Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 665
Filtrar
1.
Sci Total Environ ; 772: 145529, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33581528

RESUMO

A one-stage partial nitrification and anammox (PN/A) process was started up and operated under varying temperatures in a lab-scale sequencing batch biofilm reactor. The start­up phase took 110 days with an intermittent aeration strategy, and the removal efficiencies of ammonia­nitrogen and total nitrogen were found to be 92.22% and 76.07%, respectively. The total nitrogen removal efficiency (NRE) increased by 9.49% when temperature decreased from 30 °C to 25 °C, but declined by 83.84% from 25 °C to 20 °C. The PN process was inhibited and subsequently limited the nitrogen removal performance at 20 °C. When temperature returned to 28 °C, the NRE recovered to 67.27%, but it was still lower than the value before the decrease in temperature (79.40%). Microbial community analysis showed that the predominant ammonia oxidation bacteria and anammox bacteria were Nitrosomonas and Candidatus Kuenenia, respectively. Nitrosomonas grew, while the relative abundance of Candidatus Kuenenia increased as temperature decreased and vice versa.

2.
Carbohydr Polym ; 258: 117380, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33593586

RESUMO

A new polysaccharide from fruits of Schisandra chinensis (SCPP22) with a molecular weight of 143 ± 0.13 KDa was mainly made up of glucose and galactose. The possible structure of SCPP22 was showed that its main chain was composed of 1,4-α-d-Glup and branch was stretched from O-6 position of 1,4-ß-d-Glup. Branches consisted of T-α-d-Galp. Further, SCPP22 could reverse PCB126-induced immunosuppression, significantly enhance body weight and immune organ indices. It also significantly ameliorated oxidative injury to immune organ induced by PCB126, as shown by evaluation of SOD activities, as well as MDA levels in spleen and thymus. SCPP22 strongly stimulated cytokines production by up-regulating mRNA expression of TNF-α, INF-γ and IL-2. Mechanism investigation revealed that recovery effects of SCPP22 in immunosuppression induced by PCB126 are mainly through regulating apoptosis-related proteins expression. Schisandra polysaccharides might be applied in functional food as nutritional intervention ingredient.

3.
AIDS ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33587447

RESUMO

OBJECTIVE: Despite successful antiviral therapy, the recovery of CD4+ T cells may not be complete in certain HIV-1 infected individuals. In our previous work with humanized mice infected with CXCR4-tropic HIV-1LAI (LAI), viral protein Nef was found the major factor determining rapid loss of both CD4+ T cells and CD4+CD8+ thymocytes but its effect on early T cell development is unknown. The objective of this study is to investigate the influence of LAI Nef on the development of hematopoietic stem/progenitor cells (HSPCs) into T lymphoid cells. DESIGN: HSPC-OP9-DL1 cell co-culture and humanized mouse model was used to investigate the objective of our study in vitro and in vivo. RNA-seq was exploited to study the change of gene expression signature after nef expression in HSPCs. RESULTS: Nef expression in HSPCs was found to block their development into T lymphoid cells both in vitro and in the mice reconstituted with nef-expressing HSPCs derived from human cord blood. More surprisingly, in humanized mice nef expression preferentially suppressed the production of CD4+ T cells. This developmental defect was not the result of CD34+ cell loss. RNA-seq analysis revealed that Nef affected the expression of 176 genes in HSPCs, including those involved in TNF, TLR, and NOD-like receptor signaling pathways that are important for hematopoietic cell development. CONCLUSIONS: Our results demonstrate that Nef compromises the development of HSPCs into T lymphoid cells, especially CD4+T cells. This observation suggests that therapeutics targeting Nef may correct HIV-1 associated hematopoietic abnormalities, especially defects in T cell development.

4.
BMC Complement Med Ther ; 21(1): 24, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413347

RESUMO

BACKGROUND: Wrist-ankle acupuncture (WAA) as a kind of micro acupuncture therapy has been used to management cancer pain, however, the effects of WAA on cancer pain were controversial in the current studies. Therefore, the purpose of this meta-analysis was to critically evaluate the effect of wrist-ankle acupuncture (WAA) on cancer pain. METHODS: Seven digital databases were searched from the inception of databases to July 2020, including CNKI, Wanfang, VIP, CBM, Cochrane Library, PubMed and Embase. Randomized controlled trials conforming to the inclusion and exclusion criteria were screened and extracted; the risk of bias was evaluated using the Cochrane Collaboration criteria. The primary outcome indicators included pain relief rate and pain score, and the secondary outcome was adverse reaction incidence. All analyses were performed with Review Manager 5.3. RESULTS: A total of 13 studies with 1005 cancer patients (intervention group: 568, control group: 437) were included in this meta-analysis. The results demonstrated that the pain relief rate of experimental group (WAA / WAA + drug intervention) was better than that of control group (analgesic drug intervention), and the difference was statistically significant [RR = 1.31, 95%CI: 1.15 ~ 1.49, P < 0.01]. CONCLUSIONS: WAA has certain effect on cancer pain, and the effect of WAA combined with pharmacological intervention is better than that of drug therapy alone.

5.
Int J Mol Sci ; 22(2)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33440688

RESUMO

Hydrophobins are a family of small secreted proteins found exclusively in fungi, and they play various roles in the life cycle. In the present study, genome wide analysis and transcript profiling of the hydrophobin family in Cordyceps militaris, a well-known edible and medicinal mushroom, were studied. The distribution of hydrophobins in ascomycetes with different lifestyles showed that pathogenic fungi had significantly more hydrophobins than saprotrophic fungi, and class II members accounted for the majority. Phylogenetic analysis of hydrophobin proteins from the species of Cordyceps s.l. indicated that there was more variability among the class II members than class I. Only a few hydrophobin-encoding genes evolved by duplication in Cordyceps s.l., which was inconsistent with the important role of gene duplication in basidiomycetes. Different transcript patterns of four hydrophobin-encoding genes during the life cycle indicated the possible different functions for each. The transcripts of Cmhyd2, 3 and 4 can respond to light and were related with the photoreceptors. CmQHYD, with four hydrophobin II domains, was first found in C. militaris, and multi-domain hydrophobins were only distributed in the species of Cordycipitaceae and Clavicipitaceae. These results could be helpful for further function research of hydrophobins and could provide valuable information for the evolution of hydrophobins.

6.
Pharmacol Res Perspect ; 9(1): e00699, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33448699

RESUMO

Cardiomyocyte apoptosis is a key factor in the deterioration of cardiac function after coronary microembolization (CME). Nicorandil (NIC) affects myocardial injury, which may be related to the inhibition of apoptosis. However, the specific mechanism of cardioprotection has not been elucidated. Therefore, we analyzed the impact of NIC on cardiac function in rats subjected to CME and its effect on the high-temperature requirement peptidase 2/X-linked inhibitor of apoptosis protein/poly ADP-ribose polymerase (HtrA2/XIAP/PARP) pathway. Sprague Dawley rats were divided into four groups: Sham, CME, CME + NIC, and CME + UCF. Echocardiography was performed 9 hours after CME. Myocardial injury markers were evaluated in blood samples, and the heart tissue was collected for hematoxylin-eosin staining, hematoxylin basic fuchsin picric acid staining staining, TdT-mediated DUTP nick end labeling (TUNEL) staining, Western blot analysis of the HtrA2/XIAP/PARP pathway, and transmission electron microscopy. NIC ameliorated cardiac dysfunctioncaused by CME and reduced serum levels of CK-MB and LDH. In addition, NIC decreased myocardial microinfarct size and apoptotic index. NIC reduced the Bax/Bcl-2 ratio, levels of cleaved caspase 3/9, cytoplasmic HtrA2, and cleaved PARP, and increased the level of XIAP. The effects of NIC were similar to those of the HtrA2 inhibitor, UCF101. This study demonstrated that NIC reduces CME-induced myocardial injury, reduces mitochondrial damage, and improves myocardial function. The reduction in cardiomyocyte apoptosis by NIC may be mediated by the HtrA2/XIAP/PARP signaling pathway.

7.
Chemosphere ; 262: 127602, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32750589

RESUMO

A 1 L lab-scale anaerobic ammonium oxidation (anammox) biofilm reactor with nitrogen loading rate of 0.11 g/L d was run for 110 days with the operation temperature declining from 36 °C to 15 °C. The total inorganic nitrogen removal efficiency showed a reduction from 80% to 66%, when the temperature declined from 36 °C to 15 °C. N-acyl-l-homoserine lactones (AHLs) concentrations, especially C8-HSL and C6-HSL, declined in both water and biomass phases, and this decline indicated that the quorum sensing weakened. Microbial community analysis revealed that Candidatus Kuenenia was the predominant anammox bacteria during the entire operating period. The abundance of Candidatus Kuenenia increased from 1.43% to 22.89% when the temperature decreasing from 36 °C to 15 °C. The correlation between microbial genus and AHLs was complicated. Overall, the temperature decrease weakened the quorum sensing so that the nitrogen removal performance deteriorated, and increasing the anammox activity might be an efficient way to improve performance.


Assuntos
Reatores Biológicos/microbiologia , Homosserina/metabolismo , Lactonas/metabolismo , Microbiota , Bactérias/classificação , Biofilmes , Biomassa , Nitrogênio , Oxirredução , Percepção de Quorum , Temperatura
8.
Environ Int ; 147: 106315, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33321389

RESUMO

Industrialization and urbanization have increased the risk of heavy metal(loid)s coming from a wide range of pathways and processes. Regional environmental risk assessment mainly focuses on the regional functional layout, industrial orientation, and enterprise location. These aspects may generate immense environmental risks and hazards. However, many gaps in regional environmental risk assessment remain, particularly concerning the spatial heterogeneity of environmental processes and mechanisms affected by the industrial layout. Most of the risk estimation often neglected the risk factor interaction. Here, we developed a framework to estimate the environmental risk of heavy metal(loid)s focusing on the spatial heterogeneity of the industrial layout. This framework was operationalized by performing an integrated risk detection of heavy metal(loid)s, spatial heterogeneity identification of the industrial layout, the power of risk factors and factor interaction examination, risk factor condition quantification and key risk source apportionment. Shaoguan city, one of six trial zones for China's pollution prevention and control of heavy metal(loid)s, was taken as a case study. Among all of the natural and socioeconomic factors, the running time of the industry was the most important risk factor of the Cd, As and Pb in soil and rice in all subregions. These subregions were divided based on the spatial heterogeneity of the industrial layout. The threshold of the running time of the industry for soil Cd was 11.97 years. The power of other dominant risk factors was different in different subregions, and the joint risk of the dominant risk factors was larger than the single risk of the running time of the industry. Our results suggest that the environmental risk of heavy metal(loid)s in Shaoguan could be mitigated by adjusting the industrial structure and controlling the running time of enterprises. Our study also indicates that estimating the regional environmental risk of heavy metal(loid)s focusing on the spatial heterogeneity of the industrial layout can help define specific strategies to achieve environmentally friendly industrial development.

9.
Lancet Public Health ; 5(12): e661-e671, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33271079

RESUMO

BACKGROUND: China has a large population of older people, but has not yet undertaken a comprehensive study on the prevalence, risk factors, and management of both dementia and mild cognitive impairment (MCI). METHODS: For this national cross-sectional study, 46 011 adults aged 60 years or older were recruited between March 10, 2015, and Dec 26, 2018, using a multistage, stratified, cluster-sampling method, which considered geographical region, degree of urbanisation, economic development status, and sex and age distribution. 96 sites were randomly selected in 12 provinces and municipalities representative of all socioeconomic and geographical regions in China. Participants were interviewed to obtain data on sociodemographic characteristics, lifestyle, medical history, current medications, and family history, and then completed a neuropsychological testing battery administered by a psychological evaluator. The prevalence of dementia (Alzheimer's disease, vascular dementia, and other dementias) and MCI were calculated and the risk factors for different groups were examined using multivariable-adjusted analyses. FINDINGS: Overall age-adjusted and sex-adjusted prevalence was estimated to be 6·0% (95% CI 5·8-6·3) for dementia, 3·9% (3·8-4·1) for Alzheimer's disease, 1·6% (1·5-1·7) for vascular dementia, and 0·5% (0·5-0·6) for other dementias. We estimated that 15·07 million (95% CI 14·53-15·62) people aged 60 years or older in China have dementia: 9·83 million (9·39-10·29) with Alzheimer's disease, 3·92 million (3·64-4·22) with vascular dementia, and 1·32 million (1·16-1·50) with other dementias. Overall MCI prevalence was estimated to be 15·5% (15·2-15·9), representing 38·77 million (37·95-39·62) people in China. Dementia and MCI shared similar risk factors including old age (dementia: odds ratios ranging from 2·69 [95% CI 2·43-2·98] to 6·60 [5·24-8·32]; MCI: from 1·89 [1·77-2·00] to 4·70 [3·77-5·87]); female sex (dementia: 1·43 [1·31-1·56]; MCI: 1·51 [1·43-1·59]); parental history of dementia (dementia: 7·20 [5·68-9·12]; MCI: 1·91 [1·48-2·46]); rural residence (dementia: 1·16 [1·06-1·27]; MCI: 1·45 [1·38-1·54]); fewer years of education (dementia: from 1·17 [1·06-1·29] to 1·55 [1·38-1·73]; MCI: from 1·48 [1·39-1·58] to 3·48 [3·25-3·73]); being widowed, divorced, or living alone (dementia: from 2·59 [2·30-2·90] to 2·66 [2·29-3·10]; MCI: from 1·58 [1·44-1·73] to 1·74 [1·56-1·95]); smoking (dementia: 1·85 [1·67-2·04]; MCI: 1·27 [1·19-1·36]), hypertension (dementia: 1·86 [1·70-2·03]; MCI: 1·62 [1·54-1·71] for MCI), hyperlipidaemia (dementia: 1·87 [1·71-2·05]; MCI: 1·29 [1·21-1·37]), diabetes (dementia: 2·14 [1·96-2·34]; MCI: 1·44 [1·35-1·53]), heart disease (dementia: 1·98 [1·73-2·26]; MCI: 1·17 [1·06-1·30]), and cerebrovascular disease (dementia: 5·44 [4·95-5·97]; MCI: 1·49 [1·36-1·62]). Nine of these risk factors are modifiable. INTERPRETATION: Dementia and MCI are highly prevalent in China and share similar risk factors. A prevention strategy should be developed to target the identified risk factors in the MCI population to thwart or slow down disease progression. It is also crucial to optimise the management of dementia and MCI as an important part of China's public health system. FUNDING: Key Project of the National Natural Science Foundation of China, National Key Scientific Instrument and Equipment Development Project, Mission Program of Beijing Municipal Administration of Hospitals, Beijing Scholars Program, Beijing Brain Initiative from Beijing Municipal Science & Technology Commission, Project for Outstanding Doctor with Combined Ability of Western and Chinese Medicine, and Beijing Municipal Commission of Health and Family Planning.

10.
Parkinsonism Relat Disord ; 82: 92-97, 2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33271462

RESUMO

BACKGROUND: Retinal abnormalities measured by optical coherence tomography (OCT) have been detected in both Parkinson's disease (PD) and Alzheimer's disease (AD). Cognitive impairment is not only found in AD, but 75-90% of PD patients will also develop dementia in the late stage of disease. We assessed whether baseline retinal nerve fiber layer (RNFL) thickness predicted worsening of cognitive status over time and the correlation between RNFL thickness and the detailed impaired cognitive domains in PD. METHODS: RNFL thickness was measured using high-definition OCT in 78 non-dementia PD patients. Clinical and cognitive assessments were performed at baseline and at 3.61 ± 0.65 years follow-up. Linear mixed-effects models were used to examine associations between RNFL thickness and the changes in cognitive test scores, after adjusting for age, sex, disease duration and education. RESULTS: Analysis of outcomes according to baseline RNFL tertiles showed worse performance in global cognitive tests, delayed memory, and executive functions in patients with a thin RNFL. During follow-up, greater cognitive deterioration was found in thin RNFL tertile patients. Lower baseline average RNFL thickness was associated with greater annualized decline in Mini-Mental State Examination and Montreal Cognitive Assessment. CONCLUSION: The correlation between RNFL thickness and cognitive dysfunction suggests that OCT may be useful for predicting cognitive dysfunction in PD patients.

11.
Int J Infect Dis ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33278623

RESUMO

BACKGROUND: Linezolid presents strong antimicrobial activity against multidrug-resistant (MDR) pulmonary tuberculosis (TB), whereas its application in osteoarticular tuberculosis treatment remains understudied. Our objective was to analyze the bone penetration efficiency of linezolid in osteoarticular TB patients. METHODS: Osteoarticular TB patients, treated with 600mg q24h linezolid-containing regimens and undergoing surgery, were prospectively and consecutively enrolled. One dose linezolid was administered before surgery. Blood and bone samples were collected simultaneously during operation, and then their linezolid concentrations were detected by performing high-performance liquid chromatography-tandem mass spectrometry. Pus samples were subjected to mycobacterial culture and GeneXpert MTB/RIF assay. The minimum inhibition concentrations (MICs) and drug susceptibility testing were performed with the recovered isolates. RESULTS: 36 eligible osteoarticular TB patients were enrolled, including five MDR/rifampicin-resistant cases. All of the 12 recovered isolates had MICs ≤0.5 µg/mL for linezolid. Mean concentrations in plasma, collected 100-510 min post the preoperative dosing, were 10.43 ± 4.83 µg/mL (range 3.29-22.26 µg/mL) and median concentrations in bone were 3.93 µg/mL (range 0.61-16.34 µg/mL). The median bone/plasma penetration ratio was 0.42 (range 0.14-0.95 µg/mL). Linezolid concentration in bone had linear correlation with the drug concentration in plasma (r = 0.7873, p < 0.0001), while plasma concentration could explain 61.98% of the variation of concentration in bone (R2 = 0.6198). Notably, stratification analysis by sampling time demonstrated that samples collected 200-510 mins after dosing had very good linear relationship between bone and plasma concentrations (r = 0.9323). CONCLUSIONS: Linezolid penetrates from blood to bone efficiently, and the penetration further stabilizes ∼3 h after dosing.

12.
Front Endocrinol (Lausanne) ; 11: 574662, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362715

RESUMO

Pheochromocytoma/paraganglioma (PPGL) has a high genetic heterogeneity with 40% germline variants in known pathogenic genes. Data in Chinese on this aspect are scanty. To detect the genetic and clinical profile of Chinese PPGL patients, we examined the variants of 12 known germline pathogenic genes (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, RET, NF1, MAX, TMEM127, and KIF1B) by next-generation sequencing and Sanger sequencing in 314 Chinese PPGL subjects. Twenty nine percent of Chinese PPGL patients had germline variants and SDHB was the most frequently mutated (14.6%). The most frequent SDHB variants were in exon 2, exon 7, and IVS 7. Pathogenic variants were more likely to occur in metastatic PPGL patients, paragangliomas, and patients under 30, with the ratio being 50.7% (35/69), 35.9% (56/156), and 49.5% (52/105), respectively. Our cohort included 314 patients from a single setting. The genetic and clinical features of Chinese PPGL patients were unique in some aspects compared to their non-Chinese counterparts. Identification of genotype-phenotype relation can serve as an effective tool for genetic prioritization and clinical decision-making.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33331025

RESUMO

Reported herein is the rhodium(III)-catalyzed C-H activation of anilines bearing an N-isoquinolyl directing group for oxidative [3+2] annulation with four classes of internal alkynes, leading to atroposelective indole synthesis via dynamic kinetic annulation with C-N reductive elimination constituting the stereo-determining step. This reaction proceeds under mild conditions with high regio- and enantioselectivity and functional group compatibility.

14.
Mol Med ; 26(1): 108, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33187467

RESUMO

BACKGROUND: Acute lung injury (ALI), which is induced by numerous pathogenic factors, especially sepsis, can generate alveolar damage, pulmonary edema and vascular hyper-permeability ultimately leading to severe hypoxemia. Fibroblast growth factor-2 (FGF2) is an important member of the FGF family associated with endothelial cell migration and proliferation, and injury repairment. Here, we conducted this study aiming to evaluate the therapeutic effect of FGF2 in sepsis-induced ALI. METHODS: Recombinant FGF2 was abdominally injected into septic mice induced by cecal ligation and puncture (CLP), and then the inflammatory factors of lung tissue, vascular permeability and lung injury-related indicators based on protein levels and gene expression were detected. In vitro, human pulmonary microvascular endothelial cells (HPMEC) and mouse peritoneal macrophages (PMs) were challenged by lipopolysaccharides (LPS) with or without FGF2 administration in different groups, and then changes in inflammation indicators and cell permeability ability were tested. RESULTS: The results revealed that FGF2 treatment reduced inflammation response, attenuated pulmonary capillary leakage, alleviated lung injury and improved survival in septic mice. The endothelial injury and macrophages inflammation induced by LPS were inhibited by FGF2 administration via AKT/P38/NF-κB signaling pathways. CONCLUSION: These findings indicated a therapeutic role of FGF2 in ALI through ameliorating capillary leakage and inflammation.

15.
Brain ; 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33188687

RESUMO

Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer's disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer's disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer's disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10-19, 2.49 × 10-23, 1.35 × 10-67, and 4.81 × 10-9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P < 5.0 × 10-8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer's disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer's disease, suggesting that our models can predict Alzheimer's disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer's disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer's disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation.

16.
Org Lett ; 22(22): 9047-9052, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33166447

RESUMO

Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.

17.
Redox Biol ; 38: 101780, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33171331

RESUMO

K-ras mutations are major genetic events that drive cancer development associated with aggressive malignant phenotypes, while expression of the immune checkpoint molecule PD-L1 plays a key role in cancer evasion of the immune surveillance that also profoundly affects the patient outcome. However, the relationship between K-ras oncogenic signal and PD-L1 expressions as an important area that requires further investigation. Using both in vitro and in vivo experimental models of K-ras-driven cancer, we found that oncogenic K-ras significantly enhanced PD-L1 expression through a redox-mediated mechanism. Activation of K-rasG12V promoted ROS generation and induced FGFR1 expression, leading to a significant upregulation of PD-L1. We further showed that exogenous ROS such as hydrogen peroxide alone was sufficient to activate FGFR1 and induce PD-L1, while antioxidants could largely abrogate PD-L1 expression in K-ras mutant cells, indicating a critical role of redox regulation. Importantly, genetic knockout of FGFR1 led to a decrease in PD-L1 expression, and impaired tumor growth in vivo due to a significant increase of T cell infiltration in the tumor tissues and thus enhanced T-cell-mediated tumor suppression. Our study has identified a novel mechanism by which K-ras promotes PD-L1 expression, and suggests that modulation of ROS or inhibition of the FGFR1 pathway could be a novel strategy to abrogate PD-L1-mediated immunosuppression and thus potentially improve the efficacy of immunotherapy in K-ras-driven cancers.

18.
Front Oncol ; 10: 568059, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194652

RESUMO

Immunotherapy has revolutionized lung cancer treatment in the past decade. By reactivating the host's immune system, immunotherapy significantly prolongs survival in some advanced lung cancer patients. However, resistance to immunotherapy is frequent, which manifests as a lack of initial response or clinical benefit to therapy (primary resistance) or tumor progression after the initial period of response (acquired resistance). Overcoming immunotherapy resistance is challenging owing to the complex and dynamic interplay among malignant cells and the defense system. This review aims to discuss the mechanisms that drive immunotherapy resistance and the innovative strategies implemented to overcome it in lung cancer.

19.
Life Sci ; : 118709, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33152351

RESUMO

AIMS: Although interferon regulatory factor 7 (IRF7) has known roles in regulating the inflammatory response, vascular smooth muscle cell proliferation, and apoptosis, its role in the pathogenesis of pulmonary hypertension (PH) is unclear. We hypothesized that IRF7 overexpression could inhibit pulmonary vascular remodeling and slow the progression of PH. MAIN METHODS: IRF7 mRNA and protein levels in the lung samples and pulmonary artery smooth muscle cells (PASMCs) isolated from monocrotaline (MCT)-induced PH rats were assessed. We evaluated the effects of IRF7 on inflammation, proliferation, and apoptosis using an in vivo MCT-induced PH rat model and in vitro methods. KEY FINDINGS: We noted decreased IRF7 mRNA and protein levels in the pulmonary vasculature of MCT-induced PH rats. IRF7 upregulation attenuated pulmonary vascular remodeling, decreased the pulmonary artery systolic pressure, and improved the right ventricular (RV) structure and function. Our findings suggest that nuclear factor kappa-Bp65 (NF-κBp65) deactivation could confer pulmonary vasculature protection, reduce proinflammatory cytokine (tumor necrosis factor-α, interleukin 6) release, and decrease PASMC proliferation and resistance to apoptosis via deactivating transcription factor 3 (ATF3) signaling. ATF3 deactivation induced the downregulation of the proliferation-dependent genes proliferating cell nuclear antigen (PCNA), cyclin D1, and survivin, coupled with increased levels of B cell lymphoma-2-associated X protein (Bax)/B cell lymphoma-2 (Bcl2) ratio, and cleaved caspase-3 in PASMCs. SIGNIFICANCE: Our findings showed that IRF7 downregulation could initiate inflammation via NF-κBp65 signaling, causing PASMC proliferation via ATF3 signaling pathway activation. Therefore, IRF7 could be a potential molecular target for PH therapy.

20.
Clin Lung Cancer ; 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-33132058

RESUMO

BACKGROUND: We report our clinical outcomes of patients with recurrent non-small-cell lung cancer (NSCLC) tumors with ultra-central (UC) location treated with hypofractionated 10-fraction stereotactic body radiotherapy (hSBRT) in the context of thoracic re-irradiation. PATIENTS AND METHODS: This study was conducted from 2009 to 2017 on 20 patients with recurrent NSCLC from previous thoracic radiation treatment who underwent hSBRT to 21 total UC located recurrent tumors. The planning target volumes (PTVs) that overlapped with previous treatment fields (within the 50% isodose line) were included in this analysis with endpoints of overall survival, tumor control, and toxicity. RESULTS: The median follow-up time was 17.8 months. The median total dose of hSBRT and total biologically effective dose (BED10) were 65 Gy and 107.25 Gy, respectively. The median time from previous treatment was 14.6 months. The 1-year overall survival, progression-free survival, and local control rates were 68%, 35%, and 83%, respectively. The median time to local progression was 13.3 months. The most common toxicity was grade 2 or above pneumonitis (35%). One patient, whose tumor was abutting the esophagus, experienced grade 3 esophagitis. Two (10%) patients died from "unlikely" treatment-related hemorrhage from local tumor progression at 10 and 24 months after hSBRT. Bronchoscopic evaluation of 1 patient suggested endobronchial tumor progression, and clear radiographic evidence of treated hilar tumor progression was documented in the second patient's case. CONCLUSION: Despite having a high-risk population with recurrent ultra-central NSCLC tumors in the setting of re-irradiation, our results demonstrate that ablative doses of hSBRT may serve as a feasible option for these challenging cases and concur with current reported literature.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA