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1.
J Int Med Res ; 50(1): 3000605211067749, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34986706

RESUMO

Type B lactic acidosis is a rare complication of non-tissue perfusion abnormalities caused by solid tumors or hematologic malignancies. Herein, we present the case of a 42-year-old man with type B lactic acidosis and hypoglycemia who was found to have a diffuse large B-cell lymphoma. The cause of lactic acidosis and/or hypoglycemia is thought to be the Warburg effect, which is when the metabolic rate of a rapidly growing malignant tumor is very high and dominated by glycolysis. Systemic damage from type B lactic acidosis can occur when the increased rate of glycolysis exceeds the normal muscle and liver lactic acid clearance rate. The Warburg effect is a rare but serious condition that needs to be recognized, not only in diffuse large B-cell lymphoma, but also in other malignancies. The prognosis of lactic acidosis in patients with malignant tumors is very poor. Currently, effective chemotherapy seems to be the only hope for survival.


Assuntos
Acidose Láctica , Hipoglicemia , Linfoma Difuso de Grandes Células B , Acidose Láctica/complicações , Adulto , Humanos , Ácido Láctico , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Prognóstico
2.
AAPS J ; 24(1): 19, 2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34984579

RESUMO

Over the past decade, artificial intelligence (AI) and machine learning (ML) have become the breakthrough technology most anticipated to have a transformative effect on pharmaceutical research and development (R&D). This is partially driven by revolutionary advances in computational technology and the parallel dissipation of previous constraints to the collection/processing of large volumes of data. Meanwhile, the cost of bringing new drugs to market and to patients has become prohibitively expensive. Recognizing these headwinds, AI/ML techniques are appealing to the pharmaceutical industry due to their automated nature, predictive capabilities, and the consequent expected increase in efficiency. ML approaches have been used in drug discovery over the past 15-20 years with increasing sophistication. The most recent aspect of drug development where positive disruption from AI/ML is starting to occur, is in clinical trial design, conduct, and analysis. The COVID-19 pandemic may further accelerate utilization of AI/ML in clinical trials due to an increased reliance on digital technology in clinical trial conduct. As we move towards a world where there is a growing integration of AI/ML into R&D, it is critical to get past the related buzz-words and noise. It is equally important to recognize that the scientific method is not obsolete when making inferences about data. Doing so will help in separating hope from hype and lead to informed decision-making on the optimal use of AI/ML in drug development. This manuscript aims to demystify key concepts, present use-cases and finally offer insights and a balanced view on the optimal use of AI/ML methods in R&D.


Assuntos
Inteligência Artificial , Ensaios Clínicos como Assunto , Biologia Computacional , Desenvolvimento de Medicamentos , Aprendizado de Máquina , Pesquisa Farmacêutica , Projetos de Pesquisa , Animais , Inteligência Artificial/tendências , Biologia Computacional/tendências , Difusão de Inovações , Desenvolvimento de Medicamentos/tendências , Previsões , Humanos , Aprendizado de Máquina/tendências , Pesquisa Farmacêutica/tendências , Projetos de Pesquisa/tendências
3.
Cancer Med ; 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35023616

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations were frequently found with concomitant genetic alterations in lung adenocarcinoma (LUAD). This study aimed to investigate the profile of concomitant alterations of EGFR-mutant LUAD ≤3 cm in size and its prognostic effect on recurrence. METHODS: From January 2018 to December 2018, patients with resected LUAD ≤3 cm in size in Shanghai Chest Hospital were identified. All patients underwent capture-based targeted next-generation sequencing (NGS) with a panel of 68 lung cancer-related genes and were found with EGFR mutation. Clinicopathological and molecular characteristics and recurrence-free survival (RFS) were analyzed. RESULTS: A total of 637 patients were enrolled in this study. The top three frequent co-mutational genes were TP53 (179 of 637, 28.1%), PIK3CA (27 of 637, 4.2%), and ATM (22 of 637, 3.5%). The most common amplified genes were EGFR (37 of 637, 5.8%), followed by CDK4 (37 of 637, 5.8%) and MYC (12 of 637, 2.0%). Only TP53 mutation and EGFR amplification were adverse prognostic factors for RFS (all p < 0.001) in univariate analysis. Multivariable analysis further demonstrated that TP53 mutation and EGFR amplification were independent risk factors for RFS [(hazard ratio (HR) 2.07, 95% confidence interval (CI) 1.07-4.00, p = 0.030; HR 3.09, 95% CI 1.49-6.40, p = 0.002, respectively]. CONCLUSIONS: Concomitant TP53 mutation and EGFR amplification were poor prognostic factors for RFS in patients with EGFR-mutant resected LUAD. Our findings provide valuable understanding of the impact of concurrent alterations and implication for better implementation of precision therapy for patients.

4.
Chemosphere ; 287(Pt 3): 132305, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34563770

RESUMO

BACKGROUND: Metal exposures are suspected to associate with the risk of hyperuricemia (HUA), but the current results are still conflicting. OBJECTIVE: To investigate the associations between multiple plasma metal exposures and HUA risk. METHODS: A cross-sectional study was conducted in 1406 Chinese Han adults who underwent routine physical examination in the Eighth Affiliated Hospital of Sun Yat-Sen University in Shenzhen. The plasma levels of 13 metals were measured by the inductively coupled plasma mass spectrometry (ICP-MS). Multivariable logistic, linear regression models, least absolute shrinkage and selection operator (LASSO) penalized regression analysis, and restricted cubic spline (RCS) models were applied to assess the associations. RESULTS: The median plasma uric acid concentration in HUA group (434 µmol/L) was significantly higher than that in non-HUA group (305 µmol/L). The multivariate-adjusted odds ratios (95% confidence intervals) of HUA were 1.62(1.08-2.43) for magnesium, 1.61(1.05-2.47) for copper, 1.62(1.06-2.49) for zinc, 1.87(1.26-2.81) for arsenic, 1.50(1.01-2.23) for selenium, and 1.70(1.16-2.49) for thallium based on the single-metal logistic regression models, comparing the highest versus the lowest quartile of metal levels. Further multi-metal logistic, linear regression models and the LASSO analysis all indicated positive associations of zinc, arsenic with HUA risk or uric acid levels. RCS model indicated an inverted V-shaped positive association between zinc levels and HUA risk (p for non-linearity = 0.048, p for overall association = 0.022), while arsenic levels showed a positive and linear dose-response relationship with HUA risk (p for non-linearity = 0.892, p for overall association<0.001). CONCLUSIONS: Higher plasma levels of zinc and arsenic might increase HUA risk and showed positive dose-response relationships. Further cohort studies in larger population are required to testify our findings.


Assuntos
Hiperuricemia , Adulto , China/epidemiologia , Estudos Transversais , Humanos , Hiperuricemia/epidemiologia , Metais , Pessoa de Meia-Idade , Ácido Úrico
5.
Food Chem ; 371: 131209, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34598121

RESUMO

In this study, non-targeted and targeted metabolomics/lipidomics studies based on UPLC-QTOF-MS and UPLC-MS/MS were carried out to clarify the effects of tebuconazole and its different enantiomers on lettuce metabolites and lipids. Slight enantioselective degradation of tebuconazole was observed and six degradation metabolites were tentatively identified. The endogenous metabolites involved in carbohydrate metabolism, amino acid metabolism, nucleic acid metabolism, phenylpropanoid and flavonoid metabolism, vitamins, and lipid metabolism were significantly affected with enantioselectivity by tebuconazole exposure. Nucleotide metabolism and nicotinic acid metabolic network were significantly activated by the stimulation of tebuconazole. Rac- and (-)-R-tebuconazole caused the down-regulation of soluble sugars and subsequent amino acids and organic acids. Overall, lettuce exposed to tebuconazole was shown to have a significant impact on plant metabolism and lipid metabolism, with notable stereoselectivity. The results showed stereoselective toxicity of tebuconazole and provided a better understanding of its metabolomic and lipidomic effects on lettuce.


Assuntos
Fungicidas Industriais , Cromatografia Líquida , Fungicidas Industriais/análise , Fungicidas Industriais/toxicidade , Alface , Lipidômica , Metabolômica , Espectrometria de Massas em Tandem , Triazóis/toxicidade
6.
Front Oncol ; 11: 745150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868942

RESUMO

Background: Diabetes mellitus (DM) is a frequent comorbidity in patients with cancer. This study aimed to evaluate the prognosis of advanced non-small cell lung cancer (NSCLC) patients with DM and to assess whether an optimal glycemic control improves overall survival (OS). Methods: A total of 1279 advanced NSCLC patients including 300 (23.5%) with preexisting DM were retrospectively reviewed. The continuous relationship between glycated hemoglobin A1C (HbA1c) level and OS was analyzed by restricted cubic spline (RCS) function. Optimal HbA1c cut-off point was determined using X-tile analysis. Survival was analyzed with the Kaplan-Meier method and compared among groups stratified by diabetes status and HbA1c. Multivariable Cox proportional hazards regression analysis was employed to identify prognostic factors for OS after adjusting for baseline characteristics. Results: DM and non-DM patients had similar OS (median (95% CI): 22.85 (20.05-26.73) vs. 22.22 (20.35-24.76) months, P=0.950). The multivariate Cox regression analyses showed that DM status was not a prognostic factor for OS (HR: 0.952, 95% CI: 0.808-1.122, P=0.559). However, there existed a non-linear but generally positive relationship between the elevated HbA1c level and increased risk of overall mortality. HbA1c > 6.6% was a negative prognostic factor for OS (HR: 1.593, 95% CI: 1.113-2.280, P=0.011). The median OS (95% CI) for nondiabetic patients, DM patients with HbA1c ≤6.6% and those with HbA1c > 6.6% was 22.22 (20.01-24.43), 25.28 (21.79-28.77) and 15.45 (7.57-23.33) months, respectively. Well-controlled DM patients had a comparable crude OS (HR (95% CI): 0.90 (0.76-1.08), P=0.273] compared to nondiabetic patients while patients with HbA1c>6.6% had a worse crude OS than patients without DM (HR (95% CI): 1.70 (1.24-2.34), P=0.001]. The survival benefit of good HbA1c control was prominent in all subgroups. Conclusion: Impaired glycemic level negatively affects survival for patients with advanced NSCLC while proper glycemic control with HbA1c ≤6.6% improves the OS.

7.
Adv Sci (Weinh) ; : e2103926, 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34825527

RESUMO

With the development of society, energy shortage and environmental problems have become more and more outstanding. Solar energy is a clean and sustainable energy resource, potentially driving energy conversion and environmental remediation reactions. Thus, solar-driven chemistry is an attractive way to solve the two problems. Photothermal chemistry (PTC) is developed to achieve full-spectral utilization of the solar radiation and drive chemical reactions more efficiently under relatively mild conditions. In this review, the mechanisms of PTC are summarized from the aspects of thermal and non-thermal effects, and then the interaction and synergy between these two effects are sorted out. In this paper, distinguishing and quantifying these two effects is discussed to understand PTC processes better and to design PTC catalysts more methodically. However, PTC is still a little far away from practical. Herein, several key points, which must be considered when pushing ahead with the engineering application of PTC, are proposed, along with some workable suggestions on the practical application. This review provides a unique perspective on PTC, focusing on the synergistic effects and pointing out a possible direction for practical application.

8.
Front Oncol ; 11: 714549, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34631540

RESUMO

Objectives: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are both classified as pure and combined subtypes. Due to the low incidence and difficult diagnosis of combined LCNEC (C-LCNEC) and combined SCLC (C-SCLC), few studies have compared their clinical features and prognosis. Materials and Methods: We compared the clinical features, mutation status of driver genes (EGFR, ALK, ROS1, KRAS, and BRAF), and prognosis between C-LCNEC and C-SCLC. Univariate and multivariate Cox regression analyses were applied for survival analysis. Results: We included a total of 116 patients with C-LCNEC and 76 patients with C-SCLC in the present study. There were significant differences in distribution of smoking history, tumor location, pT stage, pN stage, pTNM stage, visceral pleural invasion (VPI), and combined components between C-LCNEC and C-SCLC (P<0.05 for all). C-SCLC was more advanced at diagnosis as compared to C-LCNEC. The incidence of EGFR mutations in C-LCNEC patients was higher than C-SCLC patients (25.7 vs. 5%, P=0.004). We found that tumor size, pN stage, peripheral CEA level, and adjuvant chemotherapy were independently prognostic factors for DFS and OS in C-LCNEC patients, while peripheral NSE level, pT stage, pN stage, VPI and adjuvant chemotherapy were independently associated with DFS and OS for C-SCLC patients (P<0.05 for all). Propensity score matching with adjustment for the confounders confirmed a more favorable DFS (P=0.032) and OS (P=0.019) in patients with C-LCNEC in comparison with C-SCLC patients upon survival analysis. Conclusions: The mutation landscape of driver genes seemed to act in different way between C-SCLC and C-LCNEC, likely by which result in clinical phenotype difference as well as better outcome in C-LCNEC.

9.
Free Radic Biol Med ; 176: 176-188, 2021 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-34610361

RESUMO

Ferroptosis is a newly defined programmed cell death pathway characterized by iron overload and lipid peroxidation. Increasing studies show that autophagy regulates testosterone synthesis and promotes ferroptosis. Testosterone is essential for sexual development and the maintenance of male characteristics. The deficiency of testosterone induced by cadmium (Cd) can severely affect male fertility. However, the underlying mechanism of testosterone reduction after Cd exposure remains blurry. In this study, we found that Cd affected iron homeostasis and elicited ferroptosis, ultimately reducing testosterone production. Mechanically, our findings revealed that Cd-induced ferroptosis depended upon the excessive activation of Heme oxygenase 1 (HMOX1) and the release of free iron from heme. Additionally, Cd exposure promoted autophagosome formation but blocked autophagosome-lysosome fusion, which attenuated the absorption of total cholesterol and triglycerides, further aggravating testosterone synthesis disorder. Collectively, Cd induced ferroptosis by iron homeostasis dysregulation, mediated by excessive activation of HMOX-1. The disruption of autophagy flow contributed to Cd-induced testicular dysfunction and attenuated testosterone synthesis.


Assuntos
Ferroptose , Autofagossomos , Autofagia , Cádmio/toxicidade , Humanos , Lisossomos , Masculino , Testosterona
10.
Front Genet ; 12: 723670, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34557222

RESUMO

Atezolizumab, an immune checkpoint inhibitor, has been approved for use in clinical practice in non-small cell lung cancer (NSCLC) patients, but potential biomarkers for response stratification still need further screening. In the present study, a total of 399 patients with high-quality ctDNA profiling results were included. The mutation status of ubiquitin-like conjugation (UBL) biological process genes (including ABL1, APC, LRP6, FUBP1, KEAP1, and TOP2A) and clinical information were further integrated. The results suggested that the patients with the clinical characteristics of male or history of smoking had a higher frequency of UBL mutation positivity [UBL (+)]; the patients who were UBL (+) had shorter progression-free survival (PFS) (1.69 vs. 3.22 months, p = 0.0007) and overall survival (8.61 vs. 16.10 months, p < 0.0001) than those patients with UBL mutation negativity [UBL (-)]; and more promising predictive values were shown in the smoker subgroup and ≤ 3 metastasis subgroup. More interestingly, we found the predictor has more performance in TP53-negative cohorts [training in an independent POPLAR and OAK cohorts (n = 200), and validation in an independent MSKCC cohort (n = 127)]. Overall, this study provides a predictor, UBL biological process gene mutation status, not only for identifying NSCLC patients who may respond to atezolizumab therapy but also for screening out the potential NSCLC responders who received other immune checkpoint inhibitors.

11.
PLoS One ; 16(8): e0255508, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34379668

RESUMO

Climate / weather factors are important factors for tourists to choose tourist destinations. With the public's attention to the influence of haze, air quality will have a profound impact on the development of tourism in tourist destinations. Based on the Epsilon-based Measure (EBM) super-efficiency model and Global Malmquist-Luenberger index analysis method, this paper aims to study the tourism development efficiency of 58 major cities in China from 2001 to 2016 and analyse the total factor productivity in the development of urban tourism and the changing driving factors in consideration of the undesirable output of haze characterised by PM2.5 emission concentration. The study findings show that the overall efficiency of tourism development of 58 cities is not high in 2001-2016, but the tourism development efficiency of all cities is increasing year by year. Under the constraint of haze, the efficiency of urban tourism development is not directly proportional to the degree of urban development. The overall redundancy rate of each input index is slightly high, and the redundancy of PM2.5 emission concentration has a considerable effect on the efficiency of urban tourism development. The overall change trend in total factor productivity in the development of urban tourism is improved, mainly due to the improvement of technological progress factors. On this basis, the corresponding policy implications are concluded according to high-efficiency and high-quality development of tourism in 58 major cities.


Assuntos
Poluentes Atmosféricos/análise , Desenvolvimento Econômico/estatística & dados numéricos , Monitoramento Ambiental/métodos , Poluição Ambiental/prevenção & controle , Material Particulado/análise , Turismo , China , Cidades/estatística & dados numéricos , Humanos , Reforma Urbana
12.
Ann Palliat Med ; 10(7): 8123-8133, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34353097

RESUMO

BACKGROUND: There has been a considerable focus on the changes of functional connections between brain regions in patients with type 2 diabetes mellitus (T2DM) by previous resting-state functional magnetic resonance imaging (rs-fMRI) studies. However, little is known about the function of brain information integration between the two hemispheres of the brain. This study explores differences in interhemispheric coordination between T2DM patients and normal control (NC) subjects using the voxel-mirrored homotopic connectivity (VMHC) method. We also assess whether differences in VMHC were relevant to cognitive dysfunction in T2DM patients. METHODS: Sixty-nine T2DM patients and 69 NC subjects were enrolled (matched for age, sex and education level). All participants underwent cognitive assessments. VMHC between brain regions was obtained by rs-fMRI analysis. Partial correlation analysis (after controlling for age, sex and education level) was used to explore the correlation between VMHC value and neuropsychological tests. RESULTS: Compared with NC subjects, T2DM patients exhibited significantly lower VMHC in the medial orbitofrontal gyrus cortex (mOFC), anterior cingulate gyrus, inferior parietal lobe, superior and middle temporal gyrus (MTG), middle occipital gyrus, and superior occipital gyrus. Moreover, after applying Bonferroni correction, the Montreal Cognitive Assessment (MoCA) score and VMHC value for the MTG were significantly positively correlated in T2DM patients. In contrast, T2DM patients exhibited higher VMHC in the cerebellum posterior lobe and tonsil and inferior temporal gyrus than the NCs. CONCLUSIONS: Our study indicates that functional coordination between homotopic brain regions is generally impaired in T2DM patients. In brain regions with decreased VMHC in the default mode network (DMN), MTG impairment could serve as a critical node for T2DM-related cognitive dysfunction. Furthermore, the increased VMHC observed in the cerebellum and inferior temporal gyrus might indicate a functional coordination mechanism.


Assuntos
Diabetes Mellitus Tipo 2 , Encéfalo/diagnóstico por imagem , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética
13.
Ann Clin Microbiol Antimicrob ; 20(1): 53, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34407803

RESUMO

BACKGROUND: Although pertussis cases globally have been controlled through the Expanded Programme on Immunization (EPI), the incidence of pertussis has increased significantly in recent years, with a "resurgence" of pertussis occurring in developed countries with high immunization coverage. Attracted by its fast-developing economy, the population of Shenzhen has reached 14 million and has become one of the top five largest cities by population size in China. The incidence of pertussis here was about 2.02/100,000, far exceeding that of the whole province and the whole country (both < 1/100,000). There are increasing numbers of reports demonstrating variation in Bordetella pertussis antigens and genes, which may be associated with the increased incidence. Fifty strains of Bordetella pertussis isolated from 387 suspected cases were collected in Shenzhen in 2018 for genotypic and molecular epidemiological analysis. METHODS: There were 387 suspected cases of pertussis enrolled at surveillance sites in Shenzhen from June to August 2018. Nasopharyngeal swabs from suspected pertussis cases were collected for bacterial culture and the identity of putative Bordetella pertussis isolates was confirmed by real-time PCR. The immunization history of each patient was taken. The acellular pertussis vaccine (APV) antigen genes for pertussis toxin (ptxA, ptxC), pertactin (prn) and fimbriae (fim2 and fim3) together with the pertussis toxin promoter region (ptxP) were analyzed by second-generation sequencing. Genetic and phylogenetic analysis was performed using sequences publicly available from GenBank, National Institutes of Health, Bethesda, MD, USA ( https://www.ncbi.nlm.nih.gov/genbank/ ). The antimicrobial susceptibility was test by Kirby-Bauer disk diffusion. RESULTS: Fifty strains of Bordetella pertussis were successfully isolated from nasopharyngeal swabs of 387 suspected cases, with a positivity rate of 16.79%, including 28 males and 22 females, accounting for 56.0% and 44.0% respectively. Thirty-eight of the 50 (76%) patients were found to be positive for B. pertussis by culture. Among the positive cases with a history of vaccination, 30 of 42 (71.4%) cases had an incomplete pertussis vaccination history according to the national recommendation. Three phylogenetic groups (PG1-PG3) were identified each containing a predominant genotype. The two vaccines strains, CS and Tohama I, were distantly related to these three groups. Thirty-one out of fifty (62%) isolates belonged to genotype PG1, with the allelic profile prn2/ptxC2/ptxP3/ptxA1/fim3-1/fim2-1. Eighteen out of fifty (36%) isolates contained the A2047G mutation and were highly resistant to erythromycin, and all belonged to genotype PG3 (prn1/ptxA1/ptxP1/ptxC1/fim3-1/fim2-1), which is closely related to the recent epidemic strains found in northern China. CONCLUSIONS: The positive rate of cases under one-year-old was significantly higher than that of other age groups and should be monitored. The dominant antigen genotypes of 50 Shenzhen isolates are closely related to the epidemic strains in the United States, Australia and many countries in Europe. Despite high rates of immunization with APV, epidemics of pertussis have recently occurred in these countries. Therefore, genomic analysis of circulating isolates of B. pertussis should be continued, for it will benefit the control of whooping cough and development of improved vaccines and therapeutic strategies.

14.
Dis Markers ; 2021: 2662031, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326905

RESUMO

Purpose: Using retinal optical coherence tomography angiography (OCTA), we aimed to investigate the changes in important indicators of cerebral microcirculatory disorders, such as the properties of the radial peripapillary capillaries, vascular complexes, and the retinal nerve fiber layer, caused by carotid stenosis and postoperative reperfusion. Methods: In this prospective longitudinal cohort study, we recruited 40 carotid stenosis patients and 89 healthy volunteers in the First Affiliated Hospital of Harbin Medical University (Harbin, China). Eyes with ipsilateral carotid stenosis constituted the experimental group, while the fellow eyes constituted the contralateral eye group. Digital subtraction angiography, CT perfusion imaging (CTP), and OCTA examinations were performed in all subjects. The vessel density of the radial peripapillary capillaries (RPC), superficial retinal vascular complexes (SVC), deep vascular complexes (DVC), choriocapillaris (CC), and the thickness of the retinal nerve fiber layer (RNFL) were assessed. Propensity-matched analysis was undertaken to adjust for covariate imbalances. Intergroup comparative analysis was conducted, and the paired sample t-test was used to evaluate the preoperative and postoperative changes in OCTA variables. Results: The ocular vessel density in the experimental group was significantly lower than that in the control group (RPC: 55.95 vs. 57.24, P = 0.0161; SVC: 48.65 vs. 52.22, P = 0.0006; DVC: 49.65 vs. 57.50, P < 0.0001). Participants with severe carotid stenosis have reduced contralateral ocular vessel density (RPC 54.30; SVC 48.50; DVC 50.80). Unilateral stenosis removal resulted in an increase in vessel density on both sides, which was detected by OCTA on the 4th day (RPC, P < 0.0001; SVC, P = 0.0104; DVC, P = 0.0104). Moreover, the ocular perfusion was consistent with that established by CTP. Conclusion: OCTA can be used for sensitive detection and accurate evaluation of decreased ocular perfusion caused by carotid stenosis and may thus have the potential for application in noninvasive detection of cerebral microcirculation disorders. This trial is registered with NCT04326842.

15.
Front Oncol ; 11: 691519, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262873

RESUMO

Objectives: Pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy (PM) both become standard of care in patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) greater than 50%. This study aimed to figure out the better treatment choice. Method: In this retrospective analysis, we compared the clinical efficacy of PM and PC as first-line treatment in NSCLC patients with a PD-L1 ≥50% and negative for genomic alterations in the EGFR and ALK genes. Result: Among the population, 115 patients received PC, and 91 patients received PM. Up to Dec 30, 2020, median follow-up was 17.13 months. The median progression-free survival (PFS) rates of PC and PM were 12.37 and 9.60 months (HR: 0.44, p < 0.001), respectively. The median overall survival (OS) rates were NE and 28.91 months (HR: 0.40, p = 0.005), respectively. Subgroup analysis found that the PFS benefit of PC was evident in most subgroups excepting patients with brain metastasis. The 1-year overall survival rates of PC and PM were 89.3% and 76.1%, respectively. The ORR was 61.7 and 46.9% (p = 0.004), respectively. Conclusion: In patients with previously untreated, PD-L1 ≥50%, advanced NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard platinum-based chemotherapy seems to be the preferred treatment, which needs to be validated by further prospective trials.

16.
Front Oncol ; 11: 671228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937084

RESUMO

Objectives: More and more encouraging evidence revealed that immunotherapy could improve clinical outcomes in patients with previously treated non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) variations. However, immunotherapy is still a controversy for NSCLC patients with EGFR mutation. Method: In this retrospective analysis, we compared the clinical efficacy of pembrolizumab monotherapy (PM), pembrolizumab combined with chemotherapy (P+C) and pembrolizumab combined with anlotinib (P+A) in NSCLC patients with EGFR mutation who had failed on EGFR-TKI and platinum-based chemotherapy. Result: Eighty-six patients were included in this study. The overall median progression free survival (PFS) was 3.24 months. Multivariate analysis suggested that EGFR L858R and combined therapy were positive prognostic factors of PFS. The overall median OS was 12.28 months. Multivariate analysis found that high PD-L1 expression (≥50%) and combined therapy seemed to be positive prognostic factors of OS. Among the population, 32 patients received PM, 26 patients received P+C and 28 patients received P+A. Up to Jan 30, 2021, the median progression-free survival was 1.5 months in the PM group, 4.30 months in the P+C group and 3.24 months in the P+A group. The median OS were 7.41, 14.92 and 15.97 months, respectively. The ORR were 3.1%, 23.1% and 21.4%. Conclusion: The addition of chemotherapy or antiangiogenic therapy to pembrolizumab resulted in significantly longer PFS, OS and ORR than pembrolizumab alone in our study. EGFR L858R might be a positive prognostic factor of PFS and high PD-L1 expression might be a positive prognostic factor of OS.

17.
Front Microbiol ; 12: 670688, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968006

RESUMO

Pathogens that cause respiratory diseases in poultry are highly diversified, and co-infections with multiple pathogens are prevalent. The H9N2 strain of avian influenza virus (AIV) and Escherichia coli (E. coli) are common poultry pathogens that limit the development of the poultry industry. This study aimed to clarify the interaction between these two pathogens and their pathogenic mechanism using a mouse model. Co-infection with H9N2 AIV and E. coli significantly increased the mortality rate of mice compared to single viral or bacterial infections. It also led to the development of more severe lung lesions compared to single viral or bacterial infections. Co-infection further causes a storm of cytokines, which aggravates the host's disease by dysregulating the JAK/STAT/SOCS and ERK1/2 pathways. Moreover, co-infection mutually benefited the virus and the bacteria by increasing their pathogen loads. Importantly, nitric oxide synthase 2 (NOS2) expression was also significantly enhanced by the co-infection. It played a key role in the rapid proliferation of E. coli in the presence of the co-infecting H9N2 virus. Therefore, our study underscores the role of NOS2 as a determinant for bacteria growth and illustrates its importance as an additional mechanism that enhances influenza virus-bacteria synergy. It further provides a scientific basis for investigating the synergistic infection mechanism between viruses and bacteria.

18.
J Virol ; 95(16): e0059421, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34037421

RESUMO

Snakehead vesiculovirus (SHVV), a kind of fish rhabdovirus isolated from diseased hybrid snakehead fish, has caused great economic losses in snakehead fish culture in China. The large (L) protein, together with its cofactor phosphoprotein (P), forms a P/L polymerase complex and catalyzes the transcription and replication of viral genomic RNA. In this study, the cellular heat shock protein 90 (Hsp90) was identified as an interacting partner of SHVV L protein. Hsp90 activity was required for the stability of SHVV L because Hsp90 dysfunction caused by using its inhibitor destabilized SHVV L and thereby suppressed SHVV replication via reducing viral RNA synthesis. SHVV L expressed alone was detected mainly in the insoluble fraction, and the insoluble L was degraded by Hsp90 dysfunction through the proteasomal pathway, while the presence of SHVV P promoted the solubility of SHVV L and the soluble L was degraded by Hsp90 dysfunction through the autophagy pathway. Collectively, our data suggest that Hsp90 contributes to the maturation of SHVV L and ensures the effective replication of SHVV, which exhibits an important anti-SHVV target. This study will help us to understand the role of Hsp90 in stabilizing the L protein and regulating the replication of negative-stranded RNA viruses. IMPORTANCE It has long been proposed that cellular proteins are involved in viral RNA synthesis via interacting with the viral polymerase protein. This study focused on identifying cellular proteins interacting with the SHVV L protein, studying the effects of their interactions on SHVV replication, and revealing the underlying mechanisms. We identified Hsp90 as an interacting partner of SHVV L and found that Hsp90 activity was required for SHVV replication. Hsp90 functioned in maintaining the stability of SHVV L. Inhibition of Hsp90 activity with its inhibitor degraded SHVV L through different pathways based on the solubility of SHVV L due to the presence or absence of SHVV P. Our data provide important insights into the role of Hsp90 in SHVV polymerase maturation, which will help us to understand the polymerase function of negative-stranded RNA viruses.


Assuntos
Proteínas de Choque Térmico HSP90/metabolismo , RNA Polimerase Dependente de RNA/metabolismo , Vesiculovirus/fisiologia , Proteínas Virais/metabolismo , Replicação Viral , Animais , Células Cultivadas , Peixes , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Fosfoproteínas/metabolismo , Estabilidade Proteica , RNA Viral/biossíntese , Infecções por Rhabdoviridae/veterinária , Infecções por Rhabdoviridae/virologia , Vesiculovirus/metabolismo
19.
Nanotechnology ; 32(37)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34044371

RESUMO

Phosphate-stabilized amorphous calcium carbonate (ACCP) has excellent biocompatibility, bioactivity, and biodegradability, and can be easily synthesized and stored. However, unmodified ACCP, as a controlled drug release carrier, decomposes rapidly in an acidic environment and highly depends on the system's pH value, which can not meet the need for long-term release of active substances, thus limiting its application scope. To realize the specific pH responsiveness of ACCP nanoparticles, we designed and synthesized monodisperse sodium alginate/ACCP (Alginate/ACCP) composite nanoparticles in this paper. After ultrasonic treatment, nanoparticles with an average particle size less than 200 nm could form stable water dispersion that could be dispersed for up to 10 d. Based on the specific pH sensitivity of sodium alginate, the drug-controlled release performance of composite nanoparticles and the therapeutic effect of drug-loaded nanoparticles on A549 cancer cells were studied. The results indicated that under the same pH condition, the curcumin (Cur) release rate of composite nanoparticles gradually decreased with sodium alginate addition. When the dosage of sodium alginate was 1.0 mg ml-1, the cumulative drug release rate of nanoparticles in 40 h was only about 35%. Besides, the drug-loaded nanoparticles showed the excellent killing ability of cancer cells, and the survival rate of cancer cells decreased in a concentration-dependent manner. Therefore, through reasonable optimization design, we can synthesize composite nanoparticles with excellent sustained-release properties to provide a new strategy for cancer cells' long-term treatment.

20.
Front Oncol ; 11: 652560, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33869057

RESUMO

Background: The frequency of epidermal growth factor receptor (EGFR) mutations and the efficacy of tyrosine kinase inhibitor (TKI) in Chinese female patients with lung squamous cell carcinoma (SCC) are unknown. This study was designed to investigate the incidence of EGFR mutations and the role of targeted therapy in advanced Chinese female lung SCC patients. Methods: Advanced female patients diagnosed with lung SCC at the Shanghai Chest Hospital between January 2013 and December 2018 were retrospectively analyzed. Results: A total of 4223 advanced lung SCC patients were screened, and there were 154 female lung SCC patients who had underwent EGFR mutation detection. Positive EGFR mutations were found in 29.9% (46/154) of female lung SCC patients, including twenty-three 19del mutation (14.9%), twenty-one 21L858R mutation (13.6%) and other mutations (1.4%, 21861Q and 20ins). For 45 EGFR positive mutation female SCC patients, the median progression-free survival (PFS) of patients who received EGFR-TKI therapy (n=38) was 8.0 months (95% CI, 5.4-10.7 months), which was significantly longer than patients who were treated with chemotherapy (8.0 vs. 3.2 months, p=0.024), and the median overall survival (OS) was also longer (24.9 months vs. 13.9 months, p=0.020). The objective response rate (ORR) was 44.7% (17/38), and the disease control rate (DCR) was 81.6% (31/38). For 105 female SCC patients with EGFR negative mutation, the median OS was 18.6 months (95% CI, 14.2-22.9 months) and it was no different from that of EGFR positive mutation patients (18.6 vs. 22.8 months, p=0.377). Conclusion: For advanced Chinese female lung SCC patients with EGFR positive mutations, targeted therapy could confer longer PFS and OS than chemotherapy, but the survival was similar with patients who were negative EGFR mutations.

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