Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.032
Filtrar
1.
Int J Mol Sci ; 21(19)2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003435

RESUMO

For hundreds of indications, mesenchymal stromal cells (MSCs) have not achieved the expected therapeutic efficacy due to an inability of the cells to reach target tissues. We show that inducing high mannose N-glycans either chemically, using the mannosidase I inhibitor Kifunensine, or genetically, using an shRNA to silence the expression of mannosidase I A1 (MAN1A1), strongly increases the motility of MSCs. We show that treatment of MSCs with Kifunensine increases cell migration toward bone fracture sites after percutaneous injection, and toward lungs after intravenous injection. Mechanistically, high mannose N-glycans reduce the contact area of cells with its substrate. Silencing MAN1A1 also makes cells softer, suggesting that an increase of high mannose N-glycoforms may change the physical properties of the cell membrane. To determine if treatment with Kifunensine is feasible for future clinical studies, we used mass spectrometry to analyze the N-glycan profile of MSCs over time and demonstrate that the effect of Kifunensine is both transitory and at the expense of specific N-glycoforms, including fucosylations. Finally, we also investigated the effect of Kifunensine on cell proliferation, differentiation, and the secretion profile of MSCs. Our results support the notion of inducing high mannose N-glycans in MSCs in order to enhance their migration potential.

2.
J Neural Eng ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33022663

RESUMO

BACKGROUND: At present, sEMG-based gesture recognition requires vast amounts of training data; otherwise, it is limited to a few gestures. This paper presents a novel dynamic energy model that decodes continuous hand actions by training small amounts of sEMG data. METHOD: The activation of forearm muscles can set the corresponding fingers in motion or state with movement trends. The moving fingers store kinetic energy, and the fingers with movement trends store potential energy. The kinetic energy and potential energy in each finger are dynamically allocated due to the adaptive-coupling mechanism of five-fingers in actual motion. Meanwhile, the sum of the two energies remains constant at a certain muscle activation. We regarded hand movements with the same direction of acceleration for five-finger as the same in energy mode and divided hand movements into ten energy modes. Independent component analysis and machine learning methods were used to model associations between sEMG signals and energy modes and expressed gestures by energy form adaptively. This theory imitates the self-adapting mechanism in actual tasks. Thus, ten healthy subjects were recruited, and three experiments mimicking activities of daily living were designed to evaluate the interface: (1) the expression of untrained gestures, (2) the decoding of the amount of single-finger energy, and (3) real-time control. RESULTS: (1) Participants completed the untrained hand movements (100 /100, p < 0.0001). (2) The interface performed better than chance in the experiment where participants pricked balloons with a needle tip (779 /1000, p < 0.0001). (3) In the experiment where participants punched a hole in the plasticine on the balloon, the success rate was over 95% (97.67±5.04 %, p <0.01). CONCLUSION: The model can achieve continuous hand actions with speed or force information by training small amounts of sEMG data, which reduces learning task complexity.

3.
J Recept Signal Transduct Res ; : 1-6, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023351

RESUMO

The pathogenesis of post-infarction ischemia-induced myocardial damage is related to hypoxia-mediated cardiomyocyte damage. In the present study, we explored the roles of ERK signaling pathway and endoplasmic reticulum (ER) stress in hypoxia-related cardiomyocyte damage. H9c2 cells were cultured under hypoxia condition in the presence of the ERK activator. Our data demonstrated that ER stress was significantly activated by hypoxia in cardiomyocyte, as evidenced by increased expression of PERK and CHOP through immunofluorescence. Interestingly, application of ERK activator significantly reduced hypoxia-mediated ER stress. Besides, ERK activation also sustained cardiomyocyte viability in the presence of hypoxia, as evidenced by decreased activities of caspase-3 and caspase-9. Altogether, our results demonstrated that ERK activation significantly promoted cardiomyocyte survival through inhibition of ER stress. This finding provides a novel insight into the molecular mechanism underlying hypoxia-mediated cardiomyocyte damage. Besides, our results also offer a potential target for the treatment and prevention of post-infarction ischemia-related myocardial damage.

4.
Radiat Oncol ; 15(1): 232, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028378

RESUMO

BACKGROUND: This study investigated the feasibility and potential clinical benefit of utilizing a new proton treatment technique: Spot-scanning proton arc (SPArc) therapy for left-sided whole breast radiotherapy (WBRT) to further reduce radiation dose to healthy tissue and mitigate the probability of normal tissue complications compared to conventional intensity modulated proton therapy (IMPT). METHODS: Eight patients diagnosed with left-sided breast cancer and treated with breast-preserving surgery followed by whole breast irradiation without regional nodal irradiation were included in this retrospective planning. Two proton treatment plans were generated for each patient: vertical intensity-modulated proton therapy used for clinical treatment (vIMPT, gantry angle 10°-30°) and SPArc for comparison purpose. Both SPArc and vIMPT plans were optimized using the robust optimization of ± 3.5% range and 5 mm setup uncertainties. Root-mean-square deviation dose (RMSD) volume histograms were used for plan robustness evaluation. All dosimetric results were evaluated based on dose-volume histograms (DVH), and the interplay effect was evaluated based on the accumulation of single-fraction 4D dynamic dose on CT50. The treatment beam delivery time was simulated based on a gantry rotation with energy-layer-switching-time (ELST) from 0.2 to 5 s. RESULTS: The average D1 to the heart and LAD were reduced to 53.63 cGy and 82.25 cGy compared with vIMPT 110.38 cGy (p = 0.001) and 170.38 cGy (p = 0.001), respectively. The average V5Gy and V20Gy of ipsilateral lung was reduced to 16.77% and 3.07% compared to vIMPT 25.56% (p = 0.001) and 4.68% (p = 0.003). Skin3mm mean and maximum dose were reduced to 3999.38 cGy and 4395.63 cGy compared to vIMPT 4104.25 cGy (p = 0.039) and 4411.63 cGy (p = 0.043), respectively. A significant relative risk reduction (RNTCP = NTCPSPArc/NTCPvIMPT) for organs at risk (OARs) was obtained with SPArc ranging from 0.61 to 0.86 depending on the clinical endpoint. The RMSD volume histogram (RVH) analysis shows SPArc provided better plan robustness in OARs sparing, including the heart, LAD, ipsilateral lung, and skin. The average estimated treatment beam delivery times were comparable to vIMPT plans when the ELST is about 0.5 s. CONCLUSION: SPArc technique can further reduce dose delivered to OARs and the probability of normal tissue complications in patients treated for left-sided WBRT.

5.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(10): 1100-1104, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33059807

RESUMO

OBJECTIVE: To study the effect of the application timing of vasoactive agents on the prognosis of children in the third stage of hand-foot-mouth disease (HFMD). METHODS: A retrospective analysis was performed on the medical data of children in the third stage of HFMD between April 2012 and September 2016. According to the application time of vasoactive agents (milrinone combined with phentolamine) after admission, the children were divided into an early stage (within 2 hours after admission) group with 32 children, a middle stage (within 2-6 hours after admission) group with 28 children, and a late stage (more than 6 hours after admission) group with 26 children. Venous blood samples were collected before vasoactive agent treatment and after 24 hours of vasoactive agent treatment to measure the levels of creatine kinase-MB (CK-MB), troponin (TnI), and brain natriuretic peptide (BNP). The recovery time of left ventricular ejection fraction (LVEF), respiratory rate, blood pressure, and heart rate were recorded. The response rate to the treatment within 72 hours of treatment was evaluated. RESULTS: The early stage group had a significantly higher overall response rate to the treatment than the middle stage and late stage groups (P<0.0167). After 24 hours of treatment, there were significant differences in heart rate, blood pressure, respiratory rate, and LVEF among the three groups (P<0.05). The early stage group showed the most significant improvement in these parameters (P<0.0167). Compared with the middle stage and late stage groups, the early stage group had significantly shorter recovery time of LVEF, respiratory rate, heart rate, and blood pressure (P<0.0167). After 24 hours of treatment, the early stage group had a significantly lower level of BNP than the middle stage and late stage groups (P<0.05). CONCLUSIONS: Vasoactive agents should be given to children with critical HFMD as early as possible to improve cardiovascular function, reduce the risk of disease progression, and improve prognosis.

6.
Medicine (Baltimore) ; 99(41): e22647, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031325

RESUMO

RATIONALE: Signet ring cell carcinoma of the stomach is prone to relapse and metastasis after traditional surgical treatment, and the prognosis is also poor. We improved the concept of treatment and conducted cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) combined with intraperitoneal (IP) and intravenous (IV) chemotherapy for a gastric signet-cell carcinoma patient. PATIENT CONCERNS: A 65-year-old male patient with complaint of intermittent hematemesis for over 10 days was referred to our hospital for treatment. The patient developed hematemesis of 800 mL without obvious causes on May 27, 2015, accompanied by dizziness and amaurosis fugax. After the bleeding was stopped with medicinal treatment, diagnostic gastroscopy revealed an ulcer at the less curvature of the stomach, with biopsy pathology diagnosis as severe atypical hyperplasia, which was confirmed to be poorly differentiated adenocarcinoma by a second biopsy. In past medical history, the patient had 5 coronary stents implanted because of coronary atherosclerotic heart disease 3 years ago. DIAGNOSIS: Gastric cancer (cT4NxMx) according to the patient's history and biopsy pathology. INTERVENTIONS: the patient was treated surgery-based multidisciplinary treatments integrating CRS + HIPEC and IP + IV adjuvant chemotherapy. The CRS was curative distal gastrectomy with D2 lymphadenectomy, and HIPEC was cisplatin 120 mg plus mitomycin C 30 mg at 43 °C, for 60 minutes. Final pathological diagnosis of after surgery was: poorly differentiate adenocarcinoma with signet-ring cells, with invasion beyond the serosal layer and into the duodenum, 10/23 lymph nodes positive, nerve invasion, vascular tumor thrombi, Borrmann type IV, Lauren type diffuse. TNM stage was pT4aN3M0, IIIC. After operation, the patient received 6 courses of IV chemotherapy with oxaliplatin and 5-fluorouracil/Tegafur Gimeracil Oteracil Potassium capsules, and IP chemotherapy with docetaxel and carboplatin. OUTCOMES: Regular follow-up till July 20, 2020, revealed that the patient has a disease-free survival of over 61+ months. LESSONS: CRS + HIPEC combined with IP + IV chemotherapy achieved long-term disease-free survival for this patient with gastric signet-ring cell carcinoma and deserve further study. This new treatment modality deserves appropriate consideration in routine clinical practice for patients with advanced gastric cancer.

7.
Aging (Albany NY) ; 122020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33027769

RESUMO

The value of combining multiple candidate genes into a panel to improve biomarker performance is increasingly emphasized. Genes associated with WNT signaling are widely-reported to provide prognostic signatures in non-small cell carcinoma (NSCLC). Screening of genes involved in this signaling pathway facilitated selection of an optimal candidate biomarker gene combination and development of an NSCLC prognostic model based on expression of these genes. Risk scores derived from the model performed well in predicting survival; in the training dataset, samples achieving a high risk score exhibit a shorter survival interval (median survival time 34.8 months, 95% CI 31.1-41.0) than did samples achieving a low risk score (median survival time 72.0 months, 95% CI 59.3-87.5, p=2e-11), and exhibited higher oncogene and lower tumor suppressor gene expression. Receiver-operator characteristic curves based on three-year survival demonstrate that the model outperformed clinical prognostic indicators. In addition, the model was validated in four independent cohorts, demonstrating robust NSCLC prognostic value. Correlation analyses reveal that the model offers efficacy independent of other clinical indicators. Gene Set Enrichment Analysis (GSEA) reveals that the model reflects variable tissue functional states relevant to NSCLC biology. In summary, the signature model shows potential as a valuable and robust NSCLC prognostic indicator.

8.
J Phys Chem B ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33052673

RESUMO

This work reports the first direct observations of binding and complex formation between transforming growth factor beta 1 (TGF-ß1) and cartilage oligomeric matrix protein (COMP) using high-resolution atomic force microscopy (AFM). Each COMP molecule consists of pentamers whose five identical monomeric units bundle at N-termini. From this central point, the five monomers' flexible arms extend outward with C-terminal domains at the distal ends, forming a bouquet-like structure. In commonly used buffer solutions, TGF-ß1 molecules typically form homodimers (majority), double dimers (minority), and aggregates (trace amount). Mixing TGF-ß1 and COMP leads to rapid binding and complex formation. The TGF-ß1/COMP complexes contain one to three COMP and multiple TGF-ß1 molecules. For complexes with one COMP, the structure is more compact and less flexible than that of COMP alone. For complexes with two or more COMP molecules, the conformation varies to a large degree from one complex to another. This is attributed to the presence of double dimers or aggregates of TGF-ß1 molecules, whose size and multiple binding sites enable binding to more than one COMP. The number and location of individual TGF-ß1 dimers are also clearly visible in all complexes. This molecular-level information provides a new insight into the mechanism of chondrogenesis enhancement by TGF-ß1/COMP complexes, i.e., simultaneous and multivalent presentation of growth factors. These presentations help explain the high efficacy in sustained activation of the signaling pathway to augment chondrogenesis.

9.
Genetica ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33052504

RESUMO

Amphibians are experiencing worldwide declines due to increasing anthropogenetic disturbances. However, the genetic variability and hence adaptability are still unknown for most frogs. We integrated the mitochondrial (ND2 gene), nuclear (TYR gene) and major histocompatibility complex (MHC) loci, to clarify the demographic patterns and immune-gene diversity of the Lolokou Sucker Frog (Amolops loloensis). Demographic analysis of the ND2 and TYR genes suggested that the Lolokou Sucker Frog experienced a population expansion within the last 10,000 years. High MHC diversity was detected, which has likely resulted from positive selection, indicating the current diversity bodes well for the species' adaptive potential to pathogenic challenges. These findings broaden our knowledge on the population history and evolution adaptation of the reclusive torrent frog, and conservation implications are provided.

10.
Int Immunopharmacol ; 89(Pt B): 106996, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33049493

RESUMO

Cardiovascular diseases remain the major cause of death worldwide. Atherosclerosis is recognized as the common ground of cardiovascular diseases. Inflammatory cytokines-induced attachment of monocytes to endothelial cells is a significant event in the progression of atherosclerosis. As a highly selective dipeptidyl peptidase (DPP)-4 inhibitor, trelagliptin is used for the treatment of type 2 diabetes mellitus (T2DM). However, whether trelagliptin possesses an inhibitory effect on endothelial dysfunction and monocyte adhesion is unknown. In the current study, we tested the effect of trelagliptin in endothelial cells. We used human aortic endothelial cells (HAECs) exposed to interleukin (IL)-1ß to mimic the microenvironment of atherosclerosis. Our results showed that trelagliptin inhibited the expression of pro-inflammatory chemokines including monocyte chemoattractant protein 1 (MCP-1), CXCL-1, and IL-6. Furthermore, trelagliptin suppressed the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Mechanistically, trelagliptin suppressed the activation of activator protein-1 (AP-1) and NF-κB signaling pathways, which modulate the inflammatory process and monocyte adhesion. Collectively, our results showed that trelagliptin had a powerful inhibitory effect on the attachment of monocytes to endothelial cells, indicating that trelagliptin might have a protective effect on cardiovascular diseases such as atherosclerosis.

11.
J Neuroimmunol ; 349: 577404, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-33068971

RESUMO

OBJECTIVE: Regulatory T cells (Tregs) play an important role in T cells. CC chemokine receptor 5 is a highly expressed chemokine receptor in T cells. They play an important role in inflammation and immune response of stroke. METHODS: Flow cytometry measured Tregs and CCR5+ Tregs in the blood of patients. Univariate and multivariate logistic regression analysis were utilized to analyze the effect of Tregs and CCR5+ Tregs on the prognosis of ischemic stroke. Receiver operating characteristic (ROC) curve was used to assess predictive values for Treg cells and CCR5+ Tregs. RESULTS: Tregs in patients with severe ischemic stroke were higher than those in mild ischemic stroke (P < 0.05), while the expression of CCR5+ Tregs were reversed (P < 0.05). The results of univariate and multivariate logistics regression analysis showed that Tregs and CCR5+ Tregs had a good predictive effect on the prognosis of ischemic stroke. The ROC curve demonstrated that the combination of Tregs and CCR+ Tregs achieved a better prediction effect (AUC = 0.758; P < 0.001). CONCLUSIONS: The combination of Tregs and CCR5+ Tregs can be used as biomarkers for the prognosis of ischemic stroke.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33074715

RESUMO

Augmented glycolysis due to metabolic reprogramming in lung myofibroblasts is critical to their pro-fibrotic phenotype. The primary glycolysis byproduct, lactate, is also secreted into the extracellular milieu, together with which, myofibroblasts and macrophages form a spatially restricted site usually described as fibrotic niche. Therefore, we hypothesized that myofibroblast glycolysis might have a non-cell autonomous effect through lactate regulating the pathogenic phenotype of alveolar macrophages. Here, we demonstrated that there was a markedly increased lactate in the conditioned media of TGF-ß1 induced lung myofibroblasts and in the bronchoalveolar lavage fluids (BALFs) from mice with TGF-ß1 or bleomycin induced lung fibrosis. Importantly, the media and BALFs promoted pro-fibrotic mediator expression in macrophages. Mechanistically, lactate induced histone lactylation in the promoters of the pro-fibrotic genes in macrophages, consistent with the upregulation of this epigenetic modification in these cells in the fibrotic lungs. The lactate inductions of the histone lactylation and pro-fibrotic gene expression were mediated by p300, as evidenced by their diminished levels in p300 knockdown macrophages. Collectively, our study establishes that in addition to protein, lipid, and nucleic acid molecules, a metabolite can also mediate intercellular regulations in the setting of lung fibrosis. Our findings shed new light on the mechanism underlying the key contribution of myofibroblast glycolysis to the pathogenesis of lung fibrosis.

13.
Pediatr Infect Dis J ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33044433

RESUMO

BACKGROUND: There are limit studies about pediatric brain abscess in China. The aim of this study was to analyze clinical characteristics and outcomes of pediatric brain abscess in recent years in China. METHODS: The clinical information of children with brain abscess hospitalized in Beijing Children's Hospital between January 1, 2007 and December 31, 2016 were retrospectively reviewed. RESULTS: Ninety-four children were enrolled in this study. A Streptococcus milleri group (13.8%) was identified as the most common causative organisms, followed by Staphylococcus aureus (6.4%). The overall mortality was 21.6%, with 50.0% of deaths happening in the first week after diagnosis. Long-term outcomes of 74 patients were assessed with Glasgow Outcome Scale-Extended Pediatric Reversion: 50 patients with a score of 1-2 (favorable outcome) and 24 patients with a score of 3-8 (unfavorable outcome). Patients with multiple abscesses (P = 0.029) and intraventricular rupture of brain abscess/hydrocephalus (P = 0.024) had higher risk of unfavorable outcomes. CONCLUSIONS: Brain abscess is a serious disease with high mortality in children; more aggressive treatments should be considered in the first week of diagnosis because of high risk of death, and for patients with multiple brain abscesses and intraventricular rupture of brain abscess/hydrocephalus because of their higher risk of unfavorable.

14.
Cell Death Dis ; 11(10): 827, 2020 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-33012781

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by chronic non-specific inflammation of the interstitial lung and extensive deposition of collagen fibers leading to destruction of lung function. Studies have demonstrated that exposure to fine particulate matter (PM2.5) increases the risk of IPF. In order to recover from PM2.5-induced lung injury, alveolar epithelial cells need to be repaired and regenerated to maintain lung function. Type 2 alveolar epithelial cells (AEC2) are stem cells in the adult lung that contribute to the lung repair process through complex signaling. Our previous studies demonstrated that RAB6, a RAS family member lowly expressed in lung cancer, inhibited lung cancer stem cell self-renewal, but it is unclear whether or not and how RAB6 may regulate AEC2 cell proliferation and self-renewal in PM2.5-induced pulmonary fibrosis. Here, we demonstrated that knockout of RAB6 inhibited pulmonary fibrosis, oxidative stress, and AEC2 cell death in PM2.5-injured mice. In addition, knockout of RAB6 decreased Dickkopf 1(DKK1) autocrine and activated proliferation, self-renewal, and wnt/ß-catenin signaling of PM2.5-injured AEC2 cells. RAB6 overexpression increased DKK1 autocrine and inhibited proliferation, self-renewal and wnt/ß-catenin signaling in AEC2 cells in vitro. Furthermore, DKK1 inhibitors promoted proliferation, self-renewal and wnt/ß-catenin signaling of RAB6 overexpressing AEC2 cells, and attenuated PM2.5-induced pulmonary fibrosis in mice. These data establish RAB6 as a regulator of DKK1 autocrine and wnt/ß-catenin signal that serves to regulate AEC2 cell proliferation and self-renewal, and suggest a mechanism that RAB6 disruption may promote AEC2 cell proliferation and self-renewal to enhance lung repair following PM2.5 injury.

15.
Cancer Lett ; 496: 16-29, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33007410

RESUMO

Despite being the subject of extensive research and clinical trials, neuroblastoma remains a major therapeutic challenge in pediatric oncology. The p53 protein is a central safeguard that protects cells against genome instability and malignant transformation. Mutated TP53 (the gene encoding p53) is implicated in many human cancers, but the majority of neuroblastomas have wild type p53 with intact transcriptional function. In fact, the TP53 mutation rate does not exceed 1-2% in neuroblastomas. However, overexpression of the murine double minute 2 (MDM2) gene in neuroblastoma is relatively common, and leads to inhibition of p53. It is also associated with other non-canonical p53-independent functions, including drug resistance and increased translation of MYCN and VEGF mRNA. The p53-MDM2 pathway in neuroblastoma is also modulated at several different molecular levels, including via interactions with other proteins (MYCN, p14ARF). In addition, the overexpression of MDM2 in tumors is linked to a poorer prognosis for cancer patients. Thus, restoring p53 function by inhibiting its interaction with MDM2 is a potential therapeutic strategy for neuroblastoma. A number of p53-MDM2 antagonists have been designed and studied for this purpose. This review summarizes the current understanding of p53 biology and the p53-dependent and -independent oncogenic functions of MDM2 in neuroblastoma, and also the regulation of the p53-MDM2 axis in neuroblastoma. This review also highlights the use of MDM2 as a molecular target for the disease, and describes the MDM2 inhibitors currently being investigated in preclinical and clinical studies. We also briefly explain the various strategies that have been used and future directions to take in the development of effective MDM2 inhibitors for neuroblastoma.

16.
Circ J ; 84(10): 1797-1806, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32893260

RESUMO

BACKGROUND: Whether ischemic stroke per se, rather than older age or additional comorbidities, accounts for the adverse prognosis of heart failure (HF) is uncertain. The present study examineed the intrinsic association of ischemic stroke with outcomes in a propensity-matched cohort.Methods and Results:Of 1,351 patients hospitalized with HF, 388 (28.7%) had prior ischemic stroke. Using propensity score for prior ischemic stroke, estimated for each patient, a matched cohort of 379 pairs of HF patients with and without prior ischemic stroke, balanced on 32 baseline characteristics was assembled. At 30 days, prior ischemic stroke was associated with significantly higher risks of the combined endpoint of all-cause death or readmission (hazard ratio [HR]: 1.91; 95% confidence interval [CI]: 1.38 to 2.65; P<0.001), all-cause death (HR: 2.08; 95% CI: 1.28 to 3.38; P=0.003), all-cause readmission (HR: 2.67; 95% CI: 1.78 to 4.01; P<0.001), and HF readmission (HR: 2.11; 95% CI: 1.19 to 3.72; P=0.010). Prior ischemic stroke was associated with a significantly higher risk of all 4 outcomes at both 6 months and 1 year. CONCLUSIONS: Prior ischemic stroke was a potent and persistent risk predictor of death and readmission among patients with HF after accounting for clinical characteristics.

17.
Stem Cell Res Ther ; 11(1): 410, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967729

RESUMO

BACKGROUND: Acute kidney injury (AKI) is a common clinical disease with complex pathophysiology and limited therapeutic choices. This prompts the need for novel therapy targeting multiple aspects of this disease. Human amnion epithelial cell (hAEC) is an ideal stem cell source. Increasing evidence suggests that exosomes may act as critical cell-cell communicators. Accordingly, we assessed the therapeutic potential of hAECs and their derived exosomes (hAECs-EXO) in ischemia reperfusion mouse model of AKI and explored the underlying mechanisms. METHODS: The hAECs were primary cultured, and hAECs-EXO were isolated and characterized. An ischemic-reperfusion injury-induced AKI (IRI-AKI) mouse model was established to mimic clinical ischemic kidney injury with different disease severity. Mouse blood creatinine level was used to assess renal function, and kidney specimens were processed to detect cell proliferation, apoptosis, and capillary density. Macrophage infiltration was analyzed by flow cytometry. hAEC-derived exosomes (hAECs-EXO) were used to treat hypoxia-reoxygenation (H/R) injured HK-2 cells and mouse bone marrow-derived macrophages to evaluate their protective effect in vitro. Furthermore, hAECs-EXO were subjected to liquid chromatography-tandem mass spectrometry for proteomic profiling. RESULTS: We found that systematically administered hAECs could improve mortality and renal function in IRI-AKI mice, decrease the number of apoptotic cells, prevent peritubular capillary loss, and modulate kidney local immune response. However, hAECs showed very low kidney tissue integration. Exosomes isolated from hAECs recapitulated the renal protective effects of their source cells. In vitro, hAECs-EXO protected HK-2 cells from H/R injury-induced apoptosis and promoted bone marrow-derived macrophage polarization toward M2 phenotype. Proteomic analysis on hAECs-EXO revealed proteins involved in extracellular matrix organization, growth factor signaling pathways, cytokine production, and immunomodulation. These findings demonstrated that paracrine of exosomes might be the key mechanism of hAECs in alleviating renal ischemia reperfusion injury. CONCLUSIONS: We reported hAECs could improve survival and ameliorate renal injury in mice with IRI-AKI. The anti-apoptotic, pro-angiogenetic, and immunomodulatory capabilities of hAECs are at least partially, through paracrine pathways. hAECs-EXO might be a promising clinical therapeutic tool, overcoming the weaknesses and risks associated with the use of native stem cells, for patients with AKI.

18.
Cell Chem Biol ; 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32966806

RESUMO

MYC is a major oncogenic transcriptional driver of most human cancers that has remained intractable to direct targeting because much of MYC is intrinsically disordered. Here, we have performed a cysteine-reactive covalent ligand screen to identify compounds that could disrupt the binding of MYC to its DNA consensus sequence in vitro and also impair MYC transcriptional activity in situ in cells. We have identified a covalent ligand, EN4, that targets cysteine 171 of MYC within a predicted intrinsically disordered region of the protein. We show that EN4 directly targets MYC in cells, reduces MYC and MAX thermal stability, inhibits MYC transcriptional activity, downregulates multiple MYC transcriptional targets, and impairs tumorigenesis. We also show initial structure-activity relationships of EN4 and identify compounds that show improved potency. Overall, we identify a unique ligandable site within an intrinsically disordered region of MYC that leads to inhibition of MYC transcriptional activity.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA