Tumor immune checkpoint therapy is a clinical treatment strategy developed based on the new principle of the inhibition of negative immune regulation. In this article, the tumor immune checkpoint therapy and the drug delivery strategies were reviewed, mainly including immunity and tumor therapy, tumor immune checkpoint therapy and its mechanism of action, clinical application of tumor immune checkpoint therapy and therapeutic drugs, immune resistance of programmed cell death protein 1 (PD1)/programmed cell death ligand 1 (PDL1) treatment and countermeasures, drug delivery strategies for tumor immune checkpoint therapeutic agents, etc. As a revolutionary new immunotherapy strategy, tumor immune checkpoint therapy has shown obvious superior therapeutic efficacy in a variety types of tumor. However, tumor immune checkpoint therapy is also faced with a big challenge, namely, immunotherapy resistance. With the discovery of new mechanism, the continuous development of new therapeutic drugs and delivery strategies, tumor immune checkpoint therapy is expected to further improve the clinical efficacy of tumor.

OBJECTIVETo investigate the expression of extracellular matrix metalloproteinase induced (EMMPRIN) in the interface tissue, and explore the role of EMMPRIN in the aseptic loosening of prostheses.

METHODSImmunohistochemistry was performed to characterize the EMMPRIN-expressing cells at sites of interface tissue around aseptic loosened hip prostheses in 16 cases. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to study the existence of EMMPRIN mRNA in interface tissue samples. And it was followed up by computer assisted image analysis in order to detect the A values of their expression. Synovium of hip joint of 8 femoral neck fracture were in control group.

RESULTSStrong immunostaining of EMMPRIN was found in the macrophages and fibroblasts of lining-like layers and vascular endothelium of synovial membrane-like interface tissue around loosened prostheses. Expression of EMMPRIN was significantly higher in interface tissue than the control synovium (z=-3.252, P=0.001). RT-PCR of interface tissue samples disclosed the presence of EMMPRIN mRNA of 14 cases. In interface tissue, the A value of EMMPRIN increased significantly compared to control synovium (P<0.01).

CONCLUSIONOver-expression of EMMPRIN up-regulates the production of matrix metalloproteinase (MMPs) in the interface tissue. And it can promote the bone destruction around prostheses. Thereby it may be one of methods to prevent and treat aseptic loosening of prostheses by repression the biology activity of EMMPRIN.

Adult ; Aged ; Arthroplasty, Replacement, Hip ; Basigin ; genetics ; physiology ; Female ; Hip Prosthesis ; Humans ; Immunohistochemistry ; Male ; Matrix Metalloproteinases ; metabolism ; Middle Aged ; Osteolysis ; physiopathology ; Prosthesis Failure ; RNA, Messenger ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Synovial Membrane ; metabolism

OBJECTIVETo explore the relationship between sample size and variance of means for personal noise exposure in weaving workers as to contributing evidence for establishing personal noise exposure measurement guideline.

METHODSA personal noise exposure measurement database from a group of weaving workers was used in the randomized re-sampling data analysis. The sampling cases were one number selecting from one to fifteen at each randomized re-sampling procedure. The randomized re-sampling was one thousand times from original personal noise exposure measurement database to get one thousands of re-sampling database. One thousands of L(Aeq.8 h) mean were calculated by re-sampling databases. The variation of randomized re-sampling means was analyzed for different re-sampling numbers.

RESULTSThe change for narrow trend of maximum, minimum, 95 percent number, 5 percent number of L(Aeq.8 h) mean was faster when randomized re-sampling number was smaller in variation vs randomized re-sampling number curve analysis. After that, the change for narrow trend of L(Aeq.8 h) mean was smooth for increasing the randomized re-sampling numbers. The 95% - 5% of L(Aeq.8 h) mean was about half for randomized re-sampling four cases (3.30 dB) vs one case (7.40 dB), and about one third for seven cases (2.44 dB), and about one fourth for eleven cases (1.85 dB).

CONCLUSIONThe sample size in personal noise exposure measurement guideline could be selected from four to eleven.

Humans ; Noise, Occupational ; statistics & numerical data ; Occupational Exposure ; statistics & numerical data ; Sample Size ; Sampling Studies

OBJECTIVETo investigate the feasibility of real-time PCR-optimized oligonucleotide probe method for detection of KRAS mutations in lung and colorectal carcinomas, as compared with Sanger sequencing method.

METHODSGenomic DNA was extracted from formalin fixed paraffin embedded samples of 221 lung carcinomas and 131 colorectal carcinomas after tumor cell content assessment and macrodissection. Real-time PCR-optimized oligonucleotide probe method and Sanger sequencing were performed to detect KRAS gene mutations. The frequency of KRAS mutation, mutation types, and their concordance were analyzed.

RESULTSKRAS mutation was detected in 6.3% (14/221) and 4.5% (10/221) of 221 lung cancer samples by using real-time PCR-optimized oligonucleotide probe method and Sanger sequencing, respectively, while in 41.2% (54/131) and 40.5% (53/131) of 131 colorectal cancer samples, respectively. There was no significant correlation between KRAS gene mutations and patients' gender and age (P > 0.05). The positive rate of KRAS codon 12 mutation was significantly higher than that of KRAS codon 13 mutation (P < 0.05). The overall concordance between real-time PCR-optimized oligonucleotide probe method and Sanger sequencing for KRAS mutation detection was 97.4%.

CONCLUSIONReal-time PCR-optimized oligonucleotide probe method provides an alternative method with high consistency and sensitivity as compared to Sanger sequencing in gene mutation detection.

Codon ; Colorectal Neoplasms ; genetics ; DNA Mutational Analysis ; methods ; Female ; Humans ; Lung Neoplasms ; genetics ; Male ; Middle Aged ; Mutation ; Oligonucleotide Probes ; Proto-Oncogene Proteins ; genetics ; Proto-Oncogene Proteins p21(ras) ; Real-Time Polymerase Chain Reaction ; methods ; Sensitivity and Specificity ; ras Proteins ; genetics

OBJECTIVETo analyze the clinical risk factors for deep vein thrombosis (DVT) after total hip and knee arthroplasty in Chinese patients who received prophylactic treatment for DVT.

METHODSWe evaluated 128 total hip arthroplasty (THA) and total knee arthroplasty (TKA) in 95 patients performed at our center from April 2004 to August 2004, which included 48 THAs in 43 patients and 80 TKAs in 52 patients. There were 27 men and 68 women with a mean age of 59.77 years (range, 23-78 years). All patients had been given low-molecular-weight heparin before operation and for 7-10 days post-operation to prevent DVT. Color Doppler ultrasonography was used to detect DVT of bilateral lower extremities in all patients before operation and at 7-10 days after operation. Nineteen clinical factors were examined preoperation and 7-10 days post-operation in order to analyze their influences on DVT formation after surgery.

RESULTSThere were 45 patients who developed DVT after operation. The incidence of DVT in all patients was 47.4% (45/95) and the incidence of proximal DVT was 3.2%. There were more asymptomatic DVT (57.8%, 26/45) than symptomatic ones, and some patients without DVT (14%, 7/50) presented some of the DVT symptoms. Logistic regression analysis demonstrated a definite association of female, obesity (representative by BMI), cement usage and diagnosed RA with DVT with odds ratio of 10.008, 3.094, 8.887, and 0.194 respectively. Other clinical factors had no statistically significant association with DVT.

CONCLUSIONSFemale, obesity, and cement usage were the risk factors for DVT after THA and TKA, and diagnosed RA was the protecting factors for DVT after THA and TKA. Other clinical factors such as age, OA, type of implant, monolateral or bilateral operation, duration of anesthesia, surgery and bandage usage for blood control, time for immobilization et al were not the risk factors for DVT.

Adult ; Aged ; Arthritis, Rheumatoid ; Arthroplasty, Replacement, Hip ; adverse effects ; Arthroplasty, Replacement, Knee ; adverse effects ; Bone Cements ; adverse effects ; Female ; Humans ; Male ; Middle Aged ; Obesity ; Postoperative Complications ; prevention & control ; Retrospective Studies ; Risk Factors ; Sex Factors ; Thrombophlebitis ; etiology ; prevention & control

Comparative pharmacokinetic (PK) analysis is often carried out throughout the entire period of drug development, the common approach for the assessment of pharmacokinetics between different treatments requires that the individual PK parameters, which employs estimation of 90% confidence intervals for the ratio of average parameters, such as AUC and Cmax, these 90% confidence intervals then need to be compared with the pre-specified equivalent interval, and last we determine whether the two treatments are equivalent. Unfortunately in many clinical circumstances, some or even all of the individuals can only be sparsely sampled, making the individual evaluation difficult by the conventional non-compartmental analysis. In such cases, nonlinear mixed effect model (NONMEM) could be applied to analyze the sparse data. In this article, we simulated a sparsely sampling design trial based on the dense sampling data from a truly comparative PK study. The sparse data were analyzed with NONMEM method, and the original dense data were analyzed with non-compartment analysis. Although the trial design and analysis methods are different, the 90% confidence intervals for the ratio of PK parameters based on 1000 Bootstrap are very similar, indicated that the analysis based on NONMEM is a reliable method to treat with the sparse data in the comparative pharmacokinetic study.
Area Under Curve ; Confidence Intervals ; Humans ; Nonlinear Dynamics ; Pharmacokinetics ; Sampling Studies

Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms ; metabolism ; pathology ; Carcinoma ; metabolism ; pathology ; Cyclin-Dependent Kinase Inhibitor p27 ; metabolism ; Female ; Humans ; Lymphatic Metastasis ; Middle Aged ; Neoplasm Staging ; Phosphorylation ; Prognosis ; S-Phase Kinase-Associated Proteins ; metabolism ; Threonine ; metabolism

The paper aimed to find the optimal combination and evaluation of the interactions of antitumor effect of the curcumin (Cur) and adriamycin (ADM) in vitro. According to the factorial design and data characteristics, the parameter method combined with the response surface approach were used to analyze the pharmacodynamic interactions of in vitro antitumor effects of the combination of Cur and ADM at different dosages. The results showed that the dose-effect relationship of the combination with the ratio of ADM-Cur 1:3 showed significant differences in comparison with either used alone. The dose-effect curve was shift left in combination. The combination of adriamycin (ADM, 0.693-2.132 micromol L(-1)) and curcumin (Cur, 2.047-6.304 micromol L(-1)) with a fixed ratio (1:3) showed a synergism. With increasing doses of the combination, there is an additive effect. Computer simulation showed a trend of decreasing difference between the observed and expected effects with the dose increasing in Cur from 6.304 to 16.0 micromol L(-1) and ADM from 2.132 to 5.3 micromol L(-1). The response surface analysis showed the optimal combination to be Cur 18.50 micromol L(-1) and ADM 3.89 micromol L(-1) with a ratio of 5:1. This study suggests that the parameter method combined with the response surface analysis provides richer and more reasonable information, and is helpful for quantitative design of drug combination therapy and to describe the nature and degree of drug interaction.
Algorithms ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacology ; Antineoplastic Agents ; administration & dosage ; pharmacology ; Cell Proliferation ; drug effects ; Computer Simulation ; Curcumin ; administration & dosage ; isolation & purification ; pharmacology ; Dose-Response Relationship, Drug ; Doxorubicin ; administration & dosage ; pharmacology ; Drug Synergism ; Humans ; K562 Cells

Objective To analyze the efficacy and safety of glimepiride treatment as initial monotherapy in newly diagnosed patients with type 2 diabetes mellitus (T2DM).Methods This was a subgroup analysis of the GREAT study,which investigated the efficacy and safety of glimepiride as initial monotherapy in Chinese patients with T2DM.This analysis was performed in 209 patients with disease duration less than 6 months and never received any anti-diabetic drugs.The change of HbA1C,fasting plasm glucose (FPG),2 h postprandial blood glucose (2hPPG),homeostasis model assessment for β-cell function index (HOMA-β),homeostasis model assessment for insulin-resistance index(HOMA-IR),the percentage of patients with HbA1C ＜ 7.0％ at endpoint and the incidence of hypoglycemia were evaluated after 16-weeks treatment.Results After 16-weeks glimepiride treatment,HbA1C value reduced significantly from baseline to endpoint,the reduction was statistically significant (9.21％ ± 1.65％ to 6.69％±0.83％,P＜0.001),69.7％ of the patients achieved HbA1C ＜7.0％ at study endpoint.Glimepiride-treated patients also achieved a significant improvement in FPG [from (10.15 ± 2.13) mmol/L to (7.23 ± 1.50) mmol/L,P＜0.001] and 2hPPG [from (17.21 ±4.14) mmol/L to (11.62 ± 3.34) mmol/L].HOMA-β was improved from 17.21± 15.19 [11.62 (2.90,115.8)] to 41.13 ± 44.12 [28.00 (5.1,360.00)],and HOMA-IR was reduced from 2.32± 1.90 [1.76 (0.60,12.80)] to 2.07 ± 1.74 [1.63 (0.4,12.3)].The incidence of all reported symptomatic hypoglycemia was 18.2％,and the incidence of confirmed hypoglycemia was 3.8％.Conclusion This analysis showed that glimepiride treatment as an initial mono-therapy could effectively improve blood glucose control in newly diagnosed patients with T2DM,and the treatment may improve islet β cell function,and the safety profile is reasonably good.

BACKGROUNDChronic obstructive pulmonary disease (COPD) has a variable natural history and not all individuals follow the same course. This study aimed to identify the prevalence and characteristics of asymptomatic COPD patients from a population-based survey in China.

METHODSA multistage cluster sampling strategy was used in a population from seven different provinces/cities. All residents (over 40 years old) were interviewed with a standardized questionnaire and spirometry. Post-bronchodilator forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) of less than 70% was defined as the diagnostic criterion of COPD. All COPD patients screened were divided into symptomatic group and asymptomatic group according to the presence or absence of chronic respiratory symptoms. Socio-demographic, personal and exposure variables were collected and analyzed.

RESULTSAmong the 1668 patients who were diagnosed with COPD from the 25 627 sampling subjects, 589 (35.3%) were asymptomatic. The age, sex, body mass index (BMI), rural and urban distributions, smoking habit and education levels were similar in the two groups. A total of 64.7% of the asymptomatic patients had no comorbidities. Cardiovascular diseases and lung cancer were more common among symptomatic COPD patients than asymptomatic group. Asymptomatic COPD group were less likely to present with poor ventilation in the kitchen, a family history of respiratory disease and recurrent childhood cough. Asymptomatic COPD patients had significantly higher FEV(1) (73.1% vs. 61.0%), FVC (91.9% vs. 82.0%), and a higher ratio of FEV(1)/FVC (62.9% vs. 58.7%) (all P < 0.001) than symptomatic group. More asymptomatic patients were underdiagnosed (91.9% vs. 54.3%, P < 0.001) than symptomatic patients.

CONCLUSIONSThis large population-based survey confirmed a high prevalence of asymptomatic COPD patients in China. More use of spirometry screening test may be important to the early detection of COPD.

Adult ; Aged ; Aged, 80 and over ; China ; epidemiology ; Educational Status ; Female ; Humans ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive ; diagnosis ; epidemiology ; Risk Factors ; Smoking ; Spirometry ; Surveys and Questionnaires