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1.
J Proteome Res ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33821641

RESUMO

In cross-linking mass spectrometry, the identification of cross-linked peptide pairs heavily relies on the ability of a database search engine to measure the similarities between experimental and theoretical MS/MS spectra. However, the lack of accurate ion intensities in theoretical spectra impairs the performance of search engines, in particular, on proteome scales. Here we introduce pDeepXL, a deep neural network to predict MS/MS spectra of cross-linked peptide pairs. To train pDeepXL, we used the transfer-learning technique because it facilitated the training with limited benchmark data of cross-linked peptide pairs. Test results on more than ten data sets showed that pDeepXL accurately predicted the spectra of both noncleavable DSS/BS3/Leiker cross-linked peptide pairs (>80% of predicted spectra have Pearson's r values higher than 0.9) and cleavable DSSO/DSBU cross-linked peptide pairs (>75% of predicted spectra have Pearson's r values higher than 0.9). pDeepXL also achieved the accurate prediction on unseen data sets using an online fine-tuning technique. Lastly, integrating pDeepXL into a database search engine increased the number of identified cross-link spectra by 18% on average.

2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 474-488, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812418

RESUMO

OBJECTIVE: To investigate the effect and mechanism of a novel emodin derivative YX-18 on Burkitt lymphoma (BL) cells. METHODS: MTT assay was used to detect the effect of YX-18 on the proliferation of BL cell lines CA46 and Raji. Annexin V-PE/7-AAD double staining assay was used for detecting the effect of YX-18 on the apoptosis of CA46 and Raji cells. PI/RNase staining was used to test the effect of YX-18 on CA46 and Raji cell cycle. JC-1 method was used to measure the changes of mitochondrial membrane potential after YX-18 treatment, and DAPI staining was used to detect the morphology of apoptotic cells. Western blot was used to analyze the distribution changes of NF-κB pathway protein (P65, P-P65, IκB, P-IκB) in the cytoplasm and cell nucleus, and also the expression changes of cyclin-related protein P21, CDK2, P-CDK2, Cycling D1, Cycling E1, and the apoptosis-related protein Caspase-3, Caspase-8, Caspase-9 and the proliferation-related protein C-MYC, BCL-2 by YX-18. Real-time fluorescence-quantitative PCR was used to evaluate the effects of YX-18 on mRNA levels of C-MYC and Ki-67 genes in CA46 and Raji cells, and EBNA-1 and EBER genes of EBV in Raji (EBV+) cells. RESULTS: Novel Emodin derivative YX-18 could effectively inhibit the proliferation of BL cell lines CA46 and Raji, showing a time-dependent effect (24, 48 and 72 h: rCA46=0.89, 0.75, 0.75, rRaji=0.87, 0.73, 0.64). IC50 of CA46 cells and Raji cells treated with YX-18 for 24 h was 1.77±0.04 µmol/L and 1.97±0.22µmol/L, respectively. CA46 cells and Raji cells were treated with YX-18 at concentration of 2.0 and 4.0 µmol/L for 24 h. Compared with the control group, both strains of cells showed a very significant apoptosis at the concentration of 2.0 and 4.0 µmol/L (P<0.01), showing a concentration-dependent effect (rCA46=0.99, rRaji=0.92). Moreover, the cleavaged Caspase-3, 8 and 9 proteins were activated by YX-18 into verious degrees in both two cell lines. Both the two cell lines displayed by YX-18 cell cycle arrest at G0/G1 phase (P<0.01) after exposed to YX-18 for 24 hours at the concentration of 1.0, 2.0 µmol/L in CA46 cells and at 0.5 and 1 µmol/L in Raji cells, respectively. YX-18 decreased expression level of cyclin D1, cyclin E1, CDK2, p-cdk2 proteins and increased p21Waf1/Cip1 level in CA46 and Raji cells. YX-18 significantly declined mitochondrial membrane potential in both cells at the concentration of 2.0 and 4.0 µmol/l (P<0.01) with concentration-dependent manner (rCA46=-0.96, rRaji=-0.99). Western blot tests indicated that YX-18 down-regulated nucleus P65 and intracellular cytoplasm P65, P-IκB, P-P65 protein, and upregulated intracellular IκB level with dose-dependent manner. Meanwhile, the expression level of the cell proliferation-related molecules C-MYC and BCL-2 was decreased significantly. YX-18 suppressed mRNA levels of C-MYC and Ki-67 in both cell lines, and EBNA-1 in EBV-positive Raji cells in a concentration-dependent way. CONCLUSION: The novel emodin derivative YX-18 can significantly inhibit the proliferation of Burkitt lymphoma cells, and induce the cell apoptosis and cycle arrest. The inhibitory effect of YX-18 on the proliferation of Burkitt lymphoma cells may be related with the effect of Caspase apoptosis pathway, the proliferation and apoptosis-related molecules, such as C-MYC and Ki-67, and also to the inhibition of NF-κB pathway.


Assuntos
Linfoma de Burkitt , Emodina , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Emodina/farmacologia , Humanos , NF-kappa B
3.
Anal Chem ; 93(14): 5815-5822, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33797898

RESUMO

Spectrum prediction using deep learning has attracted a lot of attention in recent years. Although existing deep learning methods have dramatically increased the prediction accuracy, there is still considerable space for improvement, which is presently limited by the difference of fragmentation types or instrument settings. In this work, we use the few-shot learning method to fit the data online to make up for the shortcoming. The method is evaluated using ten data sets, where the instruments includes Velos, QE, Lumos, and Sciex, with collision energies being differently set. Experimental results show that few-shot learning can achieve higher prediction accuracy with almost negligible computing resources. For example, on the data set from a untrained instrument Sciex-6600, within about 10 s, the prediction accuracy is increased from 69.7% to 86.4%; on the CID (collision-induced dissociation) data set, the prediction accuracy of the model trained by HCD (higher energy collision dissociation) spectra is increased from 48.0% to 83.9%. It is also shown that, the method is not critical to data quality and is sufficiently efficient to fill the accuracy gap. The source code of pDeep3 is available at http://pfind.ict.ac.cn/software/pdeep3.

4.
Cell Death Dis ; 12(4): 362, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824276

RESUMO

Adhesion G protein-coupled receptor A1 (ADGRA1, also known as GPR123) belongs to the G protein-coupled receptors (GPCRs) family and is well conserved in the vertebrate lineage. However, the structure of ADGRA1 is unique and its physiological function remains unknown. Previous studies have shown that Adgra1 is predominantly expressed in the central nervous system (CNS), indicating its important role in the transduction of neural signals. The aim of this study is to investigate the central function of Adgra1 in vivo and clarify its physiological significance by establishing an Adgra1-deficient mouse (Adgra1-/-) model. The results show that Adgra1-/- male mice exhibit decreased body weight with normal food intake and locomotion, shrinkage of body mass, increased lipolysis, and hypermetabolic activity. Meanwhile, mutant male mice present elevated core temperature coupled with resistance to hypothermia upon cold stimulus. Further studies show that tyrosine hydroxylase (TH) and ß3-adrenergic receptor (ß3-AR), indicators of sympathetic nerve excitability, are activated as well as their downstream molecules including uncoupling protein 1 (UCP1), coactivator 1 alpha (PGC1-α) in brown adipose tissue (BAT), and hormone-sensitive lipase (HSL) in white adipose tissue (WAT). In addition, mutant male mice have higher levels of serum T3, T4, accompanied by increased mRNAs of hypothalamus-pituitary-thyroid axis. Finally, Adgra1-/- male mice present abnormal activation of PI3K/AKT/GSK3ß and MEK/ERK pathways in hypothalamus. Overexpression of ADGRA1 in Neuro2A cell line appears to suppress these two signaling pathways. In contrast, Adgra1-/- female mice show comparable body weight along with normal metabolic process to their sex-matched controls. Collectively, ADGRA1 is a negative regulator of sympathetic nervous system (SNS) and hypothalamus-pituitary-thyroid axis by regulating PI3K/AKT/GSK3ß and MEK/ERK pathways in hypothalamus of male mice, suggesting an important role of ADGRA1 in maintaining metabolic homeostasis including energy expenditure and thermogenic balance.

5.
Ann Palliat Med ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33832319

RESUMO

Sphingosine 1-phosphate (S1P) regulates many cellular functions, such as differentiation, proliferation, migration, morphogenesis, cytoskeletal organization, adhesion, tight junction assembly, apoptosis and the localization of different cell types. S1P also controls the migration of osteoclast precursors between the blood and bone, and it keeps osteoclast precursors away from bone surfaces to reduce bone degradation, thus preventing bone decay. Osteoporosis is a systemic bone disease that predisposes patients to bone fracture due to decreased bone density and quality, disrupted bone microarchitecture, and increased bone fragility. As the global elderly population increases, the incidence of osteoporosis will greatly increase, and the associated adverse consequences will become more serious. S1P plays an important role in homeostasis, and disruption of the balance between osteoblasts and osteoclasts may induce osteoporosis. A high frequency of osteoporotic fracture is associated with increased plasma S1P levels. Studies have shown that S1P is an important therapeutic target in osteoporosis because it controls the migration of osteoclast precursors, vigorously maintains the bone mineralization process, and is a critical regulator of osteoclastogenesis. Improved understanding of the functional roles and molecular mechanisms of S1P in bone turnover could facilitate the discovery of novel targets for the treatment of osteoporosis. This review provides a critical discussion of the role of S1P in osteoporosis and treatments.

7.
Fitoterapia ; 151: 104868, 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33652077

RESUMO

Nine previously undescribed dichapetalin-type triterpenoids (1-9), along with 12 reported compounds (10-21), were isolated from the twigs of Dichapetalum gelonioides. Their chemical structures were mainly elucidated by comprehensive analysis of HRMS, 1D and 2D NMR spectroscopic data. The absolute configuration of compound 1 was further determined based on single-crystal X-ray diffraction. In addition, a part of compounds were evaluated the effects of inhibitory NO production in LPS-induced RAW264.7 macrophages.

8.
Sci Rep ; 11(1): 5022, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658578

RESUMO

We hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO). A total of 75 of 228 COPD patients were identified as ACO, which was independently associated with increased exacerbations. Microarray analysis identified 404 differentially methylated loci (DML) in ACO patients, and 6575 DML in those with rapid lung function decline in a discovery cohort. In the validation cohort, ACO patients had hypermethylated PDE9A (+ 30,088)/ZNF323 (- 296), and hypomethylated SEPT8 (- 47) genes as compared with either pure COPD patients or healthy non-smokers. Hypermethylated TIGIT (- 173) gene and hypomethylated CYSLTR1 (+ 348)/CCDC88C (+ 125,722)/ADORA2B (+ 1339) were associated with severe airflow limitation, while hypomethylated IFRD1 (- 515) gene with frequent exacerbation in all the COPD patients. Hypermethylated ZNF323 (- 296) / MPV17L (+ 194) and hypomethylated PTPRN2 (+ 10,000) genes were associated with rapid lung function decline. In vitro cigarette smoke extract and ovalbumin concurrent exposure resulted in specific DNA methylation changes of the MPV17L / ZNF323 genes, while 5-aza-2'-deoxycytidine treatment reversed promoter hypermethylation-mediated MPV17L under-expression accompanied with reduced apoptosis and decreased generation of reactive oxygen species. Aberrant DNA methylations may constitute a determinant for ACO, and provide a biomarker of airflow limitation, exacerbation, and lung function decline.

9.
BMC Genomics ; 22(1): 161, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676415

RESUMO

BACKGROUND: Stauntonia chinensis DC. belongs to subfamily Lardizabaloideae, which is widely grown throughout southern China. It has been used as a traditional herbal medicinal plant, which could synthesize a number of triterpenoid saponins with anticancer and anti-inflammatory activities. However, the wild resources of this species and its relatives were threatened by over-exploitation before the genetic diversity and evolutionary analysis were uncovered. Thus, the complete chloroplast genome sequences of Stauntonia chinensis and comparative analysis of chloroplast genomes of Lardizabaloideae species are necessary and crucial to understand the plastome evolution of this subfamily. RESULTS: A series of analyses including genome structure, GC content, repeat structure, SSR component, nucleotide diversity and codon usage were performed by comparing chloroplast genomes of Stauntonia chinensis and its relatives. Although the chloroplast genomes of eight Lardizabaloideae plants were evolutionary conserved, the comparative analysis also showed several variation hotspots, which were considered as highly variable regions. Additionally, pairwise Ka/Ks analysis showed that most of the chloroplast genes of Lardizabaloideae species underwent purifying selection, whereas 25 chloroplast protein coding genes were identified with positive selection in this subfamily species by using branch-site model. Bayesian and ML phylogeny on CCG (complete chloroplast genome) and CDs (coding DNA sequences) produced a well-resolved phylogeny of Lardizabaloideae plastid lineages. CONCLUSIONS: This study enhanced the understanding of the evolution of Lardizabaloideae and its relatives. All the obtained genetic resources will facilitate future studies in DNA barcode, species discrimination, the intraspecific and interspecific variability and the phylogenetic relationships of subfamily Lardizabaloideae.

10.
Acta Pharmacol Sin ; 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33758354

RESUMO

N-n-Butyl haloperidol iodide (F2) is a novel compound that has antiproliferative and antifibrogenic activities. In this study we investigated the therapeutic potential of F2 against liver fibrosis in mice and the underlying mechanisms. Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride (CCl4) or thioacetamide (TAA). The mice received F2 (0.75, 1.5 or 3 mg·kg-1·d-1, ip) for 4 weeks of fibrosis induction. We showed that F2 administration dose-dependently ameliorated CCl4- or TAA-induced liver fibrosis, evidenced by significant decreases in collagen deposition and c-Jun, TGF-ß receptor II (TGFBR2), α-smooth muscle actin (α-SMA), and collagen I expression in the liver. In transforming growth factor beta 1 (TGF-ß1)-stimulated LX-2 cells (a human hepatic stellate cell line) and primary mouse hepatic stellate cells, treatment with F2 (0.1, 1, 10 µM) concentration-dependently inhibited the expression of α-SMA, and collagen I. In LX-2 cells, F2 inhibited TGF-ß/Smad signaling through reducing the levels of TGFBR2; pretreatment with LY2109761 (TGF-ß signaling inhibitor) or SP600125 (c-Jun signaling inhibitor) markedly inhibited TGF-ß1-induced induction of α-SMA and collagen I. Knockdown of c-Jun decreased TGF-ß signaling genes, including TGFBR2 levels. We revealed that c-Jun was bound to the TGFBR2 promoter, whereas F2 suppressed the binding of c-Jun to the TGFBR2 promoter to restrain TGF-ß signaling and inhibit α-SMA and collagen I upregulation. In conclusion, the therapeutic benefit of F2 against liver fibrosis results from inhibition of c-Jun expression to reduce TGFBR2 and concomitant reduction of the responsiveness of hepatic stellate cells to TGF-ß1. F2 may thus be a potentially new effective pharmacotherapy for human liver fibrosis.

11.
J Integr Plant Biol ; 63(4): 772-786, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33615694

RESUMO

Active DNA demethylation is critical for altering DNA methylation patterns and regulating gene expression. The 5-methylcytosine DNA glycosylase/lyase ROS1 initiates a base-excision repair pathway for active DNA demethylation and is required for the prevention of DNA hypermethylation at 1 000s of genomic regions in Arabidopsis. How ROS1 is regulated and targeted to specific genomic regions is not well understood. Here, we report the discovery of an Arabidopsis protein complex that contains ROS1, regulates ROS1 gene expression, and likely targets the ROS1 protein to specific genomic regions. ROS1 physically interacts with a WD40 domain protein (RWD40), which in turn interacts with a methyl-DNA binding protein (RMB1) as well as with a zinc finger and homeobox domain protein (RHD1). RMB1 binds to DNA that is methylated in any sequence context, and this binding is necessary for its function in vivo. Loss-of-function mutations in RWD40, RMB1, or RHD1 cause DNA hypermethylation at several tested genomic regions independently of the known ROS1 regulator IDM1. Because the hypermethylated genomic regions include the DNA methylation monitoring sequence in the ROS1 promoter, plants mutated in RWD40, RMB1, or RHD1 show increased ROS1 expression. Importantly, ROS1 binding to the ROS1 promoter requires RWD40, RMB1, and RHD1, suggesting that this complex dictates ROS1 targeting to this locus. Our results demonstrate that ROS1 forms a protein complex with RWD40, RMB1, and RHD1, and that this novel complex regulates active DNA demethylation at several endogenous loci in Arabidopsis.

12.
Int Immunopharmacol ; 93: 107430, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33581500

RESUMO

BACKGROUND: Anti-tumor necrosis factor-alpha was regarded as an option in treatment of non-infectious uveitis. However, few studies in the far easter region have concentrated on this therapy and current studies have not emphasized the elimination of retinal vasculitis. To compare the effectiveness of adalimumab (ADA) plus conventional therapy (CT) versus CT alone in treating patients with retinal vasculitis (RV) due to refractory Behçet's uveitis (BU). DESIGN: Retrospective cohort study. METHODS: Clinical records of BU patients with previously treated but poorly controlled RV were analyzed. Patients were allocated into two groups depending on ADA use. Each group was treated for no less than 6 months between February 2015 and September 2020. The primary outcome parameter was the RV score. Best-corrected visual acuity (BCVA), number of relapses, macular thickness and ocular complications were considered concomitantly. RESULTS: Forty-two patients (72 eyes) were included; 21 patients were in CT group, and 21 patients were in ADA group. Inflammatory parameters improved in both groups. The improvement in the fluorescein angiography (FA) score and anterior chamber inflammation were significantly better in ADA group than in CT group (P < 0.05). The relapse time was significantly lower in ADA group than in CT group (P = 0.01). Daily glucocorticoid dose tapers were more evident in ADA group than in CT group (P < 0.05). Adverse events were detected in 7 patients (5 had upper respiratory tract infection and 2 had gastrointestinal discomfort) in ADA group; in CT group, upper respiratory infection and recurrent gum swelling were observed in 1 patient each. CONCLUSION: Our results indicate that ADA plus CT outperforms CT alone in patients with RV due to refractory BU. More agile ADA use in these patients should be considered to achieve optimal treatment.

13.
Antonie Van Leeuwenhoek ; 114(4): 355-364, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33548024

RESUMO

A Gram-staining-negative, non-motile, aerobic bacterium, designated 1-3T, was isolated from oil reservoir water collected from Liaohe oilfield, north-east of China. Growth was observed at 15-40 °C (optimum 37 °C) and pH 6-10 (optimum 7). The strain can grow under nitrogen-limiting condition. Phylogenetic analysis based on 16S rRNA gene sequences showed that the novel isolate was most closely related to Siccirubricoccus deserti SYSU D8009T (96.7%), followed by Paracraurococcus ruber NS89T (95.7%) and Belnapia rosea CPCC 100156T (94.9%). Genome sequencing revealed a genome size of 6.43 Mbp and a G+C content of 71.3 mol%. The average nucleotide identity values and digital DNA-DNA hybridization between 1-3T and the reference strains were all below the cut-off level (95-96% and 70%, respectively) for species delineation. The strain possessed the cytochrome P450 enzyme, which has the potential to degrade oil. The respiratory quinone was Q-10 and the major fatty acids were summed feature 8 (C18:1 ω7c/C18:1 ω6c, 38.8%), C16:0 (25.6%) and C19:0 cyclo ω8c (22.5%). The polar lipids of strain 1-3T comprised diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and three unidentified aminolipids. Based on the genotypic and phenotypic characteristics, strain 1-3T represents a novel species of genus Siccirubricoccus, for which the name Siccirubricoccus phaeus sp. nov. is proposed. The type strain of Siccirubricoccus phaeus is 1-3T (= CGMCC 1.16799T = LMG 31398T).

14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(1): 137-144, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33554810

RESUMO

OBJECTIVE: To investigate the short-term efficacy and safety of generic bortezomib in the treatment of Chinese patients with multiple myeloma (MM). METHODS: Clinical data of 62 MM patients (median age of 62 years) who had accepted at least 2 cycles of chemotherapy based on generic bortezomib in our center from December 2017 to July 2019 were retrospectively analyzed, including 47 newly diagnosed patients and 15 with disease recurrence or progression. RESULTS: Anemia, renal dysfunction, hypoproteinemia and high level of ß 2-microglobulin were all improved rapidly after induction treatment. In 56 patients who had completed at least 4 cycles of chemotherapy, the overall response rate (ORR) was 85.7%, and 64.3% of the patients achieved very good partial response (VGPR) or better, and 28.6% achieved complete remission (CR) or better. In the 19 patients who had already completed all planned induction and consolidation treatment (9 cycles of chemotherapy or 4-6 cycles of chemotherapy plus autologous hematopoietic stem cell transplantation), 84.2% achieved VGPR or better, and 57.9% achieved CR or stringent complete remission (sCR). Median follow-up time was 300 days with data cut-off date of September 20, 2019, and the progression-free survival (PFS) rate and overall survival (OS) rate were 62.1% and 85.3%, respectively. The possible adverse reactions associated with bortezomib were grade 1-2, the most common hematologic adverse reaction was thrombocytopenia (27.4%), and the most common non-hematologic adverse reaction was peripheral neuropathy (43.5%), followed by asthenia (37.1%). CONCLUSION: The disease severity can be rapidly alleviated after generic bortezomib-based chemotherapy, and a favorable short-term efficacy and survival have been observed with a generally acceptable toxicity profile. However, the long-term outcomes will be examined through further follow-up.


Assuntos
Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Intervalo Livre de Doença , Humanos , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia , Estudos Retrospectivos , Transplante Autólogo , Resultado do Tratamento
15.
Toxicol Appl Pharmacol ; 414: 115426, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524445

RESUMO

Activation of NLRP3 inflammasome is implicated in varieties of pathologies, the aim of the present study is to characterize the effect and mechanism of mitochondrial uncouplers on NLRP3 inflammasome activation by using three types of uncouplers, niclosamide, CCCP and BAM15. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increases of NLRP3 protein and IL-1ß mRNA levels in RAW264.7 macrophages and THP-1 derived macrophages. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increase of NFκB (P65) phosphorylation, and inhibited NFκB (P65) nuclear translocation in RAW264.7 macrophages. Niclosamide and BAM15 inhibited LPS-induced increase of IκBα phosphorylation in RAW264.7 macrophages, and the inhibitory effect was dependent on increased intracellular [Ca2+]i; however, CCCP showed no significant effect on IκBα phosphorylation in RAW264.7 macrophages stimulated with LPS. In conclusion, chemical mitochondrial uncouplers niclosamide, CCCP and BAM15 share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation.

16.
Neurol Sci ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33606128

RESUMO

BACKGROUND: Many studies have described the relationship between kidney stones and stroke, but the results are controversial, so we conducted this meta-analysis to estimate the relationship between kidney stones and the risk of developing stroke. METHODS: Studies were marked with a comprehensive search of PubMed, EMBASE, Google, and ISI Web of Science databases through 25 March 2020. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted, and a random-effects model or fix-effects model was used to compute the pooled combined risk estimate. Heterogeneity was reported as I2. We performed subgroup and sensitivity analysis to assess potential sources of heterogeneity. RESULTS: Eight studies of seven articles involving 3,526,808 participants were included in the meta-analysis. Overall, kidney stones were associated with a moderate risk of stroke incidence (HR, 1.24; 95% CI, 1.11-1.40; I2=79.6%; p=0.000). We conducted a sensitivity analysis by removing the studies that had a high risk of bias. Heterogeneity subsequently decreased significantly, while an increased risk of stroke in patient with kidney stones was again demonstrated (HR, 1.16; 95% CI, 1.11-1.23; I2=28.7%; p=0.000). Stratifying analysis showed that the results were more pronounced for ischemic stroke (HR, 1.14; 95% CI, 1.08-1.22; I2=15.6%; p=0.00) and the follow-up duration ≥10 years (HR, 1.18; 95% CI, 1.10-1.27; I2=31.6%; p=0.003). CONCLUSIONS: Our meta-analysis suggests that patients with kidney stones may have a modestly increased risk of developing stroke, especially in ischemic stroke. More large-scaled and clinical trials should be done to identify the relative impact of kidney stones on stroke outcomes in the future.

17.
Liver Int ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33556230

RESUMO

BACKGROUND & AIMS: In patients with unresectable hepatocellular carcinoma (HCC), the combination of atezolizumab and bevacizumab improved progression-free survival (PFS) and overall survival compared with sorafenib in the IMbrave150 trial. However, whether the price of the combination could be affordable is unknown. The current study assessed the cost-effectiveness of the combination of atezolizumab and bevacizumab as first-line systemic therapy for patients with unresectable HCC from the Chinese and American payers' perspective. METHODS: A Markov model was built based on a global, multicentre, open-label, phase III randomized trial (IMbrave150, NCT03434379) that included three states of the patient's health: stable disease (SD), progressive disease (PD) and death. Data for all medical costs were acquired from the Red Book, published literature and West China Hospital. Quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) were the primary outcomes. Sensitivity analyses were performed to evaluate the model uncertainty. RESULTS: The treatment consisting of a combination of atezolizumab and bevacizumab yielded an additional 0.53 QALYs compared with sorafenib alone, leading to an ICER of $145,546.21 per QALY in China and $168,030.21 per QALY in the USA, both beyond the willing-to-pay threshold ($28,527.00/QALY in China and $150,000.00 /QALY in the USA). The utility of the PD state was the most influential factor in the Chinese model, and the American model was the most sensitive to the price of sorafenib. The results of the models were robust across sensitivity analyses. CONCLUSION: The combination of atezolizumab and bevacizumab was not a cost-effective strategy for the first-line systemic treatment of unresectable HCC from the Chinese and American payers' perspective.

18.
Ann Palliat Med ; 2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33548999

RESUMO

BACKGROUND: Nowadays, controlling nutritional status (CONUT) has been used as a prognostic factor in variety of cancers. However, no consensus has been reached on the prognostic value of CONUT in lung cancer. In this study, we aim to investigate the role of CONUT in survival of patients with lung cancer. METHODS: EMBASE, web of science, and Medline were used to search articles in English-language journals. The association between CONUT score and survival of patients with lung cancer was evaluated by using pooled HRs and their 95% CIs. Chi-square test and I-Square was used to test heterogeneity among studies. Analyses were all performed using Stata 13.0 (Stata Corporation, College Station, TX). RESULTS: Eight studies with 1,836 patients were eventually included in this meta-analysis. The pooled results showed that high CONUT score had an unfavorable impact on OS (HR =1.63, 95% CI: 1.30-2.04), DFS (HR =1.75, 95% CI: 1.35-2.26), CSS (HR =1.45, 95% CI: 1.01-2.07) and PFS (HR =1.67, 95% CI: 0.99-2.35), compared with those with low-CONUT. CONCLUSIONS: CONUT can be used as a predictor of prognosis in patients with lung cancer. HighCONUT score was significantly associated with poor OS, DFS, CSS and PFS.

19.
Pharmacol Ther ; 223: 107817, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33587950

RESUMO

Cellular senescence constitutes a permanent state of cell cycle arrest in proliferative cells induced by different stresses. The exploration of tumor pathogenesis and therapies has been a research hotspot in recent years. Cellular senescence is a significant mechanism to prevent the proliferation of potential tumor cells, but it can also promote tumor growth. Increasing evidence suggests that cellular senescence is involved in the pathogenesis and development of hematological malignancies, including leukemia, myelodysplastic syndrome (MDS) and multiple myeloma (MM). Cellular senescence is associated with functional decline of hematopoietic stem cells (HSCs) and increased risk of hematological malignancies. Moreover, the bone marrow (BM) microenvironment has a crucial regulatory effect in the process of these diseases. The senescence-associated secretory phenotype (SASP) in the BM microenvironment establishes a protumor environment that supports the proliferation and survival of tumor cells. Therefore, a series of therapeutic strategies targeting cellular senescence have been gradually developed, including the induction of cellular senescence and elimination of senescent cells. This review systematically summarizes the emerging information describing the roles of cellular senescence in tumorigenesis and potential clinical applications, which may be beneficial for designing rational therapeutic strategies for various hematopoietic malignancies.

20.
Aesthet Surg J ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33421060

RESUMO

BACKGROUND: Nasal filler placement is associated with a high risk of blindness. The arterial supply to the upper nose overlaying the nasal bones is poorly understood. OBJECTIVES: This study attempts to visualize and analyze the deployment of the ophthalmic and facial angiosomes in the upper nose and help prevent blindness in nasal filler injections. METHODS: The arterial systems of 62 cadaveric heads were filled with lead oxide contrast, and computed tomography (CT) images were acquired and reconstructed in three-dimensions. RESULTS: Twenty-six of the cadaveric noses examined demonstrated clear CT images for the facial and ophthalmic angiosomes in the upper nose. The Type 1 upper nose (15.4 percent) is supplied by two independent ophthalmic angiosomes that communicate indirectly through choke anastomosis. The Type 2 upper nose (38.5 percent) is supplied by two ophthalmic angiosomes with true anastomosis between them. The Type 3 upper nose (46.1 percent) is supplied by both ophthalmic and facial angiosomes with true anastomoses across the dorsal midline. These true anastomoses are mediated by the radix arcade in 46 percent of the noses and involve the dorsal nasal artery in 65 percent of the cases. The anastomoses all cross the upper dorsal midline and are directly linked to the ophthalmic angiosome. CONCLUSIONS: The deployment and anastomosis of the facial and ophthalmic angiosomes in the upper nose fall into three major patterns. About 85 percent of the noses have true anastomotic arteries that cross the upper dorsal midline and are directly linked to the ophthalmic circulation. Dorsum filler injection poses a significant risk of blindness.

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