Shengli Yan

Association of the T1799A BRAF mutation with tumor extrathyroidal invasion, higher peripheral platelet counts, and over- expression of platelet-derived growth factor-B in papillary thyroid cancer

The relationship among BRAF mutation, platelet counts, and platelet-derived growth factor (PDGF) with respect to clinicopathological outcomes of papillary thyroid cancer (PTC) may play a role in PTC pathogenesis but remains undefined. We examined the T1799A BRAF mutation by direct genomic DNA sequencing in 108 primary PTC samples from a Chinese cohort and analyzed its relationship with clinicopathological, hematological, and other laboratory results as well as the levels of expression of PDGF in tumors. We found that the BRAF mutation was significantly associated with extrathyroidal invasion and advanced tumor stages III and IV. Specifically, extrathyroidal invasion was seen in 30/54 (56%) PTC with BRAF mutation versus 18/54 (33%) PTC without the mutation (P=0.02). Tumor stages III and IV were seen in 16/54 (30%) PTC with BRAF mutation versus 7/54 (13%) PTC without the mutation (P=0.04). The BRAF mutation was also significantly associated with a higher platelet count, with 249.28+/-53.76 x 10(9)/l in the group of patients with BRAF mutation versus 207.79+/-58.98 x 10(9)/l in the group without the mutation (P=0.001). An association of higher platelet accounts with extrathyroidal invasion was also seen, with 242.66+/-51.85 x 10(9)/l in patients with extrathyroidal invasion versus 218.49+/-59.10 x 10(9)/l in patients without extrathyroidal invasion (P=0.03). The BRAF T1799A-positive PTC tissues harbored a significantly higher level of PDGF-B than BRAF T1799A-negative PTC tissues. The data suggest that the BRAF T1799A mutation is associated with aggressive pathological outcomes of PTC in which high platelet counts and increased PDGF production may play a role.

Effects of RAS inhibitors on diabetic retinopathy: a systematic review and meta-analysis

BACKGROUND Results of several studies have shown a possible beneficial effect of renin-angiotensin system (RAS) inhibitors on diabetic retinopathy, but the findings were contradictory. We did a systematic review and meta-analysis to assess the effect of RAS inhibitors on diabetic retinopathy. METHODS We identified relevant publications in PubMed, Embase, Cochrane Library Central Register of Controlled Trials, and abstracts from main annual meetings. Only randomised controlled trials comparing angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) monotherapy with other antihypertensive drugs or placebo in type 1 or type 2 diabetes were eligible for inclusion in the analysis. The primary outcomes were progression and regression of diabetic retinopathy in all patients and several subgroups. Risk ratios (RRs) with corresponding 95% CIs were pooled. We also did a network meta-analysis to assess the effect of different antihypertensive drugs on diabetic retinopathy by ranking order. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42013004548. FINDINGS 21 randomised clinical trials with 13,823 participants were included in the meta-analysis. RAS inhibitors were associated with reduced risk of progression (absolute risk difference -3%, 95% CI -5 to -1; pooled RR 0.87, 95% CI 0.80-0.95; p=0.002) and increased possibility of regression of diabetic retinopathy (8%, 1-16; RR 1.39, 95% CI 1.19-1.61; p=0.00002). In normotensive patients, RAS inhibitors decreased risk of diabetic retinopathy progression (0.81, 0.69-0.94; p=0.007) and increased possibility of regression (1.43, 1.14-1.79; p=0.002). In hypertensive patients, RAS inhibitors were not associated with difference in risk of progression of diabetic retinopathy (0.93, 0.79-1.10; p=0.42) or possibility of diabetic retinopathy regression (2.21, 0.92-5.31; p=0.08). ACE inhibitors were associated with reduced risk of diabetic retinopathy progression (0.84, 0.75-0.94; p=0.002) and higher possibility of disease regression (1.50, 1.20-1.86; p=0.0003). ARBs were associated with a higher possibility of diabetic retinopathy regression (1.32, 1.07-1.61; p=0.008), but had no effect on disease progression (0.92, 0.80-1.06; p=0.25). Network meta-analysis showed the association of antihypertensive drugs with risk of diabetic retinopathy progression was lowest for ACE inhibitors, followed by ARBs, β blockers, calcium channel blockers, and placebo in rank order. The association of antihypertensive drugs with possibility of diabetic retinopathy regression was highest for ACE inhibitors, followed by ARBs, placebo, and calcium channel blockers in rank order. INTERPRETATION In patients with diabetes, RAS inhibitors reduce the risk of diabetic retinopathy, and increase the possibility of diabetic retinopathy regression. ACE inhibitors might be better than ARBs for treating diabetic retinopathy, and might exert the most beneficial effect on diabetic retinopathy of all widely used antihypertensive drug classes.

Multiple single nucleotide polymorphisms in the human urate transporter 1 (hURAT1) gene are associated with hyperuricaemia in Han Chinese

Objective The present study investigated whether single nucleotide polymorphisms (SNPs) in the human urate transporter 1 (hURAT1) gene are associated with primary hyperuricaemia (HUA) in Han Chinese people. Methods A total of 538 subjects (215 cases and 323 control subjects) were recruited from Qingdao, China. SNPs in potentially functional regions of the gene were identified and genotypes determined by direct sequencing. Association analyses were conducted using Fishers exact test and logistic regression assuming a genotype model. Results By sequencing the promoter, 10 exons, and the exon-intron junctions of the hURAT1 gene, 14 SNPs were identified. Two of the SNPs identified were associated with susceptibility to HUA. The first was a rare intron 3 (11 G→A) SNP (p=0.0005), where carriers of the ‘A’ allele had a 3.4-fold (95% CI 1.67 to 6.93) increased risk of HUA. The second was a common exon 8 (T1309C) SNP (rs7932775), where carriers of one and two ‘C’ alleles had respective fold increased risks of 1.64 (95% CI 1.07 to 2.52) and 2.32 (95% CI 1.37 to 3.95). These SNPs had a joint additive effect of risk of HUA, with those individuals carrying at least one ‘A’ allele at the intron 3 SNP and two ‘C’ alleles at rs7932775 having a 5.88-fold (95% CI 1.25 to 15.57) increased risk of HUA in comparison to those with no risk alleles. Conclusion In conjunction with other studies, our results suggest that there are multiple genetic variants within or near hURAT1 that are associated with susceptibility to HUA in Han Chinese, including a novel SNP located in intron 3.

Association between height and thyroid cancer risk: a meta-analysis of prospective cohort studies.

While several epidemiological studies have investigated the relationship between height and risk for thyroid cancer, the results were inconsistent. In the present study, a systematic review and meta‐analysis of prospective cohort studies was conducted to assess the impact of height on thyroid cancer risk. Online databases were searched up to December 30, 2014, for prospective cohort studies on the association between height and thyroid cancer risk. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random‐effects model of meta‐analysis. In all, 11 articles were included in this meta‐analysis, including 15 prospective cohort studies, containing 6,695,593 participants and 7,062 cases of thyroid cancer. By comparing the highest versus the lowest categories of height, we reported that risk of thyroid cancer was increased with height in both men (summary RR = 1.40, 95%CI 1.09–1.78, p = 0.008) and women (summary RR = 1.54, 95%CI 1.30–1.83, p < 0.001). The summary RR of thyroid cancer per 5‐cm increase in height was 1.16 (95%CI 1.09–1.23, p < 0.001). The results were similar among men (per 5‐cm increase RR = 1.13, 95%CI 1.03–1.23, p = 0.011) and women (per 5‐cm increase RR = 1.18, 95%CI 1.10–1.27, p < 0.001). No obvious risk of publication bias was observed. Our meta‐analysis provides strong evidence for a dose–response relationship between height and risk of thyroid cancer in both men and women.

Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats

The effects and possible mechanisms of adipose-derived stem cells (ASC) infusion on type 2 diabetic rats were investigated in this study. Twenty normal male Sprague-Dawley rats were included in normal control group, and 40 male diabetic rats were randomly divided into diabetic control group and ASC group (which received ASC infusion). After therapy, levels of fasting plasma glucose (FPG), HbA1c, serum insulin and C-peptide, recovery of islet cells, inflammatory cytokines, and insulin sensitivity were analyzed. After ASC infusion, compared with diabetic control group, hyperglycemia in ASC group was ameliorated in 2 weeks and maintained for about 6 weeks, and plasma concentrations of insulin and C-peptide were significantly improved (P<0.01). Number of islet β cells and concentration of vWF in islets in ASC group increased, while activity of caspase-3 in islets was reduced. Moreover, concentrations of TNF-α, IL-6 and IL-1β in ASC group obviously decreased (P<0.05). The expression of GLUT4, INSR, and phosphorylation of insulin signaling molecules in insulin target tissues were effectively improved. ASC infusion could aid in T2DM through recovery of islet β cells and improvement of insulin sensitivity. Autologous ASC infusion might be an effective method for T2DM.

Genetic and functional analysis of two missense DUOX2 mutations in congenital hypothyroidism and goiter.

Mutations in the dual oxidase 2 gene (DUOX2) impair hydrogen peroxide (H2O2) production and cause dyshormonogenesis. In addition, these mutations have been implicated in autosomal recessive congenital hypothyroidism (CH) with goiter. In this study, we identified DUOX2 mutations that were causative for CH and explored the effects of these mutations on DUOX2 function. Blood samples were collected from 10 infants born with CH and goiter to unrelated parents. We extracted genomic DNA and sequenced all exons by polymerase chain reaction direct sequencing. The effects of DUOX2 mutations were characterized by H2O2 production assays and cycloheximide (CHX) chase experiments. Sequence analysis revealed one novel DUOX2 mutation and one known DUOX2 mutation in unrelated families: c.1060C>T (p.R354W) and c.3616 G>A (p.A1206T). Both mutations impaired H2O2 production. CHX chase experiments demonstrated the DUOX2 mutants had shorter half-lives and degraded more rapidly than wild-type DUOX2. Our study identified two novel DUOX2 mutations in Chinese patients with CH and goiter, which were responsible for the deficit in the organification process.

Identification and characterization of novel PAX8 mutations in Congenital Hypothyroidism(CH) in a Chinese population

Objective Based on mutations in PAX8 is associated with thyroid dysgenesis. We aim to identify and characterize PAX8 mutations in a large cohort of congenital hypothyroidism(CH) from thyroid dysgenesis in Chinese population. Methods We screened 453 unrelated Chinese patients with CH from thyroid dysgenesis for PAX8 mutations by sequencing the whole coding regions of PAX8 on genomic DNA isolated from blood. Cell transfection assays using various vector constructs and induced mutagenesis as well as electrophoretic mobility shift assays were used to investigate the effects of selected mutations on the transcribing and binding activities of PAX8 at the promoters of target genes for thyroglobulin (TG) and thyroperoxidase (TPO). Results Five PAX8 mutations were found, yielding a mutation prevalence of 5/453 (1.1%). We selected two mutations in the critical paired domain of PAX8 and generated mutants D94N and G41V. We demonstrated G41V was unable to bind the specific sequence in the promoters of TG and TPO and activate them. D94N could bind to TG and TPO promoters and normally activate the TG promoter transcription but not the TPO promoter transcription. We also demonstrated a dominant negative role of the PAX8 mutants in impairing the function of the wild-type PAX8. Conclusion We for the first time documented the prevalence and characterized the function of PAX8 mutations in CH in Chinese population. The study specifically demonstrated the role of novel mutations D94N and G41V in impairing the function of PAX8, providing further evidence for genetic PAX8 defects as a disease mechanism in CH.

Effect of intensive insulin therapy on first-phase insulin secretion in newly diagnosed type 2 diabetic patients with a family history of the disease

Intensive insulin treatment is known to improve β-cell function in the majority of patients with newly diagnosed type 2 diabetes mellitus (T2DM), and family history (FH) is known to be an important independent risk factor for T2DM. Thus, the aim of the present study was to investigate the difference in first-phase insulin secretion and the effect of intensive insulin therapy on the improvement of β-cell function between T2DM patients with and without a FH of diabetes. Patients with newly diagnosed T2DM and healthy controls were divided into groups according to their FH of diabetes. Improvement in β-cell function was evaluated with an arginine stimulation test after two weeks of continuous subcutaneous insulin infusion (CSII). Compared with the control group, the level of fasting insulin and the homeostasis model assessment of insulin resistance (HOMA2-IR) were higher in the DM group, while the homeostasis model assessment of β-cell insulin secretion (HOMA2-%β) and the first-phase peak ratio were lower (P<0.05). In addition, the first-phase peak ratio in the FH- control group was higher compared with that in the FH+ control group (P=0.023). Following CSII, all the patients achieved excellent blood glucose control in 6.2±3.6 days, without severe adverse effects. In the DM groups, the fasting insulin level and HOMA2-IR were lower, while the HOMA2-%β and first-phase peak ratio were higher, when compared with the values prior to treatment, particularly in the FH- DM group. The HOMA2-%β in the FH+ DM group was lower compared with the FH- DM group (P=0.027). Therefore, T2DM patients with and without a FH of the disease were shown to have a good response to CSII in the improvement of insulin resistance and β-cell function; however, the improvements were less significant in patients with a FH compared with patients without a FH of diabetes.