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In this study, we investigate the veliparibinduced toxicity in cancer patients. Databases were searched for RCTs treated with veliparib. We found veliparib could increase the risk of hematologic and gastrointestinal toxicities. Anemia, neutropenia, thrombocytopenia, and nausea were the most common toxicities. Patients diagnosed with gastrointestinal tumors tend to have a higher risk of high-grade neutropenia; patients in the first-line setting tend to have a higher risk of high-grade anemia and neutropenia than those in the ≥ second line setting. Patients receiving higher dosage of veliparib tend to have a higher risk of all-grade anemia. Veliparib could also increase the risk of insomnia, myalgia, pneumonia, dyspnea, hyponatremia, and fatigue.
Assuntos
Benzimidazóis , Neoplasias , Humanos , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Antineoplásicos/efeitos adversos , Anemia/induzido quimicamenteRESUMO
PURPOSE: We aimed to compare the staging efficiency of [68Ga]Ga-DOTATATE and [68Ga]Ga-FAPI PET/CT in nasopharyngeal carcinoma (NPC) patients. METHODS: Thirty-nine patients with pathologically confirmed NPC were enrolled in this prospective study. Each patient underwent paired [68Ga]Ga-DOTATATE and [68Ga]Ga-FAPI PET/CT on 2 successive days. The accuracy of two PET/CT for assessing T, N, and M stages was compared by using head-and-neck MRI, histopathologic diagnosis and follow-up results as reference standards. The radiotracer uptake derived from two PETs was also compared. RESULTS: For treatment-naïve patients, [68Ga]Ga-DOTATATE PET/CT showed identical sensitivity for the primary tumours but clearer tumor delineation induced by higher tumour-to-background (TBR) ratio (19.1 ± 8.7 vs. 12.4 ± 7.7, P = 0.003), compared with [68Ga]Ga-FAPI PET/CT. Regarding cervical lymph node (CLN) metastases, [68Ga]Ga-DOTATATE PET had significantly better sensitivity and accuracy based on neck sides (98% vs. 82%, P < 0.001; 99% vs. 88% P = 0.008), neck levels (98% vs. 78%, 99% vs. 97%; both P < 0.001) and individual nodes (89% vs. 56%, 91% vs. 76%; both P < 0.001), and higher TBR (8.1 ± 4.1 vs. 6.3 ± 3.7, P < 0.001). Additionally, [68Ga]Ga-DOTATATE PET/CT revealed higher sensitivity and accuracy for distant metastases (96% vs. 53%, 95% vs. 52%; both P < 0.001), particularly in bone metastases (99% vs. 49%, 97% vs. 49%; both P < 0.001). For post-treatment patients, [68Ga]Ga-DOTATATE PET/CT identified one more true-negative case than [68Ga]Ga-FAPI PET/CT. CONCLUSION: [68Ga]Ga-DOTATATE PET/CT performed better than [68Ga]Ga-FAPI PET/CT in visualizing the primary tumours, detecting the metastatic lesions and identifying the local recurrence, suggesting [68Ga]Ga-DOTATATE PET/CT may be superior to [68Ga]Ga-FAPI PET/CT for NPC staging.
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MiR-200a acts as a key role in tumor malignant progression. This work purposed to assess the function of miR-200a in Wilm's tumor. Based on bioinformatics analysis, the expression, prognostic value and related pathways of miR-200a and CDC7 (a potential downstream molecule of miR-200a) in Wilm's tumor were analyzed. qRT-PCR was conducted to confirm the miR-200a level in Wilm's tumor cells. The luciferase reporter assay was carried out to verify the binding of miR-200a to 3'-UTR of CDC7. Then, the impacts of miR-200a and CDC7 on cell viability and apoptosis were measured using CCK-8 and flow cytometry assays. Also, western blot was applied to measure the expression of CDC7 as well as Wnt/ß-catenin signaling pathway-related proteins and apoptosis proteins. Herein, we revealed that miR-200a was lowly expressed in Wilm's tumor tissues and cells and the low miR-200a expression is closely bound up with death and poor outcomes. Moreover, miR-200a directly targeted and inhibited CDC7 in Wilm's tumor cells. Biological function experiments illustrated that overexpression of miR-200a reduced the viability and elevated the apoptosis of Wilm's tumor cells, while overexpression of CDC7 reversed the inhibitory impact of miR-200a on cell viability and the promoting impact of miR-200a on cell apoptosis. Besides, we revealed that miR-200a/CDC7 axis can decrease the expression of ß-Catenin, Cyclin D1 and C-Myc as well as the phosphorylation of GSK-3ß, thus inhibiting the Wnt/ß-catenin signaling pathway. Furthermore, blocking the Wnt/ß-catenin signaling pathway caused an increase on cell apoptosis, while overexpression of CDC7 can reverse these impacts. Collectively, miR-200a/CDC7 axis involved in regulating the malignant phenotype of Wilm's tumor through Wnt/ß-catenin signaling pathway, which provides a theoretical basis for targeted molecular therapy of Wilm's tumor.
Assuntos
Apoptose , Proteínas de Ciclo Celular/metabolismo , Neoplasias Renais/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Neoplásico/metabolismo , Tumor de Wilms/metabolismo , Via de Sinalização Wnt , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , MicroRNAs/genética , Proteínas de Neoplasias/genética , Proteínas Serina-Treonina Quinases/genética , RNA Neoplásico/genética , Tumor de Wilms/genética , Tumor de Wilms/patologiaRESUMO
The non-specific biodistribution of traditional chemotherapeutic drugs against tumors is the key factor that causes systemic toxicity and hinders their clinical application. In this study, a reduction-sensitive polymer conjugate micelle was manufactured to achieve tumor-specific targeting, reduce toxic side-effects and improve anti-tumor activity of a natural anti-cancer drug, hydroxycamptothecin (HCPT). Therefore, HCPT was conjugated with methoxy-poly(ethylene glycol)-poly(ß-benzyl-L-aspartate) (mPEG-PBLA) by a disulfide bond or succinate bond for the first time to obtain the mPEG-PBLA-SS-HCPT (PPSH) and mPEG-PBLA-CC-HCPT (PPCH) that would form micelles after high-speed agitation and dialysis. The PPSH micelles showed an average particle size of 126.3 nm, a low polydispersity index of 0.209, and a negative surface charge of -21.1 mV zeta potential. Transmission electron microscopy showed the PPSH micelles to have spherical morphology. PPSH had a low critical micelle concentration of 1.29 µg ml-1 with high dilution stability, storage stability and reproducibility. Moreover, the particle size of the PPSH micelles had no significant change after incubation with rat plasma for 72 h, probably resulting in high long circulation in the blood. The PPSH micelles showed significant reduction sensitivity to glutathione. Their sizes increased by 403.2 nm after 24 h post-incubation, and 87.6% drug release was achieved 48 h post-incubation with 40 mM glutathione solutions. The PPSH micelles showed stronger inhibition of HepG2 cells in vitro and growth of H-22 tumor in vivo than the PPCH and HCPT solutions after intravenous injection. The accumulation of PPSH micelles in the tumor tissue contributed to the high anti-tumor effect with little side-effect on the normal tissues. The reduction-sensitive PPSH micelles were a promising carrier of HCPT and other poorly soluble anti-cancer drugs.
Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos , Espaço Intracelular/química , Micelas , Peptídeos/química , Polietilenoglicóis/química , Animais , Camptotecina/sangue , Camptotecina/química , Camptotecina/farmacocinética , Camptotecina/farmacologia , Morte Celular/efeitos dos fármacos , Dissulfetos/química , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Oxirredução , Tamanho da Partícula , Peptídeos/síntese química , Polietilenoglicóis/síntese química , Ratos Sprague-Dawley , Succinatos/química , Distribuição TecidualRESUMO
BACKGROUND/AIMS: Immunologically and hemodynamically mediated the destruction of glomerular architecture is thought to be the major causes of end-stage renal failure. The purpose of this study is to evaluate the effect of glomerular hypertension on glomerular injury and the progression of glomerular sclerosis after Thy-1 nephritis was induced. METHOD: Thy-1 nephritis was induced in the stroke-prone spontaneously hypertensive rat strain (SHR-SP) (group SP) and in age-matched Wistar-Kyoto (WKY) (group WKY) rats, following unilateral nephrectomy (UNX), and a vehicle was injected alone in UNX SHR-SP as control (group SC). RESULT: The degree of glomerular damage in response to a single dose of anti-thy-1 antibody, and its functional consequences (eg. proteinuria, diminished GFR) are more pronounced in group SP than normotensive group WKY and hypertensive group SC without mesangial cell injury. While normotensive group WKY rats recovered completely from mesangial cell injury on day 28-42, glomeruli in group SP kept on persistent macrophage infiltration, α-SMA expression on day 42-56. In addition, glomerular capillary repair with the GECs was rarely seen in pronouncedly proliferative and sclerostic areas. The incidence of glomerular sclerosis and the level of proteinuria were markedly increased by day 56 in the group SP. CONCLUSIONS: Our results demonstrate that glomerular hypertension aggravate glomerular damage and glomerulosclerosis in this model of Thy 1 nephritis.
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Glomerulonefrite/patologia , Hipertensão Renovascular/patologia , Glomérulos Renais/patologia , Animais , Capilares/patologia , Progressão da Doença , Hemodinâmica/fisiologia , Hipertensão Renovascular/induzido quimicamente , Isoanticorpos , Rim/patologia , Masculino , Nefrectomia , Proteinúria/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
BACKGROUND: Preterm premature rupture of membranes (PPROM) is responsible for one third of all preterm births (PTBs). We have recently demonstrated that long noncoding RNAs (lncRNAs) are differentially expressed in human placentas derived from PPROM, PTB, premature rupture of the membranes (PROM), and full-term birth (FTB), and determined the major biological pathways involved in PPROM. METHODS: Here, we further investigated the relationship of lncRNAs, which are differentially expressed in spontaneous PTB (sPTB) and PPROM placentas and are found to overlap a coding locus, with the differential expression of transcribed mRNAs at the same locus. Ten lncRNAs (five up-regulated and five down-regulated) and the lncRNA-associated 10 mRNAs (six up- and four down-regulated), which were identified by microarray in comparing PPROM vs. sPTB, were then validated by real-time quantitative PCR. RESULTS: A total of 62 (38 up- and 24 down-regulated) and 1,923 (790 up- and 1,133 down-regulated) lncRNAs were identified from placentas of premature labor (sPTB + PPROM), as compared to those from full-term labor (FTB + PROM) and from premature rupture of membranes (PPROM + PROM), as compared to those from non-rupture of membranes (sPTB + FTB), respectively. We found that a correlation existed between differentially expressed lncRNAs and their associated mRNAs, which could be grouped into four categories based on the gene strand (sense or antisense) of lncRNA and its paired transcript. These findings suggest that lncRNA regulates mRNA transcription through differential mechanisms. Differential expression of the transcripts PPP2R5C, STAM, TACC2, EML4, PAM, PDE4B, STAM, PPP2R5C, PDE4B, and EGFR indicated a co-expression among these mRNAs, which are involved in the ubiquitine-proteasome system (UPS), in addition to signaling transduction and beta adrenergic signaling, suggesting that imbalanced regulation of UPS may present an additional mechanism underlying the premature rupture of membrane in PPROM. CONCLUSION: Differentially expressed lncRNAs that were identified from the human placentas of sPTB and PPROM may regulate their associated mRNAs through differential mechanisms and connect the ubiquitin-proteasome system with infection-inflammation pathways. Although the detailed mechanisms by which lncRNAs regulate their associated mRNAs in sPTB and PPROM are yet to be clarified, our findings open a new approach to explore the pathogenesis of sPTB and PPROM.
Assuntos
Ruptura Prematura de Membranas Fetais , Complexo de Endopeptidases do Proteassoma , RNA Longo não Codificante , Ubiquitina , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Transporte/genética , Regulação para Baixo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Epigênese Genética , Feminino , Ruptura Prematura de Membranas Fetais/genética , Ruptura Prematura de Membranas Fetais/patologia , Humanos , Recém-Nascido , Masculino , Fosfoproteínas/genética , Placenta/patologia , Gravidez , Nascimento Prematuro/genética , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Fosfatase 2/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina/genética , Ubiquitina/metabolismo , Regulação para CimaRESUMO
The distinct phenotypic and prognostic subclasses of human hepatocellular carcinoma (HCC) are difficult to reproduce in animal experiments. Here we have used in vivo gene targeting to insert an enhancer-promoter element at an imprinted chromosome 12 locus in mice, thereby converting â¼1 in 20,000 normal hepatocytes into a focus of HCC with a single genetic modification. A 300-kb chromosomal domain containing multiple mRNAs, snoRNAs, and microRNAs was activated surrounding the integration site. An identical domain was activated at the syntenic locus in a specific molecular subclass of spontaneous human HCCs with a similar histological phenotype, which was associated with partial loss of DNA methylation. These findings demonstrate the accuracy of in vivo gene targeting in modeling human cancer and suggest future applications in studying various tumors in diverse animal species. In addition, similar insertion events produced by randomly integrating vectors could be a concern for liver-directed human gene therapy.
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Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/genética , Animais , Metilação de DNA , Dependovirus/metabolismo , Terapia Genética/métodos , Hepatócitos/citologia , Humanos , Íntrons , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Genéticos , Mutagênicos , Fenótipo , Prognóstico , RNA Mensageiro/metabolismo , Transcrição GênicaRESUMO
The clinical use of human pluripotent stem cells and their derivatives is limited by the rejection of transplanted cells due to differences in their human leukocyte antigen (HLA) genes. This has led to the proposed use of histocompatible, patient-specific stem cells; however, the preparation of many different stem cell lines for clinical use is a daunting task. Here, we develop two distinct genetic engineering approaches that address this problem. First, we use a combination of gene targeting and mitotic recombination to derive HLA-homozygous embryonic stem cell (ESC) subclones from an HLA-heterozygous parental line. A small bank of HLA-homozygous stem cells with common haplotypes would match a significant proportion of the population. Second, we derive HLA class I-negative cells by targeted disruption of both alleles of the Beta-2 Microglobulin (B2M) gene in ESCs. Mixed leukocyte reactions and peptide-specific HLA-restricted CD8(+) T cell responses were reduced in class I-negative cells that had undergone differentiation in embryoid bodies. These B2M(-/-) ESCs could act as universal donor cells in applications where the transplanted cells do not express HLA class II genes. Both approaches used adeno-associated virus (AAV) vectors for efficient gene targeting in the absence of potentially genotoxic nucleases, and produced pluripotent, transgene-free cell lines.
Assuntos
Antígenos HLA/genética , Células-Tronco Pluripotentes/citologia , Alelos , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Linhagem Celular , Células Cultivadas , Dependovirus/genética , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Marcação de Genes , Engenharia Genética , Vetores Genéticos , Antígenos HLA/metabolismo , Haplótipos , Histocompatibilidade/genética , Homozigoto , Humanos , Células-Tronco Pluripotentes/metabolismo , Recombinação Genética , Microglobulina beta-2/genética , Microglobulina beta-2/metabolismoRESUMO
Osteogenesis imperfecta (OI) is caused by dominant mutations in the type I collagen genes. In principle, the skeletal abnormalities of OI could be treated by transplantation of patient-specific, bone-forming cells that no longer express the mutant gene. Here, we develop this approach by isolating mesenchymal cells from OI patients, inactivating their mutant collagen genes by adeno-associated virus (AAV)-mediated gene targeting, and deriving induced pluripotent stem cells (iPSCs) that were expanded and differentiated into mesenchymal stem cells (iMSCs). Gene-targeted iMSCs produced normal collagen and formed bone in vivo, but were less senescent and proliferated more than bone-derived MSCs. To generate iPSCs that would be more appropriate for clinical use, the reprogramming and selectable marker transgenes were removed by Cre recombinase. These results demonstrate that the combination of gene targeting and iPSC derivation can be used to produce potentially therapeutic cells from patients with genetic disease.
Assuntos
Colágeno/biossíntese , Colágeno/genética , Terapia Genética , Células-Tronco Pluripotentes Induzidas/transplante , Osteogênese Imperfeita/terapia , Osteogênese/genética , Adolescente , Diferenciação Celular , Criança , Pré-Escolar , Ordem dos Genes , Marcação de Genes/métodos , Técnicas de Transferência de Genes , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Mesenquimais/citologia , Osteogênese Imperfeita/genética , TransgenesRESUMO
We designed a rotary biosensor as a damping effector, with the rotation of the F(0)F(1)-ATPase driven by Adenosine Triphosphate (ATP) synthesis being indicated by the fluorescence intensity and a damping effect force being induced by the binding of an RNA molecule to its probe on the rotary biosensor. We found that the damping effect could contribute to the resonance phenomenon and energy transfer process of our rotary biosensor in the liquid phase. This result indicates that the ability of the rotary motor to operate in the vibration harmonic mode depends on the environmental conditions and mechanism in that a few molecules of the rotary biosensor could induce all of the sensor molecules to fluoresce together. These findings contribute to the theory study of the ATPase motor and future development of biosensors for ultrasensitive detection.
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Trifosfato de Adenosina/biossíntese , Técnicas Biossensoriais , Transferência Ressonante de Energia de Fluorescência , ATPases Translocadoras de Prótons/química , HIV-1/isolamento & purificação , Humanos , RNA Viral/análise , Rotação , Sensibilidade e Especificidade , VibraçãoRESUMO
A novel biosensor (immuno-rotary biosensor) was developed by conjugating deoxynivalenol (DON) monoclonal antibodies with the "rotator" ε-subunit of F(0)F(1)-ATPase within chromatophores with an ε-subunit monoclonal antibody-biotin-avidin-biotin linker to capture DON residues. The conjugation conditions were then optimized. The capture of DON was based on the antibody-antigen reaction and it is indicated by the change in ATP synthetic activity of F(0)F(1)-ATPase, which is measured via chemiluminescence using the luciferin-luciferase system with a computerized microplate luminometer analyzer. 10(-7)mg/ml of DON can be detected. The whole detection process requires only about 20min. This method has promising applications in the detection of small molecular compounds because of its rapidity, simplicity, and sensitivity.
Assuntos
Técnicas Biossensoriais , Micotoxinas/análise , ATPases Translocadoras de Prótons/análise , ATPases Translocadoras de Prótons/química , Tricotecenos/análise , Trifosfato de Adenosina/síntese química , Anticorpos Monoclonais/imunologia , Reações Antígeno-Anticorpo , Micotoxinas/imunologia , Tricotecenos/imunologiaRESUMO
The Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease characterized by segmental premature aging. Applying a two-dimensional chromatographic proteomic approach, the 2D Protein Fractionation System (PF2D), we identified 30 differentially expressed proteins in cultured HGPS fibroblasts. We categorized them into five groups: methylation, calcium ion binding, cytoskeleton, duplication, and regulation of apoptosis. Among these 30 proteins, 23 were down-regulated, while seven were up-regulated in HGPS fibroblasts as compared to normal fibroblasts. Three differentially expressed cytoskeleton proteins, vimentin, actin, and tubulin, were validated via Western blotting and characterized by immunostaining that revealed densely thickened bundles and irregular structures. Furthermore in the HGPS cells, the cell cycle G1 phase was elongated and the concentration of free cytosolic calcium was increased, suggesting intracellular retention of calcium. The results that we obtained have implications for understanding the aging process.
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Senilidade Prematura/genética , Cromatografia/métodos , Progéria/genética , Biossíntese de Proteínas , Proteômica/métodos , Apoptose/genética , Cálcio/metabolismo , Ciclo Celular/genética , Células Cultivadas , Citoesqueleto/genética , Citoesqueleto/metabolismo , Fibroblastos/metabolismo , Humanos , MetilaçãoRESUMO
Radiation resistance largely limits the survival of patients with non-small-cell lung cancer (NSCLC). To understand the mechanism underlying radiation resistance, we explored the influence of LINC01578 in radiation-resistant NSCLC cells. LINC01578, miR-216b-5p and Transducin (beta)-like 1 X-linked receptor 1 (TBL1XR1) expression was evaluated in patients with NSCLC, and their correlation with patients' prognosis was examined. Radiation-resistant NSCLC cell line (A549-RR) was induced and treated with oligonucleotide or plasmid transfection, and cell biological functions were captured. The interplay between LINC01578, miR-216b-5p and TBL1XR1 was clarified. NSCLC patients showed high LINC01578 and TBL1XR1 expression, and low miR-216b-5p expression, which was correlated to shorter patients' prognosis, respectively. LINC01578 or TBL1XR1 deficiency or miR-216b-5p elevation suppressed the functional activities of A549-RR cells. LINC01578 suppression elevated miR-216b-5p expression, consequently leading to the down-regulation of TBL1XR1. miR-216b-5p silencing or TBL1XR1 overexpression compromised LINC01578 knockdown's effects on radiation resistance of A549-RR cells. In brief, LINC01578 suppresses miR-216b-5p and enhances TBL1XR1 expression, thus to promote biological functions of radiation-resistant NSCLC cells.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Humanos , Células A549 , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/metabolismoRESUMO
ALDH1A3 and Linc00284 involve in colorectal cancer (CRC) development; however, the regulatory mechanism is still unclear. In this study, we collected clinicopathological characteristics and tissue samples from 73 CRC patients to analyze the expression of ALDH1A3, Linc00284, TGFß signaling and miR-361-5p using qPCR, Western blotting, and ELISA. Multiple CRC cell lines were evaluated in this study, and the highest level of ALDH1A3 was observed in SW480 cells. To investigate the regulatory mechanism, RIP and luciferase assays were used to validate the interaction between Linc00284, miR-361-5p, and TGFß. Proliferation, viability, migration, and invasion assays were performed to profile the effects of the ALDH1A3-Linc00284 axis in CRC cell functions, which was upregulated in CRC tissues. Knockdown ALDH1A3 or Linc00284 significantly reduced TGFß expression and suppressed the EMT process, while overexpression had opposite effects. miR-361-5p targeted TGFß directly, which negatively correlated with ALDH1A3-Linc00284 expression and CRC progression. Mechanistically, upregulation of ALDH1A3-Linc00284 promotes colorectal cancer invasion and migration by regulating miR-361-5p/TGFß signaling pathway. Dysregulation of the ALDH1A3-Linc00284-miR-361-5p-TGFß axis causes CRC invasion, which might provide a new insight into the treatment of CRC.
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Precise genetic manipulation of human pluripotent stem cells will be required to realize their scientific and therapeutic potential. Here, we show that adeno-associated virus (AAV) gene targeting vectors can be used to genetically engineer human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Different types of sequence-specific changes, including the creation and correction of mutations, were introduced into the human HPRT1 and HMGA1 genes (HPRT1 mutations being responsible for Lesch-Nyhan syndrome). Gene targeting occurred at high frequencies in both ESCs and iPSCs, with over 1% of all colony-forming units (CFUs) undergoing targeting in some experiments. AAV vectors could also be used to target genes in human fibroblasts that were subsequently used to derive iPSCs. Accurate and efficient targeting took place with minimal or no cytotoxicity, and most of the gene-targeted stem cells produced were euploid and pluripotent.
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Dependovirus/genética , Marcação de Genes , Engenharia Genética , Células-Tronco Pluripotentes , Humanos , Hipoxantina Fosforribosiltransferase/genéticaRESUMO
ABSTRACT: Induction chemotherapy (IC) and adjuvant chemotherapy (AC) are used to enhance tumor locoregional control and support early treatment for distant metastases. However, optimum combinatorial treatment of these chemoradiotherapy regimens with radiotherapy in curing locoregionally advanced nasopharyngeal carcinoma (NPC) remains unclear. Here, we evaluate the efficacy and therapeutic outcome of a combinatorial treatment strategy involving IC, intensity-modulated radiotherapy (IMRT), and AC, by retrospectively analyzing 243 NPC patients who were treated by IC followed by IMRT and AC. The rates of 3-/5-year local-regional control rate, distant failure-free rate (DFFR), progression-free survival (PFS), and overall survival (OS) were 93.3%/90.3%, 84.2%/79.4%, 79.6%/74.4%, and 84.0%/72.6%, respectively. The 3-/5-year OS rates of patients in stage III or IVA were 91.5%/75.1% and 86.5%/56.5%, respectively. Combination cisplatin with paclitaxel showed no significance in OS as compared to cisplatin plus 5-fluorouracil (P-valueâ=â.17). Total four-cycle IC and AC was significantly beneficious versus three-cycle in DFFR (P-valueâ=â.04), as well as total 6 chemotherapy cycles compared to 4 in DFFR and PFS (P-valueâ=â.03 and P-valueâ=â.01, respectively). All survival indicators were adversely affected by T-category, while N-category could only predict DFFR and PFS. Radiation dosage represented as a second prognostic factor for local control. We propose that IC combined with IMRT and AC for locoregionally advanced NPC shows effective treatment outcomes.
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Quimioterapia Adjuvante/normas , Quimioterapia de Indução/normas , Neoplasias Nasofaríngeas/terapia , Radioterapia de Intensidade Modulada/normas , Idoso , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/estatística & dados numéricos , China/epidemiologia , Feminino , Humanos , Quimioterapia de Indução/métodos , Quimioterapia de Indução/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Nasofaríngeas/epidemiologia , Neoplasias Nasofaríngeas/fisiopatologia , Prognóstico , Radioterapia de Intensidade Modulada/métodos , Radioterapia de Intensidade Modulada/estatística & dados numéricos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
In response to the outbreak of COVID-19, in accordance with the principles of 'unified command, early involvement, prompt review and scientific approval' as well as the requirements of ensuring product safety, effectiveness and controllable quality, the Center for Medical Device Evaluation (CMDE) has issued Key Points of Technical Review for the Registration of SARS-CoV-2 Nucleic Acid Tests (Key Points) to provide the requirements of tests. Because of the sustainability of the pandemic, more efforts and attempts are needed for SARS-CoV-2 detection and control. This article interprets the Key Points issued by the CMDE and provides certain refinements to wider audiences.
Assuntos
Teste de Ácido Nucleico para COVID-19/métodos , China , Humanos , SARS-CoV-2RESUMO
PROBLEM: Various etiological factors, such as infection and inflammation, may induce the adverse outcomes of pregnancy of miscarriage, stillbirth, or preterm birth. The pathogenic mechanisms associated with these adverse pregnancies are yet unclear. We hypothesized that a common pathogenic mechanism may underlie variant adverse outcomes of pregnancy, which are induced by genetic-environmental factors. The specific objective of the current study is to uncover the common molecular mechanism(s) by identifying the specific transcripts that are present in variant subtypes of pregnancy loss and preterm birth. METHOD OF STUDY: Transcriptomic profiling was performed with RNA expression microarray or RNA sequencing of placentas derived from pregnancy loss (which includes spontaneous miscarriage, recurrent miscarriage, and stillbirth) and spontaneous preterm birth, followed by bioinformatic analysis of multi-omic integration to identify pathogenic molecules and pathways involved in pathological pregnancies. RESULTS: The enrichment of common differentially expressed genes between full-term birth and preterm birth and pregnancy loss of miscarriage and stillbirth revealed different pathophysiological pathway(s), including cytokine signaling dysregulated in spontaneous preterm birth, defense response, graft-versus-host disease, antigen processing and presentation, and T help cell differentiation in spontaneous miscarriage. Thirty-three genes shared between spontaneous preterm birth and spontaneous miscarriage were engaged in pathways of interferon gamma-mediated signaling and of antigen processing and presentation. For spontaneous miscarriage, immune response was enriched in the fetal tissue of chorionic villi and in the maternal facet of the placental sac. The transcript of nerve growth factor receptor was identified as the common molecule that is differentially expressed in all adverse pregnancies: spontaneous preterm birth, stillbirth, spontaneous miscarriage, and recurrent miscarriage. Superoxide dismutase 2 was up-regulated in all adverse outcomes of pregnancy except for recurrent miscarriage. Cytokine-cytokine receptor interaction was the common pathway in spontaneous preterm birth and spontaneous miscarriage. Defense response was enriched in the fetal tissue of miscarriage and in the maternal tissue in spontaneous miscarriage. CONCLUSIONS: Our results indicated that the chemokine-cytokine pathway may play important roles in and function as a common pathogenic mechanism associated with, the different adverse outcomes of pregnancy, which demonstrated that differentially expressed transcripts could result from a common pathogenic mechanism associated with pregnancy loss and spontaneous preterm birth, although individual pregnancy outcomes may differ from each other phenotypically.
Assuntos
Quimiocinas/metabolismo , Citocinas/metabolismo , Nascimento Prematuro/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Gravidez , Resultado da Gravidez , Receptores CXCR4/genética , Receptores de Fator de Crescimento Neural/genética , Transdução de Sinais , Superóxido Dismutase/genéticaRESUMO
Tumor multidrug resistance (MDR) is one of the main reasons for the failure of clinical chemotherapy. Here, a bio-responsive anti-drug-resistant polymer micelle that can respond to the reductive GSH in the tumor microenvironment (TME) for delivery of HCPT was designed. A new type of polymer with anti-drug resistance and anti-tumor effect was synthesized and used to encapsulated HCPT to form reduction-sensitive micelles (PDSAH) by a thin-film dispersion method. It is demonstrated that the micelle formulation improves the anti-tumor activity and biosafety of HCPT, and also plays a significant role in reversing the drug resistance, which contributes to inhibiting the tumor growth and prolonging the survival time of H22 tumor-bearing mice. The results indicate that this nanoplatform can serve as a flexible and powerful system for delivery of other drugs that are tolerated by tumors or bacteria.