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2.
Virol J ; 18(1): 216, 2021 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-34743709

RESUMO

BACKGROUND: With the advancement of sequencing technologies, a plethora of noncoding RNA (ncRNA) species have been widely discovered, including microRNAs (miRNAs), circular RNAs (circRNAs), and long ncRNAs (lncRNAs). However, the mechanism of these non-coding RNAs in diseases caused by enterovirus d68 (EV-D68) remains unclear. The goal of this research was to identify significantly altered circRNAs, lncRNAs, miRNAs, and mRNAs pathways in RD cells infected with EV-D68, analyze their target relationships, demonstrate the competing endogenous RNA (ceRNA) regulatory network, and evaluate their biological functions. METHODS: The total RNAs were sequenced by high-throughput sequencing technology, and differentially expressed genes between control and infection groups were screened using bioinformatics method. We discovered the targeting relationship between three ncRNAs and mRNA using bioinformatics methods, and then built a ceRNA regulatory network centered on miRNA. The biological functions of differentially expressed mRNAs (DEmRNAs) were discovered through GO and KEGG enrichment analysis. Create a protein interaction network (PPI) to seek for hub mRNAs and learn more about protein-protein interactions. The relative expression was verified using RT-qPCR. The effects of Fos and ARRDC3 on virus replication were confirmed using RT-qPCR, virus titer (TCID50/ml), Western blotting. RESULTS: 375 lncRNAs (154 upregulated and 221 downregulated), 33 circRNAs (32 upregulated and 1 downregulated), 96 miRNAs (49 upregulated and 47 downregulated), and 239 mRNAs (135 upregulated and 104 downregulated) were identified as differently in infected group compare to no-infected group. A single lncRNA or circRNA can be connected with numerous miRNAs, which subsequently coregulate additional mRNAs, according to the ceRNA regulatory network. The majority of DEmRNAs were shown to be connected to DNA binding, transcription regulation by RNA polymerase II, transcription factor, MAPK signaling pathways, Hippo signal pathway, and apoptosis pathway, according to GO and KEGG pathway enrichment analysis. The hub mRNAs with EGR1, Fos and Jun as the core were screened through PPI interaction network. We preliminarily demonstrated that the Fos and ARRDC3 genes can suppress EV-D68 viral replication in order to further verify the results of full transcriptome sequencing. CONCLUSION: The results of whole transcriptome analysis after EV-D68 infection of RD cells were first reported in this study, and for the first time, a ceRNA regulation network containing miRNA at its center was established for the first time. The Fos and ARRDC3 genes were found to hinder viral in RD cells. This study establishes a novel insight host response during EV-D68 infection and further investigated potential drug targets.

3.
Cancer Commun (Lond) ; 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34738326

RESUMO

BACKGROUND: To date, there is no approved blood-based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker. METHODS: We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital. Training cohort and two validation cohorts were introduced for diagnostic exploration and validation. A pan-cancer cohort was used to independently explore the diagnostic potential of SEMA4C among solid tumors. Breast cancer patients who underwent mass excision prior to modified radical mastectomy were also analyzed. We hypothesized that increased pre-treatment serum SEMA4C levels, measured using optimized in-house enzyme-linked immunosorbent assay kits, could detect breast cancer. The endpoints were diagnostic performance, including area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Post-surgery pathological diagnosis was the reference standard and breast cancer staging followed the TNM classification. There was no restriction on disease stage for eligibilities. RESULTS: We included 2667 inpatients with breast lesions, 2378 patients with other solid tumors, and 1168 healthy participants. Specifically, 118 patients with breast cancer were diagnosed with stage 0 (5.71%), 620 with stage I (30.00%), 966 with stage II (46.73%), 217 with stage III (10.50%), and 8 with stage IV (0.39%). Patients with breast cancer had significantly higher serum SEMA4C levels than benign breast tumor patients and normal controls (P < 0.001). Elevated serum SEMA4C levels had AUC of 0.920 (95% confidence interval [CI]: 0.900-0.941) and 0.932 (95%CI: 0.911-0.953) for breast cancer detection in the two validation cohorts. The AUCs for detecting early-stage breast cancer (n = 366) and ductal carcinoma in situ (n = 85) were 0.931 (95%CI: 0.916-0.946) and 0.879 (95%CI: 0.832-0.925), respectively. Serum SEMA4C levels significantly decreased after surgery, and the reduction was more striking after modified radical mastectomy, compared with mass excision (P < 0.001). The positive rate of enhanced serum SEMA4C levels was 84.77% for breast cancer and below 20.75% for the other 14 solid tumors. CONCLUSIONS: Serum SEMA4C demonstrated promising potential as a candidate biomarker for breast cancer diagnosis. However, validation in prospective settings and by other study groups is warranted.

4.
J Exp Clin Cancer Res ; 40(1): 292, 2021 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-34538264

RESUMO

BACKGROUND: Ovarian cancer (OC) progression is an unmet medical challenge. Since omental metastases were palpated harder than their primary counterparts during cytoreductive surgery of patients with epithelial ovarian cancer (EOC), we were inspired to investigate OC progression from the perspective of biomechanics. METHODS: Atomic Force Microscope (AFM) was used to measure the Young's modulus of tissues. The collagen-coated polyacrylamide hydrogel (PA gel) system was prepared to mimic the soft and stiff substrates in vitro. The effect of TAGLN was evaluated both in vitro and in vivo using transwell assay, immunofluorescence, western blot analysis and immunohistochemistry. RESULTS: We quantitatively confirmed that omental metastases were stiffer and more abundant in desmoplasia compared with paired primary tumors, and further demonstrated that matrix stiffness could notably regulate OC progression. Remarkably, TAGLN, encoding an actin cross-linking/gelling protein, was identified as a potent mechanosensitive gene that could form a regulation loop with Src activation reacting to environmental stiffness, thus mediating stiffness-regulated OC progression through regulating RhoA/ROCK pathway. CONCLUSIONS: These data demonstrate that targeting extra-cellular matrix (ECM) stiffness could probably hamper OC progression, and of note, targeting TAGLN might provide promising clinical therapeutic value for OC therapy.

6.
Cancers (Basel) ; 13(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34298731

RESUMO

Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer death in women worldwide. Although early diagnosis and cancer growth inhibition has significantly improved breast cancer survival rate over the years, there is a current need to develop more effective systemic treatments to prevent metastasis. One of the most commonly altered pathways driving breast cancer cell growth, survival, and motility is the PI3K/AKT/mTOR signaling cascade. In the past 30 years, a great surge of inhibitors targeting these key players has been developed at a rapid pace, leading to effective preclinical studies for cancer therapeutics. However, the central role of PI3K/AKT/mTOR signaling varies among diverse biological processes, suggesting the need for more specific and sophisticated strategies for their use in cancer therapy. In this review, we provide a perspective on the role of the PI3K signaling pathway and the most recently developed PI3K-targeting breast cancer therapies.

7.
NPJ Precis Oncol ; 5(1): 49, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108603

RESUMO

Cancer-associated fibroblasts (CAFs) play significant roles in drug resistance through different ways. Antitumor therapies, including molecular targeted interventions, not only effect tumor cells but also modulate the phenotype and characteristics of CAFs, which can in turn blunt the therapeutic response. Little is known about how stromal fibroblasts respond to poly (ADP-ribose) polymerase inhibitors (PARPis) in ovarian cancer (OC) and subsequent effects on tumor cells. This is a study to evaluate how CAFs react to PARPis and their potential influence on PARPi resistance in OC. We discovered that OC stromal fibroblasts exhibited intrinsic resistance to PARPis and were further activated after the administration of PARPis. PARPi-challenged fibroblasts displayed a specific secretory profile characterized by increased secretion of CCL5, MIP-3α, MCP3, CCL11, and ENA-78. Mechanistically, increased secretion of CCL5 through activation of the NF-κB signaling pathway was required for PARPi-induced stromal fibroblast activation in an autocrine manner. Moreover, neutralizing CCL5 partly reversed PARPi-induced fibroblast activation and boosted the tumor inhibitory effect of PARPis in both BRCA1/2-mutant and BRCA1/2-wild type xenograft models. Our study revealed that PARPis could maintain and improve stromal fibroblast activation involving CCL5 autocrine upregulation. Targeting CCL5 might offer a new treatment modality in overcoming the reality of PARPi resistance in OC.

8.
Oncogene ; 40(22): 3845-3858, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33966038

RESUMO

PARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein ß (C/EBPß), a transcription factor, was inversely correlated with PARPi sensitivity in vitro and in vivo, both in HR-proficient condition. High C/EBPß expression enhanced PARPi tolerance; PARPi treatment in turn induced C/EBPß expression. C/EBPß directly targeted and upregulated multiple HR genes (BRCA1, BRIP1, BRIT1, and RAD51), thereby inducing restoration of HR capacity and mediating acquired PARPi resistance. C/EBPß is a key regulator of the HR pathway and an indicator of PARPi responsiveness. Targeting C/EBPß could induce HR deficiency and rescue PARPi sensitivity accordingly. Our findings indicate that HR-proficient patients may benefit from PARPi via targeting C/EBPß, and C/EBPß expression levels enable predicting and tracking PARPi responsiveness during treatment.

9.
J Intensive Care ; 9(1): 19, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602326

RESUMO

BACKGROUND: Immune and inflammatory dysfunction was reported to underpin critical COVID-19(coronavirus disease 2019). We aim to develop a machine learning model that enables accurate prediction of critical COVID-19 using immune-inflammatory features at admission. METHODS: We retrospectively collected 2076 consecutive COVID-19 patients with definite outcomes (discharge or death) between January 27, 2020 and March 30, 2020 from two hospitals in China. Critical illness was defined as admission to intensive care unit, receiving invasive ventilation, or death. Least Absolute Shrinkage and Selection Operator (LASSO) was applied for feature selection. Five machine learning algorithms, including Logistic Regression (LR), Support Vector Machine (SVM), Gradient Boosted Decision Tree (GBDT), K-Nearest Neighbor (KNN), and Neural Network (NN) were built in a training dataset, and assessed in an internal validation dataset and an external validation dataset. RESULTS: Six features (procalcitonin, [T + B + NK cell] count, interleukin 6, C reactive protein, interleukin 2 receptor, T-helper lymphocyte/T-suppressor lymphocyte) were finally used for model development. Five models displayed varying but all promising predictive performance. Notably, the ensemble model, SPMCIIP (severity prediction model for COVID-19 by immune-inflammatory parameters), derived from three contributive algorithms (SVM, GBDT, and NN) achieved the best performance with an area under the curve (AUC) of 0.991 (95% confidence interval [CI] 0.979-1.000) in internal validation cohort and 0.999 (95% CI 0.998-1.000) in external validation cohort to identify patients with critical COVID-19. SPMCIIP could accurately and expeditiously predict the occurrence of critical COVID-19 approximately 20 days in advance. CONCLUSIONS: The developed online prediction model SPMCIIP is hopeful to facilitate intensive monitoring and early intervention of high risk of critical illness in COVID-19 patients. TRIAL REGISTRATION: This study was retrospectively registered in the Chinese Clinical Trial Registry ( ChiCTR2000032161 ). vv.

12.
Mikrochim Acta ; 187(12): 671, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33225378

RESUMO

A ternary hybrid material composed of Ni nanoparticles (NPs), TiO2 NPs, and poly(L-lysine) (Ply) was used as a sensing material. It was electrodeposited in situ onto a commercial 433-MHz surface acoustic wave (SAW) resonator to construct a Ni-TiO2-Ply/SAW sensor. The Ni-TiO2-Ply sensing layer fully covered the resonant cavity of the SAW resonator. As the sensing layer completely covers the interdigital transducer and piezoelectric substrate, the sensing area is significantly increased, and the resonator is protected from damage or contamination. To detect the level of dopamine (DA) in serum, the fabrication of the Ni-TiO2-Ply sensing layer, distributions of various components in the sensing layer, and responses of the SAW biosensor to DA were investigated in detail. In addition, an electric field-assisted liquid-phase oxidation technique was developed for loading analytes onto the SAW sensors. After optimizing the pH value and L-lysine content of the sensing layer electrolyte and the pH value of the DA solution, the SAW biosensor responded to DA with a linear concentration range of 1 to 1000 nM, sensitivity of 5.77 MHz nM-1 cm-2, and limit of detection of 0.067 nM. Moreover, the sensor exhibited good selectivity, reproducibility, and stability at ambient temperature.Graphical abstract.

13.
Anal Chim Acta ; 1135: 73-82, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33070861

RESUMO

In this study, boron-doped diamond (BDD) electrodes with varied B contents are prepared to determine the feasibility of the direct usage of BDD as an electrochemical biosensor without any modification. The electrochemical performance of the electrodes was investigated through the characterization of electrochemical impedance spectroscopy for potassium ferricyanide/potassium ferrocyanide (K3Fe(CN)6/K4Fe(CN)6) redox couples, as well as through qualitative and quantitative analysis of the two biomolecules dopamine (DA) and melatonin (MLT). The results show that the B content of BDD is the primary parameter for controlling the electrocatalytic current, that is, the response sensitivity. However, the abundant crystal planes and low background current are the key factors in improving the selectivity of the biomarkers to identify multiple analytes. Considering the catalytic current and its ability to distinguish the biomolecules, BDD with a B source carrier gas flow rate of 18 sccm is used as the sensing electrode for the simultaneous detection of DA and MLT. The response peak potential difference reaches 500 mV, and the linear concentration range for the two analytes is 0.4-600 µM, with detection limits of 0.1 µM for DA and 0.003 µM for MLT. These results match those observed for electrochemical sensors modified by various sensitive materials. BDD electrodes show good chemical resistance, good stability, and no pollution and are suitable for long-term usage as biomarker sensors.


Assuntos
Técnicas Biossensoriais , Melatonina , Boro , Diamante , Dopamina , Eletrodos
14.
Nat Commun ; 11(1): 5033, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024092

RESUMO

Soaring cases of coronavirus disease (COVID-19) are pummeling the global health system. Overwhelmed health facilities have endeavored to mitigate the pandemic, but mortality of COVID-19 continues to increase. Here, we present a mortality risk prediction model for COVID-19 (MRPMC) that uses patients' clinical data on admission to stratify patients by mortality risk, which enables prediction of physiological deterioration and death up to 20 days in advance. This ensemble model is built using four machine learning methods including Logistic Regression, Support Vector Machine, Gradient Boosted Decision Tree, and Neural Network. We validate MRPMC in an internal validation cohort and two external validation cohorts, where it achieves an AUC of 0.9621 (95% CI: 0.9464-0.9778), 0.9760 (0.9613-0.9906), and 0.9246 (0.8763-0.9729), respectively. This model enables expeditious and accurate mortality risk stratification of patients with COVID-19, and potentially facilitates more responsive health systems that are conducive to high risk COVID-19 patients.


Assuntos
Infecções por Coronavirus/mortalidade , Aprendizado de Máquina , Pandemias , Pneumonia Viral/mortalidade , Idoso , Betacoronavirus , COVID-19 , China/epidemiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Medição de Risco , SARS-CoV-2 , Máquina de Vetores de Suporte
16.
Cell Transplant ; 29: 963689720958656, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907379

RESUMO

8-Chloro-adenosine (8-Cl-Ado) has been shown to exhibit its antitumor activity by inducing apoptosis in human lung cancer A549 and H1299 cells or autophagy in chronic lymphocytic leukemia, and MDA-MB-231 and MCF-7 breast cancer cells. Adenosine deaminases acting on RNA 1 (ADAR1) is tightly associated with cancer development and progression. The aim of this study was to investigate the role of ADAR1 in the proliferation of MDA-MB-231 and SK-BR-3 breast cancer cell lines after 8-Cl-Ado exposure and its possible mechanisms. After 8-Cl-Ado exposure, CCK-8 assay was performed to determine the cell proliferation; flow cytometry was used to analyze the cell cycle profiles and apoptosis; and the protein levels of ADAR1, p53, p21, and cyclin D1 were measured by western blotting. The results showed that the cell proliferation was greatly inhibited, G1 cell cycle was arrested, and apoptosis was induced after 8-Cl-Ado exposure. ADAR1 and cyclin D1 protein levels were dramatically decreased, while p53 and p21 levels were increased after 8-Cl-Ado exposure. Moreover, the cell growth inhibition was rescued, apoptosis was reduced, and p53 and p21 protein levels were downregulated, while cyclin D1 was upregulated when cells were transfected with plasmids expressing ADAR1 proteins. More importantly, RNA-binding domain of ADAR1 is critical to the cell growth inhibition of breast cancer cells exposed to 8-Cl-Ado. Together, 8-Cl-Ado inhibits the cell proliferation, induces G1 phase arrest and apoptosis at least by targeting ADAR1/p53/p21 signaling pathway. The findings may provide us with insights into the role of ADAR1 in breast cancer progression and help us better understand the effects of 8-Cl-Ado in the treatment of breast cancer.


Assuntos
2-Cloroadenosina/análogos & derivados , Adenosina Desaminase/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , 2-Cloroadenosina/farmacologia , Adenosina Desaminase/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Domínios Proteicos , Proteínas de Ligação a RNA/química , Transdução de Sinais/efeitos dos fármacos
18.
EClinicalMedicine ; 25: 100471, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32840491

RESUMO

Background: The ferocious global assault of COVID-19 continues. Critically ill patients witnessed significantly higher mortality than severe and moderate ones. Herein, we aim to comprehensively delineate clinical features of COVID-19 and explore risk factors of developing critical disease. Methods: This is a Mini-national multicenter, retrospective, cohort study involving 2,387 consecutive COVID-19 inpatients that underwent discharge or death between January 27 and March 21, 2020. After quality control, 2,044 COVID-19 inpatients were enrolled. Electronic medical records were collected to identify the risk factors of developing critical COVID-19. Findings: The severity of COVID-19 climbed up straightly with age. Critical group was characterized by higher proportion of dyspnea, systemic organ damage, and long-lasting inflammatory storm. All-cause mortality of critical group was 85•45%, by contrast with 0•58% for severe group and 0•18% for moderate group. Logistic regression revealed that sex was an effect modifier for hypertension and coronary heart disease (CHD), where hypertension and CHD were risk factors solely in males. Multivariable regression showed increasing odds of critical illness associated with hypertension, CHD, tumor, and age ≥ 60 years for male, and chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), tumor, and age ≥ 60 years for female. Interpretation: We provide comprehensive front-line information about different severity of COVID-19 and insights into different risk factors associated with critical COVID-19 between sexes. These results highlight the significance of dividing risk factors between sexes in clinical and epidemiologic works of COVID-19, and perhaps other coronavirus appearing in future. Funding: 10.13039/100000001 National Science Foundation of China.

20.
J Biol Chem ; 295(12): 4049-4063, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32005663

RESUMO

Cellular senescence is terminal cell cycle arrest that represents a prominent response to numerous anticancer therapies. The oncogene inhibitor of the apoptosis-stimulating protein of p53 (iASPP) plays essential roles in regulating cellular drug response by inhibiting apoptosis. However, whether or not it regulates chemotherapy-induced senescence (TIS) in cancer cells remains unclear. Here, using two commonly used cancer cell lines, HCT 116 and MCF-7, along with the xenograft mouse model, we found that iASPP inhibits senescence and also influences the senescence-associated secretory phenotype (SASP), which confers anticancer drug resistance independently of apoptosis. Mechanistically, iASPP is transcriptionally elevated by the p65 subunit of NF-κB in senescent cells and then translocates to the nucleus, where it binds p53 and NF-κBp65. This binding inhibits their transcriptional activities toward p21 and the key SASP factors interleukin (IL)-6/IL-8, respectively, and subsequently prevents senescence. Of note, we observed that iASPP knockdown sensitizes apoptosis-resistant cancers to doxorubicin treatment by promoting senescence both in vitro and in vivo We conclude that iASPP integrates the NF-κBp65- and p53-signaling pathways and thereby regulates cell fate in response to TIS, leading to chemotherapy resistance. These findings suggest that iASPP inhibition might be a strategy that could help restore senescence in cancer cells and improve outcomes of chemotherapy-based therapies.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Senescência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Repressoras/metabolismo , Animais , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Nus , Neoplasias/metabolismo , Neoplasias/patologia , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Ativação Transcricional , Transplante Heterólogo , Proteína Supressora de Tumor p53/metabolismo
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