Complementary effects of dapagliflozin and lobeglitazone on metabolism in a diet-induced obese mouse model.

Thiazolidinedione, an insulin sensitizer, has beneficial effects on glucose metabolism; however, there are concerns regarding weight gain and heart failure. Sodium-glucose co-transporter 2 (SGLT2) inhibitors can reduce body weight, increase diuresis, and play a protective role in heart failure. We examined the complementary effects of dapagliflozin, an SGLT2 inhibitor, and lobeglitazone, a thiazolidinedione, in high-fat diet (HFD)-induced obese mice. We treated HFD-induced obese mice with vehicle, dapagliflozin, lobeglitazone, and their combination for 12 weeks. Oral glucose tolerance and insulin tolerance tests were performed after 12-week treatment, and body composition was measured by dual-energy X-ray absorptiometry before and after treatment. We analyzed oxygen consumption rate (OCR) using 3T3-L1 cells after treatment of ß-hydroxybutyrate and/or lobeglitazone. Treatment with a combination of dapagliflozin and lobeglitazone resulted in a significant decrease in postprandial hyperglycemia compared with dapagliflozin monotherapy, but not compared with lobeglitazone monotherapy. The addition of dapagliflozin to lobeglitazone treatment did not attenuate weight gain compared with lobeglitazone monotherapy in this study. However, this combination prevented the increase of organ weight of liver and heart, and OCR in 3T3-L1 cells was increased after treatment with a combination of ß-hydroxybutyrate and lobeglitazone compared to lobeglitazone monotherapy. We confirmed the beneficial effect of lobeglitazone on glucose metabolism; however, we did not find any beneficial effect of dapagliflozin on body weight in HFD-induced obese mice. However, the protective effects of dapagliflozin and lobeglitazone combined therapy on the liver, heart, energy consumption, and ß-cell senescence are worth investigating in clinical trials.

Association of Blood Pressure With Cardio-Renal Events and Mortality in Type 2 DM: A National Health Insurance Database.

CONTEXT: The relationship of blood pressure (BP) with cardio-renal events and all-cause mortality in type 2 diabetes mellitus (T2DM) is still controversial. OBJECTIVE: To investigate the optimal BP target in Korean individuals with T2DM. METHODS: Using the Korean National Health Insurance System database, data of individuals with T2DM who underwent regular health checks from January 1, 2007, to December 31, 2007, were extracted (N = 1 800 073). Among them, a total of 326 593 individuals were included in the final study. The study population was divided into 7 groups according to their observed systolic blood pressure (SBP) (<110, 110-119, 120-129, 130-139, 140-149, 150-159, 160-169, and ≥170 mmHg) and diastolic blood pressure (DBP) (<65, 65-69, 70-74, 75-79, 80-84, 85-89, and ≥90 mmHg). Hazard ratios (HRs) of cardio-renal events and all-cause mortality according to BP categories were analyzed. RESULTS: Compared with SBP of 120-129 mmHg and DBP of 75-79 mmHg, SBP of ≥130 mmHg and DBP of ≥ 80 mmHg were associated with an increase in HR of major cardiovascular adverse events (MACEs). SBP of 120-129 mmHg and DBP 75-79 mmHg were associated with the lowest HR of all-cause mortality. Both lower BP (SBP/DBP <120/70 mm) and higher BP (SBP/DBP ≥130/80 mmHg) were associated with an increased HR of all-cause mortality. Contrary to MACE, the lower the SBP, the lower the HR of renal events. CONCLUSION: In patients with T2DM, the optimal cutoff value of BP associated with a lower incidence of MACE and mortality may be 120-129 mmHg for SBP and 75-79 mmHg for DBP. However, lower SBP may be helpful for T2DM patients with a high risk of renal disease.

Effect of atorvastatin on lipoxygenase pathway-related gene expression in an in vitro model of lipid accumulation in hepatocytes.

Lipid accumulation in hepatocytes can result from an imbalance between lipid acquisition and lipid catabolism. In recent years, it has been discovered that eicosanoids derived from arachidonic acid (AA) have the potential to create specialized pro-resolving lipid mediators to actively resolve inflammation, but it is not clear whether AA and lipoxygenases exert effects on hepatic inflammation. Here, the effects of atorvastatin on the expression of cytoplasmic phospholipase A2 (cPLA2) and lipoxygenase pathway genes (ALOX5, ALOX12, ALOX15, and ALOX15B) were evaluated in an in vitro model of palmitic acid (PA)-induced hepatocyte lipid accumulation in McA-RH7777 (McA) cells. Palmitic acid increased cPLA2 expression, intracellular AA levels, and ALOX12 expression (P < 0.05). Atorvastatin at various concentrations had no significant effects on AA levels or on cPLA2, ALOX15, and ALOX15B expressions. ALOX5 was not detected, despite multiple measurements. Pro-inflammatory IL-1ß expression levels were upregulated by PA (P < 0.01) and attenuated by atorvastatin (P < 0.001). TNFα did not differ among groups. The expression levels of anti-inflammatory IL-10 decreased in response to PA (P < 0.05), but were not affected by atorvastatin. In conclusion, in an in vitro model of lipid accumulation in McA cells, atorvastatin reduced IL-1ß; however, its effect was not mediated by AA and the lipoxygenase pathway at the established doses and treatment duration. Further research is required to investigate time-response data, as well as other drugs and integrated cell systems that could influence the lipoxygenase pathway and modulate inflammation in liver diseases.

Association between the Diabetes Drug Cost and Cardiovascular Events and Death in Korea: A National Health Insurance Service Database Analysis.

BACKGRUOUND: This study aimed to investigate the long-term effects of diabetes drug costs on cardiovascular (CV) events and death. METHODS: This retrospective observational study used data from 2009 to 2018 from the National Health Insurance in Korea. Among the patients with type 2 diabetes, those taking antidiabetic drugs and who did not have CV events until 2009 were included. Patients were divided into quartiles (Q1 [lowest]-4 [highest]) according to the 2009 diabetes drug cost. In addition, the 10-year incidences of CV events (non-fatal myocardial infarction, stroke, hospitalization for heart failure, and coronary revascularization) and CV death (death due to CV events) were analyzed. RESULTS: A total of 441,914 participants were enrolled (median age, 60 years; men, 57%). CV events and death occurred in 28.1% and 8.36% of the patients, respectively. The 10-year incidences of CV events and deaths increased from Q1 to 4. After adjusting for sex, age, income, type of diabetes drugs, comorbidities, and smoking and drinking status, the risk of CV events significantly increased according to the sequential order of the cost quartiles. In contrast, the risk of CV death showed a U-shaped pattern, which was the lowest in Q3 (hazard ratio [HR], 0.953; 95% confidence interval [CI], 0.913 to 0.995) and the highest in Q4 (HR, 1.266; 95% CI, 1.213 to 1.321). CONCLUSION: Diabetes drug expenditure affects 10-year CV events and mortality. Therefore, affording an appropriate diabetes drug cost at a similar risk of CV is an independent protective factor against CV death.

Antibacterial and Antibiofilm Activity and Mode of Action of Magainin 2 against Drug-Resistant Acinetobacter baumannii.

Antimicrobial peptides (AMPs) are promising therapeutic agents for treating antibiotic-resistant bacterial infections. Previous studies showed that magainin 2 (isolated from African clawed fogs Xenopus laevis) has antimicrobial activity against gram-positive and gram-negative bacteria. The present study was conducted to investigate the antibacterial activity of magainin 2 against Acinetobacter baumannii. Magainin 2 showed excellent antibacterial activity against A. baumannii strains and high stability at physiological salt concentrations. This peptide was not cytotoxic towards HaCaT cells and showed no hemolytic activity. Biofilm inhibition and elimination were significantly induced in all A. baumannii strains exposed to magainin 2. We confirmed the mechanism of magainin 2 on the bacterial outer and inner membranes. Collectively, these results suggest that magainin 2 is an effective antimicrobial and antibiofilm agent against A. baumannii strains.

Inhibitory effect of snake venom toxin on NF-κB activity prevents human cervical cancer cell growth via increase of death receptor 3 and 5 expression.

We previously found that snake venom toxin inhibits nuclear factor kappa B (NF-κB) activity in several cancer cells. NF-κB is implicated in cancer cell growth and chemoresistance. In our present study, we investigated whether snake venom toxin (SVT) inhibits NF-κB, thereby preventing human cervical cancer cell growth (Ca Ski and C33A). SVT (0-12 µg/ml) inhibited the growth of cervical cancer cells by the induction of apoptotic cell death. These inhibitory effects were associated with the inhibition of NF-κB activity. However, SVT dose dependently increased the expression of death receptors (DRs): DR3, DR5 and DR downstream pro-apoptotic proteins. Exploration of NF-κB inhibitor (Phenylarsine oxide, 0.1 µM) synergistically further increased SVT-induced DR3 and DR5 expressions accompanied with further inhibition of cancer cells growth. Moreover, deletion of DR3 and DR5 by small interfering RNA significantly abolished SVT-induced cell growth inhibitory effects, as well as NF-κB inactivation. Using TNF-related apoptosis-inducing ligand resistance cancer cells (A549 and MCF-7), we also found that SVT enhanced the susceptibility of chemoresistance of these cancer cells through down-regulation of NF-κB, but up-regulation of DR3 and DR5. In vivo study also showed that SVT (0.5 and 1 mg/kg) inhibited tumor growth accompanied with inactivation of NF-κB. Thus, our present study indicates that SVT could be applicable as an anticancer agent for cervical cancer, or as an adjuvant agent for chemoresistant cancer cells.

Diagnostic accuracy of plasma free metanephrines in a seated position compared with 24-hour urinary metanephrines in the investigation of pheochromocytoma.

The aim of this study was to determine the diagnostic efficacy of free metanephrines in plasma samples drawn in the seated position compared with 24-h urinary metanephrines in detecting pheochromocytomas in Asian patients. This prospective study was conducted at Samsung Medical Center between May 2010 and July 2011. The study contained 245 subjects, including 28 patients with histologically-proven pheochromocytoma, 44 with histologically-proven non-pheochromocytoma, 112 controls suspected of having tumors but with negative investigations during two or more years of follow-up, and 45 healthy normotensive volunteers. Plasma-free metanephrines were measured by LC-MS/MS. The cut-off values with optimal sensitivity and specificity for plasma metanephrine and plasma normetanephrine were 0.33 nmol/L and 0.61 nmol/L, respectively. Both the plasma metanephrines measurement and urinary metanephrines measurement had a sensitivity of 96.4% (p = 1.00). However, the urinary metanephrines measurement was significantly more specific than the plasma metanephrines measurement (94.2% vs. 75.6%; p < 0.001). When we applied cut-off values based on BMI, specificity improved from 75.6% to 87.2%, with a comparable gain in sensitivity. From a diagnostic perspective, measurement of free metanephrines in plasma drawn in the seated position is highly sensitive but insufficiently specific when compared with measurement of 24-h urinary fractionated metanephrines. The specificity may be improved by applying cut-off values based on BMI. We suggest that free metanephrines in plasma drawn from seated position can also be used as an initial screening test to ensure that pheochromocytomas are not missed in Asian patients.

Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel-Lindau (VHL) disease.

Von Hippel-Lindau (VHL) disease is an inherited tumor syndrome caused by germline mutations in the VHL tumor suppressor gene. It is characterized by hemangioblastoma in the central nervous system and retina, renal cell carcinoma, pancreatic tumor and cysts, and pheochromocytoma. In this study, we detected 26 germline mutations in the VHL gene of Korean patients, of which 1 was a novel mutation, c.417_418insT. We also integrated our data from this study with the published literature to identify 55 VHL germline mutations in Koreans, and identified a unique hotspot at codon 70. Nine unrelated patients (9/55, 16.4%) had the same amino-acid substitution at codon 70 (Glu70Lys) and showed VHL type 1 phenotypes. Although this mutation was shown to have a mild effect on VHL function, four of the nine patients (44.4%) subsequently developed multiple central nervous system hemangioblastomas or retinal hemangioblastoma. However, this hotspot has not been identified in Chinese or Japanese patients. This study provides information on the spectrum of VHL mutations in Korean VHL disease and contributes to a better understanding of VHL disease in terms of improvements in the clinical management of VHL families.

Predictive factors of durability to sitagliptin: Slower reduction of glycated hemoglobin, older age and higher baseline glycated hemoglobin.

AIMS/INTRODUCTION: The goal of the present study was to evaluate predictive factors for good efficacy and durability to sitagliptin with ongoing metformin or metformin plus glimepiride therapy in a real practice situation. The present observational study was carried out over a 60-week period and involved Korean patients with type 2 diabetes mellitus. MATERIALS AND METHODS: A total of 100 mg of sitagliptin were added once daily to the two most popular therapy regimens (group 1: metformin, group 2: metformin plus glimepiride). Before adding sitagliptin, mean initial glycated hemoglobin (HbA1c) levels were 7.8% (62 mmol/mol) and mean diabetes duration was 8.3 years. RESULTS: After 60 weeks, the mean change in HbA1c from baseline was -0.9% (-10 mmol/mol) in group 1 and -1.0% (-11 mmol/mol) in group 2. Decreased HbA1c levels were significantly associated with higher initial HbA1c and lower log-transformed C-peptide levels in a multivariate regression analysis. Logistic regression analysis showed that a sustained reduction in HbA1c levels after 12 weeks was significantly associated with older age (≥60 years), higher baseline HbA1c (group 1 ≥ 7.0% [53 mmol/mol], group 2 ≥ 7.5% [58 mmol/mol]) and slower reduction of HbA1c (ΔHbA1c <1.0% [11 mmol/mol]) in group 1 and group 2. In group 2, a higher ratio of reduction of postprandial glucose/reduction of fasting plasma glucose (ΔPPG/ΔFPG) during 12 weeks was also associated with a sustained reduction in HbA1c levels after 12 weeks. CONCLUSIONS: The effects of sitagliptin lasted more than 12 weeks in older patients with a higher baseline HbA1c, and slower reduction of HbA1c during 12 weeks.

Testosterone replacement and bone mineral density in male pituitary tumor patients.

BACKGROUND: Hypopituitarism is associated with osteoporosis and osteopenia especially when hypogonadotropic hypogonadism is present. Despite hypopituitarism being an important cause of secondary osteoporosis, osteoporosis in patients receiving surgery for pituitary tumors in Korea has not been studied. In this study, we evaluated the effects of testosterone replacement therapy (TRT) on bone mineral density (BMD) in postoperative hypogonadal patients with pituitary tumors. METHODS: To examine the effect of TRT on BMD, we performed a retrospective observational study in 21 postoperative male patients who underwent pituitary tumor surgery between 2003 and 2012 at the Ajou University Hospital. Testosterone was replaced in postoperative hypogonadal patients by regular intramuscular injection, daily oral medication, or application of transdermal gel. BMD (g/cm(2)) measurements of central skeletal sites (lumbar spine, femoral neck, and total femur) were obtained using dual-energy X-ray absorptiometry (GE Lunar). For lumbar spine BMD, L1 to L4 values were chosen for analysis. Femur neck and total femur were also analyzed. RESULTS: During the follow-up period (mean, 56 months; range, 12 to 99 months) serum testosterone levels increased with the administration of TRT (P=0.007). There was significant improvement (4.56%±9.81%) in the lumbar spine BMD compared to baseline BMD. There were no significant changes in the femur neck BMD or total femur BMD. We did not find any statistically significant relationships between changes in testosterone levels and BMD using Spearman correlation analysis. CONCLUSION: Our results indicated that TRT used in the postoperative period for hypogonadal pituitary tumor surgery patients may have beneficial effects on the BMD of the spine.

A quasi-solid-state rechargeable lithium-oxygen battery based on a gel polymer electrolyte with an ionic liquid.

A quasi-solid-state lithium-oxygen battery constructed using a gel polymer electrolyte with an ionic liquid is proposed. The battery architecture incorporates a design feature that can be easily scaled up in size for use in large systems. The feasibility study demonstrates that the battery operates successfully for repeated discharge-charge cycles.

Sequential treatment of HPV E6 and E7-expressing TC-1 cells with bortezomib and celecoxib promotes apoptosis through p-p38 MAPK-mediated downregulation of cyclin D1 and CDK2.

Interruption of the cell cycle is accompanied by changes in several related molecules that result in the activation of apoptosis. The present study was performed to verify the apoptotic effects of sequential treatment with bortezomib and celecoxib in TC-1 cells expressing the human papillomavirus (HPV) E6 and E7 proteins. In TC-1 cells sequentially treated with bortezomib and celecoxib, apoptosis was induced through decreased expression of signal transducer and activator of transcription-3 (STAT3), cyclin D1 and cyclin-dependent kinase (CDK) 2, which are major regulators of the G0/G1 cell cycle checkpoint. In addition, increased levels of p21, CHOP, BiP and p-p38 MAPK were identified in these cells. The treatment-induced apoptosis was effectively inhibited by treatment with SB203580, an inhibitor of p-p38. Moreover, the growth of tumors sequentially treated with bortezomib and celecoxib was retarded compared to the growth of tumors exposed to a single treatment with either bortezomib or celecoxib in vivo. We demonstrated that sequential treatment with bortezomib and celecoxib induced apoptosis via p-p38-mediated G0/G1 cell cycle arrest and endoplasmic reticulum (ER) stress. Sequential treatment with these two drugs could therefore be a useful therapy for cervical cancer.

Prognostic implications of radioiodine avidity and serum thyroglobulin in differentiated thyroid carcinoma with distant metastasis.

BACKGROUND: Although differentiated thyroid carcinoma (DTC) rarely develops distant metastases, the present study was performed to evaluate factors that affect the survival of patients with DTC who present with distant metastasis. METHODS: Among 4,989 patients who underwent thyroid surgery for DTC, 82 presenting with distant metastasis were analyzed. Based on radioiodine ((131)I) avidity and the thyroid-stimulating hormone-stimulated serum thyroglobulin (sTg) level at the time of metastasis, patients were divided into three groups: group 1 ((131)I uptake + sTg ≤ 215 ng/mL, n = 46), group 2 ((131)I uptake + sTg > 215 ng/mL, n = 24), group 3 (no (131)I uptake, n = 12). Disease-specific survival (DSS) was estimated using the Kaplan-Meier method. Factors predicting the outcome were evaluated using Cox proportional hazard regression analysis. RESULTS: The age of patients (p = 0.04), frequency of follicular thyroid carcinoma (p = 0.002), tumor size (p < 0.001), and number of multiple metastatic sites (p = 0.004) differed significantly among the groups. With a median follow-up after surgery of 72 months, the 5- and 10-year DSSs for all patients were 84 and 69 %, respectively. The predictors of survival were age (p = 0.004), symptoms at the time of presentation (p = 0.045), histology (p = 0.01), sites of metastasis (p = 0.03), and (131)I avidity and sTg level at the time of metastasis (p = 0.002). In the multivariate analysis, age, histology, and (131)I avidity and sTg level at the time of metastasis remained significant factors for survival. CONCLUSIONS: Certain DTC patients with distant metastasis demonstrate favorable outcomes dependent on age, histology, and (131)I avidity and sTg level at the time of metastasis.

Papillary thyroid carcinoma recurring as squamous cell carcinoma 10 years after total thyroidectomy: lessons from rapidly progressive papillary thyroid carcinoma.

Primary squamous cell carcinoma (SCC) of the thyroid is very rare. There are no reports of metastatic papillary thyroid carcinoma (PTC) converting to SCC in cervical lymph nodes following total thyroidectomy due to conventional PTC. An 86-year-old woman with a remote history of total thyroidectomy due to PTC underwent palliative neck surgery to treat recurrent bleeding originating from a metastatic tumor of the cervical lymph nodes. The resected mass was composed of mixed SCC and PTC. Although primary SCC rarely occurs in the thyroid, conversion of PTC to SCC should be suspected if preexisting PTC exhibits highly aggressive behavior.

ERK phosphorylation is not increased in papillary thyroid carcinomas with BRAF(V600E) mutation compared to that of corresponding normal thyroid tissues.

BACKGROUND: An association between a BRAF(V600E) mutation and upregulation of mitogen-activated protein kinase (MAPK) pathways in human papillary thyroid carcinoma (PTC) tissues has not been demonstrated well outside of in vitro studies. The aims of this study were to evaluate the activation status of extracellular signal-regulated kinase 1/2 (ERK1/2) in human PTCs with BRAF(V600E) mutations compared to that of corresponding normal thyroid tissue and to determine the expressions of Raf kinase inhibitor protein (RKIP) and MAPK phosphatase 3 (MKP-3), possible regulators of ERK1/2 activation. METHODS: We analyzed the presence of BRAF(V600E) mutation and the expressions of BRAF, total ERK, p-ERK, RKIP, and MKP-3 in 33 PTCs and corresponding normal thyroid gland tissues using western blot analysis. RESULTS: BRAF(V600E) mutation was found in 28 (84.8%) of 33 PTCs, 96.4% (27/28) of which showed decreased p-ERK activity, while 75% (21/28) showed increased MKP-3 expression. There were significant differences in p-ERK and MKP-3 expressions between BRAF(V600E) (+) PTCs and normal thyroid glands (p < 0.001). There were no differences in expressions of BRAF, total ERK, and RKIP between PTCs and normal thyroid tissue, irrespective of the presence of BRAF(V600E) mutation. CONCLUSIONS: In human BRAF(V600E) (+) PTCs, ERK phosphorylation is decreased compared to normal thyroid glands and the observed decrease in ERK1/2 MAPK phosphorylation in BRAF(V600E) (+) PTCs may be associated with increased MKP-3 activity.

Postoperative-stimulated serum thyroglobulin measured at the time of 131I ablation is useful for the prediction of disease status in patients with differentiated thyroid carcinoma.

BACKGROUND: This study was conducted to identify the relevant cutoff value and to evaluate the usefulness of postoperative-stimulated serum thyroglobulin (Tg) at the time of (131)I ablation for the prediction of disease status in patients with differentiated thyroid carcinoma (DTC) who received high-dose (131)I ablation therapy after total thyroidectomy. METHODS: We analyzed 218 consecutively enrolled patients who were diagnosed with DTC and underwent total thyroidectomy. All patients underwent (131)I ablation at doses of 100-200 mCi, and stimulated serum Tg was measured at the time of (131)I ablation therapy. To assess disease-free status after (131)I ablation therapy, stimulated serum Tg levels, diagnostic whole-body scan (DxWBS) and neck ultrasonography (US) were performed 6-12 months after (131)I ablation. RESULTS: The relevant cutoff value of postoperative stimulated Tg for the prediction of disease-free status was 2 ng/mL. A total of 138 patients (63.3%) showed values of <2 ng/mL. Postoperative-stimulated Tg < 2 ng/mL had a negative predictive value of 94.9%, which increased to 97.7% when low Tg was combined with negative neck US findings. CONCLUSION: Postoperative-stimulated Tg at the time of (131)I remnant ablation is a useful biochemical marker for the prediction of disease status in patients with DTC. When high-dose (131)I remnant ablation is performed after total thyroidectomy, the stimulated Tg measurement and DxWBS that are usually performed 6-12 months after (131)I ablation therapy may be skipped, at least in low- and intermediate-risk patients with postoperative stimulated Tg of < 2 ng/mL and negative neck US findings.

Postoperative spindle cell nodule after thyroidectomy: a case mimicking recurrence with anaplastic transformation of thyroid cancer.

BACKGROUND: Here, we report a case of a postoperative spindle cell nodule that mimicked recurrence with anaplastic transformation after thyroidectomy. METHODS: The course of the disease is described. The mass was studied morphologically and immunohistochemically. RESULTS: A 31-year-old woman underwent total thyroidectomy for papillary thyroid carcinoma. A mass suspected of recurrence was found 14 months later and caused dysphagia and dyspnea. An (18)F-fluorodeoxyglucose positron emission tomographic ((18)F-FDG-PET) scan showed a lesion with high uptake; however, a fine-needle aspiration biopsy (FNAB) was inconsistent with recurrent cancer. The mass was resected and was composed of elongated spindle cells, with eosinophilic cytoplasm within a myxoid background. Immunohistochemical staining was strongly positive for vimentin, focally positive for smooth muscle actin, desmin, and p53, and negative for cytokeratin AE1/AE3, Cam5.2, epithelial membrane antigen (EMA), and anaplastic lymphoma kinase (ALK-1). CONCLUSION: Although postoperative spindle cell nodules are rare after thyroid surgery, it should be considered in the differential diagnosis for recurrent masses at the operative site.

BRAFV600E mutation in fine-needle aspiration aspirates: Association with poorer prognostic factors in larger papillary thyroid carcinomas.

BACKGROUND: Recent studies have shown that BRAF(V600E) mutation is associated with poor prognostic factors in papillary thyroid carcinoma (PTC). However, there are no studies about the association of the BRAF(V600E) mutation with poor prognostic factors according to tumor size in PTC. METHODS: We investigated the prevalence of the BRAF(V600E) mutation and its association with prognostic factors according to tumor size of PTC. BRAF(V600E) mutation status was assessed in thyroid fine-needle aspiration (FNA) specimens from 605 patients before thyroidectomy for PTC, and its association with postoperative clinicopathologic factors was evaluated. RESULTS: The overall prevalence of the BRAF(V600E) mutation was 67%, and larger tumors more often had the BRAF(V600E) mutation (p for trend < .05). The BRAF(V600E) mutation was significantly associated with male sex, tumor size, extrathyroidal invasion, nodal metastasis, and advanced tumor stage (p < .05). There was a significant size-dependent relationship between the presence of the BRAF(V600E) mutation and extrathyroidal invasion, nodal metastasis, and advanced tumor stage (p for trend < .05). CONCLUSION: The prevalence of the BRAF(V600E) mutation increased with increased tumor size. Preoperative FNA-detected BRAF(V600E) mutation was associated with poor prognostic factors, and the association was stronger in larger tumors.

Euthyroid status after total thyroidectomy due to functioning lung metastases from a clear cell variant of papillary thyroid carcinoma.

BACKGROUND: Although functioning thyroid cancer metastases have been reported, they have almost never been reported for the clear cell variant of papillary thyroid carcinoma (PTC). Here we describe a patient with disseminated lung metastases of the clear cell variant of PTC who presented in the euthyroid state despite discontinuance of levothyroxine after total thyroidectomy. PATIENT FINDINGS: A 49-year-old woman underwent total thyroidectomy for the clear cell variant of PTC in March 2002. Levothyroxine replacement was initiated after total thyroidectomy, but the patient was lost to follow-up 5 years after the operation. She did not take any levothyroxine for 4 years. Upon presentation to our institution, her initial thyroid function tests were a serum thyroid-stimulating hormone (TSH) of 4.51 mIU/L (0.30-5.00), total triiodothyronine of 82 ng/dL (60-181), and free thyroxine of 1.21 ng/dL (0.89-1.76). The results of workups, including thyroid ultrasonography, chest computed tomography (CT) scan, and fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET)/CT, revealed that she had multiple metastases in the cervical lymph nodes and both lungs. She received 0.9 mg of recombinant human TSH (rhTSH) for 2 consecutive days followed by administration of 200 mCi 131I. A therapeutic whole body scan after 131I administration demonstrated intense uptake in the whole lung fields, suggesting functioning lung metastases. SUMMARY: It is extremely rare for metastatic PTC, even though it is a well-differentiated thyroid carcinoma, to produce a sufficient amount of thyroid hormones to result in euthyroid state after total thyroidectomy. To our knowledge, this is the first report of functioning lung metastases of the clear cell variant of PTC after total thyroidectomy that produced enough thyroid hormone to restore a euthyroid state. CONCLUSION: Functioning metastases from recurred PTC, particularly of the clear cell variant, are very rare. When they occur, rhTSH is required to prepare these patients for treatment with ablative doses of radioactive iodine (131I).

Promoting Li2O2 oxidation by an La(1.7)Ca(0.3)Ni(0.75)Cu(0.25)O4 layered perovskite in lithium-oxygen batteries.

We demonstrate for the first time that La(1.7)Ca(0.3)Ni(0.75)Cu(0.25)O(4) with a layered perovskite structure promotes electrochemical oxidation of Li(2)O(2) in lithium-oxygen batteries with a non-aqueous aprotic electrolyte.