Phase unwrapping algorithm for images with local high-density noise.

Due to undersampling and the local phase with local high-density noise, it is still difficult to develop a robust phase unwrapping algorithm. In order to resolve this issue, here, we propose what we believe to be a novel multiple path-following phase unwrapping (MPIPU) algorithm based on the shearing interference principle to recover the undersampling phase (non-noise). By calculating the unwrapping coefficient k, the phase iteration filling algorithm based on least-squares is developed for the high-density noise region in order to reconstruct the three-dimensional surface topography of interferometric synthetic aperture radar (InSAR) data. The proposed algorithm takes advantage of the MPIPU's ability to fill in the missing phase with fitting data and can successfully suppress the error transfer caused by the blocky noise phase iteration process. Several experiments are conducted using both simulated and actual InSAR image data. The experimental findings show that the proposed method can achieve robust phase unwrapping performance on a phase of local high-density noise.

The Associations Between CYP2D6 Metabolizer Status and Pharmacokinetics and Clinical Outcomes of Venlafaxine: A Systematic Review and Meta-Analysis.

BACKGROUND: The association between CYP2D6 metabolizer status and clinical outcomes of venlafaxine was extensively investigated previously, but no widely accepted conclusion has been reached so far. To obtain a more precise estimation of the association, a systematic review by meta-analysis was conducted in the present study. METHODS: The PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Technology of Chongqing, and Wan Fang Database were searched for eligible studies up to August 2018. RESULTS: Fourteen related studies involving 1035 patients were finally included. Significant associations were found among 3 CYP2D6 phenotypes (NM, IM, and PM) and most pharmacokinetic parameters of venlafaxine. However, CYP2D6 phenotypes were not associated with Hamilton Depression Rating Scale response of venlafaxine. In addition, we also found no significant association between CYP2D6 phenotype and overall rate of adverse events. CONCLUSIONS: CYP2D6 metabolizer status had significant influence on venlafaxine pharmacokinetics, but insufficient evidence demonstrated that CYP2D6 metabolizer status was associated with its therapeutic effects and overall rate of adverse events, which provided further evidence regarding the relationship between CYP2D6 metabolizer status and venlafaxine.

Effect of UGT2B7 genotypes on plasma concentration of valproic acid: a meta-analysis.

PURPOSE: Valproic acid (VPA) is one of the most widely used antiepileptic drugs. Recently, increasing evidence suggested that polymorphisms in UGT2B7 gene were associated with VPA pharmacokinetics, but results remained controversial. Therefore, a meta-analysis was performed to derive a more precise evaluation between C802T, C161T, and G211T polymorphisms and plasma concentration of VPA. METHODS: The PubMed, EMBASE, and the Cochrane library databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated. The mean difference (MD) and 95% confidence interval (CI) were applied to assess the strength of the relationship. RESULTS: A total of 12 studies involving 1996 related East Asia epilepsy patients were assessed. We found that the UGT2B7 G211T polymorphism was associated with adjusted plasma VPA concentration (GG versus TT: P = 0.01, I 2 = 97%; GG versus GT: P < 0.00001, I 2 = 0%). Additionally, we also observed a significantly association between the C161T polymorphism and adjusted plasma VPA concentration (CC versus CT: P = 0.01, I 2 = 77%). Nevertheless, the pooled analysis showed that the C802T polymorphism had no significant effect on adjusted serum concentration of VPA. CONCLUSIONS: The results of this meta-analysis demonstrated that UGT2B7 G211T and C161T polymorphisms were able to affect the pharmacokinetics in epilepsy patients treated with VPA, which provide further evidence for genetic effects of UGT2B7 gene on pharmacokinetics and pharmacodynamics of VPA. Epilepsy patients with these genotypes may be necessary to increase (or decrease) VPA dose to ensure its therapeutic effect.

The HRH4 rs11662595 mutation is associated with histamine H4 receptor dysfunction and with increased epithelial-to-mesenchymal transition progress in non-small cell lung cancer.

We previously demonstrated that histamine H4 receptor (HRH4) played important roles to suppress epithelial-to-mesenchymal transition (EMT) progress in non-small cell lung cancer (NSCLC). Furthermore, recent investigations suggested that genetic variations in HRH4 gene affected HRH4 function and eventually contributed to certain HRH4-related diseases. However, the relations between polymorphisms in HRH4 gene and NSCLC as well as their underlying mechanisms remain largely uninvestigated. This study aims to investigate the genetic effect of a nonsynonymous HRH4 polymorphism (rs11662595) on HRH4 function and its association with NSCLC both basically and clinically. For basic experiments, A549 cells were transfected with either wild type or rs11662595 mutated HRH4 clone and subjected to both in vitro and in vivo experiments. We showed that rs11662595 significantly decreased the ability of HRH4 to activate Gi protein, which resulted in facilitation of EMT progress, cell proliferation, and invasion behavior in vitro. Moreover, in vivo experiments also showed that rs11662595 attenuated the anti-EMT effects of HRH4 agonist in inoculated nu/nu mice. For clinical experiments, we performed a prospective cohort study among 624 NSCLC patients and further proved that rs11662595 was responsible for the prognosis, degree of malignancy and metastasis of NSCLC. In conclusion, these findings reveal that rs11662595 is a loss-of-function polymorphism that results in dysfunction of HRH4 and attenuates the anti-EMT function of HRH4 in NSCLC, which provides a promising biomarker for prognosis and therapy of NSCLC.

Development and validation of an LC-ESI-MS/MS method for the quantitation of hemslecin A in rhesus monkey plasma and its application in pharmacokinetics.

In this study, a new LC-ESI-MS/MS-based method was validated for the quantitation of hemslecin A in rhesus monkey plasma using otophylloside A as internal standard (IS). Hemslecin A and the IS were extracted from rhesus monkey plasma using liquid-liquid extraction as the sample clean-up procedure, and were subjected to chromatography on a Phenomenex Luna CN column (150 × 2.0 mm, 3.0 µm) with the mobile phase consisting of methanol and 0.02 mol/mL ammonium acetate (55:45, v/v) at a flow rate of 0.2 mL/min. Detection was performed on an Agilent G6410B tandem mass spectrometer by positive ion electrospray ionization in multiple reaction monitoring mode, monitoring the transitions m/z 580.5 [M + NH4 ](+) → 503.4 and m/z 518.2 [M + NH4 ](+) → 345.0 for hemslecin A and IS, respectively. The assay was linear over the concentration range of 0.5-200 ng/mL and was successfully applied to a pharmacokinetic study in rhesus monkeys.

Scutellarin inhibits cytochrome P450 isoenzyme 1A2 (CYP1A2) in rats.

Scutellarin is the most important flavone glycoside in the herbal drug Erigeron breviscapus (Vant.) Hand.-Mazz. It is used frequently in the clinic to treat ischemic vascular diseases in China. However, the direct relationship between scutellarin and cytochrome P450 (CYP450) is unclear. The present study investigated the in vitro and in vivo effects of scutellarin on cytochrome P450 1A2 (CYP 1A2) metabolism. According to in vitro experiments, scutellarin (10-250 µM) decreased the formation of 4-acetamidophenol in a concentration-dependent manner, with an IC50 value of 108.20 ± 0.657 µM. Furthermore, scutellarin exhibited a weak mixed-type inhibition against the activity of CYP1A2 in rat liver microsomes, with a K(i) value of 95.2 µM. Whereas in whole animal studies, scutellarin treatment for 7 days (at 5, 15, 30 mg/kg, i.p.) decreased the clearance (CL), and increased the T(1/2) (at 15, 30 mg/kg, i.p.), it did not affect the V(d) of phenacetin. Scutellarin treatment (at 5, 15, 30 mg/kg, i.p.) increased the AUC(0-∞) by 14.3%, 67.3% and 159.2%, respectively. Scutellarin at 30 mg/kg also weakly inhibited CYP1A2 activity, in accordance with our in vitro study. Thus, the results indicate that CYP1A2 is inhibited directly, but weakly, by scutellarin in vivo, and provide useful information on the safe and effective use of scutellarin in clinical practice.

Nano-hydroxyapatite/ß-tricalcium phosphate ceramics scaffolds loaded with cationic liposomal ceftazidime: preparation, release characteristics in vitro and inhibition to Staphylococcus aureus biofilms.

In the current study, nano-hydroxyapatite/ß-tricalcium phosphate (HA/ß-TCP) ceramics scaffolds loaded with cationic liposomal ceftazidime (CLCs) prepared by modified reverse phase evaporation method, the investigations of their release characteristics were performed by the dissolution tests, in vitro anti-biofilm activity of the scaffolds was studied by the determination of bacterial susceptibility with ELISA. The mean particle size, zeta potential, pH and entrapment efficiency of the CLCs studied were 161.5 ± 5.37 nm, 60.60 ± 5.24 mV, 6.90 ± 0.07 and 16.57 ± 0.13%, respectively. Electron microscopic images of the samples indicated that the liposomes were well preserved in the scaffolds and that it was the CLCs rather than free ceftazidime releasing from the scaffolds. The minimal inhibitory concentrations (MICs) to Staphylococcus aureus of free ceftazidime and its liposomal formulation were 6.00 µg/mL and the release behaviors of both CLCs and free ceftazidime from scaffolds were based on the dissolution/diffusion processes, Fick's law. These results demonstrated that CLCs could inhibit remarkably the formation of S. aureus biofilm more effectively than free ceftazidime (P < 0.05). The study demonstrated that the HA/ß-TCP ceramic scaffolds was such a material that could sustain release CLCs and maintain the adequate amounts of CLCs to absorb to biofilm. It provided an ideal way to inhibit bacterial biofilms for clinical practices.

Transarterial Chemoembolization Combined With Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors for Unresectable Hepatocellular Carcinoma: Efficacy and Systemic Immune Response.

Background: Locoregional therapy combined with systemic therapy can further improve the prognoses for HCC. However, the efficacy of TACE combined with ICIs and TKIs for HCC and whether this triple therapy can activate systemic immune response are still unknown. Purpose: To identify the efficacy of TACE+ICIs+TKIs for unresectable hepatocellular carcinoma (uHCC) and its effect on systemic immunity. Materials and Methods: This single-center retrospective study was approved by the Institutional Review Board. From August 1, 2019, to March 30, 2021, patients with uHCC who received the combination therapy of TACE+ICIs+TKIs were included. Peripheral blood samples were collected at baseline and once a month for 4 months after treatment. Lymphocyte subsets were measured by flow cytometry. Immunoglobulins were measured using the immune turbidimetric method. The dynamic change trend of circulating parameters was tested using simple linear regression. Results: Fifty-three patients with a mean age of 59 ± 10.6 years were included. TTP was 8.0 months (95% CI, 5.5-10.5) and PFS was 8.5 months (95% CI, 5.4-11.5). ORR was 52.8% and DCR was 81.1%. Twenty patients had completed analysis of biomarkers in peripheral blood. For cellular immune response, the level of circulating CD8+, CD3+ T cells and NK cells increased, the frequency of CD4+T cells and the CD4+/CD8+ ratio decreased, and among them, CD8+ T cells increased significantly. For humoral immune response, there was a significant decrease in B cells and a significant increase in Ig G, Ig κ, and Ig λ. Moreover, Ig G, Ig κ, and Ig λ were related to tumor response. Conclusion: TACE+ICIs+TKIs showed considerable efficacy in patients with uHCC. This triple therapy activated not only cell immune but also humoral immune activation. Circulating Ig G, Ig λ, and Ig κ can serve as potential biomarkers.

Upregulation of PD-L1 expression promotes epithelial-to-mesenchymal transition in sorafenib-resistant hepatocellular carcinoma cells.

BACKGROUND: The epithelial-to-mesenchymal transition (EMT) status is associated with programmed death-1 ligand 1 (PD-L1) expression in various cancers. However, the role and molecular mechanism of PD-L1 in the EMT of sorafenib-resistant hepatocellular carcinoma (HCC) cells remain elusive. In this study, we aimed to investigate the regulation of PD-L1 on the EMT in sorafenib-resistant HCC cells. METHODS: Initially, the sorafenib-resistant HCC cell lines HepG2 SR and Huh7 SR were established. Western-blot assays were used to detect the expression of PD-L1, E-cadherin, and N-cadherin. The intervention and overexpression of PD-L1 were used to explore the role of PD-L1 in the regulation of EMT in HepG2 SR and Huh7 SR cells. Cell migration and invasion were assessed by transwell assays. PD-L1 or Sterol regulatory element-binding protein 1 (SREBP-1) overexpression and knock-down were performed in order to study the mechanism of PD-L1 in sorafenib-resistant HCC cells. RESULTS: PD-L1 expression was upregulated, whereas E-cadherin levels were downregulated and N-cadherin expression was increased in HepG2 SR and Huh7 SR cells. The cell viabilities of HepG2 and Huh7 cells were lower than those of HepG2 SR and Huh7 SR cells. PD-L1 overexpression reduced E-cadherin expression and increased N-cadherin levels, whereas PD-L1 knock-down increased E-cadherin expression and decreased N-cadherin expression. PD-L1 expression promoted EMT and the migratory and invasive abilities of HepG2 SR and Huh7 SR cells. PD-L1 promoted the EMT of sorafenib-resistant HCC cells via the PI3K/Akt pathway by activating SREBP-1 expression in HepG2 SR and Huh7 SR cells. CONCLUSIONS: The findings reveal that PD-L1 expression promotes EMT of sorafenib-resistant HCC cells.

Antibacterial alkaloids from chelidonium majus linn (papaveraceae) against clinical isolates of methicillin-resistant Staphylococcus aureus.

PURPOSE: This study describes the antibacterial effect of extracts and compounds isolated from the aerial part of Chelidonium majus Linn. (Papaveraceae) acting against clinical strains of methicillin-resistant Staphylococcus aureus (MRSA). METHODS: The activities were evaluated by using the macrobroth dilution method and reported as the MICs/MBCs. RESULTS: Bioassay-guided fractionation of the most active extract from the aerial parts (EtOAc) led to the isolation of benzo[c]phenanthridine-type alkaloids 8-hydroxydihydrosanguinarine (hhS), 8-hydroxydihydrochelerythrine (hhC), which were potently active against MRSA strains. CONCLUSIONS: The selective antibacterial activity reported in this paper for 8-hydroxylated benzo[c]phenanthridine-type alkaloids isolated from C.majus opens the possibility that they could be helpful for the developing of new antibacterial agents for treating the infection of MRSA which has created nosocomial problem worldwide.

ROR1 is highly expressed in circulating tumor cells and promotes invasion of pancreatic cancer.

Pancreatic cancer (PaC) is an aggressive malignancy, which is associated with high levels of metastasis. Circulating tumor cells (CTCs), which may be considered a functional biomarker and promising treatment strategy for metastasis, are associated with the prognosis and progression of various metastatic cancers, including PaC. Receptor tyrosine kinase­like orphan receptor 1 (ROR1) expression contributes to cell metastasis and poor clinical outcomes in malignant tumors. The present study aimed to explore the function of ROR1 in PaC CTCs. Reverse transcription­quantitative polymerase chain reaction and western blot analysis were used to examine the expression of ROR1, E­cadherin and N­cadherin. Cell proliferative and invasive ability was assessed by MTT and Transwell assays, respectively. The results revealed that the mRNA and protein expression levels of ROR1 were augmented in PaC tissues. Furthermore, the mRNA expression levels of ROR1 were higher in CTCs compared with in peripheral blood cells, and ROR1 was more highly expressed in CTCs than in cells. Notably, CTCs exhibited a markedly greater proliferative and invasive capacity than PANC­1 and SW­1990 cells, whereas knockdown of endogenous ROR1 by small interfering RNA led to suppression of the invasion of CTCs. In addition, it was revealed that the mechanism underlying the effects of ROR1 on PaC CTC metastasis may involve the epithelial­mesenchymal transition process. In conclusion, ROR1 may be considered a potential biomarker and therapeutic target for the treatment of PaC.

Aptamer-drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity.

INTRODUCTION: The toxic side effects of doxorubicin (DOX) have limited its use in chemotherapy. Neither liposomal DOX nor pegylated liposomal DOX are able to completely resolve this issue. This is a proof-of-concept study testing aptamer-drug conjugate (ApDC) targeted delivery systems for chemotherapeutic drugs. METHODS: Aptamer library targeting human epidermal growth factor receptor 3 (HER3) was screened and affinity was determined by enzyme-linked immunosorbent assay. Specificity was tested in MCF-7HER3-high, BT474HER3-high, and 293THER3-negative cells using flow cytometry and confocal microscopy. We further developed a HER3 aptamer-functionalized liposome encapsulating DOX and the efficiency of this ApDC was detected by cellular uptake analysis and cell viability assay. In MCF-7 tumor-bearing mice, tumor targeting evaluation, efficacy, toxicity and preliminary pharmocokinetic study was performed. RESULTS: The candidate #13 aptamer had highest affinity (Kd =98±9.7 nM) and specificity. ApDC effectively reduces the half maximal inhibitory concentration of DOX compared with lipsome-DOX and free DOX. In vivo imaging and preliminary distribution studies showed that actively targeted nanoparticles, such as Apt-Lip-DOX molecules, could facilitate the delivery of DOX into tumors in MCF-7-bearing mice. This targeted chemotherapy caused greater tumor suppression than other groups and alleviated side effects such as weight loss, low survival rate, and organ (heart and liver) injury demonstrated by H&E staining. CONCLUSION: The results indicate that targeted chemotherapy using the aptamer-drug conjugate format could provide better tolerability and efficacy compared with non-targeted delivery in relatively low-dose toxic drugs.

IL-4Rα aptamer-liposome-CpG oligodeoxynucleotides suppress tumour growth by targeting the tumour microenvironment.

Tumour immunosuppressive microenvironments inhibit antigen-specific cellular responses and interfere with CpG-mediated immunotherapy. Overcoming tumour microenvironment (TME) immunosuppression is an important strategy for effective therapy. This study investigated the ability of a tumour-targeting IL-4Rα aptamer-liposome-CpG ODN delivery system to introduce CpG into tumours and overcome the immunosuppressive TME. The IL-4Rα-liposome-CpG delivery system was prepared. FAM-CpG visualisation was used to demonstrate tumour targeting in vitro and in vivo. Anti-tumour effects of this delivery system were evaluated in CT26 tumour-bearing mice. Mechanisms for conquering the TME were investigated. FAM-CpG was better distributed into the tumours upon treatment with IL-4Rα-liposome-FAM-CpG compared to distribution in the control group in vitro and in vivo. IL-4Rα-aptamer-liposome-CpG treatment inhibited distinct myeloid-derived suppressor cell populations in tumours and bone marrow. Similar profiles were observed for regulatory T cells in tumours. In CT26 tumour-bearing mice, IL-4Rα-liposome-CpG treatment exhibited enhanced anti-tumour activity. Increased mRNA levels of TNF-α, IL-2, and IL-12, and decreased mRNA levels of VEGF, IL-6, IL-10, MMP9, arginase-1, inducible NOS, CXCL9, p-Stat3, and NF-κB were observed in tumours upon IL-4R-liposome-CpG-treatment. The results suggested that pharmacologic targeting by the IL-4R aptamer-liposome-CpG system improves TME therapeutic benefit and provides a rationale for cancer immunotherapies.

Associations of Polymorphisms in HRH2, HRH3, DAO, and HNMT Genes with Risk of Chronic Heart Failure.

The pathophysiological functions of cardiac histamine level and related histamine receptors during the development of chronic heart failure (CHF) were intensively investigated previously. However, the relevance of polymorphisms in histamine-related genes, such as HRH2, HRH3, DAO, and HNMT, with CHF remains largely neglected. This study herein aims to analyze the clinical associations of polymorphisms in those genes with CHF risk. A total of 333 unrelated Chinese Han CHF patients and 354 ethnicity-matched healthy controls were recruited and 11 single nucleotide polymorphisms (SNPs) were genotyped. We found that the HRH3 rs3787429 polymorphism was associated with CHF risk (p < 0.001). The T allele of rs3787429 exhibited protective effect against CHF under the dominant (ORs = 0.455; 95% CIs = 0.322-0.642) and additive models (ORs = 0.662; 95% CIs = 0.523-0.838), while, for SNPs in HRH2, DAO, and HNMT, no significant associations were observed in the present study. These findings for the first time screen out one SNP (rs3787429) of HRH3 gene that was significantly associated with CHF in Chinese Han population, which may be a novel biomarker for personal prevention and treatment of CHF and provides novel highlights for investigating the contribution of this disease.

Relation of polymorphism of the histidine decarboxylase gene to chronic heart failure in Han Chinese.

Histidine decarboxylase (HDC) is a key determinant of the levels of endogenous histamine that has long been recognized to play important pathophysiological roles during development of chronic heart failure (CHF). Meanwhile, certain genetic variants in HDC gene were reported to affect the function of HDC and associated with histamine-related diseases. However, the relation between polymorphisms of HDC gene and CHF risk remains unclear. This study aims to investigate the associations between 2 nonsynonymous HDC polymorphisms (rs17740607 and rs2073440) and CHF. We designed a 2-stage case-control study, in which we genotyped 439 patients with CHF and 467 healthy controls recruited in Xi'an, China, and replicated this study in 413 patients with CHF and 452 healthy subjects in Kunming, China. We also performed in vitro experiments to further validate the functional consequences of variants positively associated with CHF. The rs17740607 polymorphism showed replicated associations with all-cause CHF according to genotype and allele distribution and also under a dominant and additive genetic model after adjusted for traditional cardiovascular-related factors. Functional experiments further demonstrated that rs17740607 polymorphism decreased the HDC activity. In conclusion, HDC rs17740607 polymorphism is at least a partial loss-of-function variant and acts as a protective factor against CHF, which provides novel highlights for investigating the contribution of CHF.

Association of CYP2C19 polymorphisms with survival of breast cancer patients using tamoxifen: results of a meta- analysis.

BACKGROUND: Previous studies accessing the association of CYP2C19 with outcomes of patients using tamoxifen for breast cancer have yielded conflicting results. The aim of this meta-analysis is to obtain a more precise estimate of effects of CYP2C19 polymorphisms and to clarify their effects on survival of the breast cancer patients using tamoxifen. MATERIALS AND METHODS: A systematic search of PubMed and Embase was performed, comparing patients with or without CYP2C19*2 and CYP2C19*17, relevant articles searched for. The following outcomes were included from the eligible studies: disease-free survival (DFS) and overall survival (OS), expressed by hazard ratios (HR) with corresponding 95% confidence interval (CI). Subgroup analysis by genotypes was also performed. Pooled estimates were calculated using random-effect model in accordance to the heterogeneity. RESULTS: Six studies met the inclusion criteria. The integrated OR on the association between CYP2C19 and DFS, calculated by the random-effect model, was 0.54 (95%CI=0.34-0.84, p=0.013). Subgroup analysis showed that both CYP2C19*2 and CYP2C19*17 were associated with increased survival. The pooled results of two studies for OS were OR=0.46 (95%CI=0.21-1.01, p=0.233). CONCLUSIONS: This meta-analysis suggests that the CYP2C19*2 and CYP2C19*17 genotypes are associated with increased survival in breast cancer patients using tamoxifen.

Associations of polymorphisms in histidine decarboxylase, histamine N-methyltransferase and histamine receptor H3 genes with breast cancer.

We previously found that genetic polymorphisms in gene coding for histamine H4 receptors were related to the risk and malignant degree of breast cancer. The roles of polymorphisms in other histamine-related genes, such as histidine decarboxylase (HDC), histamine N-methyltransferase (HNMT) and histamine H3 receptor (HRH3), remain unexplored. The aim of this study is to analyze the clinical associations of polymorphisms in HDC, HNMT and HRH3 with breast cancer. Two hundred and one unrelated Chinese Han breast cancer patients and 205 ethnicity-matched health controls were recruited for case-control investigation. Genomic DNA from the participants was extracted and 5 single nucleotide polymorphisms (SNPs) in HDC, HNMT and HRH3 were genotyped. We found that polymorphisms of HNMT and HRH3 were irrelevant with breast cancer in the present study. However, the T allele of rs7164386 in HDC significantly decreased the risk of breast cancer (adjusted odds ratios [ORs], 0.387; 95% confidence intervals [CIs], 0.208-0.720; P = 0.003). Furthermore, for HDC haplotypes, the CG haplotype of rs7164386-rs7182203 was more frequent among breast cancer patients (adjusted OR, 1.828; 95% CI, 1.218-2.744; P = 0.004) while the TG haplotype was more frequent among health controls (adjusted OR, 0.351; 95% CI, 0.182-0.678; P = 0.002). These findings indicated that polymorphisms of HDC gene were significantly associated with breast cancer in Chinese Han population and may be novel diagnostic or therapeutic targets for breast cancer. Further studies with larger participants worldwide are still needed for conclusion validation.

Activation of histamine H4 receptors decreases epithelial-to-mesenchymal transition progress by inhibiting transforming growth factor-ß1 signalling pathway in non-small cell lung cancer.

Previous investigations found that epithelial-to-mesenchymal transition (EMT) was an important character of non-small cell lung cancer (NSCLC) and it was also suggested that histamine H4 receptors may have a role in preventing EMT progress in certain kind of tumours. However, the effect of H4 receptor activation on EMT progress of NSCLC and its potential mechanisms remain unclear. Therefore, we performed both in vitro and in vivo experiments to explore the effects of specific H4 receptor agonist 4-methylhistamine and antagonist JNJ7777120 on EMT progress. We showed the expression of H4 receptors in NSCLC and found that 4-methylhistamine increased the expression of the epithelial marker E-cadherin and decreased the expression of Vimentin, the mesenchymal marker, in both NSCLC cell lines and xenograft NSCLC tumours. Pretreatment with JNJ7777120 or H4 receptor gene silencing decreased while overexpression of H4 receptors facilitated this effect of 4-methylhistamine. Furthermore, we showed that down-regulation of cyclic adenosine monophosphate (cAMP) was the secondary signalling after H4 receptor activation, which in turn resulted in inactivation of transforming growth factor-ß1 (TGF-ß1) pathway and down-regulation of several important EMT inducing factors such as ZEB1, Snail and Slug. In conclusion, these findings revealed the anti-EMT effect of histamine H4 receptor activation in NSCLC, which provide novel insight into the development mechanism of NSCLC; and H4 receptors may be a new therapeutic target for NSCLC treatment.

Plasma pharmacokinetics and tissue distribution study of roemerine in rats by liquid chromatography with tandem mass spectrometry (LC-MS/MS).

In the present study, a new LC-MS/MS method for the determination of roemerine in rat plasma and tissue samples was developed and successfully used to study the pharmacokinetics and tissue distribution of roemerine after oral and intravenous (i.v.) administration in rats. The plasma and tissue samples were processed by liquid-liquid extraction with n-hexane. Isocorydine was used as the internal standard (IS) for sample processing and analysis. The MS/MS detection was carried out by monitoring the transitions of m/z 280→249 and m/z 342→279 for roemerine and the IS, respectively. The calibration curve displayed excellent linearity over the concentration range of 10-2000ng/mL (n=8, r(2)≥0.995), and the lower limit of quantification (LLOQ) was determined to be 10ng/mL. This method was rapid, accurate, highly sensitive, and fully validated. The pharmacokinetic study showed that roemerine was rapidly absorbed and eliminated with a tmax of 0.22±0.08h, t1/2 of 1.59±0.46h, CL of 4.44±0.42L/h/kg, and Vd of 10.16±2.95µg/L following oral administration. Additionally, roemerine showed an excellent oral bioavailability of 84% and a wide tissue distribution with brain penetration. Highest concentrations of roemerine were found in the liver and lung, followed by kidney, spleen, heart, and brain, in that order.