All had palpable neck masses. And the mean maximum diameter of MTC was 2.6 cm (range 1.4 - 4.4). Seven patients underwent thyroidectomy except a 78-year-old female patient: right total and left subtotal thyroidectomy (n = 1), right total thyroidectomy (previous left total thyroidectomy for benign mass) (n = 1) and total thyroidectomy (n = 4) were performed. All procedures were accompanied by at least bilateral level VI lymph node dissection and/or with modified single/bilateral neck dissection. After the first operation, 6 patients still presented a high value of calcitonin: 1 patient died of metastasis 64 months postoperatively; 3 patients underwent reoperation at 6 months after initial operation, the calcitonin levels dropped to normal in 2/3 cases and stayed higher in 1 case; another two cases presented bilateral thyroid gland residua, local lymph node enlargement on imaging examination and elevated levels of calcitonin at 214 and 60 months postoperation respectively. However, 1/2 asymptomatic with elevated pre-operative calcitonin subjects underwent total thyroidectomy and histopathological examination showed bilateral C cell hyperplasia. The other carriers, without surgery, with normal neck images, close monitoring and a 10-month follow-up, still presented undetectable calcitonin. CONCLUSIONS: Based on family survey, integrated RET screening and serum levels of calcitonin facilitate an early diagnosis and normalize surgery to improve the prognosis. For asymptomatic RET mutation carriers, their levels of calcitonin shall guide the individualized regimen of prophylactic thyroidectomy or strict monitoring and follow-ups.
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Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Anciano , Carcinoma Neuroendocrino , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Mutación Puntual , Proto-Oncogenes Mas , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/terapia , Adulto JovenRESUMEN
Cellular senescence, characterized by stable cell cycle arrest, plays an important role in aging and age-associated pathologies. Eliminating senescent cells rejuvenates aged tissues and ameliorates age-associated diseases. Here, we identified that natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells in vitro, regardless of stimuli that induced cellular senescence, and in various tissues of aged mice and nonhuman primates in vivo. Accordingly, we developed and demonstrated that chimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression in vitro. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects. Our findings establish that NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence.
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Envejecimiento , Senescencia Celular , Subfamilia K de Receptores Similares a Lectina de Células NK , Anciano , Animales , Humanos , Ratones , Envejecimiento/patología , Ligandos , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Primates , Linfocitos T , Receptores Quiméricos de AntígenosRESUMEN
Increased propensity of bone marrow-derived mesenchymal stem cells (BM-MSCs) toward adipogenic differentiation at the expense of osteogenesis has been implicated in obesity, diabetes, and age-related osteoporosis as well as various hematopoietic disorders. Defining small molecules with role in rectifying the adipo-osteogenic differentiation imbalance is of great significance. Here, we unexpectedly found that Chidamide, a selective histone deacetylases inhibitor, exhibited remarkably suppressive effect on the in vitro induced adipogenic differentiation of BM-MSCs. Multifaceted alterations in the spectrum of gene expression were observed in Chidamide-managed BM-MSCs during adipogenic induction. Finally, we focused on REEP2, which presented decreased expression in BM-MSCs-mediated adipogenesis and was restored by Chidamide treatment. REEP2 was subsequently demonstrated as a negative regulator of adipogenic differentiation of BM-MSCs and mediated the suppressive effect of Chidamide on adipocyte development. Our findings provide the theoretical and experimental foundation for the clinical application of Chidamide for disorders associated with excessive marrow adipocytes.
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Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by abnormal cell proliferation, apoptosis repression and myeloid differentiation blockade of hematopoietic stem/progenitor cells. Developing and identifying novel therapeutic agents to reverse the pathological processes of AML are of great significance. Here in this study, we found that a fungus-derived histone deacetylase inhibitor, Apicidin, presents promising therapeutic effect on AML by inhibiting cell proliferation, facilitating apoptosis and inducing myeloid differentiation of AML cells. Mechanistic investigation revealed that QPCT is identified as a potential downstream target of Apicidin, which exhibits significantly decreased expression in AML samples compared with the normal controls and is remarkably up-regulated in AML cells upon Apicidin management. Functional study and rescue assay demonstrated that QPCT depletion further promotes cell proliferation, inhibits apoptosis and impairs myeloid differentiation of AML cells, alleviating the anti-leukemic effect of Apicidin on AML. Our findings not only provide novel therapeutic target for AML, but also lay theoretical and experimental foundation for the clinical application of Apicidin in AML patients.
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Apoptosis , Leucemia Mieloide Aguda , Humanos , Proliferación Celular , Leucemia Mieloide Aguda/tratamiento farmacológicoRESUMEN
Increasing evidence suggests that core circadian genes have major roles in the carcinogenic mechanisms of multiple human malignancies. Among these genes, the role of reticulon 2 (RTN2) in ovarian cancer (OV) has so far remained elusive. In the present study, circadian clock gene (CCG) aberrations were systematically assessed across malignancies by using Gene Expression Omnibus and The Cancer Genome Atlas data. The results indicated that various core clock genes (ULK1, ATF3, CRY2, CSF3R, DAAM2, GAS7, NPTXR, PPPIR15A and RTN2) had elevated levels in tumors in comparison with normal tissues and their low expression levels were associated with a better prognosis in OV, indicating that they may be potential candidates for novel investigational approaches. The mRNA and protein expression levels of RTN2 in OV were then further analyzed by reverse transcriptionquantitative PCR and immunohistochemistry, respectively. The results indicated that RTN2 mRNA and protein levels were increased in OV specimens in comparison with control samples. Differentially expressed CCGs, such as RTN2, were suggested as indicators of asynchronous circadian rhythms in cancer, which may provide a theoretical basis for chronotherapy.
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Relojes Circadianos , Proteínas de la Membrana , Proteínas Musculares , Proteínas del Tejido Nervioso , Neoplasias Ováricas , Carcinoma Epitelial de Ovario , Relojes Circadianos/genética , Biología Computacional , Femenino , Humanos , Proteínas de la Membrana/genética , Proteínas Musculares/genética , Proteínas del Tejido Nervioso/genética , Neoplasias Ováricas/genética , ARN Mensajero/genéticaRESUMEN
Knuckle pads and camptodactyly are overlapping symptoms associated with many genetic and environmental factors. To the best of our knowledge, all reported cases of epidermolytic palmoplantar keratoderma (EPPK) with knuckle pads have been without accompanying camptodactyly. We here report a novel KRT9 mutation-EPPK family with combined knuckle pads and camptodactyly. All the EPPK-affected individuals in this southern Chinese pedigree suffered severe diffuse palmar and plantar hyperkeratosis including hyperhidrosis and cuticle splitting: 3 females presented EPPK only, 8 adult males had notably severe knuckle pads and camptodactyly as well as EPPK, and one 6-year-old boy manifested EPPK with knuckle pads. Haplotype analysis excluded the known candidate loci for camptodactyly and/or knuckle pad-like phenotypes on chromosomes 13q12, 3q11.2-q13.12, 1q24-q25, 4p16.3 and 16q11.1-q22, while only the markers D17S1787 and D17S579 flanking KRT9 showed co-segregation with EPPK. Then a novel c.T1373C (p.L458P) mutation within the sixth exon of KRT9 was validated, and this mutation presented a more severe pathogenicity than the previously reported p.L458F. We speculated that KRT9 plays a complicated role in the genesis of EPPK with knuckle pads and camptodactyly, which needs to be further investigated.
Asunto(s)
Anomalías Múltiples/genética , Dedos/anomalías , Deformidades Congénitas de la Mano/genética , Queratina-9/genética , Queratodermia Palmoplantar Epidermolítica/genética , Mutación Missense , Adulto , Pueblo Asiatico/genética , Niño , Análisis Mutacional de ADN , Electroforesis en Gel de Poliacrilamida , Femenino , Humanos , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , LinajeRESUMEN
Gastrointestinal stromal tumors (GISTs) are common neoplasms of the gastrointestinal tract that can be treated successfully using C-kit target therapy and surgery; however, imatinib chemoresistance is a major barrier to success in therapy. The present study aimed to discover alternative pathways in imatinib-resistant GISTs. Long noncoding RNAs (lncRNAs) are newly discovered regulators of chemoresistance. Previously, we showed that the lncRNA HOTAIR was upregulated in recurrent GISTs. In this study, we analyzed differentially expressed lncRNAs after imatinib treatment and found that HOTAIR displayed the largest increase. The distribution of HOTAIR in GISTs was shifted from nucleus to cytoplasm after imatinib treatments. The expression of HOTAIR was validated as related to drug sensitivity through Cell Counting Kit-8 assays. Moreover, HOTAIR was associated strongly with cell autophagy and regulated drug sensitivity via autophagy. Mechanistically, HOTAIR correlated negatively with miRNA-130a in GISTs. The downregulation of miRNA-130a reversed HOTAIR-small interfering RNA-induced suppression of autophagy and imatinib sensitivity. We identified autophagy-related protein 2 homolog B (ATG2B) as a downstream target of miR-130a and HOTAIR. ATG2B downregulation reversed the effect of pEX-3-HOTAIR/miR-130a inhibitor on imatinib sensitivity. Finally, HOTAIR was shown to influence the autophagy and imatinib sensitivity of GIST cells in mouse tumor models. Our results suggested that HOTAIR targets the ATG2B inhibitor miR-130a to upregulate the level of cell autophagy so that promotes the imatinib resistance in GISTs.