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1.
Plant Cell Environ ; 2020 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-33011994

RESUMO

CONSTANS-LIKE (COL) family members are commonly implicated in light signal transduction during early photomorphogenesis. However, some of their functions remain unclear. Here, we propose a role for COL13 in hypocotyl elongation in Arabidopsis thaliana. We found that COL13 RNA accumulates at high levels in hypocotyls and that a disruption in the COL13 function via a T-DNA insertion or RNAi led to the formation of longer hypocotyls of Arabidopsis seedlings under red light. On the contrary, overexpression of COL13 resulted in the formation of shorter hypocotyls. Using various genetic, genomic, and biochemical assays, we proved that another COL protein, COL3, directly binds to the promoter of COL13, and the promoter region of COL3 was targeted by the transcription factor LONG HYPOCOTYL 5 (HY5), to form an HY5-COL3-COL13 regulatory chain for regulating hypocotyl elongation under red light. Additionally, further study demonstrated that COL13 interacts with COL3, and COL13 promotes the interaction between COL3 and CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1), suggesting a possible COP1-dependent COL3-COL13 feedback pathway. Our results provide new information regarding the gene network in mediating hypocotyl elongation. This article is protected by copyright. All rights reserved.

2.
Hepatol Int ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026573

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) has rapidly become a major international public health concern. This study was designed to evaluate the clinical characteristics and risk factors of COVID-19-associated liver injury. METHODS: A fraction of 657 COVID-19 patients were retrospectively analyzed. Clinical and laboratory data were derived from electronic medical records and compared between patients with or without liver injury. Multivariate logistic regression method was used to analyze the risk factors for liver injury. RESULTS: Among 657 patients, 303 (46.1%) patients had liver injury with higher rate in severe/critically ill patients [148/257 (57.6%)] than those in moderate cases [155/400 (38.8%)]. The incidence of liver injury was much higher in male [192/303 (63.4%)] than female [111/303 (36.6%)], and in severe/critical patients [148/303 (48.8%)] with percutaneous oxygen saturation ≤ 93% [89/279 (31.9%)] or peak body temperature ≥ 38.5 °C [185/301 (61.5%)] on admission. Liver injury-related inflammations included increased white blood cells, neutrophils and decreased lymphocytes. More patients with liver injury than without had increased serum IL-2R, TNFα, ferritin, hsCRP, PCT, ESR, γ-GT, and LDH. Multivariate regression analysis revealed that increasing odds of liver injury were related to male, higher serum hsCRP (≥ 10 mg/L), and neutrophil-to-lymphocyte ratio (NLR) (≥ 5). Moreover, more deceased patients (14/82 (17%)) had significantly elevated serum TBIL than discharged patients [25/532 (4.7%)]. CONCLUSION: Liver injury is a common complication in COVID-19 patients. The potential risk factors of liver injury include male, hsCRP and NLR score. A close monitor of liver function should be warned in COVID-19 patients, especially in severe/critical individuals.

3.
J Am Acad Audiol ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33036034

RESUMO

BACKGROUND: Patients with vestibular neuritis (VN) displayed differential prognosis despite of the same treatment. Thus, identifying unique characteristics in different populations and creating individually customized treatments are necessary. However, studies about the clinical features according to different ages are scarce. PURPOSE: This article compares the differences in VN patients among different age groups. RESEARCH DESIGN: A prospective study. STUDY SAMPLE: A total of 70 VN patients were enrolled in the present study. INTERVENTION: All the patients started vestibular rehabilitation at the time of initial presentation to our clinic. They were followed up at 1-month intervals using the questionnaire until 4 months. DATA COLLECTION AND ANALYSIS: Patients' clinical data including clinical presentation, vestibular testing results, treatment, and recovery was collected and analyzed with Duncan's multiple range test, the sign test, and the Kruskal-Wallis test using SPSS18.0. RESULTS: The mean age of the 70 patients was 47.2 ± 17.1, ranging from 10 to 76 years old. The sex ratios (male:female) were 3.5 in the adolescent group, 0.643 in the young adult group, 1.375 in the middle-aged group, and 0.583 in the senior group. The prevalence of hypertension and diabetes mellitus showed a significantly increasing trend from young adults to the seniors (p < 0.05). The caloric response was statistically worse in the senior group than the other groups (p < 0.05). The abnormal rates for video head impulse test, vestibular-evoked myogenic potential, and vestibular autorotation test did not differ significantly in different age groups. A significant difference between prerehabilitation and postrehabilitation total Dizziness Handicap Inventory (DHI) scores was identified in all the groups (p < 0.05). The younger patients demonstrated a greater improvement than patients in the senior group, meanwhile adolescents improved the most (p < 0.05). Hospital Anxiety and Depression Scale (HADS) was the lowest in the adolescent group (p < 0.05). DHI score at acute stage was significantly correlated with HADS (r = 0.597, p < 0.05). CONCLUSION: The canal response was statistically better for younger patients compared with the elderly. The younger patients demonstrated a greater improvement than patients in the senior group, among whom adolescents improved the most, meanwhile psychological factors played a minor role in adolescents. Self-perceived disability-handicap positively correlated with anxiety and depression in all patients.

4.
J Nutr Biochem ; 85: 108460, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32992072

RESUMO

Previous studies suggested that high consumption of saturated fatty acid (SFA) is a risk factor for liver cancer. However, it remains unclear how dietary SFA affects liver tumorigenesis. This study aimed to investigate the impact of a SFA-rich diet on hepatic tumorigenesis using hepatitis C virus core gene transgenic (HCVcpTg) mice that spontaneously developed hepatic steatosis and tumors with aging. Male HCVcpTg mice were treated for 15 months with a purified control diet or SFA-rich diet prepared by replacing soybean oil in the control diet with hydrogenated coconut oil, and phenotypic changes were assessed. In this special diet, almost all dietary fatty acids were SFA. Long-term feeding of SFA-rich diet to HCVcpTg mice increased hepatic steatosis, liver dysfunction, and the prevalence of liver tumors, likely due to stimulation of de novo lipogenesis, activation of the pro-inflammatory and pro-oncogenic transcription factor nuclear factor-kappa B (NF-κB), enhanced c-Jun N-terminal kinase/activator protein 1 (JNK/AP-1) signaling and induction of the oncogenes cyclin D1 and p62/sequestosome 1. The SFA-rich diet did not affect liver fibrosis or autophagy. Collectively, long-term SFA-rich diet consumption promoted hepatic tumorigenesis mainly through activation of lipogenesis, NF-κB, and JNK/AP-1 signaling. We therefore propose that HCV-infected patients should avoid excessive intake of SFA-rich foods to prevent liver cancer.

5.
Int J Mol Sci ; 21(18)2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32916850

RESUMO

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function mutations of tumor protein p53 (TP53). However, it remains poorly understood whether HNSCCs harboring different genetic alterations exhibit differential immune tumor microenvironments (TME). It also remains unknown whether PIK3CA hyperactivation and TP53 deletion can lead to SCC development spontaneously. Here, we analyzed the Cancer Genome Atlas (TCGA) datasets of HNSCCs and found that patients with both PIK3CA and TP53 alterations exhibited worse survival, significantly lower CD8 tumor infiltrating lymphocytes (TILs) and higher M0 macrophages than other controls. To better model human tumorigenesis, we deleted TP53 and constitutively activated PIK3CA in mouse keratin-15-expressing stem cells, which leads to the spontaneous development of multilineage tumors including SCCs, termed Keratin-15-p53-PIK3CA (KPPA) tumors. KPPA tumors were heavily infiltrated with myeloid-derived suppressor cells (MDSCs), with a drastically increased ratio of polymorphonuclear-MDSC (PMN-MDSC) versus monocytic-MDSC (M-MDSC). CD8 TILs expressed more PD-1 and reduced their polyfunctionality. Overall, we established a genetic model to mimic human HNSCC pathogenesis, manifested with an immunosuppressive TME, which may help further elucidate immune evasion mechanisms and develop more effective immunotherapies for HNSCCs.

6.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(9): 1253-1258, 2020 Sep 30.
Artigo em Chinês | MEDLINE | ID: mdl-32990230

RESUMO

OBJECTIVE: To explore the correlation of plasma N-acetyl-neuraminic acid level with Thrombolysis In Myocardial Infarction (TIMI) risk score and clinical outcomes of patients with acute coronary syndrome (ACS). METHODS: We consecutively enrolled 708 consecutive patients (401 male and 307 female, mean age 63.6±10.6 years) undergoing coronary angiography in our hospital between October, 2018 and July, 2019, including 597 patients with ACS and 111 without ACS (control group). The patients with ACS group were divided into high (n=104), moderate (n=425) and low (n=68) risk groups according to their TIMI risk scores. All the participants were examined for plasma Neu5Ac level using liquid chromatography-tandem mass spectrometry and underwent coronary angiography with their Gensini scores calculated. The patients with ACS were followed up after discharge for a mean of 15 months for the occurrence of major adverse cardiac events (Mace). Binary logistic regression analysis was performed to identify the risk factors of Mace in these patients. RESULTS: Plasma Neu5Ac levels were significantly higher in ACS group than in the control group (P < 0.05). ROC curve analysis showed that plasma Neu5Ac level could assist in the diagnosis of ACS (0.648 [0.597-0.699]) with a sensitivity of 39.2% and a specificity of 86.5% at the cutoff value of 288.50 ng/mL. In the ACS patients, plasma Neu5Ac level was significantly higher in the high-risk group than in the moderate-risk and low-risk groups (P < 0.05) and could assist in the diagnosis of a high risk (0.645 [0.588-0.703]) with a sensitivity of 42.3% and a specificity of 80.1% at the cutoff value of 327.50 ng/ mL. Plasma Neu5Ac was positively correlated with age, serum uric acid, creatinine, lipoprotein a, Ddimer, C-reactive protein, MB isoform of creatine kinase and Gensini score and negatively correlated with high-density lipoprotein level. During the followup, 80 ACS patients experienced Mace, who had significantly higher plasma Neu5Ac level than those without Mace (n=517). Logistic regression analysis showed that plasma Neu5Ac level and a history of previous stroke were independent risk factors for the occurrence of Mace. CONCLUSIONS: Plasma Neu5Ac level can provide assistance in the diagnosis and risk stratification of ACS and is an independent risk factor for prognosis of ACS patients.

7.
Exp Cell Res ; 396(2): 112310, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32991875

RESUMO

BACKGROUND: Cleft palate is a common craniofacial defect, which occurs when the palate fails to fuse during development. During fusion, the palatal shelves migrate towards the embryonic midline to form a seam. Apoptotic elimination of medial edge epithelium (MEE) cells along this seam is required for the completion of palate fusion. METHODS: Whole exome sequencing (WES) of six Chinese cleft palate families was applied to identify novel cleft palate-associated gene variants. Palatal fusion and immunofluorescence studies were performed in a murine palatal shelf organ culture model. Gene and protein expression were analyzed by qPCR and immunoblotting in murine MEE cells during seam formation in vivo. Mechanistic immunoprecipitation studies were performed in murine MEE cells in vitro. RESULTS: WES identified Bcl-2 associated anthanogene 6 (BAG6) as a novel cleft palate-associated gene. In murine MEE cells, we discovered upregulation of Bag6 and the transcription factor forkhead box protein O1 (FoxO1) during seam formation in vivo. Using a palatal shelf organ culture model, we demonstrate that nuclear-localized Bag6 enhances MEE cell apoptosis by promoting p300's acetylation of FoxO1, thereby promoting transcription of the pro-apoptotic Fas ligand (FasL). Subsequent gain- and loss-of-function studies in the organ culture model demonstrated that FasL is required for Bag6/acFoxO1-mediated activation of pro-apoptotic Bax/caspase-3 signaling, MEE apoptosis, and palate fusion. Palatal shelf contact was shown to enhance Bag6 nuclear localization and upregulate nuclear acFoxO1 in MEE cells. CONCLUSIONS: These findings demonstrate that nuclear-localized Bag6 and p300 co-operatively enhance FoxO1 acetylation to promote FasL-mediated MEE apoptosis during palate fusion.

8.
Phytochem Rev ; : 1-24, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32994757

RESUMO

Naturally occurring phenanthroindolizidine and phenanthroquinolizidine alkaloids (PIAs and PQAs) are two small groups of herbal metabolites sharing a similar pentacyclic structure with a highly oxygenated phenanthrene moiety fused with a saturated or an unsaturated N-heterocycle (indolizidine/quinolizidine moieties). Natural PIAs and PQAs only could be obtained from finite plant families (such as Asclepiadaceae, Lauraceae and Urticaceae families, etc.). Up to date, more than one hundred natural PIAs, while only nine natural PQAs had been described. PIA and PQA analogues have been applied to the development of potent anticancer agents all along because of their excellent cytotoxic activity. However, in the last two decades, other great biological properties, such as anti-inflammatory and antiviral activities were revealed successively by different pharmacological assays. Especially because of their potent antiviral activity against coronavirus (TGEV, SARS CoV and MHV) and tobacco mosaic virus, PIA and PQA analogues have attracted much pharmaceutical attention again, some of them have been used to present interesting targets for total or semi synthesis, and structure-activity relationship (SAR) study for the development of antiviral agents. In this review, natural PIA and PQA analogues obtained in the last two decades with their herbal origins, key spectroscopic characteristics for structural identification, biological activity with possible SARs and application prospects were systematically summarized. We hope this paper can stimulate further investigations on PIA and PQA analogues as an important source for potential drug discovery.

10.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(8): 673-679, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32958122

RESUMO

Objective To investigate the therapeutic effect and mechanism of paeoniflorin on dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) mice. Methods C57BL/6 male mice were randomly divided into control group, model group, 600 mg/(kg.d) mesalazine treatment group, (12.5, 25, 50) mg/(kg.d) paeoniflorin treatment group, with 10 mice in each. All mice were treated with 30 g/L DSS for 5 days except the control group. Meanwhile, the mice in the other groups were orally administrated corresponding drugs for 10 days, while the mice in the control and model groups were given equivalent volumes of distilled water. Body mass, fecal characteristics and hematochezia of the mice were observed and recorded daily, and then disease activity index (DAI) was evaluated and calculated. Pathological changes in the colon were observed by HE staining. The levels of anti-flagellin antibody, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in the serum were measured by ELISA. The expression levels of Toll-like receptor 5 (TLR5), myeloid differentiation factor 88 (MyD88) and nuclear factor kappa-Bp65 (NF-κBp65) in the colon tissues were evaluated by Western blot analysis and the activation of lymphocytes in mesenteric lymph node (MLN) was detected by flow cytometry. Results Compared with the control group, DAI scores in the model group were significantly raised, the colon length was significantly shortened, and the epithelium and intestinal gland disappeared. In addition, the serum levels of anti-flagellin antibody, IL-6, TNF-α and the protein levels of TLR5, MyD88, NF-κBp65 in the colon significantly increased, and the activation of T lymphocytes in MLN went up in the model group. All symptoms above were alleviated in the mesalazine and paeoniflorin groups compared with the model group. Conclusion Paeoniflorin can attenuate UC in mice by inhibiting the expression of flagellin and TLR5, and the activation of T cells.

11.
BMC Cardiovasc Disord ; 20(1): 404, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912159

RESUMO

BACKGROUND: N-acetylneuraminic acid (Neu5Ac) is a functional metabolite involved in coronary artery disease (CAD). We aimed to evaluate the relationship between serum Neu5Ac and the risk and prognosis of acute coronary syndrome (ACS) in a real-world prospective study. METHODS: Patients with suspected ACS who underwent coronary angiography were included. Serum Neu5Ac was measured at admission. Coronary lesion severity was evaluated by Gensini Score. GRACE risk stratification was performed at admission. Major adverse cardiac events (MACEs) were recorded during follow-up. RESULTS: A total of 766 patients, including 537 with unstable angina (UAP), 100 with myocardial infarction (MI), and 129 without CAD were included. The circulating Neu5Ac level was significantly higher in patients with MI (median [1QR]: 297[220, 374] ng/ml) than in those with UAP (227 [114, 312] ng/ml) or without CAD (207 [114, 276] ng/ml; both p < 0.001). Serum level of Neu5Ac was positively correlated with age, hypertension, serum uric acid, creatinine, MB isoform of creatine kinase (CK-MB), and Gensini score (all p < 0.05). Receiver operating characteristic curve analysis showed that a higher serum Neu5Ac was potentially associated with MI and high-risk GRACE stratification in ACS patients. Logistic analysis identified only elevated serum Neu5Ac as an independent predictor of MACEs in these patients (odds ratio [OR]: 1.003, 95% confidence interval [CI]: 1.002-1.005, p < 0.001). CONCLUSIONS: Serum Neu5Ac is associated with myocardial injury, GRACE risk category, and prognosis in ACS patients.

12.
Theranostics ; 10(21): 9702-9720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32863955

RESUMO

Rationale: The functions of fibrinogen-like protein 2 (fgl2) have been studied in many inflammatory and neoplastic diseases, but the role of fgl2 in nonalcoholic fatty liver disease has not yet been elucidated. In this study, we sought to investigate the role of fgl2 in the pathogenesis of nonalcoholic steatohepatitis (NASH). Methods: Hepatic fgl2 expression was tested in patients with nonalcoholic fatty liver (NAFL) or NASH and controls. Wild-type and fgl2-/- C57BL/6 mice were subjected to a methionine/choline-deficient (MCD) diet or a high-fat diet (HFD) to establish NASH models. Bone marrow-derived macrophages (BMDMs) stimulated with LPS or free fatty acids were used for the in vitro study. Results: In both humans and mice with NASH, macrophage accumulation was concomitant with significantly increased fgl2 expression in the liver. Fgl2 deficiency attenuated liver steatosis and inflammation in diet-induced murine models of NASH. In both liver tissues and BMDMs from NASH mice, fgl2 deficiency resulted in reduced levels of proinflammatory cytokines and reactive oxygen species (ROS) compared with levels in wild-type controls. Activation of NF-κB, p38-MAPK and NLRP3 inflammasomes was also suppressed upon fgl2 disruption. Moreover, lipogenic genes (Fasn and SREBP-2) were downregulated while lipolytic genes (PPAR and CPT1A) were upregulated in the livers of fgl2-/- NASH mice. Primary hepatocytes incubated with the medium collected from fgl2-/- BMDMs showed less fat deposition than those incubated with WT BMDMs. Furthermore, we discovered that fgl2 combined with TLR4 mediates the activation of the Myd88-dependent signaling pathway, which may contribute to inflammation and lipid metabolism disorders. Conclusions: These data suggest that fgl2 aggravates the progression of NASH through activation of NF-κB, p38-MAPK and NLRP3 inflammasomes in macrophages, which consequently induces overproduction of proinflammatory cytokines and lipid metabolism disorders. An interaction of fgl2 and TLR4 may in part contribute to the activation of inflammatory signaling pathways in macrophages.

13.
Artigo em Inglês | MEDLINE | ID: mdl-32954689

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) play critical regulatory roles in diverse biological processes and diseases. While a large number of lncRNAs have been identified in skeletal muscles until now, their function and underlying mechanisms in skeletal myogenesis remain largely unclear. METHODS: We characterized a novel functional lncRNA designated lncMGPF (lncRNA muscle growth promoting factor) using RACE, Northern blot, fluorescence in situ hybridization and quantitative real-time PCR. Its function was determined by gene overexpression, interference, and knockout experiments in C2C12 myoblasts, myogenic progenitor cells, and an animal model. The molecular mechanism by which lncMGPF regulates muscle differentiation was mainly examined by cotransfection experiments, luciferase reporter assay, RNA immunoprecipitation, RNA pull-down, and RNA stability analyses. RESULTS: We report that lncMGPF, which is highly expressed in muscles and positively regulated by myoblast determination factor (MyoD), promotes myogenic differentiation of muscle cells in vivo and in vitro. lncMGPF knockout in mice substantially decreases growth rate, reduces muscle mass, and impairs muscle regeneration. Overexpression of lncMGPF in muscles can rescue the muscle phenotype of knockout mice and promote muscle growth of wild-type mice. Mechanistically, lncMGPF promotes muscle differentiation by acting as a molecular sponge of miR-135a-5p and thus increasing the expression of myocyte enhancer factor 2C (MEF2C), as well as by enhancing human antigen R-mediated messenger RNA stabilization of myogenic regulatory genes such as MyoD and myogenin (MyoG). We confirm that pig lncRNA AK394747 and human lncRNA MT510647 are homologous to mouse lncMGPF, with conserved function and mechanism during myogenesis. CONCLUSIONS: Our data reveal that lncMGPF is a novel positive regulator of myogenic differentiation, muscle growth and regeneration in mice, pigs, and humans.

14.
Neuron ; 107(6): 1048-1070, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32970997

RESUMO

Artificial neural networks (ANNs) are essential tools in machine learning that have drawn increasing attention in neuroscience. Besides offering powerful techniques for data analysis, ANNs provide a new approach for neuroscientists to build models for complex behaviors, heterogeneous neural activity, and circuit connectivity, as well as to explore optimization in neural systems, in ways that traditional models are not designed for. In this pedagogical Primer, we introduce ANNs and demonstrate how they have been fruitfully deployed to study neuroscientific questions. We first discuss basic concepts and methods of ANNs. Then, with a focus on bringing this mathematical framework closer to neurobiology, we detail how to customize the analysis, structure, and learning of ANNs to better address a wide range of challenges in brain research. To help readers garner hands-on experience, this Primer is accompanied with tutorial-style code in PyTorch and Jupyter Notebook, covering major topics.

15.
Nucleic Acids Res ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32810235

RESUMO

Although cancer is the leading cause of disease-related mortality in children, the relative rarity of pediatric cancers poses a significant challenge for developing novel therapeutics to further improve prognosis. Patient-derived xenograft (PDX) models, which are usually developed from high-risk tumors, are a useful platform to study molecular driver events, identify biomarkers and prioritize therapeutic agents. Here, we develop PDX for Childhood Cancer Therapeutics (PCAT), a new integrated portal for pediatric cancer PDX models. Distinct from previously reported PDX portals, PCAT is focused on pediatric cancer models and provides intuitive interfaces for querying and data mining. The current release comprises 324 models and their associated clinical and genomic data, including gene expression, mutation and copy number alteration. Importantly, PCAT curates preclinical testing results for 68 models and 79 therapeutic agents manually collected from individual agent testing studies published since 2008. To facilitate comparisons of patterns between patient tumors and PDX models, PCAT curates clinical and molecular data of patient tumors from the TARGET project. In addition, PCAT provides access to gene fusions identified in nearly 1000 TARGET samples. PCAT was built using R-shiny and MySQL. The portal can be accessed at http://pcat.zhenglab.info or http://www.pedtranscriptome.org.

16.
J BUON ; 25(3): 1619-1624, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32862613

RESUMO

PURPOSE: To explore the associations between the expressions of micro ribonucleic acid (miR)-135 and miR-92a and the pathogenesis of prostate cancer, as well as their clinical significance. METHODS: A total of 40 prostate cancer patients were studied. The associations of expressions of miR-135 and miR-92a with the pathological Gleason score and expression of prostate specific antigen (PSA) were assessed, the sensitivity and specificity of miR-135 and miR-92a in the diagnosis of prostate cancer were compared, and the associations between the expressions of miR-135 and miR-92a and the prognosis of prostate cancer patients were evaluated. RESULTS: In patients with pathological Gleason score ≥8 points the expression level of miR-135 was significantly lower (p<0.05), while that of miR-92a was significantly higher than those in patients with pathological Gleason score <8 points (p<0.05). In patients with PSA expression >10 ng/mL the expression level of miR-135 was obviously lower (p<0.05), while that of miR-92a was obviously higher than those in patients with PSA expression ≤10 ng/mL (p<0.05). The expression of miR-135 was negatively correlated with the pathological Gleason score and PSA expression (p<0.05), while the expression of miR-92a was positively correlated with the pathological Gleason score and PSA expression (p<0.05). The sensitivity and specificity of miR-135 and miR-92a in the diagnosis were above 80% and about 70%, respectively. In miR-135-positive patients, the mean survival time was longer (p<0.05) and the 2-year survival rate was higher than those in miR-135-negative patients (p<0.05). In miR-92a-positive patients, the mean survival time was shorter (p<0.05) and the 2-year survival rate was lower than those in miR-92a-negative patients (p<0.05). CONCLUSIONS: The expressions of miR-135 and miR-92a are of certain value in screening prostate cancer. The prognosis and survival of patients are positively correlated with the miR-135 expression and negatively correlated with the miR-92a expression.

17.
Cancer Res ; 80(19): 4185-4198, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32816856

RESUMO

Tumor-associated macrophages (TAM) in the tumor microenvironment (TME) cooperate with cancer stem cells (CSC) to maintain stemness. We recently identified cluster of differentiation 44 (CD44) as a surface marker defining head and neck squamous cell carcinoma (HNSCC) CSC. PI3K-4EBP1-SOX2 activation and signaling regulate CSC properties, yet the upstream molecular control of this pathway and the mechanisms underlying cross-talk between TAM and CSC in HNSCC remain largely unknown. Because CD44 is a molecular mediator in the TME, we propose here that TAM-influenced CD44 signaling could mediate stemness via the PI3K-4EBP1-SOX2 pathway, possibly by modulating availability of hyaluronic acid (HA), the main CD44 ligand. HNSCC IHC was used to identify TAM/CSC relationships, and in vitro coculture spheroid models and in vivo mouse models were used to identify the influence of TAMs on CSC function via CD44. Patient HNSCC-derived TAMs were positively and negatively associated with CSC marker expression at noninvasive and invasive edge regions, respectively. TAMs increased availability of HA and increased cancer cell invasion. HA binding to CD44 increased PI3K-4EBP1-SOX2 signaling and the CSC fraction, whereas CD44-VCAM-1 binding promoted invasive signaling by ezrin/PI3K. In vivo, targeting CD44 decreased PI3K-4EBP1-SOX2 signaling, tumor growth, and CSC. TAM depletion in syngeneic and humanized mouse models also diminished growth and CSC numbers. Finally, a CD44 isoform switch regulated epithelial-to-mesenchymal plasticity as standard form of CD44 and CD44v8-10 determined invasive and tumorigenic phenotypes, respectively. We have established a mechanistic link between TAMs and CSCs in HNSCC that is mediated by CD44 intracellular signaling in response to extracellular signals. SIGNIFICANCE: These findings establish a mechanistic link between tumor cell CD44, TAM, and CSC properties at the tumor-stroma interface that can serve as a vital area of focus for target and drug discovery.

18.
J Am Chem Soc ; 142(40): 17093-17104, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-32833442

RESUMO

Combinatorial biosynthesis with fungal polyketide synthases (PKSs) promises to produce unprecedented bioactive "unnatural" natural products (uNPs) for drug discovery. Genome mining of the dothideomycete Rhytidhysteron rufulum uncovered a collaborating highly reducing PKS (hrPKS)-nonreducing PKS (nrPKS) pair. These enzymes produce trace amounts of rare S-type benzenediol macrolactone congeners with a phenylacetate core in a heterologous host. However, subunit shuffling and domain swaps with voucher enzymes demonstrated that all PKS domains are highly productive. This contradiction led us to reveal novel programming layers exerted by the starter unit acyltransferase (SAT) and the thioesterase (TE) domains on the PKS system. First, macrocyclic vs linear product formation is dictated by the intrinsic biosynthetic program of the TE domain. Next, the chain length of the hrPKS product is strongly influenced in trans by the off-loading preferences of the nrPKS SAT domain. Last, TE domains are size-selective filters that facilitate or obstruct product formation from certain priming units. Thus, the intrinsic programs of the SAT and TE domains are both part of the extrinsic program of the hrPKS subunit and modulate the observable metaprogram of the whole PKS system. Reconstruction of SAT and TE phylogenies suggests that these domains travel different evolutionary trajectories, with the resulting divergence creating potential conflicts in the PKS metaprogram. Such conflicts often emerge in chimeric PKSs created by combinatorial biosynthesis, reducing biosynthetic efficiency or even incapacitating the system. Understanding the points of failure for such engineered biocatalysts is pivotal to advance the biosynthetic production of uNPs.

19.
Langmuir ; 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32787068

RESUMO

C-doped ZnO particles have been successfully prepared by the calcination using microwave hydrothermally prepared metal-organic framework-5 (MOF-5) as the precursor. MOF-5 was turned into C-doped ZnO through calcination at 500 °C, and its cubic shape was well-maintained. X-ray photoelectron spectroscopic studies confirmed the C-doping in the ZnO. The as-prepared C-doped ZnO demonstrated a Rhodamine B (RhB) degradation efficiency of 98% in 2 h under an solar-simulated light irradiation, much higher than that of C-doped ZnO derived from MOF-5 synthesized by the ordinary hydrothermal method. The trapping experiment revealed that the crucial factors in the RhB removal were photogenerated h+ and •O2-.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32614605

RESUMO

Objectives: Fufang Banmao (FFBM) capsule, a type of Chinese medicinal formulation, has decades of history in treating hepatocellular carcinoma (HCC). This retrospective study aimed to observe the effect of FFBM capsules on the 6-month survival of patients with advanced HCC and Vp3-4 portal vein tumor thrombosis (PVTT) who received supportive therapy alone. Design: In total, 320 HCC/Vp3-4 PVTT patients underwent treatment with supportive therapy, of whom 95 took FFBM capsules and were treated with supportive therapy (FFBM group) and 225 received supportive therapy alone (control group). Comparisons of the 6-month overall survival (OS) rate of the two groups were performed. Propensity score matching (PSM) was used to match the characteristics between individuals in the two groups. A nomogram was built based on independent predictive factors for OS. Results: Cox multivariate analysis revealed that hepatic encephalopathy, aspartate transaminase (AST) and γ-glutamyl transpeptidase levels, Child-Pugh class, prothrombin time, α-fetoprotein level, largest tumor diameter, and use of FFBM capsules were independent predictive factors of OS. Variceal bleeding, alanine transaminase, AST, total bilirubin, and Barcelona Clinic for Liver Cancer stage were different at baseline in the FFBM and control groups. Analysis revealed no significant adverse effects or toxicities relevant to the medications. After PSM (1:1), 95 patient pairs were analyzed as FFBM versus control. The OS probability was remarkably higher for patients in the FFBM group than in those in the control group at 6 months (p < 0.0001). The median survival time was 4 months in the FFBM group and 2.2 months in the control group. Kaplan-Meier analysis showed significant statistical differences in the 6-month OS rates in the patients with total nomogram scores ≥84 (p < 0.0001). Conclusions: Given the satisfying survival outcomes, the results suggested that FFBM capsules should be administered to patients with HCC/Vp3-4 PVTT in the high-risk group (score ≥84). FFBM capsules have the potential for improving patient survival time in those with advanced HCC and Vp3-4 PVTT who receive supportive therapy alone, especially those in the high-risk group (score ≥84).

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