Shift in Dominance from Blocking to Stimulating Type of Thyrotropin Receptor Antibodies, Resulting in Conversion from Hypothyroidism to Hyperthyroidism during Late Pregnancy.

A 20-year-old woman with a 10-month history of treatment for Graves' disease (GD), developed hypothyroidism with a high level of thyrotropin (TSH) receptor-blocking antibodies (TBAbs). She conceived at 28 years old and was clinically euthyroid in the first and second trimester, while taking L-thyroxine. However, at 28 weeks she became hyperthyroid with an unexpected rise in TSH receptor-stimulating antibody (TSAb) levels. She was diagnosed with GD, and methimazole was initiated. Her thyroid function normalized, but the neonate became hyperthyroid. We herein report the first case of a shift in dominance from TBAbs to TSAbs in late pregnancy.

Thyrotropin receptor autoantibody (TRAb) enhance the expression of thyrotropin receptor on mouse brain vascular endothelial cells: in vivo and in vitro.

The possibility that thyrotropin receptor (TSHR) expression in non-thyroid tissue is well-documented. However, there is insufficient data on the expression of TSHR in medulla oblongata regions, particularly when focusing on the background of encephalopathy associated with hyperthyroidism. In this study, we explored the expression of the functional TSHR in Graves' disease (GD) mouse cerebral vascular endothelial cells and the effects of thyrotropin receptor autoantibody (TRAb) on its expression. A mouse model of GD was constructed with an adenovirus overexpressing TSHR289. The location and expression of the TSHR gene and protein in vivo were determined via RT-qPCR, Western blot, and immunofluorescence techniques. The effect of TRAb on the expression of functional TSHR in vitro was investigated using bEnd.3 cells. Our results show that medulla oblongata vascular endothelial cells from GD mice expressed higher levels of TSHR compared to control mice. In an in vitro experiment, novel results demonstrated that after treatment with a monoclonal TSHR-specific agonistic antibody (M22), the expression of TSHR on the bEnd.3 cells increased at both the protein and mRNA levels. Furthermore, compared with bEnd.3 cells were treated with IBMX only, those treated with M22 showed increased cAMP production. This study suggested that TSHR is expressed and functionally active in the mouse medulla oblongata and in vitro-cultured bEnd.3 cells and TRAb (M22) increased the expression of TSHR on bEnd.3 cells.

Establishment and analytical performance of light-initiated chemiluminescence assay method for detecting thyrotropin receptor antibody.

Aim: To evaluate double-antibody competitive light-initiated chemiluminescence assay method for detecting the thyrotropin receptor antibody. Materials & methods: The optimal working concentrations of competitive antibody and rTSHR were confirmed by checkerboard titration. Assay performance was assessed by precision, linearity, accuracy, limit of blank and clinical evaluation. Results: The coefficient of variation for repeatability and intermediate precision was 3.9-5.9 and 0.9-1.3%, respectively. The correlation coefficient was 0.999 by least squares linear fitting in linearity evaluation. The relative deviation ranged from -5.9 to 4.1%, and the limit of blank of the method was 0.13 IU/l. Compared with the Roche cobas system (Roche Diagnostics, Mannheim, Germany), the relationship between the two assays was shown to be significantly correlative. Conclusion: The light-initiated chemiluminescence assay method for detecting thyrotropin receptor antibody is a rapid, novel and accurate method for thyrotropin receptor antibody measurement.

Graves' disease is common in daily life. Patients often experience rapid heartbeat and weight loss. Blood tests (especially serum autoantibody levels) are meaningful in diagnosis and treatment. In this study, we used a new and useful approach to test blood markers. Compared with other methods, this new technique could perform better in terms of time and expense. Based on a full assessment, we believe that this new method will play an important role in clinical application.

Evaluation of the diagnostic performance of thyroid-stimulating immunoglobulin and thyrotropin receptor antibodies for Graves' disease.

OBJECTIVE: To evaluate thyroid-stimulating immunoglobulin (TSI) and thyrotropin receptor antibodies (TRAb) diagnostic performance for Graves' disease (GD) and determine clinical cut-off value for diagnosing GD. METHODS: Of 1369 retrospectively enrolled subjects, 1364 had a definitive diagnosis of untreated GD (GD-UT, n = 87); treated GD (GD-T, n = 206); autoimmune thyroid disease (AIT, n = 241); thyroid nodules (TN, n = 677); subacute thyroiditis (ST, n = 28); healthy subjects (HS, n = 125); other diseases with serological hyperthyroidism (n = 5) and were grouped into the following: UT-GD and control groups (AIT, TN, ST, and HS); and UT-GD and non-GD hyperthyroidism groups. Diagnostic performance of TSI and TRAb was evaluated using area under the curve (AUC) of receiver-operating characteristic (ROC) curve, and optimal clinical cut-off value was determined using maximization of Youden index. RESULTS: TRAb AUC and clinical cut-off value for diagnosing GD were 0.981 and 1.245 IU/L (sensitivity, 96.6%; specificity, 97.1%; positive predictive value [PPV], 71.8%; negative predictive value [NPV], 99.9%; positive likelihood ratio [PLR], 33.31; negative likelihood ratio [NLR, 0.035), respectively, for the GD-UT and control groups. Those for TSI were 0.992 and 0.467 IU/L (sensitivity 98.8%; specificity, 96.4%; PPV, 68.8%; NPV, 99.9%; PLR, 27.472; NLR, 0.011). Those for TRAb in GD-UT and non-GD hyperthyroidism groups were 0.923 and 1.78 IU/L (sensitivity, 92.0%; specificity, 89.1%; PPV, 93%; NPV, 87.5%; PLR, 8.44; NLR, 0.089), respectively. For TSI, these were 0.92 and 0.545 IU/L (sensitivity, 97.7%; specificity, 83.6%; PPV, 90.4%; NPV, 95.8%; PLR27.472, NLR, 0.011), respectively. CONCLUSION: TSI diagnostic performance for GD was excellent and had better sensitivity than TRAb.

The role of Graves' disease in the development of thyroid nodules and thyroid cancer.

Aim: The prevalence of thyroid nodules and the risk of thyroid cancer in patients with Graves' disease is uncertain. We aimed to evaluate the prevalence of thyroid nodules and cancer in patients with Graves' disease. Methods: Retrospective observational study of adult subjects with Graves' disease (positive autoantibodies thyrotropin receptor antibodies (TRAbs)) between 2017 and 2021 at our center was done. We evaluated the prevalence of thyroid nodules and cancer in this population and characterized the predictive factors for thyroid malignancy using linear and logistic regression models. Results: We evaluated a total of 539 patients with Graves' disease during a median follow-up of 3.3 years (25th-75th percentiles 1.5-5.2 years). Fifty-three percent had thyroid nodules and 18 (3.3%) were diagnosed with thyroid cancer (12 papillary microcarcinomas). All tumors were classified using TNM classification as T1, and only one had lymph node metastasis; there were no recordings of distant metastasis. Sex, age, body mass index, smoking, TSH, and TRAbs levels were not significantly different between patients with and without thyroid cancer. Patients with multiple nodules on ultrasound (OR 1.61, 95%CI 1.04-2.49) and with larger nodules (OR 2.96, 95%CI 1.08-8.14, for 10 mm increase in size) had a greater risk of thyroid cancer diagnosis. Conclusion: Patients with Graves' disease had a high prevalence of thyroid nodules and their nodules had a significant risk of thyroid cancer. The risk was higher in those with multiple and larger nodules. Most had low-grade papillary thyroid cancer. More studies are needed to clarify the clinical relevance of these findings.

The phenotype of Graves' orbitopathy is associated with thyrotropin receptor antibody levels.

PURPOSE: Graves' orbitopathy (GO) is a specific inflammatory disorder of the orbit characterized by a highly heterogeneous clinical phenotype. The role of thyrotropin receptor antibodies (TSH-R-Ab) has been widely researched, however there is still no evidence that these antibodies have a direct pathogenic role in this pathology. The aim of this study was to examine their relation to the individual clinical features of GO. METHODS: Ninety-one consecutive patients with GO were recruited. Total antibody concentration (TSH-R binding inhibitory immunoglobulins, TBII) and their functional activity (stimulating TSH-R-Ab, TSAb) were measured using binding immunoassay and cell-based bioassay, respectively. RESULTS: Both TSAb and TBII levels were significantly associated to the clinical parameters of GO activity. TSAb was a more sensitive serological marker compared to TBII pertaining to eyelid retraction and edema, proptosis, extra-orbital muscle disorders, diplopia, irritable eye symptoms, and photophobia. TSAb, but not TBII, was a significant predictive marker of conjunctival redness, chemosis, caruncle/plica inflammation, eye irritation, and orbital pain, (odds ratio: 3.096, p = 0.016; 5.833, p = 0.009; 6.443, p = 0.020; 3.167, p = 0.045; 2.893, p = 0.032; versus 2.187, p = 0.093; 2.775, p = 0.081; 3.824, p = 0.055; 0.952, p = 0.930; 2.226, p = 0.099, respectively). Neither TSAb nor TBII correlated with the level of proptosis (ρ = 0.259, p = 0.090, and ρ = 0.254, p = 0.104, respectively), however rising TSAb levels were strongly associated to the level of proptosis. CONCLUSIONS: TSH-R-Ab were significantly associated with GO's phenotype. Especially TSAb, as a sensitive and predictive serological biomarker, can improve diagnosis and management of GO.

Thyrotropin Receptor Autoantibody Assessment in Thyroid Eye Disease: Does the Assay Type Matter?

PURPOSE: Thyroid receptor antibodies can quantify thyroid eye disease activity, predict outcomes and aid timing of interventions. The type and generation of assay is frequently unspecified, complicating meta-analyses. To determine the clinical and biochemical relationships between a second-generation thyrotropin receptor-binding inhibition antibody (TRAb) immunoassay, detecting stimulatory and blocking antibodies, with the thyroid stimulating immunoglobulin (TSI) bridging immunoassay detecting the stimulatory component only. METHODS: Retrospective review of 100 consecutive patients attending a regional specialist service. For each patient and visit, both a TRAb and TSI were performed, and a clinical activity score (CAS) recorded. RESULTS: A significant positive correlation between TRAb and TSI (rho = 0.828, p < 0.01) but a weaker correlation between the assays and CAS (TRAb: rho = 0.439, p < 0.01; TSI: r = 0.357, p < 0.01) were found. In 10% of the episodic data, patients had a TRAb level that was disproportionately high (39.41 ± 52.84 IU/L), compared to their TSI levels (9.53 ± 12.10 IU/L) with a higher-than-average CAS (2.47 ± 1.78; range, 0-5). Within 12 months of diagnosis, a significant positive correlation between CAS and TRAb (rho = 0.503, p < 0.01) as well as between CAS and TSI (rho = 0.329, p < 0.01) were found. In patients with a diagnosis over 12 months, the correlation with CAS for both TSI and TRAb were Spearman rank correlation coefficient of 0.347 (p < 0.01) and 0.327 (p < 0.01), respectively. CONCLUSIONS: TRAb and TSI correlate strongly and to a lesser extent with the CAS. For most patients, TRAb can be replaced with the more economical TSI. TRAb also correlates better with newly diagnosed, more active patients than TSI. In a subset of patients, blocking antibodies may play a significant pathogenic role, requiring different treatment and monitoring. Further studies are required to investigate this relationship.

A Novel Monoclonal Antibody Degrades the Thyrotropin Receptor Autoantibodies in Graves' Disease.

OBJECTIVE: Autoantibodies against the thyrotropin receptor (TSH-R-Ab) are key mediators for the pathogenesis of Graves' disease (GD). TSH-R-Ab degradation was evaluated using several immunoassays within an exploratory, controlled trial in patients with GD receiving a monoclonal antibody (mAb) targeting the neonatal crystallizable fragment receptor (FcRn). METHODS: Serial measurements of TSH-R-Ab serum levels were performed using 3 different binding and cell-based assays in patients with GD either on medication or on placebo. RESULTS: In contrast to the placebo group, in which no changes were observed, a 12-week mAb therapy led to an early and significant decrease (>60%) in the serum TSH-R-Ab levels in patients with thyroidal and extrathyroidal GD, as unanimously shown in all 3 assays. These marked changes were noted already at week 7 post baseline (P <.0001 for the binding immunoassay and for the luciferase (readout) bioassay). The 3 TSH-R-Ab binding and bioassays were highly correlated in the samples of both study groups (binding immunoassay vs luciferase bioassay, r =.91, P <.001, binding vs cyclic adenosine monophosphate (cAMP) bioassay, r = 0.86, P <.001, and luciferase vs cAMP bioassay, r = 0.71, P =.006). The serological results correlated with the course of the extrathyroidal clinical parameters of GD, that is, clinical activity score and proptosis. CONCLUSION: Targeting the FcRn markedly reduces the disease-specific TSH-R-Ab in patients with GD. The novel and rapid TSH-R-Ab bioassay improves diagnosis and management of patients with GD.

Ovarian stimulation does not induce thyrotropin receptor autoantibodies in women with thyroid autoimmunity.

Women of subfertile couples with thyroid autoimmunity (TAI) have an increased risk of miscarriage when pregnant after an assisted reproductive technology (ART) treatment. This might amongst others be due to the presence of thyrotropin receptor antibodies (TSH-R-Ab) that can impede the development of the corpus luteum. TSH-R-Ab can be present in women with TAI and/or be induced by the ovarian stimulation procedure (OS) that is performed to initiate the ART. In this prospective pilot study, we determined the presence of both binding and functional TSH-R-Ab (stimulating or blocking) with five different assays before and after OS in ten women (eleven cycles) with TAI of subfertile couples and in one woman without TAI. Mean (SD) age was 38.8 (±3.2) years, median (range) cumulative OS dose 1413 (613-2925) IU/L. Median baseline serum levels of thyrotropin, free thyroxine, and thyro-peroxidase antibodies were 2.33 (2.23-2.61) mIU/L, 16.8 (14.4-18.5) pmol/L and 152 (86-326) kIU/L, respectively. Oestradiol levels increased during OS from 40 (26-56) ng/L to 963 (383-5095) ng/L; P < .01. TSH-R-Ab measurements in all subject samples were below the cut-off of the corresponding immunoassay and four bioassays before or after OS.

Epstein-Barr virus reactivation in peripheral B lymphocytes induces IgM-type thyrotropin receptor autoantibody production in patients with Graves' disease.

Epstein-Barr virus (EBV) is a human herpes virus that latently infects B lymphocytes. When EBV is reactivated, host B cells differentiate into plasma cells and produce IgM-dominant antibodies as well as many progeny virions. The aims of the present study were to confirm the IgM dominance of thyrotropin-receptor antibodies (TRAbs) produced by EBV reactivation and investigate the roles of TRAb-IgM in Graves' disease. Peripheral blood mononuclear cells (PBMCs) containing TRAb-producing cells were stimulated for EBV reactivation, and TRAb-IgM and TRAb-IgG were measured by ELISA. TRAb-IgM were purified and TSH-binding inhibitory activities were assessed using a radio-receptor assay. Porcine thyroid follicular epithelial cells were cultured with TRAb-IgM and/or complements to measure the intracellular levels of cAMP and the amount of LDH released. TRAb-IgM/TRAb-IgG (the MG ratio) was examined in sequential serum samples of Graves' disease and compared among groups of thyroid function. The results obtained showed that IgM-dominant TRAb production was induced by EBV reactivation. TRAb-IgM did not inhibit TSH binding to TSH receptors and did not transduce hormone-producing signals. However, it destroyed thyroid follicular epithelial cells with complements. The MG ratio was significantly higher in samples of hyperthyroidism or hypothyroidism than in those with normal function or in healthy controls. A close relationship was observed between TRAb-IgM produced by EBV reactivation and the development and exacerbation of Graves' disease. The present results provide novel insights for the development of prophylaxis and therapeutics for Graves' disease.

Bioassays for thyrotropin receptor autoantibodies.

Bioassays using animal models were essential tools in the discovery of thyrotropin and in enhancing our understanding of the physiology of the pituitary-thyroid axis. These same bioassays were also instrumental in the discovery of autoantibodies to the thyrotropin receptor (TSH-R-Ab) and in identifying their role in the pathophysiology of Graves' disease. The development of cell-based bioassays led to further advances in our knowledge of the functional activity of TSH-R-Ab and to the discovery that TSH-R-Ab can be either thyroid-stimulating or thyroid blocking, and that they occur in other types of autoimmune thyroid diseases (AITD) besides Graves' disease. More recently, TSH-R-Ab bioassays have been advanced from research tools to clinical laboratory tests. Whereas TSH-R-Ab can be measured with competitive-binding immunoassays, these assays do not provide information on the functional activity of TSH-R-Ab. Bioassays, in contrast, can differentiate between the stimulatory or blocking activity of TSH-R-Ab which provides clinically useful information that can inform the management of patients with AITD. The clinical use of TSH-R-Ab bioassays, however, has been limited to-date by their inherent complexity and long turn-around-time. Recent advances in biosensors have been applied to the development of TSH-R-Ab bioassays that are rapid and simple to perform. We now are entering an era in which bioassays for TSH-R-Ab can be measured routinely by virtually any clinical laboratory.

Radioiodine Ablation of Thyroid Remnants in Patients with Graves' Orbitopathy.

Our purpose was to assess response after ablation of thyroid remnants (ATR) with radioactive iodine therapy in patients with unstable Graves' orbitopathy (GO) after subtotal thyroidectomy. Methods: Thirty patients with mild (n = 4, 13%), moderate-to-severe (n = 25, 83%), or very severe GO (n = 1, 3%) were analyzed in this retrospective study. The primary endpoint was the improvement of GO-related symptoms as assessed by clinical activity scores, NOSPECS, and soft-tissue inflammation scores at 3 and 12 mo after ATR. Ablation success was defined by a decrease in 99mTc uptake on thyroid scintigraphy, remnant volume, and thyrotropin receptor antibody levels at 3 mo after ATR. Results: Twelve months after ATR, clinical activity scores, NOSPECS, and soft-tissue inflammation scores showed a significant decrease from 3.4 to 1.3 (P < 0.0001), 5.9 to 4.9 (P = 0.007), and 4.7 to 2.1 (P = 0.0001), respectively. The GO was inactive in 27 of the 30 (90%) patients after 3 mo and in 29 (97%) after 12 mo. No new activation of GO occurred. Remnant volume (1.4 vs. 0.4 cm3, P = <0.0001), mean thyrotropin receptor antibody level titer (19.02 vs. 13.37 IU/L, P < 0.0001), and 99mTc uptake (0.5% vs. 0.1%; n = 12; P = 0.04) decreased significantly until 3 mo after ATR. Discussion: Radioactive iodine therapy after thyroidectomy can successfully ablate residual thyroid remnants, leading to an improvement in GO, a reduction in inflammatory activity, and stabilization of thyroid function. Thus, scintigraphy should be considered for patients with unstable GO after thyroidectomy to rule out thyroid remnants.

TSAb Modulates Microglia M1 Polarization via Activation of the TSHR-Mediated NF-κB Signaling Pathway.

INTRODUCTION: Thyrotropin receptor-stimulating antibody (TSAb) is a pathogenic antibody in the serum of patients with Graves' disease. The binding of TSAb to thyroid-stimulating hormone receptor (TSHR) in non-thyroid tissue may be associated with the occurrence and development of Graves' disease-related complications. However, only few studies have been conducted on the effects of TSAb on the brain, and the pathogenesis of acute hyperthyroidism myopathy (ATM) is unclear. Therefore, this study aimed to explore the effect of TSAb on the polarization of BV-2 cells in the brain and its possible mechanism and provide a basic experimental basis for ATM. METHODS: BV-2 cells were treated with different concentrations of TSAb. The relative survival rate of BV-2 cells was determined using the CCK-8 assay; the migration ability of BV-2 cells was detected using the Transwell migration assay; and the expression levels of M1/M2 polarization markers (CD86, inducible nitric oxide synthase [iNOS], CD206, and arginase 1 [Arg-1]), TSHR, tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-κB) protein in BV-2 cells were measured using WB. RESULTS: Compared with the negative control group, the proliferative activity of BV-2 cells was significantly increased in the 20, 50, and 100 ng/mL TSAb groups, and the migration ability of BV-2 cells was significantly enhanced in the 50 and 100 ng/mL TSAb groups. The expression levels of M1 polarization markers (CD86 and iNOS), TSHR, TNF-α, and NF-κB protein in BV-2 cells treated with 50 and 100 ng/mL TSAb for 24 h were significantly upregulated, whereas those of M2 polarization markers (CD206 and Arg-1) significantly decreased. CONCLUSIONS: TSAb can induce abnormal activation of microglia, polarize to the M1 phenotype, and promote the inflammatory cascade reaction, in which TSHR plays a key role in NF-κB activation and proinflammatory cytokine release.

YAP Mediates Hair Cell Regeneration in Balance Organs of Chickens, But LATS Kinases Suppress Its Activity in Mice.

Loss of sensory hair cells causes permanent hearing and balance deficits in humans and other mammals, but for nonmammals such deficits are temporary. Nonmammals recover hearing and balance sensitivity after supporting cells proliferate and differentiate into replacement hair cells. Evidence of mechanical differences between those sensory epithelia and their supporting cells prompted us to investigate whether the capacity to activate YAP, an effector in the mechanosensitive Hippo pathway, correlates with regenerative capacity in acceleration-sensing utricles of chickens and mice of both sexes. After hair cell ablation, YAP accumulated in supporting cell nuclei in chicken utricles and promoted regenerative proliferation, but YAP remained cytoplasmic and little proliferation occurred in mouse utricles. YAP localization in supporting cells was also more sensitive to shape change and inhibition of MST1/2 in chicken utricles than in mouse utricles. Genetic manipulations showed that in vivo expression of the YAP-S127A variant caused robust proliferation of neonatal mouse supporting cells, which produced progeny that expressed hair cell markers, but proliferative responses declined postnatally. Expression of YAP-5SA, which more effectively evades inhibitory phosphorylation, resulted in TEAD-dependent proliferation of striolar supporting cells, even in adult utricles. Conditional deletion of LATS1/2 kinases abolished the inhibitory phosphorylation of endogenous YAP and led to striolar proliferation in adult mouse utricles. The findings suggest that damage overcomes inhibitory Hippo signaling and facilitates regenerative proliferation in nonmammalian utricles, whereas constitutive LATS1/2 kinase activity suppresses YAP-TEAD signaling in mammalian utricles and contributes to maintaining the proliferative quiescence that appears to underlie the permanence of sensory deficits.SIGNIFICANCE STATEMENT Loud sounds, ototoxic drugs, infections, and aging kill sensory hair cells in the ear, causing irreversible hearing loss and balance deficits for millions. In nonmammals, damage evokes shape changes in supporting cells, which can divide and regenerate hair cells. Such shape changes are limited in mammalian ears, where supporting cells develop E-cadherin-rich apical junctions reinforced by robust F-actin bands, and the cells fail to divide. Here, we find that damage readily activates YAP in supporting cells within balance epithelia of chickens, but not mice. Deleting LATS kinases or expressing YAP variants that evade LATS-mediated inhibitory phosphorylation induces proliferation in supporting cells of adult mice. YAP signaling eventually may be harnessed to overcome proliferative quiescence that limits regeneration in mammalian ears.

Antiepileptic drug-induced severe cutaneous adverse reactions and HLA alleles: A report of five cases with lymphocyte activation test

Antiepileptic drugs (AEDs) can induce severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. We performed HLA genotyping and lymphocyte activation tests (LATs) for five AED-induced SCAR patients (three males and two females; aged 40–66 years old). Three patients were treated with carbamazepine (CBZ) for pain control, one was treated with phenytoin (PHT) for seizure prevention, and one was treated with valproic acid (VPA) for seizure prevention. One patient was diagnosed with CBZ-induced DRESS syndrome and the remaining patients were diagnosed with SJS. All patients recovered from SCARs after stopping suspicious drugs and supportive care. LATs were conducted to confirm the culprit drug responsible for inducing SCARs; and LAT results were positive for the suspected culprit drugs, in all except in one case. HLA-A,

Regulation of the Hippo Pathway by Phosphatidic Acid-Mediated Lipid-Protein Interaction.

The Hippo pathway plays a crucial role in organ size control and tumor suppression, but its precise regulation is not fully understood. In this study, we discovered that phosphatidic acid (PA)-related lipid signaling is a key regulator of the Hippo pathway. Supplementing PA in various Hippo-activating conditions activates YAP. This PA-related lipid signaling is involved in Rho-mediated YAP activation. Mechanistically, PA directly interacts with Hippo components LATS and NF2 to disrupt LATS-MOB1 complex formation and NF2-mediated LATS membrane translocation and activation, respectively. Inhibition of phospholipase D (PLD)-dependent PA production suppresses YAP oncogenic activities. PLD1 is highly expressed in breast cancer and positively correlates with YAP activation, suggesting their pathological relevance in breast cancer development. Taken together, our study not only reveals a role of PLD-PA lipid signaling in regulating the Hippo pathway but also indicates that the PLD-PA-YAP axis is a potential therapeutic target for cancer treatment.

Risk factors associated with the activity and severity of Graves’ Ophthalmopathy among patients at the University of the Philippines Manila-Philippine General Hospital / Journal of the ASEAN Federation of Endocrine Societies

Background@#Asians with Graves’ ophthalmopathy (GO) may have earlier compressive features due to narrower orbital apex and increased orbital volume. @*Objective@#To determine the risk factors associated with activity and severity of GO among adults. @*Methodology@#This was a cross-sectional analytical study of 163 adults with Graves’ disease (GD) from the outpatient clinics of the Philippine General Hospital. Demographics, clinical data, thyrotropin receptor antibody (TRAb) and urine iodine (UIE) levels were obtained. All participants were evaluated for activity and severity of GO by a single ophthalmologist. @*Results@#The population was predominantly composed of females (81%) and nonsmokers (69%), with a mean age of 35 + 11 years and median GD duration of 2 years. Median TRAb was 8.9 U/L while UIE was 171 mcg/L. Eight percent exhibited active GO, with 85% having mild disease. Multivariate analysis showed male sex to be associated with severe disease (OR 3.71, p=0.041), while elevated TRAb was associated with both active (OR 1.03, p=0.002) and severe GO (OR 1.02, p=0.007). @*Conclusion@#Lower rates of active and severe GO were seen compared to previous reports. In this population of predominantly nonsmokers, elevated TRAb emerged as a risk factor for active and severe GO.

Clinicopathological Significance of Large Tumor Suppressor (LATS) Expression in Gastric Cancer

PURPOSE: The aims of this study were to evaluate the expression of the large tumor suppressor (LATS) genes LATS1 and LATS2 by immunohistochemical staining of gastric cancer, and to evaluate the clinicopathological significance of LATS expression and its correlation with overall survival (OS). MATERIALS AND METHODS: LATS1 and LATS2 expression in a tissue microarray was detected by immunohistochemistry, using 264 gastric cancer specimens surgically resected between July 2006 and December 2009. RESULTS: Low expression of LATS1 was significantly associated with more advanced American Joint Committee on Cancer (AJCC) stage (P=0.001) and T stage (P=0.032), lymph node (LN) metastasis (P=0.040), perineural invasion (P=0.042), poor histologic grade (P=0.007), and diffuse-type histology by the Lauren classification (P=0.033). Low expression of LATS2 was significantly correlated with older age (≥65, P=0.027), more advanced AJCC stage (P=0.001) and T stage (P=0.001), LN metastasis (P=0.004), perineural invasion (P=0.004), poor histologic grade (P<0.001), and diffuse-type histology by the Lauren classification (P<0.001). Kaplan-Meier survival analysis revealed significantly poor OS rates in the groups with low LATS1 (P=0.037) and LATS2 (P=0.037) expression. CONCLUSIONS: Expression of LATS1 or LATS2 is a significant marker for a good prognosis in patients with gastric cancer.

Expression of LATS family proteins in ovarian tumors and its significance.

Epithelial ovarian cancer is composed of a diverse group of tumors that can be derived from the fallopian tube, endometrium, or ovary. In this study, we explored the expression levels of LATS family members in ovarian tumors using normal ovaries, fallopian tubes, and endometrium as controls. Immunohistochemistry studies of LATS1, LATS2, Pax8, and calretinin were performed on normal ovary, fallopian tube, normal endometrium, and ovarian tumor sections. Statistical analyses were conducted using the χ(2) test, Fisher exact test, or Kruskal-Wallis H test. Patient survival was analyzed using the Kaplan-Meier method. LATS1 was expressed in normal ovarian epithelia, endometrium, and fallopian tubes, whereas LATS2 expression was observed in the normal fallopian tubes and endometrium. High expressions of LATS1 and LATS2 in serous cystadenomas gradually decreased in borderline cystadenomas and carcinomas, respectively. However, an opposite expression pattern was observed in mucinous tumors. Low expressions of LATS1 and LATS2 were also detected in clear cell carcinoma. Both LATS1 and LATS2 expression levels significantly correlated with recurrence and stage; LATS1 levels were also related with tumor grades in serous carcinoma. However, univariate and multivariate Cox regression analyses revealed that high expression of LATS1 was associated with better prognosis in patients with serous carcinoma. Both LATS1 and LATS2 were not related with the clinical variables in mucinous and clear cell carcinoma. LATS1 expression levels might be a valuable survival indicator in ovarian serous carcinoma.