Precise Control of Metal Active Sites of Metal-Organic Framework Nanozymes for Achieving Excellent Enzyme-Like Activity and Efficient Pancreatitis Therapy.

Acute pancreatitis (AP) is a potentially life-threatening inflammatory disease that can lead to the development of systemic inflammatory response syndrome and its progression to severe acute pancreatitis. Hence, there is an urgent need for the rational design of highly efficient antioxidants to treat AP. Herein, an optimized Cu-based metal-organic framework (MOF) nanozyme with exceptional antioxidant activity is introduced, designed to effectively alleviate AP, by engineering the metal coordination centers in MN2Cl2 (M = Co, Ni, Cu). Specifically, the Cu MOF, which benefits from a Cu active center similar to that of natural superoxide dismutase (SOD), exhibited at least four times higher SOD-like activity than the Ni/Co MOF. Theoretical analyses further demonstrate that the CuN2Cl2 site not only has a moderate adsorption effect on the substrate molecule •OOH but also reduces the dissociation energy of the product H2 O2 . Additionally, the Cu MOF nanozyme possesses the excellent catalase-like activity and •OH removal ability. Consequently, the Cu MOF with broad-spectrum antioxidant activity can efficiently scavenge reactive oxygen species to alleviate arginine-induced AP. More importantly, it can also mitigate apoptosis and necrosis of acinar cells by activating the PINK1/PARK2-mediated mitophagy pathway. This study highlights the distinctive functions of tunable MOF nanozymes and their potential bio-applications.

Aligned electrospun fiber film loaded with multi-enzyme mimetic iridium nanozymes for wound healing.

A film with elaborate microstructures that offers biomimetic properties and multi functionalities is highly desired in wound healing. Here, we develop an aligned hydrogel fiber film integrated with multi-active constituents to promote wound healing. Such fiber films are designed and constructed by photo-crosslinking the methacrylate gelatin (GelMA) doped with silver nanoparticles (Ag NPs) and iridium nanoparticles coated with polyvinylpyrrolidone (PVP-Ir NPs) in the precursor solution using electrospinning. The nature of GelMA hydrogel and the aligned arrangement of nanofibers endow the film with high-water content, self-degradability, improved bionic characteristics, oriented cell growth, and improved cell proliferation and migration. Moreover, the encapsulated nanozymes and Ag NPs offer the fiber film with superior reactive oxygen species (ROS) scavenging and antibacterial capability. The infected wound model shows that the multi-active hydrogel fiber film can reduce inflammation by killing bacteria and decomposing ROS, which accelerates the growth of new blood vessels and granulation tissue. Benefitting from these features, the versatile aligned GelMA fiber film demonstrates the clinically translational potential for wound healing.

Four Variants of SLCO2A1 Identified in Three Chinese Patients with Chronic Enteropathy Associated with the SLCO2A1 Gene.

BACKGROUND: Chronic enteropathy associated with the SLCO2A1 gene (CEAS) is an enteropathy characterized by multiple small intestinal ulcers of nonspecific histology, also known as chronic nonspecific multiple ulcers of the small intestine. The SLCO2A1 gene encodes a prostaglandin transporter (PGT). AIMS: The aim of this study was to investigate the clinical characteristics of ten Chinese patients with intestinal ulcers of unknown origin, screen them for variants of SLCO2A1, and to investigate the expression of PGT in the small intestinal mucosa of patients with CEAS. METHODS: Ten Chinese patients with intestinal ulcers of unknown origin were included in this study. Blood samples were collected for whole-exome sequencing and Sanger sequencing of candidate gene variants. Immunohistochemical staining was used to investigate the expression of PGT. RESULTS: These ten patients were clinically diagnosed with intestinal ulcers of unknown origin based on criteria established according to earlier publications. Three of them were genetically diagnosed as having CEAS and four candidate variants of the SLCO2A1 gene were identified, among which c.941-1G>A, c.178G>A and c.1681C>T were detected in patients with CEAS for the first time. The terminal ileum was involved in all three patients with CEAS in our study, which was different from the results of Japanese patients. The expression of PGT in the vascular endothelial cells of the intestinal mucosa tissues of patients with CEAS was negative or intermediate. CONCLUSION: We summarized the clinical data of ten Chinese patients with intestinal ulcers of unknown origin and identified three novel SLCO2A1 variants from three patients with CEAS. This study improves our understanding of CEAS and broadens the spectrum of SLCO2A1 variants known to cause CEAS.

Screening and verification of microRNA promoter methylation sites in hepatocellular carcinoma.

The promoter methylation mode of microribonucleic acid (miRNA) plays a crucial role in the process of hepatocellular carcinoma (HCC). Therefore, the primary purpose of this study was to screen and verify the miRNA methylation sites associated with the overall survival (OS) and clinical characteristics of HCC patients. Methylation-related data were from the Cancer Genome Atlas (TCGA). R software was utilized to screen the methylation sites. The least absolute shrinkage and selection operator algorithm was utilized to develop the miRNA promoter methylation models. Then, methylation-specific polymerase chain reaction was performed with 146 HCC tissues to verify the accuracy of the vascular infiltration-related model. Additionally, we verified the functions of vascular infiltration-related miRNA by utilizing cells transfected with miR-199a-3p mimic. The model for predicting OS of HCC patients contained eight methylation sites. The Kaplan-Meier analysis suggested that the model could divide HCC patients into high- and low-risk groups (P < .0001). COX regression analysis suggested that the model (P < .001; 95% CI, 1.264-2.709) and T category (P < .001; 95% CI, 1.472-3.119) were independent risk factors for affecting OS of HCC patients. The model for predicting vascular infiltration, pathological grade, and clinical stage contained 7, 10, and 9 methylation sites respectively, with their area under the receiver operating characteristic curve (AUC) values 0.667, 0.745, and 0.725, respectively. The functional analysis suggested that miRNA methylation is involved in various biological processes such as WNT, MAPK, and mTOR signaling pathways. The accuracy of the vascular infiltration-related model was consistent with our previous bioinformatics assay. And upregulation of miR-199a-3p decreased migration and invasion abilities. The screened miRNA promoter methylation sites can be served as biomarkers for judging OS, vascular infiltration, pathology grade, and clinical stage. It can also provide new targets for improving the treatment and prognosis of HCC patients.

Screening and verification of long noncoding RNA promoter methylation sites in hepatocellular carcinoma.

BACKGROUND: Long noncoding ribonucleic acid (lncRNA) promoter methylation is closely related to the occurrence and development of hepatocellular carcinoma (HCC). Thus, we aim to screen and verify the lncRNA promoter methylation sites associated with overall survival (OS), vascular invasion, pathological grade, and clinical stage in HCC. METHODS: Methylation-related data including clinical characteristic, transcriptome, methylation, and messenger RNA (mRNA) expression were taken from the Cancer Genome Atlas (TCGA) database. The OS, vascular invasion, pathological grade, and clinical stage-related lncRNA promoter methylation models were developed by the least absolute shrinkage and selection operator (LASSO) algorithm based on the lncRNA promoter methylation sites screened via R software. The Kaplan-Meier analysis, the area under the receiver operating characteristic (ROC) curve (AUC), the calibration curve (C-index) were performed to evaluate the performance of these models. Finally, the methylation-specific polymerase chain reaction (MS-PCR) was performed to verify the accuracy of these models based on 146 HCC tissues from our hospital. RESULTS: A total of 10 methylation sites were included in the OS-related lncRNA promoter methylation model that could effectively divide HCC patients into high-risk and low-risk groups (P < 0.0001) via survival analysis. COX univariable and multivariable regression analysis found that the OS-related model (P < 0.001, 95% CI 1.378-2.942) and T stage (P < 0.001, 95% CI 1.490-3.418) were independent risk factors affecting OS in HCC patients. The vascular invasion-related model contained 8 methylation sites with its AUC value of 0.657; the pathological grade-related model contained 22 methylation sites with its AUC value of 0.797; the clinical stage-related model contained 13 methylation sites with its AUC of 0.724. Target genes corresponded to vascular invasion-related lncRNA promoter methylation sites were involved in many kinds of biological processes in HCC such as PI3K-Akt signaling pathway. The accuracy of the vascular invasion-related model was consistent with our bioinformatics conclusion after being verified via MS-PCR. CONCLUSION: The lncRNA promoter methylation sites are closely correlated with the process of HCC and can be utilized to improve the therapy and prognosis of HCC.

Correction to: Identification of a competing endogenous RNA network associated with prognosis of pancreatic adenocarcinoma.

[This corrects the article DOI: 10.1186/s12935-020-01243-6.].

Identification of a competing endogenous RNA network associated with prognosis of pancreatic adenocarcinoma.

BACKGROUND: Emerging evidence suggests that competing endogenous RNAs plays a crucial role in the development and progress of pancreatic adenocarcinoma (PAAD). The objective was to identify a new lncRNA-miRNA-mRNA network as prognostic markers, and develop and validate a multi-mRNAs-based classifier for predicting overall survival (OS) in PAAD. METHODS: Data on pancreatic RNA expression and clinical information of 445 PAAD patients and 328 normal subjects were downloaded from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Genotype-Tissue Expression (GTEx). The weighted correlation network analysis (WGCNA) was used to analyze long non-coding RNA (lncRNA) and mRNA, clustering genes with similar expression patterns. MiRcode was used to predict the sponge microRNAs (miRNAs) corresponding to lncRNAs. The downstream targeted mRNAs of miRNAs were identified by starBase, miRDB, miRTarBase and Targetscan. A multi-mRNAs-based classifier was develop using least absolute shrinkage and selection operator method (LASSO) COX regression model, which was tested in an independent validation cohort. RESULTS: A lncRNA-miRNA-mRNA co-expression network which consisted of 60 lncRNAs, 3 miRNAs and 3 mRNAs associated with the prognosis of patients with PAAD was established. In addition, we constructed a 14-mRNAs-based classifier based on a training cohort composed of 178 PAAD patients, of which the area under receiver operating characteristic (AUC) in predicting 1-year, 3-year, and 5-year OS was 0.719, 0.806 and 0.794, respectively. The classifier also shown good prediction function in independent verification cohorts, with the AUC of 0.604, 0.639 and 0.607, respectively. CONCLUSIONS: A novel competitive endogenous RNA (ceRNA) network associated with progression of PAAD could be used as a reference for future molecular biology research.

[Clinical and genetic diagnosis in a hereditary hemorrhagic telangiectasia family].

OBJECTIVE: To investigate the clinical features and feasibility genetic diagnosis in a hereditary hemorrhagic telangiectasia (HHT) family, and to explore the application of gene mutation testing in HHT diagnosis.
 Methods: Medical histories and clinical features of a family were analyzed to diagnose HHT patients and suspected individuals according to the clinical diagnostic criteria. Sequence analysis of endoglin (ENG) and activin A receptor like type 1 (ACVRL1) gene in the proband was performed with PCR and Sanger sequencing technology. After the possible pathogenic mutation was identified in the proband, the specific mutation was detected in the suspected individuals and part of other family members. Then the genetic diagnoses were concluded.
 Results: There were 5 family members in 4 generations manifested with epistaxis. According to the clinical diagnosis criteria, the proband with epistaxis, mucocutaneous telangiectases, visceral arteriovenous malformation and family history was diagnosed as HHT; while 2 survival family members with epistaxis and family history were suspected individuals. A substitution mutation in the 5'-untranslated region(5'-UTR) of ENG c.1-127 C>T was detected in the proband and the 2 suspected individuals, which did not exist in other family members. Based on the clinical and genetic findings, the 2 clinically suspected individuals were diagnosed as HHT.
 Conclusion: There is great variability of the clinical manifestations among HHT patients. ENG c.1-127 C>T mutation is the possible pathogenic variant of the HHT family. A combination of clinical and genetic diagnosis could improve the diagnosis and treatment of HHT.

A novel two-axis load sensor designed for in situ scratch testing inside scanning electron microscopes.

Because of a lack of available miniaturized multiaxial load sensors to measure the normal load and the lateral load simultaneously, quantitative in situ scratch devices inside scanning electron microscopes and the transmission electron microscopes have barely been developed up to now. A novel two-axis load sensor was designed in this paper. With an I-shaped structure, the sensor has the function of measuring the lateral load and the normal load simultaneously, and at the same time it has compact dimensions. Finite element simulations were carried out to evaluate stiffness and modal characteristics. A decoupling algorithm was proposed to resolve the cross-coupling between the two-axis loads. Natural frequency of the sensor was tested. Linearity and decoupling parameters were obtained from the calibration experiments, which indicate that the sensor has good linearity and the cross-coupling between the two axes is not strong. Via the decoupling algorithm and the corresponding decoupling parameters, simultaneous measurement of the lateral load and the normal load can be realized via the developed two-axis load sensor. Preliminary applications of the load sensor for scratch testing indicate that the load sensor can work well during the scratch testing. Taking advantage of the compact structure, it has the potential ability for applications in quantitative in situ scratch testing inside SEMs.

Thermoresponsive Ozone-Enriched Spray Gel for Postsurgical Treatment of Hepatocellular Carcinoma.

Surgical resection of hepatocellular carcinoma suffers from a high recurrence rate. Ozone directly kills tumor cells by generating reactive oxygen species in vitro, but its high reactivity and short half-life severely limit its tumor accumulation and penetration for the treatment of tumors in vivo. Herein, a thermoresponsive ozone-enriched spray gel is developed to suppress the tumor recurrence of hepatocellular carcinoma (Huh-7 tumors). Briefly, a perfluorocarbon nanoemulsion (PFTBA@LIP) consisting of a perfluorotributylamine core and a lipid monolayer is fabricated, which is encapsulated in the thermoresponsive hydrogel. Ozone is then dissolved in the nanoemulsion owing to its high affinity to PFTBA (O3/PFTBA@LIP@Gel), which effectively improves its stability. Of note is that O3/PFTBA@LIP@Gel induces both ferroptosis and apoptosis by regulating the expression of relevant genes (GPX4, ACSL4, CDKN1A, etc.) and inducing considerable lipid peroxidation, which significantly reduces the tumor recurrence of the Huh-7 tumor by spraying the gel in the surgical cavity and prolongs the survival of tumor-bearing mice.

In Situ Sprayed Starvation/Chemodynamic Therapeutic Gel for Post-Surgical Treatment of IDH1 (R132H) Glioma.

Complete resection of isocitrate dehydrogenase 1 (IDH1) (R132H) glioma is unfeasible and the classic post-surgical chemo/radiotherapy suffers from high recurrence and low survival rate. IDH1 (R132H) cells are sensitive to low concentrations of glucose and high concentrations of reactive oxygen species (ROS) due to inherent metabolism reprograming. Hence, a starvation/chemodynamic therapeutic gel is developed to combat residual IDH1 (R132H) tumor cells after surgery. Briefly, glucose oxidase (GOx) is mineralized with manganese-doped calcium phosphate to form GOx@MnCaP nanoparticles, which are encapsulated into the fibrin gel (GOx@MnCaP@fibrin). After spraying gel in the surgical cavity, GOx catalyzes the oxidation of glucose in residual IDH1 (R132H) cells and produces H2 O2 . The generated H2 O2 is further converted into highly lethal hydroxyl radicals (•OH) by a Mn2+ -mediated Fenton-like reaction to further kill the residual IDH1 (R132H) cells. The as-prepared starvation/chemodynamic therapeutic gel shows much higher therapeutic efficacy toward IDH1 (R132H) cells than IDH1 (WT) cells, and achieves long-term survival.

Development and validation of the trans-omics model for pancreatic adenocarcinoma.

Aim: To develop a trans-omics-based molecular clinicopathological algorithm for predicting pancreatic adenocarcinoma prognosis, we performed a comprehensive analysis of the expression levels of mRNA, DNA methylation and DNA copy number in The Cancer Genome Atlas dataset. Materials & methods: Based on the least absolute shrinkage and selection operator method - COX regression analysis, a trans-omics-based classifier was established to predict overall survival. Nomogram was constructed by combining the classifier band clinical pathological characterization. Results: Based on trans-omics, we developed a 10-gene-based classifier and a molecular-clinicopathologic nomogram for predicting overall survival with satisfactory accuracy. Conclusion: Trans-omics-based classifier and molecule-clinicopathological nomogram based on the classifier can accurately predict the prognosis of pancreatic adenocarcinoma patients.

An immunogenomic signature for molecular classification in hepatocellular carcinoma.

Immunity plays an important role in tumor development. In this study, we aimed to investigate molecular classification and its prognostic value in hepatocellular carcinoma (HCC) based on immune signature. Gene set enrichment analysis (GSEA) was used to calculate scores of immune pathways for HCC and hierarchical clustering in two databases (The Cancer Genome Atlas [TCGA], Liver Cancer-RIKEN, JP [LIRI_JP]). The scores of the immune microenvironment and the proportions of 22 immune cells were also calculated. Single-sample GSEA (ssGSEA) was used to screen survival prognosis-related immune pathways and calculate the hazard radio of differentially expressed immune-related genes (IRGs), which were validated in clinical samples and multiple datasets. Based on the immune characteristics, we identified three HCC subtypes, namely immunity high (Immunity_H), immunity medium (Immunity_M), and immunity low (Immunity_L), and confirmed that the classification was reliable and predictable. Immunity_H with a higher immune and stromal score indicated better survival rate. Cox regression analysis showed that IL18RAP and IL7R were the protective genes. Immune risk score was the independent risk factor of overall survival in HCC patients. These results indicated that immunogenomic classification could distinguish HCC patients with different immune status, which could impact the prognosis of the patients with HCC.

PINK1/PARK2 dependent mitophagy effectively suppresses NLRP3 inflammasome to alleviate acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a clinically common acute inflammatory disease in digestive system, leading to systemic inflammatory response syndrome (SIRS) and severe acute pancreatitis (SAP). It was reported that PINK1/PARK2 dependent mitophagy played an important role in various inflammatory diseases. However, its role in AP has not been elucidated. Herein, we explore the effect of mitophagy in the pathogenesis of AP. METHODS: Firstly, we established cerulein-induced AP group and arginine-induced SAP group based on wild, PINK1-/- and PARK2-/- mice. Pancreatic samples were harvested for further investing the mitochondrial dynamics, mitophagy alterations, NLRP3 inflammatory pathway etc. Furthermore, peripheral blood mononuclear cells from SAP patients were collected to examine the expression of mitophagy-related indicators. Additionally, the interrelationship between mitophagy and NLRP3 inflammasome was also explored in AP. RESULTS: It was confirmed that mitochondria were damaged in both AP and SAP models. The expressions of PINK1, PARK2 and mitochondrial autophagosomes were elevated in wild AP group, which were decreased in SAP group over time. Similarly, the expressions of PINK1 and PAKR2 in peripheral blood mononuclear cells were significantly lower in SAP patients. Besides, in PINK1-/- and PARK2-/- mice AP groups, more pronounced inflammatory infiltration, increased apoptotic and necrotic levels and upregulated NLRP3 inflammasome pathway were detected. After injection with MCC950, NLRP3 inflammasome production was notably reduced in PINK1-/-and PARK2-/-mice, which effectively alleviated the pancreatic damage and inflammatory cell infiltration. CONCLUSION: Our study suggested that mitochondrial dysfunction activated PINK1/PARK2-mediated mitophagy in AP, while mitophagy was impaired in SAP. PINK1-/- and PARK2-/- mice were more sensitive to onset of SAP and the deficiency of mitophagy could lead to the formation of NLRP3 inflammasome.

Highly sensitive detection of carcinoembryonic antigen using copper-free click chemistry on the surface of azide cofunctionalized graphene oxide.

In this study, we reported a highly sensitive method for detecting carcinoembryonic antigen (CEA) based on an azide cofunctionalized graphene oxide (GO-N3) and carbon dot (CDs) biosensor system. Carbon dots-labeled DNA (CDs-DNA) combined with GO-N3 using copper-free click chemistry (CFCC), which quenched the fluorescence of the CDs via fluorescence resonance energy transfer (FRET). Upon the addition of CEA, fluorescence was recovered due to the combination of CEA and aptamer. Under optimal conditions, the relative fluorescence intensity was linear with CEA concentration in the range of 0.01-1 ng/mL (R2 = 0.9788), and the limit of detection (LOD) was 7.32 pg/mL (S/N = 3). This biosensor had a high sensitivity and good selectivity for CEA detection in serum samples, indicating that the novel sensor platform holds a great potential for CEA and other biomarkers in practical applications.

Oncogene PRR14 promotes breast cancer through activation of PI3K signal pathway and inhibition of CHEK2 pathway.

Nuclear envelope component PRR14 has been detected to be upregulated in varieties of cancers, especially in breast cancer. But its role in breast carcinogenesis is poorly understood. In this study, we show PRR14 contributes to breast carcinogenesis mainly through overexpression, which derives from elevated transcription and gene amplification. Increased PRR14 expression promotes breast cancer cell proliferation and tumor formation. Biochemical analysis reveals, in addition to previously reported activation of PI3-kinase/Akt/mTOR pathway, PRR14 overexpression regulates cell cycle in breast cancer by inhibiting CHEK2's activation, followed with the deregulation of DNA damage pathway. In correspondence, CHEK2 and PRR14 show opposite impact on breast cancer patients receiving chemotherapy. Collectively, our study is the first to document the oncogenetic role of PRR14 in breast cancer, which protects cells from apoptosis and stimulates proliferation by activating the PI3-kinase/Akt/mTOR pathway and inhibiting the CHEK2 pathway. Both of these pathways are of great influence in breast cancer and PRR14 appears to be their novel interacting node, which renders patients more resistance to chemotherapy and provides a potential therapeutic target in breast cancer.

Clinical and Genetic Analyses of 38 Chinese Patients with Peutz-Jeghers Syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disease caused by a germline mutation in the STK11 gene. It is characterized by mucocutaneous pigmentation, gastrointestinal hamartomatous polyps, and cancer predisposition. AIMS: We aimed to summarize the main clinical and genetic features of Chinese PJS patients and assessed the genotype-phenotype correlations. METHODS: Thirty-eight patients clinically diagnosed with Peutz-Jeghers syndrome were included in this study from 2016 to 2019. Combined direct sequencing and multiplex ligation-dependent probe amplification tests were used to detect germline heterogeneous STK11 mutations. RNA sequencing was performed in polyps of PJS patients and control groups to evaluate the difference in expression of STK11. The genotype-phenotype correlations were calculated by Kaplan-Meier analyses. RESULTS: All 26 probands and 12 affected relatives had germline heterogeneous STK11 mutations among which 8 variants were novel. Individuals with missense mutations had their first surgery and other symptoms significantly later than individuals with null mutations. CONCLUSION: This study expanded the spectrum of STK11 gene mutations and further elucidated individuals with null mutations of STK11 typically had an earlier onset of PJS symptoms and needed earlier management.

A novel molecular-clinicopathologic nomogram to improve prognosis prediction of hepatocellular carcinoma.

BACKGROUND: Emerging evidence suggests that long non-coding RNA (lncRNA) plays a crucial part in the development and progress of hepatocellular carcinoma (HCC). The objective was to develop novel molecular-clinicopathological prediction methods for overall survival (OS) and recurrence of HCC. RESULTS: An 8-lncRNA-based classifier for OS and a 14-lncRNA-based classifier for recurrence were developed by LASSO COX regression analysis, both of which had high accuracy. The tdROC of OS-nomogram and recurrence-nomogram indicates the satisfactory accuracy and predictive power. The classifiers and nomograms for predicting OS and recurrence of HCC were validated in the Test and GEO cohorts. CONCLUSIONS: These two lncRNA-based classifiers could be independent prognostic factors for OS and recurrence. The molecule-clinicopathological nomograms based on the classifiers could increase the prognostic value. METHODS: HCC lncRNA expression profiles from the cancer genome atlas (TCGA) were randomly divided into 1:1 training and test cohorts. Based on least absolute shrinkage and selection operator method (LASSO) COX regression model, lncRNA-based classifiers were established to predict OS and recurrence, respectively. OS-nomogram and recurrence-nomogram were developed by combining lncRNA-based classifiers and clinicopathological characterization to predict OS and recurrence, respectively. The prognostic value was accessed by the time-dependent receiver operating characteristic (tdROC) and the concordance index (C-index).

Interleukin-6, tumor necrosis factor-alpha and receptor activator of nuclear factor kappa ligand are elevated in hypertrophic gastric mucosa of pachydermoperiostosis.

Pachydermoperiostosis (PDP) is a rare inherited multisystem disease characterized with digital clubbing, pachydermia and periostosis. Variants in either HPGD or SLCO2A1 that interrupt the prostaglandin E2 (PGE2) pathway have been shown to be involved in PDP. Here, in addition to six confirmed variants in HPGD or SLCO2A1, we identified four novel SLCO2A1 variants in eight PDP patients from seven Chinese Han families. In addition, gastric mucosa hyperplasia was observed in all affected individuals and interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα) and receptor activator of nuclear factor kappa ligand (RANKL) expression were elevated in hypertrophic gastric mucosa. Two of eight patients who had severe arthralgia were treated with celecoxib. After three months, their arthralgia was partly relieved and IL-6, TNFα and RANKL expression were decreased in accordance with their relieved hypertrophic gastric mucosa. Our study broadens the variation spectrum of SLCO2A1 and suggests that the gastric mucosa hyperplasia might be a common characteristic of PDP. Moreover, celecoxib would be a considerable choice for PDP patients. We also revealed that IL-6, TNFα and RANKL may play important roles in the molecular mechanisms of gastric mucosa hyperplasia in PDP for the first time.

[Analysis and test of piezoelectric micropump for drug delivery].

With a microsystem or micropump, the release rate of drug delivery is able to be controlled easily to maintain the therapeutic efficacy. A piezoelectric membrane-valve micropump for implantable and carryhome drug delivery system is developed and tested. The influence elements of dynamic performance of the PZT actuator and valve were analyzed, and the calculation method of resonant frequency of the membrane valve was provided. Study results showed that the output performance of the micropump depended on the coupling effect of the actuator and valve. For a given actuator, the output value and the optimal frequency of a micropump could be enhanced only by valve design. Two micropumps with different valve dimensions were fabricated for comparing examination. The smaller -valve micropump obtained higher output values (the maximum flow rate and backpressure being 3.5 ml/min and 27 KPa, respectively) and two optimal frequencies (800 Hz and 3 000 Hz). The larger -valve micropump achieved lower output values (the maximum flow rate and backpressure being 3.0 ml/min and 9 KPa, respectively) and one optimal frequency (about 200 Hz). The test results suggest that the output values and optimal frequency of micropump can be improved by changing the valve dimension, and the viewpoint that checkvalve micropump works only with low acting frequency is wrong.