Maternal serum polyols and its link to gestational diabetes mellitus: A population-based nested case-control study.

CONTEXT: Sugar alcohols (also called polyols) confer a"healthy"sugar substitute. One of possible reasons to support the safe use in pregnant women is their natural origin and the presence of polyols in maternal and fetal samples during normal human gestation. But little is known about the association between circulating sugar alcohols levels and maternal metabolic disorders during pregnancy. OBJECTIVE: We aimed to detect the concentration of the polyols in participants with and without GDM, and to investigate the association between maternal serum levels of polyols and gestational diabetes mellitus (GDM), as well as newborn outcomes. DESIGN: A nested population-based case-control study was conducted in 109 women with and without GDM. Maternal concentrations of serum erythritol, sorbitol, and xylitol at fasting state were quantified using a time-of-flight mass spectrometry system. RESULT: In women with GDM, serum concentrations of erythritol and sorbitol were higher, but serum concentrations of xylitol were lower, compared with those in women without GDM. Per 1-SD increment of Box-Cox transformed concentrations of erythritol and sorbitol were associated with the increased odds of GDM by 43% and 155% (95% CI 1.07-1.92 and 95 CI%: 1.77-3.69), while a decreased odd was found for xylitol by 25% (95 CI%: 0.57-1.00). Additionally, per 1-SD increase of Box-Cox transformed concentrations of serum sorbitol was associated with a 52% increased odd of large-for-gestational-age newborns controlling for possible confounders (95% CI 1.00-2.30). CONCLUSIONS: Maternal circulating sugar alcohols levels during pregnancy were significantly associated with GDM. These findings provide the potential roles of polyols on maternal metabolic health during pregnancy.

Thigh muscle fat fraction is independently associated with impaired glucose metabolism in individuals with obesity.

Background: The aim of this study was to address the intramuscular adipose tissue (IMAT) accumulation in the lower extremities and further detect the relationship between adipose tissue (AT) distribution in the muscle and glucose metabolism in subjects with obesity. Methods: We conducted a cross-sectional study in 120 Chinese obese adults (80 male and 40 female) with BMI ≥ 28 kg/m2. MRI was applied to access the IMAT content in lower extremities. The oral glucose tolerance test was used to evaluate the glucose metabolism and insulin secretion in all individuals. The correlations between glucose metabolism and the fat content of the lower extremities were further assessed. Results: Among 120 included subjects, 54 were classified as subjects with normal glucose tolerance (NGT) and 66 with impaired glucose regulation (IGR). We presented that those with IGR had higher fat accumulation in semitendinosus, adductor magnus, gracilis and sartorius than those with NGT (all P < 0.05). In sex-specific analyses, females have higher IMAT in adductor magnus than males (P < 0.001). Males with IGR had higher fat fraction of semitendinosus and sartorius than those with NGT (P = 0.020, P = 0.014, respectively). Logistic regression analyses revealed that IMAT content in semitendinosus was the independent factor of IGR in individuals with obesity after adjustment for age, gender, triglycerides, creatinine and albumin (odds ratio: 1.13, 95% CI: 1.02-1.26, P = 0.024). Conclusions: Increased adipose tissue accumulation in thigh muscles was associated with glucose dysregulation in patients with obesity. IMAT content in semitendinosus may serve as a possible risk factor for impaired glucose metabolism.

Liver fat is superior to visceral and pancreatic fat as a risk biomarker of impaired glucose regulation in overweight/obese subjects.

AIM: To investigate the distribution of abdominal fat, particularly ectopic fat accumulation, in relation to glucose metabolism in overweight/obese patients. MATERIALS AND METHODS: This study included 257 overweight/obese subjects with body mass index ≥23 kg/m2 . All the subjects underwent an oral glucose tolerance test. Magnetic resonance imaging-proton density fat fraction was used to measure fat accumulation in the liver, pancreas and abdomen. Impaired glucose regulation (IGR) was defined as the presence of prediabetes or diabetes. RESULTS: Liver fat content (LFC) and visceral adipose tissue (VAT) were higher in overweight/obese subjects with diabetes than in those with normal glucose tolerance (NGT). No significant differences were observed in the pancreas fat content and subcutaneous fat area between subjects with NGT and IGR. LFC was an independent risk factor of IGR (odds ratio = 1.824 per standard deviation unit, 95% CI 1.242-2.679, p = .002). Compared with the lowest tertile of LFC, the multivariate-adjusted odds ratio for the prevalence of IGR in the highest tertile was 2.842 (95% CI 1.205-6.704). However, no association was observed between the VAT per standard deviation increment and tertiles after adjusting for multiple factors. For discordant visceral and liver fat phenotypes, the high LFC-low VAT and high LFC-high VAT groups had a higher prevalence of IGR than the low LFC-low VAT group. However, there was no difference in the prevalence of IGR between the low LFC-low VAT and low LFC-high VAT groups. CONCLUSION: Compared with visceral and pancreatic fat content, LFC is a superior risk biomarker for IGR in overweight/obese subjects.

The prognostic value of thyroid-stimulating immunoglobulin in the management of Graves' disease.

BACKGROUND: The bioassay of thyroid-stimulating immunoglobulin was reported to have a similar performance to the commonly used thyroid-stimulating hormone binding inhibition assay, also known as thyroid receptor antibody assay. The normal reference range of thyroid receptor antibody levels indicates the withdrawal of anti-thyroid drugs in the recent clinical guidelines. METHODS: A prospective, longitudinal observational study was conducted to evaluate the prognostic value of thyroid-stimulating immunoglobulin in patients with Graves' disease. RESULTS: A total of 77 patients with Graves' disease treated with anti-thyroid drugs were in a continuous follow-up until 1 year after anti-thyroid drugs discontinuation. Commercial kits of thyroid-stimulating immunoglobulin and M22-thyroid-stimulating hormone binding inhibition assay were used and compared. Thyroid-stimulating immunoglobulin was all negative in healthy controls, Hashimoto thyroiditis, and subacute thyroiditis. Thyroid-stimulating immunoglobulin value was highest in untreated patients with Graves' disease (p < 0.001). Under anti-thyroid drugs treatment, thyroid-stimulating immunoglobulin value decreased gradually. A total of 21 patients had positive thyroid-stimulating immunoglobulin at the end of treatment. According to clinical fate of patients with Graves' disease after withdrawal of anti-thyroid drugs, thyroid-stimulating immunoglobulin value and positivity in patients with relapse were significantly higher than that reported in patients with remission (p = 0.001, p < 0.001). After adjustment for age, gender, initial thyroid receptor antibody, initial thyroid-stimulating immunoglobulin, and thyroid receptor antibody at the end of treatment, the odds ratio of positive thyroid-stimulating immunoglobulin for the risk of relapse was 33.271 (95% confidence interval: 4.741-233.458, p < 0.001) and odds ratio of quantitative thyroid-stimulating immunoglobulin was 1.009 (95% confidence interval: 1.002-1.015, p < 0.001). CONCLUSION: Thyroid-stimulating immunoglobulin is a good predictor of relapse in patients with Graves' disease treated with anti-thyroid drugs. It might be safer to discontinue anti-thyroid drugs when thyroid-stimulating immunoglobulin and thyroid receptor antibody were both negative.

Expansion of inflammatory monocytes in periphery and infiltrated into thyroid tissue in Graves' disease.

Monocytes are important mediators of immune system and are reported to be altered in autoimmune disorders. Little is known about the pathological role of monocytes in Graves' disease (GD). Thus, we investigated monocytes in periphery and thyroid tissue in GD. Untreated GD patients were enrolled and followed up until remission. Monocytes were significantly increased and positively correlated with anti-thyrotropin receptor antibody (TRAb) in untreated GD (rcounts = 0.269, P < 0.001; rpercentage = 0.338, P < 0.001). Flow cytometry showed CD14++ CD16+ monocytes were increased and CD14++ CD16- monocytes were decreased in untreated GD (both P < 0.001). Skewed monocyte subsets were recovered in GD with remission. Serum B cell-activating factor (BAFF) was positively correlated with TRAb (r = 0.384 and P = 0.001). CD14++ CD16+ monocytes expressed higher level of BAFF in untreated GD (P < 0.05). The frequency of CD14+ monocytes and CD14+ CD16+ monocytes were significantly higher in GD thyroid tissue than in normal thyroid tissue (both P < 0.001). Our study suggested CD14++ CD16+ monocytes were significantly expanded and involved in the production of TRAb via secreting a higher level of BAFF in periphery. Besides, monocytes infiltrated into thyroid tissue and thus could serve as an important participant in GD pathogenesis.

Adipose-derived mesenchymal stem cells from obese mice prevent body weight gain and hyperglycemia.

Changes that occur to the stem cell microenvironment with disease are a major consideration that may affect the behavior and potential therapeutic efficacy of mesenchymal stem cells (MSCs). The purpose of this study is to evaluate the effects of adipose-derived MSCs (ADSCs) from obese mice with hyperglycemia on body weight and glucose homeostasis. After 10 weeks of high-fat diet, mice were injected with phosphate-buffered saline (PBS) and ADSCs derived from normal mice (N-ADSCs) or obese mice (O-ADSCs), respectively. Mice fed with standard rodent chow were injected with PBS and served as normal controls. Obese mice treated with O-ADSCs showed less body weight gain than those receiving PBS or N-ADSCs. The mice that received ADSCs, especially O-ADSCs, also showed improvement in obesity-related hyperglycemia. In particular, the inguinal fat was reduced in obese mice receiving O-ADSCs compared with other groups, probably caused by the increased lipolysis of inguinal fat. Moreover, ADSC infusion restored insulin receptor (INSR) expression in the muscle of obese mice. Differential expression of the CD90 surface marker was slightly increased, while monocyte chemoattractant protein 1 (MCP-1) was reduced in O-ADSCs compared to N-ADSCs. These data provide a theoretical basis that autologous ADSCs from obese individuals may be more effective for treating obesity and related hyperglycemia.

Sensory-based approaches in psychiatric care: A systematic mixed-methods review.

AIMS: Sensory-based approaches, including sensory room, sensory cart and specific sensory integration programs, feature various sensory stimulations to focus on a particular space or program. This systematic mixed-methods review describes the impact of sensory-based approaches in psychiatric care and summarizes the important components of sensory interventions. DESIGN: Systematic mixed-methods review was based on the guidelines by Pluye and Hong for comprehensively searching, appraising and synthesizing research evidence. DATA SOURCES: Data were collected from five databases: CINAHL, Embase, Pubmed, Web of Science and Cochrane before March 9, 2020. REVIEW METHODS: Qualitative, quantitative, mixed-methods and original studies published in English on sensory-based approaches in psychiatric care were included. The studies were selected by screening titles, abstracts and full texts, and the quality of each study was assessed by two researchers independently. The data were analysed using thematic analysis. RESULTS: Sixteen studies were chosen for review. Through data integration, four subthemes with positive effects were formed: (1) calming of the patient's mood; (2) calming of the patient's body; (3) improvement of self-care ability; and (4) improvement of the nurse-patient relationship. The sensory-based approach may also lead to negative effects. CONCLUSIONS: Several important components play important roles in the sensory-based approaches: (1) rich, culture-based, personalized sensory stimulation; (2) a quiet, safe, home-based physical environment; (3) a good one-to-one nurse-patient relationship; (4) and the cultivation of patient autonomy and self-management. Sensory-based approaches in a multicultural environment and home environment will be important topics of psychiatric care in the future. IMPACT: There is a lack of synthesis of studies on results of sensory-based approaches in psychiatric care. Four components are important to sensory interventions. It is necessary for mental health service centres and home care for the patients with psychotic disorders to use sensory-based approaches for reference.

Sucralose can improve glucose tolerance and upregulate expression of sweet taste receptors and glucose transporters in an obese rat model.

OBJECTIVES: Non-nutritive sweeteners (NNS) are widely used as replacements for table sugar in beverages and dessert. However, the metabolic effects of NNS remain controversial. This study aimed to investigate the effects of various sucralose loads on glucose metabolism and expression of sweet taste receptors (STR) and glucose transporters in a high-fat diet (HFD) rats. METHODS: Four-week-old male Sprague Dawley rats were fed a HFD for 8 weeks, then randomly divided into eight groups (6 in each group). All were gavaged with either saline, sucralose (0.54 mM or 0.78 mM), or sucrose (324 mM) with/without gurmarin, a sweet taste inhibitor, for 4 weeks, followed by an intragastric glucose tolerance test (IGGTT) with blood glucose, and plasma insulin, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) measurements. In the following week, the rats were sacrificed and the small intestine was removed for measurement of sweet taste receptor and glucose transporter expression by quantitative Reverse Transcription-Polymerase Chain Reaction. RESULTS: In HFD rats, blood glucose levels were decreased at 30, 60, and 120 min during the IGGTT after 4 weeks supplementation with 0.78 mM sucralose. TIR3 expression was increased in the duodenum and TIR2 was increased in the ileum after 324 mM sucrose supplementation. T1R3 expression was increased after 0.54 mM and 0.78 mM sucralose in the ileum, but there was no change in the expression of TIRs in the duodenum after sucralose treatments. SGLT-1 expression was increased after both 0.78 mM sucralose and 324 mM sucrose in the ileum, and only increased in the duodenum after 324 mM sucrose supplementation. CONCLUSIONS: The effects of sucralose on glucose metabolism in HFD rats are dose-dependent and related to enhanced expression of sweet taste receptors and glucose transporters. Further studies are needed to clarify the molecular mechanisms involved.

Low Doses of Sucralose Alter Fecal Microbiota in High-Fat Diet-Induced Obese Rats.

Artificial sweeteners (AS) have been widely used as sugar substitutes to reduce calorie intake. However, it was reported that high doses of AS induced glucose intolerance via modulating gut microbiota. The objective of this study was to investigate the effects of lower doses of sucralose on fecal microbiota in obesity. Eight weeks after high-fat diet (HFD), the male Sprague Dawley rats were randomly divided into four groups (6 in each group) and administrated by a daily gavage of 2 ml normal saline (CON), 0.54 mM sucralose (N054), 0.78 mM sucralose (N078), and 324 mM sucrose (S324), respectively. After 4 weeks, fecal samples were obtained and analyzed by 16S ribosomal RNA gene sequencing. The richness and diversity of fecal microbiota were not changed by sucralose or sucrose. Both 0.54 mM (0.43 mg) and 0.78 mM (0.62 mg) sucralose tended to reduce the beneficial bacteria, Lactobacillaceae and Akkermansiaceae. The relative abundance of family Acidaminoccaceae and its genus Phascolarctobacteriam were increased after 0.54 mM sucralose. In functional prediction, 0.54 mM sucralose increased profiles of carbohydrate metabolism, whereas 0.78 mM sucralose enhanced those of amino acid metabolism. The lower doses of sucralose might alter the compositions of fecal microbiota. The effects of sucralose in different dosages should be considered in the future study.

Decreased SIRT1 expression in the peripheral blood of patients with Graves' disease.

SIRT1, a class III histone/protein deacetylase (HDAC), has been associated with autoimmune diseases. There is a paucity of data about the role of SIRT1 in Graves' disease. The aim of this study was to investigate the role of SIRT1 in the pathogenesis of GD. Here, we showed that SIRT1 expression and activity were significantly decreased in GD patients compared with healthy controls. The NF-κB pathway was activated in the peripheral blood of GD patients. The reduced SIRT1 levels correlated strongly with clinical parameters. In euthyroid patients, SIRT1 expression was markedly upregulated and NF-κB downstream target gene expression was significantly reduced. SIRT1 inhibited the NF-κB pathway activity by deacetylating P65. These results demonstrate that reduced SIRT1 expression and activity contribute to the activation of the NF-κB pathway and may be involved in the pathogenesis of GD.

Applicability of adipose-derived mesenchymal stem cells in treatment of patients with type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is mainly characterized by insulin resistance (IR) and impaired insulin secretion. The chronic inflammatory process contributed to IR and could also hamper pancreatic ß cell function. However, currently applied treatment cannot reverse ß cell damage or alleviate inflammation. Mesenchymal stem cells (MSCs), the cell-based therapy for their self-renewable, differentiation potential, and immunosuppressive properties, have been demonstrated in displaying therapeutic effects in T2DM. Adipose-derived MSCs (AD-MSCs) attracted more attention due to less harvested inconvenience and ethical issues commonly accompany with bone marrow-derived MSCs (BM-MSCs) and fetal annex-derived MSCs. Both AD-MSC therapy studies and mechanism explorations in T2DM animals presented that AD-MSCs could translate to clinical application. However, hyperglycemia, hyperinsulinemia, and metabolic disturbance in T2DM are crucial for impairment of AD-MSC function, which may limit the therapeutical effects of MSCs. This review focuses on the outcomes and the molecular mechanisms of MSC therapies in T2DM which light up the hope of AD-MSCs as an innovative strategy to cure T2DM.

Serum and thyroid tissue level of let-7b and their correlation with TRAb in Graves' disease.

BACKGROUND: Abnormal microRNAs (miRNAs) were reported to be involved in the mechanism of Graves' disease (GD). Dysregulated miRNAs may be overlapping in different cells and can be secreted to circulation. We chose miRNAs which were previously reported to be differentially expressed in peripheral blood mononuclear cells (PBMCs) in patients with GD with different disease stage, detected the expression of those miRNAs in serum, corroborated the findings in thyroid tissue, and validated the target gene in vitro to investigate the possible role of circulating miRNAs in GD. METHODS: A total of 54 individuals with untreated GD, 12 individuals with GD in remission and 14 disease-free controls were enrolled. The expression of miR-142-3p, miR-154-3p, miR-431-3p, miR-590-5p, and let-7b was detected in the serum. Ten thyroid tissue samples from patients with GD and six disease-free thyroid samples were used for further validation. The potential target genes were identified and validated in vitro. RESULTS: miR-142-3p, miR-154-3p, miR-431-3p, miR-590-5p, and let-7b were present in serum and two of them (miR-142-3p and let-7b) were significantly increased in serum of patients with untreated GD (for serum miR-142-3p, P = 0.033, for serum let-7b, P = 0.026) and gradually decreased to normal levels in patients with GD in remission. Correlation analysis showed that let-7b level was strongly correlated with TRAb level (r = 0.305, P = 0.001). let-7b directly inhibited promyelocytic leukemia zinc finger (PLZF) expression and increased the expression of TSHR in thyroid cells in vitro. Furthermore, let-7b levels in GD thyroid tissue were found to be inversely correlated with PLZF levels (r = - 0.849, P = 0.033). Decreased PLZF and increased TSHR was validated in thyroid tissue in patients with GD. CONCLUSIONS: The present study confirmed that a portion of miRNAs in PBMCs were also presented and differentially expressed in serum and thyroid tissue. Upregulated in all these three compartments, let-7b may be used as a disease biomarker and therapeutic targets in patients with GD. Circulating let-7b had a strong correlation with disease severity and let-7b may participate in the production of TRAb via targeting PLZF in patients with GD.

MicroRNA-4443 Causes CD4+ T Cells Dysfunction by Targeting TNFR-Associated Factor 4 in Graves' Disease.

CONTEXT: Aberrant CD4+ T cell function plays a critical role in the process of Graves' disease (GD). MicroRNAs (miRNAs) are important regulators of T cell activation, proliferation, and cytokine production. However, the contribution of miRNAs to CD4+ T cell dysfunction in GD remains unclear. OBJECTIVE: To investigate how certain miRNA causes aberrant CD4+ T cell function in GD patients. METHODS: We compared the expression pattern of miRNAs in CD4+ T cells from untreated GD (UGD) patients with those from healthy controls. The most significantly dysregulated miRNAs were selected and their correlations with clinical parameters were analyzed. The effect of miR-4443 on CD4+ T cells cytokines production and proliferation was assessed. The potential gene target was identified and validated. RESULTS: GD patients had unique pattern of miRNA expression profile in CD4+ T cells comparing to healthy subjects. miR-10a, miR-125b, and miR-4443 were the three most significantly dysregulated miRNAs. The elevated miR-4443 levels were strongly correlated with clinical parameters in an independent dataset of UGD patients (N = 40), while miR-4443 was normally expressed in GD patients with euthyroidism and negative TRAb level. We found that miR-4443 directly inhibited TNFR-associated factor (TRAF) 4 expression to increase CD4+ T cells cytokines secretion as well as proliferation through the NF-κB pathway. Furthermore, the TRAF4 levels in GD patients were inversely correlated with miR-4443, and knocking down TRAF4 had a similar effect with miR-4443 overexpression. CONCLUSION: The increased expression of miR-4443 induced CD4+ T cells dysfunction by targeting TRAF4, which may cause GD.

Corrigendum: The genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing.

This corrects the article DOI: 10.1038/ncomms15533.

The genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing.

The genomic alterations for benign thyroid nodule, especially adenomatoid nodule, one of the most common types of hyperplasia lesion, are ill-studied. Here, we show whole-exome sequencing and/or transcriptome sequencing data on adenomatoid nodules with or without coincidental papillary thyroid carcinoma (PTC). Somatic mutation of BRAF (22/32) is only detected in PTC, while mutations in SPOP (4/38), ZNF148 (6/38) and EZH1 (3/38) are found enriched in adenomatoid nodule. In an expanded cohort of adenomatoid nodule (n=259) mutually exclusive SPOPP94R, EZH1Q571R and ZNF148 mutations are identified in 24.3% of them. Adenomatoid nodules show very few overlapped mutations and distinct gene expression patterns with their coincidental PTC. Phylogenetic tree analysis uncovers that PTCs evolved independently from their matched benign nodules. Our findings reveal that benign nodules possess a unique molecular signature that differs from PTC and provide genomic evidence for the conventional belief that PTC and benign nodules have independent origin.

Down-regulated resistin level in consequence of decreased neutrophil counts in untreated Grave's disease.

Resistin, belongs to cysteine-rich secretory protein, is mainly produced by circulating leukocytes, such as neutrophils monocytes and macrophages in humans. To date, few but controversial studies have reported about resistin concentrations in hyperthyroid patients, especially in Graves' disease (GD). We undertaked a controlled, prospective study to explore the serum resistin concentration in GD patients before and after -MMI treatment. In addition, we also investigated the main influencing factor on serum resistin level and discuessed the potential role of serum resistin plays in GD patients. 39 untreated GD (uGD) patients, including 8 males and 31 females, were enrolled in our investigation. All of these patients were prescribed with MMI treatment, in addition to 25 healthy controls. Anthropometric parameters and hormone assessment were measured. Enzyme-linked immunosorbent assay was used to detect serum resistin concentration in different stages of GD patients. Furthermore, neutrophil cell line NB4 with or without T3 treatment to detect the effect of thyroid hormones on resistin expression. The serum resistin level and neutrophil counts in untreated GD patients were significantly declined. And all of these parameters were recovered to normal after MMI treatment in ethyroid GD (eGD) and TRAb-negative conversion (nGD) patients. Resistin concentration exhibited a negative correlation with FT3 and FT4, but a positive correlation with absolute number of neutrophiles in uGD patients, whereas did not correlate with thyroid autoimmune antibodies and BMI. Neutrophile cell line, NB4, produced decreased expression of resistin when stimulated with T3. Our study showed a decrease of serum resistin level in GD patients and we suggested that the serum resistin might primarily secreted from circulating neutrophils and down-regulated by excessive thyroid hormones in GD patients.

Co-inhibition of EGFR and IGF1R synergistically impacts therapeutically on adrenocortical carcinoma.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare tumor with very poor prognosis and no effective treatment. The aim of this study was to explore a novel therapy co-targeting EGFR and IGF1R in vitro and vivo. METHODS: The expression of EGFR and IGF1R were evaluated in a series of adrenocortical tumors by immunohistochemistry. Cell viability of ACC cell lines H295R and SW13 were determined by MTT assay after treatment with the combination of EGFR inhibitor Erlotinib and IGF1R inhibitor NVP-AEW541. Apoptosis was assessed by flow cytometry. The mechanism within intracellular signaling pathways was analyzed by Western blot. Mice bearing human ACC xenografts were treated with Erlotinib and NVP-AEW541, and the effects on tumour growth were assessed. RESULTS: Our results show a significant over-expression of EGFR (66.67%) and IGF1R (80.0%) in ACC. Besides, the co-overexpression of EGFR and IGF1R was seen in 8/15 ACCs, as compared with ACAs (P<0.05). Erlotinib and NVP-AEW541 significantly inhibited cell viability and induced apoptosis by blocking phosphorylation of MEK/ERK and AKT, respectively. Meanwhile, we found that single inhibition of IGF1R induced compensatory activation of MEK/ERK, leading to sustained activation of mTOR, which represent as aggregation of EGFR and IGF1R downstream components. More importantly, the combination of Erlotinib and NVP-AEW541 enhances anti-tumour efficacy compared to treatment with either agent alone or to untreated control in vitro and vivo. CONCLUSIONS: In conclusion, coinhibition therapy targeting EGFR and IGF1R may be considerable for treatment of ACC in the future.

Genetic association between Interleukin-17A gene polymorphisms and the pathogenesis of Graves' disease in the Han Chinese population.

OBJECTIVE: Graves' disease, one of the commonest autoimmune disorders, has a complex genetic basis. Interleukin-17A (IL-17A) is an important cytokine involved in innate and adaptive immune responses. This case-control study sought to investigate genetic association between the IL-17A gene and the process of Graves' disease (GD). DESIGN AND METHODS: Our pilot study was performed on a cohort from Shanghai, which included 713 patients with GD and 756 healthy controls. A replicate cohort was from Xiamen, recruiting 444 patients with GD and 427 healthy subjects. Six single nucleotide polymorphisms (SNPs) (rs4711998, rs3819024, rs2275913, rs8193037, rs3819025 and rs3748067) within the IL-17A gene were genotyped by the SNPstream Genotyping Systems and Taqman PCR method. RESULTS: In Shanghai cohorts, the frequencies of rs8193037 alleles were strongly different between patients with Graves' disease (G, 87·6% and A, 12·4%) and healthy controls (G, 91·4% and A, 8·6%) (P = 0·00067). The A carriers were associated with increased Graves' disease risks when compared with the G carriers (OR = 1·51, 95%CI = 1·19-1·92). In replicate cohorts, the proportion of individuals carrying the A allele of rs8193037 was significantly higher in patients with Graves' disease than in controls [Graves' disease vs control, 14·3% vs 9·1%, OR = 1·66 (95% CI: 1·23-2·24), Pallele  = 0·0082]. In addition, rs8193037 and rs3748067 were found to be different in both genotype and allele distributions in Graves' disease-associated ophthalmopathy patients and controls in Shanghai cohorts. Haplotype association analysis also identified five main haplotypes of those six SNPs. CONCLUSION: These results suggested that the polymorphism of IL-17A rs8193037 was strongly associated with Graves' disease susceptibility in the Chinese Han population.z.

Increased chemokine (C-C motif) ligand 21 expression and its correlation with osteopontin in Graves' disease.

Graves' disease (GD) is a chronic autoimmune process characterized by the production of auto-antibodies that presumably consequent to the lymphocytic infiltrates in the thyroid. Chemokine (C-C motif) ligand 21 (CCL21) is important for the circulation of CC-chemokine receptor 7 (CCR7)-expressing cells. Meanwhile, osteopontin (OPN) enhances the production of proinflammatory cytokines and chemokines through NF-κB and MAPK signaling pathways in GD. Although CCL21 has been reported to play a vital role in several autoimmune diseases, little is known about the relationship between CCL21 and GD development. This study aimed to detect the CCL21 level in GD and to examine the role of OPN in regulating CCL21 production. 40 initial GD patients, 15 euthyroid GD patients, 12 TRAb-negative GD patients, and 25 healthy control donors were recruited. CCL21 levels in plasma and culture supernatants were quantified by enzyme-linked immunosorbent assay (ELISA). CD4+ T cells were isolated from peripheral blood mononuclear cells using antibody-coated magnetic beads. Quantitative polymerase chain reaction was used to determine CCL21 expression levels in CD4+ T cells. We demonstrated for the first time that plasma CCL21 levels were overexpressed in GD patients and recovered in TRAb-negative GD patients. Moreover, CCL21 levels correlated with TRAb levels and plasma OPN concentrations. Furthermore, we demonstrated that recombinant OPN increased the expression of CCL21 in a dose- and time-dependent manner. These data indicated a clinical correlation between plasma CCL21 levels and GD. CCL21 could serve as a novel biomarker for GD as well as a potential target for TRAb-positive GD treatment.

The impact of smoking on survival in renal cell carcinoma: a systematic review and meta-analysis.

Epidemiological evidence suggests that cigarette smoking is the best-established risk factor for renal cell cancer (RCC). However, the effect of smoking on survival of RCC patients remains debated. We therefore conducted a meta-analysis to investigate the impact of smoking status on overall mortality (OM), disease-specific mortality (DSM), overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) in patients with RCC. We searched Medline, Embase, and the Cochrane Central Search Library for published studies that analyzed the effect of smoking on survival or mortality of RCC. We selected 14 articles according to predefined inclusion criteria. The smoking status was categorized into never smokers and ever smokers (former smokers and/or current smokers). Summary hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated with a fixed or random effects model. Overall, 14 studies including 343,993 RCC cases were accepted for meta-analysis. Ever smoking was significantly correlated with OM (HR 1.30, 95 % CI 1.07-1.58), while no associated with poorer DSM (HR 1.23, 95 % CI 0.96-1.57). Further analysis found current (HR 1.57, 95 % CI 1.20-2.06) but not former smoking (HR 1.14, 95 % CI 0.79-1.63) was associated with a significantly increased risk of OM. Meanwhile, current smoking was associated with poorer DSM (HR 1.50, 95 % CI 1.10-2.05) in subgroup analysis. Ever smoking was significantly associated with poorer OS (HR 1.45; 95 % CI 1.00-2.09) and poorer CSS (HR 1.01; 95 % CI 1.00-1.02), compared with never smokers. Current smoking was associated with poorer PFS (HR 2.94, 95 % CI 1.89-4.58). This review provides preliminary evidence that current smoking in a patient with RCC is associated with poorer survival, demonstrating active smoking to be an independent risk for prognosis of RCC. Smoking cessation should be recommended for RCC patients.