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1.
World Neurosurg ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33444836

RESUMO

BACKGROUND: Tumor necrosis factor receptor-related factor 3 (TRAF3) interacting protein 3 (TRAF3IP3) is involved in the development of immune tissues and the immune response of the body. Down-regulated expression of TRAF3IP3 in malignant melanoma can inhibit tumor growth. The role of TRAF3IP3 in glioma is unknown. METHODS: We used the Wilcoxon rank sum test to compare the expression of TRAF3IP3 in glioma and normal tissues based on TCGA and GTEx. Logistics regression were used to evaluate the relationship between TRAF3IP3 and clinicopathological characters. Gene Set Enrichment Analysis (GSEA) and single sample GSEA (ssGSEA) was conducted to annotate biological function of TRAF3IP3. We used Kaplan-Meier and COX regression to evaluate the prognostic value of TRAF3IP3. RESULTS: We downloaded RNA-Seq data of 670 gliomas and 1157 normal tissues. TRAF3IP3 was highly expressed in gliomas(P<0.001). High expression of TRAF3IP3 and higher WHO grade (OR=3.57(2.42-5.34), P<0.001), wild-type isocitrate dehydrogenase (IDH) status (OR=4.79(3.40-6.83), P<0.001), 1P /19q non-codeletion (OR=15.32 (9.23-27.01), P<0.001), mutant epidermal growth factor receptor (EGFR) status (OR=2.77(1.65-4.81), P<0.001), worse histological type (OR=3.64(2.48-5.43), P<0.001) and worse primary therapy outcome (OR=2.29(1.47-3.61), P<0.001) were significantly correlated. Six signaling pathways were significantly enriched in the TRAF3IP3 high expression phenotype group, including JAK-STAT, interferon-γ, apoptosis, P53, programmed cell death protein 1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). High expression of TRAF3IP3 was associated with worse PFS (HR=2.39(1.39-3.01), P<0.001), DFS (HR=3.02(2.27-4.01), P<0.001) and OS(HR=2.87(2.20-3.75), P<0.001). CONCLUSIONS: TRAF3IP3 play an important role in the occurrence and development of glioma, and may be a potential biomarker for the prognosis of glioma.

2.
Sci Transl Med ; 13(576)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441426

RESUMO

Osteoarthritis (OA) is a widespread joint disease for which there are no disease-modifying treatments. Previously, we found that mice with cartilage-specific epidermal growth factor receptor (EGFR) deficiency developed accelerated knee OA. To test whether the EGFR pathway can be targeted as a potential OA therapy, we constructed two cartilage-specific EGFR overactivation models in mice by overexpressing heparin binding EGF-like growth factor (HBEGF), an EGFR ligand. Compared to wild type, Col2-Cre HBEGF-overexpressing mice had persistently enlarged articular cartilage from adolescence, due to an expanded pool of chondroprogenitors with elevated proliferation ability, survival rate, and lubricant production. Adult Col2-Cre HBEGF-overexpressing mice and Aggrecan-CreER HBEGF-overexpressing mice were resistant to cartilage degeneration and other signs of OA after surgical destabilization of the medial meniscus (DMM). Treating mice with gefitinib, an EGFR inhibitor, abolished the protective action against OA in HBEGF-overexpressing mice. Polymeric micellar nanoparticles (NPs) conjugated with transforming growth factor-α (TGFα), a potent EGFR ligand, were stable and nontoxic and had long joint retention, high cartilage uptake, and penetration capabilities. Intra-articular delivery of TGFα-NPs effectively attenuated surgery-induced OA cartilage degeneration, subchondral bone plate sclerosis, and joint pain. Genetic or pharmacologic activation of EGFR revealed no obvious side effects in knee joints and major vital organs in mice. Together, our studies demonstrate the feasibility of using nanotechnology to target EGFR signaling for OA treatment.

3.
J Clin Invest ; 131(2)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33206630

RESUMO

Bone is maintained by coupled activities of bone-forming osteoblasts/osteocytes and bone-resorbing osteoclasts. Alterations in this relationship can lead to pathologic bone loss such as osteoporosis. It is well known that osteogenic cells support osteoclastogenesis via production of RANKL. Interestingly, our recently identified bone marrow mesenchymal cell population-marrow adipogenic lineage precursors (MALPs) that form a multidimensional cell network in bone-was computationally demonstrated to be the most interactive with monocyte-macrophage lineage cells through high and specific expression of several osteoclast regulatory factors, including RANKL. Using an adipocyte-specific Adipoq-Cre to label MALPs, we demonstrated that mice with RANKL deficiency in MALPs have a drastic increase in trabecular bone mass in long bones and vertebrae starting from 1 month of age, while their cortical bone appears normal. This phenotype was accompanied by diminished osteoclast number and attenuated bone formation at the trabecular bone surface. Reduced RANKL signaling in calvarial MALPs abolished osteolytic lesions after LPS injections. Furthermore, in ovariectomized mice, elevated bone resorption was partially attenuated by RANKL deficiency in MALPs. In summary, our studies identified MALPs as a critical player in controlling bone remodeling during normal bone metabolism and pathological bone loss in a RANKL-dependent fashion.

4.
Tissue Eng Part A ; 27(1-2): 87-102, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32375579

RESUMO

Distraction osteogenesis (DO) is a well-established surgical technique for treating bone defect and limb lengthening. The major drawback of DO is the long treatment period as the external fixator has to be kept in place until consolidation is completed. Calcitonin gene-related peptide (CGRP) has been reported to promote angiogenesis by affecting endothelial progenitor cells (EPCs) in limb ischemia and wound healing. Thus, the goal of this study was to evaluate the angiogenic effect of exogenous CGRP on bone regeneration in a rat DO model. Exogenous CGRP was directly injected into the bone defect after each cycle of distraction in vivo. Microcomputed tomography, biomechanical test, and histological analysis were performed to assess the new bone formation. Angiography and immunofluorescence were performed to assess the formation of blood vessels. CD31+CD144+ EPCs in the bone defect were quantified with flow cytometry. In in vitro study, bone marrow stem cells (BMSCs) were used to investigate the effect of CGRP on EPCs production during endothelial differentiation. Our results showed that CGRP significantly promoted bone regeneration and vessel formation after consolidation. CGRP significantly increased the fraction of CD31+CD144+EPCs and the capillary density in the bone defect at the end of distraction phase. CGRP increased EPC population in the endothelial differentiation of BMSCs in vitro by activating PI3K/AKT signaling pathway. Furthermore, differentiated EPCs rapidly assembled into tube-like structures and promoted osteogenic differentiation of BMSCs. In conclusion, CGRP increased EPC population and promoted blood vessel formation and bone regeneration at the defect region in a DO model. Impact statement Distraction osteogenesis (DO) is a well-established surgical technique for limb lengthening and bone defect. The disadvantage of this technique is that external fixator is needed to be kept in place for about 12 months. This may result in increased risk of infection, financial burden, and negative psychological impacts. In this study, we have injected calcitonin gene-related peptide (CGRP) into the defect region after distraction and found that CGRP enhanced vessel formation and bone regeneration in a rat DO model. This suggests that a controlled delivery system for CGRP could be developed and applied clinically for accelerating bone regeneration in patients with DO.

5.
J Cell Mol Med ; 25(1): 367-382, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33215869

RESUMO

LLKL, a new traditional Chinese medicine formula containing Edgeworthia gardneri (Wall.) Meisn., Sibiraea angustata and Crocus sativus L. (saffron), was designed to ameliorate type 2 diabetes mellitus. Despite the therapeutic benefits of LLKL, its underlying mechanisms remain elusive. This study evaluated the LLKL anti-diabetic efficacy and its effect on gut microbiota to elucidate its mechanism of action in Zucker diabetic fatty rats. We found that administration of different LLKL concentrations (4.68, 2.34 and 1.17 g/kg/d) improved several diabetic parameters after a 6-week treatment. Moreover, LLKL modulated gut microbiota dysbiosis, increased the expression of occluding and maintained intestinal epithelial homeostasis, leading to a reduction in LPS, TNF-α and IL-6 levels. Hepatic transcriptomic analysis showed that the Toll-like receptor signalling pathway was markedly enriched by LLKL treatment. RT-qPCR results validated that LLKL treatment decreased the expressions of TLR4, MyD88 and CTSK. Furthermore, a gene set enrichment analysis indicated that LLKL enhanced the insulin signalling pathway and inhibited glycerolipid metabolism and fatty acid metabolism, which were verified by the liver biochemical analysis. These findings demonstrate that LLKL ameliorates hyperglycaemia, modulates the gut microbiota and regulates the gut-liver axis, which might contribute to its anti-diabetic effect.

6.
Biomaterials ; 268: 120576, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33271449

RESUMO

Periosteum can improve tendon-bone healing when applied to wrap the tendon graft in both animal studies and clinical trials. As magnesium (Mg) ions can significantly elevate the levels of relevant cytokines involving in the osteogenic differentiation of periosteum-derived stem cells, the Mg-pretreated periosteum may be an innovative approach for enveloping the tendon graft. To test this hypothesis, we compared the effects of Mg-pretreated periosteum (M - P) and the stainless steel (SS)-pretreated periosteum (SS-P) in ACL reconstruction. We firstly found that the released Mg ions from the Mg implants were partially accumulated in periosteum, resulting in higher Mg/Ca ratio in the M - P compared to the SS-P. Additionally, the M - P showed significantly higher expression levels of calcitonin gene-related peptide (CGRP) and periostin than the SS-P due to the decrease in Cathepsin K (CTSK). Elevation of CGRP and periostin was beneficial for the osteogenic differentiation of periosteum-derived stem cells. More importantly, we demonstrated that the M - P remarkably increased the formation of fibrocartilage at the interface between the periosteum and tendon. Collectively, M - P group demonstrated significantly prevented peri-tunnel bone loss, more osseous ingrowth into the tendon graft and higher maximum load to failure as compared to the SS-P group. In summary, our study warrants further investigations for translating the current proof-of-concept findings to optimize the delivery of CGRP, periostin, and cells as novel practical therapeutic strategy for enhancing tendon-bone interface healing in patients undergoing ACL reconstruction.

7.
Methods Mol Biol ; 2221: 29-39, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32979196

RESUMO

Bone marrow mesenchymal stem cells (MSCs) are promising therapeutic tools for tissue repair and treatment of a number of human diseases. As a result, there is substantial interest in characterizing and expanding these cells to uncover their therapeutic potential. Bone marrow mesenchymal progenitors, containing both MSCs and their proliferative progeny, are commonly isolated from the central region of rodent long bones. However, challenges exist in expanding these central mesenchymal progenitors in culture. We have designed an enzymatic digestion protocol to isolate mesenchymal progenitors within rodent long bones that resides close to the bone surface, which we termed endosteal mesenchymal progenitors. These cells are more metabolically active and more responsive to external stimuli compared to central mesenchymal progenitors. Therefore, they represent a biologically important target for MSC research. This chapter describes the approach in detail how to isolate and culture endosteal mesenchymal progenitors as well as their central counterparts from rodent long bones.

8.
Clin Exp Allergy ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33301598

RESUMO

BACKGROUND: Monocytes and macrophages are critical innate immune cells of the airways. Despite their differing functions, few clinical studies discriminate between them and little is known about their regulation in asthma. OBJECTIVE: We aimed to distinguish and quantify macrophages, monocytes and monocyte subsets in induced sputum and blood and examine their relationship with inflammatory and clinical features of asthma. METHODS: We applied flow cytometry to distinguish macrophages, monocytes and subsets in sputum and blood (n = 53; 45 asthma, 8 non-asthma) and a second asthma sputum cohort (n = 26). Monocyte subsets were identified by surface CD14/CD16 (CD14++ CD16- classical, CD14+ CD16+ intermediate and CD14+ CD16++ non-classical monocytes). Surface CD206, a marker of monocyte tissue differentiation, was measured in sputum. Relationship to airway inflammatory phenotype (neutrophilic n = 9, eosinophilic n = 14, paucigranulocytic n = 22) and asthma severity (severe n = 12, non-severe n = 33) was assessed. RESULTS: Flow cytometry- and microscope-quantified sputum differential cell proportions were significantly correlated. Sputum macrophage number was reduced (p = .036), while classical monocyte proportion was increased in asthma vs non-asthma (p = .032). Sputum classical monocyte number was significantly higher in neutrophilic vs paucigranulocytic asthma (p = .013). CD206- monocyte proportion and number were increased in neutrophilic vs eosinophilic asthma (p < .001, p = .013). Increased sputum classical and CD206- monocyte numbers in neutrophilic asthma were confirmed in the second cohort. Blood monocytes did not vary with airway inflammatory phenotype, but blood classical monocyte proportion and number were increased in severe vs non-severe asthma (p = .022, p = .011). CONCLUSION AND CLINICAL RELEVANCE: Flow cytometry allowed distinction of sputum macrophages, monocytes and subsets, revealing compartment-specific dysregulation of monocytes in asthma. We observed an increase in classical and CD206- monocytes in sputum in neutrophilic asthma, suggesting co-recruitment of monocytes and neutrophils to the airways in asthma. Our data suggest further investigation of how airway monocyte dysregulation impacts on asthma-related disease activity is merited.

9.
Respiration ; 99(12): 1109-1121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33271561

RESUMO

BACKGROUND: Reducing asthma exacerbations is a major target of current clinical guidelines, but identifying features of exacerbation-prone asthma (EPA) using multidimensional assessment (MDA) is lacking. OBJECTIVE: To systemically explore the clinical and inflammatory features of adults with EPA in a Chinese population. METHODS: We designed a cross-sectional study using the Severe Asthma Web-based Database from the Australasian Severe Asthma Network (ASAN). Eligible Chinese adults with asthma (n = 546) were assessed using MDA. We stratified patients based on exacerbation frequency: none, few (1 or 2), and exacerbation prone (≥3). Univariate and multivariable negative binomial regression analyses were performed to investigate features associated with the frequency of exacerbations. RESULTS: Of 546 participants, 61.9% had no exacerbations (n = 338), 29.6% had few exacerbations (n = 162), and 8.4% were exacerbation prone (n = 46) within the preceding year. EPA patients were characterized by elevated blood and sputum eosinophils but less atopy, with more controller therapies but worse asthma control and quality of life (all p < 0.05). In multivariable models, blood and sputum eosinophils (adjusted rate ratio = 2.23, 95% confidence interval = [1.26, 3.84] and 1.67 [1.27, 2.21], respectively), FEV1 (0.90 [0.84, 0.96]), bronchodilator responsiveness (1.16 [1.05, 1.27]), COPD (2.22 [1.41, 3.51]), bronchiectasis (2.87 [1.69, 4.89]), anxiety (2.56 [1.10, 5.95]), and depression (1.94 [1.20, 3.13]) were found. Further, upper respiratory tract infection (1.83 [1.32, 2.54]) and food allergy (1.67 [1.23, 2.25]) were at high risk of asthma symptom triggers. CONCLUSION: EPA is a clinically recognizable phenotype associated with several recognizable traits that could be addressed by targeted treatment.

10.
Bone ; 144: 115831, 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33359893

RESUMO

Bone health is often compromised after stroke and the distal radius is a common site of fragility fractures. The macro- and mircoproperties of bone tissue after stroke and their clinical correlates are understudied. The objectives of the study were to use High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT) to investigate the bone properties at the distal radius, and to identify the correlates of estimated failure load for the distal radius in people with chronic stroke. This was a cross-sectional study of 64 people with stroke (age: 60.8 ± 7.7 years, stroke duration: 5.7 ± 3.9 years) and 64 age- and sex-matched controls. Bilateral bone structural, densitometric, geometric and strength parameters of the distal radius were measured using HR-pQCT. The architecture, stiffness and echo intensity of the bilateral biceps brachii muscle and brachial artery blood flow were evaluated using diagnostic ultrasound. Other outcomes included the Fugl-Meyer Motor Assessment (FMA), Motor Activity Log (MAL), and Composite Spasticity Scale (CSS). The results revealed a significant side (paretic vs non-paretic for the stroke group, non-dominant vs dominant for controls) by group (stroke vs control) interaction effect for estimated failure load, cortical area, cortical thickness, trabecular number and trabecular separation, and all volumetric density parameters. Post-hoc analysis showed percent side-to-side differences in bone outcomes were greater in the stroke group than the control group, with the exception of trabecular thickness and intracortical porosity. Among the HR-pQCT variables, percent side-to-side difference in trabecular volumetric bone mineral density contributed the most to the percent side-to-side difference in estimated failure load in the stroke group (R2 change = 0.334, ß = 1.106). Stroke-related impairments (FMA, MAL, CSS) were found to be significant determinants of the percent side-to-side difference in estimated failure load (R2 change = 0.233, ß = -0.480). This was the first study to examine bone microstructure post-stroke. We found that the paretic distal radius had compromised bone structural properties and lower estimated failure load compared to the non-paretic side. Motor impairment was a determinant of estimated bone strength at the distal radius and may be a potential intervention target for improving bone health post-stroke.

11.
J Transl Med ; 18(1): 467, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298101

RESUMO

BACKGROUND: Late-onset asthma (LOA) is beginning to account for an increasing proportion of asthma patients, which is often underdiagnosed in the elderly. Studies on the possible relations between aging-related genes and LOA contribute to the diagnosis and treatment of LOA. Forkhead Box O3 (FOXO3) and TP53 are two classic aging-related genes. DNA methylation varies greatly with age which may play an important role in the pathogenesis of LOA. We supposed that the differentially methylated sites of FOXO3 and TP53 associated with clinical phenotypes of LOA may be useful biomarkers for the early screening of LOA. METHODS: The mRNA expression and DNA methylation of FOXO3 and TP53 in peripheral blood of 43 LOA patients (15 mild LOA, 15 moderate LOA and 13 severe LOA) and 60 healthy controls (HCs) were determined. The association of methylated sites with age was assessed by Cox regression to control the potential confounders. Then, the correlation between differentially methylated sites (DMSs; p-value < 0.05) and clinical lung function in LOA patients was evaluated. Next, candidate DMSs combining with age were evaluated to predict LOA by receiver operating characteristic (ROC) analysis and principal components analysis (PCA). Finally, HDM-stressed asthma model was constructed, and DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-AZA) were used to determine the regulation of DNA methylation on the expression of FOXO3 and TP53. RESULTS: Compared with HCs, the mRNA expression and DNA methylation of FOXO3 and TP53 vary significantly in LOA patients. Besides, 8 DMSs from LOA patients were identified. Two of the DMSs, chr6:108882977 (FOXO3) and chr17:7591672 (TP53), were associated with the severity of LOA. The combination of the two DMSs and age could predict LOA with high accuracy (AUC values = 0.924). In HDM-stressed asthma model, DNA demethylation increased the expression of FOXO3 and P53. CONCLUSIONS: The mRNA expression of FOXO3 and TP53 varies significantly in peripheral blood of LOA patients, which may be due to the regulation of DNA methylation. FOXO3 and TP53 methylation is a suitable blood biomarker to predict LOA, which may be useful targets for the risk diagnosis and clinical management of LOA.

12.
Toxins (Basel) ; 12(11)2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33202955

RESUMO

The RNA polymerase II (Pol II) transcription process is coordinated by the reversible phosphorylation of its largest subunit-carboxy terminal domain (CTD). Ssu72 is identified as a CTD phosphatase with specificity for phosphorylation of Ser5 and Ser7 and plays critical roles in regulation of transcription cycle in eukaryotes. However, the biofunction of Ssu72 is still unknown in Aspergillus flavus, which is a plant pathogenic fungus and produces one of the most toxic mycotoxins-aflatoxin. Here, we identified a putative phosphatase Ssu72 and investigated the function of Ssu72 in A. flavus. Deletion of ssu72 resulted in severe defects in vegetative growth, conidiation and sclerotia formation. Additionally, we found that phosphatase Ssu72 positively regulates aflatoxin production through regulating expression of aflatoxin biosynthesis cluster genes. Notably, seeds infection assays indicated that phosphatase Ssu72 is crucial for pathogenicity of A. flavus. Furthermore, the Δssu72 mutant exhibited more sensitivity to osmotic and oxidative stresses. Taken together, our study suggests that the putative phosphatase Ssu72 is involved in fungal development, aflatoxin production and pathogenicity in A. flavus, and may provide a novel strategy to prevent the contamination of this pathogenic fungus.

13.
Int J Mol Sci ; 21(22)2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33198267

RESUMO

Foxtail millet (Setaria italica (L.) P. Beauv) is an important food and forage crop because of its health benefits and adaptation to drought stress; however, reports of transcriptomic analysis of genes responding to re-watering after drought stress in foxtail millet are rare. The present study evaluated physiological parameters, such as proline content, p5cs enzyme activity, anti-oxidation enzyme activities, and investigated gene expression patterns using RNA sequencing of the drought-tolerant foxtail millet variety (Jigu 16) treated with drought stress and rehydration. The results indicated that drought stress-responsive genes were related to many multiple metabolic processes, such as photosynthesis, signal transduction, phenylpropanoid biosynthesis, starch and sucrose metabolism, and osmotic adjustment. Furthermore, the Δ1-pyrroline-5-carboxylate synthetase genes, SiP5CS1 and SiP5CS2, were remarkably upregulated in foxtail millet under drought stress conditions. Foxtail millet can also recover well on rehydration after drought stress through gene regulation. Our data demonstrate that recovery on rehydration primarily involves proline metabolism, sugar metabolism, hormone signal transduction, water transport, and detoxification, plus reversal of the expression direction of most drought-responsive genes. Our results provided a detailed description of the comparative transcriptome response of foxtail millet variety Jigu 16 under drought and rehydration environments. Furthermore, we identify SiP5CS2 as an important gene likely involved in the drought tolerance of foxtail millet.

14.
Microb Biotechnol ; 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33159717

RESUMO

As a pathogenic fungus, Aspergillus flavus can produce carcinogenic aflatoxins (AFs), which poses a great threat to crops and animals. Msb2, the signalling mucin protein, is a part of mitogen-activated protein kinase (MAPK) pathway which contributes to a range of physiological processes. In this study, the roles of membrane mucin Msb2 were explored in A. flavus by the application of gene disruption. The deletion of msb2 gene (Δmsb2) caused defects in vegetative growth, sporulation and sclerotia formation when compared to WT and complement strain (Δmsb2C ) in A. flavus. Using thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) analysis, it was found that deletion of msb2 down-regulated aflatoxin B1 (AFB1 ) synthesis and decreased the infection capacity of A. flavus. Consistently, Msb2 responds to cell wall stress and osmotic stress by positively regulating the phosphorylation of MAP kinase. Notably, Δmsb2 mutant exhibited cell wall defect, and it was more sensitive to inhibitor caspofungin when compared to WT and Δmsb2C . Taking together, these results revealed that Msb2 plays key roles in morphological development process, stresses adaptation, secondary metabolism and pathogenicity in fungus A. flavus.

15.
BMC Palliat Care ; 19(1): 167, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33129305

RESUMO

BACKGROUND: The predictive value of the prognostic tool for patients with advanced cancer is uncertain in mainland China, especially in the home-based palliative care (HPC) setting. This study aimed to compare the accuracy of the Palliative Prognostic Index (PPI), the Performance Status-Based Palliative Prognostic Index (PS-PPI), and the Chinese Prognosis Scale (ChPS) for patients with advanced cancer in the HPC setting in mainland China. METHODS: Patients with advanced cancer admitted to the hospice center of Yuebei People's Hospital between January 2014 and December 2018 were retrospectively calculated the scores according to the three prognostic tools. The Kaplan-Meier method was used to compare survival times among different risk groups. Receiver operating characteristic curve analysis was used to assess the predictive value. The accuracy of 21-, 42- and 90-day survival was compared among the three prognostic tools. RESULTS: A total of 1863 patients were included. Survival time among the risk groups of all prognostic tools was significantly different from each other except for the PPI. The AUROC of the ChPS was significantly higher than that of the PPI and PS-PPI for 7-, 14, 21-, 42-, 90-, 120-, 150- and 180-day survival (P < 0.05). The AUROC of the PPI and PS-PPI were not significantly different from each other (P > 0.05). CONCLUSIONS: The ChPS is more suitable than the PPI and PS-PPI for advanced cancer patients in the HPC setting. More researches are needed to verify the predictive value of the ChPS, PPI, and PS-PPI in the HPC setting in the future.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33180980

RESUMO

BACKGROUND: Conventional freehand immediate placement of dental implants is technically challenging in the jaw reconstructive surgery. Computer-aided surgery might be the best solution, however, there has not been any standard approach to ensure the accuracy and efficiency of simultaneous dental implants in fibula flap jaw reconstruction. PURPOSE: We aim to evaluate the clinical outcome of simultaneous dental implant in fibula flap using the "three-in-one" patient-specific surgical guide (3-in-1-PSSG) in an open-label, prospective, single-arm, and single-center clinical trial. MATERIALS AND METHODS: A novel computer-aided designed and three-dimensional (3D) printed 3-in-1-PSSG, which contains functions of fibula segmentation, surgical plate positioning and implant placement, was used to facilitate the reconstructive surgery and simultaneous dental implant placement. The intraoperative success of dental implant placement, implant survival rate and accuracy of dental implant placement were reported. RESULTS: From November 2018 to June 2020, 15 consecutive patients with 48 dental implants were enrolled in this study. Fifteen 3-in-1-PSSGs were fabricated with a mean number of dental implants per guide of 3.2 ± 1.5. The intraoperative success rate of this approach was 14 out of 15. With an average follow-up period of 40 weeks, the overall implant survival rate was 83.3% (40/48). Eight implants were removed due to two fibula flap failures. The mean deviation at the implant platform and implant apex were 2.8 mm (interquartile range [IQR]: 1.9-3.4) and 3.2 mm (IQR: 2.0-4.6), and the angular deviation was 2.5° (IQR: 1.1-6.8). CONCLUSIONS: Our preliminary data indicated that the 3D printed 3-in-1-PSSG facilitated simultaneous dental implant in fibula flap jaw reconstruction with a favorable intraoperative success and short-term clinical outcome. It might be a viable alternative to allow one-step immediate oral rehabilitation in patients underwent jaw reconstruction with free flaps. Long-term results with a larger sample size are warranted.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33188428

RESUMO

OBJECTIVE: To determine causal associations between genetically predicted TNF-α, IL-12p70 and IL-17 levels and risk of PsA. METHODS: The publicly available summary-level findings from genome-wide association studies (GWAS) was used to identify loci influencing normal physiological concentrations of TNF-α, IL-12p70 and IL-17 (n = 8293) among healthy individuals as exposure and a GWAS for PsA from the UK Biobank (PsA = 900, control = 462 033) as the outcome. A two-sample Mendelian randomization (MR) analysis was performed using the inverse-variance weighted (IVW), weighted median and MR-Egger regression methods. Sensitivity analysis and MR-Egger regression analysis were performed to evaluate the heterogeneity and pleiotropic effects of each variant. RESULTS: Single-nucleotide polymorphisms (SNPs) at genome-wide significance from GWASs on TNF-α, IL-12p70 and IL-17 were identified as the instrumental variables. The IVW method indicated a causal association between increased IL-17 level and risk of PsA (ß = -0.00186 per allele, s.e. = 0.00043, P = 0.002). Results were consistent in the weighted median method (ß = -0.00145 per allele, s.e. = 0.00059, P = 0.014) although the MR-Egger method suggested a non-significant association (ß = -0.00133 per allele, s.e. = 0.00087; P = 0.087). Single SNP MR results revealed that the C allele of rs117556572 was robustly associated with risk of PsA (ß = 0.00210, s.e. = 0.00069, P = 0.002). However, no evidence for a causal effect was observed between TNF-α, IL-12p70, decreased IL-17 levels and risk of PsA. CONCLUSION: Our findings provide preliminary evidence that genetic variants predisposing to higher physiological IL-17 level are associated with decreased risk of PsA.

18.
J Int Med Res ; 48(10): 300060520962291, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33050757

RESUMO

OBJECTIVE: To investigate whether the combination of D-dimer and simplified pulmonary embolism severity index (sPESI) could improve prediction of in-hospital death from pulmonary embolism (PE). METHODS: Patients with PE (n = 272) were divided into a surviving group (n = 249) and an in-hospital death group (n = 23). RESULTS: Compared with surviving patients, patients who died in hospital had significantly higher rates of hypotension and tachycardia, reduced SaO2 levels, elevated D-dimer and troponin T levels, higher sPESI scores, and were more likely to be classified as high risk. Elevated D-dimer levels and high sPESI scores were significantly associated with in-hospital death. Using thresholds for D-dimer and sPESI of 3.175 ng/mL and 1.5, respectively, the specificity for prediction of in-hospital death was 0.357 and 0.414, respectively, and the area under the receiver operating characteristic curve (AUC) was 0.665 and 0.668, respectively. When D-dimer and sPESI were considered together, the specificity for prediction of in-hospital death increased to 0.838 and the AUC increased to 0.74. CONCLUSIONS: D-dimer and sPESI were associated with in-hospital death from PE. Considering D-dimer levels together with sPESI can significantly improve the specificity of predicting in-hospital death for patients with PE.

19.
Analyst ; 145(23): 7464-7476, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33030157

RESUMO

Layered nanostructures (LNs), including two-dimensional nanosheets, nanoflakes, and planar nanodots, show large surface-to-volume ratios, unique optical properties, and desired interfacial activities. LNs are highly promising as alternative probes and platforms due to numerous merits, e.g. signal amplification, improved recognition ability, and anti-interference capacity, for emerging sensing applications. Significantly, when stimuli-responsive aggregation occurs, the modified LNs show engineered morphologies, attractive optical absorption and fluorescence characteristics, which are remarkably programmable. On the basis of the altered aggregation behaviours of LNs, as well as their modulated physical and chemical characteristics, a series of novel sensing assays exhibiting enhanced sensitivity, simple operation, multiple functions, and improved anti-interference capacity are reported, contributing to both point-of-care testing and high-throughput measurements. Herein, the aggregation-induced response sensing strategies of LNs are comprehensively summarized with the classification of materials and variation of aggregated routes aiming at understanding dimension-dependent features, expanding nanoscale biosensor applications, and addressing key issues in disease diagnosis and environmental analysis.

20.
Curr Osteoporos Rep ; 18(6): 621-632, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33030684

RESUMO

PURPOSE OF REVIEW: The goals of this review are two folds: (1) to describe the recent understandings on the roles of calcitonin gene-related peptide-α (CGRP) in bone homeostasis and the underlying mechanisms of related neuronal regulation and (2) to propose innovative CGRP-modulated approaches for enhancing bone regeneration in challenging bone disorders. RECENT FINDINGS: CGRP is predominantly produced by the densely distributed sensory neuronal fibers in bone, declining with age. Under mechanical and biochemical stimulations, CGRP releases and exerts either physiological or pathophysiological roles. CGRP at physiological level orchestrates the communications of bone cells with cells of other lineages, affecting not only osteogenesis, osteoclastogenesis, and adipogenesis but also angiogenesis, demonstrating with pronounced anabolic effect, thus is essential for maintaining bone homeostasis, with tuned nerve-vessel-bone network. In addition, its effects on immunity and cell recruitment are also crucial for bone fracture healing. Binding to the G protein-coupled receptor composited by calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1) on cellular surface, CGRP triggers various intracellular signaling cascades involving cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB). Peaking at early stage post-fracture, CGRP promotes bone formation, displaying with larger callus. Then CGRP gradually decreases over time, allowing normal or physiological bone remodeling. By elevating CGRP at early stage, low-intensity pulsed ultrasound (LIPUS), electrical stimulation, and magnesium-based bio-mineral products may promisingly accelerate bone regeneration experimentally in medical conditions like osteoporosis, osteoporotic fracture, and spine fusion. Excess CGRP expression is commonly observed in pathological conditions including cancer metastatic lesions in bone and fracture delayed- or non-healing, resulting in persistent chronic pain. To date, these discoveries have largely been limited to animal models. Clinical applications are highly desirable. Compelling evidence show the anabolic effects of CGRP on bone in animals. However, further validation on the role of CGRP and the underlying mechanisms in human skeletons is required. It remains unclear if it is type H vessel connecting neuronal CGRP to osteogenesis, and if there is only specific rather than all osteoprogenitors responsible to CGRP. Clear priority should be put to eliminate these knowledge gaps by integrating with high-resolution 3D imaging of transparent bulk bone and single-cell RNA-sequencing. Last but not the least, given that small molecule antagonists such as BIBN4096BS can block the beneficial effects of CGRP on bone, concerns on the potential side effects of humanized CGRP-neutralizing antibodies when systemically administrated to treat migraine in clinics are arising.

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