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A novel chitosan/sodium hyaluronate/iridium (CHI/SH/Ir) hydrogel nanocomposite with a unique microstructure containing vertically aligned pores is fabricated via an electrophoresis technique. The formation of orderly vertical pores in CHI/SH/Ir hydrogel nanocomposite is due to the confinement of hydrogen bubbles produced from the water electrolysis during electrophoresis that limits their lateral movement and coalescence. In a wet state, the diameter for the vertical pores is 600-700 µm. With a thickness of 500 µm, the CHI/SH/Ir hydrogel nanocomposite exhibits a porosity of 76.7 % and a water uptake of 350 %. Its tensile strength is almost doubled to 8.7 MPa, as compared to that of counterpart without the addition of iridium. In CHI/SH/Ir hydrogel nanocomposite, the iridium nanoparticles are homogeneously distributed with an average size of 3 nm. The CHI/SH/Ir electrophoresis suspension exhibits a negligible cytotoxicity. In cell migration test using the human keratinocytes HaCaT cells, the CHI/SH/Ir hydrogel nanocomposite reveals a relative migration of 122.15 ± 9.02 % (p < 0.001) as compared to the blank sample. The presence of vertically aligned pores with the use of SH and iridium nanoparticles indicates a promising opportunity in wound healing application.
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Quitosana , Ácido Hialurônico , Hidrogéis , Irídio , Nanocompostos , Cicatrização , Quitosana/química , Ácido Hialurônico/química , Cicatrização/efeitos dos fármacos , Humanos , Nanocompostos/química , Irídio/química , Hidrogéis/química , Hidrogéis/síntese química , Movimento Celular/efeitos dos fármacos , Porosidade , Células HaCaT , Resistência à TraçãoRESUMO
Loss of PTEN tumor suppressor is an important event during colorectal cancer (CRC) development and is a target for therapeutic exploitation. This study reports that bromodomain and extra-terminal motif (BET) is a synthetic lethal partner of PTEN in CRC. BET inhibition (BETi) selectively induced G1 cell cycle arrest and apoptosis in PTEN-/- CRC. Further, BETi selectively and dose-dependently suppressed the growth of PTEN-/- CRC tumor xenografts in mice and patient-derived organoids. Mechanistically, PTEN-deficient CRC cells elevated the level of cytoplasmic p21CIP1/WAF1 that is hyper-phosphorylated at Thr145 by AKT. BETi suppressed AKT activation in PTEN-deficient CRC cells, followed by the reduction in p21 phosphorylation at Thr145, thereby promoting its nuclear translocation. In addition, BETi suppressed MYC level and this in turn increased the total p21 level in the nuclei. Over-expression of a phospho-mimetic p21 mutant (T145D) significantly rescued the BETi effect on PTEN-deficient CRC. These results suggest that BETi has a dual action on p21: elevating the level of p21 by inhibiting MYC and converting the oncogenic (cytoplasmic) p21 into the tumor-suppressive (nuclear) p21 by inhibiting AKT. Taken together, this study identified the synthetic lethal interaction between PTEN and BET, and provides a potential actionable target for CRC with PTEN loss.
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Neoplasias Colorretais , Mutações Sintéticas Letais , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt , Fosforilação , Citoplasma , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , PTEN Fosfo-Hidrolase/genéticaRESUMO
The Wnt/ß-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid-liquid-phase separation (LLPS) of Axin organized the ß-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of ß-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the ß-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3ß and CK1α were unsuccessfully recruited, preventing ß-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of ß-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.
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Complexo de Sinalização da Axina , beta Catenina , Humanos , Complexo de Sinalização da Axina/genética , Proteína Axina/genética , Proteína Axina/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Separação de Fases , Mutação/genética , Via de Sinalização Wnt/genética , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismoRESUMO
BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare highly heterogeneous disease. In this paper, we present a case of NIID featured in cortical involvement in left hemisphere of brain and the imaging changes in the process of the disease. CASE PRESENTATION: A 57-year-old female was hospitalized due to recurrent attacks of headache with cognitive impairment and tremor for 2 years. The symptoms of headache episodes were reversible. The characteristic radiologic change was high intensity signal involving the grey matter-white matter junction on the brain diffusion-weighted imaging (DWI), which existed in the frontal lobe and then extended backwards. Atypical features on fluid-attenuated inversion recovery (FLAIR) sequences showing small patchy high signals in the cerebellar vermis. High signals and edema were detected on FLAIR images along the cortex of the left occipito-parieto-temporal lobes, expanding and gradually shrinking in the follow-up visit. Besides, cerebral atrophy and bilateral symmetrical leukoencephalopathy were also detected. Skin biopsy and genetic testing confirmed the diagnosis of NIID. CONCLUSION: Except for typical radiological change strongly suggesting NIID, it is also necessary to notice the insidious symptoms of NIID combining with some atypical imaging features to make an early diagnosis. Skin biopsies or genetic testing should be carried out early in patients with highly suspected NIID.
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Doenças Neurodegenerativas , Feminino , Humanos , Pessoa de Meia-Idade , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/patologia , Imageamento por Ressonância Magnética , Imagem de Difusão por Ressonância Magnética , CefaleiaRESUMO
Intercellular communication between tumor cells and immune cells regulates tumor progression including positive communication with immune activation and negative communication with immune escape. An increasing number of methods are employed to suppress the dominant negative communication in tumors such as PD-L1/PD-1. However, how to effectively improve positive communication is still a challenge. In this study, a nuclear-targeted photodynamic nanostrategy is developed to establish positive spatiotemporal communication, further activating dual antitumor immunity, namely innate and adaptative immunity. The mSiO2 -Ion@Ce6-NLS nanoparticles (NPs) are designed, whose surface is modified by ionic liquid silicon (Ion) and nuclear localization signal peptide (NLS: PKKKRKV), and their pores are loaded with the photosensitizer hydrogen chloride e6 (Ce6). Ion-modified NPs enhance intratumoral enrichment, and NLS-modified NPs exhibit nuclear-targeted characteristics to achieve nuclear-targeted photodynamic therapy (nPDT). mSiO2 -Ion@Ce6-NLS with nPDT facilitate the release of damaged double-stranded DNA from tumor cells to activate macrophages via stimulator of interferon gene signaling and induce the immunogenic cell death of tumor cells to activate dendritic cells via "eat me" signals, ultimately leading to the recruitment of CD8+ T-cells. This therapy effectively strengthens positive communication to reshape the dual antitumor immune microenvironment, further inducing long-term immune memory, and eventually inhibiting tumor growth and recurrence.
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Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Linfócitos T CD8-Positivos , Fármacos Fotossensibilizantes/farmacologia , Fotoquimioterapia/métodos , Macrófagos , Imunoterapia/métodos , Microambiente TumoralRESUMO
Leukoaraiosis (LA) appears as white matter hyperintensities on T2-weighted brain magnetic resonance imaging scans. Age and hypertension are considered the primary risk factors for LA, but its pathogenesis remains uncertain. This study aims to investigate the correlation between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and LA. A total of 140 patients with LA and 136 neuroimaging alteration-free controls were recruited in a case-control study. ACE I/D polymorphism was determined using the polymerase chain reaction method. The allele and genotype distributions of the ACE I/D polymorphism were significantly different between subjects with and without LA. Significant difference was observed in the genotypic distribution between LA patients and controls for recessive and additive models. A statistically significant association remained apparent after adjusting for potential risk factors (D/D vs. I/D + I/I: adjusted OR 3.251, 95% CI 1.185-8.918; D/D vs. I/I: adjusted OR 3.277, 95% CI 1.187-9.047). Our results indicate that the D/D genotype and D allele are important risk factors for LA. Future studies with larger populations are needed to validate our results.
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Finding the optimal design parameters for the target EM response of a metamaterial absorber is still a challenging task even if the layout of the absorber has been determined. To effectively address this issue, we introduce the idea of surrogate-based optimization into the area of metamaterial absorber design. This paper proposes a surrogate based optimization method combining artificial neural network (ANN) and trust region algorithm for metamaterial absorbers. Each optimization iteration utilizes the optimal solution from the previous iteration and the sample points surrounding it as the training dataset to build an effective ANN surrogate model. To improve the convergence of the optimization method for metamaterial absorbers based on ANN surrogate model, we incorporate a trust region algorithm. The proposed method employs a simple forward neural network architecture and requires less training data, leading to a quick convergence towards the target solution after only a few iterations. Compared to the three commonly used alternative methods, the proposed method can optimize geometric and material parameters more efficiently in the same time. The validity of the proposed method is demonstrated by two examples of electromagnetic optimizations of metamaterial absorbers.
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Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an RNA-binding protein, is associated with tumorigenesis and progression. However, the exact molecular mechanisms of IGF2BP3 in colorectal cancer (CRC) oncogenesis, progression, and drug resistance remain unclear. This study found that IGF2BP3 was upregulated in CRC tissues. Clinically, the elevated IGF2BP3 level is predictive of a poor prognosis. Functionally, IGF2BP3 enhances CRC tumorigenesis and progression both in vitro and in vivo. Mechanistically, IGF2BP3 promotes epidermal growth factor receptor (EGFR) mRNA stability and translation and further activates the EGFR pathway by serving as a reader in an N6-methyladenosine (m6A)-dependent manner by cooperating with METTL14. Furthermore, IGF2BP3 increases the drug resistance of CRC cells to the EGFR-targeted antibody cetuximab. Taken together, our results demonstrated that IGF2BP3 was a functional and clinical oncogene of CRC. Targeting IGF2BP3 and m6A modification may therefore offer rational therapeutic targets for patients with CRC.
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Neoplasias Colorretais , Receptores ErbB , Humanos , Anticorpos , Carcinogênese , Transformação Celular Neoplásica , Cetuximab , RNA MensageiroRESUMO
Colorectal cancer (CRC) driven by PTEN deficiency exhibits high risk of metastasis, advancement of tumor stages and chemotherapy resistance, where no effective therapy has been developed. In this study, we performed a synthetic lethal drug screening in CRC and found that PTEN-deficient CRC cells are highly vulnerable to MDM2 inhibition. MDM2 inhibitor treatment or its silencing selectively inhibited the growth of PTEN-deficient CRC in vitro and in mice models. Mechanistically, PTEN loss increased the level of active AKT and subsequently increased MDM2 phosphorylation, thereby limiting the p53 functions in PTEN-/- CRC cells. MDM2 inhibition in turn activated p53 in CRC, particularly in PTEN-/- CRC cells. The synthetic lethal effect of MDM2 inhibitor was largely dependent on p53, because p53 silenced cells or cells lacking p53 failed to exhibit synthetic lethality in PTEN-deficient cells. We further showed that MDM2 inhibition led to the p53-dependent reversal of Bcl2-Bax ratio, which contributed to mitochondria-mediated apoptotic cell death in PTEN-deficient CRC. This study suggests that pharmacological targeting of MDM2 could be a potential therapeutic strategy for PTEN-deficient CRC.
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Antineoplásicos , Neoplasias Colorretais , Animais , Camundongos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
In order to increase the performance of tool or mold/die, there are a lot of micro features on the surface to provide special functions, such as anti-adhesion or lubrication. The MPB (Micro Particle Bombarding) process provides a powerful technology to enhance the surface quality without damaging the micro features. The effect of MPB parameters were investigated by bombarding the surface with extremely small particles (20~200 µm in diameter) at a high velocity and pressure to obtain a better surface integrity. -The MPB has two functions, one is micro blasting for cleaning purposes and the other is micro shot peening for surface strengthening. The regression relationship between particle bombarding time and micro hardness is established to predict the surface hardness after MPB process. The experimental results reveal that the surface hardness of cermet is increased 14~66% (HV2167~HV3163) by micro particle bombarding. The micro shot peening provides a good surface integrity due to thebetter surface roughness of 0.1 µmRa and higher compress residual stress of -1393.7 MPa, which is up to 26% enhancement compared with the base material cermet. After micro shot peening, the surface hardness of the SKD11 tool steel increased from HV 686 to HV 739~985. The surface roughness of SKD 11 after micro shot peening was 0.31-0.48 µmRa, while the surface roughness after micro blasting was 0.77-1.15 µmRa. It is useful to predict the residual stress for micro blasting by surface roughness, and to estimate the residual stress after micro shot peening by surface hardness by applying the MPB process in industry in the case of SKD 11 tool steel.
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We aimed to investigate the efficacy and safety of rivaroxaban for acute and long-term management of cerebral venous sinus thrombosis (CVST). This study reviewed CVST-diagnosed patients admitted to the First Affiliated Hospital of Guangxi Medical University from January 2015 to December 2020. The primary outcome was a composite of recurrent thrombosis or major bleeding events. The secondary efficacy outcomes included a disease recovery time (DRT) presenting the time from admission to the endpoint as recovery (the modified Rankin scale [mRS] score [0-1]) within 30 and 90 days, and length of hospital stay (LHS). Patients treated with rivaroxaban (38) and warfarin (45) were enrolled in the final analysis. The primary outcome had no significant difference (5.3% vs 11.1%, P = .576) between the 2 groups. The secondary efficacy outcome regarding the median 30-d DRT was 17 days (95% confidence interval [CI], 14.6-19.4) in the rivaroxaban group, compared with 26.0 days (95% CI, 16.8-35.2) in the warfarin group (hazard ratio, 1.806; 95% CI, 1.051-3.103; log-rank P = .026). Two groups have a significant difference in LHS (P = .041). Patients with cerebral edema, intracerebral hemorrhage, and mild/moderate disability (admission mRS score [2-3]) treated with rivaroxaban recovered faster than those with warfarin (log-rank P < .05). Patients with cerebral edema, intracerebral hemorrhage, and mild/moderate disability treated with rivaroxaban had a shorter recovery time than those treated with warfarin within 1 month from admission, indicating that rivaroxaban a promising convenient therapy for CVST, helping them speedily restore social functions.
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Edema Encefálico , Trombose dos Seios Intracranianos , Humanos , Rivaroxabana/efeitos adversos , Inibidores do Fator Xa/efeitos adversos , Anticoagulantes/efeitos adversos , Edema Encefálico/induzido quimicamente , Edema Encefálico/tratamento farmacológico , População do Leste Asiático , China , Varfarina/efeitos adversos , Hemorragia Cerebral/tratamento farmacológico , Trombose dos Seios Intracranianos/tratamento farmacológico , Resultado do TratamentoRESUMO
A chitosan composite with a vertical array of pore channels is fabricated via an electrophoretic deposition (EPD) technique. The composite consists of chitosan and polyethylene glycol, as well as nanoparticles of silver oxide and silver. The formation of hydrogen bubbles during EPD renders a localized increase of hydroxyl ions that engenders the precipitation of chitosan. In addition, chemical interactions among the constituents facilitate the establishment of vertical channels occupied by hydrogen bubbles that leads to the unique honeycomb-like microstructure; a composite with a porosity of 84%, channel diameter of 488 µm, and channel length of 2 mm. The chitosan composite demonstrates an impressive water uptake of 2100% and a two-stage slow release of silver. In mass transport analysis, both Disperse Red 13 and ZnO powders show a much enhanced transport rate over that of commercial gauze. Due to its excellent structural integrity and channel independence, the chitosan composite is evaluated in a passive suction mode for an adhesive force of 9.8 N (0.56 N cm-2 ). The chitosan composite is flexible and is able to maintain sufficient adhesive force toward objects with different surface curvatures.
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Quitosana , Quitosana/química , Eletroforese , Porosidade , Polietilenoglicóis/química , HidrogênioRESUMO
Photosynthetic bacteria are beneficial to plants, but knowledge of photosynthetic bacterial community dynamics in field crops during different growth stages is scarce. The factors controlling the changes in the photosynthetic bacterial community during plant growth require further investigation. In this study, 35 microbial community samples were collected from the seedling, flowering, and mature stages of tomato, cucumber, and soybean plants. 35 microbial community samples were assessed using Illumina sequencing of the photosynthetic reaction center subunit M (pufM) gene. The results revealed significant alpha diversity and community structure differences among the three crops at the different growth stages. Proteobacteria was the dominant bacterial phylum, and Methylobacterium, Roseateles, and Thiorhodococcus were the dominant genera at all growth stages. PCoA revealed clear differences in the structure of the microbial populations isolated from leaf samples collected from different crops at different growth stages. In addition, a dissimilarity test revealed significant differences in the photosynthetic bacterial community among crops and growth stages (P<0.05). The photosynthetic bacterial communities changed during crop growth. OTUs assigned to Methylobacterium were present in varying abundances among different sample types, which we speculated was related to the function of different Methylobacterium species in promoting plant growth development and enhancing plant photosynthetic efficiency. In conclusion, the dynamics observed in this study provide new research ideas for the detailed assessments of the relationship between photosynthetic bacteria and different growth stages of plants.
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Metagenômica , Microbiota , Bactérias , Produtos Agrícolas , Sequenciamento de Nucleotídeos em Larga Escala , Metagenoma , Microbiota/genética , Microbiologia do SoloRESUMO
INTRODUCTION: Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered to be pharmacokinetically equivalent to the host liver. Although some studies have explored the roles of gut microbiota and host Cyp450s in drug pharmacokinetics, few have explored their effects on pharmacokinetic variability, especially in disease states. OBJECTIVES: In this study, we aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH), and to elucidate the contribution of gut microbiota and host Cyp450s to pharmacokinetic variability in this setting. METHODS: The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administrations of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol, after which the results were compared with those obtained from the control group. Thereafter, the pharmacokinetic variabilities of all drugs and their relations to the changes in gut microbiota and host Cyp450s were compared and analyzed. RESULTS: The exposures of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity in the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in the host Cyp2c65. Notably, gut microbiota and host Cyp450s exerted minimal effects on the pharmacokinetic variability of metoprolol. CONCLUSION: Gut microbiota and host Cyp450s co-contribute to the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug. The present findings provide new insights into the explanation of pharmacokinetic variability in disease states.
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Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Animais , Clorzoxazona/farmacologia , Metoprolol/farmacologia , Camundongos , Midazolam/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Omeprazol/farmacologia , Preparações Farmacêuticas , Fenacetina/farmacologia , Tolbutamida/farmacologiaRESUMO
Mice are the most frequently used animals in pharmacokinetic studies; however, collecting series of blood samples from mice is difficult because of their small sizes and tiny vessels. In addition, due to the small sample size, it is problematic to perform high required quantification. Thus, present work aims to find an effective strategy for overcoming these challenges using trans-resveratrol as a tool drug. Based on the idea of a joint technology, the capillary microsampling (CMS) was chosen for blood sample collection from mice after delivery of trans-resveratrol (150 mg/kg) by gavage, and a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the determination of trans-resveratrol and its main metabolites. All the mouse blood samples were exactly collected by CMS without obvious deviation. This provided credible samples for subsequent quantitative analysis. The HPLC-MS/MS method was found to be sensitive, accurate, and repeatable, and the pharmacokinetic parameters for all analytes were comparable with those reported in previous studies. However, the present joint technology offers the advantages of less animal damage, easy for sample preparation, and improved reliability. It has overcome some of the major limitations revealed in previous pharmacokinetic studies in mice and therefore provides a more effective option for future studies.
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Background: Nonalcoholic fatty liver disease (NAFLD) is a serious threat to human health worldwide, with a high genetic susceptibility. Rs2302685, a functional germline variant of LRP6, has been recently found to associate with NAFLD risk. This study was aimed to clarify the underlying mechanism associated with rs2302685 risk and its impact on pharmacotherapy in treatment of NAFLD. Methods: Venous blood samples were collected from NAFLD and non-NAFLD patients for SNP genotyping by using mass spectrometry. The Lrp6-floxdel mouse (Lrp6(+/-)) was generated to model the partial function associated with human rs2302685. The liver injury and therapeutic effects of silibinin were compared between Lrp6(+/-) and Lrp6(+/+) mice received a methionine-choline deficient (MCD) diet or normal diet. The effect of Lrp6 functional alteration on Wnt/ß-catenin-Cyp2e1 signaling activities was evaluated by a series of cellular and molecular assays. Results: The T allele of LRP6 rs2302685 was confirmed to associate with a higher risk of NAFLD in human subjects. The carriers of rs2302685 had reduced level of AST and ALT as compared with the noncarriers. The Lrp6(+/-) mice exhibited a less severe liver injury induced by MCD but a reduced response to the treatment of silibinin in comparison to the Lrp6(+/+) mice, suggesting Lrp6 as a target of silibinin. Wnt/ß-catenin-Cyp2e1 signaling together with ROS generation could be exacerbated by the overexpression of Lrp6, while decreased in response to Lrp6 siRNA or silibinin treatment under NAFLD modeling. Conclusions: The Lrp6 function affects individual susceptibility to NAFLD and the therapeutic effect of silibinin through the Wnt/ß-catenin-Cyp2e1 signaling pathway. The present work has provided an underlying mechanism for human individual susceptibility to NAFLD associated with Lrp6 polymorphisms as well as a rationale for the effective use of silibinin in NAFLD patients.
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Citocromo P-450 CYP2E1/genética , Predisposição Genética para Doença , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Transdução de Sinais/efeitos dos fármacos , Silibina/uso terapêutico , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Adulto , Animais , Gatos , Feminino , Genótipo , Humanos , Masculino , Silibina/farmacologiaRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition associated with aging, insulin resistance, metabolic syndrome, genetic factors and more. Although genetic traits are among the most important risks factors for NAFLD, the understanding of their influence is still quite limited. The present study aimed at identifying novel single nucleotide polymorphisms (SNPs) that may confer a risk for NAFLD in the Han Chinese population. METHODS: Based on the "two-hit hypothesis", candidate SNPs, including Sirtuin3 rs28365927, were genotyped by MassARRAY in B-type ultrasonography-proven NAFLD patients (n = 292) and healthy controls (n = 387). RESULTS: In a model analysis of individuals matched based on gender and age that compared 223 NAFLD and 223 non-NAFLD patients, the rs28365927 GA + AA genotype was a significant risk factor for the development of NAFLD in a dominant model. Rs28365927 was significantly associated with a higher NAFLD risk in both an additive model (A vs G) and genotypic model (GA vs GG). Among the NAFLD patients, serum levels of total bilirubin (TBIL), DBIL direct bilirubin (DBIL) and glutamic-pyruvic transaminase (ALT) in rs28365927 A allele carriers (GA + AA) were 11.1, 14.7 and 41.5% higher, respectively, than in non-carriers (GG). Furthermore, among the NAFLD patients, the carriers of Rs28365927 allele A were positively correlated with higher ALT levels. CONCLUSION: Sirtuin3 rs28365927 functional variant confers to the high risk of non-alcoholic fatty liver disease in Chinese Han population. The rs28365927 A allele significantly increased the ALT levels of NAFLD patients.
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Predisposição Genética para Doença/genética , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único/genética , Sirtuína 3/genética , Adulto , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Atherosclerosis was an important pathophysiological basis of atherothrombotic stroke, and phosphodiesterase 4D (PDE4D) polymorphism (SNP83/rs966221) was reported to be associated with the susceptibility to atherothrombotic stroke. Aim of the present study was to explore the potential association between SNP83 and carotid atherosclerosis (CAS). 204 southern Chinese Han participants were divided into two groups according to the carotid intima-media thickness (IMT) of the carotid artery: CAS group (carotid IMT ≥ 1.0 mm) and non-CAS group (carotid IMT < 1.0 mm). Carotid IMT was measured by color Doppler ultrasound. The PDE4D SNP83 polymorphism was determined by SNaPshot technique. Our study found that SNP83 was associated significantly with CAS susceptibility under the dominant, overdominant and codominant models. After adjusting for age, gender, low-density lipoprotein cholesterol, Hemoglobin A1c, cigarette smoking, hypertension history, and diabetes mellitus history, the association still remained significant (dominant model: crude OR = 2.373, 95% CI: 1.268-4.442, P = 0.007; adjusted OR = 3.129, 95% CI: 1.104-8.866, P = 0.032; overdominant model: crude OR = 1.968, 95% CI: 1.043-3.714, P = 0.037; adjusted OR = 2.854, 95% CI: 1.005-8.108, P = 0.049; codominant: crude OR = 2.102, 95% CI: 1.110-3.979, P = 0.023; adjusted OR = 2.984, 95% CI: 1.047-8.502, P = 0.041). Carotid IMT of carriers with CT + CC genotypes was higher than carriers with TT genotype (P = 0.016). Our results indicated that the SNP83/rs966221 located on PDE4D gene was significantly associated between CAS susceptibility and carotid IMT independently of conventional risk factors in a southern Chinese Han population.
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Povo Asiático/genética , Doenças das Artérias Carótidas/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Alelos , Biomarcadores , Doenças das Artérias Carótidas/diagnóstico , Espessura Intima-Media Carotídea , China , Estudos de Associação Genética , Genótipo , Humanos , Fatores de RiscoRESUMO
OBJECTIVE: To investigate the epidemiological data, prognostic factors, and treatment outcomes of bone angiosarcoma (BA). METHODS: This retrospective study was based on the Surveillance, Epidemiology, and End Results (SEER) database. The medical records of BA patients were selected from the SEER database from 1975 to 2016. Variables including patients' baseline demographics (age, sex, marital status, and year of diagnosis), tumor characteristics (tumor size, grade, and SEER Historic Stage A), and treatment (surgery and radiotherapy) were selected for further analysis. The research endpoints were overall survival (OS) and cancer-specific survival (CSS). The optimal cutoff values of continuous variables including age, year of diagnosis, and tumor size were identified using the X-tail program. Univariate Cox regression was used to identify potential prognostic factors and multivariate Cox regression was used to identify independent prognostic factors. All prognostic factors were included to predict the survival time compared to the median OS and CSS times via the novel nomograms. To validate the internal validation of nomograms, we analyzed the concordance indices (C-index). RESULTS: This study enrolled a total of 271 patients with malignant vascular bone tumors among residents of the United States between 1975 and 2016. After applying the exclusion criteria (one case without active follow-up), this study included 152 patients with BA. The median survival time of BA was significantly shorter than that of malignant vascular bone tumors for OS (9 months vs 27 months, P < 0.001). Age, year of diagnosis, tumor size, grade, stage, and surgery were identified as potential prognostic factors for OS or CSS in univariate Cox regression. However, only age (P < 0.001, P < 0.001), stage (P = 0.002, P < 0.001), and surgery (P = 0.001, P = 0.002) were independent prognostic factors for CSS and OS, respectively, in the multivariate analysis. Younger patients less than 54 years have significantly better prognosis for CSS/OS than patients between 54 and 67 years (Hazard ratios [HRs]: 1.651 [1.763-3.575], 2.557 [1.395-4.687]) and more than 67 years (HRs: 4.404 [2.237-8.670], 5.113 [2.923-8.942]). For CSS/OS, the survival time of patients with localized stage was significantly longer than that of patients with regional stage (HRs: 1.530 [0.725-3.228], 1.548 [0.834-2.873]) and that of patients with distant stage (HRs: 1.706 [0.899-3.237], 2.101 [1.254-3.520]). Patients with surgery had more survival time than patients without surgery for CSS/OS (HRs: 2.861 [1.542-5.310], 2.103 [1.308-3.379]). All factors were further included to generate nomograms for CSS and OS. The C-indexes for the internal validation of OS and CSS prediction were 0.787 (95% confidence interval [CI]: 0.738-0.836) and 0.768 (95% CI: 0.717-0.819), respectively. CONCLUSIONS: Age, stage, and surgery were closely associated with prognosis in patients with BA, and this clinical model was a favorable tool to evaluate survival possibilities.