Triglycerides: A Sensitizer but Not a Trigger for Hypertriglyceridemic Acute Pancreatitis.

BACKGROUND: The incidence of hypertriglyceridemic acute pancreatitis (HTG-AP) is increasing. Although the guideline defines the diagnostic criteria as triglyceride (TG) greater than 11.3 mmol/L, there is actually no specific threshold. Many people with hypertriglyceridemia (HTG) or obvious chyloid blood do not develop acute pancreatitis (AP). AIMS: To explore the role of HTG in the pathogenesis of AP. METHODS: Thirty-six male SD rats were randomly assigned into normal control, AP, HTG, HTG-AP, low-dose fenofibrate and high-dose fenofibrate groups. Serum indices and cytokine levels in serum, and pathological changes in pancreatic tissues were observed. The expression levels of TLR4 and NF-κBp65 in pancreatic tissues were detected by immunohistochemistry and Western blot. RESULTS: In normal rats, HTG alone did not induce AP. However, after establishing the HTG-AP model with Poloxam 407 and L-arginine, serum-free fatty acid and TG levels were positively correlated with the levels of lipase, amylase, IL-1ß, IL-6, pancreatic inflammation scores, and the expressions of TLR4 and NF-κBp65 (all P < 0.001). Expressions of TLR4 and NF-κBp65 were significantly increased in the pancreatic tissues of HTG-AP rats. Fenofibrate effectively decreased TG levels in HTG-AP rats and reduced the expression of TLR4 and NF-κBp65 (all P < 0.001). CONCLUSIONS: HTG does not directly cause AP, but rather increases the susceptibility to AP or aggravates the inflammatory response. It is more like a sensitizer of inflammation rather than an activator.

Performance evaluation of CA242 by flow fluorescence assay.

ABSTRACT: Carbohydrate antigen 24-2 (CA24-2) is usually used as a biomarker for the diagnosis of pancreatic cancer and colorectal cancer. Currentlly, a new quantitative assay kit for CA242 by flow fluorometry assay (FFA) was developed by Shanghai Tellgen Cooperation Co. Ltd. China. Therefore, we conducted the performance evaluation for it.According to the "Guiding principles on performance analysis of diagnostic reagents in vitro" and "American association of clinical laboratory standardization guidelines EP15-A2", the accuracy, precision, linear range, reportable range, biological reference interval verification, carry-over contamination rate, anti-interference capability and cross reaction of the assay kit used in TESMI F3999-Luminex200 automatic immunoassay system were evaluated. In addition, the assay kit was performed in parallel to CanAg kit (CanAg Diagnostics Products Beijing Co., Ltd.) to analyze the correlation between the 2 kits.The bias of accuracy of the new assay kit was less than 12.5% and the coefficient of variations (CVs) of precision were all less than 10.0%. The linear range of CA242 concentration of the testing kit was between 3.46 U/ml and 434.76 U/ml and the reportable range was 6.00 to 535.13 U/ml. The CA242 reference interval 0.00 to 20.00 U/ml was suitable for use in laboratory. The carry-over contamination rate was -0.14%. Correlation analysis showed a satisfactory relevance and consistency (r = 0.982, P < .001) between the new assay kit and CanAg kit, with a regression equation Y = 1.0012X to 0.878 (R2 = 0.9647, P < .001). No statistically significant difference between serum samples without interferences and samples containing lipemia, bilirubin and hemoglobin. And no cross reaction existed between the assay kit and the other tumor markers, such as carbohydrate antigen 125 (CA125), alpha-fetoprotein (AFP), and cytokeratin-19 soluble fragment (CYFRA21-1).The new CA242 quantitative assay kit possesses good detection performance when it is used in TESMI F3999-Luminex200 automatic immunoassay system, which can be used for the examination of CA242 in clinical practice.

Structure and function of DEAH-box helicase 32 and its role in cancer.

DEAH-box helicase 32 (DHX32) is an RNA helicase with unique structural characteristics that is involved in numerous biological processes associated with RNA, including ribosome biosynthesis, transcription, mRNA splicing and translation. Increasing evidence suggests that abnormal DHX32 expression contributes to cancer initiation and development, due to dysregulated cell proliferation, differentiation, apoptosis and other processes. In the current review, the discovery, structure and function of DHX32, as well as the association between abnormal DHX32 expression and tumors are discussed. DHX32 expression is downregulated in acute lymphoblastic leukemia, but upregulated in solid tumors, including colorectal and breast cancer. Furthermore, DHX32 expression levels are associated with the pathological and clinical features of the cancer. Therefore, DHX32 may serve as a novel liquid biopsy marker for auxiliary diagnosis and prognosis screening, as well as a possible target for cancer therapy. The molecular mechanism underlying the contribution of DHX32 towards the initiation and development of cancer requires further investigation for the development of anticancer treatments based on manipulating DHX32 expression and function.

Molecular Surveillance and in vitro Drug Sensitivity Study of Plasmodium falciparum Isolates from the China-Myanmar Border.

The emergence and spread of resistance in Plasmodium falciparum to the frontline treatment artemisinin-based combination therapies in Southeast Asia require close monitoring of the situation. Here, we collected 36 clinical samples of P. falciparum from the China-Myanmar border in 2014-2016, adapted these parasites to continuous culture, and performed in vitro drug assays on seven antimalarial drugs. Data for 23 parasites collected in 2010 and 2012 from the same area reported in an early study were used to assess longitudinal changes in drug sensitivity. Parasites remained highly resistant to chloroquine (CQ) and pyrimethamine, whereas they were generally sensitive to mefloquine (MFQ), lumefantrine (LMF), naphthoquine (NQ), and pyronaridine (PND). Parasites showed a similar temporal trend in sensitivity to CQ, NQ, and PND, with gradual reduction in the half-maximal inhibitory concentrations (IC50s) after 2012. The IC50s to the aminoalcohol drugs MFQ, LMF, and quinine (QN) all significantly declined in 2014, followed by various degrees of increase in 2016. Pyrimethamine displayed a continuous increase in IC50 over the years. The Dd2-like P. falciparum chloroquine-resistant transporter mutations were fixed or nearly fixed in the parasite population. The P. falciparum multidrug resistance 1 F1226Y mutation was detected in 80% parasites in 2016 and associated with reduced sensitivity to LMF and QN (P < 0.05). The N51I in P. falciparum dihydrofolate reductase and K540E/N and A581G in P. falciparum dihydropteroate synthase that are associated with antifolate resistance were either fixed or were approaching fixation in recent years. This study provides an updated picture and temporal trend of antimalarial drug resistance in the China-Myanmar border region, which will serve as a reference for antimalarial treatment.

Increasing trends of malaria in a border area of the Greater Mekong Subregion.

BACKGROUND: Intensive malaria transmission along international borders is a significant impediment to malaria elimination in the Greater Mekong Subregion (GMS) of Southeast Asia. Passive case detection (PCD) was used to study the dynamics and trends of malaria transmission at the China-Myanmar border to provide epidemiologic information for improved malaria control. METHODS: PCD was conducted in one hospital and 12 clinics near the Laiza town in northeast Myanmar from 2011 to 2016. Clinical malaria was diagnosed by microscopy and demographic information was captured using a structured questionnaire at the time of the patient's presentation for care. RESULTS: Over the study period, 6175 (19.7%) malaria cases were confirmed by microscopy from 31,326 suspected cases. The four human malaria parasite species were all identified, with Plasmodium vivax and Plasmodium falciparum accounting for 5607 (90.8%) and 481 (7.8%) of the confirmed cases, respectively. In contrast to the steady decline of malaria in the general GMS, the study site had an upward trend of malaria incidence with vivax malaria outbreaks in 2013 and 2016. Adult males, children under the age of 15, and those with occupations such as farming, being a soldier or student, had significantly higher risks of clinical malaria compared to having fevers from other aetiologies. A self-reported history of clinical malaria was also associated with a higher risk of confirmed malaria. CONCLUSIONS: The China-Myanmar border area has experienced an overall upward trend of malaria incidence in recent years with P. vivax becoming the predominant species. Evidence-based control strategies need to focus on high-risk populations.

In vitro susceptibility of Plasmodium falciparum isolates from the China-Myanmar border area to artemisinins and correlation with K13 mutations.

Mutations in the Kelch domain of the K13 gene (PF3D7_1343700) were previously associated with artemisinin resistance in Plasmodium falciparum. This study followed the dynamics of the K13 polymorphisms in P. falciparum parasites from the China-Myanmar border area obtained in 2007-2016, and their in vitro sensitivities to artesunate (AS) and dihydroartemisinin (DHA). The 50% effective concentration (EC5072h) values of 133 culture-adapted field isolates to AS and DHA, measured by the conventional 72 h SYBR Green I-based assay, varied significantly among the parasites from different years; all were significantly higher than that of the reference strain 3D7. Compared with parasites from 2007 to 2008, ring survival rates almost doubled in parasites obtained in later years. Sequencing the full-length K13 genes identified 11 point mutations present in 85 (63.9%) parasite isolates. F446I was the predominant (55/133) variant, and its frequency was increased from 17.6% (3/17) in 2007 to 55.9% (19/34) in 2014-2016. No wild-type (WT) Kelch domain sequences were found in the 34 samples obtained from 2014 to 2016. In the 2014-2016 samples, a new mutation (G533S) appeared and reached 44.1% (15/34). Collectively, parasites with the Kelch domain mutations (after amino acid 440) had significantly higher ring survival rates than the WT parasites. Individually, F446I, G533S and A676D showed significantly higher ring survival rates than the WT. Although the drug sensitivity phenotypes measured by the RSA6h and EC5072h assays may be intrinsically linked to the in vivo clinical efficacy data, the values determined by these two assays were not significantly correlated. This study identified the trend of K13 mutations in parasite populations from the China-Myanmar border area, confirmed an overall correlation of Kelch domain mutations with elevated ring-stage survival rates, and emphasized the importance of monitoring the evolution and spread of parasites with reduced artemisinin sensitivity along the malaria elimination course.

Longitudinal surveillance of drug resistance in Plasmodium falciparum isolates from the China-Myanmar border reveals persistent circulation of multidrug resistant parasites.

Multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion of Southeast Asia is a major threat to malaria elimination and requires close surveillance. In this study, we collected 107 longitudinal clinical samples of P. falciparum in 2007-2012 from the malaria hypoendemic region of the China-Myanmar border and measured their in vitro susceptibilities to 10 antimalarial drugs. Overall, parasites had significantly different IC50 values to all the drugs tested as compared to the reference 3D7 strain. Parasites were also genotyped in seven genes that were associated with drug resistance including pfcrt, pfmdr1, pfmrp1, pfdhfr, pfdhps, pfnhe1, and PfK13 genes. Despite withdrawal of chloroquine and antifolates from treating P. falciparum, parasites remained highly resistant to these drugs and mutations in pfcrt, pfdhfr, and pfdhps genes were highly prevalent and almost reached fixation in the study parasite population. Except for pyronaridine, quinine and lumefantrine, all other tested drugs exhibited significant temporal variations at least between some years, but only chloroquine and piperaquine had a clear temporal trend of continuous increase of IC50s. For the pfmrp1 gene, several mutations were associated with altered sensitivity to a number of drugs tested including chloroquine, piperaquine, lumefantrine and dihydroartemisinin. The association of PfK13 mutations with resistance to multiple drugs suggests potential evolution of PfK13 mutations amid multidrug resistance genetic background. Furthermore, network analysis of drug resistance genes indicated that certain haplotypes associated multidrug resistance persisted in these years, albeit there were year-to-year fluctuations of the predominant haplotypes.