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2.
Theranostics ; 10(24): 11144-11158, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042275

RESUMO

Rationale: Radioresistance remains the major cause of local relapse and distant metastasis in lung cancer. However, the underlying molecular mechanisms remain poorly defined. This study aimed to investigate the role and regulatory mechanism of Cyclin K in lung cancer radioresistance. Methods: Expression levels of Cyclin K were measured by immunohistochemistry in human lung cancer tissues and adjacent normal lung tissues. Cell growth and proliferation, neutral comet and foci formation assays, G2/M checkpoint and a xenograft mouse model were used for functional analyses. Gene expression was examined by RNA sequencing and quantitative real-time PCR. Protein-protein interaction was assessed by immunoprecipitation and GST pull-down assays. Results: We report that Cyclin K is frequently overexpressed and correlates with poor prognosis in lung cancer patients. Functionally, we demonstrate that Cyclin K depletion results in reduced proliferation, defective G2/M checkpoint and enhanced radiosensitivity in lung cancer. Mechanistically, we reveal that Cyclin K interacts with and promotes the stabilization of ß-catenin protein, thereby upregulating the expression of Cyclin D1. More importantly, we show that Cyclin D1 is the major effector that mediates the biological functions of Cyclin K in lung cancer. Conclusions: These findings suggest that Cyclin K positively modulates the ß-catenin/Cyclin D1 axis to promote tumorigenesis and radioresistance in lung cancer, indicating that Cyclin K may represent a novel attractive biomarker for lung cancer radiotherapy.

3.
Cytokine ; 136: 155287, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32950027

RESUMO

Haemophilus parasuis induces severe acute systemic infection in pigs, characterized by fibrinous polyserositis, polyarthritis and meningitis. Our previous study demonstrated that H. parasuis induced the activation of p38 mitogen-activated protein kinase (MAPK) pathway, increasing the expression of proinflammatory genes and mediating H. parasuis-induced inflammation. Moreover, Wnt/ß-catenin signaling activation induced by H. parasuis disrupts the adherens junction between epithelial cells and initiates the epithelial-mesenchymal transition (EMT). In the present study, p38 MAPK was found to be involved in the accumulation of nuclear location of ß-catenin during H. parasuis infection in PK-15 and NPTr cells, via modulating the expression of dickkofp-1 (DKK-1), a negative regulator of Wnt/ß-catenin signaling. We generated DKK-1 knockout cell lines by CRISPR/Cas9-mediated genome editing in PK-15 and NPTr cells, and found that knockout of DKK-1 led to the dysfunction of p38 MAPK in regulating Wnt/ß-catenin signaling activity in H. parasuis-infected cells. Furthermore, p38 MAPK activity was independent of the activation of Wnt/ß-catenin signaling during H. parasuis infection. This is the first study to explore the crosstalk between p38 MAPK and Wnt/ß-catenin signaling during H. parasuis infection. It provides a more comprehensive view of intracellular signaling pathways during pathogenic bacteria-induced acute inflammation.

4.
Pestic Biochem Physiol ; 170: 104705, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980068

RESUMO

Magnolia officinalis, as a well-known herb worldwide, has been widely used to treat multiple diseases for a long time. In this study, the petroleum ether extract from M. officinalis showed effective antifungal activity against seven plant pathogens (particularly against R. solani with an inhibition rate of 100.00% at 250 µg/mL). Honokiol and magnolol, isolated by the bioassay-guided method, exhibited greater antifungal activity than tebuconazole (EC50 = 3.07 µg/mL, p ≤ 0.001) against R. solani, which EC50 values were 2.18 µg/mL and 3.48 µg/mL, respectively. We used transcriptomics to explore the mechanism of action of honokiol against R. solani. Results indicated that honokiol may exert antifungal effects by blocking the oxidative phosphorylation metabolic pathway. Further studies indicated that honokiol induced ROS overproduction, disrupted the mitochondrial function, affected respiration, and blocked the TCA cycle, which eventually inhibited ATP production. Besides, honokiol also damaged cell membranes and caused morphological changes. This study demonstrated that the lignans isolated from M. officinalis possess the potential to be developed as botanical fungicides.


Assuntos
Lignanas/farmacologia , Magnolia , Antifúngicos/farmacologia , Bioensaio , Compostos de Bifenilo
5.
PLoS Negl Trop Dis ; 14(8): e0008648, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866168

RESUMO

The phenomenon of COVID-19 patients tested positive for SARS-CoV-2 after discharge (redetectable as positive, RP) emerged globally. The data of incidence rate and risk factors for RP event and the clinical features of RP patients may provide recommendations for virus containment and cases management for COVID-19. We prospectively collected and analyzed the epidemiological, clinical and virological data from 285 adult patients with COVID-19 and acquired their definite clinical outcome (getting PCR positive or not during post-discharge surveillance). By March 10, 27 (9.5%) discharged patients had tested positive for SARS-CoV-2 in their nasopharyngeal swab after a median duration of 7·0 days (IQR 5·0-8·0). Compared to first admission, RP patients generally had milder clinical symptoms, lower viral load, shorter length of stay and improved pulmonary conditions at readmission (p<0.05). Elder RP patients (≥ 60 years old) were more likely to be symptomatic compared to younger patients (7/8, 87.5% vs. 3/19, 18.8%, p = 0.001) at readmission. Age, sex, epidemiological history, clinical symptoms and underlying diseases were similar between RP and non-RP patients (p>0.05). A prolonged duration of viral shedding (>10 days) during the first hospitalization [adjusted odds ratio [aOR]: 5.82, 95% confidence interval [CI]: 2.50-13.57 for N gene; aOR: 9.64, 95% CI: 3.91-23.73 for ORF gene] and higher Ct value (ORF) in the third week of the first hospitalization (aOR: 0.69; 95% CI: 0.50-0.95) were associated with RP events. In conclusion, RP events occurred in nearly 10% of COVID-19 patients shortly after the negative tests, were not associated with worsening symptoms and unlikely reflect reinfection. Patients' lack of efficiency in virus clearance was a risk factor for RP result. It is noteworthy that elder RP patients (≥ 60 years old) were more susceptible to clinical symptoms at readmission.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Feminino , Hospitalização , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pandemias , Alta do Paciente , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Estudos Prospectivos , Recidiva , Fatores de Risco , Eliminação de Partículas Virais , Adulto Jovem
6.
J Int Med Res ; 48(9): 300060520945500, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32962480

RESUMO

OBJECTIVE: To evaluate the clinical efficacy of an allogeneic bone cage (Biocage; Beijing Datsing Bio-Tech Co., Ltd., Beijing, China) for treatment of single-segment lumbar degenerative disease in patients with a high risk of non-fusion. METHODS: From January 2013 to December 2016, 67 patients who underwent lumbar fusion were divided into the Biocage group (n = 33) and polyether ether ketone (PEEK) group (n = 34). The patients were followed up for 24 to 48 months. The mean intervertebral height of the fusion level, fusion rate, height of the intervertebral foramen, visual analog scale score, and Oswestry disability index were compared. RESULTS: The PEEK group had a lower fusion rate than the Biocage group (88.24% vs. 90.91%), although the difference was not statistically significant. During follow-up, the height of the intervertebral space was similar between the Biocage and PEEK groups (12.88 ± 0.45 and 12.84 ± 1.01 mm, respectively). The height of the intervertebral foramen was larger in the Biocage than PEEK group (20.67 ± 1.34 vs. 20.00 ± 2.05 mm). Good clinical efficacy was achieved in both groups. CONCLUSION: The Biocage is efficient and safe for treatment of single-segment lumbar degenerative disease in patients with a high risk of non-fusion.

7.
Water Res ; 187: 116435, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32977188

RESUMO

In this study, ultrafiltration (UF) pre-oxidation with a boron-doped diamond (BDD) electrode was employed aiming to mitigate membrane fouling during algae-laden water treatment. It was found that BDD anodizing can efficiently alleviate membrane fouling regardless of the filtration membrane material when the oxidation time was over 30 min. This was because that the cake layer fouling resistance was highly mitigated by the pre-oxidation process. The generated small molecular organics after anodic oxidation might increase the potential of pore blockage. The anodizing preferentially oxidized hydrophobic organic and fluorescent substances, which is conducive to reducing membrane fouling and improving production efficiency. Besides, disinfection byproduct precursors and harmful algae derived substances of UF filtrated solution were contained. The algae bodies tend to agglomeration and the zeta potential obviously declined after the pretreatment, which is instrumental in forming a loose cake layer structure. In addition, the interaction force between membrane and foulants also converted to a repulsion force after pre-oxidation, which implies that BDD pre-oxidation was an effective way to mitigate cake layer fouling by reducing foulant-membrane interactions. At last, the secondary organic release of a dynamic formed cake layer was proved to be limited especially for living algae cells.

8.
Inorg Chem ; 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32886495

RESUMO

Reported here are two new heterometallic chalcogenide supraclusters ([Ga56Sb16S136] and [In36Sb6S75]), which present new self-assembly modes of basic supertetraheral clusters with the assistance of antimony ions. This work demonstrates the crucial role of the added metal ions with nontetrahedral coordination geometry in developing supertetrahedral-cluster-based supraclusters with a new level of complexity.

9.
Biomaterials ; 262: 120323, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32896816

RESUMO

Overcoming epithelial barriers to enhance drug absorption is a major challenge for nanoparticle (NP)-based mucosal delivery systems. With adequate physicochemical properties, the transepithelial delivery of NPs may be efficiently enhanced. However, little is known about the role of elasticity on the transport of NPs across the polarized epithelium, especially the processes and mechanisms of endocytosis, intracellular trafficking and exocytosis. In this study, we discovered that zwitterionic hydrogel NPs with varied elasticity displayed considerably different oral insulin absorption on diabetic rats. It was found that NP elasticity strongly shaped the transepithelial behaviors of NPs, and the increase of elasticity boosted the transcytosis by improving both endocytosis and exocytosis. Elasticity also showed a profound effect on the intracellular trafficking routes of NPs, which was closely related to distribution of NPs in exocytosis pathway and their intra-endosome sphere-to-ellipsoid shape transformation. Importantly, NPs with zwitterionic surface experienced more efficient basolateral exocytosis than apical exocytosis, while the elasticity-related exocytosis enhancement appeared to be non-selective. Therefore, tailored elasticity could promote mucosal transcytosis of NPs, which was able to be further improved with biomimetic zwitterionic surface. This study may provide important knowledge for the design of functional nanovehicles to efficiently overcome mucosal epithelial barriers in the future.

10.
Virulence ; 11(1): 1279-1292, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32962530

RESUMO

The twin-arginine translocation (Tat) system is involved in a variety of important bacterial physiological processes. Conserved among bacteria and crucial for virulence, the Tat system is deemed as a promising anti-microbial drug target. However, the mechanism of how the Tat system functions in bacterial pathogenesis has not been fully understood. In this study, we showed that the Tat system was critical for the virulence of an extra-intestinal pathogenic E. coli (ExPEC) strain PCN033. A total of 20 Tat-related mutant strains were constructed, and competitive infection assays were performed to evaluate the relative virulence of these mutants. The results demonstrated that several Tat substrate mutants, including the ΔsufI, ΔamiAΔamiC double mutant as well as each single mutant, ΔyahJ, ΔcueO, and ΔnapG, were significantly outcompeted by the WT strain, among which the ΔsufI and ΔamiAΔamiC strains showed the lowest competitive index (CI) value. Results of individual mouse infection assay, in vitro cell adhesion assay, whole blood bactericidal assay, and serum bactericidal assay further confirmed the virulence attenuation phenotype of the ΔsufI and ΔamiAΔamiC strains. Moreover, the two mutants displayed chained morphology in the log phase resembling the Δtat and were defective in stress response. Our results suggest that the Tat system and its dependent cell division proteins SufI, AmiA, and AmiC play critical roles during ExPEC pathogenesis.

11.
Phys Chem Chem Phys ; 22(36): 20189-20201, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32966415

RESUMO

Recent experiments have provided unprecedented details on the hierarchical organization of the chromatin 3D structure and thus a great opportunity for understanding the mechanisms behind chromatin folding. As a bridge between experimental results and physical theory, coarse-grained polymer models of chromatin are of great value. Here, we review several popular models of chromatin folding, including the fractal globule model, loop models (the random loop model, the dynamic loop model, and the loop extrusion model), the string-and-binder switch model, and the block copolymer model. Physical models are still in great need to explain a larger variety of chromatin folding properties, especially structural features at different scales, their relation to the heterogeneous nature of the DNA sequence, and the highly dynamic nature of chromatin folding.

12.
Brief Bioinform ; 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32898860

RESUMO

Prognostic tests using expression profiles of several dozen genes help provide treatment choices for prostate cancer (PCa). However, these tests require improvement to meet the clinical need for resolving overtreatment, which continues to be a pervasive problem in PCa management. Genomic selection (GS) methodology, which utilizes whole-genome markers to predict agronomic traits, was adopted in this study for PCa prognosis. We leveraged The Cancer Genome Atlas (TCGA) database to evaluate the prediction performance of six GS methods and seven omics data combinations, which showed that the Best Linear Unbiased Prediction (BLUP) model outperformed the other methods regarding predictability and computational efficiency. Leveraging the BLUP-HAT method, an accelerated version of BLUP, we demonstrated that using expression data of a large number of disease-relevant genes and with an integration of other omics data (i.e. miRNAs) significantly increased outcome predictability when compared with panels consisting of a small number of genes. Finally, we developed a novel stepwise forward selection BLUP-HAT method to facilitate searching multiomics data for predictor variables with prognostic potential. The new method was applied to the TCGA data to derive mRNA and miRNA expression signatures for predicting relapse-free survival of PCa, which were validated in six independent cohorts. This is a transdisciplinary adoption of the highly efficient BLUP-HAT method and its derived algorithms to analyze multiomics data for PCa prognosis. The results demonstrated the efficacy and robustness of the new methodology in developing prognostic models in PCa, suggesting a potential utility in managing other types of cancer.

13.
Dalton Trans ; 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32936156

RESUMO

Dye photodegradation is an important research topic, and great efforts have been made to target the photocatalysts with highly efficient and selective performance. Reported here are two layered anion chalcogenide frameworks with semiconducting properties combined with highly open interlayer spaces, which are used as efficient photocatalysts to show excellent size and charge selectivity towards organic dye molecules. In addition, the organic templates inside the chalcogenide frameworks are exchanged via an ion-exchange process, and the resulting host frameworks with much looser internal spaces play significant roles in improving the photocatalytic activity.

14.
Sci Total Environ ; 747: 141472, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32795804

RESUMO

Cadaver decomposition as high-quality nutrient inputs may exert strong perturbation on the aquatic environments, such as high nitrogen or nitrate pollution. Denitrifying bacteria may reduce nitrate to nitrogen gas, thereby decreasing the nitrogen pollution and improving self-purification ability of aquatic ecosystem. However, how nirK denitrifying communities in water respond to cadaver decomposition remains unknown. Thus, we employed high-throughput sequencing and chemical analysis to investigate the succession of nirK-type denitrifying communities in tap water and Yellow river water (experimental groups) as well as their corresponding control groups during two important stages of fish corpse decomposition called advanced floating decay and sunken remains. Our data showed that the concentration of NH4+-N in the experimental groups increased approximately 3-4 times compared with the control groups. Proteobacteria was the predominant phylum for nirK denitrifying communities. Several potential pathogenic genera, such as Brucella and Achromobacter, were enriched in the corpse groups. Notably, nirK-type community structures were significantly impacted by cadaver decomposition. Community structures in the corpse groups become more similar with succession, indicating community convergence at the final stage. Water pH, oxidation-reduction potential (ORP) and treatment were three important factors affecting the community structures. However, water type was not a main driving factor determining carcass-associated nirK-type bacterial communities. Four phylogenetic clusters were detected in the denitrifying communities, but showed significantly different distribution between the corpse and control groups. These results provide an in-depth understanding for nirK denitrifying functional bacteria and potential pathogenic bacteria during carrion decomposition process, which offer valuable reference to environmental evaluation and management.

15.
Medicine (Baltimore) ; 99(31): e21597, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756215

RESUMO

INTRODUCTION: Since the coronavirus disease 2019 (COVID-19) outbreak in Wuhan in late 2019, controversy on the use of corticosteroids for COVID-19 has obtained increasing attention. We present 1 critically ill patient who had a rapid therapeutic response to moderate-dose corticosteroids. PATIENT CONCERNS: A 53-year-old critically ill woman from Wuhan suffered with COVID-19. DIAGNOSIS: The chest computed tomography scan was suggestive of COVID-19. The diagnosis was confirmed by a real-time reverse transcription polymerase chain reaction test for SARS-CoV-2. The critically ill status was characterized by worsening dyspnea, progressing bilateral lung consolidation, and poor oxygenation (SiO2/FiO2:110 mm Hg). INTERVENTIONS: The patient was treated with a moderate dose of intravenous corticosteroids and high-flow nasal cannula oxygen therapy. OUTCOMES: After the initiation of corticosteroids, the patient rapidly improved over the following 6 days. Serial chest computed tomography scans showed good absorption of the consolidations. The patient was discharged on Day 17 of hospitalization without obvious adverse effects. CONCLUSIONS: Early use of moderate-dose corticosteroids over a short period may enhance recovery from COVID-19 in critically ill patients.


Assuntos
Corticosteroides/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Oxigenoterapia/métodos , Pneumonia Viral/tratamento farmacológico , Betacoronavirus , Terapia Combinada , Infecções por Coronavirus/virologia , Feminino , Humanos , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Resultado do Tratamento
16.
FEMS Microbiol Lett ; 367(16)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32840567

RESUMO

The Qinghai-Tibet Plateau is a harsh environment characterized by low temperature, high altitude and hypoxia, although some native mammals may adapt well to the extreme climate. However, how animal gut microbial community structure and function adapt to extreme cold climates is not well understood. Plateau pika (Ochotona curzoniae) is an ideal animal model with which to study the effects of climate change on host adaptation by studing intestinal microorganisms. Here, we used 16S rRNA sequencing technology combined with physiological methods to investigate plateau pika gut microbiota in summer and winter. Due to limited diet resources, the pikas in winter have a lower ability of degradation and fermentation for plant-based food (reduced cellulase activity and total short-chain fatty acids) by decreasing gut microbial diversity and some functional microbes, such as fiber-degrading bacteria Oscillospira and Treponema. Metagenomic prediction showed that most of those gene functions associated with metabolism (e.g. energy metabolism and lipid metabolism) were less abundant in winter, implying that the plateau pika slows diet fermentation and weakens energy requirements in the cold season. Our results have significance for explaining the mechanism of wild plateau mammals adapting to a high-altitude cold environment from the perspective of gut microbiome.

17.
Front Immunol ; 11: 1418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32774335

RESUMO

Long non-coding RNAs are essential regulators of the inflammatory response, especially for transcriptional regulation of inflammatory genes. It has been reported that the expression of transmembrane channel-like 3 (TMC3)-AS1 is increased following lipopolysaccharide stimulation. However, the potential function of TMC3-AS1 in immunity is largely unknown. Herein, we report a specific role for TMC3-AS1 in the regulation of inflammatory gene expression. TMC3-AS1 negatively regulates the expression of interleukin 10 (IL-10) in macrophage and intestinal epithelial cell lines. Mechanistically, TMC3-AS1 may interact with p65 in the nucleus, preventing p65 from binding to the κB consensus site within IL-10 promoter. These findings suggest that TMC3-AS1 may function as an important regulator in the innate immune response.

18.
Ecotoxicol Environ Saf ; 204: 111083, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32791359

RESUMO

Due to the accumulation of heavy metals in soil ecosystems, the response of soil microorganisms to the disturbance of heavy metals were widely studied. However, little was known about the interactions among microorganisms in heavy metals and total petroleum hydrocarbons (TPH) co-contaminated soils. In the present study, the microbiota shifts of 2 different contamination types of heavy metal-TPH polluted soils were investigated. NGS sequencing approach was adopted to illustrate the microbial community structure and to predict community function. Networks were established to reveal the interactions between microbes and environmental pollutants. Results showed that the alpha diversity and OTUs number of soil microbiota were reduced under heavy metals and TPH pollutants. TPH was the major pollutant in HT1 group, in which Proteobacteria phylum increased significantly, including Arenimonas genus, Sphingomonadaceae family and Burkholderiaceae family. Moreover, the function structures based on the KEGG database of HT1 group was enriched in the benzene matter metabolism and bacterial motoricity in microbiota. In contrast, severe Cr-Pb-TPH co-pollutants in HT2 increased the abundance of Firmicutes. In details, the relative abundance of Streptococcus genus and Bacilli class raised sharply. The DNA replication functions in microbiota were enriched under severely contaminated soil as a result of high concentrations of heavy metals and TPH pollutants' damage to bacteria. Furthermore, according to the correlation analysis between microbes and the pollutants, Streptococcus, Neisseria, Aeromonas, Porphyromonas and Acinetobacter were suggested as the bioremediation bacteria for Cr and Pb polluted soils, while Syntrophaceae spp. and Immundisolibacter were suggested as the bioremediation bacteria for TPH polluted soil. The study took a survey on the microbiota shifts of the heavy metals and TPH polluted soils, and the microbe's biomarkers provided new insights for the candidate strains of biodegradation, while further researches are required to verify the biodegradation mechanism of these biomarkers.

19.
Genes (Basel) ; 11(8)2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32824735

RESUMO

Porcine ß-defensin 2 (PBD-2), expressed by different tissues of pigs, is a multifunctional cationic peptide with antimicrobial, immunomodulatory and growth-promoting abilities. As the latest generation of genome-editing tool, CRISPR/Cas9 system makes it possible to enhance the expression of PBD-2 in pigs by site-specific knock-in of pbd-2 gene into the pig genome. In this study, we aimed to generate marker-free pbd-2 knock-in pigs using the CRISPR/Cas9 and Cre/loxP systems. Two copies of pbd-2 gene linked by a T2A sequence were inserted into the porcine Rosa26 locus through CRISPR/Cas9-mediated homology-directed repair. The floxed selectable marker gene neoR, used for G418 screening of positive cell clones, was removed by cell-penetrating Cre recombinase with a recombination efficiency of 48.3%. Cloned piglets were produced via somatic cell nuclear transfer and correct insertion of pbd-2 genes was confirmed by PCR and Southern blot. Immunohistochemistry and immunofluorescence analyses indicated that expression levels of PBD-2 in different tissues of transgenic (TG) piglets were significantly higher than those of their wild-type (WT) littermates. Bactericidal assays demonstrated that there was a significant increase in the antimicrobial properties of the cell culture supernatants of porcine ear fibroblasts from the TG pigs in comparison to those from the WT pigs. Altogether, our study improved the protein expression level of PBD-2 in pigs by site-specific integration of pbd-2 into the pig genome, which not only provided an effective pig model to study the anti-infection mechanisms of PBD-2 but also a promising genetic material for the breeding of disease-resistant pigs.

20.
J Thorac Oncol ; 15(10): 1636-1646, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32781263

RESUMO

INTRODUCTION: Sintilimab, an anti-programmed death 1 antibody, plus pemetrexed and platinum had revealed promising efficacy for nonsquamous NSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to compare the efficacy and safety of sintilimab with placebo, both in combination with such chemotherapy (ClinicalTrials.gov: NCT03607539). METHODS: A total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC without sensitizing EGFR or anaplastic lymphoma kinase genomic aberration were randomized (2:1 ratio) to receive either sintilimab 200 mg or placebo plus pemetrexed and platinum once every 3 weeks for four cycles, followed by sintilimab or placebo plus pemetrexed therapy. Crossover or treatment beyond disease progression was allowed. The primary end point was progression-free survival (PFS) as judged by an independent radiographic review committee. RESULTS: As of November 15, 2019, the median follow-up was 8.9 months. The median PFS was significantly longer in the sintilimab-combination group than that in the placebo-combination group (8.9 versus 5.0 mo; hazard ratio, 0.482, 95% confidence interval [CI]: 0.362-0.643; p < 0.00001). The confirmed objective response rate was 51.9% (95% CI: 45.7%-58.0%) in the sintilimab-combination group and 29.8% (95% CI: 22.1%-38.4%) in placebo-combination group. The incidence of grade 3 or higher adverse events was 61.7% in sintilimab-combination group and 58.8% in placebo-combination group. CONCLUSIONS: In Chinese patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, the addition of sintilimab to chemotherapy with pemetrexed and platinum resulted in considerably longer PFS than with chemotherapy alone with manageable safety profiles.

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