A Single-center, Open-label, Parallel Control Study Comparing the Pharmacokinetics and Safety of a Single Oral Dose of Roflumilast and Its Active Metabolite Roflumilast N-oxide in Healthy Chinese and Caucasian Volunteers.

Roflumilast is a phosphodiesterase-4 inhibitor which treats chronic obstructive pulmonary disease (COPD). Roflumilast N-oxide is the major metabolite of roflumilast with a similar mechanism of action to roflumilast. Although racial differences in roflumilast drug disposition have been observed, the necessity of dose adjustment is subject to debate. This study compares the pharmacokinetics of a single 500 µg dose of roflumilast in healthy Chinese and Caucasian subjects under uniform conditions. Chinese subjects were found to have longer t1/2 and higher AUC0-t and Cmax than Caucasian subjects. The point estimates on the geometric mean of AUC0-t in Chinese subjects were 22% higher for roflumilast and 46% higher for roflumilast N-oxide. Point estimates on the geometric mean of Cmax were 9% and 24% higher for roflumilast and roflumilast N-oxide, respectively. Total phosphodiesterase-4 (PDE4) inhibitory (tPDE4i) activity, a theoretical parameter that describes the combined contribution to PDE4 inhibitory activity of roflumilast and roflumilast N-oxide, was 44% higher in Chinese subjects than in Caucasian subjects. With about a 10-fold higher plasma AUC compared to the parent roflumilast and a much longer observed half-life, roflumilast N-oxide has been estimated to contribute about 90% of tPDE4i, with 10% attributed to the parent compound roflumilast. Following body weight normalization, these figures were lower but remained significant. Safety analysis showed signs of reduced tolerance or different pharmacodynamic response to roflumilast in Chinese recipients than in Caucasians. Our results suggest that Chinese patients should receive a dose of roflumilast lower than 500 µg daily during future clinical trials.

Evaluation of a five-gene signature associated with stromal infiltration for diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a common non-Hodgkin lymphoma. The development of immunotherapy greatly improves the patient prognosis but there are some exceptions. Thus, screening for better biomarkers for prognostic evaluation could contribute to the treatment of DLBCL patients. AIM: To screen the novel mediators involved in the development of DLBCL. METHODS: The GSE60 dataset was applied to identify the differentially expressed genes (DEGs) in DLBCL, and the principal components analysis plot was used to determine the quality of the included samples. The protein-protein interactions were analyzed by the STRING tool. The key hub genes were entered into to the GEPIA database to determine their expressions in DLBCL. Furthermore, these hub gene alterations were analyzed in cBioportal. The UALCAN portal was employed to analyze the expression of the hub genes in different stages of DLBCL. The Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data Score was conducted to evaluate the correlation between the gene expression and tumor purity. The gene-gene correlation analysis was conducted in the GEPIA. The stromal score analysis was conducted in TIMER to confirm the correlation between the gene expression and infiltrated stromal cells. The correlation between the indicated genes and infiltration level of cancer-associated fibroblasts (CAFs) was also completed in TIMER with two methods, MCP-Counter and Tumor immune dysfunction and exclusion. The correlation between fibronectin (FN1) protein level and secreted protein acidic and cysteine-rich (SPARC) messenger ribonucleic acid expression was confirmed in the cBioportal. RESULTS: The top 20 DEGs in DLBCL were identified, and the principal components analysis plot confirmed the quality of the significant DEGs. The pairwise correlation coefficient analysis among all samples showed that these DEGs have a certain co-expression pattern. The DEGs were subjected to STRING to identify the hub genes, alpha-2-macroglobulin (A2M), cathepsin B (CTSB), FN1, matrix metallopeptidase 9 (MMP9), and SPARC. The five hub genes were confirmed to be overexpressed in DLBCL. The cBioportal portal detected these five hub genes that had gene alteration, including messenger ribonucleic acid high amplification and missense mutation, and the gene alteration percentages of A2M, FN1, CTSB, MMP9, and SPARC were 5%, 8%, 5%, 2.7%, and 5%, respectively. Furthermore, the five hub genes had a potential positive correlation with tumor stage. The correlation analysis between the five genes and tumor purity confirmed that the five genes were overexpressed in DLBCL and had a positive correlation with the development of DLBCL. More interestingly, the five genes had a significant correlation with the stromal infiltration scores. The correlation analysis between the fives genes and CAFs also showed a significant value, among which the top two genes, FN1 and SPARC, had a remarkable co-expression pattern. CONCLUSION: The top DEGs were identified, and the five hub genes were overexpressed in DLBCL. Furthermore, the gene alterations were confirmed and the positive correlation with tumor purity revealed the overexpression of the five genes and close association with the development of DLBCL. More interestingly, the five genes were positively correlated with stromal infiltration, especially in CAFs. The top two genes, FN1 and SPARC, showed a co-expression pattern, which indicates their potential as novel therapeutic targets for DLBCL.

Cytokine-induced killer cells combined with dendritic cells inhibited liver cancer cells.

OBJECTIVES: To investigate the prognosis of advanced liver cancer patients treated with CIK-DCs and the mechanism of apoptosis of HEPG 2 cells. METHODS: 67 patients were enrolled in the study. Peripheral blood mononuclear cells (PBMCs) were separated, of which adherent PBMCs used granulocyte 2 macrophage colony2 stimulating factor (GM2CSF), tumor necrosis factor 2α (TNF2α), and interleukin 24 (IL24) to induce DCs, which were sensitized with antigen of autologous or exogenous cancer cells to obtain Ag-DCs; suspended PBMCs used interferon 2γ (IFN2γ), IL-2, and CD 3 monoclonal antibody (CD3mAb) respectively, to induce CIK cells. DCs and CIK cells were cultured together. Flow cytometry was used to detect the phenotypes of DCs and CIK cells, and the blood retransfused into patients. Western blot and flow cytometer were used to analyze the growth cycle of HepG 2 cells and the expression of BAX and PCNA. RESULTS: No patients underwent complete remission, 5 obtained partial remission and 29 had stable disease. Of the 31 patients whose lesions could not be evaluated, 17 received effective treatment, showing that the immune response was enhanced. In vitro laboratory experiments revealed that DC-CIK cells markedly affected the growth cycle of HepG 2 cells. Analysis showed that DC-CIK cells enhanced the gene expression of BAX and inhibited the activity of PCNA. CONCLUSIONS: Co-cultured DCs and CIK cells inhibit the proliferation and migration of liver cancer cells by down-regulating PCNA and up-regulating BAX. This approach may be an effective method to treat advanced liver cancer.

[Distribution characteristics of organochlorine pesticides in surface water and sediments from the Mengjin wetland].

The surface water and sediments from the Mengjin wetland were collected. After seperated and concentrated by solid phase extraction and Soxhlet extraction, twenty kinds of organochlorine pesticides (OCPs) in the samples from the Mengjin wetland were analyzed by gas chromatography. In the surface water, 7 kinds of OCPs (incluing alpha-HCH, beta-HCH, gamma-HCH, delta-HCH, 4,4-DDT, heptachor and aldrin) were detected, with the detected ratio of 4.2% -62.5% and the content range of ND-12.21 ng/L. In the sediments, 4,4-DDE and 4,4-DDT were detected, with the detected ratio of 50%-75% and the content range of ND-64.58 ng/g. HCHs and DDTs in the surface water were both lower than the limited value defined by Environmental Quality Standards for Surface Water in China, while the surface sediments in the Mengjin wetland pose a bit high risk comparing with ERL and ERM value of risk evaluation. Distribution characteristics of OCPs components showed that HCHs usually had higher residue levels in surface water, while sediment was the fate of DDTs in the transfer process of materials from water to sediment. OCPs content in the surface water and sediments both decreased in the order of high water period > level water period > low water period. OCPs in the low water seasons were mainly the early residue, but OCPs in the high seasons had some new input in near term in the surface water and sediments. The results suggested that non-point source was one of the important sources of OCPs entering Mengjin wetland.

Observation on therapeutic effect of electroacupuncture plus blood-letting puncture at Weizhong (BL 40) on acute lumbar disc herniation / 中国针灸

<p><b>OBJECTIVE</b>To find a better method for treatment of acute lumbar disc herniation.</p><p><b>METHODS</b>One hundred cases were randomly divided into 2 groups. The observation group of 52 cases was treated with electroacupuncture at Yaoyangguan (GV 3), Dachangshu (BL 25), Guanyuanshu (BL 26), Xiaochangshu (BI. 27) as main points, and blood-letting puncture at stagnant collaterals nearby Weizhong (BL 40); the control group of 48 cases was treated with traction combined with electroacupuncture at main points Jiaji (EX-B 2), Shenshu (BL 23), Dachangshu (BL 25). Their therapeutic effects were observed and compared.</p><p><b>RESULTS</b>The cured rate and the cured markedly effective rate were 55.8% and 82.7% in the observation group and 33.3% and 54.2% in the control group, respectively, with significant differences between the two groups (P < 0.05, P < 0.01).</p><p><b>CONCLUSION</b>Electroacupuncture combined with blood letting puncture at stagnant collaterals nearby Weizhong (BL 40) has a signifi cant therapeutic effect on acute lumbar disc herniation.</p>

Activation of periphery group III metabotropic glutamate receptors inhibits formalin-induced activation of spinal p38-MAPK in rats / 中国应用生理学杂志

<p><b>AIM</b>To explore the effects of periphery injection of L-SOP on the activation of p38MAPK in spinal cord in formalin pain model in rats.</p><p><b>METHODS</b>Fourty-eight male Wistar rats were divided randomly into four groups (n=12): NS group and three different dose of L-SOP groups. For each group, 6 rats used to observe flinching and licking time every as nociception behavior 3 minutes in 1 hour after formalin injected and the other 6 rats used to observe the activation of p38(P-p38) by Western blotting.</p><p><b>RESULTS</b>All the three different groups of L-SOP could inhibit nociception behavior in the tonic phase,and 250 nmoVl/L and 500 nmol/L groups could suppress not only in the tonic phase but also in the acute phase. 250 nmol/L and 500 nmol/L groups could reduce activated or phosphorylated p38MAPK in spinal cord.</p><p><b>CONCLUSION</b>Periphery injection of L-SOP can reduce nociceptive behavior and phosphorylated p38MAPK in the spinal cord in formalin-induced hyperalgia, it is suggested that there is functional expression of mGluRs III in the periphery and is involved in the processing of peripheral noxious informations.</p>