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.
Humans ; East Asian People ; Neoplasms/pathology* ; Antibodies, Monoclonal, Humanized/therapeutic use*

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.
Humans ; East Asian People ; Neoplasms/pathology* ; Antibodies, Monoclonal, Humanized/therapeutic use*

ObjectiveTo explore the anti-testicular inflammation mechanism of Wuzi Yanzongwan through network pharmacological analysis and experimental verification. MethodThe active ingredients of Wuzi Yanzongwan were searched in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， and their targets were predicted via SwissTargetPredicition. GeneCards and Online Mendelian Inheritance in Man （OMIM） were used to obtain the known targets for the treatment of testicular inflammation. STRING 11.0 was employed to construct the protein-protein interaction （PPI） network， and Cytoscape 3.7.1 to construct the “herbal medicine-active ingredient-target” network of Wuzi Yanzongwan and “active ingredient-disease target” network. Metascape was used for gene ontology （GO） annotation and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment of signaling pathways. ResultA total of 72 active ingredients and 624 potential targets of Wuzi Yanzongwan were screened out， and 196 key targets were identified for the treatment of testicular inflammation by Wuzi Yanzongwan. The results of GO annotation showed that the anti-testicular inflammation targets of Wuzi Yanzongwan were involved in the biological processes such as the response to molecule of bacterial origin， the positive regulation of response to external stimulus， and the response to extracellular stimulus. KEGG pathway enrichment revealed that the major pathways associated with the treatment （P<0.01） included the pathways in cancer， epidermal growth factor receptor （EGFR） tyrosine kinase inhibitor resistance， transcriptional misregulation in cancer， calcium signaling pathway， apelin signaling pathway， and NOD-like receptor signaling pathway. Wuzi Yanzongwan may exert the anti-testicular inflammation effect by inhibiting the activation of the NLR family pyrin domain-containing 3 （NLRP3） inflammasome pathway to alleviate the inflammatory response， which verifies the prediction results based on network pharmacology to a certain extent. ConclusionThe inhibitory effect of Wuzi Yanzongwan on testicular inflammation is multi-target， multi-pathway， and multi-mechanism. The findings of this study provide evidence support for the clinical application of Wuzi Yanzongwan.

Autophagy, an evolutionarily conserved process by which components of the cell are degraded in lysosomes, may facilitate survival of cancer cells under stress conditions. 8-Azaguanine (8-AG), an inhibitor of purine nucleotide biosynthesis, shows antineoplastic activity in multiple tumor cells. However, chemoresistance has restricted its development as an anticancer agent, and the mechanism of 8-AG resistance is not fully understood. We report here that 8-AG induces a protective autophagy to eliminate its cytotoxicity, and inhibition of autophagy increases cellular sensitivity of cancer cells to 8-AG treatment. Using HepG2 or SMMC-7721 hepatic cancer cell lines, we found that 8-AG inhibited cell viability and induced intrinsic apoptosis, accompanied by the up-regulation of the pro-apoptotic protein BimS, one of Bim (also known as BCL-2-like protein 11, BCL2L11) isoforms. Furthermore, 8-AG treatment enhanced the autophagy flux by promoting the dephosphorylation and activation of Unc-51-like autophagy activating kinase 1 (ULK1) via Akt/mTORC1 (mammalian target of rapamycin complex 1) signaling inhibition. Depletion of autophagy-related gene 7 (ATG7) markedly enhanced the level of BimS, and promoted cell death in response to 8-AG. 8-AG in combination with autophagy inhibitor chloroquine (CQ) or bafilomycin A1 (Baf A1) promoted the 8-AG-induced apoptosis in hepatic cancer cells. Altogether, these findings suggest that autophagy promotes chemoresistance of cancer cells for 8-AG, and blocking autophagy increases cellular sensitivity of cancer cells to 8-AG treatment.

Objective:To investigate the effects of electroacupuncture at Baihui (DU20) and Shenting (DU24) on brain function of APP/PS1 mice. Methods:Sixteen 4-month-old APP/PS1 mice in the same litter were randomly divided into model group (n = 8) and electroacupuncture group (n = 8). Eight transgenic negative mice in the same litter were as control group. The electroacupuncture group accepted electroacupuncture at Baihui and Shenting for 16 weeks. They were assessed with Object Recognition Test before and after intervention, and observed under small animal functional magnetic resonance imaging with regional homogeneity (ReHo) analysis. Results:Compared with the control group, the discrimination ratio decreased in the model group after intervention (P < 0.05), while it increased in the electroacupuncture group compared with that in the model group (P < 0.05). Compared with the control group, ReHo of right basal forebrain and left hippocampus decreased in the model group before intervention. Compared with the control group, ReHo decreased in bilateral hippocampus group and increased in retrosplenial cortex in the model group after intervention; while it increased in bilateral hippocampus and motor cortex and decreased in anterior cingulate gyrus in the electroacupuncture group compared with that in the model group. Conclusion:Electroacupuncture at Baihui and Shenting may delay the decline of learning and memory ability in Alzheimer's disease model mice, which may relate to the regulation of functional activities in hippocampus.

Objective To investigate the effect of emodin on the gemci-tabine-resistant pancreatic cancer cell line SW1990/Gemcitabine (GEM),and explore the potential mechanism of its action .Methods The pancreatic cancer cell line SW1990 was treated by intermittently in-creasing the concentration of gemcitabine in the culture medium for 10 months, and SW1990/GEM cells were obtained.This experiment was di-vided into control group ,emodin group,gemcitabine group and combina-tion group ( emodin +gemcitabine ) .SW1990/GEM and SW1990 cells were treated with emodin ( 10 μmol · L-1) and gemcitabine ( 20 μmol· L-1) alone or those two together in three groups for 48 h, in con-trol group cells were treated with 0.1%DMSO for 48 h.Cell proliferation was analyzed by MTT.Reverse transcription -polymerase chain reaction was performed to analyze the protein and gene expression of multidrug re-sistance gene-1 ( MDR-1) .Flow cytometric was applied to analyze the function of the P-glycoprotein(P-gp).The Rhodamine l23 efflux experiment was applied to assay P -gp function in SW1990/Gemcitabine cells.Results Compared with gemcitabine group , the combination group could significantly inhibit the proliferation of SW1990/GEM cells.Treatment of SW1990/GEM and SW1990 cells with gemcitabine alone could inhibit 13.34%and 36.52%of cell viability,there was significant difference between the two group (P＜0.05). The results showed that the SW1990 /GEM cell line had an obvious resistance to gemcitabine compared with the cell line SW 1990.While SW 1990/GEM and SW 1990 cells were treated with gemcitabine combined with emodin , cell via-bility was inhibited to 40.45%and 43.87%, there was no significant difference between the two group .The emodin could enhance the anti -proliferative effect of gemcitabine on drug -resistance cell SW1990/GEM.Compared with gemcitabine group, the combination group could significantly inhibit the expression of MDR-1 gene,and the difference was statistically significant (P＜0.05).Conclusion Effect of emodin can down -regulate the expression of MDR -1 and then improve the drug resistance of gemcitabine in pancreatic cancer .

Objective To explore the effect of electroacupuncture at Baihui (DU20) and Shenting (DU24) acupoints on learning and memory ability in rats with middle cerebral artery occlusion and reperfusion (MCAO/R), and the potential mechanisms. Methods A total of 90 healthy male Sprague-Dawley rats were randomly divided into sham group (n=18) and operation group (n=72). The MCAO/R model was established by suture method in the operation group. Finally, 54 qualified rats of the operation group were randomly divided into ischemia group (n=18), electroacupuncture group (n=18) and non-acupoint group (n=18). The electroacupuncture group received electroacupuncture at Baihui (DU20) and Shenting (DU24) for 14 days. The cerebral infarction volume was measured by magnetic resonance imaging (MRI). The learning and memory ability was tested by Morris water maze. The protein expression of 5-hydroxytryptamine 1A (5-HT1A) receptor was detected by immunohistochemistry. Results There was no significant difference in the cerebral infarction volume among three groups before intervention (F=1.678, P>0.05). Compared with the ischemia group and the non-acupoint group, the cerebral infarction volume signif-icantly reduced (P<0.001);the latency significantly shortened (P<0.001) and the times crossing the platform decreased (P<0.05);the expres-sion of 5-HT1A receptor decreased in the left hippocampus (P<0.05) in the electroacupuncture group after intervention. There was no signifi-cant difference in all the indices between the non-acupoint group and the ischemia group after intervention (P>0.05). Conclusion Electroacu-puncture at Baihui (DU20) and Shenting (DU24) could effectively increase the learning and memory ability of MCAO/R rats, which might relate with inhibiting the expression of 5-HT1A receptor in hippocampus.

OBJECTIVETo compare the clinical effect of Chinese medicine (CM) and Western medicine (WM) for controlling the recurrence of pelvic endometriosis after a conservative operation.

METHODSThe study was a multi-center, randomized, parallel controlled and prospective clinical trial. Patients were randomly divided into two groups: CM group (106 cases) and WM group (102 cases). Drugs were given to patients during 1-5 days of the first menstruation after a conservative operation in both groups. Patients with stages I and II (revised American Fertility Society) were treated for 3 months, while the patients with stages III and IV were treated for 6 months. The patients in the CM group were treated using three types of Chinese herbal medicine based on syndrome differentiation. Patients in the WM group were treated using gonadotropin releasing hormone agonist (GnRH-a) or gestrinone. Patients treated with GnRH-a received add-back therapy of Tibolone Tablets once a day after 4 months of treatment. Any cases of dysmenorrheal chronic pelvic pain, menstruation and any adverse reactions of patients were recorded once a month during the preoperative and postoperative periods and once every 3 months during the follow-up period. During the preoperative, postoperative and the follow-up periods, patients underwent type B ultrasonography of the pelvis and measurements of serum CA125 levels, gynecologic examination, routine evaluations of blood, urine, hepatic function (glutamate pyruvate transaminase), renal function (blood urea nitrogen) and electrocardiograms. During the follow-up period they underwent type B pelvic ultrasonography, measurement of serum CA125 levels and further gynecologic examinations. The two treatments were compared for clinical recurrence rates, pregnancy rates and the incidence of adverse reactions.

RESULTSThe incidence and timing of recurrence of endometriosis were not significantly different between the two groups. The first pregnancy achieved by the patient in the CM group was significantly earlier than that in the WM group (P <0.05). Moreover, the incidence of adverse reactions in the WM group was significantly higher than in the CM group (P <0.01).

CONCLUSIONSTreatment with Chinese herbal medicines prevented the recurrence of endometriosis after a conservative operation, improved the conception rate and showed fewer and lighter adverse reactions than did treatment with WM therapy. Treatment with Chinese herbal medicine meets the need of patients wishing to have a child following endometriosis and is an appropriate form of clinical treatment.

Adult ; Demography ; Drugs, Chinese Herbal ; adverse effects ; therapeutic use ; Endometriosis ; drug therapy ; surgery ; Female ; Humans ; Pelvis ; surgery ; Pregnancy ; Recurrence

OBJECTIVETo investigate the effect of Chinese medicine (CM) and Western medicine (WM) on quality of life (QOL) after conservative surgery for endometriosis.

METHODSA total of 320 patients with endometriosis were randomized into two groups by using random block design, CM group (160 cases, activating blood circulation and removing blood stasis treatment based on syndrome differentiation) and WM group (160 cases, gonadotropin-releasing hormone agonist or gestrinone treatment) after conservative surgery. Treatment was given for 3-6 months (according to the revised American Fertility Society scoring system stage), and the World Health Organization QOL-BREF (WHOQOL-BREF) was applied to patients before and after treatment to assess QOL.

RESULTSThere were 136 cases in the CM group and 141 cases in the WM group completing therapy. In the CM group, the use of the WHOQOL-BREF showed that the physical, psychological and environmental scores posttreatment were significantly higher than those at pre-treatment (P < 0.05), and for 12 items (pain and discomfort, energy and fatigue, sleep and rest, mobility, activities of daily living, work capacity, negative feelings, health and social care: accessibility and quality, participation in and opportunities for recreation/leisure activities, appetite, QOL score, overall health status and QOL), the difference in scores was significant (P < 0.05). In the WM group, 4 items (pain and discomfort, opportunities for acquiring new information and skills, QOL score, overall health status and QOL) had significantly different scores post-treatment compared with those at pre-treatment (P < 0.05). Before treatment, the QOL in the two groups of patients showed no significant difference (P > 0.05). After treatment, the scores for physical health in the CM group were significantly higher than those of the WM group (P < 0.05) and the scores of 4 items (mobility, activities of daily living, sexual activity, QOL score) in the CM group were significantly higher than those in the WM group (P < 0.05).

CONCLUSIONSCM and WM treatment could improve the QOL of patients with endometriosis after conservative surgery. CM treatment is more effective than WM.

Adolescent ; Adult ; China ; Drugs, Chinese Herbal ; therapeutic use ; Endometriosis ; diagnosis ; surgery ; Female ; Follow-Up Studies ; Gonadotropin-Releasing Hormone ; antagonists & inhibitors ; therapeutic use ; Humans ; Middle Aged ; Pain Measurement ; Pain, Postoperative ; drug therapy ; physiopathology ; Patient Satisfaction ; statistics & numerical data ; Postoperative Care ; methods ; Prospective Studies ; Quality of Life ; Reference Values ; Risk Assessment ; Treatment Outcome ; Young Adult

OBJECTIVETo explore the effects of different oxygen flow rates during cardiopulmonary bypass (CPB) on myocardial ischemia-reperfusion (IR) injury in rabbits.

METHODSThirty rabbits were randomized equally into groups A, B and C to receive controlled oxygen reperfusion at low, normal and high flow rates (25, 50, and 80 ml.kg(-1).min(-1), respectively). Serum concentration of CK-MB and cTnT were tested by ELISA before the operation (T0) and after 30 min (T1), 2 h (T2), 12 h (T3) and 24 h (T4) of reperfusion. W/D, SOD and MDA of the myocardium were determined before and at 60 min after reperfusion. The ultrastructural alterations of the myocardium were observed.

RESULTSSerum concentration of CK-MB and cTnT in the 3 groups increased significantly after the operation, and their levels were the lowest in group A (P<0.05). W/D and MDA in the myocardium was also the lowest, while SOD the highest in group A (P<0.05). Ultrastructural pathologies were found in all the 3 groups, but relatively mild in group A.

CONCLUSIONLow oxygen flow rate during controlled reperfusion may protect the myocardium from IR injury in rabbits.

Animals ; Cardiopulmonary Bypass ; Myocardial Reperfusion Injury ; prevention & control ; Oxygen ; administration & dosage ; Rabbits ; Reperfusion ; methods