Exosomes derived from chemically induced human hepatic progenitors inhibit oxidative stress induced cell death.

The emerging field of regenerative medicine has revealed that the exosome contributes to many aspects of development and disease through intercellular communication between donor and recipient cells. However, the biological functions of exosomes secreted from cells have remained largely unexplored. Here, we report that the human hepatic progenitor cells (CdHs)-derived exosome (EXOhCdHs ) plays a crucial role in maintaining cell viability. The inhibition of exosome secretion treatment with GW4869 results in the acceleration of reactive oxygen species (ROS) production, thereby causing a decrease of cell viability. This event provokes inhibition of caspase dependent cell death signaling, leading to a ROS-dependent cell damage response and thus induces promotion of antioxidant gene expression or repair of cell death of hypoxia-exposed cells. Together, these findings show the effect of exosomes in regeneration of liver cells, and offer valuable new insights into liver regeneration.

Improved infrared spectroscopic discrimination between gall bladder (GB) polyps and GB cancer using component-descriptive spectral features of separated phases from bile.

This study demonstrates a unique strategy for enhancing infrared (IR) spectroscopic discrimination between gall bladder (GB) polyps and cancer. This strategy includes the separation of raw bile juice into three sections of organic, aqueous, and amphiphilic phases and a cooperative combination of all IR spectral features of each separated phase for the discrimination. Raw bile juice is viscous and complex in composition because it contains fatty acids, cholesterol, proteins, phospholipids, bilirubin, and other components; therefore, the acquisition of IR spectra providing more component-discernible information is fundamental for improving discrimination. For this purpose, raw bile juice was separated into an aqueous phase, mostly containing bile salts, an organic phase with isolated lipids, and an amphiphilic phase, mainly containing proteins. The subsequent IR spectra of each separated phase were mutually characteristic and complementary to each other. When all the IR spectral features were combined, the discrimination was improved compared to that using the spectra of raw bile juice with no separation. The cooperative integration of more component-specific spectra obtained from each separated phase enhanced the discrimination. In addition, the IR spectra of the major constituents in bile juice, such as bile acids, conjugated bile salts, lecithin, and cholesterol, were recorded to explain the IR features of each separated phase.

Nonintegrating Direct Conversion Using mRNA into Hepatocyte-Like Cells.

Recently, several researchers have reported that direct reprogramming techniques can be used to differentiate fibroblasts into hepatocyte-like cells without a pluripotent intermediate step. However, the use of viral vectors for conversion continues to pose important challenges in terms of genome integration. Herein, we propose a new method of direct conversion without genome integration with potential clinical applications. To generate hepatocyte-like cells, mRNA coding for the hepatic transcription factors Foxa3 and HNF4α was transfected into mouse embryonic fibroblasts. After 10-12 days, the fibroblasts converted to an epithelial morphology and generated colonies of hepatocyte-like cells (R-iHeps). The generated R-iHeps expressed hepatocyte-specific marker genes and proteins, including albumin, alpha-fetoprotein, HNF4α, CK18, and CYP1A2. To evaluate hepatic function, indocyanine green uptake, periodic acid-Schiff staining, and albumin secretion were assessed. Furthermore, mCherry-positive R-iHeps were engrafted in the liver of Alb-TRECK/SCID mice, and we confirmed FAH enzyme expression in Fah1RTyrc/RJ models. In conclusion, our data suggest that the nonintegrating method using mRNA has potential for cell therapy.

Knockdown of end-binding protein 1 induces apoptosis in radioresistant A549 lung cancer cells via p38 kinase-dependent COX-2 upregulation.

The role of end-binding protein 1 (EB1) in lung cancer tumorigenesis and radiotherapy remains poorly understood. In the present study, we observed that EB1 was highly expressed in lung tumor tissues compared with normal non-tumor tissues based on immunohistochemical analysis of lung cancer tissue samples obtained from human tissue microarrays. EB1 was also highly overexpressed in radioresistant lung and cervical cancer cells, which exhibited increased cell death after EB1 silencing. The cytotoxicity induced by EB1 gene knockdown was due to the activation and generation of reactive oxygen species by p38 mitogen-activated protein kinase. Notably, this signaling cascade, however not nuclear factor-κB-mediated signaling, induced the expression of cyclooxygenase-2, a key effector of apoptotic death. Our results provided new molecular evidence supporting the use of EB1 as a novel target in lung cancer therapy, especially in the case of radioresistance.

Estimation of low-dose radiation-responsive proteins in the absence of genomic instability in normal human fibroblast cells.

PURPOSE: Low-dose radiation has various biological effects such as adaptive responses, low-dose hypersensitivity, as well as beneficial effects. However, little is known about the particular proteins involved in these effects. Here, we sought to identify low-dose radiation-responsive phosphoproteins in normal fibroblast cells. MATERIALS AND METHODS: We assessed genomic instability and proliferation of fibroblast cells after γ-irradiation by γ-H2AX foci and micronucleus formation analyses and BrdU incorporation assay, respectively. We screened fibroblast cells 8 h after low-dose (0.05 Gy) γ-irradiation using Phospho Explorer Antibody Microarray and validated two differentially expressed phosphoproteins using Western blotting. RESULTS: Cell proliferation proceeded normally in the absence of genomic instability after low-dose γ-irradiation. Phospho antibody microarray analysis and Western blotting revealed increased expression of two phosphoproteins, phospho-NFκB (Ser536) and phospho-P70S6K (Ser418), 8 h after low-dose radiation. CONCLUSIONS: Our findings suggest that low-dose radiation of normal fibroblast cells activates the expression of phospho-NFκB (Ser536) and phospho-P70S6K (Ser418) in the absence of genomic instability. Therefore, these proteins may be involved in DNA damage repair processes.

Phosphoprotein profiles of candidate markers for early cellular responses to low-dose γ-radiation in normal human fibroblast cells.

Ionizing radiation causes biological damage that leads to severe health effects. However, the effects and subsequent health implications caused by exposure to low-dose radiation are unclear. The objective of this study was to determine phosphoprotein profiles in normal human fibroblast cell lines in response to low-dose and high-dose γ-radiation. We examined the cellular response in MRC-5 cells 0.5 h after exposure to 0.05 or 2 Gy. Using 1318 antibodies by antibody array, we observed ≥1.3-fold increases in a number of identified phosphoproteins in cells subjected to low-dose (0.05 Gy) and high-dose (2 Gy) radiation, suggesting that both radiation levels stimulate distinct signaling pathways. Low-dose radiation induced nucleic acid-binding transcription factor activity, developmental processes, and multicellular organismal processes. By contrast, high-dose radiation stimulated apoptotic processes, cell adhesion and regulation, and cellular organization and biogenesis. We found that phospho-BTK (Tyr550) and phospho-Gab2 (Tyr643) protein levels at 0.5 h after treatment were higher in cells subjected to low-dose radiation than in cells treated with high-dose radiation. We also determined that the phosphorylation of BTK and Gab2 in response to ionizing radiation was regulated in a dose-dependent manner in MRC-5 and NHDF cells. Our study provides new insights into the biological responses to low-dose γ-radiation and identifies potential candidate markers for monitoring exposure to low-dose ionizing radiation.

Radiotherapy diagnostic biomarkers in radioresistant human H460 lung cancer stem-like cells.

Tumor cell radioresistance is a major contributor to radiotherapy failure, highlighting the importance of identifying predictive biomarkers for radioresistance. In this work, we established a radioresistant H460 (RR-H460) cell line from parental radiosensitive H460 lung cancer cells by exposure to fractionated radiation. The radiation-resistant, anti-apoptotic phenotype of RR-H460 cell lines was confirmed by their enhanced clonogenic survival and increased expression of the radioresistance genes Hsp90 and Her-3. RR-H460 cells displayed characteristics of cancer stem-like cells (CSCs), including induction of the surface marker CD44 and stem cell markers Nanog, Oct4, and Sox2. RR-H460 cells also exhibited sphere formation and malignant behavior, further supporting a CSC phenotype. Using proteomic analyses, we identified 8 proteins that were up-regulated in RR-H460 CSC lines and therefore potentially involved in radioresistance and CSC-related biological processes. Notably, 4 of these-PAI-2, NOMO2, KLC4, and PLOD3-have not been previously linked to radioresistance. Depletion of these individual genes sensitized RR-H460 cells to radiotoxicity and additively enhancing radiation-induced apoptosis. Our findings suggest the possibility of integrating molecular targeted therapy with radiotherapy as a strategy for resolving the radioresistance of lung tumors.

Radiosensitizing effect of PSMC5, a 19S proteasome ATPase, in H460 lung cancer cells.

The function of PSMC5 (proteasome 26S subunit, ATPase 5) in tumors, particularly with respect to cancer radioresistance, is not known. Here, we identified PSMC5 as a novel radiosensitivity biomarker, demonstrating that radiosensitive H460 cells were converted to a radioresistance phenotype by PSMC5 depletion. Exposure of H460 cells to radiation induced a marked accumulation of cell death-promoting reactive oxygen species, but this effect was blocked in radiation-treated H460 PSMC5-knockdown cells through downregulation of the p53-p21 pathway. Interestingly, PSMC5 depletion in H460 cells enhanced both AKT activation and MDM2 transcription, thereby promoting the degradation of p53 and p21 proteins. Furthermore, specific inhibition of AKT with triciribine or knockdown of MDM2 with small interfering RNA largely restored p21 expression in PSMC5-knockdown H460 cells. Our data suggest that PSMC5 facilitates the damaging effects of radiation in radiation-responsive H460 cancer cells and therefore may serve as a prognostic indicator for radiotherapy and molecular targeted therapy in lung cancer patients.

Knockdown of hepatoma-derived growth factor-related protein-3 induces apoptosis of H1299 cells via ROS-dependent and p53-independent NF-κB activation.

We previously identified hepatoma-derived growth factor-related protein-3 (HRP-3) as a radioresistant biomarker in p53 wild-type A549 cells and found that p53-dependent induction of the PUMA pathway was a critical event in regulating the radioresistant phenotype. Here, we found that HRP-3 knockdown regulates the radioresistance of p53-null H1299 cells through a distinctly different molecular mechanism. HRP-3 depletion was sufficient to cause apoptosis of H1299 cells by generating substantial levels of reactive oxygen species (ROS) through inhibition of the Nrf2/HO-1 antioxidant pathway. Subsequent, ROS-dependent and p53-independent NF-κB activation stimulated expression of c-Myc and Noxa proteins, thereby inducing the apoptotic machinery. Our results thus extend the range of targets for the development of new drugs to treat both p53 wild-type or p53-null radioresistant lung cancer cells.

Association between expression of X-linked inhibitor of apoptosis protein and the clinical outcome in a BRAF V600E-prevalent papillary thyroid cancer population.

BACKGROUND: The X-linked inhibitor of apoptosis protein (XIAP) is associated with carcinogenesis, cancer progression, and metastasis through inhibition of the caspase-mediated apoptotic pathway. The BRAF(V600E) mutation is the most common genetic alteration and an established prognostic marker in papillary thyroid cancer (PTC). The prevalence of the BRAF mutation is very high and is up to 80% in Korean PTC patients. In the present study, we evaluated the potential role of XIAP expression as a novel prognostic marker to predict recurrence, in combination with the BRAF(V600E) mutational status. METHODS: The study enrolled 164 patients with conventional PTC who underwent bilateral thyroidectomy followed by immediate (131)I ablation. The presence of the BRAF(V600E) mutation was evaluated by direct sequencing. The degree of XIAP expression was evaluated by immunohistochemical (IHC) staining using a monoclonal antibody. RESULTS: The BRAF(V600E) mutation was found in 123 of 164 patients (75%) with classical PTC. XIAP expression was positive in 128 of 164 patients (75%), and positive XIAP expression was significantly associated with the presence of lateral cervical lymph node metastases (p=0.01). XIAP expression was more frequent in BRAF(V600E) mutated PTCs than in BRAF wild type PTCs (p=0.048). The BRAF(V600E) mutation was significantly associated with cancer recurrence in study subjects (hazard ratio=2.98, p=0.039). PTCs positive for the BRAF(V600E) mutation but negative for XIAP expression had a significantly higher rate of recurrent PTC (hazard ratio=4.53, p=0.012). CONCLUSION: The evaluation of XIAP expression and BRAF mutational analysis was more useful for the prediction of cancer recurrence in patients with PTC than BRAF genotype alone.

Depletion of hepatoma-derived growth factor-related protein-3 induces apoptotic sensitization of radioresistant A549 cells via reactive oxygen species-dependent p53 activation.

Biomarkers based on functional signaling have the potential to provide greater insight into the pathogenesis of cancer and may offer additional targets for anticancer therapeutics. Here, we identified hepatoma-derived growth factor-related protein-3 (HRP-3) as a radioresistance-related gene and characterized the molecular mechanism by which its encoded protein regulates the radio- and chemoresistant phenotype of lung cancer-derived A549 cells. Knockdown of HRP-3 promoted apoptosis of A549 cells and potentiated the apoptosis-inducing action of radio- and chemotherapy. This increase in apoptosis was associated with a substantial generation of reactive oxygen species (ROS) that was attributable to inhibition of the Nrf2/HO-1 antioxidant pathway and resulted in enhanced ROS-dependent p53 activation and p53-dependent expression of PUMA (p53 upregulated modulator of apoptosis). Therefore, the HRP-3/Nrf2/HO-1/ROS/p53/PUMA cascade is an essential feature of the A549 cell phenotype and a potential radiotherapy target, extending the range of targets in multimodal therapies against lung cancer.

Depletion of end-binding protein 1 (EB1) promotes apoptosis of human non-small-cell lung cancer cells via reactive oxygen species and Bax-mediated mitochondrial dysfunction.

Although end-binding protein 1 (EB1) is well known to regulate microtubule dynamics, the role of EB1 in apoptosis of non-small cell lung cancer (NSCLC) is poorly understood. Here, we investigated the molecular mechanism by which EB1 regulates apoptosis in H460, A549, and H1299 cells. Depletion of EB1 in A549 and H1299 cells, which express high levels of EB1, induced cell death in a p53-independent manner through over-production of reactive oxygen species (ROS) and Bax induction. This phenomenon was potentiated in radiation-treated EB1-knockdown cells and was largely blocked by N-acetyl-L-cysteine, a scavenger of ROS. ROS accelerated the activation of nuclear factor-kappa B (NF-κB) to promote transcriptional activity of Bax, an action that was accompanied by cytochrome c translocation and apoptosis-inducing factor (AIF) release. The NF-κB inhibitor, BAY 11-7082, potently inhibited the apoptosis induced by EB1 knockdown and radiation treatment, in association with diminished activity of the mitochondrial death pathway. Conversely, ectopic overexpression of EB1 in H460 cells, which express low levels of EB1, remarkably abrogated radiation-induced apoptosis and NF-κB-mediated mitochondrial dysfunction. Our data provide the first demonstration that down-regulation of EB1 promotes NSCLC cell death by inducing ROS-mediated, NF-κB-dependent Bax signaling cascades, a process in which cytochrome c and AIF play important roles, indicating a potential therapeutic benefit of EB1 in lung cancer.

Identification of HDAC4 as a target of γ-catenin that regulates the oncogenic K-Ras-mediated malignant phenotype of Rat2 cells.

The mechanisms by which activated Ras accelerates malignant transformation of normal cells are not fully understood. Here, we characterized the role and molecular mechanism of γ-catenin in regulating the malignant phenotype of Rat2 cells induced by codon 12-mutant K-Ras (K-Ras12V). Suppression of γ-catenin signaling by K-Ras12V was an early event and played a crucial role in promoting the acquisition of a highly metastatic phenotype of Rat2 cells. Notably, the gene encoding histone deacetylase 4 (HDAC4) was identified as a target of γ-catenin during this process. The transcription factor, lymphoid enhancer-binding factor-1 (Lef1), was involved in the modulation of HDAC4 transcription, and disruption of this pathway was a key event in promoting the invasion and migration of K-Ras12V-transduced Rat2 cells. Thus, our findings extend the range of targets for the development of new drugs for the therapy of oncogenic K-Ras-driven cancer.

Obesity is a risk factor for thyroid cancer in a large, ultrasonographically screened population.

OBJECTIVE: Obesity is a well-known risk factor for many cancers, including those of the esophagus, colon, kidney, breast, and skin. However, there are few reports on the relationship between obesity and thyroid cancer. We conducted this study to determine whether obesity is a risk factor for thyroid cancer by systematically screening a selected population by ultrasonography. DESIGN AND METHODS: We obtained data from 15,068 subjects that underwent a routine health checkup from 2007 to 2008 at the Health Screening and Promotion Center of Asan Medical Center. Thyroid ultrasonography was included in the checkup, and suspicious nodules were examined by ultrasonography-guided aspiration. Those with a history of thyroid disease or family history of thyroid cancer were excluded from this study. RESULTS: In total, 15,068 subjects, 8491 men and 6577 women, were screened by thyroid ultrasonography. Fine-needle aspiration cytology was performed in 1427 of these patients based on the predefined criteria and thyroid cancer was diagnosed in 267 patients. The prevalence of thyroid cancer in women was associated with a high BMI (per 5 kg/m(2) increase) (odds ratios (OR)=1.63, 95% CI 1.24-2.10, P<0.001), after adjustment for age, smoking status, and TSH levels. There was no positive correlation between the prevalence of thyroid cancer in men and a high BMI (OR=1.16, 95% CI 0.85-1.57, P=0.336). There was no association between age, fasting serum insulin, or basal TSH levels and thyroid cancer in either gender. CONCLUSIONS: Obesity was associated with a higher prevalence of thyroid cancer in women when evaluated in a routine health checkup setting. This association between risk factor and disease was unrelated to serum insulin and TSH levels. Additional studies are needed to understand the mechanism(s) behind the association of obesity with thyroid cancer risk.

Long-term consequence of elevated thyroglobulin in differentiated thyroid cancer.

BACKGROUND: Serum thyroglobulin (Tg) is the most sensitive biomarker for recurrence of differentiated thyroid cancer (DTC). We have assessed the changing pattern of stimulated Tg (sTg) and the clinical course of patients with no structural evidence of disease (NSED), based on imaging studies such as neck ultrasonography (US), fluorodeoxyglucose positron emission tomography, and/or chest computed tomogram (CT). We sought to determine if, in patients with DTC who had been treated with bilateral thyroidectomy and remnant ablation with radioactive iodine, sTg 1 year (sTg1) after initial treatment and repeated sTg measurements, 1-2 years after sTg1, helped predict the long-term outcome with respect to structural recurrence and biochemical remission (BR), which is defined as sTg <1 ng/mL. METHODS: We retrospectively assessed the records of patients with DTC who had been treated with bilateral thyroidectomy and remnant ablation with radioactive iodine between 1995 and 2004. The study included 186 patients who had NSED with sTg1 ≥2 ng/mL and subsequent sTg measurements (sTg2) without additional treatment. Patients were classified into three groups based on their sTg1 measurements: Group A, 2-4.9 ng/mL; Group B, 5-19.9 ng/mL; and Group C, ≥20 ng/mL. Patients were also classified into two groups based on whether sTg2, 1-2 years after sTg1, had decreased by ≥50% (Group 1) or had either decreased by <50% or increased (Group 2). sTg was measured every 1-2 years until structural recurrence or BR. RESULTS: Patients remaining in NSED showed a decrease in serial sTg. Of patients in Groups A, B, and C, 41%, 17%, and 1%, respectively, achieved BR, and there was a significant difference in the BR rate between Groups 1 and 2 (p<0.001). In patients with structural recurrence, serial sTg generally did not decrease from sTg1. There was a significant difference in the recurrence rate among Groups A, B, and C (p=0.005) and between Groups 1 and 2 (p<0.001). CONCLUSIONS: We found that 41% of patients with sTg1 in the range 2-5 ng/mL achieved BR, and that sTg1 and percent change of subsequent sTg were predictive of BR. Repeated sTg measurements are useful for predicting patient prognosis in patients with DTC.

Serum antithyroglobulin antibodies interfere with thyroglobulin detection in fine-needle aspirates of metastatic neck nodes in papillary thyroid carcinoma.

CONTEXT: It is recommended to measure thyroglobulin (Tg) levels in the needle washout fluids from fine-needle aspirations (FNAs) in patients with papillary thyroid carcinoma (PTC) who have ultrasonographically suspicious metastatic lymph nodes (LNs). However, it is not clear whether serum anti-Tg antibodies (TgAbs) interfere with the detection of Tg in needle washout fluids from FNAs (FNA-Tg). OBJECTIVE: The objective of the study was to evaluate the influence of serum TgAbs on FNA-Tg detection. DESIGN AND SETTINGS: This retrospective observational cohort study enrolled 207 patients with conventional PTC in whom FNA-Tg values had been measured. All patients initially underwent total thyroidectomy and remnant ablation. FNA-Tg levels were measured from ultrasonographically suspicious metastatic LNs of 0.5 cm or greater in the longest diameter. RESULTS: From 207 patients, 263 LNs were evaluated. Final histopathology was available for 92 LNs, of which 88 (96%) were malignant. FNA-Tg levels were lower in the LNs from serum TgAb-positive patients than in those from TgAb-negative patients (P < 0.001). In four of 13 metastatic LNs from TgAb-positive patients, the FNA-Tg levels were below 10 µg/liter including one in which both FNA-Tg and serum-stimulated Tg levels were below 1 µg/liter and stained positively for Tg in pathology. There was also one malignant LN with negative for FNA-Tg, serum-stimulated Tg, and serum TgAb but that nonetheless stained intensely for Tg. However, there were no malignant LNs with both negative cytology and negative FNA-Tg. A diagnosis based on FNA-Tg had a lower sensitivity and negative predictive value in the TgAb-positive group than in the TgAb-negative group. CONCLUSION: FNA-Tg measurement is highly reliable in the diagnosis of neck metastases in PTC patients, even in cases of negative-stimulated Tg or positive TgAb. However, high-serum TgAb levels could interfere with FNA-Tg measurements and thereby result in falsely low FNA-Tg levels.

The prognostic value of the metastatic lymph node ratio and maximal metastatic tumor size in pathological N1a papillary thyroid carcinoma.

OBJECTIVE: The presence of central neck lymph node (LN) metastases (defined as pN1a according to Tumor Node Metastasis classification) in papillary thyroid cancer (PTC) is known as an independent risk factor for recurrence. Extent of LN metastasis and the completeness of removal of metastatic LN must have an impact on prognosis but they are not easy to measure. Moreover, the significance of the size of metastatic tumors in LNs has not been clarified. This study was to evaluate the impact of the extent of LN metastasis and size of metastatic tumors on the recurrence in pathological N1a PTC. DESIGN: This retrospective observational cohort study enrolled 292 PTC patients who underwent total thyroidectomy with central neck dissection from 1999 to 2005. LN ratio was defined as the number of metastatic LNs divided by the number of removed LNs, which was regarded as variable reflecting both extent of LN metastasis and completeness of resection, and LN size as the maximal diameter of tumor in metastatic LN. RESULTS: The significant risk factors for recurrence in univariate analysis were large primary tumor size (defined as larger than 2 cm), high LN ratio (defined as higher than 0.4), and presence of macrometastasis (defined as larger than 0.2 cm). Age, sex, clinical node status, and microscopic perithyroidal extension had no effect on recurrence. In multivariate analysis, high LN ratio and presence of macrometastasis were independent risk factors for recurrence. CONCLUSION: LN ratio and size of metastatic nodes had a significant prognostic value in pathological N1a PTC. We suggest that risk stratification of pathological N1a PTC according to the pattern of LN metastasis such as LN ratio and size would give valuable information to clinicians.

Long-term clinical outcome of differentiated thyroid cancer patients with undetectable stimulated thyroglobulin level one year after initial treatment.

BACKGROUND: Measurement of the serum thyroglobulin (Tg) level with TSH stimulation (sTg) is the cornerstone of monitoring for the recurrence or persistence of differentiated thyroid cancer (DTC) in patients who have undergone surgery and remnant ablation. However, there have been several reports that an undetectable sTg could not predict the absence of future recurrence. The aim of this study was to evaluate the long-term outcome of DTC patients who achieved biochemical remission (BR, defined as sTg<1 ng/mL) after initial treatment, and to determine the role of repeated sTg measurement in detecting a clinical recurrence. METHODS: This is a retrospective observational cohort study in a tertiary referral hospital. There were 1010 DTC patients who achieved BR at 12 months after the initial treatment (surgery and ablation), and they were eligible for analysis. Among them, 787 patients had values of repeated sTg. RESULTS: Thirteen out of 1010 (1.3%) patients had clinical recurrences during a median 84 months of follow-up. All of the clinical recurrences were limited to the cervical lymph nodes without clinical evidence of distant metastasis. Among 787 patients with available repeated sTg, 10 had clinical recurrences (5 out of 750 patients with repeated sTg<1 ng/mL and 5 out of 37 patients with repeated sTg ≥ 1 ng/mL). Patients with repeated sTg ≥ 1 ng/mL had a much greater chance of disease recurrence (log-rank statistics=43.7, df=1, p<0.001). CONCLUSIONS: About 1% of DTC patients who had sTg<1 ng/mL 12 months after initial treatment had a clinical recurrence. All of clinical recurrences were loco-regional recurrences. Although repeated sTg measurement can be helpful to predict recurrence, we could not recommend it for surveillance in patients with BR due to its very low yield.

Association between STAT1 activity and BRAF mutations in papillary thyroid carcinomas.

BACKGROUND: Signal transducer and activator of transcription-1 (STAT1) plays a critical role in tumorigenesis by controlling several functions in both tumor cells and the immune system, and is considered to be a tumor suppressor. The present study evaluated the activity of STAT1 in human papillary thyroid carcinomas (PTC). METHODS: STAT1 activity was measured in nuclear extracts of tumor tissues from 35 PTC patients using an ELISA-based kit. RESULTS: STAT1 activity was significantly lower in tumors than in the surrounding normal thyroid tissues (P < 0.01). The association between STAT1 activity and clinicopathologic factors was analyzed in PTC tissues. STAT1 activity was significantly lower in tumors that measured 2 cm or more than in tumors that measured 2 cm or less (P = 0.044). Moreover, tumor size was inversely correlated with STAT1 activity (Spearman's rank correlation coefficient (rho) = -0.34, P = 0.048). In addition, tumors with BRAF mutations showed lower STAT1 activity than wild-type BRAF tumors [0.064 (0.056-0.124) vs. 0.108 (0.073-0.153) arbitrary units, P = 0.048]. CONCLUSION: STAT1 activity is suppressed in PTCs (as measured by DNA-binding activities). The tumor with T1799A BRAF mutation and tumor sizes of 2 cm or more were clinicopathologic parameters associated with lower STAT1 activity. STAT1 activity of tumor might be one of potential biomarkers for PTC's.