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1.
J Thorac Oncol ; 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33588113

RESUMO

INTRODUCTION: By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in ALK-positive non-small-cell lung cancer (NSCLC) patients. METHODS: In a multicenter phase 2 trial, ALK-positive NSCLC patients who progressed on crizotinib were treated with ensartinib. Blood samples for ctDNA analysis were collected at baseline, cycle 3 day 1 (C3D1) and disease progression (PD) and analyzed with a 212-gene panel. RESULTS: 440 samples were collected from 168 patients. Baseline TP53 mutations (20.2%) significantly correlated with inferior PFS (4.2 months vs 11.7 months, p < 0.0001). Patients with TP53 mutations had higher mutation load than those without TP53 mutations at baseline (13.79 ± 3.72 vs 4.67 ± 0.39, p < 0.001). Although there was no significant difference in mutation load between these groups at C3D1 (5.89 ± 2.25 vs 3.72 ± 0.62, p = 0.425), patients with mutated TP53 developed more mutations at PD (7.07 ± 1.25 vs 3.20 ± 0.33, p = 0.003). Frequency and abundance of secondary ALK mutations G1269A, G1202R and E1210K increased significantly at PD than baseline. In patients without secondary ALK mutations, we identified ALK-independent resistance mechanisms including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation and epigenetic dysregulation. CONCLUSIONS: Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib.

2.
Food Funct ; 12(2): 791-801, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33393951

RESUMO

Probiotics and natural products can promote humoral transport and effectively relieve intestinal motility. This study investigated the effects of probiotics in combination with konjac glucomannan (KGM) and an aqueous extract of Prunus persica on constipation. The growth promotion effect of these natural products on probiotics was investigated using co-culture in vitro. The combined effect of probiotics and natural products on constipation was observed in mice. The tryptophan, tryptamine and short-chain fatty acid levels were determined using enzyme-linked immunosorbent assay, reverse-phase high-performance liquid chromatography, and gas chromatography. The key genes and proteins involved in humoral transport were identified using real-time polymerase chain reaction, western blotting and fluorescence immunoassay. KGM promoted the growth of Bifidobacterium animalis F1-7 in vitro, and a mixture of KGM and B. animalis F1-7 effectively promoted defaecation in mice, increased the faecal water content, shortened the defaecation time and improved the gastrointestinal transit rate. In mice, the KGM + F1-7 mixture reduced the tryptophan level and increased the levels of tryptamine, acetic acid, propionic acid, butyric acid and valeric acid. In addition, the KGM + F1-7 mixture effectively increased the mRNA level of 5-HT4-G-protein-coupled receptors (5-HT4GPCR)/mucins-2 (MUC-2) and reduced the level of aquaporins (AQP3); furthermore, it upregulated the protein level of 5-HT4GPCR/MUC-2 and downregulated the protein level of AQP3. These findings indicated that the KGM + F1-7 mixture effectively improved intestinal motility and alleviated constipation through humoral transport-related pathways.

3.
Cell Death Dis ; 12(1): 67, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431821

RESUMO

Imbalance of macrophage polarization plays an indispensable role in acute lung injury (ALI), which is considered as a promising target. Matrix metalloproteinase-9 (MMP-9) is expressed in the macrophage, and has a pivotal role in secreting inflammatory cytokines. We reported that saquinavir (SQV), a first-generation human immunodeficiency virus-protease inhibitor, restricted exaggerated inflammatory response. However, whether MMP-9 could regulate macrophage polarization and inhibit by SQV is still unknown. We focused on the important role of macrophage polarization in CLP (cecal ligation puncture)-mediated ALI and determined the ability of SQV to maintain M2 over M1 phenotype partially through the inhibition of MMP-9. We also performed a limited clinical study to determine if MMP-9 is a biomarker of sepsis. Lipopolysaccharide (LPS) increased MMP-9 expression and recombinant MMP-9 (rMMP-9) exacerbated LPS-mediated M1 switching. Small interfering RNA to MMP-9 inhibited LPS-mediated M1 phenotype and SQV inhibition of this switching was reversed with rMMP-9, suggesting an important role for MMP-9 in mediating LPS-induced M1 phenotype. MMP-9 messenger RNA levels in peripheral blood mononuclear cells of these 14 patients correlated with their clinical assessment. There was a significant dose-dependent decrease in mortality and ALI after CLP with SQV. SQV significantly inhibited LPS-mediated M1 phenotype and increased M2 phenotype in cultured RAW 264.7 and primary murine bone marrow-derived macrophages as well as lung macrophages from CLP-treated mice. This study supports an important role for MMP-9 in macrophage phenotypic switching and suggests that SQV-mediated inhibition of MMP-9 may be involved in suppressing ALI during systemic sepsis.

4.
Clin Transl Sci ; 2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33382908

RESUMO

To explore a better treatment strategy for patients with advanced non-small cell lung cancer harboring sensitive epidermal growth factor receptor mutations, a total of 271 patients were retrospectively analyzed. The patients were divided into two groups: the combination group (58 cases), which received concurrent icotinib, pemetrexed, and platinum treatment, and the sequential group (213 cases), which received the sequential pemetrexed and platinum therapy, followed by icotinib treatment. The primary end points were progression-free survival (PFS) and PFS on the subsequent line of therapy (PFS2). PFS in the combination group was significantly higher compared with that in the sequential group (16.89 months vs. 9.90 months; p < 0.001). PFS in the combination group was also significantly higher than PFS2 in the sequential group (16.89 months vs. 14.05 months; p = 0.009). The overall survival (OS) of the patients was 33.22 months (95% confidence interval (CI): 26.99-37.01) in the combination group and 26.47 months (95% CI: 25.05-26.95) in the sequential group (p < 0.001). The combination group's objective response rate was superior to that of the sequential group (79.31% vs. 52.11%; p < 0.001). Propensity score matching also revealed that icotinib therapy combined with chemotherapy extended the PFS, PFS2, and OS of the patients (p < 0.0001, p = 0.003, and p = 0.001, respectively). The combination group's objective response rate was also better compared with the sequential group (79.31% vs. 51.72%; p = 0.001). In conclusion, our study demonstrated icotinib combined with chemotherapy can improve survival efficacy better than the separated two-line therapy.

5.
Future Oncol ; 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33325251

RESUMO

Background: FRESCO study demonstrated efficacy and safety of fruquintinib in metastatic colorectal cancer patients. Impact of prior targeted therapy (PTT) on efficacy and safety of fruquintinib was evaluated. Materials & methods: In this subgroup analysis of FRESCO trial, patients were divided into PTT and non-PTT subgroups, and efficacy and safety of fruquintinib were assessed, respectively. Results: In non-PTT subgroup, fruquintinib significantly prolonged overall survival (OS) and progression free survival (PFS) of patients compared with placebo. In PTT subgroup, the median OS and PFS of patients in fruquintinib arm was significantly higher than those in placebo. Treatment-emergent adverse events (TEAEs) rates were similar in both subgroups. Conclusion: Fruquintinib demonstrated clinically meaningful improvement in OS, PFS, objective response rate, and disease control rate with manageable TEAEs in both subgroups. ClinicalTrial Registration: NCT02314819 (ClinicalTrials.gov).

6.
Inflammation ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188466

RESUMO

Following publication of our article [1], we noticed an error in the "Funding" section.

7.
Food Funct ; 11(11): 9903-9911, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33094788

RESUMO

Probiotics effectively regulated lipid metabolism and improved hyperlipidemia. The purpose of this study was to further evaluate the functions of lipid-lowering strains in vivo and elucidate the mechanism. The hyperlipidemia model was constructed using a high fat diet, and four lipid-lowering strains were selected for intervention. In the four strains, the strains Lactobacillus vaginalis FN3 (FN3) and Bifidobacterium animalis subsp. Lactis F1-7 (F1-7) reduced TG, TC and LDL and increased HDL. These two strains decreased TC and TC in the liver of high fat diet fed mice, and they increased total bile acids (TBA) in feces. F1-7 and FN3 reduced the mRNA levels of Farnesoid X Receptor (FXR), recombinant Fibroblast Growth Factor 15 (FGF 15) and Niemann-Pick C1-Like 1 (NPC1L1), and up-regulated the Liver X Receptor (LXR) mRNA level. They decreased the protein expressions of FXR and NPC1L1. In addition, F1-7 up-regulated the protein expression of cholesterol 7-alpha hydroxylase (CYP7A1). In summary, Bifidobacterium animalis subsp. Lactis F1-7 and Lactobacillus vaginalis FN3 could regulate bile acid metabolism by downregulating the FXR gene and reduce the absorption of exogenous cholesterol by regulating NPC1L1. F1-7 could also participate in the FXR/FGF15 pathway to improve hyperlipidemia, which showed better effects than FN3.

8.
Zhongguo Fei Ai Za Zhi ; 23(10): 845-851, 2020 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-33070513

RESUMO

BACKGROUND: Lung cancer is the leading cause of cancer-related death, and small cell lung cancer (SCLC) has a poor prognosis in all types of lung cancer. This study evaluated the relationship between pretreatment serum apolipoprotein levels and prognosis in patients with SCLC, seeks a new index can guide diagnosis and treatment of SCLC. METHODS: This study retrospectively analyzed the clinical data of 122 patients with SCLC. The clinical results of patients with serum apolipoprotein levels within 2 weeks before treatment were collected, including apolipoprotein AI (ApoA-I), apolipoprotein B (ApoB), and the ratio of apolipoprotein B to apolipoprotein AI (ApoB/ApoA-I). Patients' progression-free survival (PFS) and overall survival (OS) are the main outcome indicators. The best critical to determine the index's value by X-tile tool. For survival analysis, Kaplan-Meier method was used for analysis, and Cox regression analysis method was used for single factor analysis and multifactor analysis. RESULTS: Compared with patients with low ApoA-I levels, patients with high ApoA-I levels (ApoA-I>1.12 g/L) had better OS (21.5 mon vs 12.3 mon, P=0.007) and PFS (7.3 mon vs 5.5 mon, P=0.017). In contrast, patients with higher ApoB/ApoA-I levels had worse median OS than patients with lower ApoB/ApoA-I levels (13.4 mon vs 20.7 mon, P=0.012). Multivariate Cox regression analysis showed that ApoA-I was an independent prognostic factor affecting PFS in SCLC patients (HR=0.67, 95%CI: 0.45-0.99, P=0.043). ApoB/ApoA-I is an independent risk factor for OS in patients with SCLC (HR=1.98, 95%CI: 1.21-3.23, P=0.007). CONCLUSIONS: Serum ApoA-I level and ApoB/ApoA-I level before treatment can be important prognostic factors for SCLC, which is helpful to judge the prognosis of patients.

9.
Adv Ther ; 37(11): 4585-4598, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32901330

RESUMO

INTRODUCTION: In FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in Chinese patients with metastatic colorectal cancer (mCRC). However, its safety profile, including adverse events of special interest (AESIs) and treatment-emergent adverse events (TEAEs) by age, sex, and body mass index (BMI), is not well known. The present analysis evaluated the safety profile and AESIs for fruquintinib in the FRESCO trial. METHODS: In FRESCO, eligible Chinese patients were randomized (2:1) to receive fruquintinib (5 mg once daily for 3 weeks, followed by 1 week off in 28-day cycles) or placebo plus best supportive care. Treatment-related AESIs and time to first occurrence of AESIs were summarized. Treatment-related TEAEs by age, sex, and BMI were also summarized. RESULTS: A total of 266 patients (95.7%) in the fruquintinib group and 97 (70.8%) in the placebo group had at least one treatment-related TEAE; the mean relative dose intensity was 92% and 98%, respectively. In the fruquintinib group, the most common (in > 40% of patients) treatment-related AESIs were hypertension (55.4%), palmar-plantar erythrodysesthesia syndrome [known as hand-foot skin reaction (HFSR)] (49.3%), and proteinuria (42.1%). The most common treatment-related grade ≥ 3 AESIs (≥ 3% of patients) were hypertension (21.2%), HFSR (10.8%), and proteinuria (3.2%); the median time to onset of these events was 10, 21, and 20 days, respectively. Subgroup analysis by age, sex, and BMI revealed that the frequencies of treatment-related TEAEs were similar across all subgroups, and were consistent with the overall safety profile of fruquintinib. CONCLUSIONS: The most common treatment-related grade ≥ 3 AEs were hypertension, HFSR, and proteinuria. The treatment-related TEAE profile of fruquintinib in Chinese patents with mCRC was comparable among different subgroups and consistent with that reported in the overall population. TRIAL REGISTRATION: Clinical Trials identifier NCT02314819.

10.
Am J Clin Oncol ; 43(9): 607-614, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889829

RESUMO

OBJECTIVE: We aim to develop and validate an effective nomogram prognostic model for patients with typical lung carcinoid tumors using a large patient cohort from the Surveillance, Epidemiology, and End Results (SEER) database. MATERIALS AND METHODS: Data from patients with typical lung carcinoid tumors between 2010 and 2015 were selected from the SEER database for retrospective analysis. Univariate and multivariate Cox analysis was performed to clarify independent prognostic factors. Next, a nomogram was formulated to predict the probability of 3- and 5-year overall survival (OS). Concordance indexes (c-index), receiver operating characteristic analysis and calibration curves were used to evaluate the model. RESULTS: The selected patients were randomly divided into a training and a validation cohort. A nomogram was established based on the training cohort. Cox analysis results indicated that age, sex, T stage, N stage, surgery, and bone metastasis were independent variables for OS. All these factors, except surgery, were included in the nomogram model for predicting 3- and 5-year OS. The internally and externally validated c-indexes were 0.787 and 0.817, respectively. For the 3-year survival prediction, receiver operating characteristic analysis showed that the areas under the curve in the training and validation cohorts were 0.824 and 0.795, respectively. For the 5-year survival prediction, the area under the curve in the training and validation cohorts were 0.812 and 0.787, respectively. The calibration plots for probability of survival were in good agreement. CONCLUSION: The nomogram brings us closer to personalized medicine and the maximization of predictive accuracy in the prediction of OS in patients with typical lung carcinoid tumors.


Assuntos
Neoplasias Ósseas/secundário , Tumor Carcinoide/mortalidade , Neoplasias Pulmonares/mortalidade , Nomogramas , Fatores Etários , Idoso , Tumor Carcinoide/secundário , Feminino , Previsões/métodos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Probabilidade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos Retrospectivos , Programa de SEER , Fatores Sexuais , Taxa de Sobrevida , Estados Unidos/epidemiologia
11.
Minerva Anestesiol ; 86(11): 1170-1179, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32959628

RESUMO

BACKGROUND: Preliminary reports suggested that presepsin was a powerful biomarker for sepsis in a general population. However, presepsin levels change with age. This study aimed to investigate the diagnostic and prognostic value of presepsin among elderly patients with sepsis in the intensive care unit (ICU). METHODS: A total of 142 elderly patients were enrolled and assorted into three groups: non-infection, infection, and sepsis. Blood samples were collected on days 1, 3 and 7 during the first week of ICU stay for presepsin measurement. Diagnostic and prognostic utilities were tested by receiver operating characteristic, cutoff levels, Kaplan Meier survival curves and hazard ratios. RESULTS: The presepsin level on days 1 and 3 were significantly higher in sepsis compared with infection (P<0.01) and non-infection (P<0.01). The diagnostic area under the curve (AUC) of presepsin was comparable to that of procalcitonin (P>0.05) and higher than that of C-reactive protein or interleukin 6 (P<0.05) on days 1 and 3. In AUC and Kaplan-Meier survival curves, presepsin on day 3 showed a significant prognostic value for 30-day mortality but was not superior to other biomarkers. CONCLUSIONS: The presepsin level was significantly higher in elderly patients with sepsis compared with the non-infection and infection groups. Presepsin has a reliable early diagnostic ability for sepsis comparable to that of PCT. However, it cannot be defined as a perfect biomarker for prognosis of 30-day mortality in elderly patients. An overall and continual assessment of all the clinical indexes for sepsis during the course of the disease is necessary.

12.
Zhongguo Fei Ai Za Zhi ; 23(9): 824-829, 2020 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-32773011

RESUMO

In recent years, lung cancer has become the leading cause of cancer-related deaths. There is increasing evidence that many lipids and lipid analogs are key regulators of tumorigenesis, and factors that affect blood lipid levels such as smoking, diet, and obesity may be associated with cancer risk. With the deepening of research on the relationship between lipids and tumorigenesis, exploring the correlation between blood lipids and lung cancer risk and prognosis has become a research hotspot. This article reviews the research progress of the relationship between blood lipid levels and the risk of lung cancer, blood lipid levels and the prognosis of lung cancer patients, and the adjustment of blood lipid drugs and the prevention and treatment of lung cancer.
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13.
Nutrition ; 79-80: 110941, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32858376

RESUMO

OBJECTIVES: The purpose of this study was to explore the effect of trimethylamine (TMA)-degrading probiotic agents on trimethylamine oxide (TMAO) and the related lipid metabolism in mice. METHODS: Ten lipid-lowering strains were detected with TMA-degradation capacity in vitro. After probiotic intervention for the mice on a high-choline diet, TMA content in cecum and TMA and TMAO in serum was explored, as well as the expression of key gene flavin-containing monooxygenase 3 (FMO3) of the TMA-TMAO metabolism. The expression of genes related to the lipid metabolism was also investigated by real-time polymerase chain reaction and Western blot. Finally, the colonization of functional strains in the intestine were examined. RESULTS: Five of 10 lipid-lowering strains effectively degraded TMA in vitro, and the TMA level in the cecum of mice were reduced after probiotic intervention. TMA level and TMAO in serum were also significantly reduced by the strains (P < 0.05), but not due to the regulation of FMO3. Probiotic agents could improve the lipid metabolism by acting on the Farnesoid X receptor and cholesterol 7-alpha hydroxy-lase. Among the strains, Bifidobacterium animalis subsp. lactis F1-3-2 showed the most prominent performance and colonized in the cecum of mice. CONCLUSIONS: Bif. animalis subsp. lactis F1-3-2 could be colonized in the cecum, and might directly degrade TMA or change the structure of intestinal flora. The strain had an effect on TMA and TMAO levels in vivo by decreasing cecum TMA. The strain was demonstrated to participate in the TMA-TMAO regulation, improve the lipid metabolism, and alleviate atherosclerosis caused by TMAO. However, FMO3 had not changed in this process, and needs further study.

14.
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.

15.
Oncol Lett ; 20(2): 1101-1110, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32724349

RESUMO

Although the prognostic value of the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and lymphocyte/white blood cell ratio (LWR) has been described in advanced non-small cell lung cancer (NSCLC), the association between complete blood cell parameters prior to disease treatment and NSCLC have yet to be identified. The aim of the present study was to assess the complete blood cell parameters prior to disease treatment in patients with advanced NSCLC. A total of 268 patients with advanced NSCLC were enrolled in this study. Clinical and laboratory data of the patients were acquired through medical records. Receiver operating characteristic curve analysis was used to determine the optimal cut-off values of the neutrophil/white blood cell ratio (NWR), NLR, platelet/white blood cell ratio (PWR), PLR, monocyte/white blood cell ratio (MWR), monocyte/lymphocyte ratio (MLR) and LWR. Kaplan-Meier univariate and multivariate Cox regression analyses were used to evaluate the effect of complete blood parameters on progression-free survival (PFS) and overall survival (OS). The optimal cut-off values were identified as 0.67 for NWR, 2.85 for NLR, 37.23 for PWR, 166.56 for PLR, 0.074 for MWR, 0.31 for MLR and 0.24 for LWR. Univariate analysis revealed that sex (P=0.038), histological type (P<0.0001), NWR (P=0.026), NLR (P=0.044) and MLR (P=0.012) were all associated with PFS, whereas histological type (P=0.003), NWR (P=0.003), NLR (P=0.015), MLR (P=0.006) and LWR (P=0.043) were significantly associated with OS in patients with advanced NSCLC. Histological type (P=0.002) was an independent prognostic factor for PFS in patients with advanced NSCLC. Whereas histological type (P=0.005), NWR (P=0.005), NLR (P=0.014), MLR (P=0.006), and LWR (P=0.034) were independent prognostic factors for OS. Taken together, the present study identified high NWR, NLR and MLR, and low LWR as independent prognostic factors for poor OS in patients with NSCLC.

16.
J Dairy Sci ; 103(9): 7761-7774, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32622592

RESUMO

Triglycerides (TG) not only provide energy for infants but have important physiological functions. Understanding the composition and structure of TG in human milk is conducive to the development of infant formulas. In this study, TG species in human milk from 3 provincial capitals (Zhengzhou, Wuhan, and Harbin) in different regions of China were determined through C18 HPLC electrospray ionization tandem mass spectrometry (MS). The results showed that in human milk from these 3 regions, oleoyl-palmitoyl-linoleoylglycerol (OPL; 16.55, 19.20, and 18.67%, respectively) was more abundant than oleoyl-palmitoyl-oleoylglycerol (OPO; 10.08, 10.22, and 12.03%, respectively). Subsequently, regioisomeric and enantiomeric analysis of main TG in the human milk were performed on silver ion and chiral HPLC atmospheric pressure chemical ionization mass spectrometry (APCI)-MS, respectively. The results showed that rac-OPL (above 85%), rac-OPO (above 85%), rac-palmitoyl-oleoyl-oleoylglycerol (PPO; above 90%), and rac-OLaO (above 70%) were the main regioisomers of OPL, OPO, PPO, and lauroyl-oleoyl-oleoylglycerol (LaOO), respectively. The relative ratios of enantiomer pairs of rac-OPL (rac-OPL1 and rac-OPL2) were about 37 and 63%, respectively.

17.
Mol Ther Oncolytics ; 18: 109-117, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32671186

RESUMO

The relentless debate on postoperative adjuvant radiotherapy in gastric adenocarcinoma (GA) has been lasting for decades. In this study, a new biomarker, named promoter methylation burden of DNA repair genes (RPMB), was established to identify the subgroup of patients who might benefit from adjuvant radiotherapy. Methylation profiles of 397 GA tumor samples were downloaded from The Cancer Genome Atlas (TCGA). RPMB for a patient was defined as the ratio of methylated DNA repair genes to the number of all DNA repair genes. Subgroup analyses in term of overall survival (OS) and disease-free survival (DFS) indicated that most of the subgroups favored the high-RMPB group. Kaplan-Meier analysis showed that overall the patients with high RPMB after R0 resection had a significantly better clinical outcome regarding DFS (hazard ratio [HR] = 0.013, p = 0.042). Additionally, high-RPMB patients, who underwent adjuvant radiotherapy with both ≥T2 tumor and positive lymph nodes, showed superior DFS in comparison with the low-RPMB group (HR = 5.35 × 10-10, n = 26, p = 0.010). RPMB might be considered as a promising biomarker for decision-making with regard to postoperative adjuvant radiotherapy for GA patients.

18.
Acta Biochim Biophys Sin (Shanghai) ; 52(8): 853-863, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32556097

RESUMO

Clear cell renal cell carcinoma (ccRCC) is a common malignancy of the genitourinary system and is associated with high mortality rates. However, the molecular mechanism of ccRCC pathogenesis is still unclear, which translates to few effective diagnostic and prognostic biomarkers. In this study, we conducted a bioinformatics analysis on three Gene Expression Omnibus datasets and identified 437 differentially expressed genes (DEGs) related to ccRCC development and prognosis, of which 311 and 126 genes are respectively down-regulated and up-regulated. The protein-protein interaction network of these DEGs consists of 395 nodes and 1872 interactions and 2 prominent modules. The Staphylococcus aureus infection and complement and coagulation cascades are significantly enriched in module 1 and are likely involved in ccRCC progression. Forty-two hub genes were screened, of which von Willebrand factor, TIMP metallopeptidase inhibitor 1, plasminogen, formimidoyltransferase cyclodeaminase, solute carrier family 34 member 1, hydroxyacid oxidase 2, alanine-glyoxylate aminotransferase 2, phosphoenolpyruvate carboxykinase 1, and 3-hydroxy-3-methylglutaryl-CoA synthase 2 are possibly related to the prognosis of ccRCC. The differential expression of all nine genes was confirmed by quantitative real-time polymerase chain reaction analysis of the ccRCC and normal renal tissues. These key genes are potential biomarkers for the diagnosis and prognosis of ccRCC and warrant further investigation.

19.
J Pathol ; 251(2): 147-159, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32222046

RESUMO

Direct quantification of exhausted T cells in human cancer is lacking, and its predictive value for checkpoint-based treatment remains poorly investigated. We sought to systematically characterize the pan-cancer landscape and molecular hallmarks of T-cell dysfunction for the purpose of precision immunotherapy. Here, we defined a transcriptional signature for T-cell exhaustion through analyzing differential gene expression between PD-1-high and PD-1-negative CD8+ T lymphocytes from primary non-small cell lung cancer (NSCLC), followed by positive correlation tests with PDCD1 in TCGA lung carcinomas. A 78-gene signature for exhausted CD8+ T cells (GET) was identified and validated to reflect dysfunctional immune state spanning different species and disease models. We discovered that GET estimation significantly correlated with intratumoral immune cytolytic activity (CYT) and T-cell-inflamed gene expression profile (GEP) across 30 solid tumor types. Miscellaneous tumor-intrinsic and -extrinsic properties, in particular leukocyte proportions, genomic abnormalities, specific mutational signatures, and signaling pathways, were notably associated with GET levels. Furthermore, higher GET expression predicted an increased likelihood of clinical response to immune checkpoint inhibitors. These findings highlight the interrelation between T-cell exhaustion and immune cytolytic activity at the pan-cancer scale. The resulting inflamed tumor microenvironment may further crosstalk with other molecular and clinicopathological factors, which should be properly considered during immunotherapy biomarker development. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Adenocarcinoma de Pulmão/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Escamosas/imunologia , Citotoxicidade Imunológica , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/patologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transcriptoma
20.
Inflammation ; 43(2): 425-432, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32130574

RESUMO

Injurious mechanical ventilation has been shown to directly affect pulmonary and systemic immune responses. How these responses propagate or attenuate remains unknown. The goal of this study was to further determine whether toll-like receptor (TLR) 4 and WNT1-inducible signaling pathway protein 1 (WISP1) could contribute to injurious mechanical ventilation, especially focusing on the role of macrophages during experimental ventilator-induced lung injury. A prospective, randomized, and controlled animal study was designed, and male, wild-type (WT) C57BL/6 mice, TLR4 knockout (TLR4-/-), and lyzTLR4 knockout (lyzTLR4-/-) mice aging 8~12 weeks were used. Animals were anesthetized and randomized to spontaneous breathing (SB) group or to high tidal volume (VT, 20 ml/kg) mechanical ventilation (HTV) group. Histological evaluation, alveolar-capillary permeability of Evan's blue albumin (EBA), WISP1 protein levels, macrophage inflammatory protein-2 (MIP-2), and interleukin-6 (IL-6) in plasma and bronchoalveolar lavage fluid (BALF) concentrations were analyzed. HTV group was associated with a significant increase of WISP1 and EBA ratio in C57BL/6 mice, a significant decrease of WISP1 protein levels, and a significant decrease of IL-6, MIP-2 in plasma, and BALF concentrations of pro-inflammatory cytokines in TLR4-/- and lyzTLR4-/- knockout mice. In TLR4-/- mice and lyzTLR4-/- mice, there were also significant differences between SB group and HTV group in terms of H&E score and EBA ratio and level of pro-inflammation cytokines. The entire TLR4-targeted mice could further improve various inflammatory changes and damages when compared with lyzTLR4-targeted mice. What is more, TLR4-/- mice and lyzTLR4-/- mice reacted differently to rWISP1 and/or BMMC treated. TLR4-/- mice had no response to rWISP1, while lyzTLR4-/- mice still showed drastic response to both treatments. TLR4 and WISP1, especially the former one, on macrophages could contribute to releasing of pro-inflammatory cytokines during ventilator-induced lung injury. Injurious mechanical ventilation may result in an immune response which is similar to that of infection.

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