Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immu-notherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histo-compatibility complex(MHC)class Ⅰ and Ⅱ antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4+and CD8+T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

Objective: To explore the clinical and genetic characteristics of children with dopa-responsive dystonia (DRD) caused by tyrosine hydroxylase (TH) gene variations. Methods: Clinical data of 9 children with DRD caused by TH gene variations diagnosed in the Department of Children Rehabilitation, the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2022 were retrospectively collected and analyzed, including the general conditions, clinical manifestations, laboratory tests, gene variations and follow-up data. Results: Of the 9 children with DRD caused by TH gene variations, 3 were males and 6 were females. The age at diagnosis was 12.0 (8.0, 15.0) months. The initial symptoms of the 8 severe patients were motor delay or degression. Clinical symptoms of the severe patients included motor delay (8 cases), truncal hypotonia (8 cases), limb muscle hypotonia (7 cases), hypokinesia (6 cases), decreased facial expression (4 cases), tremor (3 cases), limb dystonia (3 cases), diurnal fluctuation (2 cases), ptosis (2 cases), limb muscle hypertonia (1 case) and drooling (1 case). The initial symptom of the very severe patient was motor delay. Clinical symptoms of the very severe patient included motor delay, truncal hypotonia, oculogyric crises, status dystonicus, hypokinesia, decreased facial expression, and decreased sleep. Eleven TH gene variants were found, including 5 missense variants, 3 splice site variants, 2 nonsense variants, and 1 insertion variant, as well as 2 novel variants (c.941C>A (p.T314K), c.316_317insCGT (p.F106delinsSF)). Nine patients were followed up for 40 (29, 43) months, and no one was lost to follow-up. Seven of the 8 severe patients were treated by levodopa and benserazide hydrochloride tablets and 1 severe patient was treated by levodopa tablets. All the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets. Although the weight of the patients increased and the drug dosage was not increased, the curative effect remained stable and there was no obvious adverse reaction. One severe patient developed dyskinesia in the early stage of treatment with levodopa and benserazide hydrochloride tablets and it disappeared after oral administration of benzhexol hydrochloride tablets. Until the last follow-up, motor development of 7 severe patients returned to normal and 1 severe patient still had motor delay due to receiving levodopa and benserazide hydrochloride tablets for only 2 months. The very severe patient was extremely sensitive to levodopa and benserazide hydrochloride tablets and no improvement was observed in this patient. Conclusions: Most of the DRD caused by TH gene variations are severe form. The clinical manifestations are varied and easily misdiagnosed. Patients of the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets, and it takes a long time before full effects of treatment become established. Long-term effect is stable without increasing the drug dosage, and no obvious side effect is observed.
Female ; Humans ; Infant ; Male ; Benserazide/therapeutic use* ; Dystonia/genetics* ; Hypokinesia/drug therapy* ; Levodopa/pharmacology* ; Muscle Hypotonia ; Retrospective Studies ; Tyrosine 3-Monooxygenase/genetics*

This study aims to evaluate the methodological and reporting quality of diagnosis and treatment guidelines for hyperuricemia as well as the expert consensuses and promote the understanding and application of the diagnosis and treatment guidelines for hyperuricemia. With "hyperuricemia" "guidelines" "consensus" "recommendations" as the key words in titles, the authors searched for the published clinical guidelines on hyperuricemia in Chinese against CNKI, Wanfang, VIP, Medlive and the official website of the industry association. The retrieval time limit was until May 31, 2021. The appraisal of guidelines for research and evaluation Ⅱ(AGREEⅡ) and the reporting items for practice guidelines in health care(RIGHT) were employed to evaluate the methodological quality and reporting quality of 14 guidelines/consensuses included. The average scores of the guidelines/consensuses were 80.85%(48.61%-98.61%) for the domain of scope and purpose, 34.52%(0-69.44%) for the domain of stakeholder involvement, 35.53%(6.25%-92.19%) for the domain of rigor of development, 55.85%(23.61%-86.11%) for the domain of clarity of presentation, 26.19%(0-76.04%) for the domain of applicability, and 21.42%(0-50.00%) for the domain of editorial independence. Nine guidelines/consensuses were of medium overall quality with grade B recommendation, and five guidelines/consensuses were of poor quality with grade C recommendation. The RIGHT classified the fourteen guidelines/consensuses into one of high reporting quality, three of medium reporting quality, and ten of low reporting quality. The results of this study indicate that the standardization and rigor of the methodological quality and the reporting quality of the clinical guidelines/consensuses for hyperuricemia in China remain to be strengthened.
China ; Consensus ; Humans ; Hyperuricemia/drug therapy* ; Publications ; Reference Standards

OBJECTIVE: To investigate the regulation of chronic myelogenous leukemia （CML） imatinib resistant genes, in order to improve the therapeutic effect of CML imatinib resistant patients. METHODS: The human CML cell line K562 and imatinib-resistant K562 cells (K562/G01) were collected, and transcriptome of the cells were achieved by RNA-seq. The sequencing data were analyzed by using standard procedures. RESULTS: Compared with K562 cells, 464 genes were significantly changed in K562/G01 cells, including 163 up-regulated and 301 down-regulated genes. The GO function annotation analysis and KEGG pathway analysis results showed that the differentially expressed genes were mainly involved in biological processes such as oxidative phosphorylation, localization to protein organelle, ribonucleoprotein complex biogenesis and so on. Gene Set Enrichment Analysis (GSEA) plots showed that 5 gene-sets were up-regulated in K562/G01 significantly, including the pathway of TGF-beta, mTOR and CML. CONCLUSION CML imatinib resistance is associated with oxidative phosphorylation, during which the pathway of TGF-beta and mTOR are significantly up-regulated.
Drug Resistance, Neoplasm ; Gene Expression Profiling ; Humans ; Imatinib Mesylate/pharmacology* ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics*

Objective:To explore the application value of enhanced recovery after surgery (ERAS) in laparoscopic radical resection of bladder cancer and ileal bladder surgery under modular operation procedures.Methods:A retrospective selection of 42 cases of laparoscopic radical radical resection of bladder cancer and ileal bladder surgery performed by the Department of Urology, General Hospital of Southern Theater Command from January 2017 to December 2019 were divided into two groups according to the different management methods adopted during the perioperative period: ERAS management group and conventional management group, each with 21 cases. Among them, patients in the ERAS management group were managed by ERAS during the perioperative period, and patients in the conventional management group were managed by conventional management during the perioperative period. The postoperative hospital stay, first exhaust time, first defecation time, first time to get out of bed, first liquid food time, postoperative visual analogue scale (VAS) score, as well as transferrin, upper arm circumference, body mass index, plasma albumin, total protein, and total protein were compared between the two groups of patients after surgery. The measurement data conforming to the normal distribution were expressed as mean±standard deviation ( Mean± SD), and the in dependent t-test was used for comparison between groups; the measurement data of non-normal distribution were expressed as the median (interquartile range) [ M( P25, P75)], the independent sample Mann-Whitney U test was used for comparison between groups; the Chi-square test was used for comparison of enumeration data between groups. Results:The postoperative hospital stay in the ERAS group was (8.9±1.8) d, the first exhaust time was (33.4±3.2) h, the first defecation time was (60.3±7.8) h, the first time to get out of bed was (23.1±6.7) h, the first liquid food time was (82.7±18.5) h and postoperative VAS was (1.3±0.6), that were significantly reduced compared with the conventional treatment group [(12.3±2.3) d, (51.4±5.2) h, (73.0±8.1) h, (34.7±8.2) h, (109.7±21.6) h, (3.6±0.8)], the difference were statistically significant ( P<0.05). In the ERAS group, the decreased value of transferrin was [0.8 (-0.4, 2.2) g/L], the decreased value of body mass index was[1.61±0.73], the decreased value of plasma albumin was [3.5±1.5 g/L], the decrease value of total protein was[10.1±5.6 g/L] and the decrease value of prealbumin was [90.5±11.3 mg/L] were significantly lower than those of the conventional management group[(1.9(0.9, 3.6) g/L, (2.32±1.05) kg/m 2, (9.6±2.0) g/L, (16.3±4.9) g/L, (131.3±7.4) g/L], and the difference were statistically significant ( P<0.05). Conclusion:Modular laparoscopic precision resection of bladder cancer and ERAS concept after ileal bladder surgery is beneficial to shorten the hospital stay, reduce postoperative pain, have less impact on the patient′s body loss and immune function, and can speed up the patient′s postoperative recovery.

Objective: To compare the safety profile, angiographic and clinical outcomes between drug-coated balloon(DCB) only strategy versus drug eluting stent(DES) implantation in primary percutaneous coronary intervention(PCI) for acute myocardial infarction(AMI) patients. Methods: A total of 380 AMI patients who underwent primary PCI in Beijing Chaoyang Hospital from January 2016 to May 2019 were enrolled. They were allocated into DEB group(n=180) or DES group(n=200). The Primary endpoint was the major adverse cardiac events(MACE) in hospital and within 3 months after discharge, the composite event of cardiac death, non-fatal myocardial infarction(MI), target vessel revascularization(TVR) and in stent thrombosis. The secondary endpoints included: (1)TIMI blood flow grade and myocardial perfusion grade (TMP grade) of infarct-related vessels before and after PCI. (2)The degree of ST segment resolution(STR) between half hour and two hours after PCI, and STR was represented by percentage of summed ST-segment reduction between baseline and post-PCI. Using the most significant lead of ST segment elevation, calculating the rate of decline in the ST segment after treatment; or the most significant lead of the ST segment depression, to calculate the rate of recovery in the ST segment after treatment. STR<50% was defined as incomplete STR. (3)The occurrence of coronary artery dissection during operation. (4)The peak value of myocardial enzymes. (5)The incidence of bleeding in hospital and within 3 months after discharge. The inverse probability weighting method based on propensity score (IPTW) was used to compare the effects of the two treatments on MACE occurrence in the logistic regression model. Results: There was no significant difference in sex, age, risk factors of coronary heart disease, type and site of AMI, interventional therapy data(P>0.05) between the two groups. The ratio of bifurcation lesions in DCB group was significantly higher than that in DES group, and the diameter of the DCB was smaller while the length was longer than that of DES (all P<0.05). One death occurred in each group during hospitalization. Compared with the DES group, the incidence of MI ［2.8%(5/180) vs. 0.5% (1/200), P=0.10］ and TVR ［2.8%(5/180) vs. 0.5%(1/200), P=0.10］ in the DCB group during hospitalization showed an increasing trend, and were mostly associated with delayed coronary dissection. The incidence of MACE was similar between the two groups (3.3%(6/180) and 1.0%(2/200), P=0.15) during hospitalization. There was no MACE occurred in the two groups within 3 months after discharge. There was no significant difference between the two groups in TIMI grade, TMP grade, incomplete STR rate and peak value of myocardial enzyme (all P>0.05). The incidence of coronary artery dissection was significantly higher in DCB group than in DES group (8.3%(15/180) and 3.0%(6/200), P=0.02), but most of them were type B or A dissection and did not need special treatment. There was no significant difference in bleeding event between the two groups(P=0.91). Logistic regression analysis showed that there was no difference in the risk of MACE during hospitalization between DES and DCB groups for AMI patients receiving PCI (compared with DCB, OR=0.35, 95%CI 0.08-1.43, P=0.13). Conclusions: The initial safety and efficacy profiles of DCB are similar with those of DES for the AMI patients during PCI. The study highlights that the incidence of coronary dissection (type A or B) is higher post DCB treatment than post DES, but it does not affect blood flow. However, the incidence of in-hospital MI due to delayed coronary dissection trends to be higher post DCB. So we should pay close attention to the risk of delayed coronary dissection after DCB in AMI patients with de novo lesion.
Drug-Eluting Stents ; Humans ; Myocardial Infarction ; Percutaneous Coronary Intervention ; Stents ; Treatment Outcome

OBJECTIVE: To explore the clinical value of serum isoform [-2] proprostate-specific antigen (p2PSA) and its derivatives %p2PSA and prostate health index (PHI) in predicting aggressive prostate cancer (PCa). METHODS: The pre-operation serum and basic clinical data of 322 patients with PCa (including 143 patients diagnosed with PCa by transrectal ultrasound-guided prostate biopsy and 179 patients undergoing radical prostatectomy) in Peking University First Hospital were collected from August 2015 to May 2018. Serum total prostate-specific antigen (tPSA), free prostate antigen (fPSA) and fPSA/tPSA (f/t) and the p2PSA level of all these patients were measured on automatic immune analyzers DxI800, and then %p2PSA and PHI were calculated. The prostate pathologic result was considered as the gold standard to evaluate the Gleason score of the patients with PCa. Receiver operator curves (ROC) were used to assess the ability of p2PSA, %p2PSA and PHI to predict aggressive PCa (pathologic Gleason score≥7) compared with those traditional markers tPSA, fPSA and f/t. RESULTS: Among these patients, the p2PSA, %p2PSA and PHI median levels were significantly higher in patients with pathologic Gleason score≥7 than those with Gleason score<7 (p2PSA: 30.22 ng/L vs. 18.33 ng/L; %p2PSA: 2.50 vs. 1.27; PHI: 91.81 vs. 35.44; all P<0.01). The area under curve (AUC) of %p2PSA and PHI (0.770, 0.760) in predicting Gleason score≥7 were higher than those of the traditional indicators tPSA, fPSA and f/t (AUC were 0.648, 0.536 and 0.693, respectively). Among those patients diagnosed with PCa by transrectal ultrasound-guided prostate biopsy, the AUC of %p2PSA and PHI (AUC were 0.808 and 0.801, respectively) in predicting Gleason score≥7 were higher than those of the traditional indicators tPSA, fPSA and f/t (AUC were 0.729, 0.655 and 0.665 respectively). Among those patients undergoing radical prostatectomy, PHI and %p2PSA also had the trend of higher predictive value than those of the traditional indicators. The AUC of %p2PSA and PHI were 0.798 and 0.744, respectively while the AUC of tPSA, fPSA and f/t were 0.625, 0.507 and 0.697, respectively. CONCLUSION Compared with traditional markers tPSA, fPSA and f/t, %p2PSA and PHI had much higher predictive value for aggressive PCa, which may help clinicians to evaluate the therapeutic regime and make more appropriate management plan for the patients.
Humans ; Male ; Neoplasm Grading ; Prostate-Specific Antigen ; Prostatectomy ; Prostatic Neoplasms ; Protein Isoforms ; ROC Curve

OBJECTIVE: To evaluate the efficacy and safety of salvianolate in elderly patients with unstable angina pectoris (UAP). METHODS: A prospective double-blind randomized placebo-controlled multicenter trial in elderly patients with UAP from 13 third-grade class-A hospitals in China was performed. A total of 318 patients were randomly allocated in a 1:1 ratio to an experimental group (160 patients) and a control group (158 patients). The experimental group was treated with salvianolate for 14 days on the basis of conventional medicine, and the control group was given a placebo for 14 days with the same criteria. Follow-up was lasted 28 days in both groups. The primary endpoint was biweekly frequency of angina pectoris attacks. The secondary endpoints included biweekly dosage of nitroglycerin, the Seattle Angina Questionnaire, angina pectoris severity and duration, myocardial injury markers, high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), as well as major adverse cardiovascular events (MACEs). Safety was assessed according to adverse events and serious adverse events. RESULTS: Baseline characteristics were similar between treatment groups. Compared with those in the control group, the frequency of biweekly angina attacks (2.92 vs . 4.08, P=0.025), the biweekly dosage of nitroglycerin, as well as the severity and duration of angina attacks (P<0.01) were reduced by salvianolate. The Seattle Angina Questionnaire score was also significantly improved in the experimental group than in the control group (P<0.05). No significant differences were observed between the two groups with respect to the incidence of MACEs. Salvianolate was well tolerated. CONCLUSIONS Salvianolate appear to have efficacy and well tolerated for elderly patients with UAP. [ClinicalTrials.gov identifier: NCT03037047].

The aim of this paper was to investigate the anti-inflammatory effect of Tripterygium wilfordii processed with licorice on DSS-induced ulcerative colitis( UC) mice and its regulation on intestinal immune system. In this study,a DSS-induced animal model of UC mice was established,with mesalazine( Mes) as a positive drug. The pharmacodynamic effects of low( PT1) and high( PT2)doses of T. wilfordii processed with licorice were analyzed by disease activity index( DAI),colon length and colon histopathological score in mice. By detecting the expression levels of TNF-α and IL-6 cytokines in the serum of mice,immunohistochemical CD3+T and Fox P3+Treg staining in the colon of mice,the anti-inflammatory and immunoregulatory effects of T. wilfordii processed with licorice on UC mice were analyzed. The hepatotoxicity of each dose of T. wilfordii processed with licorice was also analyzed by HE staining in liver tissue of mice and ALT and AST levels in serum. The results showed that the colitis symptoms of the mice in the PT1 group and the PT2 group were alleviated,the inflammatory cell infiltration was reduced. And the expression of inflammatory factors was decreased,the difference was statistically significant compared with the model group( P<0. 05). The HE staining and ALT and AST levels in the high dose group and low dose group were not significantly different from those in the normal group. The results showed that T. wilfordii processed with licorice has the anti-inflammatory and immunomodulatory effects on UC mice,and the dose did not show significant hepatotoxicity.
Animals ; Anti-Inflammatory Agents ; pharmacology ; Colitis, Ulcerative ; drug therapy ; Dextran Sulfate ; Drugs, Chinese Herbal ; pharmacology ; Glycyrrhiza ; chemistry ; Mice ; Plant Extracts ; pharmacology ; Tripterygium ; chemistry

OBJECTIVE: To examine the clinical effects of Yisui Shengxue Granules () in the treatment of β-thalassemia and explore its mechanism on DNA methylation levels. METHODS: A randomized placebo-controlled double-blinded trial was conducted. Forty patients with β-thalassemia were recruited and distributed randomly by envelope method into an experimental group and a control group, 20 patients in each group. The patients were given Yisui Shengxue Granules in the experimental group and placebo in the control group (12 g/bag three times a day) during a 3-month intervention. Before and after 1, 2, and 3 months of treatment, peripheral intravenous blood was sampled, and blood parameters such as hemoglobin (Hb), red blood cells (RBCs), reticulocytes (Ret), and fetal hemoglobin (HbF) were analyzed. Mononuclear cells from 5 patients, who showed an obvious treatment effect, were isolated by density gradient centrifugation. DNA methylation was analyzed using an Affymetrix USA GeneChip Human Promoter 1.0 Array and Input-promoter 1.0. RESULTS: Compared with pre-treatment, there was an obvious increase in Hb and RBCs counts after 1, 2, and 3 months in the experiment group (P<0.01 or P<0.05). Meanwhile, HbF increased from the 2nd to the 3rd month (P<0.05). In the control group, Hb and RBCs showed no obvioas change. After 3-month treatment, DNA methylation results from 5 patients revealed that there were 24 hypomethylated genes and 3,685 hypermethylated genes compared with pre-treatment. Genes of insulin-like growth factor 1 receptor (IGF1R) and Janus kinase 3 (JAK3) revealed the most relations with other genes (degree: 21) and genes of 1-phosphatidylinositol-4, 5-bisphosphate phosphodiesterase gamma 2 (PLCG2) and mitogen-activated protein kinase 10 (MAPK10) showed a stronger intermediary role (betweenness centrality=0.04). CONCLUSIONS JAK3 and MAPK10 are two key genes in bone marrow and the lymphatic system, and JAK3 is likely to be related to hematopoietic cytokines in the process of early hematopoiesis. (Registration No. NCT01549080).