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Natural killer (NK) cells play a vital role in eliminating tumorigenic cells. Efficient locating and killing of target cells in complex three-dimensional (3D) environments are critical for their functions under physiological conditions. However, the role of mechanosensing in regulating NK-cell killing efficiency in physiologically relevant scenarios is poorly understood. Here, we report that the responsiveness of NK cells is regulated by tumor cell stiffness. NK-cell killing efficiency in 3D is impaired against softened tumor cells, whereas it is enhanced against stiffened tumor cells. Notably, the durations required for NK-cell killing and detachment are significantly shortened for stiffened tumor cells. Furthermore, we have identified PIEZO1 as the predominantly expressed mechanosensitive ion channel among the examined candidates in NK cells. Perturbation of PIEZO1 abolishes stiffness-dependent NK-cell responsiveness, significantly impairs the killing efficiency of NK cells in 3D, and substantially reduces NK-cell infiltration into 3D collagen matrices. Conversely, PIEZO1 activation enhances NK killing efficiency as well as infiltration. In conclusion, our findings demonstrate that PIEZO1-mediated mechanosensing is crucial for NK killing functions, highlighting the role of mechanosensing in NK-cell killing efficiency under 3D physiological conditions and the influence of environmental physical cues on NK-cell functions.
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Células Matadoras Naturais , Células Matadoras Naturais/fisiologia , Morte CelularRESUMO
Constructing 3D nanophotonic structures is regarded as an effective method to realize efficient solar-to-hydrogen conversion. These photonic structures can enhance the absorbance of photoelectrodes by the light trapping effect, promote the charge separation by designable charge transport pathway and provide a high specific surface area for catalytic reaction. However, most 3D structures reported so far mainly focused on the influence of light absorption and lacked a systematic investigation of the overall water splitting process. Herein, hematite hollow-sphere-array photoanodes are fabricated through a facile hydrothermal method with polystyrene templates. Validating by simulations and experiments, the hollow sphere array is proved to enhance the efficiency of light harvesting, charge separation and surface reaction at the same time. With an additional annealing treatment in oxygen, a photocurrent density of 2.26 mA cm-2 at 1.23 V versus reversible hydrogen electrode can be obtained, which is 3.70 times larger than that with a planar structure in otherwise the same system. This work gains an insight into the photoelectrochemical water splitting process, which is valuable for the further design of advancing solar driven water splitting devices.
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Porcine reproductive and respiratory syndrome virus (PRRSV) causes a highly transmissible disease of significant concern in the pig industry. Previous studies have demonstrated that the XM-2020 strain (a lineage 1.8 PRRSV IA/2012/NADC30) can induce special hemorrhagic injury in the small intestines. However, the specific mechanism underlying this injurious effect remains incompletely understood. In this study, we examined the pathogenic properties of XM-2020 and YC-2020 strains (a lineage 1.5 PRRSV IA/2014/NADC34) in piglets. Animal pathogenic tests revealed that with either Lineage 1 PRRSVs strains XM-2020 or YC-2020 demonstrated pronounced intestinal hemorrhage and suppression of peripheral immunological organs, comparing to JXA1 infection. Transcriptome analysis of diseased small intestines unveiled that PRRSV infection stimulated oxidative and inflammatory reactions. Remarkably, we also observed activation of the complement system alongside a notable down-regulation of complement and coagulation cascade pathways in the Lineage 1 PRRSVs infection group. Based on these findings, we propose that the primary mechanism driving the hemorrhagic injury of the small intestine caused by Lineage 1 PRRSVs is the suppression of complement and coagulation cascades resulting from immunosuppression. This discovery deepens our understanding of the pathogenicity of PRRSV in the small intestine and provides promising ways out for the development of innovative strategies aimed at controlling PRRSV.
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Proteínas do Sistema Complemento , Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Animais , Suínos , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Síndrome Respiratória e Reprodutiva Suína/virologia , Síndrome Respiratória e Reprodutiva Suína/patologia , Coagulação Sanguínea , Intestino Delgado/virologia , Intestino Delgado/patologia , Intestinos/virologia , Intestinos/patologia , Perfilação da Expressão Gênica , HemorragiaRESUMO
Triple-negative breast cancer (TNBC) is incurable and prone to widespread metastasis. Therefore, identification of key targets for TNBC progression is urgently needed. Our previous study revealed that isotoosendanin (ITSN) reduced TNBC metastasis by targeting TGFßR1. ITSN is currently used as an effective chemical probe to further discover the key molecules involved in TNBC metastasis downstream of TGFßR1. The results showed that GOT2 was the gene downstream of Smad2/3 and that ITSN decreased GOT2 expression by abrogating the activation of the TGF-ß-Smad2/3 signaling pathway through directly binding to TGFßR1. GOT2 was highly expressed in TNBC, and its knockdown decreased TNBC metastasis. However, GOT2 overexpression reversed the inhibitory effect of ITSN on TNBC metastasis both in vitro and in vivo. GOT2 interacted with MYH9 and hindered its binding to the E3 ubiquitin ligase STUB1, thereby reducing MYH9 ubiquitination and degradation. Moreover, GOT2 also enhanced the translocation of MYH9 to mitochondria and thus induced DRP1 phosphorylation, thereby promoting mitochondrial fission and lamellipodia formation in TNBC cells. ITSN-mediated inhibition of mitochondrial fission and lamellipodia formation was associated with reduced GOT2 expression. In conclusion, ITSN prevented MYH9-regulated mitochondrial fission and lamellipodia formation in TNBC cells by enhancing MYH9 protein degradation through a reduction in GOT2 expression, thus contributing to its inhibition of TNBC metastasis.
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Cardiometabolic multimorbidity (CMM) is an increasingly significant global public health concern. It encompasses the coexistence of multiple cardiometabolic diseases, including hypertension, stroke, heart disease, atherosclerosis, and T2DM. A crucial component to the development of CMM is the disruption of endothelial homeostasis. Therefore, therapies targeting endothelial cells through multi-targeted and multi-pathway approaches hold promise for preventing and treatment of CMM. Curcumin, a widely used dietary supplement derived from the golden spice Carcuma longa, has demonstrated remarkable potential in treatment of CMM through its interaction with endothelial cells. Numerous studies have identified various molecular targets of curcumin (such as NF-κB/PI3K/AKT, MAPK/NF-κB/IL-1ß, HO-1, NOs, VEGF, ICAM-1 and ROS). These findings highlight the efficacy of curcumin as a therapeutic agent against CMM through the regulation of endothelial function. It is worth noting that there is a close relationship between the progression of CMM and endothelial damage, characterized by oxidative stress, inflammation, abnormal NO bioavailability and cell adhesion. This paper provides a comprehensive review of curcumin, including its availability, pharmacokinetics, pharmaceutics, and therapeutic application in treatment of CMM, as well as the challenges and future prospects for its clinical translation. In summary, curcumin shows promise as a potential treatment option for CMM, particularly due to its ability to target endothelial cells. It represents a novel and natural lead compound that may offer significant therapeutic benefits in the management of CMM.
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Aterosclerose , Curcumina , Humanos , Células Endoteliais , Curcumina/farmacologia , Curcumina/uso terapêutico , Multimorbidade , NF-kappa B , Fosfatidilinositol 3-Quinases , EspeciariasRESUMO
Community detection has attracted tremendous interests in network analysis, which aims at finding group of nodes with similar characteristics. Various detection methods have been developed to detect homogeneous communities in multi-layer networks, where inter-layer dependence is a widely acknowledged but severely under-investigated issue. In this paper, we propose a novel stochastic block Ising model (SBIM) to incorporate the inter-layer dependence to help with community detection in multi-layer networks. The community structure is modeled by the stochastic block model (SBM) and the inter-layer dependence is incorporated via the popular Ising model. Furthermore, we develop an efficient variational EM algorithm to tackle the resultant optimization task and establish the asymptotic consistency of the proposed method. Extensive simulated examples and a real example on gene co-expression multi-layer network data are also provided to demonstrate the advantage of the proposed method.
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Algoritmos , Redes Reguladoras de GenesRESUMO
Hepatic sinusoidal obstruction syndrome (HSOS) is a death-dealing liver disease with a fatality rate of up to 67%. In the study present, we explored the efficacy of andrographolide (Andro), a diterpene lactone from Andrographis Herba, in ameliorating the monocrotaline (MCT)-induced HSOS and the underlying mechanism. The alleviation of Andro on MCT-induced rats HSOS was proved by biochemical index detection, electron microscope observation, and liver histological evaluation. Detection of hepatic ATP content, mitochondrial DNA (mtDNA) copy number, and protein expression of nuclear respiratory factor-1 (NRF1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) demonstrated that Andro strengthened mitochondrial biogenesis in livers from MCT-treated rats. Chromatin immunoprecipitation assay exhibited that Andro enhanced the occupation of nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) in the promoter regions of both PPARGC1A and NRF1. Andro also activated the NRF2-dependent anti-oxidative response and alleviated liver oxidative injury. In Nrf2 knock-out mice, MCT induced more severe liver damage, and Andro showed no alleviation in it. Furthermore, the Andro-activated mitochondrial biogenesis and anti-oxidative response were reduced in Nrf2 knock-out mice. Contrastingly, knocking out Kelch-like ECH-associated protein 1 (Keap1), a NRF2 repressor, reduced MCT-induced liver damage. Results from co-immunoprecipitation, molecular docking analysis, biotin-Andro pull-down, cellular thermal shift assay, and surface plasmon resonance assay showed that Andro hindered the NRF2-KEAP1 interaction via directly binding to KEAP1. In conclusion, our results revealed that NRF2-dependent liver mitochondrial biogenesis and anti-oxidative response were essential for the Andro-provided alleviation of the MCT-induced HSOS. Graphical Headlights: 1. Andro alleviated MCT-induced HSOS via activating antioxidative response and promoting mitochondrial biogenesis. 2. Andro-activated antioxidative response and mitochondrial biogenesis were NRF2-dependent. 3. Andro activated NRF2 via binding to KEAP1.
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Diterpenos , Hepatopatia Veno-Oclusiva , Camundongos , Ratos , Animais , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/metabolismo , Hepatopatia Veno-Oclusiva/patologia , Antioxidantes/farmacologia , Monocrotalina/efeitos adversos , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Simulação de Acoplamento Molecular , Biogênese de Organelas , Diterpenos/farmacologia , Estresse Oxidativo , Camundongos Knockout , DNA Mitocondrial/metabolismoRESUMO
BACKGROUND: To construct a predictive model of immunotherapy efficacy for patients with lung squamous cell carcinoma (LUSC) based on the degree of tumor-infiltrating immune cells (TIIC) in the tumor microenvironment (TME). METHODS: The data of 501 patients with LUSC in the TCGA database were used as a training set, and grouped using non-negative matrix factorization (NMF) based on the degree of TIIC assessed by single-sample gene set enrichment analysis (GSEA). Two data sets (GSE126044 and GSE135222) were used as validation sets. Genes screened for modeling by least absolute shrinkage and selection operator (LASSO) regression and used to construct a model based on immunophenotyping score (IPTS). RNA extraction and qPCR were performed to validate the prognostic value of IPTS in our independent LUSC cohort. The receiver operating characteristic (ROC) curve was constructed to determine the predictive value of the immune efficacy. Kaplan-Meier survival curve analysis was performed to evaluate the prognostic predictive ability. Correlation analysis and enrichment analysis were used to explore the potential mechanism of IPTS molecular typing involved in predicting the immunotherapy efficacy for patients with LUSC. RESULTS: The training set was divided into a low immune cell infiltration type (C1) and a high immune cell infiltration type (C2) by NMF typing, and the IPTS molecular typing based on the 17-gene model could replace the results of the NMF typing. The area under the ROC curve (AUC) was 0.82. In both validation sets, the IPTS of patients who responded to immunotherapy were significantly higher than those who did not respond to immunotherapy (P = 0.0032 and P = 0.0451), whereas the AUC was 0.95 (95% CI = 1.00-0.84) and 0.77 (95% CI = 0.58-0.96), respectively. In our independent cohort, we validated its ability to predict the response to cancer immunotherapy, for the AUC was 0.88 (95% CI = 1.00-0.66). GSEA suggested that the high IPTS group was mainly involved in immune-related signaling pathways. CONCLUSIONS: IPTS molecular typing based on the degree of TIIC in the TME could well predict the efficacy of immunotherapy in patients with LUSC with a certain prognostic value.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Humanos , Imunoterapia , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Tipagem Molecular , Prognóstico , Microambiente TumoralRESUMO
BACKGROUND: Rubella virus (RV) is the causative agent of rubella or German measles. Although most infections cause only mild self-limited measles-like illness, the infection in pregnant women can cause severe foetal malformation or even miscarriage, especially in the first 3 months of pregnancy. Therefore, it is of great practical significance to establish a simple and sensitive RV detection method. METHODS: The partial epitopes of the E1 and E2 proteins from Rubella Virus were selected as the target sites, the sequence of the selected antigenic sites of the E1 and E2 were linked by a linker. The expression plasmid P6T was constructed by inserting the gene into PET-32A + with a histidine Tag. The P6 protein was induced and expressed in Escherichia coli L21 (DE3) and purified by nickel column affinity. The protein P6 antigen was identified by Western blotting analysis, and an anti-P6 antibody ELISA was established to test known serum samples to evaluate the capability of this method. RESULTS: After purification, the concentration and purity of the protein P6 were 0.283 mg/mL and more than 80%, respectively. Western blotting analysis showed that the protein P6 could react with rubella virus positive serum. By ELISA, 36 negative sera and 58 positive sera were detected. The coincidence rate, specificity and sensitivity of the ELISA were 86.2%, 88.89% and 84.48%, respectively. The P6 ELISA with a kappa coefficient of 0.715, P < 0.05, indicated excellent consistency. CONCLUSIONS: The protein P6 with excellent antigenicity obtained from prokaryotic expression followed by chromatography purification could prove useful for early diagnosis of RV infection.
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Vírus da Rubéola , Rubéola (Sarampo Alemão) , Anticorpos Antivirais , Western Blotting , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Imunoglobulina G , Gravidez , Rubéola (Sarampo Alemão)/diagnóstico , Vírus da Rubéola/genéticaRESUMO
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high vascularity and frequent metastasis. Tumor-associated abnormal vasculature was reported to accelerate TNBC metastasis. Scutellarin (SC) is a natural flavonoid with a cardiovascular protective function. In this study, SC reduced TNBC metastasis and alleviated tumor-associated vascular endothelial barrier injury in vivo. SC rescued the tumor necrosis factor-α (TNFα)-induced diminishment of endothelial junctional proteins and dysfunction of the endothelial barrier in vitro. SC reduced the increased transendothelial migration of TNBC cells through a monolayer composed of TNFα-stimulated human mammary microvascular endothelial cells (HMMECs) or human umbilical vein endothelial cells (HUVECs). TNFα induced the nuclear translocation of enhancer of zeste homolog-2 (EZH2), and its chemical inhibitor GSK126 blocked TNFα-induced endothelial barrier disruption and subsequent TNBC transendothelial migration. TNF receptor 2 (TNFR2) is the main receptor by which TNFα regulates endothelial barrier breakdown. Extracellular signal-regulated protein kinase (ERK)1/2 was found to be downstream of TNFα/TNFR2 and upstream of EZH2. Additionally, SC abrogated the TNFR2-ERK1/2-EZH2 signaling axis both in vivo and in vitro. Our results suggest that SC reduced TNBC metastasis by suppressing TNFα-initiated vascular endothelial barrier breakdown through rescuing the reduced expression of junctional proteins by regulating the TNFR2-ERK1/2-EZH2 signaling pathway.
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Neoplasias de Mama Triplo Negativas , Apigenina/farmacologia , Linhagem Celular Tumoral , Glucuronatos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Proteínas Quinases , Receptores Tipo II do Fator de Necrose Tumoral , Neoplasias de Mama Triplo Negativas/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Thromboelastography (TEG) provides global assessment of hemostatic function and has been recommended to monitor potential coagulopathies during pregnancy in which hypercoagulable state is favored. In present study, we established the reference intervals (RIs) of the TEG parameters (R, K, MA, and α-angle) with Chinese pregnant women of third trimester. In addition, we examined the diagnostic efficacies of the TEG parameters in the patients diagnosed of gestational hypertension (GH), gestational diabetes mellitus (GDM), or preeclampsia (PE). METHODS: With specified including and excluding criteria, non-pregnant controls, healthy pregnant women, and pregnant women with GH, GDM, or PE had their venous blood drawn at Beijing Obstetrics and Gynecology Hospital, followed by TEG tests performed in the clinical laboratory. RESULTS: The RIs determined with the healthy pregnant women (in third trimester) for R, K, MA, and α-angle were 4.0-7.7, 1.2-3.2, 51.9-70.1, and 41.4-74.4, respectively. When compared with the healthy pregnancy group, the K value was significantly decreased in GH patients but increased in PE patients; MA was significantly lower in the PE group. In the receiver operating characteristic curve (ROC) analyses, K value was able to efficiently distinguish normal pregnancy from the GH patients, with an AUC of 0.86 which is far better than those of R (AUC = 0.57) and MA (AUC = 0.56). For the PE patients, the AUC of MA (0.69) was significantly greater than that of R (0.50). CONCLUSIONS: Thromboelastography may provide more accurate experimental basis for monitoring coagulation functions especially in pregnant women with complications of GH and PE.
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Diabetes Gestacional/diagnóstico , Hipertensão Induzida pela Gravidez/diagnóstico , Pré-Eclâmpsia/diagnóstico , Tromboelastografia/métodos , Adulto , Diabetes Gestacional/sangue , Feminino , Humanos , Hipertensão Induzida pela Gravidez/sangue , Contagem de Plaquetas , Pré-Eclâmpsia/sangue , Gravidez , Terceiro Trimestre da Gravidez , Curva ROC , Valores de ReferênciaRESUMO
Epigenetic modifications have been shown to be important for immune cell differentiation by regulating gene transcription. However, the role and mechanism of histone methylation in the development and differentiation of iNKT cells in rheumatoid arthritis (RA) mice have yet to be deciphered. The DBA/1 mouse RA model was established by using a modified GPI mixed peptide. We demonstrated that total peripheral blood, thymus, and spleen iNKT cells in RA mice decreased significantly, while iNKT1 in the thymus and spleen was increased significantly. PLZF protein and PLZF mRNA levels were significantly decreased in thymus DP T cells, while T-bet protein and mRNA were significantly increased in thymus iNKT cells. We found a marked accumulation in H3K27me3 around the promoter regions of the signature gene Zbtb16 in RA mice thymus DP T cells, and an accumulation of H3K4me3 around the promoters of the Tbx21 gene in iNKT cells. The expression levels of UTX in the thymus of RA mice were significantly reduced. The changes in the above indicators were particularly significant in the progressive phase of inflammation (11 days after modeling) and the peak phase of inflammation (14 days after modeling) in RA mice. Developmental and differentiation defects of iNKT cells in RA mice were associated with abnormal methylation levels (H3K27me3 and H3K4me3) in the promoters of key genes Zbtb16 (encoding PLZF) and Tbx21 (encoding T-bet). Decreased UTX of thymus histone demethylase levels resulted in the accumulation of H3K27me3 modification.
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Artrite Reumatoide/patologia , Lisina/metabolismo , Células T Matadoras Naturais/patologia , Regiões Promotoras Genéticas , Timo/fisiologia , Animais , Artrite Experimental/patologia , Diferenciação Celular , Epigênese Genética , Regulação da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Metilação , Camundongos Endogâmicos DBA , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Baço/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismoRESUMO
RATIONALE: Intracoronary infusion of bone marrow (BM) mononuclear cells after acute myocardial infarction (AMI) has led to limited improvement in left ventricular function. Although experimental AMI models have implicated cytokine-related impairment of progenitor cell function, this response has not been investigated in humans. OBJECTIVE: To test the hypothesis that peripheral blood (PB) cytokines predict BM endothelial progenitor cell colony outgrowth and cardiac function after AMI. METHODS AND RESULTS: BM and PB samples were collected from 87 participants 14 to 21 days after AMI and BM from healthy donors was used as a reference. Correlations between cytokine concentrations and cell phenotypes, cell functions, and post-AMI cardiac function were determined. PB interleukin-6 (IL-6) negatively correlated with endothelial colony-forming cell colony maximum in the BM of patients with AMI (estimate±SE, -0.13±0.05; P=0.007). BM from healthy individuals showed a dose-dependent decrease in endothelial colony-forming cell colony outgrowth in the presence of exogenous IL-1ß or IL-6 (P<0.05). Blocking the IL-1R or IL-6R reversed cytokine impairment. In AMI study participants, the angiogenic cytokine platelet-derived growth factor BB glycoprotein correlated positively with BM-derived colony-forming unit-endothelial colony maximum (estimate±SE, 0.01±0.002; P<0.001), multipotent mesenchymal stromal cell colony maximum (estimate±SE, 0.01±0.002; P=0.002) in BM, and mesenchymal stromal cell colony maximum in PB (estimate±SE, 0.02±0.005; P<0.001). CONCLUSIONS: Two weeks after AMI, increased PB platelet-derived growth factor BB glycoprotein was associated with increased BM function, whereas increased IL-6 was associated with BM impairment. Validation studies confirmed inflammatory cytokine impairment of BM that could be reversed by blocking IL-1R or IL-6R. Together, these studies suggest that blocking IL-1 or IL-6 receptors may improve the regenerative capacity of BM cells after AMI. CLINICAL TRIAL REGISTRATIONS: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684060.
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Células da Medula Óssea/fisiologia , Citocinas/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Infarto do Miocárdio/sangue , Medula Óssea/fisiologia , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnósticoRESUMO
BACKGROUND: As a result of physiological and metabolic changes during pregnancy, thyroid hormones can be affected significantly throughout entire three trimesters. According to the guidelines published by American Thyroid Association in 2017, it is strongly recommended to establish population-based trimester-specific and assay method-specific reference intervals (RIs) using local population. METHODS: A total of 1209 pregnant women without personal or family history of thyroid disease were recruited from July 2015 to April 2017 at Beijing Obstetrics and Gynecology Hospital. Those initially selected patients were further tested for TSH, FT4 and thyroid peroxidase antibody (aTPO), performed on the chemiluminescent platform Siemens ADVIA Centaur® XP. Only patients tested negative for aTPO were included in reference interval establishment. RIs for both TSH and FT4 were determined as 2.5th percentile to 97.5th percentile on the data distribution. RESULTS: The TSH and FT4 trimester-specific RIs were as follows: 0.59-3.54 mIU/L, 11.8-18.4 pmol/L (n = 188, 1st trimester); 0.80-4.46 mIU/L, 11.6-17.4 pmol/L (n = 133, 2nd trimester); 0.72-4.19 mIU/L, 9.7-15.1 pmol/L (n = 157, 3rd trimester). The RIs of TSH and FT4 determined by Hoffmann method for first trimester outpatient pregnant women were 0.33-3.96 mIU/L (n = 9924) and 11.7-17.5 pmol/L (n = 10039), respectively. CONCLUSION: Trimester-specific thyroid function tests RIs are distinct from those provided by assay manufacturers. The RIs determined by direct sampling and Hoffmann indirect calculation showed no statistical difference.
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Trimestres da Gravidez/sangue , Tireotropina/sangue , Tiroxina/sangue , Adulto , Estudos de Coortes , Feminino , Humanos , Gravidez , Valores de Referência , Testes de Função Tireóidea , Adulto JovemRESUMO
OBJECTIVE: To evaluate the role and the molecular mechanism of miR-30d in non-small cell lung cancer (NSCLC). RESULTS: qRT-PCR was used to detect miR-30d expression in NSCLC tissues and cell lines. miR-30d was frequently down-regulated in NSCLC and its expression was associated with clinicopathological features of NSCLCC patients. Over-expression of miR-30d notably inhibited cell migration and invasion in NSCLC cell lines. miR-30d could negatively regulate Nuclear factor I B (NFIB) by directly targeting its 3'-UTR, which was confirmed by luciferase assay. NFIB also reversed miR-30d-mediated suppression on the migration and invasion in NSCLC cell lines. CONCLUSION: miR-30d suppressed cell migration and invasion by directly targeting NFIB in NSCLC, and NFIB could partially abrogated the inhibition of biological functions by miR-30d.
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Carcinoma Pulmonar de Células não Pequenas/metabolismo , Movimento Celular/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Fatores de Transcrição NFI/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular , Linhagem Celular Tumoral , Regulação para Baixo/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genéticaRESUMO
In a period starting around 2007, the Hand, Foot, and Mouth Disease (HFMD) became wide-spreading in China, and the Chinese public health was seriously threatened. To prevent the outbreak of infectious diseases like HFMD, effective disease surveillance systems would be especially helpful to give signals of disease outbreaks as early as possible. Statistical process control (SPC) charts provide a major statistical tool in industrial quality control for detecting product defectives in a timely manner. In recent years, SPC charts have been used for disease surveillance. However, disease surveillance data often have much more complicated structures, compared to the data collected from industrial production lines. Major challenges, including lack of in-control data, complex seasonal effects, and spatio-temporal correlations, make the surveillance data difficult to handle. In this article, we propose a three-step procedure for analyzing disease surveillance data, and our procedure is demonstrated using the HFMD data collected during 2008-2009 in China. Our method uses nonparametric longitudinal data and time series analysis methods to eliminate the possible impact of seasonality and temporal correlation before the disease incidence data are sequentially monitored by a SPC chart. At both national and provincial levels, our proposed method can effectively detect the increasing trend of disease incidence rate before the disease becomes wide-spreading.
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Surtos de Doenças/estatística & dados numéricos , Doença de Mão, Pé e Boca/diagnóstico , Doença de Mão, Pé e Boca/epidemiologia , Modelos Estatísticos , Vigilância da População/métodos , Estações do Ano , China/epidemiologia , Simulação por Computador , Interpretação Estatística de Dados , Surtos de Doenças/prevenção & controle , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Incidência , Reprodutibilidade dos Testes , Medição de Risco/métodos , Sensibilidade e EspecificidadeRESUMO
MicroRNA-101(miR-101) has been shown to be down-regulated in hepatocellular carcinoma (HCC). The hepatitis B virus (HBV) is a major risk factor in the development and progression of HCC. However, the correlation between HBV and miR-101 has not yet been fully elucidated. In this study, we reported that HBV could repress miR-101-3p by inhibiting its promoter activity and identified the potential effects of miR-101-3p on some important biological properties of HCC cells by targeting Rap1b. Dual-luciferase reporter assays showed that HBV down-regulated miR-101-3p by inhibiting its promoter activity. Down-regulation of miR-101-3p promoted cell proliferation, migration, and reduced apoptosis, and resulted in up-regulation of Rap1b, while overexpression of miR-101-3p inhibited these processes. Moreover, overexpression of Rap1b was able to reverse the suppressed cell proliferation and migration mediated by miR-101-3p. Our data showed that HBV down-regulated miR-101-3p expression by inhibiting its promoter activity, which resulted in up-regulation of Rap1b, and down-regulation of miR-101-3p or up-regulation of Rap1b promoted proliferation and migration of HCC cells. This provides a new understanding of the mechanism of HBV-related HCC pathogenesis and the potential application of miR-101-3p in cancer therapy.
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Carcinoma Hepatocelular/metabolismo , Vírus da Hepatite B/fisiologia , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , Proteínas rap de Ligação ao GTP/metabolismo , Apoptose , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Regiões Promotoras GenéticasRESUMO
RAB GTPase 5A (RAB5A), a member of the Rab subfamily of small GTPases, acts as an oncogene and has been associated with various key cellular functions, including cell growth, differentiation, apoptosis and angiogenesis. Recently, it has been reported that the Rab5a gene is involved in the progression of cancer. Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers, and it is usually associated with persistent hepatitis B virus (HBV) infections. Emerging evidence suggests that HBV alters microRNA (miRNA) expression profiles, but the mechanisms underlying this process have not yet been fully elucidated. Here, we examine how HBV affects the production of miR-101-1, which has been shown to be downregulated in HCC. We found that HBV could repress miR-101-3p by inhibiting its promoter activity. Downregulation of miR-101-3p promoted cancer cell growth and migration, and a specific miR-101-3p inhibitor was able to enhance proliferation and migration. Moreover, we identified Rab5a was one of the target genes of miR-101-3p in HBV-related HCC. Forced expression of miR-101-3p in liver cell lines resulted in a marked reduction of the expression of Rab5a at both the mRNA and protein level by directly targeting the 3'untranslated region of Rab5a. Overexpression of Rab5a resulted in a reversal of the suppression of proliferation and migration of SMMC-7721 cells mediated by miR-101-3p. Taken together, our data show that HBV can downregulate miR-101-3p expression by inhibiting its promoter activity and that downregulation of miR-101-3p promotes HCC cell proliferation and migration by targeting Rab5a. This provides new insights into the mechanisms of HBV-related HCC pathogenesis.
Assuntos
Vírus da Hepatite B/fisiologia , Hepatócitos/fisiologia , MicroRNAs/antagonistas & inibidores , Proteínas rab5 de Ligação ao GTP/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , HumanosRESUMO
The effects of cross-processing lingonberry press cake (LPC) (2.5-30 %, dw/dw) with herring co-products on protein yield, oxidative stability and color of pH-shift-produced protein isolates were investigated. Even at 2.5 % LPC, the formation of volatile oxidation-derived aldehydes, including hexanal, (E)-2-hexenal, heptanal, octanal, and 2,4-heptadienal, were prevented during the actual protein isolate production. Adding 10 % LPC successfully prevented formation of all these aldehydes also during eight days ice storage which was explained by the partitioning of phenolics, especially ideain (1.09 mg/g dw) and procyanidin A1 (65.5 mg/g dw), into isolates. Although higher amounts of LPC (20-30 %) further prolonged the oxidation lag phase, it reduced total protein yield, increased the consumption of acid and base, and darkened protein isolates. Therefore, it is recommended to use 10 % LPC when pH-shift-processing sensitive fish raw materials as a route to mitigate lipid oxidation and at the same time promote industrial symbiosis and more circular food production.
RESUMO
The occurrence of acute myeloid leukemia (AML) with a simultaneous diagnosis of breast cancer (BC) is rarely reported in the literature. The present study reports the case of a 50-year-old female patient diagnosed with AML coexisting with metastatic BC. Following one cycle of treatment with azacytidine in combination with oral venetoclax for AML, the patient achieved complete remission with incomplete hematological recovery. In addition, the mass in the left breast was smaller following adjuvant chemotherapy. However, due to a refusal from the patient to accept an allogeneic hematopoietic stem cell transplantation (allo-HSCT), the patient succumbed 3 months after diagnosis due to septic shock from neutropenia following the third cycle of chemotherapy. Altogether, the present case report highlighted the application of venetoclax, an oral selective B-cell lymphoma-2 inhibitor, both in hematologic malignancies and solid neoplasms, as an effective therapeutic regimen. Considering the fatality rate associated with AML, allo-HSCT is the only available strategy that can be used to achieve the long-term survival of patients with AML and BC.