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Objective: To evaluate the safety and antitumor activity of envafolimab monotherapy in Chinese patients with advanced solid tumors. Methods: This open-label, multicenter phase I trial included dose escalation and dose expansion phases. In the dose escalation phase, patients received subcutaneous 0.1, 0.3, 1.0, 2.5, 5.0 or 10.0 mg/kg envafolimab once weekly (QW) following a modified "3+ 3" design. The dose expansion phase was performed in the 2.5 mg/kg and 5.0 mg/kg (QW) dose cohorts. Results: At November 25, 2019, a total of 287 patients received envafolimab treatment. During the dose escalation phase, no dose-limiting toxicities (DLT) was observed. In all dose cohorts, drug-related treatment-emergent adverse events (TEAEs) for all grades occurred in 75.3% of patients, and grade 3 or 4 occurred in 20.6% of patients. The incidence of immune-related adverse reactions (irAE) was 24.0% for all grades, the most common irAEs (≥2%) included hypothyroidism, hyperthyroidism, immune-associated hepatitis and rash. The incidence of injection site reactions was low (3.8%), all of which were grades 1-2. Among the 216 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 11.6% and 43.1%, respectively. Median duration of response was 49.1 weeks (95% CI: 24.0, 49.3). Pharmacokinetic (PK) exposure to envafolimab is proportional to dose and median time to maximum plasma concentration is 72-120 hours based on the PK results from the dose escalation phase of the study. Conclusion: Subcutaneous envafolimab has a favorable safety and promising preliminary anti-tumor activity in Chinese patients with advanced solid tumors.
Sujets)
Humains , Peuples d'Asie de l'Est , Tumeurs/anatomopathologie , Anticorps monoclonaux humanisés/usage thérapeutiqueRésumé
Objective: To evaluate the safety and antitumor activity of envafolimab monotherapy in Chinese patients with advanced solid tumors. Methods: This open-label, multicenter phase I trial included dose escalation and dose expansion phases. In the dose escalation phase, patients received subcutaneous 0.1, 0.3, 1.0, 2.5, 5.0 or 10.0 mg/kg envafolimab once weekly (QW) following a modified "3+ 3" design. The dose expansion phase was performed in the 2.5 mg/kg and 5.0 mg/kg (QW) dose cohorts. Results: At November 25, 2019, a total of 287 patients received envafolimab treatment. During the dose escalation phase, no dose-limiting toxicities (DLT) was observed. In all dose cohorts, drug-related treatment-emergent adverse events (TEAEs) for all grades occurred in 75.3% of patients, and grade 3 or 4 occurred in 20.6% of patients. The incidence of immune-related adverse reactions (irAE) was 24.0% for all grades, the most common irAEs (≥2%) included hypothyroidism, hyperthyroidism, immune-associated hepatitis and rash. The incidence of injection site reactions was low (3.8%), all of which were grades 1-2. Among the 216 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 11.6% and 43.1%, respectively. Median duration of response was 49.1 weeks (95% CI: 24.0, 49.3). Pharmacokinetic (PK) exposure to envafolimab is proportional to dose and median time to maximum plasma concentration is 72-120 hours based on the PK results from the dose escalation phase of the study. Conclusion: Subcutaneous envafolimab has a favorable safety and promising preliminary anti-tumor activity in Chinese patients with advanced solid tumors.
Sujets)
Humains , Peuples d'Asie de l'Est , Tumeurs/anatomopathologie , Anticorps monoclonaux humanisés/usage thérapeutiqueRésumé
<p><b>OBJECTIVE</b>This study was designed to clarify the significance of DNA methylation in the expression of runt-related transcription factor 3 (Runx3) gene.</p><p><b>METHODS</b>Reverse transcription-PCR (RT-PCR) was used to measure the expression level of Runx3 mRNA in paired samples of primary gastric cancer and corresponding non-cancerous gastric mucosa, taken from surgical specimens of 70 gastric cancer patients. Western blot was used to detect the protein expression level of Runx3 gene. The promoter methylation status of Runx3 gene was detected by methylation specific PCR (MSP). Furthermore, RT-PCR was used to mesure the expression of DNA methyltransferase 1 (Dnmtl) mRNA . The correlation of Runx3 expression and methylation with Dnmt1 mRNA expression was analyzed.</p><p><b>RESULTS</b>The mRNA expression level of Runx3 gene was significantly lower in gastric cancer than that in the matched normal gastric mucosa (0.5740 +/- 0.3580 vs. 1.7250 +/- 0.4080, P < 0.05), and the Runx3 protein expression level in gastric cancer was also significantly lower than that in the matched normal gastric mucosa (P < 0.05). Promoter hypermethylation of Runx3 gene was detected in 50.0% (28/56) of the gastric cancer samples, which resulted in a reduced expression of Runx3 mRNA. It was found that the mRNA expression level of Dnmt1 gene was significantly higher in the gastric cancer tissues with methylated Runx3 gene than that in the ones without. There was a significant correlation of Runx3 gene methylation with increased expression of Dnmtl mRNA (r = 0.64, P < 0.05).</p><p><b>CONCLUSION</b>The promoter hypermethylation may be one of the predominant inactivation mechanisms of the runt-related transcription factor 3 gene, and may be associated with carcinogenesis of human gastric cancer. Reduced Runx3 expression in gastric cancer may be partially correlated with a high level of DNA methyltransferase 1.</p>
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Adulte , Sujet âgé , Femelle , Humains , Mâle , Adulte d'âge moyen , Jeune adulte , Adénocarcinome , Génétique , Métabolisme , Sous-unité alpha 3 du facteur CBF , Génétique , Métabolisme , DNA (Cytosine-5-)-methyltransferase 1 , DNA (cytosine-5-)-methyltransferase , Génétique , Méthylation de l'ADN , Régulation négative , Régulation de l'expression des gènes tumoraux , Régions promotrices (génétique) , ARN messager , Métabolisme , Tumeurs de l'estomac , Génétique , MétabolismeRésumé
<p><b>OBJECTIVE</b>To study the relationship between monocyte chemoattractant protein-1 gene (MCP-1) -2518A/G polymorphism and acute pancreatitis (AP) in the Han population of Suzhou, China.</p><p><b>METHODS</b>The polymorphisms were detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The genotypes and allele frequencies of MCP-1 -2518A/G were calculated and analyzed in 101 AP patients including 78 mild AP (MAP) patients and 23 severe AP (SAP) patients, and 120 healthy individuals as control group.</p><p><b>RESULTS</b>The frequency of MCP-1 -2518 AA genotype in control group was significantly higher than that in SAP and MAP groups (P < 0.01). People with AG and GG genotypes had 5.896 times risk of developing MAP (P < 0.01, OR=5.896) compared with people with AA genotype. Subjects carrying G allele were at a 7-fold elevated risk for SAP (P < 0.05, OR=7.011) contrasted with subjects carrying AA genotype. However, no difference in AA genotypic distribution was noted between MAP and SAP groups (chi square=0.006, P=0.997). The frequency of G allele in healthy controls was obviously lower than that in MAP (P < 0.01, OR=0.318) and SAP groups (P < 0.01, OR=0.309). No difference of G allele frequency was found between SAP group and MAP group (P=0.623, OR=1.211).</p><p><b>CONCLUSION</b>The MCP-1 -2518 AA genotype of the population in Suzhou may be a protective genotype of AP. People with higher frequency of G allele is more likely to suffer from AP. Nonetheless, the genotype of AA and the frequency of G allele couldn't predict the risk of SAP.</p>
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Femelle , Humains , Mâle , Adulte d'âge moyen , Asiatiques , Génétique , Études cas-témoins , Chimiokine CCL2 , Génétique , Chine , Ethnologie , Ethnies , Génétique , Fréquence d'allèle , Génotype , Pancréatite , Génétique , Polymorphisme de nucléotide simpleRésumé
<p><b>AIM</b>To investigate the effect of 3,4-dihydroxyacetophenone (alpha-DHAP) on Na+, K+ -ATPase activity of injured brain mitochondria induced by ascorbate-FeSO4 and the oxygen consumption of rat brain cells stimulated by ADP.</p><p><b>METHODS</b>Na+, K+ -ATPase activity was determined according to the method of inorganic phosphate. Swelling of the brain mitochondria was detected with the method of spectrophotometer. Lipid peroxidation was detected according to the thiobarbituric acid method of spectrophotometer. Oxygen consumption was measured by oxygen electrode method.</p><p><b>RESULTS</b>The decrease of Na+, K+ -ATPase activity, mitochondria swelling and formation of lipid peroxidation were shown in rat brain mitochondria and cells induced by ascorbate-FeSO4. alpha-DHAP was shown to increase the activity of Na+, K+ -ATPase, decrease the mitochondria swelling and inhibit the production of lipid peroxidation of brain mitochondria and cells induced by ascorbate and FeSO4. alpha-DHAP can also reduce the oxygen consumption of brain cells stimulated by ADP.</p><p><b>CONCLUSION</b>alpha-DHAP can protect the structure and the function of brain mitochondria and cells by scavenging the free radical and resisting the reaction of lipid peroxidation.</p>
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Animaux , Mâle , Rats , Acétophénones , Pharmacologie , ADP , Pharmacologie , Encéphale , Biologie cellulaire , Métabolisme , Piégeurs de radicaux libres , Pharmacologie , Peroxydation lipidique , Mitochondries , Métabolisme , Gonflement mitochondrial , Consommation d'oxygène , Rat Wistar , Sodium-Potassium-Exchanging ATPase , MétabolismeRésumé
Objective To explore the changed status of the intestinal flora microecology in the model infant rats with irritable bowel syndrome(IBS) by integrative method.Methods To establish 20 infant rats model with IBS.The IBS rats were randomly divided into the treatment group A with bifico and positive control group B,and another 10 infant rats which grew up regularly were taken as negative control group C.The feces smear staining and intestinal flora detection was performed in the 3 groups respectively,meanwhile the dry and wet weight of each group rats feces and the content of water in the feces were compared.Results The intestinal flora imbalance rate of infant rats IBS group(A+B) was 70%,and there was 30% in the control group C,the difference between model group and group C was very significantly(?~2=4.34 P
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Objective To study the expression and clinical significance of?-catenin and c-myc in gastric adenocarcinoma and corresponding para cancer gastric mueosa.Methods Two hundreds and ninety seven samples were collected from 102 cases of gastric adenocarcinoma,including 102 cancerous tissues and 195 para-cancerous tissues.Each sample was made into 282,156 and 156 dots tissue microarrays.Expressions of?-catenin and c-myc proteins were detected by immunohistochemical stain- ing.Results The expressions of?-catenin and c-mye were increased gradually in the process of gastric carcinogenesis.The rates of?-catenin and c myc expression were higher in carcinoma than that in intesti- nal metaplasia( P<0.05,P<0.001).The aberrant expression of?-catenin was closely related to the depth of invasion(P<0.05),and the expression of c-myc was related to histological grade( P<0.05). The aberrant expression of?-catenin was significantly correlated with the expression of c-myc in gastric adenocarcinoma(P<0.05).Conclusions The aberrant expression of?-catenin may activate the expres sion of target gene c-myc,which plays a pivotal role in the carcinogenesis and progression of gastric adenocarcinoma.
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Objective To investigate the effects of stimulation of CD40 on the growth,prolifera- lion and apoptosis of gastric cancer cell lines,and the change of gene expression profiles of gastric cancer cell AGS.Methods The growth and proliferation of AGS cells treated with different concentrations of soluble CD40 ligand were measured by MTT in order to choose optimum stimulating concentration of so- luble CD40 ligand.Cell cycle and apoptosis of AGS cells were analyzed by flow cytometry.Gene expres- sion profiles of AGS cells were analyzed by Affymetrix U133A 2.0 after treated with soluble CD40 ligand for 48 h.Results Two?g/ml of.soluble CD40 ligand was the optimum concentration.After being cul- tured with soluble CD40 ligand for 48h,the growth of AGS cell was inhibited and blockade in G1 phase. There were 414 alterative genes found in AGS cells including 209 up-regulated genes and 205 down-regu- lated genes.Forty-five genes varied significantly(P