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1.
Food Funct ; 11(11): 10231-10241, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33169751

RESUMO

The emergence of the plasmid-mediated colistin resistance mechanism (mcr-1) makes bacterial resistance to colistin increasingly serious. This mcr-1 mediated bacterial resistance to colicin is conferred primarily through modification of lipid A in lipopolysaccharides (LPS). In our previous research, antimicrobial peptide F1 was derived from Tibetan kefir and has been shown to effectively inhibit the growth of Gram-negative bacteria (E. coli), Gram-positive bacteria (Staphylococcus aureus), and other pathogenic bacteria. Based on this characteristic of antibacterial peptide F1, we speculated that it could inhibit the growth of the colicin-resistant E. coli SHP45 (mcr-1) and not easily produce drug resistance. Studies have shown that antimicrobial peptide F1 can destroy the liposome structure of the phospholipid bilayer by destroying the inner and outer membranes of bacteria, thereby significantly inhibiting the growth of E. coli SHP45 (mcr-1), but without depending on LPS. The results of this study confirmed our hypothesis, and we anticipate that antimicrobial peptide F1 will become a safe antibacterial agent that can assist in solving the problem of drug resistance caused by colistin.

2.
Transfus Clin Biol ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33221503

RESUMO

Myelodysplastic syndrome (MDS) is a group of heterogeneous diseases derived from hematopoietic stem cells characterized by hemolytic anemia and high risk of conversion to acute leukemia [1]. MDS is an age-related disease in which approximately 80% of patients are over 60 years of age, male and female. Anemia is the most common clinical condition, and many patients are also associated with infection and bleeding. When the amount of α globin synthesis is insufficient, the remaining ß chain forms tetramer ß4, i.e. HbH. The latter forms a precipitate in red blood cells, leading to hemolytic anemia, called HbH disease, the majority of which is congenital [2], a small number of patients with myelodysplastic syndrome and acute myeloid leukemia may appear HbH (called acquired HbH disease). We reported a 71 years old male patient diagnosed as myelodysplastic syndromes (MDS) in our hospital. The patient has a negative α-thalassemia gene test. The H band is detected by hemoglobin electrophoresis. This article analyzed and discussed this case with MDS, as well reviewed MDS.

3.
Lung Cancer ; 150: 164-171, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33186858

RESUMO

OBJECTIVES: Health-related quality of life (HRQoL) data complement conventional clinical endpoints when comparing adjuvant gefitinib with chemotherapy in patients with early-stage non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations. This study aimed to assess changes in HRQoL with adjuvant gefitinib vs chemotherapy in this patient group. MATERIALS AND METHODS: In the phase III ADJUVANT trial, patients with completely resected, stage II-IIIA (N1-N2), EGFR-mutant NSCLC were randomized (1:1) to receive either gefitinib for 24 months or vinorelbine plus cisplatin (VP) every 3 weeks for four cycles. HRQoL was assessed as a secondary endpoint using the Functional Assessment of Cancer Therapy-Lung Cancer (FACT-L), Lung Cancer Symptom Scale (LCSS) questionnaires, and Trial Outcome Index (TOI) composite score. HRQoL dynamics, improvements, and time to deterioration were compared between groups. RESULTS: At baseline, 104 of 106, and 80 of 87 patients receiving gefitinib and VP, respectively, completed two questionnaires (FACT-L and LCSS). Baseline scores were balanced between groups. Although HRQoL fluctuated and gradually improved in both groups, longitudinally higher scores were reported with gefitinib than VP (FACT-L, odds ratio 418.16, 95 % confidence interval [CI] 2.75-63509.05, p =  0.019; LCSS, 1.13, 1.04-1.22, p =  0.003; TOI, 88.39, 4.40-1775.05, p =  0.003). Time to deterioration in HRQoL was delayed with gefitinib compared with VP (FACT-L, median 69 vs 6 weeks, hazard ratio 0.62, 95 % CI 0.42-0.90, p =  0.013; LCSS, median 45 vs 6 weeks, 0.63, 0.43-0.93, p =  0.020; TOI, median 164 vs 9 weeks, 0.51, 0.33-0.77, p =  0.001). CONCLUSION: Adjuvant gefitinib is associated with improved HRQoL over VP, supporting its use in patients with stage II-IIIA (N1-N2), EGFR-mutant NSCLC.

4.
Immunogenetics ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188484

RESUMO

The tumor microenvironment (TME) plays an essential role in the occurrence and progression of malignancy. The potential prognostic TME-related biomarkers of lung adenocarcinoma (LUAD) remained unclear, which were investigated in this research. The RNA-sequencing profiles and corresponding clinical parameters were extracted from TCGA and GEO databases, based on which the stromal and immune scores were calculated through the ESTIMATE algorithm. Overlapping differentially expressed genes between stromal and immune score group were analyzed by the LASSO and Random Forrest algorithms and validated in cases from our center. And a prognostic 8-gene signature was constructed using Cox regression. The infiltration of 22 hematopoietic cell phenotypes was assessed by the CIBERSORT algorithms. We found that female, elder patients, and solid predominant subtype had obviously higher stromal and immune scores. And patients with early stage LUAD received a prominently higher immune score. A high stromal or immune score meant a good prognosis. Subsequently, eight TME-related prognostic genes (ATAD5, CYP4F3, CYP4F12, ESPNL, FXYD2, GPX2, NLGN4Y, and SERPINC1) were identified by both LASSO regression and Radom Forest algorithms. High 8-gene signature group exhibited worse overall survival. Furthermore, B cell naïve, plasma cells, T cell follicular helper, and macrophages M1 were prominently more in high signature group. Nevertheless, fewer T cells CD4 memory resting, monocytes, and dendritic cell resting were identified in the high signature group. The composition of the tumor microenvironment significantly affected the prognosis of LUAD patients. We provided a new strategy for the exploration of prognostic TME-related biomarkers and immunotherapy.

5.
Mol Med Rep ; 22(6): 5293-5303, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33174028

RESUMO

S100 calcium binding protein A8 (S100A8) and A9 (S100A9) belong to the S100 family of calcium­binding proteins and have important roles in inflammation. They increase endothelial cell proliferation, thereby affecting inflammation, angiogenesis and tumorigenesis. However, the mechanism of action of S100A8/9 in endothelial cells needs further study. Therefore, the present study sought to investigate the effects of S100A8/9 on the proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs) and their mechanism of action. The viability of HUVECs was determined through a Cell Counting Kit­8 assay. The effect of S100A8/9 on the proliferation of HUVECs was detected by flow cytometry. Migration was evaluated by a Transwell migration assay. Apoptosis was evaluated by Annexin V­FITC and PI staining via flow cytometry. Western blot analysis and reverse transcription­quantitative polymerase chain reaction assays were performed to evaluate the activation of the phosphatidylinositol 3­phosphate kinase (PI3K)/Akt/mTOR pathway and mTOR complex 2 (mTORC2). We previously confirmed that S100A8/9 were consistently overexpressed at 1 and 7 days post­surgery in a rabbit vein graft model, which is the period when apoptosis changes to proliferation in neointimal hyperplasia. In the present study, proliferation, viability and migration were increased after treating HUVECs with S100A8/9. S100A8/9 stimulated the PI3K/Akt/mTOR pathway and mTORC2, which was significantly suppressed by a receptor for advanced glycation end products (RAGE)­blocking antibody. Furthermore, depleting expression of RAGE or mTORC2 protein components (rapamycin­insensitive companion of mTOR) by small interfering RNA was found to reduce the cell viability, migration and angiogenesis of S100A8/9­treated HUVECs. The development of neointimal hyperplasia is a complex process initiated by damage to endothelial cells. In conclusion, S100A8/9 has an important role in intimal hyperplasia by promoting cell growth and angiogenesis via RAGE signaling and activation of mTORC2.

6.
Int Heart J ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33191351

RESUMO

The aim of this study was to prospectively assess the efficacy, safety, and predictive effect of intravenous nifekalant administration for persistent atrial fibrillation (PerAF) after pulmonary vein isolation (PVI) with second-generation cryoballoon ablation (CBA) on 1-year atrial tachyarrhythmia (ATa) -free survival by examining the pharmacological conversion rate.One hundred and two drug-refractory, consecutive PerAF patients undergoing PVI were enrolled in this prospective observational study. After PVI, nifekalant (50 mg) was given followed by 30 minutes of observation and no further intervention. PerAF was successfully converted to sinus rhythm (SR) in 60 patients (58.8%) after a median time of 7.75 (4.13-12) minutes (group N). In the remaining 42 patients (41.2%) (group C), PerAF was successfully converted to SR by external electrical cardioversion. Nonsustained ventricular tachycardia occurred in 1 patient in group N. The left atrial volume (LAV) in group C was larger than that in group N (128.2 ± 28.2 versus 111.8 ± 24.5 mL, P = 0.002). Phrenic nerve injury occurred in 4 of 102 patients (3.9%). No other complications occurred during the procedure or within the 1-year follow-up period. At the 1-year follow-up, after a 3-month blanking period (BP), ATa-free survival during 1-year follow-up in group C was significantly lower than that in group N (50.0% versus 71.7%, P = 0.026), and the overall ATa-free survival rate was 62.7%. Two patients in group C and 4 patients in group N underwent a second procedure with radiofrequency catheter ablation. Multivariate Cox regression analysis demonstrated that unsuccessful conversion to SR (P = 0.025), ATa relapse during the BP (P = 0.000), and larger LAV (P = 0.016) were independent predictors of ATa recurrence at the 1-year follow-up.In conclusion, at the 1-year follow-up, the ATa-free survival rate after PVI with CBA for PerAF patients was 62.7%, and successful conversion to SR with nifekalant could serve as a clinical predictor of reduced ATa recurrence.

7.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(10): 1236-1240, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33198871

RESUMO

OBJECTIVE: To evaluate the clinical characteristics, diagnosis, treatment and outcome of elderly patients with acute pulmonary embolism (APE), in order to strengthen the awareness of diagnosis of APE and reduce missed diagnosis and misdiagnosis. METHODS: A retrospective analysis of clinical data of 40 elderly patients (age ≥ 60 years old) diagnosed with APE admitted to TEDA International Cardiovascular Hospital from January 2008 to December 2018, including risk factors, clinical features, symptoms and signs, laboratory tests, risk of pulmonary embolism (Wells score), simplified pulmonary embolism severity index (sPESI), radiological tests, treatment, and outcome, etc. were conducted. Receiver operating characteristic (ROC) curve was drawn to analyze the diagnostic value of Wells score and spiral CT pulmonary angiography (CTPA) in APE. RESULTS: A total of 40 elderly patients with APE were enrolled, male was 52.5%, and the age was (69.6±8.2) years old. The most common risk factor was deep vein thrombosis (DVT, 52.5%), followed by hypertension (37.5%) and heart failure (35.0%). The main clinical symptoms were exertional dyspnea (87.5%) and chest tightness (80.0%). Only 10.0% of patients had the triad of dyspnea, chest pain and hemoptysis at the same time. In addition, palpitation (65.0%) and lower limb swelling and pain (42.5%) were also common symptoms. The main clinical signs were shortness of breath (respiratory rate > 25 bpm, 80.0%), lung moist rales (52.5%), and tachycardia (heart rate > 100 bpm, 50.0%). The Wells score showed that 95% of the patients Wells ≥ 2, including moderate (Wells 2-6, 62.5%) and severe (Wells ≥ 7, 32.5%). Laboratory examination showed that 80.0% of patients had D-dimer > 0.5 mg/L, 72.5% had arterial partial pressure of oxygen (PaO2) < 60 mmHg (1 mmHg = 0.133 kPa), and 75.0% had arterial partial pressure of carbon dioxide (PaCO2) < 35 mmHg, 67.5% had brain natriuretic peptide (BNP) > 500 ng/L or N-terminal pro-BNP (NT-proBNP) > 300 ng/L, and 47.5% had cardiac troponin I (cTnI) > 0.3 µg/L. The confirmed diagnosis rate of CTPA in APE was 88.6% (31/35); 5 cases were diagnosed by pulmonary ventilation/perfusion imaging in 6 cases; 4 cases were diagnosed by magnetic resonance pulmonary angiography (MRPA). The sPESI score showed that 36 patients were moderate-risk patients [26 patients with sPESI ≥ 1, and 10 patients with sPESI 0 but right ventricular dysfunction (RVD) and/or elevated cardiac biomarkers]. Thrombolytic therapy and anticoagulant therapy were performed on 17 of them: 8 were cured, 8 were improved, and 1 died; anticoagulant therapy was performed on 18 moderate-risk patients: 9 were cured, 7 were improved, 1 left the hospital without cure, and 1 died; the other 1 moderate-risk patient with PE caused by right atrial myxoma was treated by operation and ultimately died. Four low-risk patients were treated by anticoagulant therapy: 2 were cured and 2 improved. The area under the ROC curve (AUC) of Wells score combined with CTPA was 0.82 (95% confidence interval was 0.73-0.98, P < 0.01), the sensitivity was 74.2%, and the specificity was 90.0%. CONCLUSIONS: DVT and chronic diseases are the most common risk factors for APE in the elderly patients, often accompanied by dyspnea, chest tightness, and lower limb swelling and pain. Early anticoagulation therapy in elderly APE can make a good prognosis. Wells score has an important predictive value for the diagnosis of APE, while blood D-dimer is an important exclusion parameter. CTPA test is the main diagnostic method for APE. The sPESI score can suggest risk stratification and prognosis, and further guided treatment.


Assuntos
Embolia Pulmonar , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico por imagem , Curva ROC , Estudos Retrospectivos , Troponina I , Disfunção Ventricular Direita
8.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(5): 603-608, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33210487

RESUMO

OBJECTIVE: To establish reuse process of positive pressure powered air-filter protective hoods during coronavirus disease 2019 (COVID-19) epidemic. METHODS: The procedure of pretreatment, storage, recovery, cleaning, disinfection and sterilization process of positive pressure powered air-filter protective hoods, which were used in the treatment of COVID-19 infection patients was established in Central Sterile Supply Department of the hospital. The cleaning and disinfection effects of the protective hoods after treatment were examined by magnifying glass method, residual protein detection method, real-time PCR, and agar pour plate method. RESULTS: Twenty five used protective hoods underwent totally 135 times of washing, disinfecting and sterilizing procedures. After washing, all the protein residue tests and COVID-19 nucleic acid tests showed negative results. After sterilizing, all the protective hoods met sterility requirement. All the tested protective hoods were undamaged after reprocessing. CONCLUSIONS: The established reuse procedures for used positive pressure powered air-filter protective hoods are safe.

9.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(5): 609-613, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33210488

RESUMO

OBJECTIVE: To compare three sterilizing methods for reusable medical goggles. METHODS: A total of 180 medical goggles of the same brand and same model were randomly divided into three groups. In group A the goggles were first soaked with 2000 mg/L chlorine-containing disinfectant and then cleaned manually; goggles in other two groups were sterilized using pre-programmed automatic spray cleaning and disinfection machine, the disinfection program was set to 90 ℃ for 5 min in group B and 70 ℃ for 30 min in group C. The quality of the sterilization was monitored by visual inspection with luminous magnifying glass and residual protein detection assay. User satisfaction on cleanliness of medical goggles, clarity of mirror surface and suitability of elastic bands was investigated with questionnaire survey. RESULTS: The qualification rates verified by visual inspection were 82.4%, 84.6%and 98.3%in group A, B and C, respectively, the qualification rate in group C was significantly higher than those in group B and group C (all P<0.05). The qualification rates verified by residual protein detection assay were 96.7%, 100.0%and 100.0%in group A, B and C, respectively (P>0.05). A total of 54 questionnaires were submitted for the survey. The satisfaction rates were 100.0%, 90.7%and 94.4% for cleanliness of medical goggles, clarity of mirror surface and suitability of elastic bands, respectively. CONCLUSIONS: Machinery sterilization set 70 ℃ for 30 min has better cleaning and sterilizing effects for reusable medical goggles.

10.
J Biol Chem ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33177064

RESUMO

The classical role of Vitellogenin (Vg) is providing energy reserves for developing embryos, but its roles appear to extend beyond this nutritional function, and its importance in host immune defense is garnering increasing research attention. However, Vg-regulated immunological functions are dependent on three different domains within different species and remain poorly understood. In the present study, we confirmed three conserved VG domains - LPD_N, DUF1943 and VWD - in the Chinese mitten crab (Eriocheir sinensis), highlighting functional similarities of Vg in vertebrates and invertebrates. Of these three domains, DUF1943 and VWD showed definitive bacterial binding activity via interaction with the signature components on microbial surfaces, but this activity was s not exhibited by the LPD_N domain. Antibacterial assays indicated that only the VWD domain inhibits bacterial proliferation, and this function may be conserved between different species due to the conserved amino acid residues. To further explore the relationship between Vg and polymeric immunoglobulin receptor (pIgR), we expressed EspIgR and the three Eriocheir sinensis-Vg (EsVg) domains in HEK293T cells, and co-immunoprecipitation assay demonstrated that only the DUF1943 domain interacts with EspIgR. Subsequent experiments demonstrated that EsVg regulates hemocyte phagocytosis by binding with EspIgR through the DUF1943 domain, thus promoting bacterial clearance and protecting the host from bacterial infection. To the best of our knowledge, our work is the first to report distinct domains in Vg inducing different immunological outcomes in invertebrates, providing new evidence that pIgR acts as a phagocytic receptor for Vg.

11.
Dev Comp Immunol ; : 103925, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33217412

RESUMO

Crustaceans, including crab and shrimp, generally lack lymphocytes or adaptive immunity, and they rely solely on innate immunity for pathogen defense. The white spot syndrome virus (WSSV) causes the most prevalent viral disease in penaeid shrimps, which are widely cultured species in coastal waters worldwide. Numerous studies have elucidated the role of the immune system in protecting shrimps from WSSV infection for the development of safe and effective defensive strategies against WSSV. Although WSSV has a wide host range, it appears to exhibit high pathogenicity and virulence in only penaeid shrimps. Crabs are interesting models for studying immune responses after WSSV infection. Therefore, we reviewed recent information on the innate immune responses of crabs to WSSV and mainly focused on the antiviral functions of exosome-mediated apoptosis and alternatively spliced Down syndrome cell adhesion molecule. Our review may provide novel insights into antiviral management for crustaceans, especially penaeid shrimps.

12.
Cancer ; 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33136293

RESUMO

BACKGROUND: To the authors' knowledge, little is known regarding the association between recent oncologic treatment and mortality in patients with cancer who are infected with coronavirus disease 2019 (COVID-19). The objective of the current study was to determine whether recent oncologic treatment is associated with a higher risk of death among patients with carcinoma who are hospitalized with COVID-19. METHODS: Data regarding 248 consecutive patients with carcinoma who were hospitalized with COVID-19 were collected retrospectively from 33 hospitals in Hubei Province, China, from January 1, 2020, to March 25, 2020. The follow-up cutoff date was July 22, 2020. Univariable and multivariable logistic regression analyses were performed to identify variables associated with a higher risk of death. RESULTS: Of the 248 patients enrolled, the median age was 63 years and 128 patients (52%) were male. On admission, 147 patients (59%) did not undergo recent oncologic treatment, whereas 32 patients (13%), 25 patients (10%), 12 patients (5%), and 10 patients (4%), respectively, underwent chemotherapy, surgery, targeted therapy, and radiotherapy. At the time of last follow-up, 51 patients (21%) were critically ill during hospitalization, 40 of whom had died. Compared with patients without receipt of recent oncologic treatment, the mortality rate of patients who recently received oncologic treatment was significantly higher (24.8% vs 10.2%; hazard ratio, 2.010 [95% CI, 1.079-3.747; P = .027]). After controlling for confounders, recent receipt of chemotherapy (odds ratio [OR], 7.495; 95% CI, 1.398-34.187 [P = .015]), surgery (OR, 8.239; 95% CI, 1.637-41.955 [P = .012]), and radiotherapy (OR, 15.213; 95% CI, 2.091-110.691 [P = .007]) were identified as independently associated with a higher risk of death. CONCLUSIONS: The results of the current study demonstrated a possible association between recent receipt of oncologic treatment and a higher risk of death among patients with carcinoma who are hospitalized with COVID-19.

13.
Clin Lab ; 66(11)2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33180447

RESUMO

BACKGROUND: Although increasing evidence has shown that long non-coding RNA BLACAT1 could be aberrantly expressed and used as a prognostic marker in various cancers, the results remain inconclusive. In this study, we sought to summarize the relationship between BLACAT1 (bladder cancer associated transcript 1) and relevant clinical outcomes. METHODS: Eligible studies were retrieved from the online databases PubMed and Web of Science. A meta-analysis was performed using Stata 12.0 software. The Cancer Genome Atlas (TCGA) dataset was further used to verify the results. RESULTS: A total of sixteen studies were included to evaluate the association of BLACAT1 with overall survival or clinicopathological features by pooled hazard ratio (HR) or odds ratio (OR) in cancer. In the pooled analyses stratified by clinicopathological features, BLACAT1 expressions were closely correlated with lymph node metastasis (OR = 2.52, 95% CI: 1.86 - 3.40, p = 0.000), histological differentiation (OR = 1.98, 95% CI 1.25 - 3.13, p = 0.004), and tumor stage (OR = 1.89, 1.23 - 2.91, p = 0.004), but not to tumor size (OR = 1.91, 95% CI 0.96 - 3.80, p = 0.064) or distant metastasis (OR = 3.76, 95% CI: 0.90 - 15.71, p = 0.07) in cancer. Our results manifested that elevated BLACAT1 expression was markedly associated with poor overall survival (HR = 1.62, 95% CI: 1.41 - 1.84, p = 0.000) and PFS (HR = 2.10, 95% CI: 1.28 - 2.93, p < 0.001) among twelve types of solid cancers. Subgroup analysis demonstrated a significant association between high BLACAT1 expression and shorter OS in the lung cancer (HR = 2.03, 95% CI: 1.66 - 2.40, p = 0.000), colorectal cancer (HR = 1.47, 95% CI: 1.3 - 1.64, p = 0.000). Using Cox multivariate analyses, BLACAT1 expression was found to be an independent prognostic marker for OS in cancer (HR = 1.83, 95% CI: 1.37 - 2.30). TCGA dataset also confirmed that the upregulated BLACAT1 expression was significantly correlated with poor prognosis in cancer. CONCLUSIONS: Increased BLACAT1 expression was associated with more advanced clinicopathological features and may serve as poor prognosis in various cancers.

14.
Cell Death Differ ; 2020 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-33100324

RESUMO

Transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. The post-translational phosphorylation modulations of TFEB by mTOR and ERK signaling can determine its nucleocytoplasmic shuttling and activity in response to nutrient availability. However, regulations of TFEB at translational level are rarely known. Here, we found that programmed cell death 4 (PDCD4), a tumor suppressor, decreased levels of nuclear TFEB to inhibit lysosome biogenesis and function. Mechanistically, PDCD4 reduces global pool of TFEB by suppressing TFEB translation in an eIF4A-dependent manner, rather than influencing mTOR- and ERK2-dependnet TFEB nucleocytoplasmic shuttling. Both of MA3 domains within PDCD4 are required for TFEB translation inhibition. Furthermore, TFEB is required for PDCD4-mediated lysosomal function suppression. In the tumor microenvironment, PDCD4 deficiency promotes the anti-tumor effect of macrophage via enhancing TFEB expression. Our research reveals a novel PDCD4-dependent TFEB translational regulation and supports PDCD4 as a potential therapeutic target for lysosome dysfunction related diseases.

15.
Aging (Albany NY) ; 12(19): 19421-19439, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33040048

RESUMO

Traumatic brain injury (TBI) is regarded as a high-risk factor for Alzheimer's disease (AD). Asparaginyl endopeptidase (AEP), a lysosomal cysteine protease involved in AD pathogenesis, is normally activated under acidic conditions and also in TBI. However, both the molecular mechanism underlying AEP activation-mediated TBI-related AD pathologies, and the role of AEP as an AD therapeutic target, still remain unclear. Here, we report that TBI induces hippocampus dependent cognitive deficit and synaptic dysfunction, accompanied with AEP activation, I2PP2A (inhibitor 2 of PP2A, also called SET) mis-translocation from neuronal nucleus to cytoplasm, an obvious increase in AEP interaction with SET, and tau hyperphosphorylation in hippocampus of rats. Oxygen-glucose deprivation (OGD), mimicking an acidic condition, also leads to AEP activation, SET mis-translocation, PP2A inhibition, tau hyperphosphorylation, and a decrease in synaptic proteins, all of which are abrogated by AEP inhibitor AENK in primary neurons. Interestingly, AENK restores SET back to the nucleus, mitigates tau pathologies, rescuing TBI-induced cognitive deficit in rats. These findings highlight a novel etiopathogenic mechanism of TBI-related AD, which is initiated by AEP activation, accumulating SET in cytoplasm, and favoring tau pathology and cognitive impairments. Lowering AEP activity by AEP inhibitor would be beneficial to AD patients with TBI.

16.
Cell Discov ; 6: 69, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33083004

RESUMO

As an early type of lung adenocarcinoma, ground glass nodule (GGN) has been detected increasingly and now accounts for most lung cancer outpatients. GGN has a satisfactory prognosis and its characteristics are quite different from solid adenocarcinoma (SADC). We compared the GGN adenocarcinoma (GGN-ADC) with SADC using the single-cell RNA sequencing (scRNA-seq) to fully understand GGNs. The tumor samples of five patients with lung GGN-ADCs and five with SADCs underwent surgery were digested to a single-cell suspension and analyzed using 10× Genomic scRNA-seq techniques. We obtained 60,459 cells and then classified them as eight cell types, including cancer cells, endothelial cells, fibroblasts, T cells, B cells, Nature killer cells, mast cells, and myeloid cells. We provided a comprehensive description of the cancer cells and stromal cells. We found that the signaling pathways related to cell proliferation were downregulated in GGN-ADC cancer cells, and stromal cells had different effects in GGN-ADC and SADC based on the analyses of scRNA-seq results. In GGN-ADC, the signaling pathways of angiogenesis were downregulated, fibroblasts expressed low levels of some collagens, and immune cells were more activated. Furthermore, we used flow cytometry to isolate the cancer cells and T cells in 12 GGN-ADC samples and in an equal number of SADC samples, including CD4+ T and CD8+ T cells, and validated the expression of key molecules by quantitative real-time polymerase chain reaction analyses. Through comprehensive analyses of cell phenotypes in GGNs, we provide deep insights into lung carcinogenesis that will be beneficial in lung cancer prevention and therapy.

17.
ACS Appl Mater Interfaces ; 12(43): 49012-49020, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33074666

RESUMO

Carbon dots (CDs) exhibit a wide range of desirable properties including excellent photoluminescence, photostability, and water solubility, making them ideally suitable for use in the context of drug delivery, bioimaging, and related biomedical applications. Before these CDs can be translated for use in humans, however, further research regarding their in vivo toxicity is required. Owing to their low cost, rapid growth, and significant homology to humans, zebrafish (Danio rerio) are commonly employed as in vivo model systems in the toxicity studies of nanomaterials. In the present report, our group employed a hydrothermal approach to synthesize CDs and then assessed their toxicity in zebrafish. The resultant CDs were roughly 2.4 nm spheroid particles that emitted strong blue fluorescence in response to the excitation at 365 nm. These CDs did not induce any evident embryonic toxicity or did cause any apparent teratogenic effects during hatching or development when dosed at 150 µg/mL. However, significant effects were observed in zebrafish embryos at CD concentrations >200 µg/mL, including pericardial and yolk sac edema, delayed growth, spinal cord flexure, and death. These high CD concentrations were further associated with the reduction in zebrafish larval locomotor activity and decreased dopamine levels, reduced frequencies of tyrosine hydroxylase-positive dopaminergic neurons, and multiple organ damage. Further studies will be required to fully understand the mechanistic basis for CD-mediated neurotoxicity, with such studies being essential to fully understand the translational potential of these unique nanomaterials.

18.
Proc Natl Acad Sci U S A ; 117(45): 28212-28220, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33106431

RESUMO

Somatic mutations are major genetic contributors to cancers and many other age-related diseases. Many disease-causing somatic mutations can initiate clonal growth prior to the appearance of any disease symptoms, yet experimental models that can be used to examine clonal abnormalities are limited. We describe a mosaic analysis system with Cre or Tomato (MASCOT) for tracking mutant cells and demonstrate its utility for modeling clonal hematopoiesis. MASCOT can be induced to constitutively express either Cre-GFP or Tomato for lineage tracing of a mutant and a reference group of cells simultaneously. We conducted mosaic analysis to assess functions of the Id3 and/or Tet2 gene in hematopoietic cell development and clonal hematopoiesis. Using Tomato-positive cells as a reference population, we demonstrated the high sensitivity of this system for detecting cell-intrinsic phenotypes during short-term or long-term tracking of hematopoietic cells. Long-term tracking of Tet2 mutant or Tet2/Id3 double-mutant cells in our MASCOT model revealed a dynamic shift from myeloid expansion to lymphoid expansion and subsequent development of lymphoma. This work demonstrates the utility of the MASCOT method in mosaic analysis of single or combined mutations, making the system suitable for modeling somatic mutations identified in humans.

19.
PLoS One ; 15(10): e0240359, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33104724

RESUMO

Considering that the Pc-Crash multibody dynamics software can reproduce the accident process accurately and obtain the collision parameters of pedestrian heads at the moment of head landing, the finite element analysis method can accurately analyze the injury of the pedestrian head when the boundary conditions are known. This paper combines the accident reconstruction method with the finite element analysis method to study the injury mechanism of pedestrian head impact on the ground in vehicle pedestrian collision accidents to provide a theoretical basis for pedestrian protection and the improvement of vehicle shapes. First, a real-life vehicle pedestrian collision is reproduced by Pc-Crash. The simulation results show that the rigid multibody model can accurately simulate the scene of the accident, then the speed and angle of the pedestrian head landing moment can be obtained at the same time. Second, the finite element model of human heads with a detailed facial structure is established and verified. Finally, the collision parameters obtained from the accident reconstruction are used as the boundary conditions to analyze the collision between the pedestrian head and the ground, and the biomechanical parameters, such as intracranial pressure, von Mises stress, shear stress and strain, can be determined. The results show that the stress wave will propagate inside and outside the skull and cause stress concentration in the skull and the brain tissue to varying degrees after the pedestrian head strikes the ground. When the stress exceeds a certain limit, it will cause different degrees of brain tissue injury.

20.
Medicine (Baltimore) ; 99(35): e21902, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871922

RESUMO

The function of miR-9 in osteosarcoma is not well-investigated and controversial. Therefore, we conducted meta-analysis to explore the role of miR-9 in osteosarcoma, and collected relevant TCGA data to further testify the result. In addition, bioinformatics analysis was conducted to investigate the mechanism and related pathways of miR-9-3p in osteosarcoma.Literature search was operated on databases up to February 19, 2020, including PubMed, Web of Science, Science Direct, Cochrane Central Register of Controlled Trials, and Wiley Online Library, China National Knowledge Infrastructure, China Biology Medicine disc, Chongqing VIP, and Wan Fang Data. The relation of miR-9 expression with survival outcome was estimated by hazard ratio (HRs) and 95% CIs. Meta-analysis was conducted on the Stata 12.0 (Stata Corporation, TX). To further assess the function of miR-9 in osteosarcoma, relevant data from the TCGA database was collected. Three databases, miRDB, miRPathDB 2.0, and Targetscan 7.2, were used for prediction of target genes. Genes present in these 3 databases were considered as predicted target genes of miR-9-3p. Venny 2.1 were used for intersection analysis. Subsequently, GO, KEGG, and PPI network analysis were conducted based on the overlapping target genes of miR-9-3p to explore the possible molecular mechanism in osteosarcoma.Meta-analysis shown that overexpression of miR-9 was associated with worse overall survival (OS) (HR = 4.180, 95% CI: 2.880-6.066, P < .001, I = 23.5%). Based on TCGA data, osteosarcoma patients with overexpression of miR-9-3p (HR = 1.603, 95% CI: 1.028-2.499, P = .037) and miR-9-5p (HR = 1.698, 95% CI: 1.133-2.545, P = .01) also suffered poor OS. In bioinformatics analysis, 2 significant and important pathways were enriched: Wnt signaling pathway from gene ontology analysis (gene ontology:0016055, P-adjust = .008); hippo signaling pathway from Kyoto Encyclopedia of Genes and Genomes analysis (P-adjust = .007). Moreover, network analysis relevant protein-protein interaction was visualized, revealing 117 nodes and 161 edges.High miR-9 expression was associated with poor prognosis. Based on bioinformatics analysis, this study enhanced the understanding of the mechanism and related pathways of miR-9 in osteosarcoma.


Assuntos
MicroRNAs/genética , Osteossarcoma/genética , Biologia Computacional , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Humanos , Prognóstico , Transdução de Sinais/genética
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