Mucinous cystadenocarcinoma of the breast harbours TRPS1 expressions and PIK3CA alterations.

AIMS: Breast mucinous cystadenocarcinoma (BMCA) is a rare tumour recently recognised as a distinct entity by the World Health Organisation Tumour Classification Series. BMCA is a triple-negative tumour that lacks specific immunohistochemical markers; therefore, distinguishing it from mimickers such as ovarian and pancreatic cystadenocarcinomas requires careful clinicopathological correlation. Due to its rarity, little is known about the molecular alterations that underlie BMCA. METHODS AND RESULTS: In this study, we used immunohistochemical staining methods to investigate TRPS1 (trichorhinophalangeal syndrome type 1) expression in BMCA and compare it to expression in ovarian and pancreatic mucinous cystadenocarcinomas. We also collected tumour samples from three BMCA patients for molecular analysis by MALDI-TOF mass spectrometry, real-time polymerase chain reaction, whole exome sequencing and fluorescence in-situ hybridisation. TRPS1 immunoreactivity was found only in BMCA tumour cells and not in the ovarian and pancreatic counterparts. One of the three BMCA tumours also showed a PIK3CA hot-spot mutation, which was confirmed by whole genome next-generation sequencing (NGS). No KRAS, NRAS, BRAF or AKT mutations were found. CONCLUSIONS: To our knowledge, this is the first demonstration of TRPS1 expression in BMCA patients and the first identification of a PIK3CA hotspot mutation in these tumours. These findings provide insights into the molecular mechanisms underlying BMCA tumorigenesis and suggest a potential drug target for this rare and poorly understood cancer.

Scalars Gliding through an Expanding Universe.

In this Letter, we investigate the effects of single derivative mixing in massive bosonic fields. In the regime of large mixing, we show that this leads to striking changes of the field dynamics, delaying the onset of classical oscillations and decreasing, or even eliminating, the friction due to Hubble expansion. We highlight this phenomenon with a few examples. In the first example, we show how an axionlike particle can have its number abundance parametrically enhanced. In the second example, we demonstrate that the QCD axion can have its number abundance enhanced allowing for misalignment driven axion dark matter all the way down to f_{a} of order astrophysical bounds. In the third example, we show that the delayed oscillation of the scalar field can also sustain a period of inflation. In the last example, we present a situation where an oscillating scalar field is completely frictionless and does not dilute away in time.

Primordial Anisotropies in the Gravitational Wave Background from Cosmological Phase Transitions.

Phase transitions in the early Universe can readily create an observable stochastic gravitational wave background. We show that such a background necessarily contains anisotropies analogous to those of the cosmic microwave background (CMB) of photons, and that these too may be within reach of proposed gravitational wave detectors. Correlations within the gravitational wave anisotropies and their cross-correlations with the CMB can provide new insights into the mechanism underlying primordial fluctuations, such as multifield inflation, as well as reveal the existence of nonstandard "hidden sectors" of particle physics in earlier eras.

San Huang Shel Shin Tang beta-cyclodextrin complex augmented the hepatoprotective effects against carbon tetrachloride-induced acute hepatotoxicity in rats.

BACKGROUND: San Huang Shel Shin Tang (SHSST) is a traditional herbal decoction used as a hepato-protective agent and is composed of Rheum officinale Baill, Scutellaria baicalnsis Geprgi and Coptis chinensis Franch (2:1:1 w/w). Beta-cyclodextrin (ß-CD) modification may potentially increase the solubility and spectral properties of SHSST. METHODS: In this research, the hepato-protective effects of unmodified SHSST, ß-CD modified SHSST complex (SHSSTc) and silymarin were evaluated in carbon tetrachloride (CCl4) induced acute hepatotoxicity in rats. RESULTS: SHHSTc (40 mg/kg/day) and silymarin (100 mg/kg/day) both decreased the CCl4-induced cirrhosis pathway-related transforming growth factor beta (TGF-ß) and apoptosis pathway-related caspase-8 protein expressions, but SHSST (40 mg/kg/day) did not reduce TGF-ß and caspase-8 significantly . Moreover, SHHSTc (40 mg/kg/day) enhanced the activation of insulin-like growth factor 1 receptor (IGF1R) mediated survival pathway than the silymarin (100 mg/kg/day) to protect the liver from damage induced by CCl4. CONCLUSIONS: ß-CD modification promotes hepato-protective effects of SHSST and reduces the required-dosage of the SHSST.

Anti-apoptotic effect of San Huang Shel Shin Tang cyclodextrin complex (SHSSTc) on CCl4 -induced hepatotoxicity in rats.

The metabolic loading is heavier in liver especially when injured or inflammation. San Huang Shel Shin Tang (SHSST) was an old traditional herbal decoction, which composed with Rheum officinale Baill, Scutellaria baicalnsis Geprgi and Coptis chinensis Franch (1:1:2 in weight), can provide a liver protection effects. We used a beta-cyclodextrin (ß-CD) drug modification method in reduce of the necessary dose of the SHSST. As the results, the FAS-FADD expressions leaded apoptosis in CCl4 intraperitoneal (IP) injection induced acute liver injury in rats. Silymarin, baicalein, SHSST, and SHSST ß-CD complex (SHSSTc) pretreatments protected liver through the decreasing of the expressions of FAS-FADD and downstream caspase-3 and caspase-8. Particularly, SHSSTc (30 mg/kg day) treatment enhanced cell survival pathway activation through the PI3K, Akt and Bad phosphorylation. Compared with SHSST as well as silymarin and baicalein, SHSSTc provided a magnificent liver protection effect, especially in survival pathway activation/TUNEL-apoptotic cell reduction/serum cholesterol level suppression. All these data suggested that ß-CD complex modified the SHSST and promoted the bioavailability and liver protection effects. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 663-670, 2016.

Anti-apoptosis effects on hearts of SHSST cyclodextrin complex in a carbon tetrachloride-induced cirrhotic cardiomyopathy rat model.

Cirrhotic cardiomyopathy (CCM) is a common cardiac dysfunction in patients waiting for orthotopic liver transplantation (OLT). Carbon tetrachloride (CCl4) intraperitoneal (IP) injection has been reported as successful in a cirrhosis-induced CCM model. In this work, we used the same assay for CCM induction using CCl4 (0.2 mg/kg) IP injection twice per day for 14 days during the cardiac protection drugs treatment process. The cardiac protection drugs were silymarin (100 mg/kg/day), baicalein (30 mg/kg/day), San Huang Shel Shin Tang (SHSST, 30 mg/kg/day) and ß-cyclodextrin modified SHSST (SHSSTc, 30 mg/kg/day and 300 mg/kg/day). After 4 weeks of treatment, the SHSSTc cardiac protection effects were determined through activation of the IGF1R cell survival pathway and inhibition of Fas-FADD death domain induced-apoptosis. SHSSTc cardiac protection was enhanced through ß-cyclodextrin modification, which increased bio-availability, and displayed stronger protective effects than silymarin and baicalein, both of which are well-known liver protection drugs. Thus, SHSSTc might provide the best therapeutic benefit in CCM treatment.

SHSST cyclodextrin complex prevents the fibrosis effect on CCl4-induced cirrhotic cardiomyopathy in rats through TGF-ß pathway inhibition effects.

Patients with liver cirrhosis also have subtle cardiac structure or function abnormalities. This cardiac dysfunction commonly occurs in 56% of waiting orthotopic liver transplantation (OLT) patients and is defined as cirrhotic cardiomyopathy (CCM). Up to now, there is no standard treatment because CCM does not have a solidly established diagnosis and is based on high clinical suspicion. The liver function of CCM is particularly limited, making patients vulnerable to more drug treatments. Here, we use silymarin (100 mg/kg/day), baicalein (30 mg/kg/day), San Huang Shel Shin Tang (SHSST, 30 mg/kg/day) and ß-cyclodextrin modified SHSST (SHSSTc, 30 and 300 mg/kg/day) treatments for a CCl4-induced CCM rat model. The results show that silymarin, baicalein and SHSST treatments can only slightly reduce the collagen accumulation in CCM rat hearts. However, SHSSTc treatment protects the heart in CCM and significantly inhibits collagen acumination and the fibrosis regulating transforming growth factor-ß (TGF-ß) pathway expression. SHSSTc treatments further reduced the heart weight and the ratio between left ventricular weight (LVW) and tibia length (TL). This experimental data show that water solubility improved ß-cyclodextrin modified Chinese herbal medicine formula (SHSSTc) can provide an excellent heart protection effect through TGF-ß pathway inhibition.

Bloodstream Coinfections and Antimicrobial Resistance in Hospitalized COVID-19 Patients: A Single-center Retrospective Study.

BACKGROUND/AIM: Bloodstream infections in patients with COVID-19 are linked to higher mortality rates, whilst data on epidemiology and resistance patterns remains scarce to guide management and prevent antibiotic resistance. This research focuses on the prevalence, clinical features, causative microorganisms, and antimicrobial susceptibility of bacterial and fungal secondary bloodstream co-infections in hospitalized patients with COVID-19. PATIENTS AND METHODS: In this retrospective study analysis of 230 patients with COVID-19 from Central Taiwan (June 2021 to June 2022), pathogens were identified via MALDI-TOF MS and Vitek 2 system with Clinical & Laboratory Standards Institute (CLSI) standards. RESULTS: In the cohort, 17.8% experienced bloodstream infections, resulting in a total of 45 isolates from the 41 bloodstream infection patients: predominantly gram-positive bacteria (Staphylococcus and Enterococcus) at 69%, gram-negative at 29% (Escherichia coli and Klebsiella pneumoniae), and fungi at 2%. Infected patients showed significantly elevated levels of white blood count (WBC), C-reactive protein (CRP) and procalcitonin (PCT). Of note, resistance to common antibiotics, such as fluoroquinolones, cephalosporins, and oxacillin was significant, especially in K. pneumoniae, Acinetobacter species, and S. aureus infections. CONCLUSION: Our study highlights the influence of bacterial infections in hospitalized patients with COVID-19. The bacterial infections were discovered to impact the clinical trajectory of COVID-19, potentially exacerbating or mitigating its symptoms, severity and fatality. These insights are pivotal to addressing clinical challenges in COVID-19 management and underscoring the need for tailored medical interventions. Understanding these co-infections is thus essential for optimizing patient care and improving overall outcomes in the post COVID-19 pandemic era.

Association of poly(ADP-ribose) polymerase-1 polymorphism with Tourette syndrome.

Tourette syndrome (TS) is an etiologically heterogeneous disorder, the pathogenesis of which is incompletely understood. Poly(ADP-ribose) polymerase 1 (PARP1) is involved in regulation of developmental processes and cellular differentiation, in transcription regulation, in DNA repair, and in cell death. However, the relationship between TS and single nucleotide polymorphisms (SNPs) of PARP1 is unknown. Therefore, the aim of this experiment was to test the hypothesis that whether the PARP1 SNP, rs1805404 (c.243C>T, Asp81Asp), had an association with TS. A case-control experiment was designed to test this hypothesis. 123 TS children and 122 normal children were enrolled in this study. Polymerase chain reaction restriction fragment length polymorphism was used for the detection of the PARP1 SNP, rs1805404, in TS patients and normal children. The data showed that there is a significant difference in genotype distributions between these two groups. The CT genotype was a risk factor for TS with an odds ratio of 2.34 for the CT versus TT genotype (95% CI 1.16-4.74). The data also showed this SNP had an association with TS under recessive model (P = 0.0426), and TT genotype had a protective effect against TS with an odds ratio of 0.50 (95% CI 0.26-0.98). The findings of this study suggested that variants in the PARP1 gene might play a role in susceptibility to TS.

Association of tyrosyl-DNA phosphodiesterase 1 polymorphism with Tourette syndrome in Taiwanese patients.

BACKGROUND: Genetic, environmental, immunological, and hormonal factors contribute to the etiology of Tourette syndrome (TS). From the genetic standpoint, TS is a heterogeneous disorder. In our previous study, we found that a single nucleotide polymorphism (SNP) of x-ray repair cross-complementing group 1 (XRCC1), a DNA repair gene, was associated with TS. Previous studies also showed that tyrosyl-DNA phosphodiesterase 1 (TDP1) interacts with XRCC1 to repair damaged DNA. However, the relationship between TS and SNPs of TDP1 gene is unknown. Therefore, the aim of this study was to test the hypothesis that if the TDP1 SNP, rs28365054 (c.400G>A, Ala134Thr), was associated with TS or not. METHODS: A case-control study was designed to test the hypothesis. A total of 122 TS children and 106 normal children participated in the study. We used polymerase chain reaction to identify the SNP, rs28365054, of the TDP1 gene in the TS patients and the normal children. RESULTS: A polymorphism at position rs28365054 in the TDP1 gene had a significant difference (P < 0.05) in the genotype distributions between the TS patients and the control group. The AG genotype was a risk factor for TS with an odds ratio of 2.26 for the AG versus AA genotype (95% CI 1.08-4.72). CONCLUSION: The findings of this study suggested that variants in the TDP1 gene might play a role in TS susceptibility.

High G9a Expression in DLBCL and Its Inhibition by Niclosamide to Induce Autophagy as a Therapeutic Approach.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a malignant lymphoid tumor disease that is characterized by heterogeneity, but current treatment does not benefit all patients, which highlights the need to identify oncogenic genes and appropriate drugs. G9a is a histone methyltransferase that catalyzes histone H3 lysine 9 (H3K9) methylation to regulate gene function and expression in various cancers. METHODS: TCGA and GTEx data were analyzed using the GEPIA2 platform. Cell viability under drug treatment was assessed using Alamar Blue reagent; the interaction between G9a and niclosamide was assessed using molecular docking analysis; mRNA and protein expression were quantified in DLBCL cell lines. Finally, G9a expression was quantified in 39 DLBCL patient samples. RESULTS: The TCGA database analysis revealed higher G9a mRNA expression in DLBCL compared to normal tissues. Niclosamide inhibited DLBCL cell line proliferation in a time- and dose-dependent manner, reducing G9a expression and increasing p62, BECN1, and LC3 gene expression by autophagy pathway regulation. There was a correlation between G9a expression in DLBCL samples and clinical data, showing that advanced cancer stages exhibited a higher proportion of G9a-expressing cells. CONCLUSION: G9a overexpression is associated with tumor progression in DLBCL. Niclosamide effectively inhibits DLBCL growth by reducing G9a expression via the cellular autophagy pathway; therefore, G9a is a potential molecular target for the development of therapeutic strategies for DLBCL.

Association of genetic variations in X-ray repair cross-complementing group 1 and Tourette syndrome.

BACKGROUND: X-ray repair cross-complementing group 1 (XRCC1) plays a central role in mammalian DNA repair process. The polymorphism rs25487 (Arg>Gln at codon 399) of this gene is common in Han Chinese population. OBJECTIVES: The objective of this study was to analyze the association between this functional SNP of XRCC1 and Tourette syndrome (TS) in Han Taiwan Chinese population. METHODS: Genotyping was performed by using PCR-RFLP method on 73 TS patients and 158 normal controls. RESULTS: Our data indicated that genotype frequency of A/G polymorphism at codon 399 of the patients differed from the controls (P = 0.026, OR: 2.22, 95% CI: 1.22-4.03). The allele frequency analysis also showed significant differences with higher A allele frequency in patients (P = 0.015, OR: 1.70, 95% CI: 1.11-2.62). CONCLUSION: Our study indicates that the functional SNP at codon 399 of XRCC1 is associated with TS development.

Glycyrrhiza uralensis root extract ameliorates high glucose-induced renal proximal tubular fibrosis by attenuating tubular epithelial-myofibroblast transdifferentiation by targeting TGF-ß1/Smad/Stat3 pathway.

Growing evidences indicate that high glucose toxicity-associated fibrotic effects play a pivotal role in diabetic nephropathy (DN). Tubular epithelial-myofibroblast transdifferentiation is a major hallmark of renal fibrosis event under diabetic stress. Roots of Glycyrrhiza uralensis (Radix glycyrrhizae) used as a sweetener and traditional Chinese medicine possess high potential for renal protection. In this study, a cell model for high glucose (HG) injury with HK-2 renal proximal tubular epithelial cell line and a type-II-diabetes model with Apoeem1/Narl /Narl mice was established and the beneficial effects of aqueous R. glycyrrhizae extract (RGE) was investigated. RGE-induced regulation on the high glucose-induced excessive production of TGF-ß1 and the Smad/Stat3 mechanisms of renal fibrosis were determined. HK-2 cells were challenged with 45 mM of high glucose for 48 hr. Following high glucose challenge, the cells were treated with 0.5, 1, and 1.5 mg/ml concentrations of RGE. The effect of RGE on DN was determined using high fructose diet-induced type-II-diabetes in Apoeem1/Narl /Narl mice models. Our results showed that RGE suppressed the expression of HG-induced TGFß signaling and associated fibrosis mechanism better than the pharmacological drug acarbose. These data suggest that RGE as a potential herbal supplement in attenuating fibrosis-associated diabetic nephropathy and a potential agent in diabetes treatments.

Emodin Ameliorates the Efficacy of Carfilzomib in Multiple Myeloma Cells via Apoptosis and Autophagy.

BACKGROUND: Carfilzomib, the proteasome inhibitor, can increase the overall survival rate of multiple myeloma (MM) patients undergoing targeted therapy. However, relapse and toxicity present great challenges for such treatment, so an urgent need for effective combination therapy is necessary. Emodin is a natural chemical compound that inhibits the proliferation of various cancers and can effectively combine with other treatments. In this study, we evaluated the sensitizing effect of emodin combined with carfilzomib on MM cells. METHODS: The cells were treated with emodin, carfilzomib, and a combination of drugs to determine their effects on cell proliferation and viability. The cell cycle distribution and reactive oxygen species (ROS) expression were measured by flow cytometry. The level of RNA and protein were analyzed through real-time qPCR and immunoblotting. RESULTS: Emodin acted synergistically with carfilzomib to reduce the proliferation and viability of MM cell lines in vitro. Furthermore, the combination of emodin and carfilzomib increased ROS production, inducing apoptosis and autophagy pathways via caspase-3, PARP, p62, and LC3B. CONCLUSIONS: These results provide a molecular target for combination therapy in MM patients.

The association between polymorphisms of B7 molecules (CD80 and CD86) and Graves' ophthalmopathy in a Taiwanese population.

OBJECTIVE: This study evaluates whether B7 molecules (CD80 and CD86) could be used as genetic markers for the development of Graves' ophthalmopathy (GO). DESIGN: Cross-sectional study. PARTICIPANTS: We included 471 patients with Graves' disease (GD; 200 patients with GO and 271 patients without GO) in a Chinese population in Taiwan. METHODS: An endocrinologist with substantial experience in thyroid diseases identified GO. Blood samples were taken for DNA extraction from GD subjects. The gene polymorphism of CD80 and CD86 was genotyped by polymerase chain reaction in each patient. MAIN OUTCOME MEASURES: Genotypes of CD80 and CD86 polymorphism. RESULTS: We found that the frequency of C allele at position rs_9831894 of the CD86 gene is different in patients with GD (with and without GO; chi-square test, P = 0.0017). In addition, the multifactor dimensionality reduction method was used to identify the best gene-gene interaction to predict the risk of GO. We identified an interaction between CD80_rs9289131 and CD86_rs9872483 (sign test, P = 0.0010). Moreover, the G-A haplotype was shown to have a protective effect in the development of ophthalmopathy among patients with GD (odds ratio, 0.63; 95% confidence interval, 0.44-0.90). Moreover, among patients with GO, the patients carrying the G-A haplotype had a lower level of free thyroxine T(4) than those not carrying the G-A haplotype (P = 0.0001). CONCLUSIONS: These results suggest that the polymorphisms of the CD86 gene may be used as genetic markers for making the diagnosis and prognosis of GO. Therefore, GO could be a disease with complex genetic factors, resulting from the existing gene-gene interaction found in the present study.

Association between copy number variation of complement component C4 and Graves' disease.

BACKGROUND: Gene copy number of complement component C4, which varies among individuals, may determine the intrinsic strength of the classical complement pathway. Presuming a major role of complement as an effecter in peptide-mediated inflammation and phagocytosis, we hypothesized that C4 genetic diversity may partially explain the development of Graves' disease (GD) and the variation in its outcomes. METHODS: A case-control study including 624 patients with GD and 160 healthy individuals were enrolled. CNV of C4 isotypes (C4A and C4B) genes were performed by quantitative real-time polymerase chain reaction analysis. Statistical comparison and identification of CNV of total C4, C4 isotypes (C4A and C4B) and C4 polymorphisms were estimated according to the occurrence of GD and its associated clinical features. RESULTS: Individuals with 4, 2, and 2 copies of C4, C4A and C4B genes, especially those with A2B2 polymorphism may associate with the development of GD (p = 0.001, OR = 10.994, 95% CI: 6.277-19.255; p = 0.008, OR = 1.732, 95% CI: 1.190-2.520; p = 2.420 × 10-5, OR = 2.621, 95% CI: 1.791-3.835; and p = 1.395 × 10-4, OR = 2.671, 95% CI: 1.761-4.052, respectively). Although the distribution of copy number for total C4, C4 isotypes as well as C4 polymorphisms did not associate with the occurrence of goiter, nodular hyperplasia, GO and myxedema, <2 copies of C4A may associate with high risk toward vitiligo in patients with GD (p = 0.001, OR = 5.579, 95% CI: 1.659-18.763). CONCLUSIONS: These results may be further estimated for its clinical application on GD and the vitiligo in patients with GD.

IGF IIRα-triggered pathological manifestations in the heart aggravate renal inflammation in STZ-induced type-I diabetes rats.

Pathological manifestations in either heart or kidney impact the function of the other and form the basis for the development of cardiorenal syndrome. However, the mechanism or factors involved in such scenario are not completely elucidated. In our study, to find the correlation between late fetal gene expression in diabetic hearts and their influence on diabetic nephropathy, we created a rat model with cardiac specific overexpression of IGF-IIRα, which is an alternative splicing variant of IGFIIR, expressed in pathological hearts. In this study, transgenic rats over expressing cardiac specific IGF-IIRα and non-transgenic animal models established in SD rats were administered with single dose of streptozotocin (STZ, 55 mg/Kg) to induce Type I diabetes. The correlation between IGF-IIRα and kidney damages were further determined based on their intensity of damage in the kidneys. The results show that cardiac specific overexpression of IGF-IIRα elevates the diabetes associated inflammation and morphological changes in the kidneys. The diabetic transgenic rats showed advancement in the pathological features such a renal tubular damage, collagen accumulation and enhancement in STAT3 associated mechanism of renal fibrosis. The results therefore show that that IGF-IIRα expression in the heart during pathological condition may worsen symptoms of diabetic nephropathy in rats.

Emodin inhibits the growth of hepatoma cells: finding the common anti-cancer pathway using Huh7, Hep3B, and HepG2 cells.

Emodin--a major component of Rheum palmatum L.-exerts antiproliferative effects in cancer cells that are regulated by different signaling pathways. Hepatocellular carcinoma has high-incidence rates and is associated with poor prognosis and high mortality rates. This study was designed to evaluate the effects of emodin on human hepatocarcinoma cell viability and investigate its mechanisms of action in Huh7, Hep3B, and HepG2 cells. To define the molecular changes associated with this process, expression profiles were compared in emodin-treated hepatoma cells by cDNA microarray hybridization, quantitative RT-PCRs, and Western blot analysis. G2/M phase arrest was observed in all 3 cell lines. Cell cycle regulatory gene analysis showed increased protein levels of cyclin A, cyclin B, Chk2, Cdk2, and P27 in hepatoma cells after time courses of emodin treatment, and Western blot analysis showed decreased protein levels of Cdc25c and P21. Microarray expression profile data and quantitative PCR revealed that 15 representative genes were associated with emodin treatment response in hepatoma cell lines. The RNA expression levels of CYP1A1, CYP1B1, GDF15, SERPINE1, SOS1, RASD1, and MRAS were upregulated and those of NR1H4, PALMD, and TXNIP were downregulated in all three hepatoma cells. Moreover, at 6h after emodin treatment, the levels of GDF15, CYP1A1, CYP1B1, and CYR61 were upregulated. Here, we show that emodin treatment caused G2/M arrest in liver cancer cells and increased the expression levels of various genes both in mRNA and protein level. It is likely that these genes act as biomarkers for hepatocellular carcinoma therapy.

Toll-like receptor gene polymorphisms are associated with susceptibility to Graves' ophthalmopathy in Taiwan males.

BACKGROUND: Toll-like receptors (TLRs) are a family of pattern-recognition receptors, which plays a role in eliciting innate/adaptive immune responses and developing chronic inflammation. The polymorphisms of TLRs have been associated with the risk of various autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis and rheumatorid arthritis. The aim of this study was to evaluate whether TLR genes could be used as genetic markers for the development of Graves' ophthalmopathy (GO). METHODS: 6 TLR-4 and 2 TLR-9 gene polymorphisms in 471 GD patients (200 patients with GO and 271 patients without GO) from a Taiwan Chinese population were evaluated. RESULTS: No statistically significant difference was observed in the genotypic and allelic frequencies of TLR-4 and TLR-9 gene polymorphisms between the GD patients with and without GO. However, sex-stratified analyses showed that the association between TLR-9 gene polymorphism and GO phenotype was more pronounced in the male patients. The odds ratios (ORs) was 2.11 (95% confidence interval [CI] = 1.14-3.91) for rs187084 AàG polymorphism and 1.97 (95% CI = 1.07-3.62) for rs352140 AàG polymorphism among the male patients. Increasing one G allele of rs287084 and one A allele of rs352140 increased the risk of GO (p values for trend tests were 0.0195 and 0.0345, respectively). Further, in haplotype analyses, the male patients carrying the GA haplotype had a higher risk of GO (odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.09-3.73) than those not carrying the GA haplotype. CONCLUSION: The present data suggest that TLR-9 gene polymorphisms were significantly associated with increased susceptibility of ophthalmopathy in male GD patients.

Disease association of the CD103 polymorphisms in Taiwan Chinese Graves' ophthalmopathy patients.

OBJECTIVE: To evaluate whether variations in the CD103 gene could be associated with Graves' ophthalmopathy (GO) in patients with Graves' disease. DESIGN: Case-control study. PARTICIPANTS: A total of 484 Chinese patients with Graves' disease in Taiwan, including 203 patients with GO and 281 patients without GO, were enrolled. METHODS: Five single nucleotide polymorphisms (SNPs) in CD103 were genotyped using an assay-on-demand allelic discrimination assay and detection system according to the manufacturer's instructions. MAIN OUTCOME MEASURES: Association of SNPs in CD103 with the development of GO. RESULTS: The CD103 SNP rs11652878 was associated with GO, which may decrease the risk of GO by 1.57-fold (P = 0.029). The Ht5-GCGCG haplotype, composed of 5 SNPs in the CD103 gene (rs1716, rs3744679, rs11652878, rs16953477, and rs9905739), were protective haplotypes (P = 0.010). Moreover, the heterozygous genotype (Ht5/non-Ht5) was correlated with a reduced risk of GO and high grades of goiter as compared with the non-Ht5/non-Ht5 genotype (P = 0.006 and P = 0.048, respectively). Logistic analysis confirmed the contribution of CD103 rs11652878 to the protection of GO. CONCLUSIONS: These data suggest that patients with Graves' disease in the presence of the G allele of SNP rs11652878, especially Ht5-GCGCG, in CD103 are less susceptible toward the development of GO.