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1.
J Exp Med ; 218(2)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33136155

RESUMO

Both somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytidine deaminase (AID). Dysregulation of these processes has been linked to B cell lymphomagenesis. Here we performed an in-depth analysis of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) genomes. We characterized seven genomic mutational signatures, including two B cell tumor-specific signatures, one of which is novel and associated with aberrant SHM. We further identified two major mutational signatures (K1 and K2) of clustered mutations (kataegis) resulting from the activities of AID or error-prone DNA polymerase η, respectively. K1 was associated with the immunoglobulin (Ig) switch region mutations/translocations and the ABC subtype of DLBCL, whereas K2 was related to the Ig variable region mutations and the GCB subtype of DLBCL and FL. Similar patterns were also observed in chronic lymphocytic leukemia subtypes. Thus, alterations associated with aberrant CSR and SHM activities can be linked to distinct developmental paths for different subtypes of B cell lymphomas.

2.
Mol Med Rep ; 22(6): 4567-4578, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33173977

RESUMO

The present study aimed to explore the biological functions and molecular mechanisms of the long non­coding RNA VIM antisense RNA 1 (VIM­AS1) in gastric cancer (GC). The expression of VIM­AS1 was analyzed in tissues from patients with GC and GC cell lines by reverse transcription­quantitative (RT­q)PCR. The relationship between VIM­AS1 expression and overall survival time of patients with GC was also assessed. To determine the biological functions of VIM­AS1, Cell Counting Kit­8 assay, colony formation assay, flow cytometry, wound healing assay and Transwell assay were employed. The targeting relationship among VIM­AS1, microRNA (miR)­8052 and frizzled 1 (FZD1) was verified by the dual luciferase reporter gene assay. The underlying molecular mechanism of VIM­AS1 on GC was determined by RT­qPCR and western blotting. In addition, tumor formation was detected in nude mice. The results of the present study demonstrated that VIM­AS1 was highly expressed in GC tissues and cells. In addition, VIM­AS1 expression was demonstrated to be closely related to the prognosis of patients with GC. Notably, silencing VIM­AS1 inhibited the proliferation, migration and invasion, and enhanced apoptosis of AGS and HGC­27 cells. Silencing VIM­AS1 significantly increased the protein expression levels of cleaved caspase­3, Bax and E­cadherin, but decreased the protein expression levels of Bcl­2, N­cadherin, vimentin, matrix metalloproteinase (MMP)­2, MMP­9, ß­catenin, cyclin D1, C­myc and FZD1. Additionally, silencing VIM­AS1 inhibited tumor growth in nude mice. Cumulatively, the present study demonstrated that VIM­AS1 may promote cell proliferation, migration, invasion and epithelial­mesenchymal transition by regulating FDZ1 and activating the Wnt/ß­catenin pathway in GC.

3.
Opt Lett ; 45(22): 6162-6165, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33186940

RESUMO

Imaging in low light is significant but challenging in many applications. Adding the polarization information into the imaging system compromises the drawbacks of the conventional intensity imaging to some extent. However, generally speaking, the qualities of intensity images and polarization images cannot be compatible due to the characteristic differences in polarimetric operators. In this Letter, we collected, to the best of our knowledge, the first polarimetric imaging dataset in low light and present a specially designed neural network to enhance the image qualities of intensity and polarization simultaneously. Both indoor and outdoor experiments demonstrate the effectiveness and superiority of this neural network-based solution, which may find important applications for object detection and vision in photon-starved environments.

4.
BMJ Open ; 10(11): e039900, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154057

RESUMO

INTRODUCTION: The question of how to administer adequate chemotherapy to synchronise stereotactic body radiation therapy (SBRT) treatment strategy to maximise the benefits of neoadjuvant therapy for the improved prognosis of patients with borderline resectable (BRPC) and locally advanced (LAPC) pancreatic cancer is a challenging and debatable issue. No studies have yet evaluated the efficacy of split-course SBRT as the neoadjuvant chemoradiotherapy regimen. We aimed to study whether neoadjuvant chemotherapy plus split-course SBRT results in better outcomes in BRPC and LAPC patients. METHODS AND ANALYSIS: Treatment-naïve patients with radiographically confirmed BRPC or LAPC, supporting biopsy results and no severe comorbidities will be enrolled. They will be treated with nab-paclitaxel plus gemcitabine (nab-P+Gem) chemotherapy plus split-course SBRT, followed by an investigator's choice of continuation of treatment with nab-P+Gem or surgery. nab-P+Gem chemotherapy will commence on day 1 for each of six cycles: nab-paclitaxel 125 mg/m2 intravenous infusion over approximately 30-45 min, followed by gemcitabine 1000 mg/m2 intravenous infusion over about 30 min on days 1 and 15 of each 28-day cycle. During the first and second cycles of chemotherapy, SBRT will be given as a single irradiation of 10 Gy four times (days 2 and 16 of each 28-day cycle). The primary endpoint is progression-free survival; while the secondary outcomes are the time to treatment failure, disease control rate, overall response rate, overall survival, R0 resection rate and incidence of adverse effects. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Xiehe Affiliated Hospital of Fujian Medical University (No. 2019YF015-01). Results from our study will be disseminated in international peer-reviewed journals. All study procedures were developed in order to assure data protection and confidentiality. TRIAL REGISTRATION NUMBER: NCT04289792.

5.
Nat Commun ; 11(1): 5156, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33056990

RESUMO

The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.


Assuntos
Adenocarcinoma/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Experimentais/genética , RNA Longo não Codificante/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/patologia , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Glândulas Mamárias Animais/citologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA-Seq , Transdução de Sinais/genética , Análise Serial de Tecidos , Transativadores/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Aging (Albany NY) ; 12(19): 19493-19519, 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33041264

RESUMO

Large-scale epidemiological surveys suggest that hearing loss (HL) is a significant risk factor for dementia. We previously showed that noise-induced HL (NIHL) impairs hippocampal cognitive function and decreases hippocampal neurogenesis and neuronal complexity, suggesting a causal role of HL in dementia. To further investigate the influence of acquired peripheral HL on hippocampal neurogenesis with the aging process as well as the underlying mechanism, we produced NIHL in male CBA/J mice and assessed hippocampal neurogenesis and microglial morphology in the auditory brain and hippocampus at 4 days post-noise exposure (DPN) or 1, 3, 6, or 12 months post-noise exposure (MPN) by immunofluorescence labeling. We found that the age-related decline in hippocampal neurogenesis was accelerated in mice with NIHL. Furthermore, in mice with NIHL, prolonged microglial activation occurred from 1 MPN to 12 MPN across multiple auditory nuclei, while aggravated microglial deterioration occurred in the hippocampus and correlated with the age-related decline in hippocampal neurogenesis. These results suggest that acquired peripheral HL accelerates the age-related decline in hippocampal neurogenesis and that hippocampal microglial degeneration may contribute to the development of neurodegeneration following acquired peripheral HL.

7.
Signal Transduct Target Ther ; 5(1): 214, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33033232

RESUMO

Epidermal growth factor receptor (EGFR) activation plays a pivotal role in EGFR-driven non-small cell lung cancer (NSCLC) and is considered as a key target of molecular targeted therapy. EGFR tyrosine kinase inhibitors (TKIs) have been canonically used in NSCLC treatment. However, prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs. Therefore, the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance. Here, we identified a 23-hydroxybetulinic acid derivative, namely DPBA, as a novel EGFR small-molecule ligand. It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR. Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR. DPBA did not induce EGFR dimerization, phosphorylation, and ubiquitination, but it significantly promoted EGFR degradation and repressed downstream survival pathways. Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs. Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation. The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC, particularly NSCLC with innate or acquired EGFR TKI resistance. DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.

8.
Radiat Res ; 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33064814

RESUMO

The concept of spatially fractionated radiation therapy (SFRT) was conceived over 100 years ago, first in the form of GRID, which has been applied to clinical practice since its early inception and continued to the present even with markedly improved instrumentation in radiation therapy. LATTICE radiation therapy (LRT) was introduced in 2010 as a conceptual 3D extension of GRID therapy with several uniquely different features. Since 2014, when the first patient was treated, over 150 patients with bulky tumors worldwide have received LRT. Through a brief review of the basic principles and the analysis of the collective clinical experience, a set of technical recommendations and guidelines are proposed for the clinical implementation of LRT. It is to be recognized that the current clinical practice of SFRT (GRID or LRT) is still largely based on the heuristic principles. With advancements in basic biological research and the anticipated clinical trials to systemically assess the efficacy and risk, progressively robust optimizations of the technical parameters are essential for the broader application of SFRT in clinical practice.

9.
Langmuir ; 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33095586

RESUMO

Oxidative chemical vapor deposition (oCVD) offers unique advantages as a liquid-free processing technique in synthesizing and integrating conducting polymers, including polyaniline (PANI), by enabling conformal coatings onto nanostructured substrates, like carbon nanofibers. With relatively thick nanofiber mats, the challenge is to ensure uniform coating thickness through the porous substrates. Here, the substrate temperature during oCVD is found to be a primary factor influencing PANI coating uniformity. Coating uniformity is enhanced by operating at a higher substrate temperature, where monomer adsorption is believed to be limiting relative to intrinsic reaction kinetics. Also, a higher substrate temperature leads to significantly less PANI oligomers and more PANI in the emeraldine oxidation state. A systematic study of oCVD kinetics with substrate temperature shows a reaction-limited regime at lower substrate temperatures with an activation energy of 12.0 kJ/mol, which is believed to be controlled by the self-catalyzed PANI polymerization reaction that transitions at higher substrate temperatures above 90 °C to an adsorption-limited regime as indicated by a negative activation energy of -18.8 kJ/mol. Overall, by operating within an adsorption-limited oCVD regime, more uniform oCVD PANI coatings on electrospun carbon nanofiber mats have been achieved.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32880632

RESUMO

AIM: This study evaluated the underlying factors associated with poor tuberculosis (TB) treatment outcomes among patients attending health care facilities in Galkayo, Puntland, Somalia. METHODS: An institution-based cross-sectional study was conducted between 2016 and 2017 in three selected TB clinics. Data were collected from 400 TB patients, through medical record review and structured questionnaire. Multivariate logistic regression analyses were performed. RESULTS: Of the 400 TB respondents, 57.3% were new cases, 12.3% had smear-negative TB and 12.5% had extrapulmonary TB. The median age was (35.66 ± 13.16) with majority being male (65.5%). Overall, 85% of patients were successfully treated, 9.7% failed and 5.3% defaulted. Multivariate analysis revealed that patient's body weight (odds ratio [OR]: 1.078); diabetes (OR: 8.022); family size (OR: 3.851); patients' delay in diagnosis (OR: 11.946); frequency of receiving anti-TB medication (OR: 9.068); smoker (OR: 5.723); category of patients (retreatment versus new, OR: 5.504; retreatment versus transfer in, OR: 4.957); health facilities (OR: 6.716) and treatment duration (OR: 132.091) were independent factors associated with poor TB outcomes. CONCLUSIONS: Our findings highlight the need to improve TB services for vulnerable groups. They also emphasize the need for health system strengthening, public awareness and risk of treatment interruption. This may reduce both patients' delay in seeking care and TB treatment failure in Galkayo district.

11.
Phytomedicine ; 78: 153296, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32890913

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has extensively and rapidly spread in the world, causing an outbreak of acute infectious pneumonia. However, no specific antiviral drugs or vaccines can be used. Phillyrin (KD-1), a representative ingredient of Forsythia suspensa, possesses anti-inflammatory, anti-oxidant, and antiviral activities. However, little is known about the antiviral abilities and mechanism of KD-1 against SARS-CoV-2 and human coronavirus 229E (HCoV-229E). PURPOSE: The study was designed to investigate the antiviral and anti-inflammatory activities of KD-1 against the novel SARS-CoV-2 and HCoV-229E and its potential effect in regulating host immune response in vitro. METHODS: The antiviral activities of KD-1 against SARS-CoV-2 and HCoV-229E were assessed in Vero E6 cells using cytopathic effect and plaque-reduction assay. Proinflammatory cytokine expression levels upon infection with SARS-CoV-2 and HCoV-229E infection in Huh-7 cells were measured by real-time quantitative PCR assays. Western blot assay was used to determine the protein expression of nuclear factor kappa B (NF-κB) p65, p-NF-κB p65, IκBα, and p-IκBα in Huh-7 cells, which are the key targets of the NF-κB pathway. RESULTS: KD-1 could significantly inhibit SARS-CoV-2 and HCoV-229E replication in vitro. KD-1 could also markedly reduce the production of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, MCP-1, and IP-10) at the mRNA levels. Moreover, KD-1 could significantly reduce the protein expression of p-NF-κB p65, NF-κB p65, and p-IκBα, while increasing the expression of IκBα in Huh-7 cells. CONCLUSIONS: KD-1 could significantly inhibit virus proliferation in vitro, the up-regulated expression of proinflammatory cytokines induced by SARS-CoV-2 and HCoV-229E by regulating the activity of the NF-кB signaling pathway. Our findings indicated that KD-1 protected against virus attack and can thus be used as a novel strategy for controlling the coronavirus disease 2019.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Coronavirus Humano 229E/efeitos dos fármacos , Infecções por Coronavirus , Glucosídeos/farmacologia , NF-kappa B/metabolismo , Pandemias , Pneumonia Viral , Animais , Chlorocebus aethiops , Coronavirus/efeitos dos fármacos , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Forsythia/química , Humanos , Fitoterapia , Extratos Vegetais/farmacologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/virologia , Transdução de Sinais/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacos
12.
Circ Cardiovasc Interv ; 13(9): e009232, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32895005

RESUMO

BACKGROUND: Prognostic impact of residual anatomic disease burden after functionally complete percutaneous coronary intervention (PCI), defined by post-PCI fractional flow reserve (FFR) >0.80 would be a clinically relevant question. The current study evaluated clinical outcomes at 2 years according to residual Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) score (RSS) in patients who underwent functionally complete revascularization. METHODS: A total of 1910 patients (2095 revascularized vessels) with post-PCI FFR >0.80 were selected from the International Post-PCI FFR Registry. RSS was defined as the SYNTAX score recalculated after PCI, SYNTAX revascularization index was calculated as 100×(1-RSS/pre-PCI SYNTAX score), and post-PCI FFR was measured after completion of PCI. The primary outcome was target vessel failure (TVF; a composite of cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization) at 2 years, and risk of TVF was compared according to tertile classification of RSS (0, 1-5, and >5) and post-PCI FFR (≥0.94, 0.87-0.93, and ≤0.86). RESULTS: After PCI, SYNTAX score was changed from 10.0 (Q1-Q3, 7.0-16.0) to 0.0 (Q1-Q3, 0.0-5.0) and FFR changed from 0.70±0.12 to 0.90±0.05. TVF at 2 years occurred in 4.9%, and patients with TVF showed higher pre-PCI SYNTAX score and lower post-PCI FFR than those without. However, there were no significant differences in SYNTAX revascularization index and RSS. The risk of TVF was not different according to tertile of RSS (log-rank P=0.851). Conversely, risk of TVF was different according to tertile of post-PCI FFR (log-rank P=0.009). Multivariable model showed the risk of TVF was significantly associated with post-PCI FFR (hazard ratio, 1.091 [95% CI, 1.032-1.153]; P=0.002) but not with RSS (hazard ratio, 0.969 [95% CI, 0.898-1.045]; P=0.417). CONCLUSIONS: Among patients who underwent functionally complete revascularization, residual anatomic disease burden assessed by RSS was not related with occurrence of TVF at 2 years. These results support the importance of functionally complete revascularization rather than angiographic complete revascularization. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT04012281.

13.
Chin J Nat Med ; 18(9): 696-703, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32928513

RESUMO

Hypoxia is a prominent feature of tumors. Hypoxia-inducible factor-1α (HIF-1α), a major subunit of HIF-1, is overexpressed in hypoxic tumor tissues and activates the transcription of many oncogenes. Accumulating evidence has demonstrated that HIF-1α promotes tumor angiogenesis, metastasis, metabolism, and immune evasion. Natural products are an important source of antitumor drugs and numerous studies have highlighted the crucial role of these agents in modulating HIF-1α. The present review describes the role of HIF-1α in tumor progression, summarizes natural products used as HIF-1α inhibitors, and discusses the potential of developing natural products as HIF-1α inhibitors for the treatment of cancer.

14.
Nanoscale Res Lett ; 15(1): 185, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32970277

RESUMO

We propose a planar model heterojunction based on α-borophene nanoribbons and study its electronic transport properties. We respectively consider three types of heterojunctions. Each type consists of two zigzag-edge α-borophene nanoribbons (Z αBNR), one is metallic with unpassivated or passivated edges by a hydrogen atom (1H-Z αBNR) and the other is semiconducting with the edge passivated by two hydrogen atoms (2H-Z αBNR) or a single nitrogen atom (N-Z αBNR). Using the first-principles calculations combined with the nonequilibrium Green's function, we observe that the rectifying performance depends strongly on the atomic structural details of a junction. Specifically, the rectification ratio of the junction is almost unchanged when its left metallic ribbon changes from ZBNR to 1H-Z αBNR. However, its ratio increases from 120 to 240 when the right semiconducting one varies from 2H-Z αBNR to N-Z αBNR. This rectification effect can be explained microscopically by the matching degree the electronic bands between two parts of a junction. Our findings imply that the borophene-based heterojunctions may have potential applications in rectification nano-devices.

16.
J Virol ; 94(23)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-32967957

RESUMO

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus which has become a global epidemic threat due to its rapid spread and association with serious consequences of infection, including neonatal microcephaly. Inositol-requiring enzyme 1α (IRE1α) is an endoplasmic reticulum (ER)-related transmembrane protein that mediates unfolded protein response (UPR) pathway and has been indicated to play an important role in flavivirus replication. However, the mechanism of how IRE1α affects ZIKV replication remains unknown. In this study, we explored the role of IRE1α in ZIKV infection in vitro and in vivo by using CRISPR/Cas9-based gene knockout and RNA interference-based gene knockdown techniques. Both knockout and knockdown of IRE1α dramatically reduced ZIKV replication levels, including viral RNA levels, protein expression, and titers in different human cell lines. Trans-complementation with IRE1α restored viral replication levels decreased by IRE1α depletion. Furthermore, the proviral effect of IRE1α was dependent on its kinase and RNase activities. Importantly, we found that IRE1α promoted the replication of ZIKV through upregulating the accumulation of monounsaturated fatty acid (MUFA) rate-limiting enzyme stearoyl coenzyme A (stearoyl-CoA) desaturase 1 (SCD1), which further affected the production of oleic acid (OA) and lipid droplet. Finally, our data demonstrated that in the brain tissues of ZIKV-infected mice, the replication levels of ZIKV and virus-related lesions were significantly suppressed by both the kinase and RNase inhibitors of IRE1α. Taken together, our results identified IRE1α as a ZIKV dependency factor which promotes viral replication through affecting SCD1-mediated lipid metabolism, potentially providing a novel molecular target for the development of anti-ZIKV agents.IMPORTANCE Zika virus (ZIKV) has been linked to serious neurologic disorders and causes widespread concern in the field of global public health. Inositol requiring enzyme 1α (IRE1α) is an ER-related transmembrane protein that mediates unfolded protein response (UPR) pathway. Here, we revealed that IRE1α is a proviral factor for ZIKV replication both in culture cells and mice model, which relies on its kinase and RNase activities. Importantly, we further provided evidence that upon ZIKV infection, IRE1α is activated and splices XBP1 mRNA which enhances the expression of monounsaturated fatty acids rate-limiting enzyme stearoyl coenzyme A (stearoyl-CoA) desaturase 1 (SCD1) and subsequent lipid droplet production. Our data uncover a novel mechanism of IRE1α proviral effect by modulating lipid metabolism, providing the first evidence of a close relationship between IRE1α-mediated UPR, lipid metabolism, and ZIKV replication and indicating IRE1α inhibitors as potentially effective anti-ZIKV agents.

17.
JAMA Netw Open ; 3(9): e2018162, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32997128

RESUMO

Importance: The prognostic value of pre-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) may be associated with the post-PCI FFR and their interaction. To correctly interpret the prognostic value of pre-PCI FFR, it is essential to understand to what extent the association of pre-PCI FFR with clinical outcomes is explained by post-PCI FFR. Objective: To investigate the extent to which post-PCI FFR mediates the association of pre-PCI FFR with vessel-related outcomes using an international, multicenter collaboration registry. Design, Setting, and Participants: This cohort study used pooled patient data from 4 international FFR registries. A total of 1488 patients with pre-PCI FFR of 0.80 or less who underwent elective PCI were included. Data collection was conducted from November 2011 to August 2019, and analysis was conducted from September 2019 to July 2020. Main Outcomes and Measures: The primary outcome was target vessel failure (TVF) during 2 years of follow-up. The extent to which post-PCI FFR of less than 0.90 mediated the association of pre-PCI FFR less than 0.75 (vs pre-PCI FFR of 0.75 or greater) with TVF was evaluated using a mediation analysis in a counterfactual framework. Results: Among 1488 patients, the mean (SD) age was 63.5 (9.9) years and 1161 patients (78.0%) were men. The median (interquartile range) pre-PCI and post-PCI FFR were 0.71 (0.62-0.76) and 0.88 (0.83-0.92), respectively. The direct association of low pre-PCI FFR (ie, <0.75) with TVF was significant (odds ratio, 1.81; 95% CI, 1.03-3.17; P = .04), while the mediation by post-PCI FFR level of less than 0.90 was not (indirect association: odds ratio, 1.03; 95% CI, 0.98-1.09; P = .24). In sensitivity analyses using several pre-PCI cutoffs, the mediations by post-PCI FFR were consistently weak. Conclusions and Relevance: In this study, the association of pre-PCI FFR with TVF was not significantly mediated by post-PCI FFR. Poor prognosis due to progressed atherosclerosis, represented as low FFR, may not be reversed by successful PCI that increases FFR. Therefore, the prognostic value of pre-PCI FFR may mainly reflect the global atherosclerotic burden, not the extent of the modifiable epicardial stenosis.

18.
Diabetes Res Clin Pract ; 169: 108418, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32891692

RESUMO

AIMS: Studies have shown that destruction of the intestinal barrier in type 2 diabetes (T2D) leads to increased absorption of macromolecules from intestinal. We previously exhibited that short-chain fatty acids (SCFAs) and bile acids (BAs) were significantly decreased in faeces of T2D patients. In the current study, we extended these findings by focusing on the interactions between intestinal barrier and clinical characteristics, gut microbiota, SCFAs and BAs. METHODS: 65 T2D patients and 35 healthy controls were recruited, targeted metabolomics was used to evaluate the SCFAs and BAs in their serum samples. The serum zonula occludens-1 (ZO-1) was measured by ELISA to evaluate intestinal barrier. RESULTS: Compared with the healthy controls, the serum concentrations of total SCFA, acetate and propionate were significantly increased in the T2D patients, and certain BAs were also significantly increased. In addition, the higher levels of serum ZO-1 suggested a "leaky gut" in T2D patients. The ZO-1 was comprehensively correlated with clinical characteristics, gut microbiota, SCFAs and BAs. CONCLUSION: SCFAs and BAs were excessively absorbed from the intestinal through the leaky gut, leading to higher levels of circulating SCFAs and BAs in T2D patients, and that the leaky gut might be caused by the disordered gut microbiota.

19.
J Immunol ; 205(9): 2545-2553, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32938725

RESUMO

Pharmacological activation of integrin CD11b/CD18 (αMß2, Mac-1, and CR3) shows anti-inflammatory benefits in a variety of animal models of human disease, and it is a novel therapeutic strategy. Reasoning that genetic models can provide an orthogonal and direct system for the mechanistic study of CD11b agonism, we present in this study, to our knowledge, a novel knock-in model of constitutive active CD11b in mice. We genetically targeted the Itgam gene (which codes for CD11b) to introduce a point mutation that results in the I332G substitution in the protein. The I332G mutation in CD11b promotes an active, higher-affinity conformation of the ligand-binding I/A-domain (CD11b αA-domain). In vitro, this mutation increased adhesion of knock-in neutrophils to fibrinogen and decreased neutrophil chemotaxis to a formyl-Met-Leu-Phe gradient. In vivo, CD11bI332G animals showed a reduction in recruitment of neutrophils and macrophages in a model of sterile peritonitis. This genetic activation of CD11b also protected against development of atherosclerosis in the setting of hyperlipidemia via reduction of macrophage recruitment into atherosclerotic lesions. Thus, our animal model of constitutive genetic activation of CD11b can be a useful tool for the study of integrin activation and its potential contribution to modulating leukocyte recruitment and alleviating different inflammatory diseases.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32793117

RESUMO

Though many patients with thyroid cancer may be indolent, there are still about 50% lymph node metastases and 20% the recurrence rates. There is still no ideal method to predict its relapse. In this study, we analyzed the gene transcriptome profiles of eight Gene Expression Omnibus (GEO), and next screened 77 commonly differential expressed genes. Next, Least Absolute Shrinkage and Selection Operator (LASSO) regression model was performed and seven genes (i.e., FN1, PKIA, TMEM47, FXYD6, SDC2, CD44, and GGCT) were then identified, which is highly associated with recurrence data from the Cancer Genome Atlas (TCGA) database. These patients were then divided into low and high-risk groups with specific risk-score formula. Univariate and multivariate Cox regression further revealed that the 7-mRNA signature plays a functional causative role independent of clinicopathological characteristics. The 7-mRNA-signature integrated nomogram showed better discrimination, and decision curve analysis demonstrated that it is clinically useful. Besides, patient with lower risk score shows a relatively lower level of activated dendritic cells (DCs), resting DCs, regulatory T cells and γδT cells, and process of DCs apoptotic. In conclusion, our present immune-related classifier could produce a potential tool for predicting early-relapse.

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