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1.
Hum Cell ; 34(1): 229-237, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33063235

RESUMO

Mounting evidence indicates that the long non-coding RNA (lncRNA) LINC00460 plays an oncogenic role in tumor progression; however, the role of LINC00460 in cervical cancer (CC) remains unknown. In this study, we found that LINC00460 was frequently upregulated in CC tissues and cell lines. Knockdown of LINC00460 repressed CC cell growth and invasion in vitro and attenuated tumorigenesis in vivo. Mechanistically, miR-361-3p was predicted as a direct target of LINC00460 by bioinformatics analysis, which was further confirmed by qRT-PCR, dual-luciferase reporter assays, and rescue experiments. Furthermore, miR-361-3p targeted the 3' untranslated region (UTR) of Gli1 mRNA and repressed its expression. Taken together, our study revealed that LINC00460 functions as an oncogenic lncRNA in CC, indicating the likely participation of the LINC00460/miR-361-3p/Gli1 pathway in the disease. Accordingly, our results provide new insight into CC tumorigenesis.

2.
Thorac Cancer ; 12(1): 30-39, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33111432

RESUMO

BACKGROUND: The role of adjuvant chemotherapy (ACT) for patients with stage IB-IIA non-small cell lung cancer (NSCLC) according to the eighth edition of the AJCC TNM staging system remains controversial. METHODS: Data were collected from patients with NSCLC stage IB-IIA according to the eighth edition of the AJCC TNM staging system who underwent surgical resection from 2008 to 2015. The relationship between ACT and overall survival (OS) or disease-free survival (DFS) was analyzed using the Kaplan-Meier method and Cox proportional hazards model. RESULTS: The study included 648 patients with completely resected NSCLC stage IB-IIA; 312 underwent ACT after surgical resection and 336 were placed under observation. After propensity score matching, 247 pairs of patients were matched and the five-year OS was 88.08% and 83.12% (P = 0.13) in ACT and non-ACT settings, respectively. Subgroup analyses demonstrated that ACT treatment was correlated with an improved five-year OS in patients with visceral pleural invasion (VPI) in the 3 < tumor ≤ 4 cm subgroup (93.98% and 68.93%, P < 0.01). CONCLUSIONS: ACT was not significantly associated with improved five-year OS in stage IB-IIA NSCLC patients. However, further subgroup analysis showed that patients with VPI in the 3 < tumor ≤ 4 cm (T2aN0M0, stage IB) subgroup might benefit more from ACT. Further studies are required to validate the findings and better systemic strategies need to be developed in these patients. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: For patients with stage IB-IIA NSCLC according to the eighth edition of the AJCC TNM staging system, the effect of ACT remains unclear. ACT was not significantly associated with improved five-year OS in stage IB-IIA NSCLC patients. However, it was correlated with better DFS before or after PSM. Patients with VPI in the 3 < tumor ≤ 4 cm subgroup may benefit from ACT. WHAT THIS STUDY ADDS: ACT was not significantly associated with improved five-year OS in stage IB-IIA NSCLC patients. However, it was correlated with better DFS before or after PSM. Patients with VPI in the 3 < tumor ≤ 4 cm subgroup may benefit from ACT.

3.
Thorac Cancer ; 12(1): 66-78, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33111503

RESUMO

BACKGROUND: The gut microbiome is important in the development and immunotherapy efficacy of lung cancer. However, the relationship between the intestinal flora and chemotherapy outcomes remains unclear and was investigated in this study. METHODS: We analyzed baseline stool samples from patients with locally advanced and advanced lung cancer before chemotherapy treatment, through metagenomics of the gut microbiota. The composition, diversity, function, and metabolic pathway analysis were compared among patients with different clinical outcomes. RESULTS: From 64 patients, 33 responded to treatment (responders) and 31 did not (nonresponders). Streptococcus mutans and Enterococcus casseliflavus were enriched in responders (P < 0.05), while 11 bacteria including Leuconostoc lactis and Eubacterium siraeum were enriched in nonresponders (P < 0.05) by variance analysis. Responders were associated with significantly higher Acidobacteria and Granulicella, while Streptococcus oligofermentans, Megasphaera micronuciformis, and Eubacterium siraeum were more abundant in nonresponders by Lefse analysis. Streptococcus mutans and Enterococcus casseliflavus were further identified as bacterial markers relevant to responders using unsupervised clustering, and Leuconostoc lactis and Eubacterium siraeum were related to nonresponders. The L-glutamate degradation VIII pathway was enriched in responders (P = 0.014), and the C4 photosynthetic carbon assimilation cycle, reductive TCA cycle I, and hexitol fermentation to lactate, formate, ethanol, and acetate were enriched in nonresponders (P < 0.05). Additionally, significant associations of bacterial species with clinical phenotypes were observed by Spearman correlation analysis. CONCLUSIONS: The specific gut microbiome of patients with lung cancer might be connected to the clinical outcomes of chemotherapy. KEY POINTS: Significant findings of the study Lung cancer patients with different gut microbiome compositions and microbiome metabolic pathways have different responses to chemotherapy. Microbiome species are also associated with different lung cancer clinical phenotypes. What this study adds We have identified specific gut microbiome species that can be used as relevant biomarkers for chemotherapy outcomes. This can potentially be used to guide clinical treatment decisions.

4.
World J Gastroenterol ; 26(42): 6638-6657, 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33268952

RESUMO

BACKGROUND: Colorectal cancer is a common digestive cancer worldwide. As a comprehensive treatment for locally advanced rectal cancer (LARC), neoadjuvant therapy (NT) has been increasingly used as the standard treatment for clinical stage II/III rectal cancer. However, few patients achieve a complete pathological response, and most patients require surgical resection and adjuvant therapy. Therefore, identifying risk factors and developing accurate models to predict the prognosis of LARC patients are of great clinical significance. AIM: To establish effective prognostic nomograms and risk score prediction models to predict overall survival (OS) and disease-free survival (DFS) for LARC treated with NT. METHODS: Nomograms and risk factor score prediction models were based on patients who received NT at the Cancer Hospital from 2015 to 2017. The least absolute shrinkage and selection operator regression model were utilized to screen for prognostic risk factors, which were validated by the Cox regression method. Assessment of the performance of the two prediction models was conducted using receiver operating characteristic curves, and that of the two nomograms was conducted by calculating the concordance index (C-index) and calibration curves. The results were validated in a cohort of 65 patients from 2015 to 2017. RESULTS: Seven features were significantly associated with OS and were included in the OS prediction nomogram and prediction model: Vascular_tumors_bolt, cancer nodules, yN, body mass index, matchmouth distance from the edge, nerve aggression and postoperative carcinoembryonic antigen. The nomogram showed good predictive value for OS, with a C-index of 0.91 (95%CI: 0.85, 0.97) and good calibration. In the validation cohort, the C-index was 0.69 (95%CI: 0.53, 0.84). The risk factor prediction model showed good predictive value. The areas under the curve for 3- and 5-year survival were 0.811 and 0.782. The nomogram for predicting DFS included ypTNM and nerve aggression and showed good calibration and a C-index of 0.77 (95%CI: 0.69, 0.85). In the validation cohort, the C-index was 0.71 (95%CI: 0.61, 0.81). The prediction model for DFS also had good predictive value, with an AUC for 3-year survival of 0.784 and an AUC for 5-year survival of 0.754. CONCLUSION: We established accurate nomograms and prediction models for predicting OS and DFS in patients with LARC after undergoing NT.

5.
J Immunother Cancer ; 8(2)2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33303576

RESUMO

BACKGROUND: Ephrin type-A receptors (EPHA) are members of family of receptor tyrosine kinases and are related to tumor immunogenicity and immune microenvironment, however, the association between EPHA mutation (EPHAmut ) and efficacy of immune checkpoint inhibitors (ICIs) has not been investigated in non-small cell lung cancer (NSCLC). METHODS: Multiple cohorts were used to assess the immunotherapeutic predictive performance of EPHAmut , including one discovery cohort (n=79) and two public validation cohort (cohort 1: NSCLC, n=165; cohort 2: pan-cancer, n=1662). The Cancer Genome Atlas cohort was used for prognostic analysis and mechanism exploration. RESULTS: In the discovery cohort, patients with EPHAmut had superior disease control rate (72.2% vs 36.1%, p=0.01) and progression-free survival (PFS) (HR 0.38; 95% CI 0.21 to 0.68; p<0.001) compared with those with wide-type EPHA (EPHAwt ) in NSCLC. The association between EPHAmut and immunotherapy outcomes in NSCLC was consistently observed in the validation cohorts by multivariable models (cohort 1, PFS HR 0.59; 95% CI 0.37 to 0.96; p=0.03; cohort 2, overall survival (OS) HR 0.63; 95% CI 0.41 to 0.98; p=0.04). Further pooled estimates of the discovery and validation cohorts showed that patients with EPHAmut exhibited a significantly longer PFS and OS in lung adenocarcinoma (LUAD) while not squamous cell lung cancer (LUSC). Consistently, mechanism analysis revealed that patients with EPHAmut was associated with increased T cell signatures and downregulated transforming growth factor-ß signaling compared with patients with EPHAwt in LUAD while not LUSC. CONCLUSIONS: Our results demonstrated that EPHAmut is an independent classifier that could stratify patients with LUAD for ICIs therapy. Further prospective studies are warranted. TRIAL REGISTRATION NUMBER: NCC2016JZ-03, NCC2018-092.

6.
NPJ Precis Oncol ; 4(1): 32, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33299121

RESUMO

Neoadjuvant immunotherapy provides a unique opportunity for understanding therapeutic responses. We analyzed pathologic responses in surgical specimens obtained from 31 squamous non-small cell lung cancer (NSCLC) patients receiving neoadjuvant anti-PD-1 treatment. Fifteen (48.4%) patients achieved pathologic complete response (pCR) or major pathologic response (MPR). Among them, seven (46.7%) were assessed as radiological partial response and eight (53.3%) as stable disease. Among 20 patients with pathologically identified tumor beds in lymph nodes (LNs), 10 and six patients achieved pCR/MPR in primary tumors and paired LNs, respectively. pCR was achieved in 6/19 N1 nodes and 1/7 N2 nodes. Residual viable tumor (RVT) cells in 8/9 MPR specimens had 100% immune-activated phenotype, while a median of 80% of RVT cells in pathologic nonresponse specimens presented immune-excluded/desert phenotype. These findings demonstrated that assessment of pathologic responses in both primary tumor and LNs may be important as a surrogate for assessing neoadjuvant immunotherapeutic efficacy.

7.
Front Immunol ; 11: 527750, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33324391

RESUMO

The drug resistance of first-line crizotinib therapy for ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion non-small cell lung cancer (NSCLC) is inevitable. Whether the administration of immune checkpoint inhibitor (ICI) therapy is suitable for ROS 1 fusion NSCLCs or after the development of crizotinib resistance is still unknown. In this study, five different crizotinib resistant concentration cell lines (HCC78CR1-5) from primary sensitive HCC78 cells were cultured. Ba/F3 cells expressing crizotinib sensitive ROS1 fusion and crizotinib resistant ROS1-G2032R mutation were used to explore the relationship between ROS1 fusion, ROS1-G2032R mutation and programmed death-ligand 1 (PD-L1) expression and the clinical potential of anti-PD-L1 ICI therapy. The signaling pathway net was compared between HCC78 and HCC78CR1-5 cells using RNA sequencing. Anti- PD-L1 ICI therapy was performed on mouse xenograft models with Ba/F3 ROS1 fusion or ROS1-G2032R mutation. HCC78CR1-5 showed more immunogenicity than HCC78 in immune-related pathways. The PD-L1 expression level was remarkably higher in HCC78CR1-5 with ROS1 fusion upregulation than HCC78 primary cell. Furthermore, the expression of PD-L1 was down-regulated by RNA interference with ROS1 siRNAs and up-regulated lower in Ba/F3 ROS1-G2032R resistant mutation than ROS1 fusion. Western blotting analysis showed the ROS1-SHP2 signaling pathway activation in HCC78CR1-5 cells, Ba/F3 ROS1 fusion and ROS1-G2032R resistant mutation. Mouse xenograft models with Ba/F3 ROS1 fusion showed more CD3+PD-1+ T cells both in blood and tissue, and more sensitivity than the cells with Ba/F3 ROS1-G2032R resistant mutation after anti-PD-L1 therapy. Our findings indicate that PD-L1 upregulation depends on ROS1 fusion more than ROS1-G2032R mutation. We share our insights of NSCLCs treatment management into the use of anti-PD-L1 ICI therapy in ROS1 fusion and not in ROS1-G2032R resistant mutation.

8.
J Thorac Oncol ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33166719

RESUMO

INTRODUCTION: Treatment options in the second-line extensive-stage SCLC (ED-SCLC) setting are limited. The PASSION study (ClinicalTrials.gov identifier: NCT03417895) was a phase 2 study of camrelizumab plus apatinib in ED-SCLC after platinum-based chemotherapy. METHODS: In stage I of the study, patients were randomized (1:1:1) to receive camrelizumab 200 mg every 2 weeks plus apatinib 375 mg once daily (QD), 5 days on and 2 days off, or 7 days on and 7 days off (six patients each cohort). On the basis of tolerability during the first 28-day cycle and efficacy data at stage I, one cohort was chosen to expand to 45 patients at stage II. The primary end point was objective response rate (ORR). RESULTS: From April 20, 2018 to March 12, 2019, a total of 59 patients were enrolled, with 47 patients in the QD cohort. In the QD cohort, confirmed ORR reached 34.0% (95% confidence interval: 20.9‒49.3), the median progression-free survival was 3.6 months, and the median overall survival was 8.4 months. Chemotherapy-sensitive and chemotherapy-resistant patients (defined as patients with disease relapse at ≥90 and <90 d after platinum-based chemotherapy, respectively) had comparable confirmed ORR (37.5% versus 32.3%), median progression-free survival (3.6 versus 2.7 mo), and median overall survival (9.6 versus 8.0 mo). Treatment-related adverse events of grade 3 or higher were reported in 43 of 59 patients (72.9%). Five patients (8.5%) discontinued because of treatment-related adverse events. CONCLUSIONS: Camrelizumab plus apatinib exhibited potential antitumor activity in patients with both chemotherapy-sensitive and chemotherapy-resistant ED-SCLC who had failed platinum-based chemotherapy with an acceptable toxicity profile. This phase 2 data warrant further clinical studies of camrelizumab plus apatinib in SCLC.

9.
Front Oncol ; 10: 573295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33251137

RESUMO

Colorectal cancer (CRC) is a common malignant tumor of the digestive tract and lacks specific diagnostic markers. In this study, we utilized 10 public datasets from the NCBI Gene Expression Omnibus (NCBI-GEO) database to identify a set of significantly differentially expressed genes (DEGs) between tumor and control samples and WGCNA (Weighted Gene Co-Expression Network Analysis) to construct gene co-expression networks incorporating the DEGs from The Cancer Genome Atlas (TCGA) and then identify genes shared between the GEO datasets and key modules. Then, these genes were screened via MCC to identify 20 hub genes. We utilized regression analyses to develop a prognostic model and utilized the random forest method to validate. All hub genes had good diagnostic value for CRC, but only CLCA1 was related to prognosis. Thus, we explored the potential biological value of CLCA1. The results of gene set enrichment analysis (GSEA) and immune infiltration analysis showed that CLCA1 was closely related to tumor metabolism and immune invasion of CRC. These analysis results revealed that CLCA1 may be a candidate diagnostic and prognostic biomarker for CRC.

10.
Rev Esp Enferm Dig ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33228365

RESUMO

A 41-year-old man presented to our hospital with a history of intermittent upper abdominal pain for several months. The patient had a significant surgical history of laparoscopic cholecystectomy (LC) at 1 year before. Gastroscopy revealed a foreign body penetrating the duodenal bulb wall, which resulted in chronic inflammatory changes in the surrounding tissues. Abdominal computed tomography (CT) examination revealed a 2-cm hyper-dense linear object embedded within the duodenal wall. It seemed to be a chronic perforation without significant free air or peritonitis. Given the location of the foreign body and the patient's strong will for less invasion, endoscopic removal was thought to be the optimal approach. Finally, the foreign body was successfully removed with forceps, which was proved to be the polymer clip (hem-o-lok) commonly used during laparoscopic surgery. Moreover, the site of perforation was closed with an endoscopic hemostatic clip to avoid further complications, such as bleeding and choledochoduodenal fistula. The symptoms in this patient were relieved postoperatively.

11.
Colloids Surf B Biointerfaces ; : 111480, 2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33250414

RESUMO

Lanthanide-doped upconversion nanoparticles (UCNPs) have attracted considerable attentions in the area of molecular imaging, targeted therapy and diagnosis. The UCNPs synthesized by conventional methods are usually hydrophobic and require additional surface modification to give them water solubility and biocompatibility. Herein, we designed a simple and convenient strategy for the direct synthesis of water-soluble and biocompatible lanthanum-doped UCNPs through a one-pot reaction without further purification and screening. The doping amount of lanthanide can be adjusted by simply changing the proportion of precursor in the reaction solution. The resulting water-soluble UCNPs possess excellent colloidal stability in physiological media. Under 980 nm excitation, NaGdF4:Yb3+/Er3+ and NaGdF4:Yb3+/Tm3+ nanoparticles exhibited a dominant green emission band (4S3/2→4I15/2) of Er3+ and a dominant blue emission band (1G4→3H6) of Tm3+, respectively. Toxic response was not observed with concentration up to 50 mg/L. The hemolysis to rabbit red blood cells was less than 2% in the concentration up to 20 mg/L. The NaGdF4:Yb3+/Er3+ nanoparticles exhibited a high r1 relaxivity of 4.7 mM-1s-1, demonstrating that the water-soluble and biocompatible UCNPs can be efficient T1 contrast agents. The in vivo results show that UCNPs exhibit excellent T1-weighted imaging and fluorescence imaging abilities simultaneously, and can be used as a versatile promising theranostic nanoplatform.

12.
Cancer Manag Res ; 12: 11351-11358, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192094

RESUMO

Immunotherapy provided with checkpoint inhibitors such as the programmed cell death-1 (PD-1) receptor or its ligand-1 (PD-L1) protein has been shown to be effective for treating several types of cancer, and was recently approved for use in treating malignant melanoma, advanced non-small cell lung cancer (NSCLC), urothelial carcinoma, head and neck squamous cell carcinoma, liver cancer, and additional forms of cancer. However, there is little evidence concerning its effectiveness in treating thymic squamous cell carcinoma (TSCC). Here, we report two cases of refractory TSCC that were treated with PD-1 single/combination therapy in a clinical setting. The patients exhibited variable responses to therapy without any serious adverse events. In summary, our findings show that immunotherapy provided with an immuno-checkpoint inhibitor in combination with chemotherapy/anti-angiogenesis therapy can improve the treatment response of patients with refractory TSCC. Anti-PD-1 single/combination therapy may be used as a strategy for treating advanced refractory TC.

13.
Neural Plast ; 2020: 8823111, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224190

RESUMO

High-frequency synchronization has been found in many real neural systems and is confirmed by excitatory/inhibitory (E/I) network models. However, the functional role played by it remains elusive. In this paper, it is found that high-frequency synchronization in E/I neuronal networks could improve the firing rate contrast of the whole network, no matter if the network is fully connected or randomly connected, with noise or without noise. It is also found that the global firing rate contrast enhancement can prevent the number of spikes of the neurons measured within the limited time window from being confused by noise, thereby enhancing the information encoding efficiency (quantified by entropy theory here) of the neuronal system. The mechanism of firing rate contrast enhancement is also investigated. Our work implies a possible functional role in information transmission of high-frequency synchronization in neuronal systems.

14.
ACS Appl Mater Interfaces ; 12(47): 52603-52614, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33174414

RESUMO

Modulating and optimizing the diverse parameters of photocatalysts synergistically as well as exerting these advantages fully in photocatalytic reactions are crucial for the sufficient utilization of solar energy but still face various challenges. Herein, a novel and facile urea- and KOH-assisted thermal polymerization (UKATP) strategy is first developed for the preparation of defect-modified thin-layered and porous g-C3N4 (DTLP-CN), wherein the thickness of g-C3N4 was dramatically decreased, and cyano groups, nitrogen vacancies, and mesopores were simultaneously introduced into g-C3N4. Importantly, the roles of thickness, pores, and defects can be targetedly modulated and optimized by changing the mass ratio of urea, KOH, and melamine. This can remarkably increase the specific area, improve the light-harvesting capability, and enhance separation efficiency of photoexcited charge carriers, strengthening the mass transfer in g-C3N4. Consequently, the photocatalytic hydrogen evolution efficiency of the DTLP-CN (1.557 mmol h-1 g-1, λ > 420 nm) was significantly improved more than 48.5 times with the highest average apparent quantum yield (AQY) of 18.5% and reached as high as 0.82% at 500 nm. This work provides an effective strategy for synergistically regulating the properties of g-C3N4, and opens a new horizon to design g-C3N4-based catalysts for highly efficient solar-energy conversion.

15.
JAMA Netw Open ; 3(10): e2013770, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33017026

RESUMO

Importance: Programmed cell death 1 (PD-1) antibodies have shown substantial survival benefit in patients with advanced non-small cell lung cancer (NSCLC). Toripalimab is a promising and practicable PD-1 antibody; however, its performance in NSCLC has not been established. Objectives: To assess the safety, antitumor activity, and pharmacokinetics of toripalimab in patients with advanced NSCLC and to evaluate the utility of JS311, a novel PD ligand 1 (PD-L1) immunohistochemistry (IHC) assay. Design, Setting, and Participants: This single-arm open-label phase 1 trial enrolled 41 patients with advanced NSCLC that had progressed after at least 3 lines of therapy between September 21, 2017, and June 5, 2018, with a median (interquartile range) follow-up of 14.9 (3.2-22.5) months and included a cohort study comparing JS311 with other PD-L1 IHC assays that included 280 NSCLC specimens collected from January 1, 2016, to May 21, 2018. Data collection was conducted from September 21, 2017, to September 27, 2019, and analysis was conducted from September 27, 2019, to December 30, 2019. Exposure: Enrolled patients were administered a single dose of toripalimab, under 2 manufacturing processes and scales (200 L and 500 L), for safety and pharmacokinetic analysis within 28 days, followed by subsequent multidose infusions every 2 weeks. PD-L1 expression was determined by IHC with JS311, comparing its results with results from 22C3, 28-8, and SP263 simultaneously. Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier curves, and continuous variables compared by t test or Mann-Whitney test. Correlations between PD-L1 IHC antibodies were evaluated by Spearman correlation test. Results: A total of 41 patients (29 [70.7%] men) with a median (interquartile range) age of 59 (53 to 63) years who experienced disease progression following chemotherapy were included. The most common treatment-related adverse events were rash (6 [14.6%]), increased amylase level (5 [12.2%]), and increased aspartate aminotransferase level (5 [12.2%]). In 35 patients included in the pharmacokinetic analysis, drug exposure and area under curve after 1 dose was similar under both manufacturing processes and scales (mean [SD] for 200-L group: 12 465.28 [4128.17] hour × µg/mL; for 500-L group: 12 331.42 [2472.58] hour × µg/ml). In 28 patients included in the response and survival analysis, the median PFS and OS were 2.8 (95% CI, 2.7 to 4.6) months and 13.8 months (95% CI, 10.0 months to not reached), respectively. Stratified by PD-L1 tumor proportion score of at least 50%, 1% to 49%, and less 1%, median PFS rates were 11.2 months (95% CI, 2.3 months to not evaluable), 2.3 (95% CI, 1.7 to 2.7) months, and 2.8 (95% CI, 2.7 to 4.6) months, respectively. A total of 4 anti-PD-L1 IHC antibodies were compared during PD-L1 staining, using 280 NSCLC specimens. The consistency rates between the 4 antibodies were 80.8% to 89.5% (ρ, 0.619 to 0.790) and 93.3% to 95.5% (ρ, 0.691 to 0.773), with PD-L1 tumor proportion scores of 1% and 50% as cut points, respectively. Conclusions and Relevance: In this study, toripalimab exhibited encouraging antitumor activity and manageable safety profiles among patients with heavily treated NSCLC. The novel PD-L1 IHC antibody JS311 was highly consistent with previously verified PD-L1 IHC assays.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacocinética , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Thorac Cancer ; 11(12): 3501-3509, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33075201

RESUMO

BACKGROUND: While prospective clinical studies on immunotherapy in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) are ongoing, this study aimed to investigate the outcomes of immunotherapy combinations in such a population in a real-world setting. METHODS: The clinical data of pretreated EGFR-mutated NSCLC patients who acquired EGFR-TKI resistance and received immunotherapy were retrospectively analyzed in this study. Progression-free survival (PFS) was assessed using the Kaplan-Meier log-rank test, and univariate and multivariate analysis were performed. RESULTS: A total of 31 patients were analyzed in this study. A total of 25 (80.6%) patients received combination immunotherapy. In the univariate analysis, patients who received combination immunotherapy seemingly acquired longer PFS than those who received monotherapy, although there was no significant difference (3.42 months vs. 1.61; P = 0.078; hazard ratio (HR) 0.43, 95% CI: 0.16-1.13). Patients who received antiangiogenic drugs prior to immunotherapy acquired better PFS (3.42 months vs. 1.58; P = 0.027; HR 0.37, 95% CI: 0.15-0.93), while patients with liver metastasis had inferior PFS (2.04 months vs. 3.42; P = 0.031; HR 2.83, 95% CI: 1.05-7.60). Furthermore, multivariate analysis confirmed that the above three factors had independent prognostic value. CONCLUSIONS: The study revealed that immunotherapy combinations are better choices than single-agent regimens in previously treated and EGFR-mutant NSCLC patients with progressive disease. In addition, antiangiogenic drugs administered before immunotherapy might be a favorable prognostic factor, while liver metastasis was associated with a short PFS in this setting. In future, more robust and prospective clinical trial results are expected to guide clinical practice. KEY POINTS: Significant study findings Immunotherapy-based combination therapies are better choices than single-agent regimens in heavily treated EGFR-mutant NSCLC patients. What this study adds Patients without liver metastasis and with prior antiangiogenic drugs obtained more benefit from immunotherapy in this setting.

17.
Phys Chem Chem Phys ; 22(41): 23735-23742, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33057521

RESUMO

The application of two-dimensional (2D) graphitic carbon-based materials in photocatalysis has been limited to date, because the nature and role of π-conjugated moieties in them remain unclear. Herein we propose and study bilayer BC3/C3N and BC3/BC6N van der Waals heterostructures as direct Z-scheme photocatalysts for overall water splitting using density functional theory calculations. The roles of polar π-conjugated moieties in the formation, stacking configuration, and electronic and optical properties of bilayer van der Waals heterostructures are discussed. It is shown that polar π-conjugated moieties of graphitic BCN monolayers lead to a favorable π-π interaction, determining the most stable stacking configuration, and a long-range charge transfer between components. The former makes the electronic band structure of heterostructures favor photocatalytic water splitting in efficiency and energetics. The latter generates a built-in electric field for the interface recombination of photogenerated electron-hole pairs, indicating a Z-scheme mechanism. The delocalized nature of π-conjugated electrons in monolayer components allows for high carrier mobility of bilayer heterostructures, promoting the photocatalytic reactions on graphitic BCN monolayers. These findings show that 2D π-conjugated materials, including graphitic carbon-based materials and biological systems, have great potential in the design and development of 2D metal-free direct Z-scheme photocatalysts for environmental purification and energy conversion.

18.
J Immunother Cancer ; 8(2)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33115941

RESUMO

BACKGROUND: The survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immunotherapy, collectively referred to as chemoimmunotherapy, for the treatment of squamous cell lung carcinoma (SQCLC) have been confirmed in recent clinical trials. Nevertheless, optimization of chemoimmunotherapy in order to enhance the efficacy of immune checkpoint inhibitors (ICIs) in SQCLC remains to be explored. METHODS: Cell lines, syngeneic immunocompetent mouse models, and patients' peripheral blood mononuclear cells were used in order to comprehensively explore how to enhance ectopic lymphoid-like structures (ELSs) and upregulate the therapeutic targets of anti-programmed death 1 (PD-1)/anti-PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), thus rendering SQCLC more sensitive to ICIs. In addition, molecular mechanisms underlying optimization were characterized. RESULTS: Low-dose chemotherapy contributed to an enhanced antigen exposure via the phosphatidylinositol 3-kinase/Akt/transcription factor nuclear factor kappa B signaling pathway. Improved antigen uptake and presentation by activated dendritic cells (DCs) was observed, thus invoking specific T cell responses leading to systemic immune responses and immunological memory. In turn, enhanced antitumor ELSs and PD-1/PD-L1 expression was observed in vivo. Moreover, upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and effectively synergized with anti-PD-1/PD-L1 mAbs. A possible mechanism underlying this synergy is the increase of activated type I macrophages, DCs, and cytotoxic CD8+ T cells, as well as the maintenance of intestinal gut microbiota diversity and composition. In contrast, when combining routine MTD chemotherapy with ICIs, the effects appeared to be additive rather than synergistic. CONCLUSIONS: We first attempted to optimize chemoimmunotherapy for SQCLC by investigating different combinatorial modes. Compared with the MTD chemotherapy used in current clinical practice, upfront metronomic chemotherapy performed better with subsequent anti-PD-1/PD-L1 mAb treatment. This combination approach is worth investigating in other types of tumors, followed by translation into the clinic in the future.

19.
Bioengineering (Basel) ; 7(4)2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33022929

RESUMO

Biomaterials to facilitate the restoration of cardiac tissue is of emerging importance. While there are many aspects to consider in the design of biomaterials, mechanical properties can be of particular importance in this dynamically remodeling tissue. This review focuses on one specific processing method, electrospinning, that is employed to generate materials with a fibrous microstructure that can be combined with material properties to achieve the desired mechanical behavior. Current methods used to fabricate mechanically relevant micro-/nanofibrous scaffolds, in vivo studies using these scaffolds as therapeutics, and common techniques to characterize the mechanical properties of the scaffolds are covered. We also discuss the discrepancies in the reported elastic modulus for physiological and pathological myocardium in the literature, as well as the emerging area of in vitro mechanobiology studies to investigate the mechanical regulation in cardiac tissue engineering. Lastly, future perspectives and recommendations are offered in order to enhance the understanding of cardiac mechanobiology and foster therapeutic development in myocardial regenerative medicine.

20.
Acta Physiol (Oxf) ; : e13567, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032360

RESUMO

AIMS: MOG1 is a small protein that can bind to small GTPase RAN and regulate transport of RNA and proteins between the cytoplasm and nucleus. However, the in vivo physiological role of mog1 in the heart needs to be fully defined. METHODS: Mog1 knockout zebrafish was generated by TALEN. Echocardiography, histological analysis, and electrocardiograms were used to examine cardiac structure and function. RNA sequencing and real-time RT-PCR were used to elucidate the molecular mechanism and to analyse the gene expression. Isoproterenol was used to induce cardiac hypertrophy. Whole-mount in situ hybridization was used to observe cardiac morphogenesis. RESULTS: Mog1 knockout zebrafish developed cardiac hypertrophy and heart failure (enlarged pericardium, increased nppa and nppb expression and ventricular wall thickness, and reduced ejection fraction), which was aggravated by isoproterenol. RNAseq and KEGG pathway analyses revealed the effect of mog1 knockout on the pathways of cardiac hypertrophy, dilatation and contraction. Mechanistic studies revealed that mog1 knockout decreased expression of tbx5, which reduced expression of cryab and hspb2, resulting in cardiac hypertrophy and heart failure. Overexpression of cryab, hspb2 and tbx5 rescued the cardiac oedema phenotype of mog1 KO zebrafish. Telemetry electrocardiogram monitoring showed QRS and QTc prolongation and a reduced heart rate in mog1 knockout zebrafish, which was associated with reduced scn1b expression. Moreover, mog1 knockout resulted in abnormal cardiac looping during embryogenesis because of the reduced expression of nkx2.5, gata4 and hand2. CONCLUSION: Our data identified an important molecular determinant for cardiac hypertrophy and heart failure, and rhythm maintenance of the heart.

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