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1.
Front Med ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34792736

RESUMO

Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton's tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34+ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34+ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.

2.
Org Lett ; 23(18): 7069-7073, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34459614

RESUMO

The absolute configuration of rakicidin C was predicted by comparison of optical rotation data and absolute configuration of APD-cyclic depsipeptides and further determined by total synthesis. The absolute configuration of five chiral centers was determined as 2R, 15R, 16R, 17S, and 19S. Our efficient route involves 19 longest linear steps with an overall yield of 1.49%.

4.
Int J Biol Macromol ; 185: 441-450, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34197849

RESUMO

Biomaterials for effective hemorrhage control are urgently needed in clinics as uncontrolled bleeding is associated with high mortality. Herein, we developed an injectable and in situ photo-crosslinkable hybrid hemostatic hydrogel by combining pectin methacrylate (PECMA) and gelatin methacryloyl (GelMA). This modular material system combines ionic- and photo-crosslinking chemistries to design interpenetrating networks (IPN) exhibiting tunable rheology, highly porous structure, and controllable swelling and mechanical properties. By simply changing the calcium (0-15 mM) and polymer (1.5-7%) content used for the sequential crosslinking of hydrogels via calcium gelation and UV-photopolymerization, it was possible to precisely modulate the injectability, degradation, and swelling ratio. Moreover, it is demonstrated that PECMA/GelMA hydrogels present good cytocompatibility and uniquely synergize the hemostatic properties of calcium ions on PECMA, the amine residues on GelMA, and the highly porous network toward rapid blood absorption and fast coagulation effect. An in vitro porcine skin bleeding model confirmed that the hydrogel could be directly injected into the wound and rapidly photo-crosslinked, circumventing the bleeding and decreasing the coagulation time by 39%. Importantly, the crosslinked hydrogel could be easily removed to prevent secondary wound injury. Overall, this injectable hybrid PECMA/GelMA hydrogel stands as a promising hemostatic material.


Assuntos
Cálcio/metabolismo , Gelatina/química , Metacrilatos/química , Pectinas/química , Cicatrização/efeitos dos fármacos , Animais , Linhagem Celular , Hemostasia , Injeções , Camundongos , Fenômenos Físicos , Porosidade , Suínos
5.
Mol Ther ; 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34174443

RESUMO

Myosin VI(MYO6) is an unconventional myosin that is vital for auditory and vestibular function. Pathogenic variants in the human MYO6 gene cause autosomal-dominant or -recessive forms of hearing loss. Effective treatments for Myo6 mutation causing hearing loss are limited. We studied whether adeno-associated virus (AAV)-PHP.eB vector-mediated in vivo delivery of Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes could ameliorate hearing loss in a Myo6WT/C442Y mouse model that recapitulated the phenotypes of human patients. The in vivo editing efficiency of the AAV-SaCas9-KKH-Myo6-g2 system on Myo6C442Y is 4.05% on average in Myo6WT/C442Y mice, which was ∼17-fold greater than editing efficiency of Myo6WT alleles. Rescue of auditory function was observed up to 5 months post AAV-SaCas9-KKH-Myo6-g2 injection in Myo6WT/C442Y mice. Meanwhile, shorter latencies of auditory brainstem response (ABR) wave I, lower distortion product otoacoustic emission (DPOAE) thresholds, increased cell survival rates, more regular hair bundle morphology, and recovery of inward calcium levels were also observed in the AAV-SaCas9-KKH-Myo6-g2-treated ears compared to untreated ears. These findings provide further reference for in vivo genome editing as a therapeutic treatment for various semi-dominant forms of hearing loss and other semi-dominant diseases.

6.
Probiotics Antimicrob Proteins ; 13(6): 1508-1520, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34115318

RESUMO

Prader-Willi syndrome (PWS) is a rare genetic disorder associated with developmental delay, obesity, and neuropsychiatric comorbidities. Limosilactobacillus reuteri (Lactobacillus reuteri, Lact. reuteri) has demonstrated anti-obesity and anti-inflammatory effects in previous studies. In the present study, we aim to evaluate the effects of Lact. reuteri supplementation on body mass index (BMI), social behaviors, and gut microbiota in individuals with PWS. We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 71 individuals with PWS aged 6 to 264 months (64.4 ± 51.0 months). Participants were randomly assigned to either receive daily Lact. reuteri LR-99 probiotic (6 × 1010 colony forming units) or a placebo sachet. Groupwise differences were assessed for BMI, ASQ-3, and GARS-3 at baseline, 6 weeks, and 12 weeks into treatment. Gut microbiome data was analyzed with the QIIME2 software package, and predictive functional profiling was conducted with PICRUSt-2. We found a significant reduction in BMI for the probiotic group at both 6 weeks and 12 weeks relative to the baseline (P < 0.05). Furthermore, we observed a significant improvement in social communication and interaction, fine motor function, and total ASQ-3 score in the probiotics group compared to the placebo group (P < 0.05). Altered gut microbiota was observed in the probiotic group to favor weight loss and improve gut health. The findings suggest a novel therapeutic potential for Lact. reuteri LR-99 probiotic to modulate BMI, social behaviors, and gut microbiota in Prader-Willi syndrome patients, although further investigation is warranted.Trial registration Chinese Clinical Trial Registry: ChiCTR1900022646.

7.
EBioMedicine ; 69: 103441, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34166980

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) is a group of heterogeneous hematologic malignancies correlates with poor prognosis. It is important to identify biomarkers for effective treatment of AML. Kinases participate in many regulatory pathways and biological activities in AML. Previous studies demonstrated that MAP4K1, a serine/threonine kinase, was associated with immune regulation and cancer progression. However, its role and mechanism in acute myeloid leukemia (AML) have not been explored. METHODS: RNA-seq profiling was performed for Homoharringtonine (HHT)-resistant and Homoharringtonine (HHT)-sensitive cell lines. Bioinformatic tools were used for differential analysis. Cell culture and transfection, Cell proliferation, apoptosis and Cell cycle assay, Quantitative RT-PCR, and Western blotting analysis were used to explore biological phenotypes in vitro. FINDINGS: We found that MAP4K1 was highly expressed in HHT-induced resistant AML cell lines. In addition, overexpression of MAP4K1 in AML cells induced resistance of AML cells against HHT. Not only that, the findings of this study showed that overexpression of MAP4K1 was an independent risk factor that predicts poor prognosis of AML. Further, In vitro studies showed that MAP4K1 modulated cell cycle through MAPK and DNA damage/repair pathways. Therefore, MAP4K1 is a potential target for developing therapies for AML. INTERPRETATION: This study demonstrates that MAP4K1 not only regulates HHT resistance but also independently predicts AML prognosis. In addition, understanding the regulatory mechanism of MAP4K1 reveals novel treatment strategies for resistant and refractory AML. Fundings: This work was supported by the National Natural Science Foundation of China (NSFC) (Grant No.81800199, 81670124, 82070118) and the Natural Science Foundation of Zhejiang Province (LY20H080008).


Assuntos
Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Antineoplásicos Fitogênicos/toxicidade , Apoptose , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Dano ao DNA , Reparo do DNA , Mepesuccinato de Omacetaxina/toxicidade , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Células THP-1 , Transcriptoma
8.
Ann Transl Med ; 9(8): 641, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33987339

RESUMO

Background: Whether hepatocellular carcinoma (HCC) patients with hypersplenism can benefit from splenectomy is unclear. This study aimed at exploring the efficacy and safety of concurrent splenectomy for HCC patients with hypersplenism. Methods: PubMed, EMBASE and Web of Science databases were systematically searched to compare data on the combination of hepatectomy or transhepatic arterial infusion (TAI) with splenectomy (the splenectomy group) with data on hepatectomy or TAI alone (the non-splenectomy group) for the treatment of HCC with hypersplenism. Prospective clinical trials or retrospective cohort studies from inception to May 10, 2020 were considered eligible for this analysis. The relevant outcomes, including patients' demographics, clinicopathologic characteristics, perioperative indices and long-term outcomes, were independently extracted by two investigators. Publication bias for overall survival (OS) and disease-free survival (DFS) was qualitatively assessed by funnel plots and quantitatively evaluated by Begg's and Egger's tests. Results: Nine retrospective studies including 1,650 patients were analyzed. Short-term outcomes suggested that the incidence rate of postoperative complications, including portal or splenic vein thrombosis [odds ratio (OR) =26.28, P<0.001] and pancreatic injury (OR =14.89, P=0.001), was significantly higher in the splenectomy group, whereas the perioperative mortality rate was similar between the splenectomy and non-splenectomy groups (P=0.541). Long-term outcomes indicated that the occurrence of variceal re-hemorrhage (OR =0.31, P<0.001) and tumor progress or recurrence (OR =0.62, P=0.001) was markedly reduced for patients who underwent splenectomy, while the long-term mortality rates were not statistically different between the two groups (P=0.087). The prognostic evaluation revealed that the OS and DFS were comparable between the splenectomy and non-splenectomy groups [for OS: hazard ratio (HR) =0.77, 95% confidence interval (CI): 0.53-1.13; for DFS: HR =0.87, 95% CI: 0.63-1.19]. Funnel plots suggested an HRs symmetric distribution for OS and DFS. Begg's and Egger's tests confirmed that there was no significant HR publication bias for OS and DFS. Conclusions: Due to the significant progress in surgical techniques and perioperative care, concomitant splenectomy should be considered as an optional treatment for some HCC patients with hypersplenism.

9.
Sci Total Environ ; 779: 146445, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34030268

RESUMO

High cost of microalgal biofuel is caused by all the steps in current technology, including cultivation, harvesting, lipid extraction, biofuel processing and wastewater and waste treatment. This study aims to systematically reduce these costs with one integrated process, in which carbonate is used for cell rupture, lipid extraction and biodiesel processing, and then recycled for CO2 absorption and carbon supply for a new round of algae cultivation. To reach this goal, carbonate-heating treatment with N, N' - dibutylurea which can enhance cell disruption were used for cell-wall breaking of wet Neochloris oleoabundans (UTEX 1185) biomass. Lipid extraction was fulfilled with carbonate/ethanol aqueous two phase extraction method and residual carbonate with wastewater from bottom phase was recycled to absorb CO2 to generate bicarbonate for algal cultivation with fresh medium. Taking into comprehensive consideration of cell disruption efficiency, partition coefficient, and lipid recovery, the condition of cell disruption and lipid extraction was set at 90 °C, 100 min reaction time, 1:7.5 DBU:H2O (w/w) ratio, 1:3 Na2CO3:H2O (w/w) ratio, and 9% (w/wT) ethanol concentration. The results showed that carbonate-heating treatment of wet N. oleoabundans biomass resulted in up to 90.7% cell disruption efficiency. The lipid recovery rate in carbonate/ethanol system was up to 97.9%, and the final biodiesel production was 1.30 times of that with Soxhlet method. Utilization of the waste broth after CO2 absorption with the content of 4% (v/vT) in the medium for new batch of algae cultivation resulted in biomass concentration of 1.68 g/L. The corresponding total fatty acids production was 0.35 g/L, which was 1.63 fold of that with fresh medium. This study firstly proved the feasibility of using carbonate for lipid extraction and biodiesel production and recycle waste carbonate for carbon re-supply during algae cultivation.


Assuntos
Microalgas , Biocombustíveis , Biomassa , Dióxido de Carbono , Carbonatos , Lipídeos , Águas Residuárias
10.
J Transl Med ; 19(1): 181, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33926484

RESUMO

BACKGROUND: Fatty acid oxidation (FAO) provides an important source of energy to promote the growth of leukemia cells. Carnitine palmitoyltransferase 1a(CPT1a), a rate-limiting enzyme of the essential step of FAO, can facilitate cancer metabolic adaptation. Previous reports demonstrated that CPT1a acts as a potential molecular target in solid tumors and hematologic disease. However, no systematic study was conducted to explore the prognostic value of CPT1a expression and possible treatment strategies with CPT1a inhibitor on acute myeloid leukemia (AML). METHODS: The expression of CPT1a in 325 cytogenetically normal AML (CN-AML) patients was evaluated using RT-PCR. The combination effects of ST1326 and ABT199 were studied in AML cells and primary patients. MTS was used to measure the cell proliferation rate. Annexin V/propidium iodide staining and flow cytometry analysis was used to measure the apoptosis rate. Western blot was used to measure the expression of Mcl-1. RNAseq and GC-TOFMS were used for genomic and metabolic analysis. RESULTS: In this study, we found AML patients with high CPT1a expression (n = 245) had a relatively short overall survival (P = 0.01) compared to patients in low expression group (n = 80). In parallel, downregulation of CPT1a inhibits proliferation of AML cells. We also conducted genomic and metabolic interactive analysis in AML patients, and found several essential genes and pathways related to aberrant expression of CPT1a. Moreover, we found downregulation of CPT1a sentitized BCL-2 inhibitor ABT199 and CPT1a-selective inhibitor ST1326 combined with ABT199 had a strong synergistic effect to induce apoptosis in AML cells and primary patient blasts for the first time. The underlying synergistic mechanism might be that ST1326 inhibits pGSK3ß and pERK expression, leading to downregulation of Mcl-1. CONCLUSION: Our study indicates that overexpression of CPT1a predicts poor clinical outcome in AML. CPT1a-selective inhibitor ST1326 combined with Bcl-2 inhibitor ABT199 showed strong synergistic inhibitory effects on AML.


Assuntos
Leucemia Mieloide Aguda , Apoptose , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Prognóstico , Sulfonamidas
11.
Nano Lett ; 21(8): 3418-3425, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33827216

RESUMO

Self-assembly is a powerful means to fabricate multifunctional smart nanotheranostics. However, the complicated preparation, toxicity of responsive carriers, and low loading efficiency of drug cargo hinder the outcome. Herein, we developed a responsive carrier-free noncovalent self-assembly strategy of a metallized Au(III) tetra-(4-pyridyl) porphine (AuTPyP) anticancer drug for the preparation of a heat/acid dual-stimulated nanodrug, and it generated a better photothermal effect than monomers under irradiation. The photothermal effect promoted the protonation of the hydrophobic pyridyl group and the following release into tumorous acidic microenvironments. With cRGD modification, the released drug induced the aggravation of intracellular reactive oxygen species (ROS) via the activity inhibition of thioredoxin reductase (TrxR) for synergistic chemo-photothermal therapy of tumors.


Assuntos
Antineoplásicos , Hipertermia Induzida , Nanopartículas , Porfirinas , Doxorrubicina , Ouro , Fototerapia , Terapia Fototérmica
12.
Aging (Albany NY) ; 13(7): 10468-10489, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33820874

RESUMO

We described the spatial and temporal trends of the annual leukemia incidence, prevalence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2017. Leukemia case numbers and age-standardized rates (ASRs) were extracted from the Global Burden of Disease (GBD) study 2017. The estimated annual percentage change (EAPC) in the ASR was calculated using a generalized linear model with a Gaussian distribution. The risk factors for death and DALYs due to leukemia were estimated within the comparative risk assessment framework of the GBD study. Globally, the prevalence, age-standardized prevalence rate (ASPR), and EAPC in leukemia cases in 2017 were 2.43 (95% uncertainty interval (UI) 2.19 to 2.59) million, 32.26 (95% UI 29.02 to 34.61), and 0.22% (95% CI 0.13 to 0.31, P<0.01), respectively, during 1990-2017. The trends of the age-standardized incidence, deaths, and DALY rate all significantly decreased globally. The burden of leukemia was higher in males than in female. An increasing leukemia burden was found in high-middle-sociodemographic index (SDI) countries and territories. The burden of leukemia tended to be lower in high-SDI regions than that in lower SDI regions. The rapid increases in the prevalent cases and prevalence rate of leukemia is urgent to be solved in the future.


Assuntos
Carga Global da Doença/tendências , Leucemia/epidemiologia , Humanos
13.
Genome Biol ; 22(1): 86, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33752742

RESUMO

BACKGROUND: Aging, noise, infection, and ototoxic drugs are the major causes of human acquired sensorineural hearing loss, but treatment options are limited. CRISPR/Cas9 technology has tremendous potential to become a new therapeutic modality for acquired non-inherited sensorineural hearing loss. Here, we develop CRISPR/Cas9 strategies to prevent aminoglycoside-induced deafness, a common type of acquired non-inherited sensorineural hearing loss, via disrupting the Htra2 gene in the inner ear which is involved in apoptosis but has not been investigated in cochlear hair cell protection. RESULTS: The results indicate that adeno-associated virus (AAV)-mediated delivery of CRISPR/SpCas9 system ameliorates neomycin-induced apoptosis, promotes hair cell survival, and significantly improves hearing function in neomycin-treated mice. The protective effect of the AAV-CRISPR/Cas9 system in vivo is sustained up to 8 weeks after neomycin exposure. For more efficient delivery of the whole CRISPR/Cas9 system, we also explore the AAV-CRISPR/SaCas9 system to prevent neomycin-induced deafness. The in vivo editing efficiency of the SaCas9 system is 1.73% on average. We observed significant improvement in auditory brainstem response thresholds in the injected ears compared with the non-injected ears. At 4 weeks after neomycin exposure, the protective effect of the AAV-CRISPR/SaCas9 system is still obvious, with the improvement in auditory brainstem response threshold up to 50 dB at 8 kHz. CONCLUSIONS: These findings demonstrate the safe and effective prevention of aminoglycoside-induced deafness via Htra2 gene editing and support further development of the CRISPR/Cas9 technology in the treatment of non-inherited hearing loss as well as other non-inherited diseases.

14.
Front Nutr ; 8: 587974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33681271

RESUMO

Background: Prader-Willi Syndrome (PWS) is a rare genetic disorder associated with developmental delay, obesity, and neuropsychiatric comorbidities. Bifidobacterium animalis subsp. lactis has demonstrated anti-obesity and anti-inflammatory effects in previous studies. Aim: To evaluate the effects of Bifidobacterium animalis subsp. lactis probiotics supplementation on anthropometric growth, behavioral symptoms, and gut microbiome composition in patients with PWS. Methods: Ethical Approval was issued by the Internal Review Board (IRB) of the Second Affiliated Hospital of Kunming Medical University (Review-YJ-2016-06). We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 68 patients with Prader-Willi syndrome aged 11 months-16 years (mean = 4.2 years old) who were randomly assigned to receive daily B. lactis-11 probiotics (6 × 1010 CFUs) or a placebo sachet. Weight, height, ASQ-3, ABC, SRS-2, and CGI-I were compared between the two groups at baseline and at 6 and 12 weeks into treatment. Gut microbiome data were analyzed with the QIIME 2 software package, and functional gene analysis was conducted with PICRUSt-2. Results: We found a significant increase in height (mean difference = 2.68 cm, P < 0.05) and improvement in CGI-I (P < 0.05) in the probiotics group compared to the placebo group. No significant change in weight or psychological measures were observed. Probiotic treatment altered the microbiome composition to favor weight loss and gut health and increased the abundance of antioxidant production-related genes. Conclusions: The findings suggest a novel therapeutic potential for Bifidobacterium animalis subsp. lactis probiotics in Prader-Willi syndrome patients, although further investigation is warranted.

15.
BMC Med ; 19(1): 28, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33517886

RESUMO

BACKGROUND: Although there are many clinical and molecular biomarkers in acute myeloid leukemia (AML), the novel and reliable biomarkers are still required to predict the overall survival at the time of disease diagnosis. METHODS: In order to identify independent predictors, we firstly selected 60 cytogenetically normal AML (CN-AML) patients using the propensity score analysis to balance the confounders and performed circular RNA (circRNA) sequencing. Next, one outcome related to circRNA was selected and validated in the independent cohort of 218 CN-AML patients. We then constructed circRNA-miRNA-mRNA regulated network and performed cellular metabolomic analysis to decipher the underlying biological insights. RESULTS: We identified 308 circRNAs as independent candidate predictors of overall survival. Hsa_circ_0075451 expression was validated as an independent predictor with a weak predictive ability for overall survival. The regulated network of this circular RNA indicated 84 hub genes that appear to be regulated by 10 miRNAs sponged by hsa_circ_0075451. The regulatory axis of hsa_circ_0075451 -| miR-330-5p/miR-326 -| PRDM16 was validated by the dual luciferase report assay, fluorescence in situ hybridization, and ShRNA interference assay. CONCLUSIONS: Our data demonstrates that hsa_circ_0075451 expression may independently contribute to the poor prognosis of AML and present a novel therapeutic target.


Assuntos
Biomarcadores Tumorais/metabolismo , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , RNA Mensageiro/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente/métodos , Leucemia Mieloide Aguda/genética , Masculino , Prognóstico , RNA/metabolismo , RNA Mensageiro/metabolismo , Análise de Sequência de RNA
16.
Clin Transl Med ; 11(2): e307, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33634974

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant disease with high morbidity and mortality, and the molecular mechanism for the genesis and progression is complex and heterogeneous. Biomarker discovery is crucial for the personalized and precision treatment of HCC. The accumulation of reported microRNA biomarkers makes it possible to combine computational identification with experimental validation to accelerate the discovery of novel biomarker. RESULTS: In the present work, we applied a rational computer-aided biomarker discovery model to screen for the HCC diagnosis biomarker. Two HCC-associated networks were constructed based on the microRNA and mRNA expression profiles, and the potential microRNA biomarkers were identified based on their unique regulatory and influential power in the network. These putative biomarkers were then experimentally validated. One prominent example among these identified biomarkers is MiR-378a-3p: It was shown to independently regulate several important transcription factors such as PLAGL2 and ß-catenin, affecting the ß-catenin signaling. Such mechanism may indicate a potential tumor suppressor role of MiR-378a-3p and the impact of its abnormal expression on the cell growth and invasion of HCC. CONCLUSIONS: A bioinformatics model with network topological and functional characterization was successfully applied to the identification of HCC biomarkers. The predicted microRNA biomarkers were than validated with experiments using human HCC cell lines, model animal, and clinical specimens. The results confirmed the prediction by our proposed model that miR-378a-3p was a putative biomarker for diagnosis and prognosis of HCC.

17.
Thromb Haemost ; 121(2): 192-205, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32961571

RESUMO

Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, has a favorable safety profile in patients with B cell-related malignancies. A primary adverse effect of ibrutinib is thrombocytopenia in the early stages of treatment, but platelet counts increase or recover as treatment continues. Currently, the effects of ibrutinib on megakaryopoiesis remain unclear. In this study, we investigated the mechanism by which ibrutinib induces thrombocytopenia using cord blood CD34+ hematopoietic stem cells (HSCs), a human megakaryoblastic cell line (SET-2), and C57BL/6 mice. We show that treatment with ibrutinib can suppress CD34+ HSC differentiation into megakaryocytes (MKs) and decrease the number of colony-forming unit-MKs (CFU-MKs). The ibrutinib-dependent inhibition of early megakaryopoiesis seems to mainly involve impaired proliferation of progenitor cells without induction of apoptosis. The effects of ibrutinib on late-stage megakaryopoiesis, in contrast to early-stage megakaryopoiesis, include enhanced MK differentiation, ploidy, and proplatelet formation in CD34+ HSC-derived MKs and SET-2 cells. We also demonstrated that MK adhesion and spreading, but not migration, were inhibited by ibrutinib. Furthermore, we revealed that integrin αIIbß3 outside-in signaling in MKs was inhibited by ibrutinib. Consistent with previous clinical observations, in C57BL/6 mice treated with ibrutinib, platelet counts decreased by days 2 to 7 and recovered to normal levels by day 15. Together, these results reveal the pathogenesis of ibrutinib-induced transient thrombocytopenia. In conclusion, ibrutinib suppresses early megakaryopoiesis, as evidenced by inhibition of MK progenitor cell proliferation and CFU-MK formation. Ibrutinib enhances MK differentiation, ploidy, and proplatelet formation, while it impairs integrin αIIbß3 outside-in signaling.


Assuntos
Adenina/análogos & derivados , Plaquetas/efeitos dos fármacos , Megacariócitos/efeitos dos fármacos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Trombopoese/efeitos dos fármacos , Adenina/farmacologia , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Plaquetas/citologia , Linhagem Celular , Humanos , Megacariócitos/citologia , Camundongos Endogâmicos C57BL
18.
Aesthetic Plast Surg ; 45(2): 564-569, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-31637503

RESUMO

BACKGROUND: The epicanthal fold is ordinary in the eyelids of Asians, and the aesthetic appearance of eyelid surgery could be reduced and undermined; thus, medial epicanthoplasty is commonly performed to eliminate the effect of the epicanthal fold with less scarring. At present, there are a lot of techniques that have been described for the treatment of epicanthal fold. The potential problems, however, such as visible scar or under correction in the medial canthus area are challenges to surgeons. The purpose of our study was to explore a novel and individualized design using a modified rectangle flap with acceptable functional and aesthetic outcomes. METHODS: From January 2017 to January 2018, epicanthoplasty was performed for 40 patients by using a modified rectangle flap. All patients underwent double-eyelid surgery at the same time when they needed it. The evaluation criteria included the intercanthal distance (ICD), interpupillary distance (IPD), the ratio of ICD to IPD (ICD ratio), scar visibility, and cosmetic results. RESULTS: From January 2017 to January 2018, the modified rectangle flap method was carried out on 40 patients, who were evaluated at follow-up from 7 to 15 months. The average intercanthal length was 36.9 ± 2.2 mm preoperatively and decreased significantly to 31.5 ± 1.8 mm postoperatively, 7 months after the surgery (P < 0.01). The excellent cosmetic results, in terms of an open medial canthus, were observed during follow-up periods, with no definite recurrence, hypertrophic scar, or injury of the lacrimal apparatus. The inner canthus and lacrimal caruncle are fully exposed with an invisible scar. Both the patients and the surgeon judged that the aesthetic outcomes were excellent or good. CONCLUSIONS: This modified rectangular flap is an effective and personalized method of correcting the medial folds that leave no additional scar in the medial canthal area, and the procedure meets the patient's aesthetic expectations. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Assuntos
Blefaroplastia , Grupo com Ancestrais do Continente Asiático , Estudos de Coortes , Pálpebras/cirurgia , Humanos , Estudos Retrospectivos , Resultado do Tratamento
20.
Health Sci Rep ; 4(1): e218, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33364440

RESUMO

Background and aims: Thrombolytic therapy is widely used to treat acute ischemic stroke (AIS) patients. As intracerebral hemorrhage is a life-threatening complication of this therapy, monitoring the fibrinolytic and coagulation systems is imperative. However, existing studies on plasmin inhibitor complex (PIC) and thrombin-antithrombin III complex (TAT) mostly apply the enzyme-linked immunosorbent assay (ELISA) method. The aim of this study is to establish the baseline of thrombolytic treatment for AIS patients; to monitor the fibrinolytic and coagulation system following alteplase administration; to ascertain the proper time point to predict intracerebral hemorrhage. Methods: The method used to assess a patient's intravascular situation, namely chemiluminescence, was used to quantitatively assess the PIC, TAT, and thrombomodulin (TM). Immuno-turbidimetric was used to assess the concentration of D-dimer, fibrin/fibrinogen degradation products (FDP), and the Von Willebrand factor (vWF). The Clauss clotting method was used to assay the activated partial thromboplastin time (APTT), prothrombin time (PT) and FIB. Results: PIC increased to its peak concentration at 3 hours post intravenous (IV) alteplase infusion and decreased by nearly 50% every 3 hours thereafter. After 24 hours, PIC returned to its normal range, while D-dimer and FDP decreased 3 hours later compared to PIC. PT and APTT exhibited no obvious change during the 24-hour period. TM also exhibited no changes during the treatment. Conclusion: PIC decreased 3 hours earlier than D-dimer and FDP. The combined test of PIC, D-dimer, and fibrinogen can be used to monitor the fibrinolytic system after the IV alteplase infusion. The use of IV alteplase had no impact on the endothelium. Creating a patient's individual data curve could assist in the prediction of hemorrhagic transformation (HT) and a stroke occurring.

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